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Benzene, C6H6, is an organic aromatic compound with many interesting properties. Unlike aliphatic (straight chain carbons) or other cyclic organic compounds, the structure of benzene (3 conjugated π bonds) allows benzene and its derived products to be useful in fields such as health, laboratory, and other applications such as rubber synthesis.
Introduction
Benzene derived products are well known to be pleasantly fragrant. For this reason, organic compounds containing benzene rings were classified as being "aromatic" (sweet smelling) amongst scientists in the early 19th century when a relation was established between benzene derived compounds and sweet/spicy fragrances. There is a misconception amongst the scientific community, however, that all aromatics are sweet smelling and that all sweet smelling compounds would have a benzene ring in its structure. This is false, since non-aromatic compounds, such as camphor, extracted from the camphor laurel tree, release a strong, minty aroma, yet it lacks the benzene ring in its structure (Figure 1). On the other hand, benzene itself gives off a rather strong and unpleasant smell that would otherwise invalidate the definition of an aromatic (sweet-smelling) compound. Despite this inconsistency, however, the term aromatic continues to be used today in order to designate molecules with benzene-like rings in their structures. For a modern, chemical definition of aromaticity, refer to sections Aromaticity and Hückel's Rule.
Figure 1. Top-view of camphor, along with its monoterpene unit. Notice how camphor lacks the benzene ring to be "aromatic".
Many aromatic compounds are however, sweet/pleasant smelling. Eugenol, for example, is extracted from essential oils of cloves and it releases a spicy, clove-like aroma used in perfumes. In addition, it is also used in dentistry as an analgesic.
Figure 2. Eugenol, an aromatic compound extracted from clove essential oils. Used in perfumes and as an analgesic. The benzene ring is labeled in red in the eugenol molecule.
Is it cyclohexane or is it benzene?
Due to the similarity between benzene and cyclohexane, the two is often confused with each other in beginning organic chemistry students.
Figure 3. Structure comparison between cyclohexane and benzene
If you were to count the number of carbons and hydrogens in cyclohexane, you will notice that its molecular formula is C6H12. Since the carbons in the cyclohexane ring is fully saturated with hydrogens (carbon is bound to 2 hydrogens and 2 adjacent carbons), no double bonds are formed in the cyclic ring. In contrast, benzene is only saturated with one hydrogen per carbon, leading to its molecular formula of C6H6. In order to stabilize this structure, 3 conjugated π (double) bonds are formed in the benzene ring in order for carbon to have four adjacent bonds.
In other words, cyclohexane is not the same as benzene! These two compounds have different molecular formulas and their chemical and physical properties are not the same. The hydrogenation technique can be used by chemists to convert from benzene to cyclohexane by saturating the benzene ring with missing hydrogens.
A special catalyst is required to hydrogenate benzene rings due to its unusual stability and configuration. Normal catalytic hydrogenation techniques will not hydrogenate benzene and yield any meaningful products.
What about Resonance?
Benzene can be drawn a number of different ways. This is because benzene's conjugated pi electrons freely resonate within the cyclic ring, thus resulting in its two resonance forms.
Figure 4. The Figure to the left shows the two resonance forms of benzene. The delocalized electrons are moved from one carbon to the next, thus providing stabilization energy. Ring structures stabilized by the movement of delocalized electrons are sometimes referred to as arenes.
As the electrons in the benzene ring can resonate within the ring at a fairly high rate, a simplified notation is often used to designate the two different resonance forms. This notation is shown above, with the initial three pi bonds (#1, #2) replaced with an inner ring circle (#3). Alternatively, the circle within the benzene ring can also be dashed to show the same resonance forms (#4).
The Formation of the Phenyl Group and its Derivatives
The phenyl group can be formed by taking benzene, and removing a hydrogen from it. The resulting molecular formula for the fragment is C6H5. NOTE: Although the molecular formula of the phenyl group is C6H5, the phenyl group would always have something attached to where the hydrogen was removed. Thus, the formula is often written as Ph-R, where Ph refers to the Phenyl group, and R refers to the R group attached to where the hydrogen was removed.
Figure 5. Figure demonstrating the removal of hydrogen to form the phenyl group.
Different R groups on the phenyl group allows different benzene derivatives to be formed. Phenol, Ph-OH, or C6H5OH, for example, is formed when an alcohol (-OH) group displaces a hydrogen atom on the benzene ring. Benzene, for this very same reason, can be formed from the phenyl group by reattaching the hydrogen back its place of removal. Thus benzene, similar to phenol, can be abbreviated Ph-H, or C6H6.
Figure 7: Epigallocatechin gallate (EGCG), an antioxidant found in green teas and its extracts, is famous for its potential health benefits. The molecule is a type of catechin, which is composed of multiple phenol (labeled in red) units (polyphenols - see polycyclic aromatics). Since catechins are usually found in plant extracts, they are often referred as plant polyphenolic antioxidants.
As you can see above, these are only some of the many possibilities of the benzene derived products that have special uses in human health and other industrial fields.
Nomenclature of Benzene Derived Compounds
Unlike aliphatic organics, nomenclature of benzene-derived compounds can be confusing because a single aromatic compound can have multiple possible names (such as common and systematic names) be associated with its structure. In these sections, we will analyze some of the ways these compounds can be named.
Simple Benzene Naming
Some common substituents, like NO2, Br, and Cl, can be named this way when it is attached to a phenyl group. Long chain carbons attached can also be named this way. The general format for this kind of naming is:
(positions of substituents (if >1)- + # (di, tri, ...) + substituent)n + benzene.
For example, chlorine (Cl) attached to a phenyl group would be named chlorobenzene (chloro + benzene). Since there is only one substituent on the benzene ring, we do not have to indicate its position on the benzene ring (as it can freely rotate around and you would end up getting the same compound.)
Figure 8. Example of simple benzene naming with chlorine and NO2 as substituents.
Figure 9. More complicated simple benzene naming examples - Note that standard nomenclature priority rules are applied here, causing the numbering of carbons to switch. See Nomenclature of Organic Compounds for a review on naming and priority rules.
Ortho-, Meta-, Para- (OMP) Nomenclature for Disubstituted Benzenes
Instead of using numbers to indicate substituents on a benzene ring, ortho- (o-), meta- (m-), or para (p-) can be used in place of positional markers when there are two substituents on the benzene ring (disubstituted benzenes). They are defined as the following:
• ortho- (o-): 1,2- (next to each other in a benzene ring)
• meta- (m): 1,3- (separated by one carbon in a benzene ring)
• para- (p): 1,4- (across from each other in a benzene ring)
Using the same example above in Figure 9a (1,3-dichlorobenzene), we can use the ortho-, meta-, para- nomenclature to transform the chemical name into m-dichlorobenzene, as shown in the Figure below.
Figure 10. Transformation of 1,3-dichlorobenzene into m-dichlorobenzene.
Here are some other examples of ortho-, meta-, para- nomenclature used in context:
However, the substituents used in ortho-, meta-, para- nomenclature do not have to be the same. For example, we can use chlorine and a nitro group as substituents in the benzene ring.
In conclusion, these can be pieced together into a summary diagram, as shown below:
Base Name Nomenclature
In addition to simple benzene naming and OMP nomenclature, benzene derived compounds are also sometimes used as bases. The concept of a base is similar to the nomenclature of aliphatic and cyclic compounds, where the parent for the organic compound is used as a base (a name for its chemical name. For example, the following compounds have the base names hexane and cyclohexane, respectively. See Nomenclature of Organic Compounds for a review on naming organic compounds.
Benzene, similar to these compounds shown above, also has base names from its derived compounds. Phenol (C6H5OH), as introduced previously in this article, for example, serves as a base when other substituents are attached to it. This is best illustrated in the diagram below.
Figure 14. An example showing phenol as a base in its chemical name. Note how benzene no longer serves as a base when an OH group is added to the benzene ring.
Alternatively, we can use the numbering system to indicate this compound. When the numbering system is used, the carbon where the substituent is attached on the base will be given the first priority and named as carbon #1 (C1). The normal priority rules then apply in the nomenclature process (give the rest of the substituents the lowest numbering as you could).
Figure 15. The naming process for 2-chlorophenol (o-chlorophenol). Note that 2-chlorophenol = o-chlorophenol.
Below is a list of commonly seen benzene-derived compounds. Some of these mono-substituted compounds (labeled in red and green), such as phenol or toluene, can be used in place of benzene for the chemical's base name.
Figure 16. Common benzene derived compounds with various substituents.
Common vs. Systematic (IUPAC) Nomenclature
According to the indexing preferences of the Chemical Abstracts, phenol, benzaldehyde, and benzoic acid (labeled in red in Figure 16) are some of the common names that are retained in the IUPAC (systematic) nomenclature. Other names such as toluene, styrene, naphthalene, or phenanthrene can also be seen in the IUPAC system in the same way. While the use of other common names are usually acceptable in IUPAC, their use are discouraged in the nomenclature of compounds.
Nomenclature for compounds which has such discouraged names will be named by the simple benzene naming system. An example of this would include toluene derivatives like TNT. (Note that toluene by itself is retained by the IUPAC nomenclature, but its derivatives, which contains additional substituents on the benzene ring, might be excluded from the convention). For this reason, the common chemical name 2,4,6-trinitrotoluene, or TNT, as shown in Figure 17, would not be advisable under the IUPAC (systematic) nomenclature.
In order to correctly name TNT under the IUPAC system, the simple benzene naming system should be used:
Figure 18. Systematic (IUPAC) name of 2,4,6-trinitrotoluene (common name), or TNT. Note that the methyl group is individually named due to the exclusion of toluene from the IUPAC nomenclature.
Figure 19. The common name 2,4-dibromophenol, is shared by the IUPAC systematic nomenclature. Only substituents phenol, benzoic acid, and benzaldehyde share this commonality.
Since the IUPAC nomenclature primarily rely on the simple benzene naming system for the nomenclature of different benzene derived compounds, the OMP (ortho-, meta-, para-) system is not accepted in the IUPAC nomenclature. For this reason, the OMP system will yield common names that can be converted to systematic names by using the same method as above. For example, o-Xylene from the OMP system can be named 1,2-dimethylbenzene by using simple benzene naming (IUPAC standard).
The Phenyl and Benzyl Groups
The Phenyl Group
As mentioned previously, the phenyl group (Ph-R, C6H5-R) can be formed by removing a hydrogen from benzene and attaching a substituent to where the hydrogen was removed. To this phenomenon, we can name compounds formed this way by applying this rule: (phenyl + substituent). For example, a chlorine attached in this manner would be named phenyl chloride, and a bromine attached in this manner would be named phenyl bromide. (See below diagram)
Figure 20. Naming of Phenyl Chloride and Phenyl Bromide
While compounds like these are usually named by simple benzene type naming (chlorobenzene and bromobenzene), the phenyl group naming is usually applied to benzene rings where a substituent with six or more carbons is attached, such as in the diagram below.
Figure 21. Diagram of 2-phenyloctane.
Although the diagram above might be a little daunting to understand at first, it is not as difficult as it seems after careful analysis of the structure is made. By looking for the longest chain in the compound, it should be clear that the longest chain is eight (8) carbons long (octane, as shown in green) and that a benzene ring is attached to the second position of this longest chain (labeled in red). As this rule suggests that the benzene ring will act as a function group (a substituent) whenever a substituent of more than six (6) carbons is attached to it, the name "benzene" is changed to phenyl and is used the same way as any other substituents, such as methyl, ethyl, or bromo. Putting it all together, the name can be derived as: 2-phenyloctane (phenyl is attached at the second position of the longest carbon chain, octane).
The Benzyl Group
The benzyl group (abbv. Bn), similar to the phenyl group, is formed by manipulating the benzene ring. In the case of the benzyl group, it is formed by taking the phenyl group and adding a CH2 group to where the hydrogen was removed. Its molecular fragment can be written as C6H5CH2-R, PhCH2-R, or Bn-R. Nomenclature of benzyl group based compounds are very similar to the phenyl group compounds. For example, a chlorine attached to a benzyl group would simply be called benzyl chloride, whereas an OH group attached to a benzyl group would simply be called benzyl alcohol.
Figure 22. Benzyl Group Nomenclature
Additionally, other substituents can attach on the benzene ring in the presence of the benzyl group. An example of this can be seen in the Figure below:
Figure 23. Nomenclature of 2,4-difluorobenzyl chloride. Similar to the base name nomenclatures system, the carbon in which th base substitutent is attached on the benzene ring is given the first priority and the rest of the substituents are given the lowest number order possible.
Similar to the base name nomenclature system, the carbon in which the base substituent is attached on the benzene ring is given the first priority and the rest of the substituents are given the lowest number order possible. Under this consideration, the above compound can be named: 2,4-difluorobenzyl chloride.
Commonly Named Benzene Compounds Nomenclature Summary Flowchart
Summary Flowchart (Figure 24). Summary of nomenclature rules used in commonly benzene derived compounds.
As benzene derived compounds can be extremely complex, only compounds covered in this article and other commonly named compounds can be named using this flowchart.
Determination of Common and Systematic Names using Flowchart
To demonstrate how this flowchart can be used to name TNT in its common and systematic (IUPAC) name, a replica of the flowchart with the appropriate flow paths are shown below:
Practice Problems
Q1) (True/False) The compound above contains a benzene ring and thus is aromatic.
Q2) Benzene unusual stability is caused by how many conjugated pi bonds in its cyclic ring? ____
Q3) Menthol, a topical analgesic used in many ointments for the relief of pain, releases a peppermint aroma upon exposure to the air. Based on this conclusion, can you imply that a benzene ring is present in its chemical structure? Why or why not?
Q4)
Q5) At normal conditions, benzene has ___ resonance structures.
Q6) Which of the following name(s) is/are correct for the following compound?
a) nitrohydride benzene
b) phenylamine
c) phenylamide
d) aniline
e) nitrogenhydrogen benzene
f) All of the above is correct
Q7) Convert 1,4-dimethylbenzene into its common name.
Q8) TNT's common name is: ______________________________
Q9) Name the following compound using OMP nomenclature:
Q10) Draw the structure of 2,4-dinitrotoluene.
Q11) Name the following compound:
Q12) Which of the following is the correct name for the following compound?
a) 3,4-difluorobenzyl bromide
b) 1,2-difluorobenzyl bromide
c) 4,5-difluorobenzyl bromide
d) 1,2-difluoroethyl bromide
e) 5,6-difluoroethyl bromide
f) 4,5-difluoroethyl bromide
Q13) (True/False) Benzyl chloride can be abbreviated Bz-Cl.
Q14) Benzoic Acid has what R group attached to its phenyl functional group?
Q15) (True/False) A single aromatic compound can have multiple names indicating its structure.
Q16) List the corresponding positions for the OMP system (o-, m-, p-).
Q17) A scientist has conducted an experiment on an unknown compound. He was able to determine that the unknown compound contains a cyclic ring in its structure as well as an alcohol (-OH) group attached to the ring. What is the unknown compound?
a) Cyclohexanol
b) Cyclicheptanol
c) Phenol
d) Methanol
e) Bleach
f) Cannot determine from the above information
Q18) Which of the following statements is false for the compound, phenol?
a) Phenol is a benzene derived compound.
b) Phenol can be made by attaching an -OH group to a phenyl group.
c) Phenol is highly toxic to the body even in small doses.
d) Phenol can be used as a catalyst in the hydrogenation of benzene into cyclohexane.
e) Phenol is used as an antiseptic in minute doses.
f) Phenol is amongst one of the three common names retained in the IUPAC nomenclature.
Answer Key to Practice Questions
Q1) False, this compound does not contain a benzene ring in its structure.
Q2) 3
Q3) No, a substance that is fragrant does not imply a benzene ring is in its structure. See camphor example (Figure 1)
Q4) No reaction, benzene requires a special catalyst to be hydrogenated due to its unusual stability given by its three conjugated pi bonds.
Q5) 2
Q6) b, d
Q7) p-Xylene
Q8) 2,4,6-trinitrotoluene
Q9) p-chloronitrobenzene
Q10)
Q11) 4-phenylheptane
Q12) a
Q13) False, the correct abbreviation for the benzyl group is Bn, not Bz. The correct abbreviation for Benzyl chloride is Bn-Cl.
Q14) COOH
Q15) True. TNT, for example, has the common name 2,4,6-trinitrotoluene and its systematic name is 2-methyl-1,3,5-trinitrobenzene.
Q16) Ortho - 1,2 ; Meta - 1,3 ; Para - 1,4
Q17) The correct answer is f). We cannot determine what structure this is since the question does not tell us what kind of cyclic ring the -OH group is attached on. Just as cyclohexane can be cyclic, benzene and cycloheptane can also be cyclic.
Q18) d
• David Lam | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/15%3A_Aromaticity_(Reactions_of_Benzene)/15.08%3A_The_Nomenclature_of_Monosubstituted_Benzenes.txt |
This page gives you the facts and a simple, uncluttered mechanism for the electrophilic substitution reaction between benzene and chloromethane in the presence of an aluminium chloride catalyst. Any other chloroalkane would work similarly.
The electrophilic substitution reaction between benzene and chloromethane
Alkylation means substituting an alkyl group into something - in this case into a benzene ring. A hydrogen on the ring is replaced by a group like methyl or ethyl and so on.
Benzene is treated with a chloroalkane (for example, chloromethane or chloroethane) in the presence of aluminum chloride as a catalyst. On this page, we will look at substituting a methyl group, but any other alkyl group could be used in the same way. Substituting a methyl group gives methylbenzene - once known as toluene.
$C_6H_6 + CH_3Cl \rightarrow C_6H_5CH_3 + HCl$
or better:
The aluminium chloride isn't written into these equations because it is acting as a catalyst. If you wanted to include it, you could write AlCl3 over the top of the arrow.
The formation of the electrophile
The electrophile is CH3+. It is formed by reaction between the chloromethane and the aluminum chloride catalyst.
$CH_3Cl + AlCl_3 \rightarrow ^+CH_3 + AlCl_4^-$
The electrophilic substitution mechanism
Stage one
Stage two
The hydrogen is removed by the $AlCl_4^-$ ion wh ich was formed at the same time as the $CH_3^+$ ele ctrophile . The aluminum chloride catalyst is re-generated in this second stage.
Contributors
Jim Clark (Chemguide.co.uk)
15.17: sing Coupling Reactions to Alkylate Benzene
There are many other examples of coupling reactions in organic synthesis. The Suzuki reaction is somewhat similar to the Negishi reaction.
Figure 1. The Suzuki reaction.
Reviews
• Suzuki, A. J. Organometallic Chem. 1999, 576, 147–168.
• Suzuki, A. In Metal-catalyzed Cross-coupling Reactions, Diederich, F., and Stang, P. J., Eds.; Wiley-VCH: New York, 1998, pp. 49-97.
• Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
• Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866–867.
• B-Alkyl Suzuki reaction:
• Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 2001, 40, 4544–4568.
• Solid phase:
Transmetallation
• Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461–470.
• Carrow, B.P.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2116–2119.
Reductive Elimination
• Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
Conditions
• Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437–3440.
• Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866–867.
• Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513–519.
• Miyaura, N.; Yano, T.; Suzuki, A. Tetrahedron Lett. 1980, 21, 2865–2868.
Catalysts and Ligands
• Goodson, F. E.; Wallow, T. I.; Novak, B. M. Org. Synth. 1997, 75, 61–68.
• Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem. 1999, 64, 3804-3805.
15.18: It Is Important to Have More Than One Way to Carry Out a Reaction
The reaction of aldehydes and ketones with zinc amalgam (Zn/Hg alloy) in concentrated hydrochloric acid, which reduces the aldehyde or ketone to a hydrocarbon, is called Clemmensen reduction.
Introduction
This alternative reduction involves heating a carbonyl compound with finely divided, amalgamated zinc in a hydroxylic solvent (often an aqueous mixture) containing a mineral acid such as HCl. The mercury alloyed with the zinc does not participate in the reaction, it serves only to provide a clean active metal surface.
Possible mechanism
The mechanism of Clemmensen reduction is not fully understood; intermediacy of radicals are implicated. Clemmensen reduction is complementary to Wolff-Kishner reduction, which also converts aldehydes and ketones to hydrocarbons, in that the former is carried out in strongly acidic conditions and the latter in strongly basic conditions. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/15%3A_Aromaticity_(Reactions_of_Benzene)/15.15%3A_The_Friedel-Crafts_Alkylation_of_Benzene.txt |
Benzene, C6H6, is an organic aromatic compound with many interesting properties. Unlike aliphatic (straight chain carbons) or other cyclic organic compounds, the structure of benzene (3 conjugated π bonds) allows benzene and its derived products to be useful in fields such as health, laboratory, and other applications such as rubber synthesis.
Introduction
Benzene derived products are well known to be pleasantly fragrant. For this reason, organic compounds containing benzene rings were classified as being "aromatic" (sweet smelling) amongst scientists in the early 19th century when a relation was established between benzene derived compounds and sweet/spicy fragrances. There is a misconception amongst the scientific community, however, that all aromatics are sweet smelling and that all sweet smelling compounds would have a benzene ring in its structure. This is false, since non-aromatic compounds, such as camphor, extracted from the camphor laurel tree, release a strong, minty aroma, yet it lacks the benzene ring in its structure (Figure 1). On the other hand, benzene itself gives off a rather strong and unpleasant smell that would otherwise invalidate the definition of an aromatic (sweet-smelling) compound. Despite this inconsistency, however, the term aromatic continues to be used today in order to designate molecules with benzene-like rings in their structures. For a modern, chemical definition of aromaticity, refer to sections Aromaticity and Hückel's Rule.
Figure 1. Top-view of camphor, along with its monoterpene unit. Notice how camphor lacks the benzene ring to be "aromatic".
Many aromatic compounds are however, sweet/pleasant smelling. Eugenol, for example, is extracted from essential oils of cloves and it releases a spicy, clove-like aroma used in perfumes. In addition, it is also used in dentistry as an analgesic.
Figure 2. Eugenol, an aromatic compound extracted from clove essential oils. Used in perfumes and as an analgesic. The benzene ring is labeled in red in the eugenol molecule.
Is it cyclohexane or is it benzene?
Due to the similarity between benzene and cyclohexane, the two is often confused with each other in beginning organic chemistry students.
Figure 3. Structure comparison between cyclohexane and benzene
If you were to count the number of carbons and hydrogens in cyclohexane, you will notice that its molecular formula is C6H12. Since the carbons in the cyclohexane ring is fully saturated with hydrogens (carbon is bound to 2 hydrogens and 2 adjacent carbons), no double bonds are formed in the cyclic ring. In contrast, benzene is only saturated with one hydrogen per carbon, leading to its molecular formula of C6H6. In order to stabilize this structure, 3 conjugated π (double) bonds are formed in the benzene ring in order for carbon to have four adjacent bonds.
In other words, cyclohexane is not the same as benzene! These two compounds have different molecular formulas and their chemical and physical properties are not the same. The hydrogenation technique can be used by chemists to convert from benzene to cyclohexane by saturating the benzene ring with missing hydrogens.
A special catalyst is required to hydrogenate benzene rings due to its unusual stability and configuration. Normal catalytic hydrogenation techniques will not hydrogenate benzene and yield any meaningful products.
What about Resonance?
Benzene can be drawn a number of different ways. This is because benzene's conjugated pi electrons freely resonate within the cyclic ring, thus resulting in its two resonance forms.
Figure 4. The Figure to the left shows the two resonance forms of benzene. The delocalized electrons are moved from one carbon to the next, thus providing stabilization energy. Ring structures stabilized by the movement of delocalized electrons are sometimes referred to as arenes.
As the electrons in the benzene ring can resonate within the ring at a fairly high rate, a simplified notation is often used to designate the two different resonance forms. This notation is shown above, with the initial three pi bonds (#1, #2) replaced with an inner ring circle (#3). Alternatively, the circle within the benzene ring can also be dashed to show the same resonance forms (#4).
The Formation of the Phenyl Group and its Derivatives
The phenyl group can be formed by taking benzene, and removing a hydrogen from it. The resulting molecular formula for the fragment is C6H5. NOTE: Although the molecular formula of the phenyl group is C6H5, the phenyl group would always have something attached to where the hydrogen was removed. Thus, the formula is often written as Ph-R, where Ph refers to the Phenyl group, and R refers to the R group attached to where the hydrogen was removed.
Figure 5. Figure demonstrating the removal of hydrogen to form the phenyl group.
Different R groups on the phenyl group allows different benzene derivatives to be formed. Phenol, Ph-OH, or C6H5OH, for example, is formed when an alcohol (-OH) group displaces a hydrogen atom on the benzene ring. Benzene, for this very same reason, can be formed from the phenyl group by reattaching the hydrogen back its place of removal. Thus benzene, similar to phenol, can be abbreviated Ph-H, or C6H6.
Figure 7: Epigallocatechin gallate (EGCG), an antioxidant found in green teas and its extracts, is famous for its potential health benefits. The molecule is a type of catechin, which is composed of multiple phenol (labeled in red) units (polyphenols - see polycyclic aromatics). Since catechins are usually found in plant extracts, they are often referred as plant polyphenolic antioxidants.
As you can see above, these are only some of the many possibilities of the benzene derived products that have special uses in human health and other industrial fields.
Nomenclature of Benzene Derived Compounds
Unlike aliphatic organics, nomenclature of benzene-derived compounds can be confusing because a single aromatic compound can have multiple possible names (such as common and systematic names) be associated with its structure. In these sections, we will analyze some of the ways these compounds can be named.
Simple Benzene Naming
Some common substituents, like NO2, Br, and Cl, can be named this way when it is attached to a phenyl group. Long chain carbons attached can also be named this way. The general format for this kind of naming is:
(positions of substituents (if >1)- + # (di, tri, ...) + substituent)n + benzene.
For example, chlorine (Cl) attached to a phenyl group would be named chlorobenzene (chloro + benzene). Since there is only one substituent on the benzene ring, we do not have to indicate its position on the benzene ring (as it can freely rotate around and you would end up getting the same compound.)
Figure 8. Example of simple benzene naming with chlorine and NO2 as substituents.
Figure 9. More complicated simple benzene naming examples - Note that standard nomenclature priority rules are applied here, causing the numbering of carbons to switch. See Nomenclature of Organic Compounds for a review on naming and priority rules.
Ortho-, Meta-, Para- (OMP) Nomenclature for Disubstituted Benzenes
Instead of using numbers to indicate substituents on a benzene ring, ortho- (o-), meta- (m-), or para (p-) can be used in place of positional markers when there are two substituents on the benzene ring (disubstituted benzenes). They are defined as the following:
• ortho- (o-): 1,2- (next to each other in a benzene ring)
• meta- (m): 1,3- (separated by one carbon in a benzene ring)
• para- (p): 1,4- (across from each other in a benzene ring)
Using the same example above in Figure 9a (1,3-dichlorobenzene), we can use the ortho-, meta-, para- nomenclature to transform the chemical name into m-dichlorobenzene, as shown in the Figure below.
Figure 10. Transformation of 1,3-dichlorobenzene into m-dichlorobenzene.
Here are some other examples of ortho-, meta-, para- nomenclature used in context:
However, the substituents used in ortho-, meta-, para- nomenclature do not have to be the same. For example, we can use chlorine and a nitro group as substituents in the benzene ring.
In conclusion, these can be pieced together into a summary diagram, as shown below:
Base Name Nomenclature
In addition to simple benzene naming and OMP nomenclature, benzene derived compounds are also sometimes used as bases. The concept of a base is similar to the nomenclature of aliphatic and cyclic compounds, where the parent for the organic compound is used as a base (a name for its chemical name. For example, the following compounds have the base names hexane and cyclohexane, respectively. See Nomenclature of Organic Compounds for a review on naming organic compounds.
Benzene, similar to these compounds shown above, also has base names from its derived compounds. Phenol (C6H5OH), as introduced previously in this article, for example, serves as a base when other substituents are attached to it. This is best illustrated in the diagram below.
Figure 14. An example showing phenol as a base in its chemical name. Note how benzene no longer serves as a base when an OH group is added to the benzene ring.
Alternatively, we can use the numbering system to indicate this compound. When the numbering system is used, the carbon where the substituent is attached on the base will be given the first priority and named as carbon #1 (C1). The normal priority rules then apply in the nomenclature process (give the rest of the substituents the lowest numbering as you could).
Figure 15. The naming process for 2-chlorophenol (o-chlorophenol). Note that 2-chlorophenol = o-chlorophenol.
Below is a list of commonly seen benzene-derived compounds. Some of these mono-substituted compounds (labeled in red and green), such as phenol or toluene, can be used in place of benzene for the chemical's base name.
Figure 16. Common benzene derived compounds with various substituents.
Common vs. Systematic (IUPAC) Nomenclature
According to the indexing preferences of the Chemical Abstracts, phenol, benzaldehyde, and benzoic acid (labeled in red in Figure 16) are some of the common names that are retained in the IUPAC (systematic) nomenclature. Other names such as toluene, styrene, naphthalene, or phenanthrene can also be seen in the IUPAC system in the same way. While the use of other common names are usually acceptable in IUPAC, their use are discouraged in the nomenclature of compounds.
Nomenclature for compounds which has such discouraged names will be named by the simple benzene naming system. An example of this would include toluene derivatives like TNT. (Note that toluene by itself is retained by the IUPAC nomenclature, but its derivatives, which contains additional substituents on the benzene ring, might be excluded from the convention). For this reason, the common chemical name 2,4,6-trinitrotoluene, or TNT, as shown in Figure 17, would not be advisable under the IUPAC (systematic) nomenclature.
In order to correctly name TNT under the IUPAC system, the simple benzene naming system should be used:
Figure 18. Systematic (IUPAC) name of 2,4,6-trinitrotoluene (common name), or TNT. Note that the methyl group is individually named due to the exclusion of toluene from the IUPAC nomenclature.
Figure 19. The common name 2,4-dibromophenol, is shared by the IUPAC systematic nomenclature. Only substituents phenol, benzoic acid, and benzaldehyde share this commonality.
Since the IUPAC nomenclature primarily rely on the simple benzene naming system for the nomenclature of different benzene derived compounds, the OMP (ortho-, meta-, para-) system is not accepted in the IUPAC nomenclature. For this reason, the OMP system will yield common names that can be converted to systematic names by using the same method as above. For example, o-Xylene from the OMP system can be named 1,2-dimethylbenzene by using simple benzene naming (IUPAC standard).
The Phenyl and Benzyl Groups
The Phenyl Group
As mentioned previously, the phenyl group (Ph-R, C6H5-R) can be formed by removing a hydrogen from benzene and attaching a substituent to where the hydrogen was removed. To this phenomenon, we can name compounds formed this way by applying this rule: (phenyl + substituent). For example, a chlorine attached in this manner would be named phenyl chloride, and a bromine attached in this manner would be named phenyl bromide. (See below diagram)
Figure 20. Naming of Phenyl Chloride and Phenyl Bromide
While compounds like these are usually named by simple benzene type naming (chlorobenzene and bromobenzene), the phenyl group naming is usually applied to benzene rings where a substituent with six or more carbons is attached, such as in the diagram below.
Figure 21. Diagram of 2-phenyloctane.
Although the diagram above might be a little daunting to understand at first, it is not as difficult as it seems after careful analysis of the structure is made. By looking for the longest chain in the compound, it should be clear that the longest chain is eight (8) carbons long (octane, as shown in green) and that a benzene ring is attached to the second position of this longest chain (labeled in red). As this rule suggests that the benzene ring will act as a function group (a substituent) whenever a substituent of more than six (6) carbons is attached to it, the name "benzene" is changed to phenyl and is used the same way as any other substituents, such as methyl, ethyl, or bromo. Putting it all together, the name can be derived as: 2-phenyloctane (phenyl is attached at the second position of the longest carbon chain, octane).
The Benzyl Group
The benzyl group (abbv. Bn), similar to the phenyl group, is formed by manipulating the benzene ring. In the case of the benzyl group, it is formed by taking the phenyl group and adding a CH2 group to where the hydrogen was removed. Its molecular fragment can be written as C6H5CH2-R, PhCH2-R, or Bn-R. Nomenclature of benzyl group based compounds are very similar to the phenyl group compounds. For example, a chlorine attached to a benzyl group would simply be called benzyl chloride, whereas an OH group attached to a benzyl group would simply be called benzyl alcohol.
Figure 22. Benzyl Group Nomenclature
Additionally, other substituents can attach on the benzene ring in the presence of the benzyl group. An example of this can be seen in the Figure below:
Figure 23. Nomenclature of 2,4-difluorobenzyl chloride. Similar to the base name nomenclatures system, the carbon in which th base substitutent is attached on the benzene ring is given the first priority and the rest of the substituents are given the lowest number order possible.
Similar to the base name nomenclature system, the carbon in which the base substituent is attached on the benzene ring is given the first priority and the rest of the substituents are given the lowest number order possible. Under this consideration, the above compound can be named: 2,4-difluorobenzyl chloride.
Commonly Named Benzene Compounds Nomenclature Summary Flowchart
Summary Flowchart (Figure 24). Summary of nomenclature rules used in commonly benzene derived compounds.
As benzene derived compounds can be extremely complex, only compounds covered in this article and other commonly named compounds can be named using this flowchart.
Determination of Common and Systematic Names using Flowchart
To demonstrate how this flowchart can be used to name TNT in its common and systematic (IUPAC) name, a replica of the flowchart with the appropriate flow paths are shown below:
Practice Problems
Q1) (True/False) The compound above contains a benzene ring and thus is aromatic.
Q2) Benzene unusual stability is caused by how many conjugated pi bonds in its cyclic ring? ____
Q3) Menthol, a topical analgesic used in many ointments for the relief of pain, releases a peppermint aroma upon exposure to the air. Based on this conclusion, can you imply that a benzene ring is present in its chemical structure? Why or why not?
Q4)
Q5) At normal conditions, benzene has ___ resonance structures.
Q6) Which of the following name(s) is/are correct for the following compound?
a) nitrohydride benzene
b) phenylamine
c) phenylamide
d) aniline
e) nitrogenhydrogen benzene
f) All of the above is correct
Q7) Convert 1,4-dimethylbenzene into its common name.
Q8) TNT's common name is: ______________________________
Q9) Name the following compound using OMP nomenclature:
Q10) Draw the structure of 2,4-dinitrotoluene.
Q11) Name the following compound:
Q12) Which of the following is the correct name for the following compound?
a) 3,4-difluorobenzyl bromide
b) 1,2-difluorobenzyl bromide
c) 4,5-difluorobenzyl bromide
d) 1,2-difluoroethyl bromide
e) 5,6-difluoroethyl bromide
f) 4,5-difluoroethyl bromide
Q13) (True/False) Benzyl chloride can be abbreviated Bz-Cl.
Q14) Benzoic Acid has what R group attached to its phenyl functional group?
Q15) (True/False) A single aromatic compound can have multiple names indicating its structure.
Q16) List the corresponding positions for the OMP system (o-, m-, p-).
Q17) A scientist has conducted an experiment on an unknown compound. He was able to determine that the unknown compound contains a cyclic ring in its structure as well as an alcohol (-OH) group attached to the ring. What is the unknown compound?
a) Cyclohexanol
b) Cyclicheptanol
c) Phenol
d) Methanol
e) Bleach
f) Cannot determine from the above information
Q18) Which of the following statements is false for the compound, phenol?
a) Phenol is a benzene derived compound.
b) Phenol can be made by attaching an -OH group to a phenyl group.
c) Phenol is highly toxic to the body even in small doses.
d) Phenol can be used as a catalyst in the hydrogenation of benzene into cyclohexane.
e) Phenol is used as an antiseptic in minute doses.
f) Phenol is amongst one of the three common names retained in the IUPAC nomenclature.
Answer Key to Practice Questions
Q1) False, this compound does not contain a benzene ring in its structure.
Q2) 3
Q3) No, a substance that is fragrant does not imply a benzene ring is in its structure. See camphor example (Figure 1)
Q4) No reaction, benzene requires a special catalyst to be hydrogenated due to its unusual stability given by its three conjugated pi bonds.
Q5) 2
Q6) b, d
Q7) p-Xylene
Q8) 2,4,6-trinitrotoluene
Q9) p-chloronitrobenzene
Q10)
Q11) 4-phenylheptane
Q12) a
Q13) False, the correct abbreviation for the benzyl group is Bn, not Bz. The correct abbreviation for Benzyl chloride is Bn-Cl.
Q14) COOH
Q15) True. TNT, for example, has the common name 2,4,6-trinitrotoluene and its systematic name is 2-methyl-1,3,5-trinitrobenzene.
Q16) Ortho - 1,2 ; Meta - 1,3 ; Para - 1,4
Q17) The correct answer is f). We cannot determine what structure this is since the question does not tell us what kind of cyclic ring the -OH group is attached on. Just as cyclohexane can be cyclic, benzene and cycloheptane can also be cyclic.
Q18) d
• David Lam | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/16%3A_Reactions_of_Substituted_Benzenes/16.02%3A_The_Nomenclature_of_Disubstituted_and_Polysubstituted_Benzenes.txt |
Substitution of the hydroxyl hydrogen atom is even more facile with phenols, which are roughly a million times more acidic than equivalent alcohols. This phenolic acidity is further enhanced by electron-withdrawing substituents ortho and para to the hydroxyl group, as displayed in the following diagram. The alcohol cyclohexanol is shown for reference at the top left. It is noteworthy that the influence of a nitro substituent is over ten times stronger in the para-location than it is meta, despite the fact that the latter position is closer to the hydroxyl group. Furthermore additional nitro groups have an additive influence if they are positioned in ortho or para locations. The trinitro compound shown at the lower right is a very strong acid called picric acid.
Why is phenol a much stronger acid than cyclohexanol? To answer this question we must evaluate the manner in which an oxygen substituent interacts with the benzene ring. As noted in our earlier treatment of electrophilic aromatic substitution reactions, an oxygen substituent enhances the reactivity of the ring and favors electrophile attack at ortho and para sites. It was proposed that resonance delocalization of an oxygen non-bonded electron pair into the pi-electron system of the aromatic ring was responsible for this substituent effect. Formulas illustrating this electron delocalization will be displayed when the "Resonance Structures" button beneath the previous diagram is clicked. A similar set of resonance structures for the phenolate anion conjugate base appears below the phenol structures.
The resonance stabilization in these two cases is very different. An important principle of resonance is that charge separation diminishes the importance of canonical contributors to the resonance hybrid and reduces the overall stabilization. The contributing structures to the phenol hybrid all suffer charge separation, resulting in very modest stabilization of this compound. On the other hand, the phenolate anion is already charged, and the canonical contributors act to disperse the charge, resulting in a substantial stabilization of this species. The conjugate bases of simple alcohols are not stabilized by charge delocalization, so the acidity of these compounds is similar to that of water. An energy diagram showing the effect of resonance on cyclohexanol and phenol acidities is shown on the right. Since the resonance stabilization of the phenolate conjugate base is much greater than the stabilization of phenol itself, the acidity of phenol relative to cyclohexanol is increased. Supporting evidence that the phenolate negative charge is delocalized on the ortho and para carbons of the benzene ring comes from the influence of electron-withdrawing substituents at those sites.
Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
16.07: Additional Considerations Regarding Substituent Effects
The concept of an ideal solution is fundamental to chemical thermodynamics and its applications, such as the use of colligative properties. An ideal solution or ideal mixture is a solution in which the enthalpy of solution (\(\Delta{H_{solution}} = 0\)) is zero; with the closer to zero the enthalpy of solution, the more "ideal" the behavior of the solution becomes. Since the enthalpy of mixing (solution) is zero, the change in Gibbs energy on mixing is determined solely by the entropy of mixing (\(\Delta{S_{solution}}\)).
• Raoult's Law
Raoult's law states that the vapor pressure of a solvent above a solution is equal to the vapor pressure of the pure solvent at the same temperature scaled by the mole fraction of the solvent present. At any given temperature for a particular solid or liquid, there is a pressure at which the vapor formed above the substance is in dynamic equilibrium with its liquid or solid form. At equilibrium, the rate at which the solid or liquid evaporates is equal to the rate that the gas is condensing.
• Henry's Law
Henry's law is one of the gas laws formulated by William Henry in 1803 and states: "At a constant temperature, the amount of a given gas that dissolves in a given type and volume of liquid is directly proportional to the partial pressure of that gas in equilibrium with that liquid." An equivalent way of stating the law is that the solubility of a gas in a liquid is directly proportional to the partial pressure of the gas above the liquid. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/16%3A_Reactions_of_Substituted_Benzenes/16.05%3A_The_Effect_of_Substituents_on_pKa.txt |
Aryl diazonium salts are important intermediates. They are prepared in cold (0 º to 10 ºC) aqueous solution, and generally react with nucleophiles with loss of nitrogen. Some of the more commonly used substitution reactions are shown in the following diagram. Since the leaving group (N2) is thermodynamically very stable, these reactions are energetically favored. Those substitution reactions that are catalyzed by cuprous salts are known as Sandmeyer reactions. Fluoride substitution occurs on treatment with BF4(–), a reaction known as the Schiemann reaction. Stable diazonium tetrafluoroborate salts may be isolated, and on heating these lose nitrogen to give an arylfluoride product. The top reaction with hypophosphorus acid, H3PO2, is noteworthy because it achieves the reductive removal of an amino (or nitro) group. Unlike the nucleophilic substitution reactions, this reduction probably proceeds by a radical mechanism.
These aryl diazonium substitution reactions significantly expand the tactics available for the synthesis of polysubstituted benzene derivatives. Consider the following options:
1. The usual precursor to an aryl amine is the corresponding nitro compound. A nitro substituent deactivates an aromatic ring and directs electrophilic substitution to meta locations.
2. Reduction of a nitro group to an amine may be achieved in several ways. The resulting amine substituent strongly activates an aromatic ring and directs electrophilic substitution to ortho & para locations.
3. The activating character of an amine substituent may be attenuated by formation of an amide derivative (reversible), or even changed to deactivating and meta-directing by formation of a quaternary-ammonium salt (irreversible).
4. Conversion of an aryl amine to a diazonium ion intermediate allows it to be replaced by a variety of different groups (including hydrogen), which may in turn be used in subsequent reactions.
The following examples illustrate some combined applications of these options to specific cases. You should try to conceive a plausible reaction sequence for each. Once you have done so, you may check suggested answers by clicking on the question mark for each.
Bonding to Nitrogen
A resonance description of diazonium ions shows that the positive charge is delocalized over the two nitrogen atoms. It is not possible for nucleophiles to bond to the inner nitrogen, but bonding (or coupling) of negative nucleophiles to the terminal nitrogen gives neutral azo compounds. As shown in the following equation, this coupling to the terminal nitrogen should be relatively fast and reversible. The azo products may exist as E / Z stereoisomers. In practice it is found that the E-isomer predominates at equilibrium.
Unless these azo products are trapped or stabilized in some manner, reversal to the diazonium ion and slow nucleophilic substitution at carbon (with irreversible nitrogen loss) will be the ultimate course of reaction, as described in the previous section. For example, if phenyldiazonium bisufate is added rapidly to a cold solution of sodium hydroxide a relatively stable solution of sodium phenyldiazoate (the conjugate base of the initially formed diazoic acid) is obtained. Lowering the pH of this solution regenerates phenyldiazoic acid (pKa ca. 7), which disassociates back to the diazonium ion and eventually undergoes substitution, generating phenol.
C6H5N2(+) HSO4(–) + NaOH (cold solution) C6H5N2–OH + NaOH (cold) C6H5N2–O(–) Na(+)
phenyldiazonium bisulfate phenyldiazoic acid sodium phenyldiazoate
Aryl diazonium salts may be reduced to the corresponding hydrazines by mild reducing agents such as sodium bisulfite, stannous chloride or zinc dust. The bisulfite reduction may proceed by an initial sulfur-nitrogen coupling, as shown in the following equation.
Ar-N2(+) X(–)
NaHSO3
Ar-N=N-SO3H
NaHSO3
Ar-NH-NH-SO3H
H2O
Ar-NH-NH2 + H2SO4
The most important application of diazo coupling reactions is electrophilic aromatic substitution of activated benzene derivatives by diazonium electrophiles. The products of such reactions are highly colored aromatic azo compounds that find use as synthetic dyestuffs, commonly referred to as azo dyes. Azobenzene (Y=Z=H) is light orange; however, the color of other azo compounds may range from red to deep blue depending on the nature of the aromatic rings and the substituents they carry. Azo compounds may exist as cis/trans isomer pairs, but most of the well-characterized and stable compounds are trans.
Some examples of azo coupling reactions are shown below. A few simple rules are helpful in predicting the course of such reactions:
1. At acid pH (< 6) an amino group is a stronger activating substituent than a hydroxyl group (i.e. a phenol). At alkaline pH (> 7.5) phenolic functions are stronger activators, due to increased phenoxide base concentration.
2. Coupling to an activated benzene ring occurs preferentially para to the activating group if that location is free. Otherwise ortho-coupling will occur.
3. Naphthalene normally undergoes electrophilic substitution at an alpha-location more rapidly than at beta-sites; however, ortho-coupling is preferred. See the diagram for examples of α / β notation in naphthalenes.
You should try to conceive a plausible product structure for each of the following couplings. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/16%3A_Reactions_of_Substituted_Benzenes/16.10%3A_The_Synthesis_of_Substituted_Benzenes_Using_Arenediazonium_Salts.txt |
Aryl diazonium salts are important intermediates. They are prepared in cold (0 º to 10 ºC) aqueous solution, and generally react with nucleophiles with loss of nitrogen. Some of the more commonly used substitution reactions are shown in the following diagram. Since the leaving group (N2) is thermodynamically very stable, these reactions are energetically favored. Those substitution reactions that are catalyzed by cuprous salts are known as Sandmeyer reactions. Fluoride substitution occurs on treatment with BF4(–), a reaction known as the Schiemann reaction. Stable diazonium tetrafluoroborate salts may be isolated, and on heating these lose nitrogen to give an arylfluoride product. The top reaction with hypophosphorus acid, H3PO2, is noteworthy because it achieves the reductive removal of an amino (or nitro) group. Unlike the nucleophilic substitution reactions, this reduction probably proceeds by a radical mechanism.
These aryl diazonium substitution reactions significantly expand the tactics available for the synthesis of polysubstituted benzene derivatives. Consider the following options:
1. The usual precursor to an aryl amine is the corresponding nitro compound. A nitro substituent deactivates an aromatic ring and directs electrophilic substitution to meta locations.
2. Reduction of a nitro group to an amine may be achieved in several ways. The resulting amine substituent strongly activates an aromatic ring and directs electrophilic substitution to ortho & para locations.
3. The activating character of an amine substituent may be attenuated by formation of an amide derivative (reversible), or even changed to deactivating and meta-directing by formation of a quaternary-ammonium salt (irreversible).
4. Conversion of an aryl amine to a diazonium ion intermediate allows it to be replaced by a variety of different groups (including hydrogen), which may in turn be used in subsequent reactions.
The following examples illustrate some combined applications of these options to specific cases. You should try to conceive a plausible reaction sequence for each. Once you have done so, you may check suggested answers by clicking on the question mark for each.
Bonding to Nitrogen
A resonance description of diazonium ions shows that the positive charge is delocalized over the two nitrogen atoms. It is not possible for nucleophiles to bond to the inner nitrogen, but bonding (or coupling) of negative nucleophiles to the terminal nitrogen gives neutral azo compounds. As shown in the following equation, this coupling to the terminal nitrogen should be relatively fast and reversible. The azo products may exist as E / Z stereoisomers. In practice it is found that the E-isomer predominates at equilibrium.
Unless these azo products are trapped or stabilized in some manner, reversal to the diazonium ion and slow nucleophilic substitution at carbon (with irreversible nitrogen loss) will be the ultimate course of reaction, as described in the previous section. For example, if phenyldiazonium bisufate is added rapidly to a cold solution of sodium hydroxide a relatively stable solution of sodium phenyldiazoate (the conjugate base of the initially formed diazoic acid) is obtained. Lowering the pH of this solution regenerates phenyldiazoic acid (pKa ca. 7), which disassociates back to the diazonium ion and eventually undergoes substitution, generating phenol.
C6H5N2(+) HSO4(–) + NaOH (cold solution) C6H5N2–OH + NaOH (cold) C6H5N2–O(–) Na(+)
phenyldiazonium bisulfate phenyldiazoic acid sodium phenyldiazoate
Aryl diazonium salts may be reduced to the corresponding hydrazines by mild reducing agents such as sodium bisulfite, stannous chloride or zinc dust. The bisulfite reduction may proceed by an initial sulfur-nitrogen coupling, as shown in the following equation.
Ar-N2(+) X(–)
NaHSO3
Ar-N=N-SO3H
NaHSO3
Ar-NH-NH-SO3H
H2O
Ar-NH-NH2 + H2SO4
The most important application of diazo coupling reactions is electrophilic aromatic substitution of activated benzene derivatives by diazonium electrophiles. The products of such reactions are highly colored aromatic azo compounds that find use as synthetic dyestuffs, commonly referred to as azo dyes. Azobenzene (Y=Z=H) is light orange; however, the color of other azo compounds may range from red to deep blue depending on the nature of the aromatic rings and the substituents they carry. Azo compounds may exist as cis/trans isomer pairs, but most of the well-characterized and stable compounds are trans.
Some examples of azo coupling reactions are shown below. A few simple rules are helpful in predicting the course of such reactions:
1. At acid pH (< 6) an amino group is a stronger activating substituent than a hydroxyl group (i.e. a phenol). At alkaline pH (> 7.5) phenolic functions are stronger activators, due to increased phenoxide base concentration.
2. Coupling to an activated benzene ring occurs preferentially para to the activating group if that location is free. Otherwise ortho-coupling will occur.
3. Naphthalene normally undergoes electrophilic substitution at an alpha-location more rapidly than at beta-sites; however, ortho-coupling is preferred. See the diagram for examples of α / β notation in naphthalenes.
You should try to conceive a plausible product structure for each of the following couplings.
16.12: The Mechanism for the Reaction of Amines with Nitrous Acid
This page looks at the reaction between phenylamine (also known as aniline and aminobenzene) and nitrous acid - particularly its reaction at temperatures of less than 5°C to produce diazonium salts. If you want to know about the reactions of the diazonium ions formed, you will find a link at the bottom of the page.
The reactions of phenylamine with nitrous acid
Nitrous acid (also known as nitric(III) acid) has the formula HNO2. It is sometimes written as HONO to show the way it is joined up. Nitrous acid decomposes very readily and is always made in situ. In the case of its reaction with phenylamine, the phenylamine is first dissolved in hydrochloric acid, and then a solution of sodium or potassium nitrite is added. The reaction between the hydrochloric acid and the nitrite ions produces the nitrous acid.
$H^+ (aq) + NO_2^- (aq) \rightleftharpoons HNO_2 (aq)$
Because nitrous acid is a weak acid, the position of equilibrium lies well the right. Phenylamine reacts with nitrous acid differently depending on the temperature.
The reaction on warming
If the mixture is warmed, you get a black oily product which contains phenol (amongst other things), and nitrogen gas is given off.
$CH_6H_5NH_2 + HNO_2 \rightarrow C_6H_5OH + H_2O + N_2$
The reaction at low temperatures
The solution of phenylamine in hydrochloric acid (phenylammonium chloride solution) is stood in a beaker of ice. The sodium or potassium nitrite solution is also cooled in the ice. The solution of the nitrite is then added very slowly to the phenylammonium chloride solution - so that the temperature never goes above 5°C. You end up with a solution containing benzenediazonium chloride:
The positive ion, containing the -N2+ group, is known as a diazonium ion. The "azo" bit of the name refers to nitrogen. The ionic equation for the reaction is:
Notice that the chloride ions from the acid aren't involved in this in any way. If you use hydrochloric acid, the solution will contain benzenediazonium chloride. If you used a different acid, you would just get a different salt - a sulphate or hydrogensulphate, for example, if you used sulfuric acid.
The reactions of a diazonium salt are always done with a freshly prepared solution made in this way since the solutions do not keep. Diazonium salts are very unstable and tend to be explosive as solids.
Contributors
Jim Clark (Chemguide.co.uk) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/16%3A_Reactions_of_Substituted_Benzenes/16.11%3A_The_Arenediazonium_Ion_as_an_Electrophile.txt |
The IUPAC system of nomenclature assigns a characteristic suffix to these classes. The –e ending is removed from the name of the parent chain and is replaced -anoic acid. Since a carboxylic acid group must always lie at the end of a carbon chain, it is always is given the #1 location position in numbering and it is not necessary to include it in the name.
Many carboxylic acids are called by the common names. These names were chosen by chemists to usually describe a source of where the compound is found. In common names of aldehydes, carbon atoms near the carboxyl group are often designated by Greek letters. The atom adjacent to the carbonyl function is alpha, the next removed is beta and so on.
Formula Common Name Source IUPAC Name Melting Point Boiling Point
HCO2H formic acid ants (L. formica) methanoic acid 8.4 ºC 101 ºC
CH3CO2H acetic acid vinegar (L. acetum) ethanoic acid 16.6 ºC 118 ºC
CH3CH2CO2H propionic acid milk (Gk. protus prion) propanoic acid -20.8 ºC 141 ºC
CH3(CH2)2CO2H butyric acid butter (L. butyrum) butanoic acid -5.5 ºC 164 ºC
CH3(CH2)3CO2H valeric acid valerian root pentanoic acid -34.5 ºC 186 ºC
CH3(CH2)4CO2H caproic acid goats (L. caper) hexanoic acid -4.0 ºC 205 ºC
CH3(CH2)5CO2H enanthic acid vines (Gk. oenanthe) heptanoic acid -7.5 ºC 223 ºC
CH3(CH2)6CO2H caprylic acid goats (L. caper) octanoic acid 16.3 ºC 239 ºC
CH3(CH2)7CO2H pelargonic acid pelargonium (an herb) nonanoic acid 12.0 ºC 253 ºC
CH3(CH2)8CO2H capric acid goats (L. caper) decanoic acid 31.0 ºC 219 ºC
Example (Common Names Are in Red)
Naming carboxyl groups added to a ring
When a carboxyl group is added to a ring the suffix -carboxylic acid is added to the name of the cyclic compound. The ring carbon attached to the carboxyl group is given the #1 location number.
Naming carboxylates
Salts of carboxylic acids are named by writing the name of the cation followed by the name of the acid with the –ic acid ending replaced by an –ate ending. This is true for both the IUPAC and Common nomenclature systems.
Naming carboxylic acids which contain other functional groups
Carboxylic acids are given the highest nomenclature priority by the IUPAC system. This means that the carboxyl group is given the lowest possible location number and the appropriate nomenclature suffix is included. In the case of molecules containing carboxylic acid and alcohol functional groups the OH is named as a hydroxyl substituent. However, the l in hydroxyl is generally removed.
In the case of molecules containing a carboxylic acid and aldehydes and/or ketones functional groups the carbonyl is named as a "Oxo" substituent.
In the case of molecules containing a carboxylic acid an amine functional group the amine is named as an "amino" substituent.
When carboxylic acids are included with an alkene the following order is followed:
(Location number of the alkene)-(Prefix name for the longest carbon chain minus the -ane ending)-(an –enoic acid ending to indicate the presence of an alkene and carboxylic acid)
Remember that the carboxylic acid has priority so it should get the lowest possible location number. Also, remember that cis/tran or E/Z nomenclature for the alkene needs to be included if necessary.
Naming dicarboxylic acids
For dicarboxylic acids the location numbers for both carboxyl groups are omitted because both functional groups are expected to occupy the ends of the parent chain. The ending –dioic acid is added to the end of the parent chain. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/17%3A_Carbonyl_Compounds_I-_Reactions_of_Carboxylic_Acids_and_Carboxylic_Derivatives/17.01%3A_The_Nomenclature_of_Carboxylic_Acids_and_Carboxylic_Acid_Derivatives.txt |
Structure of the carboxyl acid group
Carboxylic acids are organic compounds which incorporate a carboxyl functional group, CO2H. The name carboxyl comes from the fact that a carbonyl and a hydroxyl group are attached to the same carbon.
The carbon and oxygen in the carbonyl are both sp2 hybridized which give a carbonyl group a basic trigonal shape. The hydroxyl oxygen is also sp2 hybridized which allows one of its lone pair electrons to conjugate with the pi system of the carbonyl group. This make the carboxyl group planar an can represented with the following resonance structure.
Carboxylic acids are named such because they can donate a hydrogen to produce a carboxylate ion. The factors which affect the acidity of carboxylic acids will be discussed later.
Physical Properties of Some Carboxylic Acids
The table at the beginning of this page gave the melting and boiling points for a homologous group of carboxylic acids having from one to ten carbon atoms. The boiling points increased with size in a regular manner, but the melting points did not. Unbranched acids made up of an even number of carbon atoms have melting points higher than the odd numbered homologs having one more or one less carbon. This reflects differences in intermolecular attractive forces in the crystalline state. In the table of fatty acids we see that the presence of a cis-double bond significantly lowers the melting point of a compound. Thus, palmitoleic acid melts over 60º lower than palmitic acid, and similar decreases occur for the C18 and C20 compounds. Again, changes in crystal packing and intermolecular forces are responsible.
The factors that influence the relative boiling points and water solubilities of various types of compounds were discussed earlier. In general, dipolar attractive forces between molecules act to increase the boiling point of a given compound, with hydrogen bonds being an extreme example. Hydrogen bonding is also a major factor in the water solubility of covalent compounds To refresh your understanding of these principles Click Here. The following table lists a few examples of these properties for some similar sized polar compounds (the non-polar hydrocarbon hexane is provided for comparison).
Physical Properties of Some Organic Compounds
Formula
IUPAC Name
Molecular Weight
Boiling Point
Water Solubility
CH3(CH2)2CO2H butanoic acid 88 164 ºC very soluble
CH3(CH2)4OH 1-pentanol 88 138 ºC slightly soluble
CH3(CH2)3CHO pentanal 86 103 ºC slightly soluble
CH3CO2C2H5 ethyl ethanoate 88 77 ºC moderately soluble
CH3CH2CO2CH3 methyl propanoate 88 80 ºC slightly soluble
CH3(CH2)2CONH2 butanamide 87 216 ºC soluble
CH3CON(CH3)2 N,N-dimethylethanamide 87 165 ºC very soluble
CH3(CH2)4NH2 1-aminobutane 87 103 ºC very soluble
CH3(CH2)3CN pentanenitrile 83 140 ºC slightly soluble
CH3(CH2)4CH3 hexane 86 69 ºC insoluble
The first five entries all have oxygen functional groups, and the relatively high boiling points of the first two is clearly due to hydrogen bonding. Carboxylic acids have exceptionally high boiling points, due in large part to dimeric associations involving two hydrogen bonds. A structural formula for the dimer of acetic acid is shown here. When the mouse pointer passes over the drawing, an electron cloud diagram will appear. The high boiling points of the amides and nitriles are due in large part to strong dipole attractions, supplemented in some cases by hydrogen bonding.
Acidity of Carboxylic Acids
The pKa 's of some typical carboxylic acids are listed in the following table. When we compare these values with those of comparable alcohols, such as ethanol (pKa = 16) and 2-methyl-2-propanol (pKa = 19), it is clear that carboxylic acids are stronger acids by over ten powers of ten! Furthermore, electronegative substituents near the carboxyl group act to increase the acidity.
Compound
pKa
Compound
pKa
HCO2H 3.75 CH3CH2CH2CO2H 4.82
CH3CO2H 4.74 ClCH2CH2CH2CO2H 4.53
FCH2CO2H 2.65 CH3CHClCH2CO2H 4.05
ClCH2CO2H 2.85 CH3CH2CHClCO2H 2.89
BrCH2CO2H 2.90 C6H5CO2H 4.20
ICH2CO2H 3.10 p-O2NC6H4CO2H 3.45
Cl3CCO2H 0.77 p-CH3OC6H4CO2H 4.45
Why should the presence of a carbonyl group adjacent to a hydroxyl group have such a profound effect on the acidity of the hydroxyl proton? To answer this question we must return to the nature of acid-base equilibria and the definition of pKa , illustrated by the general equations given below. These relationships were described in an previous section of this text.
We know that an equilibrium favors the thermodynamically more stable side, and that the magnitude of the equilibrium constant reflects the energy difference between the components of each side. In an acid base equilibrium the equilibrium always favors the weaker acid and base (these are the more stable components). Water is the standard base used for pKa measurements; consequently, anything that stabilizes the conjugate base (A:(–)) of an acid will necessarily make that acid (H–A) stronger and shift the equilibrium to the right. Both the carboxyl group and the carboxylate anion are stabilized by resonance, but the stabilization of the anion is much greater than that of the neutral function, as shown in the following diagram. In the carboxylate anion the two contributing structures have equal weight in the hybrid, and the C–O bonds are of equal length (between a double and a single bond). This stabilization leads to a markedly increased acidity, as illustrated by the energy diagram displayed by clicking the "Toggle Display" button.
The resonance effect described here is undoubtedly the major contributor to the exceptional acidity of carboxylic acids. However, inductive effects also play a role. For example, alcohols have pKa's of 16 or greater but their acidity is increased by electron withdrawing substituents on the alkyl group. The following diagram illustrates this factor for several simple inorganic and organic compounds (row #1), and shows how inductive electron withdrawal may also increase the acidity of carboxylic acids (rows #2 & 3). The acidic hydrogen is colored red in all examples.
Water is less acidic than hydrogen peroxide because hydrogen is less electronegative than oxygen, and the covalent bond joining these atoms is polarized in the manner shown. Alcohols are slightly less acidic than water, due to the poor electronegativity of carbon, but chloral hydrate, Cl3CCH(OH)2, and 2,2,2,-trifluoroethanol are significantly more acidic than water, due to inductive electron withdrawal by the electronegative halogens (and the second oxygen in chloral hydrate). In the case of carboxylic acids, if the electrophilic character of the carbonyl carbon is decreased the acidity of the carboxylic acid will also decrease. Similarly, an increase in its electrophilicity will increase the acidity of the acid. Acetic acid is ten times weaker an acid than formic acid (first two entries in the second row), confirming the electron donating character of an alkyl group relative to hydrogen, as noted earlier in a discussion of carbocation stability. Electronegative substituents increase acidity by inductive electron withdrawal. As expected, the higher the electronegativity of the substituent the greater the increase in acidity (F > Cl > Br > I), and the closer the substituent is to the carboxyl group the greater is its effect (isomers in the 3rd row). Substituents also influence the acidity of benzoic acid derivatives, but resonance effects compete with inductive effects. The methoxy group is electron donating and the nitro group is electron withdrawing (last three entries in the table of pKa values).
For additional information about substituent effects on the acidity of carboxylic acids Click Here
Vinylagous Acids
Compounds in which an enolic hydroxyl group is conjugated with a carbonyl group also show enhanced acidity. To see examples of such compounds Click Here
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/17%3A_Carbonyl_Compounds_I-_Reactions_of_Carboxylic_Acids_and_Carboxylic_Derivatives/17.02%3A_The_Structures_of_Carboxylic_Acids_and_Carboxylic_Derivatives.txt |
Structure of the carboxyl acid group
Carboxylic acids are organic compounds which incorporate a carboxyl functional group, CO2H. The name carboxyl comes from the fact that a carbonyl and a hydroxyl group are attached to the same carbon.
The carbon and oxygen in the carbonyl are both sp2 hybridized which give a carbonyl group a basic trigonal shape. The hydroxyl oxygen is also sp2 hybridized which allows one of its lone pair electrons to conjugate with the pi system of the carbonyl group. This make the carboxyl group planar an can represented with the following resonance structure.
Carboxylic acids are named such because they can donate a hydrogen to produce a carboxylate ion. The factors which affect the acidity of carboxylic acids will be discussed later.
Physical Properties of Some Carboxylic Acids
The table at the beginning of this page gave the melting and boiling points for a homologous group of carboxylic acids having from one to ten carbon atoms. The boiling points increased with size in a regular manner, but the melting points did not. Unbranched acids made up of an even number of carbon atoms have melting points higher than the odd numbered homologs having one more or one less carbon. This reflects differences in intermolecular attractive forces in the crystalline state. In the table of fatty acids we see that the presence of a cis-double bond significantly lowers the melting point of a compound. Thus, palmitoleic acid melts over 60º lower than palmitic acid, and similar decreases occur for the C18 and C20 compounds. Again, changes in crystal packing and intermolecular forces are responsible.
The factors that influence the relative boiling points and water solubilities of various types of compounds were discussed earlier. In general, dipolar attractive forces between molecules act to increase the boiling point of a given compound, with hydrogen bonds being an extreme example. Hydrogen bonding is also a major factor in the water solubility of covalent compounds To refresh your understanding of these principles Click Here. The following table lists a few examples of these properties for some similar sized polar compounds (the non-polar hydrocarbon hexane is provided for comparison).
Physical Properties of Some Organic Compounds
Formula
IUPAC Name
Molecular Weight
Boiling Point
Water Solubility
CH3(CH2)2CO2H butanoic acid 88 164 ºC very soluble
CH3(CH2)4OH 1-pentanol 88 138 ºC slightly soluble
CH3(CH2)3CHO pentanal 86 103 ºC slightly soluble
CH3CO2C2H5 ethyl ethanoate 88 77 ºC moderately soluble
CH3CH2CO2CH3 methyl propanoate 88 80 ºC slightly soluble
CH3(CH2)2CONH2 butanamide 87 216 ºC soluble
CH3CON(CH3)2 N,N-dimethylethanamide 87 165 ºC very soluble
CH3(CH2)4NH2 1-aminobutane 87 103 ºC very soluble
CH3(CH2)3CN pentanenitrile 83 140 ºC slightly soluble
CH3(CH2)4CH3 hexane 86 69 ºC insoluble
The first five entries all have oxygen functional groups, and the relatively high boiling points of the first two is clearly due to hydrogen bonding. Carboxylic acids have exceptionally high boiling points, due in large part to dimeric associations involving two hydrogen bonds. A structural formula for the dimer of acetic acid is shown here. When the mouse pointer passes over the drawing, an electron cloud diagram will appear. The high boiling points of the amides and nitriles are due in large part to strong dipole attractions, supplemented in some cases by hydrogen bonding.
Acidity of Carboxylic Acids
The pKa 's of some typical carboxylic acids are listed in the following table. When we compare these values with those of comparable alcohols, such as ethanol (pKa = 16) and 2-methyl-2-propanol (pKa = 19), it is clear that carboxylic acids are stronger acids by over ten powers of ten! Furthermore, electronegative substituents near the carboxyl group act to increase the acidity.
Compound
pKa
Compound
pKa
HCO2H 3.75 CH3CH2CH2CO2H 4.82
CH3CO2H 4.74 ClCH2CH2CH2CO2H 4.53
FCH2CO2H 2.65 CH3CHClCH2CO2H 4.05
ClCH2CO2H 2.85 CH3CH2CHClCO2H 2.89
BrCH2CO2H 2.90 C6H5CO2H 4.20
ICH2CO2H 3.10 p-O2NC6H4CO2H 3.45
Cl3CCO2H 0.77 p-CH3OC6H4CO2H 4.45
Why should the presence of a carbonyl group adjacent to a hydroxyl group have such a profound effect on the acidity of the hydroxyl proton? To answer this question we must return to the nature of acid-base equilibria and the definition of pKa , illustrated by the general equations given below. These relationships were described in an previous section of this text.
We know that an equilibrium favors the thermodynamically more stable side, and that the magnitude of the equilibrium constant reflects the energy difference between the components of each side. In an acid base equilibrium the equilibrium always favors the weaker acid and base (these are the more stable components). Water is the standard base used for pKa measurements; consequently, anything that stabilizes the conjugate base (A:(–)) of an acid will necessarily make that acid (H–A) stronger and shift the equilibrium to the right. Both the carboxyl group and the carboxylate anion are stabilized by resonance, but the stabilization of the anion is much greater than that of the neutral function, as shown in the following diagram. In the carboxylate anion the two contributing structures have equal weight in the hybrid, and the C–O bonds are of equal length (between a double and a single bond). This stabilization leads to a markedly increased acidity, as illustrated by the energy diagram displayed by clicking the "Toggle Display" button.
The resonance effect described here is undoubtedly the major contributor to the exceptional acidity of carboxylic acids. However, inductive effects also play a role. For example, alcohols have pKa's of 16 or greater but their acidity is increased by electron withdrawing substituents on the alkyl group. The following diagram illustrates this factor for several simple inorganic and organic compounds (row #1), and shows how inductive electron withdrawal may also increase the acidity of carboxylic acids (rows #2 & 3). The acidic hydrogen is colored red in all examples.
Water is less acidic than hydrogen peroxide because hydrogen is less electronegative than oxygen, and the covalent bond joining these atoms is polarized in the manner shown. Alcohols are slightly less acidic than water, due to the poor electronegativity of carbon, but chloral hydrate, Cl3CCH(OH)2, and 2,2,2,-trifluoroethanol are significantly more acidic than water, due to inductive electron withdrawal by the electronegative halogens (and the second oxygen in chloral hydrate). In the case of carboxylic acids, if the electrophilic character of the carbonyl carbon is decreased the acidity of the carboxylic acid will also decrease. Similarly, an increase in its electrophilicity will increase the acidity of the acid. Acetic acid is ten times weaker an acid than formic acid (first two entries in the second row), confirming the electron donating character of an alkyl group relative to hydrogen, as noted earlier in a discussion of carbocation stability. Electronegative substituents increase acidity by inductive electron withdrawal. As expected, the higher the electronegativity of the substituent the greater the increase in acidity (F > Cl > Br > I), and the closer the substituent is to the carboxyl group the greater is its effect (isomers in the 3rd row). Substituents also influence the acidity of benzoic acid derivatives, but resonance effects compete with inductive effects. The methoxy group is electron donating and the nitro group is electron withdrawing (last three entries in the table of pKa values).
For additional information about substituent effects on the acidity of carboxylic acids Click Here
Vinylagous Acids
Compounds in which an enolic hydroxyl group is conjugated with a carbonyl group also show enhanced acidity. To see examples of such compounds Click Here
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/17%3A_Carbonyl_Compounds_I-_Reactions_of_Carboxylic_Acids_and_Carboxylic_Derivatives/17.03%3A_The_Physical_Properties_of_Carbonyl_Compounds.txt |
Carboxylic acids are widespread in nature, often combined with other functional groups. Simple alkyl carboxylic acids, composed of four to ten carbon atoms, are liquids or low melting solids having very unpleasant odors. The fatty acids are important components of the biomolecules known as lipids, especially fats and oils. As shown in the following table, these long-chain carboxylic acids are usually referred to by their common names, which in most cases reflect their sources. A mnemonic phrase for the C10 to C20 natural fatty acids capric, lauric, myristic, palmitic, stearic and arachidic is: "Curly, Larry & Moe Perform Silly Antics" (note that the names of the three stooges are in alphabetical order).
Table: \(1\): Saturated Fatty Acids
Formula Common Name Melting Point
CH3(CH2)10CO2H lauric acid 45 ºC
CH3(CH2)12CO2H myristic acid 55 ºC
CH3(CH2)14CO2H palmitic acid 63 ºC
CH3(CH2)16CO2H stearic acid 69 ºC
CH3(CH2)18CO2H arachidic acid 76 ºC
Interestingly, the molecules of most natural fatty acids have an even number of carbon atoms. Analogous compounds composed of odd numbers of carbon atoms are perfectly stable and have been made synthetically. Since nature makes these long-chain acids by linking together acetate units, it is not surprising that the carbon atoms composing the natural products are multiples of two. The double bonds in the unsaturated compounds listed on the right are all cis (or Z).
Table \(2\): Unsaturated Fatty Acids
Formula Common Name Melting Point
CH3(CH2)5CH=CH(CH2)7CO2H palmitoleic acid 0 ºC
CH3(CH2)7CH=CH(CH2)7CO2H oleic acid 13 ºC
CH3(CH2)4CH=CHCH2CH=CH(CH2)7CO2H linoleic acid -5 ºC
CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7CO2H linolenic acid -11 ºC
CH3(CH2)4(CH=CHCH2)4(CH2)2CO2H arachidonic acid -49 ºC
The following formulas are examples of other naturally occurring carboxylic acids. The molecular structures range from simple to complex, often incorporate a variety of other functional groups, and many are chiral.
Contributors
• William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
17.05: How Class I Carbonyl Compounds React
Introduction
Carboxylic acid derivatives are a group of functional groups whose chemistry is closely related. The main difference is the presence of an electronegative substituent that can act as a leaving group during nucleophile substitution reactions. Although there are many types of carboxylic acid derivatives known we will be focusing on just four: Acid halides, Acid anhydrides, Esters, and Amides.
General mechanism
1) Nucleophilic attack on the carbonyl
2) Leaving group is removed
Although aldehydes and ketones also contain a carbonyl their chemistry is distinctly different because they do not contain a suitable leaving group. Once the tetrahedral intermediate is formed aldehydes and ketones cannot reform the carbonyl. Because of this aldehydes and ketones typically undergo nucleophilic additions and not substitutions.
The relative reactivity of carboxylic acid derivatives toward nucleophile substitutions is related to the electronegative leaving group’s ability to activate the carbonyl. The more electronegative leaving groups withdrawn electron density from the carbonyl, thereby, increasing its electrophilicity.
Contributors
Prof. Steven Farmer (Sonoma State University)
17.06: Relative Reactivities of Carboxylic Acids and Carboxylic Acid Derivatives
Introduction
Carboxylic acid derivatives are a group of functional groups whose chemistry is closely related. The main difference is the presence of an electronegative substituent that can act as a leaving group during nucleophile substitution reactions. Although there are many types of carboxylic acid derivatives known we will be focusing on just four: Acid halides, Acid anhydrides, Esters, and Amides.
General mechanism
1) Nucleophilic attack on the carbonyl
2) Leaving group is removed
Although aldehydes and ketones also contain a carbonyl their chemistry is distinctly different because they do not contain a suitable leaving group. Once the tetrahedral intermediate is formed aldehydes and ketones cannot reform the carbonyl. Because of this aldehydes and ketones typically undergo nucleophilic additions and not substitutions.
The relative reactivity of carboxylic acid derivatives toward nucleophile substitutions is related to the electronegative leaving group’s ability to activate the carbonyl. The more electronegative leaving groups withdrawn electron density from the carbonyl, thereby, increasing its electrophilicity.
Contributors
Prof. Steven Farmer (Sonoma State University) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/17%3A_Carbonyl_Compounds_I-_Reactions_of_Carboxylic_Acids_and_Carboxylic_Derivatives/17.04%3A_Naturally_Occurring_Carboxylic_Acids_and_Carboxylic_Acid_Derivatives.txt |
Introduction
Carboxylic acid derivatives are a group of functional groups whose chemistry is closely related. The main difference is the presence of an electronegative substituent that can act as a leaving group during nucleophile substitution reactions. Although there are many types of carboxylic acid derivatives known we will be focusing on just four: Acid halides, Acid anhydrides, Esters, and Amides.
General mechanism
1) Nucleophilic attack on the carbonyl
2) Leaving group is removed
Although aldehydes and ketones also contain a carbonyl their chemistry is distinctly different because they do not contain a suitable leaving group. Once the tetrahedral intermediate is formed aldehydes and ketones cannot reform the carbonyl. Because of this aldehydes and ketones typically undergo nucleophilic additions and not substitutions.
The relative reactivity of carboxylic acid derivatives toward nucleophile substitutions is related to the electronegative leaving group’s ability to activate the carbonyl. The more electronegative leaving groups withdrawn electron density from the carbonyl, thereby, increasing its electrophilicity.
Contributors
Prof. Steven Farmer (Sonoma State University)
17.09: Reactions of Acid Anhydrides
Acid anhydrides are a source of reactive acyl groups, and their reactions and uses resemble those of acyl halides. Acid anhydrides tend to be less electrophilic than acyl chlorides, and only one acyl group is transferred per molecule of acid anhydride, which leads to a lower atom efficiency. The low cost, however, of acetic anhydride makes it a common choice for acetylation reactions.
• Acid Anhydrides react with alcohols to form esters
Acid Anhydrides react with alcohols to form esters
• Acid Anhydrides React with Amines to Form Amides
Acid Anhydrides react with amines to form amides
• Acid Anhydrides react with water to form carboxylic acids
Acid Anhydrides react with water to form carboxylic acids
• General Mechanism of Anhydride Reactions
Carboxylic acid derivatives are a group of functional groups whose chemistry is closely related. The main difference is the presence of an electronegative substituent that can act as a leaving group during nucleophile substitution reactions. Although there are many types of carboxylic acid derivatives known we will be focusing on just four: Acid halides, Acid anhydrides, Esters, and Amides.
• Reactions of Acid Anhydrides with Nitrogen Compounds
This page looks at the reactions of acid anhydrides with ammonia and with primary amines. These reactions are considered together because their chemistry is so similar. There is also a great similarity between acid anhydrides and acyl chlorides (acid chlorides) as far as these reactions are concerned.
• Reactions of Acid Anhydrides with Oxygen Compounds
This page looks at the reactions of acid anhydrides with water, alcohols and phenols (including the manufacture of aspirin). These reactions are all considered together because their chemistry is so similar. There is also a great similarity between acid anhydrides and acyl chlorides (acid chlorides) as far as these reactions are concerned.
17.11: Acid-Catalyzed Ester Hydrolysis and Transesterification
Introduction
Esters can be cleaved back into a carboxylic acid and an alcohol by reaction with water and a catalytic amount of acid.
Example 1:
Mechanism
1) Protonation of the Carbonyl
2) Nucleophilic attack by water
3) Proton transfer
4) Leaving group removal
Contributors
Prof. Steven Farmer (Sonoma State University)
17.12: Hydroxide-Ion-Promoted Ester Hydrolysis
Esters can be cleaved back into a carboxylic acid and an alcohol by reaction with water and a base. The reaction is called a saponification from the Latin sapo which means soap. The name comes from the fact that soap used to be made by the ester hydrolysis of fats. Due to the basic conditions a carboxylate ion is made rather than a carboxylic acid.
Mechanism
Step 1: Nucleophilic attack by hydroxide
Step 2: Leaving group removal
Step 3: Deprotonation | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/17%3A_Carbonyl_Compounds_I-_Reactions_of_Carboxylic_Acids_and_Carboxylic_Derivatives/17.07%3A_General_Mechanism_for_Nucleophilic_Addition-Elimination_Reactions.txt |
This page describes ways of hydrolyzing esters - splitting them into carboxylic acids (or their salts) and alcohols by the action of water, dilute acid or dilute alkali. It starts by looking at the hydrolysis of simple esters like ethyl ethanoate, and goes on to look at hydrolyzing bigger, more complicated ones to make soap.
Technically, hydrolysis is a reaction with water. That is exactly what happens when esters are hydrolyzed by water or by dilute acids such as dilute hydrochloric acid. The alkaline hydrolysis of esters actually involves reaction with hydroxide ions, but the overall result is so similar that it is lumped together with the other two.
Hydrolysis using water or dilute acid
The reaction with pure water is so slow that it is never used. The reaction is catalyzed by dilute acid, and so the ester is heated under reflux with a dilute acid like dilute hydrochloric acid or dilute sulfuric acid. Here are two simple examples of hydrolysis using an acid catalyst.
First, hydrolyzing ethyl ethanoate:
. . . and then hydrolyzing methyl propanoate:
Notice that the reactions are reversible. To make the hydrolysis as complete as possible, you would have to use an excess of water. The water comes from the dilute acid, and so you would mix the ester with an excess of dilute acid.
Hydrolysis using dilute alkali
This is the usual way of hydrolyzing esters. The ester is heated under reflux with a dilute alkali like sodium hydroxide solution. There are two advantages of doing this rather than using a dilute acid. The reactions are one-way rather than reversible, and the products are easier to separate. Taking the same esters as above, but using sodium hydroxide solution rather than a dilute acid:
First, hydrolyzing ethyl ethanoate using sodium hydroxide solution:
and then hydrolyzing methyl propanoate in the same way:
Notice that you get the sodium salt formed rather than the carboxylic acid itself. This mixture is relatively easy to separate. Provided you use an excess of sodium hydroxide solution, there will not be any ester left - so you don't have to worry about that. The alcohol formed can be distilled off. That's easy!
If you want the acid rather than its salt, all you have to do is to add an excess of a strong acid like dilute hydrochloric acid or dilute sulfuric acid to the solution left after the first distillation. If you do this, the mixture is flooded with hydrogen ions. These are picked up by the ethanoate ions (or propanoate ions or whatever) present in the salts to make ethanoic acid (or propanoic acid, etc). Because these are weak acids, once they combine with the hydrogen ions, they tend to stay combined. The carboxylic acid can now be distilled off.
Hydrolyzing complicated esters to make soap
This next bit deals with the alkaline hydrolysis (using sodium hydroxide solution) of the big esters found in animal and vegetable fats and oils. If the large esters present in animal or vegetable fats and oils are heated with concentrated sodium hydroxide solution exactly the same reaction happens as with the simple esters. A salt of a carboxylic acid is formed - in this case, the sodium salt of a big acid such as octadecanoic acid (stearic acid). These salts are the important ingredients of soap - the ones that do the cleaning. An alcohol is also produced - in this case, the more complicated alcohol, propane-1,2,3-triol (glycerol).
Because of its relationship with soap making, the alkaline hydrolysis of esters is sometimes known as saponification.
17.16: Reactions of Amides
Amides are reasonably reactive, usually via an attack on the carbonyl breaking the carbonyl double bond and forming a tetrahedral intermediate. Thiols, hydroxyls and amines are all known to serve as nucleophiles. Owing to their resonance stabilization, amides are less reactive under physiological conditions than esters.
17.19: The Hydrolysis of Nitriles
Nitriles can be converted to carboxylic acid with heating in sulfuric acid. During the reaction an amide intermediate is formed.
Contributors
Prof. Steven Farmer (Sonoma State University)
17.21: How Chemists Activate Carboxylic Acids
Carboxylic acids react with Thionyl Chloride (\(SOCl_2\)) to form acid chlorides. During the reaction the hydroxyl group of the carboxylic acid is converted to a chlorosulfite intermediate making it a better leaving group. The chloride anion produced during the reaction acts a nucleophile.
Mechanism
1) Nucleophilic attack on Thionyl Chloride
2) Removal of Cl leaving group
3) Nucleophilic attack on the carbonyl
4) Leaving group removal
5) Deprotonation
Contributors
Prof. Steven Farmer (Sonoma State University) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/17%3A_Carbonyl_Compounds_I-_Reactions_of_Carboxylic_Acids_and_Carboxylic_Derivatives/17.14%3A_Soaps_Detergents_and_Micelles.txt |
12.2A: Glutamine synthetase
You have already learned that the carboxylate functional group is a very unreactive substrate for an enzyme-catalyzed acyl substitution reactions. How, then, does a living system accomplish an ‘uphill’ reaction such as the one shown below, where glutamate (a carboxylate) is converted to glutamine (an amide)?
It turns out that this conversion is not carried out directly. Rather, the first conversion is from a carboxylate (the least reactive acyl transfer substrate) to an acyl phosphate (the most reactive acyl transfer substrate). This transformation requires a reaction that we are familiar with from chapter 10: phosphorylation of a carboxylate oxygen with ATP as the phosphate donor.
Note that this is just one of the many ways that ATP is used as a energy storage unit: in order to make a high energy acyl phosphate molecule from a low energy carboxylate, the cell must ‘spend’ the energy of one ATP molecule.
The acyl phosphate version of glutamate is now ready to be converted directly to an amide (glutamine) via a nucleophilic acyl substitution reaction, as an ammonia molecule attacks the carbonyl and the phosphate is expelled.
Overall, this reaction can be written as:
12.2B: Asparagine synthetase
Another common form of activated carboxylate group is an acyl adenosine phosphate. Consider another amino acid reaction, the conversion of aspartate to asparagine. In the first step, the carboxylate group of aspartate must be activated:
Once again, ATP provides the energy for driving the uphill reaction. This time, however, the activated carboxylate takes the form of an acyl adenosine (mono)phosphate. All that has happened is that the carboxylate oxygen has attacked the a-phosphate of ATP rather than the g-phosphate.
The reactive acyl-AMP version of aspartate is now ready to be converted to an amide (asparagine) via nucleophilic attack by ammonia. In the case of glutamine synthase, the source of ammonia was free ammonium ion in solution. In the case of asparagine synthase, the NH3 is derived from the hydrolysis of glutamine (this is simply another acyl substitution reaction):
The hydrolysis reaction is happening in the same enzyme active site – as the NH3 is expelled in the hydrolysis of glutamine, it immediately turns around and acts as the nucleophile in the conversion of aspartyl-AMP to asparagine:
Keep in mind that the same enzyme is also binding ATP and using it to activate aspartate – this is a busy construction zone!
Overall, this reaction can be written in condensed form as:
The use of glutamine as a ‘carrier’ for ammonia is a fairly common strategy in metabolic pathways. This strategy makes sense, as it allows cells to maintain a constant source of NH3 for reactions that require it, without the need for high solution concentrations of free ammonia.
12.2C: Glycinamide ribonucleotide synthetase
One of the early steps in the construction of purine bases (the adenine and guanine bases in DNA and RNA) involves an acyl substitution reaction with an acyl phosphate intermediate. In this case, the attacking nucleophile is not ammonia but a primary amine. The strategy, however, is similar to that of glutamine synthase. The carboxylate group on glycine is converted to an acyl phosphate, at the cost of one ATP molecule. The acyl group is then transferred to 5-phosphoribosylamine, resulting in an amide product.
12.2D: Synthetic parallel - activated carboxylic acids in the lab
Just as enzymes need to activate carboxylate groups by first converting them to acyl phosphates, human chemists working in the lab have developed methods to create derivatives of carboxylic acids that are reactive in acyl substitution reactions. When treated with SOCl2 or PCl3, a carboxylic acid can be converted to an acid chloride, a derivative in which the acyl X group is a chloride ion. Note that these reactions are very similar to the reactions we saw in section 8.5B, in which alcohols were converted into alkyl chlorides or alkyl bromides by SOCl2 and PBr3, respectively.
You will be asked to propose a mechanism for these transformations in the end-of-chapter problems.
Acid chlorides are the laboratory equivalents of acyl phosphates in biochemistry, readily donating their acyl groups to form amides, esters, or other acyl compounds according to the nucleophile selected. The general example below shows the conversion of a carboxylic acid to an amide via an acid chloride intermediate.
Acid anyhydrides are also used as activated acyl groups in the lab, although they are less reactive than acid chlorides. Acetic anhydride is a convenient acetyl group donor, as shown in this synthesis of aspirin from salicylic acid (this is an easy transformation that is often carried out in undergraduate laboratory classes).
Exercise 12.2: In the conversion of a carboxylic acid to an amide, why is it necessary to first prepare the acid chloride? In other words, why couldn't one simply react the amine directly with the carboxylic acid?
Exercise 12.3: Show how you might prepare the following compound, starting with a carboxylic acid and an amine.
Solutions
Template:ExampleEnd
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/17%3A_Carbonyl_Compounds_I-_Reactions_of_Carboxylic_Acids_and_Carboxylic_Derivatives/17.22%3A_How_Cells_Activate_Carboxylic_Acids.txt |
Structure of the carboxyl acid group
Carboxylic acids are organic compounds which incorporate a carboxyl functional group, CO2H. The name carboxyl comes from the fact that a carbonyl and a hydroxyl group are attached to the same carbon.
The carbon and oxygen in the carbonyl are both sp2 hybridized which give a carbonyl group a basic trigonal shape. The hydroxyl oxygen is also sp2 hybridized which allows one of its lone pair electrons to conjugate with the pi system of the carbonyl group. This make the carboxyl group planar an can represented with the following resonance structure.
Carboxylic acids are named such because they can donate a hydrogen to produce a carboxylate ion. The factors which affect the acidity of carboxylic acids will be discussed later.
Physical Properties of Some Carboxylic Acids
The table at the beginning of this page gave the melting and boiling points for a homologous group of carboxylic acids having from one to ten carbon atoms. The boiling points increased with size in a regular manner, but the melting points did not. Unbranched acids made up of an even number of carbon atoms have melting points higher than the odd numbered homologs having one more or one less carbon. This reflects differences in intermolecular attractive forces in the crystalline state. In the table of fatty acids we see that the presence of a cis-double bond significantly lowers the melting point of a compound. Thus, palmitoleic acid melts over 60º lower than palmitic acid, and similar decreases occur for the C18 and C20 compounds. Again, changes in crystal packing and intermolecular forces are responsible.
The factors that influence the relative boiling points and water solubilities of various types of compounds were discussed earlier. In general, dipolar attractive forces between molecules act to increase the boiling point of a given compound, with hydrogen bonds being an extreme example. Hydrogen bonding is also a major factor in the water solubility of covalent compounds To refresh your understanding of these principles Click Here. The following table lists a few examples of these properties for some similar sized polar compounds (the non-polar hydrocarbon hexane is provided for comparison).
Physical Properties of Some Organic Compounds
Formula
IUPAC Name
Molecular Weight
Boiling Point
Water Solubility
CH3(CH2)2CO2H butanoic acid 88 164 ºC very soluble
CH3(CH2)4OH 1-pentanol 88 138 ºC slightly soluble
CH3(CH2)3CHO pentanal 86 103 ºC slightly soluble
CH3CO2C2H5 ethyl ethanoate 88 77 ºC moderately soluble
CH3CH2CO2CH3 methyl propanoate 88 80 ºC slightly soluble
CH3(CH2)2CONH2 butanamide 87 216 ºC soluble
CH3CON(CH3)2 N,N-dimethylethanamide 87 165 ºC very soluble
CH3(CH2)4NH2 1-aminobutane 87 103 ºC very soluble
CH3(CH2)3CN pentanenitrile 83 140 ºC slightly soluble
CH3(CH2)4CH3 hexane 86 69 ºC insoluble
The first five entries all have oxygen functional groups, and the relatively high boiling points of the first two is clearly due to hydrogen bonding. Carboxylic acids have exceptionally high boiling points, due in large part to dimeric associations involving two hydrogen bonds. A structural formula for the dimer of acetic acid is shown here. When the mouse pointer passes over the drawing, an electron cloud diagram will appear. The high boiling points of the amides and nitriles are due in large part to strong dipole attractions, supplemented in some cases by hydrogen bonding.
Acidity of Carboxylic Acids
The pKa 's of some typical carboxylic acids are listed in the following table. When we compare these values with those of comparable alcohols, such as ethanol (pKa = 16) and 2-methyl-2-propanol (pKa = 19), it is clear that carboxylic acids are stronger acids by over ten powers of ten! Furthermore, electronegative substituents near the carboxyl group act to increase the acidity.
Compound
pKa
Compound
pKa
HCO2H 3.75 CH3CH2CH2CO2H 4.82
CH3CO2H 4.74 ClCH2CH2CH2CO2H 4.53
FCH2CO2H 2.65 CH3CHClCH2CO2H 4.05
ClCH2CO2H 2.85 CH3CH2CHClCO2H 2.89
BrCH2CO2H 2.90 C6H5CO2H 4.20
ICH2CO2H 3.10 p-O2NC6H4CO2H 3.45
Cl3CCO2H 0.77 p-CH3OC6H4CO2H 4.45
Why should the presence of a carbonyl group adjacent to a hydroxyl group have such a profound effect on the acidity of the hydroxyl proton? To answer this question we must return to the nature of acid-base equilibria and the definition of pKa , illustrated by the general equations given below. These relationships were described in an previous section of this text.
We know that an equilibrium favors the thermodynamically more stable side, and that the magnitude of the equilibrium constant reflects the energy difference between the components of each side. In an acid base equilibrium the equilibrium always favors the weaker acid and base (these are the more stable components). Water is the standard base used for pKa measurements; consequently, anything that stabilizes the conjugate base (A:(–)) of an acid will necessarily make that acid (H–A) stronger and shift the equilibrium to the right. Both the carboxyl group and the carboxylate anion are stabilized by resonance, but the stabilization of the anion is much greater than that of the neutral function, as shown in the following diagram. In the carboxylate anion the two contributing structures have equal weight in the hybrid, and the C–O bonds are of equal length (between a double and a single bond). This stabilization leads to a markedly increased acidity, as illustrated by the energy diagram displayed by clicking the "Toggle Display" button.
The resonance effect described here is undoubtedly the major contributor to the exceptional acidity of carboxylic acids. However, inductive effects also play a role. For example, alcohols have pKa's of 16 or greater but their acidity is increased by electron withdrawing substituents on the alkyl group. The following diagram illustrates this factor for several simple inorganic and organic compounds (row #1), and shows how inductive electron withdrawal may also increase the acidity of carboxylic acids (rows #2 & 3). The acidic hydrogen is colored red in all examples.
Water is less acidic than hydrogen peroxide because hydrogen is less electronegative than oxygen, and the covalent bond joining these atoms is polarized in the manner shown. Alcohols are slightly less acidic than water, due to the poor electronegativity of carbon, but chloral hydrate, Cl3CCH(OH)2, and 2,2,2,-trifluoroethanol are significantly more acidic than water, due to inductive electron withdrawal by the electronegative halogens (and the second oxygen in chloral hydrate). In the case of carboxylic acids, if the electrophilic character of the carbonyl carbon is decreased the acidity of the carboxylic acid will also decrease. Similarly, an increase in its electrophilicity will increase the acidity of the acid. Acetic acid is ten times weaker an acid than formic acid (first two entries in the second row), confirming the electron donating character of an alkyl group relative to hydrogen, as noted earlier in a discussion of carbocation stability. Electronegative substituents increase acidity by inductive electron withdrawal. As expected, the higher the electronegativity of the substituent the greater the increase in acidity (F > Cl > Br > I), and the closer the substituent is to the carboxyl group the greater is its effect (isomers in the 3rd row). Substituents also influence the acidity of benzoic acid derivatives, but resonance effects compete with inductive effects. The methoxy group is electron donating and the nitro group is electron withdrawing (last three entries in the table of pKa values).
For additional information about substituent effects on the acidity of carboxylic acids Click Here
Vinylagous Acids
Compounds in which an enolic hydroxyl group is conjugated with a carbonyl group also show enhanced acidity. To see examples of such compounds Click Here
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/17%3A_Carbonyl_Compounds_I-_Reactions_of_Carboxylic_Acids_and_Carboxylic_Derivatives/17.23%3A_Dicarboxylic_Acids_and_Their_Derivatives.txt |
Aldehydes and ketones contain the carbonyl group. Aldehydes are considered the most important functional group. They are often called the formyl or methanoyl group. Aldehydes derive their name from the dehydration of alcohols. Aldehydes contain the carbonyl group bonded to at least one hydrogen atom. Ketones contain the carbonyl group bonded to two carbon atoms.
Aldehydes and ketones are organic compounds which incorporate a carbonyl functional group, C=O. The carbon atom of this group has two remaining bonds that may be occupied by hydrogen, alkyl or aryl substituents. If at least one of these substituents is hydrogen, the compound is an aldehyde. If neither is hydrogen, the compound is a ketone.
Naming Aldehydes
The IUPAC system of nomenclature assigns a characteristic suffix -al to aldehydes. For example, H2C=O is methanal, more commonly called formaldehyde. Since an aldehyde carbonyl group must always lie at the end of a carbon chain, it is always is given the #1 location position in numbering and it is not necessary to include it in the name. There are several simple carbonyl containing compounds which have common names which are retained by IUPAC.
Also, there is a common method for naming aldehydes and ketones. For aldehydes common parent chain names, similar to those used for carboxylic acids, are used and the suffix –aldehyde is added to the end. In common names of aldehydes, carbon atoms near the carbonyl group are often designated by Greek letters. The atom adjacent to the carbonyl function is alpha, the next removed is beta and so on.
If the aldehyde moiety (-CHO) is attached to a ring the suffix –carbaldehyde is added to the name of the ring. The carbon attached to this moiety will get the #1 location number in naming the ring.
Summary of Aldehyde Nomenclature rules
1. Aldehydes take their name from their parent alkane chains. The -e is removed from the end and is replaced with -al.
2. The aldehyde funtional group is given the #1 numbering location and this number is not included in the name.
3. For the common name of aldehydes start with the common parent chain name and add the suffix -aldehyde. Substituent positions are shown with Greek letters.
4. When the -CHO functional group is attached to a ring the suffix -carbaldehyde is added, and the carbon attached to that group is C1.
Example 1
The IUPAC system names are given on top while the common name is given on the bottom in parentheses.
Aldehyde Common Names to Memorize
There are some common names that are still used and need to be memorized. Recognizing the patterns can be helpful.
Naming Ketones
The IUPAC system of nomenclature assigns a characteristic suffix of -one to ketones. A ketone carbonyl function may be located anywhere within a chain or ring, and its position is usually given by a location number. Chain numbering normally starts from the end nearest the carbonyl group. Very simple ketones, such as propanone and phenylethanone do not require a locator number, since there is only one possible site for a ketone carbonyl function. The common names for ketones are formed by naming both alkyl groups attached to the carbonyl then adding the suffix -ketone. The attached alkyl groups are arranged in the name alphabetically.
Summary of Ketone Nomenclature rules
1. Ketones take their name from their parent alkane chains. The ending -e is removed and replaced with -one.
2. The common name for ketones are simply the substituent groups listed alphabetically + ketone.
3. Some common ketones are known by their generic names. Such as the fact that propanone is commonly referred to as acetone.
Example 2
The IUPAC system names are given on top while the common name is given on the bottom in parentheses.
Ketone Common Names to Memorize
There are some common names that are still used and need to be memorized. Recognizing the patterns can be helpful.
Naming Aldehydes and Ketones in the Same Molecule
As with many molecules with two or more functional groups, one is given priority while the other is named as a substituent. Because aldehydes have a higher priority than ketones, molecules which contain both functional groups are named as aldehydes and the ketone is named as an "oxo" substituent. It is not necessary to give the aldehyde functional group a location number, however, it is usually necessary to give a location number to the ketone.
Naming Dialdehydes and Diketones
For dialdehydes the location numbers for both carbonyls are omitted because the aldehyde functional groups are expected to occupy the ends of the parent chain. The ending –dial is added to the end of the parent chain name.
Example 4
For diketones both carbonyls require a location number. The ending -dione or -dial is added to the end of the parent chain.
Naming Cyclic Ketones and Diketones
In cyclic ketones the carbonyl group is assigned location position #1, and this number is not included in the name, unless more than one carbonyl group is present. The rest of the ring is numbered to give substituents the lowest possible location numbers. Remember the prefix cyclo is included before the parent chain name to indicate that it is in a ring. As with other ketones the –e ending is replaced with the –one to indicate the presence of a ketone.
With cycloalkanes which contain two ketones both carbonyls need to be given a location numbers. Also, an –e is not removed from the end, but the suffix –dione is added.
Naming Carbonyls and Hydroxyls in the Same Molecule
When and aldehyde or ketone is present in a molecule which also contains an alcohol functional group the carbonyl is given nomenclature priority by the IUPAC system. This means that the carbonyl is given the lowest possible location number and the appropriate nomenclature suffix is included. In the case of alcohols the OH is named as a hydroxyl substituent. However, the l in hydroxyl is generally removed.
Naming Carbonyls and Alkenes in the Same Molecule
When and aldehyde or ketone is present in a molecule which also contains analkene functional group the carbonyl is given nomenclature priority by the IUPAC system. This means that the carbonyl is given the lowest possible location number and the appropriate nomenclature suffix is included. When carbonyls are included with an alkene the following order is followed:
(Location number of the alkene)-(Prefix name for the longest carbon chain minus the -ane ending)-(an -en ending to indicate the presence of an alkene)-(the location number of the carbonyl if a ketone is present)-(either an –one or and -anal ending).
Remember that the carbonyl has priority so it should get the lowest possible location number. Also, remember that cis/tran or E/Z nomenclature for the alkene needs to be included if necessary.
Aldehydes and Ketones as Fragments
• Alkanoyl is the common name of the fragment, though the older naming, acyl, is still widely used.
• Formyl is the common name of the fragment.
• Acety is the common name of the CH3-C=O- fragment.
Additional Examples of Carbonyl Nomenclature
1) Please give the IUPAC name for each compound:
Answers for Question 1
1. 3,4-dimethylhexanal
2. 5-bromo-2-pentanone
3. 2,4-hexanedione
4. cis-3-pentenal (or (Z)-3-pentenal)
5. 6-methyl-5-hepten-3-one
6. 3-hydroxy-2,4-pentanedione
7. 1,2-cyclobutanedione
8. 2-methyl-propanedial
9. 3-methyl-5-oxo-hexanal
10. cis-2,3-dihydroxycyclohexanone
11. 3-bromo-2-methylcyclopentanecarboaldehyde
12. 3-bromo-2-methylpropanal
2) Please give the structure corresponding to each name:
A) butanal
B) 2-hydroxycyclopentanone
C) 2,3-pentanedione
D) 1,3-cyclohexanedione
E) 4-hydoxy-3-methyl-2-butanone
F) (E) 3-methyl-2-hepten-4-one
G) 3-oxobutanal
H) cis-3-bromocyclohexanecarboaldehyde
I) butanedial
J) trans-2-methyl-3-hexenal
Answers to question 2: | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/18%3A_Carbonyl_Compounds_II-_Reactions_of_Aldehydes_and_Ketones__More_Reactions_of_Carboxylic_Acid_Derivatives__Reactions_of__-_Unsaturated_Carbonyl_Compounds/18.01%3A_Th.txt |
The concept of an ideal solution is fundamental to chemical thermodynamics and its applications, such as the use of colligative properties. An ideal solution or ideal mixture is a solution in which the enthalpy of solution (\(\Delta{H_{solution}} = 0\)) is zero; with the closer to zero the enthalpy of solution, the more "ideal" the behavior of the solution becomes. Since the enthalpy of mixing (solution) is zero, the change in Gibbs energy on mixing is determined solely by the entropy of mixing (\(\Delta{S_{solution}}\)).
• Raoult's Law
Raoult's law states that the vapor pressure of a solvent above a solution is equal to the vapor pressure of the pure solvent at the same temperature scaled by the mole fraction of the solvent present. At any given temperature for a particular solid or liquid, there is a pressure at which the vapor formed above the substance is in dynamic equilibrium with its liquid or solid form. At equilibrium, the rate at which the solid or liquid evaporates is equal to the rate that the gas is condensing.
• Henry's Law
Henry's law is one of the gas laws formulated by William Henry in 1803 and states: "At a constant temperature, the amount of a given gas that dissolves in a given type and volume of liquid is directly proportional to the partial pressure of that gas in equilibrium with that liquid." An equivalent way of stating the law is that the solubility of a gas in a liquid is directly proportional to the partial pressure of the gas above the liquid.
18.03: Ho
Before we consider in detail the reactivity of aldehydes and ketones, we need to look back and remind ourselves of what the bonding picture looks like in a carbonyl. Carbonyl carbons are sp2 hybridized, with the three sp2 orbitals forming soverlaps with orbitals on the oxygen and on the two carbon or hydrogen atoms. These three bonds adopt trigonal planar geometry. The remaining unhybridized 2p orbital on the central carbonyl carbon is perpendicular to this plane, and forms a ‘side-by-side’ pbond with a 2p orbital on the oxygen.
The carbon-oxygen double bond is polar: oxygen is more electronegative than carbon, so electron density is higher on the oxygen side of the bond and lower on the carbon side. Recall that bond polarity can be depicted with a dipole arrow, or by showing the oxygen as holding a partial negative charge and the carbonyl carbon a partial positive charge.
A third way to illustrate the carbon-oxygen dipole is to consider the two main resonance contributors of a carbonyl group: the major form, which is what you typically see drawn in Lewis structures, and a minor but very important contributor in which both electrons in the pbond are localized on the oxygen, giving it a full negative charge. The latter depiction shows the carbon with an empty 2p orbital and a full positive charge.
The result of carbonyl bond polarization, however it is depicted, is straightforward to predict. The carbon, because it is electron-poor, is an electrophile: it is a great target for attack by an electron-rich nucleophilic group. Because the oxygen end of the carbonyl double bond bears a partial negative charge, anything that can help to stabilize this charge by accepting some of the electron density will increase the bond’s polarity and make the carbon more electrophilic. Very often a general acid group serves this purpose, donating a proton to the carbonyl oxygen.
The same effect can also be achieved if a Lewis acid, such as a magnesium ion, is located near the carbonyl oxygen.
Unlike the situation in a nucleophilic substitution reaction, when a nucleophile attacks an aldehyde or ketone carbon there is no leaving group – the incoming nucleophile simply ‘pushes’ the electrons in the pi bond up to the oxygen.
Alternatively, if you start with the minor resonance contributor, you can picture this as an attack by a nucleophile on a carbocation.
After the carbonyl is attacked by the nucleophile, the negatively charged oxygen has the capacity to act as a nucleophile. However, most commonly the oxygen acts instead as a base, abstracting a proton from a nearby acid group in the solvent or enzyme active site.
This very common type of reaction is called a nucleophilic addition. In many biologically relevant examples of nucleophilic addition to carbonyls, the nucleophile is an alcohol oxygen or an amine nitrogen, or occasionally a thiol sulfur. In one very important reaction type known as an aldol reaction (which we will learn about in section 13.3) the nucleophile attacking the carbonyl is a resonance-stabilized carbanion. In this chapter, we will concentrate on reactions where the nucleophile is an oxygen or nitrogen.
. . . on to the next section . . .
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/18%3A_Carbonyl_Compounds_II-_Reactions_of_Aldehydes_and_Ketones__More_Reactions_of_Carboxylic_Acid_Derivatives__Reactions_of__-_Unsaturated_Carbonyl_Compounds/18.02%3A_Th.txt |
A Grignard reagent has a formula RMgX where X is a halogen, and R is an alkyl or aryl (based on a benzene ring) group. For the purposes of this page, we shall take R to be an alkyl group (e.g., CH3CH2MgBr). Grignard reagents are made by adding the halogenoalkane to small bits of magnesium in a flask containing ethoxyethane (commonly called diethyl ether or just "ether"). The flask is fitted with a reflux condenser, and the mixture is warmed over a water bath for 20 - 30 minutes.
Everything must be perfectly dry because Grignard reagents react with water. Any reactions using the Grignard reagent are carried out with the mixture produced from this reaction; you cannot separate it out in any way. Any excess Grignard reagent must be quenched before disposal.
Reactions of Grignard reagents with aldehydes and ketones
These are reactions of the carbon-oxygen double bond, and so aldehydes and ketones react in exactly the same way - all that changes are the groups that happen to be attached to the carbon-oxygen double bond. It is much easier to understand what is going on by looking closely at the general case (using "R" groups rather than specific groups) - and then slotting in the various real groups as and when you need to. The "R" groups can be either hydrogen or alkyl in any combination.
In the first stage, the Grignard reagent adds across the carbon-oxygen double bond:
Dilute acid is then added to this to hydrolyse it.
An alcohol is formed. One of the key uses of Grignard reagents is the ability to make complicated alcohols easily. What sort of alcohol you get depends on the carbonyl compound you started with - in other words, what R and R' are.
Example \(1\): Reaction with Methanal
Methanal is the simplest possible aldehyde with hydrogen as both R groups.
Assuming that you are starting with CH3CH2MgBr and using the general equation above, the alcohol you get always has the form:
Since both R groups are hydrogen atoms, the final product will be:
A primary alcohol is formed. A primary alcohol has only one alkyl group attached to the carbon atom with the -OH group on it. You could obviously get a different primary alcohol if you started from a different Grignard reagent.
Example \(2\): Reaction with Aldehyde
The next biggest aldehyde is ethanal with one of the R groups is hydrogen and the other CH3.
Again, think about how that relates to the general case. The alcohol formed is:
So this time the final product has one CH3 group and one hydrogen attached:
A secondary alcohol has two alkyl groups (the same or different) attached to the carbon with the -OH group on it. You could change the nature of the final secondary alcohol by either:
• changing the nature of the Grignard reagent - which would change the CH3CH2 group into some other alkyl group;
• changing the nature of the aldehyde - which would change the CH3 group into some other alkyl group.
Example \(3\): Reactions with Propanone
Ketones have two alkyl groups attached to the carbon-oxygen double bond. The simplest one is propanone.
This time when you replace the R groups in the general formula for the alcohol produced you get a tertiary alcohol.
A tertiary alcohol has three alkyl groups attached to the carbon with the -OH attached. The alkyl groups can be any combination of same or different. You could ring the changes on the product by:
• changing the nature of the Grignard reagent - which would change the CH3CH2 group into some other alkyl group;
• changing the nature of the ketone - which would change the CH3 groups into whatever other alkyl groups you choose to have in the original ketone.
18.06: Th
Despite the fearsome names, the structures of the two reducing agents are very simple. In each case, there are four hydrogens ("tetrahydido") around either aluminium or boron in a negative ion (shown by the "ate" ending). The "(III)" shows the oxidation state of the aluminium or boron, and is often left out because these elements only ever show the +3 oxidation state in their compounds.
The formulae of the two compounds are \(LiAlH_4\) and \(NaBH_4\). Their structures are:
In each of the negative ions, one of the bonds is a co-ordinate covalent (dative covalent) bond using the lone pair on a hydride ion (H-) to form a bond with an empty orbital on the aluminium or boron.
The reduction of an aldehyde
You get exactly the same organic product whether you use lithium tetrahydridoaluminate or sodium tetrahydridoborate. For example, with ethanal you get ethanol:
Notice that this is a simplified equation where [H] means "hydrogen from a reducing agent". In general terms, reduction of an aldehyde leads to a primary alcohol.
The reduction of a Ketone
Again the product is the same whichever of the two reducing agents you use. For example, with propanone you get propan-2-ol:
Reduction of a ketone leads to a secondary alcohol.
Using lithium tetrahydridoaluminate (lithium aluminium hydride)
Lithium tetrahydridoaluminate is much more reactive than sodium tetrahydridoborate. It reacts violently with water and alcohols, and so any reaction must exclude these common solvents. The reactions are usually carried out in solution in a carefully dried ether such as ethoxyethane (diethyl ether). The reaction happens at room temperature, and takes place in two separate stages.
In the first stage, a salt is formed containing a complex aluminium ion. The following equations show what happens if you start with a general aldehyde or ketone. R and R' can be any combination of hydrogen or alkyl groups.
The product is then treated with a dilute acid (such as dilute sulfuric acid or dilute hydrochloric acid) to release the alcohol from the complex ion.
The alcohol formed can be recovered from the mixture by fractional distillation.
Using sodium tetrahydridoborate (sodium borohydride)
Sodium tetrahydridoborate is a more gentle (and therefore safer) reagent than lithium tetrahydridoaluminate. It can be used in solution in alcohols or even solution in water - provided the solution is alkaline. Solid sodium tetrahydridoborate is added to a solution of the aldehyde or ketone in an alcohol such as methanol, ethanol or propan-2-ol. Depending on which recipe you read, it is either heated under reflux or left for some time around room temperature. This almost certainly varies depending on the nature of the aldehyde or ketone.
At the end of this time, a complex similar to the previous one is formed.
In the second stage of the reaction, water is added and the mixture is boiled to release the alcohol from the complex.
Again, the alcohol formed can be recovered from the mixture by fractional distillation. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/18%3A_Carbonyl_Compounds_II-_Reactions_of_Aldehydes_and_Ketones__More_Reactions_of_Carboxylic_Acid_Derivatives__Reactions_of__-_Unsaturated_Carbonyl_Compounds/18.04%3A_Th.txt |
Cyanohydrins have the structural formula of R2C(OH)CN. The “R” on the formula represents an alkyl, aryl, or hydrogen. In order to form a cyanohydrin, a hydrogen cyanide adds reversibly to the carbonyl group of an organic compound thus forming a hydroxyalkanenitrile adducts (commonly known and called as cyanohydrins).
Introduction
Cyanohydrin reactions occurs when an aldehyde or ketone gets treated by a cyanide anion (such as HCN) or a nitrile forming a cyanohydrin product. This special reaction is a nucleophilic addition, where the nucleophilic CN- attacks the electrophilic carbonyl carbon on the ketone, following a protonation by HCN, thereby the cyanide anion being regenerated. This reaction is also reversible.
Cyanohydrins are also intermediates for the Strecker amino acid synthesis. The preparation of displacements of sulfite by cyanide salts are also followed under cyanohydrins.
Mechanism of Cyanohydrin Formation
Acid-catalysed hydrolysis of silylated cyanohydrins has recently been shown to give cyanohydrins instead of ketones; thus an efficient synthesis of cyanohydrins has been found which works with even highly hindered ketones.
Acetone Cyanohydrins
Acetone cyanohydrins (ACH) have the structural formula of (CH3)2C(OH)CN and are extremely hazardous substances, since they rapidly decomposes in contact with water. In ACH, sulfuric acid is treated to give the sulfate ester of the methacrylamid. Preparations of other cyanohydrins are also used from ACH: for HACN to Michael acceptors and for the formylation of arenas. The treatment with lithium hydride affords anhydrous lithium cyanide.
Other Cyanohydrins
Other cyanohydrins, excluding acetone cyanohydrins, are: mandelonitrile and glycolonitrile.
Mandelonitrile have a structural formula of C6H5CH(OH)CN and occur in pits of some fruits. Glycolonitrile is an organic compound with the structural formula of HOCH2CN, which is the simplest cyanohydrin that is derived by formaldehydes.
Problems
Complete the following reactions for cyanohydrins:
1.)
2.)
3.) True or False: For a cyanohydrin to form, a fast additon of strong acid to cyanide salt is carried out to convert the salt into HCN.
4.) True or False: Cyanohydrin reactions are irreversible.
5.) What is the product for the overall reaction?
Answers
1.)
2.)
3.) False, slow addition
4.) False, reversible
5.)
Contributors
• Kathy Wong (UCD)
18.08: Th
The reaction of aldehydes and ketones with ammonia or 1º-amines forms imine derivatives, also known as Schiff bases (compounds having a C=N function). Water is eliminated in the reaction, which is acid-catalyzed and reversible in the same sense as acetal formation. The pH for reactions which form imine compounds must be carefully controlled. The rate at which these imine compounds are formed is generally greatest near a pH of 5, and drops at higher and lower pH's. At high pH there will not be enough acid to protonate the OH in the intermediate to allow for removal as H2O. At low pH most of the amine reactant will be tied up as its ammonium conjugate acid and will become non-nucleophilic.
Converting reactants to products simply
Mechanism of imine formation
1) Nucleophilic attack
2) Proton transfer
3) Protonation of OH
4) Removal of water
5) Deprotonation
Reversibility of imine forming reactions
Imines can be hydrolyzed back to the corresponding primary amine under acidic conditons.
Reactions involving other reagents of the type Y-NH2
Imines are sometimes difficult to isolate and purify due to their sensitivity to hydrolysis. Consequently, other reagents of the type Y–NH2 have been studied, and found to give stable products (R2C=N–Y) useful in characterizing the aldehydes and ketones from which they are prepared. Some of these reagents are listed in the following table, together with the structures and names of their carbonyl reaction products. Hydrazones are used as part of the Wolff-Kishner reduction and will be discussed in more detail in another module.
With the exception of unsubstituted hydrazones, these derivatives are easily prepared and are often crystalline solids - even when the parent aldehyde or ketone is a liquid. Since melting points can be determined more quickly and precisely than boiling points, derivatives such as these are useful for comparison and identification of carbonyl compounds. It should be noted that although semicarbazide has two amino groups (–NH2) only one of them is a reactive amine. The other is amide-like and is deactivated by the adjacent carbonyl group.
Problems
1)Please draw the products of the following reactions.
2) Please draw the structure of the reactant needed to produce the indicated product.
3) Please draw the products of the following reactions.
1)
2)
3)
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/18%3A_Carbonyl_Compounds_II-_Reactions_of_Aldehydes_and_Ketones__More_Reactions_of_Carboxylic_Acid_Derivatives__Reactions_of__-_Unsaturated_Carbonyl_Compounds/18.07%3A_Th.txt |
It has been demonstrated that water, in the presence of an acid or a base, adds rapidly to the carbonyl function of aldehydes and ketones establishing a reversible equilibrium with a hydrate (geminal-diol or gem-diol). The word germinal or gem comes from the Latin word for twin, geminus.
Reversibility of the Reaction
Isolation of gem-diols is difficult because the reaction is reversibly. Removal of the water during a reaction can cause the conversion of a gem-diol back to the corresponding carbonyl.
Factors Affecting the Gem-diol Equilibrium
In most cases the resulting gem-diol is unstable relative to the reactants and cannot be isolated. Exceptions to this rule exist, one being formaldehyde where the weaker pi-component of the carbonyl double bond, relative to other aldehydes or ketones, and the small size of the hydrogen substituents favor addition. Thus, a solution of formaldehyde in water (formalin) is almost exclusively the hydrate, or polymers of the hydrate. The addition of electron donating alkyl groups stabilized the partial positive charge on the carbonyl carbon and decreases the amount of gem-diol product at equilibrium. Because of this ketones tend to form less than 1% of the hydrate at equilibrium. Likewise, the addition of strong electron-withdrawing groups destabilizes the carbonyl and tends to form stable gem-diols. Two examples of this are chloral, and 1,2,3-indantrione. It should be noted that chloral hydrate is a sedative and has been added to alcoholic beverages to make a “Knock-out” drink also called a Mickey Finn. Also, ninhydrin is commonly used by forensic investigators to resolve finger prints.
Mechanism of Gem-diol Formation
The mechanism is catalyzed by the addition of an acid or base. Note! This may speed up the reaction but is has not effect on the equilibriums discussed above. Basic conditions speed up the reaction because hydroxide is a better nucleophilic than water. Acidic conditions speed up the reaction because the protonated carbonyl is more electrophilic.
Under Basic conditions
1) Nucleophilic attack by hydroxide
2) Protonation of the alkoxide
Under Acidic conditions
1) Protonation of the carbonyl
2) Nucleophilic attack by water
3) Deprotonation
Problems
1) Draw the expected products of the following reactions.
2) Of the following pairs of molecules which would you expect to form a larger percentage of gem-diol at equilibrium? Please explain your answer.
3) Would you expect the following molecule to form appreciable amount of gem-diol in water? Please explain your answer.
Answers
1)
2) The compound on the left would. Fluorine is more electronegative than bromine and would remove more electron density from the carbonyl carbon. This would destabilize the carbonyl allowing for more gem-diol to form.
3) Although ketones tend to not form gem-diols this compound exists almost entirely in the gem-diol form when placed in water. Ketones tend to not form gem-diols because of the stabilizing effect of the electron donating alkyl group. However, in this case the electron donating effects of alkyl group is dominated by the presence of six highly electronegative fluorines.
18.10: Re
In this organic chemistry topic, we shall see how alcohols (R-OH) add to carbonyl groups. Carbonyl groups are characterized by a carbon-oxygen double bond. The two main functional groups that consist of this carbon-oxygen double bond are Aldehydes and Ketones.
Introduction
It has been demonstrated that water adds rapidly to the carbonyl function of aldehydes and ketones to form geminal-diol. In a similar reaction alcohols add reversibly to aldehydes and ketones to form hemiacetals (hemi, Greek, half). This reaction can continue by adding another alcohol to form an acetal. Hemiacetals and acetals are important functional groups because they appear in sugars.
To achieve effective hemiacetal or acetal formation, two additional features must be implemented. First, an acid catalyst must be used because alcohol is a weak nucleophile; and second, the water produced with the acetal must be removed from the reaction by a process such as a molecular sieves or a Dean-Stark trap. The latter is important, since acetal formation is reversible. Indeed, once pure hemiacetal or acetals are obtained they may be hydrolyzed back to their starting components by treatment with aqueous acid and an excess of water.
Formation of Acetals
Acetals are geminal-diether derivatives of aldehydes or ketones, formed by reaction with two equivalents (or an excess amount) of an alcohol and elimination of water. Ketone derivatives of this kind were once called ketals, but modern usage has dropped that term. It is important to note that a hemiacetal is formed as an intermediate during the formation of an acetal.
Mechanism for Hemiacetal and Acetal Formation
The mechanism shown here applies to both acetal and hemiacetal formation
1) Protonation of the carbonyl
2) Nucleophilic attack by the alcohol
3) Deprotonation to form a hemiacetal
4) Protonation of the alcohol
5) Removal of water
6) Nucleophilic attack by the alcohol
7) Deprotonation by water
Formation of Cyclic Hemiacetal and Acetals
Molecules which have an alcohol and a carbonyl can undergo an intramolecular reaction to form a cyclic hemiacetal.
Intramolecular Hemiacetal formation is common in sugar chemistry. For example, the common sugar glucose exists in the cylcic manner more than 99% of the time in a mixture of aqueous solution.
Carbonyls reacting with diol produce a cyclic acetal. A common diol used to form cyclic acetals is ethylene glycol.
Acetals as Protecting Groups
The importance of acetals as carbonyl derivatives lies chiefly in their stability and lack of reactivity in neutral to strongly basic environments. As long as they are not treated by acids, especially aqueous acid, acetals exhibit all the lack of reactivity associated with ethers in general. Among the most useful and characteristic reactions of aldehydes and ketones is their reactivity toward strongly nucleophilic (and basic) metallo-hydride, alkyl and aryl reagents. If the carbonyl functional group is converted to an acetal these powerful reagents have no effect; thus, acetals are excellent protective groups, when these irreversible addition reactions must be prevented.
In the following example we would like a Grignard reagent to react with the ester and not the ketone. This cannot be done without a protecting group because Grignard reagents react with esters and ketones. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/18%3A_Carbonyl_Compounds_II-_Reactions_of_Aldehydes_and_Ketones__More_Reactions_of_Carboxylic_Acid_Derivatives__Reactions_of__-_Unsaturated_Carbonyl_Compounds/18.09%3A_Th.txt |
Organophosphorus ylides react with aldehydes or ketones to give substituted alkenes in a transformation called the Wittig reaction. This reaction is named for George Wittig who was awarded the Nobel prize for this work in 1979. A principal advantage of alkene synthesis by the Wittig reaction is that the location of the double bond is absolutely fixed, in contrast to the mixtures often produced by alcohol dehydration.
Preparation of Phosphorus Ylides
It has been noted that dipolar phosphorus compounds are stabilized by p-d bonding. This bonding stabilization extends to carbanions adjacent to phosphonium centers, and the zwitterionic conjugate bases derived from such cations are known as ylides. An ylide is defined as a compound with opposite charges on adjacent atoms both of which have complete octets. For the Wittig reaction discussed below an organophosphorus ylide, also called Wittig reagents, will be used. The ability of phosphorus to hold more than eight valence electrons allows for a resonance structure to be drawn forming a double bonded structure.
The stabilization of the carbanion provided by the phosphorus causes an increase in acidity (pKa ~35). Very strong bases, such as butyl lithium, are required for complete formation of ylides.
The ylides shown here are all strong bases. Like other strongly basic organic reagents, they are protonated by water and alcohols, and are sensitive to oxygen. Water decomposes phosphorous ylides to hydrocarbons and phosphine oxides, as shown.
Although many ylides are commercially available it is often necessary to create them synthetically. Ylides can be synthesized from an alkyl halide and a trialkyl phosphine. Typically triphenyl phosphine is used to synthesize ylides. Because a SN2 reaction is used in the ylide synthesis methyl and primary halides perform the best. Secondary halides can also be used but the yields are generally lower. This should be considered when planning out a synthesis which involves a synthesized Wittig reagent.
1) SN2 reaction
2) Deprotonation
The Wittig Reaction
The most important use of ylides in synthesis comes from their reactions with aldehydes and ketones, which are initiated in every case by a covalent bonding of the nucleophilic alpha-carbon to the electrophilic carbonyl carbon. Ylides react to give substituted alkenes in a transformation called the Wittig reaction. This reaction is named for George Wittig who was awarded the Nobel prize for this work in 1979. A principal advantage of alkene synthesis by the Wittig reaction is that the location of the double bond is absolutely fixed, in contrast to the mixtures often produced by alcohol dehydration.
Going from reactants to products simplified
Mechanism of the Wittig reaction
Following the initial carbon-carbon bond formation, two intermediates have been identified for the Wittig reaction, a dipolar charge-separated species called a betaine and a four-membered heterocyclic structure referred to as an oxaphosphatane. Cleavage of the oxaphosphatane to alkene and phosphine oxide products is exothermic and irreversible.
1) Nucleophillic attack on the carbonyl
2) Formation of a 4 membered ring
3) Formation of the alkene
Limitation of the Wittig reaction
If possible both E and Z isomer of the double bond will be formed. This should be considered when planning a synthesis involving a Wittig Reaction.
Problems
1) Please write the product of the following reactions.
2) Please indicate the starting material required to produce the product.
3) Please draw the structure of the oxaphosphetane which is made during the mechanism of the reaction given that produces product C.
4) Please draw the structure of the betaine which is made during the mechanism of the reaction given that produces product D.
5) Please give a detailed mechanism and the final product of this reaction
6) It has been shown that reacting and epoxide with triphenylphosphine forms an alkene. Please propose a mechanism for this reaction. Review the section on epoxide reactions if you need help.
Answers
1)
2)
3)
4)
5)
Nucleophillic attack on the carbonyl
Formation of a 4 membered ring
Formation of the alkene
6) Nucleophillic attack on the epoxide
Formation of a 4 membered ring
Formation of the alkene
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/18%3A_Carbonyl_Compounds_II-_Reactions_of_Aldehydes_and_Ketones__More_Reactions_of_Carboxylic_Acid_Derivatives__Reactions_of__-_Unsaturated_Carbonyl_Compounds/18.13%3A_Th.txt |
Notice that in the course of the nucleophilic addition pictured above, the hybridization of the carbonyl carbon changes from sp2 to sp3, meaning that the bond geometry changes from trigonal planar to tetrahedral. It is also important to note that if the starting carbonyl is asymmetric (in other words, if the two R groups are not equivalent), then a new stereocenter has been created. The configuration of the new stereocenter depends upon which side of the carbonyl plane the nucleophile attacks from.
If the reaction is catalyzed by an enzyme, the stereochemistry of addition is tightly controlled, and leads to one specific stereoisomer - this is because the nucleophilic and electrophilic substrates are bound in a specific positions within the active site, so that attack must occur specifically from one side. If, however, the reaction occurs uncatalyzed in solution, then either side of the carbonyl is equally likely to be attacked, and the result will be a 50:50 racemic mixture.
This is the rule for most nonenzymatic reactions, but as with most rules, there are exceptions. If, for example, the geometry of the carbonyl-containing molecule is constrained in such a way that approach by the nucleophile is less hindered from one side, a 50:50 racemic mixture will not necessarily result. Consider camphor, the distinctive-smelling compound found in many cosmetics and skin creams.
Upon inspection it is clear that topside attack and bottom side attack by a nucleophile are nonequivalent in terms of steric hindrance. A relatively simple experiment shows that, when the incoming nucleophile is a hydride ion from the common synthetic reducing agent sodium borohydride (a reaction type we will study in a later chapter), the product of bottom side attack predominates by a ratio of about 6 to 1 (see section 16.4D for more details on this experiment). We can infer from this result that approach from the bottom (si) face of the carbonyl in camphor is less hindered.
. . . on to the next section . . .
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
18.16: Nu
One of the largest and most diverse classes of reactions is composed of nucleophilic additions to a carbonyl group. Conjugation of a double bond to a carbonyl group transmits the electrophilic character of the carbonyl carbon to the beta-carbon of the double bond. These conjugated carbonyl are called enones or α, β unsaturated carbonyls. A resonance description of this transmission is shown below.
From this formula it should be clear that nucleophiles may attack either at the carbonyl carbon, as for any aldehyde, ketone or carboxylic acid derivative, or at the beta-carbon. These two modes of reaction are referred to as 1,2-addition and 1,4-addition respectively. A 1,4-addition is also called a conjugate addition.
Basic reaction of 1,2 addition
Here the nucleophile adds to the carbon which is in the one position. The hydrogen adds to the oxygen which is in the two position.
Basic reaction of 1,4 addition
In 1,4 addition the Nucleophile is added to the carbon β to the carbonyl while the hydrogen is added to the carbon α to the carbonyl.
Mechanism for 1,4 addition
1) Nucleophilic attack on the carbon β to the carbonyl
2) Proton Transfer
Here we can see why this addition is called 1,4. The nucleophile bonds to the carbon in the one position and the hydrogen adds to the oxygen in the four position.
3) Tautomerization
Going from reactant to products simplified
1,2 vs. 1,4 addition
Whether 1,2 or 1,4-addition occurs depends on multiple variables but mostly it is determined by the nature of the nucleophile. During the addition of a nucleophile there is a competition between 1,2 and 1,4 addition products. If the nucleophile is a strong base, such as Grignard reagents, both the 1,2 and 1,4 reactions are irreversible and therefor are under kinetic control. Since 1,2-additions to the carbonyl group are fast, we would expect to find a predominance of 1,2-products from these reactions.
If the nucleophile is a weak base, such as alcohols or amines, then the 1,2 addition is usually reversible. This means the competition between 1,2 and 1,4 addition is under thermodynamic control. In this case 1,4-addition dominates because the stable carbonyl group is retained.
Water
Alcohols
Thiols
1o Amines
2o Amines
HBr
Cyanides
Gilman Reagents
Another important reaction exhibited by organometallic reagents is metal exchange. Organolithium reagents react with cuprous iodide to give a lithium dimethylcopper reagent, which is referred to as a Gilman reagent. Gilman reagents are a source of carbanion like nucleophiles similar to Grignard and Organo lithium reagents. However, the reactivity of organocuprate reagents is slightly different and this difference will be exploited in different situations. In the case of α, β unsaturated carbonyls organocuprate reagents allow for an 1,4 addition of an alkyl group. As we will see later Grignard and Organolithium reagents add alkyl groups 1,2 to α, β unsaturated carbonyls
Organocuprate reagents are made from the reaction of organolithium reagents and $CuI$
$2 RLi + CuI \rightarrow R_2CuLi + LiI$
This acts as a source of R:-
$2 CH_3Li + CuI \rightarrow (CH_3)_2CuLi + LiI$
Example
Nucleophiles which add 1,2 to α, β unsaturated carbonyls
Metal Hydrides
Grignard Reagents
Organolithium Reagents
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/18%3A_Carbonyl_Compounds_II-_Reactions_of_Aldehydes_and_Ketones__More_Reactions_of_Carboxylic_Acid_Derivatives__Reactions_of__-_Unsaturated_Carbonyl_Compounds/18.14%3A_St.txt |
Alkyl hydrogen atoms bonded to a carbon atom in a a (alpha) position relative to a carbonyl group display unusual acidity. While the pKa values for alkyl C-H bonds is typically on the order of 40-50, pKa values for these alpha hydrogens is more on the order of 19-20. This can most easily be explained by resonance stabilization of the product carbanion, as illustrated in the diagram below.
In the presence of a proton source, the product can either revert back into the starting ketone or aldehyde or can form a new product, the enol. The equilibrium reaction between the ketone or aldehyde and the enol form is commonly referred to as "keto-enol tautomerism". The ketone or aldehyde is generally strongly favored in this reaction.
Because carbonyl groups are sp2 hybridized the carbon and oxygen both have unhybridized p orbitals which can overlap to form the C=O $\pi$ bond.
The presence of these overlapping p orbitals gives $\alpha$ hydrogens (Hydrogens on carbons adjacent to carbonyls) special properties. In particular, $\alpha$ hydrogens are weakly acidic because the conjugate base, called an enolate, is stabilized though conjugation with the $\pi$ orbitals of the carbonyl. The effect of the carbonyl is seen when comparing the pKa for the $\alpha$ hydrogens of aldehydes (~16-18), ketones (~19-21), and esters (~23-25) to the pKa of an alkane (~50).
Of the two resonance structures of the enolate ion the one which places the negative charge on the oxygen is the most stable. This is because the negative change will be better stabilized by the greater electronegativity of the oxygen.
Keto-enol Tautomerism
Because of the acidity of α hydrogens carbonyls undergo keto-enol tautomerism. Tautomers are rapidly interconverted constitutional isomers, usually distinguished by a different bonding location for a labile hydrogen atom and a differently located double bond. The equilibrium between tautomers is not only rapid under normal conditions, but it often strongly favors one of the isomers (acetone, for example, is 99.999% keto tautomer). Even in such one-sided equilibria, evidence for the presence of the minor tautomer comes from the chemical behavior of the compound. Tautomeric equilibria are catalyzed by traces of acids or bases that are generally present in most chemical samples.
Contributors
Prof. Steven Farmer (Sonoma State University)
• Clarke Earley (Department of Chemistry, Kent State University Stark Campus)
19.02: Keto-Enol Tautomers
Alkyl hydrogen atoms bonded to a carbon atom in a a (alpha) position relative to a carbonyl group display unusual acidity. While the pKa values for alkyl C-H bonds is typically on the order of 40-50, pKa values for these alpha hydrogens is more on the order of 19-20. This can most easily be explained by resonance stabilization of the product carbanion, as illustrated in the diagram below.
In the presence of a proton source, the product can either revert back into the starting ketone or aldehyde or can form a new product, the enol. The equilibrium reaction between the ketone or aldehyde and the enol form is commonly referred to as "keto-enol tautomerism". The ketone or aldehyde is generally strongly favored in this reaction.
Because carbonyl groups are sp2 hybridized the carbon and oxygen both have unhybridized p orbitals which can overlap to form the C=O $\pi$ bond.
The presence of these overlapping p orbitals gives $\alpha$ hydrogens (Hydrogens on carbons adjacent to carbonyls) special properties. In particular, $\alpha$ hydrogens are weakly acidic because the conjugate base, called an enolate, is stabilized though conjugation with the $\pi$ orbitals of the carbonyl. The effect of the carbonyl is seen when comparing the pKa for the $\alpha$ hydrogens of aldehydes (~16-18), ketones (~19-21), and esters (~23-25) to the pKa of an alkane (~50).
Of the two resonance structures of the enolate ion the one which places the negative charge on the oxygen is the most stable. This is because the negative change will be better stabilized by the greater electronegativity of the oxygen.
Keto-enol Tautomerism
Because of the acidity of α hydrogens carbonyls undergo keto-enol tautomerism. Tautomers are rapidly interconverted constitutional isomers, usually distinguished by a different bonding location for a labile hydrogen atom and a differently located double bond. The equilibrium between tautomers is not only rapid under normal conditions, but it often strongly favors one of the isomers (acetone, for example, is 99.999% keto tautomer). Even in such one-sided equilibria, evidence for the presence of the minor tautomer comes from the chemical behavior of the compound. Tautomeric equilibria are catalyzed by traces of acids or bases that are generally present in most chemical samples.
Contributors
Prof. Steven Farmer (Sonoma State University)
• Clarke Earley (Department of Chemistry, Kent State University Stark Campus) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/19%3A_Carbonyl_Compounds_III-_Reactions_at_the_-_Carbon/19.01%3A_The_Acidity_of_an_-_Hydrogen.txt |
For alkylation reactions of enolate anions to be useful, these intermediates must be generated in high concentration in the absence of other strong nucleophiles and bases. The aqueous base conditions used for the aldol condensation are not suitable because the enolate anions of simple carbonyl compounds are formed in very low concentration, and hydroxide or alkoxide bases induce competing SN2 and E2 reactions of alkyl halides. It is necessary, therefore, to achieve complete conversion of aldehyde or ketone reactants to their enolate conjugate bases by treatment with a very strong base (pKa > 25) in a non-hydroxylic solvent before any alkyl halides are added to the reaction system. Some bases that have been used for enolate anion formation are: NaH (sodium hydride, pKa > 45), NaNH2 (sodium amide, pKa = 34), and LiN[CH(CH3)2]2 (lithium diisopropylamide, LDA, pKa 36). Ether solvents like tetrahydrofuran (THF) are commonly used for enolate anion formation. With the exception of sodium hydride and sodium amide, most of these bases are soluble in THF. Certain other strong bases, such as alkyl lithium and Grignard reagents, cannot be used to make enolate anions because they rapidly and irreversibly add to carbonyl groups. Nevertheless, these very strong bases are useful in making soluble amide bases. In the preparation of lithium diisopropylamide (LDA), for example, the only other product is the gaseous alkane butane.
Because of its solubility in THF, LDA is a widely used base for enolate anion formation. In this application, one equivalent of diisopropylamine is produced along with the lithium enolate, but this normally does not interfere with the enolate reactions and is easily removed from the products by washing with aqueous acid. Although the reaction of carbonyl compounds with sodium hydride is heterogeneous and slow, sodium enolates are formed with the loss of hydrogen, and no other organic compounds are produced.
Examples
If the formed enolate is stabilized by more than one carbonyl it is possible to use a weaker base such as sodium ethoxide.
NaOCH2CH3 = Na+ -OCH2CH3 = NaOEt
Because of the acidity of α hydrogens, carbonyls undergo keto-enol tautomerism. Tautomers are rapidly interconverted constitutional isomers, usually distinguished by a different bonding location for a labile hydrogen atom and a differently located double bond. The equilibrium between tautomers is not only rapid under normal conditions, but it often strongly favors one of the isomers (acetone, for example, is 99.999% keto tautomer). Even in such one-sided equilibria, evidence for the presence of the minor tautomer comes from the chemical behavior of the compound. Tautomeric equilibria are catalyzed by traces of acids or bases that are generally present in most chemical samples.
However under acidic and basic conditions the equilibrium can be shifted to the right
Mechanism for Enol Formation
Acid conditions
1) Protonation of the Carbonyl
2) Enol formation
Basic conditions
1) Enolate formation
2) Protonation
19.04: How Enolate Ions and Enols React
Enolates can act as a nucleophile in Sn2 type reactions. The alpha alkylation reaction involves an α hydrogen being replaced with an alkyl group. This reaction is one of the more important for enolates because a carbon-carbon bond is formed. These alkylations are affected by the same limitations as Sn2 reactions previously discussed. Good leaving groups like chloride, bromide, iodide, tosylate, should be used. Also, secondary and tertiary leaving groups should not be used because of poor reactivity and possible competition with elimination reactions. Lastly, it is important to use a strong base, such as LDA or sodium amide, for this reaction. Using a weaker base such as hydroxide or an alkoxide leaves the possibility of multiple alkylation’s occurring.
Mechanism
Stpe 1: Enolate formation
Step 2: Sn2 attack
Example \(2\)
Please write the structure of the product for the following reactions.
19.05: Halogenation of the - Carbon and Aldehydes and Ketones
A carbonyl containing compound with $\alpha$ hydrogens can undergo a substitution reaction with halogens. This reaction comes about because of the tendency of carbonyl compounds to form enolates in basic condition and enols in acidic condition. In these cases even weak bases, such as the hydroxide anion, is sufficient enough to cause the reaction to occur because it is not necessary for a complete conversion to the enolate. For this reaction Cl2, Br2 or I2 can be used as the halogens.
General reaction
Acid Catalyzed Mechanism
Under acidic conditions the reaction occurs thought the formation of an enol which then reacts with the halogen.
Step 1: Protonation of the carbonyl
Step 2: Enol formation
Step 3: SN2 attack
Step 4: Deprotonation
Base Catalyzed Mechanism
Under basic conditions the enolate forms and then reacts with the halogen. Note! This is base promoted and not base catalyzed because an entire equivalent of base is required.
Step 1: Enolate formation
Step 2: SN2 attack
Overreaction during base promoted α halogenation
The fact that an electronegative halogen is placed on an α carbon means that the product of a base promoted α halogenation is actually more reactive than the starting material. The electron withdrawing effect of the halogen makes the α carbon even more acidic and therefor promotes further reaction. Because of this multiple halogenations can occur. This effect is exploited in the haloform reaction discussed later. If a monohalo product is required then acidic conditions are usually used.
The Haloform Reaction
Methyl ketones typically undergo halogenation three times to give a trihalo ketone due to the increased reactivity of the halogenated product as discussed above. This trihalomethyl group is an effective leaving group due to the three electron withdrawing halogens and can be cleaved by a hydroxide anion to effect the haloform reaction. The product of this reaction is a carboxylate and a haloform molecule (CHCl3, CHBr3, CHI3). Overall the haloform reaction represents an effective method for the conversion of methyl ketones to carboxylic acids. Typically, this reaction is performed using iodine because the subsequent iodoform (CHI3) is a bright yellow precipitate which is easily filtered off.
General reaction
Mechanism
1) Formation of the trihalo species
2) Nulceophilic attack on the carbonyl carbon
3) Removal of the leaving group
4) Deprotonation
Exercise $1$
Please draw the products of the following reactions
Answer | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/19%3A_Carbonyl_Compounds_III-_Reactions_at_the_-_Carbon/19.03%3A_Keto-Enol_Interconversion.txt |
Carbon is one of the most common elements on earth, and greatly influences everyday life. Common molecules containing carbon include carbon dioxide (CO2) and methane (CH4). Many scientists in a variety of fields study of carbon: biologists investigating the origins of life; oceanographers measuring the acidification of the oceans; and engineers developing diamond film tools. This article details the periodic properties of the carbon family and briefly discusses of the individual properties of carbon, silicon, germanium, tin, lead, and flerovium.
• Group 14: General Chemistry
Covers the Group 4 (IUPAC: Group 14) chemistry (carbon, silicon, germanium, tin and lead) and specifically the trend from non-metal to metal as you go down the group, and the increasing tendency towards an oxidation state of +2. Also a certain amount of chemistry of the chlorides and oxides.
• Group 14: General Properties and Reactions
Carbon is one of the most common elements on earth, and greatly influences everyday life. This article details the periodic properties of the carbon family and briefly discusses of the individual properties of carbon, silicon, germanium, tin, lead, and flerovium.
• Chemistry of Carbon (Z=6)
Organic chemistry involves structures and reactions of mainly carbon and hydrogen. Inorganic chemistry deal with interactions of all other pure elements besides carbon, amongst geo/biochemistry. So where does inorganic chemistry of carbon fit in? The inorganic chemistry of carbon also known as inorganic carbon chemistry, is the chemistry of carbon that does not fall within the organic chemistry zone.
• Chemistry of Silicon (Z=14)
Silicon, the second most abundant element on earth, is an essential part of the mineral world. Its stable tetrahedral configuration makes it incredibly versatile and is used in various way in our every day lives. Found in everything from spaceships to synthetic body parts, silicon can be found all around us, and sometimes even in us.
• Chemistry of Germanium (Z=32)
Germanium, categorized as a metalloid in group 14, the Carbon family, has five naturally occurring isotopes. Germanium, abundant in the Earth's crust has been said to improve the immune system of cancer patients. It is also used in transistors, but its most important use is in fiber-optic systems and infrared optics.
• Chemistry of Tin (Z=50)
Mentioned in the Hebrew scriptures, tin is of ancient origins. Tin is an element in Group 14 (The carbon family) and has mainly metallic properties. Tin has atomic number 50 and an atomic mass of 118.710 atomic mass units. Tin, or Sn (from the Latin name Stannum) has been known since ancient times, although it could only be obtained by extraction from its ore. Tin shares chemical similarities with germanium and lead. Tin mining began in Australia in 1872 and today Tin is used extensively.
• Chemistry of Lead (Z=82)
Although lead is not very common in the earth's crust, what is there is readily available and easy to refine. Its chief use today is in lead-acid storage batteries such as those used in automobiles. In pure form it is too soft to be used for much else. Lead has a blue-white color when first cut but quickly dulls on exposure to air, forming Pb2O, one of the few lead(I) compounds. Most stable lead compounds contain lead in oxidation states of +2 or +4.
• Chemistry of Flerovium (Z=114)
The synthesis of element 114 was reported in January of 1999 by scientists from the Joint Institute for Nuclear Research in Dubna (near Moscow) and Lawrence Livermore National Laboratory (in California). In an experiment lasting more than 40 days Russian scientists bombarded a film of Pu-244 supplied by Livermore scientists with a beam of Ca-48. One atom of element 114 was detected with a half-life of more than 30 seconds. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/19%3A_Carbonyl_Compounds_III-_Reactions_at_the_-_Carbon/19.06%3A_Halogenation_of_the_-_Carbon_of_Carboxylic_Acids-_The_Hell-Volhard-Zelinski_Reaction.txt |
For alkylation reactions of enolate anions to be useful, these intermediates must be generated in high concentration in the absence of other strong nucleophiles and bases. The aqueous base conditions used for the aldol condensation are not suitable because the enolate anions of simple carbonyl compounds are formed in very low concentration, and hydroxide or alkoxide bases induce competing SN2 and E2 reactions of alkyl halides. It is necessary, therefore, to achieve complete conversion of aldehyde or ketone reactants to their enolate conjugate bases by treatment with a very strong base (pKa > 25) in a non-hydroxylic solvent before any alkyl halides are added to the reaction system. Some bases that have been used for enolate anion formation are: NaH (sodium hydride, pKa > 45), NaNH2 (sodium amide, pKa = 34), and LiN[CH(CH3)2]2 (lithium diisopropylamide, LDA, pKa 36). Ether solvents like tetrahydrofuran (THF) are commonly used for enolate anion formation. With the exception of sodium hydride and sodium amide, most of these bases are soluble in THF. Certain other strong bases, such as alkyl lithium and Grignard reagents, cannot be used to make enolate anions because they rapidly and irreversibly add to carbonyl groups. Nevertheless, these very strong bases are useful in making soluble amide bases. In the preparation of lithium diisopropylamide (LDA), for example, the only other product is the gaseous alkane butane.
Because of its solubility in THF, LDA is a widely used base for enolate anion formation. In this application, one equivalent of diisopropylamine is produced along with the lithium enolate, but this normally does not interfere with the enolate reactions and is easily removed from the products by washing with aqueous acid. Although the reaction of carbonyl compounds with sodium hydride is heterogeneous and slow, sodium enolates are formed with the loss of hydrogen, and no other organic compounds are produced.
Examples
If the formed enolate is stabilized by more than one carbonyl it is possible to use a weaker base such as sodium ethoxide.
NaOCH2CH3 = Na+ -OCH2CH3 = NaOEt
Because of the acidity of α hydrogens, carbonyls undergo keto-enol tautomerism. Tautomers are rapidly interconverted constitutional isomers, usually distinguished by a different bonding location for a labile hydrogen atom and a differently located double bond. The equilibrium between tautomers is not only rapid under normal conditions, but it often strongly favors one of the isomers (acetone, for example, is 99.999% keto tautomer). Even in such one-sided equilibria, evidence for the presence of the minor tautomer comes from the chemical behavior of the compound. Tautomeric equilibria are catalyzed by traces of acids or bases that are generally present in most chemical samples.
However under acidic and basic conditions the equilibrium can be shifted to the right
Mechanism for Enol Formation
Acid conditions
1) Protonation of the Carbonyl
2) Enol formation
Basic conditions
1) Enolate formation
2) Protonation
19.09: Alkylating the -Carbon of Carbonyl Compounds
Enolates can act as a nucleophile in Sn2 type reactions. The alpha alkylation reaction involves an α hydrogen being replaced with an alkyl group. This reaction is one of the more important for enolates because a carbon-carbon bond is formed. These alkylations are affected by the same limitations as Sn2 reactions previously discussed. Good leaving groups like chloride, bromide, iodide, tosylate, should be used. Also, secondary and tertiary leaving groups should not be used because of poor reactivity and possible competition with elimination reactions. Lastly, it is important to use a strong base, such as LDA or sodium amide, for this reaction. Using a weaker base such as hydroxide or an alkoxide leaves the possibility of multiple alkylation’s occurring.
Mechanism
Stpe 1: Enolate formation
Step 2: Sn2 attack
Example \(2\)
Please write the structure of the product for the following reactions.
19.10: Alkylation and Acylation of the -Carbon Using an Enamine Intermediate
As previously seen, aldehydes and ketones react with 2o amines to reversibly form enamines.
Example
Reversible
Enamines act as nucleophiles in a fashion similar to enolates. Because of this enamines can be used as synthetic equivalents as enolates in many reactions. This process requires a three steps:
1. Formation of the enamine,
2. Reaction with an eletrophile to form an iminium salt,
3. Hydrolysis of the iminium salt to reform the aldehyde or ketone.
Some of the advantages of using an enamine over and enolate are enamines are neutral, easier to prepare, and usually prevent the overreaction problems plagued by enolates. These reactions are generally known as the Stork enamine reaction after Gilbert Stork of Columbia University who originated the work.
Typically we use the following 2o amines for enamine reactions
Alkylation of an Enamine
Enamined undergo an SN2 reaction with reactive alkyl halides to give the iminium salt. The iminium salt can be hydrolyzed back into the carbonyl.
Step 1: Formation of an enamine
Step 2: SN2 Alkylation
Step 3: Reform the carbonyl by hydrolysis
All three steps together:
Acylation of Enamines
Enamine can react with acid halides to form β-dicarbonyls
1) Formation of the enamine
2) Nucleophilic attack
3) Leaving group removal
4) Reform the carbonyl by hydrolysis
All three steps together:
Michael Addition using Enamines
Enamines, like other weak bases, add 1,4 to enones. The end product is a 1,5 dicarbonyl compound.
19.11: Alkylation of the -Carbon- The Michael Reaction
Enolates undergo 1,4 addition to α, β-unsaturated carbonyl compounds is a process called a Michael addition. The reaction is named after American chemist Arthur Michael (1853-1942).
Robinson Annulation
Many times the product of a Michael addition produces a dicarbonyl which can then undergo an intramolecular aldol reaction. These two processes together in one reaction creates two new carbon-carbon bonds and also creates a ring. Ring-forming reactions are called annulations after the Latin work for ring annulus. The reaction is named after English chemist Sir Robert Robinson (1886-1975) who developed it. He received the Nobel prize in chemistry in 1947. Remember that during annulations five and six membered rings are preferred. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/19%3A_Carbonyl_Compounds_III-_Reactions_at_the_-_Carbon/19.08%3A_Using_LDA_to_Form_an_Enolate_Ion.txt |
A useful carbon-carbon bond-forming reaction known as the Aldol Reaction is yet another example of electrophilic substitution at the alpha carbon in enolate anions. The fundamental transformation in this reaction is a dimerization of an aldehyde (or ketone) to a beta-hydroxy aldehyde (or ketone) by alpha C–H addition of one reactant molecule to the carbonyl group of a second reactant molecule. Due to the carbanion like nature of enolates they can add to carbonyls in a similar manner as Grignard reagents. For this reaction to occur at least one of the reactants must have α hydrogens.
Aldol Reaction Mechanism
A three step mechanism:
Step 1: Enolate formation
Step 2: Nucleophilic attack by the enolate
Step 3: Protonation
Aldol Condensation: the dehydration of Aldol products to synthesize α, β unsaturated carbonyl (enones)
The products of aldol reactions often undergo a subsequent elimination of water, made up of an alpha-hydrogen and the beta-hydroxyl group. The product of this $\beta$-elimination reaction is an α,β-unsaturated aldehyde or ketone. Base-catalyzed elimination occurs with heating. The additional stability provided by the conjugated carbonyl system of the product makes some aldol reactions thermodynamically and mixtures of stereoisomers (E & Z) are obtained from some reactions. Reactions in which a larger molecule is formed from smaller components, with the elimination of a very small by-product such as water, are termed Condensations. Hence, the following examples are properly referred to as aldol condensations. Overall the general reaction involves a dehydration of an aldol product to form an alkene:
Figure: General reaction for an aldol condensation
Going from reactants to products simply
Figure: The aldol condensatio example
Aldol Condensation Mechanism
1) Form enolate
2) Form enone
When performing both reactions together always consider the aldol product first then convert to the enone. Note! The double bond always forms in conjugation with the carbonyl.
Intramolecular aldol reaction
Molecules which contain two carbonyl functionalities have the possibility of forming a ring through an intramolecular aldol reaction. In most cases two sets of $\alpha$ hydrogens need to be considered. As with most ring forming reaction five and six membered rings are preferred.
As with other aldol reaction the addition of heat causes an aldol condensation to occur.
Mixed Aldol Reaction and Condensations
The previous examples of aldol reactions and condensations used a common reactant as both the enolic donor and the electrophilic acceptor. The product in such cases is always a dimer of the reactant carbonyl compound. Aldol condensations between different carbonyl reactants are called crossed or mixed reactions, and under certain conditions such crossed aldol condensations can be effective.
Example 4: Mixed Aldol Reactions
The success of these mixed aldol reactions is due to two factors. First, aldehydes are more reactive acceptor electrophiles than ketones, and formaldehyde is more reactive than other aldehydes. Second, aldehydes lacking alpha-hydrogens can only function as acceptor reactants, and this reduces the number of possible products by half. Mixed aldols in which both reactants can serve as donors and acceptors generally give complex mixtures of both dimeric (homo) aldols and crossed aldols. Because of this most mixed aldol reactions are usually not performed unless one reactant has no alpha hydrogens.
The following abbreviated formulas illustrate the possible products in such a case, red letters representing the acceptor component and blue the donor. If all the reactions occurred at the same rate, equal quantities of the four products would be obtained. Separation and purification of the components of such a mixture would be difficult.
AACH2CHO + BCH2CHO + NaOH → AA + BB + AB + BA
The aldol condensation of ketones with aryl aldehydes to form α,β-unsaturated derivatives is called the Claisen-Schmidt reaction. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/19%3A_Carbonyl_Compounds_III-_Reactions_at_the_-_Carbon/19.12%3A_An_Aldol_Addition_Forms_-Hydroxaldehydes_or_-Hydroxyketones.txt |
A useful carbon-carbon bond-forming reaction known as the Aldol Reaction is yet another example of electrophilic substitution at the alpha carbon in enolate anions. The fundamental transformation in this reaction is a dimerization of an aldehyde (or ketone) to a beta-hydroxy aldehyde (or ketone) by alpha C–H addition of one reactant molecule to the carbonyl group of a second reactant molecule. Due to the carbanion like nature of enolates they can add to carbonyls in a similar manner as Grignard reagents. For this reaction to occur at least one of the reactants must have α hydrogens.
Aldol Reaction Mechanism
A three step mechanism:
Step 1: Enolate formation
Step 2: Nucleophilic attack by the enolate
Step 3: Protonation
Aldol Condensation: the dehydration of Aldol products to synthesize α, β unsaturated carbonyl (enones)
The products of aldol reactions often undergo a subsequent elimination of water, made up of an alpha-hydrogen and the beta-hydroxyl group. The product of this $\beta$-elimination reaction is an α,β-unsaturated aldehyde or ketone. Base-catalyzed elimination occurs with heating. The additional stability provided by the conjugated carbonyl system of the product makes some aldol reactions thermodynamically and mixtures of stereoisomers (E & Z) are obtained from some reactions. Reactions in which a larger molecule is formed from smaller components, with the elimination of a very small by-product such as water, are termed Condensations. Hence, the following examples are properly referred to as aldol condensations. Overall the general reaction involves a dehydration of an aldol product to form an alkene:
Figure: General reaction for an aldol condensation
Going from reactants to products simply
Figure: The aldol condensatio example
Aldol Condensation Mechanism
1) Form enolate
2) Form enone
When performing both reactions together always consider the aldol product first then convert to the enone. Note! The double bond always forms in conjugation with the carbonyl.
Intramolecular aldol reaction
Molecules which contain two carbonyl functionalities have the possibility of forming a ring through an intramolecular aldol reaction. In most cases two sets of $\alpha$ hydrogens need to be considered. As with most ring forming reaction five and six membered rings are preferred.
As with other aldol reaction the addition of heat causes an aldol condensation to occur.
Mixed Aldol Reaction and Condensations
The previous examples of aldol reactions and condensations used a common reactant as both the enolic donor and the electrophilic acceptor. The product in such cases is always a dimer of the reactant carbonyl compound. Aldol condensations between different carbonyl reactants are called crossed or mixed reactions, and under certain conditions such crossed aldol condensations can be effective.
Example 4: Mixed Aldol Reactions
The success of these mixed aldol reactions is due to two factors. First, aldehydes are more reactive acceptor electrophiles than ketones, and formaldehyde is more reactive than other aldehydes. Second, aldehydes lacking alpha-hydrogens can only function as acceptor reactants, and this reduces the number of possible products by half. Mixed aldols in which both reactants can serve as donors and acceptors generally give complex mixtures of both dimeric (homo) aldols and crossed aldols. Because of this most mixed aldol reactions are usually not performed unless one reactant has no alpha hydrogens.
The following abbreviated formulas illustrate the possible products in such a case, red letters representing the acceptor component and blue the donor. If all the reactions occurred at the same rate, equal quantities of the four products would be obtained. Separation and purification of the components of such a mixture would be difficult.
AACH2CHO + BCH2CHO + NaOH → AA + BB + AB + BA
The aldol condensation of ketones with aryl aldehydes to form α,β-unsaturated derivatives is called the Claisen-Schmidt reaction. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/19%3A_Carbonyl_Compounds_III-_Reactions_at_the_-_Carbon/19.13%3A_Dehydration_of_Aldol_Addition_Products_Form__-Unsaturated_Aldehydes_and_Ketones.txt |
A useful carbon-carbon bond-forming reaction known as the Aldol Reaction is yet another example of electrophilic substitution at the alpha carbon in enolate anions. The fundamental transformation in this reaction is a dimerization of an aldehyde (or ketone) to a beta-hydroxy aldehyde (or ketone) by alpha C–H addition of one reactant molecule to the carbonyl group of a second reactant molecule. Due to the carbanion like nature of enolates they can add to carbonyls in a similar manner as Grignard reagents. For this reaction to occur at least one of the reactants must have α hydrogens.
Aldol Reaction Mechanism
A three step mechanism:
Step 1: Enolate formation
Step 2: Nucleophilic attack by the enolate
Step 3: Protonation
Aldol Condensation: the dehydration of Aldol products to synthesize α, β unsaturated carbonyl (enones)
The products of aldol reactions often undergo a subsequent elimination of water, made up of an alpha-hydrogen and the beta-hydroxyl group. The product of this $\beta$-elimination reaction is an α,β-unsaturated aldehyde or ketone. Base-catalyzed elimination occurs with heating. The additional stability provided by the conjugated carbonyl system of the product makes some aldol reactions thermodynamically and mixtures of stereoisomers (E & Z) are obtained from some reactions. Reactions in which a larger molecule is formed from smaller components, with the elimination of a very small by-product such as water, are termed Condensations. Hence, the following examples are properly referred to as aldol condensations. Overall the general reaction involves a dehydration of an aldol product to form an alkene:
Figure: General reaction for an aldol condensation
Going from reactants to products simply
Figure: The aldol condensatio example
Aldol Condensation Mechanism
1) Form enolate
2) Form enone
When performing both reactions together always consider the aldol product first then convert to the enone. Note! The double bond always forms in conjugation with the carbonyl.
Intramolecular aldol reaction
Molecules which contain two carbonyl functionalities have the possibility of forming a ring through an intramolecular aldol reaction. In most cases two sets of $\alpha$ hydrogens need to be considered. As with most ring forming reaction five and six membered rings are preferred.
As with other aldol reaction the addition of heat causes an aldol condensation to occur.
Mixed Aldol Reaction and Condensations
The previous examples of aldol reactions and condensations used a common reactant as both the enolic donor and the electrophilic acceptor. The product in such cases is always a dimer of the reactant carbonyl compound. Aldol condensations between different carbonyl reactants are called crossed or mixed reactions, and under certain conditions such crossed aldol condensations can be effective.
Example 4: Mixed Aldol Reactions
The success of these mixed aldol reactions is due to two factors. First, aldehydes are more reactive acceptor electrophiles than ketones, and formaldehyde is more reactive than other aldehydes. Second, aldehydes lacking alpha-hydrogens can only function as acceptor reactants, and this reduces the number of possible products by half. Mixed aldols in which both reactants can serve as donors and acceptors generally give complex mixtures of both dimeric (homo) aldols and crossed aldols. Because of this most mixed aldol reactions are usually not performed unless one reactant has no alpha hydrogens.
The following abbreviated formulas illustrate the possible products in such a case, red letters representing the acceptor component and blue the donor. If all the reactions occurred at the same rate, equal quantities of the four products would be obtained. Separation and purification of the components of such a mixture would be difficult.
AACH2CHO + BCH2CHO + NaOH → AA + BB + AB + BA
The aldol condensation of ketones with aryl aldehydes to form α,β-unsaturated derivatives is called the Claisen-Schmidt reaction.
19.15: A Claisen Condensation Forms a -Keto Ester
Because esters can contain $\alpha$ hydrogens they can undergo a condensation reaction similar to the aldol reaction called a Claisen Condensation. In a fashion similar to the aldol, one ester acts as a nucleophile while a second ester acts as the electrophile. During the reaction a new carbon-carbon bond is formed; the product is a β-keto ester. A major difference with the aldol reaction is the fact that hydroxide cannot be used as a base because it could possibly react with the ester. Instead, an alkoxide version of the alcohol used to synthesize the ester is used to prevent transesterification side products.
Claisen Condensation
Basic reaction
Going from reactants to products simply
Claisen Condensation Mechanism
1) Enolate formation
2) Nucleophilic attack
3) Removal of leaving group
Dieckmann Condensation
A diester can undergo an intramolecular reaction called a Dieckmann condensation.
Crossed Claisen Condensation
Claisen condensations between different ester reactants are called Crossed Claisen reactions. Crossed Claisen reactions in which both reactants can serve as donors and acceptors generally give complex mixtures. Because of this most Crossed Claisen reactions are usually not performed unless one reactant has no alpha hydrogens.
19.16: Other Crossen Condensations
Because esters can contain $\alpha$ hydrogens they can undergo a condensation reaction similar to the aldol reaction called a Claisen Condensation. In a fashion similar to the aldol, one ester acts as a nucleophile while a second ester acts as the electrophile. During the reaction a new carbon-carbon bond is formed; the product is a β-keto ester. A major difference with the aldol reaction is the fact that hydroxide cannot be used as a base because it could possibly react with the ester. Instead, an alkoxide version of the alcohol used to synthesize the ester is used to prevent transesterification side products.
Claisen Condensation
Basic reaction
Going from reactants to products simply
Claisen Condensation Mechanism
1) Enolate formation
2) Nucleophilic attack
3) Removal of leaving group
Dieckmann Condensation
A diester can undergo an intramolecular reaction called a Dieckmann condensation.
Crossed Claisen Condensation
Claisen condensations between different ester reactants are called Crossed Claisen reactions. Crossed Claisen reactions in which both reactants can serve as donors and acceptors generally give complex mixtures. Because of this most Crossed Claisen reactions are usually not performed unless one reactant has no alpha hydrogens. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/19%3A_Carbonyl_Compounds_III-_Reactions_at_the_-_Carbon/19.14%3A_The_Crossed_Aldol_Addition.txt |
Objectives
After completing this section, you should be able to
1. write an equation to illustrate the Robinson annulation reaction.
2. identify the cyclic product formed when a 1,5‑diketone is treated with base.
3. identify the carbonyl compounds and any other reagents needed to synthesize a given cyclic compound by a series of reactions, one of which is a Robinson annulation.
Key Terms
• Robinson annulation reaction
Study Notes
The building of an alicyclic compound from acyclic starting materials can present an interesting challenge to the synthetic organic chemist. One route by which such a synthesis can be achieved is through the use of the Robinson annulation reaction. This reaction, which may at first look very complex, can be readily understood once you realize that it simply involves a Michael reaction followed by an intramolecular aldol condensation. Both of these steps involve attack by enolate anions.
As in some of the other syntheses that you have studied, when you are simply given the structure of a compound and asked how it could have been prepared, it can be difficult to recognize which reactions might have been used. In this instance, keep in mind that you have studied relatively few reactions which have resulted in the formation of an alicyclic compound. Thus, when asked how such a compound might be prepared, you should keep the possibility of using a Robinson annulation reaction in mind.
The Robinson Annulation
Many times the product of a Michael addition produces a dicarbonyl which can then undergo an intramolecular aldol reaction. These two processes together in one reaction creates two new carbon-carbon bonds and also creates a ring. Ring-forming reactions are called annulations after the Latin work for ring annulus. The reaction is named after English chemist Sir Robert Robinson (1886-1975) who developed it. He received the Nobel prize in chemistry in 1947. Remember that during annulations five and six membered rings are preferred.
The nucleophilic enolate donor is typically an enolate ion or enamine of a cyclic ketone, β-keto ester or β-diketone. The electrophilic acceptor is usually an α, β-unsaturated ketone. In the example below, 2-methyl-1,3-cyclohexanedione is deprotonated to form an enolate which affects a Michael reaction addition on 3-buten-2-one forming a C-C bond. The product contains a 1,5-diketone fragment which can undergo an intramolecular aldol condensation. This occurs through creation of a new enolate at the methyl ketone which undergoes an intramolecular aldol reaction. A new C-C bond is formed to one of the ring carbonyls, creating a new six-membered ring. In the last step, the resulting alcohol is eliminated to form a α, β-unsaturated ketone as the final Robinson annulation product. Because the Robinson Annulation involves an aldol reaction, a full equivalent of base is required.
Example
Worked Example
Draw the product of the following Robinson Annulation.
Answer
Analysis: When considering the product of a Robinson annulation it is usually best to consider each reaction individually. Use the steps discussed in Section 23.10 to convert the starting materials into the product of a Michael reaction, then into the product of an intramolecular aldol condensation. If the starting materials are drawn in a skeletal structure it may be helpful to convert to a condensed formula to better keep track of carbons and hydrogens.
Formation of the Michael reaction product
Formation of the intramolecular Aldol condensation product
Planning a Synthesis Using a Robinson Annulation
The presence of a cyclic, six-membered α, β-unsaturated ketone in a target molecule suggest that a Robinson Annulation may be utilized in its synthesis. The key bond cleavages are the C=C bond of the α, β-unsaturated ketone and the C-C bond between carbons in the a and g on the opposite alkyl chain of the ketone.
Worked Example
What would be the starting materials used if the following molecule was made using a Robinson annulation?
Answer
Analysis
Solution
It is necessary to use sodium ethoxide as the reaction base due to the presence of an ester.
Exercise \(1\)
1) Provide products of the following Robinson annulations.
a)
b)
c)
2) What would be the starting materials required to make the following molecule using a Robinson annulation?
Answers
1)
a)
b)
c)
2) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/19%3A_Carbonyl_Compounds_III-_Reactions_at_the_-_Carbon/19.18%3A_The_Robinson_Annulation.txt |
Malonic ester is a reagent specifically used in a reaction which converts alkyl halides to carboxylic acids called the Malonic Ester Synthesis. Malonic ester synthesis is a synthetic procedure used to convert a compound that has the general structural formula 1 into a carboxylic acid that has the general structural formula 2.
• reaction 1:
reaction 2:
reaction 3:
reaction 4:
A more direct method to convert 3 into 4 is the reaction of 3 with the enolate ion (5) of ethyl acetate followed by hydrolysis of the resultant ester.
However, the generation of 5 from ethyl acetate quantitatively in high yield is not an easy task because the reaction requires a very strong base, such as LDA, and must be carried out at very low temperature under strictly anhydrous conditions.
Malonic ester synthesis provides a more convenient alternative to convert 3 to 4.
Malonic ester synthesis can be adapted to synthesize compounds that have the general structural formula 6.
R3, R4 = identical or different alkyl groups
eg:
reaction 1:
reaction 2:
reaction 1 (repeat):
reaction 2 (repeat):
reaction 3:
reaction 4:
Malonic Ester Synthesis
Due to the fact that Malonic ester’s α hydrogens are adjacent to two carbonyls, they can be deprotonated by sodium ethoxide (NaOEt) to form Sodio Malonic Ester.
Because Sodio Malonic Ester is an enolate, it can then be alkylated with alkyl halides.
After alkylation the product can be converted to a dicarboxylic acid through saponification and subsequently one of the carboxylic acids can be removed through a decarboxylation step.
Mechanism
1) Saponification
2) Decarboxylation
3) Tautomerization
All of the steps together form the Malonic ester synthesis.
$RX \rightarrow RCH_2CO_2H$
Example
19.20: The Malonic Ester Synthesis- A Way to Synthesize a Carboxylic Acid
Malonic ester is a reagent specifically used in a reaction which converts alkyl halides to carboxylic acids called the Malonic Ester Synthesis. Malonic ester synthesis is a synthetic procedure used to convert a compound that has the general structural formula 1 into a carboxylic acid that has the general structural formula 2.
• reaction 1:
reaction 2:
reaction 3:
reaction 4:
A more direct method to convert 3 into 4 is the reaction of 3 with the enolate ion (5) of ethyl acetate followed by hydrolysis of the resultant ester.
However, the generation of 5 from ethyl acetate quantitatively in high yield is not an easy task because the reaction requires a very strong base, such as LDA, and must be carried out at very low temperature under strictly anhydrous conditions.
Malonic ester synthesis provides a more convenient alternative to convert 3 to 4.
Malonic ester synthesis can be adapted to synthesize compounds that have the general structural formula 6.
R3, R4 = identical or different alkyl groups
eg:
reaction 1:
reaction 2:
reaction 1 (repeat):
reaction 2 (repeat):
reaction 3:
reaction 4:
Malonic Ester Synthesis
Due to the fact that Malonic ester’s α hydrogens are adjacent to two carbonyls, they can be deprotonated by sodium ethoxide (NaOEt) to form Sodio Malonic Ester.
Because Sodio Malonic Ester is an enolate, it can then be alkylated with alkyl halides.
After alkylation the product can be converted to a dicarboxylic acid through saponification and subsequently one of the carboxylic acids can be removed through a decarboxylation step.
Mechanism
1) Saponification
2) Decarboxylation
3) Tautomerization
All of the steps together form the Malonic ester synthesis.
$RX \rightarrow RCH_2CO_2H$
Example
19.21: The Acetoacetic Ester Synthesis- A Way to Synthesize a Methyl Ketone
Malonic ester is a reagent specifically used in a reaction which converts alkyl halides to carboxylic acids called the Malonic Ester Synthesis. Malonic ester synthesis is a synthetic procedure used to convert a compound that has the general structural formula 1 into a carboxylic acid that has the general structural formula 2.
• reaction 1:
reaction 2:
reaction 3:
reaction 4:
A more direct method to convert 3 into 4 is the reaction of 3 with the enolate ion (5) of ethyl acetate followed by hydrolysis of the resultant ester.
However, the generation of 5 from ethyl acetate quantitatively in high yield is not an easy task because the reaction requires a very strong base, such as LDA, and must be carried out at very low temperature under strictly anhydrous conditions.
Malonic ester synthesis provides a more convenient alternative to convert 3 to 4.
Malonic ester synthesis can be adapted to synthesize compounds that have the general structural formula 6.
R3, R4 = identical or different alkyl groups
eg:
reaction 1:
reaction 2:
reaction 1 (repeat):
reaction 2 (repeat):
reaction 3:
reaction 4:
Malonic Ester Synthesis
Due to the fact that Malonic ester’s α hydrogens are adjacent to two carbonyls, they can be deprotonated by sodium ethoxide (NaOEt) to form Sodio Malonic Ester.
Because Sodio Malonic Ester is an enolate, it can then be alkylated with alkyl halides.
After alkylation the product can be converted to a dicarboxylic acid through saponification and subsequently one of the carboxylic acids can be removed through a decarboxylation step.
Mechanism
1) Saponification
2) Decarboxylation
3) Tautomerization
All of the steps together form the Malonic ester synthesis.
$RX \rightarrow RCH_2CO_2H$
Example | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/19%3A_Carbonyl_Compounds_III-_Reactions_at_the_-_Carbon/19.19%3A_Carboxylic_Acids_with_a_Carbonyl_Group_at_the_3-Position_can_be_Decarboxylated.txt |
We come now to one of the most important mechanism types in metabolism: the carbon-carbon bond-forming 'aldol' condensation reaction.
13.3A: The general mechanism for an aldol reaction
Consider the potential pathways available to a reactive enolate intermediate once the alpha-proton has been abstracted. The oxygen, which bears most of the negative charge, could act as a base, and the result would be an enol.
Alternatively, the enolate carbon, which bears a degree of negative charge, could act as a base, which is simply the reverse of the initial deprotonation step that formed the enolate in the first place.
In both of these cases, the electron-poor species attacked by the enolate is an acidic proton. What if the electron-poor species - the electrophile - is not a proton but a carbonyl carbon? In other words, what if the enolate acts not as a base but rather as a nucleophile in a carbonyl addition (chapter 11) reaction? One possibility is that the enolate oxygen could be the nucleophile in a hemiketal-forming reaction:
Although you can find examples of this type of reaction in biochemistry, it is far more common for the enolate carbon to be the nucleophile, attacking an electrophilic carbonyl to form a new carbon-carbon bond.
Historically, the first examples of this mechanism type to be studied involved the non-enzymatic reaction of an aldehyde with itself (a so-called 'self-condensation' reaction, where 'condensation' means the formation of one larger molecule from two smaller ones).
Because the resulting product contained both an aldehyde and an alcohol functional group, the reaction was termed an 'aldol condensation', a name that has become standard for reactions of this type, whether or not an aldehyde is involved.
The enzymes that catalyze aldol reactions are called, not surprisingly, 'aldolases'.
13.3B: Typical aldolase reactions - three variations on a theme
The first step in an aldolase reaction is the deprotonation of an alpha-carbon to generate a nucleophilic carbanion. Nature has evolved several distinct strategies to stabilize the intermediate that results. Some aldolases use a metal ion to stabilize the negative charge on an enolate intermediate, while others catalyze reactions that proceed through neutral Schiff base or enol intermediates.
Let's examine first a reaction catalyzed by a so-called 'Class II' aldolase, in which a metal cation - generally Zn2+ - bound in the active site serves to stabilize the negative charge on an enolate intermediate. Fructose 1,6-bisphosphate aldolase is an enzyme that participates in both the glycolytic (sugar burning) and gluconeogenesis (sugar building) biochemical pathways. For now, we will concentrate on its role in the gluconeogenesis pathway, but we will see it again later in its glycolytic role. The reaction catalyzed by fructose 1,6-bisphosphate aldolase is a condensation between two 3-carbon sugars, glyceraldehyde-3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP), forming a six-carbon product (which leads, after three more enzymatic steps, to glucose).
In the first step of the condensation, an alpha-carbon on DHAP is deprotonated, leading to an enolate intermediate. The strategy used to stabilize this key intermediate is to coordinate the negatively-charged enolate oxygen to an enzyme-bound zinc cation.
Next, the deprotonated a-carbon attacks the carbonyl carbon of GAP in a nucleophilic addition reaction, and protonation of the resulting alcohol leads directly to the fructose 1,6-bisphosphate product.
As with many other nucleophilic carbonyl addition reactions, a new stereocenter is created in this reaction, as a planar, achiral carbonyl group is converted to a tetrahedral, chiral alcohol. The enzyme-catalyzed reaction, not surprisingly, is completely stereospecific: the DHAP substrate is positioned in the active site so as to attack the re (front)face of the GAP carbonyl group, leading to the R configuration at the new stereocenter.
Interestingly, it appears that in bacteria, the fructose bisphosphate aldolase enzyme evolved separately from the corresponding enzyme in plants and animals. In plants and animals, the same aldol condensation reaction is carried out by a significantly different mechanism, in which the key intermediate is not a zinc-stabilized enolate but an enamine. The nucleophilic substrate (DHAP) is first linked to the enzyme through the formation of an imine (also known as a Schiff base, section 11.6) with a lysine residue in the active site.
The alpha-proton is then abstracted by an active site base to form an enamine.
In the next step, the alpha-carbon attacks the carbonyl carbon of GAP, and the new carbon-carbon bond is formed. In order to release the product from the enzyme active site and free the enzyme to catalyze another reaction, the imine is hydrolyzed back to a ketone group.
There are many more examples of 'Class I' aldolase reactions in which the key intermediate is a lysine-linked imine. Many bacteria are able to incorporate formaldehyde, a toxic compound, into carbohydrate metabolism by condensing it with ribulose monophosphate. The reaction proceeds through imine and enamine intermediates.
Template:ExampleStart
Exercise 13.5:
a) Propose a complete mechanism for the condensation reaction shown above.
b) Propose a complete mechanism for the conversion of hexulose-6-phosphate (formed from the condensation of ribulose-5-phosphate and formaldehyde) into fructose-6-phosphate.
Solution
Template:ExampleEnd
Along with aldehydes and ketones, esters and thioesters can act as the nucleophilic partner in aldol condensations. In the first step of the citric acid (Krebs) cycle, acetyl CoA condenses with oxaloacetate to form (S)-citryl CoA.
Notice that in this aldol reaction, the nucleophilic intermediate is stabilized by protonation, rather than by formation of an imine (as in the Class I aldolases) or by a metal ion (as in the Class II aldolases).
13.3C: Going backwards: the retroaldol reaction
Although aldol reactions play a very important role in the formation of new carbon-carbon bonds in metabolic pathways, it is important to emphasize that they are also highly reversible: in most cases, the energy level of starting compounds and products are very close. This means that, depending on metabolic conditions, aldolases can also catalyze retro-aldol reactions (the reverse of aldol condensations, in which carbon-carbon bonds are broken). Recall that fructose 1,6-bisphosphate aldolase (section 13.3B) is active in the direction of sugar breakdown (glycolysis) as well as sugar synthesis (gluconeogenesis). In the glycolytic direction, the enzyme catalyzes - either by zinc cation or by imine/enamine mechanisms, depending on the organism - the retro-aldol cleavage of fructose bisphosphate into DHAP and GAP.
The mechanism is the exact reverse of the condensation reaction. Shown below is the mechanism for a Zn2+ - dependent (Type II) retroaldol cleavage. Notice that in the retroaldol reaction, the enolate intermediate is the leaving group, rather than the nucleophile.
The key thing to keep in mind when looking for a possible retro-aldol mechanism is that, when the carbon-carbon bond breaks, the electrons must have some place to go, where they will be stabilized by resonance. Generally, this means that there must be a carbonyl or imine group on the next carbon. If there is no adjacent carbonyl or imine group, the carbon-carbon bond is not free to break.
Here are two more examples of retro-aldol reactions. Bacterial carbohydrate metabolism involves this reversible, class I retro-aldol cleavage: (Proc. Natl. Acad. Sci 2001, 98, 3679).
Template:ExampleStart
Exercise 13.6: Draw the structure of the enamine intermediate in the retroaldol reaction shown above.
Solution
Template:ExampleEnd
Another interesting example is the retro-aldol cleavage of indole-3-glycerol phosphate, a step in the biosynthesis of tryptophan.
Look carefully at this reaction - how is the leaving group stabilized? There is an imine group involved, but no participation by an enzymatic lysine. The imine is 'built into' the starting compound, available from the initial tautomerization of the cyclic enamine group in indole-3-glycerol phosphate.
Template:ExampleStart
Exercise 13.7: Draw the reverse (aldol condensation) direction of the reaction above.
Solution
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13.3D: Going both ways: transaldolase
An enzyme called transaldolase, which is part of the 'pentose phosphate pathway' of carbohydrate metabolism, catalyzes an interesting combination of class I aldol and retro-aldol reactions. The overall reaction, which can proceed in either direction depending on metabolic requirements, converts 3- and 7-carbon sugars into 6- and 4-carbon sugars. Essentially, a 3-carbon unit breaks off from a ketone sugar (ketose) and then is condensed directly with an aldehyde sugar (aldose).
Let's follow the progress of the reaction in the left-to-right direction as depicted above. Because this is a class I aldolase, the first step is the formation of an imine linkage between the ketone carbon of fructose-6-phosphate (F6P) and a lysine group from the enzyme. The enzyme-substrate adduct then undergoes a retro-aldol step to free glyceralde-3-phosphate (GAP), which leaves the active site.
The second substrate, erythrose 4-phosphate (E4P), enters the active site, and an aldol condensation occurs between E4P and the 3-carbon fragment remaining from the cleavage of fructose-6-phosphate.
The final step is hydrolysis of the imine and subsequent dissociation of sedoheptulose 7-phosphate from the active site.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/19%3A_Carbonyl_Compounds_III-_Reactions_at_the_-_Carbon/19.23%3A_Reactions_at_the_-Carbon_in_Biological_Systems.txt |
Synthetic organic chemists have a wide range of reagents at their disposal for the reduction or oxidation of functional groups in organic compounds. The reagent to be used for any given transformation must be chosen carefully in order to ensure that only the desired functional group or groups is effected: some reducing agents, for example, will act on ketones and aldehydes but leave alkenes and carboxylic acid derivatives untouched, while other will reduce all of these functional groups. Different redox reagents will also transform groups to different extents: we will soon see oxidizing agents, for example, that will transform a primary alcohol to a carboxylic acid, and others that, given the same primary alcohol, will produce an aldehyde. Similarly, reduction of an alkyne can produce a cis-alkene, a trans-alkene, or an alkane, depending on the reducing agent used. In this section, we will take a look at the action of some of the most important redox reactions – those that are used most frequently in the laboratory, and those which, perhaps more importantly for some of you, tend to make their appearance on standardized tests such as the MCAT. A much more complete discussion of redox reagents can be found in advanced organic synthesis textbooks and reference sources. It also important to bear in mind that increasingly, synthetic organic chemists are figuring out how to use redox enzymes as tools to catalyze the reactions that they wish to carry out in the lab (Curr. Opin. Biotechnol. 2003, 14, 427; Adv. Biochem. Eng. Biotechnol. 2005, 92, 261).
16.13A: Metal hydride reducing agents
In the organic synthesis laboratory, carbonyl groups can be reduced using hydride transfer reactions that are mechanistically similar to biochemical reactions with NAD(P)H. Three common reducing agents are sodium borohydride (NaBH4), lithium aluminum hydride (LiAlH4), and diisobutyl aluminum hydride (DIBAH).
For example, when sodium borohydride is stirred in solution with an aldehyde or ketone, a hydride ion adds to the carbonyl carbon to form a 2o alcohol (from a ketone) or a 1o alcohol (from an aldehyde).
Sodium borohydride is a relatively mild reducing agent, and reactions are typically run in water, methanol, or ethanol solvent. One mole of NaBH4is capable of reducing four moles of ketone or aldehyde. Carboxylic acid derivatives and alkene double bounds are not affected.
LiAlH4 works in a manner similar to NaBH4, but is much more reactive. It will react violently with protic solvents (like water or methanol), and so an organic solvent such as diethyl ether must be used. LiAlH4 will not affect alkene double bonds, but unlike NaBH4 it will reduce carboxylic acids and esters (to 1o alcohols), amides (to amines), nitriles (to 1oamines), and can even be used in reductive ring-opening reactions with epoxides to form alcohols.
DIBAH has only one hydride to deliver (as opposed to four for NABH4 and LiAlH4), and if only one molar equivalent is used it can reduce an ester to an aldehyde. Using LiAlH4 would reduce the ester to a primary alcohol, as would using two molar equivalents of DIBAH.
In all of these metal hydride reductions, hydride addition can occur from either side of the carbonyl, meaning that reduction of an asymmetrical ketone will result in a racemic mix of both R and S alcohols. For most ketones, this mixture will be present at a ratio of approximately 50:50, because the likelihood of hydride attack is equal at either side. In some cases, however, the two faces presented by the ketone group are not equivalent. Camphor, a natural compound with a distinctive smell that is used in many cosmetics and home health products, is a case in point. Looking at the structure of the camphor molecule, you can see that, because of the conformational rigidity of the fused ring structure, the re and si faces of the carbonyl group are not equivalent - approach by a nucleophile appears to be less hindered from the bottom (si) side than from the top (re) side, (it is easier to visualize this if you build a model).
This can be confirmed by analyzing the 1H NMR spectrum of the purified product from a reaction with NaBH4. This spectrum is actually quite complex, because it is not a pure sample but a mixture of two different diastereomers - there are many overlapping peaks and complex splitting patterns that are difficult to interpret. Fortunately, however, the signals corresponding to the hydrogen atom of interest (HT and HB for the products of topside and bottomside attack, respectively) are quite distinct - they are both in a region of the spectrum devoid of any other peaks. HT in one diastereomer has a chemical shift of 4.0 ppm, while HB in the other diastereomer has a chemical shift of 3.6 ppm. The integration value of these two peaks relative to one another is of course equal to the ratio of the two diastereomers in the product mixture and, as expected, integration shows that there is substantially more of the product that results from bottomside attack. (Pavia, et al., "Introduction to Organic Laboratory Techniques - A Contemporary Approach", 2nd ed. 1982, CBS College Publishing, Philadelphia USA).
16.13B: Catalytic hydrogenation and the trans fat issue
In section 16.5, we saw several examples of enzymatic alkene hydrogenation reactions. In the organic chemistry lab, hydrogenation of alkenes is generally carried out with hydrogen gas on the surface of a metal catalyst such as platinum, palladium, or nickel. This process is usually referred to as catalytic hydrogenation. Although the exact mechanism by which the reaction occurs is still a topic of debate, the general picture is fairly clear. Empty orbitals on the metal allow for hydrogen to be adsorbed on the catalytic surface. The alkene also complexes to the metal surface, as the π electrons in the double bond also interact with empty metal orbitals. At this point, hydrogen is inserted into the double bond, and the reduced alkane product is released.
Because this reaction takes place on a planar surface, addition of hydrogen occurs on the same face of the double bond - a syn addition, in other words. The catalytic hydrogenation of 1,2-dimethylcyclopentane will yield, for example, the cis dimethylcycloalkane product, with little or no formation of a trans product.
It is not only alkene double bonds that are reduced by catalytic hydrogenation: alkynes are reduced to alkanes, aldehydes and ketones are reduced to their corresponding alcohols, and nitro groups are reduced to amines. Carboxylic acid derivatives, however, are not affected, and aromatic double bonds are also left untouched.
Catalytic hydrogenation of alkenes is currently a hot topic in food chemistry. Margarine is produced by partial hydrogenation of double bonds in the unsaturated fatty acids in liquid vegetable oils, usually with a nickel catalyst. Complete hydrogenation would produce fully saturated fatty acids and lead to a lard-like product that is too hard to spread on toast, so conditions are adjusted to ensure that only some of the double bonds are hydrogenated while others are left in place, resulting in a soft and spreadable product. This process is called partial hydrogenation. (review the chemical basis of the relationship between lipid saturation and melting point in section 2.4D).
Recently, however, scientists have become increasingly worried about the presence of unnatural fatty acids found in margarine and other food products made from partially hydrogenized oils. Natural unsaturated fatty acids have mainly cis double bonds. In the unnatural fatty acids found in margarines, the naturally-occurring cis stereochemistry has been converted to trans. Trans-fatty acids have been associated with heart disease and some forms of cancer.
It appears that these unnatural trans fatty acid isomers are unintentionally produced by the hydrogenation process. The problem is that there is no control over the regiochemistry or stereochemistry of the reverse (dehydrogenation) reaction. Because only a limited amount of hydrogen is used in order to achieve partial (rather then complete) hydrogenation, the process is reversible, meaning that double bonds tend to re-form - and when they do, it is often in the lower-energy trans configuration, rather than the natural cis configuration. The figure below shows the partial hydrogenation of a linoleic acid hydrocarbon over a nickel catalyst, resulting in oleic acid, which is the desired cis-unsaturated product, as well as elaidic acid, the undesirable trans fat product.
Food producers are increasingly adopting alternative hydrogenation technologies and production strategies in order to offer products that are free of trans fatty acids. (See J. Am. Diet. Assoc. 2006, 106, 867 for a detailed review of this topic).
What if we want to convert the triple bond of an alkyne to the double bond of an alkene, rather than all the way to an alkane single bond? Fortunately, there is a way to do this – an even better, we can choose whether to make a cis or a trans double bond! To convert an alkyne to a cis-alkene, we carry out catalytic hydrogenation reaction using what is known as a ‘Lindlar catalyst" – finely powdered palladium depositied on calcium carbonate and modified with lead salts. This is essentially a less reactive version of the normal transition metal catalyst used in hydrogenation of alkenes.
If we want to make a trans alkene, we use sodium metal and liquid ammonia in a very different type of reaction – the ‘dissolving metal reduction’:
This reaction mechanism is thought to occur through radical intermediates, but we will not concern ourselves with exactly how it works.
16.13C: Reduction of carbonyl carbons to methylene
There are two principle methods for reducing the carbonyl group of a ketone to a simple methylene (CH2) carbon. The mechanism for the Clemmensen reduction is not well understood, but you will be asked to propose a mechanism for the Wolff-Kishner reduction in the end-of-chapter problems.
The Clemmensen reduction:
The Wolff-Kishner reduction:
16.13D: Laboratory oxidation reactions
The laboratory oxidation of an alcohol to form an aldehyde or ketone is mechanistically different from the biochemical oxidations with NAD(P)+ that we saw earlier in this chapter. The general picture of laboratory oxidations is illustrated below. Essentially what happens is that the hydroxide hydrogen of the alcohol is replaced by a leaving group (X in the figure below).
Then, a base can abstract the proton bound to the alcohol carbon, which results in elimination of the X leaving group and formation of a new carbon-oxygen double bond. As you can see by looking closely at this general mechanism, tertiary alcohols cannot be oxidized in this way – there is no hydrogen to abstract in the final step!
A common method for oxidizing secondary alcohols to ketones uses chromic acid (H2CrO4) as the oxidizing agent. Chromic acid, also known as Jones reagent, is prepared by adding chromium trioxide (CrO3) to aqueous sulfuric acid.
A mechanism for the chromic acid oxidation of a ketone is shown below.
Note that the chromium reagent has lost two bonds to oxygen in this reaction, and thus has been reduced (it must have been reduced - it is the oxidizing agent!).
Ketones are not oxidized by chromic acid, so the reaction stops at the ketone stage. In contrast, primary alcohols are oxidized by chromic acid first to aldehydes, then straight on to carboxylic acids.
It is actually the hydride form of the aldehyde that is oxidized (recall from section 11.3 that aldehydes in aqueous solution exist in rapid equilibrium with their hydrate forms).
One of the hydroxyl groups of the hydrate attacks chromic acid, and the reaction proceeds essentially as shown for the oxidation of a secondary alcohol.
Under some conditions, chromic acid will even oxidize a carbon in the benzylic position to a carboxylic acid (notice that a carbon-carbon bond is broken in this transformation).
A number of other common oxidizing agents are discussed below.
The pyridinium chlorochromate (PCC) and Swern oxidation reactions are useful for oxidizing primary alcohols to aldehydes. Further oxidation of the aldehyde to the carboxylic acid stage does not occur with these reagents, because the reactions are carried out in anhydrous (water-free) organic solvents such as dichloromethane, and therefore the hydrate form of the aldehyde is not able to form.
The Swern oxidation uses dimethylsulfoxide and oxalyl chloride, followed by addition of a base such as triethylamine. The actual oxidizing species in this reaction is the dimethylchlorosulfonium ion, which forms from dimethylsulfoxide and oxalyl chloride.
You will be asked to propose a mechanism for these reactions in the end of chapter problems.
Pyridinium chlorochromate is generated by combining chromium trioxide, hydrochloric acid, and pyridine.
The PCC and Swern oxidation conditions can both also be used to oxidize secondary alcohols to ketones.
Silver ion, Ag(I), is often used to oxidize aldehydes to ketones. Two common reaction conditions are:
The set of reagents in the latter reaction conditions are commonly known as ‘Tollens’ reagent’.
Alkenes are oxidized to cis-1,2-diols by osmium tetroxide (OsO4). The stereospecificity is due to the formation of a cyclic osmate ester intermediate. Osmium tetroxide is used in catalytic amounts, and is regenerated by N-methylmorpholine-N-oxide.
cis-1,2-diol compounds can be oxidized to dialdehydes (or diketones, depending on the substitution of the starting diol) using periodic acid:
Alkenes can also be oxidized by treatment with ozone, O3. In ozonolysis, the carbon-carbon double bond is cleaved, and the alkene carbons are converted to aldehydes:
Dimethyl sulfide or zinc is added in the work-up stage of the reaction in order to reduce hydrogen peroxide, which is formed in the reaction, to water.
Alternatively, hydrogen peroxide and aqueous base can be added in the workup to obtain carboxylic acids:
Potassium permanganate (KMnO4) is another very powerful oxidizing agent that will oxidize primary alcohols and aldehydes to carboxylic acids. KMnO4 is also useful for oxidative cleavage of alkenes to ketones and carboxylic acids:
Finally, alkenes can be oxidized to epoxides using a 'peroxyacid' such as m-chloroperoxybenzoic acid. Notice the presence of a third oxygen in the peroxyacid functional group.
The mechanism is similar to that of the biological epoxidation catalyzed by squalene epoxidase (section 16.10A), with the π electrons in the alkene double bond attacking the 'outer' oxygen of the peroxyacid and cleaving the reactive O-O peroxide bond.
Uncatalyzed epoxidation of an asymmetric alkene generally results in two diastereomeric epoxide products, with the epoxide adding either from above or below the plane of the alkene.
Epoxides are very useful intermediates in organic synthesis. Because most naturally occurring molecules (including those with medicinal properties) are chiral, control of stereochemistry is one of the most important challenges facing a synthetic chemist attempting to synthesize a naturally occurring molecule in the laboratory. In what was arguably one of the most important discoveries in synthetic organic chemistry in recent decades, Barry Sharpless of Stanford University reported in 1980 that he and his colleagues had developed a method to stereoselectively epoxidize asymmetric alkenes which contained an alcohol in the allylic position. The ‘Sharpless asymmetric oxidation’ is achieved with the use of a chiral catalyst composed of (+) or (-) diethyltartrate and an organotitanium compound (J. Am. Chem. Soc. 1980, 102, 5974). Depending on which stereoisomer of diethyltartrate is used, the peroxyacid oxygen tends to add to either the top or bottom plane of the alkene.
This technique allows for the specific introduction of two new stereocenters at an alkene position, which as you can imagine makes it an extremely useful synthetic tool.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/20%3A_More_About_Oxidation-Reduction_Reactions/20.01%3A_Oxidation-Reduction_Reactions_of_Organic_Compounds-_An_Overview.txt |
The most common sources of the hydride Nucleophile are lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4). Note! The hydride anion is not present during this reaction; rather, these reagents serve as a source of hydride due to the presence of a polar metal-hydrogen bond. Because aluminum is less electronegative than boron, the Al-H bond in LiAlH4 is more polar, thereby, making LiAlH4 a stronger reducing agent.
Addition of a hydride anion (H:-) to an aldehyde or ketone gives an alkoxide anion, which on protonation yields the corresponding alcohol. Aldehydes produce 1º-alcohols and ketones produce 2º-alcohols.
In metal hydrides reductions the resulting alkoxide salts are insoluble and need to be hydrolyzed (with care) before the alcohol product can be isolated. In the sodium borohydride reduction the methanol solvent system achieves this hydrolysis automatically. In the lithium aluminum hydride reduction water is usually added in a second step. The lithium, sodium, boron and aluminum end up as soluble inorganic salts at the end of either reaction. Note! LiAlH4 and NaBH4 are both capable of reducing aldehydes and ketones to the corresponding alcohol.
Mechanism
This mechanism is for a LiAlH4 reduction. The mechanism for a NaBH4 reduction is the same except methanol is the proton source used in the second step.
1) Nucleopilic attack by the hydride anion
2) The alkoxide is protonated
Properties of Hydride Sources
Two practical sources of hydride-like reactivity are the complex metal hydrides lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4). These are both white (or near white) solids, which are prepared from lithium or sodium hydrides by reaction with aluminum or boron halides and esters. Lithium aluminum hydride is by far the most reactive of the two compounds, reacting violently with water, alcohols and other acidic groups with the evolution of hydrogen gas. The following table summarizes some important characteristics of these useful reagents.
Problems
1) Please draw the products of the following reactions:
2) Please draw the structure of the molecule which must be reacted to produce the product.
3) Deuterium oxide (D2O) is a form of water where the hydrogens have been replaced by deuteriums. For the following LiAlH4 reduction the water typically used has been replaced by deuterium oxide. Please draw the product of the reaction and place the deuterium in the proper location. Hint! Look at the mechanism of the reaction.
1)
2)
3)
20.04: Oxidation of Alcohols
This page looks at the oxidation of alcohols using acidified sodium or potassium dichromate(VI) solution. This reaction is used to make aldehydes, ketones and carboxylic acids, and as a way of distinguishing between primary, secondary and tertiary alcohols.
Oxidizing the different types of alcohols
The oxidizing agent used in these reactions is normally a solution of sodium or potassium dichromate(VI) acidified with dilute sulfuric acid. If oxidation occurs, then the orange solution containing the dichromate(VI) ions is reduced to a green solution containing chromium(III) ions. The electron-half-equation for this reaction is as follows:
$Cr_2O_7^{2-} + 14H^+ + 6e^- \rightarrow 2Cr^{3+} + 7H_2O$
Primary alcohols
Primary alcohols can be oxidized to either aldehydes or carboxylic acids, depending on the reaction conditions. In the case of the formation of carboxylic acids, the alcohol is first oxidized to an aldehyde, which is then oxidized further to the acid.
An aldehyde is obtained if an excess amount of the alcohol is used, and the aldehyde is distilled off as soon as it forms. An excess of the alcohol means that there is not enough oxidizing agent present to carry out the second stage, and removing the aldehyde as soon as it is formed means that it is not present to be oxidized anyway!
If you used ethanol as a typical primary alcohol, you would produce the aldehyde ethanal, $CH_3CHO$. The full equation for this reaction is fairly complicated, and you need to understand the electron-half-equations in order to work it out.
$3CH_3CH_2OH + Cr_2O_7^{2-} + 8H^+ \rightarrow 3CH_3CHO + 2Cr^{3+} + 7H_2O$
In organic chemistry, simplified versions are often used that concentrate on what is happening to the organic substances. To do that, oxygen from an oxidizing agent is represented as $[O]$. That would produce the much simpler equation:
It also helps in remembering what happens. You can draw simple structures to show the relationship between the primary alcohol and the aldehyde formed.
Full oxidation to carboxylic acids
An excess of the oxidizing agent must be used, and the aldehyde formed as the half-way product should remain in the mixture. The alcohol is heated under reflux with an excess of the oxidizing agent. When the reaction is complete, the carboxylic acid is distilled off. The full equation for the oxidation of ethanol to ethanoic acid is as follows:
$3CH_3CH_2OH + 2Cr_2O_7^{2-} + 16H+ \rightarrow 3CH_3COOH + 4Cr^{3+} + 11H_2O$
The more typical simplified version looks like this:
$CH_3CH_2OH + 2[O] \rightarrow CH_3COOH + H_2O$
Alternatively, you could write separate equations for the two stages of the reaction - the formation of ethanal and then its subsequent oxidation.
$CH_3CH_2OH + [O] \rightarrow CH_3CHO + H_2O$
$CH_3CHO + [O] \rightarrow CH_3COOH$
This is what is happening in the second stage:
Secondary alcohols
Secondary alcohols are oxidized to ketones - and that's it. For example, if you heat the secondary alcohol propan-2-ol with sodium or potassium dichromate(VI) solution acidified with dilute sulfuric acid, propanone is formed. Changing the reaction conditions makes no difference to the product. Folloiwng is the simple version of the equation, showing the relationship between the structures:
If you look back at the second stage of the primary alcohol reaction, you will see that an oxygen inserted between the carbon and the hydrogen in the aldehyde group to produce the carboxylic acid. In this case, there is no such hydrogen - and the reaction has nowhere further to go.
Tertiary alcohols
Tertiary alcohols are not oxidized by acidified sodium or potassium dichromate(VI) solution - there is no reaction whatsoever. If you look at what is happening with primary and secondary alcohols, you will see that the oxidizing agent is removing the hydrogen from the -OH group, and a hydrogen from the carbon atom is attached to the -OH. Tertiary alcohols don't have a hydrogen atom attached to that carbon.
You need to be able to remove those two particular hydrogen atoms in order to set up the carbon-oxygen double bond.
Using these reactions as a test for the different types of alcohols
First, the presence of an alcohol must be confirmed by testing for the -OH group. The liquid would need to be verified as neutral, free of water and that it reacted with solid phosphorus(V) chloride to produce a burst of acidic steamy hydrogen chloride fumes. A few drops of the alcohol would be added to a test tube containing potassium dichromate(VI) solution acidified with dilute sulfuric acid. The tube would be warmed in a hot water bath.
Determining the tertiary alcohol
In the case of a primary or secondary alcohol, the orange solution turns green. With a tertiary alcohol, there is no color change. After heating, the following colors are observed:
Distinguishing between the primary and secondary alcohols
A sufficient amount of the aldehyde (from oxidation of a primary alcohol) or ketone (from a secondary alcohol) must be produced to be able to test them. There are various reactions that aldehydes undergo that ketones do not. These include the reactions with Tollens' reagent, Fehling's solution and Benedict's solution, and these reactions are covered on a separate page.
These tests can be difficult to carry out, and the results are not always as clear-cut as the books say. A much simpler but fairly reliable test is to use Schiff's reagent. Schiff's reagent is a fuchsin dye decolorized by passing sulfur dioxide through it. In the presence of even small amounts of an aldehyde, it turns bright magenta.
It must, however, be used absolutely cold, because ketones react with it very slowly to give the same color. If you heat it, obviously the change is faster - and potentially confusing. While you are warming the reaction mixture in the hot water bath, you can pass any vapors produced through some Schiff's reagent.
• If the Schiff's reagent quickly becomes magenta, then you are producing an aldehyde from a primary alcohol.
• If there is no color change in the Schiff's reagent, or only a trace of pink color within a minute or so, then you are not producing an aldehyde; therefore, no primary alcohol is present.
Because of the color change to the acidified potassium dichromate(VI) solution, you must, therefore, have a secondary alcohol. You should check the result as soon as the potassium dichromate(VI) solution turns green - if you leave it too long, the Schiff's reagent might start to change color in the secondary alcohol case as well. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/20%3A_More_About_Oxidation-Reduction_Reactions/20.03%3A_Chemoselective_Reactions.txt |
This page looks at ways of distinguishing between aldehydes and ketones using oxidizing agents such as acidified potassium dichromate(VI) solution, Tollens' reagent, Fehling's solution and Benedict's solution.
Why do aldehydes and ketones behave differently?
You will remember that the difference between an aldehyde and a ketone is the presence of a hydrogen atom attached to the carbon-oxygen double bond in the aldehyde. Ketones don't have that hydrogen.
The presence of that hydrogen atom makes aldehydes very easy to oxidize (i.e., they are strong reducing agents). Because ketones do not have that particular hydrogen atom, they are resistant to oxidation, and only very strong oxidizing agents like potassium manganate (VII) solution (potassium permanganate solution) oxidize ketones. However, they do it in a destructive way, breaking carbon-carbon bonds. Provided you avoid using these powerful oxidizing agents, you can easily tell the difference between an aldehyde and a ketone. Aldehydes are easily oxidized by all sorts of different oxidizing agents: ketones are not.
What is formed when aldehydes are oxidized?
It depends on whether the reaction is done under acidic or alkaline conditions. Under acidic conditions, the aldehyde is oxidized to a carboxylic acid. Under alkaline conditions, this couldn't form because it would react with the alkali. A salt is formed instead.
Building equations for the oxidation reactions
If you need to work out the equations for these reactions, the only reliable way of building them is to use electron-half-equations. The half-equation for the oxidation of the aldehyde obviously varies depending on whether you are doing the reaction under acidic or alkaline conditions.
Under acidic conditions:
$RCHO + H_2O \rightarrow RCOOH + 2H^+ +2e^- \tag{1}$
Under alkaline conditions:
$RCHO + 3OH^- \rightarrow RCOO^- + 2H_2O +2e^- \tag{2}$
These half-equations are then combined with the half-equations from whatever oxidizing agent you are using. Examples are given in detail below.
Specific examples
In each of the following examples, we are assuming that you know that you have either an aldehyde or a ketone. There are lots of other things which could also give positive results. Assuming that you know it has to be one or the other, in each case, a ketone does nothing. Only an aldehyde gives a positive result.
Using acidified potassium dichromate(VI) solution
A small amount of potassium dichromate(VI) solution is acidified with dilute sulphuric acid and a few drops of the aldehyde or ketone are added. If nothing happens in the cold, the mixture is warmed gently for a couple of minutes - for example, in a beaker of hot water.
ketone No change in the orange solution.
aldehyde Orange solution turns green.
The orange dichromate(VI) ions have been reduced to green chromium(III) ions by the aldehyde. In turn the aldehyde is oxidized to the corresponding carboxylic acid. The electron-half-equation for the reduction of dichromate(VI) ions is:
$Cr_2O_7^{2-} + 14H^+ + 6e^- \rightarrow 2Cr^{3+} + 7H_2O \tag{3}$
Combining that with the half-equation for the oxidation of an aldehyde under acidic conditions:
$RCHO + H_2O \rightarrow RCOOH + 2H^+ +2e^- \tag{4}$
. . . gives the overall equation:
$2RCHO + Cr_2O_7^{2-} + 8H^+ \rightarrow 3RCOOH +2Cr^{3+}+ 4H_2O \tag{5}$
Using Tollens' reagent (the silver mirror test)
Tollens' reagent contains the diamminesilver(I) ion, [Ag(NH3)2]+. This is made from silver(I) nitrate solution. You add a drop of sodium hydroxide solution to give a precipitate of silver(I) oxide, and then add just enough dilute ammonia solution to redissolve the precipitate. To carry out the test, you add a few drops of the aldehyde or ketone to the freshly prepared reagent, and warm gently in a hot water bath for a few minutes.
ketone No change in the colorless solution.
aldehyde The colorless solution produces a grey precipitate of silver, or a silver mirror on the test tube.
Figure 1: Tollens' test for aldehyde: left side positive (silver mirror), right side negative. from Wikipedia
Aldehydes reduce the diamminesilver(I) ion to metallic silver. Because the solution is alkaline, the aldehyde itself is oxidized to a salt of the corresponding carboxylic acid. The electron-half-equation for the reduction of of the diamminesilver(I) ions to silver is:
$Ag(NH_3)_2^+ + e^- \rightarrow Ag + 2NH_3 \tag{6}$
Combining that with the half-equation for the oxidation of an aldehyde under alkaline conditions:
$RCHO + 3OH^- \rightarrow RCOO^- + 2H_2O +2e^- \tag{7}$
gives the overall equation:
$2Ag(NH_3)_2^+ + RCHO + 3OH^- \rightarrow 2Ag + RCOO^- + 4NH_3 +2H_2O \tag{8}$
Using Fehling's solution or Benedict's solution
Fehling's solution and Benedict's solution are variants of essentially the same thing. Both contain complexed copper(II) ions in an alkaline solution.
• Fehling's solution contains copper(II) ions complexed with tartrate ions in sodium hydroxide solution. Complexing the copper(II) ions with tartrate ions prevents precipitation of copper(II) hydroxide.
• Benedict's solution contains copper(II) ions complexed with citrate ions in sodium carbonate solution. Again, complexing the copper(II) ions prevents the formation of a precipitate - this time of copper(II) carbonate.
Both solutions are used in the same way. A few drops of the aldehyde or ketone are added to the reagent, and the mixture is warmed gently in a hot water bath for a few minutes.
ketone No change in the blue solution.
aldehyde The blue solution produces a dark red precipitate of copper(I) oxide.
Figure 2: Fehling's test. Left side negative, right side positive. from Wikipedia
Aldehydes reduce the complexed copper(II) ion to copper(I) oxide. Because the solution is alkaline, the aldehyde itself is oxidized to a salt of the corresponding carboxylic acid. The equations for these reactions are always simplified to avoid having to write in the formulae for the tartrate or citrate ions in the copper complexes. The electron-half-equations for both Fehling's solution and Benedict's solution can be written as:
$2Cu^{2+}_{complexed} + 2OH^- + 2e^- \rightarrow Cu_2O + H_2O \tag{9}$
Combining that with the half-equation for the oxidation of an aldehyde under alkaline conditions:
$RCHO + 3OH^- \rightarrow RCOO^- + 2H_2O +2e^- \tag{10}$
to give the overall equation:
$RCHO + 2Cu^{2+}_{complexed} + 5OH^- \rightarrow RCOO^- + Cu_2O + 3H_2O \tag{11}$
Contributors
Jim Clark (Chemguide.co.uk) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/20%3A_More_About_Oxidation-Reduction_Reactions/20.05%3A_Oxidation_of_Aldehydes_and_Ketones.txt |
Learning Objectives
• Describe the chemistry of the oxygen group.
• Give the trend of various properties.
• Remember the names of Group 16 elements.
• Explain the Frasch process.
• Describe properties and applications of $\mathrm{H_2SO_4}$.
• Explain properties and applications of $\mathrm{H_2S}$.
Sulfur is a chemical element that is represented with the chemical symbol "S" and the atomic number 16 on the periodic table. Because it is 0.0384% of the Earth's crust, sulfur is the seventeenth most abundant element following strontium. Sulfur also takes on many forms, which include elemental sulfur, organo-sulfur compounds in oil and coal, H2S(g) in natural gas, and mineral sulfides and sulfates. This element is extracted by using the Frasch process (discussed below), a method where superheated water and compressed air are used to draw liquid sulfur to the surface. Offshore sites, Texas, and Louisiana are the primary sites that yield extensive amounts of elemental sulfur. However, elemental sulfur can also be produced by reducing H2S, commonly found in oil and natural gas. For the most part, though, sulfur is used to produce SO2(g) and H2SO4.
Known from ancient times (mentioned in the Hebrew scriptures as brimstone) sulfur was classified as an element in 1777 by Lavoisier. Pure sulfur is tasteless and odorless with a light yellow color. Samples of sulfur often encountered in the lab have a noticeable odor. Sulfur is the tenth most abundant element in the known universe.
Sulfur at a Glance
Atomic Number 16
Atomic Symbol S
Atomic Weight 32.07 grams per mole
Structure orthorhombic
Phase at room temperature solid
Classification nonmetal
Physical Properties of Sulfur
Sulfur has an atomic weight of 32.066 grams per mole and is part of group 16, the oxygen family. It is a nonmetal and has a specific heat of 0.706 J g-1 oC-1. The electron affinity is 200 kJ mol-1 and the electronegativity is 2.58 (unitless). Sulfur is typically found as a light-yellow, opaque, and brittle solid in large amounts of small orthorhombic crystals. Not only does sulfur have twice the density of water, but it is also insoluble in water. On the other hand, sulfur is highly soluble in carbon disulfide and slightly soluble in many common solvents. Sulfur can also vary in color and blackens upon boiling due to carbonaceous impurities. Even as little as 0.05% of carbonaceous matter darkens sulfur significantly.
Most sulfur is recovered directly as the element from underground deposits by injecting super-heated water and piping out molten sulfur (sulfur melts at 112o C). Compared to other elements, sulfur has the most allotropes. While the S8 ring is the most common allotrope, there are 6 other structures with up to 20 sulfur atoms per ring.
• Under appropriate conditions, sulfur vapor can contain $S$, $S_2$, $S_4$, $S_6$, and $S_8$.
• At room temperature, rhombic sulfur (Sα) is a stable solid comprising cyclic $S_8$ molecules.
• At 95.5 °C, rhombic sulfur becomes monoclinic sulfur (Sβ). The crystal structure found in monoclinic sulfur differs from that of rhombic sulfur. Monoclinic sulfur is also made up of $S_8$molecules.
• Monoclinic sulfur becomes liquid sulfur (Sλ) at 119 °C. Liquid sulfur is a straw-colored liquid made up of $S_8$ molecules and other cyclic molecules containing a range of six to twenty atoms.
• At 160 oC, this becomes a dark, viscous liquid called liquid sulfur (Sμ). The molecules are still made up of eight sulfur atoms, but the molecule opens up and transforms from a circle into a long spiral-chain molecule.
• At 180 °C, the chain length and viscosity reach their maximum. Chains break and viscosity decreases at temperatures that exceed 180 °C.
• Sulfur vapor is produced when liquid boils at 445 °C. In the vapor that is produced, $S_8$ molecules dominate, but as the vapor continues to heat up, the molecules break up into smaller groups of sulfur atoms.
• To produce plastic sulfur, S is poured into cold water. Plastic sulfur is rubberlike and is made up of long, spiral-chain molecules. If plastic sulfur sits for long, it will reconvert to rhombic sulfur.
While oxygen has fewer allotropes than sulfur, including $\ce{O}$, $\ce{O_2}$, $\ce{O_3}$, $\ce{O_4}$, $\ce{O_8}$, metallic $\ce{O}$ (and four other solid phases), many of these actually have a corresponding sulfur variant. However, sulfur has more tendency to catenate (the linkage of atoms of the same element into longer chains). Here are the values of the single and double bond enthalpies:
$\begin{array}{c|r} \ce {O-O} & \ce{142\ kJ/mol} \ \ce {S–S} & \ce{268\ kJ/mol} \ \ce {O=O} & \ce{499\ kJ/mol} \ \ce {S=S} & \ce{352\ kJ/mol} \ \end{array} \nonumber$
This means that $\ce{O=O}$ is stronger than $\ce{S=S}$, while $\ce{O–O}$ is weaker than $\ce{S–S}$. So, in sulfur, single bonds are favored and catenation is easier than in oxygen compounds. It seems that the reason for the weaker $\ce{S=S}$ double bonds has its roots in the size of the atom: it's harder for the two atoms to come to a small enough distance, so that the $p$ orbital overlap is small and the $\pi$ bond is weak. This is attested by looking down the periodic table: $\ce{Se=Se}$ has an even weaker bond enthalpy of $\ce{272 kJ/mol}$.
What happens when the solid sulfur melts? The $\ce{S8}$ molecules break up. When suddenly cooled, long chain molecules are formed in the plastic sulfur which behave like rubber. Plastic sulfur transforms into rhombic sulfur over time.
Compounds
Reading the following reactions, figure out and notice the change of the oxidation state of $\ce{S}$ in the reactants and products. Common oxidation states of sulfur are -2, 0, +4, and +6. Sulfur (brimstone, stone that burns) reacts with $\ce{O2}$ giving a blue flame (Figure $1$):
$\ce{S + O_2 \rightarrow SO_2} \nonumber$
$\ce{SO2}$ is produced whenever a metal sulfide is oxidized. It is recovered and oxidized further to give $\mathrm{SO_3}$, for production of $\mathrm{H_2SO_4}$. $\mathrm{SO_2}$ reacts with $\mathrm{H_2S}$ to form $\mathrm{H_2O}$ and $\ce{S}$.
$\mathrm{2 SO_2 + O_2 \rightleftharpoons 2 SO_3} \nonumber$
$\mathrm{SO_3 + H_2O \rightleftharpoons H_2SO_4} \;\;(\text{a valuable commodity}) \nonumber$
$\mathrm{SO_3 + H_2SO_4 \rightleftharpoons H_2S_2O_7} \;\;\; (\text{pyrosulfuric acid}) \nonumber$
Sulfur reacts with sulfite ions in solution to form thiosulfate,
$\ce{S + SO_3^{2-} -> S_2O_3^{2-}} \nonumber$
but the reaction is reversed in an acidic solution.
Oxides
There are many different stable sulfur oxides, but the two that are commonly found are sulfur dioxide and sulfur trioxide. Sulfur dioxide is a commonly found oxide of sulfur. It is a colorless, pungent, and nonflammable gas. It has a density of 2.8 kg/m3 and a melting point of -72.5 oC. Because organic materials are more soluble in $SO_2$ than in water, the liquid form is a good solvent. $SO_2$ is primarily used to produce $SO_3$. The direct combustion of sulfur and the roasting of metal sulfides yield $SO_2$ via the contact process:
$\underbrace{S(s) + O_2(g) \rightarrow SO_2(g)}_{\text{Direct combustion}} \nonumber$
$\underbrace{2 ZnS(s) + 3 O_2(g) \rightarrow 2 ZnO(s) + 2 SO_2(g)}_{\text{Roasting of metal sulfides}} \nonumber$
Sulfur trioxide is another one of the commonly found oxides of sulfur. It is a colorless liquid with a melting point of 16.9 oC and a density of kg/m3. $SO_3$ is used to produce sulfuric acid. $SO_2$ is used in the synthesis of $SO_3$:
$\underbrace{2 SO_2 (g) + O_2(g) \rightleftharpoons 2 SO_3(g)}_{\text{Exothermic, reversible reaction}} \nonumber$
This reaction needs a catalyst to be completed in a reasonable amount of time with $V_2O_5$ being the catalyst most commonly used.
Hydrogen Sulfide H2S
• Hydrogen sulfide, $\ce{H2S}$, is a diprotic acid. The equilibria below, $\mathrm{H_2S \rightleftharpoons HS^- + H^+} \nonumber$ $\mathrm{HS^- \rightleftharpoons S^{2-} + H^+} \nonumber$ have been discussed in connection with Polyprotic Acids.
Other Sulfur-containing Compounds
Perhaps the most significant compound of sulfur used in modern industrialized societies is sulfuric acid ($H_2SO_4$). Sulfur dioxide ($SO_2$) finds practical applications in bleaching and refrigeration but it is also a nuisance gas resulting from the burning of sulfurous coals. Sulfur dioxide gas then reacts with the water vapor in the air to produce a weak acid, sulfurous acid ($H_2SO_3$), which contributes to the acid rain problem.
• Sulfuric acid, H2SO4, is produced by reacting $SO_3$ with water. However, this often leads to pollution problems. SO3(g) is reacted with 98% H2SO4 in towers full of ceramic material to produce H2S2O7 or oleum. Water is circulated in the tower to maintain the correct concentration and the acid is diluted with water at the end in order to produce the correct concentration. Pure sulfuric acid has no color and odor, and it is an oily, hygroscopic liquid. However, sulfuric acid vapor produces heavy, white smoke and a suffocating odor.
• Dilute sulfuric acid, H2SO4(aq), reacts with metals and acts as a strong acid in common chemical reactions. It is used to produce H2(g) and liberate CO2(g) and can neutralize strong bases.
• Concentrated sulfuric acid, H2SO4 (conc.), has a strong affinity for water. In some cases, it removes H and O atoms. Concentrated sulfuric acid is also a good oxidizing agent and reacts with some metals.
$C_{12}H_{22}O_{11}(s) \rightarrow 12 C(s) + 11 H_2O(l) \nonumber$
(Concentrated sulfuric acid used in forward reaction to remove H and O atoms.)
Applications of Sulfuric Acid
• as a strong acid for making $\ce{HCl}$ and $\mathrm{HNO_3}$.
• as an oxidizing agent for metals.
• as a dehydrating agent.
• for manufacture of fertilizer and other commodities.
• Sulfurous acid (H2SO3) is produced when $SO_2$(g) reacts with water. It cannot be isolated in its pure form; however, it forms salts as sulfites. Sulfites can act as both reducing agents and oxidizing agents.
O2(g) + 2 SO32-(aq) $\rightarrow$ 2 SO42- (aq) (Reducing agent)
2 H2S(g) + 2 H+(aq) + SO32-(aq) $\rightarrow$ 3 H2O(l) + 3 S(s) (Oxidizing agent)
H2SO3 is a diprotic acid that acts as a weak acid in both steps, and H2SO4 is also a diprotic acid but acts as a strong acid in the first step and a weak acid in the second step. Acids like NaHSO3 and NaHSO4 are called acid salts because they are the product of the first step of these diprotic acids.
Boiling elemental sulfur in a solution of sodium sulfite yields thiosulfate. Not only are thiosulfates important in photographic processing, but they are also common analytical reagents used with iodine (like in the following two reactions).
$2 Cu^{2+}_{(aq)} + 5 I^-_{(aq)} \rightarrow 2 CuI_{(s)} + I^-_{3(aq)} \nonumber$
$I^-_{3(aq)} + 2 S_2O^{2-}_{3(aq)} \rightarrow 3 I^-_{(aq)} + S_4O^{2-}_{6(aq)} \nonumber$
with excess triiodide ion titrated with Na2S2O3(aq).
Other than sulfuric acid, perhaps the most familiar compound of sulfur in the chemistry lab is the foul-smelling hydrogen sulfide gas, $H_2S$, which smells like rotten eggs.
• Sulfur halides are compounds formed between sulfur and the halogens. Common compounds include SF2, S2F2, SF4, and SF6. While SF4 is a powerful fluorinating agent, SF6 is a colorless, odorless, unreactive gas. Compounds formed by sulfur and chloride include S2Cl2, SCl4, and SCl2. SCl2 is a red, bad-smelling liquid that is utilized to produce mustard gas ($S(CH_2CH_2Cl)_2$).
$SCl_2 + 2CH_2CH_2 \rightarrow S(CH_2CH_2Cl)_2 \nonumber$
Production -The Frasch Process
Sulfur can be mined by the Frasch process. This process has made sulfur a high purity (up to 99.9 percent pure) chemical commodity in large quantities. Most sulfur-containing minerals are metal sulfides, and the best known is perhaps pyrite ($\mathrm{FeS_2}$, known as fool's gold because of its golden color). The most common sulfate-containing mineral is gypsum, $\mathrm{CaSO_4 \cdot 2H_2O}$, also known as plaster of Paris.
The Frasch process is based on the fact that sulfur has a comparatively low melting point. The process forces (99.5% pure) sulfur out by using hot water and air. In this process, superheated water is forced down the outermost of three concentric pipes. Compressed air is pumped down the center tube, and a mixture of elemental sulfur, hot water, and air comes up the middle pipe. Sulfur is melted with superheated water (at 170 °C under high pressure) and forced to the surface of the earth as a slurry.
Sulfur is mostly used for the production of sulfuric acid, $\ce{H2SO4}$. Most sulfur mined by the Frasch process is used in industry for the manufacture of sulfuric acid. Sulfuric acid, the most abundantly produced chemical in the United States, is manufactured by the contact process. Most (about 70%) of the sulfuric acid produced in the world is used in the fertilizer industry. Sulfuric acid can act as a strong acid, a dehydrating agent, and an oxidizing agent. Its applications use these properties. Sulfur is an essential element of life in sulfur-containing proteins.
Applications
Sulfur has many practical applications. As a fungicide, sulfur is used to counteract apple scab in organically farmed apple production. Other crops that utilize sulfur fungicides include grapes, strawberries, and many vegetables. In general, sulfur is effective against mildew diseases and black spot. Sulfur can also be used as an organic insecticide. Sulfites are frequently used to bleach paper and preserve dried fruit.
The vulcanization of rubber includes the use of sulfur as well. Cellophane and rayon are produced with carbon disulfide, a product of sulfur and methane. Sulfur compounds can also be found in detergents, acne treatments, and agrichemicals. Magnesium sulfate (epsom salt) has many uses, ranging from bath additives to exfoliants. Sulfur is being increasingly used as a fertilizer as well. Because standard sulfur is hydrophobic, it is covered with a surfactant by bacteria before oxidation can occur. Sulfur is therefore a slow-release fertilizer. Lastly, sulfur functions as a light-generating medium in sulfur lamps.
Concentrated sulfuric acid was once one of the most produced chemicals in the United States; the majority of the H2SO4 that is now produced is used in fertilizer. It is also used in oil refining, production of titanium dioxide, and in emergency power supplies and car batteries. The mineral gypsum, or calcium sulfate dihydrate, is used in making plaster of Paris. Over one million tons of aluminum sulfate is produced each year in the United States by reacting H2SO4 and Al2O3. This compound is important in water purification. Copper sulfate is used in electroplating. Sulfites are used in the paper making industry because they produce a substance that coats the cellulose in the wood and frees the fibers of the wood for treatment.
Emissions and the Environment
Particles, SO2(g), and H2SO4 mist are the components of industrial smog. Because power plants burn coal or high-sulfur fuel oils, SO2(g) is released into the air. When catalyzed on the surfaces of airborne particles, SO2 can be oxidized to SO3. A reaction with NO2 works as well as shown in the following reaction:
$SO_{2(g)} + NO_{2(g)} \rightarrow SO_{3(g)} + NO_{(g)} \nonumber$
H2SO4 mist is then produced after SO3 reacts with water vapor in the air. If H2SO4 reacts with airborne NH3, (NH4)2SO4 is produced. When SO2(g) and H2SO4 reach levels that exceed 0.10 ppm, they are potentially harmful. By removing sulfur from fuels and controlling emissions, acid rain and industrial smog can be kept under control. Processes like fluidized bed combustion have been presented to remove SO2 from smokestack gases.
• Dhawale, S.W. "Thiosulfate: An interesting sulfur oxoanion that is useful in both medicine and industry--but is implicated in corrosion." J. Chem. Educ. 1993, 70, 12.
• Lebowitz, Samuel H. "A demonstration working model of the Frasch process for mining sulfur." J. Chem. Educ. 1931, 8, 1630.
• Nagel, Miriam C. "Herman Frasch, sulfur king (PROFILES)." J. Chem. Educ. 1981, 58, 60.
• Riethmiller, Steven. "Charles H. Winston and Confederate Sulfuric Acid." J. Chem. Educ. 1995 72 575.
• Sharma, B. D. "Allotropes and polymorphs." J. Chem. Educ. 1987, 64, 404.
• Silverstein, Todd P.; Zhang, Yi. "Sugar Dehydration without Sulfuric Acid: No More Choking Fumes in the Classroom!" J. Chem. Educ. 1998 75 748.
• Tykodi, R. J. "In praise of thiosulfate." J. Chem. Educ. 1990, 67, 146.
• Thomas Jefferson National Accelerator Facility - Office of Science Education."It's Elemental-The Element Sulfur." Jefferson Lab.
• Sulfur's Electron Shell
Problems
1. Draw a diagram that summarizes the allotropy of sulfur. Use symbols, arrows, and numbers.
2. Direct combustion of sulfur is the only method for producing SO2(g). True or False.
3. Sulfites are not oxidizing agents. They are good reducing agents. True or False.
4. Give the reaction for the production of sulfur trioxide.
5. Choose the incorrect statement.
1. Sulfur produces cellophane and rayon.
2. Standard sulfur is hydrophobic.
3. SO2 can oxidize to SO3
4. Sulfur influences the development of acid rain and industrial smog.
5. All of the above are correct.
6. Which reaction is responsible for the destruction of limestone and marble statues and buildings?
1. $\ce{CaCO3 \rightarrow CaO + CO2}$
2. $\ce{SO2 + H2O \rightarrow H2SO3}$
3. $\ce{BaO + CO2 \rightarrow BaCO3 \rightarrow BaSO3}$ upon reaction with $\ce{SO2}$
4. $\ce{CaCO3 + H2O \rightarrow Ca(OH)2 + CO2}$
5. $\ce{CaCO3 + SO2 \rightarrow CaSO3 + CO2 \rightarrow CaSO4}$ upon oxidation
7. Give the formula of thiosulfate ion.
8. What is the oxidation state of $\ce{S}$ in $\ce{SF6}$, $\ce{H2SO4}$, $\ce{NaHSO4}$, $\ce{SO4^2-}$, and $\ce{SO3}$?
9. What is the phase of sulfur at 298 K? Enter the type of crystals.
10. Give the name of the process by which sulfur is forced out of the ground using hot water and air.
Solutions
1. The diagram may be drawn in any way. However, the symbols (S2), (S4), (S6), (S?), and (S8(g)) must be included. The temperatures should be written next to the arrows.
2. False
3. False
4. $2 SO_{2(g)} + O_{2(g)} \rightarrow 2 SO_{3(g)}$
5. A
6. e.
Consider...
$\ce{SO2}$ in $\ce{H2SO3}$ is the acid in acid rain, which attacks $\ce{CaCO3}$, marble. $\ce{SO2}$ reduces pigments in organic matter.
7. $\ce{S2O3^2-}$
Consider...
Sulfate is $\ce{SO4^2-}$; replacement of an $\ce{O}$ by an $\ce{S}$ gives thiosulfate $\ce{S2O3^2-}$. The two $\ce{S}$ in $\ce{S2O3^2-}$ have different oxidation states: one is +6, the other is (-2), average +2.
8. 6
Consider...
Oxidation state for $\ce{S}$ in $\ce{H2SO3}$, $\ce{SO3^2-}$, $\ce{SO2}$, etc. is 4. The oxidation state of $\ce{S}$ is the same for all in the list.
9. rhombic sulfur
Consider...
The term rhombic describes a type of crystal. Monoclinic sulfur is meta stable at 298 K.
10. Frasch process
Consider...
The Frasch process is used to mine elemental sulfur.
20.08: Oxidative Cleavage of 12 Diols
The noble gases (Group 18) are located in the far right of the periodic table and were previously referred to as the "inert gases" due to the fact that their filled valence shells (octets) make them extremely nonreactive. The noble gases were characterized relatively late compared to other element groups.
Thumbnail: Vial of glowing ultrapure neon. (CC SA; Jurii via http://images-of-elements.com/neon.php). | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/20%3A_More_About_Oxidation-Reduction_Reactions/20.06%3A_Designing_a_Synthesis_VIII-_Controlling_Stereochemistry.txt |
In the IUPAC system of nomenclature, functional groups are normally designated in one of two ways. The presence of the function may be indicated by a characteristic suffix and a location number. This is common for the carbon-carbon double and triple bonds which have the respective suffixes ene and yne. Halogens, on the other hand, do not have a suffix and are named as substituents, for example: (CH3)2C=CHCHClCH3 is 4-chloro-2-methyl-2-pentene. If you are uncertain about the IUPAC rules for nomenclature you should review them now.
Amines are derivatives of ammonia in which one or more of the hydrogens has been replaced by an alkyl or aryl group. The nomenclature of amines is complicated by the fact that several different nomenclature systems exist, and there is no clear preference for one over the others. Furthermore, the terms primary (1º), secondary (2º) & tertiary (3º) are used to classify amines in a completely different manner than they were used for alcohols or alkyl halides. When applied to amines these terms refer to the number of alkyl (or aryl) substituents bonded to the nitrogen atom, whereas in other cases they refer to the nature of an alkyl group. The four compounds shown in the top row of the following diagram are all C4H11N isomers. The first two are classified as 1º-amines, since only one alkyl group is bonded to the nitrogen; however, the alkyl group is primary in the first example and tertiary in the second. The third and fourth compounds in the row are 2º and 3º-amines respectively. A nitrogen bonded to four alkyl groups will necessarily be positively charged, and is called a 4º-ammonium cation. For example, (CH3)4N(+) Br(–) is tetramethylammonium bromide.
• The IUPAC names are listed first and colored blue. This system names amine functions as substituents on the largest alkyl group. The simple -NH substituent found in 1º-amines is called an amino group. For 2º and 3º-amines a compound prefix (e.g. dimethylamino in the fourth example) includes the names of all but the root alkyl group.
• The Chemical Abstract Service has adopted a nomenclature system in which the suffix -amine is attached to the root alkyl name. For 1º-amines such as butanamine (first example) this is analogous to IUPAC alcohol nomenclature (-ol suffix). The additional nitrogen substituents in 2º and 3º-amines are designated by the prefix N- before the group name. These CA names are colored magenta in the diagram.
• Finally, a common system for simple amines names each alkyl substituent on nitrogen in alphabetical order, followed by the suffix -amine. These are the names given in the last row (colored black).
Many aromatic and heterocyclic amines are known by unique common names, the origins of which are often unknown to the chemists that use them frequently. Since these names are not based on a rational system, it is necessary to memorize them. There is a systematic nomenclature of heterocyclic compounds, but it will not be discussed here.
21.02: More About the Acid-Base Properties of Amines
Boiling Point and Water Solubility
It is instructive to compare the boiling points and water solubility of amines with those of corresponding alcohols and ethers. The dominant factor here is hydrogen bonding, and the first table below documents the powerful intermolecular attraction that results from -O-H---O- hydrogen bonding in alcohols (light blue columns). Corresponding -N-H---N- hydrogen bonding is weaker, as the lower boiling points of similarly sized amines (light green columns) demonstrate. Alkanes provide reference compounds in which hydrogen bonding is not possible, and the increase in boiling point for equivalent 1º-amines is roughly half the increase observed for equivalent alcohols.
Compound CH3CH3 CH3OH CH3NH2 CH3CH2CH3 CH3CH2OH CH3CH2NH2
Mol.Wt. 30 32 31 44 46 45
Boiling
Point ºC
-88.6º 65º -6.0º -42º 78.5º 16.6º
The second table illustrates differences associated with isomeric 1º, 2º & 3º-amines, as well as the influence of chain branching. Since 1º-amines have two hydrogens available for hydrogen bonding, we expect them to have higher boiling points than isomeric 2º-amines, which in turn should boil higher than isomeric 3º-amines (no hydrogen bonding). Indeed, 3º-amines have boiling points similar to equivalent sized ethers; and in all but the smallest compounds, corresponding ethers, 3º-amines and alkanes have similar boiling points. In the examples shown here, it is further demonstrated that chain branching reduces boiling points by 10 to 15 ºC.
Compound CH3(CH2)2CH3 CH3(CH2)2OH CH3(CH2)2NH2 CH3CH2NHCH3 (CH3)3CH (CH3)2CHOH (CH3)2CHNH2 (CH3)3N
Mol.Wt. 58 60 59 59 58 60 59 59
Boiling
Point ºC
-0.5º 97º 48º 37º -12º 82º 34º
The water solubility of 1º and 2º-amines is similar to that of comparable alcohols. As expected, the water solubility of 3º-amines and ethers is also similar. These comparisons, however, are valid only for pure compounds in neutral water. The basicity of amines (next section) allows them to be dissolved in dilute mineral acid solutions, and this property facilitates their separation from neutral compounds such as alcohols and hydrocarbons by partitioning between the phases of non-miscible solvents.
Basicity of Amines
A review of basic acid-base concepts should be helpful to the following discussion. Like ammonia, most amines are Brønsted and Lewis bases, but their base strength can be changed enormously by substituents. It is common to compare basicity's quantitatively by using the pKa's of their conjugate acids rather than their pKb's. Since pKa + pKb = 14, the higher the pKa the stronger the base, in contrast to the usual inverse relationship of pKa with acidity. Most simple alkyl amines have pKa's in the range 9.5 to 11.0, and their water solutions are basic (have a pH of 11 to 12, depending on concentration). The first four compounds in the following table, including ammonia, fall into that category.
The last five compounds (colored cells) are significantly weaker bases as a consequence of three factors. The first of these is the hybridization of the nitrogen. In pyridine the nitrogen is sp2 hybridized, and in nitriles (last entry) an sp hybrid nitrogen is part of the triple bond. In each of these compounds (shaded red) the non-bonding electron pair is localized on the nitrogen atom, but increasing s-character brings it closer to the nitrogen nucleus, reducing its tendency to bond to a proton.
Compound
NH3 CH3C≡N
pKa 11.0 10.7 10.7 9.3 5.2 4.6 1.0 0.0 -1.0 -10.0
Secondly, aniline and p-nitroaniline (first two green shaded structures) are weaker bases due to delocalization of the nitrogen non-bonding electron pair into the aromatic ring (and the nitro substituent). This is the same delocalization that results in activation of a benzene ring toward electrophilic substitution. The following resonance equations, which are similar to those used to explain the enhanced acidity of ortho and para-nitrophenols illustrate electron pair delocalization in p-nitroaniline. Indeed, aniline is a weaker base than cyclohexyl amine by roughly a million fold, the same factor by which phenol is a stronger acid than cyclohexanol. This electron pair delocalization is accompanied by a degree of rehybridization of the amino nitrogen atom, but the electron pair delocalization is probably the major factor in the reduced basicity of these compounds. A similar electron pair delocalization is responsible for the very low basicity (and nucleophilic reactivity) of amide nitrogen atoms (last green shaded structure). This feature was instrumental in moderating the influence of amine substituents on aromatic ring substitution, and will be discussed further in the section devoted to carboxylic acid derivatives.
Conjugated amine groups influence the basicity of an existing amine. Although 4-dimethylaminopyridine (DMAP) might appear to be a base similar in strength to pyridine or N,N-dimethylaniline, it is actually more than ten thousand times stronger, thanks to charge delocalization in its conjugate acid. The structure in the gray box shows the locations over which positive charge (colored red) is delocalized in the conjugate acid. This compound is often used as a catalyst for acyl transfer reactions.
Finally, the very low basicity of pyrrole (shaded blue) reflects the exceptional delocalization of the nitrogen electron pair associated with its incorporation in an aromatic ring. Indole (pKa = -2) and imidazole (pKa = 7.0), see above, also have similar heterocyclic aromatic rings. Imidazole is over a million times more basic than pyrrole because the sp2 nitrogen that is part of one double bond is structurally similar to pyridine, and has a comparable basicity.
Although resonance delocalization generally reduces the basicity of amines, a dramatic example of the reverse effect is found in the compound guanidine (pKa = 13.6). Here, as shown below, resonance stabilization of the base is small, due to charge separation, while the conjugate acid is stabilized strongly by charge delocalization. Consequently, aqueous solutions of guanidine are nearly as basic as are solutions of sodium hydroxide.
The relationship of amine basicity to the acidity of the corresponding conjugate acids may be summarized in a fashion analogous to that noted earlier for acids:
Strong bases have weak conjugate acids, and weak bases have strong conjugate acids.
Acidity of Amines
We normally think of amines as bases, but it must be remembered that 1º and 2º-amines are also very weak acids (ammonia has a pKa = 34). In this respect it should be noted that pKa is being used as a measure of the acidity of the amine itself rather than its conjugate acid, as in the previous section. For ammonia this is expressed by the following hypothetical equation:
NH3 + H2O ____> NH2(–) + H2O-H(+)
The same factors that decreased the basicity of amines increase their acidity. This is illustrated by the following examples, which are shown in order of increasing acidity. It should be noted that the first four examples have the same order and degree of increased acidity as they exhibited decreased basicity in the previous table. The first compound is a typical 2º-amine, and the three next to it are characterized by varying degrees of nitrogen electron pair delocalization. The last two compounds (shaded blue) show the influence of adjacent sulfonyl and carbonyl groups on N-H acidity. From previous discussion it should be clear that the basicity of these nitrogens is correspondingly reduced.
Compound C6H5SO2NH2
pKa 33 27 19 15 10 9.6
The acids shown here may be converted to their conjugate bases by reaction with bases derived from weaker acids (stronger bases). Three examples of such reactions are shown below, with the acidic hydrogen colored red in each case. For complete conversion to the conjugate base, as shown, a reagent base roughly a million times stronger is required.
C6H5SO2NH2 + KOH C6H5SO2NH(–) K(+) + H2O a sulfonamide base
(CH3)3COH + NaH (CH3)3CO(–) Na(+) + H2 an alkoxide base
(C2H5)2NH + C4H9Li (C2H5)2N(–) Li(+) + C4H10 an amide base
Important Reagent Bases
The significance of all these acid-base relationships to practical organic chemistry lies in the need for organic bases of varying strength, as reagents tailored to the requirements of specific reactions. The common base sodium hydroxide is not soluble in many organic solvents, and is therefore not widely used as a reagent in organic reactions. Most base reagents are alkoxide salts, amines or amide salts. Since alcohols are much stronger acids than amines, their conjugate bases are weaker than amide bases, and fill the gap in base strength between amines and amide salts. In the following table, pKa again refers to the conjugate acid of the base drawn above it.
Base Name Pyridine Triethyl
Amine
Hünig's Base Barton's
Base
Potassium
t-Butoxide
Sodium HMDS LDA
Formula (C2H5)3N (CH3)3CO(–) K(+) [(CH3)3Si]2N(–) Na(+) [(CH3)2CH]2N(–) Li(+)
pKa 5.3 10.7 11.4 14 19 26 35.7
Pyridine is commonly used as an acid scavenger in reactions that produce mineral acid co-products. Its basicity and nucleophilicity may be modified by steric hindrance, as in the case of 2,6-dimethylpyridine (pKa=6.7), or resonance stabilization, as in the case of 4-dimethylaminopyridine (pKa=9.7). Hünig's base is relatively non-nucleophilic (due to steric hindrance), and like DBU is often used as the base in E2 elimination reactions conducted in non-polar solvents. Barton's base is a strong, poorly-nucleophilic, neutral base that serves in cases where electrophilic substitution of DBU or other amine bases is a problem. The alkoxides are stronger bases that are often used in the corresponding alcohol as solvent, or for greater reactivity in DMSO. Finally, the two amide bases see widespread use in generating enolate bases from carbonyl compounds and other weak carbon acids.
Nonionic Superbases
An interesting group of neutral, highly basic compounds of nitrogen and phosphorus have been prepared, and are referred to as superbases. To see examples of these compounds Click Here. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/21%3A_More_About_Amines_(Heterocylic_Compounds)/21.01%3A_More_about_Amine_Nomenclature.txt |
Electrophilic Substitution at Nitrogen
Ammonia and many amines are not only bases in the Brønsted sense, they are also nucleophiles that bond to and form products with a variety of electrophiles. A general equation for such electrophilic substitution of nitrogen is:
2 R2ÑH + E(+) R2NHE(+) R2ÑE + H(+) (bonded to a base)
A list of some electrophiles that are known to react with amines is shown here. In each case the electrophilic atom or site is colored red.
Electrophile RCH2–X RCH2–OSO2R R2C=O R(C=O)X RSO2–Cl HO–N=O
Name Alkyl Halide Alkyl Sulfonate Aldehyde or Ketone Acid Halide or Anhydride Sulfonyl Chloride Nitrous Acid
Alkylation
It is instructive to examine these nitrogen substitution reactions, using the common alkyl halide class of electrophiles. Thus, reaction of a primary alkyl bromide with a large excess of ammonia yields the corresponding 1º-amine, presumably by an SN2 mechanism. The hydrogen bromide produced in the reaction combines with some of the excess ammonia, giving ammonium bromide as a by-product. Water does not normally react with 1º-alkyl halides to give alcohols, so the enhanced nucleophilicity of nitrogen relative to oxygen is clearly demonstrated.
$2 RCH_2Br + \underbrace{NH_3}_{\text{large excess}} \rightarrow RCH_2NH_2 + NH_4^{(+)} Br^{(–)}$
It follows that simple amines should also be more nucleophilic than their alcohol or ether equivalents. If, for example, we wish to carry out an SN2 reaction of an alcohol with an alkyl halide to produce an ether (the Williamson synthesis), it is necessary to convert the weakly nucleophilic alcohol to its more nucleophilic conjugate base for the reaction to occur. In contrast, amines react with alkyl halides directly to give N-alkylated products. Since this reaction produces HBr as a co-product, hydrobromide salts of the alkylated amine or unreacted starting amine (in equilibrium) will also be formed.
2 RNH2 + C2H5Br RNHC2H5 + RNH3(+) Br(–) RNH2C2H5(+) Br(–) + RNH2
Unfortunately, the direct alkylation of 1º or 2º-amines to give a more substituted product does not proceed cleanly. If a 1:1 ratio of amine to alkyl halide is used, only 50% of the amine will react because the remaining amine will be tied up as an ammonium halide salt (remember that one equivalent of the strong acid HX is produced). If a 2:1 ratio of amine to alkylating agent is used, as in the above equation, the HX issue is solved, but another problem arises. Both the starting amine and the product amine are nucleophiles. Consequently, once the reaction has started, the product amine competes with the starting material in the later stages of alkylation, and some higher alkylated products are also formed. Even 3º-amines may be alkylated to form quaternary (4º) ammonium salts. When tetraalkyl ammonium salts are desired, as shown in the following example, Hünig's base may be used to scavenge the HI produced in the three SN2 reactions. Steric hindrance prevents this 3º-amine (Hünig's base) from being methylated.
C6H5NH2 + 3 CH3I + Hünig's base C6H5N(CH3)3(+) I(–) + HI salt of Hünig's base
The Hinsberg Test: Reaction with benzenesulfonyl chloride
Another electrophilic reagent, benzenesulfonyl chloride, reacts with amines in a fashion that provides a useful test for distinguishing primary, secondary and tertiary amines (the Hinsberg test). As shown in the following equations, 1º and 2º-amines react to give sulfonamide derivatives with loss of HCl, whereas 3º-amines do not give any isolable products other than the starting amine. In the latter case a quaternary "onium" salt may be formed as an intermediate, but this rapidly breaks down in water to liberate the original 3º-amine (lower right equation).
The Hinsberg test is conducted in aqueous base (NaOH or KOH), and the benzenesulfonyl chloride reagent is present as an insoluble oil. Because of the heterogeneous nature of this system, the rate at which the sulfonyl chloride reagent is hydrolyzed to its sulfonate salt in the absence of amines is relatively slow. The amine dissolves in the reagent phase, and immediately reacts (if it is 1º or 2º), with the resulting HCl being neutralized by the base. The sulfonamide derivative from 2º-amines is usually an insoluble solid. However, the sulfonamide derivative from 1º-amines is acidic and dissolves in the aqueous base. Acidification of this solution then precipitates the sulfonamide of the 1º-amine. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/21%3A_More_About_Amines_(Heterocylic_Compounds)/21.03%3A_Amines_React_as_Bases_and_as_Nucleophiles.txt |
Preparation of Primary Amines
Although direct alkylation of ammonia by alkyl halides leads to 1º-amines, alternative procedures are preferred in many cases. These methods require two steps, but they provide pure product, usually in good yield. The general strategy is to first form a carbon-nitrogen bond by reacting a nitrogen nucleophile with a carbon electrophile. The following table lists several general examples of this strategy in the rough order of decreasing nucleophilicity of the nitrogen reagent. In the second step, extraneous nitrogen substituents that may have facilitated this bonding are removed to give the amine product.
Nitrogen
Reactant
Carbon
Reactant
1st Reaction
Type
Initial Product
2nd Reaction
Conditions
2nd Reaction
Type
Final Product
N3(–) RCH2-X or
R2CH-X
SN2 RCH2-N3 or
R2CH-N3
LiAlH4 or
4 H2 & Pd
Hydrogenolysis RCH2-NH2 or
R2CH-NH2
C6H5SO2NH(–) RCH2-X or
R2CH-X
SN2 RCH2-NHSO2C6H5 or
R2CH-NHSO2C6H5
Na in NH3 (liq) Hydrogenolysis RCH2-NH2 or
R2CH-NH2
CN(–) RCH2-X or
R2CH-X
SN2 RCH2-CN or
R2CH-CN
LiAlH4 Reduction RCH2-CH2NH2 or
R2CH-CH2NH2
NH3 RCH=O or
R2C=O
Addition /
Elimination
RCH=NH or
R2C=NH
H2 & Ni
or NaBH3CN
Reduction RCH2-NH2 or
R2CH-NH2
NH3 RCOX Addition /
Elimination
RCO-NH2 LiAlH4 Reduction RCH2-NH2
NH2CONH2
(urea)
R3C(+) SN1 R3C-NHCONH2 NaOH soln. Hydrolysis R3C-NH2
A specific example of each general class is provided in the diagram below. In the first two, an anionic nitrogen species undergoes an SN2 reaction with a modestly electrophilic alkyl halide reactant. For example #2 an acidic phthalimide derivative of ammonia has been substituted for the sulfonamide analog listed in the table. The principle is the same for the two cases, as will be noted later. Example #3 is similar in nature, but extends the carbon system by a methylene group (CH2). In all three of these methods 3º-alkyl halides cannot be used because the major reaction path is an E2 elimination.
The methods illustrated by examples #4 and #5 proceed by attack of ammonia, or equivalent nitrogen nucleophiles, at the electrophilic carbon of a carbonyl group. A full discussion of carbonyl chemistry is presented later, but for present purposes it is sufficient to recognize that the C=O double bond is polarized so that the carbon atom is electrophilic. Nucleophile addition to aldehydes and ketones is often catalyzed by acids. Acid halides and anhydrides are even more electrophilic, and do not normally require catalysts to react with nucleophiles. The reaction of ammonia with aldehydes or ketones occurs by a reversible addition-elimination pathway to give imines (compounds having a C=N function). These intermediates are not usually isolated, but are reduced as they are formed (i.e. in situ). Acid chlorides react with ammonia to give amides, also by an addition-elimination path, and these are reduced to amines by LiAlH4.
The 6th example is a specialized procedure for bonding an amino group to a 3º-alkyl group (none of the previous methods accomplishes this). Since a carbocation is the electrophilic species, rather poorly nucleophilic nitrogen reactants can be used. Urea, the diamide of carbonic acid, fits this requirement nicely. The resulting 3º-alkyl-substituted urea is then hydrolyzed to give the amine.
One important method of preparing 1º-amines, especially aryl amines, uses a reverse strategy. Here a strongly electrophilic nitrogen species (NO2(+)) bonds to a nucleophilic carbon compound. This nitration reaction gives a nitro group that can be reduced to a 1º-amine by any of several reduction procedures.
The Hofmann rearrangement of 1º-amides provides an additional synthesis of 1º-amines. To learn about this useful procedure Click Here.
Preparation of Secondary and Tertiary Amines
Of the six methods described above, three are suitable for the preparation of 2º and/or 3º-amines. These are
1. Alkylation of the sulfonamide derivative of a 1º-amine. Gives 2º-amines.
2. Reduction of alkyl imines and dialkyl iminium salts. Gives 2º & 3º-amines.
3. Reduction of amide derivatives of 1º & 2º-amines. Gives 2º & 3º-amines.
Examples showing the application of these methods to the preparation of specific amines are shown in the following diagram. The sulfonamide procedure used in the first example is similar in concept to the phthalimide example #2 presented in the previous diagram. In both cases the acidity of the nitrogen reactant (ammonia or amine) is greatly enhanced by conversion to an imide or sulfonamide derivative. The nucleophilic conjugate base of this acidic nitrogen species is then prepared by treatment with sodium or potassium hydroxide, and this undergoes an SN2 reaction with a 1º or 2º-alkyl halide. Finally, the activating group is removed by hydrolysis (phthalimide) or reductive cleavage (sulfonamide) to give the desired amine. The phthalimide method is only useful for preparing 1º-amines, whereas the sulfonamide procedure may be used to make either 1º or 2º-amines.
Examples #2 & #3 make use of the carbonyl reductive amination reaction (method #4 in the preceding table. This versatile procedure may be used to prepare all classes of amines (1º, 2º & 3º), as shown here and above. A weak acid catalyst is necessary for imine formation, which takes place by amine addition to the carbonyl group, giving a 1-aminoalcohol intermediate, followed by loss of water. The final reduction of the C=N double bond may be carried out catalytically (Pt & Pd catalysts may be used instead of Ni) or chemically (by NaBH3CN). The imine or enamine intermediates are normally not isolated, but are immediately reduced to the amine product.
Another general method for preparing all classes of amines makes use of amide intermediates, easily made from ammonia or amines by reaction with carboxylic acid chlorides or anhydrides. These stable compounds may be isolated, identified and stored prior to the final reduction. Examples #4 & #5 illustrate applications of this method. As with the previous method, 1º-amines give 2º-amine products, and 2º-amines give 3º-amine products. The last example (#6) shows how 4º-ammonium salts may be prepared by repeated (exhaustive) alkylation of amines. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/21%3A_More_About_Amines_(Heterocylic_Compounds)/21.04%3A_Synthesis_of_Amines.txt |
In the IUPAC system of nomenclature, functional groups are normally designated in one of two ways. The presence of the function may be indicated by a characteristic suffix and a location number. This is common for the carbon-carbon double and triple bonds which have the respective suffixes ene and yne. Halogens, on the other hand, do not have a suffix and are named as substituents, for example: (CH3)2C=CHCHClCH3 is 4-chloro-2-methyl-2-pentene. If you are uncertain about the IUPAC rules for nomenclature you should review them now.
Amines are derivatives of ammonia in which one or more of the hydrogens has been replaced by an alkyl or aryl group. The nomenclature of amines is complicated by the fact that several different nomenclature systems exist, and there is no clear preference for one over the others. Furthermore, the terms primary (1º), secondary (2º) & tertiary (3º) are used to classify amines in a completely different manner than they were used for alcohols or alkyl halides. When applied to amines these terms refer to the number of alkyl (or aryl) substituents bonded to the nitrogen atom, whereas in other cases they refer to the nature of an alkyl group. The four compounds shown in the top row of the following diagram are all C4H11N isomers. The first two are classified as 1º-amines, since only one alkyl group is bonded to the nitrogen; however, the alkyl group is primary in the first example and tertiary in the second. The third and fourth compounds in the row are 2º and 3º-amines respectively. A nitrogen bonded to four alkyl groups will necessarily be positively charged, and is called a 4º-ammonium cation. For example, (CH3)4N(+) Br(–) is tetramethylammonium bromide.
• The IUPAC names are listed first and colored blue. This system names amine functions as substituents on the largest alkyl group. The simple -NH substituent found in 1º-amines is called an amino group. For 2º and 3º-amines a compound prefix (e.g. dimethylamino in the fourth example) includes the names of all but the root alkyl group.
• The Chemical Abstract Service has adopted a nomenclature system in which the suffix -amine is attached to the root alkyl name. For 1º-amines such as butanamine (first example) this is analogous to IUPAC alcohol nomenclature (-ol suffix). The additional nitrogen substituents in 2º and 3º-amines are designated by the prefix N- before the group name. These CA names are colored magenta in the diagram.
• Finally, a common system for simple amines names each alkyl substituent on nitrogen in alphabetical order, followed by the suffix -amine. These are the names given in the last row (colored black).
Many aromatic and heterocyclic amines are known by unique common names, the origins of which are often unknown to the chemists that use them frequently. Since these names are not based on a rational system, it is necessary to memorize them. There is a systematic nomenclature of heterocyclic compounds, but it will not be discussed here.
21.06: Aromatic Six-Membered-Ring Heterocycles
In the IUPAC system of nomenclature, functional groups are normally designated in one of two ways. The presence of the function may be indicated by a characteristic suffix and a location number. This is common for the carbon-carbon double and triple bonds which have the respective suffixes ene and yne. Halogens, on the other hand, do not have a suffix and are named as substituents, for example: (CH3)2C=CHCHClCH3 is 4-chloro-2-methyl-2-pentene. If you are uncertain about the IUPAC rules for nomenclature you should review them now.
Amines are derivatives of ammonia in which one or more of the hydrogens has been replaced by an alkyl or aryl group. The nomenclature of amines is complicated by the fact that several different nomenclature systems exist, and there is no clear preference for one over the others. Furthermore, the terms primary (1º), secondary (2º) & tertiary (3º) are used to classify amines in a completely different manner than they were used for alcohols or alkyl halides. When applied to amines these terms refer to the number of alkyl (or aryl) substituents bonded to the nitrogen atom, whereas in other cases they refer to the nature of an alkyl group. The four compounds shown in the top row of the following diagram are all C4H11N isomers. The first two are classified as 1º-amines, since only one alkyl group is bonded to the nitrogen; however, the alkyl group is primary in the first example and tertiary in the second. The third and fourth compounds in the row are 2º and 3º-amines respectively. A nitrogen bonded to four alkyl groups will necessarily be positively charged, and is called a 4º-ammonium cation. For example, (CH3)4N(+) Br(–) is tetramethylammonium bromide.
• The IUPAC names are listed first and colored blue. This system names amine functions as substituents on the largest alkyl group. The simple -NH substituent found in 1º-amines is called an amino group. For 2º and 3º-amines a compound prefix (e.g. dimethylamino in the fourth example) includes the names of all but the root alkyl group.
• The Chemical Abstract Service has adopted a nomenclature system in which the suffix -amine is attached to the root alkyl name. For 1º-amines such as butanamine (first example) this is analogous to IUPAC alcohol nomenclature (-ol suffix). The additional nitrogen substituents in 2º and 3º-amines are designated by the prefix N- before the group name. These CA names are colored magenta in the diagram.
• Finally, a common system for simple amines names each alkyl substituent on nitrogen in alphabetical order, followed by the suffix -amine. These are the names given in the last row (colored black).
Many aromatic and heterocyclic amines are known by unique common names, the origins of which are often unknown to the chemists that use them frequently. Since these names are not based on a rational system, it is necessary to memorize them. There is a systematic nomenclature of heterocyclic compounds, but it will not be discussed here. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/21%3A_More_About_Amines_(Heterocylic_Compounds)/21.05%3A_Aromatic_Five-Membered-Ring_Heterocycles.txt |
Nature abounds with nitrogen compounds, many of which occur in plants and are referred to as alkaloids. Structural formulas for some representative alkaloids and other nitrogen containing natural products are displayed below, and we can recognize many of the basic structural features listed above in their formulas. Thus, Serotonin and Thiamine are 1º-amines, Coniine is a 2º-amine, Atropine, Morphine and Quinine are 3º-amines, and Muscarine is a 4º-ammonium salt.
The reader should be able to recognize indole, imidazole, piperidine, pyridine, pyrimidine & pyrrolidine moieties among these structures. These will be identified by pressing the "Show Structures" button under the diagram.
Nitrogen atoms that are part of aromatic rings , such as pyridine, pyrrole & imidazole, have planar configurations (sp2 hybridization), and are not stereogenic centers. Nitrogen atoms bonded to carbonyl groups, as in caffeine, also tend to be planar. In contrast, atropine, coniine, morphine, nicotine and quinine have stereogenic pyramidal nitrogen atoms in their structural formulas (think of the non-bonding electron pair as a fourth substituent on a sp3 hybridized nitrogen). In quinine this nitrogen is restricted to one configuration by the bridged ring system. The other stereogenic nitrogens are free to assume two pyramidal configurations, but these are in rapid equilibrium so that distinct stereoisomers reflecting these sites cannot be easily isolated.
It should be noted that structural factors may serve to permit the resolution of pyramidal chiral amines. Two examples of such 3º-amines, compared with similar non-resolvable analogs, are shown in the following diagram. The two nitrogen atoms in Trögers base are the only stereogenic centers in the molecule. Because of the molecule's bridged structure, the nitrogens have the same configuration and cannot undergo inversion. The chloro aziridine can invert, but requires a higher activation energy to do so, compared with larger heterocyclic amines. It has in fact been resolved, and pure enantiomers isolated. An increase in angle strain in the sp2-hybridized planar transition state is responsible for the greater stability of the pyramidal configuration. The rough estimate of angle strain is made using a C-N-C angle of 60º as an arbitrary value for the three-membered heterocycle.
Of course, quaternary ammonium salts, such as that in muscarine, have a tetrahedral configuration that is incapable of inversion. With four different substituents, such a nitrogen would be a stable stereogenic center.
A Structure Formula Relationship
Recall that the molecular formula of a hydrocarbon (CnHm) provides information about the number of rings and/or double bonds that must be present in its structural formula. In the formula shown below a triple bond is counted as two double bonds.
Rings + Double Bonds in a CnHm Hydrocarbon= (2n + 2 - m)/2
Compound
Molecular
Formula
Revised
Formula
Calculated
Rings + C=Z
Coniine C8H17N C9H18 1
Nicotine C10H14N2 C12H16 5
Morphine C17H19NO3 C18H20 9
This molecular formula analysis may be extended beyond hydrocarbons by a few simple corrections. These are illustrated by the examples in the table above, taken from the previous list of naturally occurring amines.
• The presence of oxygen does not alter the relationship.
• All halogens present in the molecular formula must be replaced by hydrogen.
• Each nitrogen in the formula must be replaced by a CH moiety. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/21%3A_More_About_Amines_(Heterocylic_Compounds)/21.07%3A_Amine_Heterocycles_Have_Important_Roles_in_Nature.txt |
If a monosaccharide has a carbonyl function on one of the inner atoms of the carbon chain it is classified as a ketose. Dihydroxyacetone may not be a sugar, but it is included as the ketose analog of glyceraldehyde. The carbonyl group is commonly found at C-2, as illustrated by the following examples (chiral centers are colored red). As expected, the carbonyl function of a ketose may be reduced by sodium borohydride, usually to a mixture of epimeric products. D-Fructose, the sweetest of the common natural sugars, is for example reduced to a mixture of D-glucitol (sorbitol) and D-mannitol, named after the aldohexoses from which they may also be obtained by analogous reduction. Mannitol is itself a common natural carbohydrate.
Although the ketoses are distinct isomers of the aldose monosaccharides, the chemistry of both classes is linked due to their facile interconversion in the presence of acid or base catalysts. This interconversion, and the corresponding epimerization at sites alpha to the carbonyl functions, occurs by way of an enediol tautomeric intermediate.
Because of base-catalyzed isomerizations of this kind, the Tollens' reagent is not useful for distinguishing aldoses from ketoses or for specific oxidation of aldoses to the corresponding aldonic acids. Oxidation by HOBr is preferred for the latter conversion.
22.05: The Reactions of Monosaccharides in Basic Solutions
Enols, enolates, and enamines are reactive intermediates in many isomerization reactions. Isomerizations can involve either the interconversion of constitutional isomers, in which bond connectivity is altered, or of stereoisomers, where the stereochemical configuration is changed. Enzymes which interconvert constitutional isomers are called isomerases, while those which catalyze the interconversion of enantiomers and epimers are called racemases and epimerases, respectively.
13.2A: Carbonyl isomerization
Two important chemical steps in the glycolytic pathway, catalyzed by the enzymes phosphoglucose isomerase and triose phosphate isomerase, involve successive keto-enol tautomerization steps. In both reactions, the location of a carbonyl group on a sugar molecule is shifted back and forth by a single carbon, as ketones are converted to aldehydes and back again - this is a conversion between two constitutional isomers.
Let's look first at the triosephosphate isomerase reaction, in the ketone to aldehyde direction. The ketone species, dihydroxyacetone phosphate (DHAP) is first converted to its enol tautomer with the assistance of an enzymatic acid/base pair (actually, this particular intermediate is known as an 'ene-diol' rather than an enol, because there are hydroxyl groups on both sides of the carbon-carbon double bond). The initial proton donor is positioned in the active site near the carbonyl carbon, and significantly lowers the pKa of the alpha-proton.
The second step, leading to glyceraldehyde phosphate (GAP), is simply another tautomerization, this time in the reverse direction. However, because there happens to be a hydroxyl group on C1, the carbonyl can form here as well as at C2. Notice that DHAP is achiral while GAP is chiral, and that a new chiral center is introduced at C2. The catalytic base abstracts the pro-R proton from behind the plane of the page, then gives the same proton back to C2, again from behind the plane of the page.
In the phosphoglucose isomerase reaction, glucose-6-phosphate (an aldehyde sugar) and fructose-6-phosphate (a ketone sugar) are interconverted in a very similar fashion.
The enzyme ribose-5-phosphate isomerase (EC 5.3.1.6), which is active in both the Calvin cycle and the pentose phosphate pathway, catalyzes an analogous aldehyde-to-ketone isomerization between two five-carbon sugars.
Template:exampleStart
Exercise 13.3: draw the ene-diol intermediate in the phosphoglucose isomerase reaction above.
Solution
Template:exampleEnd
13.2B: Stereoisomerization at chiral carbons
The enolate form of a carbonyl is a common intermediate in a type of stereoisomerization reaction known as an epimerization. Recall from section 3.7A that the term 'epimer' refers to a pair of diastereomers that differ at a single stereocenter. The five-carbon sugar phosphates ribulose-5-phosphate and xylulose-5-phosphate, for example, are epimers: they are identical except for their stereochemistry at C3. A reaction in the Calvin cycle, which plants use to incorporate, or 'fix', the carbon atom from carbon dioxide into sugars, involves the interconversion of these two sugar phosphate epimers - in other words, inversion of configuration at C3.
The reaction is simply a deprotonation at C3 to form an enolate, followed by reprotonation to return to the ketone.
The key to epimerization is that deprotonation and reprotonation occur at opposite sides of the planar, sp2-hybridized intermediate. In the epimerase reaction shown here, a coordinated pair of aspartate residues is located at opposite sides of the enzyme's active site. Asp1, which is ionized at the start of the catalytic cycle, abstracts the C3 proton from the front side of the plane of the page, converting C3 from a chiral tetrahedral center to an achiral, planar group. When reprotonation occurs, it is Asp2, on the back side of the plane of the page, which donates the proton, resulting in inversion of stereochemistry at C3 (J. Molec. Biol. 2003, 326, 127-135).
Notice another thing about this epimerization reaction: the key intermediate is an enolate anion, stabilized by coordination to a zinc cation (a Lewis acid). Contrast this with the phosphoglucase isomerase reaction (section 13.2A), where stabilization of the key intermediate was achieved by proton donation to form a short-lived enol species.
There are many more examples of reactions in which the stereochemistry of an a-carbon in a carbonyl compound is inverted. The short polypeptides that form part of the peptidoglycan cell wall structure in bacteria contain some D-amino acids, which have the opposite stereochemistry at the a-carbon compared to the L-amino acids that are found almost exclusively in proteins. Enzymes called amino acid racemases catalyze the conversion between the L and D forms of these amino acids. While many amino acid racemases depend on the coenzyme pyridoxal phosphate to stabilize the key carbanion intermediate (we'll study these reactions in section 14.4B), others proceed through an enolate intermediate. Glutamate racemase, which converts L-glutamate to D-glutamate, is an example (Biochemistry 2001, 40, 6199). Although many mechanistic details are as yet unknown, it has been demonstrated that, at least for some of the cofactor-independent racemases, a pair of cysteine residues serves as the catalytic acid/base pair.
Template:exampleStart
Exercise 13.4: Propose a likely mechanism for glutamate racemase, showing stereochemistry throughout.
Solution
Template:exampleEnd
13.2C: Alkene isomerization in the degradation of unsaturated fatty acids
The oxidation pathway for unsaturated fatty acids (in other words, fatty acids whose hydrocarbon chains contain one or more double bonds) involves the 'shuffling' of the position of carbon-carbon double bonds in the chain. This is accomplished by enoyl CoA isomerase, through an enolate intermediate. Here, the cis double bond between C3 and C4 is isomerized to a trans double bond between C2 and C3.
The catalytic acid and base groups are glutamate and/or aspartate residues (J. Biol Chem 2001, 276, 13622).
In section 15.3A, we will see a different example of an alkene isomerization reaction mechanism in which the key intermediate is a carbocation, rather than an enolate.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/22%3A_The_Organic_Chemistry_of_Carbohydrates/22.04%3A_The_Configurations_of_Ketoses.txt |
Overview
Emil Fischer made use of several key reactions in the course of his carbohydrate studies. These are described here, together with the information that each delivers.
Oxidation
As noted above, sugars may be classified as reducing or non-reducing based on their reactivity with Tollens', Benedict's or Fehling's reagents. If a sugar is oxidized by these reagents it is called reducing, since the oxidant (Ag(+) or Cu(+2)) is reduced in the reaction, as evidenced by formation of a silver mirror or precipitation of cuprous oxide. The Tollens' test is commonly used to detect aldehyde functions; and because of the facile interconversion of ketoses and aldoses under the basic conditions of this test, ketoses such as fructose also react and are classified as reducing sugars.
When the aldehyde function of an aldose is oxidized to a carboxylic acid the product is called an aldonic acid. Because of the 2º hydroxyl functions that are also present in these compounds, a mild oxidizing agent such as hypobromite must be used for this conversion (equation 1). If both ends of an aldose chain are oxidized to carboxylic acids the product is called an aldaric acid. By converting an aldose to its corresponding aldaric acid derivative, the ends of the chain become identical (this could also be accomplished by reducing the aldehyde to CH2OH, as noted below). Such an operation will disclose any latent symmetry in the remaining molecule. Thus, ribose, xylose, allose and galactose yield achiral aldaric acids which are, of course, not optically active. The ribose oxidation is shown in equation 2 below.
1.
2.
3.
Other aldose sugars may give identical chiral aldaric acid products, implying a unique configurational relationship. The examples of arabinose and lyxose shown in equation 3 above illustrate this result. Remember, a Fischer projection formula may be rotated by 180º in the plane of projection without changing its configuration.
Reduction
Sodium borohydride reduction of an aldose makes the ends of the resulting alditol chain identical, HOCH2(CHOH)nCH2OH, thereby accomplishing the same configurational change produced by oxidation to an aldaric acid. Thus, allitol and galactitol from reduction of allose and galactose are achiral, and altrose and talose are reduced to the same chiral alditol. A summary of these redox reactions, and derivative nomenclature is given in the following table.
Derivatives of HOCH2(CHOH)nCHO
HOBr Oxidation
——>
HOCH2(CHOH)nCO2H
an Aldonic Acid
HNO3 Oxidation
——>
H2OC(CHOH)nCO2H
an Aldaric Acid
NaBH4 Reduction
——>
HOCH2(CHOH)nCH2OH
an Alditol
Osazone Formation
1.
2.
The osazone reaction was developed and used by Emil Fischer to identify aldose sugars differing in configuration only at the alpha-carbon. The upper equation shows the general form of the osazone reaction, which effects an alpha-carbon oxidation with formation of a bis-phenylhydrazone, known as an osazone. Application of the osazone reaction to D-glucose and D-mannose demonstrates that these compounds differ in configuration only at C-2.
Chain Shortening and Lengthening
1.
2.
These two procedures permit an aldose of a given size to be related to homologous smaller and larger aldoses. The importance of these relationships may be seen in the array of aldose structures presented earlier, where the structural connections are given by the dashed blue lines. Thus Ruff degradation of the pentose arabinose gives the tetrose erythrose. Working in the opposite direction, a Kiliani-Fischer synthesis applied to arabinose gives a mixture of glucose and mannose. An alternative chain shortening procedure known as the Wohl degradation is essentially the reverse of the Kiliani-Fischer synthesis.
Fischer's train of logic in assigning the configuration of D-glucose
1. Ribose and arabinose (two well known pentoses) both gave erythrose on Ruff degradation. As expected, Kiliani-Fischer synthesis applied to erythrose gave a mixture of ribose and arabinose.
2. Oxidation of erythrose gave an achiral (optically inactive) aldaric acid. This defines the configuration of erythrose.
3. Oxidation of ribose gave an achiral (optically inactive) aldaric acid. This defines the configuration of both ribose and arabinose.
4. Ruff shortening of glucose gave arabinose, and Kiliani-Fischer synthesis applied to arabinose gave a mixture of glucose and mannose.
5. Glucose and mannose are therefore epimers at C-2, a fact confirmed by the common product from their osazone reactions.
6. A pair of structures for these epimers can be written, but which is glucose and which is mannose?
To determine which of these epimers was glucose, Fischer made use of the inherent C2 symmetry in the four-carbon dissymmetric core of one epimer (B). This is shown in the following diagram by a red dot where the symmetry axis passes through the projection formula. Because of this symmetry, if the aldehyde and 1º-alcohol functions at the ends of the chain are exchanged, epimer B would be unchanged; whereas A would be converted to a different compound.
Fischer looked for and discovered a second aldohexose that represented the end group exchange for the epimer lacking the latent C2 symmetry (A). This compound was L-(+)-gulose, and its exchange relationship to D-(+)-glucose was demonstrated by oxidation to a common aldaric acid product. The remaining epimer is therefore mannose.
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/22%3A_The_Organic_Chemistry_of_Carbohydrates/22.06%3A_The_Oxidation-Reduction_Reactions_of_Monosaccharides.txt |
Overview
Emil Fischer made use of several key reactions in the course of his carbohydrate studies. These are described here, together with the information that each delivers.
Oxidation
As noted above, sugars may be classified as reducing or non-reducing based on their reactivity with Tollens', Benedict's or Fehling's reagents. If a sugar is oxidized by these reagents it is called reducing, since the oxidant (Ag(+) or Cu(+2)) is reduced in the reaction, as evidenced by formation of a silver mirror or precipitation of cuprous oxide. The Tollens' test is commonly used to detect aldehyde functions; and because of the facile interconversion of ketoses and aldoses under the basic conditions of this test, ketoses such as fructose also react and are classified as reducing sugars.
When the aldehyde function of an aldose is oxidized to a carboxylic acid the product is called an aldonic acid. Because of the 2º hydroxyl functions that are also present in these compounds, a mild oxidizing agent such as hypobromite must be used for this conversion (equation 1). If both ends of an aldose chain are oxidized to carboxylic acids the product is called an aldaric acid. By converting an aldose to its corresponding aldaric acid derivative, the ends of the chain become identical (this could also be accomplished by reducing the aldehyde to CH2OH, as noted below). Such an operation will disclose any latent symmetry in the remaining molecule. Thus, ribose, xylose, allose and galactose yield achiral aldaric acids which are, of course, not optically active. The ribose oxidation is shown in equation 2 below.
1.
2.
3.
Other aldose sugars may give identical chiral aldaric acid products, implying a unique configurational relationship. The examples of arabinose and lyxose shown in equation 3 above illustrate this result. Remember, a Fischer projection formula may be rotated by 180º in the plane of projection without changing its configuration.
Reduction
Sodium borohydride reduction of an aldose makes the ends of the resulting alditol chain identical, HOCH2(CHOH)nCH2OH, thereby accomplishing the same configurational change produced by oxidation to an aldaric acid. Thus, allitol and galactitol from reduction of allose and galactose are achiral, and altrose and talose are reduced to the same chiral alditol. A summary of these redox reactions, and derivative nomenclature is given in the following table.
Derivatives of HOCH2(CHOH)nCHO
HOBr Oxidation
——>
HOCH2(CHOH)nCO2H
an Aldonic Acid
HNO3 Oxidation
——>
H2OC(CHOH)nCO2H
an Aldaric Acid
NaBH4 Reduction
——>
HOCH2(CHOH)nCH2OH
an Alditol
Osazone Formation
1.
2.
The osazone reaction was developed and used by Emil Fischer to identify aldose sugars differing in configuration only at the alpha-carbon. The upper equation shows the general form of the osazone reaction, which effects an alpha-carbon oxidation with formation of a bis-phenylhydrazone, known as an osazone. Application of the osazone reaction to D-glucose and D-mannose demonstrates that these compounds differ in configuration only at C-2.
Chain Shortening and Lengthening
1.
2.
These two procedures permit an aldose of a given size to be related to homologous smaller and larger aldoses. The importance of these relationships may be seen in the array of aldose structures presented earlier, where the structural connections are given by the dashed blue lines. Thus Ruff degradation of the pentose arabinose gives the tetrose erythrose. Working in the opposite direction, a Kiliani-Fischer synthesis applied to arabinose gives a mixture of glucose and mannose. An alternative chain shortening procedure known as the Wohl degradation is essentially the reverse of the Kiliani-Fischer synthesis.
Fischer's train of logic in assigning the configuration of D-glucose
1. Ribose and arabinose (two well known pentoses) both gave erythrose on Ruff degradation. As expected, Kiliani-Fischer synthesis applied to erythrose gave a mixture of ribose and arabinose.
2. Oxidation of erythrose gave an achiral (optically inactive) aldaric acid. This defines the configuration of erythrose.
3. Oxidation of ribose gave an achiral (optically inactive) aldaric acid. This defines the configuration of both ribose and arabinose.
4. Ruff shortening of glucose gave arabinose, and Kiliani-Fischer synthesis applied to arabinose gave a mixture of glucose and mannose.
5. Glucose and mannose are therefore epimers at C-2, a fact confirmed by the common product from their osazone reactions.
6. A pair of structures for these epimers can be written, but which is glucose and which is mannose?
To determine which of these epimers was glucose, Fischer made use of the inherent C2 symmetry in the four-carbon dissymmetric core of one epimer (B). This is shown in the following diagram by a red dot where the symmetry axis passes through the projection formula. Because of this symmetry, if the aldehyde and 1º-alcohol functions at the ends of the chain are exchanged, epimer B would be unchanged; whereas A would be converted to a different compound.
Fischer looked for and discovered a second aldohexose that represented the end group exchange for the epimer lacking the latent C2 symmetry (A). This compound was L-(+)-gulose, and its exchange relationship to D-(+)-glucose was demonstrated by oxidation to a common aldaric acid product. The remaining epimer is therefore mannose.
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/22%3A_The_Organic_Chemistry_of_Carbohydrates/22.07%3A_Monosaccharides_Form_Crystalline_Osazones.txt |
Overview
Emil Fischer made use of several key reactions in the course of his carbohydrate studies. These are described here, together with the information that each delivers.
Oxidation
As noted above, sugars may be classified as reducing or non-reducing based on their reactivity with Tollens', Benedict's or Fehling's reagents. If a sugar is oxidized by these reagents it is called reducing, since the oxidant (Ag(+) or Cu(+2)) is reduced in the reaction, as evidenced by formation of a silver mirror or precipitation of cuprous oxide. The Tollens' test is commonly used to detect aldehyde functions; and because of the facile interconversion of ketoses and aldoses under the basic conditions of this test, ketoses such as fructose also react and are classified as reducing sugars.
When the aldehyde function of an aldose is oxidized to a carboxylic acid the product is called an aldonic acid. Because of the 2º hydroxyl functions that are also present in these compounds, a mild oxidizing agent such as hypobromite must be used for this conversion (equation 1). If both ends of an aldose chain are oxidized to carboxylic acids the product is called an aldaric acid. By converting an aldose to its corresponding aldaric acid derivative, the ends of the chain become identical (this could also be accomplished by reducing the aldehyde to CH2OH, as noted below). Such an operation will disclose any latent symmetry in the remaining molecule. Thus, ribose, xylose, allose and galactose yield achiral aldaric acids which are, of course, not optically active. The ribose oxidation is shown in equation 2 below.
1.
2.
3.
Other aldose sugars may give identical chiral aldaric acid products, implying a unique configurational relationship. The examples of arabinose and lyxose shown in equation 3 above illustrate this result. Remember, a Fischer projection formula may be rotated by 180º in the plane of projection without changing its configuration.
Reduction
Sodium borohydride reduction of an aldose makes the ends of the resulting alditol chain identical, HOCH2(CHOH)nCH2OH, thereby accomplishing the same configurational change produced by oxidation to an aldaric acid. Thus, allitol and galactitol from reduction of allose and galactose are achiral, and altrose and talose are reduced to the same chiral alditol. A summary of these redox reactions, and derivative nomenclature is given in the following table.
Derivatives of HOCH2(CHOH)nCHO
HOBr Oxidation
——>
HOCH2(CHOH)nCO2H
an Aldonic Acid
HNO3 Oxidation
——>
H2OC(CHOH)nCO2H
an Aldaric Acid
NaBH4 Reduction
——>
HOCH2(CHOH)nCH2OH
an Alditol
Osazone Formation
1.
2.
The osazone reaction was developed and used by Emil Fischer to identify aldose sugars differing in configuration only at the alpha-carbon. The upper equation shows the general form of the osazone reaction, which effects an alpha-carbon oxidation with formation of a bis-phenylhydrazone, known as an osazone. Application of the osazone reaction to D-glucose and D-mannose demonstrates that these compounds differ in configuration only at C-2.
Chain Shortening and Lengthening
1.
2.
These two procedures permit an aldose of a given size to be related to homologous smaller and larger aldoses. The importance of these relationships may be seen in the array of aldose structures presented earlier, where the structural connections are given by the dashed blue lines. Thus Ruff degradation of the pentose arabinose gives the tetrose erythrose. Working in the opposite direction, a Kiliani-Fischer synthesis applied to arabinose gives a mixture of glucose and mannose. An alternative chain shortening procedure known as the Wohl degradation is essentially the reverse of the Kiliani-Fischer synthesis.
Fischer's train of logic in assigning the configuration of D-glucose
1. Ribose and arabinose (two well known pentoses) both gave erythrose on Ruff degradation. As expected, Kiliani-Fischer synthesis applied to erythrose gave a mixture of ribose and arabinose.
2. Oxidation of erythrose gave an achiral (optically inactive) aldaric acid. This defines the configuration of erythrose.
3. Oxidation of ribose gave an achiral (optically inactive) aldaric acid. This defines the configuration of both ribose and arabinose.
4. Ruff shortening of glucose gave arabinose, and Kiliani-Fischer synthesis applied to arabinose gave a mixture of glucose and mannose.
5. Glucose and mannose are therefore epimers at C-2, a fact confirmed by the common product from their osazone reactions.
6. A pair of structures for these epimers can be written, but which is glucose and which is mannose?
To determine which of these epimers was glucose, Fischer made use of the inherent C2 symmetry in the four-carbon dissymmetric core of one epimer (B). This is shown in the following diagram by a red dot where the symmetry axis passes through the projection formula. Because of this symmetry, if the aldehyde and 1º-alcohol functions at the ends of the chain are exchanged, epimer B would be unchanged; whereas A would be converted to a different compound.
Fischer looked for and discovered a second aldohexose that represented the end group exchange for the epimer lacking the latent C2 symmetry (A). This compound was L-(+)-gulose, and its exchange relationship to D-(+)-glucose was demonstrated by oxidation to a common aldaric acid product. The remaining epimer is therefore mannose.
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/22%3A_The_Organic_Chemistry_of_Carbohydrates/22.08%3A_Lengthening_the_Chain-_The_Kiliani-Fischer_Synthesis.txt |
Overview
Emil Fischer made use of several key reactions in the course of his carbohydrate studies. These are described here, together with the information that each delivers.
Oxidation
As noted above, sugars may be classified as reducing or non-reducing based on their reactivity with Tollens', Benedict's or Fehling's reagents. If a sugar is oxidized by these reagents it is called reducing, since the oxidant (Ag(+) or Cu(+2)) is reduced in the reaction, as evidenced by formation of a silver mirror or precipitation of cuprous oxide. The Tollens' test is commonly used to detect aldehyde functions; and because of the facile interconversion of ketoses and aldoses under the basic conditions of this test, ketoses such as fructose also react and are classified as reducing sugars.
When the aldehyde function of an aldose is oxidized to a carboxylic acid the product is called an aldonic acid. Because of the 2º hydroxyl functions that are also present in these compounds, a mild oxidizing agent such as hypobromite must be used for this conversion (equation 1). If both ends of an aldose chain are oxidized to carboxylic acids the product is called an aldaric acid. By converting an aldose to its corresponding aldaric acid derivative, the ends of the chain become identical (this could also be accomplished by reducing the aldehyde to CH2OH, as noted below). Such an operation will disclose any latent symmetry in the remaining molecule. Thus, ribose, xylose, allose and galactose yield achiral aldaric acids which are, of course, not optically active. The ribose oxidation is shown in equation 2 below.
1.
2.
3.
Other aldose sugars may give identical chiral aldaric acid products, implying a unique configurational relationship. The examples of arabinose and lyxose shown in equation 3 above illustrate this result. Remember, a Fischer projection formula may be rotated by 180º in the plane of projection without changing its configuration.
Reduction
Sodium borohydride reduction of an aldose makes the ends of the resulting alditol chain identical, HOCH2(CHOH)nCH2OH, thereby accomplishing the same configurational change produced by oxidation to an aldaric acid. Thus, allitol and galactitol from reduction of allose and galactose are achiral, and altrose and talose are reduced to the same chiral alditol. A summary of these redox reactions, and derivative nomenclature is given in the following table.
Derivatives of HOCH2(CHOH)nCHO
HOBr Oxidation
——>
HOCH2(CHOH)nCO2H
an Aldonic Acid
HNO3 Oxidation
——>
H2OC(CHOH)nCO2H
an Aldaric Acid
NaBH4 Reduction
——>
HOCH2(CHOH)nCH2OH
an Alditol
Osazone Formation
1.
2.
The osazone reaction was developed and used by Emil Fischer to identify aldose sugars differing in configuration only at the alpha-carbon. The upper equation shows the general form of the osazone reaction, which effects an alpha-carbon oxidation with formation of a bis-phenylhydrazone, known as an osazone. Application of the osazone reaction to D-glucose and D-mannose demonstrates that these compounds differ in configuration only at C-2.
Chain Shortening and Lengthening
1.
2.
These two procedures permit an aldose of a given size to be related to homologous smaller and larger aldoses. The importance of these relationships may be seen in the array of aldose structures presented earlier, where the structural connections are given by the dashed blue lines. Thus Ruff degradation of the pentose arabinose gives the tetrose erythrose. Working in the opposite direction, a Kiliani-Fischer synthesis applied to arabinose gives a mixture of glucose and mannose. An alternative chain shortening procedure known as the Wohl degradation is essentially the reverse of the Kiliani-Fischer synthesis.
Fischer's train of logic in assigning the configuration of D-glucose
1. Ribose and arabinose (two well known pentoses) both gave erythrose on Ruff degradation. As expected, Kiliani-Fischer synthesis applied to erythrose gave a mixture of ribose and arabinose.
2. Oxidation of erythrose gave an achiral (optically inactive) aldaric acid. This defines the configuration of erythrose.
3. Oxidation of ribose gave an achiral (optically inactive) aldaric acid. This defines the configuration of both ribose and arabinose.
4. Ruff shortening of glucose gave arabinose, and Kiliani-Fischer synthesis applied to arabinose gave a mixture of glucose and mannose.
5. Glucose and mannose are therefore epimers at C-2, a fact confirmed by the common product from their osazone reactions.
6. A pair of structures for these epimers can be written, but which is glucose and which is mannose?
To determine which of these epimers was glucose, Fischer made use of the inherent C2 symmetry in the four-carbon dissymmetric core of one epimer (B). This is shown in the following diagram by a red dot where the symmetry axis passes through the projection formula. Because of this symmetry, if the aldehyde and 1º-alcohol functions at the ends of the chain are exchanged, epimer B would be unchanged; whereas A would be converted to a different compound.
Fischer looked for and discovered a second aldohexose that represented the end group exchange for the epimer lacking the latent C2 symmetry (A). This compound was L-(+)-gulose, and its exchange relationship to D-(+)-glucose was demonstrated by oxidation to a common aldaric acid product. The remaining epimer is therefore mannose.
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/22%3A_The_Organic_Chemistry_of_Carbohydrates/22.09%3A_Shortening_the_Chain-_The_Wohl_Degradation.txt |
The four chiral centers in glucose indicate there may be as many as sixteen (24) stereoisomers having this constitution. These would exist as eight diastereomeric pairs of enantiomers, and the initial challenge was to determine which of the eight corresponded to glucose. This challenge was accepted and met in 1891 by the German chemist Emil Fischer. His successful negotiation of the stereochemical maze presented by the aldohexoses was a logical tour de force, and it is fitting that he received the 1902 Nobel Prize for chemistry for this accomplishment. One of the first tasks faced by Fischer was to devise a method of representing the configuration of each chiral center in an unambiguous manner. To this end, he invented a simple technique for drawing chains of chiral centers, that we now call the Fischer projection formula.
At the time Fischer undertook the glucose project it was not possible to establish the absolute configuration of an enantiomer. Consequently, Fischer made an arbitrary choice for (+)-glucose and established a network of related aldose configurations that he called the D-family. The mirror images of these configurations were then designated the L-family of aldoses. To illustrate using present day knowledge, Fischer projection formulas and names for the D-aldose family (three to six-carbon atoms) are shown below, with the asymmetric carbon atoms (chiral centers) colored red.
The last chiral center in an aldose chain (farthest from the aldehyde group) was chosen by Fischer as the D / L designator site. If the hydroxyl group in the projection formula pointed to the right, it was defined as a member of the D-family. A left directed hydroxyl group (the mirror image) then represented the L-family. Fischer's initial assignment of the D-configuration had a 50:50 chance of being right, but all his subsequent conclusions concerning the relative configurations of various aldoses were soundly based. In 1951 x-ray fluorescence studies of (+)-tartaric acid, carried out in the Netherlands by Johannes Martin Bijvoet (pronounced "buy foot"), proved that Fischer's choice was correct.
It is important to recognize that the sign of a compound's specific rotation (an experimental number) does not correlate with its configuration (D or L). It is a simple matter to measure an optical rotation with a polarimeter. Determining an absolute configuration usually requires chemical interconversion with known compounds by stereospecific reaction paths.
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
22.11: Monosaccharides Form Cyclic Hemiacetals
As noted above, the preferred structural form of many monosaccharides may be that of a cyclic hemiacetal. Five and six-membered rings are favored over other ring sizes because of their low angle and eclipsing strain. Cyclic structures of this kind are termed furanose (five-membered) or pyranose (six-membered), reflecting the ring size relationship to the common heterocyclic compounds furan and pyran shown on the right.
Ribose, an important aldopentose, commonly adopts a furanose structure, as shown in the following illustration. By convention for the D-family, the five-membered furanose ring is drawn in an edgewise projection with the ring oxygen positioned away from the viewer. The anomeric carbon atom (colored red here) is placed on the right. The upper bond to this carbon is defined as beta, the lower bond then is alpha.
The cyclic pyranose forms of various monosaccharides are often drawn in a flat projection known as a Haworth formula, after the British chemist, Norman Haworth. As with the furanose ring, the anomeric carbon is placed on the right with the ring oxygen to the back of the edgewise view. In the D-family, the alpha and beta bonds have the same orientation defined for the furanose ring (beta is up & alpha is down). These Haworth formulas are convenient for displaying stereochemical relationships, but do not represent the true shape of the molecules. We know that these molecules are actually puckered in a fashion we call a chair conformation. Examples of four typical pyranose structures are shown below, both as Section 3.8: Fischer and Haworth projections and as the more representative chair conformers. The anomeric carbons are colored red.
The size of the cyclic hemiacetal ring adopted by a given sugar is not constant, but may vary with substituents and other structural features. Aldolhexoses usually form pyranose rings and their pentose homologs tend to prefer the furanose form, but there are many counter examples. The formation of acetal derivatives illustrates how subtle changes may alter this selectivity. A pyranose structure for D-glucose is drawn in the rose-shaded box on the left. Acetal derivatives have been prepared by acid-catalyzed reactions with benzaldehyde and acetone. As a rule, benzaldehyde forms six-membered cyclic acetals, whereas acetone prefers to form five-membered acetals. The top equation shows the formation and some reactions of the 4,6-O-benzylidene acetal, a commonly employed protective group. A methyl glycoside derivative of this compound (see below) leaves the C-2 and C-3 hydroxyl groups exposed to reactions such as the periodic acid cleavage, shown as the last step. The formation of an isopropylidene acetal at C-1 and C-2, center structure, leaves the C-3 hydroxyl as the only unprotected function. Selective oxidation to a ketone is then possible. Finally, direct di-O-isopropylidene derivatization of glucose by reaction with excess acetone results in a change to a furanose structure in which the C-3 hydroxyl is again unprotected. However, the same reaction with D-galactose, shown in the blue-shaded box, produces a pyranose product in which the C-6 hydroxyl is unprotected. Both derivatives do not react with Tollens' reagent. This difference in behavior is attributed to the cis-orientation of the C-3 and C-4 hydroxyl groups in galactose, which permits formation of a less strained five-membered cyclic acetal, compared with the trans-C-3 and C-4 hydroxyl groups in glucose. Derivatizations of this kind permit selective reactions to be conducted at different locations in these highly functionalized molecules. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/22%3A_The_Organic_Chemistry_of_Carbohydrates/22.10%3A_The_Stereochemistry_of_Glucose-_The_Fischer_Proof.txt |
Acetal derivatives formed when a monosaccharide reacts with an alcohol in the presence of an acid catalyst are called glycosides. This reaction is illustrated for glucose and methanol in the diagram below. In naming of glycosides, the "ose" suffix of the sugar name is replaced by "oside", and the alcohol group name is placed first. As is generally true for most acetals, glycoside formation involves the loss of an equivalent of water. The diether product is stable to base and alkaline oxidants such as Tollen's reagent. Since acid-catalyzed aldolization is reversible, glycosides may be hydrolyzed back to their alcohol and sugar components by aqueous acid.
The anomeric methyl glucosides are formed in an equilibrium ratio of 66% alpha to 34% beta. From the structures in the previous diagram, we see that pyranose rings prefer chair conformations in which the largest number of substituents are equatorial. In the case of glucose, the substituents on the beta-anomer are all equatorial, whereas the C-1 substituent in the alpha-anomer changes to axial. Since substituents on cyclohexane rings prefer an equatorial location over axial (methoxycyclohexane is 75% equatorial), the preference for alpha-glycopyranoside formation is unexpected, and is referred to as the anomeric effect.
Glycosides abound in biological systems. By attaching a sugar moiety to a lipid or benzenoid structure, the solubility and other properties of the compound may be changed substantially. Because of the important modifying influence of such derivatization, numerous enzyme systems, known as glycosidases, have evolved for the attachment and removal of sugars from alcohols, phenols and amines. Chemists refer to the sugar component of natural glycosides as the glycon and the alcohol component as the aglycon.
Two examples of naturally occurring glycosides and one example of an amino derivative are displayed above. Salicin, one of the oldest herbal remedies known, was the model for the synthetic analgesic aspirin. A large class of hydroxylated, aromatic oxonium cations called anthocyanins provide the red, purple and blue colors of many flowers, fruits and some vegetables. Peonin is one example of this class of natural pigments, which exhibit a pronounced pH color dependence. The oxonium moiety is only stable in acidic environments, and the color changes or disappears when base is added. The complex changes that occur when wine is fermented and stored are in part associated with glycosides of anthocyanins. Finally, amino derivatives of ribose, such as cytidine play important roles in biological phosphorylating agents, coenzymes and information transport and storage materials.
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
22.16: Disaccharides
When the alcohol component of a glycoside is provided by a hydroxyl function on another monosaccharide, the compound is called a disaccharide. Four examples of disaccharides composed of two glucose units are shown in the following diagram. The individual glucopyranose rings are labeled A and B, and the glycoside bonding is circled in light blue. Notice that the glycoside bond may be alpha, as in maltose and trehalose, or beta as in cellobiose and gentiobiose. Acid-catalyzed hydrolysis of these disaccharides yields glucose as the only product. Enzyme-catalyzed hydrolysis is selective for a specific glycoside bond, so an alpha-glycosidase cleaves maltose and trehalose to glucose, but does not cleave cellobiose or gentiobiose. A beta-glycosidase has the opposite activity.
In order to draw a representative structure for cellobiose, one of the glucopyranose rings must be rotated by 180º, but this feature is often omitted in favor of retaining the usual perspective for the individual rings. The bonding between the glucopyranose rings in cellobiose and maltose is from the anomeric carbon in ring A to the C-4 hydroxyl group on ring B. This leaves the anomeric carbon in ring B free, so cellobiose and maltose both may assume alpha and beta anomers at that site (the beta form is shown in the diagram). Gentiobiose has a beta-glycoside link, originating at C-1 in ring A and terminating at C-6 in ring B. Its alpha-anomer is drawn in the diagram. Because cellobiose, maltose and gentiobiose are hemiacetals they are all reducing sugars (oxidized by Tollen's reagent). Trehalose, a disaccharide found in certain mushrooms, is a bis-acetal, and is therefore a non-reducing sugar. A systematic nomenclature for disaccharides exists, but as the following examples illustrate, these are often lengthy.
• Cellobiose : 4-O-β-D-Glucopyranosyl-D-glucose (the beta-anomer is drawn)
• Maltose : 4-O-α-D-Glucopyranosyl-D-glucose (the beta-anomer is drawn)
• Gentiobiose : 6-O-β-D-Glucopyranosyl-D-glucose (the alpha-anomer is drawn)
• Trehalose : α-D-Glucopyranosyl-α-D-glucopyranoside
Although all the disaccharides shown here are made up of two glucopyranose rings, their properties differ in interesting ways. Maltose, sometimes called malt sugar, comes from the hydrolysis of starch. It is about one third as sweet as cane sugar (sucrose), is easily digested by humans, and is fermented by yeast. Cellobiose is obtained by the hydrolysis of cellulose. It has virtually no taste, is indigestible by humans, and is not fermented by yeast. Some bacteria have beta-glucosidase enzymes that hydrolyze the glycosidic bonds in cellobiose and cellulose. The presence of such bacteria in the digestive tracts of cows and termites permits these animals to use cellulose as a food. Finally, it may be noted that trehalose has a distinctly sweet taste, but gentiobiose is bitter.
Disaccharides made up of other sugars are known, but glucose is often one of the components. Two important examples of such mixed disaccharides are displayed above. Lactose, also known as milk sugar, is a galactose-glucose compound joined as a beta-glycoside. It is a reducing sugar because of the hemiacetal function remaining in the glucose moiety. Many adults, particularly those from regions where milk is not a dietary staple, have a metabolic intolerance for lactose. Infants have a digestive enzyme which cleaves the beta-glycoside bond in lactose, but production of this enzyme stops with weaning. Cheese is less subject to the lactose intolerance problem, since most of the lactose is removed with the whey. Sucrose, or cane sugar, is our most commonly used sweetening agent. It is a non-reducing disaccharide composed of glucose and fructose joined at the anomeric carbon of each by glycoside bonds (one alpha and one beta). In the formula shown here the fructose ring has been rotated 180º from its conventional perspective.
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/22%3A_The_Organic_Chemistry_of_Carbohydrates/22.13%3A_Formation_of_Glycosides.txt |
As the name implies, polysaccharides are large high-molecular weight molecules constructed by joining monosaccharide units together by glycosidic bonds. They are sometimes called glycans. The most important compounds in this class, cellulose, starch and glycogen are all polymers of glucose. This is easily demonstrated by acid-catalyzed hydrolysis to the monosaccharide. Since partial hydrolysis of cellulose gives varying amounts of cellobiose, we conclude the glucose units in this macromolecule are joined by beta-glycoside bonds between C-1 and C-4 sites of adjacent sugars. Partial hydrolysis of starch and glycogen produces the disaccharide maltose together with low molecular weight dextrans, polysaccharides in which glucose molecules are joined by alpha-glycoside links between C-1 and C-6, as well as the alpha C-1 to C-4 links found in maltose. Polysaccharides built from other monosaccharides (e.g. mannose, galactose, xylose and arabinose) are also known, but will not be discussed here.
Over half of the total organic carbon in the earth's biosphere is in cellulose. Cotton fibers are essentially pure cellulose, and the wood of bushes and trees is about 50% cellulose. As a polymer of glucose, cellulose has the formula (C6H10O5)n where n ranges from 500 to 5,000, depending on the source of the polymer. The glucose units in cellulose are linked in a linear fashion, as shown in the drawing below. The beta-glycoside bonds permit these chains to stretch out, and this conformation is stabilized by intramolecular hydrogen bonds. A parallel orientation of adjacent chains is also favored by intermolecular hydrogen bonds. Although an individual hydrogen bond is relatively weak, many such bonds acting together can impart great stability to certain conformations of large molecules. Most animals cannot digest cellulose as a food, and in the diets of humans this part of our vegetable intake functions as roughage and is eliminated largely unchanged. Some animals (the cow and termites, for example) harbor intestinal microorganisms that breakdown cellulose into monosaccharide nutrients by the use of beta-glycosidase enzymes.
Cellulose is commonly accompanied by a lower molecular weight, branched, amorphous polymer called hemicellulose. In contrast to cellulose, hemicellulose is structurally weak and is easily hydrolyzed by dilute acid or base. Also, many enzymes catalyze its hydrolysis. Hemicelluloses are composed of many D-pentose sugars, with xylose being the major component. Mannose and mannuronic acid are often present, as well as galactose and galacturonic acid.
Starch is a polymer of glucose, found in roots, rhizomes, seeds, stems, tubers and corms of plants, as microscopic granules having characteristic shapes and sizes. Most animals, including humans, depend on these plant starches for nourishment. The structure of starch is more complex than that of cellulose. The intact granules are insoluble in cold water, but grinding or swelling them in warm water causes them to burst.
The released starch consists of two fractions. About 20% is a water soluble material called amylose. Molecules of amylose are linear chains of several thousand glucose units joined by alpha C-1 to C-4 glycoside bonds. Amylose solutions are actually dispersions of hydrated helical micelles. The majority of the starch is a much higher molecular weight substance, consisting of nearly a million glucose units, and called amylopectin. Molecules of amylopectin are branched networks built from C-1 to C-4 and C-1 to C-6 glycoside links, and are essentially water insoluble. Representative structural formulas for amylose and amylopectin are shown above. The branching in this diagram is exaggerated, since on average, branches only occur every twenty five glucose units.
Hydrolysis of starch, usually by enzymatic reactions, produces a syrupy liquid consisting largely of glucose. When cornstarch is the feedstock, this product is known as corn syrup. It is widely used to soften texture, add volume, prohibit crystallization and enhance the flavor of foods. Glycogen is the glucose storage polymer used by animals. It has a structure similar to amylopectin, but is even more highly branched (about every tenth glucose unit). The degree of branching in these polysaccharides may be measured by enzymatic or chemical analysis.
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/22%3A_The_Organic_Chemistry_of_Carbohydrates/22.17%3A_Polysaccharides.txt |
Cotton, probably the most useful natural fiber, is nearly pure cellulose. The manufacture of textiles from cotton involves physical manipulation of the raw material by carding, combing and spinning selected fibers. For fabrics the best cotton has long fibers, and short fibers or cotton dust are removed. Crude cellulose is also available from wood pulp by dissolving the lignan matrix surrounding it. These less desirable cellulose sources are widely used for making paper.
In order to expand the ways in which cellulose can be put to practical use, chemists have devised techniques for preparing solutions of cellulose derivatives that can be spun into fibers, spread into a film or cast in various solid forms. A key factor in these transformations are the three free hydroxyl groups on each glucose unit in the cellulose chain, --[C6H7O(OH)3]n--. Esterification of these functions leads to polymeric products having very different properties compared with cellulose itself.
• Cellulose Nitrate, first prepared over 150 years ago by treating cellulose with nitric acid, is the earliest synthetic polymer to see general use. The fully nitrated compound, --[C6H7O(ONO2)3]n--, called guncotton, is explosively flammable and is a component of smokeless powder. Partially nitrated cellulose is called pyroxylin. Pyroxylin is soluble in ether and at one time was used for photographic film and lacquers. The high flammability of pyroxylin caused many tragic cinema fires during its period of use. Furthermore, slow hydrolysis of pyroxylin yields nitric acid, a process that contributes to the deterioration of early motion picture films in storage.
• Cellulose Acetate, --[C6H7O(OAc)3]n--, is less flammable than pyroxylin, and has replaced it in most applications. It is prepared by reaction of cellulose with acetic anhydride and an acid catalyst. The properties of the product vary with the degree of acetylation. Some chain shortening occurs unavoidably in the preparations. An acetone solution of cellulose acetate may be forced through a spinneret to generate filaments, called acetate rayon, that can be woven into fabrics.
• Viscose Rayon, is prepared by formation of an alkali soluble xanthate derivative that can be spun into a fiber that reforms the cellulose polymer by acid quenching. The following general equation illustrates these transformations. The product fiber is called viscose rayon.
Many complex polysaccharides are found in nature. The galactomannans, consisting of a mannose backbone with galactose side groups, are an interesting and useful example. A (1-4)-linked beta-D-mannose chain is adorned with 1-6-linked alpha-D-galactose units, as shown in the diagram below. The ratio of galactose to mannose usually ranges from 1:2 to 1:4. An important source of this substance is the guar bean, grown principally in northwestern India, and Pakistan. Altough guar protein is not of nutritional value to humans (guar means 'cow food' in Hindi), the bean is important as a source of guar gum, a galactomannan which forms a gel in water. The food industry uses this material as a stabilizer in ice cream, cream cheese and salad dressings.
Recently, guar gum has becomes an essential ingredient for mining oil and natural gas in a process called hydraulic fracturing. The demand for guar has increased to such a degree that the poor farmers in northwestern India have had their lives transformed by unexpected wealth.
Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/22%3A_The_Organic_Chemistry_of_Carbohydrates/22.18%3A_Some_Naturally_Occurring_Products_Derived_from_Carbohydrates.txt |
Intermolecular forces are the attractive or repulsive forces between molecules. They are separated into two groups; short range and long range forces. Short range forces happen when the centers of the molecules are separated by three angstroms (10-8 cm) or less. Short range forces tend to be repulsive, where the long range forces that act outside the three angstroms range are attractive. Long range forces are also known as Van der Waals forces. They are responsible for surface tension, friction, viscosity and differences between actual behavior of gases and that predicted by the ideal gas law. Intermolecular forces are responsible for most properties of all the phases. The viscosity, diffusion, and surface tension are examples of physical properties of liquids that depend on intermolecular forces. Vapor pressure, critical point, and boiling point are examples of properties of gases. Melting and sublimation are examples of properties of solids that depend on intermolecular forces.
• Hydrogen Bonding
A hydrogen bond is a special type of dipole-dipole attraction which occurs when a hydrogen atom bonded to a strongly electronegative atom exists in the vicinity of another electronegative atom with a lone pair of electrons. These bonds are generally stronger than ordinary dipole-dipole and dispersion forces, but weaker than true covalent and ionic bonds.
• Hydrophobic Interactions
Hydrophobic interactions describe the relations between water and hydrophobes (low water-soluble molecules). Hydrophobes are nonpolar molecules and usually have a long chain of carbons that do not interact with water molecules. The mixing of fat and water is a good example of this particular interaction. The common misconception is that water and fat doesn’t mix because the Van der Waals forces that are acting upon both water and fat molecules are too weak.
• Multipole Expansion
A multipole expansion is a series expansion of the effect produced by a given system in terms of an expansion parameter which becomes small as the distance away from the system increases. Therefore, the leading one or terms in a multipole expansion are generally the strongest. The first-order behavior of the system at large distances can therefore be obtained from the first terms of this series, which is generally much easier to compute than the general solution.
• Overview of Intermolecular Forces
Intermolecular forces are forces between molecules. Depending on its strength, intermolecular forces cause the forming of three physical states: solid, liquid and gas. The physical properties of melting point, boiling point, vapor pressure, evaporation, viscosity, surface tension, and solubility are related to the strength of attractive forces between molecules. These attractive forces are called Intermolecular Forces.
• Specific Interactions
Intermolecular forces are forces of attraction or repulsion which act between neighboring particles (atoms, molecules or ions). They are weak compared to the intramolecular forces, which keep a molecule together (e.g., covalent and ionic bonding).
• Van der Waals Forces
Van der Waals forces' is a general term used to define the attraction of intermolecular forces between molecules. There are two kinds of Van der Waals forces: weak London Dispersion Forces and stronger dipole-dipole forces.
23.02: The Configuration of the Amino Acids
Proteins, from the Greek proteios, meaning first, are a class of organic compounds which are present in and vital to every living cell. In the form of skin, hair, callus, cartilage, muscles, tendons and ligaments, proteins hold together, protect, and provide structure to the body of a multi-celled organism. In the form of enzymes, hormones, antibodies, and globulins, they catalyze, regulate, and protect the body chemistry. In the form of hemoglobin, myoglobin and various lipoproteins, they effect the transport of oxygen and other substances within an organism.
Contributors and Attributions
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
23.03: The Acid-Base Properties of Amino Acids
Proteins, from the Greek proteios, meaning first, are a class of organic compounds which are present in and vital to every living cell. In the form of skin, hair, callus, cartilage, muscles, tendons and ligaments, proteins hold together, protect, and provide structure to the body of a multi-celled organism. In the form of enzymes, hormones, antibodies, and globulins, they catalyze, regulate, and protect the body chemistry. In the form of hemoglobin, myoglobin and various lipoproteins, they effect the transport of oxygen and other substances within an organism.
Contributors and Attributions
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
23.04: The Isoelectric Point
Proteins, from the Greek proteios, meaning first, are a class of organic compounds which are present in and vital to every living cell. In the form of skin, hair, callus, cartilage, muscles, tendons and ligaments, proteins hold together, protect, and provide structure to the body of a multi-celled organism. In the form of enzymes, hormones, antibodies, and globulins, they catalyze, regulate, and protect the body chemistry. In the form of hemoglobin, myoglobin and various lipoproteins, they effect the transport of oxygen and other substances within an organism.
Contributors and Attributions
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
23.05: Separating Amino Acids
Proteins, from the Greek proteios, meaning first, are a class of organic compounds which are present in and vital to every living cell. In the form of skin, hair, callus, cartilage, muscles, tendons and ligaments, proteins hold together, protect, and provide structure to the body of a multi-celled organism. In the form of enzymes, hormones, antibodies, and globulins, they catalyze, regulate, and protect the body chemistry. In the form of hemoglobin, myoglobin and various lipoproteins, they effect the transport of oxygen and other substances within an organism.
Contributors and Attributions
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
23.06: The Synthesis of Amino Acids
Proteins, from the Greek proteios, meaning first, are a class of organic compounds which are present in and vital to every living cell. In the form of skin, hair, callus, cartilage, muscles, tendons and ligaments, proteins hold together, protect, and provide structure to the body of a multi-celled organism. In the form of enzymes, hormones, antibodies, and globulins, they catalyze, regulate, and protect the body chemistry. In the form of hemoglobin, myoglobin and various lipoproteins, they effect the transport of oxygen and other substances within an organism.
Contributors and Attributions
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
23.07: The Resolution of Racemic Mixtures of Amino Acids
Proteins, from the Greek proteios, meaning first, are a class of organic compounds which are present in and vital to every living cell. In the form of skin, hair, callus, cartilage, muscles, tendons and ligaments, proteins hold together, protect, and provide structure to the body of a multi-celled organism. In the form of enzymes, hormones, antibodies, and globulins, they catalyze, regulate, and protect the body chemistry. In the form of hemoglobin, myoglobin and various lipoproteins, they effect the transport of oxygen and other substances within an organism.
Contributors and Attributions
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/23%3A_The_Organic_Chemistry_of_Amino_Acids_Peptides_and_Proteins/23.01%3A_Classification_and_Nomenclature_of_Amino_Acids.txt |
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le
23.10: The Strategy of Peptide Bond Synthesis- N-Protection and C-Activation
Proteins, from the Greek proteios, meaning first, are a class of organic compounds which are present in and vital to every living cell. In the form of skin, hair, callus, cartilage, muscles, tendons and ligaments, proteins hold together, protect, and provide structure to the body of a multi-celled organism. In the form of enzymes, hormones, antibodies, and globulins, they catalyze, regulate, and protect the body chemistry. In the form of hemoglobin, myoglobin and various lipoproteins, they effect the transport of oxygen and other substances within an organism.
Contributors and Attributions
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
23.11: Automated Peptide Synthesis
Proteins, from the Greek proteios, meaning first, are a class of organic compounds which are present in and vital to every living cell. In the form of skin, hair, callus, cartilage, muscles, tendons and ligaments, proteins hold together, protect, and provide structure to the body of a multi-celled organism. In the form of enzymes, hormones, antibodies, and globulins, they catalyze, regulate, and protect the body chemistry. In the form of hemoglobin, myoglobin and various lipoproteins, they effect the transport of oxygen and other substances within an organism.
Contributors and Attributions
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
23.12: An Introduction to Protein Structure
Secondary structure refers to the shape of a folding protein due exclusively to hydrogen bonding between its backbone amide and carbonyl groups. Secondary structure does not include bonding between the R-groups of amino acids, hydrophobic interactions, or other interactions associated with tertiary structure. The two most commonly encountered secondary structures of a polypeptide chain are α-helices and beta-pleated sheets. These structures are the first major steps in the folding of a polypeptide chain, and they establish important topological motifs that dictate subsequent tertiary structure and the ultimate function of the protein.
• Protein Folding
• Secondary Structure: α-Helices
An α-helix is a right-handed coil of amino-acid residues on a polypeptide chain, typically ranging between 4 and 40 residues. This coil is held together by hydrogen bonds between the oxygen of C=O on top coil and the hydrogen of N-H on the bottom coil.
• Secondary Structure: β-Pleated Sheet
This structure occurs when two (or more, e.g. ψ-loop) segments of a polypeptide chain overlap one another and form a row of hydrogen bonds with each other. This can happen in a parallel arrangement or in anti-parallel arrangement. Parallel and anti-parallel arrangement is the direct consequence of the directionality of the polypeptide chain.
• Secondary Structure: α-Pleated Sheet
A similar structure to the beta-pleated sheet is the α-pleated sheet. This structure is energetically less favorable than the beta-pleated sheet, and is fairly uncommon in proteins. An α-pleated sheet is characterized by the alignment of its carbonyl and amino groups; the carbonyl groups are all aligned in one direction, while all the N-H groups are aligned in the opposite direction.
• The Structure of Proteins
This page explains how amino acids combine to make proteins and what is meant by the primary, secondary and tertiary structures of proteins. Quaternary structure isn't covered. It only applies to proteins consisting of more than one polypeptide chain.
Thumbnail: Structure of human hemoglobin. The proteins α and β subunits are in red and blue, and the iron-containing heme groups in green. (CC BY-SA 3.0; Zephyris). | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/23%3A_The_Organic_Chemistry_of_Amino_Acids_Peptides_and_Proteins/23.08%3A_Peptide_Bonds_and_Disulfide_Bonds.txt |
Secondary structure refers to the shape of a folding protein due exclusively to hydrogen bonding between its backbone amide and carbonyl groups. Secondary structure does not include bonding between the R-groups of amino acids, hydrophobic interactions, or other interactions associated with tertiary structure. The two most commonly encountered secondary structures of a polypeptide chain are α-helices and beta-pleated sheets. These structures are the first major steps in the folding of a polypeptide chain, and they establish important topological motifs that dictate subsequent tertiary structure and the ultimate function of the protein.
• Protein Folding
• Secondary Structure: α-Helices
An α-helix is a right-handed coil of amino-acid residues on a polypeptide chain, typically ranging between 4 and 40 residues. This coil is held together by hydrogen bonds between the oxygen of C=O on top coil and the hydrogen of N-H on the bottom coil.
• Secondary Structure: β-Pleated Sheet
This structure occurs when two (or more, e.g. ψ-loop) segments of a polypeptide chain overlap one another and form a row of hydrogen bonds with each other. This can happen in a parallel arrangement or in anti-parallel arrangement. Parallel and anti-parallel arrangement is the direct consequence of the directionality of the polypeptide chain.
• Secondary Structure: α-Pleated Sheet
A similar structure to the beta-pleated sheet is the α-pleated sheet. This structure is energetically less favorable than the beta-pleated sheet, and is fairly uncommon in proteins. An α-pleated sheet is characterized by the alignment of its carbonyl and amino groups; the carbonyl groups are all aligned in one direction, while all the N-H groups are aligned in the opposite direction.
• The Structure of Proteins
This page explains how amino acids combine to make proteins and what is meant by the primary, secondary and tertiary structures of proteins. Quaternary structure isn't covered. It only applies to proteins consisting of more than one polypeptide chain.
Thumbnail: Structure of human hemoglobin. The proteins α and β subunits are in red and blue, and the iron-containing heme groups in green. (CC BY-SA 3.0; Zephyris).
23.14: The Secondary Structure of Proteins
Secondary structure refers to the shape of a folding protein due exclusively to hydrogen bonding between its backbone amide and carbonyl groups. Secondary structure does not include bonding between the R-groups of amino acids, hydrophobic interactions, or other interactions associated with tertiary structure. The two most commonly encountered secondary structures of a polypeptide chain are α-helices and beta-pleated sheets. These structures are the first major steps in the folding of a polypeptide chain, and they establish important topological motifs that dictate subsequent tertiary structure and the ultimate function of the protein.
• Protein Folding
• Secondary Structure: α-Helices
An α-helix is a right-handed coil of amino-acid residues on a polypeptide chain, typically ranging between 4 and 40 residues. This coil is held together by hydrogen bonds between the oxygen of C=O on top coil and the hydrogen of N-H on the bottom coil.
• Secondary Structure: β-Pleated Sheet
This structure occurs when two (or more, e.g. ψ-loop) segments of a polypeptide chain overlap one another and form a row of hydrogen bonds with each other. This can happen in a parallel arrangement or in anti-parallel arrangement. Parallel and anti-parallel arrangement is the direct consequence of the directionality of the polypeptide chain.
• Secondary Structure: α-Pleated Sheet
A similar structure to the beta-pleated sheet is the α-pleated sheet. This structure is energetically less favorable than the beta-pleated sheet, and is fairly uncommon in proteins. An α-pleated sheet is characterized by the alignment of its carbonyl and amino groups; the carbonyl groups are all aligned in one direction, while all the N-H groups are aligned in the opposite direction.
• The Structure of Proteins
This page explains how amino acids combine to make proteins and what is meant by the primary, secondary and tertiary structures of proteins. Quaternary structure isn't covered. It only applies to proteins consisting of more than one polypeptide chain.
Thumbnail: Structure of human hemoglobin. The proteins α and β subunits are in red and blue, and the iron-containing heme groups in green. (CC BY-SA 3.0; Zephyris). | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/23%3A_The_Organic_Chemistry_of_Amino_Acids_Peptides_and_Proteins/23.13%3A_How_to_Determine_the_Primary_Structure_of_a_Polypeptide_or_Protein.txt |
Secondary structure refers to the shape of a folding protein due exclusively to hydrogen bonding between its backbone amide and carbonyl groups. Secondary structure does not include bonding between the R-groups of amino acids, hydrophobic interactions, or other interactions associated with tertiary structure. The two most commonly encountered secondary structures of a polypeptide chain are α-helices and beta-pleated sheets. These structures are the first major steps in the folding of a polypeptide chain, and they establish important topological motifs that dictate subsequent tertiary structure and the ultimate function of the protein.
• Protein Folding
• Secondary Structure: α-Helices
An α-helix is a right-handed coil of amino-acid residues on a polypeptide chain, typically ranging between 4 and 40 residues. This coil is held together by hydrogen bonds between the oxygen of C=O on top coil and the hydrogen of N-H on the bottom coil.
• Secondary Structure: β-Pleated Sheet
This structure occurs when two (or more, e.g. ψ-loop) segments of a polypeptide chain overlap one another and form a row of hydrogen bonds with each other. This can happen in a parallel arrangement or in anti-parallel arrangement. Parallel and anti-parallel arrangement is the direct consequence of the directionality of the polypeptide chain.
• Secondary Structure: α-Pleated Sheet
A similar structure to the beta-pleated sheet is the α-pleated sheet. This structure is energetically less favorable than the beta-pleated sheet, and is fairly uncommon in proteins. An α-pleated sheet is characterized by the alignment of its carbonyl and amino groups; the carbonyl groups are all aligned in one direction, while all the N-H groups are aligned in the opposite direction.
• The Structure of Proteins
This page explains how amino acids combine to make proteins and what is meant by the primary, secondary and tertiary structures of proteins. Quaternary structure isn't covered. It only applies to proteins consisting of more than one polypeptide chain.
Thumbnail: Structure of human hemoglobin. The proteins α and β subunits are in red and blue, and the iron-containing heme groups in green. (CC BY-SA 3.0; Zephyris).
23.16: The Quaternary Structure of Proteins
Secondary structure refers to the shape of a folding protein due exclusively to hydrogen bonding between its backbone amide and carbonyl groups. Secondary structure does not include bonding between the R-groups of amino acids, hydrophobic interactions, or other interactions associated with tertiary structure. The two most commonly encountered secondary structures of a polypeptide chain are α-helices and beta-pleated sheets. These structures are the first major steps in the folding of a polypeptide chain, and they establish important topological motifs that dictate subsequent tertiary structure and the ultimate function of the protein.
• Protein Folding
• Secondary Structure: α-Helices
An α-helix is a right-handed coil of amino-acid residues on a polypeptide chain, typically ranging between 4 and 40 residues. This coil is held together by hydrogen bonds between the oxygen of C=O on top coil and the hydrogen of N-H on the bottom coil.
• Secondary Structure: β-Pleated Sheet
This structure occurs when two (or more, e.g. ψ-loop) segments of a polypeptide chain overlap one another and form a row of hydrogen bonds with each other. This can happen in a parallel arrangement or in anti-parallel arrangement. Parallel and anti-parallel arrangement is the direct consequence of the directionality of the polypeptide chain.
• Secondary Structure: α-Pleated Sheet
A similar structure to the beta-pleated sheet is the α-pleated sheet. This structure is energetically less favorable than the beta-pleated sheet, and is fairly uncommon in proteins. An α-pleated sheet is characterized by the alignment of its carbonyl and amino groups; the carbonyl groups are all aligned in one direction, while all the N-H groups are aligned in the opposite direction.
• The Structure of Proteins
This page explains how amino acids combine to make proteins and what is meant by the primary, secondary and tertiary structures of proteins. Quaternary structure isn't covered. It only applies to proteins consisting of more than one polypeptide chain.
Thumbnail: Structure of human hemoglobin. The proteins α and β subunits are in red and blue, and the iron-containing heme groups in green. (CC BY-SA 3.0; Zephyris). | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/23%3A_The_Organic_Chemistry_of_Amino_Acids_Peptides_and_Proteins/23.15%3A_The_Tertiary_Structure_of_Proteins.txt |
It has been demonstrated that water, in the presence of an acid or a base, adds rapidly to the carbonyl function of aldehydes and ketones establishing a reversible equilibrium with a hydrate (geminal-diol or gem-diol). The word germinal or gem comes from the Latin word for twin, geminus.
Reversibility of the Reaction
Isolation of gem-diols is difficult because the reaction is reversibly. Removal of the water during a reaction can cause the conversion of a gem-diol back to the corresponding carbonyl.
Factors Affecting the Gem-diol Equilibrium
In most cases the resulting gem-diol is unstable relative to the reactants and cannot be isolated. Exceptions to this rule exist, one being formaldehyde where the weaker pi-component of the carbonyl double bond, relative to other aldehydes or ketones, and the small size of the hydrogen substituents favor addition. Thus, a solution of formaldehyde in water (formalin) is almost exclusively the hydrate, or polymers of the hydrate. The addition of electron donating alkyl groups stabilized the partial positive charge on the carbonyl carbon and decreases the amount of gem-diol product at equilibrium. Because of this ketones tend to form less than 1% of the hydrate at equilibrium. Likewise, the addition of strong electron-withdrawing groups destabilizes the carbonyl and tends to form stable gem-diols. Two examples of this are chloral, and 1,2,3-indantrione. It should be noted that chloral hydrate is a sedative and has been added to alcoholic beverages to make a “Knock-out” drink also called a Mickey Finn. Also, ninhydrin is commonly used by forensic investigators to resolve finger prints.
Mechanism of Gem-diol Formation
The mechanism is catalyzed by the addition of an acid or base. Note! This may speed up the reaction but is has not effect on the equilibriums discussed above. Basic conditions speed up the reaction because hydroxide is a better nucleophilic than water. Acidic conditions speed up the reaction because the protonated carbonyl is more electrophilic.
Under Basic conditions
1) Nucleophilic attack by hydroxide
2) Protonation of the alkoxide
Under Acidic conditions
1) Protonation of the carbonyl
2) Nucleophilic attack by water
3) Deprotonation
Problems
1) Draw the expected products of the following reactions.
2) Of the following pairs of molecules which would you expect to form a larger percentage of gem-diol at equilibrium? Please explain your answer.
3) Would you expect the following molecule to form appreciable amount of gem-diol in water? Please explain your answer.
Answers
1)
2) The compound on the left would. Fluorine is more electronegative than bromine and would remove more electron density from the carbonyl carbon. This would destabilize the carbonyl allowing for more gem-diol to form.
3) Although ketones tend to not form gem-diols this compound exists almost entirely in the gem-diol form when placed in water. Ketones tend to not form gem-diols because of the stabilizing effect of the electron donating alkyl group. However, in this case the electron donating effects of alkyl group is dominated by the presence of six highly electronegative fluorines.
24.04: Nucleophilic Catalysis
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/24%3A_Catalysis/24.03%3A_Base_Catalysis.txt |
Learning Objectives
Make sure you thoroughly understand the following essential ideas which have been presented above. It is especially important that you know the precise meanings of all the highlighted terms in the context of this topic.
• Write the equation for the proton transfer reaction involving a Brønsted-Lowry acid or base, and show how it can be interpreted as an electron-pair transfer reaction, clearly identifying the donor and acceptor.
• Give an example of a Lewis acid-base reaction that does not involve protons.
• Write equations illustrating the behavior of a given non-aqueous acid-base system.
The Brønsted-Lowry proton donor-acceptor concept has been one of the most successful theories of Chemistry. But as with any such theory, it is fair to ask if this is not just a special case of a more general theory that could encompass an even broader range of chemical science. In 1916, G.N. Lewis of the University of California proposed that the electron pair is the dominant actor in acid-base chemistry. The Lewis theory did not become very well known until about 1923 (the same year that Brønsted and Lowry published their work), but since then it has been recognized as a very powerful tool for describing chemical reactions of widely different kinds and is widely used in organic and inorganic chemistry. According to Lewis,
• An acid is a substance that accepts a pair of electrons, and in doing so, forms a covalent bond with the entity that supplies the electrons.
• A base is a substance that donates an unshared pair of electrons to a recipient species with which the electrons can be shared.
In modern chemistry, electron donors are often referred to as nucleophiles, while acceptors are electrophiles.
Proton-Transfer Reactions Involve Electron-Pair Transfer
Just as any Arrhenius acid is also a Brønsted acid, any Brønsted acid is also a Lewis acid, so the various acid-base concepts are all "upward compatible". Although we do not really need to think about electron-pair transfers when we deal with ordinary aqueous-solution acid-base reactions, it is important to understand that it is the opportunity for electron-pair sharing that enables proton transfer to take place.
This equation for a simple acid-base neutralization shows how the Brønsted and Lewis definitions are really just different views of the same process. Take special note of the following points:
• The arrow shows the movement of a proton from the hydronium ion to the hydroxide ion.
• Note carefully that the electron-pairs themselves do not move; they remain attached to their central atoms. The electron pair on the base is "donated" to the acceptor (the proton) only in the sense that it ends up being shared with the acceptor, rather than being the exclusive property of the oxygen atom in the hydroxide ion.
• Although the hydronium ion is the nominal Lewis acid here, it does not itself accept an electron pair, but acts merely as the source of the proton that coordinates with the Lewis base.
The point about the electron-pair remaining on the donor species is especially important to bear in mind. For one thing, it distinguishes a Lewis acid-base reaction from an oxidation-reduction reaction, in which a physical transfer of one or more electrons from donor to acceptor does occur. The product of a Lewis acid-base reaction is known formally as an "adduct" or "complex", although we do not ordinarily use these terms for simple proton-transfer reactions such as the one in the above example. Here, the proton combines with the hydroxide ion to form the "adduct" H2O. The following examples illustrate these points for some other proton-transfer reactions that you should already be familiar with.
Another example, showing the autoprotolysis of water. Note that the conjugate base is also the adduct.
Ammonia is both a Brønsted and a Lewis base, owing to the unshared electron pair on the nitrogen. The reverse of this reaction represents the hydrolysis of the ammonium ion.
Because $\ce{HF}$ is a weak acid, fluoride salts behave as bases in aqueous solution. As a Lewis base, F accepts a proton from water, which is transformed into a hydroxide ion.
The bisulfite ion is amphiprotic and can act as an electron donor or acceptor.
Acid-base Reactions without Transferring Protons
The major utility of the Lewis definition is that it extends the concept of acids and bases beyond the realm of proton transfer reactions. The classic example is the reaction of boron trifluoride with ammonia to form an adduct:
$\ce{BF_3 + NH_3 \rightarrow F_3B-NH_3}$
One of the most commonly-encountered kinds of Lewis acid-base reactions occurs when electron-donating ligands form coordination complexes with transition-metal ions.
Exercise $1$
Here are several more examples of Lewis acid-base reactions that cannot be accommodated within the Brønsted or Arrhenius models. Identify the Lewis acid and Lewis base in each reaction.
1. $\ce{Al(OH)_3 + OH^{–} \rightarrow Al(OH)_4^–}$
2. $\ce{SnS_2 + S^{2–} \rightarrow SnS_3^{2–}}$
3. $\ce{Cd(CN)_2 + 2 CN^– \rightarrow Cd(CN)_4^{2+}}$
4. $\ce{AgCl + 2 NH_3 \rightarrow Ag(NH_3)_2^+ + Cl^–}$
5. $\ce{Fe^{2+} + NO \rightarrow Fe(NO)^{2+}}$
6. $\ce{Ni^{2+} + 6 NH_3 \rightarrow Ni(NH_3)_5^{2+}}$
Applications to organic reaction mechanisms
Although organic chemistry is beyond the scope of these lessons, it is instructive to see how electron donors and acceptors play a role in chemical reactions. The following two diagrams show the mechanisms of two common types of reactions initiated by simple inorganic Lewis acids:
In each case, the species labeled "Complex" is an intermediate that decomposes into the products, which are conjugates of the original acid and base pairs. The electric charges indicated in the complexes are formal charges, but those in the products are "real".
In reaction 1, the incomplete octet of the aluminum atom in $\ce{AlCl3}$ serves as a better electron acceptor to the chlorine atom than does the isobutyl part of the base. In reaction 2, the pair of non-bonding electrons on the dimethyl ether coordinates with the electron-deficient boron atom, leading to a complex that breaks down by releasing a bromide ion.
Non-aqueous Protonic Acid-Base Systems
We ordinarily think of Brønsted-Lowry acid-base reactions as taking place in aqueous solutions, but this need not always be the case. A more general view encompasses a variety of acid-base solvent systems, of which the water system is only one (Table $1$). Each of these has as its basis an amphiprotic solvent (one capable of undergoing autoprotolysis), in parallel with the familiar case of water.
The ammonia system is one of the most common non-aqueous system in Chemistry. Liquid ammonia boils at –33° C, and can conveniently be maintained as a liquid by cooling with dry ice (–77° C). It is a good solvent for substances that also dissolve in water, such as ionic salts and organic compounds since it is capable of forming hydrogen bonds. However, many other familiar substances can also serve as the basis of protonic solvent systems as Table $1$ indicates:
Table $1$: Popular Solvent systems
solvent
autoprotolysis reaction
pKap
water 2 H2O → H3O+ + OH 14
ammonia 2 NH3 → NH4+ + NH2 33
acetic acid 2 CH3COOH → CH3COOH2+ + CH3COO 13
ethanol 2 C2H5OH → C2H5OH2+ + C2H5O 19
hydrogen peroxide 2 HO-OH → HO-OH2+ + HO-O 13
hydrofluoric acid 2 HF → H2F+ + F 10
sulfuric acid 2 H2SO4 → H3SO4+ + HSO4 3.5
One use of nonaqueous acid-base systems is to examine the relative strengths of the strong acids and bases, whose strengths are "leveled" by the fact that they are all totally converted into H3O+ or OH ions in water. By studying them in appropriate non-aqueous solvents which are poorer acceptors or donors of protons, their relative strengths can be determined.
24.06: Intramolecular Reactions
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le
24.07: Intramolecular Catalysis
Contributors and Attributions
• Nathalie Interiano | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/24%3A_Catalysis/24.05%3A_Metal-Ion_Catalysis.txt |
Nicotinamide is from the niacin vitamin. The NAD+ coenzyme is involved with many types of oxidation reactions where alcohols are converted to ketones or aldehydes. It is also involved in the first enzyme complex 1 of the electron transport chain.The structure for the coenzyme, NAD+, Nicotinamide Adenine Dinucleotide is shown in Figure $1$.
Role of NAD+
One role of $NAD^+$ is to initiate the electron transport chain by the reaction with an organic metabolite (intermediate in metabolic reactions). This is an oxidation reaction where 2 hydrogen atoms (or 2 hydrogen ions and 2 electrons) are removed from the organic metabolite. (The organic metabolites are usually from the citric acid cycle and the oxidation of fatty acids--details in following pages.) The reaction can be represented simply where M = any metabolite.
$MH_2 + NAD^+ \rightarrow NADH + H^+ + M: + \text{energy}$
One hydrogen is removed with 2 electrons as a hydride ion ($H^-$) while the other is removed as the positive ion ($H+$). Usually the metabolite is some type of alcohol which is oxidized to a ketone.
Figure $1$
Alcohol Dehydrogenase
The NAD+ is represented as cyan in Figure $2$. The alcohol is represented by the space filling red, gray, and white atoms. The reaction is to convert the alcohol, ethanol, into ethanal, an aldehyde.
$CH_3CH_2OH + NAD^+ \rightarrow CH_3CH=O + NADH + H^+$
This is an oxidation reaction and results in the removal of two hydrogen ions and two electrons which are added to the NAD+, converting it to NADH and H+. This is the first reaction in the metabolism of alcohol. The active site of ADH has two binding regions. The coenzyme binding site, where NAD+ binds, and the substrate binding site, where the alcohol binds. Most of the binding site for the NAD+ is hydrophobic as represented in green. Three key amino acids involved in the catalytic oxidation of alcohols to aldehydes and ketones. They are ser-48, phe 140, and phe 93.
Figure $2$: Active site of Alcohol Dehydrogenase
25.02: Flavin Adenine Dinucleotide and Flavin Mononucleotind- Vitamin B
The structure shown on the left is for FAD and is similar to NAD+ in that it contains a vitamin-riboflavin, adenine, ribose, and phosphates. As shown it is the diphosphate, but is also used as the monophosphate (FMN).
Introduction
In the form of FMN it is involved in the first enzyme complex 1 of the electron transport chain. A FMN (flavin adenine mononucleotide) as an oxidizing agent is used to react with NADH for the second step in the electron transport chain. The simplified reaction is:
NADH + H+ + FMN → FMNH2 + NAD+
Red.Ag. Ox.Ag.
Note the fact that the two hydrogens and 2e- are "passed along" from NADH to FFMN. Also note that NAD+ as a product is back to its original state as an oxidizing agent ready to begin the cycle again. The FMN has now been converted to the reducing agent and is the starting point for the third step.
Coenzyme Q or Ubiquinone
Ubiquinone: As its name suggests, is very widely distributed in nature. There are some differences in the length of the isoprene unit (in bracket on left) side chain in various species. All the natural forms of CoQ are insoluble in water, but soluble in membrane lipids where they function as a mobile electron carrier in the electron transport chain. The long hydrocarbon chain gives the non-polar property to the molecule.
CoQ acts as a bridge between enzyme complex 1 and 3 or between complex 2 and 3. Electrons are transferred from NADH along with two hydrogens to the double bond oxygens in the benzene ring. These in turn convert to alcohol groups. The electrons are then passed along to the cytochromes in enzyme complex 3.
Coenzyme A
Although not used in the electron transport chain, Coenzyme A is a major cofactor which is used to transfer a two carbon unit commonly referred to as the acetyl group. The structure has many common features with NAD+ and FAD in that it has the diphosphate, ribose, and adenine. In addition it has a vitamin called pantothenic acid, and finally terminated by a thiol group. The thiol (-SH) is the sulfur analog of an alcohol (-OH). The acetyl group (CH3C=O) is attached to the sulfur of the CoA through a thiol ester type bond. Acetyl CoA is important in the breakdown of fatty acids and is a starting point in the citric acid cycle. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/25%3A_Compounds_Derived_from_Vitamins/25.01%3A_The_Vitamin_Needed_for_Many_Redox_Reactions-_Vitamin_B3.txt |
Solutions to exercises
Thiamine diphosphate (TPP) is another very important coenzyme which, like PLP, acts as an electron sink to stabilize key carbanion intermediates. The important part of the TPP molecule from a catalytic standpoint is its thiazole ring.
14.5A: The benzoin condensation reaction
In a very simple experiment that can performed in an undergraduate organic chemistry lab, benzaldehyde (a liquid compound at room temperature that is used as an artificial cherry flavoring) self-condenses to form benzoin (a crystalline solid) when stirred in ethanol with a catalytic amount of sodium hydroxide and thiamine.
The laboratory synthesis of benzoin is interesting because it mimics the mechanism of TPP-dependant enzymatic reactions in biological systems. This reaction is not catalyzed by an enzyme – rather, the thiamine molecule acts on its own, playing a similar catalytic role to that played by its diphosphate ester cousin (TPP) in enzymatic reactions.
Look carefully at the connectivity of the starting compounds and product in the benzoin condensation. Essentially what has happened is that the carbonyl carbon of one benzaldehyde molecule has somehow been turned into a nucleophile, and has attacked a second benzaldehyde molecule in a nucleophilic carbonyl addition reaction.
This probably seems quite strange - we know that carbonyl carbons are good electrophiles, but how can they be nucleophilic? For the aldehyde carbon to be a nucleophile, it would have to be deprotonated, and become a carbonyl anion. But aldehyde protons are not at all acidic!
The thiamine catalyst is the key: it allows the formation of what is essentially the equivalent of a nucleophilic benzaldehyde carbanion. Let's follow the benzoin condensation reaction mechanism through step-by-step, and see how thiamine accomplishes this task.
The important part of the thiamine molecule is the thiazole ring (look again at the structure of thiamine diphosphate on the previous page), thus we will draw thiamine (and later, thiamine diphosphate) using R groups to depict the unreactive parts of the molecule. The first step of the benzoin condensation is deprotonation of thiamine by hydroxide.
It may surprise you to learn that this proton is acidic. The reason for its acidity lies partly in the ability of the neighboring sulfur atom to accept, in its open d orbitals, some of the excess electron density of the conjugate base. Another reason is that the positive charge on the nitrogen helps to stabilize the negative charge on the conjugate base. The deprotonated thiazole is called an ylide, which is a species with adjacent positively and negatively charged atoms.
The negatively charged carbon on the thiazole ylide next attacks the carbonyl of the first benzaldehyde molecule in a nucleophilic carbonyl addition (from here on out, thiamine will be colored green in order to help you to focus on the chemistry going on with the substrate).
In the resulting molecule, what used to be the aldehyde hydrogen is now acidic - this is so because, when the proton is abstracted by hydroxide, the negative charge on the conjugate base is stabilized by resonance with the positively-charged thiazole ring of thiamine. This is the function of thiamine: it acts as an electron sink, accepting electron density so as to allow for the formation of what amounts to a carbonyl anion.
Now the first benzaldehyde molecule, assisted by thiamine, can finally act as a nucleophile, attacking the carbonyl of a second benzaldehyde (step 3).
Once this is accomplished, the thiamine ylide can be kicked off as the original carbonyl on the first benzaldehyde re-forms (step 4). The thiamine ylide is now free to catalyze another reaction.
14.5B: The transketolase reaction
Now let's look at a biochemical reaction carried out by an enzyme called transketolase, with the assistance of thiamine diphosphate. Transketolase is one of a series of enzymes (along with ribulose-5-phosphate-3-epimerase, which we considered in section 13.2B) in the 'Calvin cycle' of carbon fixation in plants. Animals and bacteria also use transketolase in sugar metabolism. In the transketolase reaction, a 2-carbon unit (in the smaller, red box) is transferred between two sugar molecules:
First, let's consider how this reaction might hypothetically proceed without the assistance of the TPP cofactor. The breaking off of the 2-carbon unit from fructose-6-phosphate might be depicted as a kind of retro-aldol event:
This would lead to glyceraldehyde-3-phosphate, the first product, plus an intermediate in the form of a carbonyl anion.
Continuing to think hypothetically, this strange 2-carbon ionic intermediate could attack the glyceraldehyde-3-phosphate carbonyl, resulting in sedoheptulose-7-phosphate, the second product.
Everything in this hypothetical scenario is fine, chemically speaking, with one major exception: the carbonyl anion intermediate. It would be an extremely high energy, unlikely species. But we have seen something like this before, haven't we, in the non-enzymatic benzoin condensation reaction above! This is exactly the kind of carbanion that thiamine (this time in its diphosphate form, TPP) makes possible. The carbonyl anion is generated in different ways in the two reactions: in the benzoin condensation it is the result of the deprotonation of benzaldehyde, while in the transketolase it results from a retro-aldol-like cleavage. But that doesn't really matter - what does matter is that in each case, a thiazole ring is present to modify the starting carbonyl group and act as an electron sink, allowing it to take on a negative charge. Here, then, is the real (as opposed to hypothetical) transketolase reaction, with the role of TPP revealed.
Make sure that you can follow the electron movement throughout the mechanism, that you can see how TPP acts as an electron sink cofactor, and that you clearly recognize the mechanistic parallels to the benzoin condensation.
14.5C: Pyruvate decarboxylase
The thiamine diphosphate coenzyme also assists in the decarboxylation of an acyl group, such as in this reaction catalyzed by pyruvate decarboxylase (this is a key reaction in the fermentation of glucose to ethanol by yeast):
In this example, the TPP-stabilized carbonyl carbanion simply acts as a base rather than as a nucleophile, abstracting a proton from an enzymatic acid to form acetaldehyde.
Example 14.7
Propose a mechanism for the reaction catalyzed by pyruvate decarboxylase.
14.5D: Synthetic parallel - carbonyl nucleophiles via dithiane anions
Nature uses thiamine to generate the equivalent of a nucleophilic carbonyl anion, but with the specific exception of the benzoin condensation, a chemist working in an organic synthesis laboratory before the mid-1970's had no equivalent procedure. In 1975, E. J. Corey and Dieter Seebach reported that they had developed a method to accomplish reactions such as the following, in which aldehyde carbons act as nucleophiles in SN2 and carbonyl addition reactions (J. Org. Chem. 1975, 40, 231).
In this technique, the aldehyde is first converted to a cyclic thioketal using 1,3-propanedithiol and acid catalyst - this is the same as the method used to 'protect' aldehydes as cyclic acetals, discussed in section 11.4B, except that a dithiol is used instead of a diol.
The original aldehyde proton is now somewhat acidic, because the empty d orbitals on the two adjacent sulfur atoms are able to delocalize excess electron density of the conjugate base. A strong base, such as an organolithium compound (section 13.6B) will deprotonate the cyclic thioacetal, which can then act as a nucleophile, attacking an alkyl halide or a carbonyl electrophile (the latter case is illustrated below):
The thioacetal can then be hydrolyzed back to an aldehyde group, a process that is facilitated by the use of methyl iodide.
Example 14.8
Show a mechanism for the hydrolysis of a cyclic thioacetal, in the presence of catalytic acid and methyl iodide. Propose a role for methyl iodide in this reaction.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/25%3A_Compounds_Derived_from_Vitamins/25.03%3A_Thiamine_Pyrophosphate-_Vitamin_B1.txt |
13.5A: The metabolic context of carboxylation and decarboxylation
Some of the most important carbon-carbon bond-forming and bond-breaking processes in biological chemistry involve the gain or loss, by an organic molecule, of a single carbon in the form of CO2. You undoubtedly have seen this chemical equation before in an introductory biology or chemistry class:
6CO2 + 6H2O + energy → C6H12O6 + 6O2
This of course represents the photosynthetic process, by which plants (and some bacteria) harness energy from sunlight to build glucose from individual carbon dioxide molecules. The key chemical step in which carbon dioxide is 'fixed' (in other words, condensed with an existing organic molecule) is called a carboxylation reaction. It is catalyzed by the enzyme ribulose 1,5-bisphosphate carboxylase, commonly known as Rubisco, in the 'Calvin cycle' of carbon fixation.
The reverse chemical equation is also probably familiar to you:
C6H12O6 + 6O2 → 6CO2 + 6H2O + energy
This equation expresses what happens in respiration: the oxidative breakdown of glucose to form carbon dioxide, water, and energy. In the course of this transformation, each of the carbon atoms of glucose is eventually converted to individual CO2 molecules. The actual chemical step by which a carbon atom, in the form of carbon dioxide, breaks off from a larger organic molecule is called a decarboxylation reaction. The key decarboxylation steps in the conversion of glucose to carbon dioxide occur in the citric acid (Krebs) cycle and the pentose phosphate pathway.
Let's now look at the organic mechanisms of some carboxylation and decarboxylation reactions.
13.5B: The carboxylation mechanism of Rubisco, the carbon fixing enzyme
Carboxylation reactions are essentially just aldol condensations, except that the carbonyl electrophile is CO2 rather than a ketone or aldehyde. The mechanism for Rubisco, the key carbon-fixing enzyme in plants and photosynthetic bacteria (and the most abundant enzyme on earth!), is shown below. Magnesium ion plays a key charge-stabilizing role throughout the reaction. Step 1, not surprisingly, is deprotonation of an alpha-carbon to form an enolate.
Step 2 is simply an intramolecular proton transfer, which has the effect of creating a different enolate intermediate and making C2 into the nucleophile for an aldol-like attack on CO2 (step 3). Carbon dioxide has now been 'fixed' into organic form - it has become a carboxylate group on a six-carbon sugar derivative.
To follow the Rubisco mechanism through to its endpoint:
Step 4 is a retro-Claisen mechanism, with a water nucleophile and enolate leaving group. After protonation of this enolate, we are left with two molecules of 3-phosphoglycerate, which are incorporated into the 'gluconeogenesis' pathway of glucose synthesis.
Example 13.8
Propose a complete mechanism for the retro-Claisen reaction in the figure above.
13.5C: Decarboxylation
Mechanistically, a decarboxylation has parallels to retro-aldol cleavage reactions:
Just as in retro-aldol reactions, the electrons from the broken carbon-carbon bond have to have some place to go - they must, in other words, be stabilized - for the decarboxylation step to take place. Quite often, the electrons are stabilized by the formation of an enolate, as is the case in the general mechanism pictured above. This of course means that a carbonyl group must be positioned beta to (i.e. two carbons down from) the carboxylate carbon. If there is no stable place for the electrons in the carbon-carbon bond to go, then a decarboxylation is very unlikely.
Be especially careful, when drawing decarboxylation mechanisms, to resist the temptation to treat the CO2 molecule as the leaving group:
This is not what a decarboxylation looks like! In a decarboxylation step, it is the organic part of the molecule that is, in fact, the leaving group, 'pushed off' by the electrons on the carboxylate.
Below are two important key b-carbonyl decarboxylation steps in glucose metabolism, each representing a point at which a carbon derived from glucose is released as CO2.
Example 13.9
Exercise 13.9: Draw mechanistic arrows showing the first step in each of the reactions shown above.
The reaction catalyzed by acetoacetate decarboxylase relies on an imine group, rather than a carbonyl, to stabilize the carbanion intermediate. This is a mechanistic parallel to a type II retro-aldolase reaction.
Example 13.10
Exercise 13.10: Draw a mechanism for the decarboxylation step in the reaction above.
There are some examples of decarboxylation reactions in which the carbanion intermediate goes on to form a new carbon-carbon bond, rather than becoming protonated as in the example we have seen so far. This reaction in the fatty acid biosynthetic pathway is a decarboxylation followed by a Claisen condensation. A thiol group on an 'acyl carrier protein' (section 12.3D) is part of the thioester functional group in this reaction.
An interesting variation on decarboxylation in the synthesis of tyrosine in bacteria is shown below.
Template:ExampleStart
Example 13.11
a) Draw a mechanism for the reaction above.
b) Draw hypothetical decarboxylation mechanisms showing the formation of alternate products A and B from the same starting compound:
c) How would you describe in words the relationship between the actual product and hypothetical products A and B? Which of the three would you expect to be most thermodynamically stable, and why?
In chapter 14, we will see decarboxylation reactions occurring in several other mechanistic contexts.
13.5D: Biotin is a CO2-carrying coenzyme
Recall from section 6.5B that many enzymes are dependent upon the assistance of coenzymes, which are small (relative to protein) organic molecules that bind - covalently or non-covalently - in an enzyme's active site and help it to catalyze its reaction. S-adenosylmethionine (SAM, section 9.1A) and ATP (section 10.2) are two examples that we have encountered so far, and we will see several more in the chapters ahead. Although Rubisco (described in part B of this section) is an exception, most enzymes that catalyze carboxylation reactions are dependent upon a coenzyme called biotin, which serves as a temporary carrier of carbon dioxide.
Pyruvate carboxylase, the enzyme catalyzing the first step of the gluconeogensis pathway, is a good example of a biotin-dependent carboxylation reaction. Notice that the CO2 in this reaction is derived from bicarbonate, unlike the Rubisco reaction in which CO2 is 'fixed' directly from the atmosphere.
Biotin is covalently attached to the enzyme through an amide linkage to an active site lysine.
The exact mechanism by which biotin-dependent carboxylation reactions operate is still not completely understood, however the following is a likely picture. First, the bicarbonate ion is phosphorylated by ATP (step 1, see section 10.2), and thus is activated for decarboxylation, which generates free CO2 (step 2).
Biotin's job is to hold on to the carbon dioxide molecule until pyruvate comes into the active site. Carboxylation of biotin involves deprotonation of the amide nitrogen to form an enolate-like intermediate (step 3 - amides have a pKa of approximately 17, and this is lowered by the presence of an active site acid near the oxygen). This step is followed by attack of the nucleophilic nitrogen on carbon dioxide to form carboxybiotinylated enzyme (step 4).
When a pyruvate molecule binds, rearrangement of the active site architecture causes the previous step to go in reverse (step 5), freeing the CO2 and generating a biotin base to deprotonate the alpha-carbon of pyruvate so that it can condense, in an aldol-like fashion, with CO2 to form oxaloacetate (steps 6-7).
If you have studied some biochemistry, you may have heard about biotin in a somewhat different context that what is discussed in this section. A protein called avidin, found in abundance in egg white, binds non-covalently and extremely tightly to biotin (in fact, avidin-biotin is the tightest protein-ligand binding pair known to science). Biochemists often make use of this property by covalently linking a biomolecule of interest to biotin. The 'biotinylated' species can then be easily isolated from a complex mixture by running the mixture through an 'affinity column' that is coated with avidin.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/25%3A_Compounds_Derived_from_Vitamins/25.04%3A_Biotin-_Vitamin_H.txt |
Solutions to exercises
In section 6.5, we were introduced to the concept of coenzymes - small organic molecules that assist enzymes in doing a particular chemical job. We have seen many specific examples since then: SAM as a methyl group donor, ATP as a phosphoryl group donor, Coenzyme A as an activator for acyl transfer reactions, and most recently glutathione as a 'nucleophile for hire' in the cis/trans isomerization described in section 14.2A.
In this section and the next, we will consider two very important coenzymes that help to stabilize carbanion intermediates in many diverse enzymatic reactions. They may be familiar to you already if you occasionally look at the nutritional information on food packages: thiamine diphosphate (TPP) is the diphosphate ester of thiamine (otherwise known as vitamin B1), and pyridoxal phosphate (PLP), is a derivative of vitamin B6.
Unlike plants and many bacteria, humans do not have the biosynthetic enzymes to make these molecules, so we must get them in our diet.
Many enzymes involved in the metabolism of amino acids make use of PLP as a coenzyme. The basic function of PLP is to act as an 'electron sink', the meaning of which will become clear as we examine in detail the mechanisms of some PLP-dependant reactions. Most of these reactions will be familiar - they include amino acid racemizations, eliminations, additions, and retro-aldol or retro-Claisen cleavages. What will be new is the use of PLP to stabilize the carbanion intermediates in each of these reactions.
14.4A: PLP and the Schiff base linkage to lysine
In the first step of virtually all PLP-dependant reactions, the aldehyde group of the coenzyme forms an imine (Schiff base) linkage with a lysine side chain on the enzyme. (In order to help you to focus on the chemistry happening with the amino acid substrates, the PLP molecule in subsequent figures is colored green - it will be very helpful to refer to color figures).
Generally, the next step (step 2 in the figure above) is an imine exchange, as the amine nitrogen on the amino acid substrate replaces the enzyme lysine nitrogen in the imine linkage. This substrate-coenzyme adduct is stabilized by a favorable hydrogen bond between the phenol of PLP and the imine nitrogen.
14.4B: PLP-dependent amino acid racemases
With these preliminaries accomplished, the real PLP chemistry is ready to start. Let's look first at the reaction catalyzed by PLP-dependent alanine racemase. In section 13.2B we saw an example of a PLP-independent amino acid racemase reaction, in which the negatively-charged intermediate was simply the enolate form of a carboxylate.
Many other amino acid racemases, however, require the participation of PLP. Once it is linked to PLP in the active site, the a-proton of alanine can be abstracted by an active site base (step 3 below). The negative charge on the carbanion intermediate can, of course, be delocalized to the carboxylate group of alanine. The PLP coenzyme, however, provides a much expanded network of conjugated π-bonds over which the electron density can be delocalized all the way down to the PLP nitrogen.
This is what we mean when we say that the job of PLP is to act as an ‘electron sink’: the coenzyme is extremely efficient at absorbing, or delocalizing, the excess electron density on the deprotonated a-carbon of the reaction intermediate. PLP is helping the enzyme to increase the acidity of the a-hydrogen by stabilizing the conjugate base. A PLP-stabilized carbanion intermediate is commonly referred to as a quinonoid intermediate.
In the remaining steps of the alanine racemase reaction, reprotonation occurs on the opposite side of the substrate (step 4), leading to the D-amino acid.
All that remains is another imine exchange (step 5), which frees the D-alanine product and re-attaches PLP to the enzymatic lysine side-chain.
14.4C: PLP-dependent decarboxylation
In the alanine racemase reaction above, PLP assisted in breaking the Cα-H bond of the amino acid. Some PLP-dependant enzymes can catalyze the breaking of the bond between Cα and the carboxylate carbon in an amino acid by stabilizing the resulting carbanion intermediate: these are simply decarboxylation reactions. One of the final steps in the synthesis of lysine is a PLP-dependent decarboxylation.
14.4D: PLP-dependent retro-aldol and retro-Claisen reactions
Still other PLP-dependant enzymes catalyze the breaking of the bond between the alpha-carbon and the first carbon on the amino acid side chain - this is referred to as a Cα-Cβ cleavage, and it actually is a variation on the retro-aldol reaction (section 13.3C). When serine is degraded, it is first converted to glycine by serine hydroxymethyltransferase.
The retro-aldol step occurs from the PLP-serine Schiff base adduct, as the electrons from the broken bond are stabilized by the electron-sink network of the coenzyme. Just like in a standard retroaldol step, these electrons then go on to form a new carbon-hydrogen bond, leading to a PLP-glycine adduct which is freed by imine exchange.
Note that, in this reaction just as in the racemase reaction described previously, the key intermediate is a PLP-stabilized carbanion, or quinonoid.
What happens to the formaldehyde produced in this reaction? Recall from section 11.4D that it is incorporated into the coenzyme tetrahydrofolate to form 5,10-methylenetetrahydrofolate.
PLP also assists in retro-Claisen cleavage reactions (section 13.4B), such as this step in the degradation of threonine:
14.4E: PLP-dependent transamination reactions
One of the most important steps in the degradation of amino acids is elimination of the amino nitrogen atom in the form of urea, which is excreted in the urine. While the metabolic details of this 'urea cycle' are outside of the scope of this text, what is important to understand is that nitrogen atoms from many of the amino acids must be shuttled first to glutamate before being processed for elimination:
The reaction in which the nitrogen group from an amino acid is transferred to alpha-ketoglutarate is accomplished by PLP-dependent enzymes called transaminases. Once again, the first step is abstraction of the alpha-proton from the PLP-amino acid adduct.
However, in the transaminase reactions this initial deprotonation step is immediately followed by a reprotonation at what was originally the aldehyde carbon of PLP (step 2 above), which results in a new carbon-nitrogen double bond (i.e., an imine) between the a-carbon and the nitrogen of the original amino acid. This imine is then hydrolyzed (step 3 above) - this is the step where the nitrogen is removed from the amino acid to form an alpha-keto acid, which can be degraded further.
The coenzyme, which now carries an amine group and is therefore called pyridoxamine phospate (PMP), next transfers the amine group to alpha-ketoglutarate (to form glutamate) through an exact reversal of the whole process we have just seen.
In the overall transaminase reaction, the PLP coenzyme not only provides an electron sink, it also serves as a temporary 'storage space' for a nitrogen atom as it is passed from one amino acid to another.
Example 14.5
Show a complete, step-by-step mechanism for the second half of the transaminase reaction (transfer of the amine group from PLP to a-ketoglutarate to form glutamate).
Transaminase reactions also function in the biosynthesis direction for alanine, aspartate, and glutamate. Alanine, for example, is synthesized from pyruvate by the transfer of an amino group from glutamate.
14.4F: PLP-dependent beta-elimination and beta-substitution reactions
Two more reaction types in the PLP toolbox are beta-eliminations and beta-substitutions. Serine dehydratase catalyzes a beta-elimination of the hydroxyl group of serine, leading eventually to pyruvate.
After forming the normal imine linkage with PLP, the a-proton of serine is abstracted by a basic active-site lysine residue (step 1), and the coenzyme stabilizes the conjugate base.
After elimination of water (step 2), the dehydrated substrate is freed from the PLP coenzyme (step 3) by Schiff base transfer, tautomerizes to the imine form (step 4), and then is hydrolyzed to pyruvate (step 5).
A beta-substitution is simply beta-elimination followed directly by the reverse reaction (Michael addition) with a different nucleophile:
As with virtually all PLP-dependent reactions, the coenzyme serves to stabilize the carbanion intermediates.
In many bacteria, the synthesis of cysteine from serine relies upon a PLP-dependent beta-substitution step. In this pathway, serine is first acetylated by acetyl-CoA (an acyl transfer reaction).
The acetylated serine forms an imine linkage with PLP, then undergoes an elimination (steps 1-2 below) in which the acetyl group is expelled (acetyl is, of course, a much weaker base / better leaving group than a hydroxide - thus the function of the initial serine acetylation step).
A sulfhydryl ion (SH-) then attacks in a Michael addition (steps 3-4), with the intermediate stabilized again by the electron-sink property of PLP. Finally, the cysteine product is released from PLP (step 5) via an imine exchange reaction with an active site lysine.
14.4G: PLP-dependent gamma-elimination and gamma-substitution reactions
The electron sink capability of PLP allows some enzymes to catalyze eliminations at the gamma (γ) carbon of an amino acid side chain, rather than at the beta-carbon:
The secret to understanding the mechanism of a gamma-elimination is that PLP acts as an electron sink twice - it absorbs the excess electron density from not one but two proton abstractions. As an example, let's look at the cystathionine gamma-lyase reaction, which is part of the methionine degradation pathway.
Cystathionine first links to PLP in the normal way, using the amino group that is furthest away from the sulfur atom. In a familiar step, the alpha-proton is then abstracted by an enzymatic base (step 1), and the electron density is absorbed by PLP.
Next comes the new part - before anything happens to the electron density from the first proton abstraction, a second proton, this time from the beta-position on the side chain, is abstracted, forming an enamine intermediate (step 2) This is made possible by the acidic phenolic proton on the pyridoxal ring of PLP. It is this second proton abstraction that is part of a recognizable elimination reaction, as the thiol group (which is actually a cysteine amino acid) leaves and a new pi-bond forms between Cβ and Cγ(step 3). This pi-bond is short-lived, however, as the electron density from the first proton abstraction, which has been 'hiding' in PLP all this time, finally bounces back and protonates Cγ (step 4) With the usual imine transfer to an enzymatic lysine, the final product, 2-aminocrotonate, is released in step 5.
Another related reaction is the PLP-dependant gamma-substitution, which starts off like a gamma-elimination, then reverses itself with the addition of a different nucleophile.
In the synthesis of methionine, cystathionine (the starting compound in the previous gamma-elimination!) is obtained from O-succinyl homoserine and cysteine in a PLP-dependent gamma-substitution.
Example 14.6
Draw a complete mechanism for the cystathionine synthase reaction pictured above.
14.4H: Altering the course of a PLP reaction through site-directed mutagenesis
We have seen how PLP-dependent enzymes catalyze a group of reaction types - racemizations, retroaldols, transamininations, and eliminations - which, despite their apparent diversity, are all characterized by a critical carbanion intermediate that is stabilized by the electron sink of the PLP coenzyme. Given the similarities in the chemistry, it would be reasonable to propose that the active site architecture of these enzymes might also be quite close. This idea was nicely illustrated by an experiment in which site-directed mutagenesis on a single active site amino acid of PLP-dependent alanine racemase was sufficient to turn it into a retro-aldolase when provided with a suitable alternate substrate (J. Am. Chem. Soc. 2003, 125, 10158).
The catalytic base that abstracts the alpha-proton in the alanine racemase reaction is a tyrosine, assisted by a nearby histidine (see figure below). When researchers mutated the tyrosine to an alanine, and substituted beta-hydroxytyrosine for the alanine substrate, a retro-aldol reaction was catalyzed with remarkable efficiency.
Notice what has happened here: the basic histidine, with no tyrosine to deprotonate because of the mutation, instead abstracts a proton from the beta-hydroxyl group of the new substrate, setting up a retroaldol cleavage. What the researchers did, essentially, was to swap a beta-hydroxy amino acid substrate (capable of undergoing retroaldol cleavage) for the normal alanine substrate, then reposition the active site basic group so that a different acidic proton was abstracted. That was all it took to change a racemase into a retroaldolase, because the necessary electron sink system was all left in place. Why did they use the unnatural amino acid beta-hydroxy tyrosine for the retro-aldol substrate rather than threonine, which also has a beta-hydroxyl group and is closer in structure to alanine? The researchers figured that the phenyl ring of beta-hydroxy tyrosine would fit nicely in the space left empty due to the removal of the enzymatic tyrosine from the active site. To reiterate: the point of this experiment was to demonstrate how similar the chemistry being catalyzed by different PLP-dependent enzymes really is - and, as a corollary, how similar the active sites are. Even though one would not normally consider a racemization to be closely related to a retroaldol cleavage, the mechanistic themes are very close, as evidenced by researchers' ability to change the reaction product by making a single active site mutation.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/25%3A_Compounds_Derived_from_Vitamins/25.05%3A_Pyridoxal_Phosphate-_Vitamin_B6.txt |
Cobalamin, or Vitamin B12, is the largest and the most complex out of all the types of Vitamins. The discovery of Cobalamin was made as scientists were seeking to find a cure for pernicious anemia, an anemic disease caused by an absence of intrinsic factor in the stomach. Cobalamin was studied, purified, and collected into small red crystals, and its crystallize structure was determined during an X ray analysis experiment conducted by Scientist Hodkin. A molecule structure of Cobalamin is simple, yet contains a lot of different varieties and complexes as shown in Figure \(1\). The examination of the vitamin’s molecular structure helps scientists to have a better understanding of how the body utilizes Vitamin B12 into building red blood cells and preventing pernicious anemia syndromes.
The metalloenzyme structure of Cobalamin presents a corrin ring with Cobalt, the only metal in the molecule, positioned right in the center of the structure by four coordinated bonds of nitrogen from four pyrrole groups. These four subunit groups are separated evenly on the same plane, directly across from each other. They are also connected to each other by a C-CH3 methylene link on the other sides, by a C-H on one side and by two pyrroles directly coming together. Together, they form a perfect corrin ring as shown in figure 2. The fifth ligand connected to Cobalt is a nitrogen coming from the 5,6-dimethhylbenzimidazole. It presents itself as an axial running straight down from the cobalt right under the corrin ring. This benzimidazole is also connected to a five carbon sugar, which eventually attaches itself to a phosphate group, and then straps back to the rest of the structure. Since the axial is stretched all the way down, the bonding between the Cobalt and the 5,6-dimethylbenzimidazole is weak and can sometimes be replaced by related molecules such as a 5-hydrozyl-benzimidazole, an adenine, or any other similar group. In the sixth position above the Corrin ring, the active site of Cobalt can directly connect to several different types of ligands. It can connect to CN to form a Cyanocobalami, to a Methyl group to form a methylcobalamin, to a 5’-deoxy adenosy group to form an adenosylcobalamin, and OH, Hydroxycobalamin. Cobalt is always ready to oxidize from 1+ change into 2+ and 3+ in order to match up with these R groups that are connected to it. For example, Hydroxocobalamin contains cobalt that has a 3+ charge while Methyladenosyl contains a cobalt that has a 1+ Charge.
The point group configuration of Cobalamin is C4v. In order to determine this symmetry, one must see that the structure is able to rotate itself four times and will eventually arrive back to its original position. Furthermore, there are no sigma h plane and no perpendicular C2 axe. However, since there are sigma v planes that cut the molecules into even parts, it is clear to determine that the structure of Cobalamin is a C4v. With Cobalt being the center metal of the molecule, Cobalamin carried a distorted octahedral configuration. The axial that connects Cobalt to the 5,6 dimethyl benzimidazole is stretched all the way down to the bottom. Its distance is several times longer than the distance from the Cobalt and the attached R group above it. This sometimes can also be referred to as a tetragonal structure. The whole shape overall is similar to an octahedral, but the two axial groups are different and separated into uneven distances. Since there is only one metalloenzyme center in the system, the point group and configuration just mentioned is also assigned to the structure as a whole. Since the metallocoenzyme structure is stretched out, it is quite weakly coordinated and can be break apart or replaced with other groups as mentioned above.
Scientists have shown that both IR and Raman Spectroscopy were used to determine the structure of the molecule. This is determined by observing the character tables of point group C4v, the point group symmetry of Cobalamin. On the IR side, one can see that there are groups such as drz, (x, y), (rz, ry). On the other hand, on the Raman side, there are groups such as x square +y square, z square, x square – y square, xy, xz, yz. The Raman side indicated that there were stretching modes in the molecule and relates back to the stretching of the 5,6 dimethyl benzimidazole axial that connected directly below the Cobalt metal. The stretching can be seen in Figure 3.
Cobalamin enzymes can catalyze a few different types of reactions. One of them is the reaction of Intramolecular rearrangements. During this rearrangement coenzyme is exchanged to the two groups attached to adjacent carbon atoms. Another reaction involves transferring the methyl group in certain methylation reactions, such as the conversion of homocysteine to methionine, biosysnthesis of choline and thymine etc. These interactions can bring beneficial values to the biological bodies.
Cobalamin has many beneficial effects in regard to biological existences. They play a role to maintain healthy body system and help to aid the production of the body’s genetic materials. Cyanocobalamin, one type of cobalamin, works to generate the forming of red blood cells and heal many different damages in the nervous system. Cobalamin also serves as a vital role in the metabolism of fatty acids essential for the maintainence of myelin. Studies have shown that people with Vitamin B12 deficiency will reveal irregular destruction of the myeline shealth, which leads to parlysis and death. Some of the other symptoms of the lack of cobalamin are poor growth, megaloblastic bone marrow, Gi tract changes, Leucoopenia and hyper-segmented nutrophills, degenerative changes in spinal cord and nervous system and excretion of methyl malonic acid and homocystin in urine.
Throughout the years, Vitamin B12 has shown to be essential for the functioning of the nervous system and the production of red blood cell. A study conducted by researchers at the National Institutes of Health, Trinity College Dublin, suggested that a deficiency in Vitamin B12 might increase the risk of neural tubes defect in children (Miller). Therefore, by studying the structure and function of Cobalamin, scientists can experiment and form Vitamin B12 in their laboratories and serve the community as a whole. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/25%3A_Compounds_Derived_from_Vitamins/25.06%3A_Coenzyme_B12-_Vitamin_B12.txt |
The use of food by organisms is termed nutrition. Vitamins and minerals necessary for biochemical processes. There are three general categories of food: (1) Essential fiber which are non-digestible polysaccharide material, essential for normal functioning of animal digestive systems (i.e. colon), (2) Energy-yielding nutrients which are protein, carbohydrate and lipid and (3) Micronutrients.
Protein
Animals are unable to synthesize certain amino acids (humans can only make 10 of the 20 common amino acids). The amino acids that an animal is unable to synthesize must be obtained from the diet (i.e. by consuming plants or microorganisms), and these amino acids are termed "essential amino acids".
Excess dietary protein becomes a source of metabolic energy
• Glucogenic amino acids: can be converted into glucose
• Ketogenic amino acids: can be converted into fatty acids or keto acids
• If plenty of fats and carbohydrates are available, then the glucogenic and ketogenic amino acids from excess dietary protein are converted to triacylglycerol and stored as fat
Protein is an important source of nitrogen in the diet. Protein within the body is constantly turning over (i.e. being degraded and resynthesized). Furthermore, there is a general demand for protein synthesis when an organism is growing. The Nitrogen Balance refers to the relationship between the supply and demand for nitrogen (i.e. protein) within an organism.
• A positive nitrogen balance means that the organism is taking in more protein that it needs for growth or turnover
• A negative nitrogen balance means that the organism is not getting enough protein for its normal turnover, or growth. This would represent a nutritional deficiency of protein
Carbohydrate
Carbohydrates are also an essential structural component of nucleic acids, nucleotides, glycoproteins and glycolipids. However, the principle role of carbohydrate in the diet is production of metabolic energy.
• Simple sugars are metabolized in the glycolytic pathway to release energy
• Complex carbohydrates are degraded into simple sugars, which then enter the glycolytic pathway
• Metabolism can make use of a wide variety of sugars for energy production. However, the brain relies solely on glucose for an energy source
• When dietary carbohydrate exceeds the supply needed for energy requirements, it is converted to glycogen and triacylglycerols for storage
• When dietary carbohydrate is in short supply, ketone bodies are formed from acetate units to provide fuel for the brain
Lipids
Fatty acids and triacylglycerols can be used as fuel by many tissues in the human body. Phospholipids are essential components of all biological membranes
• Excess dietary fat is stored as triacylglycerols in adipose tissue
• A deficiency of dietary fat is problematic because some fatty acids cannot be synthesized by the human body, and must be obtained through diet. These are termed
• essential fatty acids
• The human body cannot synthesize linoleic, linolenic or arachidonic fatty acids. These are key components of biological membranes, and arachidonic acid is a precursor of prostaglandins (an important class of hormones). These are therefore considered essential fatty acids
Fiber
"Dietary fiber" refers to molecules that cannot be broken down by enzymes in the human body.
• Cellulose (polysaccharide component of plant cell walls). Required for proper function of colon.
• Lignins (plant polymer of aromatic ring structures). Absorbs organic molecules in the digestive system (binds cholesterol).
Vitamins and minerals
Vitamins are essential nutrients that are required in the diet because they cannot be synthesized by human metabolic enzymes. Often, only trace levels are required, but a shortage can result in disease or death.
• A common categorization of human vitamins is whether they are
• water soluble or fat soluble compounds.
Coenzymes are low molecular weight molecules that provide unique chemical functionalities for certain enzyme/coenzyme complexes.
• Coenzymes may act as carriers of specific functional groups (e.g. methyl or acyl groups)
• They can provide chemically reactive groups that the common 20 amino acid side chains cannot provide
• Coenzymes are
• usually modified in the course of a reaction, and subsequently chemically regenerated back to their useful active form. Thus, this recycling of coenzymes means that only small concentrations are required.
• All the
• water soluble vitamins (with the exception of vitamin C) are coenzymes or precursors of coenzymes.
Summary of water soluble and fat soluble vitamins:
Common name
Chemical name
Related cofactor(s)
Water Soluble Vitamins
Vitamin B1
Thiamine
Thiamine pyrophosphate
Vitamin B2
Riboflavin
Flavin adenine dinucleotide (FAD)
Flavin mononucleotide (FMN)
Vitamin B6
Pyridoxal, pyridoxine, pyridoxamine
Pyridoxal phosphate
Vitamin B12
Cobalamin
5'-deoxyadenosylcobalamin
Methylcobalamin
Niacin
Nicotinic acid
Nicotinamide adenine dinucleotide (NAD+)
Nicotinamide adenine dinucleotide phosphate (NADP+)
Vitamin B3
Pantothenic acid
Coenzyme A
Biotin
Biotin-lysine conjugates (biocytin)
Lipoic acid
Lipoyl-lysine conjugates (lipoamide)
Folic acid
Tetrahydrofolate
Vitamin C
L-ascorbate
Fat Soluble Vitamins
Vitamin A
Retinol
Vitamin D2
Ergocalciferol
Vitamin D3
Cholecalciferol
Vitamin E
a-Tocopherol
Vitamin K
Vitamin B1: Thiamine and thiamine pyrophosphate
Thiamine is the precursor of thiamine pyrophosphate (TPP):
• TPP is a coenzyme
• It is a coenzyme for certain enzymes involved in carbohydrate metabolism
• It catalyzes the synthesis or cleavage of bonds to carbonyl carbons
Niacin (Nicotinic Acid) and nicotinamide coenzymes
Nicotinamide is an essential part of two important coenzymes: nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+).
• The reduced forms of these coenzymes are NADH and NADPH
• The coenzymes participate in
• redox reactions via the direct transfer of hydride (H-) ions either to or from the cofactor and a substrate. The hydride transfer carries two electrons along with it (a proton transfer in acid/base catalysis carries no electrons)
• The hydride transfer involves the C4 carbon of the nicotinamide ring. The quaternary amine of the nicotinamide ring acts as an electron sink to promote acceptance of a hydride ion, or to facilitate leaving of a hydride ion.
• Enzymes that are involved in such redox reactions are called
• dehydrogenases
• The nucleotide part of the molecule does not enter into any chemistry, but
• is important for recognition and binding to enzymes that will use FMN or FAD as a cofactor.
Vitamin B2: Riboflavin
Riboflavin is a constituent of riboflavin 5'-phosphate (flavin mononucleotide, or FMN) and flavin adenine dinucleotide (FAD). The nucleotide part of the molecule does not enter into any chemistry, but is important for recognition and binding to enzymes that will use FMN or FAD as a cofactor.
The isoalloxazine ring is the core structure of the different flavin molecules. It is yellow in color and the word "flavin" is derived from the latin word for yellow, flavus.
• Flavin coenzymes can exists in three different redox states, and each state has a different color (the reduced form is colorless)
• Flavin molecules can participate in both
• one- and two- electron transfer reactions
Vitamin B3: pantothenic acid and coenzyme A
Pantothenic acid is a component of coenzyme A (CoA). The two main functions of CoA are:
a-hydrogen of the acyl group for removal as a proton
1. Activation of acyl groups (R-COX) for transfer to nucleophilic acceptors
2. Activation of the
Both of these functions involve the reactive sulfhydryl group through the formation of thioester linkages with acyl groups
• The 4-phosphopantetheine part of CoA is also used in the same way in
• acyl carrier proteins (ACP's) involved in fatty acid biosynthesis
Vitamin B6: Pyridoxine and pyridoxal phosphate
The biologically active form of vitamin B6 is pyridoxal-5-phosphate (PLP), however, the nutritional requirements can be met by either pyridoxine, pyridoxal or pyridoxol.
PLP participates in a wide variety of reactions involving amino acids, including:
• Transamination
• a- and b-decarboxylation
• b- and g- elimination (not to be confused with painful elimination)
• Racemization
• Aldol reactions
These involve bonds to the amino acid Ca as well as side chain carbons. The wide variety of reactions is due to the ability of PLP to form stable Schiff base adducts with a-amino groups of amino acids:
• In PLP-dependent enzymes, the PLP is present in a Schiff base linkage with the
• e-amino group of an acitve site lysine
• Rearrangement to a Schiff base with the arriving amino acid substrate is a
• transaldiminization reaction
Vitamin B12: Cyanocobalamin
Vitamin B12 is not made by any animal or plant, it is produced by only a few species of bacteria. Once in the food chain, vitamin B12 is obtained by animals by eating other animals, but plants are sadly deficient. Therefore, herbivorous animals (and vegetarians) can suffer a deficiency. The structure contains a cobalt ion, coordinated within a corrin ring structure:
Vitamin B12 (cyanocobalamin) is converted in the body into two coenzymes:
1. 5'-deoxyadenosylcobalamin (the predominant form)
2. Methylcobalamin
Vitamin B12 coenzymes participate in three types of reactions:
1. Intramolecular rearrangements
2. Reductions of ribonucleotides to deoxyribonucleotides in certain bacteria
3. Methyl group transfers (these use methylcobalamin for this purpose)
Vitamin C (L-Ascorbate)
L-Ascorbate is a reducing sugar (has a reactive ene-diol structure) that is involved in the following biochemical processes:
• Hydroxylation of proline and lysine residues in collagen. Without these post-translational modifications the triple helix of collagen is unstable and connective tissue loses its integrity. This is the problem in the disease known as
• scurvy.
• Mobilization of iron, stimulation of immune system, anti-oxidant for scavenging of reactive free-radicals.
Almost all animals can synthesize vitamin C (its in the pathway of carbohydrate synthesis). Humans and great apes have suffered a mutation in the last enzyme in the pathway of synthesis for L-ascorbate (mutation occurred about 10-40 million years ago). Since that time, all great apes (of which humans are a member) must get L-ascorbate from their diet (fresh fruits and vegetable contain an abundance). Thus, for the great apes L-ascorbate is a "vitamin" (another way of looking at it is that all great apes suffer an in-born error in metabolism). Humans still have the gene for the enzyme to make vitamin C. However, it has suffered a couple of deletions that introduce a frame shift mutation, in addition to numerous point mutations.
Biotin
Biotin acts as a mobile carboxyl group carrier in a variety of enzymatic carboxylation reactions.
• Synthesized by intestinal bacteria (finaly, they do something for you)
• Biotin is bound covalently to the enzyme as a prosthetic group via an
• e-amino group of a lysine residue in the enzyme
• This biotin-lysine conjugated amino acid is termed a "biocytin" residue
• The lysine side-chain acts as a flexible "tether" for the biotin, and this flexibility allows the transfer of carboxylate groups within the enzyme
• It is the carrier for the most oxidized form of carbon
• - CO2 (using bicarbonate as the carboxylating agent). The carbon dioxide binds as a carboxy group to one of the ring nitrogens in the biotin
Lipoic Acid
Lipoic acid contains two sulfur atoms that can exist as a disulfide bonded pair, or as two free sulfhydrils. Conversion between the two forms involves a redox reaction (the two free sulfhydrils represent the reduced form). Lipoic acid is typically found covalently attached to a lysine side chain in enzymes that use it as a cofactor, as a lipoamide complex.
• Lipoic acid is an
• acyl group carrier (R-CO-X)
• It also functions to transfer electrons during oxidation and decarboxylation of
• a-keto acids
• Pyruvate dehydrogenase and
• a-ketoglutarate dehydrogenase use lipoic acid as a cofactor
• Its not clear whether a dietary deficiency of lipoic acid contributes to a disease state, so its not technically considered a vitamin
Folic Acid
Folic acid derivatives (i.e. "folates") are acceptors and donors of one-carbon units for all oxidation levels of carbon (except for the most oxidized form - CO2. See biotin above).
• The active coenzyme form is tetrahydrofolate (THF). Folate is reduced to THF by the action of tetrahydrofolate reductase.
• Three different oxidation states of carbon can bind to THF. These are oxidation states of -2 (methanol group), 0 (formaldehyde group) and +2 (formate group)
• These groups are attached to the THF molecule at either the N5 or N10 atom positions
• The biosynthetic pathways of
• methionine, homocysteine, purines, and thymine rely one one-carbon units being provided by THF.
Vitamin A: Retinol
Vitamin A occurs as an ester (Retinyl ester), aldehyde (Retinal) or acidic form (Retinoic acid).
• It is a fat soluble vitamin, and is synthesized from isoprene building blocks
• Obtained directly from an animal diet, or synthesized from
• b-carotene provided by plants
• It is essential to vision. Retinol transported to the eyes is oxidized by retinol dehydrogenase to produce trans-retinal. Trans-retinal is converted to 11-cis-retinal by retinal isomerase. The aldehyde group of retinal forms a Schiff base with a lysin of the protein opsin, to form rhodopsin (the light-sensitive pigment of vision).
• Vitamin A is essential for various biological processes - including fetal development and sperm development. But excessive vitamin A is toxic.
Vitamin D: Ergocalciferol (D2) and cholecalciferol (D3)
Cholecalciferol is produced in the skin of animals by the action of U.V. light on the precursor molecule 7-dehydrocholesterol.
• Light energy induces bond-breakage (between carbons 9 and 10) and formation of previtamin D3. Spontaneous isomerization produces D3
• Ergocalciferol is produced by the action of U.V. light on the plant sterol ergosterol.
• Since humans can produce D3 from 7-dehydrocholesterol, vitamin D3 is technically not really a vitamin
• Cholecalciferol is really a prohormone. Derivatives of this compound
• regulate calcium and phosphate metabolism.
• Inadequate intestinal absorption of calcium and phosphate can result in demineralization of bones, and the disease Rickets.
Vitamin E: Tocopherol
a-Tocopherol is a potent antioxidant, however, molecular details of its function are not clearly understood.
• Fatty acids in membranes are susceptible to oxidative damage
• Vitamin E is fat soluble and may protect membrane fatty acids from oxidation
• A deficiency of vitamin E results in red blood cells that are susceptible to oxidative damage
• Retinal damage in premature infants, due to supplemental oxygen, may be preventable by administering vitamin E
Vitamin K: Napthoquinone
Vitamin K is essential to the blood-clotting process. Vitamin K is required for the post-translational modification to produce g-carboxy glutamic acid from glutamic acid. Such modified residues can bind Ca2+, which is an essential part of the process in the clotting cascade.
g-carboxy glutamic acids in their structure
• Prothrombin ("factor II"), and factors VII, IX and X are serine proteases that participate in a protease activation cascade that is involved in blood coagulation, and have
Contributors and Attributions
• Dr Michael Blaber
25.08: Vitamin KH2- Vitamin K
The essential dietary substances called vitamins are commonly classified as "water soluble" or "fat soluble". Water soluble vitamins, such as vitamin C, are rapidly eliminated from the body and their dietary levels need to be relatively high. The recommended daily allotment (RDA) of vitamin C is 100 mg, and amounts as large as 2 to 3 g are taken by many people without adverse effects. The lipid soluble vitamins, shown in the diagram below, are not as easily eliminated and may accumulate to toxic levels if consumed in large quantity. The RDA for these vitamins are:
• Vitamin A 800 μg ( upper limit ca. 3000 μg)
• Vitamin D 5 to 10 μg ( upper limit ca. 2000 μg)
• Vitamin E 15 mg ( upper limit ca. 1 g)
• Vitamin K 110 μg ( upper limit not specified)
From this data it is clear that vitamins A and D, while essential to good health in proper amounts, can be very toxic. Vitamin D, for example, is used as a rat poison, and in equal weight is more than 100 times as poisonous as sodium cyanide.
From the structures shown here, it should be clear that these compounds have more than a solubility connection with lipids. Vitamins A is a terpene, and vitamins E and K have long terpene chains attached to an aromatic moiety. The structure of vitamin D can be described as a steroid in which ring B is cut open and the remaining three rings remain unchanged. The precursors of vitamins A and D have been identified as the tetraterpene beta-carotene and the steroid ergosterol, respectively.
Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/25%3A_Compounds_Derived_from_Vitamins/25.07%3A_Tetrahydrofolate-_Folic_Acid.txt |
10.1A: Nomenclature and abbreviations
Phosphoryl groups are derivatives of phosphoric acid, a strong acid that is commonly used in the laboratory. The fully deprotonated conjugate base of phosphoric acid is called a phosphate ion, or inorganic phosphate (often abbreviated 'Pi'). When two phosphate groups are linked to each other, the linkage is referred to as a 'phosphate anhydride', and the ion is called 'inorganic pyrophosphate' (abbreviation PPi).
When a phosphate ion is attached to a carbon atom on an organic molecule, the chemical linkage is referred to as a phosphate ester, and the whole species is called an organic monophosphate. Glucose-6-phosphate is an example.
If an organic molecule is linked to two or three phosphate groups, the resulting species are called organic diphosphates and organic triphosphates.
Isopententyl diphosphate and adenosine triphosphate (ATP) are good examples:
Oxygen atoms in phosphate groups are referred to either 'bridging' and 'non-bridging', depending on their position. An organic diphosphate has two bridging and five non-bridging oxygens.
When a single phosphate is linked to two organic groups, the term 'phosphate diester' is used. The backbone of DNA is composed of phosphate diesters.
The term 'phosphoryl group' is a general way to refer to all of the phosphate-based groups mentioned in the paragraphs above.
Recall (section 1.4A) that phosphate groups on organic structures are sometimes abbreviated simply as 'P', a convention that we will use throughout this text. For example, glucose-6-phosphate and isopentenyl diphosphate are often depicted as shown below. Notice that the 'P' abbreviation includes the oxygen atoms and negative charges associated with the phosphate groups.
10.1B: Acid constants and protonation states
Phosphoric acid is triprotic, meaning that it has three acidic hydrogens available to donate, with pKa values of 2.1, 7.2, and 12.3, respectively. These acid constant values tell us that, at the physiological pH of approximately 7.3, all phosphoric acid species in solution will have donated at least one proton, and more than half will have donated two, meaning that the average charge on the phosphate ion is slightly higher than -1.5. Organic monophosphates, diphosphates, and triphosphates are predominantly deprotonated at pH 7.3, meaning that they carry charges of slightly less than -2, -3, and -4, respectively. By convention, they are usually drawn in their fully deprotonated states.
10.1C: Bonding in phosphines and phosphates
Looking at the location of phosphorus on the periodic table, you might expect it to bond and react in a fashion similar to nitrogen, which is located just above it in the fifth column. Indeed, phosphines - phosphorus analogs of amines - are commonly used in the organic laboratory.
Just like in amines, the central phosphorus atom in a phosphine is sp3 hybridized, with a lone pair of electrons occupying one of the four sp3 hybrid orbitals. In the case of phosphines, however, the sp3 orbitals are hybrids of a single 3s orbital and three 3p orbitals, rather than 2s and 2p orbitals as in amines.
In biological molecules, the most important form of phosphorus is not phosphine, but the phosphoryl group. The four oxygen substituents in phosphoryl groups are arranged about the central phosphorus atom with tetrahedral geometry, however there are a total of five bonds to phosphorus - four s igmabonds and one delocalized pi bond. The reason that phosphorus can break the 'octet rule' is that it is on the third row of the periodic table, and thus has d orbitals available for bonding. In the hybrid orbital picture for phosphate ion (PO4 3-), a single 3s and three 3p orbitals combine to form four sp3 hybrid orbitals with tetrahedral geometry. Four of the five valance electrons on phosphorus occupy sp3 orbitals, and the fifth occupies an unhybridized d orbital.
The phosphorus is thus able to form five bonding interactions, rather than three as is phosphine. The four sp3 orbitals on phosphorus are each able to overlap with an sp2 orbital on an oxygen atom (forming a tetrahedral framework), while a delocalized fifth bond (a pi bond) is formed by side-by-side overlap of the d orbital on phosphorus with 2p orbitals on the oxygens.
The -3 charge on a fully deprotonated phosphate ion is spread evenly over the four oxygens, and each phosphorus-oxygen bond can be considered have some double bond character.
In phosphate esters, diesters, and anhydrides the pi bonding is delocalized primarily over the non-bridging bonds, while the bridging bonds have mainly single-bond character. In a phosphate diester, for example, the two non-bridging oxygens share a -1 charge, as illustrated by the two major resonance contributors. In the resonance contributors in which the bridging oxygens are shown as double bonds, there is an additional separation of charge - thus these contributors are minor and make a relatively unimportant contribution to the overall bonding picture.
Template:examplestart
Exercise 10.1: Draw all of the resonance structures showing the delocalization of charge on a (fully deprotonated) organic monophosphate. If a 'bond order' of 1.0 is a single bond, and a bond order of 2.0 is a double bond, what is the approximate bond order of bridging and non-bridging P-O bonds?
Solution
Template:exampleEnd
Throughout this chapter, phosphoryl groups are usually drawn without attempting to show tetrahedral geometry, and π bonds and negative charges will often be shown as localized to one position. This is done for the sake of simplification - however it is important always to remember that the phosphoryl group is really tetrahedral, and that the pi electrons are delocalized over the non-bridging bonds.
10.1D: Phosphoryl transfer reactions - the general picture
In a phosphoryl transfer reaction, a phosphoryl group is transferred from a phosphoryl group donor molecule (designated 'R2' in the figure below) to a phosphoryl group acceptor (designated 'R1'). The figure below illustrates the transfer of a single phosphate group from R2 to R1:
An alcohol, for example, can be transformed into an organic monophosphate by accepting one of the phosphate groups of ATP (we'll learn more about ATP soon).
An organic monophosphate is converted back to an alcohol when it transfers its phosphate group to a water molecule:
In the course of this chapter, we will see many other types of phosphoryl transfer reactions, but they all can be described by essentially the same mechanism.
Let's look more closely at the phosphoryl transfer reaction mechanism, using as an example the transfer of a phosphate group from adenosine triphosphate (ATP) to the C6 hydroxyl group of glucose, a reaction catalyzed by glucose kinase.
To simplify things in the mechanistic discussion to come, we'll abbreviate this reaction as:
One very important aspect of biological phosphoryl transfer reactions is that the electrophilicity of the phosphorus atom is enhanced by the Lewis acid (electron-accepting) effect of one or more magnesium ions. Phosphoryl transfer-catalyzing enzymes bind Mg2+ ions in such a way that they can interact with non-bridging phosphoryl oxygens on the substrate.
The positively charged metal ions stabilize negative charge on the oxygen atoms, which has the effect of increasing the dipole moment of the phosphorus-oxygen bond. The phosphorus therefore has a larger partial positive charge, which makes it a better electrophile.
A phosphoryl transfer reaction is very much like a SN2 reaction at a carbon. Just like in an SN2 reaction, the nucleophile in a phosphoryl transfer approaches the electrophilic center from the backside, opposite the leaving group. As the nucleophile gets closer and the leaving group begins its departure, the bonding geometry at the phosphorus atom changes from tetrahedral to trigonal bipyramidal at the transition state. As the phosphorus-nucleophile bond gets shorter and the phosphorus-leaving group bond grows longer, the bonding picture around the phosphorus atom returns to its original tetrahedral state, but the stereochemical configuration has been 'flipped', or inverted.
In the trigonal bipyramidal transition state, the five substituents are not equivalent: the three non-bridging oxygens are said to be equatorial (forming the base of a trigonal bipyramid), while the nucleophile and the leaving group are said to be apical (occupying the tips of the two pyramids).
Although stereochemical inversion in phosphoryl transfer reactions is predicted by theory, the fact that phosphoryl groups are achiral made it impossible to observe the phenomenon directly until 1978, when a group of researchers was able to synthesize organic phosphate esters in which stable oxygen isotopes 17O and 18O were specifically incorporated. This created a chiral phosphate center.
Subsequent experiments with phosphoryl transfer-catalyzing enzymes confirmed that these reactions proceed with stereochemical inversion. (Nature 1978 275, 564; Ann Rev Biochem 1980 49, 877).
10.1E: Phosphoryl transfer reactions - concerted, addition-elimination, or dissociative?
In the above discussion, the phosphoryl transfer reaction mechanism was depicted as passing through a concerted SN2-like transition state, with both apical bonds in some stage of breaking or forming at the top of the 'energy hill':
This is not the only mechanism that has been proposed for these reactions - in fact, two other possible mechanisms have been suggested.
In an alternative two-step mechanistic model, the nucleophile could attack first, forming a pentavalent, trigonal bipyramidal intermediate, (as apposed to a pentavalent transition state). The reaction is completed when the leaving group is expelled. The intermediate species would occupy an energy valley between the two transition states.
This is often referred to as an 'addition-elimination' mechanism - the nucleophile adds to the phosphate first, forming a pentavalent intermediate, and then the leaving group is eliminated.
A pentavalent intermediate is not possible for an SN2 reaction at a carbon center, because carbon, as a second-row element, does not have any d orbitals and cannot form five bonds. Phosphorus, on the other hand, is a third-row element and is quite capable of forming more than four bonds. Phosphorus pentachloride, after all, is a stable compound that has five bonds to chlorine arranged in trigonal bipyramidal geometry around the central phosphorus.
The phosphorus atom in PCl5 (and in the hypothetical pentavalent intermediate pictured above) is considered to be sp3d hybridized:
There is a third possibility: the reaction could proceed in a dissociative, SN1-like manner. In this model, the phosphorus-leaving group bond breaks first, resulting in a 'metaphosphate' intermediate. This intermediate, which corresponds to the carbocation intermediate in an SN1 reaction, is then attacked by the nucleophile to form the reaction product.
So what is the actual mechanism for a phosphoryl transfer reaction - concerted, addition-elimination, or dissociative? Chemists love to investigate and argue about questions like this! Just like with the SN1/SN2 argument discussed in the previous chapter, it really boils down to one question. Which happens first, bond-forming or bond-breaking - or do these two events occur at the same time? From the evidence accumulated to date, it appears that enzymatic phosphoryl transfer reactions may occur by all three mechanisms - and often somewhere in between - depending on the nature of the nucleophile, the electrophile, and the leaving group, as well as on the active-site architecture of the enzyme catalyzing the reaction. Although it is thought that many phosphoryl transfer reactions, both enzymatic and non-enzymatic, proceed with some degree of dissociative (SN1-like) character, there is not yet a clear understanding of exactly what happens between starting compound and product. Considering the importance of phosphoryl transfer reactions in metabolic pathways, this area is clearly a very promising one for further investigation. (FASEB J. 1995 9, 1585; Trends Biochem Sci. 2004 29, 495).
For the sake of simplicity and clarity, phosphoryl transfers in this text will generally be depicted as concerted, SN2-like reactions, in two dimensions, with a localized double bond. but you should be always keep in mind the existence of a pentavalent, trigonal bipyramidal transition state/intermediate. Also, be aware that in other books and articles these reactions may be drawn somewhat differently.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/26%3A_The_Organic_Chemistry_of_Metabolic_Pathways/26.01%3A_ATP_is_Used_for_Phosphoryl_Transfer_Reactions.txt |
10.1A: Nomenclature and abbreviations
Phosphoryl groups are derivatives of phosphoric acid, a strong acid that is commonly used in the laboratory. The fully deprotonated conjugate base of phosphoric acid is called a phosphate ion, or inorganic phosphate (often abbreviated 'Pi'). When two phosphate groups are linked to each other, the linkage is referred to as a 'phosphate anhydride', and the ion is called 'inorganic pyrophosphate' (abbreviation PPi).
When a phosphate ion is attached to a carbon atom on an organic molecule, the chemical linkage is referred to as a phosphate ester, and the whole species is called an organic monophosphate. Glucose-6-phosphate is an example.
If an organic molecule is linked to two or three phosphate groups, the resulting species are called organic diphosphates and organic triphosphates.
Isopententyl diphosphate and adenosine triphosphate (ATP) are good examples:
Oxygen atoms in phosphate groups are referred to either 'bridging' and 'non-bridging', depending on their position. An organic diphosphate has two bridging and five non-bridging oxygens.
When a single phosphate is linked to two organic groups, the term 'phosphate diester' is used. The backbone of DNA is composed of phosphate diesters.
The term 'phosphoryl group' is a general way to refer to all of the phosphate-based groups mentioned in the paragraphs above.
Recall (section 1.4A) that phosphate groups on organic structures are sometimes abbreviated simply as 'P', a convention that we will use throughout this text. For example, glucose-6-phosphate and isopentenyl diphosphate are often depicted as shown below. Notice that the 'P' abbreviation includes the oxygen atoms and negative charges associated with the phosphate groups.
10.1B: Acid constants and protonation states
Phosphoric acid is triprotic, meaning that it has three acidic hydrogens available to donate, with pKa values of 2.1, 7.2, and 12.3, respectively. These acid constant values tell us that, at the physiological pH of approximately 7.3, all phosphoric acid species in solution will have donated at least one proton, and more than half will have donated two, meaning that the average charge on the phosphate ion is slightly higher than -1.5. Organic monophosphates, diphosphates, and triphosphates are predominantly deprotonated at pH 7.3, meaning that they carry charges of slightly less than -2, -3, and -4, respectively. By convention, they are usually drawn in their fully deprotonated states.
10.1C: Bonding in phosphines and phosphates
Looking at the location of phosphorus on the periodic table, you might expect it to bond and react in a fashion similar to nitrogen, which is located just above it in the fifth column. Indeed, phosphines - phosphorus analogs of amines - are commonly used in the organic laboratory.
Just like in amines, the central phosphorus atom in a phosphine is sp3 hybridized, with a lone pair of electrons occupying one of the four sp3 hybrid orbitals. In the case of phosphines, however, the sp3 orbitals are hybrids of a single 3s orbital and three 3p orbitals, rather than 2s and 2p orbitals as in amines.
In biological molecules, the most important form of phosphorus is not phosphine, but the phosphoryl group. The four oxygen substituents in phosphoryl groups are arranged about the central phosphorus atom with tetrahedral geometry, however there are a total of five bonds to phosphorus - four s igmabonds and one delocalized pi bond. The reason that phosphorus can break the 'octet rule' is that it is on the third row of the periodic table, and thus has d orbitals available for bonding. In the hybrid orbital picture for phosphate ion (PO4 3-), a single 3s and three 3p orbitals combine to form four sp3 hybrid orbitals with tetrahedral geometry. Four of the five valance electrons on phosphorus occupy sp3 orbitals, and the fifth occupies an unhybridized d orbital.
The phosphorus is thus able to form five bonding interactions, rather than three as is phosphine. The four sp3 orbitals on phosphorus are each able to overlap with an sp2 orbital on an oxygen atom (forming a tetrahedral framework), while a delocalized fifth bond (a pi bond) is formed by side-by-side overlap of the d orbital on phosphorus with 2p orbitals on the oxygens.
The -3 charge on a fully deprotonated phosphate ion is spread evenly over the four oxygens, and each phosphorus-oxygen bond can be considered have some double bond character.
In phosphate esters, diesters, and anhydrides the pi bonding is delocalized primarily over the non-bridging bonds, while the bridging bonds have mainly single-bond character. In a phosphate diester, for example, the two non-bridging oxygens share a -1 charge, as illustrated by the two major resonance contributors. In the resonance contributors in which the bridging oxygens are shown as double bonds, there is an additional separation of charge - thus these contributors are minor and make a relatively unimportant contribution to the overall bonding picture.
Template:examplestart
Exercise 10.1: Draw all of the resonance structures showing the delocalization of charge on a (fully deprotonated) organic monophosphate. If a 'bond order' of 1.0 is a single bond, and a bond order of 2.0 is a double bond, what is the approximate bond order of bridging and non-bridging P-O bonds?
Solution
Template:exampleEnd
Throughout this chapter, phosphoryl groups are usually drawn without attempting to show tetrahedral geometry, and π bonds and negative charges will often be shown as localized to one position. This is done for the sake of simplification - however it is important always to remember that the phosphoryl group is really tetrahedral, and that the pi electrons are delocalized over the non-bridging bonds.
10.1D: Phosphoryl transfer reactions - the general picture
In a phosphoryl transfer reaction, a phosphoryl group is transferred from a phosphoryl group donor molecule (designated 'R2' in the figure below) to a phosphoryl group acceptor (designated 'R1'). The figure below illustrates the transfer of a single phosphate group from R2 to R1:
An alcohol, for example, can be transformed into an organic monophosphate by accepting one of the phosphate groups of ATP (we'll learn more about ATP soon).
An organic monophosphate is converted back to an alcohol when it transfers its phosphate group to a water molecule:
In the course of this chapter, we will see many other types of phosphoryl transfer reactions, but they all can be described by essentially the same mechanism.
Let's look more closely at the phosphoryl transfer reaction mechanism, using as an example the transfer of a phosphate group from adenosine triphosphate (ATP) to the C6 hydroxyl group of glucose, a reaction catalyzed by glucose kinase.
To simplify things in the mechanistic discussion to come, we'll abbreviate this reaction as:
One very important aspect of biological phosphoryl transfer reactions is that the electrophilicity of the phosphorus atom is enhanced by the Lewis acid (electron-accepting) effect of one or more magnesium ions. Phosphoryl transfer-catalyzing enzymes bind Mg2+ ions in such a way that they can interact with non-bridging phosphoryl oxygens on the substrate.
The positively charged metal ions stabilize negative charge on the oxygen atoms, which has the effect of increasing the dipole moment of the phosphorus-oxygen bond. The phosphorus therefore has a larger partial positive charge, which makes it a better electrophile.
A phosphoryl transfer reaction is very much like a SN2 reaction at a carbon. Just like in an SN2 reaction, the nucleophile in a phosphoryl transfer approaches the electrophilic center from the backside, opposite the leaving group. As the nucleophile gets closer and the leaving group begins its departure, the bonding geometry at the phosphorus atom changes from tetrahedral to trigonal bipyramidal at the transition state. As the phosphorus-nucleophile bond gets shorter and the phosphorus-leaving group bond grows longer, the bonding picture around the phosphorus atom returns to its original tetrahedral state, but the stereochemical configuration has been 'flipped', or inverted.
In the trigonal bipyramidal transition state, the five substituents are not equivalent: the three non-bridging oxygens are said to be equatorial (forming the base of a trigonal bipyramid), while the nucleophile and the leaving group are said to be apical (occupying the tips of the two pyramids).
Although stereochemical inversion in phosphoryl transfer reactions is predicted by theory, the fact that phosphoryl groups are achiral made it impossible to observe the phenomenon directly until 1978, when a group of researchers was able to synthesize organic phosphate esters in which stable oxygen isotopes 17O and 18O were specifically incorporated. This created a chiral phosphate center.
Subsequent experiments with phosphoryl transfer-catalyzing enzymes confirmed that these reactions proceed with stereochemical inversion. (Nature 1978 275, 564; Ann Rev Biochem 1980 49, 877).
10.1E: Phosphoryl transfer reactions - concerted, addition-elimination, or dissociative?
In the above discussion, the phosphoryl transfer reaction mechanism was depicted as passing through a concerted SN2-like transition state, with both apical bonds in some stage of breaking or forming at the top of the 'energy hill':
This is not the only mechanism that has been proposed for these reactions - in fact, two other possible mechanisms have been suggested.
In an alternative two-step mechanistic model, the nucleophile could attack first, forming a pentavalent, trigonal bipyramidal intermediate, (as apposed to a pentavalent transition state). The reaction is completed when the leaving group is expelled. The intermediate species would occupy an energy valley between the two transition states.
This is often referred to as an 'addition-elimination' mechanism - the nucleophile adds to the phosphate first, forming a pentavalent intermediate, and then the leaving group is eliminated.
A pentavalent intermediate is not possible for an SN2 reaction at a carbon center, because carbon, as a second-row element, does not have any d orbitals and cannot form five bonds. Phosphorus, on the other hand, is a third-row element and is quite capable of forming more than four bonds. Phosphorus pentachloride, after all, is a stable compound that has five bonds to chlorine arranged in trigonal bipyramidal geometry around the central phosphorus.
The phosphorus atom in PCl5 (and in the hypothetical pentavalent intermediate pictured above) is considered to be sp3d hybridized:
There is a third possibility: the reaction could proceed in a dissociative, SN1-like manner. In this model, the phosphorus-leaving group bond breaks first, resulting in a 'metaphosphate' intermediate. This intermediate, which corresponds to the carbocation intermediate in an SN1 reaction, is then attacked by the nucleophile to form the reaction product.
So what is the actual mechanism for a phosphoryl transfer reaction - concerted, addition-elimination, or dissociative? Chemists love to investigate and argue about questions like this! Just like with the SN1/SN2 argument discussed in the previous chapter, it really boils down to one question. Which happens first, bond-forming or bond-breaking - or do these two events occur at the same time? From the evidence accumulated to date, it appears that enzymatic phosphoryl transfer reactions may occur by all three mechanisms - and often somewhere in between - depending on the nature of the nucleophile, the electrophile, and the leaving group, as well as on the active-site architecture of the enzyme catalyzing the reaction. Although it is thought that many phosphoryl transfer reactions, both enzymatic and non-enzymatic, proceed with some degree of dissociative (SN1-like) character, there is not yet a clear understanding of exactly what happens between starting compound and product. Considering the importance of phosphoryl transfer reactions in metabolic pathways, this area is clearly a very promising one for further investigation. (FASEB J. 1995 9, 1585; Trends Biochem Sci. 2004 29, 495).
For the sake of simplicity and clarity, phosphoryl transfers in this text will generally be depicted as concerted, SN2-like reactions, in two dimensions, with a localized double bond. but you should be always keep in mind the existence of a pentavalent, trigonal bipyramidal transition state/intermediate. Also, be aware that in other books and articles these reactions may be drawn somewhat differently.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/26%3A_The_Organic_Chemistry_of_Metabolic_Pathways/26.02%3A_The_Three_Mechanisms_for_Phosphoryl_Transfer_Reactions.txt |
10.1A: Nomenclature and abbreviations
Phosphoryl groups are derivatives of phosphoric acid, a strong acid that is commonly used in the laboratory. The fully deprotonated conjugate base of phosphoric acid is called a phosphate ion, or inorganic phosphate (often abbreviated 'Pi'). When two phosphate groups are linked to each other, the linkage is referred to as a 'phosphate anhydride', and the ion is called 'inorganic pyrophosphate' (abbreviation PPi).
When a phosphate ion is attached to a carbon atom on an organic molecule, the chemical linkage is referred to as a phosphate ester, and the whole species is called an organic monophosphate. Glucose-6-phosphate is an example.
If an organic molecule is linked to two or three phosphate groups, the resulting species are called organic diphosphates and organic triphosphates.
Isopententyl diphosphate and adenosine triphosphate (ATP) are good examples:
Oxygen atoms in phosphate groups are referred to either 'bridging' and 'non-bridging', depending on their position. An organic diphosphate has two bridging and five non-bridging oxygens.
When a single phosphate is linked to two organic groups, the term 'phosphate diester' is used. The backbone of DNA is composed of phosphate diesters.
The term 'phosphoryl group' is a general way to refer to all of the phosphate-based groups mentioned in the paragraphs above.
Recall (section 1.4A) that phosphate groups on organic structures are sometimes abbreviated simply as 'P', a convention that we will use throughout this text. For example, glucose-6-phosphate and isopentenyl diphosphate are often depicted as shown below. Notice that the 'P' abbreviation includes the oxygen atoms and negative charges associated with the phosphate groups.
10.1B: Acid constants and protonation states
Phosphoric acid is triprotic, meaning that it has three acidic hydrogens available to donate, with pKa values of 2.1, 7.2, and 12.3, respectively. These acid constant values tell us that, at the physiological pH of approximately 7.3, all phosphoric acid species in solution will have donated at least one proton, and more than half will have donated two, meaning that the average charge on the phosphate ion is slightly higher than -1.5. Organic monophosphates, diphosphates, and triphosphates are predominantly deprotonated at pH 7.3, meaning that they carry charges of slightly less than -2, -3, and -4, respectively. By convention, they are usually drawn in their fully deprotonated states.
10.1C: Bonding in phosphines and phosphates
Looking at the location of phosphorus on the periodic table, you might expect it to bond and react in a fashion similar to nitrogen, which is located just above it in the fifth column. Indeed, phosphines - phosphorus analogs of amines - are commonly used in the organic laboratory.
Just like in amines, the central phosphorus atom in a phosphine is sp3 hybridized, with a lone pair of electrons occupying one of the four sp3 hybrid orbitals. In the case of phosphines, however, the sp3 orbitals are hybrids of a single 3s orbital and three 3p orbitals, rather than 2s and 2p orbitals as in amines.
In biological molecules, the most important form of phosphorus is not phosphine, but the phosphoryl group. The four oxygen substituents in phosphoryl groups are arranged about the central phosphorus atom with tetrahedral geometry, however there are a total of five bonds to phosphorus - four s igmabonds and one delocalized pi bond. The reason that phosphorus can break the 'octet rule' is that it is on the third row of the periodic table, and thus has d orbitals available for bonding. In the hybrid orbital picture for phosphate ion (PO4 3-), a single 3s and three 3p orbitals combine to form four sp3 hybrid orbitals with tetrahedral geometry. Four of the five valance electrons on phosphorus occupy sp3 orbitals, and the fifth occupies an unhybridized d orbital.
The phosphorus is thus able to form five bonding interactions, rather than three as is phosphine. The four sp3 orbitals on phosphorus are each able to overlap with an sp2 orbital on an oxygen atom (forming a tetrahedral framework), while a delocalized fifth bond (a pi bond) is formed by side-by-side overlap of the d orbital on phosphorus with 2p orbitals on the oxygens.
The -3 charge on a fully deprotonated phosphate ion is spread evenly over the four oxygens, and each phosphorus-oxygen bond can be considered have some double bond character.
In phosphate esters, diesters, and anhydrides the pi bonding is delocalized primarily over the non-bridging bonds, while the bridging bonds have mainly single-bond character. In a phosphate diester, for example, the two non-bridging oxygens share a -1 charge, as illustrated by the two major resonance contributors. In the resonance contributors in which the bridging oxygens are shown as double bonds, there is an additional separation of charge - thus these contributors are minor and make a relatively unimportant contribution to the overall bonding picture.
Template:examplestart
Exercise 10.1: Draw all of the resonance structures showing the delocalization of charge on a (fully deprotonated) organic monophosphate. If a 'bond order' of 1.0 is a single bond, and a bond order of 2.0 is a double bond, what is the approximate bond order of bridging and non-bridging P-O bonds?
Solution
Template:exampleEnd
Throughout this chapter, phosphoryl groups are usually drawn without attempting to show tetrahedral geometry, and π bonds and negative charges will often be shown as localized to one position. This is done for the sake of simplification - however it is important always to remember that the phosphoryl group is really tetrahedral, and that the pi electrons are delocalized over the non-bridging bonds.
10.1D: Phosphoryl transfer reactions - the general picture
In a phosphoryl transfer reaction, a phosphoryl group is transferred from a phosphoryl group donor molecule (designated 'R2' in the figure below) to a phosphoryl group acceptor (designated 'R1'). The figure below illustrates the transfer of a single phosphate group from R2 to R1:
An alcohol, for example, can be transformed into an organic monophosphate by accepting one of the phosphate groups of ATP (we'll learn more about ATP soon).
An organic monophosphate is converted back to an alcohol when it transfers its phosphate group to a water molecule:
In the course of this chapter, we will see many other types of phosphoryl transfer reactions, but they all can be described by essentially the same mechanism.
Let's look more closely at the phosphoryl transfer reaction mechanism, using as an example the transfer of a phosphate group from adenosine triphosphate (ATP) to the C6 hydroxyl group of glucose, a reaction catalyzed by glucose kinase.
To simplify things in the mechanistic discussion to come, we'll abbreviate this reaction as:
One very important aspect of biological phosphoryl transfer reactions is that the electrophilicity of the phosphorus atom is enhanced by the Lewis acid (electron-accepting) effect of one or more magnesium ions. Phosphoryl transfer-catalyzing enzymes bind Mg2+ ions in such a way that they can interact with non-bridging phosphoryl oxygens on the substrate.
The positively charged metal ions stabilize negative charge on the oxygen atoms, which has the effect of increasing the dipole moment of the phosphorus-oxygen bond. The phosphorus therefore has a larger partial positive charge, which makes it a better electrophile.
A phosphoryl transfer reaction is very much like a SN2 reaction at a carbon. Just like in an SN2 reaction, the nucleophile in a phosphoryl transfer approaches the electrophilic center from the backside, opposite the leaving group. As the nucleophile gets closer and the leaving group begins its departure, the bonding geometry at the phosphorus atom changes from tetrahedral to trigonal bipyramidal at the transition state. As the phosphorus-nucleophile bond gets shorter and the phosphorus-leaving group bond grows longer, the bonding picture around the phosphorus atom returns to its original tetrahedral state, but the stereochemical configuration has been 'flipped', or inverted.
In the trigonal bipyramidal transition state, the five substituents are not equivalent: the three non-bridging oxygens are said to be equatorial (forming the base of a trigonal bipyramid), while the nucleophile and the leaving group are said to be apical (occupying the tips of the two pyramids).
Although stereochemical inversion in phosphoryl transfer reactions is predicted by theory, the fact that phosphoryl groups are achiral made it impossible to observe the phenomenon directly until 1978, when a group of researchers was able to synthesize organic phosphate esters in which stable oxygen isotopes 17O and 18O were specifically incorporated. This created a chiral phosphate center.
Subsequent experiments with phosphoryl transfer-catalyzing enzymes confirmed that these reactions proceed with stereochemical inversion. (Nature 1978 275, 564; Ann Rev Biochem 1980 49, 877).
10.1E: Phosphoryl transfer reactions - concerted, addition-elimination, or dissociative?
In the above discussion, the phosphoryl transfer reaction mechanism was depicted as passing through a concerted SN2-like transition state, with both apical bonds in some stage of breaking or forming at the top of the 'energy hill':
This is not the only mechanism that has been proposed for these reactions - in fact, two other possible mechanisms have been suggested.
In an alternative two-step mechanistic model, the nucleophile could attack first, forming a pentavalent, trigonal bipyramidal intermediate, (as apposed to a pentavalent transition state). The reaction is completed when the leaving group is expelled. The intermediate species would occupy an energy valley between the two transition states.
This is often referred to as an 'addition-elimination' mechanism - the nucleophile adds to the phosphate first, forming a pentavalent intermediate, and then the leaving group is eliminated.
A pentavalent intermediate is not possible for an SN2 reaction at a carbon center, because carbon, as a second-row element, does not have any d orbitals and cannot form five bonds. Phosphorus, on the other hand, is a third-row element and is quite capable of forming more than four bonds. Phosphorus pentachloride, after all, is a stable compound that has five bonds to chlorine arranged in trigonal bipyramidal geometry around the central phosphorus.
The phosphorus atom in PCl5 (and in the hypothetical pentavalent intermediate pictured above) is considered to be sp3d hybridized:
There is a third possibility: the reaction could proceed in a dissociative, SN1-like manner. In this model, the phosphorus-leaving group bond breaks first, resulting in a 'metaphosphate' intermediate. This intermediate, which corresponds to the carbocation intermediate in an SN1 reaction, is then attacked by the nucleophile to form the reaction product.
So what is the actual mechanism for a phosphoryl transfer reaction - concerted, addition-elimination, or dissociative? Chemists love to investigate and argue about questions like this! Just like with the SN1/SN2 argument discussed in the previous chapter, it really boils down to one question. Which happens first, bond-forming or bond-breaking - or do these two events occur at the same time? From the evidence accumulated to date, it appears that enzymatic phosphoryl transfer reactions may occur by all three mechanisms - and often somewhere in between - depending on the nature of the nucleophile, the electrophile, and the leaving group, as well as on the active-site architecture of the enzyme catalyzing the reaction. Although it is thought that many phosphoryl transfer reactions, both enzymatic and non-enzymatic, proceed with some degree of dissociative (SN1-like) character, there is not yet a clear understanding of exactly what happens between starting compound and product. Considering the importance of phosphoryl transfer reactions in metabolic pathways, this area is clearly a very promising one for further investigation. (FASEB J. 1995 9, 1585; Trends Biochem Sci. 2004 29, 495).
For the sake of simplicity and clarity, phosphoryl transfers in this text will generally be depicted as concerted, SN2-like reactions, in two dimensions, with a localized double bond. but you should be always keep in mind the existence of a pentavalent, trigonal bipyramidal transition state/intermediate. Also, be aware that in other books and articles these reactions may be drawn somewhat differently.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/26%3A_The_Organic_Chemistry_of_Metabolic_Pathways/26.03%3A_The_High-Energy_Character_of_Phosphoanhydride_Bonds.txt |
Learning Objectives
• To describe the importance of ATP as a source of energy in living organisms.
Adenosine triphosphate (ATP), a nucleotide composed of adenine, ribose, and three phosphate groups, is perhaps the most important of the so-called energy-rich compounds in a cell. Its concentration in the cell varies from 0.5 to 2.5 mg/mL of cell fluid.
Energy-rich compounds are substances having particular structural features that lead to a release of energy after hydrolysis. As a result, these compounds are able to supply energy for biochemical processes that require energy. The structural feature important in ATP is the phosphoric acid anhydride, or pyrophosphate, linkage:
The pyrophosphate bond, symbolized by a squiggle (~), is hydrolyzed when ATP is converted to adenosine diphosphate (ADP). In this hydrolysis reaction, the products contain less energy than the reactants; there is a release of energy (> 7 kcal/mol). One reason for the amount of energy released is that hydrolysis relieves the electron-electron repulsions experienced by the negatively charged phosphate groups when they are bonded to each other (Figure 20.1.1).
Energy is released because the products (ADP and phosphate ion) have less energy than the reactants [ATP and water (H2O)].
The general equation for ATP hydrolysis is as follows:
$ATP + H_2O → ADP + P_i + 7.4\; kcal/mol \nonumber$
If the hydrolysis of ATP releases energy, its synthesis (from ADP) requires energy. In the cell, ATP is produced by those processes that supply energy to the organism (absorption of radiant energy from the sun in green plants and breakdown of food in animals), and it is hydrolyzed by those processes that require energy (the syntheses of carbohydrates, lipids, proteins; the transmission of nerve impulses; muscle contractions). In fact, ATP is the principal medium of energy exchange in biological systems. Many scientists call it the energy currency of cells.
$P_i$ is the symbol for the inorganic phosphate anions $H_2PO_4^−$ and $HPO_4^{2−}$.
ATP is not the only high-energy compound needed for metabolism. Several others are listed in Table $1$. Notice, however, that the energy released when ATP is hydrolyzed is approximately midway between those of the high-energy and the low-energy phosphate compounds. This means that the hydrolysis of ATP can provide energy for the phosphorylation of the compounds below it in the table. For example, the hydrolysis of ATP provides sufficient energy for the phosphorylation of glucose to form glucose 1-phosphate. By the same token, the hydrolysis of compounds, such as creatine phosphate, that appear above ATP in the table can provide the energy needed to resynthesize ATP from ADP.
Table $1$: Energy Released by Hydrolysis of Some Phosphate Compounds
Type Example Energy Released (kcal/mol)
acyl phosphate
1,3-bisphosphoglycerate (BPG) −11.8
acetyl phosphate −11.3
guanidine phosphates
creatine phosphate −10.3
arginine phosphate −9.1
pyrophosphates
PPi* → 2Pi −7.8
ATP → AMP + PPi −7.7
ATP → ADP + Pi −7.5
ADP → AMP + Pi −7.5
sugar phosphates
glucose 1-phosphate −5.0
fructose 6-phosphate −3.8
AMP → adenosine + Pi −3.4
glucose 6-phosphate −3.3
glycerol 3-phosphate −2.2
*PPi is the pyrophosphate ion.
Summary
The hydrolysis of ATP releases energy that can be used for cellular processes that require energy. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/26%3A_The_Organic_Chemistry_of_Metabolic_Pathways/26.04%3A_Why_ATP_is_Kinetically_Stable_in_a_Cell.txt |
Learning Objectives
• To describe how carbohydrates, fats, and proteins are broken down during digestion.
We have said that animals obtain chemical energy from the food—carbohydrates, fats, and proteins—they eat through reactions defined collectively as catabolism. We can think of catabolism as occurring in three stages (Figure \(1\)). In stage I, carbohydrates, fats, and proteins are broken down into their individual monomer units: carbohydrates into simple sugars, fats into fatty acids and glycerol, and proteins into amino acids. One part of stage I of catabolism is the breakdown of food molecules by hydrolysis reactions into the individual monomer units—which occurs in the mouth, stomach, and small intestine—and is referred to as digestion.
In stage II, these monomer units (or building blocks) are further broken down through different reaction pathways, one of which produces ATP, to form a common end product that can then be used in stage III to produce even more ATP. In this chapter, we will look at each stage of catabolism—as an overview and in detail.
The conversion of food into cellular energy (as ATP) occurs in three stages.
Digestion of Carbohydrates
Carbohydrate digestion begins in the mouth (Figure \(2\)) where salivary α-amylase attacks the α-glycosidic linkages in starch, the main carbohydrate ingested by humans. Cleavage of the glycosidic linkages produces a mixture of dextrins, maltose, and glucose. The α-amylase mixed into the food remains active as the food passes through the esophagus, but it is rapidly inactivated in the acidic environment of the stomach.
The primary site of carbohydrate digestion is the small intestine. The secretion of α-amylase in the small intestine converts any remaining starch molecules, as well as the dextrins, to maltose. Maltose is then cleaved into two glucose molecules by maltase. Disaccharides such as sucrose and lactose are not digested until they reach the small intestine, where they are acted on by sucrase and lactase, respectively. The major products of the complete hydrolysis of disaccharides and polysaccharides are three monosaccharide units: glucose, fructose, and galactose. These are absorbed through the wall of the small intestine into the bloodstream.
Digestion of Proteins
Protein digestion begins in the stomach (Figure \(3\)), where the action of gastric juice hydrolyzes about 10% of the peptide bonds. Gastric juice is a mixture of water (more than 99%), inorganic ions, hydrochloric acid, and various enzymes and other proteins.
The pain of a gastric ulcer is at least partially due to irritation of the ulcerated tissue by acidic gastric juice.
The hydrochloric acid (HCl) in gastric juice is secreted by glands in the stomach lining. The pH of freshly secreted gastric juice is about 1.0, but the contents of the stomach may raise the pH to between 1.5 and 2.5. HCl helps to denature food proteins; that is, it unfolds the protein molecules to expose their chains to more efficient enzyme action. The principal digestive component of gastric juice is pepsinogen, an inactive enzyme produced in cells located in the stomach wall. When food enters the stomach after a period of fasting, pepsinogen is converted to its active form—pepsin—in a series of steps initiated by the drop in pH. Pepsin catalyzes the hydrolysis of peptide linkages within protein molecules. It has a fairly broad specificity but acts preferentially on linkages involving the aromatic amino acids tryptophan, tyrosine, and phenylalanine, as well as methionine and leucine.
Protein digestion is completed in the small intestine. Pancreatic juice, carried from the pancreas via the pancreatic duct, contains inactive enzymes such as trypsinogen and chymotrypsinogen. They are activated in the small intestine as follows (Figure \(4\)): The intestinal mucosal cells secrete the proteolytic enzyme enteropeptidase, which converts trypsinogen to trypsin; trypsin then activates chymotrypsinogen to chymotrypsin (and also completes the activation of trypsinogen). Both of these active enzymes catalyze the hydrolysis of peptide bonds in protein chains. Chymotrypsin preferentially attacks peptide bonds involving the carboxyl groups of the aromatic amino acids (phenylalanine, tryptophan, and tyrosine). Trypsin attacks peptide bonds involving the carboxyl groups of the basic amino acids (lysine and arginine). Pancreatic juice also contains procarboxypeptidase, which is cleaved by trypsin to carboxypeptidase. The latter is an enzyme that catalyzes the hydrolysis of peptide linkages at the free carboxyl end of the peptide chain, resulting in the stepwise liberation of free amino acids from the carboxyl end of the polypeptide.
Aminopeptidases in the intestinal juice remove amino acids from the N-terminal end of peptides and proteins possessing a free amino group. Figure \(5\) illustrates the specificity of these protein-digesting enzymes. The amino acids that are released by protein digestion are absorbed across the intestinal wall into the circulatory system, where they can be used for protein synthesis.
This diagram illustrates where in a peptide the different peptidases we have discussed would catalyze hydrolysis the peptide bonds.
Digestion of Lipids
Lipid digestion begins in the upper portion of the small intestine (Figure \(6\)). A hormone secreted in this region stimulates the gallbladder to discharge bile into the duodenum. The principal constituents of bile are the bile salts, which emulsify large, water-insoluble lipid droplets, disrupting some of the hydrophobic interactions holding the lipid molecules together and suspending the resulting smaller globules (micelles) in the aqueous digestive medium. These changes greatly increase the surface area of the lipid particles, allowing for more intimate contact with the lipases and thus rapid digestion of the fats. Another hormone promotes the secretion of pancreatic juice, which contains these enzymes.
The lipases in pancreatic juice catalyze the digestion of triglycerides first to diglycerides and then to 2‑monoglycerides and fatty acids:
The monoglycerides and fatty acids cross the intestinal lining into the bloodstream, where they are resynthesized into triglycerides and transported as lipoprotein complexes known as chylomicrons. Phospholipids and cholesteryl esters undergo similar hydrolysis in the small intestine, and their component molecules are also absorbed through the intestinal lining.
The further metabolism of monosaccharides, fatty acids, and amino acids released in stage I of catabolism occurs in stages II and III of catabolism.
Summary
During digestion, carbohydrates are broken down into monosaccharides, proteins are broken down into amino acids, and triglycerides are broken down into glycerol and fatty acids. Most of the digestion reactions occur in the small intestine. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/26%3A_The_Organic_Chemistry_of_Metabolic_Pathways/26.05%3A_The_Four_Stages_of_Catabolism.txt |
Learning Objectives
• To describe the reactions needed to completely oxidize a fatty acid to carbon dioxide and water.
Like glucose, the fatty acids released in the digestion of triglycerides and other lipids are broken down in a series of sequential reactions accompanied by the gradual release of usable energy. Some of these reactions are oxidative and require nicotinamide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD). The enzymes that participate in fatty acid catabolism are located in the mitochondria, along with the enzymes of the citric acid cycle, the electron transport chain, and oxidative phosphorylation. This localization of enzymes in the mitochondria is of the utmost importance because it facilitates efficient utilization of energy stored in fatty acids and other molecules.
Fatty acid oxidation is initiated on the outer mitochondrial membrane. There the fatty acids, which like carbohydrates are relatively inert, must first be activated by conversion to an energy-rich fatty acid derivative of coenzyme A called fatty acyl-coenzyme A (CoA). The activation is catalyzed by acyl-CoA synthetase. For each molecule of fatty acid activated, one molecule of coenzyme A and one molecule of adenosine triphosphate (ATP) are used, equaling a net utilization of the two high-energy bonds in one ATP molecule (which is therefore converted to adenosine monophosphate [AMP] rather than adenosine diphosphate [ADP]):
The fatty acyl-CoA diffuses to the inner mitochondrial membrane, where it combines with a carrier molecule known as carnitine in a reaction catalyzed by carnitine acyltransferase. The acyl-carnitine derivative is transported into the mitochondrial matrix and converted back to the fatty acyl-CoA.
Steps in the β-Oxidation of Fatty Acids
Further oxidation of the fatty acyl-CoA occurs in the mitochondrial matrix via a sequence of four reactions known collectively as β-oxidation because the β-carbon undergoes successive oxidations in the progressive removal of two carbon atoms from the carboxyl end of the fatty acyl-CoA (Figure $1$).
The first step in the catabolism of fatty acids is the formation of an alkene in an oxidation reaction catalyzed by acyl-CoA dehydrogenase. In this reaction, the coenzyme FAD accepts two hydrogen atoms from the acyl-CoA, one from the α-carbon and one from the β-carbon, forming reduced flavin adenine dinucleotide (FADH2).
Next, the trans-alkene is hydrated to form a secondary alcohol in a reaction catalyzed by enoyl-CoA hydratase. The enzyme forms only the L-isomer.
The secondary alcohol is then oxidized to a ketone by β-hydroxyacyl-CoA dehydrogenase, with NAD+ acting as the oxidizing agent. The reoxidation of each molecule of NADH to NAD+ by the electron transport chain furnishes 2.5–3 molecules of ATP.
The final reaction is cleavage of the β-ketoacyl-CoA by a molecule of coenzyme A. The products are acetyl-CoA and a fatty acyl-CoA that has been shortened by two carbon atoms. The reaction is catalyzed by thiolase.
The shortened fatty acyl-CoA is then degraded by repetitions of these four steps, each time releasing a molecule of acetyl-CoA. The overall equation for the β-oxidation of palmitoyl-CoA (16 carbon atoms) is as follows:
Because each shortened fatty acyl-CoA cycles back to the beginning of the pathway, β-oxidation is sometimes referred to as the fatty acid spiral.
The fate of the acetyl-CoA obtained from fatty acid oxidation depends on the needs of an organism. It may enter the citric acid cycle and be oxidized to produce energy, it may be used for the formation of water-soluble derivatives known as ketone bodies, or it may serve as the starting material for the synthesis of fatty acids. For more information about the citric acid cycle, see Section 20.4.
Looking Closer: Ketone Bodies
In the liver, most of the acetyl-CoA obtained from fatty acid oxidation is oxidized by the citric acid cycle. However, some of the acetyl-CoA is used to synthesize a group of compounds known as ketone bodies: acetoacetate, β-hydroxybutyrate, and acetone. Two acetyl-CoA molecules combine, in a reversal of the final step of β-oxidation, to produce acetoacetyl-CoA. The acetoacetyl-CoA reacts with another molecule of acetyl-CoA and water to form β-hydroxy-β-methylglutaryl-CoA, which is then cleaved to acetoacetate and acetyl-CoA. Most of the acetoacetate is reduced to β-hydroxybutyrate, while a small amount is decarboxylated to carbon dioxide and acetone.
The acetoacetate and β-hydroxybutyrate synthesized by the liver are released into the blood for use as a metabolic fuel (to be converted back to acetyl-CoA) by other tissues, particularly the kidney and the heart. Thus, during prolonged starvation, ketone bodies provide about 70% of the energy requirements of the brain. Under normal conditions, the kidneys excrete about 20 mg of ketone bodies each day, and the blood levels are maintained at about 1 mg of ketone bodies per 100 mL of blood.
In starvation, diabetes mellitus, and certain other physiological conditions in which cells do not receive sufficient amounts of carbohydrate, the rate of fatty acid oxidation increases to provide energy. This leads to an increase in the concentration of acetyl-CoA. The increased acetyl-CoA cannot be oxidized by the citric acid cycle because of a decrease in the concentration of oxaloacetate, which is diverted to glucose synthesis. In response, the rate of ketone body formation in the liver increases further, to a level much higher than can be used by other tissues. The excess ketone bodies accumulate in the blood and the urine, a condition referred to as ketosis. When the acetone in the blood reaches the lungs, its volatility causes it to be expelled in the breath. The sweet smell of acetone, a characteristic of ketosis, is frequently noticed on the breath of severely diabetic patients.
Because two of the three kinds of ketone bodies are weak acids, their presence in the blood in excessive amounts overwhelms the blood buffers and causes a marked decrease in blood pH (to 6.9 from a normal value of 7.4). This decrease in pH leads to a serious condition known as acidosis. One of the effects of acidosis is a decrease in the ability of hemoglobin to transport oxygen in the blood. In moderate to severe acidosis, breathing becomes labored and very painful. The body also loses fluids and becomes dehydrated as the kidneys attempt to get rid of the acids by eliminating large quantities of water. The lowered oxygen supply and dehydration lead to depression; even mild acidosis leads to lethargy, loss of appetite, and a generally run-down feeling. Untreated patients may go into a coma. At that point, prompt treatment is necessary if the person’s life is to be saved.
ATP Yield from Fatty Acid Oxidation
The amount of ATP obtained from fatty acid oxidation depends on the size of the fatty acid being oxidized. For our purposes here. we’ll study palmitic acid, a saturated fatty acid with 16 carbon atoms, as a typical fatty acid in the human diet. Calculating its energy yield provides a model for determining the ATP yield of all other fatty acids.
The breakdown by an organism of 1 mol of palmitic acid requires 1 mol of ATP (for activation) and forms 8 mol of acetyl-CoA. Recall from Table 20.4.1 that each mole of acetyl-CoA metabolized by the citric acid cycle yields 10 mol of ATP. The complete degradation of 1 mol of palmitic acid requires the β-oxidation reactions to be repeated seven times. Thus, 7 mol of NADH and 7 mol of FADH2 are produced. Reoxidation of these compounds through respiration yields 2.5–3 and 1.5–2 mol of ATP, respectively. The energy calculations can be summarized as follows:
ATP Yield from Fatty Acid Oxidation
1 mol of ATP is split to AMP and 2Pi −2 ATP
8 mol of acetyl-CoA formed (8 × 12) 96 ATP
7 mol of FADH2 formed (7 × 2) 14 ATP
7 mol of NADH formed (7 × 3) 21 ATP
Total 129 ATP
The number of times β-oxidation is repeated for a fatty acid containing n carbon atoms is n/2 – 1 because the final turn yields two acetyl-CoA molecules.
The combustion of 1 mol of palmitic acid releases a considerable amount of energy:
$C_{16}H_{32}O_2 + 23O_2 → 16CO_2 + 16H_2O + 2,340\; kcal \nonumber$
The percentage of this energy that is conserved by the cell in the form of ATP is as follows:
$\mathrm{\dfrac{energy\: conserved}{total\: energy\: available}\times100=\dfrac{(129\: ATP)(7.4\: kcal/ATP)}{2,340\: kcal}\times100=41\%} \nonumber$
The efficiency of fatty acid metabolism is comparable to that of carbohydrate metabolism, which we calculated to be 42%. For more information about the efficiency of fatty acid metabolism, see II of Carbohydrate Catabolism" data-cke-saved-href="/Bookshelves/Introductory_Chemistry/Basics_of_General_Organic_and_Biological_Chemistry_(Ball_et_al.)/20:_Energy_Metabolism/20.05:_Stage_II_of_Carbohydrate_Catabolism" href="/Bookshelves/Introductory_Chemistry/Basics_of_General_Organic_and_Biological_Chemistry_(Ball_et_al.)/20:_Energy_Metabolism/20.05:_Stage_II_of_Carbohydrate_Catabolism" data-quail-id="91">Section 20.5.
The oxidation of fatty acids produces large quantities of water. This water, which sustains migratory birds and animals (such as the camel) for long periods of time.
Summary
• Fatty acids, obtained from the breakdown of triglycerides and other lipids, are oxidized through a series of reactions known as β-oxidation.
• In each round of β-oxidation, 1 molecule of acetyl-CoA, 1 molecule of NADH, and 1 molecule of FADH2 are produced.
• The acetyl-CoA, NADH, and FADH2 are used in the citric acid cycle, the electron transport chain, and oxidative phosphorylation to produce ATP. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/26%3A_The_Organic_Chemistry_of_Metabolic_Pathways/26.06%3A_The_Catabolism_of_Fats.txt |
Learning Objectives
• Describe the function of glycolysis and identify its major products.
• Describe how the presence or absence of oxygen determines what happens to the pyruvate and the NADH that are produced in glycolysis.
• Determine the amount of ATP produced by the oxidation of glucose in the presence and absence of oxygen.
In stage II of catabolism, the metabolic pathway known as glycolysis converts glucose into two molecules of pyruvate (a three-carbon compound with three carbon atoms) with the corresponding production of adenosine triphosphate (ATP). The individual reactions in glycolysis were determined during the first part of the 20th century. It was the first metabolic pathway to be elucidated, in part because the participating enzymes are found in soluble form in the cell and are readily isolated and purified. The pathway is structured so that the product of one enzyme-catalyzed reaction becomes the substrate of the next. The transfer of intermediates from one enzyme to the next occurs by diffusion.
Steps in Glycolysis
The 10 reactions of glycolysis, summarized in Figures $1$ and $2$, can be divided into two phases. In the first 5 reactions—phase I—glucose is broken down into two molecules of glyceraldehyde 3-phosphate. In the last five reactions—phase II—each glyceraldehyde 3-phosphate is converted into pyruvate, and ATP is generated. Notice that all the intermediates in glycolysis are phosphorylated and contain either six or three carbon atoms.
• When glucose enters a cell, it is immediately phosphorylated to form glucose 6-phosphate, in the first reaction of phase I. The phosphate donor in this reaction is ATP, and the enzyme—which requires magnesium ions for its activity—is hexokinase. In this reaction, ATP is being used rather than being synthesized. The presence of such a reaction in a catabolic pathway that is supposed to generate energy may surprise you. However, in addition to activating the glucose molecule, this initial reaction is essentially irreversible, an added benefit that keeps the overall process moving in the right direction. Furthermore, the addition of the negatively charged phosphate group prevents the intermediates formed in glycolysis from diffusing through the cell membrane, as neutral molecules such as glucose can do.
• In the next reaction, phosphoglucose isomerase catalyzes the isomerization of glucose 6-phosphate to fructose 6-phosphate. This reaction is important because it creates a primary alcohol, which can be readily phosphorylated.
• The subsequent phosphorylation of fructose 6-phosphate to form fructose 1,6-bisphosphate is catalyzed by phosphofructokinase, which requires magnesium ions for activity. ATP is again the phosphate donor.
• Fructose 1,6-bisphosphate is enzymatically cleaved by aldolase to form two triose phosphates: dihydroxyacetone phosphate and glyceraldehyde 3-phosphate.
• Isomerization of dihydroxyacetone phosphate into a second molecule of glyceraldehyde 3-phosphate is the final step in phase I. The enzyme catalyzing this reaction is triose phosphate isomerase.
When a molecule contains two phosphate groups on different carbon atoms, the convention is to use the prefix bis. When the two phosphate groups are bonded to each other on the same carbon atom (for example, adenosine diphosphate [ADP]), the prefix is di.
In steps 4 and 5, aldolase and triose phosphate isomerase effectively convert one molecule of fructose 1,6-bisphosphate into two molecules of glyceraldehyde 3-phosphate. Thus, phase I of glycolysis requires energy in the form of two molecules of ATP and releases none of the energy stored in glucose.
In the initial step of phase II (Figure $2$), glyceraldehyde 3-phosphate is both oxidized and phosphorylated in a reaction catalyzed by glyceraldehyde-3-phosphate dehydrogenase, an enzyme that requires nicotinamide adenine dinucleotide (NAD+) as the oxidizing agent and inorganic phosphate as the phosphate donor. In the reaction, NAD+ is reduced to reduced nicotinamide adenine dinucleotide (NADH), and 1,3-bisphosphoglycerate (BPG) is formed.
• BPG has a high-energy phosphate bond (Table $1$) joining a phosphate group to C1. This phosphate group is now transferred directly to a molecule of ADP, thus forming ATP and 3-phosphoglycerate. The enzyme that catalyzes the reaction is phosphoglycerate kinase, which, like all other kinases, requires magnesium ions to function. This is the first reaction to produce ATP in the pathway. Because the ATP is formed by a direct transfer of a phosphate group from a metabolite to ADP—that is, from one substrate to another—the process is referred to as substrate-level phosphorylation, to distinguish it from the oxidative phosphorylation discussed in Section 20.4.
• In the next reaction, the phosphate group on 3-phosphoglycerate is transferred from the OH group of C3 to the OH group of C2, forming 2-phosphoglycerate in a reaction catalyzed by phosphoglyceromutase.
• A dehydration reaction, catalyzed by enolase, forms phosphoenolpyruvate (PEP), another compound possessing a high-energy phosphate group.
• The final step is irreversible and is the second reaction in which substrate-level phosphorylation occurs. The phosphate group of PEP is transferred to ADP, with one molecule of ATP being produced per molecule of PEP. The reaction is catalyzed by pyruvate kinase, which requires both magnesium and potassium ions to be active.
Table $1$: Maximum Yield of ATP from the Complete Oxidation of 1 Mol of Glucose
Reaction Comments Yield of ATP (moles)
glucose → glucose 6-phosphate consumes 1 mol ATP −1
fructose 6-phosphate → fructose 1,6-bisphosphate consumes 1 mol ATP −1
glyceraldehyde 3-phosphate → BPG produces 2 mol of cytoplasmic NADH
BPG → 3-phosphoglycerate produces 2 mol ATP +2
phosphoenolpyruvate → pyruvate produces 2 mol ATP +2
pyruvate → acetyl-CoA + CO2 produces 2 mol NADH
isocitrate → α-ketoglutarate + CO2 produces 2 mol NADH
α-ketoglutarate → succinyl-CoA + CO2 produces 2 mol NADH
succinyl-CoA → succinate produces 2 mol GTP +2
succinate → fumarate produces 2 mol FADH2
malate → oxaloacetate produces 2 mol NADH
2 cytoplasmic NADH from glycolysis yields 2–3 mol ATP per NADH (depending on tissue) +4 to +6
2 NADH from the oxidation of pyruvate yields 3 mol ATP per NADH +6
2 FADH2 from the citric acid cycle yields 2 ATP per FADH2 +4
3 NADH from the citric acid cycle yields 3 ATP per NADH +18
Net yield of ATP: +36 to +38
In phase II, two molecules of glyceraldehyde 3-phosphate are converted to two molecules of pyruvate, along with the production of four molecules of ATP and two molecules of NADH.
To Your Health: Diabetes
Although medical science has made significant progress against diabetes , it continues to be a major health threat. Some of the serious complications of diabetes are as follows:
• It is the leading cause of lower limb amputations in the United States.
• It is the leading cause of blindness in adults over age 20.
• It is the leading cause of kidney failure.
• It increases the risk of having a heart attack or stroke by two to four times.
Because a person with diabetes is unable to use glucose properly, excessive quantities accumulate in the blood and the urine. Other characteristic symptoms are constant hunger, weight loss, extreme thirst, and frequent urination because the kidneys excrete large amounts of water in an attempt to remove excess sugar from the blood.
There are two types of diabetes. In immune-mediated diabetes, insufficient amounts of insulin are produced. This type of diabetes develops early in life and is also known as Type 1 diabetes, as well as insulin-dependent or juvenile-onset diabetes. Symptoms are rapidly reversed by the administration of insulin, and Type 1 diabetics can lead active lives provided they receive insulin as needed. Because insulin is a protein that is readily digested in the small intestine, it cannot be taken orally and must be injected at least once a day.
In Type 1 diabetes, insulin-producing cells of the pancreas are destroyed by the body’s immune system. Researchers are still trying to find out why. Meanwhile, they have developed a simple blood test capable of predicting who will develop Type 1 diabetes several years before the disease becomes apparent. The blood test reveals the presence of antibodies that destroy the body’s insulin-producing cells.
Type 2 diabetes, also known as noninsulin-dependent or adult-onset diabetes, is by far the more common, representing about 95% of diagnosed diabetic cases. (This translates to about 16 million Americans.) Type 2 diabetics usually produce sufficient amounts of insulin, but either the insulin-producing cells in the pancreas do not release enough of it, or it is not used properly because of defective insulin receptors or a lack of insulin receptors on the target cells. In many of these people, the disease can be controlled with a combination of diet and exercise alone. For some people who are overweight, losing weight is sufficient to bring their blood sugar level into the normal range, after which medication is not required if they exercise regularly and eat wisely.
Those who require medication may use oral antidiabetic drugs that stimulate the islet cells to secrete insulin. First-generation antidiabetic drugs stimulated the release of insulin. Newer second-generation drugs, such as glyburide, do as well, but they also increase the sensitivity of cell receptors to insulin. Some individuals with Type 2 diabetes do not produce enough insulin and thus do not respond to these oral medications; they must use insulin. In both Type 1 and Type 2 diabetes, the blood sugar level must be carefully monitored and adjustments made in diet or medication to keep the level as normal as possible (70–120 mg/dL).
Metabolism of Pyruvate
The presence or absence of oxygen determines the fates of the pyruvate and the NADH produced in glycolysis. When plenty of oxygen is available, pyruvate is completely oxidized to carbon dioxide, with the release of much greater amounts of ATP through the combined actions of the citric acid cycle, the electron transport chain, and oxidative phosphorylation. However, in the absence of oxygen (that is, under anaerobic conditions), the fate of pyruvate is different in different organisms. In vertebrates, pyruvate is converted to lactate, while other organisms, such as yeast, convert pyruvate to ethanol and carbon dioxide. These possible fates of pyruvate are summarized in Figure $2$. The conversion to lactate or ethanol under anaerobic conditions allows for the reoxidation of NADH to NAD+ in the absence of oxygen.
ATP Yield from Glycolysis
The net energy yield from anaerobic glucose metabolism can readily be calculated in moles of ATP. In the initial phosphorylation of glucose (step 1), 1 mol of ATP is expended, along with another in the phosphorylation of fructose 6-phosphate (step 3). In step 7, 2 mol of BPG (recall that 2 mol of 1,3-BPG are formed for each mole of glucose) are converted to 2 mol of 3-phosphoglycerate, and 2 mol of ATP are produced. In step 10, 2 mol of pyruvate and 2 mol of ATP are formed per mole of glucose.
For every mole of glucose degraded, 2 mol of ATP are initially consumed and 4 mol of ATP are ultimately produced. The net production of ATP is thus 2 mol for each mole of glucose converted to lactate or ethanol. If 7.4 kcal of energy is conserved per mole of ATP produced, and the total amount of energy that can theoretically be obtained from the complete oxidation of 1 mol of glucose is 670 kcal (as stated in the chapter introduction), the energy conserved in the anaerobic catabolism of glucose to two molecules of lactate (or ethanol) is as follows:
$\mathrm{\dfrac{2\times 7.4\: kcal}{670\: kcal}\times100=2.2\%} \nonumber$
Thus anaerobic cells extract only a very small fraction of the total energy of the glucose molecule.
Contrast this result with the amount of energy obtained when glucose is completely oxidized to carbon dioxide and water through glycolysis, the citric acid cycle, the electron transport chain, and oxidative phosphorylation as summarized in Table $1$. Note the indication in the table that a variable amount of ATP is synthesized, depending on the tissue, from the NADH formed in the cytoplasm during glycolysis. This is because NADH is not transported into the inner mitochondrial membrane where the enzymes for the electron transport chain are located. Instead, brain and muscle cells use a transport mechanism that passes electrons from the cytoplasmic NADH through the membrane to flavin adenine dinucleotide (FAD) molecules inside the mitochondria, forming reduced flavin adenine dinucleotide (FADH2), which then feeds the electrons into the electron transport chain. This route lowers the yield of ATP to 1.5–2 molecules of ATP, rather than the usual 2.5–3 molecules. A more efficient transport system is found in liver, heart, and kidney cells where the formation of one cytoplasmic NADH molecule results in the formation of one mitochondrial NADH molecule, which leads to the formation of 2.5–3 molecules of ATP.The total amount of energy conserved in the aerobic catabolism of glucose in the liver is as follows:
$\mathrm{\dfrac{38\times7.4\: kcal}{670\: kcal}\times100=42\%} \nonumber$
Conservation of 42% of the total energy released compares favorably with the efficiency of any machine. In comparison, automobiles are only about 20%–25% efficient in using the energy released by the combustion of gasoline.
As indicated earlier, the 58% of released energy that is not conserved enters the surroundings (that is, the cell) as heat that helps to maintain body temperature. If we are exercising strenuously and our metabolism speeds up to provide the energy needed for muscle contraction, more heat is produced. We begin to perspire to dissipate some of that heat. As the perspiration evaporates, the excess heat is carried away from the body by the departing water vapor.
Summary
• The monosaccharide glucose is broken down through a series of enzyme-catalyzed reactions known as glycolysis.
• For each molecule of glucose that is broken down, two molecules of pyruvate, two molecules of ATP, and two molecules of NADH are produced.
• In the absence of oxygen, pyruvate is converted to lactate, and NADH is reoxidized to NAD+. In the presence of oxygen, pyruvate is converted to acetyl-CoA and then enters the citric acid cycle.
• More ATP can be formed from the breakdown of glucose when oxygen is present. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/26%3A_The_Organic_Chemistry_of_Metabolic_Pathways/26.07%3A_The_Catabolism_of_Carbohydrates.txt |
Learning Objectives
• To describe how excess amino acids are degraded.
The liver is the principal site of amino acid metabolism, but other tissues, such as the kidney, the small intestine, muscles, and adipose tissue, take part. Generally, the first step in the breakdown of amino acids is the separation of the amino group from the carbon skeleton, usually by a transamination reaction. The carbon skeletons resulting from the deaminated amino acids are used to form either glucose or fats, or they are converted to a metabolic intermediate that can be oxidized by the citric acid cycle. The latter alternative, amino acid catabolism, is more likely to occur when glucose levels are low—for example, when a person is fasting or starving.
Transamination
Transamination is an exchange of functional groups between any amino acid (except lysine, proline, and threonine) and an α-keto acid. The amino group is usually transferred to the keto carbon atom of pyruvate, oxaloacetate, or α-ketoglutarate, converting the α-keto acid to alanine, aspartate, or glutamate, respectively. Transamination reactions are catalyzed by specific transaminases (also called aminotransferases), which require pyridoxal phosphate as a coenzyme.
In an α-keto acid, the carbonyl or keto group is located on the carbon atom adjacent to the carboxyl group of the acid.
Oxidative Deamination
In the breakdown of amino acids for energy, the final acceptor of the α-amino group is α-ketoglutarate, forming glutamate. Glutamate can then undergooxidative deamination, in which it loses its amino group as an ammonium (NH4+) ion and is oxidized back to α-ketoglutarate (ready to accept another amino group):
This reaction occurs primarily in liver mitochondria. Most of the NH4+ ion formed by oxidative deamination of glutamate is converted to urea and excreted in the urine in a series of reactions known as the urea cycle.
The synthesis of glutamate occurs in animal cells by reversing the reaction catalyzed by glutamate dehydrogenase. For this reaction nicotinamide adenine dinucleotide phosphate (NADPH) acts as the reducing agent. The synthesis of glutamate is significant because it is one of the few reactions in animals that can incorporate inorganic nitrogen (NH4+) into an α-keto acid to form an amino acid. The amino group can then be passed on through transamination reactions, to produce other amino acids from the appropriate α-keto acids.
The Fate of the Carbon Skeleton
Any amino acid can be converted into an intermediate of the citric acid cycle. Once the amino group is removed, usually by transamination, the α-keto acid that remains is catabolized by a pathway unique to that acid and consisting of one or more reactions. For example, phenylalanine undergoes a series of six reactions before it splits into fumarate and acetoacetate. Fumarate is an intermediate in the citric acid cycle, while acetoacetate must be converted to acetoacetyl-coenzyme A (CoA) and then to acetyl-CoA before it enters the citric acid cycle.
Those amino acids that can form any of the intermediates of carbohydrate metabolism can subsequently be converted to glucose via a metabolic pathway known as gluconeogenesis. These amino acids are called glucogenic amino acids. Amino acids that are converted to acetoacetyl-CoA or acetyl-CoA, which can be used for the synthesis of ketone bodies but not glucose, are called ketogenic amino acids. Some amino acids fall into both categories. Leucine and lysine are the only amino acids that are exclusively ketogenic. Figure \(2\) summarizes the ultimate fates of the carbon skeletons of the 20 amino acids.
Career Focus: Exercise Physiologist
An exercise physiologist works with individuals who have or wish to prevent developing a wide variety of chronic diseases, such as diabetes, in which exercise has been shown to be beneficial. Each individual must be referred by a licensed physician. An exercise physiologist works in a variety of settings, such as a hospital or in a wellness program at a commercial business, to design and monitor individual exercise plans. A registered clinical exercise physiologist must have an undergraduate degree in exercise physiology or a related degree. Some job opportunities require a master’s degree in exercise physiology or a related degree.
Summary
Generally the first step in the breakdown of amino acids is the removal of the amino group, usually through a reaction known as transamination. The carbon skeletons of the amino acids undergo further reactions to form compounds that can either be used for the synthesis of glucose or the synthesis of ketone bodies.
26.10: The Citric Acid Cycle
Sections/problems listed with an asterisk (*) do not discuss the exact reaction indicated, but do discuss a closely related reaction.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/26%3A_The_Organic_Chemistry_of_Metabolic_Pathways/26.09%3A_The_Catabolism_of_Proteins.txt |
10.2A: ATP - the principle phosphoryl group donor
Enzymes called kinases catalyze the transfer of phosphoryl groups to organic molecules. The source of the phosphoryl group in most phosphorylation reactions is a molecule called adenosine triphosphate, abbreviated ATP.
Notice that there are essentially three parts to the molecule: an adenine nucleoside base, a five-carbon sugar (ribose), and a triphosphate group. The three phosphates are designated by Greek letters a, b, and g. Adenosine diphosphate (ADP) and adenosine monophosphate (AMP) are also important players in the reactions of this chapter.
You will see ATP, ADP, and AMP abbreviated in many different ways in this text and throughout the biochemical literature. For example, the three structures below are all abbreviated depictions of ATP:
The following exercise will give you some practice in recognizing different abbreviations for biological molecules that contain phosphate groups.
Template:ExampleStart
Exercise 10.2: Below are a number of representations, labeled A-S, of molecules that contain phosphoryl groups. Different abbreviations are used. Arrange A-S into groups of drawings that depict the same molecule, using different abbreviations (or no abbreviation at all).
You are probably familiar with the physiological role of ATP from your biology classes - it is commonly called 'the cell's energy currency'. What this means is that ATP stores - for a very short time - some of the energy derived from the oxidation of fuel molecules like carbohydrates or fats (in plants and photosynthetic bacteria, the energy comes from sunlight). The energy in ATP is stored in the two high-energy phosphate anhydride linkages.
When we speak of the energy of an ATP molecule being 'spent', what we mean is that a phosphoryl group is being transferred from ATP to some other acceptor molecule, making the acceptor molecule more reactive. For example, in many phosphoryl transfer reactions (such as the phosphorylation of glucose, which we used as an example in section 10.1D) the gamma (γ) phosphate of ATP is transferred to an organic acceptor, releasing ADP.
In other reactions, the base, ribose, and the alpha phosphate is transferred to the organic molecule to form an organic-AMP adduct, while inorganic pyrophosphate (PPi) is released.
Occasionally, the beta and gamma phosphate groups are transferred together, with the release of AMP.
In all of these reactions, a relatively stable organic molecule is being transformed into a higher energy phosphorylated product. This activated product can then go on to react in ways that its more stable, non-phosphorylated counterpart could not - phosphoryl groups, as we know, are much better leaving groups in nucleophilic substitution reactions than the hydroxyl group of alcohols. Even though the conversion of a lower-energy starting compound into a higher energy product is, by itself, a thermodynamically uphill process, the overall phosphoryl transfer reaction is thermodynamically downhill, because the conversion of ATP into ADP or AMP - the breaking of a phosphate anhydride bond - releases a great deal of energy. In other words, the energy stored in the phosphate anhydride bond of ATP has been 'spent' to create an activated (higher energy) molecule. When AMP or ADP is converted back to ATP, energy from fuel molecules (or from sunlight) is required to re-form the high energy anhydride bond (this process is the subject of discussion later in this section)
The explanation for why the phosphate anhydrides linkages in ATP are so energetic lies primarily in the concept of charge separation. Recall from section 10.1 that ATP, at the physiological pH of ~7, is almost completely ionized with a total charge of close to -4. When one of the two anhydride bonds is broken, the negative charges on the phosphate groups are able to separate, eliminating some of the same-charge repulsion that existed in ATP. One way to picture this is as a coil springing open.
Another reason has to do with the energy of solvation by water. When the gamma phosphate of ATP is transferred to an alcohol, for example, surrounding water molecules are able to form more hydrogen-bonding interactions with the products (ADP and the organic phosphate) than was possible with ATP and alcohol. These additional solvation interactions stabilize the products of the phosphorylation reaction relative to the starting compounds.
You will learn more about the thermodynamic role of ATP in metabolic pathways if you take a class in biochemistry - what is most important to understand at this point is that, because of the energy stored in its phosphate anhydride bonds, ATP is a powerful phosphoryl group donor, and is used as such in many important biochemical reactions. Some examples are discussed in the remainder of this section.
10.2B: Monophosphorylation of alcohols
Recall that almost all biomolecules are charged species, which 1) keeps them water soluble, and 2) prevents them from diffusing across lipid bilayer membranes. Although many biomolecules are ionized by virtue of negatively charged carboxylate and positively charged amino groups, the most common ionic group in biologically important organic compounds is phosphate - thus the phosphorylation of alcohol groups is a critical metabolic step. In alcohol phosphorylations, ATP is almost always the phosphate donor, and the mechanism is very consistent: the alcohol oxygen acts as a nucleophile, attacking the gamma-phosphorus of ATP and expelling ADP (look again, for example, at the glucose kinase reaction that we first saw in section 10.1D).
+ B-H
The glucose kinase reaction is the first step in glycolysis, a metabolic pathway in which the 6-carbon sugar glucose is broken down into two 3-carbon fragments called pyruvate. The third step of glycolysis also a kinase reaction: this time, it is the hydroxyl group on carbon #1 of fructose-6-phosphate that is phosphorylated (step 2 of glycolysis is the isomerization of glucose-6-phosphate to fructose-6-phosphate, a reaction we will study in section 13.2A) Once again, ATP is the phosphate donor in the fructose-6-phosphate kinase reaction:
Now, when the 6-carbon sugar breaks into two 3-carbon pieces, each piece has its own phosphate group (the carbon-carbon bond-breaking step is a reaction that we will learn about in section 13.3C).
The biological activity of many proteins is regulated by means of a very similar phosphorylation reaction catalyzed by protein kinases. In these reactions, the side chain hydroxyl groups on serine, threonine, and tyrosine residues of certain proteins are modified with the gamma phosphate from ATP.
Notice the new " ATP in, ADP out" notation used in this figure, showing that ATP is converted to ADP in the course of the reaction. From here on, we will frequently use this shorthand convention to indicate when common molecules such as ATP, water, or phosphate are participants in a reaction, either as reactants or products.
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Exercise 10.3: draw a mechanism for the kinase reaction above, using appropriate abbreviations for ATP and ADP.
Solution
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The conversion of a neutral hydroxyl group to a charged phosphate represents a very dramatic change in the local architecture of the protein, and thus it may behave very differently when phosphorylated, in terms of its overall conformation and ability to bind to small molecules or other proteins. A protein's biological function, whatever that may be, may be turned 'off' until the phosphorylation of a specific serine, threonine, or tyrosine serves as an activating 'on' switch (or vice-versa). In order to reverse the process and 'flip the switch' again, the phosphate group must be removed by a phosphatase enzyme, a reaction which we will examine later in this chapter (section 10.3).
Template:ExampleStart
Exercise 10.4: Threonine kinase catalyzes the phosphorylation of the side chain hydroxyl group of threonine residues in proteins. Draw the structure, including the configuration of all stereocenters, of a phosphothreonine residue. Explain how you can predict the stereochemistry of the side chain.
Solution
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10.2C: Diphosphorylation of alcohols
We have just seen how alcohol groups can be converted to monophosphates using ATP as the phosphate donor. In some biochemical pathways, the next step is the addition of a second phosphate group to form a diphosphate. In the early stages of the biosynthesis of ‘isoprenoid’ compounds such as cholesterol, for example, two phosphates are added sequentially to a primary alcohol group on an intermediate compound called mevalonate. The first phosphorylation is essentially the same as the reactions described in part B of this section.
In the second phosphorylation reaction, the gamma phosphate of a second ATP molecule is transferred to an oxygen atom on the first phosphate, forming a new phosphate anhydride linkage.
Another example of a diphosphorylation reaction takes place in a single step, rather than sequentially. Phosphoribosyl diphosphate (PRPP) is a very important intermediate compound in the biosynthesis of nucleotides and some amino acids, and is the product of the diphosphorylation of ribose-5-phosphate.
In this reaction, two phosphate groups (the beta and the gamma) are transferred together from ATP to a hydroxyl on ribose-5-phosphate. Notice that the beta phosphorus of ATP is the electrophile in this case, rather then the alpha phosphorus. Consequentially, the reaction results in the conversion on one ATP to one AMP, rather than two ATPs to two ADPs.
Are we getting more for our 'ATP money' in this one-step diphosphorylation? Not really - in order to convert the energy-poor AMP back up to the energy-rich ATP, the cell first has to transfer a phosphate from a second ATP molecule in a reaction catalyzed by an enzyme called adenylate kinase.
So in the end, the diphosphorylation reaction still costs the cell two ATP-to-ADP conversions.
It is worth noting that both of the diphosphate groups produced in these reactions end up as leaving groups in subsequent nucleophilic substitution reactions. Mevalonate diphosphate is eventually converted to isoprenyl diphosphate, the substrate for protein prenyltransferase (section 9.3). PRPP is the starting point for the biosynthesis of both pyrimidine (C and U/T) and purine (G, and A) nucleotides. The SN1 displacement of pyrophosphate in pyrimidine biosynthesis is shown below.
10.2D: Phosphorylation of carboxylates
Thus far we have seen alcohol oxygens and phosphate oxygens acting as nucleophilic accepting groups in phosphoryl transfer reactions. Consider next the first step of the reaction catalyzed by the enzyme glutamine synthase:
Once again in this reaction, the gamma-phosphate of ATP is transferred to an oxygen acceptor - however in this case the acceptor is a carboxylate oxygen, and the product is an acyl phosphate. As we shall see in chapter 12, acyl phosphates are commonly referred to as 'activated carboxylates', and are primed to undergo reactions called 'nucleophilic acyl substitutions'.
Template:ExampleStart
Exercise 10.5: Draw a mechanism for the acyl-phosphate-forming reaction above, using appropriate abbreviations for ATP and ADP.
Solution
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10.2E: Generation of nucleotide phosphates
Activation of the side chain carboxylate of aspartate is somewhat different from the parallel activation of glutamate shown above. While the carboxylate group in glutamate accepts a simple phosphate group from ATP, the carboxylate in aspartate attacks the alpha-phosphate of ATP, displacing inorganic pyrophosphate and accepting an entire AMP group.
The resulting 'acyl adenosine phosphate', which is technically a phosphate diester, is another form of 'activated carboxylate' that we will learn more about in chapter 12.
For some interesting variations on the phosphoryl transfer reaction, consider the early steps of isoprenoid biosynthesis in bacteria (this is a completely different pathway than that mentioned in section 10.2C, which is operative in animals). In the first step, the oxygen of a monophosphate ester attacks the a phosphate of CTP (not ATP!) to expel inorganic pyrophosphate.
In step 2, a second hydroxyl group is phosphorylated in the normal way by an ATP-dependent kinase, and in step 3 that phosphate proceeds to attack the first of the two phosphates on the nucleotide diphosphate diester, expelling CMP and forming a cyclic diphosphate. Several more steps lead to the formation of isopentenyl diphosphate, the building block molecule for all isoprenoid compounds.
10.2F: Regeneration of ATP from ADP
Throughout this section we have seen reactions in which the energy contained in an ATP anhydride bond is 'spent', and ADP or AMP is formed as a result. In order to regenerate ATP, a phosphate group must be transferred to ADP, which is of course a thermodynamically uphill reaction requiring the input of energy from the breakdown of fuel molecules or, in the case of plants, from sunlight. By far the most important source of ATP regeneration is the enzyme ATP synthase, which catalyzes the direct condensation between inorganic phosphate and ADP.
Despite the apparent simplicity of the chemistry going on here, ATP synthase is an extremely large, complex, and fascinating enzyme, with multiple protein subunits and a intricate 'molecular motor' design. The reaction must be 'driven' uphill by using the energy from a proton gradient that is set up across the inner mitochondrial membrane. You will learn much more about this amazing biochemical machine if you take a course in biochemistry.
Two other reactions in the gycolytic (sugar breakdown) pathway also result in the generation of ATP from ADP, but these are minor physiological sources of ATP compared to ATP synthase. Phosphoglycerate kinase (named according to the reverse of the reaction shown below) transfers a phosphate from an acyl phosphate to ADP.
Note that here the leaving group is a carboxylate group.
Pyruvate kinase (again the name refers to the reverse reaction) catalyzes a less familiar-looking phosphate transfer.
We will revisit this reaction in section 13.1A.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/26%3A_The_Organic_Chemistry_of_Metabolic_Pathways/26.11%3A_Oxidative_Phosphorylation.txt |
Anabolic reactions are those that lead to the synthesis of biomolecules. In contrast to the catabolic reactions just discussed (glycolysis, TCA cycle and electron transport/oxidative phosphorylation) which lead to the oxidative degradation of carbohydrates and fatty acids and energy release, anabolic reactions lead to the synthesis of more complex biomolecules including biopolymers (glycogen, proteins, nucleic acids) and complex lipids. Many biosynthetic reactions, including those for fatty acid synthesis, are reductive and hence require reducing agents. Reductive biosynthesis and complex polymer formation require energy input, usually in the form of ATP whose exergonic cleavage is coupled to endergonic biosynthesis.
Cells have evolved interesting mechanism so as not to have oxidative degradation reactions (which release energy) proceed at the same time and in the same cell as reductive biosynthesis (which requires energy input). Consider this scenario. You dive into a liver cell and find palmitic acid, a 16C fatty acid. From where did it come? Was it just synthesized by the liver cell or did it just enter the cell from a distant location such as adipocytes (fat cells). Should it be oxidized, which should happen if there is a demand for energy production by the cell, or should the liver cell export it, perhaps to adipocytes, which might happen if there is an excess of energy storage molecules? Cells have devised many ways to distinguish these opposing needs. One is by using a slightly different pool of redox reagents for anabolic and catabolic reactions. Oxidative degradation reactions typically use the redox pair NAD+/NADH (or FAD/FADH2) while reductive biosynthesis often uses phosphorylated variants of NAD+, NADP+/NADPH. In addition, cells often carry out competing reactions in different cellular compartments. Fatty acid oxidation of our example molecule (palmitic acid) occurs in the mitochondrial matrix, while reductive fatty acid synthesis occurs in the cytoplasm of the cell. Fatty acids entering the cell destined for oxidative degradation are transported into the mitochondria by the carnitine transport system. This transport system is inhibited under conditions when fatty acid synthesis is favored. We will discuss the regulation of metabolic pathways in a subsequent section. One of the main methods, as we will see, is to activate or inhibit key enzymes in the pathways under a given set of cellular conditions. The key enzyme in fatty acid synthesis, acetyl-CoA carboxylase, is inhibited when cellular conditions require fatty acid oxidation.
The following examples give short descriptions of anabolic pathways. Compare them to the catabolic pathways from the previous section.
• Glucose synthesis, better known as Gluconeogenesis: In glycolysis, glucose (C6H12O6), a 6C molecule, is converted to two, 3C molecules (pyruvate) in an oxidative process that requires NAD+ and makes two net ATP molecules. In a few organs, most predominately in the liver, the reverse pathway can take place. The liver does this to provide glucose to the brain when the body is deficient in circulating glucose, for example, under fasting and starving conditions. (The liver under these conditions can get its energy from oxidation of fatty acids). The reactions in gluconeogenesis are the same reactions in glycolysis but run in reverse, with the exception of three glycolytic steps which are essentially irreversible. These three steps have bypass enzymes in the gluconeogenesis pathway. Although the synthesis of glucose is a reductive pathway, it uses NADH instead of NADPH as the redundant as the same enzyme used in glycolysis is simply run in reverse. Gluconeogenesis, which also occurs in the cortex of the kidney, is more than just a simple reversal of glycolysis, however. It can be thought of as the net synthesis of glucose from non-carbohydrate precursors. Pyruvate, as seen in the section on catabolism, can be formed from protein degradation to glucogenic amino acids which can be converted to pyruvate. It can also be formed from triacylglycerides from the 3C molecule glycerol formed and released from adipocytes after hydrolysis of three fatty acids from triacylglycerides. However, in humans, glucose can not be made in net fashion from fatty acids. Fatty acids can be converted to acetyl-CoA by fatty acid oxidation. The resulting acetyl-CoA can not form pyruvate since the enzyme that catalyzes the formation for acetyl-CoA from pyruvate, pyruvate dehydrogenase, is irreversible and there is no bypass reaction known. The acetyl-CoA can enter the TCA cycle but since the pathway is cyclic and proceeds in one direction, it can not form in net fashion oxaloacetate. Although oxaloacetate can be remove from the TCA cycle and be use to form phosphoenolpyuvate, a glycolytic intermediate, one acetyl-CoA condenses with one oxaloacetate to form citrate which leads back to one oxaloacetate. Hence fatty acids can not be converted to glucose and other sugars in a net fashion.
• Pentose Phosphate Shunt: This two-part pathway doesn't appear to start as a reductive biosynthetic pathway as the first part is the oxidative conversion of a glycolytic intermediate, glucose-6-phosphate, to ribulose-5-phosphate. The next, nonoxidative branch leads to the formation of ribose-5-phosphate, a key biosynthetic intermediate in nucleic acid synthesis as well as erthyrose-4-phosphate used for biosynthesis of aromatic amino acids . The oxidative branch is important in reductive biosynthesis as it is a major source of the reductant NADPH used in biosynthetic reactions.
• Fatty acid and isoprenoid/sterol biosynthesis: Acetyl-CoA is the source of carbon atoms for the synthesis of more complex lipids such as fatty acids, isoprenoids, and sterols. When energy needs in a cell are not high, citrate, the condensation product of oxaloacetate and acetyl-CoA in the TCA cycle, builds up in the mitochondrial matrix. It is then transported by the citrate transporter (an inner mitochondrial membrane protein) to the cytoplasm, where it is cleaved back to oxaloacetate and acetyl-CoA by the cytoplasmic enzyme citrate lyase. The oxaloacetate is returned to the mitochondria by conversion first to malate (reduction reaction using NADH), which can move back into the mitochondria through the malate transporter, or further conversion to pyruate, using the cytosolic malic enzyme, which uses NADP+ to oxidize malate to pyruvate which then enters the mitochondria. The acetyl-CoA formed in the cytoplasm can then be used in reductive biosynthesis using NADPH as the reductant to form fatty acids, isoprenoids, and sterols. The NADPH for the reduction comes from the oxidative branch of the pentose phosphate pathway and from the reaction catalyzed by malic enzyme. The liver cells can still run the glycolytic pathway as the NADH/NAD+ ratio is low in the cytoplasm while NADPH/NADP+ ratio is high.
Now its time to see how the various pathways fit together to form an integrated set of pathways. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/26%3A_The_Organic_Chemistry_of_Metabolic_Pathways/26.12%3A_Anabolism.txt |
Fatty acids are merely carboxylic acids with long hydrocarbon chains. The hydrocarbon chain length may vary from 10-30 carbons (most usual is 12-18). The non-polar hydrocarbon alkane chain is an important counter balance to the polar acid functional group. In acids with only a few carbons, the acid functional group dominates and gives the whole molecule a polar character. However, in fatty acids, the non-polar hydrocarbon chain gives the molecule a non-polar character.
• Hydrogenation of Unsaturated Fats and Trans Fat
Saturated fats have a chain like structure which allows them to stack very well forming a solid at room temperature. Unsaturated fats are not linear due to double bonded carbons which results in a different molecular shape because the sp2 carbons are trigonal planar. This causes the fat molecules to poorly stack resulting in fats that are liquid at room temperature. Unsaturated fats can be converted to saturated fats via hydrogenation reactions.
• Introduction to Fatty Acids
Fatty acids are carboxylic acids with long hydrocarbon chains. There are two groups of fatty acids--saturated and unsaturated. Recall that the term unsaturated refers to the presence of one or more double bonds between carbons as in alkenes. A saturated fatty acid has all bonding positions between carbons occupied by hydrogens. The melting points for the saturated fatty acids follow the boiling point principle observed previously.
• Prostaglandins
Prostaglandins were first discovered and isolated from human semen in the 1930s by Ulf von Euler of Sweden. Thinking they had come from the prostate gland, he named them prostaglandins. It has since been determined that they exist and are synthesized in virtually every cell of the body. Prostaglandins, are like hormones in that they act as chemical messengers, but do not move to other sites, but work right within the cells where they are synthesized.
Thumbnail: A ball-and-stick diagram of arachidonic acid. (Public Domain; SubDural12). Arachidonic acid is a polyunsaturated fatty acid present in the phospholipids of membranes of the body's cells, and is abundant in the brain, muscles, and liver.
27.02: Waxes are High-Molecular-Weight Esters
Waxes are esters of fatty acids with long chain monohydric alcohols (one hydroxyl group). Natural waxes are often mixtures of such esters, and may also contain hydrocarbons. The formulas for three well known waxes are given below, with the carboxylic acid moiety colored red and the alcohol colored blue.
Spermaceti Beeswax Carnuba wax
CH3(CH2)14CO2-(CH2)15CH3 CH3(CH2)24CO2-(CH2)29CH3 CH3(CH2)30CO2-(CH2)33CH3
Waxes are widely distributed in nature. The leaves and fruits of many plants have waxy coatings, which may protect them from dehydration and small predators. The feathers of birds and the fur of some animals have similar coatings which serve as a water repellent. Carnuba wax is valued for its toughness and water resistance.
27.03: Fats and Oils are Triacylclycerols
Triglycerides are esters of fatty acids and a trifunctional alcohol - glycerol (IUPAC name is 1,2,3-propantriol). The properties of fats and oils follow the same general principles as already described for the fatty acids. The important properties to be considered are: melting points and degree of unsaturation from component fatty acids.
Introduction
Since glycerol has three alcohol functional groups, three fatty acids must react to make three ester functional groups. The three fatty acids may or may not be identical. In fact, three different fatty acids may be present. The synthesis of a triglyceride is another application of the ester synthesis reaction. To write the structure of the triglyceride you must know the structure of glycerol and be given or look up the structure of the fatty acid in the table.
Table \(1\):The common fats and oils including fatty acid content are listed below.
Fat or Oil Saturated Unsaturated
Palmitic Stearic Oleic Linoleic Other
Animal Origin
Butter 29 9 27 4 31
Lard 30 18 41 6 5
Beef 32 25 38 3 2
Vegetable Origin
Corn oil 10 4 34 48 4
Soybean 7 3 25 56 9
Peanut 7 5 60 21 7
Olive 6 4 83 7 -
Synthesis of a Triglyceride
Since glycerol, (IUPAC name is 1,2,3-propantriol), has three alcohol functional groups, three fatty acids must react to make three ester functional groups. The three fatty acids may or may not be identical. In fact, three different fatty acids may be present. nThe synthesis of a triglyceride is another application of the ester synthesis reaction. To write the structure of the triglyceride you must know the structure of glycerol and be given or look up the structure of the fatty acid in Table \(1\) - find lauric acid.
Glycerol
The simplified reaction reveals the process of breaking some bonds and forming the ester and the by product, water. Refer to the graphic on the left for the synthesis of trilauroylglycerol. First, the -OH (red) bond on the acid is broken and the -H (red) bond on the alcohol is also broken. Both join to make HOH, a water molecule. Secondly, the oxygen of the alcohol forms a bond (green) to the acid at the carbon with the double bond oxygen. This forms the ester functional group. This process is carried out three times to make three ester groups and three water molecules.
Structure of a Triglyceride
As you can see from the graphic on the left, the actual molecular model of the triglyceride does not look at all like the line drawing. The reason for this difference lies in the concepts of molecular geometry. Trilauroylglycerol. All of the above factors contribute to the apparent "T" shape of the molecule.
Problems
Quiz: Which acid (short chain or fatty) would most likely be soluble in water?
... in hexane?
1 Practice writing out a triglyceride of stearic acid. Again look up the formula of stearic acid and use the structure of glycerol.
2. Write down your answers. Then check the answers from the drop down menu.
What is the molecular geometry of all three carbons in glycerol (look at model above)?
What is the molecular geometry of the carbon at the center of the ester group?
What is the molecular geometry of the single bond oxygen?
• Snell, Foster D. "Soap and glycerol." J. Chem. Educ. 1942, 19, 172. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/27%3A_The_Organic_Chemistry_of_Lipids/27.01%3A_Fatty_Acids_Are_Long-Chain_Carboxylic_Acids.txt |
Phospholipids are the main constituents of cell membranes. They resemble the triglycerides in being ester or amide derivatives of glycerol or sphingosine with fatty acids and phosphoric acid. The phosphate moiety of the resulting phosphatidic acid is further esterified with ethanolamine, choline or serine in the phospholipid itself. The following diagram shows the structures of some of these components. Clicking on the diagram will change it to display structures for two representative phospholipids. Note that the fatty acid components (R & R') may be saturated or unsaturated.
As ionic amphiphiles, phospholipids aggregate or self-assemble when mixed with water, but in a different manner than the soaps and detergents. Because of the two pendant alkyl chains present in phospholipids and the unusual mixed charges in their head groups, micelle formation is unfavorable relative to a bilayer structure. If a phospholipid is smeared over a small hole in a thin piece of plastic immersed in water, a stable planar bilayer of phospholipid molecules is created at the hole. As shown in the following diagram, the polar head groups on the faces of the bilayer contact water, and the hydrophobic alkyl chains form a nonpolar interior. The phospholipid molecules can move about in their half the bilayer, but there is a significant energy barrier preventing migration to the other side of the bilayer.
This bilayer membrane structure is also found in aggregate structures called liposomes. Liposomes are microscopic vesicles consisting of an aqueous core enclosed in one or more phospholipid layers. They are formed when phospholipids are vigorously mixed with water. Unlike micelles, liposomes have both aqueous interiors and exteriors.
A cell may be considered a very complex liposome. The bilayer membrane that separates the interior of a cell from the surrounding fluids is largely composed of phospholipids, but it incorporates many other components, such as cholesterol, that contribute to its structural integrity. Protein channels that permit the transport of various kinds of chemical species in and out of the cell are also important components of cell membranes.
The interior of a cell contains a variety of structures (organelles) that conduct chemical operations vital to the cells existence. Molecules bonded to the surfaces of cells serve to identify specific cells and facilitate interaction with external chemical entities. The sphingomyelins are also membrane lipids. They are the major component of the myelin sheath surrounding nerve fibers. Multiple Sclerosis is a devastating disease in which the myelin sheath is lost, causing eventual paralysis.
27.05: Prostaglandis Regulate Physiological Responses
Prostaglandins were first discovered and isolated from human semen in the 1930s by Ulf von Euler of Sweden. Thinking they had come from the prostate gland, he named them prostaglandins. It has since been determined that they exist and are synthesized in virtually every cell of the body. Prostaglandins, are like hormones in that they act as chemical messengers, but do not move to other sites, but work right within the cells where they are synthesized.
Introduction
Prostaglandins are unsaturated carboxylic acids, consisting of of a 20 carbon skeleton that also contains a five member ring. They are biochemically synthesized from the fatty acid, arachidonic acid. See the graphic on the left. The unique shape of the arachidonic acid caused by a series of cis double bonds helps to put it into position to make the five member ring. See the prostaglandin in the next panel
Prostaglandin Structure
Prostaglandins are unsaturated carboxylic acids, consisting of of a 20 carbon skeleton that also contains a five member ring and are based upon the fatty acid, arachidonic acid. There are a variety of structures one, two, or three double bonds. On the five member ring there may also be double bonds, a ketone, or alcohol groups. A typical structure is on the left graphic.
Functions of Prostaglandins
There are a variety of physiological effects including:
1. Activation of the inflammatory response, production of pain, and fever. When tissues are damaged, white blood cells flood to the site to try to minimize tissue destruction. Prostaglandins are produced as a result.
2. Blood clots form when a blood vessel is damaged. A type of prostaglandin called thromboxane stimulates constriction and clotting of platelets. Conversely, PGI2, is produced to have the opposite effect on the walls of blood vessels where clots should not be forming.
3. Certain prostaglandins are involved with the induction of labor and other reproductive processes. PGE2 causes uterine contractions and has been used to induce labor.
4. Prostaglandins are involved in several other organs such as the gastrointestinal tract (inhibit acid synthesis and increase secretion of protective mucus), increase blood flow in kidneys, and leukotriens promote constriction of bronchi associated with asthma.
Effects of Aspirin and other Pain Killers
When you see that prostaglandins induce inflammation, pain, and fever, what comes to mind but aspirin. Aspirin blocks an enzyme called cyclooxygenase, COX-1 and COX-2, which is involved with the ring closure and addition of oxygen to arachidonic acid converting to prostaglandins. The acetyl group on aspirin is hydrolzed and then bonded to the alcohol group of serine as an ester. This has the effect of blocking the channel in the enzyme and arachidonic can not enter the active site of the enzyme. By inhibiting or blocking this enzyme, the synthesis of prostaglandins is blocked, which in turn relives some of the effects of pain and fever. Aspirin is also thought to inhibit the prostaglandin synthesis involved with unwanted blood clotting in coronary heart disease. At the same time an injury while taking aspirin may cause more extensive bleeding.
Contributors
Charles Ophardt (Professor Emeritus, Elmhurst College); Virtual Chembook | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/27%3A_The_Organic_Chemistry_of_Lipids/27.04%3A_Phospholipids_and_Sphingolipids_are_Components_of_Membranes.txt |
Compounds classified as terpenes constitute what is arguably the largest and most diverse class of natural products. A majority of these compounds are found only in plants, but some of the larger and more complex terpenes (e.g. squalene & lanosterol) occur in animals. Terpenes incorporating most of the common functional groups are known, so this does not provide a useful means of classification. Instead, the number and structural organization of carbons is a definitive characteristic. Terpenes may be considered to be made up of isoprene (more accurately isopentane) units, an empirical feature known as the isoprene rule. Because of this, terpenes usually have \(5n\) carbon atoms (\(n\) is an integer), and are subdivided as follows:
Classification Isoprene Units Carbon Atoms
monoterpenes 2 C10
sesquiterpenes 3 C15
diterpenes 4 C20
sesterterpenes 5 C25
triterpenes 6 C30
Isoprene itself, a C5H8 gaseous hydrocarbon, is emitted by the leaves of various plants as a natural byproduct of plant metabolism. Next to methane it is the most common volatile organic compound found in the atmosphere. Examples of C10 and higher terpenes, representing the four most common classes are shown in the following diagrams. Most terpenes may be structurally dissected into isopentane segments. How this is done can be seen in the diagram directly below.
Figure: Monoterpenes and diterpenes
The isopentane units in most of these terpenes are easy to discern, and are defined by the shaded areas. In the case of the monoterpene camphor, the units overlap to such a degree it is easier to distinguish them by coloring the carbon chains. This is also done for alpha-pinene. In the case of the triterpene lanosterol we see an interesting deviation from the isoprene rule. This thirty carbon compound is clearly a terpene, and four of the six isopentane units can be identified. However, the ten carbons in center of the molecule cannot be dissected in this manner. Evidence exists that the two methyl groups circled in magenta and light blue have moved from their original isoprenoid locations (marked by small circles of the same color) to their present location. This rearrangement is described in the biosynthesis section. Similar alkyl group rearrangements account for other terpenes that do not strictly follow the isoprene rule.
Figure: Triterpenes
Polymeric isoprenoid hydrocarbons have also been identified. Rubber is undoubtedly the best known and most widely used compound of this kind. It occurs as a colloidal suspension called latex in a number of plants, ranging from the dandelion to the rubber tree (Hevea brasiliensis). Rubber is a polyene, and exhibits all the expected reactions of the C=C function. Bromine, hydrogen chloride and hydrogen all add with a stoichiometry of one molar equivalent per isoprene unit. Ozonolysis of rubber generates a mixture of levulinic acid ( \(CH_3COCH_2CH_2CO_2H\) ) and the corresponding aldehyde. Pyrolysis of rubber produces the diene isoprene along with other products.
The double bonds in rubber all have a Z-configuration, which causes this macromolecule to adopt a kinked or coiled conformation. This is reflected in the physical properties of rubber. Despite its high molecular weight (about one million), crude latex rubber is a soft, sticky, elastic substance. Chemical modification of this material is normal for commercial applications. Gutta-percha (structure above) is a naturally occurring E-isomer of rubber. Here the hydrocarbon chains adopt a uniform zig-zag or rod like conformation, which produces a more rigid and tough substance. Uses of gutta-percha include electrical insulation and the covering of golf balls. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/27%3A_The_Organic_Chemistry_of_Lipids/27.06%3A_Terpenes_Contain_Carbon_Atoms_in_Multiples_of_Five.txt |
Compounds classified as terpenes constitute what is arguably the largest and most diverse class of natural products. A majority of these compounds are found only in plants, but some of the larger and more complex terpenes (e.g. squalene & lanosterol) occur in animals. Terpenes incorporating most of the common functional groups are known, so this does not provide a useful means of classification. Instead, the number and structural organization of carbons is a definitive characteristic. Terpenes may be considered to be made up of isoprene (more accurately isopentane) units, an empirical feature known as the isoprene rule. Because of this, terpenes usually have \(5n\) carbon atoms (\(n\) is an integer), and are subdivided as follows:
Classification Isoprene Units Carbon Atoms
monoterpenes 2 C10
sesquiterpenes 3 C15
diterpenes 4 C20
sesterterpenes 5 C25
triterpenes 6 C30
Isoprene itself, a C5H8 gaseous hydrocarbon, is emitted by the leaves of various plants as a natural byproduct of plant metabolism. Next to methane it is the most common volatile organic compound found in the atmosphere. Examples of C10 and higher terpenes, representing the four most common classes are shown in the following diagrams. Most terpenes may be structurally dissected into isopentane segments. How this is done can be seen in the diagram directly below.
Figure: Monoterpenes and diterpenes
The isopentane units in most of these terpenes are easy to discern, and are defined by the shaded areas. In the case of the monoterpene camphor, the units overlap to such a degree it is easier to distinguish them by coloring the carbon chains. This is also done for alpha-pinene. In the case of the triterpene lanosterol we see an interesting deviation from the isoprene rule. This thirty carbon compound is clearly a terpene, and four of the six isopentane units can be identified. However, the ten carbons in center of the molecule cannot be dissected in this manner. Evidence exists that the two methyl groups circled in magenta and light blue have moved from their original isoprenoid locations (marked by small circles of the same color) to their present location. This rearrangement is described in the biosynthesis section. Similar alkyl group rearrangements account for other terpenes that do not strictly follow the isoprene rule.
Figure: Triterpenes
Polymeric isoprenoid hydrocarbons have also been identified. Rubber is undoubtedly the best known and most widely used compound of this kind. It occurs as a colloidal suspension called latex in a number of plants, ranging from the dandelion to the rubber tree (Hevea brasiliensis). Rubber is a polyene, and exhibits all the expected reactions of the C=C function. Bromine, hydrogen chloride and hydrogen all add with a stoichiometry of one molar equivalent per isoprene unit. Ozonolysis of rubber generates a mixture of levulinic acid ( \(CH_3COCH_2CH_2CO_2H\) ) and the corresponding aldehyde. Pyrolysis of rubber produces the diene isoprene along with other products.
The double bonds in rubber all have a Z-configuration, which causes this macromolecule to adopt a kinked or coiled conformation. This is reflected in the physical properties of rubber. Despite its high molecular weight (about one million), crude latex rubber is a soft, sticky, elastic substance. Chemical modification of this material is normal for commercial applications. Gutta-percha (structure above) is a naturally occurring E-isomer of rubber. Here the hydrocarbon chains adopt a uniform zig-zag or rod like conformation, which produces a more rigid and tough substance. Uses of gutta-percha include electrical insulation and the covering of golf balls. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/27%3A_The_Organic_Chemistry_of_Lipids/27.07%3A_How_Terpenes_Are_Biosynthesized.txt |
The important class of lipids called steroids are actually metabolic derivatives of terpenes, but they are customarily treated as a separate group. Steroids may be recognized by their tetracyclic skeleton, consisting of three fused six-membered and one five-membered ring, as shown in the diagram to the right. The four rings are designated A, B, C & D as noted, and the peculiar numbering of the ring carbon atoms (shown in red) is the result of an earlier misassignment of the structure. The substituents designated by R are often alkyl groups, but may also have functionality. The R group at the A:B ring fusion is most commonly methyl or hydrogen, that at the C:D fusion is usually methyl. The substituent at C-17 varies considerably, and is usually larger than methyl if it is not a functional group. The most common locations of functional groups are C-3, C-4, C-7, C-11, C-12 & C-17. Ring A is sometimes aromatic. Since a number of tetracyclic triterpenes also have this tetracyclic structure, it cannot be considered a unique identifier.
Steroids are widely distributed in animals, where they are associated with a number of physiological processes. Examples of some important steroids are shown in the following diagram. Norethindrone is a synthetic steroid, all the other examples occur naturally. A common strategy in pharmaceutical chemistry is to take a natural compound, having certain desired biological properties together with undesired side effects, and to modify its structure to enhance the desired characteristics and diminish the undesired. This is sometimes accomplished by trial and error.
The generic steroid structure drawn above has seven chiral stereocenters (carbons 5, 8, 9, 10, 13, 14 & 17), which means that it may have as many as 128 stereoisomers. With the exception of C-5, natural steroids generally have a single common configuration. This is shown in the last of the toggled displays, along with the preferred conformations of the rings.
Chemical studies of the steroids were very important to our present understanding of the configurations and conformations of six-membered rings. Substituent groups at different sites on the tetracyclic skeleton will have axial or equatorial orientations that are fixed because of the rigid structure of the trans-fused rings. This fixed orientation influences chemical reactivity, largely due to the greater steric hindrance of axial groups versus their equatorial isomers. Thus an equatorial hydroxyl group is esterified more rapidly than its axial isomer.
It is instructive to examine a simple bicyclic system as a model for the fused rings of the steroid molecule. Decalin, short for decahydronaphthalene, exists as cis and trans isomers at the ring fusion carbon atoms. Planar representations of these isomers are drawn at the top of the following diagram, with corresponding conformational formulas displayed underneath. The numbering shown for the ring carbons follows IUPAC rules, and is different from the unusual numbering used for steroids. For purposes of discussion, the left ring is labeled A (colored blue) and the right ring B (colored red). In the conformational drawings the ring fusion and the angular hydrogens are black.
The trans-isomer is the easiest to describe because the fusion of the A & B rings creates a rigid, roughly planar, structure made up of two chair conformations. Each chair is fused to the other by equatorial bonds, leaving the angular hydrogens (Ha) axial to both rings. Note that the bonds directed above the plane of the two rings alternate from axial to equatorial and back if we proceed around the rings from C-1 to C-10 in numerical order. The bonds directed below the rings also alternate in a complementary fashion.
Conformational descriptions of cis- decalin are complicated by the fact that two energetically equivalent fusions of chair cyclohexanes are possible, and are in rapid equilibrium as the rings flip from one chair conformation to the other. In each of these all chair conformations the rings are fused by one axial and one equatorial bond, and the overall structure is bent at the ring fusion. In the conformer on the left, the red ring (B) is attached to the blue ring (A) by an axial bond to C-1 and an equatorial bond to C-6 (these terms refer to ring A substituents). In the conformer on the right, the carbon bond to C-1 is equatorial and the bond to C-6 is axial. Each of the angular hydrogens (Hae or Hea) is oriented axial to one of the rings and equatorial to the other. This relationship reverses when double ring flipping converts one cis-conformer into the other.
Cis-decalin is less stable than trans-decalin by about 2.7 kcal/mol (from heats of combustion and heats of isomerization data). This is due to steric crowding (hindrance) of the axial hydrogens in the concave region of both cis-conformers, as may be seen in the model display activated by the following button. This difference is roughly three times the energy of a gauche butane conformer relative to its anti conformer. Indeed three gauche butane interactions may be identified in each of the cis-decalin conformations, as will be displayed by clicking on the above conformational diagram. These gauche interactions are also shown in the model.
Steroids in which rings A and B are fused cis, such as the example on the right, do not have the sameconformational mobility exhibited by cis-decalin. The fusion of ring C to ring B in a trans configuration prevents ring B from undergoing a conformational flip to another chair form. If this were to occur, ring C would have to be attached to ring B by two adjacent axial bonds directed 180º apart. This is too great a distance to be bridged by the four carbon atoms making up ring C. Consequently, the steroid molecule is locked in the all chair conformation shown here. Of course, all these steroids and decalins may have one or more six-membered rings in a boat conformation. However the high energy of boat conformers relative to chairs would make such structures minor components in the overall ensemble of conformations available to these molecules.
Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
27.09: How Nature Synthesizes Cholesterol
Contributors and Attributions
• Nathalie Interiano
27.10: Synthetic Steroids
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/27%3A_The_Organic_Chemistry_of_Lipids/27.08%3A_How_Steriods_Are_Chemical_Messengers.txt |
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le
28.02: Other Important Nucleotides
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le
28.03: Nucleic Acids Are Composed of Nucleotide Subunits
Intermolecular forces are the attractive or repulsive forces between molecules. They are separated into two groups; short range and long range forces. Short range forces happen when the centers of the molecules are separated by three angstroms (10-8 cm) or less. Short range forces tend to be repulsive, where the long range forces that act outside the three angstroms range are attractive. Long range forces are also known as Van der Waals forces. They are responsible for surface tension, friction, viscosity and differences between actual behavior of gases and that predicted by the ideal gas law. Intermolecular forces are responsible for most properties of all the phases. The viscosity, diffusion, and surface tension are examples of physical properties of liquids that depend on intermolecular forces. Vapor pressure, critical point, and boiling point are examples of properties of gases. Melting and sublimation are examples of properties of solids that depend on intermolecular forces.
• Hydrogen Bonding
A hydrogen bond is a special type of dipole-dipole attraction which occurs when a hydrogen atom bonded to a strongly electronegative atom exists in the vicinity of another electronegative atom with a lone pair of electrons. These bonds are generally stronger than ordinary dipole-dipole and dispersion forces, but weaker than true covalent and ionic bonds.
• Hydrophobic Interactions
Hydrophobic interactions describe the relations between water and hydrophobes (low water-soluble molecules). Hydrophobes are nonpolar molecules and usually have a long chain of carbons that do not interact with water molecules. The mixing of fat and water is a good example of this particular interaction. The common misconception is that water and fat doesn’t mix because the Van der Waals forces that are acting upon both water and fat molecules are too weak.
• Multipole Expansion
A multipole expansion is a series expansion of the effect produced by a given system in terms of an expansion parameter which becomes small as the distance away from the system increases. Therefore, the leading one or terms in a multipole expansion are generally the strongest. The first-order behavior of the system at large distances can therefore be obtained from the first terms of this series, which is generally much easier to compute than the general solution.
• Overview of Intermolecular Forces
Intermolecular forces are forces between molecules. Depending on its strength, intermolecular forces cause the forming of three physical states: solid, liquid and gas. The physical properties of melting point, boiling point, vapor pressure, evaporation, viscosity, surface tension, and solubility are related to the strength of attractive forces between molecules. These attractive forces are called Intermolecular Forces.
• Specific Interactions
Intermolecular forces are forces of attraction or repulsion which act between neighboring particles (atoms, molecules or ions). They are weak compared to the intramolecular forces, which keep a molecule together (e.g., covalent and ionic bonding).
• Van der Waals Forces
Van der Waals forces' is a general term used to define the attraction of intermolecular forces between molecules. There are two kinds of Van der Waals forces: weak London Dispersion Forces and stronger dipole-dipole forces. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/28%3A_The_Chemistry_of_Nucleic_Acids/28.01%3A_Nucleosides_and_Nucleotides.txt |
Ensemble properties result from being or relating to the greater in number of atoms in a sample. This are in contrast to atomic or molecular properties.
• Capillary Action
Capillary action can be defined as the ascension of liquids through slim tube, cylinder or permeable substance due to adhesive and cohesive forces interacting between the liquid and the surface. When intermolecular bonding of a liquid itself is substantially inferior to a substances’ surface it is interacting, capillarity occurs. Also, the diameter of the container as well as the gravitational forces will determine amount of liquid raised.
• Cohesive and Adhesive Forces
Cohesive and adhesive forces are associated with bulk (or macroscopic) properties and hence the terms are not applicable to discussion of atomic and molecular properties. When a liquid comes into contact with a surface (such as the walls of a graduated cylinder or a tabletop), both cohesive and adhesive forces will act on it. These forces govern the shape which the liquid takes on.
• Contact Angles
Contact angle is one of the common ways to measure the wettability of a surface or material. Wetting refers to the study of how a liquid deposited on a solid (or liquid) substrate spreads out or the ability of liquids to form boundary surfaces with solid states. The wetting, as mentioned before is determined by measuring the contact angle, which the liquid forms in contact with the solids or liquids. The wetting tendency is larger, the smaller the contact angle or the surface tension is.
• Surface Tension
Surface tension is the energy, or work, required to increase the surface area of a liquid due to intermolecular forces. Since these intermolecular forces vary depending on the nature of the liquid (e.g. water vs. gasoline) or solutes in the liquid (e.g. surfactants like detergent), each solution exhibits differing surface tension properties.
• Unusual Properties of Water
With 70% of our earth being ocean water and 65% of our bodies being water, it is hard to not be aware of how important it is in our lives. There are 3 different forms of water, or H2O: solid (ice), liquid (water), and gas (steam). Because water seems so ubiquitous, many people are unaware of the unusual and unique properties of water, including:
• Vapor Pressure
Pressure is the average force that material (gas, liquid or solid) exert upon the surface, e.g. walls of a container or other confining boundary. Vapor pressure or equilibrium vapor pressure is the pressure of a vapor in thermodynamic equilibrium with its condensed phases in a closed container. All liquids and solids have a tendency to evaporate or sublime into a gaseous form and all gases have a tendency to condense back to their liquid or solid form.
• Viscosity
Viscosity is another type of bulk property defined as a liquid’s resistance to flow. When the intermolecular forces of attraction are strong within a liquid, there is a larger viscosity. An example of this phenomenon is imagining a race between two liquids down a windshield. Which would you expect to roll down the windshield faster honey or water? Obviously from experience one would expect water to easily speed right past the honey, a fact that reveals honey has a much higher viscocity than wate
• Wetting Agents
A substance is referred to as a wetting agent if it lowers the surface tension of a liquid and thus allows it to spread more easily.
Thumbnail: A water drop on a lotus leaf surface showing contact angles of approximately 147°. (Public Domain; Na2jojon). | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/28%3A_The_Chemistry_of_Nucleic_Acids/28.04%3A_Why_DNA_Does_Not_Have_A_2-_OH_Group.txt |
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le
28.06: DNA and Heredity
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le
28.07: The Biosynthesis of RNA is Called Transcription
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/28%3A_The_Chemistry_of_Nucleic_Acids/28.05%3A_The_Biosynthesis_of_DNA_is_Called_Replication.txt |
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le
28.09: The Biosynthesis of Proteins Is Called Translation
Contributors and Attributions
• Nathalie Interiano
28.10: Why DNA Contains Thymine Instead of Uracil
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le
28.11: How the Base Sequence of DNA Is Determined
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le
28.12: The Polymerase Chain Reaction (PCR)
Contributors and Attributions
• Nathalie Interiano
28.13: Genetic Engineering
Contributors and Attributions
• Nathalie Interiano
28.14: The Laboratory Synthesis of DNA Strands
Contributors and Attributions
• Nathalie Interiano | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/28%3A_The_Chemistry_of_Nucleic_Acids/28.08%3A_There_Are_Three_Kinds_of_RNA.txt |
Polymers are long chain, giant organic molecules are assembled from many smaller molecules called monomers. Polymers consist of many repeating monomer units in long chains, sometimes with branching or cross-linking between the chains. A polymer is analogous to a necklace made from many small beads (monomers). A chemical reaction forming polymers from monomers is called polymerization, of which there are many types. A common name for many synthetic polymer materials is plastic, which comes from the Greek word "plastikos", suitable for molding or shaping.
In the following illustrated example, many monomers called styrene are polymerized into a long chain polymer called polystyrene. The squiggly lines indicate that the polymer molecule extends further at both the left and right ends. In fact, polymer molecules are often hundreds or thousands of monomer units long.
Introduction
Many objects in daily use from packing, wrapping, and building materials include half of all polymers synthesized. Other uses include textiles, many electronic appliance casings, CD's, automobile parts, and many others are made from polymers. A quarter of the solid waste from homes is plastic materials - some of which may be recycled as shown in the table below.
Some products, such as adhesives, are made to include monomers which can be polymerized by the user in their application.
Types of Polymers
There are many types of polymers including synthetic and natural polymers.
Synthetic polymers
• Plastics
• Elastomers - solids with rubber-like qualities
• Rubber (carbon backbone often from hydrocarbon monomers)
• silicones (backbone of alternating silicon and oxygen atoms).
• Fibers
• Solid materials of intermediate characteristics
• Gels or viscous liquids
Classification of Polymers
• Homopolymers: These consist of chains with identical bonding linkages to each monomer unit. This usually implies that the polymer is made from all identical monomer molecules. These may be represented as : -[A-A-A-A-A-A]- Homopolymers are commonly named by placing the prefix poly in front of the constituent monomer name. For example, polystyrene is the name for the polymer made from the monomer styrene (vinylbenzene).
• Copolymers: These consist of chains with two or more linkages usually implying two or more different types of monomer units. These may be represented as : -[A-B-A-B-A-B]-
Polymers classified by mode of polymerization
• Addition Polymers: The monomer molecules bond to each other without the loss of any other atoms. Addition polymers from alkene monomers or substituted alkene monomers are the biggest groups of polymers in this class. Ring opening polymerization can occur without the loss of any small molecules.
• Condensation Polymers: Usually two different monomer combine with the loss of a small molecule, usually water. Most polyesters and polyamides (nylon) are in this class of polymers. Polyurethane Foam in graphic above.
Polymers classified by Physical Response to Heating
Thermoplastics
Plastics that soften when heated and become firm again when cooled. This is the more popular type of plastic because the heating and cooling may be repeated and the thermoplastic may be reformed.
Thermosets
These are plastics that soften when heated and can be molded, but harden permanently. They will decompose when reheated. An example is Bakelite, which is used in toasters, handles for pots and pans, dishes, electrical outlets and billiard balls.
Recycled Plastics
Recycle Code Abbreviation and Chemical Name of Plastic Types of Uses and Examples
1 PET - polyethylene terephthalate Many types of clear plastic consumer bottles, including clear, 2-liter beverage bottles
2 HDPE - High density polyethylene Milk jugs, detergent bottles, some water bottles, some grocery plastic bags
3 PVC - Polyvinyl chloride Plastic drain pipe, shower curtains, some water bottles
4 LDPE - Low density polyethylene Plastic garbage and other bags, garment bags, snap-on lids such as coffee can lids
5 PP - Polypropylene Many translucent (or opaque) plastic containers; containers for some products such as yogurt, soft butter, or margarine; aerosol can tops; rigid bottle caps; candy wrappers; bottoms of bottles
6 PS - Polystyrene Hard clear plastic cups, foam cups, eating utensils, deli food containers, toy model kits, some packing popcorn
7 Other Polycarbonate is a common type, Biodegradable, Some packing popcorn
Contributors
• Charles Ophardt, Professor Emeritus, Elmhurst College; Virtual Chembook | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/29%3A_Synthetic_Polymers/29.01%3A_There_Are_Two_Major_Classes_of_Synthetic_Polymers.txt |
All the monomers from which addition polymers are made are alkenes or functionally substituted alkenes. The most common and thermodynamically favored chemical transformations of alkenes are addition reactions. Many of these addition reactions are known to proceed in a stepwise fashion by way of reactive intermediates, and this is the mechanism followed by most polymerizations. A general diagram illustrating this assembly of linear macromolecules, which supports the name chain growth polymers, is presented here. Since a pi-bond in the monomer is converted to a sigma-bond in the polymer, the polymerization reaction is usually exothermic by 8 to 20 kcal/mol. Indeed, cases of explosively uncontrolled polymerizations have been reported.
It is useful to distinguish four polymerization procedures fitting this general description.
• Radical Polymerization The initiator is a radical, and the propagating site of reactivity (*) is a carbon radical.
• Cationic Polymerization The initiator is an acid, and the propagating site of reactivity (*) is a carbocation.
• Anionic Polymerization The initiator is a nucleophile, and the propagating site of reactivity (*) is a carbanion.
• Coordination Catalytic Polymerization The initiator is a transition metal complex, and the propagating site of reactivity (*) is a terminal catalytic complex.
Radical Chain-Growth Polymerization
Virtually all of the monomers described above are subject to radical polymerization. Since this can be initiated by traces of oxygen or other minor impurities, pure samples of these compounds are often "stabilized" by small amounts of radical inhibitors to avoid unwanted reaction. When radical polymerization is desired, it must be started by using a radical initiator, such as a peroxide or certain azo compounds. The formulas of some common initiators, and equations showing the formation of radical species from these initiators are presented below.
By using small amounts of initiators, a wide variety of monomers can be polymerized. One example of this radical polymerization is the conversion of styrene to polystyrene, shown in the following diagram. The first two equations illustrate the initiation process, and the last two equations are examples of chain propagation. Each monomer unit adds to the growing chain in a manner that generates the most stable radical. Since carbon radicals are stabilized by substituents of many kinds, the preference for head-to-tail regioselectivity in most addition polymerizations is understandable. Because radicals are tolerant of many functional groups and solvents (including water), radical polymerizations are widely used in the chemical industry.
In principle, once started a radical polymerization might be expected to continue unchecked, producing a few extremely long chain polymers. In practice, larger numbers of moderately sized chains are formed, indicating that chain-terminating reactions must be taking place. The most common termination processes are Radical Combination and Disproportionation. These reactions are illustrated by the following equations. The growing polymer chains are colored blue and red, and the hydrogen atom transferred in disproportionation is colored green. Note that in both types of termination two reactive radical sites are removed by simultaneous conversion to stable product(s). Since the concentration of radical species in a polymerization reaction is small relative to other reactants (e.g. monomers, solvents and terminated chains), the rate at which these radical-radical termination reactions occurs is very small, and most growing chains achieve moderate length before termination.
The relative importance of these terminations varies with the nature of the monomer undergoing polymerization. For acrylonitrile and styrene combination is the major process. However, methyl methacrylate and vinyl acetate are terminated chiefly by disproportionation.
Another reaction that diverts radical chain-growth polymerizations from producing linear macromolecules is called chain transfer. As the name implies, this reaction moves a carbon radical from one location to another by an intermolecular or intramolecular hydrogen atom transfer (colored green). These possibilities are demonstrated by the following equations
Chain transfer reactions are especially prevalent in the high pressure radical polymerization of ethylene, which is the method used to make LDPE (low density polyethylene). The 1º-radical at the end of a growing chain is converted to a more stable 2º-radical by hydrogen atom transfer. Further polymerization at the new radical site generates a side chain radical, and this may in turn lead to creation of other side chains by chain transfer reactions. As a result, the morphology of LDPE is an amorphous network of highly branched macromolecules.
Cationic Chain-Growth Polymerization
Polymerization of isobutylene (2-methylpropene) by traces of strong acids is an example of cationic polymerization. The polyisobutylene product is a soft rubbery solid, Tg = _70º C, which is used for inner tubes. This process is similar to radical polymerization, as demonstrated by the following equations. Chain growth ceases when the terminal carbocation combines with a nucleophile or loses a proton, giving a terminal alkene (as shown here).
Monomers bearing cation stabilizing groups, such as alkyl, phenyl or vinyl can be polymerized by cationic processes. These are normally initiated at low temperature in methylene chloride solution. Strong acids, such as HClO4 , or Lewis acids containing traces of water (as shown above) serve as initiating reagents. At low temperatures, chain transfer reactions are rare in such polymerizations, so the resulting polymers are cleanly linear (unbranched).
Anionic Chain-Growth Polymerization
Treatment of a cold THF solution of styrene with 0.001 equivalents of n-butyllithium causes an immediate polymerization. This is an example of anionic polymerization, the course of which is described by the following equations. Chain growth may be terminated by water or carbon dioxide, and chain transfer seldom occurs. Only monomers having anion stabilizing substituents, such as phenyl, cyano or carbonyl are good substrates for this polymerization technique. Many of the resulting polymers are largely isotactic in configuration, and have high degrees of crystallinity.
Species that have been used to initiate anionic polymerization include alkali metals, alkali amides, alkyl lithiums and various electron sources. A practical application of anionic polymerization occurs in the use of superglue. This material is methyl 2-cyanoacrylate, CH2=C(CN)CO2CH3. When exposed to water, amines or other nucleophiles, a rapid polymerization of this monomer takes place.
Ziegler-Natta Catalytic Polymerization
An efficient and stereospecific catalytic polymerization procedure was developed by Karl Ziegler (Germany) and Giulio Natta (Italy) in the 1950's. Their findings permitted, for the first time, the synthesis of unbranched, high molecular weight polyethylene (HDPE), laboratory synthesis of natural rubber from isoprene, and configurational control of polymers from terminal alkenes like propene (e.g. pure isotactic and syndiotactic polymers). In the case of ethylene, rapid polymerization occurred at atmospheric pressure and moderate to low temperature, giving a stronger (more crystalline) product (HDPE) than that from radical polymerization (LDPE). For this important discovery these chemists received the 1963 Nobel Prize in chemistry.
Ziegler-Natta catalysts are prepared by reacting certain transition metal halides with organometallic reagents such as alkyl aluminum, lithium and zinc reagents. The catalyst formed by reaction of triethylaluminum with titanium tetrachloride has been widely studied, but other metals (e.g. V & Zr) have also proven effective. The following diagram presents one mechanism for this useful reaction. Others have been suggested, with changes to accommodate the heterogeneity or homogeneity of the catalyst. Polymerization of propylene through action of the titanium catalyst gives an isotactic product; whereas, a vanadium based catalyst gives a syndiotactic product.
Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/29%3A_Synthetic_Polymers/29.02%3A_Chain-Growth_Polymers.txt |
Symmetrical monomers such as ethylene and tetrafluoroethylene can join together in only one way. Monosubstituted monomers, on the other hand, may join together in two organized ways, described in the following diagram, or in a third random manner. Most monomers of this kind, including propylene, vinyl chloride, styrene, acrylonitrile and acrylic esters, prefer to join in a head-to-tail fashion, with some randomness occurring from time to time. The reasons for this regioselectivity will be discussed in the synthetic methods section.
If the polymer chain is drawn in a zig-zag fashion, as shown above, each of the substituent groups (Z) will necessarily be located above or below the plane defined by the carbon chain. Consequently we can identify three configurational isomers of such polymers. If all the substituents lie on one side of the chain the configuration is called isotactic. If the substituents alternate from one side to another in a regular manner the configuration is termed syndiotactic. Finally, a random arrangement of substituent groups is referred to as atactic. Examples of these configurations are shown here.
Many common and useful polymers, such as polystyrene, polyacrylonitrile and poly(vinyl chloride) are atactic as normally prepared. Customized catalysts that effect stereoregular polymerization of polypropylene and some other monomers have been developed, and the improved properties associated with the increased crystallinity of these products has made this an important field of investigation. The following values of Tg have been reported.
Polymer
Tg atactic
Tg isotactic
Tg syndiotactic
PP
–20 ºC
0 ºC
–8 ºC
PMMA
100 ºC
130 ºC
120 ºC
The properties of a given polymer will vary considerably with its tacticity. Thus, atactic polypropylene is useless as a solid construction material, and is employed mainly as a component of adhesives or as a soft matrix for composite materials. In contrast, isotactic polypropylene is a high-melting solid (ca. 170 ºC) which can be molded or machined into structural components.
Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
29.04: Polymerization of Dienes The Manufacture of Rubber
Rubber is an example of an elastomer type polymer, where the polymer has the ability to return to its original shape after being stretched or deformed. The rubber polymer is coiled when in the resting state. The elastic properties arise from the its ability to stretch the chains apart, but when the tension is released the chains snap back to the original position. The majority of rubber polymer molecules contain at least some units derived from conjugated diene monomers (see Polymerization of Conjugated Dienes). Such conjugated diene monomers have a constructive backbone of at least four carbon atoms with a double-single-double bond reactive core (C=C-C=C ). Most if not practically all such dienes undergo 1,4-addition to the polymer chain, where 1 and 4 refer to the 1st and 4th carbons of the backbone unit, which become single-bonded to the rest of the polymer chain. The diene's double bonds turn into single bonds, and the single bond between them turns into a Z or E configured double bond, depending on the polymerization conditions. The unit's backbone thus becomes like this (-C-C=C-C-). Rubber gets its elasticity when the formed double bond gets the Z configuration. For 1,3-butadiene, Z is equivalent to a cis and E is equivalent to a trans configuration.
Natural Rubber
Natural rubber is an addition polymer that is obtained as a milky white fluid known as latex from a tropical rubber tree. Natural rubber is from the monomer isoprene (2-methyl-1,3-butadiene), which is a conjugated diene hydrocarbon as mentioned above. In natural rubber, most of the double fonds formed in the polymer chain have the Z configuration, resulting in natural rubber's elastomer qualities.
Charles Goodyear accidentally discovered that by mixing sulfur and rubber, the properties of the rubber improved in being tougher, resistant to heat and cold, and increased in elasticity. This process was later called vulcanization after the Roman god of fire. Vulcanization causes shorter chains to cross link through the sulfur to longer chains. The development of vulcanized rubber for automobile tires greatly aided this industry.
Synthetic Rubber
Important conjugated dienes used in synthetic rubbers include isoprene (2-methyl-1,3-butadiene), 1,3-butadiene, and chloroprene (2-chloro-1,3-butadiene). Polymerized 1,3-butadiene is mostly referred to simply as polybutadiene. Polymerized chloroprene was developed by DuPont and given the trade name Neoprene. In a number of cases, monomers which are not dienes are also used for certain types of synthetic rubber, often copolymerized with dienes. Some of the most commercially important addition polymers are the copolymers. These are polymers made by polymerizing a mixture of two or more monomers. An example is styrene-butadiene rubber (SBR) - which is a copolymer of 1,3-butadiene and styrene which is mixed in a 3 to 1 ratio, respectively.
SBR rubber was developed during World War II when important supplies of natural rubber were cut off. SBR is more resistant to abrasion and oxidation than natural rubber and can also be vulcanized. More than 40% of the synthetic rubber production is SBR and is used in tire production. A tiny amount is used for bubble-gum in the unvulcanized form. Nitrile rubber is copolymerized from butadiene and acrylonitrile (H2C=CH-CN). Butyl rubber is copolymerized from isobutylene [which is methylpropene H2C=C(CH3)2 ] and a small percentage of isoprene. Silicone rubber and other compounds, chemically called polysiloxanes, are not from conjugated dienes but have repeating units like -O-SiR2- where R is some organic radical group like methyl.
Needle Through a Balloon
The polymer rubber chains exist in random loose clumps in the unstretched state. At the nipple end of the balloon, there is lots of rubber and therefore many, many polymer chains - still loosely coiled. These chains can be pierced without popping the balloon because the the chains can still be stretched. This is because they allow the skewer in between the chains without breaking the chains or the bonds that connect them. But on the sides of the balloon, these chains are stretched almost to their limit and very far apart. The piercing is too much for the stretched chains and they break apart, and the balloon pops.
Contributors
• Charles Ophardt, Professor Emeritus, Elmhurst College; Virtual Chembook
• Henry A. Padleckas | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/29%3A_Synthetic_Polymers/29.03%3A_Stereochemistry_of_Polymerization__Ziegler-_Natta_Catalysts.txt |
The synthesis of macromolecules composed of more than one monomeric repeating unit has been explored as a means of controlling the properties of the resulting material. In this respect, it is useful to distinguish several ways in which different monomeric units might be incorporated in a polymeric molecule. The following examples refer to a two component system, in which one monomer is designated A and the other B.
• Statistical Copolymers: Also called random copolymers. Here the monomeric units are distributed randomly, and sometimes unevenly, in the polymer chain: ~ABBAAABAABBBABAABA~.
• Alternating Copolymers: Here the monomeric units are distributed in a regular alternating fashion, with nearly equimolar amounts of each in the chain: ~ABABABABABABABAB~.
• Block Copolymers: Instead of a mixed distribution of monomeric units, a long sequence or block of one monomer is joined to a block of the second monomer: ~AAAAA-BBBBBBB~AAAAAAA~BBB~.
• Graft Copolymers: As the name suggests, side chains of a given monomer are attached to the main chain of the second monomer: ~AAAAAAA(BBBBBBB~)AAAAAAA(BBBB~)AAA~.
Addition Copolymerization
Most direct copolymerizations of equimolar mixtures of different monomers give statistical copolymers, or if one monomer is much more reactive a nearly homopolymer of that monomer. The copolymerization of styrene with methyl methacrylate, for example, proceeds differently depending on the mechanism. Radical polymerization gives a statistical copolymer. However, the product of cationic polymerization is largely polystyrene, and anionic polymerization favors formation of poly(methyl methacrylate). In cases where the relative reactivities are different, the copolymer composition can sometimes be controlled by continuous introduction of a biased mixture of monomers into the reaction.
Formation of alternating copolymers is favored when the monomers have different polar substituents (e.g. one electron withdrawing and the other electron donating), and both have similar reactivities toward radicals. For example, styrene and acrylonitrile copolymerize in a largely alternating fashion.
Some Useful Copolymers
Monomer A
Monomer B
Copolymer
Uses
H2C=CHCl
H2C=CCl2
Saran
films & fibers
H2C=CHC6H5
H2C=C-CH=CH2
SBR
styrene butadiene rubber
tires
H2C=CHCN
H2C=C-CH=CH2
Nitrile Rubber
adhesives
hoses
H2C=C(CH3)2
H2C=C-CH=CH2
Butyl Rubber
inner tubes
F2C=CF(CF3)
H2C=CHF
Viton
gaskets
A terpolymer of acrylonitrile, butadiene and styrene, called ABS rubber, is used for high-impact containers, pipes and gaskets.
Block Copolymerization
Several different techniques for preparing block copolymers have been developed, many of which use condensation reactions (next section). At this point, our discussion will be limited to an application of anionic polymerization. In the anionic polymerization of styrene described above, a reactive site remains at the end of the chain until it is quenched. The unquenched polymer has been termed a living polymer, and if additional styrene or a different suitable monomer is added a block polymer will form. This is illustrated for methyl methacrylate in the following diagram.
Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
29.06: Step-Growth Polymers
A large number of important and useful polymeric materials are not formed by chain-growth processes involving reactive species such as radicals, but proceed instead by conventional functional group transformations of polyfunctional reactants. These polymerizations often (but not always) occur with loss of a small byproduct, such as water, and generally (but not always) combine two different components in an alternating structure. The polyester Dacron and the polyamide Nylon 66, shown here, are two examples of synthetic condensation polymers, also known as step-growth polymers. In contrast to chain-growth polymers, most of which grow by carbon-carbon bond formation, step-growth polymers generally grow by carbon-heteroatom bond formation (C-O & C-N in Dacron & Nylon respectively). Although polymers of this kind might be considered to be alternating copolymers, the repeating monomeric unit is usually defined as a combined moiety.
Examples of naturally occurring condensation polymers are cellulose, the polypeptide chains of proteins, and poly(β-hydroxybutyric acid), a polyester synthesized in large quantity by certain soil and water bacteria. Formulas for these will be displayed below by clicking on the diagram.
Characteristics of Condensation Polymers
Condensation polymers form more slowly than addition polymers, often requiring heat, and they are generally lower in molecular weight. The terminal functional groups on a chain remain active, so that groups of shorter chains combine into longer chains in the late stages of polymerization. The presence of polar functional groups on the chains often enhances chain-chain attractions, particularly if these involve hydrogen bonding, and thereby crystallinity and tensile strength. The following examples of condensation polymers are illustrative.
Note that for commercial synthesis the carboxylic acid components may actually be employed in the form of derivatives such as simple esters. Also, the polymerization reactions for Nylon 6 and Spandex do not proceed by elimination of water or other small molecules. Nevertheless, the polymer clearly forms by a step-growth process. Some Condensation Polymers
The difference in Tg and Tm between the first polyester (completely aliphatic) and the two nylon polyamides (5th & 6th entries) shows the effect of intra-chain hydrogen bonding on crystallinity. The replacement of flexible alkylidene links with rigid benzene rings also stiffens the polymer chain, leading to increased crystalline character, as demonstrated for polyesters (entries 1, 2 &3) and polyamides (entries 5, 6, 7 & 8). The high Tg and Tm values for the amorphous polymer Lexan are consistent with its brilliant transparency and glass-like rigidity. Kevlar and Nomex are extremely tough and resistant materials, which find use in bullet-proof vests and fire resistant clothing.
Many polymers, both addition and condensation, are used as fibers The chief methods of spinning synthetic polymers into fibers are from melts or viscous solutions. Polyesters, polyamides and polyolefins are usually spun from melts, provided the Tm is not too high. Polyacrylates suffer thermal degradation and are therefore spun from solution in a volatile solvent. Cold-drawing is an important physical treatment that improves the strength and appearance of these polymer fibers. At temperatures above Tg, a thicker than desired fiber can be forcibly stretched to many times its length; and in so doing the polymer chains become untangled, and tend to align in a parallel fashion. This cold-drawing procedure organizes randomly oriented crystalline domains, and also aligns amorphous domains so they become more crystalline. In these cases, the physically oriented morphology is stabilized and retained in the final product. This contrasts with elastomeric polymers, for which the stretched or aligned morphology is unstable relative to the amorphous random coil morphology.
This cold-drawing treatment may also be used to treat polymer films (e.g. Mylar & Saran) as well as fibers.
Step-growth polymerization is also used for preparing a class of adhesives and amorphous solids called epoxy resins. Here the covalent bonding occurs by an SN2 reaction between a nucleophile, usually an amine, and a terminal epoxide. In the following example, the same bisphenol A intermediate used as a monomer for Lexan serves as a difunctional scaffold to which the epoxide rings are attached. Bisphenol A is prepared by the acid-catalyzed condensation of acetone with phenol. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/29%3A_Synthetic_Polymers/29.05%3A_Copolymers.txt |
A large number of important and useful polymeric materials are not formed by chain-growth processes involving reactive species such as radicals, but proceed instead by conventional functional group transformations of polyfunctional reactants. These polymerizations often (but not always) occur with loss of a small byproduct, such as water, and generally (but not always) combine two different components in an alternating structure. The polyester Dacron and the polyamide Nylon 66, shown here, are two examples of synthetic condensation polymers, also known as step-growth polymers. In contrast to chain-growth polymers, most of which grow by carbon-carbon bond formation, step-growth polymers generally grow by carbon-heteroatom bond formation (C-O & C-N in Dacron & Nylon respectively). Although polymers of this kind might be considered to be alternating copolymers, the repeating monomeric unit is usually defined as a combined moiety.
Examples of naturally occurring condensation polymers are cellulose, the polypeptide chains of proteins, and poly(β-hydroxybutyric acid), a polyester synthesized in large quantity by certain soil and water bacteria. Formulas for these will be displayed below by clicking on the diagram.
Characteristics of Condensation Polymers
Condensation polymers form more slowly than addition polymers, often requiring heat, and they are generally lower in molecular weight. The terminal functional groups on a chain remain active, so that groups of shorter chains combine into longer chains in the late stages of polymerization. The presence of polar functional groups on the chains often enhances chain-chain attractions, particularly if these involve hydrogen bonding, and thereby crystallinity and tensile strength. The following examples of condensation polymers are illustrative.
Note that for commercial synthesis the carboxylic acid components may actually be employed in the form of derivatives such as simple esters. Also, the polymerization reactions for Nylon 6 and Spandex do not proceed by elimination of water or other small molecules. Nevertheless, the polymer clearly forms by a step-growth process. Some Condensation Polymers
The difference in Tg and Tm between the first polyester (completely aliphatic) and the two nylon polyamides (5th & 6th entries) shows the effect of intra-chain hydrogen bonding on crystallinity. The replacement of flexible alkylidene links with rigid benzene rings also stiffens the polymer chain, leading to increased crystalline character, as demonstrated for polyesters (entries 1, 2 &3) and polyamides (entries 5, 6, 7 & 8). The high Tg and Tm values for the amorphous polymer Lexan are consistent with its brilliant transparency and glass-like rigidity. Kevlar and Nomex are extremely tough and resistant materials, which find use in bullet-proof vests and fire resistant clothing.
Many polymers, both addition and condensation, are used as fibers The chief methods of spinning synthetic polymers into fibers are from melts or viscous solutions. Polyesters, polyamides and polyolefins are usually spun from melts, provided the Tm is not too high. Polyacrylates suffer thermal degradation and are therefore spun from solution in a volatile solvent. Cold-drawing is an important physical treatment that improves the strength and appearance of these polymer fibers. At temperatures above Tg, a thicker than desired fiber can be forcibly stretched to many times its length; and in so doing the polymer chains become untangled, and tend to align in a parallel fashion. This cold-drawing procedure organizes randomly oriented crystalline domains, and also aligns amorphous domains so they become more crystalline. In these cases, the physically oriented morphology is stabilized and retained in the final product. This contrasts with elastomeric polymers, for which the stretched or aligned morphology is unstable relative to the amorphous random coil morphology.
This cold-drawing treatment may also be used to treat polymer films (e.g. Mylar & Saran) as well as fibers.
Step-growth polymerization is also used for preparing a class of adhesives and amorphous solids called epoxy resins. Here the covalent bonding occurs by an SN2 reaction between a nucleophile, usually an amine, and a terminal epoxide. In the following example, the same bisphenol A intermediate used as a monomer for Lexan serves as a difunctional scaffold to which the epoxide rings are attached. Bisphenol A is prepared by the acid-catalyzed condensation of acetone with phenol. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/29%3A_Synthetic_Polymers/29.07%3A_Classes_of_Step-Growth_Polymers.txt |
A comparison of the properties of polyethylene (both LDPE & HDPE) with the natural polymers rubber and cellulose is instructive. As noted above, synthetic HDPE macromolecules have masses ranging from 105 to 106 amu (LDPE molecules are more than a hundred times smaller). Rubber and cellulose molecules have similar mass ranges, but fewer monomer units because of the monomer's larger size. The physical properties of these three polymeric substances differ from each other, and of course from their monomers.
• HDPE is a rigid translucent solid which softens on heating above 100º C, and can be fashioned into various forms including films. It is not as easily stretched and deformed as is LDPE. HDPE is insoluble in water and most organic solvents, although some swelling may occur on immersion in the latter. HDPE is an excellent electrical insulator.
• LDPE is a soft translucent solid which deforms badly above 75º C. Films made from LDPE stretch easily and are commonly used for wrapping. LDPE is insoluble in water, but softens and swells on exposure to hydrocarbon solvents. Both LDPE and HDPE become brittle at very low temperatures (below -80º C). Ethylene, the common monomer for these polymers, is a low boiling (-104º C) gas.
• Natural (latex) rubber is an opaque, soft, easily deformable solid that becomes sticky when heated (above. 60º C), and brittle when cooled below -50º C. It swells to more than double its size in nonpolar organic solvents like toluene, eventually dissolving, but is impermeable to water. The C5H8 monomer isoprene is a volatile liquid (b.p. 34º C).
• Pure cellulose, in the form of cotton, is a soft flexible fiber, essentially unchanged by variations in temperature ranging from -70 to 80º C. Cotton absorbs water readily, but is unaffected by immersion in toluene or most other organic solvents. Cellulose fibers may be bent and twisted, but do not stretch much before breaking. The monomer of cellulose is the C6H12O6 aldohexose D-glucose. Glucose is a water soluble solid melting below 150º C.
To account for the differences noted here we need to consider the nature of the aggregate macromolecular structure, or morphology, of each substance. Because polymer molecules are so large, they generally pack together in a non-uniform fashion, with ordered or crystalline-like regions mixed together with disordered or amorphous domains. In some cases the entire solid may be amorphous, composed entirely of coiled and tangled macromolecular chains. Crystallinity occurs when linear polymer chains are structurally oriented in a uniform three-dimensional matrix. In the diagram on the right, crystalline domains are colored blue.
Increased crystallinity is associated with an increase in rigidity, tensile strength and opacity (due to light scattering). Amorphous polymers are usually less rigid, weaker and more easily deformed. They are often transparent.
Three factors that influence the degree of crystallinity are:
i) Chain length
ii) Chain branching
iii) Interchain bonding
The importance of the first two factors is nicely illustrated by the differences between LDPE and HDPE. As noted earlier, HDPE is composed of very long unbranched hydrocarbon chains. These pack together easily in crystalline domains that alternate with amorphous segments, and the resulting material, while relatively strong and stiff, retains a degree of flexibility. In contrast, LDPE is composed of smaller and more highly branched chains which do not easily adopt crystalline structures. This material is therefore softer, weaker, less dense and more easily deformed than HDPE. As a rule, mechanical properties such as ductility, tensile strength, and hardness rise and eventually level off with increasing chain length.
The nature of cellulose supports the above analysis and demonstrates the importance of the third factor (iii). To begin with, cellulose chains easily adopt a stable rod-like conformation. These molecules align themselves side by side into fibers that are stabilized by inter-chain hydrogen bonding between the three hydroxyl groups on each monomer unit. Consequently, crystallinity is high and the cellulose molecules do not move or slip relative to each other. The high concentration of hydroxyl groups also accounts for the facile absorption of water that is characteristic of cotton.
Natural rubber is a completely amorphous polymer. Unfortunately, the potentially useful properties of raw latex rubber are limited by temperature dependence; however, these properties can be modified by chemical change. The cis-double bonds in the hydrocarbon chain provide planar segments that stiffen, but do not straighten the chain. If these rigid segments are completely removed by hydrogenation (H2 & Pt catalyst), the chains lose all constrainment, and the product is a low melting paraffin-like semisolid of little value. If instead, the chains of rubber molecules are slightly cross-linked by sulfur atoms, a process called vulcanization which was discovered by Charles Goodyear in 1839, the desirable elastomeric properties of rubber are substantially improved. At 2 to 3% crosslinking a useful soft rubber, that no longer suffers stickiness and brittleness problems on heating and cooling, is obtained. At 25 to 35% crosslinking a rigid hard rubber product is formed. The following illustration shows a cross-linked section of amorphous rubber. By clicking on the diagram it will change to a display of the corresponding stretched section. The more highly-ordered chains in the stretched conformation are entropically unstable and return to their original coiled state when allowed to relax
Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
29.09: Biodegradable Polymers
Most plastics crumble into ever-tinier fragments as they are exposed to sunlight and the elements. Except for the small amount that's been incinerated–and it's a very small amount–every bit of plastic ever made still exists, unless the material's molecular structure is designed to favor biodegradation. Unfortunately, cleaning up the garbage patch is not a realistic option, and unless we change our disposal and recycling habits, it will undoubtedly get bigger. One sensible solution would require manufacturers to use natural biodegradable packaging materials whenever possible, and consumers to conscientiously dispose of their plastic waste. Thus, instead of consigning all plastic trash to a land fill, some of it may provide energy by direct combustion, and some converted for reuse as a substitute for virgin plastics. The latter is particularly attractive since a majority of plastics are made from petroleum, a diminishing resource with a volatile price.
The energy potential of plastic waste is relatively significant, ranging from 10.2 to 30.7MJ kg Ã, suggesting application as an energy source and temperature stabilizer in municipal incinerators, thermal power plants and cement kilns. The use of plastic waste as a fuel source would be an effective means of reducing landfill requirements while recovering energy. This, however, depends on using appropriate materials. Inadequate control of combustion, especially for plastics containing chlorine, fluorine and bromine, constitutes a risk of emitting toxic pollutants.
Whether used as fuels or a source of recycled plastic, plastic waste must be separated into different categories. To this end, an identification coding system was developed by the Society of the Plastics Industry (SPI) in 1988, and is used internationally. This code, shown on the right, is a set of symbols placed on plastics to identify the polymer type, for the purpose of allowing efficient separation of different polymer types for recycling. The abbreviations of the code are explained in the following table.
PETE
HDPE
V
LDPE
polyethylene
terephthalate
high density
polyethylene
polyvinyl chloride
low density
polyethylene
PP
PS
OTHER
polypropylene
polystyrene
polyesters, acrylics
polyamides, teflon etc.
Despite use of the recycling symbol in the coding of plastics, there is consumer confusion about which plastics are readily recyclable. In most communities throughout the United States, PETE and HDPE are the only plastics collected in municipal recycling programs. However, some regions are expanding the range of plastics collected as markets become available. (Los Angeles, for example, recycles all clean plastics numbered 1 through 7) In theory, most plastics are recyclable and some types can be used in combination with others. In many instances, however, there is an incompatibility between different types that necessitates their effective separation. Since the plastics utilized in a given manufacturing sector (e.g. electronics, automotive, etc.) is generally limited to a few types, effective recycling is often best achieved with targeted waste streams.
Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/29%3A_Synthetic_Polymers/29.08%3A_Physical_Properties_of_Polymers.txt |
An important body of chemical reactions, differing from ionic or free radical reactions in a number of respects, has been recognized and extensively studied. Among the characteristics shared by these reactions, three in particular set them apart:
1. They are relatively unaffected by solvent changes, the presence of radical initiators or scavenging reagents, or (with some exceptions) by electrophilic or nucleophilic catalysts.
2. They proceed by a simultaneous (concerted) series of bond breaking and bond making events in a single kinetic step, often with high stereospecificity.
3. In agreement with 1 & 2, no ionic, free radical or other discernible intermediates lie on the reaction path.
Since reactions of this kind often proceed by nearly simultaneous reorganization of bonding electron pairs by way of cyclic transition states, they have been termed pericyclic reactions. The four principle classes of pericyclic reactions are termed: Cycloaddition, Electrocyclic, Sigmatropic, and Ene Reactions. The cycloaddition and ene reactions are shown in their intermolecular format. Corresponding intramolecular reactions, which create an additional ring, are well known.
All these reactions are potentially reversible (note the gray arrows). The reverse of a cycloaddition is called cycloreversion and proceeds by a ring cleavage and conversion of two sigma-bonds to two pi-bonds. The electrocyclic reaction shown above is a ring forming process. The reverse electerocyclic ring opening reaction proceeds by converting a sigma-bond to a pi-bond. As shown, the retro ene reaction cleaves an unsaturated compound into two unsaturated fragments. Finally, sigmatropic bond shifts may involve a simple migrating group, as shown in the example above, or may take place between two pi-electron systems (e.g. the Cope rearrangement).
The general descriptions shown above provide a basis for reaction classification, but care must be taken to assure that a given transformation is truly concerted. Unfortunately, this is not a trivial determination, often requiring a combination of isotope labeling and stereochemical studies to arrive at a plausible conclusion. There is also a subtle distinction to be made between a synchronous reaction in which all bond-making and bond-breaking events take place in unison, and a multi-stage concerted process in which some events precede others without generating an intermediate state.
Although some pericyclic reactions occur spontaneously, most require the introduction of energy in the form of heat or light, with a remarkable product dependence on the source of energy used. An appreciation of the stereoselective structural changes these reactions promote is best achieved by inspecting some individual examples.
30.02: Molecular Orbitals and Orbital Symmetry
In 1965 R. B. Woodward and Roald Hoffmann of Harvard University proposed and demonstrated that concerted reactions proceed most readily when there is congruence between the orbital symmetries of the reactants and products. In other words, when the bonding character of all occupied molecular orbitals is preserved at all stages of a concerted molecular reorganization, that reaction will most likely take place. The greater the degree of bonding found in the transition state for the reaction, the lower will be its activation energy and the greater will be the reaction rate.
A general introduction to molecular orbitals was presented earlier. The simple compound ethene is made up of six atoms held together by six covalent bonds, as described in the following illustration. A molecular orbital diagram of ethene is created by combining the twelve atomic orbitals associated with four hydrogen atoms and two sp2 hybridized carbons to give twelve molecular orbitals. Six of these molecular orbitals (five sigma & one pi-orbital) are bonding, and are occupied by the twelve available valence shell electrons. The remaining six molecular orbitals are antibonding, and are empty.
Proper molecular orbitals are influenced by all the nuclei in a molecule, and require consideration of the full structure and symmetry of a molecule for their complete description. For most purposes, this level of treatment is not needed, and more localized orbitals serve well. In the case of ethene and other isolated double bonds, descriptions of the localized π orbitals will be displayed by clicking on the above diagram. Several important characteristics of molecular orbitals need to be pointed out, and this diagram will serve to illustrate them.
1. The spatial distribution of electron density for most occupied molecular orbitals is discontinuous, with regions of high density separated by regions of zero density, e.g. a nodal plane. The π-orbital on the left has one nodal plane (colored light blue), and the π*-orbital on the right has a second nodal plane (colored yellow). As a rule, higher energy molecular orbitals have a larger number of nodal surfaces or nodes.
2. The wave functions that describe molecular orbitals undergo a change in sign at nodal surfaces. This phase change is sometimes designated by plus and minus signs associated with discrete regions of the orbital, but this notation may sometimes be confused for an electric charge. In the above diagram, regions having one phase sign are colored blue, while those having an opposite sign are colored red.
3. These localized orbitals may be classified by two independent symmetry operations ; a mirror plane perpendicular to the functional plane and bisecting the the molecule (colored yellow above), and a two-fold axis of rotation (C2) created by the intersection of this mirror plane with the common nodal plane (colored light blue). The π-orbital on the left is symmetric (S) with respect to the mirror plane, but antisymmetric (A) when rotated 180º, a C2 operation. The opposite is true for the π*-orbital on the right, which has a mirror plane symmetry of A and a C2 symmetry of S. Such symmetry characteristics play an important role in creating the orbital diagrams used by Woodward and Hoffmann to rationalize pericyclic reactions.
The original approach of Woodward and Hoffmann involved construction of an "orbital correlation diagram" for each type of pericyclic reaction. The symmetries of the appropriate reactant and product orbitals were matched to determine whether the transformation could proceed without a symmetry imposed conversion of bonding reactant orbitals to antibonding product orbitals. If the correlation diagram indicated that the reaction could occur without encountering such a symmetry-imposed barrier, it was termed symmetry allowed. If a symmetry barrier was present, the reaction was designated symmetry-forbidden. Two related methods of analyzing pericyclic reactions are the transition state aromaticity approach, and the frontier molecular orbital approach. Each of these methods has merit, and a more detailed description of each may be examined by clicking the appropriate button below.
Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/30%3A_Pericyclic_Reactions/30.01%3A_There_Are_Three_Kinds_of_Pericyclic_Reactions.txt |
An electrocyclic reaction is the concerted cyclization of a conjugated π-electron system by converting one π-bond to a ring forming σ-bond. The reverse reaction may be called electrocyclic ring opening. Two examples are shown on the right. The electrocyclic ring closure is designated by blue arrows, and the ring opening by red arrows. Once again, the number of curved arrows that describe the bond reorganization is half the total number of electrons involved in the process.
In the first case, trans,cis,trans-2,4,6-octatriene undergoes thermal ring closure to cis-5,6-dimethyl-1,3-cyclohexadiene. The sterospecificity of this reaction is demonstrated by closure of the isomeric trans,cis,cis-triene to trans-5,6-dimethyl-1,3-cyclohexadiene, as noted in the second example.
By clicking on this diagram two examples of thermal electrocyclic opening of cyclobutenes to conjugated butadienes will be displayed. This mode of reaction is favored by relief of ring strain, and the reverse ring closure (light blue arrows) is not normally observed. Photochemical ring closure can be effected, but the stereospecificity is opposite to that of thermal ring opening.
30.04: Cycloaddition Reactions
A concerted combination of two π-electron systems to form a ring of atoms having two new σ bonds and two fewer π bonds is called a cycloaddition reaction. The number of participating π-electrons in each component is given in brackets preceding the name, and the reorganization of electrons may be depicted by a cycle of curved arrows - each representing the movement of a pair of electrons. These notations are illustrated in the drawing on the right. The ring-forming cycloaddition reaction is described by blue arrows, whereas the ring-opening cycloreversion process is designated by red arrows. Note that the number of curved arrows needed to show the bond reorganization is half the number total in the brackets.
The most common cycloaddition reaction is the [4π+2π] cyclization known as the Diels-Alder reaction. In Diels-Alder terminology the two reactants are referred to as the diene and the dienophile. The following diagram shows two examples of [4π+2π] cycloaddition, and in the second equation a subsequent light induced [2π+2π] cycloaddition. In each case the diene reactant is colored blue, and the new σ-bonds in the adduct are colored red. The stereospecificity of these reactions should be evident. In the first example, the acetoxy substituents on the diene have identical E-configurations, and they remain cis to each other in the cyclic adduct. Likewise, the ester substituents on the dienophile have a trans-configuration which is maintained in the adduct. The reactants in the second equation are both monocyclic, so the cycloaddition adduct has three rings. The orientation of the quinone six-membered ring with respect to the bicycloheptane system (colored blue) is endo, which means it is oriented cis to the longest or more unsaturated bridge. The alternative configuration is called exo.
Since the dienophile (quinone) has two activated double bonds, a second cycloaddition reaction is possible, provided sufficient diene is supplied. The second cycloaddition is slower than the first, so the monoadduct shown here is easily prepared in good yield. Although this [4+2] product is stable to further heating, it undergoes a [2+2] cycloaddition when exposed to sunlight. Note the loss of two carbon-carbon π-bonds and the formation of two σ-bonds (colored red) in this transformation. Also note that the pi-subscript is often omitted from the [m+n] notation for the majority of cycloadditions involving π-electron systems.
Reaction 3 is an intramolecular Diels-Alder reaction. Since the diene and dienophile are joined by a chain of atoms, the resulting [4+2] cycloaddition actually forms two new rings, one from the cycloaddition and the other from the linking chain. Once again the addition is stereospecific, ignoring the isopropyl substituent, the ring fusion being cis and endo. The fourth reaction is a [6+4] cycloaddition. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/30%3A_Pericyclic_Reactions/30.03%3A_Electrocyclic_Reactions.txt |
Molecular rearrangements in which a σ-bonded atom or group, flanked by one or more π-electron systems, shifts to a new location with a corresponding reorganization of the π-bonds are called sigmatropic reactions. The total number of σ-bonds and π-bonds remain unchanged. These rearrangements are described by two numbers set in brackets, which refer to the relative distance (in atoms) each end of the σ-bond has moved, as illustrated by the first equation in the diagram below. The most common atom to undergo sigmatropic shifts is hydrogen or one of its isotopes. The second equation in the diagram shows a facile [1,5] hydrogen shift which converts a relatively unstable allene system into a conjugated triene. Note that this rearrangement, which involves the relocation of three pairs of bonding electrons, may be described by three curved arrows.
These reactions are particularly informative in that [1,3] hydrogen shifts are not observed. The reactant in the first equation is a deuterium labeled 1,3,5-cyclooctatriene. On heating, this compound equilibrates with its 1,3,6-triene isomer, and the two deuterium atoms are scrambled among the four locations noted. If [1,3] or [1,7] hydrogen shifts were taking place, the deuterium atoms would be distributed equally among all eight carbon atoms. On prolonged heating, or at higher temperatures these cyclooctatrienes undergo electrocyclic ring opening to 1,3,5,7-octatetraene and reclosure to vinyl-1,3-cyclohexadienes.
The second example shows another [1,5] hydrogen shift, from the proximal methyl group to the carbonyl oxygen atom. The resulting dienol rapidly exchanges OH for OD before the [1,5] shift reverses. In this manner the reactive methyl is soon converted to CD3. Since hydrogens alpha to a carbonyl group are known to undergo acid or base catalyzed exchange by way of enol intermediates, we might expect the α'-CH2 group to exchange as well. However, if care is taken to remove potential acid or base catalysts, the thermal [1,3] shift necessary for the exchange is found to be very slow.
Cope and Claisen rearrangements
The [3,3] sigmatropic rearrangement of 1,5-dienes or allyl vinyl ethers, known respectively as the Cope and Claisen rearrangements, are among the most commonly used sigmatropic reactions. Three examples of the Cope rearrangement are shown in the following diagram. Reactions 1 and 2 (top row) demonstrate the stereospecificity of this reaction. The light blue σ-bond joins two allyl groups, oriented so their ends are near each other. Since each allyl segment is the locus of a [1,3] shift, the overall reaction is classified as a [3,3] rearrangement. The three pink colored curved arrows describe the redistribution of three bonding electron pairs in the course of this reversible rearrangement. The diene reactant in the third reaction is drawn in an extended conformation. This molecule must assume a coiled conformation (as above) before the [3,3] rearrangement can take place. The product of this rearrangement is an enol which immediately tautomerizes to its keto form. Such variants are termed the oxy-Cope rearrangement, and are useful because the reverse rearrangement is blocked by rapid ketonization. If the hydroxyl substituent is converted to an alkoxide salt, the activation energy of the rearrangement is lowered significantly.
The degenerate or self-replicating Cope rearrangement has been a fascinating subject of research. For examples .
Two examples of the Claisen Rearrangement may be seen by clicking on the above diagram. Reaction 4 is the classic rearrangement of an allyl phenyl ether to an ortho-allyl phenol. The methyl substituent on the allyl moiety serves to demonstrate the bonding shift at that site. The initial cyclohexadienone product immediately tautomerizes to a phenol, regaining the stability of the aromatic ring. Reaction 5 is an aliphatic analog in which a vinyl group replaces the aromatic ring. In both cases three pairs of bonding electrons undergo a reorganization.
By clicking on the above diagram a second time two examples of [2,3] sigmatropic rearrangements will be displayed. The allylic sulfoxide in reaction 6 rearranges reversibly to a less stable sulfenate ester. The weak S-O bond may be reductively cleaved by trimethyl phosphite to an allylic alcohol and a thiol (not shown). Reaction 7 shows a similar rearrangement of a sulfur ylide to a cyclic sulfide. The [2,3]-Wittig rearrangement is yet another example.
30.06: Pericyclic Reactions in Biological Systems
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le
30.07: Summary of the Selection Rules for Pericyclic Reactions
Before pericyclic reactions can be put to use in a predictable and controlled manner, a broad mechanistic understanding of the factors that influence these concerted transformations must be formulated. The simplest, albeit least rigorous, method for predicting the configurational path favored by a proposed pericyclic reaction is based upon a transition state electron count. In most of the earlier examples, pericyclic reactions were described by a cycle of curved arrows, each representing a pair of bonding electrons. The total number of electrons undergoing reorganization is always even, and is either a 4n+2 or 4n number (where n is an integer). Once this electron count is made, the following table may be used for predictions.
Thermal
Reactions
Transition State Class
Configurational Preference
4n + 2 (aromatic)
Suprafacial or Disrotatory
4n (antiaromatic)
Antarafacial or Conrotatory
Photochemical
Reactions
Transition State Class
Configurational Preference
4n + 2 (aromatic)
Antarafacial or Conrotatory
4n (antiaromatic)
Suprafacial or Disrotatory
Although this modest mnemonic does not make explicit use of molecular orbitals, more rigorous methods that are founded on the characteristics of such orbitals have provided important insight into these reactions. Since pericyclic reactions proceed by a cyclic reorganization of bonding electron pairs, it is necessary to evaluate changes in the associated molecular orbitals that take place in going from reactants to products. The following section describes approaches of this kind. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/30%3A_Pericyclic_Reactions/30.05%3A_Sigmatropic_Rearrangements.txt |
A very broad definition of a drug would include "all chemicals other than food that affect living processes." If the affect helps the body, the drug is a medicine. However, if a drug causes a harmful effect on the body, the drug is a poison. The same chemical can be a medicine and a poison depending on conditions of use and the person using it. Another definition would be "medicinal agents used for diagnosis, prevention, treatment of symptoms, and cure of diseases." Contraceptives would be outside of this definition unless pregnancy were considered a disease.
• Anti-Cancer Drugs I
• Anti-Cancer Drugs II
• Antidepressants
Antidepressant drugs are used to restore mentally depressed patients to an improved mental status. Depression results from a deficiency of norepinephrine at receptors in the brain. Mechanisms that increase their effective concentration at the receptor sites should alleviate depression.
• Barbiturates and Benzodiazepines
Barbiturates are central nervous system depressants and are similar, in many ways, to the depressant effects of alcohol.
• Drugs Acting Upon the Central Nervous System
Chemical influences are capable of producing a myriad of effects on the activity and function of the central nervous system. Since our knowledge of different regions of brain function and the neurotransmitters in the brain is limited, the explanations for the mechanisms of drug action may be vague. The known neurotransmitters are: acetylcholine which is involved with memory and learning; norepinephrine which is involved with mania-depression and emotions.
• Drug Activity
Page notifications Off Barbiturates and Benzodiazepines Drug Receptor Interactions picture_as_pdf Batch Donate Table of contents A very broad definition of a drug would include "all chemicals other than food that affect living processes." If the affect helps the body, the drug is a medicine. However, if a drug causes a harmful effect on the body, the drug is a poison. The same chemical can be a medicine and a poison depending on conditions of use and the person using it.
• Drug Receptor Interactions
Drugs interact with receptor sites localized in macromolecules which have protein-like properties and specific three dimensional shapes. A minimum three point attachment of a drug to a receptor site is required. In most cases a rather specific chemical structure is required for the receptor site and a complementary drug structure. Slight changes in the molecular structure of the drug may drastically change specificity.
• Enzyme Inhibition
Although activation of enzymes may be exploited therapeutically, most effects are produced by enzyme inhibition.
• Hallucinogenic Drugs
Hallucinogenic agents, also called psychomimetic agents, are capable of producing hallucinations, sensory illusions and bizarre thoughts. The primary effect of these compounds is to consistently alter thought and sensory perceptions.
• Local Anesthetics
Local anesthetics are agents that reversibly block the generation and conduction of nerve impulses along a nerve fiber. They depress impulses from sensory nerves of the skin, surfaces of mucosa, and muscles to the central nervous system. These agents are widely used in surgery, dentistry, and ophthalmology to block transmission of impulses in peripheral nerve endings.
• Misc Antibiotics
Antibiotics are specific chemical substances derived from or produced by living organisms that are capable of inhibiting the life processes of other organisms.
• Narcotic Analgesic Drugs
Narcotic agents are potent analgesics which are effective for the relief of severe pain. Analgesics are selective central nervous system depressants used to relieve pain. The term analgesic means "without pain". Even in therapeutic doses, narcotic analgesics can cause respiratory depression, nausea, and drowsiness.
• Penicillin
The penicillins were the first antibiotics discovered as natural products from the mold Penicillium.
• Sulfa Drugs
Sulfonamides are synthetic antimicrobial agents with a wide spectrum encompassing most gram-positive and many gram-negative organisms. These drugs were the first efficient treatment to be employed systematically for the prevention and cure of bacterial infections.
Thumbnail: Ritalin SR 20 mg, a brand-name sustained-release formulation of methylphenidate. (CC SA-BY 3.0; Sponge). | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/31%3A_The_Organic_Chemistry_of_Drugs-_Discovery_and_Design/31.01%3A_Naming_Drugs.txt |
A very broad definition of a drug would include "all chemicals other than food that affect living processes." If the affect helps the body, the drug is a medicine. However, if a drug causes a harmful effect on the body, the drug is a poison. The same chemical can be a medicine and a poison depending on conditions of use and the person using it. Another definition would be "medicinal agents used for diagnosis, prevention, treatment of symptoms, and cure of diseases." Contraceptives would be outside of this definition unless pregnancy were considered a disease.
• Anti-Cancer Drugs I
• Anti-Cancer Drugs II
• Antidepressants
Antidepressant drugs are used to restore mentally depressed patients to an improved mental status. Depression results from a deficiency of norepinephrine at receptors in the brain. Mechanisms that increase their effective concentration at the receptor sites should alleviate depression.
• Barbiturates and Benzodiazepines
Barbiturates are central nervous system depressants and are similar, in many ways, to the depressant effects of alcohol.
• Drugs Acting Upon the Central Nervous System
Chemical influences are capable of producing a myriad of effects on the activity and function of the central nervous system. Since our knowledge of different regions of brain function and the neurotransmitters in the brain is limited, the explanations for the mechanisms of drug action may be vague. The known neurotransmitters are: acetylcholine which is involved with memory and learning; norepinephrine which is involved with mania-depression and emotions.
• Drug Activity
Page notifications Off Barbiturates and Benzodiazepines Drug Receptor Interactions picture_as_pdf Batch Donate Table of contents A very broad definition of a drug would include "all chemicals other than food that affect living processes." If the affect helps the body, the drug is a medicine. However, if a drug causes a harmful effect on the body, the drug is a poison. The same chemical can be a medicine and a poison depending on conditions of use and the person using it.
• Drug Receptor Interactions
Drugs interact with receptor sites localized in macromolecules which have protein-like properties and specific three dimensional shapes. A minimum three point attachment of a drug to a receptor site is required. In most cases a rather specific chemical structure is required for the receptor site and a complementary drug structure. Slight changes in the molecular structure of the drug may drastically change specificity.
• Enzyme Inhibition
Although activation of enzymes may be exploited therapeutically, most effects are produced by enzyme inhibition.
• Hallucinogenic Drugs
Hallucinogenic agents, also called psychomimetic agents, are capable of producing hallucinations, sensory illusions and bizarre thoughts. The primary effect of these compounds is to consistently alter thought and sensory perceptions.
• Local Anesthetics
Local anesthetics are agents that reversibly block the generation and conduction of nerve impulses along a nerve fiber. They depress impulses from sensory nerves of the skin, surfaces of mucosa, and muscles to the central nervous system. These agents are widely used in surgery, dentistry, and ophthalmology to block transmission of impulses in peripheral nerve endings.
• Misc Antibiotics
Antibiotics are specific chemical substances derived from or produced by living organisms that are capable of inhibiting the life processes of other organisms.
• Narcotic Analgesic Drugs
Narcotic agents are potent analgesics which are effective for the relief of severe pain. Analgesics are selective central nervous system depressants used to relieve pain. The term analgesic means "without pain". Even in therapeutic doses, narcotic analgesics can cause respiratory depression, nausea, and drowsiness.
• Penicillin
The penicillins were the first antibiotics discovered as natural products from the mold Penicillium.
• Sulfa Drugs
Sulfonamides are synthetic antimicrobial agents with a wide spectrum encompassing most gram-positive and many gram-negative organisms. These drugs were the first efficient treatment to be employed systematically for the prevention and cure of bacterial infections.
Thumbnail: Ritalin SR 20 mg, a brand-name sustained-release formulation of methylphenidate. (CC SA-BY 3.0; Sponge). | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/31%3A_The_Organic_Chemistry_of_Drugs-_Discovery_and_Design/31.02%3A_Lead_Compounds.txt |
Unlike other drugs which act in the region of the synapse, local anesthetics are agents that reversibly block the generation and conduction of nerve impulses along a nerve fiber. They depress impulses from sensory nerves of the skin, surfaces of mucosa, and muscles to the central nervous system. These agents are widely used in surgery, dentistry, and ophthalmology to block transmission of impulses in peripheral nerve endings.
Introduction
Most local anesthetics can be represented by the following general formula. In both the official chemical name and the proprietary name, a local anesthetic drug can be recognized by the "-caine" ending. The ester linkage can also be an amide linkage. The most recent research indicates that the local anesthetic binds to a phospholipid in the nerve membrane and inhibits the ability of the phospholipid to bind Ca+2 ions.
Practically all of the free-base forms of the drugs are liquids. For this reason most of these drugs are used as salts (chloride, sulfate, etc.) which are water soluble, odorless, and crystalline solids. As esters these drugs are easily hydrolyzed with consequent loss of activity. The amide form of the drug is more stable and resistant to hydrolysis.
Benzocaine and Lidocaine
Two local anesthtics are shown below.
Contributors
Narcotic agents are potent analgesics which are effective for the relief of severe pain. Analgesics are selective central nervous system depressants used to relieve pain. The term analgesic means "without pain". Even in therapeutic doses, narcotic analgesics can cause respiratory depression, nausea, and drowsiness. Long term administration produces tolerance, psychic, and physical dependence called addiction.
Introduction
Narcotic agents may be classified into four categories:
1. Morphine and codeine - natural alkaloids of opium.
2. Synthetic derivatives of morphine such as heroin.
3. Synthetic agents which resemble the morphine structure.
4. Narcotic antagonists which are used as antidotes for overdoses of narcotic analgesics.
The main pharmacological action of analgesics is on the cerebrum and medulla of the central nervous system. Another effect is on the smooth muscle and glandular secretions of the respiratory and gastro-intestinal tract. The precise mechanism of action is unknown although the narcotics appear to interact with specific receptor sites to interfere with pain impulses.
Receptor Site
A schematic for an analgesic receptor site may look as shown in the graphic below with morphine. Three areas are needed: a flat areas to accommodate a flat nonpolar aromatic ring, a cavity to accept another series of rings perpendicular, and an anionic site for polar interaction of the amine group.
Enkephalins
Recently investigators have discovered two compounds in the brain called enkephalins which resemble morphine in structure. Each one is a peptide composed of 5 amino acids and differ only in the last amino acid. The peptide sequences are: tyr-gly-gly-phe-leu and tyr-gly-gly-phe-met. Molecular models show that the structures of the enkephalins has some similarities with morphine. The main feature in common appears to be the aromatic ring with the -OH group attached (tyr). Methadone and other similar analgesics have 2 aromatic rings which would be similar to the enkephalins (tyr and phe).
Analgesics may relieve pain by preventing the release of acetylcholine. Enkephalin molecules are released from a nerve cell and bind to analgesic receptor sites on the nerve cell sending the impulse. The binding of enkephalin or morphine-like drugs changes the shape of the nerve sending the impulse in such a fashion as to prevent the cell from releasing acetylcholine. As a result, the pain impulse cannot be transmitted and the brain does not preceive pain.
Morphine and Codeine
Morphine exerts a narcotic action manifested by analgesia, drowsiness, changes in mood, and mental clouding. The major medical action of morphine sought in the CNS is analgesia. Opiates suppress the "cough center" which is also located in the brain stem, the medulla. Such an action is thought to underlie the use of opiate narcotics as cough suppressants. Codeine appears to be particularly effective in this action and is widely used for this purpose.
Narcotic analgesics cause an addictive physical dependence. If the drug is discontinued, withdrawal symptoms are experienced. Although the reasons for addiction and withdrawal symptoms are not completely known, recent experiments have provided some information. A nucleotide known as cyclicadenosine monophosphate (cAMP) is synthesized with the aid of the enzyme adenylate cyclase. Enkephalin and morphine-like drugs inhibit this enzyme and thus decrease the amount of cAMP in the cells. In order to compensate for the decreased cAMP, the cells synthesize more enzyme in an attempt to produce more cAMP. Since more enzyme has been produced, more morphine is required as an inhibitor to keep the cAMP at a low level. This cycle repeats itself causing an increase in the tolerance level and increasing the amounts of morphine required. If morphine is suddenly withheld, withdrawal symptoms are probably caused by a high concentration of cAMP since the synthesizing enzyme, adenylate cyclase, is no longer being inhibited.
Morphine and codeine are contained in opium from the poppy (Papaver Somniterum) plant found in Turkey, Mexico, Southeast Asia, China, and India. This plant is 3-4 feet tall with 5-8 egg shaped capsules on top. Ten days after the poppy blooms in June, incisions are made in the capsules permitting a milky fluid to ooze out. The following day the gummy mass (now brown) is carefully scraped off and pressed into cakes of raw opium to dry.
Opium contains over 20 compounds but only morphine (10%) and codeine (0.5%) are of any importance. Morphine is extracted from the opium and isolated in a relatively pure form. Since codeine is in such low concentration, it is synthesized from morphine by an ether-type methylation of an alcohol group. Codeine has only a fraction of the potency compared to morphine. It is used with aspirin and as a cough suppressant.
Heroin
Heroin is synthesized from morphine by a relatively simple esterification reaction of two alcohol (phenol) groups with acetic anhydride (equivalent to acetic acid). Heroin is much more potent than morphine but without the respiratory depression effect. A possible reason may be that heroin passes the blood-brain barrier much more rapidly than morphine. Once in the brain, the heroin is hydrolyzed to morphine which is responsible for its activity.
Synthetic narcotic analgesics include meperidine and methadone. Meperidine is the most common subsitute for morphine. It exerts several pharmacological effects: analgesic, local anesthetic, and mild antihistamine. This multiple activity may be explained by its structural resemblance to morphine, atropine, and histamine.
Methadone is more active and more toxic than morphine. It can be used for the relief of may types of pain. In addition it is used as a narcotic substitute in addiction treatment because it prevents morphine abstinence syndrome. Methadone was synthesized by German chemists during Wold War II when the United States and our allies cut off their opium supply. And it is difficult to fight a war without analgesics so the Germans went to work and synthesized a number of medications in use today, including demerol and darvon which is structurally simular to methadone. And before we go further lets clear up another myth. Methadone, or dolophine was not named after Adolf Hitler. The "dol" in dolophine comes from the latin root "dolor." The female name Dolores is derived from it and the term dol is used in pain research to measure pain e.g., one dol is 1 unit of pain.
Even methadone, which looks strikingly different from other opioid agonists, has steric forces which produce a configuration that closely resembles that of other opiates. See the graphic on the left and the top graphic on this page. In other words, steric forces bend the molecule of methadone into the correct configuration to fit into the opiate receptor. When you take methadone it first must be metabolized in the liver to a product that your body can use. Excess methadone is also stored in the liver and blood stream and this is how methadone works its 'time release trick' and last for 24 hours or more. Once in the blood stream metabolized methadone is slowly passed to the brain when it is needed to fill opiate receptors. Methadone is the only effective treatment for heroin addiction. It works to smooth the ups and down of heroin craving and allows the person to function normally.
Narcotic Antagonists
Narcotic Antagonists prevent or abolish excessive respiratory depression caused by the administration of morphine or related compounds. They act by competing for the same analgesic receptor sites. They are structurally related to morphine with the exception of the group attached to nitrogen.
Nalorphine precipitates withdrawal symptoms and produces behavioral disturbances in addition to the antogonism action. Naloxane is a pure antagonist with no morphine like effects. It blocks the euphoric effect of heroin when given before heroin. Naltrexone became clinically available in 1985 as a new narcotic antagonist. Its actions resemble those of naloxone, but naltrexone is well is well absorbed orally and is long acting, necessitating only a dose of 50 to 100 mg. Therefore, it is useful in narcotic treatment programs where it is desired to maintain an individual on chronic therapy with a narcotic antagonist. In individuals taking naltrexone, subsequent injection of an opiate will produce little or no effect. Naltrexone appears to be particularly effective for the treatment of narcotic dependence in addicts who have more to gain by being drug-free rather than drug dependant
Contributors and Attributions
• Charles Ophardt, Professor Emeritus, Elmhurst College; Virtual Chembook
• Poppies image from: leda.lycaeum.org | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/31%3A_The_Organic_Chemistry_of_Drugs-_Discovery_and_Design/31.03%3A_Molecular_Modification.txt |
Ensemble properties result from being or relating to the greater in number of atoms in a sample. This are in contrast to atomic or molecular properties.
• Capillary Action
Capillary action can be defined as the ascension of liquids through slim tube, cylinder or permeable substance due to adhesive and cohesive forces interacting between the liquid and the surface. When intermolecular bonding of a liquid itself is substantially inferior to a substances’ surface it is interacting, capillarity occurs. Also, the diameter of the container as well as the gravitational forces will determine amount of liquid raised.
• Cohesive and Adhesive Forces
Cohesive and adhesive forces are associated with bulk (or macroscopic) properties and hence the terms are not applicable to discussion of atomic and molecular properties. When a liquid comes into contact with a surface (such as the walls of a graduated cylinder or a tabletop), both cohesive and adhesive forces will act on it. These forces govern the shape which the liquid takes on.
• Contact Angles
Contact angle is one of the common ways to measure the wettability of a surface or material. Wetting refers to the study of how a liquid deposited on a solid (or liquid) substrate spreads out or the ability of liquids to form boundary surfaces with solid states. The wetting, as mentioned before is determined by measuring the contact angle, which the liquid forms in contact with the solids or liquids. The wetting tendency is larger, the smaller the contact angle or the surface tension is.
• Surface Tension
Surface tension is the energy, or work, required to increase the surface area of a liquid due to intermolecular forces. Since these intermolecular forces vary depending on the nature of the liquid (e.g. water vs. gasoline) or solutes in the liquid (e.g. surfactants like detergent), each solution exhibits differing surface tension properties.
• Unusual Properties of Water
With 70% of our earth being ocean water and 65% of our bodies being water, it is hard to not be aware of how important it is in our lives. There are 3 different forms of water, or H2O: solid (ice), liquid (water), and gas (steam). Because water seems so ubiquitous, many people are unaware of the unusual and unique properties of water, including:
• Vapor Pressure
Pressure is the average force that material (gas, liquid or solid) exert upon the surface, e.g. walls of a container or other confining boundary. Vapor pressure or equilibrium vapor pressure is the pressure of a vapor in thermodynamic equilibrium with its condensed phases in a closed container. All liquids and solids have a tendency to evaporate or sublime into a gaseous form and all gases have a tendency to condense back to their liquid or solid form.
• Viscosity
Viscosity is another type of bulk property defined as a liquid’s resistance to flow. When the intermolecular forces of attraction are strong within a liquid, there is a larger viscosity. An example of this phenomenon is imagining a race between two liquids down a windshield. Which would you expect to roll down the windshield faster honey or water? Obviously from experience one would expect water to easily speed right past the honey, a fact that reveals honey has a much higher viscocity than wate
• Wetting Agents
A substance is referred to as a wetting agent if it lowers the surface tension of a liquid and thus allows it to spread more easily.
Thumbnail: A water drop on a lotus leaf surface showing contact angles of approximately 147°. (Public Domain; Na2jojon). | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/31%3A_The_Organic_Chemistry_of_Drugs-_Discovery_and_Design/31.04%3A_Random_Screening.txt |
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le
31.06: Receptors
The vast majority of drugs show a remarkably high correlation of structure and specificity to produce pharmacological effects. Experimental evidence indicates that drugs interact with receptor sites localized in macromolecules which have protein-like properties and specific three dimensional shapes. A minimum three point attachment of a drug to a receptor site is required. In most cases a rather specific chemical structure is required for the receptor site and a complementary drug structure. Slight changes in the molecular structure of the drug may drastically change specificity.
Introduction
Several chemical forces may result in a temporary binding of the drug to the receptor. Essentially any bond could be involved with the drug-receptor interaction. Covalent bonds would be very tight and practically irreversible. Since by definition the drug-receptor interaction is reversible, covalent bond formation is rather rare except in a rather toxic situation. Since many drugs contain acid or amine functional groups which are ionized at physiological pH, ionic bonds are formed by the attraction of opposite charges in the receptor site.
Polar-polar interactions as in hydrogen bonding are a further extension of the attraction of opposite charges. The drug-receptor reaction is essentially an exchange of the hydrogen bond between a drug molecule, surrounding water, and the receptor site.
Finally hydrophobic bonds are formed between non-polar hydrocarbon groups on the drug and those in the receptor site. These bonds are not very specific but the interactions do occur to exclude water molecules. Repulsive forces which decrease the stability of the drug-receptor interaction include repulsion of like charges and steric hindrance. Steric hindrance refers to certain 3-dimensional features where repulsion occurs between electron clouds, inflexible chemical bonds, or bulky alkyl groups.
Drug Interaction with Receptor Site
• A neurotransmitter has a specific shape to fit into a receptor site and cause a pharmacological response such as a nerve impulse being sent. The neurotransmitter is similar to a substrate in an enzyme interaction. After attachment to a receptor site, a drug may either initiate a response or prevent a response from occurring. A drug must be a close "mimic" of the neurotransmitter.
• An agonist is a drug which produces a stimulation type response. The agonist is a very close mimic and "fits" with the receptor site and is thus able to initiate a response.
• An antagonist drug interacts with the receptor site and blocks or depresses the normal response for that receptor because it only partially fits the receptor site and can not produce an effect. However, it does block the site preventing any other agonist or the normal neurotransmitter from interacting with the receptor site. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/31%3A_The_Organic_Chemistry_of_Drugs-_Discovery_and_Design/31.05%3A_Serendipity_in_Drug_Development.txt |
Learning Objectives
• Explain what an enzyme inhibitor is.
• Distinguish between reversible and irreversible inhibitors.
• Distinguish between competitive and noncompetitive inhibitors.
Previously, we noted that enzymes are inactivated at high temperatures and by changes in pH. These are nonspecific factors that would inactivate any enzyme. The activity of enzymes can also be regulated by more specific inhibitors. Many compounds are poisons because they bind covalently to particular enzymes or kinds of enzymes and inactivate them (Table \(1\)).
Table \(1\): Poisons as Enzyme Inhibitors
Poison Formula Example of Enzyme Inhibited Action
arsenate \(\ce{AsO4^{3−}}\) glyceraldehyde 3-phosphate dehydrogenase substitutes for phosphate
iodoacetate \(\ce{ICH2COO^{−}}\) triose phosphate dehydrogenase binds to cysteine \(\ce{SH}\) group
diisopropylfluoro-phosphate (DIFP; a nerve poison) acetylcholinesterase binds to serine \(\ce{OH}\) group
Irreversible Inhibition: Poisons
An irreversible inhibitor inactivates an enzyme by bonding covalently to a particular group at the active site. The inhibitor-enzyme bond is so strong that the inhibition cannot be reversed by the addition of excess substrate. The nerve gases, especially Diisopropyl fluorophosphate (DIFP), irreversibly inhibit biological systems by forming an enzyme-inhibitor complex with a specific OH group of serine situated at the active sites of certain enzymes. The peptidases trypsin and chymotrypsin contain serine groups at the active site and are inhibited by DIFP.
Reversible Inhibition
A reversible inhibitor inactivates an enzyme through noncovalent, more easily reversed, interactions. Unlike an irreversible inhibitor, a reversible inhibitor can dissociate from the enzyme. Reversible inhibitors include competitive inhibitors and noncompetitive inhibitors. (There are additional types of reversible inhibitors.) A competitive inhibitor is any compound that bears a structural resemblance to a particular substrate and thus competes with that substrate for binding at the active site of an enzyme. The inhibitor is not acted on by the enzyme but does prevent the substrate from approaching the active site.
The degree to which a competitive inhibitor interferes with an enzyme’s activity depends on the relative concentrations of the substrate and the inhibitor. If the inhibitor is present in relatively large quantities, it will initially block most of the active sites. But because the binding is reversible, some substrate molecules will eventually bind to the active site and be converted to product. Increasing the substrate concentration promotes displacement of the inhibitor from the active site. Competitive inhibition can be completely reversed by adding substrate so that it reaches a much higher concentration than that of the inhibitor.
Studies of competitive inhibition have provided helpful information about certain enzyme-substrate complexes and the interactions of specific groups at the active sites. As a result, pharmaceutical companies have synthesized drugs that competitively inhibit metabolic processes in bacteria and certain cancer cells. Many drugs are competitive inhibitors of specific enzymes.
A classic example of competitive inhibition is the effect of malonate on the enzyme activity of succinate dehydrogenase (Figure \(1\)). Malonate and succinate are the anions of dicarboxylic acids and contain three and four carbon atoms, respectively. The malonate molecule binds to the active site because the spacing of its carboxyl groups is not greatly different from that of succinate. However, no catalytic reaction occurs because malonate does not have a CH2CH2 group to convert to CH=CH. This reaction will also be discussed in connection with the Krebs cycle and energy production.
To Your Health: Penicillin
Chemotherapy is the strategic use of chemicals (that is, drugs) to destroy infectious microorganisms or cancer cells without causing excessive damage to the other, healthy cells of the host. From bacteria to humans, the metabolic pathways of all living organisms are quite similar, so the search for safe and effective chemotherapeutic agents is a formidable task. Many well-established chemotherapeutic drugs function by inhibiting a critical enzyme in the cells of the invading organism.
An antibiotic is a compound that kills bacteria; it may come from a natural source such as molds or be synthesized with a structure analogous to a naturally occurring antibacterial compound. Antibiotics constitute no well-defined class of chemically related substances, but many of them work by effectively inhibiting a variety of enzymes essential to bacterial growth.
Penicillin, one of the most widely used antibiotics in the world, was fortuitously discovered by Alexander Fleming in 1928, when he noticed antibacterial properties in a mold growing on a bacterial culture plate. In 1938, Ernst Chain and Howard Florey began an intensive effort to isolate penicillin from the mold and study its properties. The large quantities of penicillin needed for this research became available through development of a corn-based nutrient medium that the mold loved and through the discovery of a higher-yielding strain of mold at a United States Department of Agriculture research center near Peoria, Illinois. Even so, it was not until 1944 that large quantities of penicillin were being produced and made available for the treatment of bacterial infections.
Penicillin functions by interfering with the synthesis of cell walls of reproducing bacteria. It does so by inhibiting an enzyme—transpeptidase—that catalyzes the last step in bacterial cell-wall biosynthesis. The defective walls cause bacterial cells to burst. Human cells are not affected because they have cell membranes, not cell walls.
Several naturally occurring penicillins have been isolated. They are distinguished by different R groups connected to a common structure: a four-member cyclic amide (called a lactam ring) fused to a five-member ring. The addition of appropriate organic compounds to the culture medium leads to the production of the different kinds of penicillin.
The penicillins are effective against gram-positive bacteria (bacteria capable of being stained by Gram’s stain) and a few gram-negative bacteria (including the intestinal bacterium Escherichia coli). They are effective in the treatment of diphtheria, gonorrhea, pneumonia, syphilis, many pus infections, and certain types of boils. Penicillin G was the earliest penicillin to be used on a wide scale. However, it cannot be administered orally because it is quite unstable; the acidic pH of the stomach converts it to an inactive derivative. The major oral penicillins—penicillin V, ampicillin, and amoxicillin—on the other hand, are acid stable.
Some strains of bacteria become resistant to penicillin through a mutation that allows them to synthesize an enzyme—penicillinase—that breaks the antibiotic down (by cleavage of the amide linkage in the lactam ring). To combat these strains, scientists have synthesized penicillin analogs (such as methicillin) that are not inactivated by penicillinase.
Some people (perhaps 5% of the population) are allergic to penicillin and therefore must be treated with other antibiotics. Their allergic reaction can be so severe that a fatal coma may occur if penicillin is inadvertently administered to them. Fortunately, several other antibiotics have been discovered. Most, including aureomycin and streptomycin, are the products of microbial synthesis. Others, such as the semisynthetic penicillins and tetracyclines, are made by chemical modifications of antibiotics; and some, like chloramphenicol, are manufactured entirely by chemical synthesis. They are as effective as penicillin in destroying infectious microorganisms. Many of these antibiotics exert their effects by blocking protein synthesis in microorganisms.
Initially, antibiotics were considered miracle drugs, substantially reducing the number of deaths from blood poisoning, pneumonia, and other infectious diseases. Some seven decades ago, a person with a major infection almost always died. Today, such deaths are rare. Seven decades ago, pneumonia was a dreaded killer of people of all ages. Today, it kills only the very old or those ill from other causes. Antibiotics have indeed worked miracles in our time, but even miracle drugs have limitations. Not long after the drugs were first used, disease organisms began to develop strains resistant to them. In a race to stay ahead of resistant bacterial strains, scientists continue to seek new antibiotics. The penicillins have now been partially displaced by related compounds, such as the cephalosporins and vancomycin. Unfortunately, some strains of bacteria have already shown resistance to these antibiotics.
Some reversible inhibitors are noncompetitive. A noncompetitive inhibitor can combine with either the free enzyme or the enzyme-substrate complex because its binding site on the enzyme is distinct from the active site. Binding of this kind of inhibitor alters the three-dimensional conformation of the enzyme, changing the configuration of the active site with one of two results. Either the enzyme-substrate complex does not form at its normal rate, or, once formed, it does not yield products at the normal rate. Because the inhibitor does not structurally resemble the substrate, the addition of excess substrate does not reverse the inhibitory effect.
Feedback inhibition is a normal biochemical process that makes use of noncompetitive inhibitors to control some enzymatic activity. In this process, the final product inhibits the enzyme that catalyzes the first step in a series of reactions. Feedback inhibition is used to regulate the synthesis of many amino acids. For example, bacteria synthesize isoleucine from threonine in a series of five enzyme-catalyzed steps. As the concentration of isoleucine increases, some of it binds as a noncompetitive inhibitor to the first enzyme of the series (threonine deaminase), thus bringing about a decrease in the amount of isoleucine being formed (Figure \(2\)).
Summary
An irreversible inhibitor inactivates an enzyme by bonding covalently to a particular group at the active site. A reversible inhibitor inactivates an enzyme through noncovalent, reversible interactions. A competitive inhibitor competes with the substrate for binding at the active site of the enzyme. A noncompetitive inhibitor binds at a site distinct from the active site. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/31%3A_The_Organic_Chemistry_of_Drugs-_Discovery_and_Design/31.07%3A_Drugs_as_Enzyme_Inhibitors.txt |
The rate of a chemical reaction is the change in concentration over the change in time.
Introduction
The rate of a chemical reaction is the change in concentration over the change in time and is a metric of the "speed" at which a chemical reactions occurs and can be defined in terms of two observables:
1. The Rate of Disappearance of Reactants $-\dfrac{\Delta[Reactants]}{\Delta{t}} \nonumber$ Note this is negative because it measures the rate of disappearance of the reactants.
2. The Rate of Formation of Products $\dfrac{\Delta{[Products]}}{\Delta{t}} \nonumber$ This is the rate at which the products are formed.
They both are linked via the balanced chemical reactions and can both be used to measure the reaction rate.
Problems
1. Consider the reaction $2A + B \longrightarrow C$. The concentration of [A] is 0.54321M and the rate of reaction is $3.45 \times 10^{-6} M/s$. What Concentration will [A] be 3 minutes later?
2. Consider the reaction $A + B \longrightarrow C$. The rate of reaction is 1.23*10-4. [A] will go from a 0.4321 M to a 0.4444 M concentration in what length of time?
3. Write the rate of the chemical reaction with respect to the variables for the given equation. $2A+3B \rightarrow C+2D \nonumber$
4. True or False: The Average Rate and Instantaneous Rate are equal to each other.
5. How is the rate of formation of a product related to the rates of the disappearance of reactants.
Contributors
• Albert Law, Victoria Blanchard, Donald Le
31.09: Quantitative Structure-Activity Relationships (QSAR)
Quantitative structure–activity relationship models (QSAR models) are regression or classification models used in the chemical and biological sciences and engineering. Like other regression models, QSAR regression models relate a set of "predictor" variables (X) to the potency of the response variable (Y), while classification QSAR models relate the predictor variables to a categorical value of the response variable.
In QSAR modeling, the predictors consist of physico-chemical properties or theoretical molecular descriptors of chemicals; the QSAR response-variable could be a biological activity of the chemicals. QSAR models first summarize a supposed relationship between chemical structures and biological activity in a data-set of chemicals. Second, QSAR models predict the activities of new chemicals.
Related terms include quantitative structure–property relationships (QSPR) when a chemical property is modeled as the response variable. "Different properties or behaviors of chemical molecules have been investigated in the field of QSPR. Some examples are quantitative structure–reactivity relationships (QSRRs), quantitative structure–chromatography relationships (QSCRs) and, quantitative structure–toxicity relationships (QSTRs), quantitative structure–electrochemistry relationships (QSERs), and quantitative structure–biodegradability relationships (QSBRs)."
As an example, biological activity can be expressed quantitatively as the concentration of a substance required to give a certain biological response. Additionally, when physicochemical properties or structures are expressed by numbers, one can find a mathematical relationship, or quantitative structure-activity relationship, between the two. The mathematical expression, if carefully validated, can then be used to predict the modeled response of other chemical structures.[12]
A QSAR has the form of a mathematical model:
Activity = f (physiochemical properties and/or structural properties) + error
The error includes model error (bias) and observational variability, that is, the variability in observations even on a correct model.
• Essential steps in QSAR studies
• The principal steps of QSAR/QSPR include
• Selection of data set and extraction of structural/empirical descriptors,
• variable selection,
• model construction, and
• validation evaluation.
31.11: Combinatorial Organic Synthesis
Contributors and Attributions
• Nathalie Interiano
31.12: Antiviral Drugs
Sulfonamides are synthetic antimicrobial agents with a wide spectrum encompassing most gram-positive and many gram-negative organisms. These drugs were the first efficient treatment to be employed systematically for the prevention and cure of bacterial infections.
Contributors and Attributions
Charles Ophardt (Professor Emeritus, Elmhurst College); Virtual Chembook
31.13: Economics of Drugs (Governmental Regulations)
Contributors and Attributions
• Nathalie Interiano | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Bruice)/31%3A_The_Organic_Chemistry_of_Drugs-_Discovery_and_Design/31.08%3A_Designing_a_Suicide_Substrate.txt |
The nuclear atom
The precise physical nature of atoms finally emerged from a series of elegant experiments carried out between 1895 and 1915. The most notable of these achievements was Ernest Rutherford's famous 1911 alpha-ray scattering experiment, which established that
• Almost all of the mass of an atom is contained within a tiny (and therefore extremely dense)nucleus which carries a positive electric charge whose value identifies each element and is known as the atomic number of the element.
• Almost all of the volume of an atom consists of empty space in which electrons, the fundamental carriers of negative electric charge, reside. The extremely small mass of the electron (1/1840 the mass of the hydrogen nucleus) causes it to behave as a quantum particle, which means that its location at any moment cannot be specified; the best we can do is describe its behavior in terms of the probability of its manifesting itself at any point in space. It is common (but somewhat misleading) to describe the volume of space in which the electrons of an atom have a significant probability of being found as the electron cloud. The latter has no definite outer boundary, so neither does the atom. The radius of an atom must be defined arbitrarily, such as the boundary in which the electron can be found with 95% probability. Atomic radii are typically 30-300 pm.
Protons and neutrons
The nucleus is itself composed of two kinds of particles. Protons are the carriers of positive electric charge in the nucleus; the proton charge is exactly the same as the electron charge, but of opposite sign. This means that in any [electrically neutral] atom, the number of protons in the nucleus (often referred to as the nuclear charge) is balanced by the same number of electrons outside the nucleus.
Because the electrons of an atom are in contact with the outside world, it is possible for one or more electrons to be lost, or some new ones to be added. The resulting electrically-charged atom is called an ion.
The other nuclear particle is the neutron. As its name implies, this particle carries no electrical charge. Its mass is almost the same as that of the proton. Most nuclei contain roughly equal numbers of neutrons and protons, so we can say that these two particles together account for almost all the mass of the atom.
Atomic Number (Z)
What single parameter uniquely characterizes the atom of a given element? It is not the atom's relative mass, as we will see in the section on isotopes below. It is, rather, the number of protons in the nucleus, which we call the atomic number and denote by the symbol Z. Each proton carries an electric charge of +1, so the atomic number also specifies the electric charge of the nucleus. In the neutral atom, the Z protons within the nucleus are balanced by Z electrons outside it.
Atomic numbers were first worked out in 1913 by Henry Moseley, a young member of Rutherford's research group in Manchester.
Moseley searched for a measurable property of each element that increases linearly with atomic number. He found this in a class of X-rays emitted by an element when it is bombarded with electrons. The frequencies of these X-rays are unique to each element, and they increase uniformly in successive elements. Moseley found that the square roots of these frequencies give a straight line when plotted against Z; this enabled him to sort the elements in order of increasing atomic number.
You can think of the atomic number as a kind of serial number of an element, commencing at 1 for hydrogen and increasing by one for each successive element. The chemical name of the element and its symbol are uniquely tied to the atomic number; thus the symbol "Sr" stands for strontium, whose atoms all have Z = 38.
Mass number (A)
This is just the sum of the numbers of protons and neutrons in the nucleus. It is sometimes represented by the symbol A, so
A=Z+N
in which Z is the atomic number and N is the neutron number.
Nuclides and their Symbols
The term nuclide simply refers to any particular kind of nucleus. For example, a nucleus of atomic number 7 is a nuclide of nitrogen. Any nuclide is characterized by the pair of numbers (Z ,A). The element symbol depends on Z alone, so the symbol 26Mg is used to specify the mass-26 nuclide of magnesium, whose name implies Z=12. A more explicit way of denoting a particular kind of nucleus is to add the atomic number as a subscript. Of course, this is somewhat redundant, since the symbol Mg always implies Z=12, but it is sometimes a convenience when discussing several nuclides.
Two nuclides having the same atomic number but different mass numbers are known as isotopes. Most elements occur in nature as mixtures of isotopes, but twenty-three of them (including beryllium and fluorine, shown in the table) are monoisotopic. For example, there are three natural isotopes of magnesium: 24Mg (79% of all Mg atoms), 25Mg (10%), and 26Mg (11%); all three are present in all compounds of magnesium in about these same proportions.
Approximately 290 isotopes occur in nature. The two heavy isotopes of hydrogen are especially important— so much so that they have names and symbols of their own:
Deuterium accounts for only about 15 out of every one million atoms of hydrogen. Tritium, which is radioactive, is even less abundant. All the tritium on the earth is a by-product of the decay of other radioactive elements.
Atomic weights
Atoms are of course far too small to be weighed directly; weight measurements can only be made on the massive (but unknown) numbers of atoms that are observed in chemical reactions. The early combining-weight experiments of Dalton and others established that hydrogen is the lightest of the atoms, but the crude nature of the measurements and uncertainties about the formulas of many compounds made it difficult to develop a reliable scale of the relative weights of atoms. Even the most exacting weight measurements we can make today are subject to experimental uncertainties that limit the precision to four significant figures at best.
The periodic table
The elements are arranged in a periodic table, which is probably the single most important learning aid in chemistry. It summarizes huge amounts of information about the elements in a way that facilitates the prediction of many of their properties and chemical reactions. The elements are arranged in seven horizontal rows, in order of increasing atomic number from left to right and top to bottom. The rows are called periods, and they are numbered from 1 to 7. The elements are stacked in such a way that elements with similar chemical properties form vertical columns, called groups, numbered from 1 to 18 (older periodic tables use a system based on roman numerals). Groups 1, 2, and 13–18 are the main group elements, listed as A in older tables. Groups 3–12 are in the middle of the periodic table and are the transition elements, listed as B in older tables. The two rows of 14 elements at the bottom of the periodic table are the lanthanides and the actinides, whose positions in the periodic table are indicated in group 3.
Atomic Orbitals
An orbital is the quantum mechanical refinement of Bohr’s orbit. In contrast to his concept of a simple circular orbit with a fixed radius, orbitals are mathematically derived regions of space with different probabilities of having an electron.
One way of representing electron probability distributions was illustrated in Figure 6.5.2 for the 1s orbital of hydrogen. Because Ψ2 gives the probability of finding an electron in a given volume of space (such as a cubic picometer), a plot of Ψ2 versus distance from the nucleus (r) is a plot of the probability density. The 1s orbital is spherically symmetrical, so the probability of finding a 1s electron at any given point depends only on its distance from the nucleus. The probability density is greatest at r = 0 (at the nucleus) and decreases steadily with increasing distance. At very large values of r, the electron probability density is very small but not zero.
In contrast, we can calculate the radial probability (the probability of finding a 1s electron at a distance r from the nucleus) by adding together the probabilities of an electron being at all points on a series of x spherical shells of radius r1, r2, r3,…, rx − 1, rx. In effect, we are dividing the atom into very thin concentric shells, much like the layers of an onion (part (a) in Figure 6.6.1), and calculating the probability of finding an electron on each spherical shell. Recall that the electron probability density is greatest at r = 0 (part (b) in Figure 6.6.1), so the density of dots is greatest for the smallest spherical shells in part (a) in Figure 6.6.1. In contrast, the surface area of each spherical shell is equal to 4πr2, which increases very rapidly with increasing r (part (c) in Figure 6.6.1). Because the surface area of the spherical shells increases more rapidly with increasing r than the electron probability density decreases, the plot of radial probability has a maximum at a particular distance (part (d) in Figure 6.6.1). Most important, when r is very small, the surface area of a spherical shell is so small that the total probability of finding an electron close to the nucleus is very low; at the nucleus, the electron probability vanishes (part (d) in Figure 6.6.1).
Figure 6.6.1 Most Probable Radius for the Electron in the Ground State of the Hydrogen Atom. (a) Imagine dividing the atom’s total volume into very thin concentric shells as shown in the onion drawing. (b) A plot of electron probability density Ψ2 versus r shows that the electron probability density is greatest at r = 0 and falls off smoothly with increasing r. The density of the dots is therefore greatest in the innermost shells of the onion. (c) The surface area of each shell, given by 4πr2, increases rapidly with increasing r. (d) If we count the number of dots in each spherical shell, we obtain the total probability of finding the electron at a given value of r. Because the surface area of each shell increases more rapidly with increasing r than the electron probability density decreases, a plot of electron probability versus r (the radial probability) shows a peak. This peak corresponds to the most probable radius for the electron, 52.9 pm, which is exactly the radius predicted by Bohr’s model of the hydrogen atom.
For the hydrogen atom, the peak in the radial probability plot occurs at r = 0.529 Å (52.9 pm), which is exactly the radius calculated by Bohr for the n = 1 orbit. Thus the most probable radius obtained from quantum mechanics is identical to the radius calculated by classical mechanics. In Bohr’s model, however, the electron was assumed to be at this distance 100% of the time, whereas in the Schrödinger model, it is at this distance only some of the time. The difference between the two models is attributable to the wavelike behavior of the electron and the Heisenberg uncertainty principle.
Figure 6.6.2 compares the electron probability densities for the hydrogen 1s, 2s, and 3s orbitals. Note that all three are spherically symmetrical. For the 2s and 3s orbitals, however (and for all other s orbitals as well), the electron probability density does not fall off smoothly with increasing r. Instead, a series of minima and maxima are observed in the radial probability plots (part (c) in Figure 6.6.2). The minima correspond to spherical nodes (regions of zero electron probability), which alternate with spherical regions of nonzero electron probability.
Figure 6.6.2: Probability Densities for the 1s, 2s, and 3s Orbitals of the Hydrogen Atom. (a) The electron probability density in any plane that contains the nucleus is shown. Note the presence of circular regions, or nodes, where the probability density is zero. (b) Contour surfaces enclose 90% of the electron probability, which illustrates the different sizes of the 1s, 2s, and 3s orbitals. The cutaway drawings give partial views of the internal spherical nodes. The orange color corresponds to regions of space where the phase of the wave function is positive, and the blue color corresponds to regions of space where the phase of the wave function is negative. (c) In these plots of electron probability as a function of distance from the nucleus (r) in all directions (radial probability), the most probable radius increases as n increases, but the 2s and 3s orbitals have regions of significant electron probability at small values of r.
s Orbitals
Three things happen to s orbitals as n increases (Figure 6.6.2):
1. They become larger, extending farther from the nucleus.
2. They contain more nodes. This is similar to a standing wave that has regions of significant amplitude separated by nodes, points with zero amplitude.
3. For a given atom, the s orbitals also become higher in energy as n increases because of their increased distance from the nucleus.
Orbitals are generally drawn as three-dimensional surfaces that enclose 90% of the electron density, as was shown for the hydrogen 1s, 2s, and 3s orbitals in part (b) in Figure 6.6.2. Although such drawings show the relative sizes of the orbitals, they do not normally show the spherical nodes in the 2s and 3s orbitals because the spherical nodes lie inside the 90% surface. Fortunately, the positions of the spherical nodes are not important for chemical bonding.
p Orbitals
Only s orbitals are spherically symmetrical. As the value of l increases, the number of orbitals in a given subshell increases, and the shapes of the orbitals become more complex. Because the 2p subshell has l = 1, with three values of ml (−1, 0, and +1), there are three 2p orbitals.
Figure 6.6.3: Electron Probability Distribution for a Hydrogen 2p Orbital. The nodal plane of zero electron density separates the two lobes of the 2p orbital. As in Figure 6.6.2, the colors correspond to regions of space where the phase of the wave function is positive (orange) and negative (blue).
The electron probability distribution for one of the hydrogen 2p orbitals is shown in Figure 6.6.3. Because this orbital has two lobes of electron density arranged along the z axis, with an electron density of zero in the xy plane (i.e., the xy plane is a nodal plane), it is a 2pz orbital. As shown in Figure 6.6.4, the other two 2p orbitals have identical shapes, but they lie along the x axis (2px) and y axis (2py), respectively. Note that each p orbital has just one nodal plane. In each case, the phase of the wave function for each of the 2p orbitals is positive for the lobe that points along the positive axis and negative for the lobe that points along the negative axis. It is important to emphasize that these signs correspond to the phase of the wave that describes the electron motion, not to positive or negative charges.
Figure 6.6.4 The Three Equivalent 2p Orbitals of the Hydrogen Atom
The surfaces shown enclose 90% of the total electron probability for the 2px, 2py, and 2pz orbitals. Each orbital is oriented along the axis indicated by the subscript and a nodal plane that is perpendicular to that axis bisects each 2p orbital. The phase of the wave function is positive (orange) in the region of space where x, y, or z is positive and negative (blue) where x, y, or z is negative.
Just as with the s orbitals, the size and complexity of the p orbitals for any atom increase as the principal quantum number n increases. The shapes of the 90% probability surfaces of the 3p, 4p, and higher-energy p orbitals are, however, essentially the same as those shown in Figure 6.6.4.
The number of valence electrons
The number of valence electrons of an element can be determined by the periodic table group (vertical column) in which the element is categorized. With the exception of groups 3–12 (the transition metals), the units digit of the group number identifies how many valence electrons are associated with a neutral atom of an element listed under that particular column.
The periodic table of the chemical elements
Periodic table group Valence
electrons
Group 1 (I) (alkali metals) 1
Group 2 (II) (alkaline earth metals) 2
Groups 3-12 (transition metals) 2* (The 4s shell is complete and cannot hold any more electrons)
Group 13 (III) (boron group) 3
Group 14 (IV) (carbon group) 4
Group 15 (V) (pnictogens) 5
Group 16 (VI) (chalcogens) 6
Group 17 (VII) (halogens) 7
Group 18 (VIII or 0) (noble gases) 8**
* The general method for counting valence electrons is generally not useful for transition metals. Instead the modified d electron count method is used.
** Except for helium, which has only two valence electrons.
Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Smith)/01%3A_Structure_and_Bonding/1.01%3A_The_Periodic_Table.txt |
Bonding Overview
Why are some substances chemically bonded molecules and others are an association of ions? The answer to this question depends upon the electronic structures of the atoms and nature of the chemical forces within the compounds. Although there are no sharply defined boundaries, chemical bonds are typically classified into three main types: ionic bonds, covalent bonds, and metallic bonds. In this chapter, each type of bond wil be discussed and the general properties found in typical substances in which the bond type occurs
1. Ionic bonds results from electrostatic forces that exist between ions of opposite charge. These bonds typically involves a metal with a nonmetal
2. Covalent bonds result from the sharing of electrons between two atoms. The bonds typically involves one nonmetallic element with another
3. Metallic bonds These bonds are found in solid metals (copper, iron, aluminum) with each metal bonded to several neighboring groups and bonding electrons free to move throughout the 3-dimensional structure.
Each bond classification is discussed in detail in subsequent sections of the chapter. Let's look at the preferred arrangements of electrons in atoms when they form chemical compounds.
Figure 8.1.1 G. N. Lewis and the Octet Rule. (a) Lewis is working in the laboratory. (b) In Lewis’s original sketch for the octet rule, he initially placed the electrons at the corners of a cube rather than placing them as we do now.
Lewis Symbols
At the beginning of the 20th century, the American chemist G. N. Lewis (1875–1946) devised a system of symbols—now called Lewis electron dot symbols, often shortened to Lewis dot symbols—that can be used for predicting the number of bonds formed by most elements in their compounds. Each Lewis dot symbol consists of the chemical symbol for an element surrounded by dots that represent its valence electrons.
Note
Lewis Dot symbols:
• convenient representation of valence electrons
• allows you to keep track of valence electrons during bond formation
• consists of the chemical symbol for the element plus a dot for each valence electron
To write an element’s Lewis dot symbol, we place dots representing its valence electrons, one at a time, around the element’s chemical symbol. Up to four dots are placed above, below, to the left, and to the right of the symbol (in any order, as long as elements with four or fewer valence electrons have no more than one dot in each position). The next dots, for elements with more than four valence electrons, are again distributed one at a time, each paired with one of the first four. For example, the electron configuration for atomic sulfur is [Ne]3s23p4, thus there are six valence electrons. Its Lewis symbol would therefore be:
Fluorine, for example, with the electron configuration [He]2s22p5, has seven valence electrons, so its Lewis dot symbol is constructed as follows:
The number of dots in the Lewis dot symbol is the same as the number of valence electrons, which is the same as the last digit of the element’s group number in the periodic table. Lewis dot symbols for the elements in period 2 are given in Figure 8.1.2.
Lewis used the unpaired dots to predict the number of bonds that an element will form in a compound. Consider the symbol for nitrogen in Figure 8.1.2. The Lewis dot symbol explains why nitrogen, with three unpaired valence electrons, tends to form compounds in which it shares the unpaired electrons to form three bonds. Boron, which also has three unpaired valence electrons in its Lewis dot symbol, also tends to form compounds with three bonds, whereas carbon, with four unpaired valence electrons in its Lewis dot symbol, tends to share all of its unpaired valence electrons by forming compounds in which it has four bonds.
Figure 8.1.2: Lewis Dot Symbols for the Elements in Period 2
The Octet Rule
Lewis’s major contribution to bonding theory was to recognize that atoms tend to lose, gain, or share electrons to reach a total of eight valence electrons, called an octet. This so-called octet rule explains the stoichiometry of most compounds in the s and p blocks of the periodic table. We now know from quantum mechanics that the number eight corresponds to one ns and three np valence orbitals, which together can accommodate a total of eight electrons. Remarkably, though, Lewis’s insight was made nearly a decade before Rutherford proposed the nuclear model of the atom. An exception to the octet rule is helium, whose 1s2 electron configuration gives it a full n = 1 shell, and hydrogen, which tends to gain or share its one electron to achieve the electron configuration of helium.
Lewis dot symbols can also be used to represent the ions in ionic compounds. The reaction of cesium with fluorine, for example, to produce the ionic compound CsF can be written as follows:
No dots are shown on Cs+ in the product because cesium has lost its single valence electron to fluorine. The transfer of this electron produces the Cs+ ion, which has the valence electron configuration of Xe, and the F ion, which has a total of eight valence electrons (an octet) and the Ne electron configuration. This description is consistent with the statement that among the main group elements, ions in simple binary ionic compounds generally have the electron configurations of the nearest noble gas. The charge of each ion is written in the product, and the anion and its electrons are enclosed in brackets. This notation emphasizes that the ions are associated electrostatically; no electrons are shared between the two elements.
Note
Atoms often gain, lose, or share electrons to achieve the same number of electrons as the noble gas closest to them in the periodic table.
Ionic bonding
Ions are atoms or molecules which are electrically charged. Cations are positively charged and anions carry a negative charge. Ions form when atoms gain or lose electrons. Since electrons are negatively charged, an atom that loses one or more electrons will become positively charged; an atom that gains one or more electrons becomes negatively charged.
Ionic bonding is the attraction between positively- and negatively-charged ions. These oppositely charged ions attract each other to form ionic networks (or lattices). Electrostatics explains why this happens: opposite charges attract and like charges repel. When many ions attract each other, they form large, ordered, crystal lattices in which each ion is surrounded by ions of the opposite charge. Generally, when metals react with non-metals, electrons are transferred from the metals to the non-metals. The metals form positively-charged ions and the non-metals form negatively-charged ions.
Generating Ionic Bonds
Ionic bonds form when metals and non-metals chemically react. By definition, a metal is relatively stable if it loses electrons to form a complete valence shell and becomes positively charged. Likewise, a non-metal becomes stable by gaining electrons to complete its valence shell and become negatively charged. When metals and non-metals react, the metals lose electrons by transferring them to the non-metals, which gain them. Consequently, ions are formed, which instantly attract each other—ionic bonding.
Example 8.2.1a: Sodium Chloride
For example, in the reaction of Na (sodium) and Cl (chlorine), each Cl atom takes one electron from a Na atom. Therefore each Na becomes a Na+ cation and each Cl atom becomes a Cl- anion. Due to their opposite charges, they attract each other to form an ionic lattice. The formula (ratio of positive to negative ions) in the lattice is NaCl.
2Na(s)+Cl2(g)2NaCl(s)
For full video of making NaCl from sodium metal and chlorine gase, see https://www.youtube.com/watch?v=WVonuBjCrNo. These ions are arranged in solid NaCl in a regular three-dimensional arrangement (or lattice):
Figure: NaCl lattice. (left) 3-D structure and (right) simple 2D slice through lattes. Images used with permission from Wikipedia and Mike Blaber.
The chlorine has a high affinity for electrons, and the sodium has a low ionization potential. Thus the chlorine gains an electron from the sodium atom. This can be represented using electron-dot symbols (here we will consider one chlorine atom, rather than Cl2):
The arrow indicates the transfer of the electron from sodium to chlorine to form the Na+ metal ion and the Cl- chloride ion. Each ion now has an octet of electrons in its valence shell:
• Na+: 2s22p6
• Cl-: 3s23p6
The importance of noble gas structures
At a simple level a lot of importance is attached to the electronic structures of noble gases like neon or argon which have eight electrons in their outer energy levels (or two in the case of helium). These noble gas structures are thought of as being in some way a "desirable" thing for an atom to have.
You may well have been left with the strong impression that when other atoms react, they try to achieve noble gas structures. As well as achieving noble gas structures by transferring electrons from one atom to another as in ionic bonding, it is also possible for atoms to reach these stable structures by sharing electrons to give covalent bonds.
Some very simple covalent molecules
Chlorine
For example, two chlorine atoms could both achieve stable structures by sharing their single unpaired electron as in the diagram.
The fact that one chlorine has been drawn with electrons marked as crosses and the other as dots is simply to show where all the electrons come from. In reality there is no difference between them. The two chlorine atoms are said to be joined by a covalent bond. The reason that the two chlorine atoms stick together is that the shared pair of electrons is attracted to the nucleus of both chlorine atoms.
Hydrogen
Hydrogen atoms only need two electrons in their outer level to reach the noble gas structure of helium. Once again, the covalent bond holds the two atoms together because the pair of electrons is attracted to both nuclei.
Hydrogen chloride
The hydrogen has a helium structure, and the chlorine an argon structure. Most of the simple molecules you draw do in fact have all their atoms with noble gas structures. For example:
Even with a more complicated molecule like PCl3, there's no problem. In this case, only the outer electrons are shown for simplicity. Each atom in this structure has inner layers of electrons of 2, 8. Again, everything present has a noble gas structure.
Cases where the simple view throws up problems
Boron trifluoride, BF3
A boron atom only has 3 electrons in its outer level, and there is no possibility of it reaching a noble gas structure by simple sharing of electrons. Is this a problem? No. The boron has formed the maximum number of bonds that it can in the circumstances, and this is a perfectly valid structure.
Energy is released whenever a covalent bond is formed. Because energy is being lost from the system, it becomes more stable after every covalent bond is made. It follows, therefore, that an atom will tend to make as many covalent bonds as possible. In the case of boron in BF3, three bonds is the maximum possible because boron only has 3 electrons to share.
Note: You might perhaps wonder why boron doesn't form ionic bonds with fluorine instead. Boron doesn't form ions because the total energy needed to remove three electrons to form a B3+ ion is simply too great to be recoverable when attractions are set up between the boron and fluoride ions.
A more sophisticated view of covalent bonding
The bonding in methane, CH4
What is wrong with the dots-and-crosses picture of bonding in methane?
We are starting with methane because it is the simplest case which illustrates the sort of processes involved. You will remember that the dots-and-crossed picture of methane looks like this.
There is a serious mis-match between this structure and the modern electronic structure of carbon, 1s22s22px12py1. The modern structure shows that there are only 2 unpaired electrons to share with hydrogens, instead of the 4 which the simple view requires.
You can see this more readily using the electrons-in-boxes notation. Only the 2-level electrons are shown. The 1s2 electrons are too deep inside the atom to be involved in bonding. The only electrons directly available for sharing are the 2p electrons. Why then isn't methane CH2?
Promotion of an electron
When bonds are formed, energy is released and the system becomes more stable. If carbon forms 4 bonds rather than 2, twice as much energy is released and so the resulting molecule becomes even more stable.
There is only a small energy gap between the 2s and 2p orbitals, and so it pays the carbon to provide a small amount of energy to promote an electron from the 2s to the empty 2p to give 4 unpaired electrons. The extra energy released when the bonds form more than compensates for the initial input.
The carbon atom is now said to be in an excited state. Now that we've got 4 unpaired electrons ready for bonding, another problem arises. In methane all the carbon-hydrogen bonds are identical, but our electrons are in two different kinds of orbitals. You aren't going to get four identical bonds unless you start from four identical orbitals.
Hybridization
The electrons rearrange themselves again in a process called hybridization. This reorganizes the electrons into four identical hybrid orbitals called sp3 hybrids (because they are made from one s orbital and three p orbitals). You should read "sp3" as "s p three" - not as "s p cubed".
sp3 hybrid orbitals look a bit like half a p orbital, and they arrange themselves in space so that they are as far apart as possible. You can picture the nucleus as being at the center of a tetrahedron (a triangularly based pyramid) with the orbitals pointing to the corners. For clarity, the nucleus is drawn far larger than it really is.
What happens when the bonds are formed?
Remember that hydrogen's electron is in a 1s orbital - a spherically symmetric region of space surrounding the nucleus where there is some fixed chance (say 95%) of finding the electron. When a covalent bond is formed, the atomic orbitals (the orbitals in the individual atoms) merge to produce a new molecular orbital which contains the electron pair which creates the bond.
Four molecular orbitals are formed, looking rather like the original sp3 hybrids, but with a hydrogen nucleus embedded in each lobe. Each orbital holds the 2 electrons that we've previously drawn as a dot and a cross.
The principles involved - promotion of electrons if necessary, then hybridisation, followed by the formation of molecular orbitals - can be applied to any covalently-bound molecule. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Smith)/01%3A_Structure_and_Bonding/1.02%3A_Bonding.txt |
Using Lewis Dot Symbols to Describe Covalent Bonding
This sharing of electrons allowing atoms to "stick" together is the basis of covalent bonding. There is some intermediate distant, generally a bit longer than 0.1 nm, or if you prefer 100 pm, at which the attractive forces significantly outweigh the repulsive forces and a bond will be formed if both atoms can achieve a completen s2np6 configuration. It is this behavior that Lewis captured in his octet rule. The valence electron configurations of the constituent atoms of a covalent compound are important factors in determining its structure, stoichiometry, and properties. For example, chlorine, with seven valence electrons, is one electron short of an octet. If two chlorine atoms share their unpaired electrons by making a covalent bond and forming Cl2, they can each complete their valence shell:
Each chlorine atom now has an octet. The electron pair being shared by the atoms is called a bonding pair ; the other three pairs of electrons on each chlorine atom are called lone pairs. Lone pairs are not involved in covalent bonding. If both electrons in a covalent bond come from the same atom, the bond is called a coordinate covalent bond.
We can illustrate the formation of a water molecule from two hydrogen atoms and an oxygen atom using Lewis dot symbols:
The structure on the right is the Lewis electron structure, or Lewis structure, for H2O. With two bonding pairs and two lone pairs, the oxygen atom has now completed its octet. Moreover, by sharing a bonding pair with oxygen, each hydrogen atom now has a full valence shell of two electrons. Chemists usually indicate a bonding pair by a single line, as shown here for our two examples:
The following procedure can be used to construct Lewis electron structures for more complex molecules and ions:
1. Arrange the atoms to show specific connections. When there is a central atom, it is usually the least electronegative element in the compound. Chemists usually list this central atom first in the chemical formula (as in CCl4 and CO32−, which both have C as the central atom), which is another clue to the compound’s structure. Hydrogen and the halogens are almost always connected to only one other atom, so they are usually terminal rather than central.
Note the Pattern
The central atom is usually the least electronegative element in the molecule or ion; hydrogen and the halogens are usually terminal.
2. Determine the total number of valence electrons in the molecule or ion. Add together the valence electrons from each atom. (Recall from Chapter 2 that the number of valence electrons is indicated by the position of the element in the periodic table.) If the species is a polyatomic ion, remember to add or subtract the number of electrons necessary to give the total charge on the ion. For CO32−, for example, we add two electrons to the total because of the −2 charge.
3. Place a bonding pair of electrons between each pair of adjacent atoms to give a single bond. In H2O, for example, there is a bonding pair of electrons between oxygen and each hydrogen.
4. Beginning with the terminal atoms, add enough electrons to each atom to give each atom an octet (two for hydrogen). These electrons will usually be lone pairs.
5. If any electrons are left over, place them on the central atom. We explain in Section 4.6 that some atoms are able to accommodate more than eight electrons.
6. If the central atom has fewer electrons than an octet, use lone pairs from terminal atoms to form multiple (double or triple) bonds to the central atom to achieve an octet. This will not change the number of electrons on the terminal atoms.
Now let’s apply this procedure to some particular compounds, beginning with one we have already discussed.
H2O
1. Because H atoms are almost always terminal, the arrangement within the molecule must be HOH.
2. Each H atom (group 1) has 1 valence electron, and the O atom (group 16) has 6 valence electrons, for a total of 8 valence electrons.
3. Placing one bonding pair of electrons between the O atom and each H atom gives H:O:H, with 4 electrons left over.
4. Each H atom has a full valence shell of 2 electrons.
5. Adding the remaining 4 electrons to the oxygen (as two lone pairs) gives the following structure:
This is the Lewis structure we drew earlier. Because it gives oxygen an octet and each hydrogen two electrons, we do not need to use step 6.
OCl−
1. With only two atoms in the molecule, there is no central atom.
2. Oxygen (group 16) has 6 valence electrons, and chlorine (group 17) has 7 valence electrons; we must add one more for the negative charge on the ion, giving a total of 14 valence electrons.
3. Placing a bonding pair of electrons between O and Cl gives O:Cl, with 12 electrons left over.
4. If we place six electrons (as three lone pairs) on each atom, we obtain the following structure:
Each atom now has an octet of electrons, so steps 5 and 6 are not needed. The Lewis electron structure is drawn within brackets as is customary for an ion, with the overall charge indicated outside the brackets, and the bonding pair of electrons is indicated by a solid line. OCl− is the hypochlorite ion, the active ingredient in chlorine laundry bleach and swimming pool disinfectant.
CH2O
1. Because carbon is less electronegative than oxygen and hydrogen is normally terminal, C must be the central atom. One possible arrangement is as follows:
2. Each hydrogen atom (group 1) has one valence electron, carbon (group 14) has 4 valence electrons, and oxygen (group 16) has 6 valence electrons, for a total of [(2)(1) + 4 + 6] = 12 valence electrons.
3. Placing a bonding pair of electrons between each pair of bonded atoms gives the following:
Six electrons are used, and 6 are left over.
4. Adding all 6 remaining electrons to oxygen (as three lone pairs) gives the following:
Although oxygen now has an octet and each hydrogen has 2 electrons, carbon has only 6 electrons.
5. There are no electrons left to place on the central atom.
6. To give carbon an octet of electrons, we use one of the lone pairs of electrons on oxygen to form a carbon–oxygen double bond:
Both the oxygen and the carbon now have an octet of electrons, so this is an acceptable Lewis electron structure. The O has two bonding pairs and two lone pairs, and C has four bonding pairs. This is the structure of formaldehyde, which is used in embalming fluid.
An alternative structure can be drawn with one H bonded to O. Formal charges, discussed later in this section, suggest that such a structure is less stable than that shown previously.
Example
Write the Lewis electron structure for each species.
1. NCl3
2. S2
3. NOCl
Given: chemical species
Asked for: Lewis electron structures
Strategy:
Use the six-step procedure to write the Lewis electron structure for each species.
Solution:
1. Nitrogen is less electronegative than chlorine, and halogen atoms are usually terminal, so nitrogen is the central atom. The nitrogen atom (group 15) has 5 valence electrons and each chlorine atom (group 17) has 7 valence electrons, for a total of 26 valence electrons. Using 2 electrons for each N–Cl bond and adding three lone pairs to each Cl account for (3 × 2) + (3 × 2 × 3) = 24 electrons. Rule 5 leads us to place the remaining 2 electrons on the central N:
Nitrogen trichloride is an unstable oily liquid once used to bleach flour; this use is now prohibited in the United States.
2. In a diatomic molecule or ion, we do not need to worry about a central atom. Each sulfur atom (group 16) contains 6 valence electrons, and we need to add 2 electrons for the −2 charge, giving a total of 14 valence electrons. Using 2 electrons for the S–S bond, we arrange the remaining 12 electrons as three lone pairs on each sulfur, giving each S atom an octet of electrons:
3. Because nitrogen is less electronegative than oxygen or chlorine, it is the central atom. The N atom (group 15) has 5 valence electrons, the O atom (group 16) has 6 valence electrons, and the Cl atom (group 17) has 7 valence electrons, giving a total of 18 valence electrons. Placing one bonding pair of electrons between each pair of bonded atoms uses 4 electrons and gives the following:
Adding three lone pairs each to oxygen and to chlorine uses 12 more electrons, leaving 2 electrons to place as a lone pair on nitrogen:
Because this Lewis structure has only 6 electrons around the central nitrogen, a lone pair of electrons on a terminal atom must be used to form a bonding pair. We could use a lone pair on either O or Cl. Because we have seen many structures in which O forms a double bond but none with a double bond to Cl, it is reasonable to select a lone pair from O to give the following:
All atoms now have octet configurations. This is the Lewis electron structure of nitrosyl chloride, a highly corrosive, reddish-orange gas.
Exercise
Write Lewis electron structures for CO2 and SCl2, a vile-smelling, unstable red liquid that is used in the manufacture of rubber.
Answer:
Formal Charges
It is sometimes possible to write more than one Lewis structure for a substance that does not violate the octet rule, as we saw for CH2O, but not every Lewis structure may be equally reasonable. In these situations, we can choose the most stable Lewis structure by considering the formal charge on the atoms, which is the difference between the number of valence electrons in the free atom and the number assigned to it in the Lewis electron structure. The formal charge is a way of computing the charge distribution within a Lewis structure; the sum of the formal charges on the atoms within a molecule or an ion must equal the overall charge on the molecule or ion. A formal charge does not represent a true charge on an atom in a covalent bond but is simply used to predict the most likely structure when a compound has more than one valid Lewis structure.
To calculate formal charges, we assign electrons in the molecule to individual atoms according to these rules:
• Nonbonding electrons are assigned to the atom on which they are located.
• Bonding electrons are divided equally between the bonded atoms.
For each atom, we then compute a formal charge:
To illustrate this method, let’s calculate the formal charge on the atoms in ammonia (NH3) whose Lewis electron structure is as follows:
A neutral nitrogen atom has five valence electrons (it is in group 15). From its Lewis electron structure, the nitrogen atom in ammonia has one lone pair and shares three bonding pairs with hydrogen atoms, so nitrogen itself is assigned a total of five electrons [2 nonbonding e− + (6 bonding e−/2)]. Substituting into Equation 5.3.1, we obtain
A neutral hydrogen atom has one valence electron. Each hydrogen atom in the molecule shares one pair of bonding electrons and is therefore assigned one electron [0 nonbonding e− + (2 bonding e−/2)]. Using Equation 4.4.1 to calculate the formal charge on hydrogen, we obtain
The hydrogen atoms in ammonia have the same number of electrons as neutral hydrogen atoms, and so their formal charge is also zero. Adding together the formal charges should give us the overall charge on the molecule or ion. In this example, the nitrogen and each hydrogen has a formal charge of zero. When summed the overall charge is zero, which is consistent with the overall charge on the NH3 molecule.
Typically, the structure with the most charges on the atoms closest to zero is the more stable Lewis structure. In cases where there are positive or negative formal charges on various atoms, stable structures generally have negative formal charges on the more electronegative atoms and positive formal charges on the less electronegative atoms. The next example further demonstrates how to calculate formal charges.
Example
Calculate the formal charges on each atom in the NH4+ ion.
Given: chemical species
Asked for: formal charges
Strategy:
Identify the number of valence electrons in each atom in the NH4+ ion. Use the Lewis electron structure of NH4+ to identify the number of bonding and nonbonding electrons associated with each atom and then use Equation 4.4.1 to calculate the formal charge on each atom.
Solution:
The Lewis electron structure for the NH4+ion is as follows:
The nitrogen atom shares four bonding pairs of electrons, and a neutral nitrogen atom has five valence electrons. Using Equation 4.4.1, the formal charge on the nitrogen atom is therefore
formalcharge(N)=5−(0+82)=0
Each hydrogen atom in has one bonding pair. The formal charge on each hydrogen atom is therefore
formalcharge(H)=1−(0+22)=0
The formal charges on the atoms in the NH4+ ion are thus
Adding together the formal charges on the atoms should give us the total charge on the molecule or ion. In this case, the sum of the formal charges is 0 + 1 + 0 + 0 + 0 = +1.
Exercise
Write the formal charges on all atoms in BH4-
Answer:
If an atom in a molecule or ion has the number of bonds that is typical for that atom (e.g., four bonds for carbon), its formal charge is zero.
Using Formal Charges to Distinguish between Lewis Structures
As an example of how formal charges can be used to determine the most stable Lewis structure for a substance, we can compare two possible structures for CO2. Both structures conform to the rules for Lewis electron structures.
CO2
1. C is less electronegative than O, so it is the central atom.
2. C has 4 valence electrons and each O has 6 valence electrons, for a total of 16 valence electrons.
3. Placing one electron pair between the C and each O gives O–C–O, with 12 electrons left over.
4. Dividing the remaining electrons between the O atoms gives three lone pairs on each atom:
This structure has an octet of electrons around each O atom but only 4 electrons around the C atom.
5. No electrons are left for the central atom.
6. To give the carbon atom an octet of electrons, we can convert two of the lone pairs on the oxygen atoms to bonding electron pairs. There are, however, two ways to do this. We can either take one electron pair from each oxygen to form a symmetrical structure or take both electron pairs from a single oxygen atom to give an asymmetrical structure:
Both Lewis electron structures give all three atoms an octet. How do we decide between these two possibilities? The formal charges for the two Lewis electron structures of CO2 are as follows:
Both Lewis structures have a net formal charge of zero, but the structure on the right has a +1 charge on the more electronegative atom (O). Thus the symmetrical Lewis structure on the left is predicted to be more stable, and it is, in fact, the structure observed experimentally. Remember, though, that formal charges do not represent the actual charges on atoms in a molecule or ion. They are used simply as a bookkeeping method for predicting the most stable Lewis structure for a compound.
Note the Pattern
The Lewis structure with the set of formal charges closest to zero is usually the most stable
Example
The thiocyanate ion (SCN), which is used in printing and as a corrosion inhibitor against acidic gases, has at least two possible Lewis electron structures. Draw two possible structures, assign formal charges on all atoms in both, and decide which is the preferred arrangement of electrons.
Given: chemical species
Asked for: Lewis electron structures, formal charges, and preferred arrangement
Strategy:
A Use the step-by-step procedure to write two plausible Lewis electron structures for SCN.
B Calculate the formal charge on each atom using Equation 4.4.1.
C Predict which structure is preferred based on the formal charge on each atom and its electronegativity relative to the other atoms present.
Solution:
A Possible Lewis structures for the SCN ion are as follows:
B We must calculate the formal charges on each atom to identify the more stable structure. If we begin with carbon, we notice that the carbon atom in each of these structures shares four bonding pairs, the number of bonds typical for carbon, so it has a formal charge of zero. Continuing with sulfur, we observe that in (a) the sulfur atom shares one bonding pair and has three lone pairs and has a total of six valence electrons. The formal charge on the sulfur atom is therefore 6−(6+22)=−1.5−(4+42)=−1 In (c), nitrogen has a formal charge of −2.
C Which structure is preferred? Structure (b) is preferred because the negative charge is on the more electronegative atom (N), and it has lower formal charges on each atom as compared to structure (c): 0, −1 versus +1, −2.
Exercise
Salts containing the fulminate ion (CNO) are used in explosive detonators. Draw three Lewis electron structures for CNO and use formal charges to predict which is more stable. (Note: N is the central atom.)
Answer:
The second structure is predicted to be more stable.
Contributors
• Anonymous | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Smith)/01%3A_Structure_and_Bonding/1.03%3A_Lewis_Structures.txt |
Three cases can be constructed that do not follow the octet rule, and as such, they are known as the exceptions to the octet rule. Following the Octet Rule for Lewis Dot Structures leads to the most accurate depictions of stable molecular and atomic structures and because of this we always want to use the octet rule when drawing Lewis Dot Structures. However, it is hard to imagine that one rule could be followed by all molecules. There is always an exception, and in this case, three exceptions. The octet rule is violated in these three scenarios:
1. When there are an odd number of valence electrons
2. When there are too few valence electrons
3. When there are too many valence electrons
Exception 1: Species with Odd Numbers of Electrons
The first exception to the Octet Rule is when there are an odd number of valence electrons. An example of this would be Nitrogen (II) Oxide (NO ,refer to figure one). Nitrogen has 5 valence electrons while Oxygen has 6. The total would be 11 valence electrons to be used. The Octet Rule for this molecule is fulfilled in the above example, however that is with 10 valence electrons. The last one does not know where to go. The lone electron is called an unpaired electron. But where should the unpaired electron go? The unpaired electron is usually placed in the Lewis Dot Structure so that each element in the structure will have the lowest formal charge possible. The formal charge is the perceived charge on an individual atom in a molecule when atoms do not contribute equal numbers of electrons to the bonds they participate in. The formula to find a formal charge is:
Formal Charge= [# of valence e- the atom would have on its own] - [# of lone pair electrons on that atom]
- [# of bonds that atom participates in]
No formal charge at all is the most ideal situation. An example of a stable molecule with an odd number of valence electrons would be nitrogen monoxide. Nitrogen monoxide has 11 valence electrons. If you need more information about formal charges, see Lewis Structures. If we were to imagine nitrogen monoxide had ten valence electrons we would come up with the Lewis Structure (Figure 8.7.1):
Figure 8.7.1. This is if Nitrogen monoxide has only ten valence electrons, which it does not.
Let's look at the formal charges of Figure 8.7.2 based on this Lewis structure. Nitrogen normally has five valence electrons. In Figure 8.7.1, it has two lone pair electrons and it participates in two bonds (a double bond) with oxygen. This results in nitrogen having a formal charge of +1. Oxygen normally has six valence electrons. In Figure 8.7.1, oxygen has four lone pair electrons and it participates in two bonds with nitrogen. Oxygen therefore has a formal charge of 0. The overall molecule here has a formal charge of +1 (+1 for nitrogen, 0 for oxygen. +1 + 0 = +1). However, if we add the eleventh electron to nitrogen (because we want the molecule to have the lowest total formal charge), it will bring both the nitrogen and the molecule's overall charges to zero, the most ideal formal charge situation. That is exactly what is done to get the correct Lewis structure for nitrogen monoxide (Figure 8.7.2):
Figure 8.7.2. The proper Lewis structure for NO molecule
Free Radicals
There are actually very few stable molecules with odd numbers of electrons that exist, since that unpaired electron is willing to react with other unpaired electrons. Most odd electron species are highly reactive, which we call Free Radicals. Because of their instability, free radicals bond to atoms in which they can take an electron from in order to become stable, making them very chemically reactive. Radicals are found as both reactants and products, but generally react to form more stable molecules as soon as they can. In order to emphasize the existence of the unpaired electron, radicals are denoted with a dot in front of their chemical symbol as with OH, the hydroxyl radical. An example of a radical you may by familiar with already is the gaseous chlorine atom, denoted Cl. Interestingly, odd Number of Valence Electrons will result in the molecule being paramagnetic.
Exception 2: Incomplete Octets
The second exception to the Octet Rule is when there are too few valence electrons that results in an incomplete Octet. There are even more occasions where the octet rule does not give the most correct depiction of a molecule or ion. This is also the case with incomplete octets. Species with incomplete octets are pretty rare and generally are only found in some beryllium, aluminum, and boron compounds including the boron hydrides. Let's take a look at one such hydride, BH3 (Borane).
If one was to make a Lewis structure for BH3 following the basic strategies for drawing Lewis structures, one would probably come up with this structure (Figure 8.7.3):
Figure 8.7.3
The problem with this structure is that boron has an incomplete octet; it only has six electrons around it. Hydrogen atoms can naturally only have only 2 electrons in their outermost shell (their version of an octet), and as such there are no spare electrons to form a double bond with boron. One might surmise that the failure of this structure to form complete octets must mean that this bond should be ionic instead of covalent. However, boron has an electronegativity that is very similar to hydrogen, meaning there is likely very little ionic character in the hydrogen to boron bonds, and as such this Lewis structure, though it does not fulfill the octet rule, is likely the best structure possible for depicting BH3 with Lewis theory. One of the things that may account for BH3's incomplete octet is that it is commonly a transitory species, formed temporarily in reactions that involve multiple steps.
Let's take a look at another incomplete octet situation dealing with boron, BF3 (Boron trifluorine). Like with BH3, the initial drawing of a Lewis structure of BF3 will form a structure where boron has only six electrons around it (Figure 8.7.4).
Figure 8.7.4
If you look Figure 8.7.4, you can see that the fluorine atoms possess extra lone pairs that they can use to make additional bonds with boron, and you might think that all you have to do is make one lone pair into a bond and the structure will be correct. If we add one double bond between boron and one of the fluorines we get the following Lewis Structure (Figure 8.7.5):
Figure 8.7.5
Each fluorine has eight electrons, and the boron atom has eight as well! Each atom has a perfect octet, right? Not so fast. We must examine the formal charges of this structure. The fluorine that shares a double bond with boron has six electrons around it (four from its two lone pairs of electrons and one each from its two bonds with boron). This is one less electron than the number of valence electrons it would have naturally (Group Seven elements have seven valence electrons), so it has a formal charge of +1. The two flourines that share single bonds with boron have seven electrons around them (six from their three lone pairs and one from their single bonds with boron). This is the same amount as the number of valence electrons they would have on their own, so they both have a formal charge of zero. Finally, boron has four electrons around it (one from each of its four bonds shared with fluorine). This is one more electron than the number of valence electrons that boron would have on its own, and as such boron has a formal charge of -1.
This structure is supported by the fact that the experimentally determined bond length of the boron to fluorine bonds in BF3 is less than what would be typical for a single bond (see Bond Order and Lengths). However, this structure contradicts one of the major rules of formal charges: Negative formal charges are supposed to be found on the more electronegative atom(s) in a bond, but in the structure depicted in Figure 8.7.5, a positive formal charge is found on fluorine, which not only is the most electronegative element in the structure, but the most electronegative element in the entire periodic table (χ=4.0). Boron on the other hand, with the much lower electronegativity of 2.0, has the negative formal charge in this structure. This formal charge-electronegativity disagreement makes this double-bonded structure impossible.
However the large electronegativity difference here, as opposed to in BH3, signifies significant polar bonds between boron and fluorine, which means there is a high ionic character to this molecule. This suggests the possibility of a semi-ionic structure such as seen in Figure 8.7.6:
Figure 8.7.6
None of these three structures is the "correct" structure in this instance. The most "correct" structure is most likely a resonance of all three structures: the one with the incomplete octet (Figure 8.7.4), the one with the double bond (Figure 8.7.5), and the one with the ionic bond (Figure 8.7.6). The most contributing structure is probably the incomplete octet structure (due to Figure 8.7.5 being basically impossible and Figure 8.7.6 not matching up with the behavior and properties of BF3). As you can see even when other possibilities exist, incomplete octets may best portray a molecular structure.
As a side note, it is important to note that BF3 frequently bonds with a F- ion in order to form BF4- rather than staying as BF3. This structure completes boron's octet and it is more common in nature. This exemplifies the fact that incomplete octets are rare, and other configurations are typically more favorable, including bonding with additional ions as in the case of BF3 .
Example 8.7.1: NF3
Draw the Lewis structure for boron trifluoride (BF3).
SOLUTION
1. Add electrons (3*7) + 3 = 24
2. Draw connectivities:
3. Add octets to outer atoms:
4. Add extra electrons (24-24=0) to central atom:
5. Does central electron have octet?
• NO. It has 6 electrons
• Add a multiple bond (double bond) to see if central atom can achieve an octet:
6. The central Boron now has an octet (there would be three resonance Lewis structures)
However...
• In this structure with a double bond the fluorine atom is sharing extra electrons with the boron.
• The fluorine would have a '+' partial charge, and the boron a '-' partial charge, this is inconsistent with the electronegativities of fluorine and boron.
• Thus, the structure of BF3, with single bonds, and 6 valence electrons around the central boron is the most likely structure
BF3 reacts strongly with compounds which have an unshared pair of electrons which can be used to form a bond with the boron:
Exception 3: Expanded Valence Shells
More common than incomplete octets are expanded octets where the central atom in a Lewis structure has more than eight electrons in its valence shell. In expanded octets, the central atom can have ten electrons, or even twelve. Molecules with expanded octets involve highly electronegative terminal atoms, and a nonmetal central atom found in the third period or below, which those terminal atoms bond to. For example, PCl5 is a legitimate compound (whereas NCl5) is not:
Note
Expanded valence shells are observed only for elements in period 3 (i.e. n=3) and beyond
The 'octet' rule is based upon available ns and np orbitals for valence electrons (2 electrons in the s orbitals, and 6 in the p orbitals). Beginning with the n=3 principle quantum number, the d orbitals become available (l=2). The orbital diagram for the valence shell of phosphorous is:
Hence, the third period elements occasionally exceed the octet rule by using their empty d orbitals to accommodate additional electrons. Size is also an important consideration:
• The larger the central atom, the larger the number of electrons which can surround it
• Expanded valence shells occur most often when the central atom is bonded to small electronegative atoms, such as F, Cl and O.
There is currently much scientific exploration and inquiry into the reason why expanded valence shells are found. The top area of interest is figuring out where the extra pair(s) of electrons are found. Many chemists think that there is not a very large energy difference between the 3p and 3d orbitals, and as such it is plausible for extra electrons to easily fill the 3d orbital when an expanded octet is more favorable than having a complete octet. This matter is still under hot debate, however and there is even debate as to what makes an expanded octet more favorable than a configuration that follows the octet rule.
One of the situations where expanded octet structures are treated as more favorable than Lewis structures that follow the octet rule is when the formal charges in the expanded octet structure are smaller than in a structure that adheres to the octet rule, or when there are less formal charges in the expanded octet than in the structure a structure that adheres to the octet rule.
Example 8.7.2: The SO24 ion
Such is the case for the sulfate ion, SO4-2. A strict adherence to the octet rule forms the following Lewis structure:
Figure 8.7.12
If we look at the formal charges on this molecule, we can see that all of the oxygen atoms have seven electrons around them (six from the three lone pairs and one from the bond with sulfur). This is one more electron than the number of valence electrons then they would have normally, and as such each of the oxygens in this structure has a formal charge of -1. Sulfur has four electrons around it in this structure (one from each of its four bonds) which is two electrons more than the number of valence electrons it would have normally, and as such it carries a formal charge of +2.
If instead we made a structure for the sulfate ion with an expanded octet, it would look like this:
Figure 8.7.13
Looking at the formal charges for this structure, the sulfur ion has six electrons around it (one from each of its bonds). This is the same amount as the number of valence electrons it would have naturally. This leaves sulfur with a formal charge of zero. The two oxygens that have double bonds to sulfur have six electrons each around them (four from the two lone pairs and one each from the two bonds with sulfur). This is the same amount of electrons as the number of valence electrons that oxygen atoms have on their own, and as such both of these oxygen atoms have a formal charge of zero. The two oxygens with the single bonds to sulfur have seven electrons around them in this structure (six from the three lone pairs and one from the bond to sulfur). That is one electron more than the number of valence electrons that oxygen would have on its own, and as such those two oxygens carry a formal charge of -1. Remember that with formal charges, the goal is to keep the formal charges (or the difference between the formal charges of each atom) as small as possible. The number of and values of the formal charges on this structure (-1 and 0 (difference of 1) in Figure 8.7.12, as opposed to +2 and -1 (difference of 3) in Figure 8.7.12) is significantly lower than on the structure that follows the octet rule, and as such an expanded octet is plausible, and even preferred to a normal octet, in this case.
Example 8.7.3: The ICl4 Ion
Draw the Lewis structure for ICl4 ion.
SOLUTION
1. Count up the valence electrons: 7+(4*7)+1 = 36 electrons
2. Draw the connectivities:
3. Add octet of electrons to outer atoms:
4. Add extra electrons (36-32=4) to central atom:
5. The ICl4- ion thus has 12 valence electrons around the central Iodine (in the 5d orbitals)
Expanded Lewis structures are also plausible depictions of molecules when experimentally determined bond lengths suggest partial double bond characters even when single bonds would already fully fill the octet of the central atom. Despite the cases for expanded octets, as mentioned for incomplete octets, it is important to keep in mind that, in general, the octet rule applies. | textbooks/chem/Organic_Chemistry/Map%3A_Organic_Chemistry_(Smith)/01%3A_Structure_and_Bonding/1.04%3A_Lewis_Structures_Continued.txt |
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