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From the author—About *Organic Chemistry: A Tenth Edition*

*Organic Chemistry: A Tenth Edition*, like previous editions, is intended for a two-semester introductory organic chemistry course. I recognize that many students in this course are biology or pre-med majors so, when appropriate, I bring in biological examples. Color is used consistently through the texts and illustrations. Problems are categorized (see below) and vary in level. My goal is to be as economical as possible with changes so that the overall length of *Organic Chemistry* does not increase.

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Additional resources

Structure and Bonding

Why This Chapter?

Atomic Structure: The Nucleus

Atomic Structure: Orbitals

Atomic Structure: Electron Configurations

Development of Chemical Bonding Theory

Describing Chemical Bonds: Valence Bond Theory

sp3 Hybrid Orbitals and the Structure of Methane

sp3 Hybrid Orbitals and the Structure of Ethane

sp2 Hybrid Orbitals and the Structure of Ethylene

sp Hybrid Orbitals and the Structure of Acetylene

Hybridization of Nitrogen, Oxygen, Phosphorus, and Sulfur

Describing Chemical Bonds: Molecular Orbital Theory

Drawing Chemical Structures

Polar Covalent Bonds; Acids and Bases

Why This Chapter?

Polar Covalent Bonds and Electronegativity

Polar Covalent Bonds and Dipole Moments

Formal Charges

Resonance

Rules for Resonance Forms

Drawing Resonance Forms

Acids and Bases: The Brønsted–Lowry Definition

Acid and Base Strength

Predicting Acid–Base Reactions from pKa Values

Organic Acids and Organic Bases

Organic Acids

Organic acids are characterized by the presence of a positively polarized hydrogen atom (blue in electrostatic potential maps) and are of two main kinds: acids such as methanol and acetic acid that contain a hydrogen atom bonded to an electronegative oxygen atom (O–H) and those such as acetone ([link]) that contain a hydrogen atom bonded to a carbon atom next to a $\text{C=O}$ bond ($\text{O=C–C–H}$).

Organic Bases

Organic bases are characterized by the presence of an atom (reddish in electrostatic potential maps) with a lone pair of electrons that can bond to H+. Nitrogen-containing compounds such as methylamine are the most common organic bases and are involved in almost all metabolic pathways, but oxygen-containing compounds can also act as bases when reacting with a sufficiently strong acid. Note that some oxygen-containing compounds can act both as acids and as bases depending on the circumstances, just as water can. Methanol and acetone, for instance, act as acids when they donate a proton but as bases when their oxygen atom accepts a proton.

Acids and Bases: The Lewis Definition

Lewis Acids and the Curved Arrow Formalism

The fact that a Lewis acid is able to accept an electron pair means that it must have either a vacant, low-energy orbital or a polar bond to hydrogen so that it can donate H+ (which has an empty 1*s* orbital). Thus, the Lewis definition of acidity includes many species in addition to H+. For example, various metal cations, such as Mg2+, are Lewis acids because they accept a pair of electrons when they form a bond to a base. We’ll also see in later chapters that certain metabolic reactions begin with an acid–base reaction between Mg2+ as a Lewis acid and an organic diphosphate or triphosphate ion as the Lewis base.

Lewis Bases

The Lewis definition of a base—a compound with a pair of nonbonding electrons that it can use to bond to a Lewis acid—is similar to the Brønsted–Lowry definition. Thus, H2O, with its two pairs of nonbonding electrons on oxygen, acts as a Lewis base by donating an electron pair to an H+ in forming the hydronium ion, H3O+.

Noncovalent Interactions between Molecules

Organic Compounds: Alkanes and Their Stereochemistry

Why This Chapter?

Functional Groups

Functional Groups with Carbon–Carbon Multiple Bonds

Alkenes, alkynes, and arenes (aromatic compounds) all contain carbon–carbon multiple bonds. *Alkenes* have a double bond, *alkynes* have a triple bond, and *arenes* have alternating double and single bonds in a six-membered ring of carbon atoms. They look different, but because of their structural similarities, they also have chemical similarities.

Functional Groups with Carbon Singly Bonded to an Electronegative Atom

Alkyl halides (haloalkanes), alcohols, ethers, alkyl phosphates, amines, thiols, sulfides, and disulfides all have a carbon atom singly bonded to an electronegative atom—halogen, oxygen, nitrogen, or sulfur. Alkyl halides have a carbon atom bonded to halogen (–X), alcohols have a carbon atom bonded to the oxygen of a hydroxyl group (–OH), ethers have two carbon atoms bonded to the same oxygen, organophosphates have a carbon atom bonded to the oxygen of a phosphate group (–OPO32−), amines have a carbon atom bonded to a nitrogen, thiols have a carbon atom bonded to the sulfur of an –SH group, sulfides have two carbon atoms bonded to the same sulfur, and disulfides have carbon atoms bonded to two sulfurs that are joined together. In all cases, the bonds are polar, with the carbon atom bearing a partial positive charge (*δ*+) and the electronegative atom bearing a partial negative charge (*δ*–).

Functional Groups with a Carbon–Oxygen Double Bond (Carbonyl Groups)

The carbonyl group*,* $\text{C=O}$ (pronounced car-bo-**neel**) is common to many of the families listed in [link]. Carbonyl groups are present in a majority of organic compounds and in practically all biological molecules. These compounds therefore behave similarly in many respects but differ depending on the identity of the other atoms bonded to the carbonyl-group carbon. Aldehydes have at least one hydrogen bonded to the $\text{C=O}$, ketones have two carbons bonded to the $\text{C=O}$, carboxylic acids have an –OH group bonded to the $\text{C=O}$, esters have an ether-like oxygen bonded to the $\text{C=O}$, thioesters have a sulfide-like sulfur bonded to the $\text{C=O}$, amides have an amine-like nitrogen bonded to the $\text{C=O}$, acid chlorides have a chlorine bonded to the $\text{C=O}$, and so on. In all these functional groups, the carbonyl carbon atom bears a partial positive charge (*δ*+), and the oxygen bears a partial negative charge (*δ*–).

Alkanes and Alkane Isomers

Alkyl Groups

Naming Alkanes

Properties of Alkanes

Conformations of Ethane

Conformations of Other Alkanes

Organic Compounds: Cycloalkanes and Their Stereochemistry

Why This Chapter?

Naming Cycloalkanes

Cis–Trans Isomerism in Cycloalkanes

Stability of Cycloalkanes: Ring Strain

Conformations of Cycloalkanes

Cyclopropane

Cyclopropane is the most strained of all rings, primarily due to the angle strain caused by its 60° C−C−C bond angles. In addition, cyclopropane has considerable torsional strain because the C−H bonds on neighboring carbon atoms are eclipsed ([link]).

Cyclobutane

Cyclobutane has less angle strain than cyclopropane but has more torsional strain because of its larger number of ring hydrogens. As a result, the total strain for the two compounds is nearly the same—110 kJ/mol (26.4 kcal/mol) for cyclobutane versus 115 kJ/mol (27.5 kcal/mol) for cyclopropane. Cyclobutane is not quite flat but is slightly bent so that one carbon atom lies about 25° above the plane of the other three ([link]). The effect of this slight bend is to increase angle strain but to decrease torsional strain, until a minimum-energy balance between the two opposing effects is achieved.

Cyclopentane

Cyclopentane was predicted by Baeyer to be nearly strain-free, but it actually has a total strain energy of 26 kJ/mol (6.2 kcal/mol). Although planar cyclopentane has practically no angle strain, it has a large torsional strain. Cyclopentane therefore twists to adopt a puckered, nonplanar conformation that strikes a balance between increased angle strain and decreased torsional strain. Four of the cyclopentane carbon atoms are in approximately the same plane, with the fifth carbon atom bent out of the plane. Most of the hydrogens are nearly staggered with respect to their neighbors ([link]).

Conformations of Cyclohexane

Axial and Equatorial Bonds in Cyclohexane

Conformations of Monosubstituted Cyclohexanes

Conformations of Disubstituted Cyclohexanes

Conformations of Polycyclic Molecules

Stereochemistry at Tetrahedral Centers

Why This Chapter?

Enantiomers and the Tetrahedral Carbon

The Reason for Handedness in Molecules: Chirality

Optical Activity

Pasteur’s Discovery of Enantiomers

Sequence Rules for Specifying Configuration

Diastereomers

Meso Compounds

Racemic Mixtures and the Resolution of Enantiomers

A Review of Isomerism

Chirality at Nitrogen, Phosphorus, and Sulfur

Prochirality

Chirality in Nature and Chiral Environments

An Overview of Organic Reactions

Why This Chapter?

Kinds of Organic Reactions

How Organic Reactions Occur: Mechanisms

Polar Reactions

An Example of a Polar Reaction: Addition of HBr to Ethylene

Using Curved Arrows in Polar Reaction Mechanisms

Radical Reactions

Describing a Reaction: Equilibria, Rates, and Energy Changes

Describing a Reaction: Bond Dissociation Energies

Describing a Reaction: Energy Diagrams and Transition States

Describing a Reaction: Intermediates

A Comparison Between Biological Reactions and Laboratory Reactions

Alkenes: Structure and Reactivity

Why This Chapter?

Industrial Preparation and Use of Alkenes

Calculating the Degree of Unsaturation

Naming Alkenes

Cis–Trans Isomerism in Alkenes

Alkene Stereochemistry and the E,Z Designation

Stability of Alkenes

Electrophilic Addition Reactions of Alkenes

Orientation of Electrophilic Additions: Markovnikov’s Rule

Carbocation Structure and Stability

The Hammond Postulate

Evidence for the Mechanism of Electrophilic Additions: Carbocation Rearrangements

Alkenes: Reactions and Synthesis

Why This Chapter?

Preparing Alkenes: A Preview of Elimination Reactions

Halogenation of Alkenes: Addition of X2

Halohydrins from Alkenes: Addition of HO-X

Hydration of Alkenes: Addition of H2O by Oxymercuration

Hydration of Alkenes: Addition of H2O by Hydroboration

Reduction of Alkenes: Hydrogenation

Oxidation of Alkenes: Epoxidation and Hydroxylation

Oxidation of Alkenes: Cleavage to Carbonyl Compounds

Addition of Carbenes to Alkenes: Cyclopropane Synthesis

Radical Additions to Alkenes: Chain-Growth Polymers

Biological Additions of Radicals to Alkenes

Reaction Stereochemistry: Addition of H2O to an Achiral Alkene

Reaction Stereochemistry: Addition of H2O to a Chiral Alkene

Alkynes: An Introduction to Organic Synthesis

Why This Chapter?

Naming Alkynes

Preparation of Alkynes: Elimination Reactions of Dihalides

Reactions of Alkynes: Addition of HX and X2

Hydration of Alkynes

Mercury(II)-Catalyzed Hydration of Alkynes

Alkynes don’t react directly with aqueous acid but will undergo hydration readily in the presence of mercury(II) sulfate as a Lewis acid catalyst. The reaction occurs with Markovnikov regiochemistry, so the −OH group adds to the more highly substituted carbon and the −H attaches to the less highly substituted one.

Hydroboration–Oxidation of Alkynes

Borane adds rapidly to an alkyne just as it does to an alkene, and the resulting vinylic borane can be oxidized by H2O2 to give an enol, which tautomerizes to either a ketone or an aldehyde, depending on the alkyne. Hydroboration–oxidation of an internal alkyne such as 3-hexyne is straightforward and gives a ketone, but hydroboration–oxidation of a terminal alkyne is more complex because two molecules of borane often add to the triple bond, complicating the situation. To prevent this double addition, a bulky, sterically encumbered borane such as bis(1,2-dimethylpropyl)borane, known commonly as disiamylborane is used in place of BH3. When a terminal alkyne such as 1-butene reacts with disiamylborane, addition to the triple bond occurs normally, but a second addition is hindered by the bulk of the dialkylborane. Oxidation with H2O2 then gives an enol, which tautomerizes to the aldehyde.

Reduction of Alkynes

Oxidative Cleavage of Alkynes

Alkyne Acidity: Formation of Acetylide Anions

Alkylation of Acetylide Anions

An Introduction to Organic Synthesis

Organohalides

Why This Chapter?

Names and Structures of Alkyl Halides

Preparing Alkyl Halides from Alkanes: Radical Halogenation

Preparing Alkyl Halides from Alkenes: Allylic Bromination

Stability of the Allyl Radical: Resonance Revisited

Preparing Alkyl Halides from Alcohols

Reactions of Alkyl Halides: Grignard Reagents

Organometallic Coupling Reactions

Oxidation and Reduction in Organic Chemistry

Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

Why This Chapter?

The Discovery of Nucleophilic Substitution Reactions

The SN2 Reaction

Characteristics of the SN2 Reaction

Steric Effects in the SN2 Reaction

The first SN2 reaction variable to look at is the structure of the substrate. Because the SN2 transition state involves partial bond formation between the incoming nucleophile and the alkyl halide carbon atom, it seems reasonable that a hindered, bulky substrate should prevent easy approach of the nucleophile, making bond formation difficult. In other words, the transition state for reaction of a sterically hindered substrate, whose carbon atom is “shielded” from the approach of the incoming nucleophile, is higher in energy and forms more slowly than the corresponding transition state for a less hindered substrate ([link]).

The Nucleophile

Another variable that has a major effect on the SN2 reaction is the nature of the nucleophile. Any species, either neutral or negatively charged, can act as a nucleophile as long as it has an unshared pair of electrons; that is, as long as it is a Lewis base. If the nucleophile is negatively charged, the product is neutral; if the nucleophile is neutral, the product is positively charged.

The Leaving Group

Still another variable that can affect the SN2 reaction is the nature of the group displaced by the incoming nucleophile, the leaving group. Because the leaving group is expelled with a negative charge in most SN2 reactions, the best leaving groups are those that best stabilize the negative charge in the transition state. The greater the extent of charge stabilization by the leaving group, the lower the energy of the transition state and the more rapid the reaction. But as we saw in [link], the groups that best stabilize a negative charge are also the weakest bases. Thus, weak bases such as Cl–, Br–, and tosylate ion make good leaving groups, while strong bases such as OH– and NH2– make poor leaving groups.

The Solvent

The rates of SN2 reactions are strongly affected by the solvent. Protic solvents—those that contain an –OH or –NH group—are generally the worst for SN2 reactions, while polar aprotic solvents, which are polar but don’t have an –OH or –NH group, are the best.

A Summary of SN2 Reaction Characteristics

The effects on SN2 reactions of the four variables—substrate structure, nucleophile, leaving group, and solvent—are summarized in the following statements and in the energy diagrams of [link]:

The SN1 Reaction

Characteristics of the SN1 Reaction

The Substrate

According to the Hammond postulate ([link]), any factor that stabilizes a high-energy intermediate also stabilizes the transition state leading to that intermediate. Because the rate-limiting step in an SN1 reaction is the spontaneous, unimolecular dissociation of the substrate to yield a carbocation, the reaction is favored whenever a stabilized carbocation intermediate is formed. The more stable the carbocation intermediate, the faster the SN1 reaction.

The Leaving Group

We said during the discussion of SN2 reactivity that the best leaving groups are those that are most stable; that is, those that are the conjugate bases of strong acids. An identical reactivity order is found for the SN1 reaction because the leaving group is directly involved in the rate-limiting step. Thus, the SN1 reactivity order is

The Nucleophile

The nature of the nucleophile plays a major role in the SN2 reaction but does not affect an SN1 reaction. Because the SN1 reaction occurs through a rate-limiting step in which the added nucleophile has no part, the nucleophile can’t affect the reaction rate. The reaction of 2-methyl-2-propanol with HX, for instance, occurs at the same rate regardless of whether X is Cl, Br, or I. Furthermore, neutral nucleophiles are just as effective as negatively charged ones, so SN1 reactions frequently occur under neutral or acidic conditions.

The Solvent

What about the solvent? Do solvents have the same effect in SN1 reactions that they have in SN2 reactions? The answer is both yes and no. Yes, solvents have a large effect on SN1 reactions, but no, the reasons for the effects on SN1 and SN2 reactions are not the same. Solvent effects in the SN2 reaction are due largely to stabilization or destabilization of the nucleophile *reactant,* while solvent effects in the SN1 reaction are due largely to stabilization or destabilization of the *transition state*.

A Summary of SN1 Reaction Characteristics

The effects on SN1 reactions of the four variables—substrate, leaving group, nucleophile, and solvent—are summarized in the following statements:

Biological Substitution Reactions

Elimination Reactions: Zaitsev’s Rule

The E2 Reaction and the Deuterium Isotope Effect

The E2 Reaction and Cyclohexane Conformation

The E1 and E1cB Reactions

The E1 Reaction

Just as the E2 reaction is analogous to the SN2 reaction, the SN1 reaction has a close analog called the E1 reaction (for elimination, unimolecular). The E1 reaction can be formulated as shown in [link], with the elimination of HCl from 2-chloro-2-methylpropane.

The E1cB Reaction

In contrast to the E1 reaction, which involves a carbocation intermediate, the E1cB reaction takes place through a carbanion intermediate. Base-induced abstraction of a proton in a slow, rate-limiting step gives an anion, which expels a leaving group on the adjacent carbon. The reaction is particularly common in substrates that have a poor leaving group, such as –OH, two carbons removed from a carbonyl group, as in $\text{HOC–CH–C═O}$. The poor leaving group disfavors the alternative E1 and E2 possibilities, and the carbonyl group makes the adjacent hydrogen unusually acidic by resonance stabilization of the anion intermediate. We’ll look at this acidifying effect of a carbonyl group in **Section 22.5**.

Biological Elimination Reactions

A Summary of Reactivity: SN1, SN2, E1, E1cB, and E2

Structure Determination: Mass Spectrometry and Infrared Spectroscopy

Why This Chapter?

Mass Spectrometry of Small Molecules: Magnetic-Sector Instruments

Interpreting Mass Spectra

Mass Spectrometry of Some Common Functional Groups

Alcohols

Alcohols undergo fragmentation in a mass spectrometer by two pathways: *alpha cleavage* and *dehydration*. In the *α*-cleavage pathway, a C–C bond nearest the hydroxyl group is broken, yielding a neutral radical plus a resonance-stabilized, oxygen-containing cation. This type of fragmentation is seen in the spectrum of 2-pentanol in [link].

Amines

The *nitrogen rule* of mass spectrometry says that a compound with an odd number of nitrogen atoms has an odd-numbered molecular weight. The logic behind the rule comes from the fact that nitrogen is trivalent, thus requiring an odd number of hydrogen atoms. The presence of nitrogen in a molecule is often detected simply by observing its mass spectrum. An odd-numbered molecular ion usually means that the unknown compound has one or three nitrogen atoms, and an even-numbered molecular ion usually means that a compound has either zero or two nitrogen atoms.

Halides

The fact that some elements have two common isotopes gives their mass spectra a distinctive appearance. Chlorine, for example, exists as two isotopes, 35Cl and 37Cl, in roughly a 3 : 1 ratio. In a sample of chloroethane, three out of four molecules contain a 35Cl atom and one out of four has a 37Cl atom. In the mass spectrum of chloroethane ([link] we see the molecular ion (M) at *m*/*z* = 64 for ions that contain a 35Cl and another peak at *m*/*z* = 66, called the M + 2 peak, for ions containing a 37Cl. The ratio of the relative abundance of M : M + 2 is about 3 : 1, a reflection of the isotopic abundances of chlorine.

Carbonyl Compounds

Ketones and aldehydes that have a hydrogen on a carbon three atoms away from the carbonyl group undergo a characteristic mass-spectral cleavage called the McLafferty rearrangement. The hydrogen atom is transferred to the carbonyl oxygen, a C–C bond between the alpha and beta carbons is broken, and a neutral alkene fragment is produced. The charge remains with the oxygen-containing fragment.

Mass Spectrometry in Biological Chemistry: Time-of-Flight (TOF) Instruments

Spectroscopy and the Electromagnetic Spectrum

Infrared Spectroscopy

Interpreting Infrared Spectra

Infrared Spectra of Some Common Functional Groups

Alkanes

The IR spectrum of an alkane is fairly uninformative because no functional groups are present and all absorptions are due to C–H and C–C bonds. Alkane C–H bonds show a strong absorption from 2850 to 2960 cm–1, and saturated C–C bonds show a number of bands in the 800 to 1300 cm–1 range. Since most organic compounds contain saturated alkane-like portions, most organic compounds have these characteristic IR absorptions. The C–H and C–C bands are clearly visible in the three spectra shown previously in [link].

Alkenes

Alkenes show several characteristic stretching absorptions. Vinylic =C–H bonds absorb from 3020 to 3100 cm–1, and alkene $\text{C═C}$ bonds usually absorb near 1650 cm–1, although in some cases their peaks can be rather small and difficult to see clearly when the alkene is symmetric, or nearly so. Both absorptions are visible in the 1-hexene spectrum in [link]b.

Alkynes

Alkynes show a $\text{C≡C}$ stretching absorption at 2100 to 2260 cm–1, an absorption that is much more intense for terminal alkynes than for internal alkynes. Terminal alkynes such as 1-hexyne also have a characteristic $\text{≡C–H}$ stretching absorption at 3300 cm–1 ([link]c). This band is diagnostic for terminal alkynes because it is fairly intense and quite sharp.

Aromatic Compounds

Aromatic compounds, such as benzene, have a weak C–H stretching absorption at 3030 cm–1, just to the left of a typical saturated C–H band. In addition, they have a series of weak absorptions in the 1660 to 2000 cm–1 range and a series of medium-intensity absorptions in the 1450 to 1600 cm–1 region. These latter absorptions are due to complex molecular motions of the entire ring. The C–H out-of-plane bending region for benzene derivatives, between 650 to 1000 cm–1, gives valuable information about the ring’s substitution pattern, as it does for the substitution pattern of alkenes ([link]).

Alcohols

The O–H functional group of alcohols is easy to spot. Alcohols have a characteristic band in the range 3400 to 3650 cm–1 that is usually broad and intense. Hydrogen bonding between O–H groups is responsible for making the absorbance so broad. If an O–H stretch is present, it’s hard to miss this band or to confuse it with anything else.

Amines

The N–H functional group of amines is also easy to spot in the IR, with a characteristic absorption in the 3300 to 3500 cm–1 range. Although alcohols absorb in the same range, an N–H absorption band is much sharper and less intense than an O–H band.

Carbonyl Compounds

Carbonyl functional groups are the easiest to identify of all IR absorptions because of their sharp, intense peak in the range 1670 to 1780 cm–1. Most important, the exact position of absorption within this range can often be used to identify the exact kind of carbonyl functional group—aldehyde, ketone, ester, and so forth.

Structure Determination: Nuclear Magnetic Resonance Spectroscopy

Why This Chapter?

Nuclear Magnetic Resonance Spectroscopy

The Nature of NMR Absorptions

Chemical Shifts

Chemical Shifts in 1H NMR Spectroscopy

Integration of 1H NMR Absorptions: Proton Counting

Spin–Spin Splitting in 1H NMR Spectra

1H NMR Spectroscopy and Proton Equivalence

More Complex Spin–Spin Splitting Patterns

Uses of 1H NMR Spectroscopy

13C NMR Spectroscopy: Signal Averaging and FT–NMR

Characteristics of 13C NMR Spectroscopy

DEPT 13C NMR Spectroscopy

Uses of 13C NMR Spectroscopy

Conjugated Compounds and Ultraviolet Spectroscopy

Why This Chapter?

Stability of Conjugated Dienes: Molecular Orbital Theory

Electrophilic Additions to Conjugated Dienes: Allylic Carbocations

Kinetic versus Thermodynamic Control of Reactions

The Diels–Alder Cycloaddition Reaction

Characteristics of the Diels–Alder Reaction

The Dienophile

The Diels–Alder cycloaddition reaction occurs most rapidly if the alkene component, called the dienophile (“diene lover”), has an electron-withdrawing substituent group. Thus, ethylene itself reacts sluggishly, but propenal, ethyl propenoate, maleic anhydride, benzoquinone, propenenitrile, and similar compounds are highly reactive. Note also that alkynes, such as methyl propynoate, can act as Diels–Alder dienophiles.

The Diene

Just as the dienophile component has certain constraints that affect its reactivity, so too does the conjugated diene component. The diene must adopt what is called an *s*-cis conformation, meaning “cis-like” about the *s*ingle bond, to undergo a Diels–Alder reaction. Only in the *s*-cis conformation are carbons 1 and 4 of the diene close enough to react through a cyclic transition state.

Diene Polymers: Natural and Synthetic Rubbers

Ultraviolet Spectroscopy

Interpreting Ultraviolet Spectra: The Effect of Conjugation

Conjugation, Color, and the Chemistry of Vision

Benzene and Aromaticity

Why This Chapter?

Naming Aromatic Compounds

Structure and Stability of Benzene

Aromaticity and the Hückel 4n + 2 Rule

Aromatic Ions

Aromatic Heterocycles: Pyridine and Pyrrole

Polycyclic Aromatic Compounds

Spectroscopy of Aromatic Compounds

Infrared Spectroscopy

As we saw in the brief introduction to infrared spectroscopy ([link]), aromatic rings show a characteristic C–H stretching absorption at 3030 cm–1 and a series of peaks in the 1450 to 1600 cm–1 range of the infrared spectrum. The aromatic C–H band at 3030 cm–1 generally has low intensity and occurs just to the left of a typical saturated C–H band.

Ultraviolet Spectroscopy

Aromatic rings are detectable by ultraviolet spectroscopy because they contain a conjugated *π* electron system. In general, aromatic compounds show a series of bands, with a fairly intense absorption near 205 nm and a less intense absorption in the 255 to 275 nm range. The presence of these bands in the ultraviolet spectrum of a molecule is a sure indication of an aromatic ring. [link] shows the ultraviolet spectrum of benzene.

Nuclear Magnetic Resonance Spectroscopy

Aromatic hydrogens are strongly deshielded by the ring and absorb between 6.5 and 8.0 *δ.* The spins of nonequivalent aromatic protons on substituted rings often couple with each other, giving rise to spin–spin splitting patterns that can identify the substitution of the ring.

Chemistry of Benzene: Electrophilic Aromatic Substitution

Why This Chapter?

Electrophilic Aromatic Substitution Reactions: Bromination

Other Aromatic Substitutions

Aromatic Halogenation

Chlorine and iodine can be introduced into aromatic rings by electrophilic substitution reactions just as bromine can, but fluorine is too reactive and only poor yields of monofluoroaromatic products are obtained by direct fluorination. Instead, other sources of “F+” are used, in which a fluorine atom is bonded to a positively charged nitrogen. One of the most common such reagents goes by the acronym F-TEDA-BF4 in the presence of trifluoromethanesulfonic acid (TfOH). (You don’t need to know the full name of F-TEDA, which is sold under the name Selectfluor.)

Aromatic Nitration

Aromatic rings are nitrated by reaction with a mixture of concentrated nitric and sulfuric acids. The electrophile is the nitronium ion, NO2+, which is formed from HNO3 by protonation and loss of water. The nitronium ion reacts with benzene to yield a carbocation intermediate, and loss of H+ from this intermediate gives the neutral substitution product, nitrobenzene ([link]).

Aromatic Sulfonation

Aromatic rings can be sulfonated by reaction with so-called fuming sulfuric acid, a mixture of H2SO4 and SO3. The reactive electrophile is either ${\text{HSO}}_{3}{}^{+}$ or neutral SO3, depending on reaction conditions, and substitution occurs by the same two-step mechanism seen previously for bromination and nitration ([link]). Note, however, that the sulfonation reaction is readily reversible. It can occur either forward or backward, depending on the reaction conditions. Sulfonation is favored in strong acid, but desulfonation is favored in hot, dilute aqueous acid.

Aromatic Hydroxylation

Direct hydroxylation of an aromatic ring to yield a hydroxybenzene (a *phenol*) is difficult and rarely done in the laboratory but occurs much more frequently in biological pathways. An example is the hydroxylation of *p*-hydroxyphenylacetate to give 3,4-dihydroxyphenylacetate. The reaction is catalyzed by *p*-hydroxyphenylacetate-3-hydroxylase and requires molecular oxygen plus the coenzyme reduced flavin adenine dinucleotide, abbreviated FADH2.

Alkylation and Acylation of Aromatic Rings: The Friedel–Crafts Reaction

Substituent Effects in Electrophilic Substitutions

Activating and Deactivating Effects

What makes a group either activating or deactivating? The common characteristic of all activating groups is that they donate electrons to the ring, thereby making the ring more electron-rich, stabilizing the carbocation intermediate, and lowering the activation energy for its formation. Conversely, the common characteristic of all deactivating groups is that they withdraw electrons from the ring, thereby making the ring more electron-poor, destabilizing the carbocation intermediate, and raising the activation energy for its formation.

Ortho- and Para-Directing Activators: Alkyl Groups

Inductive and resonance effects account not only for reactivity but also for the orientation of electrophilic aromatic substitutions. Take alkyl groups, for instance, which have an electron-donating inductive effect and are ortho and para directors. The results of toluene nitration are shown in [link].

Ortho- and Para-Directing Activators: OH and NH2

Hydroxyl, alkoxyl, and amino groups are also ortho–para activators, but for a different reason than for alkyl groups. As described earlier in this section, hydroxyl, alkoxyl, and amino groups have a strong, electron-donating resonance effect that outweighs a weaker electron-withdrawing inductive effect. When phenol is nitrated, for instance, reaction can occur either ortho, meta, or para to the –OH group, giving the carbocation intermediates shown in [link]. The ortho and para intermediates are more stable than the meta intermediate because they have more resonance forms, including one particularly favorable form that allows the positive charge to be stabilized by electron donation from the substituent oxygen atom. The intermediate from the meta reaction has no such stabilization.

Ortho- and Para-Directing Deactivators: Halogens

Halogens are deactivating because their stronger electron-withdrawing inductive effect outweighs their weaker electron-donating resonance effect. Although weak, that electron-donating resonance effect is nevertheless felt only at the ortho and para positions and not at the meta position ([link]). Thus, a halogen substituent can stabilize the positive charge of the carbocation intermediates from ortho and para reaction in the same way that hydroxyl and amino substituents can. The meta intermediate, however, has no such stabilization and is therefore formed more slowly.

Meta-Directing Deactivators

The influence of meta-directing substituents can be explained using the same kinds of arguments used for ortho and para directors. Look at the nitration of benzaldehyde, for instance ([link]). Of the three possible carbocation intermediates, the meta intermediate has three favorable resonance forms, whereas the ortho and para intermediates have only two. In both ortho and para intermediates, the third resonance form is unfavorable because it places the positive charge directly on the carbon that bears the aldehyde group, where it is disfavored by a repulsive interaction with the positively polarized carbon atom of the C=O group. Hence, the meta intermediate is more favored and is formed faster than the ortho and para intermediates.

A Summary of Substituent Effects in Electrophilic Aromatic Substitution

A summary of the activating and directing effects of substituents in electrophilic aromatic substitution is shown in [link].

Trisubstituted Benzenes: Additivity of Effects

Nucleophilic Aromatic Substitution

Benzyne

Oxidation of Aromatic Compounds

Oxidation of Alkyl Side Chains

Despite its unsaturation, the benzene ring is inert to strong oxidizing agents such as KMnO4, which will cleave alkene carbon–carbon bonds ([link]). It turns out, however, that the presence of the aromatic ring has a dramatic effect on the reactivity of alkyl side chains. These side chains react rapidly with oxidizing agents and are converted into carboxyl groups, –CO2H.The net effect is conversion of an alkylbenzene into a benzoic acid, $\text{Ar–R}\to \text{Ar}–{\text{CO}}_{2}\text{H}$. Butylbenzene is oxidized by aqueous KMnO4 to give benzoic acid, for instance.

Bromination of Alkylbenzene Side Chains

Side-chain bromination at the benzylic position occurs when an alkylbenzene is treated with *N*-bromosuccinimide (NBS). For example, propylbenzene gives (1-bromopropyl)benzene in 97% yield on reaction with NBS in the presence of benzoyl peroxide, (PhCO2)2, as a radical initiator. Bromination occurs exclusively in the benzylic position next to the aromatic ring and does not give a mixture of products.

Reduction of Aromatic Compounds

Catalytic Hydrogenation of Aromatic Rings

Just as aromatic rings are generally inert to oxidation, they’re also inert to catalytic hydrogenation under conditions that reduce typical alkene double bonds. As a result, it’s possible to reduce an alkene double bond selectively in the presence of an aromatic ring. For example, 4-phenyl-3-buten-2-one is reduced to 4-phenyl-2-butanone using a palladium catalyst at room temperature and atmospheric pressure. Neither the benzene ring nor the ketone carbonyl group is affected.

Reduction of Aryl Alkyl Ketones

In the same way that an aromatic ring activates a neighboring (benzylic) C–H toward oxidation, it also activates a benzylic carbonyl group toward reduction. Thus, an aryl alkyl ketone prepared by Friedel–Crafts acylation of an aromatic ring can be converted into an alkylbenzene by catalytic hydrogenation over a palladium catalyst. Propiophenone, for instance, is reduced to propylbenzene by catalytic hydrogenation. Because the net effect of Friedel–Crafts acylation followed by reduction is the preparation of a primary alkylbenzene, this two-step sequence of reactions makes it possible to circumvent the carbocation rearrangement problems associated with direct Friedel–Crafts alkylation using a primary alkyl halide ([link]).

Synthesis of Polysubstituted Benzenes

Alcohols and Phenols

Why This Chapter?

Naming Alcohols and Phenols

Properties of Alcohols and Phenols

Preparation of Alcohols: A Review

Alcohols from Carbonyl Compounds: Reduction

Reduction of Aldehydes and Ketones

Aldehydes are easily reduced to give primary alcohols, and ketones are reduced to give secondary alcohols.

Reduction of Carboxylic Acids and Esters

Carboxylic acids and esters are reduced to give primary alcohols.

Alcohols from Carbonyl Compounds: Grignard Reaction

Reactions of Alcohols

Conversion of Alcohols into Alkyl Halides

Tertiary alcohols react with either HCl or HBr at 0 °C by an SN1 mechanism through a carbocation intermediate. Primary and secondary alcohols are much more resistant to acid, however, and are best converted into halides by treatment with either SOCl2 or PBr3 through an SN2 mechanism.

Conversion of Alcohols into Tosylates

Alcohols react with *p*-toluenesulfonyl chloride (tosyl chloride, *p*-TosCl) in pyridine solution to yield alkyl tosylates, ROTos ([link]). Only the O–H bond of the alcohol is broken in this reaction; the C–O bond remains intact, so no change of configuration occurs if the oxygen is attached to a chirality center. The resultant alkyl tosylates behave much like alkyl halides, undergoing both SN1 and SN2 substitution reactions.

Dehydration of Alcohols to Yield Alkenes

A third important reaction of alcohols, both in the laboratory and in biological pathways, is their dehydration to give alkenes. Because of the usefulness of the reaction, a number of methods have been devised for carrying out dehydrations. One method that works particularly well for tertiary alcohols is the acid-catalyzed reaction discussed in [link]. For example, treatment of 1-methylcyclohexanol with warm, aqueous sulfuric acid in a solvent such as tetrahydrofuran results in loss of water and formation of 1-methylcyclohexene.

Conversion of Alcohols into Esters

Alcohols react with carboxylic acids to give esters, a reaction that is common in both the laboratory and living organisms. In the laboratory, the reaction can be carried out in a single step if a strong acid is used as catalyst. More frequently, though, the reactivity of the carboxylic acid is enhanced by first converting it into a carboxylic acid chloride, which then reacts with the alcohol.

Oxidation of Alcohols

Protection of Alcohols

Phenols and Their Uses

Reactions of Phenols

Electrophilic Aromatic Substitution Reactions

The hydroxyl group is a strongly activating, ortho- and para-directing substituent in electrophilic aromatic substitution reactions ([link]). As a result, phenols are highly reactive substrates for electrophilic halogenation, nitration, sulfonation, and Friedel–Crafts reactions.

Oxidation of Phenols: Quinones

Phenols don’t undergo oxidation in the same way as alcohols because they don’t have a hydrogen atom on the hydroxyl-bearing carbon. Instead, oxidation of a phenol yields a 2,5-cyclohexadiene-1,4-dione, or quinone. Many different oxidizing agents will accomplish the transformation, but potassium nitrosodisulfonate [(KSO3)2NO], called Fremy’s salt, is often used.

Spectroscopy of Alcohols and Phenols

Infrared Spectroscopy

Alcohols have a strong C–O stretching absorption near 1050 cm–1 and a characteristic O–H stretching absorption at 3300 to 3600 cm–1. The exact position of the O–H stretch depends on the extent of hydrogen-bonding in the molecule. Unassociated alcohols show a fairly sharp absorption near 3600 cm–1, whereas hydrogen-bonded alcohols show a broader absorption in the 3300 to 3400 cm–1 range. The hydrogen-bonded hydroxyl absorption appears at 3350 cm–1 in the IR spectrum of cyclohexanol ([link]).

Nuclear Magnetic Resonance Spectroscopy

Carbon atoms bonded to electron-withdrawing –OH groups are deshielded and absorb at a lower field in the 13C NMR spectrum than do typical alkane carbons. Most alcohol carbon absorptions fall in the range 50 to 80 *δ,* as shown in the following drawing for cyclohexanol:

Mass Spectrometry

As noted in [link], alcohols undergo fragmentation in the mass spectrometer by two characteristic pathways, alpha cleavage and dehydration. In the alpha-cleavage pathway, a C–C bond nearest the hydroxyl group is broken, yielding a neutral radical plus a resonance-stabilized, oxygen-containing cation.

Ethers and Epoxides; Thiols and Sulfides

Why This Chapter?

Names and Properties of Ethers

Preparing Ethers

The Williamson Ether Synthesis

The most generally useful method of preparing ethers is the Williamson ether synthesis, in which an alkoxide ion reacts with a primary alkyl halide or tosylate in an SN2 reaction. As we saw in [link], the alkoxide ion is normally prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH.

Alkoxymercuration of Alkenes

We saw in [link] that alkenes react with water in the presence of mercuric acetate to yield a hydroxymercuration product. Subsequent treatment with NaBH4 breaks the C–Hg bond and yields the alcohol. A similar alkoxymercuration reaction occurs when an alkene is treated with an alcohol in the presence of mercuric acetate or, even better, mercuric trifluoroacetate, (CF3CO2)2Hg. Demercuration by reaction with NaBH4 then yields an ether. The net result is Markovnikov addition of the alcohol to the alkene.

Reactions of Ethers: Acidic Cleavage

Cyclic Ethers: Epoxides

Reactions of Epoxides: Ring-Opening

Acid-Catalyzed Epoxide Opening

Epoxides are cleaved by treatment with acid just as other ethers are, but under much milder conditions because of ring strain. As we saw in [link], dilute aqueous acid at room temperature is sufficient for facilitating the hydrolysis of epoxides to give 1,2-diols, also called *vicinal glycols.* (The word *vicinal* means “adjacent,” and a *glycol* is a diol.) The epoxide cleavage takes place by SN2-like backside attack of a nucleophile on the protonated epoxide, giving a trans-1,2-diol as product.

Base-Catalyzed Epoxide Opening

Unlike other ethers, epoxide rings can be cleaved by bases and nucleophiles as well as by acid. Although an ether oxygen is normally a poor leaving group in an SN2 reaction ([link]), the strain of the three-membered ring causes epoxides to react with hydroxide ion at elevated temperatures.

Crown Ethers

Thiols and Sulfides

Thiols

Thiols, also called **mercaptans**, are sulfur analogs of alcohols. They are named by the same system used for alcohols, with the suffix -*thiol* used in place of -*ol.* The –SH group itself is referred to as a mercapto group. Like alcohols, thiols are weakly acidic; the p*K*a of CH3SH, for instance, is 10.3. Unlike alcohols, however, thiols don’t typically form hydrogen bonds because the sulfur atom is not sufficiently electronegative.

Sulfides

Sulfides are the sulfur analogs of ethers just as thiols are the sulfur analogs of alcohols. Sulfides are named by following the same rules used for ethers, with *sulfide* used in place of *ether* for simple compounds and *alkylthio* used in place of *alkoxy* for more complex substances.

Spectroscopy of Ethers

Infrared Spectroscopy

Ethers are difficult to identify by IR spectroscopy. Although they show an absorption due to C–O single-bond stretching in the range 1050 to 1150 cm–1, many other kinds of absorptions occur in the same range. [link] shows the IR spectrum of diethyl ether and identifies the C–O stretch. Phenyl alkyl ethers show two strong absorbances for C–O stretching at 1050 and 1250 cm–1. [link] shows the IR spectrum of anisole.

Nuclear Magnetic Resonance Spectroscopy

Hydrogens on carbon next to an ether oxygen are shifted downfield from the normal alkane resonance and show 1H NMR absorptions in the region 3.4 to 4.5 *δ*. This downfield shift is clearly seen in the spectrum of dipropyl ether shown in [link].

Aldehydes and Ketones: Nucleophilic Addition Reactions

Why This Chapter?

Naming Aldehydes and Ketones

Naming Aldehydes and Ketones

Preparing Aldehydes

Perhaps the best method of aldehyde synthesis is by oxidation of a primary alcohol, as we saw in [link]. The reaction is usually carried out using the Dess–Martin periodinane reagent in dichloromethane solvent at room temperature:

Preparing Ketones

For the most part, methods of ketone synthesis are similar to those for aldehydes. Secondary alcohols are oxidized by a variety of reagents to give ketones ([link]). The choice of oxidant depends on such factors as reaction scale, cost, and acid or base sensitivity of the alcohol. The Dess–Martin periodinane is a common choice although chromic acid (H2CrO4) was frequently used in older work.

Oxidation of Aldehydes and Ketones

Nucleophilic Addition Reactions of Aldehydes and Ketones

Nucleophilic Addition of H2O: Hydration

Nucleophilic Addition of HCN: Cyanohydrin Formation

Nucleophilic Addition of Hydride and Grignard Reagents: Alcohol Formation

Addition of Hydride Reagents: Reduction

We saw in [link] that the most common method for preparing alcohols, both in the laboratory and in living organisms, is by the reduction of carbonyl compounds. Aldehydes are reduced with sodium borohydride (NaBH4) to give primary alcohols, and ketones are reduced similarly to give secondary alcohols.

Addition of Grignard Reagents, RMgX

Just as aldehydes and ketones undergo nucleophilic addition with hydride ion to give alcohols, they undergo a similar addition with Grignard reagent nucleophiles, R:– +MgX. Aldehydes give secondary alcohols on reaction with Grignard reagents in ether solution, and ketones give tertiary alcohols.

Nucleophilic Addition of Amines: Imine and Enamine Formation

Nucleophilic Addition of Hydrazine: The Wolff–Kishner Reaction

Nucleophilic Addition of Alcohols: Acetal Formation

Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

Biological Reductions

Conjugate Nucleophilic Addition to α,β‑Unsaturated Aldehydes and Ketones

Conjugate Addition of Amines

Both primary and secondary amines add to *α*,*β*-unsaturated aldehydes and ketones to yield *β*-amino aldehydes and ketones rather than the alternative imines. Under typical reaction conditions, both modes of addition occur rapidly. But because the reactions are reversible, they generally proceed with thermodynamic control rather than kinetic control ([link]), so the more stable conjugate addition product is often obtained with the complete exclusion of the less stable direct addition product.

Conjugate Addition of Water

Water can add reversibly to *α*,*β*-unsaturated aldehydes and ketones to yield *β*-hydroxy aldehydes and ketones, although the position of the equilibrium generally favors unsaturated reactant rather than saturated adduct. Related additions to *α*,*β*-unsaturated carboxylic acids occur in numerous biological pathways, such as the citric acid cycle of food metabolism in which *cis*-aconitate is converted into isocitrate by conjugate addition of water to a double bond.

Conjugate Addition of Alkyl Groups: Organocopper Reactions

The conjugate addition of an alkyl or other organic group to an *α*,*β*-unsaturated ketone (but not aldehyde) is one of the more useful 1,4-addition reactions, just as direct addition of a Grignard reagent is one of the more useful 1,2-additions.

Spectroscopy of Aldehydes and Ketones

Infrared Spectroscopy

Aldehydes and ketones show a strong $\text{C═O}$ bond absorption in the IR region from 1660 to 1770 cm–1, as the spectra of benzaldehyde and cyclohexanone demonstrate ([link]). In addition, aldehydes show two characteristic C–H absorptions between 2700–2760 and 2800–2860 cm–1. These absorbances are important for distinguishing between aldehydes and ketones. The higher-frequency absorbance is sometimes obscured in cases where the compound has numerous saturated C–H groups, but the lower-frequency peak is almost always visible.

Nuclear Magnetic Resonance Spectroscopy

Aldehyde protons (RC**H**O) absorb near 10 *δ* in the 1H NMR spectrum and are very distinctive because no other absorptions occur in this region. The aldehyde proton shows spin–spin coupling with protons on the neighboring carbon, with coupling constant *J* ≈ 3 Hz. Acetaldehyde, for example, shows a quartet at 9.79 *δ* for the aldehyde proton, indicating that there are three protons neighboring the –CHO group ([link]).

Mass Spectrometry

As discussed in [link], aliphatic aldehydes and ketones that have hydrogens on their gamma (*γ*) carbon atoms undergo a characteristic mass spectral cleavage called the McLafferty rearrangement. A hydrogen atom is transferred from the *γ* carbon to the carbonyl oxygen, the bond between the *α* and *β* carbons is broken, and a neutral alkene fragment is produced. The charge remains with the oxygen-containing fragment.

Carboxylic Acids and Nitriles

Why This Chapter?

Naming Carboxylic Acids and Nitriles

Carboxylic Acids, RCO2H

Simple carboxylic acids derived from open-chain alkanes are systematically named by replacing the terminal –*e* of the corresponding alkane name with -*oic acid.* The –CO2H carbon atom is numbered C1.

Nitriles, $\text{RC≡N}$

Compounds containing the $\text{–C≡N}$ functional group are called nitriles and can undergo some chemistry similar to that of carboxylic acids. Simple open-chain nitriles are named by adding -*nitrile* as a suffix to the alkane name, with the nitrile carbon numbered C1.

Structure and Properties of Carboxylic Acids

Biological Acids and the Henderson–Hasselbalch Equation

Substituent Effects on Acidity

Preparing Carboxylic Acids

Hydrolysis of Nitriles

Carboxylic acids can be prepared from nitriles on heating with aqueous acid or base by a mechanism that we’ll discuss in Section 20.7. Since nitriles themselves are usually made by SN2 reaction of a primary or secondary alkyl halide with CN–, the two-step sequence of cyanide displacement followed by nitrile hydrolysis is a good way to make a carboxylic acid from an alkyl halide ($\text{RBr}\to \text{RC≡N}\to {\text{RCO}}_{2}\text{H}$). Note that the product acid has one more carbon than the starting alkyl halide. One example occurs in a commercial route for the synthesis of the nonsteroidal anti-inflammatory drug ibuprofen. (See Chapter 15 *Chemistry Matters*.)

Carboxylation of Grignard Reagents

Another method for preparing carboxylic acids is by reaction of a Grignard reagent with CO2 to yield a metal carboxylate, followed by protonation to give a carboxylic acid. This carboxylation reaction is usually carried out by bubbling a stream of dry CO2 gas through a solution of the Grignard reagent. The organomagnesium halide adds to a $\text{C═O}$ bond of carbon dioxide in a typical nucleophilic carbonyl addition reaction, and protonation of the carboxylate by addition of aqueous HCl in a separate step then gives the free carboxylic acid. For example:

Reactions of Carboxylic Acids: An Overview

Chemistry of Nitriles

Preparation of Nitriles

The simplest method of nitrile preparation is the SN2 reaction of CN– with a primary or secondary alkyl halide, as discussed in [link]. Another method for preparing nitriles is by dehydration of a primary amide, RCONH2. Thionyl chloride is often used for this reaction, although other dehydrating agents such as POCl3 also work.

Reactions of Nitriles

Like a carbonyl group, a nitrile group is strongly polarized and has an electrophilic carbon atom. Nitriles therefore react with nucleophiles to yield *sp*2-hybridized imine anions in a reaction analogous to the formation of a *sp*3-hybridized alkoxide ion by nucleophilic addition to a carbonyl group.

Spectroscopy of Carboxylic Acids and Nitriles

Infrared Spectroscopy

Carboxylic acids have two characteristic IR absorptions that make the –CO2H group easily identifiable. The O–H bond of the carboxyl group gives rise to a very broad absorption over the range 2500 to 3300 cm–1. The $\text{C═O}$ bond shows an absorption between 1710 and 1760 cm–1. The exact position of $\text{C═O}$ absorption depends both on the structure of the molecule and on whether the acid is free (monomeric) or hydrogen-bonded (dimeric). Free carboxyl groups absorb at 1760 cm–1, but the more commonly encountered dimeric carboxyl groups absorb in a broad band centered around 1710 cm–1. As with other carbonyl-containing functional groups, conjugation with an alkene or benzene ring lowers the frequency of the $\text{C═O}$ stretch by 20 to 30 cm–1.

Nuclear Magnetic Resonance Spectroscopy

Carboxyl carbon atoms absorb in the range 165 to 185 *δ* in the 13C NMR spectrum, with aromatic and *α*,*β*-unsaturated acids near the upfield end of the range (∼165 *δ*) and saturated aliphatic acids near the downfield end (∼185 *δ*). Nitrile carbons absorb in the range 115 to 130 *δ*.

Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Reactions

Why This Chapter?

Naming Carboxylic Acid Derivatives

Acid Halides, RCOX

Acid halides are named by identifying first the acyl group and then the halide. As described in [link] and shown in [link], the acyl group name is derived from the carboxylic acid name by replacing the -*ic acid* or -*oic acid* ending with -*oyl,* or the -*carboxylic acid* ending with -*carbonyl.* To keep things interesting, however, IUPAC recognizes eight exceptions for which a -*yl* rather than an -*oyl* ending is used: formic (formyl), acetic (acetyl), propionic (propionyl), butyric (butyryl), oxalic (oxalyl), malonic (malonyl), succinic (succinyl), and glutaric (glutaryl).

Acid Anhydrides, RCO2COR*′*

Symmetrical anhydrides of unsubstituted monocarboxylic acids and cyclic anhydrides of dicarboxylic acids are named by replacing the word *acid* with *anhydride.*

Esters, RCO2R*′*

Esters are named by first identifying the alkyl group attached to oxygen and then the carboxylic acid, with the -*ic acid* ending replaced by -*ate.*

Amides, RCONH2

Amides with an unsubstituted –NH2 group are named by replacing the -*oic acid* or -*ic acid* ending with -*amide,* or by replacing the -*carboxylic acid* ending with -*carboxamide.*

Thioesters, RCOSR*′*

Thioesters are named like the corresponding esters. If the related ester has a common name, the prefix *thio*- is added to the name of the carboxylate: acetate becomes thioacetate, for instance. If the related ester has a systematic name, the -*oate* or -*carboxylate* ending is replaced by -*thioate* or -*carbothioate:* butanoate becomes butanethioate and cyclohexanecarboxylate becomes cyclohexanecarbothioate, for instance.

Acyl Phosphates, RCO2PO32– and RCO2PO3R*′*–

Acyl phosphates are named by citing the acyl group and adding the word *phosphate.* If an alkyl group is attached to one of the phosphate oxygens, it is identified after the name of the acyl group. In biological chemistry, acyl adenosyl phosphates are particularly common.

Nucleophilic Acyl Substitution Reactions

Relative Reactivity of Carboxylic Acid Derivatives

Both the initial addition step and the subsequent elimination step can affect the overall rate of a nucleophilic acyl substitution reaction, but the addition is usually the rate-limiting step. Thus, any factor that makes the carbonyl group more reactive toward nucleophiles favors the substitution process.

Reactions of Carboxylic Acids

Conversion of Carboxylic Acids into Acid Chlorides

In the laboratory, carboxylic acids are converted into acid chlorides by treatment with thionyl chloride, SOCl2.

Conversion of Carboxylic Acids into Acid Anhydrides

Acid anhydrides can be derived from two molecules of carboxylic acid by heating to remove 1 equivalent of water. Because of the high temperatures needed, however, only acetic anhydride is commonly prepared this way.

Conversion of Carboxylic Acids into Esters

Perhaps the most useful reaction of carboxylic acids is their conversion into esters. There are many methods for accomplishing this, including the SN2 reaction of a carboxylate anion with a primary alkyl halide that we saw in [link].

Conversion of Carboxylic Acids into Amides

Amides are difficult to prepare by direct reaction of carboxylic acids with amines because amines are bases that convert acidic carboxyl groups into their unreactive carboxylate anions. Thus, the –OH must be replaced by a better, nonacidic leaving group to carry out a nucleophilic acyl substitution. In practice, amides are often prepared by activating the carboxylic acid with a carbodiimide ($\text{R–N═C═N–R}$), followed by addition of the amine. Dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropylcarbodiimide (EDEC) are commonly used.

Conversion of Carboxylic Acids into Alcohols

We said in [link] that carboxylic acids are reduced by LiAlH4 to give primary alcohols, but we deferred a discussion of the reaction mechanism at that time. In fact, the reduction is a nucleophilic acyl substitution reaction in which –H replaces –OH to give an aldehyde that is further reduced by nucleophilic addition to produce a primary alcohol. The aldehyde intermediate is much more reactive than the starting acid, so it reacts instantly and is not isolated.

Biological Conversions of Carboxylic Acids

The direct conversion of a carboxylic acid to an acyl derivative by nucleophilic acyl substitution does not occur in biological chemistry. As in the laboratory, the acid must first be activated by converting the –OH into a better leaving group. This activation is often accomplished in living organisms by reaction of the acid with adenosine triphosphate (ATP) to give an acyl adenosyl phosphate, or *acyl adenylate,* a mixed anhydride combining a carboxylic acid and adenosine monophosphate (AMP, also known as adenylic acid). In the biosynthesis of fats, for example, a long-chain carboxylic acid reacts with ATP to give an acyl adenylate, followed by subsequent nucleophilic acyl substitution of a thiol group in coenzyme A to give the corresponding acyl CoA ([link]).

Chemistry of Acid Halides

Preparation of Acid Halides

Acid chlorides are prepared from carboxylic acids by reaction with thionyl chloride (SOCl2), as we saw in the previous section. Similar reaction of a carboxylic acid with phosphorus tribromide (PBr3) yields the acid bromide.

Reactions of Acid Halides

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by –OH to yield an acid, by –OCOR to yield an anhydride, by –OR to yield an ester, by –NH2 to yield an amide, or by R′ to yield a ketone. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we’ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides.

Chemistry of Acid Anhydrides

Preparation of Acid Anhydrides

Acid anhydrides are typically prepared by nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion, as we saw in the previous section. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way.

Reactions of Acid Anhydrides

The chemistry of acid anhydrides is similar to that of acid chlorides, although anhydrides react more slowly. Thus, acid anhydrides react with water to form acids, with alcohols to form esters, with amines to form amides, and with LiAlH4 to form primary alcohols. Only the ester- and amide-forming reactions are commonly used, however.

Chemistry of Esters

Preparation of Esters

Esters are usually prepared from carboxylic acids by the methods already discussed. Thus, carboxylic acids are converted directly into esters by SN2 reaction of a carboxylate ion with a primary alkyl halide or by Fischer esterification of a carboxylic acid with an alcohol in the presence of a mineral acid catalyst. In addition, acid chlorides are converted into esters by treatment with an alcohol in the presence of base ([link]).

Reactions of Esters

Esters undergo the same kinds of reactions that we’ve seen for other carboxylic acid derivatives, but they are less reactive toward nucleophiles than either acid chlorides or anhydrides. All their reactions are applicable to both acyclic and cyclic esters, called lactones.

Chemistry of Amides

Preparation of Amides

Amides are usually prepared by reaction of an amine with an acid chloride ([link]). Ammonia, monosubstituted amines, and disubstituted amines all undergo the reaction.

Reactions of Amides

Chemistry of Thioesters and Acyl Phosphates: Biological Carboxylic Acid Derivatives

Polyamides and Polyesters: Step-Growth Polymers

Polyamides (Nylons)

The best known step-growth polymers are the polyamides, or *nylons,* first prepared in 1930 by Wallace Carothers at the DuPont Company by heating a diamine with a diacid. For instance, nylon 66 is prepared by reaction of adipic acid (hexanedioic acid) with hexamethylenediamine (1,6-hexanediamine) at 280 °C. The designation “66” indicates the number of carbon atoms in the diamine (the first 6) and the diacid (the second 6).

Polyesters

The most generally useful polyester is made by reaction between dimethyl terephthalate (dimethyl 1,4-benzenedicarboxylate) and ethylene glycol (1,2-ethanediol). The product is used under the trade name Dacron to make clothing fiber or tire cord and under the name Mylar to make recording tape. The tensile strength of poly(ethylene terephthalate) film is nearly equal to that of steel.

Sutures and Biodegradable Polymers

Because plastics are too often thrown away rather than recycled, much work has been carried out on developing biodegradable polymers, which can be broken down rapidly in landfills by soil microorganisms. Among the most common biodegradable polymers are poly(glycolic acid) (PGA), poly(lactic acid) (PLA), and poly(hydroxybutyrate) (PHB). All are polyesters and are therefore susceptible to hydrolysis of their ester links. Copolymers of PGA with PLA have found a particularly wide range of uses. A 90/10 copolymer of poly(glycolic acid) with poly(lactic acid) is used to make absorbable sutures, for instance. The sutures are entirely hydrolyzed and absorbed by the body within 90 days after surgery.

Spectroscopy of Carboxylic Acid Derivatives

Infrared Spectroscopy

All carbonyl-containing compounds have intense IR absorptions in the range 1650 to 1850 cm–1. As shown in [link] the exact position of the absorption provides information about the specific kind of carbonyl group. For comparison, the IR absorptions of aldehydes, ketones, and carboxylic acids are included in the table, along with values for carboxylic acid derivatives.

Nuclear Magnetic Resonance Spectroscopy

Hydrogens on the carbon next to a carbonyl group are slightly deshielded and absorb near 2 *δ* in the 1H NMR spectrum, although the exact identity of the carbonyl group can’t be determined. [link] shows the 1H NMR spectrum of ethyl acetate.

Carbonyl Alpha-Substitution Reactions

Why This Chapter?

Keto–Enol Tautomerism

Reactivity of Enols: α-Substitution Reactions

Alpha Halogenation of Aldehydes and Ketones

Alpha Bromination of Carboxylic Acids

Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation

Reactivity of Enolate Ions

Alkylation of Enolate Ions

The Malonic Ester Synthesis

One of the oldest and best known carbonyl alkylation reactions is the malonic ester synthesis, a method for preparing a carboxylic acid from an alkyl halide while lengthening the carbon chain by two atoms.

The Acetoacetic Ester Synthesis

Just as the malonic ester synthesis converts an alkyl halide into a carboxylic acid, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone having three more carbons.

Direct Alkylation of Ketones, Esters, and Nitriles

Both the malonic ester synthesis and the acetoacetic ester synthesis are easy to carry out because they involve relatively acidic dicarbonyl compounds. As a result, sodium ethoxide in ethanol can be used to prepare the necessary enolate ions. Alternatively, however, it’s also possible in many cases to directly alkylate the *α* position of *mono*carbonyl compounds. A strong, sterically hindered base such as LDA is needed so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used.

Biological Alkylations

Alkylations are rare but not unknown in biological chemistry. One example occurs during biosynthesis of the antibiotic indolmycin from indolylpyruvate when a base abstracts an acidic hydrogen from an *α* position and the resultant enolate ion carries out an SN2 alkylation reaction on the methyl group of *S*-adenosylmethionine (SAM; [link]). Although it’s convenient to speak of “enolate ion” intermediates in biological pathways, it’s unlikely that they exist for long in an aqueous cellular environment. Rather, proton removal and alkylation probably occur at essentially the same time ([link]).

Carbonyl Condensation Reactions

Why This Chapter?

Carbonyl Condensations: The Aldol Reaction

Carbonyl Condensations versus Alpha Substitutions

Dehydration of Aldol Products: Synthesis of Enones

Using Aldol Reactions in Synthesis

Mixed Aldol Reactions

Intramolecular Aldol Reactions

The Claisen Condensation Reaction

Mixed Claisen Condensations

Intramolecular Claisen Condensations: The Dieckmann Cyclization

Conjugate Carbonyl Additions: The Michael Reaction

Carbonyl Condensations with Enamines: The Stork Enamine Reaction

The Robinson Annulation Reaction

Some Biological Carbonyl Condensation Reactions

Biological Aldol Reactions

Aldol reactions occur in many biological pathways but are particularly common in carbohydrate metabolism, where enzymes called *aldolases* catalyze the addition of a ketone enolate ion to an aldehyde. Aldolases occur in all organisms and are of two types. Type I aldolases occur primarily in animals and higher plants; type II aldolases occur primarily in fungi and bacteria. Both types catalyze the same kind of reaction, but type I aldolases operate through an enamine while type II aldolases require a metal ion (usually Zn2+) as a Lewis acid and operate through an enolate ion.

Biological Claisen Condensations

Claisen condensations, like aldol reactions, also occur in a large number of biological pathways. In fatty-acid biosynthesis, for instance, an enolate ion generated by decarboxylation ([link]) of malonyl ACP adds to the carbonyl group of another acyl group bonded through a thioester linkage to a synthase enzyme. The tetrahedral intermediate that results then expels the synthase, giving acetoacetyl ACP. (The abbreviation ACP stands for acyl carrier protein, which forms thioester bonds to acyl groups.)

Amines and Heterocycles

Why This Chapter?

Naming Amines

Structure and Properties of Amines

Basicity of Amines

Basicity of Arylamines

Biological Amines and the Henderson–Hasselbalch Equation

Synthesis of Amines

Reduction of Nitriles, Amides, and Nitro Compounds

We’ve already seen in [link] and [link] how amines can be prepared by reduction of nitriles and amides with LiAlH4. The two-step sequence of SN2 displacement with CN– followed by reduction thus converts an alkyl halide into a primary alkylamine having an additional carbon atom. Amide reduction converts carboxylic acids and their derivatives into amines with the same number of carbon atoms.

SN2 Reactions of Alkyl Halides

Ammonia and other amines are good nucleophiles in SN2 reactions. As a result, the simplest method of alkylamine synthesis is by SN2 alkylation of ammonia or an alkylamine with an alkyl halide. If ammonia is used, a primary amine results; if a primary amine is used, a secondary amine results; and so on. Even tertiary amines react rapidly with alkyl halides to yield quaternary ammonium salts, R4N+ X–.

Reductive Amination of Aldehydes and Ketones

Amines can be synthesized in a single step by treatment of an aldehyde or ketone with ammonia or an amine in the presence of a reducing agent, a process called reductive amination. For example, amphetamine, a central nervous system stimulant, is prepared commercially by reductive amination of phenyl-2-propanone with ammonia using hydrogen gas over a nickel catalyst as the reducing agent. In the laboratory, either NaBH4 or the related NaBH(OAc)3 is commonly used (OAc = acetate).

Hofmann and Curtius Rearrangements

Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and the Curtius rearrangement. Although the Hofmann rearrangement involves a primary amide and the Curtius rearrangement involves an acyl azide, both proceed through similar mechanisms.

Reactions of Amines

Alkylation and Acylation

We’ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide ([link] and [link]). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine.

Hofmann Elimination Reaction

Like alcohols, amines can be converted into alkenes by an elimination reaction. But because an amide ion, NH2–, is such a poor leaving group, it must first be converted into a better leaving group. In the Hofmann elimination reaction, an amine is completely methylated by reaction with an excess amount of iodomethane to produce the corresponding quaternary ammonium salt. This salt then undergoes elimination to give an alkene on heating with a base, typically silver oxide, Ag2O. For example, 1-methylpentylamine is converted into 1-hexene.

Reactions of Arylamines

Electrophilic Aromatic Substitutions

An amino group is strongly activating and ortho- and para-directing in electrophilic aromatic substitution reactions ([link]). This high reactivity of amino-substituted benzenes can be a drawback at times because it’s often difficult to prevent polysubstitution. Reaction of aniline with Br2, for instance, takes place rapidly and yields the 2,4,6-tribrominated product. The amino group is so strongly activating that it’s not possible to stop at the monobromo stage.

Diazonium Salts: The Sandmeyer Reaction

Primary arylamines react with nitrous acid, HNO2, to yield stable *arenediazonium salts*, $\text{Ar–}\stackrel{+}{\text{N}}\text{≡N}{\rule{0.2em}{0ex}}{\text{X}}^{-}$, a process called a *diazotization* reaction. Alkylamines also react with nitrous acid, but the corresponding alkanediazonium products are so reactive they can’t be isolated. Instead, they lose nitrogen instantly to yield carbocations. The analogous loss of N2 from an arenediazonium ion to yield an aryl cation is disfavored by the instability of the cation.

Diazonium Coupling Reactions

Arenediazonium salts undergo a coupling reaction with activated aromatic rings such as phenols and arylamines to yield brightly colored azo compounds, $\mathbf{\text{Ar–N=N–A}}{\mathbf{\text{r}}}^{\mathbf{\prime }}$.

Heterocyclic Amines

Pyrrole and Imidazole

Pyrrole, the simplest five-membered unsaturated heterocyclic amine, is obtained commercially by treatment of furan with ammonia over an alumina catalyst at 400 °C. Furan, the oxygen-containing analog of pyrrole, is obtained by acid-catalyzed dehydration of the five-carbon sugars found in oat hulls and corncobs.

Pyridine and Pyrimidine

Pyridine is the nitrogen-containing heterocyclic analog of benzene. Like benzene, pyridine is a flat, aromatic molecule, with bond angles of 120° and C–C bond lengths of 139 pm, intermediate between typical single and double bonds. The five carbon atoms and the *sp*2-hybridized nitrogen atom each contribute one *π* electron to the aromatic sextet, and the lone-pair electrons occupy an *sp*2 orbital in the plane of the ring ([link]).

Polycyclic Heterocycles

As we saw in [link], quinoline, isoquinoline, indole, and purine are common polycyclic heterocycles. The first three contain both a benzene ring and a heterocyclic aromatic ring, while purine contains two heterocyclic rings joined together. All four ring systems occur commonly in nature, and many compounds with these rings have pronounced physiological activity. The quinoline alkaloid quinine, for instance, is widely used as an antimalarial drug; tryptophan is a common amino acid; and the purine adenine is a constituent of nucleic acids.

Spectroscopy of Amines

Infrared Spectroscopy

Primary and secondary amines can be identified by a characteristic N–H stretching absorption in the 3300 to 3500 cm–1 range of the IR spectrum. Alcohols also absorb in this range ([link]), but amine absorption bands are generally sharper and less intense than hydroxyl bands. Primary amines show a pair of bands at about 3350 and 3450 cm–1 from the symmetric and asymmetric stretching modes, and secondary amines show a single band at 3350 cm–1. Tertiary amines have no absorption in this region because they have no N–H bonds. [link] recalls the IR spectrum of cyclohexylamine from [link].

Nuclear Magnetic Resonance Spectroscopy

Amines are difficult to identify solely by 1H NMR spectroscopy because N–H hydrogens tend to appear as broad signals without clear-cut coupling to neighboring C–H hydrogens. As with O–H absorptions ([link]), amine N–H absorptions can appear over a wide range and are best identified by adding a small amount of D2O to the sample. Exchange of N–D for N–H occurs, and the N–H signal disappears from the NMR spectrum.

Mass Spectrometry

The *nitrogen rule* of mass spectrometry says that a compound with an odd number of nitrogen atoms has an odd-numbered molecular weight. Thus, the presence of nitrogen in a molecule is detected simply by observing its mass spectrum. An odd-numbered molecular ion usually means that the unknown compound has one or three nitrogen atoms, and an even-numbered molecular ion usually means that a compound has either zero or two nitrogen atoms. The logic behind the rule derives from the fact that nitrogen is trivalent, thus requiring an odd number of hydrogen atoms. For example, morphine has the formula C17H19NO3 and a molecular weight of 285 amu.

Biomolecules: Carbohydrates

Why This Chapter?

Classification of Carbohydrates

Representing Carbohydrate Stereochemistry: Fischer Projections

D,L Sugars

Configurations of the Aldoses

Cyclic Structures of Monosaccharides: Anomers

Reactions of Monosaccharides

Ester and Ether Formation

Monosaccharides behave as simple alcohols in much of their chemistry. For example, carbohydrate –OH groups can be converted into esters and ethers, which are often easier to work with than the free sugars. Because of their many hydroxyl groups, monosaccharides are usually soluble in water but insoluble in organic solvents such as ether. They are also difficult to purify and have a tendency to form syrups rather than crystals when water is removed. Ester and ether derivatives, however, are soluble in organic solvents and are easily purified and crystallized.

Glycoside Formation

We saw in [link] that treatment of a hemiacetal with an alcohol and an acid catalyst yields an acetal.

Biological Ester Formation: Phosphorylation

In living organisms, carbohydrates occur not only in the free form but also linked through their anomeric center to other molecules such as lipids (glycolipids) or proteins (glycoproteins). Collectively called *glycoconjugates,* these sugar-linked molecules are components of cell walls that are crucial to the mechanism by which different cell types recognize one another.

Reduction of Monosaccharides

Treatment of an aldose or ketose with NaBH4 reduces it to a polyalcohol called an alditol. The reduction occurs by reaction of the open-chain form present in the aldehyde/ketone $⇄$ hemiacetal equilibrium. Although only a small amount of the open-chain form is present at any given time, that small amount is reduced, more is produced by opening of the pyranose form, that additional amount is reduced, and so on, until the entire sample has undergone reaction.

Oxidation of Monosaccharides

Like other aldehydes, aldoses are easily oxidized to yield the corresponding carboxylic acids, called aldonic acids. A buffered solution of aqueous Br2 is often used for this purpose.

Chain Lengthening: The Kiliani–Fischer Synthesis

Much early activity in carbohydrate chemistry was devoted to unraveling the stereochemical relationships among monosaccharides. One of the most important methods used was the *Kiliani–Fischer synthesis*, which results in the lengthening of an aldose chain by one carbon atom. The C1 aldehyde group of the starting sugar becomes C2 of the chain-lengthened sugar, and a new C1 carbon is added. For example, an aldopentose is converted by Kiliani–Fischer synthesis into two aldohexoses.

Chain Shortening: The Wohl Degradation

Just as the Kiliani–Fischer synthesis lengthens an aldose chain by one carbon, the *Wohl degradation* shortens an aldose chain by one carbon. Wohl degradation is almost the exact opposite of the Kiliani–Fischer sequence. That is, the aldose aldehyde carbonyl group is first converted into a nitrile, and the resulting cyanohydrin loses HCN under basic conditions—the reverse of a nucleophilic addition reaction.

The Eight Essential Monosaccharides

Disaccharides

Maltose and Cellobiose

Disaccharides contain a glycosidic acetal bond between the anomeric carbon of one sugar and an –OH group at any position on the other sugar. A glycosidic bond between C1 of the first sugar and the –OH at C4 of the second sugar is particularly common. Such a bond is called a 1→4 link.

Lactose

Lactose is a disaccharide that occurs naturally in both human and cow’s milk. It is widely used in baking and in commercial milk formulas for infants. Like maltose and cellobiose, lactose is a reducing sugar. It exhibits mutarotation and is a 1→4-*β*-linked glycoside. Unlike maltose and cellobiose, however, lactose contains two different monosaccharides—D-glucose and D-galactose—joined by a *β*-glycosidic bond between C1 of galactose and C4 of glucose.

Sucrose

Sucrose, or ordinary table sugar, is probably the most abundant pure organic chemical in the world. Whether from sugar cane (20% sucrose by weight) or sugar beets (15% by weight), and whether raw or refined, all table sugar is sucrose.

Polysaccharides and Their Synthesis

Cellulose

Cellulose consists of several thousand D-glucose units linked by 1→4-*β*-glycoside bonds like those in cellobiose. Different cellulose molecules then interact to form a large aggregate structure held together by hydrogen bonds.

Starch and Glycogen

Potatoes, corn, and cereal grains contain large amounts of *starch,* a polymer of glucose in which the monosaccharide units are linked by 1→4-*α*-glycoside bonds like those in maltose. Starch can be separated into two fractions: amylose and amylopectin. Amylose accounts for about 20% by weight of starch and consists of several hundred glucose molecules linked together by 1→4-*α*-glycoside bonds.

Polysaccharide Synthesis

With numerous –OH groups of similar reactivity, polysaccharides are so structurally complex that their laboratory synthesis has long been a particularly difficult problem. Several methods have recently been devised, however, that have greatly simplified the problem. Among these approaches is the *glycal assembly method*.

Some Other Important Carbohydrates

Biomolecules: Amino Acids, Peptides, and Proteins

Why This Chapter?

Structures of Amino Acids

Amino Acids and the Henderson–Hasselbalch Equation: Isoelectric Points

Synthesis of Amino Acids

The Amidomalonate Synthesis

A more general method for preparation of *α*-amino acids is the *amidomalonate synthesis,* a straightforward extension of the malonic ester synthesis ([link]). The reaction begins with the conversion of diethyl acetamidomalonate into an enolate ion by treatment with base, followed by SN2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to yield an *α*-amino acid. For example, aspartic acid can be prepared from ethyl bromoacetate, BrCH2CO2Et:

Reductive Amination of *α*-Keto Acids

Yet another method for the synthesis of *α*-amino acids is by reductive amination of an *α*-keto acid with ammonia and a reducing agent. Alanine, for instance, is prepared by treatment of pyruvic acid with ammonia in the presence of NaBH4. As described in [link], the reaction proceeds through formation of an intermediate imine which is then reduced.

Enantioselective Synthesis

The synthesis of an *α*-amino acid from an achiral precursor by any of the methods just described yields a racemic mixture, with equal amounts of *S* and *R* enantiomers. To use an amino acid in the laboratory synthesis of a naturally occurring protein, however, the pure *S* enantiomer must be obtained.

Peptides and Proteins

Amino Acid Analysis of Peptides

Peptide Sequencing: The Edman Degradation

Peptide Synthesis

Automated Peptide Synthesis: The Merrifield Solid-Phase Method

Protein Structure

Enzymes and Coenzymes

How Do Enzymes Work? Citrate Synthase

Biomolecules: Lipids

Why This Chapter?

Waxes, Fats, and Oils

Soap

Phospholipids

Prostaglandins and Other Eicosanoids

Terpenoids

The Mevalonate Pathway to Isopentenyl Diphosphate

As shown in [link], the mevalonate pathway begins with the conversion of acetate to acetyl CoA, followed by Claisen condensation to yield acetoacetyl CoA. A second carbonyl condensation reaction with a third molecule of acetyl CoA, this one an aldol-like process, then yields the six-carbon compound 3-hydroxy-3-methylglutaryl CoA, which is reduced to give mevalonate. Phosphorylation, followed by loss of CO2 and phosphate ion, completes the process.

Conversion of Isopentenyl Diphosphate to Terpenoids

The conversion of isopentenyl diphosphate (IPP) to terpenoids begins with its isomerization to dimethylallyl diphosphate, abbreviated DMAPP and formerly called dimethylallyl pyrophosphate. These two C5 building blocks then combine to give the C10 unit geranyl diphosphate (GPP). The corresponding alcohol, geraniol, is itself a fragrant terpenoid that occurs in rose oil.

Steroids

Steroid Hormones

In humans, most steroids function as hormones, chemical messengers that are secreted by endocrine glands and carried through the bloodstream to target tissues. There are two main classes of steroid hormones: the *sex hormones,* which control maturation, tissue growth, and reproduction, and the *adrenocortical hormones,* which regulate a variety of metabolic processes.

Sex Hormones

Testosterone and androsterone are the two most important male sex hormones, or androgens. Androgens are responsible for the development of male secondary sex characteristics during puberty and for promoting tissue and muscle growth. Both are synthesized in the testes from cholesterol. Androstenedione is another minor hormone that has received particular attention because of its use by prominent athletes.

Biosynthesis of Steroids

Biomolecules: Nucleic Acids

Why This Chapter?

Nucleotides and Nucleic Acids

Base Pairing in DNA

Replication of DNA

Transcription of DNA

Translation of RNA: Protein Biosynthesis

DNA Sequencing

DNA Synthesis

The Polymerase Chain Reaction

The Organic Chemistry of Metabolic Pathways

Why This Chapter?

An Overview of Metabolism and Biochemical Energy

Catabolism of Triacylglycerols: The Fate of Glycerol

Catabolism of Triacylglycerols: β-Oxidation

Biosynthesis of Fatty Acids

Catabolism of Carbohydrates: Glycolysis

Conversion of Pyruvate to Acetyl CoA

The Citric Acid Cycle

Carbohydrate Biosynthesis: Gluconeogenesis

Catabolism of Proteins: Deamination

Transamination

Deamination is usually accomplished by a transamination reaction in which the  –NH2 group of the amino acid is exchanged with the keto group of *α*-ketoglutarate, forming a new *α*-keto acid plus glutamate. The overall process occurs in two parts, is catalyzed by aminotransferases, and involves participation of the coenzyme pyridoxal phosphate, abbreviated PLP, a derivative of pyridoxine (vitamin B6). The aminotransferases differ in their specificity for amino acids, but the mechanism remains the same.

Regeneration of PLP from PMP

With PLP plus the *α*-amino acid now converted into PMP plus an *α*-keto acid, PMP must be transformed back into PLP to complete the catalytic cycle. The conversion occurs by another transamination reaction, this one between PMP and an *α*-keto acid, usually *α*-ketoglutarate. The products are PLP plus glutamate, and the mechanism is the exact reverse of that shown in [link]. That is, PMP and *α*-ketoglutarate give an imine; the PMP–*α*-ketoglutarate imine undergoes tautomerization of the $\text{C}\text{═}\text{N}$ bond to give a PLP–glutamate imine; and the PLP–glutamate imine reacts with a lysine residue on the enzyme in a transimination process to yield PLP–enzyme imine plus glutamate.

Some Conclusions about Biological Chemistry

Orbitals and Organic Chemistry: Pericyclic Reactions

Why This Chapter?

Molecular Orbitals of Conjugated Pi Systems

Electrocyclic Reactions

Stereochemistry of Thermal Electrocyclic Reactions

Photochemical Electrocyclic Reactions

Cycloaddition Reactions

Stereochemistry of Cycloadditions

Sigmatropic Rearrangements

Some Examples of Sigmatropic Rearrangements

A Summary of Rules for Pericyclic Reactions

Synthetic Polymers

Why This Chapter?

Chain-Growth Polymers

Stereochemistry of Polymerization: Ziegler–Natta Catalysts

Copolymers

Step-Growth Polymers

Polycarbonates

Polycarbonates are like polyesters, but their carbonyl group is linked to two  –OR groups, [$\text{O}\text{═}\text{C}{\left(\text{OR}\right)}_{2}$]. Lexan, for instance, is a polycarbonate prepared from diphenyl carbonate and a diphenol called bisphenol A. Lexan has unusually high impact strength, making it valuable for use in machinery housings, telephones, bicycle safety helmets, and bulletproof glass.

Polyurethanes

A urethane is a carbonyl-containing functional group in which the carbonyl carbon is bonded to both an  –OR group and an  –NR2 group. As such, a urethane is halfway between a carbonate and a urea.

Olefin Metathesis Polymerization

Intramolecular Olefin Metathesis

Polymer Structure and Physical Properties

Nomenclature of Polyfunctional Organic Compounds

Name Part 1. The Suffix: Functional-Group Precedence

Although a polyfunctional organic molecule might contain several different functional groups, we must choose just one suffix for nomenclature purposes. It’s not correct to use two suffixes. Thus, keto ester **1** must be named either as a ketone with an -*one* suffix or as an ester with an -*oate* suffix, but it can’t be named as an -*onoate.* Similarly, amino alcohol **2** must be named either as an alcohol (-*ol*) or as an amine (-*amine*), but it can’t be named as an -*olamine* or -*aminol.*

Name Part 2. The Parent: Selecting the Main Chain or Ring

The parent, or base, name of a polyfunctional organic compound is usually easy to identify. If the principal group of highest priority is part of an open chain, the parent name is that of the longest chain containing the largest number of principal groups. For example, compounds **6** and **7** are isomeric aldehydo amides, which must be named as amides rather than as aldehydes according to [link]. The longest chain in compound **6** has six carbons, and the substance is named 5-methyl-6-oxohexanamide. Compound **7** also has a chain of six carbons, but the longest chain that contains both principal functional groups has only four carbons. Thus, compound **7** is named 4-oxo-3-propylbutanamide.

Name Parts 3 and 4. The Prefixes and Locants

With the parent name and the suffix established, the next step is to identify and give numbers, or *locants,* to all substituents on the parent chain or ring. The substituents include all alkyl groups and all functional groups other than the one cited in the suffix. For example, compound **12** contains three different functional groups (carboxyl, keto, and double bond). Because the carboxyl group is highest in priority and the longest chain containing the functional groups has seven carbons, compound **12** is a heptenoic acid. In addition, the parent chain has a keto (oxo) substituent and three methyl groups. Numbering from the end nearer the highest-priority functional group gives the name (*E*)-2,5,5-trimethyl-4-oxo-2-heptenoic acid. Look back at some of the other compounds we’ve named to see other examples of how prefixes and locants are assigned.

Writing the Name

With the name parts established, the entire name can be written out. Several additional rules apply:

Additional Reading

Further explanations of the rules of organic nomenclature can be found online at ACD Labs (accessed May 2023) and in the following references:

Acidity Constants for Some Organic Compounds

Glossary

Periodic Table