Formation and Stability of the 4-Methoxyphenonium Ion in Aqueous Solution
The reaction of 2-methoxyphenylethyl tosylate (MeO-1-Ts) is first-order in [N3\xe2\x88\x92]. A carbon-13 NMR analysis of the products of the reactions of MeO-1-[\xce\xb1\xe2\x80\x9313C]Ts shows the formation of MeO-1-[\xce\xb2\xe2\x80\x9313C]OH and MeO-1-[\xce\xb2\xe2\x80\x9313C]N3 from the trapping of a symmetrical 4-methoxyphenonium ion reaction intermediate 2+. An analysis of the rate and product data provides a value of kaz/ks = 83 M\xe2\x88\x921 for partitioning of 2+ between addition of azide ion and solvent. These data set a limit for the lifetime of 2+ in aqueous solution.
<!>EXPERIMENTAL<!>Carbon-13 NMR Analyses<!>Kinetic and product studies
<p>The barriers for addition of the solvent water to many simple carbocations are known.1 There is good evidence that secondary alkyl carbocations are too unstable to exist in water for the time of a bond vibration,2,3 and that solvent reorganization with a rate constant kr ≈ 1011 s−1 is the rate rate-limiting step for addition of water to simple tertiary carbocations (ks ≈ 3 × 1012 s−1, Scheme 1).4 Electron-donating α–substituents such as methoxy5 and 4-methoxyphenyl6,7 (Scheme 1) are required to give carbocations with lifetimes long enough to permit diffusion-controlled bimolecular trapping by added nucleophiles. This leaves bridging phenonium ions, which were at one time the subject of intense interest in studies to characterize internal [anchimeric] nucleophilic assistance to solvolysis.8 The chemical community continues to study the generation and reaction of these electrophiles;9,10 however, there has been no work to determine their lifetimes in aqueous solution.</p><p>The first-order rate constant kAcOH for acetolysis of ring substituted 2-phenylethyl tosylates (X-1-Ts) is insensitive to changes in electron-withdrawing substituents –X at the aromatic ring (Hammett substituent constant ρ× ≥ ≥0.19), but electron-donating substituents (ρ+ × < −0.19) cause large increases in kAcOH. For example, acetolysis of MeO-1-Ts at 115 °C is 34- times faster than acetolysis of the parent 2-phenylethyl tosylate H-1-Ts.11 This elegant study shows that acetolysis of MeO-1-Ts proceeds with intramolecular displacement of the tosylate ion leaving group to form the bridging 4-methoxyphenonium ion (2+, Scheme 2). The symmetrical cation 2+ has also been observed by proton NMR in strongly acidic solution.12</p><p>We prepared MeO-1-[α–13C]Ts and determined a value of ksolv = 1.95 × 10−6 s−1 for solvolysis in 50/50 (v/v) TFE/H2O (I = 0.5, NaClO4) at 25 °C. A value of (kNu)obs = 3.6 (± 0.1) × 10−6 M−1s−1 under the same conditions was determined as the slope of a linear plot (not shown) of kobs against [N3−]. Table 1 reports: (1) The yields of the products of reactions of azide ion and solvent with MeO-1-[α–13C]Ts in 50/50 (v/v) TFE/H2O (I = 0.5, NaClO4) and at 25 °C that were determined by HPLC analyses. (2) The relative yields of MeO-1-OH and MeO-1-N3 labeled with carbon-13 in the α–and β positions (Scheme 3), that were determined by carbon-13 NMR analyses. There was only a low yield of the trifluoroethyl ether MeO-1-OTFE (Footnote a, Table 1).</p><p>The total yield of MeO-1-N3 is very much greater than expected if these products were formed exclusively by a bimolecular nucleophilic displacement reaction with (kNu)obs/ksolv = 1.9 M−1. For example only a 2% yield of MeO-1-N3 is predicted for the bimolecular substitution reaction of 0.01 M azide ion, but the observed yield is 47% (Table 1). The additional MeO-1-N3 forms by trapping of 2+ (kaz, Scheme 3). Similar yields of MeO-1-[α–13C]N3 and MeO-1- [β–13C]N3 from trapping of 2+ are observed for the reaction of MeO-1-[α–13C]Ts in the presence of 0.01 M NaN3 (Table 1). The increase in the excess of the α– compared to the β-labeled product for reactions at the higher [N3−] is due to bimolecular substitution of N3− at MeO- 1-[α–13C]Ts. Essentially identical yields of the α– and β-carbon-13 labeled alcohol form as products of solvolysis of MeO-1-[α–13C]Ts ([N3−] = 0 M); but, an excess of the α–carbon-13 alcohol is observed for reactions at high [N3−]. This is consistent with azide ion catalysis of addition of water (kB, Scheme 3) to either the sulfonyl group or to the [α–13C]-carbon of MeO-1-[α–13C]Ts.</p><p>Figure 1 shows the effect of increasing [N3−] on the azide ion selectivity (kaz/ks)obs (eq 1) for the reaction of MeO-1-[α–13C]Ts, where fRN3 and fROSolv are the fractional yields of MeO-1- N3, and (MeO-1-OH + MeO-1-OTFE), respectively (Table 1). A linear increase in (kaz/ks)obs (M−1) with increasing [N3−] was observed in an earlier study of the reactions of 4-methoxybenzyl derivatives, which proceed by competing azide ion bimolecular substitution and trapping of the 4-methoxybenzyl carbocation intermediate.6 By comparison, the downward break in the correlation shown in Figure 1 is consistent with the formation of additional MeO-1-[α–13C]OSolv from azide anion catalysis of the direct addition of water to substrate [kB, (M−1 s−1), Scheme 3]. The solid line shows the theoretical fit of data from Figure 1 to eq 2 derived for Scheme 3 [the derivation is given as Supporting Information], using [(kNu + kB)/ksolv] = (3.64 × 10−6 M−1 s−1)/(1.95 × 10−6 s−1) = 1.9 M−1 determined above; and, values of kaz/ks = 83 M−1 and kB/kNu = 0.016 for the variable parameters obtained from the nonlinear least squares fit of these data. There is good agreement between the total observed yields of MeO-1-N3 (fRN3)T, and the theoretical yields calculated from eq 3 using the above three rate constant ratios (Table 3).</p><p>
</p><p>The azide ion selectivity of kaz/ks = 83 M−1 requires that the lifetime of 2+ in water is sufficiently long to allow for its diffusion through the nucleophilic solvent, and selection for reaction with strongly nucleophilic azide anion.13,14 The upper limit for kaz is kd ≈ 5 × 109 M−1 s−1 for a diffusion-controlled reaction of 2+.15 Combining this and kaz/ks = 83 M−1 gives an upper limit of ks ≤ 6 × 107 s−1 for addition of solvent. We expect that ks for addition of solvent to 2+ is smaller than 2 × 108 s−1 observed for the 4-methoxybenzyl carbocation, because ks = 3.4 × 10−3 s−1 for addition of solvent to the neutral spiro[2,5]-octa-1,4-diene-3-one16 is 1000-fold smaller than ks = 3.3 s−1 for addition of solvent to the unsubsituted p-quinone methide 4,17 while O-methylation of 4 causes a 108-fold increase in electrophile reactivity.18 We suggest that the rate constants for addition of nucleophiles to 2+ lie closer to ks = 105 s−1 and kaz = 107 M−1 s−1 for the addition of azide ion and solvent, that are estimated from kaz/ks = 83 M−1, and assuming that O-methylation causes similar ≈108-fold increases in ks for addition of solvent to 3 and 4.</p><p>The value of log(kaz/ks) = 1.9 for the reaction of 2+ is smaller than the Swain-Scott nucleophilicity parameter of n = 3.9 determined for the reaction of azide anion with methyl bromide.19 This decrease in selectivity for nucleophile addition to the more reactive electrophile might reflect the different diffusion-limited (kd = kaz = 5 × 109 M−1 s−1) and activation-limited rate constants for addition of azide ion and solvent to 2+, if ks = 6 × 107 s−1 for addition of solvent to 2+. However, we suggest that this decrease in selectivity with increasing electrophile reactivity is due to a change in the structure of the transition state for nucleophile addition, that results in a weakening in the bonding to the reacting nucleophile.20 A similar shift in transition state structure has been proposed to rationalize the smaller selectivity of methyl perchlorate compared to methyl iodide towards reaction with nucleophilic anions.19</p><!><p>Potassium [13C]-cyanide (99% enriched) was purchased from ISOTEC. All other organic and inorganic chemicals were reagent grade from commercial sources and were used without further purification. 2-(4-Methoxyphenyl)-[1-13C]ethanol [MeO-1-[α–13C]OH] was synthesized by a published procedures.21</p><!><p>Proton-decoupled 13C-NMR spectra were recorded at 100.4 MHz. Chemical shifts were measured in ppm, relative to a value of δ = 77.0 ppm for CDCl3. A pulse angle of 45° was employed to obtain spectra centered at 55.0 ppm, which spanned 7042.25 Hz and contained 65,000 k data points (0.107 Hz/pt). Several delay times between FT pulses, ranging from 8 to 70 s, were examined. Identical ratios of the peak areas for carbon-1 and carbon-2 of 2-(4-methoxyphenyl)ethyl derivatives were observed 35 and 70 s delay times; and, the longer relaxation time of 70 s was used for these spectra. Generally > 1,000 FT transients were averaged before determining the final spectra.</p><!><p>The progress of the reactions of MeO-1-[α–13C]Ts in 50/50 (v/v) TFE/H2O (I = 0.5, NaClO4) and at 25 °C in the absence or in the presence of N3− was monitored by HPLC analyses as described in earlier work.6,18 The reactions were initiated by making a 100-fold dilution of 2-(4-methoxyphenyl)ethyl tosylate dissolved in acetonitrile into 20 mL of 50/50 (v/v) TFE/H2O (I = 0.5 (NaClO4). The final substrate concentration was 2 mM for reactions in the presence of 0, 0.1, 0.2 and 0.3 M azide anion and 0.3 mM for reactions in the presence of 0.01 and 0.03 M azide anion. At specified times aliquots of 100 μL were applied directly onto an HPLC column for analysis. The reactant and products were separated by gradient elution using a mixed MeOH/H2O solvent.22 The peaks for the substrate and product were monitored at 276 nm, which is λmax for 2-(4-methoxyphenyl)ethyl alcohol and 2-(4- methoxyphenyl)ethyl azide. A value of εROTs/εR-Nu = 1.17 for the ratio of extinction coefficients of MeO-1-Ts and MeO-1-OH at 276 nm was determined by comparing the HPLC peak areas at 276 nm of known concentrations of MeO-1-Ts and MeO-1-OH. The sum of the peak areas from HPLC analyses at 276 nm for MeO-1-OH and MeO-1-N3 remained constant as [N3−] was increased from 0.00 [100% yield of MeO-1-OSolv] to 0.30 M [97% yield of MeO-1-N3]. This shows that these products have the same extinction coefficient at λmax = 276 nm.</p><p>The decrease in the HPLC peak area (AROTs) for the reactant MeO-1-Ts was monitored for ca 2-reaction halftimes; and, first-order reaction rate constants were determined as the slopes of semi-logarithmic plots of reaction progress fS (eq 1) against time, where ΣARNu is the sum of the peak areas for the products MeO-1-OH (AROH) MeO-1-OCH2CF3 (AROTFE) and MeO-1-N3 (ARN3). The ratio of the yields of the products of the reactions of MeO-1-Ts in 50/50 (v/v) TFE/H2O at I = 0.5 (NaClO4) was determined directly from the ratio of the HPLC peak areas for the products using eq 5, because MeO-1-OSolv and MeO-1-N3 have the same extinction coefficient at λmax = 276 nm (see above).</p><p>At ca two halftimes for the reaction of MeO-1-[α–13C]Ts the remaining substrate and the products were extracted into either ether or toluene. The organic layer was washed with water, dried over MgSO4 and then removed using a rotary evaporator. The resulting sample was dissolved in 0.6 mL of CDCl3 for 13C-NMR analysis. The relative yields of products labeled with carbon-13 in the α– and β–position were determined by integration of the following product peaks: MeO-1-[α–13C]OH at 63.83 ppm; MeO-1-[β–13C]OH at 38.24 ppm; MeO-1- [α–13C]OCH2CF3 at 73.87 ppm; MeO-1-[β–13C]OCH2CF3 at 35.23 ppm; MeO-1-[α–13C]N3 at 52.69 ppm; MeO-1-[β–13C]N3 at 34.19 ppm.</p>