A simple method to determine kinetic deuterium isotope effects provides evidence that proton transfer to carbon proceeds over and not through the reaction barrier.

We report a fast, simple and general method to determine primary kinetic isotope effects (KIEs) on proton transfer in hydroxylic solvents, and its application to obtain primary deuterium isotope effects on protonation of ring-substituted α-methoxystyrenes X-1 (Scheme 1) over a broad range of temperature and thermodynamic driving force. These data provide evidence that hydron transfer at X-1 proceeds by passing over a reaction barrier, as opposed to tunneling through the barrier; and, insight into the relationship between the primary kinetic isotope effect and the transition state structure. Scheme 1 Proton transfer at carbon is an apparently simple reaction, whose profound importance in chemistry and biology has led to interest in providing a theoretical description of the reaction coordinate profile.1 Kinetic isotope effects on proton transfer at carbon can be predicted by theory and determined by experiment. Advances in theory and computational power have been incorporated into recent theoretical studies on KIEs,2 but there has been little effort to extend classic experimental studies using modern experimental methods. Studies of this type are needed to provide a reality check for theory. Ratios of second-order rate constants, kH/kD, have been reported for lyonium-ion-catalyzed protonation of a broad series of vinyl ethers in H2O and in D2O.3 This ratio decreases with decreasing vinyl ether reactivity from kH/kD = 4.1 for protonation of ethyl cyclooctenyl ether (kH = 623 M−1 s−1 at 25°) to kH/kD = 2.4 for protonation of phenyl vinyl ether (kH = 0.00328 M−1 s−1). These data may be explained either by a model in which there is increasing zero-point-energy (zpe) of the O-L bond maintained in the transition state for proton transfer as the reaction becomes strongly thermodynamically favorable or unfavorable;4 or, by including a correction for quantum mechanical tunneling through the reaction barrier, that is largest when ΔGo = 0.5 A similar correlation between the KIE and reactivity has been reported for deprotonation of H- and D-labeled carbon acids.5 The correlation between reaction driving force and kH/kD for the effectively irreversible protonation of vinyl ethers to form oxocarbenium ions - the first step in their hydrolysis reactions - is poor.3 This is because of the broad range of the structures of the reacting carbon bases examined. Further, the absolute thermodynamic driving force for vinyl ether protonation is generally not known, nor can the experimental rate constant ratio kH/kD for these reactions in H2O and in D2O be easily partitioned into the contribution of the primary KIE and the secondary solvent deuterium isotope effect.3 We have determined the product isotope effect (PIE) on the specific acid-catalyzed protonation of X-1 in 50/50 (v/v) H2O/D2O (I = 1.0, KCl) at 25 °C by 1H NMR analyses (eq 1),6 where ACH3 and ACH2D are, respectively, the peak areas for the singlet for the −CH3 group at (2.56 − 2.78) ppm and for the 0.012 ppm upfield shifted triplet for the −CH2D group of X-3 (Scheme 1).7a-8 PIEs from competition experiments, where −H and −D labeled products form in a single reaction vessel, are more precise and easier to interpret than KIEs determined for separate reactions in H2O and D2O because: (1) There are no errors from differences in the conditions for reactions in H2O and D2O, such as temperature and [L+]. (2) There is no need to correct for the secondary solvent KIE when the H- and D-labeled products form in the same solvent. PIE=[ACH3]1.5[ACH2D] (1) Values of the PIE for protonation of X-1 by L3O+ (Scheme 1), determined in five reactions at different [L+], are shown in Figure 1A. The variation in the values of the PIE determined for reactions in solutions that contain different [L+] is less than ±2%. The PIEs for the lyonium ion catalyzed reactions were calculated as the average of these 5 determinations and range from PIE = 8.1 for protonation of 4-MeO-1 (●, Figure 1A) to 7.3 for protonation of 3,5-di-NO2-1 (▼). Figure 1B (●) shows a plot of log PIE for protonation of X-1 against the recently reported values of ΔG° for proton transfer from H3O+ to X-1 to form X-2+.9 Figure 1 (A) The PIE for protonation of X-1 (Scheme 1) in acidic solutions of 50/50 (v/v) H2O/D2O: (●), 4-MeO-1; (▼), 3,5-di-NO2-1. (B) The change in the PIE and KIE with changing ΔG° for protonation of X-1 by L3O+: (●), ... The PIEs for protonation of X-1 in 50/50 (v/v) H2O/D2O that contains L3O+ provide a measure of the fractionation of H and D between L2O and the transition state for this proton transfer reaction, while the KIEs for protonation by L3O+ measures the fractionation of H and D between L3O+ and this same transition state.10 Values of the KIE = 5.6 and 5.0 for protonation of 4-MeO-1 and 3,5-di-NO2-1, respectively were calculated as (kH/kD) = 0.69(PIE), where φH = 0.69 corrects for the more favorable fractionation of hydrogen compared to deuterium from L2O to L3O+ that has the effect of enriching L3O+ in hydrogen (Figure 1B, ▼).10 Also shown on Figure 1B are values of the Bronsted coefficients α determined for protonation of X-1 by substituted alkane carboxylic acids.9 PIEs were determined at T = 25 − 86 °C and at T = 5 − 70 °C, respectively, for protonation of 3,5-di-NO2-1 and 4-MeO-1 in 50/50 (v/v) H2O/D2O that contains L3O+.7b Figure 2 shows linear Arrhenius plots of these data. The slopes and intercepts of these correlations give [(Ea)H − (Ea)D] = −1.25 and −1.17 kcal/mol for the difference in the activation barriers for the reaction of the different isotopes, and of (AH/AD) = 1.00 and 0.95 for protonation of 4-MeO-1 and 3,5-di-NO2-1, respectively.11 Figure 2 Arrhenius type plots of PIEs for the reactions of 4-MeO-1 (●) and 3,5-di-NO2-1 (▼) in 50/50 (v/v) H2O/D2O at I = 1.0 (KCl). The results from Figure 1B are consistent with the maximum KIE observed for thermoneutral proton transfer at carbon,4,5 but show that there is not a large change from this maximum as the driving force for proton transfer is changed by ca 9 kcal/mol.9 The values of [(Ea)H − (Ea)D] ≈ −1.2 kcal/mol are consistent with the conclusion that most or all of the zpe of the LO-L bond (ν = 3400 cm−1 for L = H) is lost at the transition state for protonation of X-1 by L3O+. The ratios (AH/AD) = 1.0 for nearly thermoneutral protonation of 4-MeO-1 and for endothermic protonation of 3,5-di-NO2-1 are consistent with a semiclassical model for proton transfer in which there is minimal tunneling of the hydron through the reaction barrier at T = 278 − 359 K.12 One explanation for the isotope effect maximum observed for thermoneutral proton transfer is that there are equal force constants for the partial C-H and O-H bonds at the reaction transition state, so that the proton remains stationary and there are no residual zpe associated with the symmetric transition state stretching mode.4 However, this explanation for the KIE maximum cannot be simply reconciled with the Bronsted coefficients of ca. 0.6 for thermoneutral protonation of X-1.9 These coefficients are consistent with a transition state [X-1]‡ in which there is more than 50% transfer of the proton from the Bronsted acid catalyst to the carbon base X-1, and a stronger partial C-H bond compared with the partial O-H bond. Bronsted coefficients provide a measure of the change in apparent charge at the reacting atoms on proceeding to the transition state, compared with the unit change in charge for the reference equilibrium reaction.13 It is possible that these Bronsted parameters overestimate the extent of formal proton transfer to X-1, which is measured as the apparent change in charge at the reaction center, because of a lag in the “neutralization” of charge by aqueous solvation.14 Theoretical calculations that reproduce Bronsted parameters and KIEs determined by experiment have the potential to provide a more realistic description of the transition state for these proton reactions, and solidify or suggest alternative interpretations of these experimental data.