Secondary Deuterium Isotope Effects for Enolization Reactions

Abstract

Secondary R-and β-deuterium isotope effects for enolization reactions and equilibria have been determined by ab initio calculations, 1 H NMR spectroscopy, and triton exchange kinetics. Kinetic and equilibrium R-deuterium isotope effects for hydroxide ion-catalyzed enolization of acetaldehyde calculated by ab initio methods are normal and depend on the orientation of the secondary hydrogen with respect to the carbonyl group. The computed transition state structure indicates a small degree of bond rehybridization at the transition state. Experimentally measured secondary isotope effects on the deuteroxide ion-catalyzed proton exchange of acetophenone are k H /k D ) 1.08 ( 0.07 for R-CH 3 exchange and k H /k D ) 0.96 ( 0.08 for R-CH 2 D exchange. For R-CH 2 T exchange in water, the corresponding secondary isotope effect is k H /k D ) 1.06 ( 0.02, assuming the rule of the geometric mean is valid. These effects are smaller than the calculated equilibrium isotope effect for formation of the enolate ion-water complex: K H /K D ) 1.11-1.22 at the MP2 level. The normal kinetic isotope effects are smaller than might be expected due to a loss in hyperconjugation of the out-of-plane C-H bond and a lag in structural reorganization that contributes to the intrinsic barrier for proton transfer from carbon. Ionization of protonated acetone gives rise to an inverse secondary isotope effect of 0.97/D for the C-L bond adjacent to the carbonyl group and is consistent with a loss in hyperconjugation upon formation of the neutral ketone.

Computational Study of the Influence of Solvent on 16O/18O Equilibrium Isotope Effects in Phosphate Deprotonation Reactions

“…Limited attempts to account for the influence of the solvent on isotope effects at the microscopic level have been reported previously. 37,38 Inclusion of a single 37,38 or two 38 water molecules was found to improve the calculated H/D EIE on enolization of acetaldehyde 37 and the 16 O/ 18 O KIE on decarboxylation of 4-pyridylacetic acid zwitterion. 38 A comparison of microscopic and macroscopic approaches in the latter study 38 showed that the SM5.42 continuum solvent model 39 gave significantly better energetic results than the two-water cluster representation, while the obtained KIEs were of similar accuracy with the discrete and continuum representations.…”

Path integral evaluation of equilibrium isotope effects

“…II, we describe a rigorous quantum-mechanical methodology to compute the EIE. Section III presents the [1,5] sigmatropic hydrogen shift reactions on which we test the methodology, explains how ab initio methods can be combined with the PI to compute the EIE, and discusses in detail symmetry effects in these reactions. Section IV explains the implementation of the method in Amber 10 and describes details of calculations and error analysis of our PIMD simulations.…”

“…We describe the implementation of the methodology in the molecular dynamics package Amber 10. The method is tested on three [1,5] sigmatropic hydrogen shift reactions. Because of the computational expense, we use ab initio potentials to evaluate the equilibrium isotope effects within the harmonic approximation, and then the path integral method together with semiempirical potentials to evaluate the anharmonicity corrections.…”

Computational investigations of carbonyl reactions: Comparison between nucleophilic addition versus enolate formation in the reaction of acetaldehyde with hydroxide ion

“…The frequency calculations on the stationery points for the enolate-forming reaction were also use to calculate deuterium kinetic isotope effects, the results of which are presented elsewhere. 24 Monte Carlo simulations were performed on an isothermal-isobaric ensemble consisting of the reacting system plus 263 water molecules in a cubic box with dimensions ca 20 x 20 x 20 A3. Periodic boundary conditions were employed.…”