Examination of Michael addition reactivity towards glutathione by transition-state calculations

Abstract

Kinetic rate constants (k(GSH)) for the reaction of compounds acting as Michael acceptors with glutathione (GSH) were modelled by quantum chemical transition-state calculations at the B3LYP/6-31G** and B3LYP/TZVP level. The data set included α, β-unsaturated aldehydes, ketones and esters, with double bonds and triple bonds, linear and cyclic systems, both with and without substituents in the α-position. Predicted values for k(GSH) were found to be in good agreement with experimental k(GSH) values. Factors affecting rate constants have been elucidated, especially solvent effects and the influence of steric hindrance. Solvent effects were examined by adding explicit solvent molecules to the system and by using a polarizable continuum solvent model. Detailed analysis of transition-state energies shows that the reaction is reversible. The reactive enolic intermediate plays an important role in Michael addition to GSH, while the subsequent keto-enol-tautomerism is not rate limiting.