COMPUTER-SIMULATION OF PHENYL ESTER CLEAVAGE BY BETA-CYCLODEXTRIN IN SOLUTION

Molecular dynamics free energy perturbation simulations utilizing the empirical valence bond model are used to study the catalytic action of beta-cyclodextrin in ester hydrolysis. Reaction routes for nucleophil ic attack on m-tert-butylphenyl acetate by the secondary alkoxide ions O2(-) and O3(-) of cyclodextrin giving the R and S stereoisomers of t he ester tetrahedral intermediate are examined. Only the reaction path leading to the S isomer at O2 shows an activation barrier that is low er (by about 3 kcal/mol) than the barrier for the corresponding refere nce reaction in water. The calculated rate acceleration is in excellen t agreement with experimental data. The catalytic action is accompanie d by distortion of the macrocycle structure that enables strong bindin g of the nonpolar part of the substrate along most of the reaction pat h.