Computational simulation of mechanism and isotope effects on acetal heterolysis as a model for glycoside hydrolysis

Abstract

DFT calculations for the equilibrium isotope effect for deuterium substitution at the anomeric centre Cα in 2-(p-nitrophenoxy)tetrahydropyran with continuum solvation show significant variation in the range of relative permittivity 2 ≤ ϵ ≤ 10. One-dimensional scans of potential energy (with implicit solvation by water) or of free energy (from QM/MM potentials of mean force with explicit aqueous solvation with a hybrid AM1/OPLS method) for heterolysis of the bond between Cα and the nucleofuge do not show a transition state. A two-dimensional free-energy surface that considers also the distance between Cα and a nucleophilic water indicates a pre-association DN∗ANint mechanism with a transition state involving nucleophilic attack upon an ion-pair intermediate, and this is supported by good agreement between the mean values of the calculated and experimental α-D KIEs. However, the magnitudes of the standard deviations about the mean values for the making and breaking C-O bonds suggest that the transition state is rather plastic, with Cα-Onu≈2 ± 0.4 Å and Cα-Olg≈3 ± 0.5 Not only is nucleophilic solvent assistance necessary, but there is also evidence for electrophilic assistance through specific hydrogen bonding to the nucleofuge.