QM/MM kinetic isotope effects for chloromethane hydrolysis in water

Abstract

Computational simulations for chloromethane hydrolysis have been performed using hybrid quantum-mechanical/molecular-mechanical methods with explicit solvation by large numbers of water molecules. In the first part of the paper, we present results for 2° 2H3, 1° 14C, and 1° 37Cl kinetic isotope effects (KIEs) at 298 K with both the AM1/TIP3P and B3LYP/6-31G* QM methods for the nucleophile H2O and electrophile CH3Cl surrounded by 496 solvating TIP3P water molecules. An initial Hessian computed for a subset of this system including up to 104 MM water molecules was reduced in size by successive deletion of rows and columns, and KIEs were evaluated for each. We suggest that accurate calculations of KIEs in solvated systems should involve a subset Hessian including the substrate together with any solvent atoms making specific interactions with any isotopically substituted atom. In the second part of the paper, the ensemble-averaged 2° α-2H3 KIE calculated with the B3LYP/6-31+G(d,p)/TIP3P method is shown to be in good agreement with experiment. This comparison is meaningful because it includes consideration of uncertainties owing to sampling of a range of representative thermally accessible solvent configurations. We also present ensemble-averaged 14C and 37Cl KIEs which have not as yet been determined experimentally. Copyright © 2013 John Wiley & Sons, Ltd.