Simulation of slow reaction with quantum character: Neutral hydrolysis of carboxylic ester

By computer simulation, using both quantum and classical dynamics, we deter mined the rate constant and the kinetic isotope effect of the rate-determin ing step in the neutral hydrolysis of p-methoxyphenyl dichloroacetate in aq ueous solution. This step involves a proton transfer concerted with the for mation of a C-O bond. A method of biased sampling was used; the Gibbs free energy of the biased configuration from which proton transfer is likely to occur was determined by a combination of semiempirical quantum calculations and thermodynamic integration. The proton dynamics was modeled with the qu antum-dynamical density matrix evolution method that includes nonadiabatic pathways. The proton dynamics is driven by a fluctuating proton potential t hat was derived from a classical molecular dynamics simulation of the syste m including solvent. The calculated rate constant of 3 x 10(-2) s(-1) agree s within the error of the calculation with the experimentally observed valu e of 2.78 x 10(-3). The calculated pseudo-first-order kinetic isotope effec t of 3.9 is in good agreement with the experimentally observed value of 3.2 . The results show the feasibility of computational approaches to slow reac tions in complex environments, where proton transfer with an essential quan tum-dynamical nature is the rate-limiting step. (C) 1999 John Wiley & Sons, Inc.