Combined QM/MM and path integral simulations of kinetic isotope effects in the proton transfer reaction between nitroethane and acetate ion in water

An integrated Feynman path integral‐free energy perturbation and umbrella sampling (PI‐FEP/UM) method has been used to investigate the kinetic isotope effects (KIEs) in the proton transfer reaction between nitroethane and acetate ion in water. In the present study, both nuclear and electronic quantum effects are explicitly treated for the reacting system. The nuclear quantum effects are represented by bisection sampling centroid path integral simulations, while the potential energy surface is described by a combined quantum mechanical and molecular mechanical (QM/MM) potential. The accuracy essential for computing KIEs is achieved by a FEP technique that transforms the mass of a light isotope into a heavy one, which is equivalent to the perturbation of the coordinates for the path integral quasiparticle in the bisection sampling scheme. The PI‐FEP/UM method is applied to the proton abstraction of nitroethane by acetate ion in water through molecular dynamics simulations. The rule of the geometric mean and the Swain–Schaad exponents for various isotopic substitutions at the primary and secondary sites have been examined. The computed total deuterium KIEs are in accord with experiments. It is found that the mixed isotopic Swain–Schaad exponents are very close to the semiclassical limits, suggesting that tunneling effects do not significantly affect this property for the reaction between nitroethane and acetate ion in aqueous solution. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008