Hybrid approach for free energy calculations with high-level methods: Application to the SN 2 reaction of CH Cl3 and O H- in water

We present an approach to calculate the free energy profile along a condensed-phase reaction path based on high-level electronic structure methods for the reactive region. The bulk of statistical averaging is shifted toward less expensive descriptions by using a hierarchy of representations that includes molecular mechanics, density functional theory, and coupled cluster theories. As an application of this approach we study the reaction of CH Cl3 with O H- in aqueous solution.