Finding Free-Energy Landmarks of Chemical Reactions.

We propose a novel approach to search for free-energy landmarks, i.e., minima and the saddle points, of chemical reactions in an automated manner using a combination of steepest descent and gentlest ascent methods. A numerical approach is suggested to improve the sampling efficiency of the second derivatives of the free-energy surface, which is required in the gentlest ascent method. This technique opens a way to identify free-energy landmarks of bond-breaking/creating processes in which the underlying potential energy surface is described using on-the-fly electronic structure calculations. As demonstrations of the approach, we present applications to the ring-opening of cis-1,2-dimethylbenzocyclobutene using the semiempirical PM7 method, focusing on the temperature dependence of the paths and barrier of the reaction, and we study an SN2 reaction in aqueous solution using a semiempirical QM/MM approach combining PM7 with the TIP3P water model.