Transition-state optimization by the free energy gradient method: Application to aqueous-phase Menshutkin reaction between ammonia and methyl chloride

The transition state (TS) for the Menshutkin reaction H3N+CH3Cl→H3NCH3++Cl− in aqueous solution was located on the free energy surface (FES) by the free energy gradient (FEG) method. The solute–solvent system was described by a hybrid quantum mechanical and molecular mechanical (QM/MM) method. The reaction path in water was found to deviate largely from that in the gas phase. It was concluded that, in such a reaction including charge separation, TS structure optimization on an FES is inevitable for obtaining valid information about a TS in solution.