Chapter 14 Solvent Effects on Organic Reactions from QM/MM Simulations

A QM/MM approach, where reactants are treated quantum mechanically in the presence of a large number of explicit solvent molecules modeled with molecular mechanics, is better suited to explore solute–solvent interactions. This chapter focuses on determining the origin of solvent effects for three different organic reactions: Menshutkin, nucleophilic aromatic substitution (SNAr), and Kemp decarboxylation. QM/MM/MC simulations have been applied to a series of organic reactions with good success in reproducing the observed substrate and solvent effects on the free energies of activation and reaction. The overall quantitative success supports the utility of the present QM/MM/MC approach using PDDG/PM3 as the QM method. The importance of variations in specific solute–solvent interactions along the reaction paths is evident in the ion pairing in chloroform for the Kemp decarboxylation, in the failure of DFT/PCM calculations to reproduce the rate retardation in the SNAr reaction, and in the rate enhancement computed for the Menshutkin reaction in water over dimethyl sulfoxide (DMSO).