Computer-aided molecular design of solvents for accelerated reaction kinetics

Solvents can significantly alter the rates and selectivity of liquid-phase organic reactions, often hindering the development of new synthetic routes or, if chosen wisely, facilitating routes by improving rates and selectivities. To address this challenge, a systematic methodology is proposed that quickly identifies improved reaction solvents by combining quantum mechanical computations of the reaction rate constant in a few solvents with a computer-aided molecular design (CAMD) procedure. The approach allows the identification of a high-performance solvent within a very large set of possible molecules. The validity of our CAMD approach is demonstrated through application to a classical nucleophilic substitution reaction for the study of solvent effects, the Menschutkin reaction. The results were validated successfully by in situ kinetic experiments. A space of 1,341 solvents was explored in silico, but required quantum-mechanical calculations of the rate constant in only nine solvents, and uncovered a solvent that increases the rate constant by 40%.