Understanding and quantifying the impact of solute-solvent van der Waals interactions on the selectivity of...

The majority of enantioselective organocatalytic reactions occur in apolar or weakly polar organic solvents. Nevertheless, the influence of solute-solvent van der Waals forces on the relative kinetics of competitive pathways remains poorly understood. In this study, we provide a first insight into the nature and strength of these interactions at the transition state level using advanced computational tools, shedding light into their influence on the selectivity. In addition, we introduce a series of computational tools tailored for detailed exploration of the role of the organic solvent across diverse research disciplines. As a case study, we selected a highly relevant asymmetric organocatalytic transformation catalyzed by a chiral Brønsted acid. Our analysis reveals that strong dispersion interactions exist between the transition state and the solvent, predominantly involving specific groups of the catalyst rather than being uniformly distributed around the solute. Short-range repulsion between the transition state and the solvent often counteracts the effect of these dispersion forces on the transition state energy, resulting in a minimal overall influence of solute-solvent van der Waals forces on enantioselectivity. However, for certain geometric configurations of the transition states, the effect these interactions remains significant, favoring specific reaction channels. These results suggest that integrating solvent structural and electronic information into catalyst design strategies could offer new avenues for tuning selectivity of organocatalytic processes.