Non-continuum solvation using the EC-RISM method applied to predict tautomer ratios, pKa and enantiomeric excess of alkylation reactions

The three-dimensional “reference interaction site model” (3D-RISM) integral equation theory is a statisticalmechanical approach to predict liquid state structural and thermodynamic features. It is based on approximate solute-solvent correlation functions to be computed on a 3D grid as a function of the interaction potential between the solute and the solvent sites, circumventing the need of costly sampling of explicit solvent degrees of freedom. In combination with quantum-chemical calculations within the embedded cluster (EC-)RISM framework [1] the theory allows for studying chemical reactions in solution with an accuracy not reached by traditional continuum solvation methods. In particular, it improves upon dielectric continuum solvation by taking solvent granularity into account and also provides a means towards physically cavity formation and dispersion free Energies without introducing artificial boundaries and empirically fitted radii. We outline the general framework and show application examples from pKa and tautomeric ratio estimation [2] as well as enantiomeric excess prediction for stereoselective alkylation reactions in organic solvent.