Quantum chemical pKa prediction for complex organic molecules

Abstract

Numerous types of quantum chemical calculations and protocols have been successfully applied to computing pKa of small, uncomplicated organic molecules. Here, we argue for the need to shift attention to more challenging molecules that are marked by an interplay of complicating factors such as conformational, tautomeric, steric, and other effects. The challenge is not in choosing the right quantum chemical method and solvation model but in combining the existing methods to simultaneously and accurately describe the breadth of chemical and physical phenomena that give rise to the experimentally observed pKa. The complexity of the phenomena that must be considered begs for the need for a greater automation of pKa prediction workflows. We review our experience with these challenges and outline paths for future progress in the direction of tackling pKa prediction of complex organic molecules.