Quantum chemical pKa prediction for complex organic molecules

Numerous types of quantum chemical calculations and protocols have been successfully applied to computing pK(a) 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 pK(a). The complexity of the phenomena that must be considered begs for the need for a greater automation of pK(a) prediction workflows. We review our experience with these challenges and outline paths for future progress in the direction of tackling pK(a) prediction of complex organic molecules.