Quantum chemical pKa prediction for complex organic molecules

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 confor...

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Bibliographic Details
Published in:International journal of quantum chemistry 2018-06, Vol.118 (12), p.n/a
Main Authors: Philipp, Dean M., Watson, Mark A., Yu, Haoyu S., Steinbrecher, Thomas B., Bochevarov, Art D.
Format: Article
Language:English
Subjects:
Chemistry
complex
Complexity
Molecular chains
Organic chemistry
Physical chemistry
pKa
prediction
protonation
quantum
Quantum chemistry
Quantum physics
Solvation
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Summary: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. pKa prediction of complex molecules characterized by large size, multiple functional groups, tautomerism, symmetry, and other complicating factors calls for sophisticated quantum chemical workflows that explicitly take into account 3D effects and conformational flexibility. This perspectives discusses challenges and possible steps forward in this difficult research field.
ISSN:0020-7608
1097-461X
DOI:10.1002/qua.25561