PK-Yay: A Black-Box Method Using Density Functional Theory and Implicit Solvation Models to Compute Aqueous pKa Values of Weak and Strong Acids.

Abstract

The concept of pKa is very important in chemistry and biology. Over the past two decades, electronic structure calculations have made huge strides toward becoming reliable counterparts to experiments in determining solution-phase pKa values. However, invariably, the computation of pKa values involves the use of methods whose error bars are intrinsically larger (definitely >2 kcal/mol with density functionals) than the accuracy desired for the estimation of pKa values (<1 or 1.5 pKa units). This scenario presents an ample scope for innovation in developing systematic error cancellation methods even today. In this work, we have developed the pK-Yay method. It is a user-friendly black-box method used to compute aqueous pKa values of strong and weak acids employing routinely used and computationally inexpensive density functionals and implicit solvation models. It does not require the use of any explicit solvent molecule or modifying any other parameter in an electronic structure program. As part of evaluating the method, a comprehensive test set of 26 weak and strong organic and mineral acids covering 35 pKa units (20 to -15) was assembled. The detailed description of the method, its performance with different functionals (ωB97X-D performed best for organic acids with a mean absolute error (MAE) of 0.8 pKa units, and B2-PLYP performed best for strong acids with an MAE of 1.6 pKa units), the strengths and limitations in the present version, and a future scope to improve the accuracy and reduce its empirical nature are presented herein.