Accurate Prediction of Acidity Constants in Aqueous Solution via Density Functional Theory and Self-Consistent Reaction Field Methods

We have developed a protocol for computing the acidity constant (pKa) of organic compounds via ab initio quantum chemistry and continuum solvation methods. Density functional (DFT) calculations employing large basis sets are used to determine the gas-phase deprotonation energies. Solvation effects are treated via a self-consistent reaction field (SCRF) formalism involving accurate numerical solution of the Poisson−Boltzmann equation. Dielectric radii are parametrized for each functional group of interest to optimize solvation free energy calculations for neutral and charged species. While the intrinsic accuracy of these approaches is quite impressive (errors on the order of a few kcal/mol), it is not quite good enough to achieve the target accuracy that we have set for pKa prediction of 0.5 pKa units. Consequently, two further empirical parameters, scaling and additive factors, are determined for every functional group of interest by linear fitting directly to pKa data for a training set. With this additi...