Development of a Direct Method to Calculate pKa Using Electronic Structure Methods

A new methodology for calculating pKa was developed, based on a direct method in aqueous solution. From a selective adjustment of the free energy of the solvated proton, using molecules with a well-defined experimental property as reference, an appropriate value for can be determined using explicit or not explicit water molecules and an implicit SMD model. The selected reference set plays an important role in the prediction and the selection of chemically diverse molecules contributes to a better estimate of the pKa value. Considering the SMD solvation model, different levels of calculations were investigated: the semi-empirical (AM1 and PM6), density functional (M06-2X, LSDA, among others), with the aug-cc-pVTZ basis. The method is effective in predicting the pKa of 44 monoprotic carboxylic acid molecules, with several pKa shifts less than one unit. Less costly methods were very efficient in predicting pKa such as semi-empirical levels without explicit water and the LSDA/aug-cc-pVTZ level containing or not explicit molecules.