Solv-ccCA: Implicit Solvation and the Correlation Consistent Composite Approach for the Determination of pKa.

Direct theoretical methods are advantageous for the prediction of pKa, as relative methods rely upon the experimental values of reference acid molecules that can limit application of the method to well-characterized systems. Here, a direct route is introduced, which incorporates the SMD universal solvation model1 within the correlation consistent Composite Approach (ccCA). This Solv-ccCA methodology has been used for the prediction of theoretical pKa values for nitrogen-containing species to within a mean absolute deviation (MAD) of 1.0 pKa unit from experimental values by utilizing a thermodynamic cycle that combines gas-phase and solution-phase calculations. Several density functionals, including B3LYP, B97-1, B97-2, B98, BMK, M06, and M06-2X, were also evaluated for use with SMD and for comparison to Solv-ccCA.