Absolute and relative pKa calculations of mono and diprotic pyridines by quantum methods

Abstract Gas-phase deprotonation free energies and aqueous solvation free energies of 10 monoprotic and 6 diprotic pyridines were calculated using CBS-QB3 and HF/CPCM or B3LYP/CPCM methods. The results have been processed considering three thermodynamic cycles for absolute and relative p K a calculations. In these cycles, different experimental values of solvation free energies for proton, water and hydronium were considered. Moreover, calculated ab initio and DFT values were used when possible. Results show that the inclusion of explicit single water molecule interacting with pyridine nitrogen improves predictions in 1.5 p K a units. Water molecule causes an increase in the solute–solvent surface interaction and allows the continuum method to reproduce correct solvation free energy differences between acids and bases. The correct combination of computational methodology and thermodynamic cycle leads to very accurate results, with mean absolute errors of 0.3–0.5 p K a units for monoprotic and 0.7–0.9 p K a units for diprotic pyridines.