The existing quantum chemical methods to accurately predict pK<inf>a</inf> and to determine the trade-off between accuracy and computational cost have been evaluated by ab initio and density functional theory with the B3LYP functional and 6-31+G(d) basis sets and polarizable continuum solvation model. The calculated free energies for determination of pK<inf>a</inf> values, and intermolecular hydrogen bonds in aqueous solutions of octopamine and 6-aminopenicillanic acid have been computed. This study shows that there is reasonable agreement between the theoretically calculated pK<inf>a</inf> values and the experimentally determined pK<inf>a</inf> values for the acid-base reactions obtained by potentiometric and spectrophotometric methods reported in the literature.