Calculation of Absolute and Relative Acidities of Substituted Imidazoles in Aqueous Solvent

Abstract

We calculate free energy changes of ionization reactions in aqueous solvent using a self-consistent reaction field method. In the calculations all species are treated as quantum mechanical solutes coupled to a solvent dielectric continuum. We show for a series of substituted imidazole compounds that both absolute and relative pKa values for the deprotonation of nitrogen on the imidazole ring can be obtained with an average absolute deviation of 0.8 units from experiment. This degree of accuracy is possible only if the solutes are treated at the correlated level using either G2 type or density functional theory. Inconsistencies in published experimental free energies of hydration that might undermine the reliability of the calculated absolute pKa values are discussed.