Computational determination of aqueous pKa values of protonated benzimidazoles (part 1).

Benzimidazoles are the organic compounds investigated in this work. The experimental determination of the pKa values of protonated benzimidazoles in water is a challenge because of their low solubility. In addition, some derivatives are involved in tautomeric equilibria which increase the complexity of the theoretical pKa determinations. In the present study, different approaches are considered to develop a methodology for the accurate prediction of aqueous pKa values of protonated benzimidazoles at 298.15 K. We have considered different reaction schemes for approximating the acid dissociation equilibrium; two distinct equations are used for the calculation of pKa values, and a number of levels of theory and empirical corrections are applied in the process of working toward this aim. The best correlations between the experimental and calculated data are obtained at the B3LYP/6-31+G(d,p)-PCM(opt) level of theory. The predictive capabilities of the methodologies attempted are tested with two compounds that were not included in the set of benzimidazoles initially investigated. The direct calculations differ significantly from the expected values, but the pKa values calculated using the correlation equations are very similar and in reasonable agreement with the expected pKa values.