Estimation of pKa Using Semiempirical Molecular Orbital Methods. Part 2: Application to Amines, Anilines and Various Nitrogen Containing Heterocyclic Compounds.

The pKa of a compound directly influences its biopharmaceutical profile. This article describes the development of a method for estimating pKa values for a number of nitrogen containing chemical structures using semiempirical QM properties derived from frontier electron theory. Typically, the property giving the best correlation with pKa was the electrophilic superdelocalisability of the nitrogen atom resulting in regression equations with r2 values up to 0.94. The advantages of this technique are in the simplicity of the models and the speed of calculation, suggesting that this method could be widely applied to the estimation of pKa values. The success of this approach is discussed in relation to other methods.