Prediction of pK a Values of Substituted Aliphatic Acids and Bases

Abstract

Free energy changes produced by inserting substituents into organic molecules are approximately additive. Hence, the simplest way to use a linear free energy relationship for predicting the pKa of an aliphatic acid or amine where the pKa of the parent compound is known, is to add to it increments of pKa (∆pKa values) corresponding to the free energy changes produced by inserting the individual substituents. Finally, the total is adjusted by applying statistical factors or other corrections such as a decrease of 0.2 in the pKa value of an amine for every methyl group bound to the nitrogen, or an increase of 0.2 if the nitrogen atom forms part of a ring.