Of the eight amines investigated by Sarstre et al. six are primary amines and the remaining two are di- and trimethylamine. The errors in the pKa values predicted using PM6 based methods are significantly larger for dimethylamine (3.7) and trimethylamine (5.2) compared to the primary amines (0.2 - 1.2). The MAD for amines drops from 1.5 to 0.6 if these two amines are removed. Here we investigate whether the accuracy of PM6-based predictions of amines can be improved by using different reference molecules for primary, secondary, and tertiary amines.
Table \ref{tab:amines} lists experimental and predicted pKa values for six secondary and tertiary amines shown in Figure x. The third column lists PM6-D3H+/SMD predicted pKa values using ethylamine as a reference value, whereas the fourth column lists the corresponding pKa values predicted using di- and tri-ethylamine as reference for secondary and tertiary amines, respectively. Switching reference from ethylamine lowers the MAD from 4.4 to 0.7 for the secondary amines and from 6.8 to 2.3 for tertiary amines.