Prediction of Aqueous pKa Values forGuanidine-Containing Compounds Using Ab Initio Gas-PhaseEquilibrium Bond Lengths

摘要

In this work, we demonstrate the existence of linear relationships between gas-phase equilibrium bond lengths of the guanidine skeleton of 2-(arylamino)imidazolines and their aqueous pKa value. For a training set of 22 compounds, in the most stable conformation of their lowest energy tautomeric form, three bonds were found to exhibit r² and q² values >0.95 and root-mean-squared-error of estimation values ≤0.25 when regressed individually against pKa. The equations describing these one-bond-length linear relationships, in addition to a multiple linear regression model using all three bond lengths, were then used to predict the experimental pKa values of an external test set of further 27 derivatives. The optimal protocol we derive here shows an overall mean absolute error (MAE) of 0.20 and standard deviation of errors of 0.18 for the test set. Predictions for a second test set of diphenyl-based bis(2-iminoimidazolidines) yielded an MAE of 0.27 and a standard deviation of 0.10. The predictive power ofthe optimal model is further demonstrated by its ability to correcterroneously reported experimental values. Finally, a previously establishedguanidine model is recalibrated at a new level of theory, and predictionsare made for novel phenylguanidine derivatives, showing an MAE ofjust 0.29. The protocols established and tested here pass both ofRoy’s modern and stringent MAE-based criteria for a “good”quantitative structure–activity relationship/quantitative structure–propertyrelationship model predictivity. Notably, the ab initio bond lengthhigh correlation subset protocol developed in this work demonstrateslower MAE values than the Marvin program by ChemAxon for all testsets.