Abstract
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 of the optimal model is further demonstrated by its ability to correct erroneously reported experimental values. Finally, a previously established guanidine model is recalibrated at a new level of theory, and predictions are made for novel phenylguanidine derivatives, showing an MAE of just 0.29. The protocols established and tested here pass both of Roy’s modern and stringent MAE-based criteria for a “good” quantitative structure–activity relationship/quantitative structure–property relationship model predictivity. Notably, the ab initio bond length high correlation subset protocol developed in this work demonstrates lower MAE values than the Marvin program by ChemAxon for all test sets.
Highlights
IntroductionHaving a measure for the propensity of a molecule to lose or gain a proton, under given conditions, (e.g., pH, solvent, and temperature) has applications in numerous fields
Having a measure for the propensity of a molecule to lose or gain a proton, under given conditions, has applications in numerous fields
We have demonstrated the existence of conformation-specific linear relationships between the bond length and pKa
Summary
Having a measure for the propensity of a molecule to lose or gain a proton, under given conditions, (e.g., pH, solvent, and temperature) has applications in numerous fields. Biochemical reactions may be rationalized with insight into the protonation state of the reacting species. The absorption, diffusion, metabolism, excretion, and toxicity profiles of a drug candidate strongly depends on its ionization state under physiological conditions. The measurement of pKa values of small, weakly acidic molecules (pKa range 2−15) may be achieved accurately via a variety of methods, including ultraviolet−visible spectrometry, potentiometry, or nuclear magnetic resonance spectroscopy, to name a few. An accurate method for the determination of pKa without the need for synthesis offers great advantage in the context of early-stage drug and agrochemical discovery, when thousands of potential compounds must be assessed for target specificity and selectivity. The pursuit of a fast, accurate, and allencompassing pKa prediction method is still a key challenge in chemistry, and in particular, the prediction accuracy of bases is of much interest.[2−4]
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