Prediction of the tautomer stability and acidity of phenacylpyridines in aqueous solution

Abstract

In this work, the aqueous acidity and tautomeric equilibrium constants are predicted in a systematic manner for the family of 2-, 3- and 4-phenacylpyridines which exhibit simultaneous keto–enol and imine–enamine tautomerism. The computational approach is based on electronic structure methods rooted in density functional theory, on an implicit SMD solvation model, and on thermodynamic cycles. In some instances, the high-quality hybrid CBS-QB3 method is used to obtain accurate gas-phase Gibbs free energies. The cationic, neutral, anionic and zwitterionic states of phenacylpyridines are considered, subject to a careful conformational analysis. Provided that a flexible enough basis set is used, estimated aqueous $${\text{p}}K_{{\mathrm{a}}}$$ and $${\text{p}}K_{{\mathrm{t}}}$$ values based on direct thermodynamic cycle correlate well with experimental data and show a reasonable quantitative agreement. On the other hand, it is found that the proton exchange scheme does not improve the accuracy of the predictions and different reference compounds are needed for each different type of the acidic site. Therefore, the errors herein are beyond systematic control. We use our results to present a brief discussion of the factors influencing the accuracy for the prediction of $${\text{p}}K_{{\mathrm{a}}}$$ and $${\text{p}}K_{{\mathrm{t}}}$$ for phenacylpyridines and presumably for other tautomeric compounds with multiple acidic centers.