Tautomeric Equilibria Revised

The comprehension of the molecular stability is important to predict the relative reactivity of the chemical agents and the relative yields of desirable products. However, for decades, the prediction on the proton tautomeric equilibrium by wavefunction (WF) and density functional (DFT) methods show that a quantitative agreement with the relative energy is a challenge. We revise the molecular orbital analysis in the classic tautomeric 2-pyridone/2-hydroxypyridine case, (Wong et al. 1992). Our findings reveal the unsatisfactory level of reproducibility of orbital energies as responsible
for the remarkable contrast between the WF and DFT results. The correction leads the estimation of the relative stability in excellent agreement with experiments. The
analogous approach for other tautomeric compounds corroborates the reliability of our description and its potential application, e.g., on the development of the molecular
switches, computer-aided drug design, and new DFT functionals. A software tool for Gaussian 09 package, in the support information, is available on the author's ORCiD page.