Tautomeric Equilibrium Revisited: proton-tautomerism in solvent and the fundamentals of molecular stability prediction.

Abstract

Understanding the molecular stability is important for predicting the relative reactivity of chemical agents and the relative yields of desirable products. However, over decades, a consistent estimate of a particular chemical equilibrium (proton-tautomerism) has proven challenging. We revisit the molecular orbital analysis in the classic tautomeric oxo-hydroxy case, i.e., 2-pyridone/2-hydroxypyridine in gas-phase and solution, (Wong et al. 1992). Our results indicate the possibility of tuning the tautomeric equilibrium through directing groups. Our findings also reveal the lack of <a></a>reproducibility of orbital energies as responsible for the remarkable contrast between the results of the wavefunction and density functional methods. Our proposal leads the correction in the estimation of relative stability in excellent agreement with experiments in gas-phase and solution. The analogous approach for different compounds corroborates the reliability of our description on the molecular stability and its potential application, e.g., a guide to estimate the relative stability of molecules, to measure the confidence of the proposed reaction mechanisms by different theoretical methods, development of the molecular switches and computer-aided drug design. A software tool for Gaussian 09 package, in the support information, is available on the author's ORCiD page.<br>

Favipiravir tautomerism: a theoretical insight

“…The keto-enol tautomerism of 2-hydroxy pyridine (1) is one of the most studied tautomeric cases, both theoretically and experimentally. Very detailed description of the effects of the used level of theory can be found in [7,29,30]. For gas phase, most of the density functionals overestimate (some of them very strongly) the keto form stability, while…”

Favipiravir Tautomerism: A Short Theoretical Report

“…The keto-enol tautomerism of 2-hydroxy pyridine (1) is one of the most studied tautomeric cases, both theoretically and experimentally. Very detailed description of the effects of the used level of theory can be found in 7,36,37 . For gas phase most of the density functionals overestimate (some of them very strongly) the keto form stability, while HF and post-HF methods predict more, but not dramatically, stable 1E.…”

Theoretical investigation of tautomerism of 2- and 4-pyridones: origin, substituent and solvent effects

“…Results are sensitive to method and basis set. 6 d ,24,33 At the beginning of our work, we optimized two tautomers of 2-pyridone by using one pure DFT functional and five hybrid DFT functionals, all in combination with the Pople's 6-311+G(d,p) basis set. 34 The following functionals were used: BLYP 35 a , b (pure), B3LYP 35 (20% exact Hartree–Fock (HF) exchange), the long-range corrected CAM-B3LYP 36 (19% HF exchange at short range and 65% HF exchange at long range), the long-range corrected wB97XD 37 (22% HF exchange at short range and 100% HF exchange at long range) also having empirical dispersion correction, BHandHLYP 38 (50% HF exchange) and M06-2X 39 (54% HF exchange).…”

“…22,23 Because of its simple structure and similarity to nucleic acid bases (thymine, cytosine and uracil) the 2-pyridone/2-hydroxypyridine pair is considered as a prototype system to study lactam/lactim tautomerization. 24 2-Pyridone is also a constituent of many biologically active natural products and pharmaceuticals, 25 DNA base analogue, 26 an important building block in synthesis 27 and shows the potential to direct molecular association by formation of hydrogen bonds. 28 The 4-pyridone structure can also be found in biologically active compounds, 29 in synthetic building blocks 30 and self-assembling building blocks, forming hydrogen bonds with extraordinary stability.…”