The Thermodynamic and Kinetic Properties of 2-Hydroxypyridine/2-Pyridone Tautomerization: A Theoretical and Computational Revisit

Abstract

The gas-phase thermal tautomerization reaction between 2-hydroxypyridine (2-HPY) and 2-pyridone (2-PY) was investigated by applying 6-311++G** and aug-cc-pvdz basis sets incorporated into some density functional theory (DFT) and coupled cluster with singles and doubles (CCSD) methods. The geometrical structures, dipole moments, HOMO-LUMO energy gaps, total hyperpolarizability, kinetics and thermodynamics functions were monitored against the effects of the corrections imposed on these functionals. The small experimental energy difference between the two tautomers of 3.23 kJ/mol; was a real test of the accuracy of the applied levels of theory. M062X and CCSD methods predicted the preference of 2-HPY over 2-PY by 5–9 kJ/mol; while B3LYP functional favoured 2-PY by 1–3 kJ/mol. The CAM-B3LYP and ωB97XD functionals yielded mixed results depending on the basis set used. The source of preference of 2-HPY is the minimal steric hindrance and electrostatic repulsion that subdued the huge hyperconjugation in 2-PY. A 1,3-proton shift intramolecular gas-phase tautomerization yielded a high average activation of 137.152 kJ/mol; while the intermolecular mixed dimer interconversion gave an average barrier height of 30.844 kJ/mol. These findings are boosted by a natural bond orbital (NBO) technique. The low total hyperpolarizabilities of both tautomers mark out their poor nonlinear optical (NLO) behaviour. The enhancement of the total hyperpolarizability of 2-HPY over that of 2-PY is interpreted by the bond length alternation.

Fitting quantum machine learning potentials to experimental free energy data: predicting tautomer ratios in solution

“…The gas phase internal energy difference between the two tautomers is ∼0.7 kcal/mol in favor of the enol form (2-HPY), while in water an internal energy difference of 2.8 kcal/mol was reported in favour of 2-PY. In cyclohexane, both tautomer coexist in comparable concentration while the 2-PY is dominant in solid state and polar solvents [7].…”

Fitting quantum machine learning potentials to experimental free energy data: Predicting tautomer ratios in solution

“…The copyright holder for this preprint this version posted October 27, 2020. ; https://doi.org/10.1101/2020.10.24.353318 doi: bioRxiv preprint October 27, 2020 in water an internal energy difference of 2.8 kcal/mol was reported in favour of 2-PY. In cyclohexane, both tautomer coexist in comparable concentration while the 2-PY is dominant in solid state and polar solvents [10].…”

“…The gas phase internal energy difference between the two tautomers is circa 0.7 kcal/mol in favor of the enol form (2-HPY), while in water an internal energy difference of 2.8 kcal/mol was reported in favour of 2-PY. In cyclohexane, both tautomer coexist in comparable concentration while the 2-PY is dominant in solid state and polar solvents [10].…”

Structure, Antimicrobial Activity, Hirshfeld Analysis, and Docking Studies of Three Silver(I) Complexes-Based Pyridine Ligands

“…In [Ag(2-pyridone)NO 3 ] n complex, both N and O are connected to Lewis acids (H + and Ag + ) and also the C-C distances: 1.425-1.436Å; and C-O distances: 1.266-1.273 Å, give no clear clue about whether this is the keto-or enol-form. In fact, looking at Figure 5 it seems that it falls right in the area that could be considered to correspond to the transition state and indeed the transition state of the tautomerization has been shown theoretically to go through a similar dimerization [57].…”

“…It has been agreed for quite some time that it is the 2-pyridone form and not the tautomer 2-hydroxy-pyridine that is the most stable form of this molecule in the solid state, but in the gas phase 2-hydroxy-pyridine is favored and in solution sometime delicate equilibriums exist [56,57]. Depending on substitution pattern, similar molecules may prefer either forms, but a search of the Cambridge Structure Database (CSD) showed that the 2-pyridone form is prevalent, as illustrated in the plot of C1-O1 versus C1-C2 shown in Figure 5.…”