Replacement of Oxygen by Sulfur in Small Organic Molecules. 3. Theoretical Studies on the Tautomeric Equilibria of the 2OH and 4OH-Substituted Oxazole and Thiazole and the 3OH and 4OH-Substituted Isoxazole and Isothiazole in the Isolated State and in Solution.

Peter Nagy

doi:10.3390/ijms17071094

Abstract

This follow-up paper completes the author’s investigations to explore the in-solution structural preferences and relative free energies of all OH-substituted oxazole, thiazole, isoxazole, and isothiazole systems. The polarizable continuum dielectric solvent method calculations in the integral-equation formalism (IEF-PCM) were performed at the DFT/B97D/aug-cc-pv(q+(d))z level for the stable neutral tautomers with geometries optimized in dichloromethane and aqueous solution. With the exception of the predictions for the predominant tautomers of the 3OH isoxazole and isothiazole, the results of the IEF-PCM calculations for identifying the most stable tautomer of the given species in the two selected solvents agreed with those from experimental investigations. The calculations predict that the hydroxy proton, with the exception for the 4OH isoxazole and 4OH isothiazole, moves preferentially to the ring nitrogen or to a ring carbon atom in parallel with the development of a C=O group. The remaining, low-fraction OH tautomers will not be observable in the equilibrium compositions. Relative solvation free energies obtained by the free energy perturbation method implemented in Monte Carlo simulations are in moderate accord with the IEF-PCM results, but consideration of the ΔGsolv/MC values in calculating ΔGstot maintains the tautomeric preferences. It was revealed from the Monte Carlo solution structure analyses that the S atom is not a hydrogen-bond acceptor in any OH-substituted thiazole or isothiazole, and the OH-substituted isoxazole and oxazole ring oxygens may act as a weak hydrogen-bond acceptor at most. The molecules form 1.0−3.4 solute−water hydrogen bonds in generally unexplored numbers at some specific solute sites. Nonetheless, hydrogen-bond formation is favorable with the NH, C=O and OH groups.

Highlights

Tautomeric equilibration of suitable molecules is of large practical importance both in chemical syntheses and in general, where intermolecular interactions play a crucial role [1,2]
The polarizable continuum dielectric solvent method calculations in the integral-equation formalism (IEF-PCM) were performed at the DFT/B97D/aug-cc-pv(q+(d))z level for the stable neutral tautomers with geometries optimized in dichloromethane and aqueous solution
Relative solvation free energies obtained by the free energy perturbation method implemented in Monte Carlo simulations are in moderate accord with the IEF-PCM results, but consideration of the ∆Gsolv/MC values in calculating ∆Gstot maintains the tautomeric preferences

Summary

Introduction

Tautomeric equilibration of suitable molecules is of large practical importance both in chemical syntheses and in general, where intermolecular interactions play a crucial role [1,2]. With the exception of the 3OH isoxazole and 3OH isothiazole species, the preference has not changed upon solvation, but since the calculated relative free energies have been shifted in the condensed phase, the in-solution composition differs from that in the gas phase. The opposite signs for ∆Gsolv by the two methods for 1c Ñ 1d and 2c Ñ 2d in water would cause changes in the ∆Gstot of 13–14 kJ/mol if the ∆Gsolv/MC were used Consideration of such a ∆Gsolv/MC value, so different from ∆Gsolv/PCM, in equation 1 has still no qualitative effect: the stability of the 2-one, NH form relative to the 2-one, C5H species further increases both for oxazole and thiazole. Consideration of the MC results is, important mainly in aqueous solution to evaluate the underestimated effects of the solutesolvent hydrogen-bond formation, which is an inherent feature of the PCM method

Equilibration Mechanism

Solution Structure Simulations

Conclusions