Heterocycles are frequently appearing structure-building elements in drug candidates. The present paper investigates the consequences of the replacement of the oxygen atom by a sulfur atom in the isomeric rings of 5OH-oxazole and 5OH-isoxazole. Theoretical calculations at the B97D/aug-cc-pvqz level (with five additional “d” functions on the S atom) and considering the CCSD(T) level at the complete basis set limit followed the structural and concomitant free energy changes for the four title molecules in the isolated state, and in dichloromethane and water solvents. The selected species are subject to both conformational and tautomeric transformations. The polarizable continuum method (PCM) was applied for in-solution geometry optimization and estimation of the free energy components. In addition, explicit solvent Monte Carlo simulations were performed to calculate the relative solvation free energies of selected tautomers. This latter method allows for presenting solute atom - solvent atom radial distribution functions and the estimation of the number solute-solvent hydrogen bonds. The tautomeric preferences for the oxygen and sulfur containing species, which are sometimes different, were discussed and the calculated results were compared with experimental measurements for the structure composition available for 5OH-isoxazole and its methyl derivatives of in water. Potential of mean force curves were calculated for the 5-one tautomers of 5OH-isothiazole in dichloromethane and the possible tautomeric pathways for this solute in a non-protic solvent was discussed.
Keywords: Conformational/tautomeric equilibria, Monte Carlo, PCM, potential of mean force, solution structure, tautomerization mechanism.
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