Solvation keto-enol tautomerism

The solvent polarity, which is defined as the overall solvation capability of a liquid derived from all possible, non-specific and specific intermolecular interactions between solute and solvent molecules [4], cannot be represented by a single value encompassing all aspects, but constants such as the refractive index, the dielectric constant, the Hildebrand solubility parameter, the permanent dipole moment, the partition coefficient logP [5] or the normalised polarity parameter TN [6] are generally employed to describe the polarity of a medium. The effect of a solvent on the equilibrium position of chemical reactions, e.g. the keto-enol tautomerism, may also be used. However, these constants reflect only on some aspects of many possible interactions of the solvent, and the assignment to specific interactions is difficult if not impossible. 

The keto-enol tautomerism of the dihydroxy perylenequinones 33a-d was studied by H, and "C NMR spectroscopy " (equation 13). The most important factors determining the tautomeric equilibrium in these helix-shaped systems are the substituent effects, the strength of intramolecular phenol-quinone hydrogen bonds, the distortion from planarity of the perylenequinone structure and solvation as well as aggregation effects. 

In addition to heterocycles, other molecular systems have attracted theoretical attention with respect to prediction of tautomeric equilibria and solvation effects thereon. The most commonly studied example in this class is the equilibrium between formamide and formamidic acid, discussed in the next section. In addition, some continuum modeling of solvation effects on keto/enol equilibria have appeared these are presented in section 4.2.2.2. We note that the equilibrium... 

Although the tautomeric ratios of the 4 species have not been measured directly, it is known that in aqueous solution the keto-N2H form dominates, while the keto-NlH form is only detectable in non-polar solvents. An analysis of experimental data concluded that in aqueous solution the stability (lowest free energy) is in the order keto-N2H > imino-N2H > enol-NlH > keto-NIH. In the gas phase, calculations predict that the keto-N2H form is the least stable. While solvation is found to favour this species, which is the most polar, this stabilisation is not enough to reverse the order of stability. It is thus clearly predicted that the keto-NIH tautomer is the most stable in... 

However, it is clear that vibrational spectroscopy has considerable use beyond the identification of polymorphs and solvates. The infrared spectra obtained on the polymorphs of acetohexamide and selected derivatives has been used to study the tautomerism of the drug compound [127]. It was deduced in this work that Form A existed in the enol form, stabilized by the intramolecular bonding between the O—H and groups that produces a six-membered ring. Form B was characterized by the existence of the keto form, with the urea carbonyl group being intermolecular bonding to a sulfonamide N—H functionality. This behavior can be contrasted with that noted for spironolactone, where no evidence was found for the existence of enolic tautomers in any of the four polymorphs [128]. 

A polar solvent like water introduces a dramatic shift in the tautomeric preferences of cytosine, leading to a stabilization of the keto-amino tautomer. Thus, experimental data precludes the existence of significant amount of imino or enol tautomers of cytosine in aqueous solution [144]. MC-FEP and SCRF calculations [118] indicate that the preferential solvation of the keto-amino tautomer in front of the keto-imino and enol-amino tautomers amounts to around 4 and 7 kcal/mol. Therefore, the enol and imino tautomers of cytosine are predicted to be 6-7 kcal/mol less stable than the canonical keto-amino tautomer [118]. 

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