4-Hydroxy-2-pyridinone tautomers

The monodentate function in 2-hydroxypyridines is commonly described by O-coordination in the pyridinol tautomeric form 21 or N-coordination in the pyridinone tautomer 22. The N,0-chelation is observed in both pyridinol 23 and pyridinone 24. Bridging function of 2-pyridones can be of two principal types 25 and 26 (95CCR313, 97ACR89). The bridging function 27 in 4-hydroxypyridine derivatives is quite common. A similar situation is observed in hydroxy quinoline analogues. 

Since polar solvents would be expected to stabilize polar forms, a retreat towards the hydroxy tautomer (71) would be predicted in solvents less polar than water, and in the vapour phase. This is borne out in practice at equilibrium both 2- and 4-hydroxypyridine (as well as the 3-hydroxy compound, which even in water exists as an approximate 1 1 mixture of OH and NH forms) exist as such, rather than as the pyridinones. However, the 2- and 4-quinolinones remain in the NH (keto) forms, even in the vapour phase. Hydrocarbon or other solvents of very low polarity would be expected to give results similar to those in the vapour phase, but intermolecular association by hydrogen bonding often leads to a considerably greater proportion of polar tautomers being present than would otherwise have been predicted (77ACR186, 78JOC177). 

Table 11 summarizes the main results on the tautomerism of mono-hydroxy-, -mercapto-, -amino- and -methyl-azines and their benzo derivatives, in water. At first sight the equilibrium between 2-hydroxypyridine (71) and pyridin-2-one (72) is one between a benzenoid and a non-benzenoid molecule respectively (71a 72a). However, the pyridinone evidently has a continuous cyclic p- orbital system, containing six it- electrons, the usual aromatic count, if the carbonyl group contributes none. This assumption implies the formula (72b), from which by redistribution of electrons we arrive at (72c), which has the same benzenoid system as (71a). Further canonical forms (71b, 71c) can be drawn of (71) which correspond to the non-benzenoid forms of (72). The elusive property of aromaticity is therefore possessed by both tautomers, although not necessarily by both equally. When the carbonyl oxygen of (72) is replaced by less electronegative atoms, as in the imine tautomers of amino heterocycles, or the methylene tautomers of methyl derivatives, the tendency towards polarization in forms corresponding to (72b) and (72c) is considerably less, and the amino and methyl tautomers are therefore favoured in most instances. 

The tautomerism of 2-hydroxypyridine in the gas phase has also been studied by microwave spectroscopy using both a conventional spectrometer and a jet-cooled millimeter-wave spectrometer. The spectra attributable to both (Z)-hydroxy tautomer and 2-pyridinone were observed in all cases, the relative abundance being 3 1 in favor of the hydroxy form. No ( )-hydroxy isomer has been detected (93JPC46). The increased stability of the <7,v-hydroxy tautomer compared to the tra/iv-isomer is confirmed by CNDO/2 calculations (AE— 0.64 kcal/mol), whereas the semiempirical effective pair correlation energy method favors the fra/iv-isomer by 0.69 kcal/mol (90BCJ2981). 

Another useful method for the elucidation of the hydroxypyrazine-pyrazinone tautomerism is UV spectral analysis. The objective structure in solution is easily estimated by comparison with the UV spectra of the proton-fixed compounds of two tautomers, O-methylated (22) and A-methylated derivatives (23), which are prepared by methylation of the hydroxypyrazines or pyrazinones with diazomethane (Scheme 2). For example, 6-amino-5-benzyl-3-methyl-2(177)-pyrazinone (21 R = Me, R = CHzPh, X = NH2) has been shown to predominate over the hydroxy form (20) because of its nearly identical UV spectrum with the corresponding V-methylated derivative (23) <93JOC7542>. In contrast, 6-chloro-2-hydroxypyrazines (20 R, R = Me or Ph, X = Cl) exist in the hydroxy form rather than as the tautomeric amide, which is an exceptional example of predominance of the hydroxy form with parallels in the chloro-pyridinone field <7UCS(C)2977>. 

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