Hydroxypyrazoles, tautomerism

The problem of tautomerism is simpler in the case of 1-substituted pyrazolin-3-ones since only two forms, the OH (140a) and the NH (140b), are possible. The OH form is the more stable and is the only one present in the crystal (Section 4.04.1.3.1). In protic solvents, like water or methanol, the equilibrium position is much more evenly balanced between the OH and NH forms. Finally, 4-hydroxypyrazoles (141) exist as such. A CNDO/2 calculation justifies the result that 4-hydroxy tautomers are relatively more stable than... 

The 1-hydroxypyrazoles exist as the neutral structure (151a) and not in the iV-oxide form (151b), although in water there is a small percentage of the latter present. For tautomerism of 2-hydroxyindazole see (82JOC4323). 

The chelated tautomeric forms shown are prepared for 4-ethoxycar-bonyl-l,2,3-thiadiazC le-5-one 250 and 3,5-dibenzoyl-4-hydroxypyrazole 251 [76AHC(S1), pp. 359,384]. 

Examples of the fixation of very minor prototropic tautomeric forms on complexation are known in the series of complexes of l-(2 -pyridyl)-5-hydroxypyrazoles 383 [76AHC(S1), p. 333 70ZOB1114] and 2-[2 -hydroxy (A-tosylaminophenyl)]benzazoles 385 (Scheme 142) (98ZOB496). 

The case of anion tautomerism is less frequent and it is only found in functional derivatives, for instance, in the conjugated bases of 3,5-diphenyl-4-hydroxypyrazole (525). 

The parent structure 87 constitutes a tautomeric form of 1-hydroxypyrazole 88 (Scheme 24). 1-Hydroxypyrazoles 88 make up a self-contained group of compounds, which will not be covered in the present review. 

Tautomerism of 3-hydroxypyrazoles unsubstituted on nitrogen is more complex. A detailed investigation of 3-hydroxy-5-methylpyrazole disclosed that the major tautomers in aqueous solution (polar medium) are 264 and 265, whereas in cyclohexane solution (nonpolar medium) the major tautomers are 264 and 266 <1976AHC(S1)346>. 

Substituted derivatives. The 4-substituted analogues can in principle exist as two uncharged tautomeric forms 270 and 271 and as the type B mesoionic tautomer 272. All the evidence shows that these compounds exist predominantly as the NH2, OH, or SH tautomers 270. The equilibrium between the pyrazole 273 and the mesoionic tautomer 274 has been shown to favor the hydroxypyrazole 273 strongly (AG 6.15 kcal mol-1) <1972T463>. 

The lactim/lactam tautomerism of hydroxamic acids and their O-alkyl and O-acyl derivatives has also been studied [146], Hydroxamic acids exist in the solid state and in polar solvents as the lactam tautomer only, whereas in nonpolar solvents the hydroximic tautomer is also present. Further analogous solvent-dependent lactim/lactam equilibria have been observed for certain Schiff bases (prepared from anilines and 2(4)-hydroxybenzaldehyde [256] or 2-hydroxynaphthaldehyde [257]), for 3-hydroxypyrazole [258], and for 3-methyl-l-phenylpyrazolin-5-one [259]. 

As discussed in the General Chapter (Section 4.01.5), imidazoles with potential hydroxy, thiol and amino substituents can exist in a variety of tautomeric forms. In contrast to the hydroxypyrazoles which have been studied in detail, comparatively little is known about the corresponding 1,3-diazoles. Many of the imidazoles are not easily accessible synthetically, and they may not be particularly stable e.g. 4-hydroxyimidazoles). Amino derivatives... 

The most important contribution to pyrazolinone tautomerism is the inclusion of solvent elfects on the theoretical calculations <90JCS(P2)195, 93JA2352). Theoretical calculations of the relative stabilities of the four tautomers of pyrazolinone (3-hydroxypyrazole A (OH form), 3-pyrazolin-5-one B (NH form), 5-hydroxypyrazole C (OH-form), and 2-pyrazolin-5-one D (CH form)) have been considered a challenge to theory <93JA2352> theory predicts the order D < A < C < B in the gas phase, which is different from the experimental results in solution <84CHEC-I(5)167>. 

Pyrazol-3-ones are known to be ambient compounds and depending on the solvent in which they are dissolved can exist in several tautomeric forms. Usually is less polar solvents such as chloroform pyrazol-3-one tautomers are dominant, whereas in more polar solvents such as dimethylsulfoxide 3-hydroxypyrazole tautomers are dominant. The most recent review article on this topic has been presented by Katritzky and co-workers (00AHC(76)157). 

Several years later other workers used the same method to confirm that pyrazol-3,5-diones 51a,b/5-hydroxypyrazol-3-ones 52a,b exist as tautomeric mixtures in solution. The reactions with diazomethane took place in a mixture of diethyl ether and methanol and afforded a mixture of the respective pyrazol-3,5-diones 53a,b and 5-methoxypyrazol-3-ones 54a,b. The suitability of these structurally fixed methyl derivatives as model compounds in the study of the tautomeric structures by NMR spectroscopy was investigated (80CB3910) (Scheme 16). 

Although UV data are available for the 3-hydroxy derivatives of this ring system, no IR details have been published. Accordingly it is unclear which of the possible tautomeric structures (14-16) best represents these compounds. Possibly, as with 5-hydroxypyrazoles, the hydroxy form 14 is less stable than oxo tautomers such as 16. Ultraviolet and infrared data are, however, available for the 6-hydroxy derivatives (17). In the solid state there is surprisingly no evidence for a carbonyl group in the infrare(. The presence of a broad band from 2300 to 3100 cm (v C=NH) is taken as indicating the importance of the dipolar structure 18 at the expense of the neutral forms 17 and 19. 

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