3 pyrazole annular tautomers

All the N-unsubstituted pyrazoles (129) in solution (and probably in the gas phase) are mixtures of annular tautomers in different proportions, depending on the nature of the substituents R and R. In the majority of cases the difference of free energy between both tautomers is low enough for the chemical reactivity to be unrelated to the equilibrium constant. 

It has been recognized [76AHC(S1), p. 272 84CHEC-I(5)167 87AHC (41)187 96CHEC-II(3)1] that virtually all N-unsubstituted pyrazoles in solution are mixtures of annular tautomers whose relative populations depend on the nature of the substituents R and R, the temperature, and the nature of the solvent. 

Introduction. Annular tautomers are prototropic tautomers in which the migrating proton is restricted to ring atoms, which for azoles are usually nitrogen atoms, e.g., 239 240 and 241 242. For unsubstituted pyrazole 239 (R = R2 = H) and imidazole 241 (R = H) the two tautomers are identical, but this does not apply to substituted derivatives. For triazoles and tetrazoles the unsubstituted rings can occur as two distinct tautomers. However, interconversion occurs readily and such tautomers cannot usually be separated. In rare examples where prototropic tautomers can be separated as discrete crystal forms they are referred to as desmotropes, e.g., isomers 147 and 148 (Section 2.4.3.4). Further examples of desmotropes are 3-methyl-4-nitropyrazole 239 (R1 = N02, R2 = Me) and 5-methyl-4-nitropyrazole 240 (R1 = N02, R2 = Me) <1994CC1143>. 

Only three systems belong to this group pyrazole (3), l//-indazole (4) and 2//-indazole (isoindazole 5). The fused carbon atoms in indazoles are numbered 3a and 7a. When R = H, annular tautomerism (76AHC(Si)i) makes the 3- and 5-positions of pyrazoles equivalent and thus the name 3(5)-R-pyrazole means that the compound is a mixture of tautomers with the substituent R in position 3 and in position 5. The same applies to TV-unsubstituted indazoles however, the numbering is identical in both tautomers and thus 3-R-indazole means either (4) or (5) (R or R = H). Since the indazole tautomer is largely predominant (Section 4.04.1.5.1), indazoles are usually represented by the formula (4). 

Examples of dynamic processes involving two, three, or four identical tautomers (degenerate or autotrope annular tautomerism) have been found in pyrazoles (type 2 of Table VII). Thus, 3,5-diphenyl-4-bromopyr-azole and 3,5-di-ferf-butylpyrazole (dimers), 3,5-dimethyl-pyrazole (trimer). 

The influence of intramolecular hydrogen bonds on the annular tautomerism of pyrazoles in the case of 3(5)-C02H and C02Me substituents was rationalized through B3LYP/6-31+G calculations of 106 tautomers and conformers [69], It appears that the O-H -N hydrogen bond (52a, 53a) is stronger than the N-H O one (52b, 53b, 54a, 54b). 

Unsymmetrical /i-diketones can form two )S-keto-enol tautomers, (90a), (90b). The corresponding N//-pyrazoles— readily synthesized from the diketones—exhibit annular tautomerism, (91a), (91b). These tautomerisms have been probed via AMI semiempirical calculations that show that the two phenomena are related in each case the position of equilibrium is strongly influenced by whether or not the CC double bond is part of (another) ring system (the Mills-Nixon effect). 

A systematic study of annular tautomerism of N//-pyrazoles in the solid state has been published <88CJCl 141 > in each case the tautomer present in the solid state was identified and the conclusion is always in agreement with the result obtained by x-ray crystallography, when available. The only compound for which the solution was not clear was 3(5)-phenyl-5(3)-methylpyrazole (64)) (Section... 

Primary cycloaddition products are the 3H-pyrazoles 22, which tautomerize to the IH-pyrazoles 23. With unsymmetrical alkynes, the regiochemistry of diazoalkane cycloaddition is ambivalent and dependent on sterical and electronic effects [324]. Mono-acceptor-substituted alkynes react regioselectively for instance, propargylaldehyde and diazomethane lead to the pyrazole-5-aldehyde (25), which equilibrates with its annular 3-tautomer 24 ... 

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