Tautomerization of pyrazole

After the publication of a book on the prototropic tautomerism of aromatic heterocycles (76AHC(Sl)l) which covered the literature up to 1975, the study of the tautomerism of pyrazoles has not made great strides. In this section the main conclusions of this earlier review will be summarized and comments on a few recent and significant references added. 

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). 

Pyrazoles. The annular tautomerism of pyrazoles has been thoroughly studied both experimentally <2000AHC(76)157> and theoretically <2001AHC(81)1>. A systematic study of annular tautomerism of NH-pyrazoles in the solid state has been published <1988CJC1141>. 

Although much work is still devoted to tautomerism of pyrazole derivatives, the methodology and the main conclusions remain unaltered. As an example of study of the tautomerism of pyr-azolinones using C NMR spectroscopy see <91JHC641> for the case of pyrazolone T. Katritzky... 

Similar to the Paal-Knorr pyrrole synthesis, the Knorr pyrazole synthesis is the most common synthetic method for the preparation of pyrazoles. The Knorr pyrazole synthesis involves the cyclocondensation of an appropriate hydrazine, 1, which acts as a bidentate nucleophile, with the three carbon unit of a 1,3-dicarbonyl moiety, 2, featuring two electrophilic carbons. With unsymmetrical substrates having two electrophilic centers (Ra R4), mixtures of regioisomers 3a and 3b are often obtained in reactions with substituted hydrazines (Ri H). However, when Ri = H, the prototropic tautomerism of pyrazoles renders 3a equivalent to 3b. 

The excellent review The use of NMR spectroscopy to study tautomerism [3] by Jose Elguero s group was mentioned already in the introduction to this chapter. Jose s working team deals inter alia especially with the annular tautomerism of pyrazoles and pyrazolones. This review gives the perfect overview. This research was (and is) continued, for example, the pyrazole tautomerism of phosphonylpyrazoles was studied by low-temperature H and NMR analysis [89]. Tautomerism of the 3-hydroxyindazoles in solution and in the solid state was studied by the Elguero group [90] as well. 

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). 

To illustrate the results summarized in Table IX, some examples are discussed in detail. The large number of papers discussing the annular tautomerism of azoles (first column) is exemplified by the studies concerning benzotriazole (57). Wofford, Forkey, and Russell, using pyrazoles and imi-... 

JA4105) (Section V,A) (2) that of 1,2,3-triazole and 3(5)-methylpyr-azole and the reason why they are liquid at room temperature (89JCC426) (Section V,D,2) and (3) the tautomerism of C-methyl-pyrazoles and -imidazoles (90JA1303) (Section which have already all been dis-... 

The first condition is obviously met for the degenerate tautomeric reactions which were also termed as autotropic rearrangements [76AHC(S1), p. 268]. An illustrative and the most thoroughly studied example of such a tautomeric rearrangement is the interconversion of the degenerate isomers of pyrazole 1 (Scheme 1). 

Tautomeric Equilibria and Preferred Tautomeric Forms of Pyrazoles 2... 

Accounting for this effect, it was possible to apply dynamic NMR spectroscopy to measure energy barriers to the prototropic rearrangements of pyrazoles. Temperature-variable spectra of a series of 4-substituted pyra-zoles 5 and 6 have been studied in methanol-d4 solutions and the free energy barriers of the degenerate type 2a 2b tautomerization reported (93CJC1443). 

Numerous data on kinetics of annular tautomerism have been obtaifled for the degenerate rearrangements of pyrazole derivatives. Since all these rearrangements were found to be intramolecular, we can compare kinetic measurements carried out in different media. The following order of increase in migration ability of various groups is established ... 

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