Pyrazole annular tautomerism

Such modifications can be produced either in the kinetic aspects (proton transfer) or in the equilibrium constant. Both effects are mediated by intramolecular hydrogen bonds. For instance, Navarro et al. (93MI69) showed that the rate of proton transfer between the two nitrogen atoms of pyrazole (annular tautomerism) is considerably reduced in macrocycles containing oxygen or nitrogen atoms in the macroring. 

Annular tautomerism (e.g. 133 134) involves the movement of a proton between two annular nitrogen atoms. For unsubstituted imidazole (133 R = H) and pyrazole (135 R = H) the two tautomers are identical, but this does not apply to substituted derivatives. For triazoles and tetrazoles, even the unsubstituted parent compounds show two distinct tautomers. Flowever, interconversion occurs readily and such tautomers cannot be separated. Sometimes one tautomeric form predominates. Thus the mesomerism of the benzene ring is greater in (136) than in (137), and UV spectral comparisons show that benzotriazole exists predominantly as (136). 

Table 36 summarizes the known annular tautomerism data for azoles. The tautomeric preferences of substituted pyrazoles and imidazoles can be rationalized in terms of the differential substituent effect on the acidity of the two NFI groups in the conjugate acid, e.g. in (138 EWS = electron-withdrawing substituent) the 2-NFI is more acidic than 1-NFI and hence for the neutral form the 3-substituted pyrazole is the more stable. 

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). 

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-... 

Fluorine-19 NMR has also been used to study annular tautomerism in pyra-zoles, both for fluoro- and for trifluoromethyl-pyrazoles (99H355). Comparison of data chemical shifts and V coupling constants of 64a and 64b]... 

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 ... 

Low temperatures studies, for instance in THF at 175K, can elucidate annular tautomerism (92JCS(P2)1737) a large collection of 15N chemical shifts of NH-pyrazoles with tautomerism frozen has been published (94MRC699). The tautomerism is also frozen in the solid state. Thus two 15N shifts at 150 ppm (NH) and 222 ppm ( = N-) are observed for solid imidazole the average is close to the single signal at 186 ppm found in solution. 

A systematic study of annular tautomerism of NH-pyrazoles in the solid state has been published (88CJC1141). 

Obviously the annular tautomerism of, for instance pyrazoles, and the resonance forms of 1,2-dihydrocyclobutabenzene are fundamentally different, but one can assume that the experimentally measurable equilibrium constant in 48 will reflect the Mills-Nixon effect [62-65], Calculations show that the effect should be very considerable with small rings (cyclobutane, 48, cyclopropane, 42) that are difficult to synthesize. However, we have succeeded in preparing compound 49 that exists as 49a, as predicted by the Mills-Nixon effect [65],... 

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>. 

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). 

Low temperature studies, for instance in THF at 175 K, gives information on the annular tautomerism of N/f-pyrazoles (see Section 3.01.4.4.1) <92JCS(P2)1737> a large collection of N chemical shifts of N/f-pyrazoles (frozen tautomerism) has been published <94MRC699>. 

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... 

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. 

---