Tautomerism, annular

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). 

Pyrazole Equivalent Electron-withdrawing group prefers 3-position 

Structure of Five-membered Rings with Two or More Heteroatoms 

The situation is more complex for triazoles and tetrazoles where qther effects such as lone-pair repulsions intervene see discussion in (76AHC(SD296). 

The discovery that 3,5-dimethylpyrazoIe shows prototropic, tautomerism in the solid state (crystallography and CPMAS NMR) has been one of the most important discoveries since the mid- 

One of the rare NH-pyrazoles which is liquid at room temperature is 3(5)-methylpyrazole (11). The pure liquid is probably a 50 50 mixture of both tautomers in solution 92JOC3938 (the same conclusion is true for 3(5),4-dimethylpyrazole 90JA1303 . The inclusion of the compound in a host affords a 1 1 1 complex of the host with both tautomers present in the crystal. This has allowed the determination of the x-ray structure of (11a) and (11b) simultaneously 88CL106l . Theoretical calculations at the 6-31G //6-31G level (see Section 3.01.2.1) on 3(5)-methylpyrazole (11) lead to the conclusion that 3-methyl tautomer (11a) is slightly more stable than 5-methyl tautomer (11b) by 0.4 kcal mol 89MI 30l-oi . Moreover, the 3-methyl tautomer appears to be more acidic and more basic than the 5-methyl one. 

Two related compounds were prepared afterwards 93ccii39 and one of them, a 1 1 complex of the host and pyrazole (7) crystallizes in the form of a tetramer which presents proton transfer in the solid state involving nitrogen and oxygen atoms. The system has been studied by a combination of x-ray crystallography and dynamic high resolution solid state NMR spectroscopy. 

The tautomerism between 3-trifluoromethyl-5-methylpyrazole (44a) and 3-methyl-5-trifluoro-methylpyrazole (44b) has been discussed in detail 83IC774 the authors favor tautomer (44a). In the case of 3(5),4-polymethylenepyrazoles 91JHC647 , the position of the tautomeric equilibrium is directed by the Mills-Nixon effect thus, the 3,4-trimethylene tautomer (65b) is much more stable than the 4,5-one (65a) (AG = 1.3 kcal moU ) 94NJC269 (the x-ray structure of its hydrochloride has been determined 93Mi 30i-02 . The fact that campho[c]pyrazole (221) (see Section 3.01.10.1.2(ii)) exists in the solid state and in solution as the 2//-tautomer is another consequence of the Mills-Nixon effect 93AX(C)724 . 

The first example of desmotropy (two tautomers that crystallize in two different crystals) in azoles has been found by x-ray crystallography it concerns 3-methyl-4-nitropyrazole (66a) and its tautomer, 5-methyl-4-nitropyrazole (66b) 94CC1143 . 

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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). 

Annular tautomerism does not occur in isothiazoles or benzisothiazoles. Substituent tautomers can sometimes be distinguished by chemical methods, but it is important that reaction mechanisms and the relative rates of interconversion of tautomeric starting materials or isomeric reaction products are carefully investigated. Physical methods only will be considered in this section, and references to original publications can be found in a comprehensive review (76AHC(S1)1). 

Imidazole, 4-methyl-annular tautomerism, 5, 363 association, 5, 362 boiling point, 5, 362 bromination, 5, 398 deuteration, 5, 417 diazo coupling, 5, 403 hydrogen bonding, S, 350 hydroxymethylation, 5, 404 iodination, 5, 400 kinetics, 5, 401 mass spectra, 5, 358 melting point, 5, 362 methylation, 5, 364 sulfonation, 5, 397 synthesis, 5, 479-480, 482, 484, 489 Imidazole, 5-methyl-annular tautomerism, 5, 363 Imidazole, l-methyl-4-chloro-ethylation, 5, 386 Imidazole, l-methyl-5-chloro-ethylation, 5, 386 nitration, 5, 395... 

Annular tautomerism of azoles and benzazoles [the nonaromatic tautomers of imidazole 17, 2H and 4(5)H have been calculated at the MP2/6-31G level to be about 15 kcal mol less stable than the IH tautomer (95JOC2865)]. We present here the case of 4(5)-substituted imidazoles, different from the histamine, histidine, and derivatives already discussed. By analogy with these histamines, 4-methylimidazole 17a is often named distal [N(t)H] and 5-methylimidazole 17b, proximal [N(7t)H] (Scheme 9). 

The calculation of the proton affinities (PA) for a pair of tautomers and the comparison with experimental data [generally from ICR measurements (Section VII,F)] has been the subject of a series of publications with increasing sophistication (Table IV). Such calculations concerning the annular tautomerism of azoles and benzazoles have been reviewed [87AHC(41)187]. 

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). 

There was never any doubt that the major tautomer in the case of in-dazole 27 is the IH-one 27a (Scheme 16), and C chemical shifts compared with those of the two V-methyl derivatives confirmed that this is the case in DMSO-dg (770MR716). NMR has been used to determine the equilibrium isomeric composition of N-CHROH, N-C(CH3)20H, N-COCH3 and N-Si(CH3)3 derivatives for azoles and benzazoles, the conclu-sipn being that this composition parallels the annular tautomeric composition [78JCS(P2)99]. The tautomerism of 1-hydroxybenzotriazole was also studied... 

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]... 

Both tautomers at RT (unusual) Both tautomers on cooling (Kt) Annular tautomerism in azoles (AG and 4G )... 

The largest series of papers (third column) is related to the study of annular tautomerism in azoles. This class of tautomerism is especially well suited for DNMR because in many cases Kt = 1 (autotrope) and because the activation barriers are in the range easy to be measured by NMR. To... 

We now discuss the annular tautomerism of azoles. For 5-phenyltetra-zole, the 2//-tautomer was found predominant in polyvinyl alcohol film (based on the determination of polarization angles of electronic transition... 

In the field of azoles, Catalan, Abboud, and Elguero [87AHC(41)187] carried out a series of studies which show the interest of the ICR method for a case where the correction always corresponds to an N-methylation effect which can be estimated accurately. This is the case for (1) the annular tautomerism of indazole and its relationship with the annulation effect... 

D. General Conclusions on the Factors Affecting Annular Tautomerism. 201... 

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