Imidazoles annular tautomerism

Equilibrium Constants Kt = 14a/14b) for Imidazole Annular Tautomerism as Determined erom Measurements... 

Table 8 K-j- Values for Imidazole Annular Tautomerism <76AhC(S1)280>...

Table 8 Ky Values for Imidazole Annular Tautomerism (76ahcis1)2So)...

This special case of prototropy is known as annular tautomerism (see p 111). In solution, equilibria are established so rapidly that the separate tautomers cannot be isolated. However, their presence can be demonstrated by spectroscopic methods. In this case, e.g. R = CH3, the compound is known as 4(5)-methylimidazole. With certain substituents R, the equilibrium lies predominantly to one side, for instance, in the case of the nitro compound (4-nitroimidazole) or with the methoxy compound (5-methoxy-imidazole). Annular tautomerism has also been demonstrated for 4,5-disubstituted imidazoles ... 

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. 

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). 

While dealing with imidazoles, an important characteristic is their annular tautomerism. A tautomeric equilibrium for many imidazoles is rapidly achieved at room temperature. In some tautomeric pairs, though, one tautomer often predominates over the other. For instance, 4(5)-bromoimidazole favors the 4-bromo-tautomer in a 30 1 ratio, whereas 4(5)-nitroimidazole exists predominantly as the 4-nitro tautomer (700 1) [11]. 4(5)-Methoxyimidazole has a ratio of 2.5 1 for the 4- and 5-methoxy tautomers. 

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. 

The crystal molecular structure of /V1-hydroxylophine A -oxide (= I -hydroxy-2,4,5-triphenyl-17/-imidazole 3-oxide) (59) has been determined [72], This compound presents a case of degenerate or autotrope tautomerism (59a and 59b are identical), which is very common in annular tautomerism of NH-azoles but very rare in functional tautomerism [40], In the solid state, the tautomeric proton is in the middle between two consecutive monomers of the catemer [59]n [72],... 

Disubstituted 1/f-imidazoles are classic examples of prototropic annular tautomerism. Depending on the nature of substituents, one tautomer may predominate over the other, as in the case of trifluoromethyl-substituted imidazole 50, where form 50A is the major component in solution in DMSO or CH3CN. In an unusual case, the two tautomers, 4-nitro-5-methoxyimidazole 136A and 5-nitro-4-methoxyimidazole 136B, were found as a 50 50 mixture in the crystal structure (Scheme 30) <2004AXB191>. 

Since 1970 there have been a number of studies of imidazole tautomerism, and aspects have been reviewed. In fact imidazoles provide one of the best-studied examples of annular tautomerism of the type shown in Eq. (21), and Kj values have been calculated for a variety of 4(5)-sub-stituted imidazoles and the results summarized. Charton s application of the Hammett equation to heteroaromatic tautomerism - has... 

Alkylation, acylation, sulfonation and silylation occur on the N-atoms of imidazoles [116]. Other reagents substitute onto the C-atoms 4 and 5, which are equivalent as a result of annular tautomerism. 

Benzimidazole, Ka = 5.68, is less basic than imidazole, but with i Ka = 12.75 is more strongly NH-acidic [121]. Like imidazoles, benzimidazoles display annular tautomerism in solution, e.g. ... 

For historical reasons, the numbering of purine (imidazo[4,5-d]pyrimidine) does not comply with lUPAC rules. The X-ray structure of purine shows that the imidazole part is planar and the fused pyrimidine ring deviates from a coplanar arrangement (see Fig. 6.20). Purine exists in two tautomeric forms, namely 7i/-purine 1 and 9//-purine 2, which are in equal concentration in solution (annular tautomerism). In the solid state, the 7//-form is dominant ... 

C NMR studies, especially in the solid state (83H(20)1713), are of value in studies of tautomerism (83H(20)1713, 86ZC378). Solid state studies on imidazole (and pyrazole) show there are three distinct signals for the annular carbon atoms (imidazole C-2, 136.3 C-4, 126.8 C-5, 115.3 ppm). Proton exchange does not occur in the solid, hence the compounds resemble their crystal structures. Comparison with the corresponding chemical shifts for 1-methylimidazole (137.6, 129.3, 119.7 ppm) implies that the tautomerism has been frozen in the solid state (81CC1207). Solid-state examination of 2,2 -bis-lH-imidazole also reveals frozen tautomerism. 

When the imidazole ring already has a substituent at C-4 or C-5 then there will be a directional effect imposed on electrophilic attack at annular nitrogen. As outlined earlier (Section 4.02.1.3) this orientation may be related to the tautomeric nature of the substrate. In spite of the inherent pitfalls in equating tautomeric nature with chemical reactivity there are examples which seem only to be explicable in terms of a major tautomer reacting, e.g. methylation of 4-nitroimidazole. Substituents at C-2 can only affect the rate of a reaction at ring nitrogen. 

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