5 6>Substituted benzimidazoles, tautomerism

Not much information has been added in recent years to the earlier studies of tautomeric equilibria of benzimidazoles based on basicity measurements [76AHC(S1), p. 292]. For 5(6)- and 4(7)-substituted benzimidazoles and 2-methyl-5(6)-substituted benzimidazoles values are very close to 1, which indicates near equivalence in the stability of N1(H) and N3(H) tautomers. The tautomeric equilibria of 2-substituted (H, NH2, OMe, CN) 5-nitrobenzimidazoles and 4-nitrobenzimidazoles were analyzed with the use of semiempirical MINDO/3 and INDO methods. It was predicted that electron-releasing groups in position 2 shifted the equilibria to the 6-NO2 and 4-NO2 tautomers, respectively. 

By using basicity data, Ridd and Smith- showed that 5-nitro- and 5-chloro-benzimidazole and their 2-methyl analogs exist essentially as mixtures of equivalent amounts of 29 and 30, and, in agreement with this ratio, 5-substituted benzimidazoles form comparable amounts of 1- and 3-derivatives on alkylation,- showing earlier alkylation ratios- to be erroneous. There are, however, other factors which can lead to the predominance of one tautomeric form. Basicity measurements indicate that 31 is preferred to the alternative non-hydro-... 

Electrophilic attack in imidazole is usually most facile at an annular nitrogen, and there are many examples of Af-aUcylation, -protonation, -acylation, cyanation, -arylation and -silylation. A-Nitration is much less common A-oxidation is virtually non-existent. When an annular nitrogen becomes substituted, tautomerism in the molecules is blocked, and mixtures of isomers are usually formed with substituted benzimidazoles and 4(5)-substituled imidazoles. 

Imidazoles and benzimidazoles unsubstituted on nitrogen exhibit fast prototropic tautomerism which leads to equilibrium mixtures of unsymmetrically substituted compounds, for example, 4(5)-substituted imidazoles, 4(7)- or 5(6)-substituted benzimidazoles. The proton exchange is an intermolecular process (which may involve a protic solvent), and is so fast on the NMR time scale that only one species is usually apparent in the spectrum. iV-Substituted azoles cannot exhibit such tautomerism, and strongly acidic media also inhibit proton exchange. Much work since the mid-1980s has focussed on determination of the proportions of isomers in tautomeric mixtures, with theoretical studies applied to the gas phase (and solution), and solid state studies are also receiving considerable attention. Extrapolation of the results of gas phase and solid state studies to solution, though, can only be less than perfect. 

The parent compoimd, benzimidazole, is a crystalline solid with a melting point of 169-171 °C. Benzimidazoles, like imidazoles, exist as a tautomeric pair of compounds. The tautomerism of 1//-benzimidazoles is sufficiently rapid that the compormds are observed as a single species on the NMR timescale at room temperature. 1//-Benzimidazoles with substituents at the 4(7) or 5(6) positions appear to be a single compound rather than a tautomeric mixture however, replacement of the NH proton with an alkyl group or other substituent results in formation of a pair of regioisomeric compounds. Thus, regiospecificity is a consideration in the synthesis of all Y-substituted benzimidazoles that bear any substituents at the C4-C7 positions. 

Stabilization of a metal-substituted derivative of a minor tautomeric form of the Ugand was reported for the complexes of mixed benzothiazo-line-benzimidazole (388 —> 389) (71ZOB1370 98POL381) and benzothia-zoline-pyridine ligands (390 —> 391/392) (Scheme 144) (77JA7704). 

Most electrophilic substitutions in benzimidazole (31 R = H) occur primarily in the 5-position. In multiple bromination the order followed, 5 > 7 > 6,4 > 2, parallels molecular orbital calculations. In benzimidazole itself the 4(7)- and 5(6)-positions are tautomerically equivalent. Fusion of a benzene ring deactivates C-2 to electrophilic attack to such an extent that it is around 5000 times less reactive than the 2-position of imidazole. Strong electron donors at C-5 direct halogenation to the 4-position, whereas electron-withdrawing groups favor C-4 or C-6 substitution (84MI21). 

A detailed analysis of substituent effects on the pKa values of imidazoles and tetrazoles as well as benzimidazoles and naphthimidazoles has been made.308 The ortho effect is shown to parallel that of 2-substituted pyridines and quinolines47 190 and application of the Hammett equation to the tautomerism of these systems is also considered. The equation also satisfies the effect of substituents on the basicity of the nitrogen in the 1-position for 1-pyrazolines.309... 

Attempts to correlate reaction mechanisms, electron density calculations and experimental results have met with only limited success. As mentioned in the previous chapter (Section 4.06.2), the predicted orders of electrophilic substitution for imidazole (C-5 > -2 > -4) and benzimidazole (C-7>-6>-5>-4 -2) do not take into account the tautomeric equivalence of the 4- and 5-positions of imidazole and the 4- and 7-, 5- and 6-positions of benzimidazole. When this is taken into account the predictions are in accord with the observed orientations of attack in imidazole. Much the same predictions can be made by considering the imidazole molecule to be a combination of pyrrole and pyridine (74) — the most likely site for electrophilic attack is C-5. Furthermore, while sets of resonance structures for the imidazole and benzimidazole neutral molecules (Schemes 1 and 2, Section 4.06.2) suggest that all ring carbons have some susceptibility to electrophilic attack, consideration of the stabilities of the expected tr-intermediates (Scheme 29) supports the commonly observed preference for 5- (or 4-) substitution. In benzimidazole attack usually occurs first at C-5 and a second substituent enters at C-6 unless other substituent effects intervene. 

The SCF calculations (Section 4.06.2) predict the sequence of electrophilic attack in benzimidazole as 7 > 6 > 5 > 4, although positions 4 and 7, and 5 and 6 are tautomerically equivalent in iV-unsubstituted benzimidazoles. Substitution appears to occur with greatest facility in the 5- (or 6-) positions. Bromination in acetic acid of 2-amino-l-methylben-zimidazole occurs at C-6. It can be seen from Table 5 (Section 4.07.1.4.5) that aqueous bromination of benzimidazole itself occurs most readily at C-5, followed by C-7, as it does in the 1- and 2-methyl analogues (78JCS(P2)865). Some of the experimental results are summarized in Scheme 93. Chlorination of both benzimidazole and 2-methylbenzimidazole give the 4,5,6-trichloro product. Nitration and sulfonation, too, occur most readily at position 5 with either sulfuric or chlorsulfonic acids being effective in the latter reaction. 

Acyl-substituted imidazoles have distinctive UV and IR spectra, and can exist as hydrates in solution, e.g. imidazole-2-carbaldehyde. The aldehyde group is sufficiently electron withdrawing to assist nucleophilic displacement of an adjacent halogen atom. The normal aldehyde derivatives such as oximes, acetals and hydrazones can be formed, and the kinetics of oxime formation with the 4-carbaldehyde have been studied. The tautomeric ratio (zwitterion uncharged aldehyde form) of 1-substituted imidazole- and benzimidazole-2-aldoximes rises in parallel with an increase in basicity of the parent molecule (73CHE1074). These compounds have been shown by NMR studies to adopt the syn configuration. With hydrazine hydrate, imidazole-4,5-dicarbaldehydes give imidazo[4,5-d]pyridazines (208 Scheme 110). 

Sridharan V, Saravanan S, Muthusubramanian S, Sivasubramanian S. NMR investigation of hydrogen bonding and 1,3-tautomerism in 2-(2-hydroxy-5-substituted-aryl) benzimidazoles. Magn Reson Chem 2005 43(7) 551-556. 

Hydrogen bonding and 1,3-tautomerism have been studied by Siidharan et al for a series of 2-(2-hydroxy-5-substituted-aryl)benzimidazoles for which H-H couplings across three- and four-bonds have been measured in various solvents. 

Changing the identity of the ortho substituent of aryl azides dramatically influences its reactivity toward transition metals. Shen and Driver discovered that substitution of a vinyl group with an iminyl moiety enables Fe(II)-catalyzed benzimidazole (65) formation (Scheme 16.29) [48]. It was proposed that coordination of iron(II) bromide to the imino nitrogen of 64 facilitates the C—N bond formation through nucleophilic attack of an azido nitrogen to the activated imino carbon, leading to B. Expulsion of N2 followed by tautomerization affords the benzimidazoles 65. 

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