Tautomerism in imidazoles

A complicating factor in imidazoles is tautomerism. Imidazole tautomerizes rapidly in solution and consists of two identical tautomers. This becomes a problem, though, in an unsymmetrically substituted imidazole, and tautomerism means 4-methylimidazole is in equilibrium with 5-methylimidazole. Depending upon substituents, one tautomer may predominate. Tautomerism of this kind cannot occur with -substituted imidazoles it is totally dependent upon the presence of an N-H group. Tautomerism is also not possible with oxazoles or thiazoles. 

Therefore, when we meet structures for the imidazole-containing amino acid histidine, we may encounter either of the tautomeric forms shown. Though there 

The imidazole ring of histidine acid-base properties 

The amino acid histidine contains an imidazole ring. We have just seen that unsubstituted imidazole as a base has p/Ca 7.0. From the Henderson-Hasselbalch equation 

The imidazole side-chain of histidine has a value of 6.0, making it a weaker base than the unsubstituted imidazole. This reflects the electron-withdrawing inductive effect of the amino group, or, more correctly the ammonium ion, since amino acids at pH values around neutrality exist as doubly charged zwitterionic forms (see Box 4.7). Using the Henderson-Hasselbalch equation, this translates to approximately 9% ionization of the heterocyclic side-chain of histidine at pH 7 (see Box 4.7). In proteins, plCa values for histidine side-chains are estimated to be in range 6-7, so that the level of ionization will, therefore, be somewhere between 9 and 50%, depending upon the protein. 

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All triazoles, tetrazoles, and unsymmetrically substituted imidazoles and pyrazoles can exist in two tautomeric forms, e.g., 1 2 and 3 4. However, attempts to isolate the individual tautomers have been unsuccessful, always leading to one isomer (for summaries of this aspect of the tautomerism of imidazoles, see references 1 and 2). Although the isolation of both tautomers of a number of com-... 

Besides pyrazoles and imidazoles, we have extended these studies to other azoles, for instance to C-halogeno 1/7-1, , 4-triazoles 60 (X = Cl, Br) [73] (for DFT studies of other C-substituted 1,2,4-triazoles, see [74]) and to 5-substituted tetrazoles 61 (X = H, CH3, t-Bu, C6H5, Cl, CF3, N02) [75], The 1,2,4-triazole series 60 was examined regarding tautomerism in solution and in the solid state (the most stable is 60a and the least stable 60c). The paper on 5-substituted tetrazoles 61 concerns, besides tautomerism, their ionization (proton loss) to tetrazolate anion 62. 

Whatever be the difficulties in dealing satisfactorily with the problem of the lactam-lactim tautomerism in hydroxypurines, the predominance of the lactam tautomer granted, there remains the problem of the detailed structure of the most probable lactam form for each isomer. The problem is essentially that of the site of location of the imidazole proton. From that point of view forms 34-38 have to be considered for 2-hydroxypurine, forms 39—42 for 6-hydroxypurine (hypoxanthine), and forms 43-45 for 8-hydroxypurine. There are, in addition, some betaine tautomeric forms but these are probably of low stability and will not be considered further. Before describing the results of theoretical calculations, it may be useful to indicate that from the experimental point of view we may, in this respect, turn again for significant evidence to infrared spectroscopy... 

In general, IR spectroscopy has neither been a particularly valuable structural tool in imidazole chemistry, nor has it found particular application in tautomerism studies. The IR spectra of nitroimidazoles and their salts have been claimed to indicate that the salt formation involves only the nitro function, with the formation of an isoimidazole ring (17). In polynitroimidazoles only one of the nitro functions appears to be involved in such salt formation <70AHC(12)103, 74CRV279, 80AHC(27)24l). 

When the imidazole ring is considered to be something resembling a pyrrole-pyridine combination (1) it would appear that any electrophilic attack should take place preferably at C-5 (pyrrole-or, pyridine-j8). Such a model, though, fails to take account of the tautomeric equivalence of C-4 and C-5 (Section 4.06.5.1). The overall reactivities of imidazole and benzimidazole can be inferred from sets of resonance structures in which the dipolar contributors have finite importance (Section 4.06.2) or by mesomeric structures such as (2). These predict electrophilic attack in imidazole at N-3 or any ring carbon atom, nucleophilic attack at C-2 or C-1, and also the amphoteric nature of the molecule. In benzimidazole the acidic and basic properties, the preference for nucleophilic attack at C-2 and the tendency for electrophiles to react at the fused benzene ring can be readily rationalized. 

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. 

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. 

When unsymmetrical imidazoles are alkylated, mixtures of isomeric products are usually formed, e.g. methylafion of 4(5)-methylimidazole gives about equal quantities of the 1,4- and 1,5-dimethylimidazoles under a variety of reaction conditions. The orientation of A-alkylation of such unsymmetrical imidazoles is controlled by a number of factors (reaction conditions, polar and steric natures of the substituent(s), the nature of the alkylating agent, solvent, tautomerism in the substrate) [2], An understanding of these factors can help with the preferential synthesis of one of the possible isomers (6) and... 

Aminonitrone-A -hydroxyaminoimine tautomerism in 2-substituted l-hydroxy-4,4,5,5-tetramethyl-4,5-dihydro-l//-imidazole 140 is considered to be an acid-base equilibrium with the ratio between the forms dictated by the ratio of their acidity constants. A substituent with a positive mesomeric and/or inductive effect stabilizes the nitrone form 140A more effectively than the A-hydroxyaminoimino form 140B (Scheme 35) <2004JST(697)49>. ... 

The increasing interest in C-NMR spectroscopy has resulted in a number of such studies in the imidazole field. Carbon-13 chemical shifts in a variety of solvents have been reported for imidazoles, 4-methyl-imidazole and its cation, phenylimidazoles, 1-acetylimidazole, and Fe(III) porphyrin-imidazole complexes.The influence of Mn(II) and Cu(II) on nuclear relaxation rates in imidazole has been studied C-2 appears at lowest field (136.2), while C-4 and C-5 are at 122.3 Hz. While C-NMR studies have been of some value in conformational studies,the shifts are of limited value only in ascertaining positions of tautomeric equilibrium for rapidly interconverting tautomers. ... 

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