Methylimidazole tautomers

A theoretical ab initio study of the gas-phase basicities of methyldiazoles (90JA1303) included a discussion of the 4(5)-methylimidazole tautomer-ism. The RHF/4-31G calculations led to the conclusion that the 4-methyl tautomeric form 14a (R = Me, R = R = H) is 5.2 kJ moP more stable than its 5-methyl counterpart 14b. It was emphasized that this result is to be considered as basic-set dependent. However, a recent theoretical study [94JST(T)45] showed that, starting from the RHF/6-31G level, all the more accurate approximations indicate a higher intrinsic stability for the 4-methyl tautomer. At the MP2/6-31G level, the total energy of the 4-methyl tautomer is 0.7 kJ mol lower than that of the 5-methyl tautomer. Inclusion of solvation effects can, thus, strongly affect the position of the tautomeric equilibrium 14a 14b. Recently, a systematic theoretical study... 

Generally the name of a compound should correspond to the most stable tautomer (76AHCS1, p. 5). This is often problematic when several tautomers have similar stabilities, but is a simple and reasonable rule whose violation could lead to naming phenol as cyclohexadienone. Different types of tautomerism use different types of nomenclature. For instance, in the case of annular tautomers both are named, e.g., 4(5)-methylimidazole, while for functional tautomerism, usually the name of an individual tautomer is used because to name all would be cumbersome. In the case of crystal structures, the name should reflect the tautomer actually found therefore, 3-nitropyrazole should be named as such (97JPOC637) and not as 3(5)-nitropyrazole. 

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). 

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. 

Crystalline 2-methylimidazole exhibits different 13C (CPMAS) chemical shifts for C-4 and C-5 (125.0, 115.7 ppm). The average (120.3 ppm) is close to that reported for imidazole in deuterated DMSO (121.2 ppm). These results imply that solid state chemical shifts can be used instead of N-methyl models in tautomerism studies (87H(26)333). For imidazole the solid state l3C shifts are 137.6 (C-2), 129.3 (C-4), and 119.7 (C-5) (81JA6011). No proton exchange occurs in the solid, and the data support a structure resembling the crystal structure. Cooling imidazole solutions has not yet allowed the detection of individual tautomers, but by symmetry the compound exists in equal tautomeric forms, as does pyrazole (81CC1207). 

The tautomer 82c of 3-methylimidazole, however, was found in the 1 1 complex with rac-17. X-ray structure analysis of the above inclusion complex showed that molecules of 82c act as hydrogen-bond donors and acceptors between two dimeric assemblies of binaphthyl molecules (Scheme 2). Methyl groups are located in the vicinity of the dimeric host. However, steric hindrance of this methyl group is less important for the energetics of crystal construction than formation of two hydrogen bonds. 

For instance, the imidazole shown above exists as a rapidly equilibrating mixture of 4-methyl 3.8 and 5-methyl 3.9 tautomers, and is referred to as 4(5)-methylimidazole. It must again be stressed that tautomerisation and resonance are totally different. Mesomeric representations 3.7a,b are not interconverting like tautomers 3.8 and 3.9 this is simply a means to describe an intermediate hybrid structure. 

The presence of prototropic tautomerism can also be demonstrated when an attempt is made to synthesize the two individual tautomers of a pair. Both synthetic pathways (Scheme 11) lead to the same compound , or to a product mixture which behaves as if it was a single compound. The ultimate product (23) (in reality it is a tautomeric mixture which acts as a single compound) can be named 4(or 5)-ethyl-5(or 4)-methylimidazole, but it is now accepted practice to assume that workers in the field are aware of the implications of the simpler form of nomenclature, 4-ethyl-5-methylimidazole. When the NH group is... 

Aminoimidazoles are rather unstable and have not been studied extensively, but despite the absence of a specific study of their tautomerism it is possible to gather some evidence in favour of the amino tautomer of types (35 X = NH) (39 X = NH) or (47 X = NH). Imino structures (e.g. 34, 38, 44 X = NH) require the appropriate CH signals in the NMR spectrum these are absent, and the IR spectra display characteristic bands for NH2. The X-ray structure for 4-acetamido-2-bromo-5-isopropyl-1-methylimidazole confirms the structure (65) rather than the tautomer (66) (Scheme 21). On the basis of CNMR evidence, 2-arylamino-2-imidazolines prefer to exist in the arylimino forms (B-77MI40600). 

As described above, 4-methylimidazole and 5-methylimidazole are in a tautomeric equilibrium even at room temperature. Theoretical calculations show that the two tautomers are almost equally stable[10,ll]. Therefore, the regiospecific alkylation of 4(5)-methylimidazole(4-MI) has never been reported. 

Worth et al used the thermodynamic cycle method to study the simpler variant 4-(5-) methylimidazole (Figure 4). Here the side-chain is a methyl group, and the calculated equilibrium constant for this system is in good agreement with the known experimental data. It is found that the free energy difference in both phases is small, slightly favouring the N3H tautomer. 

Imidazoles with a ring iV-hydrogen are subject to tautomerism, which becomes evident in unsymmetri-cally substituted compounds such as the methylimidazole shown. This special feature of imidazole chemistry means that to write simply 4-methylimidazole would be misleading, for this molecule is in rapid tautomeric equilibrium with 5-methylimidazole. All such tautomeric pairs are inseparable and the convention used to cover this phenomenon is to write 4(5)-methylimidazole . In some pairs, one tantomer predominates, for example 4(5)-nitroimidazole favours the 4-nitro-tautomer by 400 1. 

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 ... 

Total energies of the neutral and protonated imidazole (13), 2-methylimidazole (14), 4-methylimidazole (15)l 4-chloroimidazole (16)Fl,4-nitroimidazole (17) l, ethylamine (18), Na-methyl-ethylamine (19), Na,Na-dimethyl-ethylamine (20), thiazole (21), and 2-aminothiazole (22) were also calculated at the same level than previous molecules, and they are presented in Table 6. Tautomers for 15-17 are considered N(s)-H. 

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