4 -Nitroimidazole, tautomerism

Theoretical studies of the relative stabilities of tautomers 14a and 14b were carried out mostly at the semiempirical level. AMI and PM3 calculations [98JST(T)249] of the relative stabilities carried out for a series of 4(5)-substituted imidazoles 14 (R = H, R = H, CH3, OH, F, NO2, Ph) are mostly in accord with the conclusion based on the Charton s equation. From the comparison of the electronic spectra of 4(5)-phenylimidazole 14 (R2 = Ph, R = R3 = H) and 2,4(5)-diphenylimidazole 14 (R = R = Ph, R = H) in ethanol with those calculated by using ir-electron PPP method for each of the tautomeric forms, it follows that calculations for type 14a tautomers match the experimentally observed spectra better (86ZC378). The AMI calculations [92JCS(P1)2779] of enthalpies of formation of 4(5)-aminoimidazole 14 (R = NH2, R = R = H) and 4(5)-nitroimidazole 14 (R = NO2, R = R = H) point to tautomers 14a and 14b respectively as being energetically preferred in the gas phase. Both predictions are in disagreement with expectations based on Charton s equation and the data related to basicity measurements (Table III). These inconsistencies may be... 

An unusual observation was noted when ethanolic solutions of 2-alkyl-4(5)-aminoimidazoles (25 R = alkyl) were allowed to react with diethyl ethoxymethylenemalonate (62 R = H) [92JCS(P1)2789]. In addition to anticipated products (70), which were obtained in low yield ( 10%), the diimidazole derivatives (33 R = alkyl) were formed in ca.30% yield. The mechanism of formation of the diimidazole products (33) has been interpreted in terms of a reaction between the aminoimidazole (25) and its nitroimidazole precursor (27) during the reduction process. In particular, a soft-soft interaction between the highest occupied molecular orbital (HOMO) of the aminoimidazole (25) and the lowest unoccupied molecular orbital (LUMO) of the nitroimidazole (27) is favorable and probably leads to an intermediate, which on tautomerism, elimination of water, and further reduction, gives the observed products (33). The reactions of amino-imidazoles with hard and soft electrophiles is further discussed in Section VI,C. 

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. 

Pd(0)-catalyzed allylations of 4(5)-nitroimidazole, 2-methyl-4(5)-nitroimidazole, 4(5)-bromoimidazole and 4(5)-methoxyimidazole resulted in complicated mixtures, which did not necessarily reflect the tautomeric ratios of the starting material [7], For example, poor regioselectivity for the products (70 and 71) was observed in the Tsuji-Trost reaction of 4(5)-bromoimidazole with cinnamyl carbonate. However, the same reaction with 4(5)-nitroimidazole and 2-methyl-4(5)-nitroimidazole led predominantly to the l-allylation products. In addition, removal of the 77-imidazole allyl groups can be selectively effected under mild conditions by Pd-catalyzed ic-allyl chemistry [55],... 

Two tautomeric equilibria have been considered for substituted imidazoles, that between 2-imidazolone 3 and its 2-hydroxyimidazole tautomer 4 [268] and also that between the 1H and 3H tautomers of 4-nitroimidazole, 6 and 5, respectively [269, 270], Karelson et al. used the D02 model with a spherical cavity of 2.5 A radius and found 2-imidazolone to be better solvated than its tautomer by 7.7 kcal/mol at the AMI level. [The asterisk in D02 indicates that the reaction field... 

The enteric bacterium Enterobacter cloacae produces a nitroreductase that reduces nitrofurans, nitroimidazoles, nitrobenzene derivatives, and quinones (Bryant DeLuca, 1991). This oxygen-insensitive enzyme has been purified and is known to require FMN to transfer reducing equivalents from NAD(P)H to the nitroaromatic compounds, TNT being the preferred substrate. Aerobically, this enzyme reduces nitrofurazone through the hydroxylamine intermediate, which then tautomerizes to yield an oxime end-product. Anaerobically, however, the reduction proceeds to the fully reduced amine adduct. When E. cloacae was grown in the presence of TNT, the nitroreductase activity increased five- to tenfold. 

Nitroimidazole in solution (amphiprotic medium) is stabilized as the 5-nitro isomer due to formation of hydrogen bond with an aprotic protophilic solvent [1124], The medium favors displacement of the tautomeric equilibrium toward the 4-nitro isomer via formation of a solvate complex at the same time 4-nitroimi-dazole acts as hydrogen-bond acceptor. The specific solvatochromic effect in the UV spectrum of 4-nitroimidazole is caused by the electronic configuration of the excited jr,ji -state [1124],... 

The results of the tautomeric equilibrium study of 4(5)-nitroimidazole show that in the gas phase both tautomers have similar energy, but in the solution the 4-tautomer is more stable than the 5-nitro one [256, 1124], The dipole moment of 4(5)-nitroimidazole is practically the same as that of l-methyl-4-nitroimidazole (Table 3.72). 

The use of mass spectrometry in tautomerism studies of azoles, in particular of 4(5)-nitroimidazoles [1297, 1301], 2-methyl-4(5)-nitroimidazoles [367] and 3(5)-methyl-5(3)-nitropyrazole [1282], can afford only qualitative information. 

Photoelectron spectra (PE) experimental of some 4-nitropyrazoles, nitroimidazoles, [1119, 1405] and nitrobenzimidazoles [1193, 1406] have been recorded and interpreted in terms of semiempirical AM-1 method. PE spectroscopy is not a widely used method to study tautomeric equilibria in the gas phase although it can give excellent results. PE spectra data and 6-31G/6-31G calculations show that in the gas phase tautomers 4-nitro- and 5-nitroimidazole have the similar energy [1301], However in water, 4-nitroimidazole is much more stable (8AG°=3.5 kcal/mol >99% at 25°C.) than the 5-nitro tautomer. The authors [1301] show that this is conditioned by solvation effect. Probably it is connected with the large difference in dipole moments of the tautomers (see Table 3.72). 

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). 

Another way to study tautomerism is through p/iTa measurements. A comparison of the basic pATa values for 4(5)-nitroimidazole with those of l-methyI-4- (29) and l-methyl-5-nitroimidazole (30) leads one to the conclusion that the 4-nitro tautomer (28) predominates (Scheme 13) in fact the 4-nitro 5-nitro ratio has been computed as about 400 1. In this experiment the methylated compounds serve as fixed models in which the nitro substituent is fixed in each of the two possible orientations. The influence of the methyl group can be shown to be small by comparison of the pATa values for imidazole ( 7.0) and 1-methyl-imidazole ( 7.1), and hence l-methyl-4-nitroimidazoIe resembles the major tautomer. 

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. 

As a rule of thumb one ean assume that reactions which are carried out in basic media involve the anion (5), which A -alkylates to give mainly the 1,4 isomer (6) if R is bulky or electron-withdrawing. In free base alkylations the tautomeric mixture (3) (4) reacts. An electron-withdrawing substituent (R) will ensure that much of the reaction will be with the major tautomer (3) even if that tautomer is the less reactive. The product mixture formed will have mainly 1,5 regiochemistry (7), e.g. 4(5)-nitroimidazole methylated in basic medium gives mainly l-methyl-4-nitroimidazole in neutral media l-methyl-5-nitroimidazole forms almost exclusively. Sterically demanding groups, however, favour the 1,4 isomer. Table 7.1.1 lists some other examples. 

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 ... 

The tautomeric character of the imidazole system is involved in the synthesis of the related dmg dimetridazole (9.52, 1,2-dimethyl-5-nitroimidazole), which is an effective agent against trichomonal infections in veterinary medicine (Scheme 9.28). The synthesis involves the nitration of 2-methylimidazole to form 2-methyl-5-nitroimidazole (9.50), followed by N-methylation. However, compound 9.50 is involved in tautomeric equilibrium with compound 9.51 (2-methyl-4-nitroimidazole), which would give an isomer (9.53) on methylation. This can be avoided by the proper choice of solvent. Using a nonpolar solvent for methylation with dimethyl sulfate, the desired 9.52 is the predominant product. Tautomerism is a complicating factor in imidazole chemistry where an NH unit is present, and N-alkyl derivatives are more commonly encountered. We will see this factor again with the purines. 

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