Imidazole group tautomerism

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. 

The tautomeric ratio of B to A for histidine in water (Eq. 2-6) has been estimated, using 15N- and 13C-NMR, as 5.0 when the a-amino group is proto-nated and as 2.5 when at high pH it is unprotonated.17 This tautomerism of the imidazole group is probably important to the function of many enzymes and other proteins for example, if Ne of structure A (Eq. 2-6) is embedded in a protein, a proton approaching from the outside can induce the tautomerism shown with the release of a proton in the interior of the protein, perhaps at the active site of an enzyme. The form protonated on Ns (B of Eq. 2-6), which is the minor form in solution, predominates in some positions within proteins.18... 

Trypsin in which Asp 102 has been replaced by Asn has 1 ()4 times less catalytic activity than natural trypsin at neutral pH. From the crystal structure of the mutant enzyme it appears that the imidazole group of His 57 is held by the Asn side chain in the wrong tautomeric form for catalysis. Explain. Compare this incorrect tautomeric form with that in the initial structure shown in Fig. 12-11. 

Resonance and tautomerism are closely related. Thus the acidity of carbon-bound hydrogen in ketones, which allows formation of enol tautomers, is a direct result of the fact that the enolate anion produced by dissociation of one of these hydrogen atoms is stabilized by resonance. Similarly, tautomerism in the imidazole group of histidines is related to resonance in the imidazolium cations. 

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. 

Halogen atoms in the 2-position of imidazoles, thiazoles and oxazoles (542) undergo nucleophilic substitution reactions. The conditions required are more vigorous than those used, for example, for a- and y-halogenopyridines, but much less severe than those required for chlorobenzene. Thus in compounds of type (542 X = Cl, Br) the halogen atom can be replaced by the groups NHR, OR, SH and OH (in the last two instances, the products tautomerize see Sections 4.02.3.7 and 4.02.3.8.1). 

The main conclusion on the influence of substituents in the imidazole ring on the state of the tautomeric equilibria 14a 14b is that electron-withdrawing groups favor the 4-position, i.e., the tautomers 14a with = Hal, NO2, and so on, are the energetically preferable species. Application of Charton s equation, Kt = [4-R Im]/[5-R Im] = 3.2 was discussed in detail [76AHC(S1) 96CHEC-II(3)77]. The equation was found to be in a qualitative agreement with the experimental data presented in Table III. 

Fyrazoles and indazoles, imidazoles and benzimidazoles/ and benzotriazoles which possess a free NH group are associated and have been considered to exhibit mesohydric tautomerism see discussion in Volume 1, article I, Section I,C. 

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 strictly dehned region of chemical shifts of C2, C4, and C5 atoms in A-oxides of 4A-imidazoles allows to dehne clearly the position of the A-oxide oxygen atom (102). Chemical shifts of the a-C nitrone group in a-N-, O-, and S-substituted nitrones are located in the region of 137 to 150 ppm (388, 413). On the basis of 13C NMR analysis of 3-imidazoline-3-oxide derivatives, the position of tautomeric equilibria in amino-, hydroxy-, and mercapto- nitrones has been estimated. It is shown that tautomeric equilibria in OH- and SH-derivatives are shifted toward the oxo and thioxo forms (approximately 95%), while amino derivatives remain as amino nitrones (413). In the compounds with an intracyclic amino group, an aminonitrone (A) - A-hydroxyaminoimino (B) tautomeric equilibrium was observed (Scheme 2.76), depending on both, the nature of the solvent and the character of the substituent in position 2 of the heterocycle (414). 

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],... 

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