Imidazoles tautomerization

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 relationship between the delocalized imidazole anion and imidazole itself is rather like that between an enolate anion and an enol. It will come as no surprise that imidazole tautomerizes rapidly at room temperature in solution. For the parent compound the two tautomers are the same, but with unsymmetrical imidazoles the tautomerism is more interesting. We will explore this question alongside electrophilic aromatic substitution of imidazoles. 

Since 1970 there have been a number of studies of imidazole tautomerism, and aspects have been reviewed. In fact imidazoles provide one of the best-studied examples of annular tautomerism of the type shown in Eq. (21), and Kj values have been calculated for a variety of 4(5)-sub-stituted imidazoles and the results summarized. Charton s application of the Hammett equation to heteroaromatic tautomerism - has... 

As was discussed for imidazole, tautomerism makes it difficult to predict the position of the proton in this component of the purine structure. In adenine, the proton is largely found at the 9-position, whereas in guanine a mixture of the two forms is present in solution. In nucleosides, it is the 9-position that is attached to the sugar moiety as noted in section 3.2.3. The numbering in purines is exceptional to the mles of nomenclature but is accepted by the International Union of Pure and Applied Chemistry (lUPAC). It is illustrated in Figure 9.2. 

Annular tautomerism (e.g. 133 134) involves the movement of a proton between two annular nitrogen atoms. For unsubstituted imidazole (133 R = H) and pyrazole (135 R = H) the two tautomers are identical, but this does not apply to substituted derivatives. For triazoles and tetrazoles, even the unsubstituted parent compounds show two distinct tautomers. Flowever, interconversion occurs readily and such tautomers cannot be separated. Sometimes one tautomeric form predominates. Thus the mesomerism of the benzene ring is greater in (136) than in (137), and UV spectral comparisons show that benzotriazole exists predominantly as (136). 

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. 

The differential effects of sterlc hindrance and tautomeric content in the imidazole series are illustrated in Scheme 6 (80AHC(27)24i). 

A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

The 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes and -pyrroles is possible (499 500 503 504 501 502), as well as a zwitterionic... 

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). 

Imidazole, 2-amino-1 -methyl-4,5-diphenyl-tautomerism, 5, 368 Imidazole, 2-aroyl-mass spectra, 5, 360 synthesis, 5, 391, 402 UV spectra, 5, 356 Imidazole, 4-aroyl-synthesis, 5, 474 Imidazole, C-aroyl-UV spectra, 5, 356 Imidazole, aryl-nitration, 5, 396, 433 oxidation, 5, 433 Imidazole, 1-aryl-dipole moments, 5, 351 dearylation, 5, 449 ethylation, 5, 448 H NMR, 5, 353 hydroxymethylation, 5, 404 rearrangement, 5, 108 synthesis, 5, 390 thermal rearrangement, 5, 363 Imidazole, 2-aryl-chlorosulfonation, 5, 397 synthesis, 5, 475 Imidazole, 4-aryl-bromination, 5, 399 Imidazole, C-aryl-electrophilic substitution, 5, 432-433 nitration, 5, 433 Imidazole, N-aryl-reactions, 5, 448-449 structure, 5, 448-449 Imidazole, arylmercapto-... 

Imidazole, 2-aryl-4-phenyl-5-trifluoromethyl-synthesis, 5, 483 Imidazole, azido-reactions, 5, 442 Imidazole, 2-azido-, 5, 415 cyclization, 6, 980 reactions, 5, 96 with sodium, 5, 442 tautomerism, 5, 371 Imidazole, benzoyl-IR spectra, 5, 30 Imidazole, 2-benzoyl-4-phenyl-... 

Imidazole, 2-ethyl-1 -ethoxycarbonyl-4-methyl-decarboxylation, 5, 392 Imidazole, 4-ethyl-5-methyl-tautomerism, S, 363 Imidazole, 5-ethyl-4-methyl-tautomerism, S, 363... 

Imidazole, 4-methyl-annular tautomerism, 5, 363 association, 5, 362 boiling point, 5, 362 bromination, 5, 398 deuteration, 5, 417 diazo coupling, 5, 403 hydrogen bonding, S, 350 hydroxymethylation, 5, 404 iodination, 5, 400 kinetics, 5, 401 mass spectra, 5, 358 melting point, 5, 362 methylation, 5, 364 sulfonation, 5, 397 synthesis, 5, 479-480, 482, 484, 489 Imidazole, 5-methyl-annular tautomerism, 5, 363 Imidazole, l-methyl-4-chloro-ethylation, 5, 386 Imidazole, l-methyl-5-chloro-ethylation, 5, 386 nitration, 5, 395... 

Imidazole-4,5-dicarboxylic acids, coupling, 5, 403 decarboxylation, 5, 434 1-substituted synthesis, 5, 468 synthesis, 5, 362, 402, 484 Imidazole-4,5-dione, l-alkyl-2-phenyl-synthesis, 5, 129, 479 Imidazole-2,4-diones tautomerism, 5, 370 Imidazole-4,5-diones tautomerism, 5, 370 Imidazole-2,4-dithione, 5,5-diphenyl-tautomerism, 5, 370 Imidazole-2,4-dithiones tautomerism, 5, 370 Imidazolepropanol synthesis, 5, 486 Imidazoles accelerators epoxy resins, 1, 407... 

Imidazole-5-thione, 4,4-diphenyl-tautomerism, 5, 368 3 H-Imidazole-2-thione, 1,3-dimethyl-structure, 5, 367 Imidazole-2-thiones acidity, 5, 367 betaines, 5, 372 synthesis, 5, 481 tautomerism, 5, 367 3H-Imidazole-2-thiones synthesis, 5, 473, 6, 992 Imidazolides deacylation, 5, 453 mass spectra, 5, 360 phosphoric acid reactions, 5, 454 reactions, 5, 451-453 Imidazolidine, l-alkyl-3-phenyl-N-oxidation, 5, 427 Imidazolidine, 1,3-benzyl-2-phenyl-oxidation, S, 427... 

Chichibabin reaction, 5, 409-410 UV spectra, 5, 356 Naphthimidazoles, 2-amino-tautomerism, 5, 368 Naphth[2,3-h]imidazoles oxidation, 5, 405 Naphth[l,2-d]imidazolium salts nucleophilic substitution, 5, 412 Naphth[l, 2-h]isoquinolines... 

Up to the present the principal interest in heteroaromatic tautomeric systems has been the determination of the position of equilibrium, although methods for studying fast proton-transfer reactions (e.g., fluorescence spectroscopy and proton resonance ) are now becoming available, and more interest is being shown in reactions of this type (see, e.g., references 21 and 22 and the references therein). Thus, the reactions of the imidazolium cation and imidazole with hydroxyl and hydrogen ions, respectively, have recently been demonstrated to be diffusion controlled. ... 

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