Imidazole amino-, tautomeric forms

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

The 2-amino- and 2-acylamino-l- -aminoanthraquinones (231) are also photolabile, giving imidazoles of type 225 or acyldihydro-imidazoles (221).111 This may suggest that the photoreaction follows a different mechanism from that of the thermal process, and is more related to the reactions of benzoquinones described below. Thus, mesomeric or tautomeric forms such as 232 and 233 may be invoked to explain the photoreactions, by analogy with the corresponding benzoquinone imines described below. 

As discussed in the General Chapter (Section 4.01.5), imidazoles with potential hydroxy, thiol and amino substituents can exist in a variety of tautomeric forms. In contrast to the hydroxypyrazoles which have been studied in detail, comparatively little is known about the corresponding 1,3-diazoles. Many of the imidazoles are not easily accessible synthetically, and they may not be particularly stable e.g. 4-hydroxyimidazoles). Amino derivatives... 

The best known of the potential mercaptoimidazoles are the imidazoline-2- and benz-imidazoline-2-thiones, which resemble imidazolin-2-ones in that the tautomeric form (53 X = S) is the preferred form. The crystal structure and the HNMR spectrum of 1,3-dimethyl-3H-imidazoline-2-thione have been interpreted as showing partial double bond character in the N—C—N system, but no aromaticity (70CC56). However, the preference for a betaine structure (56) rather than (57) or (58) should be accepted with caution since it is really only a resonance structure similar to others which undoubtedly contribute to the overall structures of oxo-, thio- and amino-imidazoles. Measurement of the piSTa values for a series of imidazoline-2-thiones substituted variously on C-4, C-5, N-1 and N-3 by hydrogen, phenyl or methyl shows that all of the values are similar. Approximate Kr values calculated show that these compounds exist even more in the thione forms (53, X = S 58) than do the corresponding thiazoline-2-thiones and oxazoline-2-thiones. The UV spectra in aqueous solution support thione structures, as do dipole moment and X-ray studies (76AHC(S1)280, p. 400). 

Histamine is made up of an imidazole ring which can exist in two tautomeric forms as shown in Fig. 13.4. Attached to the imidazole ring there is a two-carbon chain with a terminal a-amino group. The pKa of this amino group is 9.80, which means that at a plasma pH of 7.4, the side-chain of histamine is 99.6 per cent ionized. 

Figure 19.48 Reactive tautomeric forms of vinylog of 2-amino-imidazole (according to Al Mourabit and Potier 2001).

Oroidin and its derivatives may also read with themselves by oxidative coupling, giving dimers whose typical example is mauritiamine, isolated in 1996. This particular readivity of oroidin is due to the large number of tautomeric forms of the vinylog moiety of 2-amino-imidazole, the main effect of which is that the carbon 5 on the imidazole can become either an electrophilic or a nucleophilic site (Al Mourabit and Potier, 2001). The main tautomeric forms are shown in Figure 19.48. 

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. 

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). 

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... 

Calculation of the heats of combustion for imidazoles suggest that, in substituent-nucleus tautomerism, the tautomer with the mobile proton on nitrogen should be more stable than that with it on carbon, and that the amino forms of amines, and the carbonyl forms of hydroxy compounds, are preferred. ... 

The secondary amino group of the indole ring in tryptophan has a low field shift (293 ppm), probably because of rapid tautomerism with the C = N indolenine form, in which the nitrogen has a 7i-bonded structure. However, the equilibrium favours the indole form, the deshielding contribution from the ru-electrons in the indolenine form is, therefore, small, moving the chemical shift of the indole nitrogen atom in tryptophan to much higher field than in imidazole, but to lower field than in the saturated counterpart, proline. 

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