Imidazole, tautomeric forms

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). 

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... 

MO studies (AMI and AMI-SMI) on the tautomerism and protonation of 2-thiopurine have been reported [95THE(334)223]. Heats of formation and relative energies have been calculated for the nine tautomeric forms in the gas phase. Tire proton affinities were determined for the most stable tautomers 8a-8d. Tire pyrimidine ring in the thiones 8a and 8b has shown a greater proton affinity in comparison with the imidazole ring, or with the other tautomers. In solution, the thione tautomers are claimed to be more stabilized by solvent effects than the thiol forms, and the 3H,1H tautomer 8b is the most stable. So far, no additional experimental data or ab initio calculations have been reported to confirm these conclusions. 

All triazoles, tetrazoles, and unsymmetrically substituted imidazoles and pyrazoles can exist in two tautomeric forms, e.g., 1 2 and 3 4. However, attempts to isolate the individual tautomers have been unsuccessful, always leading to one isomer (for summaries of this aspect of the tautomerism of imidazoles, see references 1 and 2). Although the isolation of both tautomers of a number of com-... 

Optically active imidazol-4-one-5-acetic acid has been prepared by Kny and Witkop, and therefore it must exist as 108 or 109 rather than as 110. Similarly, Grob and Ankli -- have presented ultraviolet and infrared spectral evidence for compounds of type 111 existing in the 0X0 form. These same investigators considered structure 112 rather than 113 to represent the predominant tautomeric form of the O-methyl derivatives how ever, it would be most surprising if this conclusion were correct. 

In isocytosine and anthranilic acid it seems that any given molecule is always of the same tautomeric form in the crystal that is, the proton is not moving from site to site in the hydrogen bond. In general, however, the question of whether the proton is localized or not was difficult to answer until the advent of solid-state NMR Thus, for example, there has been much controversy as regards imidazole, 48. On the one hand there were the proponents of delocalization on this basis Zimmerman introduced his controversial theory of proto-merism (106). Others argued for localization. Recently evidence from high-resolution l3C NMR of the solid has provided evidence in support of the latter (107). A similar situation exists for pyrazole, 49 (107). 

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

The H-NMR signal for the proton at C-4 in 88 (Scheme 26), the only 4H-imidazole known to be stable in this tautomeric form, is found at S 5.17. Only single examples of a base (79) and a cation (74) " with a proton at C-2 have had spectra recorded (Scheme 26) no data are available for protons at C-5. 

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). 

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. 

There is general consensus on the fact that the endogenous agonist histamine, 2-(imidazole-4-yl)ethylamine, binds to the receptor in its monocationic state (protonated at the side chain amine group). The monocationic form is predominantly (96.6%) present at pH 7.4 [11]. In this state, the neutral imidazole ring can exist in two different tautomeric forms, denominated by proximal (it) and tele (x), respectively (Figure 1). 

All potent H3 ligands posses an imidazole ring. In it s neutral form, the imidazole can exist in two tautomeric forms (Nre and NT, respectively). At present, it is not clear which tautomeric form is recognised by the receptor. 

Imidazole ring of distal cystidine participates in the reaction shaped as fixed tautomeric form III. 

This precaution stated, a simultaneous theoretical investigation of the essential spectroscopic features of the lactam and lactim forms of the three fundamental monohydroxypurines yields some interesting results. These are summarized in Table XII, together with the corresponding experimental data, which in the case of lactim forms refer to the methoxy derivatives. As in all these compounds there is besides the lactam-lactim tautomerism, the possibility of an oscillation of the imidazole proton between the different N atoms of the ring system, Table XII indicates the exact tautomeric form or forms to which the calculations refer. In case of the lactam forms these are the most probable tautomers of such forms obtained in the study described in the next section. For the lactim forms they are the a priori most probable ones. 

Whatever be the difficulties in dealing satisfactorily with the problem of the lactam-lactim tautomerism in hydroxypurines, the predominance of the lactam tautomer granted, there remains the problem of the detailed structure of the most probable lactam form for each isomer. The problem is essentially that of the site of location of the imidazole proton. From that point of view forms 34-38 have to be considered for 2-hydroxypurine, forms 39—42 for 6-hydroxypurine (hypoxanthine), and forms 43-45 for 8-hydroxypurine. There are, in addition, some betaine tautomeric forms but these are probably of low stability and will not be considered further. Before describing the results of theoretical calculations, it may be useful to indicate that from the experimental point of view we may, in this respect, turn again for significant evidence to infrared spectroscopy... 

Furthermore, certain substituted imidazoles can exist in two tautomeric forms. 

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. 

It is not possible to separate the isomers of imidazole in which the 4- or 5-positions are substituted (and the imino nitrogen is unsubstituted), although, as mentioned previously (Section III,G), they are reported to enter into chemical reactions in one of the tautomeric forms.226,305 Exchange of the imino hydrogen atom across the... 

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). 

In the MAS NMR spectra of histidine-dipeptides, the C chemical shifts for and C span a large range (up to 13 ppm) and are highly influenced by the tautomer effect and intermolecular interactions <2005JA12544>. The imidazole ring chemical shifts of 50 (158.6, 123.8 (Vcf = 36.0), 131.0 ppm, Scheme 14) resemble more closely those of l-methyl-5-(/i-tolyl)-4-trifluoromethyl-l//-imidazole (137.6, 128.8 ( cF = 37.4Hz), 133.0ppm). Based on this observation, it was proposed that in the solid state 50 most likely assumes the tautomeric form 50a rather than 50b <2001JHC773>. 

Now purine itself exists in two tautomeric forms (I and II), presumably in a state of equilibrium, but when a hydrogen of the imidazole nucleus ia substituted, the resulting derivative is of one form or the other. In formula I, there are replaceable hydrogen atoms at positions ... 

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