2- imidazole, calculations tautomerism

Annular tautomerism of azoles and benzazoles [the nonaromatic tautomers of imidazole 17, 2H and 4(5)H have been calculated at the MP2/6-31G level to be about 15 kcal mol less stable than the IH tautomer (95JOC2865)]. We present here the case of 4(5)-substituted imidazoles, different from the histamine, histidine, and derivatives already discussed. By analogy with these histamines, 4-methylimidazole 17a is often named distal [N(t)H] and 5-methylimidazole 17b, proximal [N(7t)H] (Scheme 9). 

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. 

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). 

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... 

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). 

Attempts to correlate reaction mechanisms, electron density calculations and experimental results have met with only limited success. As mentioned in the previous chapter (Section 4.06.2), the predicted orders of electrophilic substitution for imidazole (C-5 > -2 > -4) and benzimidazole (C-7>-6>-5>-4 -2) do not take into account the tautomeric equivalence of the 4- and 5-positions of imidazole and the 4- and 7-, 5- and 6-positions of benzimidazole. When this is taken into account the predictions are in accord with the observed orientations of attack in imidazole. Much the same predictions can be made by considering the imidazole molecule to be a combination of pyrrole and pyridine (74) — the most likely site for electrophilic attack is C-5. Furthermore, while sets of resonance structures for the imidazole and benzimidazole neutral molecules (Schemes 1 and 2, Section 4.06.2) suggest that all ring carbons have some susceptibility to electrophilic attack, consideration of the stabilities of the expected tr-intermediates (Scheme 29) supports the commonly observed preference for 5- (or 4-) substitution. In benzimidazole attack usually occurs first at C-5 and a second substituent enters at C-6 unless other substituent effects intervene. 

Histamine, a biologically important imidazole derivative, is in multiple acid-base and tautomeric equilibria in aqueous solution. Tautomeric and basic center preferences for isolated neutral and monoprotonated histamine have been studied by ab initio calculations (HF, MP2, and DFT), and the polarizable continuum model (PCM) has been... 

Progress has been made in the interpretation of the ESR spectrum of 2,4,5-triphenylimidazolyl radicals by examining the spectra of the partially and completely deuterated species and by the application of simple molecular orbital (MO) calculations. It is evident that the radicals are not planar. Some ambiguity is still present since INDO calculations indicate that the imidazyl radical should be close to a (z-radical, while ESR shows that the triphenylimidazyl radical is of the n type. The results of ESR studies of imidazole anion-radicals have been thought to demonstrate that they exist in the tautomeric a-pyrrolenine form (84) rather than 85. However, a... 

In the application of theoretical studies to the azole field many of these have attempted to achieve comparisons within the range of azole molecules. Thus, calculations of electron densities, dipole moments, and energies of formation give values that reflect the decrease in azole stability as the number of nitrogen atoms increase. ° Good correlations between a and total electron densities and and chemical shifts have been obtained. " Calculations (SCF) of n-electron distributions for the ground state of imidazole do not take into account the tautomeric equivalence of the 4-and 5-positions, but predict the order of electrophilic substitution as 5 > 2 > 4242,243 Various other quantum-mechanical calculations have... 

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. ... 

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... 

The effects on the 2-substituted compound of alkyl, aryl, and halogen substituents in the imidazole ring have also been examined, and although the rates for the 5-substituents were represented satisfactorily by quantum-mechanical calculations of 7c-electron densities for the imidazole neutral molecule predict the order of substitution as 5 > 4 > 2, but the tautomeric equivalence of the 4- and 5-positions is not taken into account. In addition, there are probably few occasions on which electrophilic substitution takes place with the neutral molecule the conjugate acid or conjugate base may be the reactive species. 

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