Tautomeric forms of imidazole

The results were compared with theoretical calculations for 4-methyl Imidazole (Fig. 8). At low pH corresponding to the protonated Imldazollum Ion, the agreement between theory and experiment Is remarkably good. At high pH corresponding to the neutral Imldeizole moiety, It becomes necessary to consider the two tautomeric forms of Imidazole. The observed coupling constant Is related to the fractional population of the N-1 protonated tautomer, f, by ... 

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. 

Despite this success, burimamide was not suitable for clinical trials since its antagonist activity was still too low for oral administration. Further developments were needed. Attention was now directed to the imidazole ring of burimamide and, in particular, to the various possible tautomeric forms of this ring. It was argued that if one particular tautomer was preferred for binding with the H2 receptor, then activity might be enhanced by modifying the burimamide structure to favour that tautomer. 

The pH dependence of the C-N one-bond couplings on the protonation state and tautomeric form of the imidazole ring has been used by Shimba et al for quantitative idendification of the protonation state of histidines in vitro and in vivo. The compound studied was the bacterial protein NmerA, and the intracellular pH of 7.1 has been determined in the Escherichia coli cytoplasm. 

The tautomeric form of l-methyl-2-thiohydantoin added easily to the C=C double bond of (triphenylphosphoranylidene)ketene. A subsequent intramolecular cyclization afforded a thioxo-(triphenylphosphoranylidene-)hexahydro-furo-[2,3-d]imidazol-5-one (Scheme 99). ... 

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. 

Two air- and moisture stable secondary phosphine oxides, namely 2- tert-butylhydrophosphoryl)- -aryl-1//-imidazoles were synthesized. The reaction was accompanied by a side-reaction giving rise to a tricyclic phosphine oxide (Scheme 22). The reaction of the phosphinous acid tautomeric form of the above synthesized P-ligands with Pd(DOD)Cl2 gave the corresponding mono - and di -palladium complexes (Scheme 23). ... 

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. 

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-... 

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. 

The chemical structure of histamine has similarities to the structures of other biogenic amines, but important differences also exist. Chemically, histamine is 2-(4-imidazolyl)ethylamine (Fig. 14-1). The ethylamine backbone is a common feature of many of the amine transmitters (e.g. dopamine, norepinephrine and serotonin). However, the imidazole nucleus, absent from other known transmitters, endows histamine with several distinct chemical properties. Among these is prototypic tautomerism, a property that permits it to exist in two different chemical forms (Fig. 14-1). The tautomeric properties of histamine are thought to be critical in the... 

The 1,3-dipoles were generated by the addition of Et3N in 20% excess. Only imidazole was basic enough to generate a nitrile oxide in the absence of triethy-lamine. Due to prototropic tautomerism, reactions of triazoles and tetrazoles led to mixtures of two isomers. With unsubstituted pyrazole and imidazole only one hydroximoylazole was formed (117). 

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). 

The various tautomers and rotamers of alloxan have been examined in detail by the MNDO method and it is predicted that the keto form is most important in the gas phase, although in solution the monohydroxy forms are also thought to contribute. A mass spectral study has been used to investigate the enol-keto tautomeric equilibria of a series of substituted salicylaldehyde and 2-hydroxynaphthaldehyde Schiff bases. In neutral, ethanolic solutions, the cis- and trans-tm forms of 4,5-dimethyl-2-(2 -hydroxyphenyl)imidazoles (393) and (394) have been found to exist in equilibrium in the ground state. However, in neutral aqueous solutions, the trans-eao and keto forms (394) and (395) were the only species detected. Deuterium isotope effects on... 

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). 

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. 

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