Imidazole ring reactivity

A modification of this method, related to the Beckmann rearrangement, entails treatment of a ketoxime with one equivalent of CDI, then four to five equivalents of a reactive halide such as allyl bromide or methyl iodide (R3X) under reflux in acetonitrile for 0.5-1.5 h. Quatemization of the imidazole ring effectively promotes the reaction by increasing the electron-withdrawing effect. The target amides then are obtained by hydrolysis. High yields, neutral conditions, and a very simple procedure make this modification of the synthesis of amides by azolides a very useful alternative. 1243... 

Recognizing the distinct difference in reactivity for each site of N-protected 2,4,5-triiodoimidazole 23, Ohta s group successfully arylated 23 regioselectively [32, 33], In the total synthesis of nortopsentin C, they coupled 23 with one equivalent of 3-indolylboronic acid 24 to elaborate imidazolylindole 25. The Suzuki reaction occurred regioselectively at C(2) of the imidazole ring. 

Fig. 3.6. Stereoelectronic control of the cleavage of the tetrahedral intermediate during hydrolysis of a peptide bond by a serine hydrolase. The thin lines represent the reactive groups of the enzyme (serine, imidazole ring of histidine) the thick lines represent the tetrahedral intermediate of the transition state. The full circles are O-atoms open circles are N-atoms. The dotted lines represent H-bonds the thick double arrow indicates an unfavorable dipole-dipole interaction [21]. A (R)-configured N-center B (S)-configured N-center.

Two factors are responsible for the high reactivity of the imidazolides as acylating reagents. One is the relative weakness of the amide bond. Because of the aromatic character of imidazole, there is little of the N —> C=0 delocalization that stabilizes normal amides. The reactivity of the imidazolides is also enhanced by protonation of the other imidazole nitrogen, which makes the imidazole ring a better leaving group. 

Eq. 3-47) at low enough pH (below 6) that the reaction becomes quite selective for histidine.70 287 Reactivity with this reagent is often used as an indication of histidine in a protein.288-290. The reaction may be monitored by observation of NMR resonances of imidazole rings.288 290... 

This is of relevance to the mechanism of carbonic anhydrase. This enzyme, which catalyzes the hydration of C02, has at its active site a Zn2+ ion ligated to the imidazole rings of three of its histidines. The classic mechanism for the reaction is that the fourth ligand is a water molecule which ionizes with a pKa of 7.37 The reactive species is considered to be the zinc-bound hydroxyl. Chemical studies show that zinc-bound hydroxyls are no exception to the rule of high reactivity. The H20 in structure 2.31 ionizes with a pKa of 8.7 and catalyzes the hydration of carbon dioxide and acetaldehyde.38... 

The close proximity of functional groups in 1,2-disubstituted benzenes can sometimes bring about an unexpected reactivity. Attempts to N-alkylate ortho-nitroani-lines under strongly basic reaction conditions, for instance, lead to the formation of N-alkoxybenzimidazoles (Scheme 6.10). The main force driving this reaction is the formation of an imidazole ring, a heteroarene with high resonance energy and thermal stability. 

The 6th rank in terms of acylation reactivity that is attributed to the acyl imidazolides in Table 6.1 (entry 10) is also plausible. In the acyl imidazolides, the free electron pair of the acylated N atom is essentially unavailable for stabilization of the C=0 double bond by resonance because it is part of the -electron sextet, which makes the imidazole ring an aromatic compound. This is why acyl imidazolides, in contrast to normal amides (entry 2 in Table 6.1) can act as acylating agents. Nevertheless, acyl imidazolides do not have the same acylation capacity as acylpyridinium salts because the aromatic stabilization of five-mem-bered aromatic compounds—and thus of imidazole—is considerably smaller than that of six-membered aromatic systems (e. g., pyridine). This means that the resonance form of the acyl imidazolides printed red in Table 6.1 contributes to the stabilization of the C=0 double bond. For a similar reason, there is no resonance stabilization of the C=0 double bond in N-acylpyridinium salts in the corresponding resonance form, the aromatic sextet of the pyridine would be destroyed in exchange for a much less stable quinoid structure. 

Methylation of normacrorine with dimethyl sulfate gave a 2 1 mixture of 116 and 117. On the basis of the negative inductive effect of the quinolyl substituent on the imidazole ring, one would expect on methylation in nonbasic medium isomacrorine to be the major product. The fact that, contrary to this expectation the main product is macrorine, can be explained by assuming a shielding of the most reactive imidazole nitrogen (N") by the quinolyl substitutent. 

When the imidazole ring is considered to be something resembling a pyrrole-pyridine combination (1) it would appear that any electrophilic attack should take place preferably at C-5 (pyrrole-or, pyridine-j8). Such a model, though, fails to take account of the tautomeric equivalence of C-4 and C-5 (Section 4.06.5.1). The overall reactivities of imidazole and benzimidazole can be inferred from sets of resonance structures in which the dipolar contributors have finite importance (Section 4.06.2) or by mesomeric structures such as (2). These predict electrophilic attack in imidazole at N-3 or any ring carbon atom, nucleophilic attack at C-2 or C-1, and also the amphoteric nature of the molecule. In benzimidazole the acidic and basic properties, the preference for nucleophilic attack at C-2 and the tendency for electrophiles to react at the fused benzene ring can be readily rationalized. 

When the imidazole ring already has a substituent at C-4 or C-5 then there will be a directional effect imposed on electrophilic attack at annular nitrogen. As outlined earlier (Section 4.02.1.3) this orientation may be related to the tautomeric nature of the substrate. In spite of the inherent pitfalls in equating tautomeric nature with chemical reactivity there are examples which seem only to be explicable in terms of a major tautomer reacting, e.g. methylation of 4-nitroimidazole. Substituents at C-2 can only affect the rate of a reaction at ring nitrogen. 

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