Imidazoles acyl, reactivity

The acylation of the carbanions derived from nitroalkanes with acyl imidazoles or alkoxy-carbonylimidazoles takes place at the carbon atom to yield a-nitro ketones or a-nitro esters, respectively (Eq. 5.10).21 The lithium salts of nitroalkanes were isolated and used in THF or DMSO in the original procedure. Later, potassium salts generated in situ on treatment with r-BuOK in DMSO are reactive enough to give a-nitro ketones in good yield (Eq. 5.11).22... 

Probably the most important property of these compounds is the propensity of iV-acyl-imidazoles and -benzimidazoles (as well as other azoles) to become involved in reactions which result in acylation of an attacking nucleophile. The compounds are unlike other tertiary amides in that there is little or no contribution from resonance structures of type (251) to the hybrid (Scheme 142) hence the positive nature of the carbonyl carbon is undiminished. The electron pair on the annular nitrogen is part of the aromatic sextet. The compounds are known as azolides generally, and more specifically as imidazolides . Because the annular nitrogens are not directly adjacent imidazolides are more reactive than the corresponding pyrazolides. 

Imidazole is a better nucleophile than water, so imidazole reacts faster with the ester than water does. The acyl imidazole that is formed is particularly reactive because the positively charged nitrogen makes imidazole a very good leaving group. Therefore, it is hydrolyzed much more rapidly than the ester would have been. Because formation of the acyl imidazole and its subsequent hydrolysis are both faster than ester hydrolysis, imidazole increases the rate of ester hydrolysis. 

Activation of Carboxylic Acids Synthesis of Acyl Imidazoles. iV,AA-Carbonyldiimidazole (1) converts carboxylic acids into the corresponding acylimidazoles (2) (eq 1). The method can be applied to a wide range of aliphatic, aromatic, and heterocyclic carboxylic acids, including some examples (such as formic acid and vitamin A acid) where acid chloride formation is difficult. The reactivity of (2) is similar to that of acid chlorides, but the former have the advantage that they are generally crystalline and easily handled. Isolation of (2) is sirr5>le, but often unnecessary further reaction with nucleophiles is usually performed in the same reaction vessel. Conversion of (2) into acid chlorides (via reaction with HCl), hydrazides, hydroxamic acids, and peroxy esters have all been described. Preparation of the more irr5)ortant carboxylic acid derivatives is described below. 

Anilines were also effectively amidated by this procedure. Since aniline-derived acyl-imidazole intermediates are slow reacting considering addition, the removal of the solvent has an accelerating effect (Scheme 3.33, Table 3.17). The difference is most pronounced in the case of a less-reactive substrate (entry 4). 

Acylation of the NH group is not a real remedy because acyl-imidazoles are reactive compounds. For instance, the p-toluenesulfonyl group might be transferred onto other nucleophiles, such as the amino group, alcoholic or phenolic hydroxyls and quite readily to the hydroxyl group of the additive 1-hydroxy-benzotriazole ... 

Finally, while it is not obvious how both the amine-component and the carboxyl component could be applied in polymeric form, this dilemma was solved (Cohen et al. 1981) by the introduction of a mediator. A solution of imidazole is circulated through separate beds of the insoluble reactive carboxyl-component and the polymer-bound amine-component. The acyl-imidazoles generated in the active ester bed are excellent acylating agents which transfer... 

At first sight the reactivity of acylated imidazoles is therefore unexpected but their acylating ability is comparable with that of acid anhydrides or chlorides. This can be seen in a comparison of the susceptibility to hydrolysis of N-acetyIpyrrole and N-acetylimidazole (6). 

In general, acylation reactions for chromatography are carried out with three main types of acylating reagent acid anhydrides, acid halides and reactive acyl derivatives such as acylated imidazoles, acylated amides or acylated phenols, and the different types are chosen for different reasons. Acyl halides are highly reactive, which may be important with compounds that are difficult to acylate, because of steric factors for instance. A drawback to acyl halides is that a basic acceptor for the halogen acid produced in the reaction is usually required (equation (8)),... 

Histidine-bearing surfactants deacylate 4-nitrophenyl acetate by a nucleophilic mechanism as evidenced by Fourier transform n.m.r. The intermediate acyl-imidazole is deacylated by phosphate ion." By contrast, the dephosphorylation of 4-nitrophenyl diphenylphosphate by micelles bearing an imidazole group occurs by general base catalysis. The rate enhancement is caused almost entirely by increased concentration of the reactive groups at the micellar surface." ... 

Ac-Imidazole, PtCl2(C2H4), 23°, 0.5-144 h, 51-87% yield. Platinum(II) acts as a template to catalyze the acetylation of the pyridinyl alcohol, C5H4N(CH2) CH20H. Normally, acylimidazoles are not very reactive acylating agents with alcohols. 

The reactive 1-acyl-3-alkylimidazolium species also plays a role in acylation of alcohols with carboxylic anhydrides or carboxylic acid chlorides using 1-substituted imidazoles as catalysts.[145] In this case the reactive species is formed in situ ... 

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