Acetylimidazole acetate

Pyrrole and alkylpyrroles can be acylated by heating with acid anhydrides at temperatures above 100 °C. Pyrrole itself gives a mixture of 2-acetyl- and 2,5-diacetyl-pyrrole on heating with acetic anhydride at 150-200 °C. iV-Acylpyrroles are obtained by reaction of the alkali-metal salts of pyrrole with an acyl halide. AC-Acetylimidazole efficiently acetylates pyrrole on nitrogen (65CI(L)1426). Pyrrole-2-carbaldehyde is acetylated on nitrogen in 80% yield by reaction with acetic anhydride in methylene chloride and in the presence of triethylamine and 4-dimethylaminopyridine (80CB2036). 

Direct acylation of imidazole can also be achieved with carboxylic acid anhydrides. For example, if imidazole is dissolved at room temperature in acetic anhydride, crystals of iV-acetylimidazole begin to separate out after removal of excess anhydride and the resulting acetic acid under vacuum at 60 °C, nearly pure iV-acetylimidazole (m.p. 100-102 °C) is obtained in almost quantitative yield.[4]... 

On the other hand, with propionic anhydride as substrate, in which case there is no solubility problem, the course of the reaction was very much the same as in the experiments with acetic anhydride. The rate constants for decomposition of propionylimidazole are strikingly similar to those for acetylimidazole. 

V-Acetylimidazole [2466-76-4] M 110.1, m 101.5-102.5°. Crystd from isopropenyl acetate. Dried in a vacuum over P2O5. 

The detection of intermediates depends upon the relative values of the rate constants for their formation and decay (see Chapter 4). An example is the imidazole-catalysed hydrolysis of aryl acetates where the concentration of acetylimidazole builds up and decays subsequently by hydrolysis. A stepwise process is manifestly obvious if, during a kinetic study, an intermediate species is observed to accumulate and then decay to give products (Fig. 11.6A)[12,13]. The nature of the measuring device is not relevant to the argument but is likely to be spectroscopic (see Chapters 2 and 9). The direct observation of an intermediate depends on a build-up of its concentration to a measurable level and this requires that the decay to the product is relatively slow. The simplest possible case of a stepwise process is shown in Scheme 11.15 and this also happens to be one of the most generally applicable mechanisms (see Chapter 4). 

Fig. 11.6 (A) Spectroscopic detection of acetylimidazole in the imidazole-catalysed hydrolysis of 4-nitro-phenyl acetate at pH 5 (D) and at pH 6 (E) curves are calculated from data in reference [12] and the curve for the acetate ion product (C) is for pH 5. (B) Reaction of imidazole with 4-nitrophenyl acetate (k) and the hydrolysis of acetyl imidazole (k2) curves constructed from data in references [13] and [12].

Acetic anhydride (5-1, A-l) iV-Acetylimidazole (5-1, A-6) Aldehyde/NaBH4 (6-8, A-l) iV-Bromosuccinimide (8-9, A-8) Butanedione... 

Demonstration of reversible nucleophilic reaction Inhibition of catalysis by added product of reaction Inhibition of nucleophilic comp(ment of acetate catsdyzed acetylimidazole hydrolysis by added imidazole 89... 

In synthesis of peptides containing adjacent sterically hindered or N-substituted amino acids, complete chain propagation may not be obtainable. More accessible sites on the resin may continue to grow well, whereas more hindered sites may fail, but couple in a later step with a less hindered amino acid, e.g. glycine. In these cases, dehberate termination by acetylation can prevent contanoination of the product by omission sequences which may be more difficult to remove during purification than a shorter acetylated peptide. Both acetylimidazole and acetic anhydride have been used successfully for such acetylation acetylimidazole is the more reactive of these two reagents. 

This can be perfomed with either acetylimidazole or acetic anhydride. 

This derivative of lysine has thus far been identified only in histones (see DeLange and Smith, 1971, 1974), but may also be produced in other proteins by chemical acetylation, e.g. with acetylimidazole, or acetic anhydride. Since the e-amide bond is acid-labile, this derivative may be present in other proteins, which have not been hydrolyzed and analyzed by enzymic methods (see 2.11). 

Acetylimidazolium ion reacts with acetate to the extent of 78 % by the general base path and 22 % by direct nucleophilic interaction (Jeneks et al., 1966). This was demonstrated by the inhibition of the hydrolysis of acetylimidazole in acetate buffers by low concentrations of imidazole. This inhibition, which is due to the back reaction of equation (23),... 

In the case of apparent general acid catalysis of acetylimidazole hydrolysis, the mechanism can be defined as a specific acid-general base process by comparison with the general base catalysis of N-methyl,N -acetylimidazolium ion. The rate of disappearance of N-methyl,N -acetylimidazolium ion in water at 25° is proportional to the concentration of the basic form of buffer components such as acetate, phosphate, N-methylimidazole, etc., (equation 30) (Wolfenden and Jencks, 1961). The buffer terms show a 1 1 correlation with the general acid-catalyzed rate of acetylimidazole disappearance (Jencks and Carriuolo, 1959) in water at 25°, when the rate expression for the latter reaction is written in terms of equation (32) rather than equation (31), that is, in terms of a general base-catalyzed hydration of protonated acetylimidazole (pX= 3-6). 

Furthermore, the rate of hydrolysis of N-acetyl,N -methylimidazolium ion is exactly the same as that of fully protonated acetylimidazole, and the values of given in equation (30) are equal or nearly equal to the corresponding values of k, given in equation (32). The reaction paths and mechanism for these two compounds therefore are no doubt the same the substitution of N-methyl for N—H makes no difference in terms of reactivity. Product studies have not been extensively carried out on these two compounds. It is known that phenolates interact with acetylimidazolium ion exclusively by the nucleophilic path (Gerstein and Jencks, 1964) and that the acetate reaction occurs 78% via the general base-catalyzed hydrolytic path (Jencks et ah, 1966 Section... 

The large negative entropies of activation and the large solvent isotope effects are no doubt intimately related. It is quite conceivable that these effects arise from a general catalysis by water of the water reaction. General base catalysis is known to occur in the hydrolysis of acetic anhydride by acetate, acetylp3rridinium ion by acetate (Bunton et al., 1961), acetylimidazole by imidazole, N-methyl,N -acetylimidazolium ion by N-methylimidazole, l-(N,N-dimethylcarbamoyl)pyridinium ion by pyridine (Johnson and Rumon, 1965), and ethyl haloacetates by weak bases (Jencks and Carriuolo, 1961). It is most reasonable then that the water reaction be similarily a base-catalyzed process. The isotope effects... 

Acetylation Acetic anhydride. N-Acetoxyphthalimide. 2- and 3-Acetoxypyridine. Acetyl chloride. N-Acetylimidazole. Boron trifluoride. Catalysts (see Acetic anhydride). Ketene. Magnesium. Methyl oxocarbonium hexafluoroantimonate. Perchloric acid. Phenyl acetate. Pyridine. Sodium acetate. Tetraelhylammonium acetate. p-Toluenesulfonic acid. Tri-n-hexylethyl ammonium hydroxide. 2,4,6-Triisopropylbenzenesulfonyl chloride. Trityl-sodium. Zinc chloride. 

J. Gerstein and WP Jencks, Equilibria and Rates for Acetyl Transfer among Substituted Phenyl Acetates, Acetylimidazole, O-Acetylhydroxamic Acid and Thiol Esters, J. Am. Chem. Soc., 1964, 86, 4655. 

An interesting mechanistic application of free energy relationships in calculating rate constants concerns the reactivity of the putative intermediate in the reaction of imidazole with 4-nitrophenyl acetate. The putative stepwise process (Scheme 15) involves a zwitterionic tetrahedral intermediate which would decompose to the product A-acetylimidazole, subsequently hydrolysing to acetate ion and imidazole. 

Acylation of aquatic humic substances with acetic anhydride in a variety of solvents was found to be unsatisfactory because of dehydration and 7r-bond formation. The mild acylating reagent, A-acetylimidazole, did not give complete acylations of hindered hydroxyl groups. Acetyl chloride was tested under a variety of conditions and gave complete derivatization of primary and secondary hydroxyls under the conditions shown in reaction (3) ... 

Isopropenyl acetate, obtained from ketene and acetone, reacts as an activated ester of acetic acid and, like its generator ketene, acetylates amides highly exothermally at room temperature.784 Even 1-acetylimidazole, which is difficult to prepare in other ways, is thus obtained from imidazole in 94% yield.785... 

An often occurring mechanistic problem is the diagnosis of general base or nucleophilic catalysis which give identical kinetics. Imidazole is a well known catalyst for the hydrolysis of 4-nitrophenyl acetate in water and it is known to involve nucleophilic attack because iV-acetylimidazole has been observed from ultraviolet spectral work [17]. The absence of a solvent deuterium isotope effect confirms the operation of the nucleophilic pathway (Table 7) because a primary isotope effect is expected for the general base mechanism. 

M. L. Bender (Illinois Institute of Technology, Chicago, III.) We have found that imidazole, a constituent of chymotrypsin catalyzes the hydrolysis of p-nitrophenyl acetate at 25° and pH 7. The reaction occurs in a stepwise manner, as does the enzymatic reaction, with the intermediate formation of acetylimidazole, which is subsequently hydrolyzed by water. While a serine hydroxyl of chymotrypsin, as proposed by Dr. Gutfreund (Lecture 29), could be converted to acetylserine, there is no obvious way in which it could hydrolyze, whereas this possibility occurs straightforwardly with the imidazole-catalyzed sequence. 

---