Acetylation of aromatics

Scheme 5.1-67 The acetylation of aromatics with supported ionic liquids (FK 700 is a type of amorphous silica made by Degussa).

ACETYLATION OF AROMATIC AMINES Acetyl derivatives of aromatic amines may be prepared either with acetic anhydride or acetic acid or with a mixture of both reagents. Primary amines react readily upon warming with acetic anhydride to yield, in the first instance, the mono-acetyl derivative, for example ... 

It is generally admitted that over zeolites, acetylation of aromatic substrates with acetic anhydride (AA) is catalyzed by protonic acid sites. The direct participation of Lewis sites was excluded by using two BEA samples with similar protonic acidities, but with very different Lewis acidities indeed, these samples were shown to have quasi-similar activities. The currently accepted mechanism is shown in Figure 12.6 for the anisole acetylation example. The limiting step of the process is the attack of anisole molecules by acylium ions. 

The reported gas-phase acylations with Nafion-H catalyst were generally carried out at the boiling point of the hydrocarbon to be acylated. The yield of aroylation reaction depends on the relative amount of the catalyst used. Optimum yields were obtained when 10-30% of Nafion-H was employed relative to the aroyl halide. Although this procedure allows very clean reactions with no complex formation and easy work-up procedures, it is presently limited to only aroylation. Attempted acetylation of aromatics with acetyl chloride under similar conditions led to thermal HC1 elimination from the latter to form ketene and products thereof. In the reaction of acetyl chloride by itself with Nafion-H, diketene was detected by IR and NMR... 

J. LeWalter, U. Korallus, Blood Protein Conjugates and Acetylation of Aromatic Amines New Findings on Biological Monitoring , Int. Arch. Occup. Envir. Elealth, 56,179-196 (1985). 

The most important kind of acetylation reaction is the acetylation of aromatic amines. This converts the ionizable amine group to a nonionizable group, to which the acetyl group is attached. 

As a consequence, some acetylated products are not as soluble in water as the parent compounds. In some cases, acetylation of aromatic amines makes them less active as toxicants, particularly in binding with DNA, whereas in other cases, they are made more active. In the latter case, activity can be due to a cytochrome P-450 catalyzed attachment of an -OH group to the acetylated nitrogen, leading to a positively charged electrophilic species capable of binding with DNA. 

Table 3.3 Liquid and gas phase acetylation of aromatic hydrocarbons (S) with acetic anhydride (AA) over zeolites... 

Figure 3.1 Acetylation at 373 K with acetic anhydride of a series of aromatic compounds over HBEA-15 zeolite. Conversion (XSUB) of anisole ( ), 2-methoxynaphthalene (x), m-xylene ( ), toluene ( ), 2-methylnaphthalene (o) and fluorobenzene (a) versus time. Reprinted from Journal of Catalysis, Vol. 230, Guidotti et al. Acetylation of aromatic compounds with H-BEA zeolite the influence of the substituents on the reactivity and on the catalyst stability, pp. 375-383, Copyright (2005), with permission from Elsevier...

The reactivity of acetic acid is much weaker than that of AA and the aromatic ring can generally be acetylated with acetic acid over zeolite catalysts only at high temperatures (gas phase reactions).[62,63] This acetylation appears also at low temperatures (liquid phase reactions), but only with hydroxyarene substrates as a secondary transformation of aryl acetates rapidly formed through O acylation. This section will be split into two parts gas phase acetylation of aromatic substrates without hydroxyl substituents and transformation of aryl acetates, the so-called Fries rearrangement. 

Therefore the acetylation of aromatics over zeolites proceeds through the two step mechanism formulated by Olah (31) ... 

From these two examples of liquid phase acetylation of aromatics over zeolite catalysts the following conclusions can be drawn ... 

The Phase II acetylation of aromatic hydroxyl-amineS/ the products of Phase I metabolism of aromatic amineS/ constitutes a toxic metabolic pathway that has been implicated in carcinogenesis/ as illustrated in Scheme 11.36. Rapid acetylators (with respect to NAT2) have been shown to be associated with an increased risk of colon cancer. The mechanism of this toxicity has implicated the intermediacy of the reactive... 

A catalyst of the Friedel-Craft type, which promotes the acetylation of aromatic compounds, has been prepared using aluminum as sacrificial anode [177,178]. 

One common polymorphism in the United States is for N-acetyltransferase, an enzyme involved in phase II reactions. N-acetyltransferase catalyzes the acetylation of aromatic amines and hydrazines, and other classes of xenobiotics. People characterized as slow acetylators have relatively low N-acetytransf-erase activity. Consequently, slow acetylators are more sensitive to the toxic effects of certain types of drugs, including sulfa drugs. In addition, a study of workers exposed to benzidine in the dye industry suggested a link between the slow acetylator phenotype and the development of bladder cancer. 

Mixed anhydrides of formic acid with acids, such as acetic formic anhydride, are stable but give acetylation of aromatic compounds with evolution of carbon monoxide (ref. 22). 

Table 4.8 Acetylation of aromatics with AAN over BEA in a fixed-bed reactor at 90°C-150°C for 6-7 h...

Smith, K., El-Hiti, G. A., Jayne, A. J., and Butters, M. 2003. Acetylation of aromatic ethers using acetic anhydride over solid acid catalysts in a solvent-free system scope of the reaction for substituted ethers. Org. Biomol. Chem. 1 1560-1564. 

Acetylation of aromatic compounds containing electron-donating substituents gives ortho- and para-compounds Almost exclusively, but meta-derivatives are also formed in alkylations. Details concerning orientation should be sought in standard works and the literature.270 2713 505 507... 

Acetylation of amines, phenols, and thiols. This reagent readily transfers two acetyl groups to amines, phenols, and thiols under mild conditions (25°) with conversion to 1,4-diacetylglycouril. Ahphatic primary amines react most readily in fact, primary amino groups can be selectively acetylated in the presence of a secondary amino group. Acetylation of aromatic amines is slower, but can be catalyzed by an acid (e. g., acetic acid). Phenols are also acetylated, but aminophenols can be selectively N-acetylated. Thiophenols and alkyl thiols are acetylated readily, but alcohols react only slowly, even at elevated temperatures. ... 

Experiments on the role of the adrenal hormones in fat metabolism have suggested that the cortical hormones exert a direct effect on fatty acid oxidation preceding the formation of acetyl-CoA (Lipsett and Moore, 1952). Neither the acetylation of aromatic amines (Dumm and Ralli, 1951) nor the formation of ketone bodies from pyruvate in a malonate blocked system (Lipsett and Moore, 1952) were influenced by adrenalectomy. 

At the present time the data suggest multiple points of action of the adrenocortical hormones. Of the reactions which Villee et al. (1952) suggested might be influenced by the adrenocortical hormones, the condensation of pyruvate with oxaloacetate is known to require coenzyme A, as was described earlier. However, both Lipsett and Moore s (1952) experiments showing that the production of ketone bodies from pyruvate was not influenced by adrenalectomy and the observation that the acetylation of aromatic amines was not influenced by adrenalectomy (Dumm and Ralli, 1951) appear to exclude the reactions leading to the production of acetyl-CoA from pyruvate as probable points of action of the adrenocortical hormones. Therefore, of the reactions leading to the production of citrate from pyruvate and oxaloacetate, the most likely to be influenced by the adrenocortical hormones would appear to be the final condensation of acetyl-CoA with oxaloacetate. If further work should establish a direct influence of the adrenocortical hormones on the condensation of acetyl-CoA with oxaloacetate, an additional basis for the interrelations between pantothenic acid and the functions of the cortical hormones would be established. 

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