Aromatic amines, acetylation

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 ... 

In general, benzoylation of aromatic amines finds less application than acetylation in preparative work, but the process is often employed for the identification and characterisation of aromatic amines (and also of hydroxy compounds). Benzoyl chloride (Section IV, 185) is the reagent commonly used. This reagent is so slowly hydrolysed by water that benzoylation can be carried out in an aqueous medium. In the Schotten-Baumann method of benzoylation the amino compound or its salt is dissolved or suspended in a slight excess of 8-15 per cent, sodium hydroxide solution, a small excess (about 10-15 per cent, more than the theoretical quantity) of benzoyl chloride is then added and the mixture vigorously shaken in a stoppered vessel (or else the mixture is stirred mechanically). Benzoylation proceeds smoothly and the sparingly soluble benzoyl derivative usually separates as a solid. The sodium hydroxide hydrolyses the excess of benzoyl chloride, yielding sodium benzoate and sodium chloride, which remain in solution ... 

Certain ortho substituted derivatives of aromatic amines are difficult to acetylate under the above conditions owing to steric hindrance. The process is facilitated by the addition of a few drops of concentrated sulphuric acid (compare Section IV,47), which acts as a catalyst, and the use of a large excess of acetic anhydride. 

Controlled halogenation can be achieved by halogenation of the A/-acetyl derivative of the aromatic amine, followed by hydrolysis of the acetyl... 

Nitration. Direct nitration of aromatic amines with nitric acid is not a satisfactory method, because the amino group is susceptible to oxidation. The amino group can be protected by acetylation, and the acetylamino derivative is then used in the nitration step. Nitration of acetanilide in sulfuric acid yields the 4-nitro compound that is hydroly2ed to -rutroaruline [100-01-6]. 

MDA reacts similarly to other aromatic amines under the proper conditions. For example, nitration, bromination, acetylation, and dia2oti2ation (1 3) all give the expected products. Much of the chemistry carried out on MDA takes advantage of the diftmctionality of the molecule in reacting with multiftmctional substrates to produce low and high molecular weight polymers. 

A Methylanthrapyridone and Its Derivatives. 6-Bromo-3-methylanthrapyridone [81-85-6] (75) is an important iatermediate for manufacturiag dyes soluble ia organic solvents. These solvent dyes are prepared by replacing the bromine atom with various kiads of aromatic amines. 6-Bromo-3-methylanthrapyridone is prepared from 1-methyl amino-4-bromoanthra quin one (43) by acetylation with acetic anhydride followed by ring closure ia alkaU. The startiag material of this route is anthraquiaoae-l-sulfonic acid (16). 

Iodosobenzene diacetate is used as a reagent for the preparation of glycol diacetates from olefins,9 for the oxidation of aromatic amines to corresponding azo compounds,10 for the ring acetylation of N-arylacetamides,11 for oxidation of some phenols to phenyl ethers,12 and as a coupling agent in the preparation of iodonium salts.13 Its hydrolysis to iodosobenzene constitutes the best synthesis of that compound.14... 

In a related procedure, even benzene and substituted benzenes (e.g., PhMe, PhCl, xylenes) can be converted to phenols in good yields with sodium perborate F3CS020H. " Aromatic amines, N-acyl amines, and phenols were hydroxylated with H2O2 in SbFs—HF. Pyridine and quinoline were converted to their 2-acetoxy derivatives in high yields with acetyl hypofluorite AcOF at -75°C. ... 

Aromatic amines are initially metabolized by aromatic and A -hydroxylation (oxidation reactions) and Y-acetylation. Following aromatic ring hydroxylation, the ring structure may be further conjugated with glucuronic acid or sulfate (Parkinson 1996). N-hydroxylation results in the potential methemoglobin-generating metabolite,... 

Aromatic amines 4 are metabolised in vivo by cytochrome P450 mediated oxidation to phenolic and hydroxylamine derivatives 5 and 6. Phase II conjugation of the latter with PAPS or acyl transferase results in formation of the sulfuric or acetic acid esters 7. Nitrogen conjugation to give the A-acetyl analogues is also possible (Scheme l).54 65... 

From appraisal of their respective resonance stabilisation, arylnitrenium ions and alkoxynitrenium ions should form with similar facility. On account of the fact that A-acetoxy-A-acetyl arylamines 7 are penultimate carcinogens in the metabolism of aromatic amines, A-acyloxy-A-alkoxyamides 3 were designed to test their potential as DNA-damaging agents. 

The major substrates for acetylation are primary aromatic amines, hydroxylamines (both the oxygen and the nitrogen can be acetylated), and hydrazines (11). The cofactor is acetyl Co-A, which is a thioester (Fig. 7.6). 

The enzyme can also catalyze the transfer of an acetyl group from an N-acetylated hydroxylamine (hydroxamic acid) to form an acetoxy product, i.e., an N to O transacetylation and this pathway does not require acetyl Co-A (12). A-hydroxy-4-acetylaminobiphenyl provides an example of this conversion as shown in Figure 7.7. The significance of this pathway is that it leads to the activation of the hydroxamic acid because acetoxy derivatives of aromatic amines are chemically reactive and many are carcinogens such as the heterocyclic amines formed when meat is heated to a high temperature, e.g., 2-amino-1-mcthyl-6-phenylirnidaz()[4,5-i ]pyri(linc. 

The main problem encountered during electrophilic substitution reactions of aromatic amines is that of their veiy high reactivity. Substitution tends to occur at ortho- and para-positions. If we have to prepare monosubstituted aniline derivative, how can the activating effect of -NH group be controlled This can be done by protecting the -NH group by acetylation with acetic anhydride, then carrying out the desired substitution followed by hydrolysis of the substituted amide to the substituted amine. 

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