General Papers ARKIVOC 2004 (i) 55-63
Results and Discussion
Acetylation of aromatic amines has been carried out in aqueous media but with a limited number of substrates.8 The same has been achieved using amine, hydrochloric acid, concentrated solution of sodium acetate (5 M) and acetic anhydride.9 We thought to add sodium bicarbonate to an aqueous solution of amine hydrochloride, which will liberate free amine and react with acetic anhydride and convert the liberated acetic acid to sodium acetate in the medium. Aliphatic and aromatic amines are basic in nature and can easily be protonated by mineral acids. To test our hypothesis and to optimise the reaction conditions, aniline 4 was converted to water-soluble anilinium hydrochloride using aqueous HCl. The protonated ammonium species is nonnucleophilic due to non-availability of the lone pair of electrons on the nitrogen atom. Thus, when acetic anhydride was added to an aqueous solution of amine hydrochloride no acetylation occurred. However, upon addition of basic salts, such as NaHCO3 to the above medium, free amines were liberated, which reacted immediately with acetic anhydride, precipitating the acetylated product with the evolution of carbon dioxide. The reaction works best when the final pH of the medium is ca. 5.5, approximately one pKa unit higher compared to that of acetic acid (pKa 4.8). Protonation of amine in an acidic medium has been confirmed by hypochromic shifts at 226 nm and 276 nm for (p-p*) and (n-p*) respectively, by titrating a dilute solution of 2fluoroaniline 5 with a dilute solution of HCl using UV spectrophotometer. A hyperchromic shift of these transitions upon addition of a dilute solution of sodium bicarbonate confirms the regeneration of free amines.
As shown in Table 1 several amines underwent acetylation very smoothly in good yields. The optimised acetylation reaction was performed by adding acetic anhydride (1.5 equiv) to the substrate amine hydrochloride (pH ca.1.6) dissolved in water followed by addition of NaHCO3 in one lot to obtain a final pH ca. 5.5. The methodology works well for both aliphatic, 1-2 and aromatic, 3-9 amines, as reported in Table 1.10 Primary amines of varying electronic and steric factors, substrate 3-9 were examined. It is interesting to note that in most of these cases the product precipitates in less than 5 minutes. It has been observed that the acetylation of aryl amines performed in an organic reaction medium, substrate containing electron-donating groups in the aromatic ring facilitate the reaction, whereas electron-withdrawing groups slow down the reaction. No such effect was observed by the present methodology and all the substrates react with equal rates. However, aryl amines gave better yields as compared to alkyl amines. Chiral amines 10 can be easily acetylated with complete retention of optical activity. Phenol and thiophenol reacted slowly under the identical conditions giving poor yields. Thus, by taking advantage of the differential reactivity between nucleophiles, we were able to carry out chemoselective acetylation of amines over phenols and thiols. Thus, in a competitive acetylation reaction with an equimolar mixture of aniline 4 and phenol by this procedure, the amine is acetylated selectively leaving the phenol unaffected.
ISSN 1424-6376 Page 56 ©ARKAT USA, Inc
