Bromination of acetamide

Dissolve 36 g. of sodium hydroxide in 160 ml. of water contained in a 500 ml. conical flask, and chill the stirred solution to 0-5° in ice-water. Now add io-8 ml. (32-4 g.) of bromine slowly to the stirred solution exercise care in manipulating liquid bromine ) during this addition the temperature rises slightly, and it should again be reduced to 0-5°. Add a solution of 12 g. of acetamide in 20 ml. of water, in small portions, to the stirred hypobromite solution so that the temperature of the mixture does not exceed 20° the sodium acet-bromoamide is thus obtained in the alkaline solution. Now remove the flask from the ice-water, and set it aside at room temperature for 30 minutes. 

Nitrosomethylurea. Acetamide method. To a solution of 59 g. of acetamide in 88 g. (28 ml.) of bromine (1) in a 4-litre beaker add dropwise, with hand stining, a solution of 40 g. of sodium hydroxide in 160 ml. of water. Heat the resulting yellow reaction mixture on a steam bath until eflfervescence sets in (2), after which continue the heating for 2-3 minutes. CrystaUisation of the product from the yellow or red coloured solution usually commences immediately. Cool in an ice bath for 1-2 hours, collect the product by suction filtration, wash with a little ice-cold water, and dry in the air. The yield of colourless acetylmethylurea, m.p. 178-180°, is 50 g. 

A mixture of acetamide (30 g. = 0-5 mole) and bromine (80 g. = 26 c.c.) in a half-litre flask is kept well cooled with water while enough of a solution of 50 g. of potassium hydroxide in 350 c.c. of water is added to change the initially red-brown colour into a pale yellow this requires most of the alkali. The solution is now run from a dropping funnel in an unbroken jet into a solution of 80 g. of potassium hydroxide in 150 c.c. of water, maintained at 70°-75° in a litre flask. The operation lasts for several minutes. Until the reaction mixture becomes colourless (one quarter to half an hour) the temperature is maintained at 70°-75°, and then the methylamine is distilled with steam. An adapter is fixed to the lower end of the condenser and dips 1 cm. below the surface of the liquid in the receiver (100 c.c. of approximately 5 N-hydrochloric acid2). As soon as the liquid which forms in the condenser is no longer alkaline the distillation is discontinued and the contents of the receiver are evaporated to dryness in a porcelain basin on the water bath. The last traces of water are removed by allowing the basin to stand over night in a vacuum desiccator. The dried material is boiled with absolute alcohol, which dissolves the methylamine hydrochloride but not the ammonium chloride with which it is mixed. The clear filtrate obtained when the ammonium chloride is removed by filtration is concentrated to a small volume and the methylamine hydrochloride is allowed to crystallise out in the cold. The salt is filtered with suction, washed with a little alcohol, and dried in a desiccator. Yield 15-20 g. 

Anodic oxidation of j9-methylbenzyl-sulfonic ester, -carboxylic ester, and -nitrile in Et3N-3HF/CH3CN affords fluorides and acetamides at tbe metbyl (Me) and substituted (CH2E) benzyl position Me/CH2E = 24/76 (E = C02Et), 9/91(CN), 69/31 (SOsEt). In tbe radical bromination of these compounds, substitution at CH3 is enhanced [20],... 

Twenty grams of acetamide (0.34 mole) is dissolved in 54 g. of bromine (0.34 mole) contained in a 500-ml. Erlenmeyer flask, and the solution is cooled to 0-5° in an ice bath. An ice-cold aqueous 50% potassium hydroxide solution is added in small portions with swirling and cooling until the color becomes a light yellow. Approximately 33-34 ml. of the caustic solution is required. The nearly solid reaction mixture is allowed to stand at 0-5° for 2-3 hours. 

Hofmann s Reaction.—One more important reaction of the acid amides is that known as Hofmann s reaction. When an acid amide is treated with bromine in an alkaline solution the final product is an alkyl ami/ie containing one less carbon than the amide. The steps in the reaction are represented in the case of acetamide as... 

Acetamide is useful in the bromination of acid-sensitive compounds since it forms a stable complex with hydrogen bromide, CH3CONH2 HBr, which is insoluble in common bromination solvents. ... 

This reagent is prepared in 85% yield by bromination of N.N-dimethylcyano-acetamide in HOAC-AC2O. ... 

As substitution-products of ammonium iodide which contain two, three, and four alkyl groups are obtained along with methylammonium iodide by the action of ammonia on methyl iodide—a fact explained below—the compound is most readily prepared in the pure condition from acetamide by what is known as Hofmann s reaction. When an amide is treated with bromine and an aqueous solution of sodium hydroxide, the first reaction which takes place consists in the replacement of one of the hydrogen atoms in the amido group by bromine. The equation for the reaction in the case of acetamide is,—... 

Now for the second nitrogen substituent. Bromination of the less electron deficient end of the diene with N-bromoacetamide in the presence of SnBr4 leads to an intermediate brom-onium ion which is opened by the acetamide by-product at the more reactive end adjacent to the alkene, giving a trans diaxial product. 

---