James 0. Schreck
The Hofmann Amide Rearrangement
Colorado State College Greeley, 80631
T h e preparation of pure primary amines via the Hofmann reaction is a very good example of a molecular rearrangement ( 1 ) . Thereaction is, in effect, the elimination of the carbonyl group of the amide. More exactly, it is known that the amide, by treatment with hromine and alkali, is first converted to an N-bromoamide. The N-bromoamide then undergoes a decomposition in which t,he R group (alkyl or aryl) migrates from the carbon atom to the nitrogen atom, the organic product being an isocyanate. In the presence of water and excess base, the isocyanate is hydrolyzed to an amine. Both the N-bromoamide and the isocyanate are said to be intermediates in the reaction. Students are taught that an intermediate in a chemical reaction is a species which is formed, preferably in detectable amounts, from the reactants and which, under the reaction conditions, is eventually converted to the reaction product or products, and strictly speaking, at a rate no less than that of the uninterrupted reaction (8). I n the following experiment N-bromobenzamide and phenyl isocyanate are subjected to the same conditions required to convert benzamide to aniline to demonstrate that the former two compounds could be intermediates in the Hofmann rearrangement of benzamide. In all three reactions, the reaction product, aniline, is isolated as acetanilide. In addition to demonstrating a principle in organic chemistry, this experiment incorporates many techniques learned by the beginning organic student: synthesis, recrystallization from a mixed solvent, steam distillation and derivative preparation. Furthermore, the reagents required are common chemicals usually found in an organic laboratory. Benzamide to Aniline (3)
A solution of sodium hypobromite is prepared in a 250-ml Erlenmeyer flask by adding 5.0 ml (0.09 mole) of hromine to a chilled solution of 12.0 g (0.30 mole) of sodium hydroxide in 100 ml of water. The solution is swirled to dissolve the bromine, and cooled further to It is much easier to maintain the temperature a t 70-7R°C if the mixture is brought to this temperature with gradual warming. Rapid heating will cause the temperature to suddenly rise and generally abovethe range required iar rearrangement to occur. This results in a decrease in yield oi aniline. I f too much dilute hydrochloric acid has been added, the scetanilide may not come out of the acid solution. The equilibrium can he shifted by adding a. few milliliters of a. fairly concentrated solution of aodium acetate. Anhydrous acetate was used n .~ d in this ex~eriment.hut the trihvdrate ran h e.u . ' It sh~;uldhe cn~yl~usizrcl 11;s~if r l ~ c.V-bcc~r~a~l~r.nrnmide is to II? rcvry~IaIIiz~~I fr~w vhlmd, mi, i l aholdd hr fuirlv dry Ihefore~ ijf tllr ~ I I T P.\'-b11m10I.anrl L T 111cwntcr nuikrs t h crysldli~btiw~ henzamide difficult ~~
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below 5°C. To the cold solution is added, in portions, 6.1 g (0.05 mole) of finely divided benzamide, and the mixture is shaken after each addition and for an additional ten minutes after all the benzamide has been added. If a few particles of benzamide do not dissolve, it is best to filter the solution. The clear, yellow solution is then transferred to a 500-ml, round-bottom flask, and slowly heated to and maintained at 70-75'C for twenty minutes.' During the heating period, the solution changes from a yellow to a red-brown color, and after about fifteen minutes a dark, oily layer begins to form on top. The reaction mixture has the odor of aniline and is subjected to a steam distillation. The steam distillate is made barely acidic with dilute hydrochloric acid, decolorized with charcoal, and filtered with suction. To the resulting clear solution is added 5.0 ml (0.05 mole) of acetic anhydride followed immediately by 4.1 g (0.05 mole) of sodium a ~ e t a t e . ~The mixture is stirred well, chilled, and filtered with suction, and the crystalline acetanilide is washed with several portions of ice-water and dried. The product is sufficiently pure and need not be recrystallized. Yield: 2.5 g. Synthesis of N-Bromobenzamide (4)
Ten grams (0.08 mole) of finely divided benzamide is added, in portions, to 150 ml of an ice-cold solution of sodium hypobromite. The sodium hypobromite solution, contained in a 250-ml Erlenmeyer flask is freshly prepared from 5.0 ml (0.09 mole) of bromine and 9.0 g (0.23 mole) of sodium hydroxide. The mixture is shaken after each portion is added and then for ten minutes longer after the final portion is added. The mixture is filtered rapidly with suction into a cold solution of 9.0 ml of glacial acetic acid in 25 ml of water containing crushed ice. The precipitated N-bromobenzamide is removed by filtration, washed by stirring it in 150 ml of ice-cold water, and removed by suction filtration. The crude product (yield: 14 g) can be directly converted to aniline without recrystallization. However, the crude product can be recrystallized from boiling chloroform to which petroleum ether (6O-100°C) is added until turbidity just disappears and then the mixture co01ed.~ The resulting white crystals melt a t 130-31' (4). N-Bromobenzamide to Aniline
The experimental conditions are exactly the same as those described above for the conversion of benzamide to aniline, except that in place of the benzamide, 10.0 g (0.05 mole) of the previously prepared N-bromobenzamide is added to the freshly prepared ice-cold
sodium hypobromite solution. The aniline is isolated as acetanilide. Yield: 2.0 g. Phenyl Isocyanate to Aniline
phenyl isocyanate (CAUTION: lachrymator). The remainder of the experiment is carried out as described above.4 The yield of acetanilide is 1.9 g.
To 100 ml of an ice-cold, freshly prepared solution of sodium hypobromite is added 5.5 ml (0.05 mole) of
Literature Cited
"small amount of tarry mat,erial iarms in this case when the mixture is heated to 70-7.i0C and is probably due t,o a side reaetion between phenyl isocyanate and aniline. The by-product is probably N,N'-diphenylurea. The question might well arise that in such a high ooncenbration of hypohromite solution the phenyl isocyanate is converted to N-hromohenmmide which is then converted to the amide. However, there appears to be no evidence to substantiate this.
therein. (2) GOULD,E. S., "Mechanism and Structure in Organic Chernistry," Henry Halt and Co., New York, 1959, Chaps 5 rtnd 6. (3) WALLIS,E. S., A N D LANE,J. F. in "Orgmi~Reactions 111,)) (Editor: ADAM% R.), John Wilev & Sons. Inc.. New York. 1946, p. 280. (4) H.kusr,n, C. R., A N D RENFROW, Jr., W. B.,J. Am. Chem. Soe., 59, 121(1937).
(1) HINE,J., "Physical Organic Chemistry," 2nd ed., McGmwHill, New York, 1962, pp. 334-35 and references cited
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