A Publication
of Reliable Methods
for the Preparation
of Organic Compounds
Annual Volume
Org. Synth. 1931, 11, 4
DOI: 10.15227/orgsyn.011.0004
[Isobutyric acid, α-amino-]
Submitted by H. T. Clarke and H. J. Bean.
Checked by C. S. Marvel and C. F. Bailey.
1. Procedure
A filtered solution of 200 g. (3.7 moles) of ammonium chloride in 500 cc. of water is placed in a 3-l. round-bottomed flask. The flask is surrounded by an ice bath and cooled to 5–10°. A solution of 175 g. (3 moles) of acetone in 500 cc. of ether is added with stirring (Note 1). Then a solution of 160 g. (3.2 moles) of sodium cyanide in 350 cc. of water is added, with stirring, at such a rate that the temperature never exceeds 10° (Note 2).
The reaction mixture is stirred for one hour after all the cyanide has been added and then is allowed to stand overnight. The ether layer is separated and the aqueous liquor is extracted with six 300-cc. portions of ether. The ether extracts are combined and the ether is distilled. The residue, which consists mainly of acetone cyanohydrin, is diluted with 800 cc. of methyl alcohol. The solution is cooled and saturated with ammonia gas (Note 3). The reaction mixture is allowed to stand for two or three days (Note 4), and the excess ammonia is expelled by a current of air. The methyl alcohol is removed by distillation as completely as possible, and 600 cc. of water is added to the residue. Then 1 kg. of 48 per cent hydrobromic acid is added and the mixture is refluxed for two hours.
The hydrobromic acid is distilled under reduced pressure on a steam bath. The residue is treated with 400–500 cc. of water, and the solution is again concentrated under reduced pressure to remove as much hydrobromic acid as possible (Note 5).
The residue is dissolved in fifteen to twenty times its weight of methyl alcohol (Note 6) and filtered, and an excess of pyridine (Note 7) is added. The free amino acid separates on standing overnight. It is collected on a Büchner funnel, washed thoroughly with methyl alcohol, and dried. The yield is 92–102 g. (30–33 per cent of the theoretical amount). If a pyridine-free product is desired, it is dissolved in 200 cc. of warm water and filtered, and the filtrate is poured into 2 l. of methyl alcohol (Note 8). There is less than 10 g. of product in the mother liquors. It may be isolated by evaporating to dryness, washing with methyl alcohol, and purifying by reprecipitation in the same way.
2. Notes
1. Vigorous stirring is necessary to obtain the best results.
2. The reaction temperature may rise to 15° without lowering the yield. If the temperature falls to 0°, the reaction does not take place readily.
3. The excess of ammonia is necessary to cause the formation of the aminonitrile from the acetone cyanohydrin formed in the first stage of the process.
4. In some runs this time was only twenty-four hours and no serious diminution of the yield was noted.
5. After addition of the water and subsequent evaporation almost to dryness it is well to add another small portion of water (25–75 cc.) and again evaporate to dryness to ensure the complete removal of hydrobromic acid. This should be done several times if necessary.
6. The amount of methyl alcohol should not exceed 3 l.; otherwise the amino acid will be precipitated incompletely. Long stirring in the cold may be necessary to effect complete solution, though apparently no difficulty is encountered if the residue does not dissolve completely.
7. The minimum amount of pyridine necessary is determined by the amount of hydrobromic acid remaining in the residue. An excess of pyridine does no harm. If it is desired to use the minimum amount pyridine is added in small portions until the solution is neutral to Congo red, and then an additional 250 g. is added.
8. A further small quantity may be obtained by evaporating the mother liquor to a small volume on a steam bath, allowing it to crystallize, and washing the crystals with methyl alcohol.
3. Discussion
The only satisfactory method of preparing α-aminoisobutyric acid is the Strecker synthesis1 in one or another of its modifications.2 The process of isolating the product by treating an alcoholic solution of the hydrobromide with pyridine is essentially the same as that developed for glycine;3 alternatively, aniline may be used.4
This preparation is referenced from:

References and Notes
  1. Strecker, Ann. 75, 28 (1850).
  2. Tiemann and Friedländer, Ber. 14, 1970 (1881); Marckwald, Neumark, and Stelzner, ibid. 24, 3283 (1891); Gulewitsch, ibid. 33, 1900 (1900); Hellsing, ibid. 37, 1923 (1904); Gulewitsch and Wasmus, ibid. 39, 1184 (1906); Zelinsky and Stadnikoff, ibid. 39, 1726 (1906); Cocker and Lapworth, J. Chem. Soc. 1931, 1391.
  3. Org. Syn. 4, 31 (1925).
  4. Benedict, J. Am. Chem. Soc. 51, 2277 (1929).

Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

ammonia (7664-41-7)

methyl alcohol (67-56-1)

ether (60-29-7)

ammonium chloride (12125-02-9)

aniline (62-53-3)

sodium cyanide (143-33-9)

hydrobromide (10035-10-6)

acetone (67-64-1)

pyridine (110-86-1)

Glycine (513-29-1)

Acetone cyanohydrin (75-86-5)

α-Aminoisobutyric acid,
Isobutyric acid, α-amino- (62-57-7)