Org. Synth. 1935, 15, 64
DOI: 10.15227/orgsyn.015.0064
[Butyric acid, γ-phenyl-]
Submitted by E. L. Martin
Checked by C. R. Noller and F. M. McMillan.
1. Procedure
Amalgamated zinc is prepared by shaking for five minutes a mixture of 120 g. of mossy zinc, 12 g. of mercuric chloride, 200 cc. of water, and 5–6 cc. of concentrated hydrochloric acid contained in a 1-l. round-bottomed flask. The solution is decanted and the following reagents are added, in the order named, to the zinc: 75 cc. of water, 175 cc. of concentrated hydrochloric acid, 100 cc. of toluene, and 50 g. (0.28 mole) of β-benzoylpropionic acid (p. 81). The flask is fitted with a vertical condenser connected to a gas absorption trap (Note 1), and the reaction mixture is boiled vigorously for twenty-five to thirty hours (Note 2). Three 50-cc. portions of concentrated hydrochloric acid are added at approximately six-hour intervals during the refluxing period.
After cooling to room temperature the layers are separated. The aqueous layer is diluted with 200 cc. of water and extracted with three 75-cc. portions of ether. The toluene layer and the ether extracts are combined, washed with water, and dried over calcium chloride. The solvents are removed by distillation under reduced pressure on the steam bath, after which the γ-phenylbutyric acid is distilled at 178–181°/19 mm. (148–154°/8–10 mm., 125–130°/3 mm.). The yield of acid, which melts at 46–48° (Note 3), is 38–41 g. (82–89 per cent of the theoretical amount) (Note 4).
2. Notes
1. Considerable hydrogen chloride is driven off during the initial heating, and it might appear that it would be advantageous to use constant-boiling instead of concentrated hydrochloric acid. If this is done, however, the product has a melting point of 40–44° and the yield is somewhat lower.
2. If the refluxing is interrupted for any reason, great care must be exercised to avoid frothing on heating again. The upper part of the flask may be occasionally brushed with a free flame. Once the two layers are well mixed, boiling proceeds smoothly.
3. The recorded melting points vary from 47° to 51°. The acid may be crystallized from hot water (75 cc. per g.) but the recovery is only about 50 per cent. No other suitable solvent or combination of solvents was discovered. Redistillation raises the melting point to 47–48° with only mechanical losses.
4. The procedure described differs from that published in Org. Syn. 15, 64, by the addition of toluene to the reaction mixture. In the presence of toluene the concentration of organic material in the aqueous layer is extremely small and polymolecular reactions take place to a smaller extent than in the original procedure. As a result the yield of pure product is greater.
When the modified procedure is applied to the preparation of higher-melting compounds, for example the γ-naphthylbutyric acids, the layers are separated after cooling to 50–60°, benzene is used for the extraction, and the combined benzene-toluene solution is clarified with Norite while still wet; it is then concentrated somewhat and allowed to cool for crystallization. In preparing methoxylated acids, such as γ-anisyl- or γ-veratrylbutyric acid, some demethylation occurs. When this happens the toluene layer and extracts are mixed with an excess of dilute sodium hydroxide solution and the organic solvents are removed by steam distillation. The alkaline solution is treated at 80° with an excess of methyl sulfate, the solution is clarified with Norite, cooled, and acidified, whereupon the product separates in good condition.
3. Discussion
Of the several methods by which γ-phenylbutyric acid has been obtained, those of preparative value are the decarboxylation of γ-phenylethylmalonic acid;1 the carbonation of γ-phenylpropylmagnesium bromide;2 and the reduction of β-benzoylpropionic acid with amalgamated zinc and hydrochloric acid3 or of its hydrazone with sodium ethoxide.4 The use of toluene in the Clemmensen reduction of β-benzoylpropionic acid and almost a score of related compounds has been described by Martin.5

References and Notes
  1. Fischer and Schmitz, Ber. 39, 2212 (1906).
  2. Grignard, Compt. rend. 138, 1049 (1904); Rupe and Proske, Ber. 43, 1233 (1910).
  3. Krollpfeiffer and Schäfer, ibid. 56, 620 (1923).
  4. Staudinger and Müller, ibid. 56, 713 (1923).
  5. Martin, J. Am. Chem. Soc. 58, 1438 (1936).

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

amalgamated zinc


γ-naphthylbutyric acids

γ-anisyl- or γ-veratrylbutyric acid

γ-phenylethylmalonic acid

calcium chloride (10043-52-4)

hydrogen chloride,
hydrochloric acid (7647-01-0)

Benzene (71-43-2)

ether (60-29-7)

sodium hydroxide (1310-73-2)

Norite (7782-42-5)

toluene (108-88-3)

zinc (7440-66-6)

sodium ethoxide (141-52-6)

mercuric chloride (7487-94-7)

methyl sulfate (75-93-4)

β-Benzoylpropionic acid (2051-95-8)

γ-Phenylbutyric acid,
Butyric acid, γ-phenyl- (1821-12-1)

γ-phenylpropylmagnesium bromide