Org. Synth. 1952, 32, 92
DOI: 10.15227/orgsyn.032.0092
PHENYLACETAMIDE
[Acetamide, 2-phenyl-]
Submitted by Wilhelm Wenner
1
Checked by William S. Johnson and Robert E. Ireland.
1. Procedure
In a 3-l. three-necked round-bottomed flask equipped with glass joints are placed 200 g. (1.71 moles) of benzyl cyanide (Note 1) and 800 ml. of 35% hydrochloric acid (Note 2). The flask is fitted with a reflux condenser, a thermometer, and an efficient mechanical stirrer (Note 3). At a bath temperature of about 40° (Note 4) the mixture is stirred vigorously. Within a period of 20–40 minutes the benzyl cyanide goes into solution (Note 3). During this time, the temperature of the reaction mixture rises about 10° above that of the bath. The homogeneous solution is kept in the bath with, or without, stirring for an additional 20–30 minutes (Note 5). The warm water in the bath is replaced by tap water at about 15–20°, and the thermometer is replaced by a dropping funnel from which 800 ml. of cold distilled water is added with stirring (Note 6). After the addition of about 100–150 ml., crystals begin to separate. When the total amount of water has been added, the mixture is cooled externally with ice water for about 30 minutes (Note 7). The cooled mixture is filtered by suction. Crude phenylacetamide remains on the filter and is washed with two 100-ml. portions of water. The crystals are then dried at 50–80°. The yield of crude phenylacetamide is 190–200 g. (82–86%). It is sufficiently pure for most purposes although it contains traces of phenylacetic acid. If pure phenylacetamide is desired, the crude, wet solid is stirred for about 30 minutes with 500 ml. of a 10% solution of sodium carbonate, collected on a suction funnel, washed with two 100-ml. portions of cold water, and dried. The yield of this product is 180–190 g. (78–82%); m.p. 154–155° (Note 8) and (Note 9).
2. Notes
1.
The quality of the
benzyl cyanide markedly affects the yields. Material prepared according to directions given previously
2 is satisfactory. Several commercially available grades were also found to be usable without distillation.
2.
The
hydrochloric acid must be of at least 30% strength.
3.
Efficient stirring is of prime importance for satisfactory reaction, because intimate mixing of the heterogeneous mixture is necessary. The rate of dissolution of the nitrile depends on the efficiency of the stirring.
4.
The reaction proceeds slowly at lower temperatures. Temperatures above 50° are not recommended because of the high volatility of
hydrochloric acid.
5.
This additional warming ensures complete reaction of some dissolved
benzyl cyanide. The
phenylacetamide is not readily hydrolyzed under these conditions.
6.
The rate of addition is not critical.
7.
If
phenylacetic acid is desired, the suspension of
phenylacetamide is refluxed with stirring and the
phenylacetamide redissolves. After about 30 minutes, the mixture becomes turbid and the product begins to separate as an oil. After 6 hours the mixture is cooled, first with tap water and then by an
ice-water bath. When the temperature has dropped to about 40–50°, the
phenylacetic acid crystallizes. After cooling at 0° for about 4 hours (the acid is rather soluble in warm water), the mixture is filtered by suction. The crude, colorless
phenylacetic acid is washed with two 100-ml. portions of cold water and dried in a
desiccator. The yield of crude acid is
180–195 g. (
77.5–84%). It melts at
66–70° and is sufficiently pure for most purposes. The mother liquor on extraction with two
150-ml. portions of benzene and evaporation yields an additional
3–5 g. of acid. To prepare the pure acid, vacuum distillation (as described by Adams and Thal
3) is simpler and gives higher yields than recrystallization from
ligroin.
8.
Further purification is effected by recrystallization from
95% ethanol or benzene, yielding the pure compound of m.p.
156°.
9.
The following arylacetamides have been prepared from the corresponding nitriles by the same method in the indicated yields:
4 p-methylphenylacetamide (
70%),
p-isopropylphenylacetamide (
90%),
1-naphthylacetamide (
54%),
5,6,7,8-tetrahydro-2-naphthylacetamide (
90%),
p-methoxyphenylacetamide (
76%),
3,4-dimethoxyphenylacetamide (
82%), and
2,3-dimethoxyphenylacetamide (
91%). Only in the cases of the alkoxy-substituted nitriles are the resulting amides soluble in the reaction mixture; the other nitriles do not dissolve completely at any time during the reaction.
3. Discussion
Phenylacetamide has been obtained by a wide variety of reactions: from
benzyl cyanide with water at 250–260°;
5 from
benzyl cyanide with water and
cadmium oxide at 240°;
6 from
benzyl cyanide with
sulfuric acid;
7,8 by saturation of an
acetone solution of benzyl cyanide with
potassium hydrosulfide;
9 from
benzyl cyanide with
sodium peroxide;
10 by electrolytic reduction of
benzyl cyanide in
sodium hydroxide;
11 from
ethyl phenylacetate with alcoholic
12 or aqueous
13 ammonia; from
phenylacetic acid with
ammonium acetate14 or
urea;
15 from
diazoacetophenone with
ammoniacal silver solution;
16 from
phenylacetic acid imino ether hydrochloride and water;
17 from
acetophenone with
ammonium polysulfide;
18 from
benzoic acid;
19 by heating the
ammonium salt of phenylacetic acid;
20 and by heating
cinnamic acid with a mixture of
sulfur and ammonium hydroxide.
21
The literature on the preparation of
phenylacetic acid is reviewed in an earlier volume of this series.
3
The present method is that of Wenner
22 and is applicable to other arylacetonitriles.
4
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
ligroin
ammonium polysulfide
ammoniacal silver
ethanol (64-17-5)
sulfuric acid (7664-93-9)
hydrochloric acid (7647-01-0)
ammonia (7664-41-7)
Benzene (71-43-2)
ammonium acetate (631-61-8)
sodium hydroxide (1310-73-2)
sodium carbonate (497-19-8)
Benzoic acid (65-85-0)
sulfur (7704-34-9)
acetone solution of benzyl cyanide (67-64-1)
Acetophenone (98-86-2)
Benzyl cyanide (140-29-4)
Phenylacetic acid (103-82-2)
urea (57-13-6)
sodium peroxide
ammonium hydroxide (1336-21-6)
potassium hydrosulfide (1310-61-8)
cinnamic acid (621-82-9)
Ethyl phenylacetate (101-97-3)
cadmium oxide
Phenylacetamide,
Acetamide, 2-phenyl- (103-81-1)
1-naphthylacetamide (86-86-2)
5,6,7,8-tetrahydro-2-naphthylacetamide
3,4-dimethoxyphenylacetamide
2,3-dimethoxyphenylacetamide
Diazoacetophenone (3282-32-4)
phenylacetic acid imino ether hydrochloride
p-methylphenylacetamide
p-isopropylphenylacetamide
p-methoxyphenylacetamide (6343-93-7)
ammonium salt of phenylacetic acid
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