Phenylacetic acid from benzyl cyanide

Preparation of benzyl cyanide. Place 100 g. of powdered, technical sodium cyanide (97-98 per cent. NaCN) (CAUTION) and 90 ml. of water in a 1 litre round-bottomed flask provided with a reflux condenser. Warm on a water bath until the sodium cyanide dissolves. Add, by means of a separatory funnel fitted into the top of the condenser with a grooved cork, a solution of 200 g. (181-5 ml.) of benzyl chloride (Section IV.22) in 200 g. of rectified spirit during 30-45 minutes. Heat the mixture in a water bath for 4 hours, cool, and filter off the precipitated sodium chloride with suction wash with a little alcohol. Distil off as much as possible of the alcohol on a water bath (wrap the flask in a cloth) (Fig. II, 13, 3). Cool the residual liquid, filter if necessary, and separate the layer of crude benzyl cyanide. (Sometimes it is advantageous to extract the nitrile with ether or benzene.) Dry over a little anhydrous magnesium sulphate, and distil under diminished pressure from a Claisen flask, preferably with a fractionating side arm (Figs. II, 24, 2-5). Collect the benzyl cyanide at 102-103°/10 mm. The yield is 160 g. 

This product is sufficiently pure for the preparation of phenylacetic acid and its ethyl ester, but it contains some benzyl tso-cyanide and usually develops an appreciable colour on standing. The following procedure removes the iso-cyanide and gives a stable water-white compound. Shake the once-distilled benzyl cyanide vigorously for 5 minutes with an equal volume of warm (60°) 60 per cent, sulphuric acid (prepared by adding 55 ml. of concentrated sulphuric acid to 100 ml. of water). Separate the benzyl cyanide, wash it with an equal volume of sa+urated sodium bicarbonate solution and then with an equal volume of half-saturated sodium chloride solution- Dry with anhydrous magnesium sulphate and distil under reduced pressure. The loss in washing is very small (compare n-Butyl Cyanide, Section 111,113, in which concentrated hydrochloric acid is employed). 

Hydrolysis of benzyl cyanide to phenylacetic acid. Into a 500 ml. round-bottomed flask, provided with a reflux condenser, place 100 ml. 

Hydrolysis of benzyl cyanide to phenylacetamide. In a 1500 ml. three-necked flask, provided with a thermometer, reflux condenser and efficient mechanical stirrer, place 100 g. (98 ml.) of benzyl]cyanide and 400 ml. of concentrated hydrochloric acid. Immerse the flask in a water bath at 40°. and stir the mixture vigorously the benzyl cyanide passes into solution within 20-40 minutes and the temperature of the reaction mixture rises to about 50°, Continue the stirring for an additional 20-30 minutes after the mixture is homogeneous. Replace the warm water in the bath by tap water at 15°, replace the thermometer by a dropping funnel charged with 400 ml. of cold distilled water, and add the latter with stirring crystals commence to separate after about 50-75 ml. have been introduced. When all the water has been run in, cool the mixture externally with ice water for 30 minutes (1), and collect the crude phenylacetamide by filtration at the pump. Remove traces of phenylacetic acid by stirring the wet sohd for about 30 minutes with two 50 ml. portions of cold water dry the crystals at 50-80°. The yield of phenylacetamide, m.p. 154-155°, is 95 g. RecrystaUisation from benzene or rectified spirit raises the m.p. to 156°. 

---

The procedure is based upon the standard method of Wis-licenus.1 Ethyl phenylmalonate has also been obtained from benzyl cyanide and ethyl carbonate. Phenylmalonic acid has been prepared by carbonation of the enolate of phenylacetic acid. ... 

Preparation of Phenylacetic Acid from aZp/ a-Tolunitrile (Benzyl Cyanide)... 

The third most significant application for benzyl chloride is the production of benzyl cyanide. Benzyl cyanide is obtained from benzyl chloride by the reaction with sodium cyanide. The most important product derived from benzyl cyanide is phenylacetic acid, which is easily obtained by hydrolysis. 

Place 75 g. (74 ml.) of benzyl cyanide (Section IV,160), 125 g. (153 ml.) of rectifled spirit and 150 g. (68 ml.) of concentrated sulphuric acid in a 750 ml. round-bottomed flask, fitted with an efficient reflux condenser. Reflux the mixture, which soon separates into Wo layers, gently for 8 hoius, cool and pour into 350 ml. of water. Separate the upper layer. Dissolve it in about 75 ml. of ether (1) in order to facilitate the separation of the layers in the subsequent washing process. Wash the ethereal solution carefully with concentrated sodium bicarbonate solution until effervescence ceases and then with water. Dry over 10 g. of anh3 drous magnesium sulphate for at least 30 minutes. Remove the solvent with the aid of the apparatus shown in Fig. II, 13, 4 and distil from an air bath (Fig. II, 5, 3). The ethyl phenylacetate passes over at 225-229° (mainly 228°) as a colourless liquid the yield is 90 g. Alternatively, the residue after removal of the ether may be distilled in a Claisen flask under diminished pressm (Fig. II, 20, 1) collect the ester at 116-lI8°/20 mm. 

Benzyl cyanide (40 g. = 0 33 mole) is heated in a round-bottomed flask (capacity 0-5 1.), with a mixture of 50 c.c. of concentrated sulphuric acid and 30 c.c. of water. The flask is provided with an upright air condenser, and is placed in a conical (Babo) air bath. The heating is continued until the appearance of small bubbles of vapour indicates that a reaction, which rapidly becomes violent, has set in the liquid boils up, and white fumes are emitted. It is allowed to cool and then two volumes of water are added. After some time the phenylacetic acid which has crystallised out is filtered off with suction. If a sample of the material does not form a clear solution with sodium carbonate in water (presence of phenylacetamide), the whole of the crude material is shaken with sodium carbonate solution and the mixture is filtered. From the clear filtrate phenylacetic acid is reprecipitated with sulphuric acid, and can be recrystallised directly from a rather large volume of hot water or, after drying, from petrol ether. Because of its low melting point (76°) it often separates at first as an oil, but it can also be conveniently purified by distillation in vacuo from a sausage flask.2... 

The benzyl cyanide, prepared according to the procedure as outlined, is collected over a 50 range. It varies in appearance from a colorless to a straw-colored liquid and often develops appreciable color upon standing. For a product of special purity, it should be redistilled under diminished pressure and collected over a 1-20 range. For most purposes, such as the preparation of phenylacetic acid or ester, the fraction boiling i35-i40°/38 mm. is perfectly satisfactory. 

In a 5-I. round-bottom flask, fitted with a mechanical stirrer and reflux condenser, are mixed 1150 cc. of water, 840 cc. of commercial sulfuric acid and 700 g. of benzyl cyanide (preparation III, p. 9). The mixture is heated under a reflux condenser and stirred for three hours, cooled slightly and then poured into 2 1. of cold water. The mixture should be stirred so that a solid cake is not formed the phenylacetic acid is then filtered off. This crude material should be melted under water and washed by decantation several times with hot water. These washings, on cooling, deposit a small amount of phenylacetic acid which is filtered off and added to the main portion of material. The last of the hot water is poured off from the material while it is still molten and it is then transferred to a 2-1. Claisen distilling flask and distilled in vacuo. A small amount of water comes over first and is rejected about 20 cc., containing an appreciable amount of benzyl cyanide, then distils. This fraction is used in the next run. The distillate boiling i76-i89°/5o mm. is collected separately and solidifies on standing. It is practically pure phenylacetic acid, m. p. 76-76.5° it amounts to 630 g. (77.5 per cent of the theoretical amount). As the fraction which is returned to the second run of material contains a considerable portion of phenylacetic acid, the yield actually amounts to at least 80 per cent. 

Diclofenac Diclofenac, 2-[(2,6-dichlorophenyl)-amino]-phenylacetic acid (3.2.42), is synthesized from 2-chIorobenzoic acid and 2,6-dichloroaniline. The reaction of these in the presence of sodium hydroxide and copper gives iV-(2,6-dichlorophenyl)anthranyIic acid (3.2.38), the carboxylic group of which undergoes reduction by lithium aluminum hydride. The resulting 2-[(2,6-dicholorphenyl)-amino]-benzyl alcohol (3.2.39) undergoes further chlorination by thionyl chloride into 2-[(2,6-dichlorophenyl)-amino]-ben-zylchloride (3.2.40) and further, upon reaction with sodium cyanide converts into... 

Phenylacetic acid. Into a 500-ml round-bottomed flask, provided with a reflux condenser, place 100 ml of water, 100 ml of concentrated sulphuric acid and 100 ml of glacial acetic arid add lOOg (98 ml, 0.85 mol) of benzyl cyanide. Heat under reflux for 45-60 minutes hydrolysis is then complete. Pour the mixture into 2-3 volumes of water with stirring. Filter the crude arid at the pump. Melt the crude material under water, and wash it two or three times with small volumes of hot water the acid solidifies on cooling. Test a small portion for the presence of phenylacetamide (m.p. 155 °C) by dissolving in sodium carbonate solution. If a clear solution results, phenylacetamide is absent if the solution is not clear, shake the whole of the crude product with excess of sodium carbonate solution, filter and precipitate the phenylacetic arid from the clear filtrate by the addition of dilute sulphuric arid. Filter off the phenylacetic acid and recrystallise it from hot water or, better, light petroleum (b.p. 40-60 °C). The yield of pure acid, 77 °C, is 50 g (43%). Small quantities of acid may be recovered from the mother-liquors by extraction with ether, but this is rarely worth while. Alternatively the acid may be purified by distillation under reduced pressure, b.p. 140-150 °C/20mmHg. The p.m.r. spectrum should be recorded and compared with that shown in Fig. 3.47. The 13C-n.m.r. spectrum is shown in Fig. 3.55. 

Phenylacetic acid (phenylethanoic acid, 11), the simplest example of this type of compound, is prepared from benzyl chloride by the displacement of chloride by cyanide ion and subsequent hydrolysis to the acid (Scheme 5.13). 

Homogeneous, aqueous tv o-phase catalysis is also of industrial interest for the production of the important intermediate phenylacetic acid (PAA), -which is used in perfume and pesticides syntheses. The previous process (benzyl chloride to benzyl cyanide -with hydrolysis of the latter) suffered from the formation of large amounts of salt (1400 kg per kg of PAA). The new carbonylation method reduces the amount of salt by 60% and makes use of the great cost difference between —CN and —CO [79-81]. Finally, the Suzuki coupling of aryl halides and arylboronic acids, substituting Pd/TPPMS with Pd/TPPTS catalysts, should be also mentioned. 

Increasing the temperature to 350 °C results in decarbonylation of the phenylpyruvic acid methyl ester derivatives and the phenyl acetic ester is formed with a ratio of 65 % a-ketoester to 35 % acetic acid ester. Until now the industrial process for the synthesis of phenylacetic acid ester has started from benzyl chloride, which is converted to benzyl cyanide by KCN, followed by hydrolysis. Every step of this reaction must be performed in a separate reactor and special measures must be taken for handling large amounts of toxic KCN. The new route is certainly an environmentally benign alternative [8,27]. 

If phenylacetic acid is desired free from foreign odor, it seems advantageous to use a process due to Mann,627 in which benzyl cyanide is hydrolysed by alkali instead of by acid ... 

---