SYNTHESIS OF AMINOACETONITRILE AND GLYCINE (Aminoacetic acid)

N-Methyleneaminoacetonitrile

• Place 160g (3 mol) of ammonium chloride in a 2-litre flange or three-necked flask surrounded by a large bath containing a cooling mixture of ice and salt (fume cupboard). 

• Add 450 ml (6 mol) of filtered 40 per cent w/v formaldehyde solution and stir the mixture with an efficient mechanical stirrer. 

• When the temperature has reached °C, begin the dropwise addition of a solution of 150g (3 mol) of sodium cyanide (98% pure) (CAUTION) in 250 ml of water; the addition should take about 5 hours and the temperature throughout should be kept between and 5 °C. 

• When half of the cyanide solution has been added and all of the ammonium chloride has dissolved begin the simultaneous gradual addition of 100 ml of glacial acetic acid, and adjust the rate so that addition is complete by the end of the remaining 2.5 hours. 

• Stir the mixture for a further period of 1 hour, and then filter off the product and wash it with a little cold water. 

• Transfer the filter-cake to a beaker, stir thoroughly with 500 ml of water to remove soluble salts, filter, wash with a little more water and dry in a vacuum desiccator. The yield of N-methyleneaminoacetonitrile (1) is 120g (59%), m.p. 127-128 °C.

Aminoacetonitrile sulphate:

• Cautiously add 85 ml of concentrated sulphuric acid to 400 ml of rectified spirit in a 1-litre conical flask and adjust the temperature to 50 °C. 

• Add rapidly 102g (1.5 mol) of dried powdered N-methyl-eneaminoacetonitrile, shake vigorously until the solid has dissolved and continue shaking while the product crystallises. 

• Cool in an ice bath for 4 hours, filter and wash the product with a little cold rectified spirit. 

• Dissolve the crude product in a minimum of water, filter off traces of insoluble matter and run the solution with stirring into 400 ml of cold rectified spirit. 

• Cool well, filter off the purified aminonitrile salt and wash it with a little cold rectified spirit. The yield is 105g (67%), m.p. 164 °C (decomp.).

Hydrolysis to glycine

• Boil a suspension of 79g (0.25 mol) of barium hydroxide octahydrate in 175 ml of water in a 500-ml round-bottomed flask and add in portions 21g (0.1 mol) of aminoacetonitrile sulphate. 

• Fit a reflux condenser and continue boiling until no more ammonia is evolved (about 3 hours). 

• Transfer the suspension to a beaker, add 50 per cent v/v aqueous sulphuric acid (about 20 ml) until precipitation of the barium is complete and the solution is slightly acidic, and digest on a steam bath. 

• Filter the suspension through a medium-speed filter paper (e.g. Whatman No. 30) using gentle suction, and adjust the filtrate to neutrality by carefully adding saturated barium hydroxide solution. 

• Digest further and decant the supernatant solution through a similar filter paper (this is best done under gravity), suspend the precipitate in a little hot water and add this to the filter. 

• Concentrate the filtrate under reduced pressure using a rotary evaporator until a thick suspension is obtained, and complete the precipitation of the glycine by adding 100 ml of methanol. 

• Cool well and filter off the crude glycine (about 12g). 

• Dissolve the product in 25 ml of hot water, add gradually 125 ml of methanol, cool, filter and dry the crystals in an oven at 50 °C. The yield of glycine, m.p. c. 250 °C (decomp.), is 11.2g (75%).

Aminoacetonitrile:

• Stir a suspension of 88g (0.4 mol) of the nitrile sulphate in 100 ml of dry methanol in a 500-ml three-necked flask cooled in crushed ice. 

• Add a few crystals of phenolphthalein as an indicator, pass a slow stream of nitrogen through the flask and run in during 1 hour a solution of sodium methoxide in methanol prepared from 17g (0.75 mol) of sodium and 350 ml of dry methanol; the suspension should at no time be allowed to become permanently alkaline to phenolphthalein. 

• Filter, and remove the methanol and distil the residue under reduced pressure under nitrogen. The yield of amino-acetonitrile, b.p. 73.5°C/15mmHg, is 35g (83% based on sodium). Store the product at 0°C under nitrogen.

Notes to keep in mind:

1. The product in fact has a trimeric structure.

Cognate preparation: DL-2-Aminophenylacetic acid (𝛼-phenylglycine)

• Dissolve 10g (0.2 mol) of sodium cyanide in 40 ml of water, add 11g (0.2 mol) of ammonium chloride and shake until dissolved. Add a solution of 21g (0.2 mol) of redistilled benzaldehyde in 40 ml of methanol and shake vigorously. 

• The mixture soon becomes warm; allow it to stand at ambient temperature for 2 hours, shaking occasionally. 

• Then add 100 ml of water and shake well, and extract out the oily aminonitrile which separates using two portions (60 ml and 40 ml) of toluene. 

• Combine the toluene layers, wash twice with water and extract with two 60 ml portions of 5ᴍ hydrochloric acid. 

• Boil the acid extract under reflux for 22 hours (CARE: hydrogen cyanide is evolved). 

• Cool and filter through a small plug of cotton wool to remove a little tarry matter. 

• Basify the solution by adding about 40 ml of concentrated ammonia solution (d 0.88) with stirring and cooling, collect the resulting precipitate by filtration and wash it with 100 ml of cold water and then with 15 ml of warm ethanol. 

• The crude material is almost colourless; the yield is 11.5g after drying in an oven at 50 °C. 

• To purify the phenylglycine, dissolve it in 80 ml of 1ᴍ sodium hydroxide, add 50 ml of ethanol and clarify the solution by adding a little decolourising charcoal, warming and filtering. 

• Heat the filtrate almost to boiling and neutralise by slowly adding with stirring 16 ml of 5ᴍ hydrochloric acid. 

• Filter off the purified DL-phenylglycine, wash it with 10 ml of ethanol followed by 20 ml of water and dry at 50 °C; the yield of colourless glistening plates is 9g (30%). 

• The compound has no m.p.; when placed in a rapidly heated melting point apparatus when the temperature reaches 275 °C, it sublimes between 300 and 310 °C, depending upon the rate of heating.