2-Chloroacetic acid

Glycine is the simplest member of a large and very important class of compounds, the a-amino-carboxylic acids. TTiere are many different methods available for the synthesis of amino-acids, but glycine can be readily prepared by the action of an excess of ammonia on chloroacetic acid ... 

Add 15 g, of chloroacetic acid to 300 ml. of aqueous ammonia solution d, o-88o) contained in a 750 ml. conical flask. (The manipulation of the concentrated ammonia should preferably be carried out in a fume-cupboard, and great care taken to avoid ammonia fumes.) Cork the flask loosely and set aside overnight at room temperature. Now concentrate the solution to about 30 ml. by distillation under reduced pressure. For this purpose, place the solution in a suitable distilling-flask with some fragments of unglazed porcelain, fit a capillary tube to the neck of the flask, and connect the flask through a water-condenser and receiver to a water-pump then heat the flask carefully on a water-bath. Make the concentrated solution up to 40 ml. by the addition of water, filter, and then add 250 ml. of methanol. Cool the solution in ice-water, stir well, and set aside for ca. I hour, when the precipitation of the glycine will be complete. 

Acetic acid can be chlorinated by gaseous chlorine in the presence of red phosphorus as catalyst to yield successively mono-, di-, and tri-chloroacetic acid the reaction proceeds better in bright sunlight. If the chlorination is stopped when approximately one molecule of chlorine per molecule of acetic acid is absorbed the main product is monochloroacetic acid ... 

Ethyl cyanoacetate, a substance of importance in synthetical work, is prepared from chloroacetic acid by the following series of reactions ... 

Chloroacetic acid must be handled with great care as it causes blisters on the skin. 

Dissolve 180 g. of commercial ammonium carbonate in 150 ml. of warm water (40-50°) in a 700 ml. flask. Cool to room temperature and add 200 ml. of concentrated ammonia solution (sp. gr. 0 88). Introduce slowly, with swirling of the contents of the flask, a solution of 50 g. of chloroacetic acid (Section 111,125) in 50 ml. of water [CAUTION do not allow chloroacetic acid to come into contact with the skin as unpleasant burns will result]. Close the flask with a solid rubber stopper and fix a thin copper wire to hold the stopper in place do not moisten the portion of the stopper in contact with the glass as this lubrication will cause the stopper to slide out of the flask. Allow the flask to stand for 24-48 hours at room temperature. Transfer the mixture to a distilling flask and distil in a closed apparatus until the volume is reduced to 100-110 ml. A convenient arrangement is to insert a drawn-out capillary tube into the flask, attach a Liebig s condenser, the lower end of which fits into a filter flask (compare Fig.//, 1) and connect the... 

Carry out this preparation in the fume cupboard. Dissolve 100 g. of chloroacetic acid (Section 111,125), contained in a large porcelain basin or casserole, in 200 ml. of water. Warm the solution to about 50°, using a 200° thermometer as a stirring rod. Introduce 90 g. of pure, powdered sodium bicarbonate in small quantities at a time with stirring maintain the temperature at 50-60° until effervescence ceases. Now add 80 g. of pure, finely-powdered potassium cyanide (or an equivalent quantity of sodium cyanide), stir the mixture without further warming until the... 

Conduct the preparation in the fume cupboard. Dissolve 250 g. of redistilled chloroacetic acid (Section 111,125) in 350 ml. of water contained in a 2 -5 litre round-bottomed flask. Warm the solution to about 50°, neutralise it by the cautious addition of 145 g. of anhydrous sodium carbonate in small portions cool the resulting solution to the laboratory temperature. Dissolve 150 g. of sodium cyanide powder (97-98 per cent. NaCN) in 375 ml. of water at 50-55°, cool to room temperature and add it to the sodium chloroacetate solution mix the solutions rapidly and cool in running water to prevent an appreciable rise in temperature. When all the sodium cyanide solution has been introduced, allow the temperature to rise when it reaches 95°, add 100 ml. of ice water and repeat the addition, if necessary, until the temperature no longer rises (1). Heat the solution on a water bath for an hour in order to complete the reaction. Cool the solution again to room temperature and slowly dis solve 120 g. of solid sodium hydroxide in it. Heat the solution on a water bath for 4 hours. Evolution of ammonia commences at 60-70° and becomes more vigorous as the temperature rises (2). Slowly add a solution of 300 g. of anhydrous calcium chloride in 900 ml. of water at 40° to the hot sodium malonate solution mix the solutions well after each addition. Allow the mixture to stand for 24 hours in order to convert the initial cheese-Uke precipitate of calcium malonate into a coarsely crystalline form. Decant the supernatant solution and wash the solid by decantation four times with 250 ml. portions of cold water. Filter at the pump. 

Aryloxyacetic acids. Phenols, in the presence of alkah, react with chloroacetic acid to give aryloxyacetic acids ... 

To a mixture of 10 g. of the compound and 3-5 ml. of 33 per cent, sodium hydroxide solution in a test-tube, add 2-5 ml. of 50 per cent, chloroacetic acid solution. If necessary, add a little water to dissolve the sodium salt of the phenol. Stopper the test-tube loosely and heat on agently-boiling water bath for an hour. After cooling, dilute with 10 ml. of water, acidify to Congo red with dilute hydrochloric acid, and extract with 30 ml. of ether. Wash the ethereal extract with 10 ml, of water, and extract the aryloxyacetic acid b shaking with 25 ml. of 5 per cent, sodium carbonate solution. Acidify the sodium carbonate extract (to Congo red) with dilute hydrochloric acid, collect the aryloxyacetic acid which separates, and recrystallise it from hot water. 

Phenylglycine-o-carboxylic acid. In a 750 ml. round-bottomed flask, fitted with a reflux condenser, place 14 g. of anthranilic acid (Section IV,170), 10 g. of chloroacetic acid, 20 g. of anhydrous sodium carbonate and 200 ml. of water. Reflux the mixture for. 3 hours, then pour into a beaker, cool, render shghtly acid with concentrated hy dro-chloric acid, and allow to stand overnight. Filter off the crude acid and wash it with water. Recrystalhse from hot water with the aid of a little decolourising carbon, and dry the acid at 100°. The yield of phenyl-glycine-o-carboxyhc acid, m.p. 208°, is 12 g. 

Synthesis Chlorine is the cheapest of the halogens, so it will be better to use chloroacetic acid ... 

Dyatlova (193) reports the preparation of product 49, resulting from the dialkylation of 2-aminothiazole with a-chloroacetic acid under mild conditions (Scheme 36). 

Compounds of this type were first obtained from chloroacetic acid and seienourea (1) by Hofmann in 1889. who also assigned them the imino"... 

In 1880, Liebermann and Voltzkow (40), and then Voltzkow (41), condensing chloroacetic acid with both ethyl N-phenylthiocarbamate and p-tolylisothiocyanate obtained homologous compounds to which they attributed formulas 40 and 41, whereas their structure probably derives from that of 38 by substituting an aryl group on the cyclic nitrogen. 

In 1873, almost simultaneously, Maly (24), Volhard (38), and Nencki (42) studied the action of thiourea on chloroacetic acid. As mentioned previously, they believed the product to be the thioanalog of hydantoin and called it thiohydantoin with formula 34. 

In 1875, Mulder (43) extended the synthesis reaction of thiohydantoine to the ethyl ester and amide of chloroacetic acid. Claus (44) demonstrated the acidic properties of thiohydantoin and its ability to form metallic salts. 

In 1879, Lange (47) prepared N,N -diphenylthiohydantoin (m.p. 178°C) by condensing chloroacetic acid with N,N -dipheny thiourea and attributed to it structure 43, noting however that it was difficult to derive from 1-43 the structure of the monophenyl derivative (m.p. 148 C)... 

In 1877, Nencki (22) condensing ammonium thiocyanate with chloroacetic acid, attributed the name rhodaninic acid (Rhodaninsaure) to the compound he obtained. He noted the ability of rhodaninic acid to give colored derivatives with ferric salts. 

It has also been found that p-nitrophenylthiourea (235) reacts with chloroacetic acid by boiling in alcohol for 2 hr to afford 2-p-nitropheny-limino-4-thiazolidone and its derivatives (236) (Scheme 122) (434). 

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