Cyanoacetate, ethyl

Gyanoacetamide. Place 150 ml. of concentrated aqueous ammonia solution (sp. gr. 0-88) in a 500 ml. wide-mouthed conical flask and add 200 g. (188 ml.) of ethyl cyanoacetate. Shake the cloudy mixture some heat is evolved and it becomes clear in about 3 minutes. Stand the loosely stoppered flask in an ice-salt mixture for 1 hour, filter rapidly with suction, and ash the solid with two 25 ml. portions of ice-cold ethanol. Dry in the air the yield of pale yellow cyanoacetamide is 110 g. (1). Recrystallise from 190 ml. of 95 per cent, ethanol a colourless product, m.p. 119-120 , is deposited with practically no loss. 

The colour test is not specific for a-amino acids other primary amino compounds and also ammonia give a blue colouration with ninhydrin. 

Crystalline derivatives of amino acids are usually produced by reaction at the amino group by treatment with appropriate reagents in alkaline solution  

Benzoates. Dissolve 0-5 g. of the amino acid in 10 ml. of 10 per cent, sodium bicarbonate solution and add 1 g. of benzoyl chloride. Shake the mixture vigorously in a stoppered test-tube remove the stopper from time to time since carbon dioxide is evolved. When the odour of benzoyl chloride has disappeared, acidify with dilute hydrochloric acid to Congo red and filter. Extract the solid with a little cold ether to remove any benzoic acid which may be present. RecrystaUise the benzoyl derivative which remains from hot water or from dilute alcohol. 

Excess of the reagent should be avoided, if possible. If excess of dinitrobenzoyl chloride is used, this appears as the acid in the precipitate obtained upon acidih- 

3 5-Dinitrobenzoates. The following experimental details are for glycine (aminoacetic acid) and may be easily adapted for any other amino acid. Dissolve 0-75 g. of glycine in 20 ml. of N sodium hydroxide solution and add 2 32 g. of finely powdered 3 5-dinitrobenzoyl chloride. Shake the mixture vigorously in a stoppered test-tube the acid chloride soon dissolves. Continue the shaking for 2 minutes, filter (if necessary) and acidify with dilute hydrochloric acid to Congo red. Recrystallise the derivative immediately from water or 50 per cent, alcohol. 

2-3 minutes (compare the corresponding test for Acids, Section 111,85, (i)). 

0-25 per cent, aqueous solution of ninhydrin (tiiketohydrindene hydrate), a blue colouration is produced. 

ClCH2C02Na+NaCN - CNCH2C02Na+NaCl CNCH2C02H+C2Hs0H - CNCH-C02C2H5+H20 

The solution is filtered if not clear, and the cyanoacetic acid is set free (hood) by adding with thorough stirring 600 cc. (a slight excess) of commercial hydrochloric acid (sp. gr. 1.156). The solution is evaporated on a water bath at 60-70° (Note 3) under a pressure of 20 30 mm. and the evaporation continued until practically 110 more distillate (Note 4) comes over. To 

On evaporating the alcoholic solution under reduced pressure from a water bath held at 50-60° (Note 6) the residue weighs about 540 g. A mixture of 600 cc. of absolute alcohol and 10 cc. of concentrated sulfuric acid (Note 7) is then added. The mixture is then heated on the water bath under a reflux condenser for three hours. The excess of alcohol and some of the water formed are removed by distillation under reduced pressure and the residue again heated for two hours with 300 cc. of absolute alcohol and an additional 4 cc. of concentrated sulfuric acid. The alcohol is removed by distillation under reduced pressure, and when the ester has cooled to room temperature, the sulfuric acid is neutralized with a concentrated solution of sodium carbonate the ester (upper layer) is separated, and the aqueous solution extracted with ether, or preferably benzene about one-tenth of the yield is in the extract. The combined products are placed in a i-l. distilling flask and distilled under reduced pressure after the solvent and alcohol and water have been removed. The ester is collected at 94-990, chiefly at 97-98°/x6 mm. (Note 8). The yield of a product analyzing about 97-98 per cent ethyl cyanoacetate amounts to 474-492 g. (77-80 per cent of the theoretical amount) (Note 9). 

If the reaction between the cyanide and chloroacetatc becomes too vigorous, hydrogen cyanide is set free and partly changed to brown material and a corresponding amount of glycollate is formed. 

The color at this stage should be yellow or a light brown. 

A mixture of 625 g.of chloroacetic add and 940 g. of cracked ice in a large battery jar is accurately neutralized to litmus with a cold solution of sodium hydroxide containing 333 g. per 1. about 825 cc. is required. The temperature must not be allowed to rise above 30° during the neutralization. 

A solution is now made (in the hood) of 387.5 g. of sodium cyanide (1.174 mol.) in 780 cc. of water. This is heated, gently at first to induce rapid solution, and finally to boiling. To the hot solution is added 300 cc. of the sodium chloroacetate solution, and the flame is removed as soon as the action begins. When the vigorous reaction has subsided somewhat, another 300-cc. portion is added this is continued until all has been added. The mixture is then boiled for five minutes, and finally, cooled under the tap for half an hour (Note 1). 

To the solution (in the hood) is added slowly, with stirring, 767 cc. of 43 per cent sulfuric acid (sp. gr. 1.333), or its equivalent of about this concentration. Some hydrogen cyanide is evolved from the excess cyanide present. The volume is now 4400 cc. The mixture is left to stand for five minutes to allow any salts to precipitate, and filtered in a centrifuge or by suction, the salt being saved for future use. The aqueous solution is evaporated under diminished pressure, using a 2-1. Pyrex distilling flask fitted with a dropping funnel and a capillary tube for 

To the reaction mixture is added 15 cc. of concentrated sulfuric acid and the flask is placed in an oil bath connections are made to the rest of the apparatus and heating is commenced. About 70 cc. of alcohol will distil over before the temperature of the mixture reaches no°. Meanwhile, 600 cc. of 95 per cent ethyl alcohol is placed in the i-l. flask. As soon as the temperature reaches 110° this alcohol is boiled so that a rapid stream of vapor passes into the reaction mixture—the temperature should remain at no°. More alcohol is added to that in the i-l. flask until 800 cc. has been added heating is continued until all has been vaporized, whereupon the safety tube is opened at once. The flask is removed from the oil bath and allowed to cool. This esterification takes about three hours. The distillate obtained during the process consists of dilute alcohol. 

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The Michael Addition Reaction consists in the addition of the sodio-derivative of ethyl acetoacetate, ethyl malonate or ethyl cyanoacetate to an olefine group... 

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

Two compounds, which may be prepared from ethyl cyanoacetate and also find application in synthetical work, may be included here. Cyanoacetamide, prepar from ethyl cyanoacetate and concentrated ammonia solution ... 

Ethyl cyanoacetate (Section 111,131) is sometimes preferable to diethyl malonate for the synthesis of acids. It forms a sodio derivative with sodium ethoxide ... 

Acetone Ethyl cyanoacetate Ethyl i opropylidene cyanoacetate... 

Into a 500 nil. round-bottomed flask, provided with a double surface condenser, place 50 g. (63 ml.) of pure, dry acetone, 50 g. (47 ml.) of ethyl cyanoacetate (Section 111,131) and 0 -5 g. of piperidine. Allow to stand for 60 hours and heat on a water bath for 2 hours. Treat the cold reaction mixture with 100 ml. of ether, wash with dilute hydrochloric acid, then with water, and dry over anhydrous sodium or magnesium sulphate. Distil under diminished pressure and collect the ethyl fsopropylidene cyanoacetate (ethyl a-cyano-pp-dimethylacrylate) at 114-116°/14mm.(l). The yield is 39 g. 

When acetone is condensed with ethyl cyanoacetate in the presence of a solution of anhydrous ammonia in absolute alcohol at —5°, the ammonium salt of the dicyano-imlde (I) is precipitated. Upon dissolving this salt in water and adding excess of concentrated hydrochloric acid, the crystalline dicyano-imide (II) is obtained. Hydrolysis of the last-named with strong sulphuric acid affords p p dimethylglutaric acid (III). 

The above is an example of the Guareschi reaction. It is applicable to most dialkyl ketones and to alicyclic ketones (e.g., cyclohexanone, cyc/opentanone, etc.). The condensation product (I) is probably formed by a simple Knoe-venagel reaction of the ketone and ethyl cyanoacetate to yield ethyl a-cyano-pp dimethylacrylate (CH3)2C=C(CN)COOCjHj, followed by a Michael ad tion of a second molecule of ethyl cyanoacetate finally, the carbethoxyl groups are converted to the cyclic imide structure by the action of ammonia. 

The preparation of ethyl cyanoacetate proceeds via ethyl chloroacetate and begins with acetic acid Wnte a sequence of reactions descnbmg this synthesis... 

Health and Safety Factors. The following toxicities have been reported for cyanoacetic acid oral LD q (rat) 1500 mg/kg subcutaneous LD q (rabbit), 1900 mg/kg and subcutaneous LD q (frog) 1300 mg/kg (29). Eor ethyl cyanoacetate the following toxicities have been reported interperitoneal LD q (mice), 750 mg/kg subcutaneous LD q (rabbits), 1500 mg/kg and subcutaneous LD q (frogs), 4000 mg/kg. 

Physical Properties. The physical properties of cyanoacetic acid [372-09-8] NM7—CH2COOH (28) ate summarized in Table 4. The industrially most important esters ate methyl cyanoacetate [105-34-0] and ethyl cyanoacetate [105-56-6]. Both esters ate miscible with alcohol and ether and immiscible with water. 

Table 4. Physical Properties of Cyanoacetic Acid, Methyl Cyanoacetate, and Ethyl Cyanoacetate...

Property Cyanoacetic acid Methyl cyanoacetate Ethyl cyanoacetate... 

Methyl cyanoacetate and ethyl cyanoacetate are produced by Lonza ia Switzerland and Hbls ia the United States, as well as Juzen and Tateyama ia Japan. The total production capacity is estimated to be ia the range of 10,000 metric tons per year. The market price for both esters ia bulk shipments was around 6/kg ia 1993. 

Analytical and Test Methods. Potentiometic titration is an analytical method for cyanoacetic acid. Methyl and ethyl cyanoacetates are usually analyzed by gas chromatography usiag the same equipment as for the malonates but with a higher column and iajector temperatures, namely 150 and 200°C, respectively. 

Health and Safety Factors. Handling of cyanoacetic acid and cyanoacetates do not present any specific danger or health hazard if handled with the usual precautions. Cyanoacetic acid is classified as a moderate irritant (skin irritation, rabbits) and has an LD q (oral, rats) of 1500 mg/kg. Methyl and ethyl cyanoacetate are both classified as slight irritants (skin irritation, rabbits) and have an LD q (oral, rats) of 3062 and 2820 mg/kg, respectively. Transport classification cyanoacetic acid RID/ADR 8 IMDG-Code 8 lATA/ICAO 6.1. Methyl and ethyl cyanoacetate RID/ADR 6.1 IMDG-Code 6.1 lATA/ICAO 6.1. 

Halogenopyrimidines react with active methylene groups, such as those in diethyl malonate, ethyl cyanoacetate, ketene diethylacetal, etc. For example, 4-chloro-6-methyl-5-nitropyrimidin-2-amine (454) and dimethyl sodiomalonate give dimethyl 2-amino-6-methyl-5-nitropyrimidin-4-ylmalonate (455) (63ZOB3132) 2-chloro-4,6-... 

If the substituent at the 3-position is a group that can be eliminated as an anion (such as Cr, CN and NJ), the reaction proceeds without the cleavage of the C(3)—C(4) bond in the isoxazole ring and involves the ejection of the 3-substituent as an anion. For example, 3-cyanoisoxazole (114) reacted with sodium ethoxide at room temperature to give ethyl cyanoacetate (115) via an intermediate cyanoketene (32G436). 

D A R A P S K I Amino Acid Synthesis (see Curtius) Amino acid synthesis from ethyl cyanoacetates... 

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