Acids cyanoacetic

C8H10N4O2. An alkaloid occurring in tea, coffee and guarana, from which it may be prepared by extraction, It is also manufactured by the methylation of theobromine and by the condensation of cyanoacetic acid with urea. Crystallizes with H2O or anhydrous from organic solvents. M.p. (anhydrous) 235"C, sublimes at 176 C. Odourless, and with a very bitter taste. Caffeine acts as a stimulant and diuretic, and is a constituent of cola drinks, tea and coffee. 

The physical properties of cyanoacetic acid [372-09-8] and two of its ester derivatives are Hsted ia Table 11 (82). The parent acid is a strong organic acid with a dissociation constant at 25°C of 3.36 x 10. It is prepared by the reaction of chloroacetic acid with sodium cyanide. It is hygroscopic and highly soluble ia alcohols and diethyl ether but iasoluble ia both aromatic and aUphatic hydrocarbons. It undergoes typical nitrile and acid reactions but the presence of the nitrile and the carboxyUc acid on the same carbon cause the hydrogens on C-2 to be readily replaced. The resulting malonic acid derivative decarboxylates to a substituted acrylonitrile ... 

The methyl and ethyl esters of cyanoacetic acid are slightly soluble ia water but are completely miscible ia most common organic solvents including aromatic hydrocarbons. The esters, like the parent acid, are highly reactive, particularly ia reactions involving the central carbon atom however, the esters tend not to decarboxylate. They are prepared by esterification of cyanoacetic acid and are used principally as chemical iatermediates. 

Table 11. Some Physical Properties of Cyanoacetic Acid and Methyl and Ethyl Esters ...

Cyanoacetic acid, NCCH2COOH Methyl ester, NCCH2COOCH3 Ethyl ester, NCCH2COOC2H3... 

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. 

Uses. Although cyanoacetic acid can be used in appHcations requiring strong organic acids, its principal use is in the preparation of malonic esters and other reagents used in the manufacture of pharmaceuticals, eg, barbital, caffeine, and B vitamins (see Alkaloids Hypnotics Vitamins). Cyanoacetic acid can be used for the preparation of heterocycHc ketones. 

Major industrial uses for chloroacetic acid are in the manufacture of cellulose ethers (mainly carboxymethylceUulose, CMC), herbicides, and thioglycolic acid. Other industrial uses include manufacture of glycine, amphoteric surfactants, and cyanoacetic acid. 

Reaction of chloroacetic acid with cyanide ion yields cyanoacetic acid [372-09-8] C2H2NO2, (8) which is used in the formation of coumarin, malonic acid and esters, and barbiturates. Reaction of chloroacetic acid with hydroxide results in the formation of glycoUc acid [79-14-1]. 

Hydrogen Cyanide Process. This process, one of two used for the industrial production of malonates, is based on hydrogen cyanide [74-90-8] and chloroacetic acid [79-11-8]. The intermediate cyanoacetic acid [372-09-8] is esterified in the presence of a large excess of mineral acid and alcohol. 

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... 

Reactions. The chemical properties of cyanoacetates ate quite similar to those of the malonates. The carbonyl activity of the ester function is increased by the cyano group s tendency to withdraw electrons. Therefore, amidation with ammonia [7664-41-7] to cyanoacetamide [107-91-5] (55) or with urea to cyanoacetylurea [448-98-2] (56) proceeds very easily. An interesting reaction of cyanoacetic acid is the Knoevenagel condensation with aldehydes followed by decarboxylation which leads to substituted acrylonitriles (57) such as (29), or with ketones followed by decarboxylation with a shift of the double bond to give P,y-unsaturated nitriles (58) such as (30) when cyclohexanone [108-94-1] is used. 

Manufacture. Cyanoacetic acid and cyanoacetates are iadustrially produced by the same route as the malonates starting from a sodium chloroacetate solution via a sodium cyanoacetate solution. Cyanoacetic acid is obtained by acidification of the sodium cyanoacetate solution followed by organic solvent extraction and evaporation. Cyanoacetates are obtained by acidification of the sodium cyanoacetate solution and subsequent esterification with the water formed being distilled off. Other processes reported ia the Hterature iavolve the oxidation of partially oxidized propionittile [107-12-0] (59). Higher esters of cyanoacetic acid are usually made through transesterification of methyl cyanoacetate ia the presence of alumiaiumisopropoxide [555-31-7] as a catalyst (60). 

Economic Aspects. In order to avoid the extraction and evaporation steps, most of the cyanoacetic acid derivatives are made directiy from solution therefore, only a small portion of the acid produced is traded. Cyanoacetic acid is produced by Boehringer-Tngelheim and Knoil ia Germany, Juzen ia Japan, as well as Hbls ia the United States. When sold ia tons, the price of cyanoacetic acid was 9/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. 

Uses. In many cases cyanoacetic acid, cyanoacetates, or cyanoacetamide can be used alternatively. The traded cyanoacetic acid is mainly iatended for the synthesis of the cough remedy dextromethorphan [125-71-3] (31) (61) (see Expectorants, antitussives, and related agents) and of the fungicide cymoxanil [57966-95-7] (32) (62) (see Fungicides,agricultural). 

Otherwise cyanoacetic acid is directiy converted as a solution with 1,3-dimethylurea [96-31-1] iato 2-cyano-A/,AT-dimethylcarbamoyl acetamide [39615-79-7] which is further upgraded iato the diuretics theophylline [58-55-9] (33 where R = H) and caffeiae [58-08-2] (33, where R = CH3) (63). 

Reaction with Alkyl Halide. The active methylene group of an Al-acylamino-malonic acid ester or Ai-acylamino cyanoacetic acid ester condenses readily with primary alkyl hahdes. 

Beryllium, calcium, boron, and aluminum act in a similar manner. Malonic acid is made from monochloroacetic acid by reaction with potassium cyanide followed by hydrolysis. The acid and the intermediate cyanoacetic acid are used for the synthesis of polymethine dyes, synthetic caffeine, and for the manufacture of diethyl malonate, which is used in the synthesis of barbiturates. Most metals dissolve in aqueous potassium cyanide solutions in the presence of oxygen to form complex cyanides (see Coordination compounds). 

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