Ethyl-chloroacetate

The halogen derivatives of ethyl acetate are compounds which have been known for some time and are used nowadays for organic syntheses both in the laboratory and in industry. They have a powerful action on the eyes and were used as war gases in the war of 1914-18. 

They are commonly prepared by the esterification of ethyl alcohol by the corresponding acids monochloracetic, bromoacetic, etc., using sulphuric acid as dehydrating agent. This acid first reacts with alcohol to form ethyl hydrogen sulphate  

The compounds of this type have the halogen atom bound very unstably to the remainder of the molecule. It is easily split off by the action of water, alkaline solutions and ammonia. This instability considerably reduces the value of these substances as war gases. 

Ethyl chloroacetate may easily be prepared by the reaction of chloroacetyl chloride with alcohol, or by means of the action of ethyl alcohol on monochloroacetic acid in presence of sulphuric acid  

It is also prepared by the action of phosphorus pentachloride on ethyl glycoUate  

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This reaction involves the condensation of an aldehyde or ketone with an a-halo ester in the presence of a basic condensing agent (sodium ethoxlde, sodamide, finely divided sodium or potassium iert.-butoxide) to give a glycldio (or ap-epoxy) ester. Thus acetophenone and ethyl chloroacetate yield phenyl-methylglycidic ester (I) ... 

Girard s reagent T is carbohydrazidomethyltrimethylammonium chloride (I) and is prepared by the reaction of the quaternary ammonium salt formed from ethyl chloroacetate and trimethylamine with hydrazine hydrate in alco-hoUc solution ... 

Girard s reagent P , C5H5NCH2C0NHNH2 C1. In a 1-htre threenecked flask, equipped as in the previous preparation, place 200 ml. of absolute ethyl alcohol, 63 g. (64 -5 ml.) of pure anhydrous pyridine and 98 - 5 g. (84 5 ml.) of ethyl chloroacetate. Heat the mixture under reflux for 2-3 hours until the formation of the quaternary salt is complete acidify a small test-portion with dilute sulphuric acid it should dissolve completely and no odour of ethyl chloroacetate should be apparent. Cool the mixture in ice and salt. Replace the thermometer by a dropping funnel, and add a solution of 40 g. of 100 per cent, hydrazine hydrate in 60 ml. of absolute ethanol all at once. A vigorous exothermic reaction soon develops and is accompanied by vigorous effervescence. The pro duct separates almost immediately. When cold, filter with suction, wash... 

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

Two chloroacetate esters of industrial importance are methyl chloroacetate [96-34-4] C2H C102, and ethyl chloroacetate [105-39-5]., Their... 

Both esters have a sweet pungent odor and present a vapor inhalation ha2ard. They are rapidly absorbed through the skin and hydroly2ed to chloroacetic acid. The oral LD q for ethyl chloroacetate is between 50 and 100 mg/kg (52). 

Chloroacetate esters are usually made by removing water from a mixture of chloroacetic acid and the corresponding alcohol. Reaction of alcohol with chloroacetyl chloride is an anhydrous process which Hberates HCl. Chloroacetic acid will react with olefins in the presence of a catalyst to yield chloroacetate esters. Dichloroacetic and trichloroacetic acid esters are also known. These esters are usehil in synthesis. They are more reactive than the parent acids. Ethyl chloroacetate can be converted to sodium fluoroacetate by reaction with potassium fluoride (see Fluorine compounds, organic). Both methyl and ethyl chloroacetate are used as agricultural and pharmaceutical intermediates, specialty solvents, flavors, and fragrances. Methyl chloroacetate and P ionone undergo a Dar2ens reaction to form an intermediate in the synthesis of Vitamin A. Reaction of methyl chloroacetate with ammonia produces chloroacetamide [79-07-2] C2H ClNO (53). 

Carbon Monoxide Process. This process involves the insertion of carbon monoxide [630-08-0] into a chloroacetate. According to the hterature (34) in the first step ethyl chloroacetate [105-39-5] reacts with carbon monoxide in ethanol [64-17-5] in the presence of dicobalt octacarbonyl [15226-74-1], Co2(CO)g, at typical temperature of 100°C under a pressure of 1800 kPa (18 bars) and at pH 5.7. Upon completion of the reaction the sodium chloride formed is separated along with the catalyst. The ethanol, as well as the low boiling point components, is distilled and the nonconverted ethyl chloroacetate recovered through distillation in a further column. The cmde diethyl malonate obtained is further purified by redistillation. This process also apphes for dimethyl malonate and diisopropyl malonate. 

The methylation of N-methyl derivatives of maleic hydrazide gives in general O-alkylated products. The opposite results are obtained with benzyl halides as alkylating agents. In this case the O-benzyl derivative (71) is formed, which is then further benzylated to the lV,0-dibenzyl derivative (72). When ethyl chloroacetate is used, the direction of alkylation is dependent on pH. At pH above 8, O-alkylation occurs at pH below 8, N-alkylation takes place exclusively in neutral and acidic solutions only IV-alkylated products are formed. 

Phenylisoxazolin-5-one condensed with anthranal to give a tricyclic isoxazolylquinoline (Scheme 72) <78CZ264). 3-Methyl-4-phenylazoisoxazoline-5-thione reacted with ethyl chloroacetate for form an intermediate isoxazolethiol, which on heating generated a 1,2,3-triazole (Scheme 73). 

From ethyl chloroacetate and sodium cyanide, and by esteri-fying cyanoacetic acid. Stephens, J. Soc. Chem. Ind. 43, 313T, 327T (1924). 

In a 3-I. three-necked, round-bottomed flask fitted with a mechanical stirrer, reflux condenser, and separatory funnel is placed 400 cc. of absolute alcohol (Note i). Through the condenser tube is added slowly, 23 g. (i gram atom) of dean sodium cut into thin slices. The completion of the reaction is hastened by heating the flask on a steam bath. When the sodium has dissolved completely, 143 g. (i.i moles) of ethyl acetoacetate is introduced slowly. Alter starting the mechanical stirrer, 123 g. (i mole) of ethyl chloroacetate (Note 2) is added slowly over a period of an hour, and the reaction mixture is refluxed for five to six hours. At this point the reaction mixture should no longer give an alkaline reaction with moist litmus. 

Ethyl chloroacetate boiling at 142-145° was used. This ester can be prepared readily by refluxing for six hours a mixture of 200 g. of chloroacetic acid, 120 g. of absolute alcohol, and 25 g. of concentrated sulfuric acid. The product is purified in the conventional way, and the yield is 185 g. (70 per cent of the theoretical amount). 

Ethyl acetosuccinate has been prepared by the interaction of ethyl sodio-acetoacetate and ethyl chloroacetate or broino-acetate. The method given above is a modification of that given by Conrad. ... 

Two different all-aromatic crowns have been reported ". In 1975, de Jong, Siegel and Cram reported the synthesis of a tri-binaphthyl system in which each oxygen was bound to a naphthalene ring, but aliphatic bridges were used to join the binaphthyl units. Relatives of this compound are discussed further in Sect. 3.13. The synthesis of this molecule (Structure 17, below) was not simple, but was relatively straightforward. An interesting feature of it was the use of ethyl chloroacetate followed by LAH reduction to attach ethyleneoxy units to the naphthol unit. 

Much interesting work has been done in the last ten years on the bridging of pyrrole and piperidine rings. Early in their work on this subject Clemo and Metcalfe (1937) prepared quinuclidine (V) by the reduction of 3-ketoquinuclidine (IV), the latter resulting from the hydrolysis and decarboxylation of the product (III) of a Dieckmann internal alkylation, applied to ethyl piperidine-l-acetate-4-carboxylate (II), itself made by condensing ethyl piperidine-4-carboxylate (I) with ethyl chloroacetate. 

A dry 500-ml round-bottomed three-necked flask fitted with a stirrer, internal thermometer, and a pressure-equalized dropping funnel is placed under nitrogen and the flask is charged with 0.148 mole of freshly distilled cyclohexanone and 0.148 mole of freshly distilled ethyl chloroacetate. A solution of 6.0 g of potassium and 125 mL of dry terr-butyl alcohol is introduced into the dropping funnel, and the system is exhausted and... 

In this connection it is important to mention the finding that the thioxo derivatives (52) can be converted in several ways to the 3,5-dioxo derivatives. By alkylation with methyl iodide in alkaline solution, methylmercapto derivatives (53) are produced which are readily hydrolyzed to dioxo derivatives. A similar course is followed in the reaction with ethyl chloroacetate. Finally, oxidation with hypo-... 

In this connection the course of the reaction of 3-thioxo derivative (52) with chloroacetic acid was studied in detail, the reaction being important for the transformation to dioxotriazine derivatives. In this reaction, the carboxymethylmercapto derivatives (94) must be expected as intermediates. The ethyl esters of these compounds (93) (R — CHaCeHs, R = CeHs) Were isolated by Cattelain after reaction with ethyl chloroacetate. " When the reaction is performed in the usual preparative way using 10% aqueous solution of chloroacetic acid, it requires 3-5 hr of boiling. In an alkaline solution (with a... 

In an attempt to prepare ethyl 3-indolylacetate (225) by the action of ethyl chloroacetate on indole magnesium iodide, only unidentified oily products were obtained under a variety of different experimental conditions. However, when indole magnesium iodide was treated with ethyl -chloropropionate in other, a product, identified as 3-[)3-(l-indolyl)propionyl]indole (226) by its behavior on alkaline hydrolysis and by the number of active hydrogen atoms it contained, was obtained. ... 

Acetic anhydride Sodium bicarbonate Hydrogen chloride Ethyl chloroacetate... 

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