Chloroacetic acid chloride

Lidocaine Lidocaine, 2-(diethylamino)-A-(2,6-dimethylphenyl)acetamide (2.2.2), is synthesized from 2,6-dimethylaniline upon reaction with chloroacetic acid chloride, which gives a-chloro-2,6-dimethylacetanilide (2.1.1), and its subsequent reaction with diethy-lamine [11]. 

A reactor was charged with methyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta-[b]furan-7-carboxylate (25.0 g) and 2-chloroacetic acid chloride (16.0 g) dissolved in 180 ml of THF and then cooled to below 20°C and treated with the drop-wise addition of pyridine (10.7 g). The solution was stirred at ambient temperature for 1 hour and then combined with 5% aqueous solution of sodium hydrogen carbonate (40 g). Following an ordinary posttreatment workup, 31.5 g of product were isolated after recrystallization from isopropyl ether. 

A totally different approach to bis-carbene ligands on a cyclic scaffold comes from Burgess and coworkers [351], They start from AA -dimethyl-l,2-diaminocyclohexane and acetylate this compound with chloroacetic acid chloride. Addition of an N-substituted imidazole yields the chiral bis-imidazolium salt (see Figure 3.110). Reaction with silver(I) oxide and carbene transfer to palladium(II) completes the reaction sequence. 

Another interesting approach to an NHC ligand with a chiral, bridging wingtip group was introduced by Perry et al. [45] and uses enantiomerically pure 1,2-diamino-cyclohexane as the scaffold. Reaction with chloroacetic acid chloride and subsequently with DIPP-imidazole yields the imidazolium salt that can be reacted with silver(I) oxide [46] to the respective silver(I) NHC complex. Subsequent carbene transfer to palladium(II) renders the chiral palladium(II) carbene transfer that can be used in catalysis (see Figure 5.9). 

Note In the Burgess route, the alkyl bridge (two carbon atoms) comes from the aspartic acid sidechain, whereas the Nanchen and Pfaltz route introduces the alkyl bridge with the chloroacetic acid chloride (linker length variable). 

SYNS CHLORACETYL CHLORIDE CHLORID KYSELINYCHLOROCTOVE CHLOROACETIC ACID CHLORIDE CHLOROACETIC CHLORIDE CHLORURE de CHLORACETYLE (FRENCH) iMONOCHLOROACETYL CHLORIDE... 

CHLOROACETIC ACID CHLORIDE see CEC250 CHLOROACETTC ACID, ETHYL ESTER see EHG500 CHLOROACETIC ACID METHYL ESTER see MF775 CHLOROACETIC ACID SODIUM SALT see SFU500 CHLOROACETIC ACID, soUd (UN 1751) (DOT) see CEAOOO... 

CHLOROACETIC ACID CHLORIDE (79-04-9) Forms corrosive vapors with air. Violent decomposition in water, producing chloroacetic acid and hydrogen chloride gas. Violent reaction with combustibles, alcohols, metal powders, sodium amide, many organic materials and compounds, causing toxic fumes and the danger of fire and explosion. Aqueous solution is incompatible with caustics, alkalis, alcohols, aliphatic amines, alkanolamines, ammonia, caustics, epichlorohydrin, isocyanates, alkylene oxides, sulfuric acid. 

Beilstein Handbook Reference) Acetyl chloride, chloro- BRN 0605439 Chloracetyl chloride Chlorid kyseliny ohioroclove Chloroacetic acid chloride Chloroxetic chloride Chlorure de chloracetyle EINECS 201-171-6 HSDB 973 Monochloroacetyl chloride UN1752. Used in organic synthesis. Liquid mp = -22° bp = 220° (explosive) very soluble in organic solvents. 

Synonyms/Trade Names Chloroacetic acid chloride, Chloroacetic chloride, Monochloroacetyl chloride... 

CAS-No [79-04-9] chloracetyl cMorid chloroacetic acid chloride monochloroacatyl chloride... 

Synonyms CAC Chloracetic chlroide Chloroacetic acid chloride Chloroacetyl chloride Monochloroacetyl chloride Empirical C2H2CI2O Formula CICH2COCI... 

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. 

The AC may react with methyl chloride or alpha-chloroacetic acid via a direct displacement reaction (eq. 2). The derivatives would be methyl cellulose or carboxymethyl cellulose. 

Chloroacetic acid can be esterified and aminated to provide useful chemical intermediates. Amphoteric agents suitable as shampoos have been synthesized by reaction of sodium chloroacetate with fatty amines (4,5). Reactions with amines (6) such as ammonia, methylamine, and trimethylamine yield glycine [66-40-6J, sarcosine [107-97-17, and carhoxymethyltrimethylammonium chloride, respectively. Reaction with aniline forms /V-phenylglycine [103-01 -5] a starting point for the synthesis of indigo (7). 

Manufacture. Most chloroacetic acid is produced by the chlorination of acetic acid using a suitable catalyst such as acetic anhydride (9—12). The remainder is produced by the hydrolysis of trichloroethylene with sulfuric acid (13,14) or by reaction of chloroacetyl chloride with water. 

Dichloroacetic acid is produced in the laboratory by the reaction of chloral hydrate [302-17-0] with sodium cyanide (31). It has been manufactured by the chlorination of acetic and chloroacetic acids (32), reduction of trichloroacetic acid (33), hydrolysis of pentachloroethane [76-01-7] (34), and hydrolysis of dichloroacetyl chloride. Due to similar boiling points, the separation of dichloroacetic acid from chloroacetic acid is not practical by conventional distillation. However, this separation has been accompHshed by the addition of a eotropeforming hydrocarbons such as bromoben2ene (35) or by distillation of the methyl or ethyl ester. 

Chloroacetyl chloride [79-04-9] (CICH2COCI) is the corresponding acid chloride of chloroacetic acid (see Acetyl chloride). Physical properties include mol wt 112.94, C2H2CI2O, mp —21.8 C, bp 106°C, vapor pressure 3.3 kPa (25 mm Hg) at 25°C, 12 kPa (90 mm Hg) at 50°C, and density 1.4202 g/mL and refractive index 1.4530, both at 20°C. Chloroacetyl chloride has a sharp, pungent, irritating odor. It is miscible with acetone and bensene and is initially insoluble in water. A slow reaction at the water—chloroactyl chloride interface, however, produces chloroacetic acid. When sufficient acid is formed to solubilize the two phases, a violent reaction forming chloroacetic acid and HCl occurs. 

Since chloroacetyl chloride can react with water in the skin or eyes to form chloroacetic acid, its toxicity parallels that of the parent acid. Chloroacetyl chloride can be absorbed through the skin in lethal amounts. The oral LD q for rats is between 120 and 250 mg/kg. Inhalation of 4 ppm causes respiratory distress. ATLV of 0.05 ppm is recommended (28,41). 

Chloroacetyl chloride is manufactured by reaction of chloroacetic acid with chlorinating agents such as phosphoms oxychloride, phosphoms trichloride, sulfuryl chloride, or phosgene (42—44). Various catalysts have been used to promote the reaction. Chloroacetyl chloride is also produced by chlorination of acetyl chloride (45—47), the oxidation of 1,1-dichloroethene (48,49), and the addition of chlorine to ketene (50,51). Dichloroacetyl and trichloroacetyl chloride are produced by oxidation of trichloroethylene or tetrachloroethylene, respectively. 

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). 

Bromoacetic acid can be prepared by the bromination of acetic acid in the presence of acetic anhydride and a trace of pyridine (55), by the HeU-VoUiard-Zelinsky bromination cataly2ed by phosphoms, and by direct bromination of acetic acid at high temperatures or with hydrogen chloride as catalyst. Other methods of preparation include treatment of chloroacetic acid with hydrobromic acid at elevated temperatures (56), oxidation of ethylene bromide with Aiming nitric acid, hydrolysis of dibromovinyl ether, and air oxidation of bromoacetylene in ethanol. 

A wide variety of quaternaries can be prepared. Alkylation with benzyl chloride may produce quaternaries that are biologically active, namely, bactericides, germicides, or algaecides. Reaction of a tertiary amine with chloroacetic acid produces an amphoteric compound, a betaine. 

Cellulose chloroacetates (30) and aminoacetates (30,31), acetate sorbates (32), and acetate maleates (33) have been prepared but are not commercially important. These esters are made from hydrolyzed cellulose acetate with the appropriate anhydride or acid chloride in pyridine. 

Glycine ethyl ester hydrochloride has been prepared by the action of absolute alcohol and hydrogen chloride on glycine from glycyl chloride and alcohol by the action of ammonia or hexamethylenetetramine on chloroacetic acid, and subsequent hydrolysis with alcoholic hydrochloric acid and by the action of hydrogen chloride and alcohol on methyleneamino-acetonitrile. ... 

Chlorine Chemistry Comicil (CCC), 270 Chlorine dioxide, 38 Chlorine trifluoride, 38 Chlomiephos, 38 Chlomiequat chloride, 38 Chloroacetaldhyde, 38 Chloroacetic acid, 38 2-Chloroacetophenone, 38 Chloroacetyl chloride, 38 Chloroanihnes, 39 Chlorobenzene, 39... 

This ester was designed as a protective group for the 2-position in glycosyl donors. It has the stability of the benzoate during glycosylation, but has the ease of removal of the chloroacetate. It is readily introduced through the acid chloride... 

The use of acid chlorides instead of acid anhydrides has also been described. Wittig and coworkers converted propiophenone 31 to chromone 32 in 50% yield with chloroacetyl chloride in the presence of sodium chloroacetate at 190 C. Despite the acid chloride s increased reactivity, a high temperature was still required. 

A) Preparation of p-Acetylphenoxyacetic Acid p-Hydroxy-acetophenone is treated with chloroacetic acid in aqueous solution in the presence of sodium hydroxide. The desired acid is then isolated from its sodium salt in a total yield of 80 to 82%, excess of p-hydroxy-acetophenone having been extracted with methylene chloride. 

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