Chloroacetyl chloride

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. 

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. 

Much of the chloroacetyl chloride produced is used captively as a reactive intermediate. It is useful in many acylation reactions and in the production of adrenalin [51-43-4] diazepam [439-15-5] chloroacetophenone [532-27-4] chloroacetate esters, and chloroacetic anhydride [541-88-8]. A major use is in the production of chloroacetamide herbicides (3) such as alachlor [15972-60-8]. 

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). 

Chlorine adds to ketene to form chloroacetyl chloride [79-04-9] (78). Chloroacetyl chloride (CAC) is used in large volume in the manufacture of the pre-emergence herbicides alachlor [15972-60-8] and butachlor [23184-66-9]. It is estimated that the CAC requirement for this appHcation was in excess of 45,000 metric tons in 1992. Significant volumes of CAC are also used in pharmaceutical manufacture, such as anesthetics of the Hdocaine type, and in the production of the tear gas chloroacetophenone [532-27-4]. Other commercial methods for the manufacture of CAC have been described (79). 

When heated for eight hours at 200°C and 91.2 MPa (900 atm) in the presence of aluminum, methylene chloride reacts with carbon monoxide to yield chloroacetyl chloride, CH2CICOCI (10). 

The trans isomer is more reactive than the cis isomer ia 1,2-addition reactions (5). The cis and trans isomers also undergo ben2yne, C H, cycloaddition (6). The isomers dimerize to tetrachlorobutene ia the presence of organic peroxides. Photolysis of each isomer produces a different excited state (7,8). Oxidation of 1,2-dichloroethylene ia the presence of a free-radical iaitiator or concentrated sulfuric acid produces the corresponding epoxide [60336-63-2] which then rearranges to form chloroacetyl chloride [79-04-9] (9). 

The original commercial source of E was extraction from bovine adrenal glands (5). This was replaced by a synthetic route for E and NE (Eig. 1) similar to the original pubHshed route of synthesis (6). Eriedel-Crafts acylation of catechol [120-80-9] with chloroacetyl chloride yields chloroacetocatechol [99-40-1]. Displacement of the chlorine by methylamine yields the methylamine derivative, adrenalone [99-45-6] which on catalytic reduction yields (+)-epinephrine [329-65-7]. Substitution of ammonia for methylamine in the sequence yields the amino derivative noradrenalone [499-61-6] which on reduction yields (+)-norepinephrine [138-65-8]. The racemic compounds were resolved with (+)-tartaric acid to give the physiologically active (—)-enantiomers. The commercial synthesis of E and related compounds has been reviewed (27). The synthetic route for L-3,4-dihydroxyphenylalanine [59-92-7] (l-DOPA) has been described (28). 

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... 

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. 

Mingoia reported that 2-chloroacetyl-3-methylindole (139) was obtained by the action of chloroacetyl chloride on the skatole Grignard reagent. ... 

The structure of ( )-169 is determined to have a ( )-3a,3a -bispyrrolo[2,3-(j] indole skeleton by carrying out X-ray single crystallographic analysis of its derivative 252 (99H1237). Compound 252 is obtained from ( )-169 by the following sequence of reactions (1) alkaline hydrolysis of ( )-169 to 249 (88%), (2) conversion of 249 to 251 (71%) by treatment with NaH and chloroacetyl chloride, (3) substitution of chlorine on the chloroacetyl group for acetate 252 (93%) by the reaction with NaOAc. 

Reaction of 2-(arylmethyleneamino)pyridines 335 and styrenes in the presence of hydroquinone afforded 2,4-diaryl-3,4-dihydro-2/f-pyrido[l,2-n]pyrimidines 336 by means of an inverse electron demand Diels-Alder reaction (95MI10). Reaction of 2-(benzylideneamino)pyridines 337 and chloroacetyl chloride gave 2-aryl-4//-pyrido[l,2-n]pyrimidin-4-ones 338 (97JMC2266). 

Hydroxy-3-(4-biphenyl)perhydropyrido[l,2-c][l,4]oxazine was obtained in the reaction of 2-piperidinemethanol and 4-bromoacetylbiphenyl in a mixture of acetone and Et20 at room temperature (00JMC609, 00MIP13). Perhydropyrido[l,2-c][l,4]oxazin-l-one 298 was obtained in the reaction of quinoline derivative 297 and chloroacetyl chloride (OOMIPl). 

Alkylation of the monocarbamate of piperazine with the halide, 173, affords 174 after removal of the protecting group by saponification. Alkylation of the amine with the chloroamide, 175 (obtained from amine, 176, and chloroacetyl chloride) gives the local anesthetic lidoflazine (177). ... 

In a similar vein, acylation of ami noketone 67 with chloroacetyl chloride affords the corresponding chloroamide 68. Reaction of that intermediate with ammonia serves to form the diazepine ring, possibly via the glycinamide. The product bentazepam (69) is described as a tranquilizer. ... 

---