Chloromethyl methyl ether, carcinogenicity

Chloromethylation can be efficiently effected using chloromethyl methyl ether, in the presence of Lewis acids. However, due to its carcinogenic nature, extreme care should be exercised in its use (46). Alternatively, paraformaldehyde—HCl/ZnCl2 can be used as the chloromethylating agent. 

CH3OCH2CI, i-Pr2NEt, 0 , 1 h 25°, 8 h, 86% yield. This is the most commonly employed procedure for introduction of the MOM group. The reagent chloromethyl methyl ether is reported to be carcinogenic. 

CH3OCH2OCH3, Zn/BrCH2C02Et, 0° CH3COCI, 0-20°, 2 h, 75-85%. A number of methoxymethyl esters were prepared by this method, which avoids the use of the carcinogen chloromethyl methyl ether. 

Zn, (CH30)2CH2, BrCH2C02Et, 80-82% yield. Formation of the meth-oxymethyl thioether with dimethoxymethane avoids the use of the carcinogen chloromethyl methyl ether. The reaction forms an intermediate zinc thiolate, which then forms the monothioacetal. 

Suitable precautions should be taken in utilizing this procedure, since substantial quantities of the volatile, known carcinogen, chloromethyl methyl ether, as well as the volatile and flammable methyl chloride, form under the reaction conditions. While intermediates like 15 and 16 have been postulated in a number of publications and patents in this area, no experimental evidence has been reported that describes the presence or foimation of detectable quantities of these species. 

Drew, R.T., Laskin, S., Kuschner, M., and Nelson, N. Inhalation carcinogenicity of alpha halo ethers. I. The acute inhalation toxicity of chloromethyl methyl ether and bis(chloromethyl)ether, Arch. Environ. Health, 30(2) 61-69, 1975. 

ACGIH has designated chloromethyl methyl ether as an A2-suspected human carcinogen a numerical threshold limit value is not recommended. 

Dichloromethyl methyl ether (98%) was purchased from Aldrich Chemical Company, Inc. (listed as a, a-dichloromethyl methyl ether), and used without purification. Better results can be obtained if the material is distilled under nitrogen prior to use. Unlike chloromethyl methyl ether and bis(chloromethyl) ether, dichloromethyl methyl ether is reported to have no significant carcinogenic activity.6 However, as a precaution it should be handled carefully in a well-ventilated hood. 

CAUTTON Chloromethyl methyl ether (Mom-Cl) is a poison by inhalation and is a suspected human carcinogen. Appropriate safety precautions and procedures should be adopted when handling this substance. 

Chloromethyl methyl ether and bis-chloromethyl ether (CICH2 OCH2Cl) in common with several alkylating agents possess carcinogenic properties in experimental animals and have been listed as assumed human carcinogens similar hazardous properties associated with dichloromethyl methyl ether have not been reported but it would be prudent to handle this compound with due care. 

A number of cases of inhalation exposure of humans to BCME have occurred in the workplace. However, data on BCME concentrations in workplace air are rarely available, and exposure to BCME often occurs in conjunction with exposure to other chemicals, particularly chloromethyl methyl ether (CME). Consequently, there are no reliable dose-response data in humans. The effects of inhalation of BCME have been investigated in animals, with principal emphasis on carcinogenic effects. Available data on the health effects of inhalation of BCME are summarized in Table 2-1 and Figure 2-1 and are discussed below. 

Van Duuren BL. 1989. Comparison of potency of human carcinogens vinyl chloride, chloromethyl methyl ether and bis(chloromethyl)ether. Environ Res 49 143-151. 

Chloromethylation.1 Chloromethyl methyl ether has been generally used for electrophilic aromatic chloromethylation, but it is highly toxic and now considered a carcinogen. Chloromethylation can be effected by use of a trimethylsilyl ether (1) of a chlorohydrin prepared as shown from trioxane and chlorotrimethylsilane in the presence of stannic chloride in chloroform. This reagent, generated in situ, is effective for chloromethylation of styrene in the presence of SnCl4 any excess is easily decomposed by hydrolysis. Bromomethylation is possible by replacement of ClSi(CH3)3 by BrSi(CH3)3. 

Chloromethylation of arenes. This acid cliloride can be used instead of the suspected carcinogen chloromethyl methyl ether (9 102) for chloromethylation of some arenes. The reaction is conducted in CH,NOi or t S, under standard Friedel-Crafts conditions (AlCl, catalysis). This chloromethylation is particularly useful for aryl ethers substituted in the o- or p-position by an electron-v, ithdrawing group (yields —50-90%). 

Chloromethyl methyl ether, 1, 132-135 5, 120 7, 61-62. The conventional synthesis produces the potent carcinogen bis(chloromethyl) ether as a by-product. A new preparation (equations I and II) is free from this drawback. Methanol is required only in a catalytic amount, since it is regenerated as the ether is formed. The by-product is methyl acetate. 

The reaction of chloromethyl methyl ether (MOM-Cl, a carcinogen) with an alkoxide or with an alcohol in the presence of /-Pr2NEt (Hiinig s base) furnishes the corresponding formaldehyde acetal. Alkylation of 3°-alcohols requires the more reactive MOM-I, derived from MOM-Cl and Nal in the presence of /-ProNEt. ... 

The phosphorane derived from triphenylphosphine and chloromethyl methyl ether (MOM-Cl, carcinogenic) reacts with aldehydes or ketones to furnish the corresponding enol ethers. These on acid hydrolysis produce one-carbon homologated aldehydes or lead to the conversion of a keto into an aldehyde group, respectively. ... 

In the past, the chloromethyl group was added to the aromatic skeleton of the resin via reaction with chloromethyl methyl ether. The polarity of the C-X bond in the primary halide was enhanced for the electrophilic attack by adding zinc chloride as Lewis acid to the reaction mixture. Since chloromethyl methyl ether is suspected of being carcinogenic and is no longer commercially available, Fritz et al. [18] devised a method in which chloromethyl methyl ether is prepared in situ and reacted with the resin. 

Chloromethyl methyl ether, used for the preparation of methoxymethyl ether is a carcinogen. It is desirable to convert the phenol into a tetrahydropyranyl ether using dihydropyran. 

WARNING Chloromethyl methyl sulfide has a very unpleasant, penetrating odor and should be handled in a properly ventilated fume hood. Also, because of its structural similarity to chloromethyl methyl ether which is highly toxic and an OSHA-regulated carcinogen, this sulfide should be handled as a substance having potentially similar toxic properties. 

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