Chloromethylated zinc derivative

There are a number of variations of the Friedel-Crafts reactions that are useful in synthesis. The introduction of chloromethyl substituents is brought about by reaction with formaldehyde in concentrated hydrochloric acid and halide salts, especially zinc chloride.62 The reaction proceeds with benzene and activated derivatives. The reactive electrophile is probably the chloromethylium ion. 

From crude xylene, formalin, and hydrogen chloride followed by reduction of the chloromethyl derivative with zinc dust and alkali, v. Braun and Nelles, Ber. 67, 1094 (1934). 

There is an alternative method of making functional derivatives for polymerization. Durene can be condensed with formaldehyde in the presence of hydrochloric acid and zinc chloride to give the bis-chloromethyl durene(75). This can be converted into a number of derivatives from which polymers can be made, e.g. durene-1,4-dicarboxylic acid for polyamides(76), the diacetic acid for polyesters(77,78) or for polyamides(79), the diisocyanatomethyl derivative for polyureas and polyurethanes(80,81), the dimethanol derivative for polyurethanes(82) and for epoxies(83), while the bis chloromethyl derivative has also been proposed for making polyethers (with bisphenol A)(84). In each case, the attraction from the durene derivative has been the introduction of higher melting points and inproved softening properties. None of these polymers have been commercialized, possibly in part because of the difficulty of obtaining durene at suitable-prices. 

Blanc reaction. In carrying out the reaction of p-bromotoluene with formaldehyde and a Lewis acid catalyst to obtain the isomeric chloromethyl derivatives for use in a synthesis of methylcholanthrene, Fieser and Seligman18 fused a mixture of anhydrous zinc chloride with 1% of aluminum chloride and let it cool, added p-bromotoluene and paraformaldehyde, and passed a slow stream of hydrogen chloride into the mixture while heating it at 45-50° for 18 hrs. Use of the special catalyst increased the yield about threefold over that obtained with zinc chloride alone. 

Protection and Deprotection.—In a substantial paper, Barton and co-workers have discussed in detail the protection of carboxylic acid functions in penicillin derivatives by conversion into the corresponding acylhydrazines, acylhydrazones, and dihydro-heteroaromatic amides. An alternative method for the methoxymethyl-ation of free acids, which avoids the use of toxic chloromethyl methyl ether, is by prior conversion into the zinc bromide salt followed by reaction with acetyl chloride and methylaP (Scheme 14). 

Certain other reactions of aromatic molecules are closely related to the Friedel-Crafts reaction. The introduction of chloromethyl groups is brought about by formaldehyde in concentrated hydrochloric acid in the presence of halide salts, especially zinc chloride. The reaction is restricted in scope to benzene and derivatives with electron-releasing substituents. Several mechanistic pathways could be operative in the chloromethylation reaction, but the active electrophile is probably protonated chloromethyl alcohol. 

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