Science of Synthesis

Pfeiffer, W. D., Science of Synthesis, (2007) 35, 155.

A chloromethyl group may be introduced into a benzene ring by an electrophilic reaction involving the use of formaldehyde or paraformaldehyde and hydrogen chloride in the presence of a catalyst. The catalyst used most frequently is zinc(II) chloride.[‌1‌–‌3‌] In other instances, however, sufficient catalytic effect is obtained with a protic acid alone (hydrochloric acid,[‌4‌,‌5‌] sulfuric acid,[‌6‌,‌7‌] phosphoric acid,[‌8‌,‌9‌] chlorosulfonic acid–methanol,[‌10‌] and acetic acid[‌10‌]). The catalysts used in chloromethylation by Friedel–Crafts-type reactions include aluminum trichloride,[‌11‌] tin(IV) chloride,[‌12‌] tin(II) chloride,[‌1‌,‌2‌] and boron phosphate.[‌3‌] The first chloromethylation reaction was described in 1898.[‌3‌] Blanc demonstrated the wide scope of the halogen methylation reaction in 1923.[‌1‌,‌2‌] The chloromethylation reaction of arenes is more difficult in the presence of electron-withdrawing groups such as nitro, cyano, or carboxy. Accumulation of methyl groups in the ring supports chloromethylation. The second substitution of alkylarenes takes place in the 4- or 2-position. Under specific conditions, dichloromethyl compounds can also be formed. In some cases, diarylmethane byproducts can be obtained. Highly reactive compounds (naphthalene, anisole, phenols, and polymethylbenzenes) tend to yield this type of product, and it is often difficult or impossible to isolate the intermediate chloromethyl derivative. Previous coverage of this area can be found in Houben–Weyl, Vol. 5/3, pp 1001–1004.

References

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• 8.Meeeee-Meee, (8888) 8/8, 8888.
• 8.Meeeee-Meee, (8888) M 8e, 888.