Blanc Chloromethylation refers to the reaction in which aromatic compounds react with formaldehyde and hydrogen chloride in the presence of anhydrous zinc chloride as a catalyst to form chloromethylated aromatic compounds. This reaction was first reported by Grassi-Cristaldi and Maselli in 1898 and later expanded by Blanc in 1923, hence the name Blanc Chloromethylation Reaction.

The Blanc chloromethylation reaction holds significant industrial value and is one of the key methods for synthesizing chloromethylated aromatic compounds. These products are widely used in pharmaceutical synthesis, dye manufacturing, and other areas of organic synthesis.

Reagents: Chloromethylating agents (e.g., formaldehyde/HCl), proton acids, catalysts (e.g., zinc chloride)
Reactants: Aromatic compounds
Products: Chloromethylated aromatic compounds
Reaction type: Substitution reaction

Experimental Tips:

• The reaction is typically carried out under anhydrous conditions to minimize byproducts and improve yield and purity;

• Electrophilic reagents such as chloromethyl ether or methoxymethylacetyl chloride can also be used directly in the reaction;

• High reactant concentrations can lead to secondary addition, producing diphenylmethanes;

• The reaction may generate trace amounts of bis(chloromethyl) ether, a highly carcinogenic compound—appropriate safety precautions must be taken;

• Electron-donating groups (e.g., alkyl, alkoxy) on the aromatic ring facilitate the reaction. However, aromatic derivatives with multiple donating or strongly conjugated groups are prone to side reactions. In contrast, electron-withdrawing groups (e.g., halogens, nitro, carboxyl) tend to reduce the reaction yield.

Reaction Mechanism

Original References:

• Blanc, Gustave Louis. Bulletin de la Société Chimique de France, 1923, 4 (33): 313–319.

• Grassi, G.; Maselli, C. Gazzetta Chimica Italiana, 1898, 28 (2): 477–500.

Popular Citations:

• Biological Evaluation of Noscapine analogues as Potent and Microtubule-Targeted Anticancer Agents. Sci Rep. 2019, 9, 19542.

• Blanc Reaction of Aromatic Compounds Catalyzed by Ionic Liquids. Chinese Journal of Chemical Engineering. 2008, 16(3), 357–360.