Blanc Chloromethylation Reaction

What is the Blanc Chloromethylation?

Blanc chloromethylation is the reaction of aromatic compounds with HCl, formaldehyde (formalin, a solution of formaldehyde in water) or chloromethyl ether under Lewis acid catalysis to introduce chloromethyl groups into aromatic compounds. This reaction has important applications in organic synthesis and chemical production.

Mechanism of Blanc Chloromethylation

The reaction mechanism is similar to Friedel-Crafts acylation, that is, formaldehyde reacts with zinc chloride to form electrophilic species, which then undergo aromatic electrophilic substitution reaction with aromatic compounds to generate hydroxymethylated intermediates (benzyl alcohol is further chlorinated).

Fig 1. Blanc chloromethylation reaction and its mechanism. [1]

Application Examples of Blanc Chloromethylation

Chloromethyl ethers [such as (ClCH₂)₂O, CICH₂OMe] and methoxyacetyl chloride can also be used directly as electrophilic species in the reaction. The reaction can also be carried out in ionic liquids.

• Example 1: Qiao Kun et al. attempted the Blanc chloromethylation reaction of benzene and its derivatives and chloromethyl ether in a chloroaluminate room temperature ionic liquid reaction medium consisting of 1-alkylpyridine halides, 1-methyl-3-alkylimidazolium quaternary ammonium salts and trimethylamine hydrochloride and anhydrous AlCl₃. The reaction has moderate to high conversion (84.2%~92.3%) and selectivity (68.3%~91.1%). [2]
• Example 2: In the synthesis of the natural product (S)-equol, regioselective chloromethylation is the first step in the synthesis [3]. 3-Bromoanisole was reacted with formaldehyde and hydrogen chloride gas, and the products obtained after fractionation had narrow boiling points in gas chromatography. The ¹H NMR spectrum showed three different products, which means that the reaction actually formed three regioisomers. The product distributions of three isomers (2a-c) were determined by analogy with the ¹H NMR shifts of similar chemical structures.

Fig 2. Synthetic examples via Blaise reaction.

Related Products

CAS No.	Structure	Product
20949-84-2		4-Thiazolecarboxaldehyde,2-methyl-
54221-96-4		6-Methoxypyridine-2-carbaldehyde
374538-01-9		4-Fluoro-3-formylphenylboronic acid
14510-06-6		8-Hydroxyquinoline-2-carboxaldehyde
5392-12-1		2-Methoxy-1-Naphthaldehyde
17610-00-3		3,5-Bis(tert-butyl)benzaldehyde
51359-78-5		4-(Bromomethyl)benzaldehyde
1192-58-1		N-Methylpyrrole-2-carboxaldehyde
10031-82-0		4-Ethoxybenzaldehyde
5910-87-2		Trans,Trans-2,4-Nonadienal
728-87-0		Benzenemethanol,4-methoxy-a-(4-methoxyphenyl)-
119-53-9		2-Hydroxy-2-phenylacetophenone
5400-80-6		2-Bromo-1-indanol

References

1. Li, Jie Jack. Name Reactions: A Collection of Detailed Reaction Mechanisms, 2006, 61-62.
2. Deng, YouQuan, et al. Acta Chimica Sinica, 2003, 61(1), 133.
3. Heemstra, Jennifer M., et al. Organic letters, 2006, 8(24), 5441-5443.