Halex Reaction

Mechanism + Description

The Halex reaction is a specific SNAr reaction involving nucleophilic displacement of a leaving group (usually chloride) by a fluoride anion to generate the corresponding aryl/heteroaryl fluoride. The Halex reaction is widely used on scale to make fluorinated fine chemicals.

General comments

Typically Halex reactions are carried out at high temperature using dipolar aprotic solvents normally used for SNAr reactions. KF is the usual source of fluoride, although other more soluble fluoride sources like CsF or R4NF are sometimes used. Reactions are typically heterogeneous, and phase transfer catalysts are often employed to transfer fluoride anions into solution. As for SNAr reactions with N/O/S nucleophiles, the halex reaction works best with heteroaromatics and electron –deficient arenes.

 

Key references

Synthesis 2010 June 1; 2010(11): 1804–1821 C–F Bond Formation for the Synthesis of Aryl Fluorides

Journal of Fluorine Chemistry 1993, 61,193-216 Fluoride ion as a nucleophile and a leaving group in aromatic nucleophilic substitution reactions

J. Org. Chem., 2016, 81, 10672–10682 Computational and Experimental Studies of RegioselectiveSNAr Halide Exchange (Halex) Reactions of Pentachloropyridine

Tetrahedron Letters 51 (2010) 432–434 Facile nucleophilic fluorination of primary alkyl halides using

Industrial Chemistry Library Volume 8, 1996, Pages 244-292 Fluorination of aromatic compounds by halogen exchange with fluoride anions ("halex" reaction)

 

Relevant scale up examples solvents under pressure

Org. Process Res. Dev., 2014, 18 , 1045–1054

© 2015 Green Chemistry Institute Pharmaceutical Roundtable. All rights reserved.