Halogen Exchange Halex Reactions

These reactions, involving nucleophilic displacement of other halogens by fluoride anion are important industrially and of some use in the laboratory for electron-deficient rings. The exchange/equilibrium of with is of use in PET (see 31.2.3). Nitro is also a good leaving group for this process in a number of systems purines (27.5), pyridines (8.3.2) and 1,2,4-triazoles (29.1.1.2). 

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Perfluoroheteroaromatic compounds [25, 26], in which all the hydrogen atom substituents of the heterocyclic ring have been replaced by fluorine atoms, were first synthesized in the 1960s by reaction of potassium fluoride with appropriate perchlorinated heteroaromatic precursors [25, 26] and a range of perfluorinated heteroaromatic systems may be accessed by halogen exchange (Halex) techniques as shown in Figure 11.3. 

FLUORINATION OF AROMATIC COMPOUNDS BY HALOGEN EXCHANGE WITH FLUORIDE ANIONS ("HALEX" REACTION)... 

In all cases (Tables 16, 17), DMSO is the best solvent, concerning both kinetics and yields of the halogen exchange, but its sensitivity to bases and its poor thermal stability do not favour its use in practice. For other solvents, the scale of efficiency is somewhat dependent on the substrate (and may be, as a consequence, on the temperature). For instance, sulfolane is better than NMP in the case of 3,4-dichloronitrobenzene and the reverse is true for 2,4-dichloronitrobenzene. Reactions are very slow in benzonitrile which, in practice, is devoted to Halex reactions on very stable substrates, like polychlorobenzenes, at temperatures above 300°C. N,N-dimethylethyleneurea (DMEU) and N,N-dimethylpropyleneurea (DMPU), claimed to replace advantageously the carcinogenic HMPT, are not suited to aromatic halogen-exchange. 

An alternative approach to the synthesis of l-fluoroisoquinoUnes was accomplished by the nucleophilic aromatic substimtion (SnAt) [12], The chlorine-fluorine exchange reaction (Halex reaction) [13, 14] was effected in 1-chloroisoquinoIines with potassium fluoride to provide l-fluoroisoquinoUnes in high yield (Schane 2). In the case of 1,3-dichloroisoquinoline used as a substrate, 3-chloro-l-fluoroisoquinoline was selectively obtained despite the use of an excess of potassium fluoride. The chemoseleclivity was attributed to the lability of the carbon-halogen bond at the 1-position of the isoquinoline ring. 

Methods to synthesise 6-fluoro substituted purines have included reactions involving tertiary amine displacement of a 6-halo substituent and subsequent fluoride displacement of the intermediate, diazotization-fluorodediazonation strategies, direct HALEX (HALogen Exchange) reactions, ring closure of an appropriately substituted precursor and SnAt chemistry on a 6-nitropurine. 

Nucleophilic substitution can be employed to introduce fluorine into specific positions within an aromatic ring, and the Halex (halogen exchange) reaction is commonly used in industty. ° Unlike aliphatic reactions, elimination is usually not an issue for aromatic substrates, and as such, strongly basic nucleophilic sources of fluoride can be utilised in the reaction. The reaction works for electron deficient aromatics and is generally carried out... 

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