Halex process

The selection of the solvent can affect a reaction drastically. In the Halex process for the conversion of 2,4-dichloronitrobenzene with KF to 2,4-difluoronitrobenzene, no reaction occurs in toluene as a solvent, presumably because KF has negligible solubility in toluene. In water, in which KF is highly soluble, no reaction occurs either, due to poor solubility of 2,4-dichloronitrobenzene in water and heavy solvation of fluoride rendering it ineffective. Dimethylformamide is suitable as the solvent KF has some solubility, while the product KCl precipitates (Atherton and Jones, 1995). 

An industrially important application of the lipophilic tetrakis(dimethylamino) phosphonium fluoride is as a phase-transfer catalyst in the Halex process for technical synthesis of fluoroarenes. 

When we started to study this reaction, reported informations, which, on the other hand, were dispersed and sometimes difficult to link together, led us to think that the Halex process, when performed with alkaline fluorides, was more complex than already reported. Thus, we tried to quantify the effect of all significant parameters in a reliable way, in order to optimize the results, especially for the manufacture of 2,4-difluoronitrobenzene, and to have a deeper knowledge of the mechanism. 

Among different conditions for Halex process one of the most effective for low activated substrates is (N,N -dimethylimidazolidino)tetramethylguanidinium chloride 37 (CNC) using as phase-transfer catalyst. The synthesis and using of the catalyst were developed in 2006 by LANXESS Deutschland GmbH in a course of Fluoxastrobin intermediate 39 development [70] (Scheme 10). It should be noted, that traditional phase-transfer catalysts does not work well in the transformation and in original Bayer synthesis stepwise fluorination was used [71]. 

Historically, aryl fluorides were prepared by either Balz-Schiemann-type reactions or though the Halex process [70-75], Although a number of these procedures were quite successful, many of them required the use of toxic reagents or harsh conditions. To address these issues and provide practical routes to aryl fluorides, a host of alternative protocols have been developed [6, 76-78]. In addition to this work, a number of methods for the synthesis of aryl halides have been developed. The following sections will highlight several practical versions. 

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