The Halex Process

7 Think Negative - Orthogonal Reactivity of Perfluoroaromatic and Perfluoroolefinic Systems 

The w-system is, in addition, destabilized by a repulsive interaction between the lone electron pairs on the fluorine atoms and the r-orbitals on the sp hybridized carbon atoms. Nucleophilic attack on the carbon induces re-hybridization to the sp state, relieving some of this repulsive strain. 

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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. 

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. 

Another potential application of perfluorocarbons is their use as bulking agents where the volume of conventional solvent is reduced by replacement with a perfluorocarbon. Although the halex reaction is a successful industrial process, there are problems recovering the toxic dipolar aprotic solvents. Chambers [80] has shown that, on a preparative scale, up to 75% of the sulfolane can be replaced in the halex reaction by an equivalent volume of perfluorohydrophenanthrene (b. pt. = 215°C). On cooling the reaction mixture, it is a simple matter to separate off the fluorous solvent at the end of the reaction for recycling. 

Potassium fluoride is the cheapest source of fluoride and is thus widely used on large scale. However, it is only slightly soluble in aprotic solvents and large difficulties arise from this fact both on a process point of view and on a fundamental point of view (concerning the elucidation of the mechanism). Thus, the Halex reaction has been also studied with organosoluble fluorides. 

It has been already reported that, with organosoluble ammonium chlorides, water favours the Retro-Halex reaction which competes with hydrolysis. Similar experiments showed that this process does not occur under heterogeneous conditions (aromatic fluoride and solid KC1 or CsCl in aprotic solvent), whatever are the substrates, the solvent and the source of inorganic chloride, provided that the water content of the latter remains around or below 1 % by weight. This point has been confirmed independently in a very recent paper (ref. 41). However, when 10 % wt of water is added to potassium chloride, the Retro-Halex has been observed, though hydrolysis was the major process (ref. 17) ... 

Surprisingly, the solubilization of KF is a slow process, the rate of which is of the same order of magnitude as that of the Halex reaction. Moreover, the lowest solubilization rate is observed in DMSO which, however, is the best solvent for fluorination. Despite this contradiction, such a solubilization rate could be consistent with case 1 (Table 27), concerning the rate-limiting step. However, a simple treatment of the conversion of aryl chloride against time clearly demonstrates that this process is first-order relative to ArCl. Such a result rules out case 1. The same conclusion has been drawn in a very recent paper (ref. 41). 

The DFA process has two reaction stages separated by an intermediates batch distillation stage. In the first halex reaction, the chlorine atoms of DCNB are replaced with fluorine atoms by reaction with potassium fluoride in a solvent, dimethylacetamide (DMAC). This forms 2,4-difluoronitrobenzene (DFNB), with the reaction accelerated by a catalyst, tetramethylammonium-chloride (TMAC). The second reaction stage is the catalytic hydrogenation of the distilled DFNB in methanol to form DFA. The catalyst is removed by filtration and the solvent is recovered by distillation from the finished product. 

Days before the explosion there had been problems with the process. There were repeated problems with water incursion in the DMAC/DFNB stream. After the explosion, substantial amounts of acetic acid were found in the solvent recovered for recycling to the reactor. Laboratory-scale trials showed that acetic acid would react vigorously with DCNB, lifting the halex reactor temperature rapidly from 433 to 513 K. At this temperature a second exotherm started, leading to an explosive decomposition. 

Extensive research has been focused on introducing fluorine into molecules, which can modify their physicochemical properties. Nowadays, around 30% of pharmaceutical compounds contain fluorine. Several methodologies are available and are mainly based on the use of readily commercially available fluorinating reagents. Usually, for aromatic systems, the Balz-Schiemann or the Halex reactions are the processes of choice, whereas for aliphatic systems, electrophilic or nucleophilic fluorinations are required. Despite the fact that cheap starting materials are used in these processes, the harsh conditions remained an obstacle due to poor functional group tolerance. 

The INTEC process follows similar principles to other aqueous chloride electrowinning systems, but uses Halex in place of chlorine gas, avoiding the difficulties of handhng chlorine. Halex is a strong oxidant and can attack many minerals including pyrite. Consequently, there is less selectivity... 

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]. 

For this reason, industrial fluorinations of aromatics are performed by other routes, mostly via the Schiemann or Halex reaction [54, 55]. As these processes are multi-step syntheses, they suffer from low total selectivity and waste production and demand high technical expenditure, i.e. a need for several pieces of apparatus. 

Halex [Halogen exchange] A process for making fluoro-aromatic compounds by reacting the corresponding chloro- or bromo-aromatic comounds with an inorganic fluoride, usually potassium fluoride. Widely used for the manufacture of fluoro-intermediates. 

The first Halex experiments have been carried out with neat chloroaromatics at high temperatures (400 - 500 °C) but the introduction of dipolar aprotic solvents in the late 50 s brought a dramatic improvement for the use of this process on a large scale under realistic conditions (0° < 200 - 250 °C) (ref. 4). It can be noticed that protic solvents, which decrease the nucleophilicity of the fluoride anion by strong hydrogen-bonding, are less adapted than aprotic ones. Commonly used dipolar aprotic solvents are dimethylsulfoxide (DMSO), tetramethylenesulfone (or... 

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