Halex reaction

Halex reaction Halfan [36167-63-2] Half-life data Half-lives Halftones Halide glasses Halide ions Halides... 

Halex rates can also be increased by phase-transfer catalysts (PTC) with widely varying stmctures quaternary ammonium salts (51—53) 18-crown-6-ether (54) pytidinium salts (55) quaternary phosphonium salts (56) and poly(ethylene glycol)s (57). Catalytic quantities of cesium duoride also enhance Halex reactions (58). 

The inertness of chlorine in the meta position in Halex reactions is of commercial value. For example, 3,4-dichloronitroben2ene [99-54-7] forms 3-chloro-4-duoronitroben2ene [350-30-1/, which is then reduced to 3-chloro-4-duoroaniline [367-21-5] for incorporation in the herbicide damprop—isopropyl or the duoroquinolone antibacterials, nordoxacin and pedoxacin. 

Explosions have been reported during preparation of duoronitroaromatics by the Halex reaction on a laboratory or industrial scale (9-duoronitroben2ene (65) 2,4-dinitroduoroben2ene (66) 2,4-diduoronitroben2ene (67) and l,5-diduoro-2,4-dinitroben2ene (68). 

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. 

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. 

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

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. 

Hydrated tetraalkylammonium fluorides can be, nevertheless, used in "Halex reactions but water, the nucleophilicity of which is enhanced by hydrogen-bonding with F, competes with the fluoride and delivers phenols and diaryl ethers as byproducts. A typical situation is shown below for 3,4-dichloronitrobenzene (ref. 17). 

In practice, only monohydrogenofluorides are efficient for Halex reactions. Moreover, two equivalents of Bu4NHF2 are needed to obtain quite quantitatively 2 from 1 but, under the above conditions, the reaction is completely chemoselective (Fig. 3) (refs. 17,18). 

However, water enhances dramatically this Retro-Halex reaction but only when performed on very activated substrates (ref. 17). 

An explanation could be found in the fact that the fluoride anion can be far more strongly solvated than the chloride anion hydration could thus be an effective driving force for the Retro-Halex reaction. 

Thus, solubility values from Table 12 (or other papers) must be taken with care for kinetic calculations, especially when relations for homogeneous systems are used. For instance, these values cannot be taken into account to explain the reported difference of reactivity between several alkaline fluorides in Halex reaction (ref. 17)... 

However, small amounts of water have been claimed to be beneficial for the Halex reaction (refs. 34 - 40) and we examined this point quantitatively. It is very clear that at 180°C, the temperature needed to get a valuable conversion of dichloronitrobenzenes, water has a deleterious effect on the yield of... 

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) ... 

Table 16. Influence of the solvent on Halex reaction for 3,4-dichloronitrobenzene...

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. 

As for the Halex reaction in homogeneous medium, it could be thought that potassium hydrogenofluorides would be a valuable alternative to potassium fluoride all the more so since its lattice energy is close to that of potassium chloride ... 

Comparison between Tables 14 and 15 clearly demonstrates that caesium fluoride is far more effective than potassium fluoride towards 2,4-dichloronitrobenzene. As some papers reported about the addition of CsF as catalyst in the Halex reaction using KF (refs. 42 - 46), we quantified the behaviour of CsF-KF mixtures to look for some synergistic effect. 

However, the caesium effect is less pronounced in DMSO (Table 19). Concerning the role of the solvent in the Halex reaction, it can be observed that the scale of efficiency is not modified when the molar ratio of CsF remains lower than 8 % but, for larger ratios, all the solvents, except DMSO, tend to become similar. 

Table 19. Catalysis of the "Halex reaction with caesium or rubidium salts...

Table 20. Catalytic effect of inorganic salts on Halex reaction... 

Phase-transfer agents are the most popular catalysts for the Halex reaction with alkaline fluorides. All types of transfer agents have been claimed tetraalkyl-ammonium halides (refs. 34, 48), Aliquat 336 (ref. 49), branched pyridinium halides (eventually supported on a polymer) (refs. 50 to 53), tetraalkylphosphonium chlorides (refs. 42, 54 - 57) or bromides (ref. 12), crown-ethers (refs. 58, 59) eventually associated with Ph4PBr (refs. 43, 60), tris-(dioxa-3,6-heptyl)amine (TDA-1) (ref. 61) or polyethyleneglycols (PEG) (ref. 62). 

The [2.2.2] cryptand is not more effective than tetramethylammonium chloride and cannot be used in very low concentrations (no effect for 0.02 %). Thus, its cost and toxicity preclude its industrial use. Other catalysts like TDA-1 or Et3N,3HF have no significant effect. Phtaloyl dichloride, though claimed to be useful for the l Halex reaction (refs. 63, 64), does not bring any improvement in sulfolane, even at 180°C, and, moreover, induces side-reactions in DMSO. The same is true for polyethyleneglycols. 

Under conditions mentionned in Table 21, tetramethylammonium chloride is more effective than caesium fluoride to improve the Halex reaction on DCNB at 130°C (refs. 65 - 67). However, a synergistic effect is observed when combining these two catalysts (Table 22). 

As the Halex reaction using alkaline fluorides is carried out in an heterogeneous system, the influence of the physical state of the solids must be taken into account. Several pre-treatments of potassium fluoride have been proposed to improve its performances which are evidently linked to the area of the solid surface. Spray-drying (refs. 68, 69) and freeze-drying (ref. 70) are now considered as more activating treatments of KF than calcination. Very recently, however, slow recrystallisation in methanol has been claimed to deliver a potassium fluoride which is even more effective than the spray-dried one (ref. 41). Some comparisons are given on Figure 8, Table 24 and Pictures 1 and 2. 

KC1 crystals after Halex reaction on DCNB for 3 h. at 130°C in DMSO without sonication... 

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