Fluorobenzene acetylation

Dihalo-5-fluoroben/oic acids, obtained by oxidation of the corresponding acetophenones, have received considerable attention as intermediates for antibac-tenal fluoroquinolones [3reacts with acetyl chloride to give 2,4,5-trifluoroacetophenone [29] (equation 19) 1,3,5-Tn-fluorobenzene and 1,2-difluorobenzene yield 2,4,6-trifluoroacetophenone and 3,4-difluoroacetophenone, respectively [30] (equations 20 and 21). 

The acetylation over protonic zeolites of aromatic substrates with acetic anhydride was widely investigated. Essentially HFAU, HBEA, and HMFI were used as catalysts, most of the reactions being carried out in batch reactors, often in the presence of solvent. Owing to the deactivation effect of the acetyl group, acetylation is limited to monoacetylated products. As could be expected in electrophilic substitution, the reactivity of the aromatic substrates is strongly influenced by the substituents, for example, anisole > m-xylene > toluene > fluorobenzene. Moreover, with the poorly activated substrates (m-xylene, toluene, and fluoroben-zene) there is a quasi-immediate inhibition of the reaction. It is not the case with activated substrates such as anisole and more generally aromatic ethers. It is why we have chosen the acetylation of anisole and 2-methoxynaphtalene as an example. 

Figure 3.1 Acetylation at 373 K with acetic anhydride of a series of aromatic compounds over HBEA-15 zeolite. Conversion (XSUB) of anisole ( ), 2-methoxynaphthalene (x), m-xylene ( ), toluene ( ), 2-methylnaphthalene (o) and fluorobenzene (a) versus time. Reprinted from Journal of Catalysis, Vol. 230, Guidotti et al. Acetylation of aromatic compounds with H-BEA zeolite the influence of the substituents on the reactivity and on the catalyst stability, pp. 375-383, Copyright (2005), with permission from Elsevier...

With this in mind, how would you expect fluorobenzene to react Most election density is removed first from the ortho positions by induction, then from the meta positions, and then from the para position. Any conjugation of the lone pairs on fluorine with the tc system would increase the electron density in the ortho and para positions. Both effects favour the para position and this is where most substitution occurs. But is the ring more or less reactive than benzene This is hard to say and the honest answer is that sometimes fluorobenzene is more reactive in the para position than benzene (for example, in proton exchange and in acetylation—see later) and sometimes it is less reactive than benzene (for example, in nitration). In all cases, fluorobenzene is significantly more reactive than the other halobenzenes. We appreciate that this is a rather surprising conclusion, but the evidence supports it. 

However, species resulting from AAN self-condensation, such as compounds 24,25, and 26, are also present (Figure 4.5). These compounds do not appear in the acetylation of anisole and 2-MN, which shows only a limited decrease in the reaction rate with the reaction time. On the other hand, they play a more significant role than aromatic ketones in the inhibition of the acetylation reaction and are the major products retained in the zeolite during the acetylation of fluorobenzene, which occurs very slowly and with a significant decrease in the reaction rate. 

Acetylation of chlorobenzene under the same conditions affords p-chloroacetophenone with even higher selectivity (p m=99.5 0.5). Acetylation of hromohenzene and fluorobenzene afford the para isomers exclusively. The para meta and para.ortho selectivities exhibited hy AcCl/AlCls are greater than those exhibited by most other Friedel-Crafts electrophiles. 

Friedel-Crafts acylation of fluorobenzene using bromo[l- C]acetyl chloride provided exclusively 2-bromo-4 -fluoro[carbonyl- C]acetophenone 1821. which was an early intermediate in the synthesis of [ C]fluvastatin (85), a HMG-CoA reductase inhibitor ". Reaction of 82 with N-isopropylaniline followed by ZnCla-mediated cyclization of the resulting /3-aminoketone 83 gave 3-(4-fluorophenyl)-l-isopropyl-l//-[3- C]indole 1841. a key intermediate in the synthetic pathway selected. 

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