Fluorination aromatic systems

The S Ar reaction between thiolates and fluorinated aromatic systems requires, in general, high temperatures and polar, aprotic solvents. Furthermore, the selectivity is low. ... 

Photochemistry of fluorinated aromatic systems has made an important contribution to the study of valence isomers because it has been possible to isolate and characterise some species on which there had previously only been speculation. Some of these, as might be expected, are very unstable (sometimes, treacherously so) towards reverting to... 

Partial fluorination [50] and perfluorination [5/] of aromatic systems can be accomplished electrochemically. A number of other reagents add fluorine to benzene and its derivatives, as elaborated in equation 5 [52, 53, 54, 551... 

Systems usually fluonnated by electropositive fluorine reagents include acti-vated alkenes (enol ethers, enol acetates, silyl enol ethers, and enamines), activated aromatic systems, certain slightly activated carbon-hydrogen bonds, and selected organometallics. 

The fluoroxy reagents react readily with activated aromatic systems (Table 1) to give moderate yields of fluoroaromatic compounds. The fluorine atom shows a preference for ortho orientation because of complexation between the fluoroxy reagent and the ring substituent [75, 22] Nucleophilic attack by the substrate on... 

Polynuclear aromatics react with fluoroxy reagents to give high yields of ortho substitution products accompanied by varying yields of geminal difluoro products Thegeminal difluonnation occurs presumably by an addition-elimination mechanism [27 28, 29, 30, 31, 32] Unactivated aromatic systems are fluorinated in lower yield to give monofluonnated products (Table 1, entries 6 and 7) Examples of fluonnation of polynuclear systems [/5, 21, 25, 30, 32, 7 ] are shown m equations 7-10... 

The above examples indicate a general behavior which roughly parallels that found in homocyclic aromatic systems. The less usual order, I >Br >C1, found for the non-activated halogenofurans is reminiscent of the similar order I > Br > Cl > F, observed by Tronov and Kruger for the halogenobenzenes. Again, it would be of interest to establish the position of fluorine in the order of reactivity of the halogenofurans. 

It is interesting to note that all the new aromatic systems, as described, undergo displacement polymerizations in DMAC solvent by the K2CO3 method, except perfluoroalkylene [10] and amide activated polymerization [9], which were performed in NMP solvent. The displacement polymerization in DMAC solvent was carried out at 155-164°C. poly(aryl ether ketones) require less reaction time (3-6 h) than other aromatic systems for synthesis of polyethers [15]. Synthesis of the fluorinated polyether as reported by Irvin et al. [16] was carried out at room temperature for 16 h (Mw = 75,000), whereas the same polymer by Mercer et al. [17] was synthesized at 120°C for 17 h (Mw = 78,970). 

A second fluorine substituent shields in the ortho- and especially in the para-position, but one in the meta-position deshields, with 1,3-5-trifluorobenzene having the most deshielded fluorines in a polyfluoro-aromatic system (Scheme 3.58). On the other hand, hexafluorobenzene has highly shielded fluorines. The fluorine spectra of these multifluoro-benzenes are second order in nature and their appearance is thus not generally predicable on the basis of first-order logic. 

Flecainide (Tambocor) is a fluorinated aromatic hydrocarbon examined initially for its local anesthetic action and subsequently found to have antiarrhythmic effects. Flecainide inhibits the sodium channel, leading to conduction slowing in all parts of the heart, but most notably in the His-Purkinje system and ventricular myocardium. It has relatively minor effects on repolarization. Flecainide also inhibits abnormal auto-maticity. 

Significant through-space scalar couplings have been observed only in rare cases and in very close spatial proximity and usually 19F is involved in such couplings102-105, e.g., in the following fluorinated polycyclic aromatic systems ... 

Reversible dimerization reactions have been described for a number of aromatic radical ions. In aromatic oligomers and polymers with a more extensive delocalization of the charge and the spin such dimerizations are disfavoured. This was shown in a study of several aromatic molecules with extended it systems at different redox stages179. An extensive overview on fluorinated aromatic radical anions has been presented180. 

Fluorine is an especially powerful ortho director in lithiation of aromatic systems Gilday Negri Widdowson Tetrahedron 1989, 45, 4605. 

It has been a basic principle that one fluorine atom or trifluoromethyl group in a biologically active molecule enhances its lipophilicity. Smart3 argues that this rule holds only for fluorinated aromatics and fluorine adjacent to 7r-bonded systems. 

It is interesting to note that a number of researchers have attempted, more or less successfully, to construct reliable mathematical models which combine structural elements and experimental data to predict the toxicities of new substances not yet experimentally tested for humans and other species.110152 Furthermore pharmacology, toxicity, metabolism and enzyme-inhibiting effects of fluorine-containing aromatic systems (e.g., anilines, ben-zothiadiazines, butyrophenones, corticoids, phenothiazines, steroids, uracils) have been discussed in depth in the literature.153-156... 

Diazotization in the presence of boron trifluoride enables diazonium tetrafluoroborates to be isolated from the reaction mixture and purified. Subsequent controlled decomposition produces the required fluoroaromatic. Although explosion hazards and the toxicity of the isolated salts are significant concerns with this process, known as the Balz-Schiemann process, 4,4 -di-fluorobenzophenone (BDF. 6) has been prepared by this route as a monomer for the production of the engineering plastic poly(ether ether ketone) , or PEEK , by condensation with 1,4-dihydroxybenzene in the presence of potassium carbonate. BDF 6 is superior to its chlorine analog because in aromatic systems the nucleophilic displacement of fluorine is more facile than that of chlorine, leading to a shorter polymerization time and a better quality product containing less degradation impurities. 

Vanadium pentafluoride replaces benzylic hydrogen by fluorine but also adds fluorine to the aromatic system, giving fluonnated cyclohexadienes and cyclohexenes [5] (equation 5)... 

Fluoromethylbenzoic acids, metallation, 9, 26-27 Fluoro(phenyl) complexes, with platinum(II), 8, 482 Fluorosilanes, elimination in fluorinated alkene activation, 1, 732 in fluorinated aromatic activation, 1, 731 and hydrodefluorination, 1, 748 Fluorosilicate anions, hypercoordinated anions, 3, 484 Fluorotoluenes, metallation, 9, 21 Fluorous alkylstannanes, preparation, 3, 820 Fluorous biphasic system, as green solvent, 12, 844 Fluorous ligands, with supercritical carbon dioxide, 1, 82 Fluorous media... 

The reaction cannot be performed in fully fluorinated apolar solvents such as octafluorotoluene, which is probably because of missing polarization of fluorine that is necessary to attack the aromatic system. Polar solvents such as methanol or acetonitrile provide better environments for fluorination [308]. Formic acid as a protic solvent gives even better results and is also quite inert as this small molecule has no labile site for fluorine attack [274]. 

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