Fluorination of Aromatics

Also chain growth to oligomerization is not uncommon, coating and blocking reactors by precipitation. Furthermore, the insolubility of fluorine in most solvents challenges reactant dosing because the gas-liquid interface, typically not well defined, is now the means to determine and control mass transfer and reaction rate and selectivity. 

The issues to be solved for direct fluorinations are heat release and mass transfer via the gas-liquid interface. Multiphase microstructured reactors enable process intensification [230,248-250,304—306]. Often geometrically well-defined interfaces are formed with large specific values, for example, up to 20 000 m2/m3 and even more. These areas can be easily accessible, as flow conditions are often highly periodic and transparent microreactors are available. For the nondispersing 

The distribution of isomers is consistent to an electrophilic mechanism with fluorine cation intermediates. 

A small amount of side-chain fluorination was observed [274], Benzyl fluoride was formed in about the same extent as the meta isomer. Small amounts of difluoro-toluenes and trifluorotoluenes as well as some unidentified high-boiling compounds were also found [274]. Additional products were not detected [308], 

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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Oxidative Fluorination of Aromatic Hydrocarbons. The economically attractive oxidative fluorination of side chains in aromatic hydrocarbons with lead dioxide or nickel dioxide in Hquid HF stops at the ben2al fluoride stage (67% yield) (124). 

Chemistry of Organic Fluorine Compounds II Table 1. Fluorination of Aromatics... 

Table 3. Comparison of Electrophilic Fluorination of Aromatic Amino Acids with [ F]fluorine or [ F]acetyl Hypofluorite" [25]...

M. A., Jensen, K. F., Microchemical systems for direct fluorination of aromatics, in Matlosz, M., Ehreeld, W, Baselt,... 

DE Mas, N., Heat effects in a microreactor for direct fluorination of aromatics, in Proceedings of the 6th International Conference on Microreaction Technology, IMRET 6, pp. 184-185 (11-14 March 2002), AIChE Pub. 

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. 

Geakauskas, V., Direct liquid-phase fluorination of aromatic compounds,... 

Conte, L., Gambaretto, G. P., Napoli, M., Fraccaro, C., Legnaro, E., Liquid-phase fluorination of aromatic compounds by elemental fluorine, J. Fluorine Chem. 70 (1995) 175-179. 

De Mas N, Gunther A, Schmidt MA, Jensen KF (2003) Microfabricated Multiphase Reactors for the Selective Direct Fluorination of Aromatics. Ind Eng Chem Res 42 698-710... 

Safety precautions applicable to direct liquid phase fluorination of aromatic compounds are discussed [1]. Attention is drawn to the hazards attached to the use of many newer fluorinating agents [2], In a study of fluorination reactions of hafnium and zirconium oxides by the fluoroxidisers xenon difluoride, chlorine trifluoride and bromine trifluoride, reactivity decreased in the order given [3],... 

Research on the fluorination of aromatic amines has provided access to 4-fluoro-2,l,3-benzo-thiadiazole (77). Treatment of 4-amino-2,l,3-benzothiadiazole (1) with nitrosonium tetra-fluoroborate (NOBF4), followed by heating of the resulting diazonium salt, gave the aryl fluoride (77) in 23% yield <92SC73>. 

Fluorination of aromatic rings (other than via carbanions)... 

Fluorination of aromatic rings (other than those via carbanions described above) consists principally of fluorodehydrogenation and fluorodemetallation reactions, both ofwhich are thought to proceed via an arenium ion mechanism (Scheme 25) [85]. 

Scheme 25. The arenium ion mechanism of electrophilic fluorination of aromatic rings via fluorodehydrogenation or fluorodemetallation reactions.

Another example of a direct electrophilic fluorination of aromatic rings is the synthesis of the purine derivatives 8-[ F]fluoroganciclovir, 8-[ F]fluoropenciclo-vir and 8-[ F]fluoroacyclovir (Scheme 27). The radiochemical yields obtained for these compounds are low, about 1%, but no protecting group is required, allowing a one-step radiosynthesis [107]. 

Several studies on the direct fluorination of aromatic compounds have been carried out and, although the reaction conditions were not the same in each case, there are several generalisations that can be made [136-143]. 

Table 5. Fluorination of Aromatic Compounds with l-Fluoro-4-(4-pyridyl)pyridinium Boron Trifluoride Tetrafluoroborate (31) and l-Fluoro-l -methyl-4,4 -bipyridinium Ditriflate (32)67...

Table 15. Fluorination of Aromatic Compounds with Ar-Fluorobis(tri-fluoromethylsulfonyl)amine (Id) (CDC13, 22CC)118...

Tetrabutylphosphonium hydrogen difluoride [Bu4PF (HF)] and dihydrogen trifluoride [Bu4PF (HF)2] have been shown to be expedient reagents for nucleophilic fluorination of aromatic substrates containing a chlorine or bromine atom or a nitro group under mild conditions in non polar solvents. Thus, for example l-chloro-4-nitrobenzene (28) is converted to l-fluoro-4-nitrobenzene (29) in 90% yield.219... 

Room-temperature fluorination of aromatic compounds with cesium fluoroxysulfate is generally run in the presence of a polar solvent like acetonitrile and a catalyst like boron trifluoride. Thus benzene yields fluorobenzene (22). 

Partially proton-exchanged Na faujasite X, in turn, is the best catalyst for selective monochlorination with tert-butyl hypochlorite.258 NaX, NaY, and NaKL zeolites used in the chlorination of toluene with sulfuryl chloride undergo rapid deactivation because of the accumulation of polychlorinated toluenes in the pores of the catalysts and dealumination.259, 260 Direct electrophilic fluorination of aromatics can be effected by using Selectfluor in the presence of triflic acid.261 Electrophilic fluorination may also be carried out by R2NF and R3N+FA reagents.262 Elemental fluorine may also act as a powerful electrophile in acidic media (sulfuric acid, trifluoroacetic acid, or formic acid), but monosubstituted aromatics give isomeric mixtures.263-265... 

A somewhat related report in which equally impressive selectivity and yield (60—90%) were obtained Cacou and Wolf have studied the low temperature direct fluorination of aromatic compounds in CC13 F (100). They have established that under appropriate conditions molecular fluorination proceeds on substituted benzenes and tolulenes with similar selectivity and orientation as has been commonly observed for other halogens. For example reaction with nitrobenzene gives 80% meta substitution and reaction with tolulene gives 60% ortho substitution. The conversions were reported in this study and found to average 0.01%. 

Direct fluorination of aromatic rings is so exothermic that a tarry mixture of products is obtained. Reaction of benzene with the xenon fluorides, XeF2 or XeF4, does give fluorobenzene, but the mechanism is probably free radical rather than polar.137... 

The exploration of new process regimes is tightly correlated to the task of chemical production [3, 8, 25]. Microreactors will then not only serve to investigate processes of macroreactors under ideal or otherwise not feasible conditions, but are expected to partially replace macroreactors for different applications. An example for a reaction which can hardly be achieved even on a laboratory scale is the direct fluorination of aromatics. 

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