Fluorination of aromatic compounds

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. 

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],... 

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...

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). 

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%. 

Hessel, V., Ehrfeld, W Golbig, K Haverkamp, V., Lowe, H., Storz, M., Wille, C., Guber, A., Jahnisch, K. and Baerns, M. (2000) Gas/liquid microreactors for direct fluorination of aromatic compounds using elemental fluorine, in Microreaction Technology 3rd International Conference on Microreaction Technology, Proceedings... 

The terms tetrafluoroammonium, perfluoroammonium, tetra-fluoronitrogen(V), and tetrafluoronitronium have been used to describe NF4+. Most authors prefer to call this the tetrafluoroammonium ion. The polarity of the bond is NF4+ is different from that in NH4+ for NF4+ the nitrogen atom has a formal oxidation state of +5. NF4+ salts are important for solid propellant NF3-F2 gas generators or reagents for the electrophilic fluorination of aromatic compounds. 

The fluorination of aromatic compounds in inert solvents, such as acetonitrile, carbon tetrachloride, and Freons, with dilute elemental fluorine (0.76 % to 12"/o in Nj) at temperatures ranging from — 78 to — 25 C results in the controlled substitution of hydrogen by fluo-The distribution of products indicates an electrophilic process, for example the... 

The fluorination of aromatic compounds with xenon difluoride has been extensively investigated. The fluorination of benzene with xenon difluoride in the presence of hydrogen fluoride as a catalyst results in the formation of fluorobenzene in 68% yield. Monosub-stituted aromatic systems are reported to give high yields of monofluorinated compounds, the isomer distributions of which arc similar to those observed in electrophilic substitution (Table... 

By the choice of a symmetrical substrate or a substrate containing only one activated position selective fluorinations of aromatic compounds have been achieved (Table 17). 

In contrast, Rozhkov and coworkers found that Et3N HF salt and Et4NF-3HF were highly effective for conducting selective fluorination, particularly for nuclear fluorination of aromatic compounds (see Sec. II) [13]. This seems to be the first major breakthrough in anodic partial fluorination. 

In 1970, Rozhkov and coworkers reported the first example of anodic partial fluorination of aromatic compound [Eq. (3)] [14,15]. They found that anodic oxidation of naphthalene in Et4NF-3HF/MeCN provided 1-fluoronaphthalene mainly, while the use of Et4NF instead of Et4NF-3HF led to the efficient formation of 1,4-difluoronaphthalene solely. 

Although clean, direct fluorination of aromatic compounds is possible [21], the selectivity of this process is not yet high enough for commercialization. Arenes are best fluorinated in acidic solvents such as sulfuric acid or formic acid, to obtain an electrophilic mechanism (Scheme 2.8). The main obstacle to large-scale industrial application of the potentially inexpensive direct fluorination of aromatic compounds is the difficult separation of the regioisomers and other by-products ivith higher or lower fluorine content. 

A new method, recently developed at DuPont [81], is based on the copper-catalyzed oxidative fluorination of aromatic compounds with hydrofluoric acid in the presence of oxygen (Scheme 2.31). 

One of the first reagents used for electrophilic fluorination ivas xenon difluoride (XeF2) [168], a solid which is easy to handle and which can be used in solvents which are relatively inert toward oxidation, for example acetonitrile and dichloromethane. The reactivity is mostly determined by its strong oxidizing power, rendering its mode of action more oxidative than electrophilic fluorination. With XeF2 not only are typical electrophilic fluorinations of aromatic compounds possible but also the Hunsdiecker-like fluorodecarboxylation of carboxylic acids and fluori-native rearrangements of carbonyl compounds to difluoromethyl ethers [169-171] (Scheme 2.76.). 

Although electrophilic fluorination of aromatic compounds can be achieved by use of a tvide range of different NF-reagents (Scheme 2.89), lack of sufficient selectivity in the fluorination and difficulty of separating the fluoro isomers, because of their very similar boiling points, remains a problem. For this reason, electrophilic fluorination of aromatic compounds, either -with NF-reagents or with elemental fluorine, is used only in few special cases. For production-scale synthesis Flalex and Balz-Schiemann chemistry remain unrivaled. 

Scheme 2.89 Electrophilic fluorination of aromatic compounds [183b, 190, 197, 198].

V. Hessel, W. Ehrfeld, K. Golbig, V. Haverkamp, H. Lowe, M. Storz, C. Wille, Gas/ Liquid Microreactors for direct Fluorination of Aromatic Compounds Using Elemental Fluorine, in W. Ehrfeld (Ed.), Proceedings of the 3rd International Conference on Microreaction Technology (IMRET3), Springer, Berlin, 1999, p. 526. 

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

Fluorination of aromatic compounds. The reaction of various indoles takes place at room temperature in aq MeCN to afford 3-fluoroxindoles. 4-Substituted phenols are converted to 4-fluoro-2,5-cyclohexadienones. ... 

Aromatic fluorinated compounds are of considerable interest for the preparation of biologically active substances. Several fluorination reagents such as CF3OF or F2 require special equipment and experience to handle safely. (CF3S02)2NF (55) is stable for long periods at room temperature and found to be an efficient reagent for nuclear fluorination of aromatic compounds. Typical examples are shown in equation 2939. In addition to the utility in the direct aromatic fluorinations, 55 is also useful in the fluorination of carbon... 

Electrophilic fluorination. Fluorination of aromatic compounds is effective in 98% formic acid or sulfuric acid with a 1 9 mixture of F2-N2 at room temperature. The yield for direct fluorination of 1,3-dicarbonyl compounds by this system varies from 15% to 90%. 

Fluorination of aromatic compounds. Phenols and pyrrole derivatives afford fluorinated products on reaction with XeFi. 

Fluorination of aromatic compounds. Fluoroaromatic hydrocarbons can be obtained in satisfactory yield with this reagent, although biphenyls and even polyphenyls are often formed as by-products. The fluorination requires catalysis by hydrogen fluoride. ... 

---