Electrophilic fluorination aromatic compound

Direct fluorination, therefore, is not particularly effective for the preparation of mono-fluorinated aromatic compounds from monosubstituted precursors since, in these cases, electrophilic fluorination gives mixtures of isomeric products. However, when there are two or more groups in the aromatic substrate which activate the same carbon atom towards electrophilic attack, as in the case of 4-fluorobenzoic acid (Table 5), then direct fluorination is an efficient method for the preparation of fluoroaromatic compounds (Fig. 57) [148]. 

A nucleophilic mechanism can be applied in reductions with complex hydrides of highly fluori-nated aliphatic and alicyclic fluoroalkenes with electron-deficient C = C bonds the hydride anion adds as a strong nucleophilic agent to the more electrophilic carbon atom the intermediate anion can then lose a fluoride ion either from the original C = C bond, or from the allylic position finishing an SN2 displacement of the fluorine. Thus, the reductions of vinylic C-F bonds with hydrides proceed by a nucleophilic addition-elimination mechanism. Displacement of fluorine in highly fluorinated aromatic compounds proceeds by the same mechanism ... 

Wide spectrum of fluorinated aromatic compounds has been synthesized by electrophilic fluorination of arylboronic acids. So 3-fluoropyridine (63) has been obtained from 3-pyridine boronic acids 86 and F-TEDA-BF4 in 72 % yield [76] (Scheme 32). 

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]. 

These compounds can be prepared by using either classical processes for synthesis of amino acids (starting from the ad hoc precursor bearing fluorine on the aromatic moiety) or electrophilic fluorination of the arene moiety (e.g., elemental fluorine, xenon fluoride, acetyl hypofluorite). Although these methods are often poorly regioselective, they are useful for the preparation of F labeled molecules used in PET, for example, F tyrosine and dihydrophenylalanine (L-Dopa). ... 

The fluorination of other activated aromatic compounds, such as anisole and phenol, undergo monofluorination mainly in the ortho and para positions, whereas the fluorination of deactivated aromatics, such as nitrobenzene, trifluoromethylbenzene and benzoic acid, give predominantly the corresponding meta fluoro-derivatives which is consistent with a typical electrophilic substitution process. Also, fluoro-, chloro- and bromo-benzenes are deactivated with respect to benzene itself but are fluorinated preferentially in the ortho and para positions [139]. At higher temperatures, polychlorobenzenes undergo substitution and addition of fluorine to give chlorofluorocyclohexanes [136]. 

Extensive work on the interaction of aromatic compounds with xenon difluoride has been carried out in order to investigate the reaction mechanism and the scope of the fluorination depending on the substituents electronic nature.26-59 62 It has been found that benzene and substituted aromatics react with xenon difluoride at room temperature in the presence of hydrogen fluoride to form the typical products of electrophilic fluorination contaminated with low quantities of difluoro-substituted molecules. 

It should be noted that fluorodiazonium hexafluoroantimonate (4) also reacts with aromatic compounds, forming fluorobenzenes, in low yield.193 A more recent report concerns the electrophilic fluorination of methane to fluoromethane using fluorodiazonium and tetrafluoroammonium salts.198... 

F-Teda BF4 is effective for the selective addition of fluorine to steroids in good yield, re-gioselectively and, in many cases, stereoselectively at the 6- and 16-positions, under very mild reaction conditions (Table 7).92 Further, 6 will also efficiently fluorinate silyl and alkyl enolates, enamides, carbanions, a-alkenes and actived aromatic compounds (Table 8). As an extension of this method F-Teda BF+ has been used for the electrophilic fluorination of (fluorovinyl)tin compounds affording terminal fluoroalkenes (see Table 9).88... 

The electrophilic fluorine of AcOF was also used for aromatic fluorinations. Activated aromatic compounds produced mainly the ortho fluoro derivatives in yields of up to 85%267. The dominant ortho substitution was a result of the addition of AcOF across the most electron-rich region of the aromatic ring. A subsequent spontaneous elimination of AcOH restored the aromaticity, but in cases where this was not possible the resulting cyclohexa-diene reacted very rapidly with the reagent and tars were obtained. Only in certain cases and with careful monitoring could the corresponding adducts be isolated (equation 151.)... 

Acetyl hypofluorite also cleaves the carbon-mercury bond which provides an easy entry to many fluoroethers. Since the electrophilic fluorine attacks the electrons of the C—Hg bond, the reaction proceeds with a full retention of configuration. Several l-fluoro-2-methoxy derivatives were prepared from the corresponding olefins271, formally accomplishing the addition of the elements of MeOF across a double bond (equation 153)272. Such reactions were also used for the fluorination of very activated aromatic compounds (equation 154)273. 

Because of the presence of nitrogen in the aromatic ring, electrons in pyridine are distributed in such a way that their density is higher in positions 3 and 5 (the P-positions). In these positions, electrophilic substitutions such as halogenation, nitration, and sulfonation take place. On the contrary, positions 2, 4, and 6 (a- and y-positions, respectively) have lower electron density and are therefore centers for nucleophilic displacements such as hydrolysis or Chichibabin reaction. In the case of 3,5-dichlorotrifluoropyridine, hydroxide anion of potassium hydroxide attacks the a- and y-positions because, in addition to the effect of the pyridine nitrogen, fluorine atoms in these position facilitate nucleophilic reaction by decreasing the electron density at the carbon atoms to which they are bonded. In a rate-determining step, hydroxyl becomes attached to the carbon atoms linked to fluorine and converts the aromatic compound into a nonaromatic Meisenheimer complex (see Surprise 67). To restore the aromaticity, fluoride ion is ejected in a fast step, and hydroxy pyridines I and J are obtained as the products [58],... 

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... 

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. 

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].

In view of their high electronegativity, fluorine atoms accumulated in the benzene ring substantially increase the electrophilicity of the carbon atoms. This creates conditions for high mobility of the fluorine atoms of polyfluorinated aromatic compounds in nucleophilic substitution reactions and hence for intramolecular nucleophilic cyclizations by the elimination of the fluorine atom ortho to the... 

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