Electrophilic aromatic substitution fluorine

Turning now to electrophilic aromatic substitution in (trifluoromethyl)benzene we con sider the electronic properties of a trifluoromethyl group Because of their high elec tronegativity the three fluorine atoms polarize the electron distribution m their ct bonds to carbon so that carbon bears a partial positive charge... 

Aryl chlorides and bromides are conveniently prepared by electrophilic aromatic substitution. The reaction is limited to chlorination and bromination. Fluorination is difficult to control iodi-nation is too slow to be useful. 

The selective electrophilic aromatic substitution carried out by displacement of a metallic substituent (Hg, Sn) ( F-fluorodemetallation) using [ F]p2 or [ F]AcOF remains a method of choice to introduce a fluorine atom on a specific position. In the early preparations of [6- F]fluoro-L-DOPA, the reaction of a 6-substituted mercuric derivative with [ F]acetyl hypofluorite yielded the expected compound in 11 % yield [73,74]. Reaction of a mercuric precursor, free or on a modified polystyrene support P-CH2-COOHg(DOPA precursor) allows the preparation of [ F]fluoro-L-DOPA in an overall yield up to 23 %. The polymer supports are easily prepared, require no special treatment for storage and are convenient to use in automated production [75]. 

The effect of monofluorination on alkene or aromatic reactivity toward electrophiles is more difficult to predict Although a-fluonne stabilizes a carbocation relative to hydrogen, its opposing inductive effect makes olefins and aromatics more electron deficient. Fluorine therefore is activating only for electrophilic reactions with very late transition states where its resonance stabilization is maximized The faster rate of addition of trifluoroacetic acid and sulfuric acid to 2-fluoropropene vs propene is an example [775,116], but cases of such enhanced fluoroalkene reactivity in solution are quite rare [127] By contrast, there are many examples where the ortho-para-dueeting fluorine substituent is also activating in electrophilic aromatic substitutions [128]... 

Remember from Section 12.16 that it is the more activating substituent that determines the regioselectivity of electrophilic aromatic substitution when an arene bears two different substituents. Methoxy is a strongly activating substituent fluorine is slightly deactivating. Friedel-Crafts acylation takes place at the position para to the methoxy group. 

In nitration, an electrophilic aromatic substitution, the electrophile is a nitronium cation. It attacks the benzene ring in the place of the highest electron density. In o-fluorotoluene, there are several positions of high electron density ortho and para with respect to the methyl group, and ortho and para with respect to fluorine. Both substituents, methyl and fluorine, direct the entering electrophile to the activated positions. Whose influence is stronger, that of the methyl group, or that of fluorine ... 

A Effect of fluorine as a substituent in the ring on electrophilic aromatic substitution... 

Perfluoroarenes were also found to be highly reactive coupling partners in intermolecular direct arylation [68, 69]. A wide range of aryl halides can be employed, including heterocycles such as pyridines, thiophenes, and quinolines. A fluorinated pyridine substrate may also be cross-coupled in high yield and it was also found that the site of arylation preferentially occurs adjacent to fluorine substituents when fewer fluorine atoms are present. Interestingly, the relative rates established from competition studies reveal that the rate of the direct arylation increases with the amount of fluorine substituents on the aromatic ring. In this way, it is inversely proportional to the arene nucleophilicity and therefore cannot arise from an electrophilic aromatic substitution type process (Scheme 7). 

By stabilizing the cyclohexadienyl cation intermediate, lone-pair donation from fluorine counteracts the inductive effect to the extent that the rate of electrophilic aromatic substitution in fluorobenzene is, in most cases, only slightly less than that of benzene. With the other halogens, lone-pair donation is sufficient to make them ortho, para directors, but is less than that of fluorine. 

To exploit the synthetic versatility of aryl diazonium salts, be prepared to reason backward. When you see a fluorine attached to a benzene ring, for example, realize that it probably will have to be introduced by a Schiemann reaction of an arylamine realize that the required arylamine is derived from a nitroarene, and that the nitro group is introduced by nitration. Be aware that an unsubstituted position of a benzene ring need not have always been that way. It might once have borne an amino group that was used to control the orientation of electrophilic aromatic substitution reactions before being removed by reductive deamination. The strategy... 

In another study, Arkin and Hazer modified the PHA-Cl into quaternary ammonium salts, thiosulfate moieties and phenyl derivatives. In addition, they cross-linked the modified PHA-Cl with benzene by electrophilic aromatic substitution using a Friedel-Crafts reaction. The random composition of PHA-Cl was calculated from its H NMR spectrum by comparing the relative peak areas of the methine protons on the polymer backbone. Hence, increased chlorination of the methyl protons caused the peak of methine protons to be moved further downfield. In addition, the PHA-Cl mole fractions were calculated by comparing the peak areas of protons on chlorinated a-carbons and protons on p-carbons. Samsuddin et al. ° described a process for the direct fluorination of PHBHHx at elevated pressure in the... 

Electrophilic Aromatic Substitution. The fluorine substi tution of the silicon suppresses the normal ipso attack of elec trophiles of arylsilanes, allowing nitration of the ring (eq 6). When the corresponding dichlorosilane is used, significant... 

Chapter 16—Chemistry of Benzene Electrophilic Aromatic Substitution. Coverage of aromatic fluorination has been added to Section 16.2 to reflect the increasing importance of fluorinated compounds in pharmaceutical chemistry. 

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