Addition of fluorine

The fluorination reaction is best described as a radical-chain process involving fluorine atoms (19) and hydrogen abstraction as the initiation step. If the molecule contains unsaturation, addition of fluorine also takes place (17). Gomplete fluorination of complex molecules can be conducted using this method (see Fluorine compounds, organic-direct fluorination). 

Addition of fluorine to 3-chloro- and 3-acetoxycholest-5-ene likewise furnishes crystalline difluorides. The product derived from cholesterol acetate in 10-20% yield is identical with the 5a,6a-difluoride (3) prepared by Barnes and Djerassi by the PbF procedure (see below). Fluorination of cholest-5-en-3-one does not proceed satisfactorily. 

Addition of fluorine to double bonds preparation of 3 -chloro-5, 6a-difluoro-5o -cholestane by addition of fluorine, 453... 

Many different reagents are available that allow the addition of fluorine to a double bond as exemplified in equation 1 for the addition to cw-stibene [1, 2 3 4]... 

However, when the addition is performed 111 a nucleopliilic solvent such as methanol, cleavage of the imine linkage occurs to give difliioroamino compounds [78] (equation 12) W, At-Difluorotrifluoromethylamine can be prepared from or from thiocyanates, as shown in equation 13 [79, 80] Another way to produce difluoroamino compounds is the addition of fluorine to nitriles by means of AgFj [Sf ] or C0F3 [S/]... 

Although fluonnation of peroxoanions [S2] has been examined, the major emphasis in the fluonnation of oxygenated material is the preparation offhioroxy compounds The simplest, trifluoromethyl hypofluorite, can be prepared almost quantitatively by the action of fluorine on carbonyl fluoride (fluorophosgene) in the presence of various catalysts [Si, 84] Addition of fluorine to trifluoroacetic acid [S5] or its sodium salt [S6] gives rise to FjCF(OF)2 Long-chain fluoroxy compounds can also... 

Reactions of the halogen iluorides with other unsaturated functional groups are generally reported only with highly fluorinated substrates Hexafluorobenzene and denvatives [118] and octaflvoronaphthalene [119] react with mixtures of bromine and bromine trifluoride by 1,4 addition of fluorine followed by addition of bromine fluoride across a reniatning double bond (equation 22)... 

Addition of fluorine and carbon to nucleophilic olefins is little studied, a rare example being the photochemical addition of benzotrifluonde to electron-rich cyclic olefins [202] (equation 40)... 

In contrast, additions of fluorine and carbon to fluormated olefins are widely investigated The best known processes involve reactions of olefins with fluoride ion to generate carbanionic intermediates [203] that are trapped in situ by carbon-based electrophiles. 

Direct fluorination of five-membered heterocyles gave products that were dependent on the heterocycle. For example, pyrrole yielded tar, whereas there was predominantly syn 1,4- addition of fluorine to furan (90G749). 

Pentafluoropyridine is less reactive toward addition of fluorine by BrF2+ than polyfluorobenzenes. The product is perfluoro-l-aza-1,3-cyclohexadiene (81JOU879). 

Under ordinary conditions fluorine itself is too reactive to give simple addition it attacks other bonds and mixtures are obtained. However, F2 has been successfully added to certain double bonds in an inert solvent at low temperatures (—78°C), usually by diluting the F2 gas with Ar or Addition of fluorine has also been accomplished with other reagents (e.g., p-Tol—IF2/Et3N 5 HF) and a mixture of PbOa and SF4. ... 

Because of its high reactivity, special precautions must be taken with reactions of fluorine and its use is somewhat specialized.44 Nevertheless, there is some basis for comparison with the less reactive halogens. Addition of fluorine to Z- and E-1-propenylbenzene is not stereospecific, but syn addition is somewhat favored.45 This result is consistent with formation of a cationic intermediate. 

Presumably prepared by addition of fluorine to dehydrochlorinated product of DDT. c In Chemical Abstracts and in English summary of article (91). Body of paper refers to compound as p,p -dichlorodiphenyldifluorodichloroethane, but gives no analytical data. 

The incorporation of fluorine into a molecule has been widely used to alter the pharmacokinetic properties and overall drug-like properties of compounds. This includes affecting the metabolism, oral absorption, and brain penetration of these molecules [18]. Metabolism can be affected by addition of fluorine directly at or adjacent to the site of metabolism. In addition, substitution with fluorine can increase the lipophilicity of compounds which has been shown to dramatically affect both oral absorption and brain penetration. Finally, the electron-withdrawing characteristic of fluorine has been exploited to lower the P-gp liability of compounds and modulate the pKa of adjacent groups which resulted in increased brain exposure. In the following section, representative examples will highlight the powerful nature of fluorine to modulate overall drug-like properties. 

The enantioselective addition of a nucleophile to a carbonyl group is one of the most versatile methods for C C bond formation, and this reaction is discussed in Chapter 2. Trifluoromethylation of aldehyde or achiral ketone via addition of fluorinated reagents is another means of access to fluorinated compounds. Trifluoromethyl trimethylsilane [(CF SiCFs] has been used by Pra-kash et al.87 as an efficient reagent for the trifluoromethylation of carbonyl compounds. Reaction of aldehydes or ketones with trifluoromethyltrime-thylsilane can be facilitated by tetrabutyl ammonium fluoride (TBAF). In 1994, Iseki et al.88 found that chiral quaternary ammonium fluoride 117a or 117b facilitated the above reaction in an asymmetric manner (Scheme 8-42). 

To keep the precipitating polymers in the dispersed state throughout the polymerization, requires steric stabilizers. This problem is classically tackled via copolymerization with fluoroalkylmethacrylates or the addition of fluorinated surfactants, both being only weak steric stabilizers. DeSimone el al. also applied a fluorinated block copolymer,9 proving the superb stabilization efficiency of such systems via a rather small particle size. One goal of the present chapter is therefore an investigation of our fluorinated block copolymers as steric stabilizers in low-cohesion-energy solvents. 

Fluorine is the most electrophilic halogen and only few examples of controlled addition of fluorine to carbon-carbon double bonds have been reported56 Milder reagents, such as XeF2, are generally used to form fluorine addition products. 

Since metal ions play key roles in cellular physiological processes many specific reporter molecules have been developed, mostly as fluorescent indicators incorporating extended aromatic and conjugated structures, where the wavelength of fluorescence depends upon specific binding of a metal ion. Several F NMR reporters have been created by addition of fluorine atoms (Table 5). 

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