Fluorination directed

Replacement of Hydrogen. Three methods of substitution of a hydrogen atom by fluorine are (/) reaction of a G—H bond with elemental fluorine (direct fluorination, (2) reaction of a G—H bond with a high valence state metal fluoride like Agp2 or GoF, and (J) electrochemical fluorination in which the reaction occurs at the anode of a cell containing a source of fluoride, usually HF. 

Direct Fluorination. This is a more recently developed method for the synthesis of perfluorinated compounds. In this process, fluorine gas is passed through a solution or suspension of the reactant in a nonreactive solvent such as trichlorotrifluoroethane (CFC-113). Sodium fluoride may also be present in the reaction medium to remove the coproduct hydrogen fluoride. There has been enormous interest in this area since the early 1980s resulting in numerous journal pubHcations and patents (7—9) (see Fluorine compounds, organic-direct fluorination). Direct fluorination is especially useful for the preparation of perfluoroethers. 

Prepa.ra.tlon There are five methods for the preparation of long-chain perfluorinated carboxyUc acids and derivatives electrochemical fluorination, direct fluorination, telomerization of tetrafluoroethylene, oligomerization of hexafluoropropylene oxide, and photooxidation of tetrafluoroethylene and hexafluoropropylene. 

Fluorination. Direct fluorination of quinoline was accompanied by extensive fragmentation of the heteroring, but trifluoromethyl hypofluorite in trichlorofluoromethane at -70°C converted 5-fluoro-8-hydroxyquino-line into the 5,7-difluoro-8-hydroxy product (72JMC987). Quinoline, itself, was perfluorinated by fluorine and cobalt(III) fluoride (56JCS783), whereas cesium tetrafluorocobaltate at around 350°C converted it into a mixture of saturated polyfluoro compounds (82JFC413). It is much more satisfactory to introduce fluorine by nucleophilic methods. 

COMPOUNDS AND SUBSTITUENTS WITH FLUORINE DIRECTLY BOUND TO A HETEROATOM... 

It is not normally possible to add fluorine directly to alkenes as the reaction is so exothermic that bond fission occurs. Many alkenes will not add iodine directly either, and when the reaction does occur it is usually readily reversible. Alkynes are also found to undergo preferential, though not exclusive, ANTI addition of halogens, e.g. with butyne-l,2-dioic acid (17) ... 

Violent explosions occur when fluorine directly contacts liquid hydrocarbons, even at —210 with anthracene or turpentine, or solid methane at — 190°C with liquid fluorine. Many lubricants ignite in fluorine [1,2]. Contact and reaction under carefully controlled conditions with catalysis can now be effected smoothly [3], Gaseous hydrocarbons (town gas, methane) ignite in contact with fluorine, and mixtures with unsaturated hydrocarbons (ethylene, acetylene) may explode on exposure to sunlight. Each bubble of fluorine passed through benzene causes ignition, but a rapid stream may lead to explosion [4],... 

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. 

Tellurium combines with halogens forming halides at different oxidation states. While with fluorine, direct fluorination of the metal produces tellurium hexafluoride, TeFe, a colorless gas with a repulsive odor ... 

Recently, it has been shown that /1-diketones [126],/ -ketoesters (Fig. 48) [126] and N, N-dialkyl-/ -ketoamides [127] can be fluorinated directly, in high yield, at convenient temperatures (0 10 °C), in polar solvents such as formic acid or acetonitrile. As in the case of the pyruvates, the overall rate of reaction was a... 

Although alcohols can be fluorinated directly with selenium tetrafluoride, yields can be disappointing because of rearrangement/polymerization due to the presence of hydrogen fluoride produced during the reaction. Higher yields have been obtained when the reaction is performed in the presence of 1 equivalent of pyridine, which forms a 1 1 donor-acceptor complex with selenium tetrafluoride. The reaction proceeds in two distinct steps first is the reaction of the alcohol with the complex to form an alkoxyselenium trifluoride, the second is the thermal decomposition to the alkyl fluoride. 

A more practical synthesis of perbromate is to use fluorine directly as the oxidizing agent-... 

Acetyl hypofluorite reacts smoothly with 1,3-dicarbonyl compounds or their enolates264. Even lithium enolates of monocarbonyl derivatives265 or methylene phosphonates, analogous to the AZT drug266, can be fluorinated directly, eliminating the need to prepare the... 

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 ... 

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