Mechanism electrophilic fluorination

Bromination and chlorination of alkanes and cycloalkanes can also take place by an electrophilic mechanism if the reaction is catalyzed by AgSbF. "2 Direct chlorination at a vinylic position by an electrophilic mechanism has been achieved with benzenescleninyl chloride PhSe(0)Cl and AIC13 or AIBr3. n However, while some substituted alkenes give high yields of chloro substitution products, others (such as styrene) undergo addition of Cl2 to the double bond (5-26).113 Electrophilic fluorination has already been mentioned (p. 690). 

Among the fluorinating agents of practical significance,44 only fluoroxytrifluoro-methane45 and iV-fluoroperfluoroalkylsulfonimides46 were shown to fluorinate aromatic hydrocarbons by an electrophilic mechanism. 

Free-radical halogenation of hydrocarbons induced thermally or photochemically can be performed with all four halogens, each exhibiting certain specificities. Because of the thermodynamics of the process, however, only chlorination (and bromination) are of practical importance.31,106-108 Fluorination with elemental fluorine is also possible. This reaction, as discussed above (see Section 10.1.1), follows an electrophilic mechanism in the solution phase.109,110 Under specific conditions, however, free-radical fluorination can be performed. 

The distribution of isomers is consistent to an electrophilic mechanism with fluorine cation intermediates. 

More recently. Chambers and coworkers reported electrophilic fluorination of saturated hydrocarbons using elemental fluorine and Selectfluor. Hexane, cyclohexane, bicylic hydrocarbons, and various hexyl derivatives with electron-withdrawing substituents were fluorinated in acetonitrile. Secondary carbons are substituted predominantly to yield a mixture of monofluorinated products. Since product distributions with elemental fluorine were very similar to those obtained with Selectfluor (an established electrophilic fluorinating agent) an electrophilic mechanism with the involvement of the transition state 61 could be suggested for both fluorination processes. 

On the laboratory scale, the tendency of elemental fluorine to initiate radical chain reactions resulting in tar formation can be controlled by appropriate choice of solvent. The solvent system CFCI3/CHCI3, sometimes with additional 10% ethanol, serves as an effective radical scavenger. The reaction enthalpy is controlled by dilution of the substrate in this solvent, by dilution of the fluorine gas with nitrogen or helium, and by use of a low reaction temperature. Under these conditions, the selective fluorination of cyclohexane derivatives in the tertiary axial position is possible in reasonable yields [16] (Scheme 2.4), supposedly by an electrophilic mechanism. 

Scheme 2.4 Direct fluorination of aliphatic compounds in the tertiary position by an electrophilic mechanism [16].

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. 

Recent computational studies [23[ on the structure and charge distribution of hydrogen bonded F2 suggest a more differentiated view on the supposedly electrophilic mechanism of direct fluorination of aliphatic and aromatic hydrocarbons. Ab-initio calculations indicate that even for the complex of Fj with the extremely strong hydrogen-bond donor F3F as a model system, the energy of complex formation is very low - only 0.38 kcal mol (MP2/6-31+G //MP2/6-31+G level of theory, ZPE and BSSE correction) [24] (Scheme 2.9). Because of the low polarizabil-... 

The mechanism of electrophilic fluorination (real electrophilic F+ transfer vs. a two-step single electron/fluorine radical transfer Scheme 2.82) has been a matter of controversy for some time [187]. There is, however, a general consensus that the high enthalpy of formation of the F cation in the gas phase (420 kcal mol precludes a truly electrophilic mechanism. A mechanism proceeding via a pure 8 2 pathway at the electrophilic fluorine also seems unlikely [187b]. Detailed studies of product distribution for NF-type reagents under different reaction conditions indicate a two-step mechanism via an electron transfer with subsequent fluorine radical transfer [183b] (Scheme 2.83). 

Newer QM/MM simulations of the electrophilic fluorination of a malonate coordinated to a titanium center with a simplified Selectfluor (F-TEDA) analog [189] throw a new light on the electron transfer/fluorine transfer mechanism. During the approach of the electrophilic fluorine toward the carbon nucleophile an electron is transferred from the nucleophile to Selectfluor, then fluorine is transferred to the nucleophile. Interestingly, the transition state for transfer of the fluorine radical is formed only if a polar solvent (acetonitrile) is used. If the simulation is carried out in vacuo, the reaction stops after the initial electron transfer. 

For toluene fluorination, the impact of micro-reactor processing on the ratio of ortho-, meta- and para-isomers for monofluorinated toluene could be deduced and explained by a change in the type of reaction mechanism. The ortho-, meta- and para-isomer ratio was 5 1 3 for fluorination in a falling film micro reactor and a micro bubble column at a temperature of-16 °C [164,167]. This ratio is in accordance with an electrophilic substitution pathway. In contrast, radical mechanisms are strongly favored for conventional laboratory-scale processing, resulting in much more meta-substitution accompanied by imcontroUed multi-fluorination, addition and polymerization reactions. 

For example, direct fluorinations with elemental fluorine are kept imder control in this way, at very low conversion and by entrapping the molecules in a molecular-sieve reactor. As with some other aromatic substitutions they can proceed by either radical or electrophilic paths, if not even more mechanisms. The products are dif ferent then this may involve position isomerism, arising from different substitution patterns, when the aromatic core already has a primary substituent further, there may be changed selectivity for imdefined addition and polymeric side products (Figure 1.31). It is justified to term this and other similar reactions new , as the reaction follows new elemental paths and creates new products or at least new... 

An interesting dinically useful prodrug is 5-fluorouracil, which is converted in vivo to 5-fluoro-2 -deoxyuridine 5 -monophosphate, a potent irreversible inactivator of thymidylate synthase It is sometimes charaderized as a dead end inactivator rather than a suicide substrate since no electrophile is unmasked during attempted catalytic turnover. Rathei since a fluorine atom replaces the proton found on the normal substrate enzyme-catalyzed deprotonation at the 5 -position of uracil cannot occur. The enzyme-inactivator covalent addud (analogous to the normal enzyme-substrate covalent intermediate) therefore cannot break down and has reached a dead end (R. R. Rando, Mechanism-Based Enzyme Inadivators , Pharm. Rev. 1984,36,111-142). 

Scheme 12. Mechanisms of electrophilic fluorination of a carbon-carbon double bond.

Addition of P F]F2 (or CH3C02f F]F) at the double bond of substituted 2,4-dioxypyrimidines (Scheme 16) allows the preparation of the fluorine-18-labelled nucleic acid base 5-[ F]fluorouracil [91-94] and the nucleoside 2 -deoxy-5-[ F]fluorouridine [95-97]. The reaction, usually carried out in acetic acid, demonstrates an excellent regioselectivity, with only the 5-[ F]fluoro derivatives obtained because the C-5 position is the unique activated position for reaction with an electrophile in these systems. The mechanism of this reaction has been studied and the intermediate 5,6-fluoro-acetoxy adduct (or the 5,6-fluoro-hydroxy adduct if the solvent is water) has been isolated and characterised [92]. 

For example, the fluorination with [ F]F2 of diazepam, a 1,4-benzodiazepine (Scheme 18), gives the 3-fluoro derivative in up to 60% radiochemical yield [100]. The mechanism proposed is the electrophilic reaction of [ F]F2 with the enol form of the amide (stabilised by conjugation) yielding, after fluorine attachment and reformation of the carbonyl group, the a-fluoroketo derivative. 

Scheme 25. The arenium ion mechanism of electrophilic fluorination of aromatic rings via fluorodehydrogenation or fluorodemetallation reactions.

The proposed mechanism for the inactivation of RDPR by tezacitabine is detailed in Figure 7.58. Conversely to the radical A generated from the cytidine phosphate, the radical A formed from the 2 -fluoromethylene-2-deoxycytidine cannot eliminate a water molecule (Figures 7.57 and 7.58). It undergoes an isomerization into a new radical B centered on the fluorine-substituted carbon. This latter finally provides, after several steps, a high electrophilic entity D able to add the subunit Rj of the enzyme. The resulting covalent adduct of D with the enzyme has been identified. ... 

In principle, two mechanisms involving either one or two-electron transfer from the aromatic substrate to fluorine may occur and, in practice, the mechanism of fluorination of any given aromatic molecule probably lies between these two extremes. The distinction between electron transfer (Path A, Fig. 55) and SN2-type processes (Path B, Fig. 55) in reactions between various electrophilic fluorinating agents and nucleophiles has been addressed by Differding [144, 145] but these principles can also be applied to reactions involving elemental fluorine. 

The general mechanism for electrophilic substitution on saturated carbons has been suggested by Olah and involves a nonclassical 3-center 2-electron carbonium ion 3.39 Tertiary fluorination provides unique support for this. Since the electrophile attacks neither the carbon... 

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. 

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