Fluorine 18 atom substitution reactions

J. G. Moehlmann and J. D. McDonald, Infrared chemiluminescence investigation of fluorine atom substituted reactions, J. Chem. Phys. 62 3052 (1975). 

In contrast to saturated hydrocarbons, the unsaturated hydrocarbons react with atomic fluorine by two pathways, i.e. (atomic fluorine addition at >C=C< double bond and hydrogen substitution by fluorine atoms. The reaction of fluorine with aromatic hydrocarbons proceeds with the formation of F-derivatives and hydrogen atoms break off ... 

The driving force of these fluorinations is the weakness of the C — X (X = B. Si, Sn) bond, that facilitates ipso substitution of these functional groups by a fluorine atom in reactions with electrophilic fluorinating reagents and, in some cases, with elemental fluorine. 

The dependence of the reaction rate on the degree of fluorine atom substitution is remarkable. Andreades concluded that the large substituent effects could not be attributed to polar effects alone (29). However, the observations of Holtz and Streitwieser (4,28) indicate that this conclusion was premature. For example, l-hydryl-F-bicyclo[2.2.1]heptane, X, is 10 more reactive than the 1,4-dihydryl compound, XI. Clearly, the dipolar field effect of the 4 fluorine atom in X has a major influence on the reaction rate and the short range inductive... 

Hie formation of CH F and CF F following ener tlc F atomic substitution reactions in fluorinated methanes (71-75) and ethanes 60. 66) has been well documented. Lindner and Pauwels obtained direct evidence for C0F F production in unpublished recoil F experiments with fluoromethanes (7. 75). Although CF F was identified as the C0F F precursor through competitive experiments with C3F6 scavenger, the detailed mechanism for process 28 was not established. 

Often the substitution of fluorine atoms for hydrogen atoms in a polymer chain markedly increases the thermal stabiUty of the base polymer this is tme for polyimides. A typical fluorinated polyimide is prepared from the reaction of 2,2-bis(3,4-dicarboxyphenyl)hexafluoropropane dianhydride and 2,2-bis-(4-amino phenyl)hexafluoropropane according to the following reaction (36) ... 

Fluorination presents problems of the other extreme. Both steps in the substitution chain reaction are so exothermic that the reaction is violent if not performed under carefully controlled conditions. Furthermore, fluorine atoms are capable of cleaving carbon-carbon bonds ... 

The reactivities of the substrate and the nucleophilic reagent change vyhen fluorine atoms are introduced into their structures This perturbation becomes more impor tant when the number of atoms of this element increases A striking example is the reactivity of alkyl halides S l and mechanisms operate when few fluorine atoms are incorporated in the aliphatic chain, but perfluoroalkyl halides are usually resistant to these classical processes However, formal substitution at carbon can arise from other mecharasms For example nucleophilic attack at chlorine, bromine, or iodine (halogenophilic reaction, occurring either by a direct electron-pair transfer or by two successive one-electron transfers) gives carbanions These intermediates can then decompose to carbenes or olefins, which react further (see equations 15 and 47) Single-electron transfer (SET) from the nucleophile to the halide can produce intermediate radicals that react by an SrnI process (see equation 57) When these chain mechanisms can occur, they allow reactions that were previously unknown Perfluoroalkylation, which used to be very rare, can now be accomplished by new methods (see for example equations 48-56, 65-70, 79, 107-108, 110, 113-135, 138-141, and 145-146)... 

A fluormated enol ether formed by the reaction of sodium ethoxide with chlorotnfluoroethylene is much less reactive than the starting fluoroolefin To replace the second fluorine atom, it is necessary to reflux the reaction mixture. The nucleophilic substitution proceeds by the addition-elimination mechanism [30] (equation 26). 

Nucleophilic substitution reactions involving the replacement of chlorine (or bromine or fluorine) atoms on the phosphorus have been among the most well studied reactions of cyclophosphazenes... 

Fluorophosphates (phosphorfluoridates), which are important for backbone modified oligonucleotides in molecular biology, are generally synthesized from phosphoric imi-dazolides or triazolides and acylfluorides. In these reactions, for example, the azole group (of the phosphoric or phosphinic imidazolide) is substituted by a fluorine atom, forming an acylazole compound as by-product.[202],[2033... 

Fluorobenzene-type compounds have been used as functional groups in homobifunctional crosslinking agents (Chapter 4, Section 4). Their reaction with amines involves nucleophilic displacement of the fluorine atom with the amine derivative, creating a substituted aryl amine bond (Reaction 9). Detection reagents incorporating reactive aryl chemistry include 2,4-dinitrofluorobenzene and trinitrobenzenesulfonate (Eisen et al., 1953). These compounds form... 

A very impressive example of the synthetic utility of this chemistry is the one-pot enantioselective double G-H activation reaction of 86 to generate chiral spiran 87 (Equation (73)).172 In this case, the phthalimide catalyst Rh2(enantiotopically selective aromatic C-H insertions of diazo ketoesters (Equation (74)).216 Moreover, dirhodium(n) tetrakisIA-tetrafluorophthaloyl- )-/ /-leucinate], Rh2(hydrogen atoms of the parent dirhodium(n) complex are substituted by fluorine atoms, dramatically enhances the reactivity and enantioselectivity (up to 97% ee). Catalysis... 

Aizenberg and Milstein [78] have found rhodium complex-catalyzed reactions between polyfluorobenzenes and hydrosilanes which resulted in the substitution of fluorine atoms by hydrogen and were both chemoselective and regioselective (Eq. (6) ... 

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]. 

One modification of the Bingel reaction involves DBU as a base. Initial experiments showed that exposure of CgQpjg to DBU leads to a complete loss of fluorine [71]. Fortunately this defluorination does not take place in the presence of diethyl bromomalonate. Reaction of CgQpjg with DBU and diethylbromomalonate in toluene at room temperature yields three products and unreacted CgQpjg [67, 71]. The three products are the result of mono-, bis- and tris-substitution their relative yield depends on how fast the base is added. The reaction does not - as in the usual Bingel reaction - proceed via a nucleophilic addition reaction to one double bond but as a nucleophilic substitution with a Sj.j2 -mechanism. The bromomalonate anion attacks a double bond in 5-position to one of the least sterically hindered fluorine atoms, which leads to the loss of this fluorine. The bromine atom is not replaced (Scheme 9.6). 

Under the influence of a Lewis acid, Cjq can be arylated via a Eriedel-Crafts reaction (see Section 8.6). A similar reaction occurs with CggEjg where ipso substitution of fluorine atoms takes place [68]. The fluorofullerene is treated with FeClj in benzene for two weeks (Scheme 9.8). Electrophilic substitution leads to arylated C5QFjg Ph with n = 1-3. Probably due to steric reasons the 5-substitution is not observed in this arylation. 

The Balz-Schiemann and Wallach reactions The Balz-Schiemann reaction (the thermal decomposition of an aryl diazonium salt. Scheme 46) was for many years the only practical method for the introduction of a fluorine atom into an aromatic ring not bearing electron-withdrawing substituents. This reaction, first reported in the late 1800s, was studied in fluorine-18 chemistry as early as 1967 [214]. It involves the generation of an aryl cation by thermal decomposition, which then reacts with solvent, nucleophiles or other species present to produce a substituted aromatic compound. Use of fluorine-18-labelled... 

Preparation of a-monofluoromethyl amino acids is not easy. Indeed, although the amino acids can easily be hydroxymethylated, substitution of the hydroxyl by a fluorine atom is not always easy (SF4, DAST). On the other hand, preparation of monofluoroketones (substrates of the Strecker reaction) involves the use of highly toxic fluoroacetonitrile. ° ... 

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