Fluorinated methyl ions, reactions

In attempts to establish information about the relative heats of formation of various fluorinated methyl ions, studies (33,34, 38,39) have been carried out examining the directions of fluoride and hydride transfer reactions between fluoromethyl ions and various fluorinated methanes. Some studies (38,39) have also included ions and molecules containing chlorine atoms. Although the more quantitative aspects of this work will be covered in detail later in our discussion of the thermochemistry of fluorinated ions, it is interesting to examine here the relative Importances of competing reaction channels, shown in Table III. It should be pointed out that at sufficiently high pressures, stabilization of the dimethyl fluoronium Ion intermediates of the reactions is observed ( ). 

Benzene derivatives such as m-methylanisole (40) can be converted to distonic carbene ions. Reaction of 40 with O occurs with loss of H2, generating the conventional carbene anion 41 this anion reacts with molecular fluorine by dissociative ET, followed by nucleophilic attack of F on the methyl group, forming 42. In contrast to phenyhnethylene, 42 has a singlet ground state however, upon protonation it gives rise to the triplet state of m-hydroxyphenyl-methylene. This interesting reaction can be viewed as a spin-forbidden proton-transfer reaction. 

Nucleophilic Reactions. The strong electronegativity of fluorine results in the facile reaction of perfluoroepoxides with nucleophiles. These reactions comprise the majority of the reported reactions of this class of compounds. Nucleophilic attack on the epoxide ring takes place at the more highly substituted carbon atom to give ring-opened products. Fluorinated alkoxides are intermediates in these reactions and are in equiUbrium with fluoride ion and a perfluorocarbonyl compound. The process is illustrated by the reaction of methanol and HFPO to form methyl 2,3,3,3-tetrafluoro-2-methoxypropanoate (eq. 4). 

All lation. In alkylation, the dialkyl sulfates react much faster than do the alkyl haHdes, because the monoalkyl sulfate anion (ROSO ) is more effective as a leaving group than a haHde ion. The high rate is most apparent with small primary alkyl groups, eg, methyl and ethyl. Some leaving groups, such as the fluorinated sulfonate anion, eg, the triflate anion, CF SO, react even faster in ester form (4). Against phenoxide anion, the reaction rate is methyl triflate [333-27-7] dimethyl sulfate methyl toluenesulfonate [23373-38-8] (5). Dialkyl sulfates, as compared to alkyl chlorides, lack chloride ions in their products chloride corrodes and requires the use of a gas instead of a Hquid. The lower sulfates are much less expensive than lower bromides or iodides, and they also alkylate quickly. 

The formation of ethyl cyano(pentafluorophenyl)acetate illustrates the intermolecular nucleophilic displacement of fluoride ion from an aromatic ring by a stabilized carbanion. The reaction proceeds readily as a result of the activation imparted by the electron-withdrawing fluorine atoms. The selective hydrolysis of a cyano ester to a nitrile has been described. (Pentafluorophenyl)acetonitrile has also been prepared by cyanide displacement on (pentafluorophenyl)methyl halides. However, this direct displacement is always aecompanied by an undesirable side reaetion to yield 15-20% of 2,3-bis(pentafluoro-phenyl)propionitrile. 

Noyori and coworkers found that tetrafluorosilane or trimethylsilyl tri-flate catalyzes the condensation of appropriately protected glycopyranosyl fluorides with trimethylsilyl ethers or alcohols. The strong affinity of silicon for fluorine was considered to be the driving force for this reaction. In the case of Sip4, attack of a nucleophile on the glycosyl cation-SiFj ion-pair intermediate was anticipated. Thus, condensation of 2,3,4,6-tetra-O-benzyl-a- and - -D-glucopyranosyl fluorides (47a and 47fi) with methyl... 

Thymidylate synthase (TS) is the enzyme that converts 2-deoxyuridine monophosphate into thymidine monophosphate. This is a key step in the biosynthesis of DNA. This enzymatic reaction of methylation involves the formation of a ternary complex between the substrate, the enzyme, and tetrahydrofolic acid (CH2FAH4). The catalytic cycle involves the dissociation of this complex and the elimination of FAH4. It is initiated by pulling out the proton H-5, thus generating an exocyclic methylene compound. As the release of a F" " ion is energetically forbidden, the fluorine atom that replaces the proton H-5 cannot be pulled out by the base. This leads to inhibition of the enzyme (Figure 7.2). 

Although the products differ considerably in these two reactions, presumably the mechanisms are not drastically different The negative hydroxide ion attacks the most positive atom in the organic iodide. In methyl iodide this is the carbon atom (, > jyc) and the iodide ion is displaced. In Ihe trifluoromethy) iodide the fluorine atoms induce a positive charge on the carbon which increases its electronegativity until it is greater than that of iodine and thus induces a positive charge on the iodine. The latter is thus attacked hy the hydroxide km with the formation of hypoiodous acid, which then loses an H+ in the alkaline medium to form IO . 

Minkwitz et al.604 have prepared the hexafluorometalates of cations 308. The reaction of a,a-dichloromethyl methyl ether in HF-Lewis acid solution at —78°C leads to the formation of chloro cation 308-C1, whereas at -65°C fluoro derivative 308-F is isolated as a result of chlorine-fluorine exchange [Eq. (3.80)]. Interestingly, the chlorine atom and the methyl group are trans in the hexafluoroantimonate salt of cation 308-C1, whereas the fluorine atom and the methyl group are cis in cation 308-F. The arrangement of the C—O—C—H atoms is nearly planar with F/Cl—C—O—C torsion angles of 2.84° (308-F) and 179.0° (308-C1). The C Obond distances (1.224 and 1.479 A for cation 308-F, and 1.252 and 1.517 A for cation 308-C1) reveal dominant oxonium ion character. 

Electrochemical fluorination of pyridine in the presence of a source of fluoride ion gave 2-fluoropyridine in 22% yield (85M11). With xenon difluoride, pyridine formed 2-fluoropyridine (35%), 3-fluoropyridine (20%), and 2,6-difluoropyridine (11%) in a reaction unlikely to be a conventional electrophilic substitution. Xenon hexafluoride has also been used (76JFC179). With cesium fluoroxysulfate at room temperature in ether or chloroform, the major product was 2-fluoropyridine (61 and 47%, respectively). Some 2-chloropyridine was also formed in chloroform solution. In methanol the entire product was 2-methoxypyridine (90TL775). Fluorine, diluted with argon in acetic acid, gave a 42% yield of the 5-fluoro derivative of l-methyl-2-pyridone [82H( 17)429],... 

The chemistry involved in nucleophilic aromatic substitution is well reflected in the reactions of a variety of nucleophiles with methyl penta-fluorophenyl ether (Ingemann et al 1982a). For most of the nucleophiles such as alkoxide, thiolate, enolate and (un)substituted allyl anions, the dominant reaction channel is the attack upon the fluoro-substituted carbon atoms, as is the case for OH-. The latter ion reacts approximately 75% by attack upon the fluoro-substituted carbon atoms and the remaining 25% by Sn2 (20%) and ipso (5%) substitution as summarized in (41). In the attack upon the fluorinated carbon atoms, the interesting observation is made that a F- ion is displaced via an anionic o-complex to form a F- ion/molecule complex, which is not observed to dissociate into F- as a free ionic product. 

These results clearly show that the potential energy surface can contain a series of minima. The fact that selectivity in re-attack by the F ions can be observed indicates that the differences between the energy barriers for the secondary reactions control the distribution of the final products. The multistep character of these processes is further illustrated by the reactions observed when enolate anions are used as reactant ions. The ambident enolate anions may react with methyl pentafluorophenyl ether at the carbon or the oxygen site. If they react with the carbon site at the fluorine-bearing carbon atoms, then the molecule in the F ion/molecule complex formed contains relatively acidic hydrogen atoms so that proton transfer to the displaced F ion may occur. An example is given in (47) where the enolate anion, generated by HF loss, is not observed. An intramolecular nucleophilic aromatic substitution occurs instead and leads to a second F ion/ molecule complex. The F" ion in this complex then re-attacks the substituted benzofuran molecule formed, either by proton transfer or SN2 substitution. 

Phenylenediamine and 2-aminophenol initially give N-arylimidoyl fluoride. Elimination of hydrogen fluoride from the product and further intramolecular nucleophilic cyclization lead to perfluoroalkyl derivatives of benzimidazole and benzoxazole, respectively. In the case of 2-aminothio-phenol, the reaction occurs at the sulfur atom and forms a carbanion. If RF is fluorine, then the carbanion is destabilized by the interaction of the lone electron pairs of fluorine with the center, and the stabilization reactions occur with participation of the proton. If, however, RF is the trifluoro-methyl group, the negative charge is stabilized by it. The fluoride ion is eliminated with further intramolecular nucleophilic cyclization. 

Hydrolysis is probably a more complex process, since 3,4-bis(trifluoro-methyl)perfluorohexa-2,4-diene gives a cyclic product—perfluorotetra-methylfuran 46 (94JCS(P1)3119, 90JCS(CC)1127). The reaction involves vinyl substitution of fluorine with subsequent fast electrocyclization of the intermediate carbanion accompanied by fluoride ion elimination. An analogous reaction of 3,4-bis(trifluoromethyl)perfluorohexa-2,4-diene with sodium sulfide or thiourea forms perfluorotetramethylthiophene 47 (90JCS(CC)1127). 

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