Fluoride ion as a leaving group

The wide range of reactivity of the carbon-fluorine bond, referred to at the begiiming of this chapter, must obviously be attributable to variations in the mechanism of the substitution process and, in particular, to the amount of bond breaking in the transition state [28]. 

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In the first nucleophilic aromatic substitution that we showed you, we used fluoride ion as a leaving group. Fluoride works very well in these reactions, and even such a simple compound as 2-nitro-fluorobenzene reacts efficiently with a variety of nucleophiles, as in these examples. 

The synthesis of aromatic azides (Scheme 37) from aryl halides with azide ions (SxAr) is particularly successful with systems that carry an activating substituent, an electron-withdrawing group, either in the ortho or the para position relative to the potential leaving group." -" A table with numerous examples can be found in the literature." Fluoride ion as a leaving group is superior to the other halides. Dipolar aprotic solvents, such as DMF for instance, have their special merits in these transformations, too. The reaction of 2,4- or 2,6-dinitroaryl halides with azide ions was shown to be accelerated in micelles or in the presence of quaternary ammonium salts." ... 

Cyclization of difunctional compounds is illustrated by the acyloin condensation of diesters (Fig. 19), conventionally performed with sodium in refluxing solvents, and improved by the presence of trimethylchlorosilane. A practical improvement was made with the use of technical-grade TMSCl and ultrasonically dispersed sodium.Thus, the reaction occurs at 0°C in 0.5 to 3 h. An experimental description is given in Ch. 9, p. 331. A chiral center at the a-position of the carbonyl does not suffer racemization. With p-halo esters, cyclizations lead to cyclopropyl derivatives in high yields, except with sterically hindered substrates. A similar reaction occurs with zinc and oxazabutadienes substituted by trifluoromethyl groups, with a fluoride ion as the leaving group (Eq. 15).ii ... 

Entries 6 and 7 in Table 3.3 are additional linkers based on intramolecular nucleophilic cleavage. In Entry 6, it is an imidazole that efficiently catalyzes the saponification of the ester linkage, whereas in Entry 7 a hydroquinone is O-alkylated intramole-cularly, with the carboxylate acting as a leaving group. Esters of resin-bound (2-hydro-xyethyl)silanes have also been used as linkers, which can be cleaved by treatment with either TFA or fluoride ions (TBAF in THF [76]). 

I- is the fastest. This order parallels the decrease in basicity that occurs as one proceeds down a column of the periodic table. Fluoride ion (F ) is so slow that it is not commonly used as a leaving group. 

Fluoride ion is usually a poor leaving group because it is not very polarizable. Fluoride serves as the leaving group in the Sanger reagent (2,4-dinitrofluorobenzene), used in the determination of peptide structures (Chapter 24). Explain why fluoride works as a leaving... 

To introduce a (S-fluoro group at the C-2 position of a ribonucleoside, one may first try an Sn2 reaction of a fluoride ion with a 2 -hydroxyl group activated as a leaving group, such as triflate. However, in most cases, its nucleobase (both pyrimidine and purine) prevents this reaction because (a) steric hindrance of the nucleobase interrupts the nucleophilic (F-) attack from the top face, and (b) the nucleobase reacts intramolecularly with its own sugar moiety. Therefore, 2 -P-fluoro substitution is generally more difficult than the corresponding a-fluoro substitution. 

Fluoride Ion as Nucleophile and a Leaving Group in Aromatic Nucleophilic Substitution Reactions ... 

Acylsilanes react with alkylmetals to give a-silylated alcohols, which can be readily desilylated by fluoride ion-induced hydrolysis with stereochemical retention. For this reason, they have been used as aldehyde equivalents for highly stereo- and regioselective synthesis of alcohols.227-228b When acylsilanes or alkylmetals have a leaving group at... 

Figure 14.11 Nucleophilic aliphatic substitution of a mesylate ester leaving group using fluoride ion as cesium salt in protic and aprotic organic solvents.

O Hagan and coworkers recently found that fluorodesulfuration is not only a versatile tool for the synthetic organic chemist but also - in a non-oxidative variant - so far the only known pathway in nature for enzymatic incorporation of inorganic fluoride ions into secondary metabolites [166] (Scheme 2.75). As the key step of this enzymatic reaction sequence a trialkylsulfonium ion (SAM) reacts with inorganic fluoride in a nucleophilic replacement with methionine as the leaving group. 

Because the Hofmann elimination reaction occurs in an anti-Zaitsev maimer, anti-Zaitsev elimination is also referred to as Hofmann elimination. We have previously seen anti-Zaitsev elimination in the E2 reactions of alkyl fluorides as a result of fluoride ion being a poorer leaving group than chloride, bromide, or iodide ions. As in a Hofmann elimination reaction, the poor leaving group results in a carbanion-like transition state rather than an alkene-like transition state (Section 11.2). 

The stabilization of a -carbonium ion is also involved in the reaction of an allylsilane with an electrophile (Eq. 14.16). An advantage of silicon over other metals in this context is that it does not undergo 1,3 shifts, and so the point of attachment of the electrophile can be reliably predicted (Eq. 14.17). This stabilization of the carbonium ion also has stereochemical implications Eq. 14.18 shows how the stereochemistry of a vinylsilicon reagent can be retained on protonation. A TMS group on carbon has been described as a superproton m that it leaves easily, especially with fluoride ion as nucleophile (Eq. 14.19) consistent with the high Si—F bond strength. 

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