Fluoride as a nucleophile

Reminder of the anion-stabilizing ability of sulfones and the excellence of the mesylate lea 1 group (Chapter 46) plus the special role of fluoride as a nucleophile for silicon. 

Even more reactive towards acetylcholinesterase are the organophosphorus derivatives developed as chemical warfare nerve agents, e.g. sarin. Such compounds react readily with the enzyme and form very stable addition intermediates. It is unusual to see fluoride as a leaving group, as in sarin, but its presence provides a huge inductive effect, thus accelerating the initial nucleophilic addition step (see also Section 13.7). 

As the size of an atom increases, its outer electrons move further away from the attractive force of the nucleus. The electrons are held less tightly and are said to be more polarizable. Fluoride is a nucleophile having hard or low polarizability, with its electrons held close to the nucleus, and it must approach the carbon nucleus closely before orbital overlap can occur. The outer shell of the soft iodide has loosely held electrons, and these can easily shift and overlap with the carbon atom at a relatively long distance. 

Full details77 have been provided for the optimized preparation of (trifluo-romethyl)trimethylsilane (Ruppert s Reagent78). It acts as a nucleophilic trifluoromethide equivalent, normally under fluoride ion initiation, reacting readily with a variety of carbonyl electrophiles and related species79. 

Treatment of acyclic bisthiocyanate 114 with tetrabutylammonium fluoride (TBAF) in dry tetrahydrofuran (THF) gave 1,2-dithiepane 113 in 66% yield (Equation 36). It is suggested that the fluoride ion acted as a nucleophile, which... 

Fluorinated -alkenes and -cycloalkenes have a special relationship with their hydrocarbon analogues, usually exhibiting a chemistry that is complementary. For example, the fluorinated systems are frequently susceptible to nucleophilic attack, in some cases dramatically so, and therefore reactions of nucleophiles with fluorinated alkenes often reveal unique new chemistry. This chapter covers electrochemical reduction, principles governing orientation and reactivity of fluorinated alkenes towards nucleophiles, fluoride ion as a nucleophile and the mirror-image relationship of this chemistry with that of proton-induced reactions, reactions with nitrogen-, oxygen-, carbon- centred nucleophiles etc., and, finally, chemistry of some oligomers of fluorinated -alkenes and -cycloalkenes. 

By contrast, molecules like hydrogen fluoride or aluminium chloride prefer to react as electrophiles. This is because the nucleophilic centres in both these molecules (halogen atoms) are weak, whereas the electrophilic centres (H or AI) are strong. Water is a molecule that can react equally well as a nucleophile or as an electrophile. For example, water reacts as a nucleophile with a proton and as an electrophile with an anion ... 

Different compounds which complex the fluoride anion were recently developed. Sapphyrine (1) is a porphyrin with 5 pyrrole rings, and when it is doubly protonated it can exclusively complex F in its cavity68. Similarly, Seppelt prepared the thermally stable salt 2 with a bulky cation where the fluoride can be completely desolvated, thus increasing its efficiency as a nucleophile and a base69. 

Fluorinated epoxides are very important synthetically. Perfluoroalkenes can be oxidized by numerous means to the corresponding epoxides. The most commonly encormtered epoxide is hexafluoropropene oxide (HFPO), which is made from hexafluoropropene and is used in the synthesis of oligomers and as a source of difluorocarbene. HFPO is a colorless, nonflammable gas, boiling at -27.4 °C it can be ring-opened easily by nncleophiles or electrophiles imder a variety of conditions. HFPO can be rearranged by flnoride ion to perfluoropropionyl flnoride and by Lewis acids snch as UO2 to hexafluoroacetone (HFA). Nncleophiles typically attack the most substituted carbon of the epoxide, freeing the oxyanion to lose fluoride or act as a nucleophile itself Some examples of HFPO reactivity are shown in Scheme 3. 

Albanese, D., Landini, D., Penso, M. Hydrated Tetrabutylammonium Fluoride as a Powerful Nucleophilic Fluorinating Agent. J. Org. Chem. 

I n 1993, the first cinchona-catalyzed enantioselective Mukaiyama-type aldol reaction of benzaldehyde with the silyl enol ether 2 of 2-methyl-l -tetralone derivatives was achieved by Shioiri and coworkers by using N-benzylcinchomnium fluoride (1, 12 mol%) [2]. However, the observed ee values and diastereoselectivities were low to moderate (66-72% for erythro-3 and 13-30% ee for threo-3) (Scheme 8.1). The observed chiral inductioncan be explained by the dual activation mode ofthe catalyst, that is, the fluoride anion acts as a nucleophilic activator of the silyl enol ethers and the chiral ammonium cation activates the carbonyl group of benzaldehyde. Further investigations on the Mukaiyama-type aldol reaction with the same catalyst were tried later by the same [ 3 ] and another research group [4], but in all cases the enantioselectivities were too low for synthetic applications. 

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. 

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