Perfluoroalkyl electrophilicity

Like perfluoroalkylation, electrophilic a,a-dihydroperfluoroalkylation can be efficiently performed by the use of the appropriate (a,a-dihydroperfluoroalkyl)phenyliodonium salts. A wide range of nucleophiles were alkylated under mild conditions. Most of the reactions can occur by a ligand coupling taking place on an intermediate trisubstituted iodane(UI) compound. This is the case of the reactions with carbanions, amines, alkoxides, phenoxides, thiolates and carboxylic acid ammonium salts. Dialkylation of aniline was also obtained by using two molar equivalents of the iodonium reagent.219,220 (Table 5.11)... 

Additions of halogen fluorides to the more electrophilic perfluonnated olefins generally require different conditions Reactions of iodine fluoride, generated in situ from iodine and iodine pentafluoride [62 102 103, /05] or iodine, hydrogen fluoride, and parapeiiodic aud [104], with fluormated olefins (equations 8-10) are especially well studied because the perfluoroalkyl iodide products are useful precursors of surfactants and other fluorochemicals Somewhat higher temperatures are required compared with reactions with hydrocarbon olefins Additions of bromine fluoride, from bromine and bromine trifluonde, to perfluonnated olefins are also known [lOti]... 

Ketones and imines with adjacent perfluoroalkyl moieties show sharply reduced abilities to interact with electrophiles. Hexafluoroacetone is not protonated even in superacidic media... 

Silyl enol ethers have also been used as a trap for electrophilic radicals derived from a-haloesters [36] or perfluoroalkyl iodides [32]. They afford the a-alkylated ketones after acidic treatment of the intermediate silyl enol ethers (Scheme 19, Eq. 19a). Similarly, silyl ketene acetals are converted into o -pcriluoroalkyl esters upon treatment with per fluoro alkyl iodides [32, 47]. The Et3B/02-mediated diastereoselective trifluoromethylation [48,49] (Eq. 19b) and (ethoxycarbonyl)difluoromethylation [50,51] of lithium eno-lates derived from N-acyloxazolidinones have also been achieved. More recently, Mikami [52] succeeded in the trifluoromethylation of ketone enolates... 

The perfluoroalkyl Grignard reagents participate in a wide variety of functionalization reactions with electrophiles as illustrated in Scheme 9 [27-35]. 

Fluorinated radicals play a significant role in synthetic organo-fluorine chemistry, for example, in electrophilic radical addition to alkenes, single-electron transfer reactions (SET), telomerization of fluoroalkenes with perfluoroalkyl iodides, polymerization to fluoropolymers and copolymers, and thermal, photochemical and radiation destruction of fluorocarbons. Furthermore, such free radicals are of interest for studying structures, reaction kinetics and ESR spectroscopic parameters.38... 

Perfluoroalkyl)methyl-substituted electrophilic cyclopropanes are synthesized in excellent yields by a chromium (III) chloride/iron powder-promoted reaction of perfluoroalkyl iodides with allylamalonic ester and its analogues (equation 51)67. Oxidative coupling of... 

Peptidyl fluoromethyl ketones are widely used as fairly potent inhibitors for a variety of proteases, including serine, cysteine, and aspartyl proteases. Unlike other halomethyl ketones (Section 15.1.3), fluoromethyl ketones are reversible transition-state mimics. The electron-withdrawing fluorine(s) next to the carbonyl group enhances the electrophilicity of the a-fluoroalkyl ketone functionality, thereby making the carbonyl more susceptible to nucleophilic attack. a-Fluoroalkyl ketones are good mimics of peptide bonds due to the small size of the fluorine and the stability of C F bonds. There are three general classes of peptidyl fluoromethyl ketones fluoromethyl ketones (irreversible inhibitors of cysteine proteases), difluoromethyl ketones (reversible inhibitors of both serine and aspartyl proteases), and trifluoromethyl/perfluoroalkyl ketones, which typically exist in hydrated forms and are excellent inhibitors of both serine and cysteine proteasesJ1 ... 

The rates of bromine atom abstraction by tris(trimethylsilyl)silyl radicals from a range of /Jara-substitutcd benzyl bromides has indicated that the silyl radical is nucleophilic. In addition both the polar and spin-delocalization effects of the substituents play a role in the abstraction reaction with the latter effect greater than for H-atom abstractions.166 The perfluoroalkylation of aromatics and alkenes has been investigated using C4F9I as the source of C,. Measurement of rate constants indicated that perfluoroalkyl radicals were 2-3 orders of magnitude more reactive than the corresponding alkyl radicals. This was attributed primarily to the reaction enthalpy and far less to the electrophilic nature of the radicals.167... 

The selective oxidation of C—H bonds in alkanes under mild conditions continues to attract interest from researchers. A new procedure based upon mild generation of perfluoroalkyl radicals from their corresponding anhydrides with either H2O2, m-CPBA, AIBN, or PbEt4 has been described. Oxidation of ethane under the reported conditions furnishes propionic acid and other fluorinated products.79 While some previously reported methods have involved metal-mediated functionalization of alkanes using trifluoroacetic acid/anhydride as solvent, these latter results indicate that the solvent itself without metal catalysis can react as an oxidant. As a consequence, results of these metal-mediated reactions should be treated with caution. The absolute rate constants for H-abstraction from BU3 SnH by perfluorinated w-alkyl radicals have been measured and the trends were found to be qualitatively similar to that of their addition reactions to alkenes.80 a,a-Difluorinated radicals were found to have enhanced reactivities and this was explained as being due to their pyramidal nature while multifluorinated radicals were more reactive still, owing to their electrophilic nature.80... 

Calculated equilibrium geometries, bond lengths, and charge densities have been compared for halonium ions (1-5 X = Cl or Br) derived from the addition of halogen electrophiles to fluoro-substituted terminal alkenes (R = alkyl or perfluoroalkyl with... 

Perfluoroalkyl(phenyl)iodonium sulfonates 42 (also known as FITS reagents), as well as lFf,lff-perfluoroalkyl(aryl)iodonium triflates 44, have found practical application as electrophilic fluoro alkylating reagents toward a... 

Pearson has observed that the reactivity of various organic substrates, including radicals, can be correlated with their absolute electronegativies [56]. It can be seen that although trifluoromethyl and pentafluoroethyl radicals are much more electronegative than the more nucleophilic alkyl radicals, such as ferf-butyl, methyl itself should not be much more nucleophilic than trifluoromethyl. Nucleophilicities of alkyl radicals increase CH3 < 1° < 2° < 3°. Although there are not sufficient IP or EA data available to substantiate the issue, the reactivity studies which are described in Sect. 5 demonstrate that the electrophilicities of perfluoroalkyl radicals increase CF3 1° < 2° < 3°. 

Although the high electrophilicity of perfluoroalkyl radicals is probably the dominant factor giving rise to their high reactivities, there are a number of other factors which undoubtedly also contribute. 

The electrophilic character of n-perfluoroalkyl radicals was confirmed by a correlation of the rates of addition of the n-C8F17 radical to a series of para-substituted styrenes with Hammett o values, as shown in Fig. 3. The p value is negative (-0.53), as would be expected for an electrophilic reactant [115]. 

A group of perfluoroalkyl radicals which do exhibit marked increases in reactivity due to enhanced electrophilicity are the branched, 2° and 3° perfluoroalkyl radicals, specifically the perfluoro-iso-propyl and tert-butyl radicals [118]. 

As in the case for alkene additions, if the SOMO of the radical is relatively high in energy, such as is the case for alkyl radicals, the principal interaction with the abstractable X-H bond will be with its unoccupied a MO (one-electron-two-orbital type), and such a radical would be considered nucleophilic. If the SOMO is relatively low in energy, such as is the case for perfluoroalkyl radicals, the principal interaction with the abstractable X-H bond will be with its occupied a MO (three-electron-two-orbital type), and the radical is considered electrophilic. Either way, a good match-up in polarities in an H-atom transition state will give rise to beneficial transition state charge-transfer interaction [130,136,137]. 

In the system with three CF2 groups, i.e. 22, the radical takes on perfluoroalkyl character and the impact on cyclization rate is magnified still further. The dominant factor which has been credited for giving rise to the high reactivities of perfluoro-n-alkyl radicals in their additions to alkenes, particularly to electron-rich alkenes, is their high electrophilicities. That is, charge transfer interactions, e.g. [(CF3CF2CF2) s (alkene)l5+]] stabilize an early transition state and lower both the enthalpic and entropic barriers to reaction. 

A difficult process to execute successfully is addition of an electrophilic per-fluoroalkyl radical to an ethene which is itself substituted with a perfluoroalkyl group. However, Hu and Hu have reported a smooth conversion of this type using NiCl2 6H20/Al/alkene/RFI in a ratio of 0.2 2 1.5 1 in CH3CN at RT [258],... 

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