Friedel–Crafts Reaction of Benzyl Fluorides: Selective Activation of CF Bonds as Enabled by Hydrogen Bonding

Abstract

A Friedel-Crafts benzylation of arenes with benzyl fluorides has been developed. The reaction produces 1,1-diaryl alkanes in good yield under mild conditions without the need for a transition metal or a strong Lewis acid. A mechanism involving activation of the CÀF bond through hydrogen bonding is proposed. This mode of activation enables the selective reaction of benzylic C À F bonds in the presence of other benzylic leaving groups.

Activation of Primary and Secondary Benzylic and Tertiary Alkyl (sp3)C-F Bonds Inside a Self-Assembled Molecular Container

“…Following the findings of Paquin et al (Champagne et al, 2014, 2015a,b) we propose an autocatalytic cycle starting with the encapsulation of a substrate molecule (see Scheme 2). The fluorine substituent likely is interacting via a hydrogen bond to a water molecule of the assembly.…”

“…After elimination of a proton and subsequent recombination with fluoride to form HF, the alkene is released from the inner cavity. With its superior hydrogen bond donating ability (Checinska and Grabowski, 2006; Champagne et al, 2014) hydrogen fluoride acts as catalytically active species in ensuing cycles.…”

“…Although the topic of organic fluorides as hydrogen bond acceptors is controversial, increasing evidence indicates a weak interaction (Champagne et al, 2015a). A mild method of activation for benzylic fluorides via hydrogen bonding was recently developed by Paquin et al (Champagne et al, 2014, 2015b). Hexafluoroisopropanol (HFIP) serves as hydrogen bond donor to the fluorine atom, which destabilizes the C-F bond to then generate a benzylic cation, which can be intercepted by an arene nucleophile in a Friedel-Crafts reaction.…”

“…Hexafluoroisopropanol (HFIP) serves as hydrogen bond donor to the fluorine atom, which destabilizes the C-F bond to then generate a benzylic cation, which can be intercepted by an arene nucleophile in a Friedel-Crafts reaction. HF is liberated after the conversion and replaces HFIP as the catalytically active species because of its higher hydrogen bond donating ability (Rosenberg, 2012; Champagne et al, 2014).…”

Catalytic enantioselective addition of organoboron reagents to fluoroketones controlled by electrostatic interactions

“…Hydrogen-bonding with a suitably situated proton donor is supported by computational 28 and experimental findings 24,29 . There is general agreement that, as pointed out long ago by Pauling 30 and utilized in recent development of catalytic reactions 31,32 , fluoride ions are effective H-bonding acceptors. There is nevertheless evidence 2,33 that, because of fluorine's exceptional electronegativity and low polarizability, a C–F bond may not participate in strong hydrogen-bonding 34 ; fluorocarbons are after all more hydrophobic than even hydrocarbons.…”