A review of frustrated Lewis pair enabled monoselective C-F bond activation

Abstract

Frustrated Lewis pair (FLP) bond activation chemistry has greatly developed over the last two decades since the seminal report of metal-free reversible hydrogen activation. Recently, FLP systems have been utilized to allow monoselective C-F bond activation (at equivalent sites) in polyfluoroalkanes. The problem of 'over-defluorination' in the functionalization of polyfluoroalkanes (where multiple fluoro-positions are uncontrollably functionalized) has been a long-standing chemical problem in fluorocarbon chemistry for over 80 years. FLP mediated monoselective C-F bond activation is complementary to other solutions developed to address 'over-defluorination' and offers several advantages and unique opportunities. This perspective highlights some of these advantages and opportunities and places the development of FLP mediated C-F bond activation into the context of the wider effort to overcome 'over-defluorination'.

Fig. 1. Fluorocarbons containing sp³ fluorine positions are vitally important to many modern technologies and can act as blowing agents, refrigerants, polymers, imaging agents and pharmaceuticals.

Fig. 2. Fluorocarbons can be accessed via a ‘bottom-up’ approach where fluorine is added to substrate or via a ‘top-down’ approach where fluorine is selectively removed from a polyfluorocarbon to form a second-generation fluorocarbon. Top-down approaches must overcome the high C–F bond strength and the propensity for polyfluorocarbon positions to ‘over-defluorinate’.

Fig. 3. Selective C–F bond activation of CF₃ and CF₂ groups adjacent to alkene or carbonyl positions generates fluoroalkene products that possess stable sp² C–F bonds. E = Electrophile, Nu = nucleophile, M = metal, TBA = tetrabutylammonium.

Fig. 4. One or two electron reduction of CF₃ groups supported by arenes, amides and esters allows selective defluorination as the functionalized products of such reactions have higher reduction potentials than the fluorocarbon starting materials. The reduction can be achieved; (b) electrochemically, (c) photolytically or (d) chemically. TBA = Tetrabutylammonium, 18-C-6 = 18-crown-6 ether.

Fig. 5. Transition metals can mediate selective defluorination (stoichiometrically and catalytically). Recently, transition metal catalysis has allowed for the enantioselective generation of chiral fluorides from achiral difluorides.

Fig. 6. Strong Lewis acids tethered in close proximity to CF₃ groups allow for kinetically controlled selective defluorination. This approach was first reported by Lectka and has been subsequently developed by Yoshida and Hosoya. Nu = nucleophile.

Fig. 7. Thermodynamic FLP exhibit an FLP ground state. This provides a thermodynamic platform to enhance reactivity. Kinetic FLP cooperate synergistically to activate bonds through concerted transition states involving both the Lewis acid and Lewis base. LB = Lewis base, LA = Lewis acid, LP = Lewis pair.

Fig. 8. (a) The first report of controlled monoselective C–F bond activation in a polyfluoroalkane by an FLP. (b) Selective C–F bond activation by a phosphine masked silylium Lewis acid. (c) Selective activation of PhCF₃ by a phosphorus(v) Lewis acid and P(o-Tol)₃. (d) FLP activation of 2,2,2-trifluoroacetophenone by an FLP to generate a difluoroenolate product.

Fig. 9. FLP mediated activation reported by Young utilizing phosphine, pyridine and sulfide Lewis bases. Reactions that are catalytic in Lewis acid are possible with the use of a fluoride sequestering agent (e.g. Me₃SiNTf₂). The reaction works for difluoromethyl, trifluoromethyl and distal difluoride groups in a variety of chemical environments.

Fig. 10. Young reported that a Lewis acid assisted S_N1 mechanism was found to be experimentally and theoretically more plausible than a kinetic FLP pathway. However, a thermodynamic FLP ground state was also found to be critical for reactivity, with the reversible FLP of THT/B(C₆F₅)₃ unable to activate benzotrifluorides while activation of benzotrifluorides occurred under ambient conditions with the thermodynamic FLPs TPPy/B(C₆F₅)₃ and P(o-Tol)₃/B(C₆F₅)₃. Level of theory: PCM(DCM)-B3LYP-D3/Def2TZVPP//PCM(DCM)-DB3LYP-D3/Def2SVP (quasi-harmonic entropic correction). See ref. for details.

Fig. 11. The products of FLP mediated selective C–F bond activation are in equilibrium with the starting materials and require a fluoride sequestration agent to facilitate catalysis. Free energies in kcal mol⁻¹ given in parentheses.

Fig. 12. A large number of functionalization reactions are possible post C–F bond activation. Judicious choice of Lewis base allows for specific functionalization. Thus far, formal hydrodefluorination, nucleophilic substitution, photoredox alkylation, nucleophilic transfer, Suzuki–Miyaura coupling and Wittig olefination have been demonstrated as post-activation functionalisations.

Fig. 13. Stereoselective FLP C–F bond activation enabled through the use of a chiral Lewis base partner. The use of an enantiopure chiral base allows the generation of enantiomerically enriched products through S_N2 substitution of the diastereomeric activation salts. Yields based on NMR, isolated yields in parentheses. See ref. for details.

Fig. 14. Synthesis of fluorine-18 labelled CF₃ and CF₂H groups is possible via FLP selective activation followed by Lewis base substitution with [¹⁸F]F⁻. This methodology greatly simplifies the radiosynthesis of the fluorine-18 isotopologues as it allows the non-labelled target compound to be used as a starting material. Yields correspond to radiochemical conversions (RCC). See ref. for details.

Kenneth Lye

Rowan D. Young