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

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'.

Experimental and computational insights into the mechanism of FLP mediated selective C-F bond activation.

Frustrated Lewis pairs (FLP) comprising of B(C6F5)3 (BCF) and 2,4,6-triphenylpyridine (TPPy), P(o-Tol)3 or tetrahydrothiophene (THT) have been shown to mediate selective C-F activation in both geminal and chemically equivalent distal C-F sites. In comparison to other reported attempts of C-F activation using BCF, these reactions appear surprisingly facile. We investigate this reaction through a combination of experimental and computational chemistry to understand the mechanism of the initial C-F activation event and the origin of the selectivity that prevents subsequent C-F activation in the monoactivated salts. We find that C-F activation likely occurs via a Lewis acid assisted SN1 type pathway as opposed to a concerted FLP pathway (although the use of an FLP is important to elevate the ground state energy), where BCF is sufficiently Lewis acidic to overcome the kinetic barrier for C-F activation in benzotrifluorides. The resultant intermediate salts of the form [ArCF2(LB)][BF(C6F5)3] (LB = Lewis base) are relatively thermodynamically unstable, and an equilibrium operates between the fluorocarbon/FLP and their activation products. As such, the use of a fluoride sequestering reagent such as Me3SiNTf2 is key to the realisation of the forward C-F activation reaction in benzotrifluorides. Selectivity in this reaction can be attributed to both the installation of bulky Lewis bases geminal to residual C-F sites and from electronic re-ordering of kinetic barriers (of C-F sites in products and starting materials) arising from the electron withdrawing nature of the pyridinium, phosphonium and sulfonium groups.

Fluorine-18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C-F Bond Activation.

We report a general method for the labeling of both CF3 and CF2 H groups in a broad range of chemical settings (aryl, oxide, sulfide). The method utilizes frustrated Lewis pair mediated selective C-F activation to formally substitute fluorine-19 with fluorine-18 in a two-step defluorination/radiofluorination process, and as such can utilize the target compounds as starting materials. The radiotracer precursors can be isolated as stable salts prior to radiofluorination. The method delivers good radiochemical yields and molar activities (up to 35.2±6.5 % non-decay corrected isolated activity yields and 12.0±1.7 GBq µmol-1 molar activities) and is shown to be applicable to biologically relevant compounds. The ability to utilize the target compound as the starting material and the synthetic simplicity of the method coupled with the ever-increasing use of CF3 and CF2 H groups in pharmaceuticals makes this method attractive for drug and radiotracer development.