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’.


Introduction
Over the last century organouorine chemistry has become intrinsically important in an array of elds. 1 Fluorocarbons are invaluable as refrigerants and blowing agents, in polymer and materials chemistry, in pharmaceuticals and agrochemicals, in imaging science and radiology, and in lubricants and surfactants (Fig. 1).Despite examples of environmental and health concerns for certain uorocarbons, the uorocarbon market continues to expand. 2 For example, 4th generation refrigerants and blowing agents based on hydrouoroolens are being introduced to replace high global warming potential hydro-uorocarbons, and uorocarbons represent over 20% of marketed pharmaceuticals and 50% of marketed agrochemicals. 3 The growth of the uorocarbon sector is contingent upon the unique properties that uorine containing motifs possess.The high bond dissociation energies of C-F bonds renders them stable to denigratory chemical and biological processes, the highly polarized C-F bond promotes solubility, 'uorine' effects give rise to unique preferred geometries, and uorine containing motifs are excellent bioisosteres for hydroxyl, keto, methyl and amido groups (inter alia). 4onsequently, methods to incorporate uorine into sp 3 C-F positions are highly developed. 5Early methods relied upon

Kenneth Lye
Mr Kenneth Lye Kenneth Lye, a nal-year PhD student at the National University of Singapore, earned his BSc (Hons) in the year 2020.He later had a short stint as a research assistant in Prof. Rowan Young's group where he then decided to pursue his PhD.He is currently working on the selective C-F bond activation of poly-uorinated biomolecules via a frustrated Lewis pair approach and is interested in improving the capabilities of drug research in the medical and pharmaceutical industries.using hydrogen uoride (HF) or HF surrogates, however, a number of methods have been developed that utilize sulfonyl uorides, electrophilic uorine and uoroalkylation.Such methods constitute a 'bottom-up' approach to the synthesis of uorocarbons.
With the wide availability of uorocarbons, methods for C-F functionalization have also been developed. 6In modern chemistry, such methods render sp 3 C-F bonds as versatile synthetic handles to access a wide range of subsequent chemical groups.In general, the majority of sp 3 C-F functionalization technologies are conceived for carbon positions with a single appended uoride.Indeed, most of these synthetic strategies cannot be applied to the functionalization of a single uoride in polyuorocarbons containing equivalent C-F positions.This is due to the higher stability of more uorinated carbon positions arising from increased polarity of the C-F bond.This renders functionalized products much more reactive than the parent polyuorocarbon starting materials and results in 'over-deuorination' (Fig. 2).
More recently, attention has turned to overcoming the hurdle of 'over-deuorination' giving opportunities for selective activation of single sp 3 C-F bonds in polyuorocarbons as a 'top-down' route to accessing new uorocarbons. 7This approach has a number of advantages, namely; (i) a vast array of 2nd generation uorocarbons are readily accessible from a single parent uorocarbon.In most instances, these 2nd generation uorocarbons contain F n−1 as compared to the parent uorocarbon, (ii) the use of uorinating reagents are avoided.This avoids employing potentially harmful reagents with many uorinating reagents generating hydrogen uoride as a side-product, (iii) it provides the ability for more specic chemo and/or regioselectivity as compared to utilizing uorinating reagents with the pre-existing polyuorocarbon group dictating site selection, (iv) it allows for late-stage functionalization and derivatization, and (v) it allows for a wide variety of functional group installation inuenced by the method of selective C-F functionalization employed.In most instances each selective C-F functionalization method introduces restrictions on both the uorocarbon substrates employed and the functionalization that is possible.
Early success for selective C-F functionalization was achieved by Hiyama through S N 2 0 substitution reactions of tri-uoromethyl styrenes with silyl anion nucleophiles (Fig. 3b).The reaction relied upon the transformation of the product C-F bonds to sp 2 hybridisation rendering them thermodynamically more stable than the sp 3 C-F bonds in the starting material.Such a strategy has been widely used for 3,3,3-triuoroallyls and triuoromethyl ketones but is contingent upon an adjacent psystem (vinyl or carbonyl) (Fig. 3a). 8Similar transformations are possible via alternative mechanistic pathways (e.g. S N 1 0 , addition/elimination, see Fig. 3c and d) but rely on the same thermodynamic preference for sp 2 C-F bonds over sp 3 C-F bonds.
Périchon later demonstrated that benzotriuorides were more prone to electrochemical reduction than diuoromethylene derivatives owing to the higher electron withdrawing ability of the CF 3 group (Fig. 4b).Such a strategy allowed the resultant phenyl diuoromethylide to attack acetone, N,Ndimethylformamide and carbon dioxide electrophiles. 9The synthetic utility of this approach has recently been revived by a number of groups. 10The same reaction has also been reported using stoichiometric chemical reductants (Fig. 4d) 11 and a similar approach is possible based on single electron reduction by photoreductive dyes or homolysis of silicon-element bonds (Fig. 4c). 12Currently, reductive strategies are most efficient with electron decient benzotriuoride and tri-uoromethyl esters/amides.Electrophilic coupling has been demonstrated for protons, deuterons, carbon dioxide, amides, alkenes, ketones/aldehydes, and imines.However, radical diuoromethylbenzenes generated from this approach can also be utilized in transition metal catalysed and radical-radical coupling reactions to install aryls, suldes, oxides, selenides and amines (Fig. 4).
A limited number of reports exist for selective deuorination of diuoromethyl and triuoromethyl groups using metal catalysis (Fig. 5). 13Importantly, these reports include the rst 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'.
Selective deuorination of benzotriuorides has also been mediated by strong Lewis acids.Kinetic selection strategies have been based on tethered Lewis acid sites encroaching the triuoromethyl group (Fig. 6a).As such, the Lewis acid attacks the most spatially accessible C-F bond rather than the weakest C-F bond.Such an approach was rst demonstrated by Lectka in 1997 utilising arenium Lewis acids generated from diazonium precursors (Fig. 6b) but has been rened to be synthetically useful more recently by Yoshida and Hosoya (Fig. 6c). 14enerally, the methods for selective deuorination introduced above suffer from limited substrate scope and/or functionalization possibilities.These strategies cannot effect selective deuorination in diuoromethyl or triuoromethyl alkanes (e.g.1,1-diuoroethane), in diuoromethyl or tri-uoromethyl groups attached to heteroatoms (e.g.diuorothiomethoxybenzene or triuoromethoxybenzene) or between chemically equivalent C-F bonds at distal positions (e.g.1,3-diuoropropane).In contrast, the application of frustrated  Lewis pairs to the problem of selective deuorination has demonstrated a very wide substrate scope of polyuorocarbons and allows a vast array of functionalization opportunities, including applications in stereoselective deuorination and radiosynthesis.

Frustrated Lewis pairs
The term 'frustrated Lewis pair' (FLP) was introduced in 2007, however, the FLP concept is under ongoing renement. 15Early examples of main group Lewis acids and bases that failed to form stable observable Lewis adducts can be considered 'thermodynamic FLP' where the ground state of the Lewis pair is the frustrated form.However, much interest has arisen in the ability of FLPs to reduce activation barriers for bond cleavage through cooperative concerted transition states involving both Lewis acid components. 16Such systems can be considered 'kinetic FLP'.It is important to note that an FLP system may be thermodynamic and/or kinetic, and that certain reaction advantages will arise from both of these aspects.Thermodynamically preferred Lewis pairs with a kinetically accessible FLP   state have also exhibited kinetic FLP reactivity and have been termed 'reversible FLPs' (Fig. 7).
Seminal reports on FLP systems focused on main group element bases/acids due to their unheralded reactivity (e.g. the rst examples of metal-free reversible dihydrogen cleavage).Recognized FLP systems have been expanded to include alkali metal, transition metal and even single atom acids and bases. 17Initial reactivity of FLP systems focused on the cleavage of a range of hydrogen element bonds (e.g.H-H, H-C, H-Si, H-B, H-O, H-N, H-Cl) but more recently activation of bonds in CO, N 2 and CO 2 (inter alia) has been demonstrated. 18Despite the apparent ability of FLP systems to mimic single site transition metal catalysts, very few reports exist for FLP activation of carbon halogen positions, despite C-X activation being a pillar of transition metal reactivity. 19

FLP mediated C-F activation
The rst instance of C-F bond activation induced by an FLP was reported by Stephan in 2012. 20Activation of uoromethyl groups with B(C 6 F 5 ) and P t Bu 3 resulted in phosphonium uoroborate salts of the type [RP t Bu 3 ][BF(C 6 F 5 ) 3 ].Notably, the substrate 1,3-diuoroproporane was activated using B(C 6 F 5 ) 3 and PH t Bu 2 to generate [F(CH 2 ) 3 PH t Bu 2 ][BF(C 6 F 5 ) 3 ] almost quantitatively where only a single C-F reacted with the FLP (Fig. 8a).Although the two uorine atoms reside on different carbon positions, this report remains the rst example of a monoselective activation of chemically equivalent positions in a polyuoroalkane by an FLP.
Stephan later reported that a silylium phosphine adduct was capable of single C-F bond activation in tri-uoromethylbenzene, diuoromethylbenzene and diuorodiphenylmethane (Fig. 8b). 21The silylium acted as both the Lewis acid and a thermodynamic sink for the liberated uoride (in the formation of a silyl uoride product), while the concomitantly generated carbocation was captured by the phosphine motif to generate a uoroalkylphosphonium product.DFT studies revealed that dissociation of the phosphine was not required for the silicon Lewis acid to abstract uoride, and as such the system is not technically a thermodynamic nor a kinetic FLP.Stephan also demonstrated that the activated uorocarbons could be released from the phosphine Lewis base in the presence of hydroxide representing a formal monoselective hydrodeuorination reaction.A similar selective C-F bond activation of PhCF 3 utilizing a phosphorus(V) dication as a strong Lewis acid and P(o-Tol) 3 as a Lewis base was reported by Dielmann in 2019 (Fig. 8c). 22tephan also reported on the FLP mediated monoselective activation of 2,2,2-triuoroacetophenone (Fig. 8d). 23It was known that the electron rich phosphine P(NMe 2 ) 3 reacted with triuoroacetophenone to give a mixture of products. 24Stephan utilized the electronically similar but structurally constrained phosphine P(MeNCH 2 CH 2 ) 3 N in combination with BPh 3 to both stabilize the phosphonium (which resulted from reduction of the carbonyl position) and to sequester uoride liberated in the reaction.As such, the conversion of triuoroacetophenone to a diuoroenolate in a high yield of 87% was possible.
In 2018 Young utilized borane and phosphine FLPs to activate diuoromethyl positions in a range of uorocarbons (Fig. 9a). 25The reaction was found to work with affordable and commercially available Lewis acid/base mixtures such as boron triuoride and triphenylphosphine.However, the most effective phosphine proved to be P(o-Tol) 3 in combination with B(C 6 F 5 ) 3 .The reaction was later made catalytic in Lewis acid with the addition of Me 3 SiNTf 2 as a uoride sequestering agent 26 and extended to the nitrogen Lewis base 2,4,6-triphenylpyridine (TPPy) and the sulde bases tetrahydrothiophene (THT) and dimethylsulde. 27It was found that the reaction was capable of selectively activating C-F bonds of diuoromethyl groups hosted by a range of chemical supports including aryl, heteroaryl, alkyl, alkenyl, oxide and sulde groups.
Similar reaction conditions allowed the selective activation of triuoromethyl groups, although the reaction was found to only proceed with phosphine and pyridine Lewis bases (i.e.P(o-Tol) 3 and TPPy) rather than sulde bases (Fig. 9b). 28The reaction was found to be compatible with aryl, heteroaryl, alkenyl, oxide and sulde supported triuoromethyl groups.However, in contrast to the activation of diuoromethylalkenyls (that gave geminal substitution), activation of a,a,a-tri-uoromethylstyrenes resulted in S N 2 0 substitution and generation of a diuoroolen product. 29he concept was also extended to chemically equivalent distal uorides.As such selective activation of a single C-F bond in alkyl and aryl linked monouoromethyl, diuoromethyl and triuoromethyl groups was possible (Fig. 9c). 27

Mechanistic studies on FLP mediated C-F bond activation
A number of mechanistic studies have been conducted to reveal the active reaction pathways for FLP mediated C-F bond activation.Fernandez conducted theoretical studies on the FLP system reported by Young. 30He found that an FLP mechanism was preferred over an S N 1 type mechanism and identied a 5coordinate carbon-centred structure as a key intermediate.Chatteraj later performed theoretical studies on a simplied lutidine/alane system (that had not been experimentally authenticated) with a similar calculated FLP pathway to that of Fernandez. 31n contrast, Young reported a combined experimental and theoretical study that corroborated an S N 1 pathway. 32Young's study found that the reaction of benzotriuorides and benzo-diuorides with a variety of FLP systems was independent of Lewis base concentration, and a Hammett plot analysis revealed large negative r-values (−3 to −7) consistent with an S N 1 process for the C-F bond activation step.The proposed theoretical model supported this mechanism with a kinetic barrier of 25.2 kcal mol −1 for the activation of PhCF 3 with B(C 6 F 5 ) 3 and TPPy via an S N 1 pathway versus a barrier of 28.4 kcal mol −1 for an FLP pathway (Fig. 10).Despite the preference for an S N 1 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.Me 3 SiNTf 2 ).The reaction works for difluoromethyl, trifluoromethyl and distal difluoride groups in a variety of chemical environments.

Perspective
Chemical Science pathway over a kinetic FLP pathway, Young determined that a thermodynamic FLP was necessary for the reaction to proceed under practical conditions with Lewis pair formation between TPPy and B(C 6 F 5 ) 3 being endergonic by 3.0 kcal mol −1 .Indeed, it was found that THT and B(C 6 F 5 ) 3 formed a reversible FLP with a 1-2 kcal mol −1 thermodynamic penalty for Lewis pair dissociation that inhibited reactivity with benzotriuorides.
Young's theoretical model also revealed that the carbocation intermediate accessed via an S N 1 pathway is relatively unstable with respect to the kinetic barrier for C-F bond cleavage meaning that the barrier to nucleophilic attack of this intermediate rivalled that of C-F bond activation as the rate limiting step.This result likely explains why efforts by others to activate benzotriuoride using B(C 6 F 5 ) 3 in combination with poorer nucleophiles has failed.For example, B(C 6 F 5 ) 3 failed to catalyse the hydrodeuorination and Friedel-Cras arylation of benzotriuoride. 33he formation of the product [PhCF 2 (TPPy)][BF(C 6 F 5 ) 3 ] was found to be slightly endergonic by 1.2 kcal (versus the FLP ground state) and the low kinetic barrier allows for a dynamic equilibrium.For substrates where the equilibrium lies towards the starting materials, the addition of a uoride sequestering reagent (e.g.Me 3 SiNTf 2 ) is requisite for reaction turn-over and productive reactivity (Fig. 11).Importantly, Young examined subsequent deuorination steps and discovered that the kinetic barrier for deuorination of the cationic uorocarbon salt fragments was substantially raised (even for distal C-F Fig. 10 Young reported that a Lewis acid assisted S N 1 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(C 6 F 5 ) 3 unable to activate benzotrifluorides while activation of benzotrifluorides occurred under ambient conditions with the thermodynamic FLPs TPPy/B(C 6 F 5 ) 3 and P(o-Tol) 3 /B(C 6 F 5 ) 3 .Level of theory: PCM(DCM)-B3LYP-D3/Def2TZVPP//PCM(DCM)-DB3LYP-D3/Def2SVP (quasi-harmonic entropic correction).See ref. 32 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.

Chemical Science
Perspective positions).For example, the second deuorination event for PhCF 2 H using B(C 6 F 5 ) 3 and P(o-Tol) 3 was 6 kcal mol −1 higher in energy than the rst deuorination step and 13.6 kcal mol −1 higher in energy than deuorination of BnF. 32An increased kinetic barrier for deuorination of a cationic uorocarbon further supports an S N 1 mechanism.Similar to Young's proposed Lewis acid assisted S N 1 mechanism, Stephan conducted DFT studies on his silylium mediated C-F bond activation (Fig. 8b) that suggested a Lewis acid assisted S N 1 mechanism. 21In contrast to Young's system, the ground state of Stephan's system was a strained 4-member silyl phosphonium ring.The ability of silicon to accommodate higher coordination (cf.boron) resulted in uoride abstraction by silicon prior to phosphine decoordination, and as such there was no thermodynamic penalty required for silicon-phosphorous dissociation (i.e. a reversible FLP wasn't necessary for reactivity).The resultant intermediate carbocation generated aer C-F bond activation was subsequently captured by the liberated phosphine.

Applications
FLP mediated monoselective C-F bond activation allows the capture of the activated uorocarbon fragment with a range of Lewis base partners.As stated above, these Lewis base partners can play a pivotal role in the activation reaction (through the formation of thermodynamic FLPs), however, such Lewis bases also act as nucleofuges for further reactivity.Indeed, deconvoluting the C-F bond functionalization process into 'activation' and 'functionalization' steps allows for an extremely extensive array of functionalization possibilities.Further, the relative stabilities of the salts resulting from C-F bond activation allows for 'customization' of the activation reaction based on the reactivity of the cationic uorocarbon fragment and the desired functionalization.With respect to heterolysis, phosphonium salts are more stable than pyridinium salts and pyridinium salts are more stable than sulfonium salts, while a higher resonance stability of the cationic uorocarbon fragment leads to a less stable salt.
As described above, FLP systems provide a general method of selective C-F bond activation for a wide selection of poly-uoroalkanes.Indeed, apart from spanning multiple substrate classes that are specic to other activation approaches (e.g.diuoromethyl(hetero)arenes, triuoromethyl(hetero)arenes, triuoromethylalkenes, triuoromethylketones), FLP mediated selective C-F bond activation allows derivatization of unique substrates that are resistant to activation by any other method (e.g.diuoroalkanes, diuoro(thio)methyoxides, triuoro(thio) methyoxides).The ability to install suldes, phosphines and pyridines as nucleofuges provides the ability for a vast array of functionalization opportunities allowing convenient access to a diverse range of derivatives from a common uorocarbon starting material (Fig. 12).
The derivatization of phosphonium, sulfonium and pyridinium salts is highly developed for non-uorinated reagents, and (in-principle) such chemistry is applicable to the products of FLP monoselective C-F bond activation.Notably, Katritzky salts (containing TPPy) have recently become popular in the redox coupling community to install alkyl, alkenyl, aryl and boryl groups (inter alia), 33 alkyl sulfonium salts were shown to be excellent electrophilic partners in palladium catalysed coupling chemistry by Libeskind 34 and alkyl phosphonium salts have a rich coupling chemistry history in Wittig olenation and redox alkylation. 35,36tephan demonstrated formal hydrodeuorination of PhCF 3 , PhCF 2 H and Ph 2 CF 2 via phosphonium salts. 21][27][28][29] Young has demonstrated that the installation of phosphonium and pyridinium groups allows for the uorocarbon fragment to act as a radical or anionic nucleophile in alkylation and benzylation reactions in a similar fashion to reductive strategies.However, given the lower energies required for C-N and C-P bond cleavage (as compared to C-F bond cleavage) a greater functional group tolerance is possible using FLP activated salts as compared to benzotriuorides activated by reductive approaches directly.For example, aryl bromides have been shown to be incompatible with alkyl redox coupling conditions, 12 while Young has demonstrated high yields of redox alkylation products from phosphonium uorobenzyl salts featuring bromo groups.
Young has also shown that activated uorocarbon fragments can be utilized as electrophilic partners (Fig. 12).As such, a general approach to monoselective nucleophilic substitution of uoride in polyuoroalkanes has been realized. 27,28Young has demonstrated that both sulde and pyridine groups are readily displaced by a range of nucleophiles including halides, azides, cyanide, thiocyante, nitrate, oxides, suldes, carboxylates, N-heterocycles, pyridines, phosphines and amines (inter alia).Young has shown that the basicity of the nucleofuge (e.g.THT, TPPy) can be matched to both the desired nucleophile and the uorocarbon substrate to provide optimum reaction yields.
Young has also demonstrated that Katritzky salts can be utilized in metal catalysed couplings. 27For example, nickel and palladium were shown to catalyse Suzuki-Miyori couplings with arylboronates to provide access to uorinated diaryl methanes.In principle, Negishi couplings, reductive couplings and borylations (inter alia) are accessible using a similar approach.34b Lastly, uorinated alkyl phosphonium salts have been shown to facilitate Wittig olenation reactions. 25Due to the requirement of an a-hydrogen preceding ylide formation, this type of functionalization is restricted to diuoromethyl or uoromethyl substrates.The presence of an a-uoro group facilitates ylide formation with moderate strength bases (e.g.lithium amides).Generally, uoroalkenes are challenging to access, and this protocol allows for one-pot synthesis of uoroolenes directly from diuoromethylalkanes in good yield and selectivity.

Stereoselective fluoroalkane synthesis
As discussed above, displacement of pyridine and sulde Lewis bases from activated uorocarbon fragments is a facile process.As such, exchange of Lewis bases readily occurs in solution via an S N 1 process.Recently, Young has reported that this process allows stereochemical control in the activation of enantiotopic diuorides. 37The majority of synthetic approaches to access stereoenriched uorocarbon centres rely upon 'bottom-up' approaches that need to introduce uorine, whereas stereoselective FLP mediated C-F bond activation is a 'top-down' approach that selectively removes uorine to generate a stereoenriched uorocarbon centre. 38Apart from the attraction of using pre-existing polyuorocarbons, this method also allows the generation of uorocarbon centres that are not accessible using other developed approaches (e.g.centres that cannot be generated from stereoselective electrophilic uorination reagents, uoride addition or elaboration).
The stereoselective FLP mediated C-F bond activation reactions reported by Young relied upon the use of chiral Lewis bases, giving rise to diastereomeric activation products (Fig. 13).As such, the rate of chiral Lewis base exchange and the free energy difference between the diastereomers controlled the selectivity of the reaction.It was found that diuoromethylarenes containing ortho substituents combined with chiral dia-lkylsuldes gave optimum results, with selectivity as high as dr = 95 : 5 observed.Utilizing enantiopure (R,R)-2,5-dimethylthiolane gave rise to epimers that could be derivatized via S N 2 substitution reactions to generate enantioenriched uorocarbons.Young demonstrated how this method could be utilized to access a uorinated analogue to Runamide in ca 70% ee.Enantioenriched benzyluorides subtended by heteroatoms are difficult to generate using existing 'bottom-up' enantioselective uorination approaches.

Direct access to radiolabelled fluorocarbons
Fluorine nds a unique role in radiology where the half-life and emission energy of the synthetic isotope uorine-18 render it the most practical for positron emission tomography (PET) imaging. 39Apart from well-established applications in diagnostic medicine, PET imaging has been shown to be a powerful tool in pharmacokinetics and drug development. 40Diuoromethyl and triuoromethyl groups have become a pillar of modern pharmaceuticals, 41 thus the ability to generate uorine-18 isotopologues of drugs under development would accelerate their metabolic studies.
'Bottom-up' approaches to incorporating uorine-18 into CF 2 H and CF 3 positions suffer from the need to implement custom synthetic pathways to install uorine-18 at a late stage.This contrasts with synthetic strategies to non-labelled compounds that install CF 3 and CF 2 H groups early in the synthetic route. 42As stated above, FLP mediated removal of uoride from diuoromethyl and triuoromethyl positions is

Chemical Science Perspective
a dynamic equilibrium, where uoride (in the form of [BF(C 6 F 5 ) 3 ] − ) displaces the Lewis base on the activated uorocarbon fragment to regenerate the uorocarbon starting material.As such, [ 18 F]F − can be utilized as a uoride source to generate isotopologues from the non-labelled target in a twostep process.Such a synthetic strategy not only allows the installation of CF 3 and CF 2 H units early in the synthetic route but allows direct use of the target compound as a starting material, greatly simplifying the radiosynthesis of uorine-18 labelled CF 3 and CF 2 H groups in a wide range of chemical settings. 43oung reported on the FLP mediated C-F bond activation and isolation of a range of diuoromethyl and triuoromethyl containing compounds including bioactive targets (and commercially available pharmaceuticals).These were then utilized in radiouorination to generate the radiolabelled targets (Fig. 14). 44The radiouorination step was shown to proceed quickly under mild conditions (5-15 minutes, 70-120 °C) and demonstrated good functional group tolerance.Given the mild conditions of the radiouorination step, good radiochemical yields and molar activities were achieved.For example, a sample of [ 18 F]PhCF 3 was isolated in a non-decay corrected activity yield (AY) of 35.2 ± 6.5%, a non-decay corrected molar activity (A m ) of 12.0 ± 1.7 GBq mmol −1 and a radiochemical purity (RCP) greater than 99% starting from low initial activities (3-5 GBq).Other approaches to generate uorine-18 labelled CF 3 groups that require harsher reaction conditions generally suffer from uoride scrambling and A m greater than 10 GBq mmol −1 are difficult to achieve starting from low initial activities.

Conclusion
Fluorocarbons have proven invaluable chemicals that are required for a range of modern technologies, and their use will continue despite any concerns over their environmental persistence.Consequently, the need to access a diverse variety of second-generation uorocarbons via selective C-F bond functionalization is well-recognised.FLP systems offer a unique solution to the problem of 'over-deuorination' in poly-uoroalkanes and allow selective activation of C-F bonds in CF 3 and CF 2 R motifs supported by a wide range chemical supports including aryl, heteroaryl, alkyl, alkenyl, silyl, carbonyl, oxide and sulde groups (inter alia).Notably, FLP systems have been shown to activate small uorocarbon refrigerants (uoroalkanes) selectively, a transformation not possible using other selective C-F bond functionalization approaches.Combined experimental and theoretical studies by Stephan, Young, Fernandez and Chatterjee suggest that thermodynamic FLP systems are important platforms to promote reactivity but that uorocarbon activation proceeds via a Lewis acid assisted S N 1 mechanistic pathway.Further, these theoretical studies have quantied the elevation of the kinetic barrier for over deuorination steps, uncovering the basis for the highly monoselective reaction.
Importantly, products of FLP mediated C-F bond activation can be functionalized with pre-established coupling chemistry protocols that can (in-principle) install almost any functional group.Hydrogenolysis, alkylation, arylation, olenation, electrophilic transfer and nucleophilic transfer functionalizations have all been demonstrated.
Thus far, only a small sample of FLP systems have been explored in C-F bond activation.These include archetypal Lewis acids B(C 6 F 5 ) 3 , Al(C 6 F 5 ) 3 and BF 3 , as well as newly developed phosphorus(V) dicationic and silylphosphonium Lewis acids.Lewis base exploration has been a little more adventurous, with pyridines, phosphines and thioethers all utilized in FLP mediated C-F bond activation.The importance of FLP combinations for both the activation steps and subsequent functionalization has become apparent, and FLP components can be customized based on the characteristics of the C-F bond to be targeted.
Utilizing chiral Lewis bases, FLP mediated C-F bond activation also allows stereoselective desymmetrization of enantiotopic diuorides.This provides a rare example of a 'topdown' approach to stereoenriched uorocarbon centres.Stereoselective FLP mediated C-F bond activation provides a complementary synthetic strategy to existing stereoselective uorination methods and provides access to stereoenriched uorocarbon centres that would otherwise be difficult to generate.
The products of FLP mediated C-F bond activation have also been demonstrated to allow direct access to uorine-18 labelled CF 3 and CF 2 H groups.This allows the use of target compound as the starting material and can greatly simplify radiosynthesis of pharmaceutical isotopologues utilized in pharmacokinetic studies.
A multitude of opportunities present themselves for future development of FLP mediated C-F bond activation.Proof-ofprinciple for the use of FLP mediated C-F bond activation in radiochemistry, stereoselective synthesis and C-F derivatization have been reported (and discussed above) but the development and application of these chemistries is on-going.Further, the ability of FLPs to mimic transition metal chemistry may allow FLPs to act as multifunctional catalysts in cascade reactions.For example, the ability of FLPs to (selectively) activate both C-F and H-H bonds may allow for hydrodeuorination reactions that utlilise hydrogen gas as opposed to molecular hydrides.Given that the larger area of FLP chemistry has been well-developed over the last two decades, activation of uorocarbons could be coupled with heterogeneous FLPs, 45 frustrated radical pairs (FRPs), 46 transition metal FLPs 17-19 and the FLP activation of small molecules (e.g.N 2 , CO, CO 2 ) 16 to enhance the utility of FLP mediated C-F bond activation.Given that FLP catalysed activation of benzotriuoride was only demonstrated in 2020, the ability of FLP systems to efficiently and conveniently generate second generation uorocarbons is only beginning to be realized by the greater chemical community and the future contributions that FLPs will make to selective C-F bond activation look set to explode.

Fig. 1
Fig. 1 Fluorocarbons containing sp 3 fluorine positions are vitally important to many modern technologies and can act as blowing agents, refrigerants, polymers, imaging agents and pharmaceuticals.

Fig. 3
Fig. 3 Selective C-F bond activation of CF 3 and CF 2 groups adjacent to alkene or carbonyl positions generates fluoroalkene products that possess stable sp 2 C-F bonds.E = Electrophile, Nu = nucleophile, M = metal, TBA = tetrabutylammonium.

Fig. 4
Fig. 4 One or two electron reduction of CF 3 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
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
Fig.6Strong Lewis acids tethered in close proximity to CF 3 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
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
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 PhCF 3 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. 12 A
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
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 N 2 substitution of the diastereomeric activation salts.Yields based on NMR, isolated yields in parentheses.See ref. 37 for details.Fig. 14 Synthesis of fluorine-18 labelled CF 3 and CF 2 H groups is possible via FLP selective activation followed by Lewis base substitution with [ 18 F]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. 44 for details.