Access to novel fluorovinylidene ligands via exploitation of outer-sphere electrophilic fluorination: new insights into C–F bond formation and activation†

Metal vinylidene complexes are widely encountered, or postulated, as intermediates in a range of important metal-mediated transformations of alkynes. However, fluorovinylidene complexes have rarely been described and their reactivity is largely unexplored. By making use of the novel outer-sphere electrophilic fluorination (OSEF) strategy we have developed a rapid, robust and convenient method for the preparation of fluorovinylidene and trifluoromethylvinylidene ruthenium complexes from non-fluorinated alkynes. Spectroscopic investigations (NMR and UV/Vis), coupled with TD-DFT studies, show that fluorine incorporation results in significant changes to the electronic structure of the vinylidene ligand. The reactivity of fluorovinylidene complexes shows many similarities to non-fluorinated analogues, but also some interesting differences, including a propensity to undergo unexpected C–F bond cleavage reactions. Heating fluorovinylidene complex [Ru(η-C5H5)(PPh3)2(CvC{F}R)][BF4] led to C–H activation of a PPh3 ligand to form an orthometallated fluorovinylphosphonium ligand. Reaction with pyridine led to nucleophilic attack at the metal-bound carbon atom of the vinylidene to form a vinyl pyridinium species, which undergoes both C–H and C–F activation to give a novel pyridylidene complex. Addition of water, in the presence of chloride, leads to anti-Markovnikov hydration of a fluorovinylidene complex to form an α-fluoroaldehyde, which slowly rearranges to its acyl fluoride isomer. Therefore, fluorovinylidenes ligands may be viewed as synthetic equivalents of 1-fluoroalkynes providing access to reactivity not possible by other routes.


Introduction
The unique properties of the carbon-fluorine bond can enhance many fundamental properties of biologically relevant molecules including bioavailability, metabolic stability and lipophilicity, with approximately 30% of agrochemicals and 20% of all pharmaceuticals now containing fluorine. [1][2][3][4][5][6][7][8][9] The use of 18 F-labelled imaging agents in positron emission tomography (PET) is also a highly active area of medical research. 10,11 As such, new facile and selective synthetic methods for the introduction of fluorine into organic frameworks are highly desirable. Of particular interest are examples which offer high selectivity, controlled regiochemistry that is complementary to other methodologies and/or the ability to synthesise C-F bonds in less common environments.
The development of novel catalytic procedures for C-F bond formation is highly desirable and can offer significant advantages over traditional stoichiometric processes. Recent years have seen many advances using enzymatic-, 12 organo-or photo-catalytic 13 methods for the synthesis of fluoro-organic compounds. Alongside these, transition-metal-promoted reactions have played an increasingly prominent role, 14 particularly in the formation of aryl fluorides. 15 Complementary studies on C-F bond cleavage 4,[16][17][18][19][20] and hydrodefluorination by metal complexes provide insight into the functionalization of readily available fluorine-rich substrates. 13,[21][22][23] Metal-mediated C-F bond forming methodologies using both nucleophilic and electrophilic sources of fluorine have been developed. 5,6,15,24 Our interest has focused on reactions involving electrophilic fluorinating reagents, a number of which are commercially available. 25,26 They have been utilized in metal-catalyzed C-F bond formation reactions, which are believed to proceed either by oxidative fluorination of palladium [27][28][29] or silver 30 to form a high-oxidation-state metal-fluoride complex, 31 followed by C-F reductive elimination, or through single-electron processes with either copper 32 or palladium catalysts. 2,[33][34][35] In addition, a wealth of Lewis-acidicmetal-mediated electrophilic fluorination reactions have been developed, which do not involve metal-based redox chemistry. [36][37][38][39] We have recently described a new mechanism for the formation of C-F bonds within the coordination sphere of a redox-active metal complex using electrophilic fluorinating reagents (Scheme 1a). 40,41 Reaction of pyridylidene complex [I] with a latent source of "F + " results in selective C-F bond formation to give [II] + . Reaction of [II] + with a further equivalent of 1-fluoro-2,4,6-trimethylpyridinium (FTMP) salt (in the presence of a catalytic amount of a base), or [I] with two equivalents of FTMP, gives the difluorinated analogue [III] + . Experimental and computational studies indicate that this process involves direct fluorination of the ligand, without Ru-F bond formation, and is hence referred to as an outersphere electrophilic fluorination (OSEF) reaction.
We believe that the OSEF reaction in Scheme 1a is a general process and recent reports that an outer-sphere fluorination step may be involved in palladium-catalysed C-F bond formation 42 and the fluorination of alkyne ligands in the coordination sphere of platinum 43 support this idea. It is therefore important to gain a deeper understanding of the scope of OSEF reactions and the reactivities of the novel fluorinated ligand systems that are formed.
The conversion of [I] to [II] + may be viewed as the transformation of an alkenyl ligand to a fluorinated carbene (Scheme 1b) and by analogy we postulated that the corresponding reaction of an alkynyl ligand via OSEF might provide facile and selective formation of very unusual fluorovinylidene ligands (Scheme 1c). Fluorovinylidene complexes have rarely been describedlimited examples of dimeric iridium [44][45][46][47] and iron 48 complexes have been reported via activation of fluorinated organic precursors such as H 2 CvCHF (iridium) and CF 2 (COCl) 2 (iron). Since the availability of these precursors with a range of substitution patterns is restricted, this approach does not represent a general method for the synthesis and exploitation of fluorovinylidenes complexes, and hence their reactivity is largely unexplored. However, the potential importance of these ligands as intermediates in catalytic processes is highlighted by the large number of catalytic reactions that proceed via non-fluorinated vinylidene intermediates. [49][50][51][52] We now demonstrate the successful preparation of fluorovinylidene complexes by OSEF from readily available, nonfluorinated alkynes. Studies of their reactivity clearly demonstrate that these complexes may indeed provide important routes to fluorinated compounds. The fluorovinylidenes ligands may act as fluoroalkyne equivalents therefore offering access to reactivity patterns of compounds which are otherwise difficult to prepare and handle.

Results and discussion
Synthesis and characterization of fluorine-and trifluoromethyl-containing vinylidene complexes By analogy with related electrophilic additions (H + , 53    In a similar manner to electrophilic fluorination, the electrophilic incorporation of -CF 3 groups into the framework of organic compounds is also desirable. 10,39,57,58  showed no change on cooling to 195 K, indicating that the vinylidene was undergoing rapid rotation on the NMR timescale. The deep green colour of the fluorovinylidene complexes is due to an absorption band at ca. 690 nm, which showed no significant solvatochromism (ESI †). With the aid of TD-DFT studies this transition was shown to be dominated by HOMO → LUMO character. In the HOMO ( Fig. 1) a fluorine lone pair has an anti-bonding interaction with the π-system of the vinylidene ligand (which is itself anti-bonding with respect to a metal-centred orbital). The LUMO has a contribution from a p-orbital on the fluorine and an orbital based on the metalbound carbon.
Additional spectroscopic data of the other halogen-substituted vinylidene complexes [Ru(η 5 -C 5 H 5 )(vCvC{E}C 6 H4-4-R) (PPh 3 ) 2 ]X 54 (E = Cl, ‡ Br and I) and the CF 3 -containing complex, [7a]BF 4 , support an interplay between σand π-effects on the Scheme 2 (i) CH 2 Cl 2 solution, -2,4,6-trimethylpyridine. *NFSI was used as the fluorinating agent. (ii) CH 2 Cl 2 solution, -"HF" (iii) CH 2 Cl 2 solution, 4 h, r.t., -dibenzothiophene.   (Fig. 2). One is orange (λ max = 742 nm) and one green (λ max = 692 nm) and they differ primarily in the orientation of the fluorine atom and phenyl group of the vinylidene ligand and the geometry around the β-carbon (ESI †). Dissolution of both crystals in CH 2 Cl 2 gave essentially identical UVvis and NMR spectra showing that the two crystalline forms convert to the same species in solution. We propose that the observed species is a time-averaged signal for the different rotameric forms. Different agostic isomers of the same organometallic complex have been shown to produce crystals with markedly different electronic spectra, 61 however, in the case of [3a]PF 6 subtle changes to the structure in the solid state has a pronounced effect on the photophysical properties of the system by altering the energy of the HOMO-LUMO transition.

Reactions of fluorine-containing vinylidene complexes
Attempted displacement of FCuCPh. The facile syntheses of complexes [3]BF 4 has allowed an exploration of the reactivity of these species to evaluate the effects of fluorine incorporation into vinylidene ligands. In the case of half-sandwich ruthenium complexes with either mono-62,63 or di-substituted vinylidene ligands 64 reaction with NCMe has been shown to reverse the alkyne-vinylidene tautomerisation and generate [Ru(η 5 -L)(NCMe)(PPh 3 ) 2 ] + , (L = C 5 H 5 , [9] + ) liberating the corresponding alkynes HCuCR and PhCuCR respectively. These studies have permitted detailed kinetic insight into the nature of the alkyne-vinylidene interconversion. 65 However, heating a sample of [3a] + in NCMe-d 3 did not result in an analogous reaction to form [9] + and FCuCPh. Instead, the major product from the reaction was [10a]BF 4 , in which a coordinated alkene ligand has been formed from a combination of vinylidene and phosphine ligands, the latter having undergone an orthometallation process (Scheme 3). The 31 P NMR spectrum of  Other products form on heating at higher temperature (80°C), but after ca. two weeks at 50°C, the reaction was reasonably selective (70% conversion based on 31 P NMR spectroscopy). A complex related to [10a]BF 4 has been reported previously from the nucleophilic attack of PPh 3 at a coordinated ( protio)vinylidene. 66 It is proposed that [10a]BF 4 is formed by initial loss of PPh 3 , followed by attack of the free phosphine at the metal-bound carbon of the fluorovinylidene. C-H activation and hydride migration subsequently leads to [10a]BF 4 . This is supported by the fact that the dppe-containing fluorovinylidene complex [Ru(η 5 -C 5 H 5 )(vCvC{F}Ph) (dppe)]N(SO 2 Ph) 2 , [3e]N(SO 2 Ph) 2 ( prepared from [Ru(η 5 -C 5 H 5 ) (-CuCPh)(dppe)] and 2b) is unchanged on heating at 100°C for 14 days in NCMe-d 3 . These data indicate that the conversion of the fluorovinylidene to its alkyne form does not proceed under any of these conditions.
Reaction of fluorovinylidene complex with pyridine: C-H and C-F bond activation. Many of the catalytic applications of ruthenium vinylidene complexes exploit the electrophilicity of the metal-bound carbon atom. 49,50,52,67 For example, we have recently demonstrated that nucleophilic attack by pyridine at a coordinated vinylidene was a key step in ruthenium-mediated C-H functionalization reactions, 68 [11]BF 4 was confirmed by X-ray crystallography (Fig. 3), which showed that the alkenyl ligand had adopted a Z-configuration. We have previously proposed that this type of alkenyl complex was a key intermediate in the direct C-H functionalization of the pyridine, 68 and the previous inability to observe such a species was principally owing to its low intrinsic concentration due to competitive deprotonation of the vinylidene ligand. Evidently, the presence of the fluorine atom allows for the observation and characterization of this species.
On standing in pyridine solution, [11]BF 4 underwent a further reaction to give [12]BF 4 and free PPh 3 . Monitoring this reaction by NMR spectroscopy indicated that this process proceeds through a number of phosphorus-and fluorine-containing intermediates. The molecular structure of [12]BF 4 (Fig. 4 as its pyridine solvate) showed that this species was a novel pyridylidene complex had been formed by activation of a C-H bond of the pyridine group in [11]BF 4 , incorporation of a second pyridine molecule and formal loss of HF, the fate of which could not be determined.
A potential mechanism for the conversion of [3a]BF 4 to [12]BF 4 was investigated by a DFT study. Given the changes in molecularity during the proposed mechanism there are significant differences in the relative zero-point-energy-corrected electronic energies (E SCF+ZPE ) and Gibbs energies of different states. The following discussion refers solely to the Gibbs energies at 298 K, although both are presented in Fig. 5. In the first step, nucleophilic attack of pyridine occurs at the metal-bound carbon atom of the vinylidene in [3a] + (taken as the reference point for the calculations) to give [11-Z] + [11-E] + +155 kJ mol −1 ) and thermodynamically unfavorable (+65 kJ mol −1 ) when compared to the formation of the Z-isomer. This appears to be due to an unfavourable interaction between the PPh 3 ligands and the Phgroup of the alkenyl ligand in the E-isomer. In contrast, however, defluorination from [F] is far more accessible from the E-isomer of the alkene complex ([F-E]) than from the Z-isomer (TS  (Fig. 6a) would be readily accessible from complexes such as [A] + . 39 Rotation of vinylidene ligands, which will interchange the Eand Z-isomers, is a low energy process. 70,71 We tentatively propose that at some point following state [11-Z] + the system isomerises and follows the E-isomer pathway.

Dalton Transactions Paper
The formation of [11] + is rapid and a second, slower, reaction subsequently gives [12] + . In addition to supporting our previous observation that the [Ru(η 5 -C 5 H 5 )(PPh 3 )] + fragment may selectively activate pyridine in the 2-position, 68,72 the DFT study also provides an explanation as to why no alkenylated pyridine is observed in the fluorine-containing system. The key transition state in this process involves C-N bond cleavage in [F-E] via TS [F-E][J-E] which at +150 kJ mol −1 lies higher in energy than TS [F-E][G] + (Fig. 6b) implying that defluorination is preferred to C-N bond cleavage.
It appears that C-F bond cleavage in this system occurs by a pyridinium-assisted fluoride abstraction. This process is related  to Hughes' studies on half-sandwich iridium complexes in which α-fluoride abstraction leads to a cationic carbene complex. 73,74 In this case, a cationic alkyne complex is the product of the fluoride loss from the β-position of complex [F], which then undergoes nucleophilic attack by pyridine.
Hydrolysis of fluorovinylidene complexes: formation of an α-fluoroaldehyde and acyl-fluoride. The observation that fluorovinylidenes ligands are susceptible to nucleophilic attack, in a similar way to their non-fluorinated analogues, prompted us to explore this type of reaction with a view to generating fluorinated organic molecules. Vinylidene complexes are well known to undergo hydrolysis and hydration via nucleophilic attack of water at the α-carbon of the vinylidene. 75,76 The products of hydration depend on the ligands present at the metal. Careful design has allowed the development of Ru-catalysts for the anti-Markovnikov hydration of terminal alkynes via vinylidene intermediates. [77][78][79][80][81]82 We were therefore interested in understanding the reactivity of [3]BF 4 with water. However, [3a]BF 4 proved to be relatively stable in the presence of water, in the absence of other additives. Addition of either stoichiometric or excess water to a CH 2 Cl 2 solution of [3a]BF 4 at room temperate did not result in an immediate reaction. Addition of one equivalent of a base, 1,4-diazabicyclo[2.2.2]octane (DABCO), and water (either stoichiometric water or ten equivalents) resulted in the formation of a number of new compounds. The major new species were identified, by 31 P{ 1 H} NMR spectroscopy, as [Ru(η 5 -C 5 H 5 )Cl(PPh 3 ) 2 ], [13], and, remarkably, [Ru(η 5 -C 5 H 5 ) (CuCPh)(PPh 3 ) 2 ], [1a] the latter corresponding to the formal loss of "F + " from the fluorovinylidene. 83 Monitoring the reactions over an extended period (ca. two weeks) at room temperature showed almost total conversion to [13]. Heating the reactions at 50°C increased the rate of conversion but not the final product distribution. This should be contrasted with the reaction of [4a] + with water which results in the formation of [Ru(η 5 -C 5 H 5 )(CO)(PPh 3 ) 2 ] + and toluene. 76 In contrast, hydrolysis of [3a]BF 4 in the presence of chloride as an additive (introduced as N n Bu 4 Cl·H 2 O §) results in the selective, if slow, formation of [Ru(η 5 -C 5 H 5 )Cl(PPh 3 ) 2 ], [13] and the acyl-fluoride 14 (Scheme 5a), which has resulted from formal hydration of the vinylidene ligand and isomerisation of the resulting α-fluoroaldehyde (vide infra). Compound 14 was identified on the basis of characteristic resonances in the 19 F (δ 43.7, t, 3 J HF = 1.5 Hz), 1 H (δ 3.84, d, 3 J HF = 1.5 Hz), and 13 C{ 1 H} NMR spectra (δ 39.2, d, 2 J CF = 54 Hz, CH 2 ; 162.1, d, 2 J CF = 362.3 Hz, COF) matching those previously reported. 84 Monitoring the reaction by NMR spectroscopy demonstrated that [13] and 14 were formed at approximately the same rate. Compound 14 was isolated by sublimation and proved to be highly moisture sensitive.
The formation of 14 is somewhat surprising as it appears that either fluoro-or phenyl-migration must have occurred. Given that the reaction of [3a]BF 4 with NCMe did not give rise to the alkyne FCuCPh and [9]BF 4 (which would also require  F or Ph migration) it might be presumed that these are highenergy pathways in this system, although phenyl-migration in di-substituted vinylidene complexes is well established. 64,[85][86][87][88] In order to gain further mechanistic insight into this process, the 13 [15] and the α-fluoroaldehyde 16 (identified by resonances in the 1 H and 19 F NMR spectra at δ 9.72 (dd, 3 J HF = 7.6 Hz, 5 J HH = 0.7 Hz and δ −191.7 (dd, 2 J HF = 47.0 Hz, 3 J HF = 7.6 Hz) respectively) was observed, Scheme 5c. 89 Over the course of 6 days the resonances for 16 decreased in intensity to be replaced by those for 14. It is proposed that anti-Markovnikov hydration of the vinylidene [77][78][79]82 occurs to give 16 which then undergoes a slower isomerisation to 14. DFT calculations indicate that 16 is 97 kJ mol −1 higher in energy (ΔG 298 ) than 14 so this conversion is thermodynamically favoured and aldehydes such as 16 have been reported to be unstable. 90 The overall process is summarised in Scheme 5d.
The reaction of metal alkynyl complexes (derived from terminal alkynes) with "F + " followed by hydrolysis and liberation of α-fluoroaldehydes represents a stepwise functionalization of alkynes with the incorporation of both new functionality and the generation of a new stereocentre. This type of reactivity is highly desirable as the fluorinated vinylidene ligands are effectively acting as synthetic equivalents of 1-fluoroalkynes. Work is underway in our groups to exploit these stoichiometric observations for the development of catalytic protocols for combined alkyne functionalization and fluorination.

Conclusions
The reaction between alkynyl complexes [1] and electrophilic fluorinating and trifluoromethylating agents offers a highly selective and simple route for the direct formation of C-F and C-CF 3 bonds and the construction of novel fluorinated vinylidene ligands. Although the addition of other electrophiles to alkynyl complexes has been reported, it is remarkable that the highly oxidising sources of "F + " result in selective C-F bond formation rather than direct fluorination of the metal complexes. These data demonstrate that OSEF (or analogous trifluoromethylation) represents a complementary approach to current metal-mediated routes for electrophilic C-F bond formation and may be applicable to a range of organometallic systems.
As the new fluorinated ligands were retained within the coordination sphere of ruthenium it was possible to evaluate the effects of incorporation of the fluorine and explore subsequent reactivity. Reactions of fluorovinylidene complexes with nucleophiles such as pyridine and water show many similarities to the reactivity of non-fluorinated vinylidenes. As these 25 are important intermediates in a range of metal-catalysed reactions, this suggests that access to fluorinated analogues offers new opportunities for the formation of novel fluorinated organic compounds without re-writing the rule book in terms of their reactivity. Indeed, our observation of anti-Markovnikov hydration of fluorovinylidenes, a key reaction of non-fluorinated analogues, to form both new functionality and a new stereocentre in the α-fluoroaldehyde products supports this argument. In addition to applications in synthesis, the introduction of fluorine into ligands of organometallic complexes may significantly alter metal-ligand bonding and, for example, may be used to blue-shift the emission from luminescent iridium complexes. [91][92][93][94] In summary, it has been demonstrated how OSEF allows for the facile formation of C-F (and C-CF 3 bonds) in metal alkynyl complexes to be achieved and that C-F bond cleavage, assisted by a pyridinium salt, may occur from the β-position of an organic ligand.