breaking c–f bonds via nucleophilic attack of coordinated ligands: transformations from c–f to...

Breaking C−F Bonds via Nucleophilic Attack of Coordinated Ligands:Transformations from C−F to C−X Bonds (X= H, N, O, S)Ainara Nova,† Ruben Mas-Balleste,‡ and Agustí Lledos*,§

†Institute of Chemical Research of Catalonia (ICIQ), Avinguda Paısos Catalans 16, 43007 Tarragona, Spain‡Departamento de Quımica Inorganica, Universidad Autonoma de Madrid, 28049 Madrid, Spain§Departament de Quımica, Universitat Autonoma de Barcelona, 08193 Cerdanyola del Valles, Barcelona, Spain

ABSTRACT: In this review, transformations of C−F to C−X bondsmediated by transition-metal complexes are considered from the ligand’sperspective. In C−F bond activation reactions, the ligands (L) bondedto transition-metal complexes can act as spectators but can also assist thereaction. The latter case is important in the heterolytic cleavage of C−Fbonds by nucleophilic addition reactions. When L is an electrophile (E),the assistance of the ligand facilitates the fluoride departure when the metal attacks at C. In contrast, when L is a nucleophile (X),the ligand is responsible for the nucleophilic addition and the reaction leads to a new C−X bond, allowing the direct func-tionalization of C−F bonds. This article presents an overview of the reactions that are initiated by the nucleophilic attack of acoordinated ligand (a hydride or an N-, O-, or S-nucleophile) to a CF carbon resulting in formation of a new C−H, C−N, C−O,or C−S bond. The possible mechanisms are discussed. The attack of a nucleophilic ligand at the electrophilic carbon of a C−Fbond is comparable to fluoride elimination by organic nucleophiles. However, the presence of the metal center introduces newfeatures in this process, both in the selectivity and in the thermodynamics. Herein these effects are analyzed. Thus, the aim of thisreview is to show how these kinds of processes put together the best of both organic and inorganic worlds in order to achieve awide range of reactions with fluorinated compounds.

1. INTRODUCTIONCarbon−fluorine bonds are among the most inert function-alities in chemistry,1 and their selective activation and transfor-mation under mild conditions remains as a challenging goal.Despite these difficulties, the fact that a wide variety ofpharmaceuticals and materials contain fluorinated compounds2

fueled intense research into C−F bond activation andsignificant achievements have been obtained in the past fewyears.3 However, much work remains to be done to establishC−F bond activation routes as a general synthetically usefulstrategy to access to functional fluorinated compounds.4

Although the main drawback for this process was supposedto have thermodynamics as its origin, it has gained acceptancelately the idea that the lack of reactivity of the C−F bond ismainly of kinetic origin.5 While the C−F bond is the strongestsingle bond to carbon, the bonds that fluorine forms after itsbreaking (H−F, P−F, Si−F, B−F, M−F, ...) are as strong oreven stronger than C−F and the energy cost for breaking a C−Fbond can be recovered by formation of a E−F bond.6 Thus, themain goal in C−F bond activation is to devise syntheticstrategies allowing the C−F bond breaking with low barriers. Tothis aim, the use of transition-metal complexes has been widelypursued, as demonstrated in this special issue of Organometallics.There are several strategies for C−F bond activation based

on the reactivity of transition-metal complexes. Scheme 1 sum-marizes the different alternatives classified by the final prod-ucts obtained. These products can incorporate both a metal−carbon and a metal−fluoride bond or only one new bond(metal−carbon or metal−fluoride). In the presence of ligands

or additives able to trap fluoride (E), E−F species can be alsoformed. When X− species or ligands are present, the formation ofC−X bonds can go together with the formation of the [M]−Fbond. The high stability of the reaction products mainly deter-mined by the strength of the M−F bond is the driving force forsome of these reactions but is also the main drawback to usethese kinds of transformations as synthetic strategies. Processesleading to M−C bond formation are usually fueled by the highstability of E−F bonds. The challenge to convert these processesinto synthetically useful reactions consists on further function-alization of the M−C bond, which is not always easy to achieve.In an ideal synthetic route the C−F rupture should go along withC-functionalization entailing simultaneous C−X formation.Despite its strength, the C−F bond has a weakness in its high

polarity.7 The polar character of the C−F bond offers routes for

Special Issue: Fluorine in Organometallic Chemistry

Received: October 25, 2011Published: November 29, 2011

Scheme 1. General Classification of C−F Bond ActivationProcesses Considering the Final Products of the Reactions

Review

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its heterolytic rupture. Nucleophilic substitution of the fluo-ride anion by organic nucleophiles is a strategy widely followed(Scheme 2). Recent reviews show a vast amount of work done

in this direction.3a In fact, the C−F bond is often the easiestC−halogen bond to be activated by nucleophilic aromatic sub-stitution (addition + elimination), which is the trend oppositeto that observed in the SN2 reactions of aliphatic halides.8 Thistendency is a consequence of the major polarity of this bond thatfacilitates the addition step, which usually is the rate-determiningstep in SNAr. Organic nucleophiles able to activate C−F bondsare usually sulfur-, oxygen-, and nitrogen-based systems.8 How-ever, selectivity using organic nucleophiles is the main challenge,because the control of the number and position of fluorine atomsto be activated is not always easy to achieve.9

Confronting a polar carbon−fluorine bond with a metal−ligand bond that is also polar opens appealing reaction routes:a nucleophilic metal can attack the electrophilic carbon of theC−F bond (Scheme 3, left), but when a coordinated ligand isnucleophilic enough, it can also attack the C−F carbon atom(Scheme 3, right).

The attack of nucleophilic metal centers at the C−F bondresults in the formation of compounds with stable M−C bondsand fluoride release. It requires further assistance by an electro-phile which traps the leaving fluoride. A coordinated ligand canplay the same role. In this direction a novel mechanism foraromatic C−F bond activation has been characterized involvingthe addition of a C−F bond across a [M−PR3] moiety via afour-membered transition state. This phosphine-assisted C−Fbond activation is initiated by nucleophilic attack of the electron-rich metal center (Pt, Ni, Ir) at the electrophilic carbon atomwith concerted fluoride transfer to the accepting phospine ligandwith Lewis acid character.10 A similar boryl-assisted pathway thatinvolves nucleophilic attack of rhodium with concerted transferof fluorine onto the boron center of a Bpin ligand (Bpin =pinacolboryl) has been recently characterized by DFTcalculations.11

The attack of a nucleophilic ligand at the electrophilic carbonof a C−F bond is reminiscent of fluoride elimination by organicnucleophiles, resulting in the transformation of a C−F bond toa C−X bond. However, the presence of the metal introducesnew features in this process, both in the selectivity (it can directthe attack toward a specific position of a fluoroaromatic ring)

and in the thermodynamics (the leaving fluoride can end upcoordinated to the metal center). These reactions constitute anoteworthy example of the role that coordinated ligands canplay in metal-based C−F bond activations and are susceptibleto be employed in useful synthetic transformations. Although anumber of C−F bond activation processes described in theliterature could suit this mechanistic description, few of themhave been the object of detailed mechanistic studies. Moreover,the literature on this topic is quite dispersed and C−F bondactivation has not been reviewed from this perspective.In this review the C−F bond activation with transition-metal

complexes will be considered from the ligand’s perspective.The article will focus on the reactions that are initiated bythe nucleophilic attack of a coordinated ligand (a hydride or aN-, O-, or S-nucleophile) at a CF carbon, resulting in formationof a new C−H, C−N, C−O, or C−S bond. These reactionsimply the cleavage of a C−F bond but also the transfer ofcoordinated ligands to the organic substrate. The followingsections present general mechanistic trends and prototypicalexamples of each transformation, classified by the nature of thenucleophilic ligand, offering a general overview of a growingfield in the area of metal-mediated organic transformations.

2. GENERAL ASPECTS OF REACTION PATHWAYS ANDMECHANISMS2.1. General View of the Mechanisms. This review

looks at the C−F bond activation process from the ligand’sviewpoint. The general mechanisms describing the reactionscovered in this review are represented in a simplified manner inScheme 4. The specific examples and references that apply to

this scheme are presented in sections 3 and 4 of this review.The essential differences between the two pathways are the geom-etry in which the nucleophilic ligand attacks the C−F bond, thepassive or active role of the metal center, and the fate of theleaving fluoride.

2.1.1. Pathway a. This mechanism consists on the directattack of the nucleophilic ligand to the C−F carbon bond, whichimplies the concerted cleavage of C−F bond and formation ofa C−X bond. It can be described as SN2 or SNAr dependingon the substrate activated. Thus, orientation of the nucleophilicattack can vary. Due to the inherent inertness of C−F bonds, itis difficult to generate carbocationic species as a result of C−Fcleavage previous to nucleophilic attack, precluding SN1 path-ways. Thus, SN2 processes are expected. Indeed, the examplesstudied suggest a transition state in which the entering nucleo-phile replaces the leaving fluoride. According to the SN2 mechanism,the transition state should present an X−C−F angle close to180° and X···C and C···F distances in the midway of formationand cleavage, respectively. Given the generally observed inabilityof the F− ion to act as the leaving group in SN2 reactions, these

Scheme 2. Nucleophilic Attack at the C−F Bond

Scheme 3. Possible Nucleophilic Attack of a Metal−LigandBond at a C−F Bond

Scheme 4. General Scheme of Mechanisms Followed ToActivate C−F Bonds by Means of Nucleophilic Attack ofCoordinated Ligands

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kind of reactions should be assisted by the stabilization offluoride anion by any of the strategies presented in section 2.2.When the organofluorate substrate is an aromatic molecule,the mechanism of this reaction can be described as an aromaticnucleophilic substitution (SNAr). This mechanism is usuallybelieved to follow a two-step process: addition of the nucleophileto the aromatic ring, forming the so-called Meisenheimer inter-mediate, and elimination of the leaving group.12 However, in manycases such intermediate is not a real intermediate, but instead, itis the transition state.13 In any case, if it is not a transition state,the Meisenheimer complex is a high-energy intermediate specieswhich usually cannot be isolated or even detected.2.1.2. Pathway b. An alternative mechanism consists of a

concerted pathway where the nucleophilic ligand is transferredfrom the metal onto the fluoroorganic substrate and the dis-placed fluorine migrates directly to the metal center. The transi-tion state for this process involves the direct C−F bond acti-vation with a metal center with an available coordination site.The structure of such a transition state is described as a four-membered ring where the C−F fragment is oriented in a side-on fashion with respect to the metal center. In this transitionstate, one M−F and one C−X bond are in the midway of beingformed and one C−F and one M−X bond are being cleaved.Alternatively, this mechanism can be viewed as a four-electron−four-center σ-bond metathesis. The key point in this process isthat the vacant site at the metal center is now readily availableto directly accept the displaced fluoride leaving group. In thiscase, stabilization of fluoride anion is achieved by M−F bondformation and no additional assistance is required for this reac-tion. Preference for pathway a or b is determined by the existenceof a coordination vacancy in the metal center. Thus, coordinativelysaturated metal centers will proceed through pathway a if enoughstabilization for the F− leaving group is available.2.2. Collecting the Pieces after the Attack: Consider-

ations about the Final Fate of the Fluorine Atom. Activationof C−F bonds by means of nucleophilic attack is an overallquite unfavorable process. Thus, the high thermodynamic andkinetic inertness of C−F should be somehow over-come. On this way, generation of free fluoride anions is usuallynot feasible and the fluoride leaving group should be stabilized.Different strategies to reach this goal have been reported, whichare shown in Scheme 5. In general, it is required that an electro-philic group interact with fluoride anions.

When a coordination site is available in the coordinationsphere of the metal center, the departure of fluoride is stabilizedby formation of a M−F coordination (eq a in Scheme 5). It isworth mentioning that the formation of M−F bonds does not

necessarily imply an oxidative addition pathway, which, bydefinition, implies an increase of the oxidation state of themetal center. When a coordinated ligand acts as a nucleophile,even if an M−F bond is formed, the oxidation state of metalcenter remains unaltered. The inertness of M−F bonds is onone hand a powerful driving force for C−F bond activation. Onthe other hand, this inertness often precludes recycling of themetal compound in catalytic cycles.Different alternatives to M−F bond formation have been

described. The most common of these are the consequence ofthe high stability of H−F or Si−F bonds (eqs b and c inScheme 5).6 Protons are available to form HF in acid media orprotic solvents. In this case, protonation of the fluoride leavinggroup pushes the reaction. On the other hand, the proton inHF can be originated by hydride transfer from the metal com-plex. In order to force the reaction to proceed is also verycommon addition of silanes14 or aluminates15 of formulas R3SiHand R2AlH that act as hydride donors and as fluoride acceptors.Thus, in the case of hydrodefluorination, the stoichiometricreagent that acts as a generator of metal hydrides is thecorresponding silane or aluminate that produces stoichiometricamounts of R3SiF and R2AlF as subproducts. PPh3 has also beenadded to trap the fluoride to form Ph3PF2.

16

In a recent report, it was shown that the presence of a lithiumcation in solution assisted the nucleophilic attack of alkyl groupsat 3,3-difluoropropenes (eq d in Scheme 5).17 This effect isattributable to the formation of insoluble lithium fluoride, whichpushes the equilibrium toward the formation of fluoride anionacting as a leaving group. Despite the fact that this effect is, at thismoment, only observed in reactions of organolithium specieswith difluoropropenes, it could be exported to different metal-based C−F bond activations.All the synergic effects presented above consist of the for-

mation of strong E−-F bonds. However, a more subtle effecthas been reported, which can be described as supramolecularassistance of a SN2 process in which the fluorine atom acts as aleaving group. In particular, cleavage of the Csp

3−F bond in 1,3-difluoro-2-propanol by nucleophilic attack was mediated by theOH group in assisting the departure of the fluoride anion bymeans of hydrogen bonding (eq e in Scheme 5).18 In this case,the assistance was provided by an OH group enclosed in thestructure of the substrate. However, inspired by these findings,different strategies can be envisaged. One could be the additionof protic molecules able to establish hydrogen bonding withfluoride leaving groups. On the other hand, ligand design couldallow introducing proton donor groups in the secondary coordina-tion sphere of metal centers. In fact, a similar approach hasbeen reported for supramolecular assistance in O−O activationin metal−porphyrin compounds.19

3. NUCLEOPHILIC ATTACK BY LIGANDS CONTAININGS-, O-, OR N-DONOR ATOMS

3.1. S-Nucleophiles. Sulfur-containing species such asthiolate (RS−) and polysulfide (Sn

2−; n = 1−3) anions havebeen found to activate the C−F bond in organic compounds.Such processes can be understood as nucleophilic substitutionof the fluoride anion by the organic nucleophile with formationof a C−S bond. This reaction has found synthetic applicationswith fluoroaromatic compounds, including heteroaromatics, thereactions with which often proceed smoothly under mild condi-tions.20 Recent reports demonstrate that sulfide anions coordi-nated to metal centers can act similarly.

Scheme 5. Different Strategies To Stabilize the FluorideLeaving Group



It has been reported over the past decade that sulfur atomsin the {Pt2S2} core of [L2Pt(μ-S)2PtL2] complexes can act aspowerful nucleophiles toward metal centers, protic acids, andorganic electrophiles.21 This behavior was rationalized by theanalysis of the electronic structure of such compounds show-ing a high electron density located on the bridging sulfurligand.22 In particular, [L2Pt(μ-S)2PtL2] compounds weredescribed to cause cleavage of C−X (X = Cl, Br, I) bonds.23

Prompted by these results, we explored the reactivity of [Pt2(μ-S)2-(dppp)2] (dppp = 1,3-bis(diphenylphosphino)propane) witharomatic24 and aliphatic18 fluoro compounds. A summary of theexperimental results proving that the reactivity of the {Pt2S2}core can be extended to the activation of aromatic and evenaliphatic C−F bonds is presented in Scheme 6.When an excess of perfluoropyridine is added to a solution of

[Pt2(μ-S)2(dppp)2] in toluene at 0 °C, p-C−F bond activationtakes place, giving [Pt2(μ-S)2{μ-(p-SC5F4N)(dppp)2]. Treat-ment of [Pt2(μ-S)2(dppp)2] with an excess of perfluorobenzenein toluene under harsher conditions (toluene reflux for 5 days)yielded [Pt(o-S2C6F4)(dppp)], resulting from the activation oftwo C−F bonds in ortho positions in perfluorobenzene, and[Pt3(μ-S)2(dppp)3]F2.

24 The high nucleophilicity of the sulfuratoms in [Pt2(μ-S)2(dppp)2] triggers a Csp

3−F activation processin 1,3-difluoro-2-propanol in toluene reflux that leads to the[Pt2(μ-S)2{μ-p-SCH2CH(OH)CH2F}(dppp)2]F product.18

In all the cases the C−F bond activation is accompanied bythe formation of carbon−sulfur bonds. The mechanism of theseC−F bond activation processes was disclosed by DFT studies,which demonstrated the nucleophilic substitution character ofthe C−F bond activation by the {Pt2S2} core and unraveled thesubtle differences in this common mechanism, depending onthe substrate specificities.A DFT study of the reaction of [Pt2(μ-S)2(dppp)2] with per-

fluoropyridine (pfp) and perfluorobenzene (pfb)18,24 revealedthat for both substrates the reaction takes place through an aro-matic nucleophilic substitution (SNAr) mechanism. This mecha-nism is usually believed to follow a two-step process: additionof the nucleophile to the aromatic ring, forming the so-calledMeisenheimer intermediate, and elimination of the leaving

fluoride. However, in this case, the Meisenheimer complex isnot a real intermediate; instead, it is the transition state.13 Thereaction initiates with the attack of the bridging sulfido ligand in[Pt2(μ-S)2(dppp)2] at one carbon atom of the aromatic ringand the concomitant departure of the fluoride anion. The geom-etries depicted in Figure 1 agree with a half-broken C−F bondand a half-formed C−S bond in the transition-state structures.

The energy profiles in toluene shown in Figure 2 account forthe different experimental conditions and evolution of the reac-tion with perfluoropyridine and perfluorobenzene. The first C−Fbond activation (via TS1) is much easier in pfp than in pfb(energy barriers of 20.6 and 31.6 kcal mol−1, respectively).This difference between the energy barriers of pfb and pfpin the first fluoride substitution is not observed for the secondsubstitution. Thus, the energy barrier to activate the second

Scheme 6. Reactions between [Pt2(μ-S)2(dppp)2] and Aromatic and Aliphatic Fluoro Compounds

Figure 1. Geometries of transition states TS1 (top) and TS2 (bottom)for the first and second nucleophilic attacks of [Pt2(μ-S)2(dppp)2] atperfluoropyridine. Distances for the analogous transition states withperfluorobenzene are given in parentheses.



C−F (via TS2) in perfluoropyridine is 32.5 kcal mol−1, similarto that calculated for pfb (31.9 kcal mol−1). This energy barriercan not be surpassed under the experimental reactionconditions with pfp (0 °C), and consequently the reactionstops after the first C−F bond activation, giving the X-raycharacterized product [Pt2(μ-S){μ-p-SC5F4N}(dppp)2]

+.25 Thesimilar barriers found in the second C−F bond activation forpfp and pfb point out that, in contrast to the first activation, inwhich the barrier height is determined by the substrate nature,the second activation barrier is governed by the decreasednucleophilicity of the bridging sulfur in the monoarylatedproduct of the first C−F bond activation.26

The reaction with perfluorobenzene was performed underharder conditions (toluene reflux, 5 days). In this way enoughenergy has been given to the system to overcome the secondbarrier (TS2) and a second C−F nucleophilic substitution takesplace. The fragmentation of the product obtained (min2) results information of the experimentally characterized products (Scheme 6).Nucleophilic aromatic substitution in pyridines is favored at

the ortho and para positions, because then the negative chargeis effectively delocalized at the nitrogen position. It is well estab-lished that in general the order of activation of pentafluoropyr-idine toward nucleophilic attack follows the sequence 4-fluorine >2-fluorine > 3-fluorine.9,27 In agreement with a SNAr mecha-nism in the product of the reaction with perfluoropyridine thesubstitution has occurred at the para position of the ring. Wehave also computed the profile for the C−F bond activationtaking place at the ortho position, finding a higher barrier (28.5kcal mol−1, vs 20.6 kcal mol−1 for the para activation) and a lessstable product (o-min1 6.7 kcal mol−1 above p-min1). Thus,para substitution of pfp is preferred both kinetically andthermodynamically.Despite the fact that fluoride is not a good leaving group, the

barrier for its elimination is decreased when the leaving F− isable to interact with species that can stabilize its negative charge.In this way, the leaving fluoride is stabilized by interaction with

the aliphatic chain of the phosphine in TS1 and TS2 (F···CH inter-actions) and the eliminated fluoride is placed near the phosphine Patoms in the ion pair products min1 andmin2 (F···P interactions).We explored theoretically the C−F bond activation process

in 1,3-difluoropropanol that leads to the [Pt2(μ-S)2{μ-p-SCH2-CH(OH)CH2F}(dppp)2]F product.18,28 The calculated barrierin toluene is high (36.6 kcal mol−1), in agreement with the experi-mental conditions required for the reaction of [Pt2(μ-S)2(dppp)2]with 1,3-difluoro-2-propanol. The transition state for this reaction,shown in Figure 3, agrees with a SN2 mechanism where the

entering nucleophile is the bridging sulfur ligand that replacesthe leaving fluoride. According to the SN2 mechanism the anglebetween the entering and leaving nucleophiles in the transitionstate is close to 180° (S−C−F angle of 171.9°).Given the generally observed inability of the F− ion to act as

a leaving group in SN2 reactions, the proposed pathway is unusualfor activating C−F bonds. Two reasons account for the suitabilityof a SN2 mechanism to operate in this system: the outstandingnucleophilicity of the {Pt2S2} core and the assistance of non-covalent interactions in the departure of the fluoride anion.Indeed, inspection of the transition-state geometry shows that

Figure 2. Energy profiles (in kcal mol−1) in toluene for the C−F bond activation with [Pt2(μ-S)2(dppp)2] of perfluorobenzene (red) andperfluoropyridine (blue).

Figure 3. Geometry of the transition state for the nucleophilic attackof [Pt2(μ-S)2(dppp)2] at 1,3-difluoropropanol.



the presence of the OH group stabilizes the transition state bymeans of a strong F···OH hydrogen bond that provides anelectrophilic assistance to the C−F cleavage. The role of theOH group in the fluoride elimination was also evaluated byattempting the reactivity of [Pt2(μ-S)2(dppp)2] toward 1,3-difluoropropane in which the OH group is absent. No reactionwas observed. The energy of the calculated transition state(about 40 kcal mol−1)23e is higher than that of 1,3-difluoro-2-propanol. Although the S···C bond-forming and C···F bond-breaking distances (2.372 and 2.035 Å, respectively) are similarto those for 1,3-difluoropropanol (Figure 3), a much greaterdeviation of the S−C−F angle (156.5°) from the ideal value of180° is found. The reason for such behavior is that, in theabsence of an alcohol group, the leaving fluoride anion is positionedto be slightly stabilized by weaker C−H···F interactions with thealkyl chain of the chelating diphosphine ligand.Overall, the combined experimental and theoretical study of

C−F bond activation by [Pt2(μ-S)2(dppp)2] proves the viabilityof nucleophilic substitution mechanisms with metal-bonded S-nucleophiles to achieve the C−F bond activation of aromaticand activated aliphatic substrates. Stabilization of the leavingfluoride seems to be crucial in these processes. This stabiliza-tion is achieved by H-bonding (in the case of 1,3-difluoro-propanol) or C−H···F and P···F interactions (in the case of pfpor pfb).Recently reported C−F bond activations that produce C−S

bond formation for which no mechanistic data are availablecan also be analyzed as nucleophilic attack of S-nucleophiles atC−F bonds (Scheme 7).

Arroyo and Torrent found that the thermolysis reaction ofthe osmium(III) complex [Os(SC6F5)3(PMe2Ph)2] in refluxingtoluene causes cleavage of ortho C−F bonds, affording[Os(SC6F5)2(S2C6F4)(PMe2Ph)].

29a They proposed that a nucleo-philic attack of a thiolate sulfur atom at the carbon atom ofan activated o-C−F bond took place. Then, the same authorsfurther developed this reaction, reporting thermal reactions of[Os(SC6F5)4P(C6H4X)3] (X = CF3, Cl, F, H, CH3, OCH3) inrefluxing toluene in which the starting thiolate ligands (SC6F5)

−

are transformed into C6F5SC6F4S.29b When X = H, the thermo-

lysis reaction involves the rupture of the ortho C−F bond fromthe original SC6F5 ring with C−S bond formation to generatenew complexes with a sulfido ligand and an Os−F bond as thefirst observed and isolated complexes (Scheme 7, top). A plausiblemechanism for such a transformation entails nucleophilic attackby a thiolate sulfur atom at the electrophilic ortho carbon of theadjacent ligand with fluoride elimination and trapping of theleaving fluoride by the metal.30

A significant contribution to the development of aromaticC−F substitutions allowing substitution of C−F by C−S bondsin a catalytic way was reported by Yamaguchi and co-workers.16

They communicated that in the presence of [RhH(PPh3)4] and1,2-bis(diphenylphosphino)benzene (dppBz) fluorobenzenederivatives with electron-withdrawing groups react in refluxingchlorobenzene with disulfides to give the corresponding arylsulfides in high yields (Scheme 7, bottom). Fluorobenzene wasinert under the reaction conditions employed, indicating theimportant role of electron-withdrawing groups. Added PPh3traps the fluoride to form PPh3F2.

16 Nucleophilic aromatic sub-stitution of the aryl fluoride with rhodium thiolate was proposedas a possible pathway for this process.

3.2. O-Nucleophiles. The ability of hydroxyl, alkoxy, andaryloxy groups to replace fluorine in organofluorine compounds bymeans of nucleophilic substitution processes is well documented.31

Although the mechanism of the set of reactions involvingtransition-metal complexes depicted in Scheme 8 has not been

established, these reactions could operate through a nucleo-philic attack of the coordinated O-nucleophile at the ortho car-bon of the fluorinated ring. These processes cause eliminationof fluorine from fluorinated aromatic compounds to form C−Obonds.In the early 1990s, Roundhill reported that the complex

trans-[PtMe(THF)(PPh2C6F5)2]+ reacts with hydroxide ions at

ambient temperature to form the oxocarboplatinum complextrans-[PtMe(2-OC6F4PPh2)(PPh2C6F5)] (Scheme 8, top). Theoxoplatinacycle product complex has been formed from nucleo-philic attack by OH− at the ortho carbon of the pentafluoro-phenyl ring, followed by deprotonation to yield the product.32

Methoxide ion can be expected to show reactivity similar to

Scheme 7. C−F Bond Activation Processes in the Presenceof Transition-Metal Complexes and S-Nucleophiles

Scheme 8. C−F Bond Activation Processes in the Presenceof Transition-Metal Complexes and O-nucleophiles



that of hydroxide ion, except that now it is unlikely that C−Ocleavage will occur to give the oxaplatinacycle. Accordingly,treating trans-[PtCH3(THF)(PPh2C6F5)2]

+ with excess sodiummethoxide resulted in the formation of the complex trans-[PtCH3(OCH3)(PPh2C6F3(OCH3)2-2,6)2] where all the orthofluorines have been replaced by methoxides.No reaction occurs between uncomplexed PPh2C6F5 and

aqueous KOH. The fluoride ortho substitution is therefore inducedby phosphine coordination to platinum. The substitution patternobserved between trans-[PtMe(THF)(PPh2C6F5)2]

+ and theO-nucleophiles (only the ortho fluorines are replaced by themethoxy group) agrees with an intramolecular nature of thesesubstitution reactions. An easy initial substitution of a THF ligandby a hydroxyl or methoxy ligand places the O-nucleophile in closeproximity to the fluorine at the 2-position of the pentafluorophenylgroup of the coordinated phosphine. Subsequent intramolecularnucleophilic attack of the OR− ligand at the electrophilic carbonresults in substitution (Scheme 9).

Braun described the reactivity of [PdMe2(L-L)] (L-L =Me2NCH2CH2NMe2, Cy2PCH2PCy2) toward pentafluoropyridinein the presence of water.33 The pyridyloxy complexes [PdMe-(OC5NF4)(L-L)] are formed by C−F bond activation at the4-position of the heteroaromatic ring (Scheme 8, middle). Aplausible mechanism invokes initial palladium-mediated nucleophilicattack of fluorine by a hydroxyl group, similar to that depicted inScheme 9. The observed preference for C−F bond activation at the4-position of pfp, which is the vulnerable position for nucleophilicattack,9,27,34 is a good indication that the reaction likely proceedsthrough this pathway.The formation of [Os(SC6F4H)2(2-OSC6F3H)(PPh3)] from

[Os(SC6F4H)4(PPh3)] and KOH implies the cleavage of an o-C−Fbond at a SC6F4H ligand and its simultaneous replacement by anoxygen atom with the formation of a thiolate-phenoxide ligand(Scheme 8, bottom).35 The reaction could also proceed bynucleophilic displacement of o-fluorine by OH− similarlyto the mechanism shown in Scheme 9 for the formation ofthe oxaplatinacycle.Hughes reported that treatment of the perfluorobenzyl rho-

dium complex [Cp*Rh(PMe3)(CF2C6F5)(I)] with moist silveroxide affords the oxametallacycle [Cp*(PMe3)Rh(OC6F5CF2)].

36

Two possible mechanisms have been proposed for this trans-formation, both involving nucleophilic attack from a OH−

(coordinated or not) at the ortho position of the perfluoro-benzyl ring, causing HF elimination to give the observedproduct. The proposed intramolecular mechanism is shown inScheme 10.3.3. N-Nucleophiles. Despite the fact that it is well docu-

mented that both nonaromatically and aromatically bondedfluorines can be substituted by organic N-nucleophiles as aminesand amides,37 the reactivity of such nucleophiles in transition-metal

systems regarding C−F bond activation has hardly been explored.In most of the cases describing the formation of C−N bonds fromsubstitution of fluorines by N-nucleophiles C−F bond activationwas not the goal.Roundhill extended the study of the reactions of (penta-

fluorophenyl)phosphine platinum complexes with oxygen nucle-ophiles to the reaction with amide ions.32 The complex trans-[PtMe(THF)(PPh2C6F5)2]

+ reacts with sodium amide to yield thecyclometalated complex trans-[PtMe(2-NHC6F4PPh2)(PPh2-C6F5NH2)] (Scheme 11, top). The reaction with amide anioncan follow an pathway analogous to that outlined in Scheme 9.

Deck has reported C−F bond activation reactions of perfluoro-aryl-substituted metallocenes with tetrakis(dimethylamido)-titanium(IV) (Scheme 11, bottom).38

[Ti(NMe2)4] reacts with 3-(pentafluorophenyl)indene and(pentafluorophenylcyclopentadiene) via intramolecular, nucleo-philic substitution of the ortho C−F groups by Ti−NMe2 groupsto afford aminated arylindenes and arylcyclopentadienes. Thiswork demonstrated that aryl C−F bonds positioned in closeproximity to the inner coordination sphere of early-transition-metalamides can be subject to nucleophilic C−F bond activation.Analogous fluoride/amine exchanges, upon complexation offluoroaryl-substituted tripodal amine ligands to molydnemum39a andhafnium,39b have been reported by Schrock. In the latter examplethe hafnium source was [Hf(NMe2)4] and its reaction with freeligand led to compounds in which one or two dimethylaminogroups had been exchanged with one or two ortho fluorides on the2,6-difluorophenyl rings.The reaction of the imidozirconocene complex [Zr]NCMe3

with pentafluoropyridine, resulting in activation of the ortho C−Fbond and yielding an N,N-bidentate 2-NCMe3C5F4N ligand and aZr−F bond,40 could also be explained on the same grounds.

Scheme 9. Suggested Mechanism for the Reaction of trans-[PtMe(THF)(PPh2C6F5)2]

+ with Oxygen (X = O) andNitrogen (X = NH) Nucleophiles

Scheme 10. Possible Intramolecular Mechanism for theFormation of [Cp*(PMe3)Rh(OC6F5CF2)]

Scheme 11. C−F Bond Activation Processes in the Presenceof Transition-Metal Complexes and N-Nucleophiles



4. NUCLEOPHILIC ATTACK BY HYDRIDE LIGANDS:HYDRODEFLUORINATION

Hydrodefluorination reactions have great interest not onlyfrom a synthetic point of view but also in the detoxificationof halogenated pollutants. These reactions can be performedby heterogeneous or homogeneous catalysis, and dihydrogen,hydrosilanes, or metal hydrides can be used as hydride sources.3a

In the cases where transition-metal hydrides are used, a widerange of different mechanisms have been proposed: from elec-tron transfer reactions to oxidative addition/reductive elimination,insertion/β-elimination, and nucleophilic addition processes.3a,30

Discrimination between these mechanisms is, in many cases,difficult due to the impossibility of detecting intermediates.Therefore, selection of those processes where the hydride acts asthe nucleophile is, in many times, limited to those cases wherethe other mechanisms can be discarded. For instance, complexesthat cannot be oxidized are good candidates for these reactions.However, the clearest selection is made on the basis of theo-retical calculations, which permit characterizing not only highlyreactive intermediates but also the transition states. In addition tothe reactions that clearly follow a nucleophilic addition mecha-nism, in this section we have included reactions where a σ-bondmetathesis mechanism has been proposed. These cases can beconsidered as nucleophilic addition of hydride with assistance ofthe fluoride departure by the metal in a concerted way.Early transition metals such as Ti, Zr, and Hf have been

shown to be efficient reagents for C−F to C−H transformation.In particular, metallocene zirconium dihydride complexes havebeen exhaustively studied by the group of Jones, showing a veryrich chemistry not only for the number of substrates that can behydrodefluorinated but also by the number of different mecha-nisms followed by these reactions.41 Oxidative addition reac-tions are not common with these complexes because they arenormally d0 species, which cannot be oxidized. Therefore, thenumber of possible mechanisms is reduced to radical reactionsand processes of insertion/β-elimination, nucleophilic addition,and σ-bond metathesis.With aromatic substrates, the insertion/β-elimination mech-

anism is normally discarded, due to the low stability of aryneintermediates. Instead, nucleophilic addition or σ-bond metathesishas been proposed. Distinguishing between these two mecha-nisms is difficult on the basis of experimental data; however, it hasbeen done in the hydrogenation of hexafluorobenzene42 and

fluorobenzene43 by [Cp*2ZrH2] (eqs a and b in Scheme 12).Formation of pentafluorobenzene in reaction a was proposed tofollow a σ-bond metathesis mechanism due to the hydridic characterof H and the strong fluorophilicity of Zr. The TS for this reaction isdepicted at the top of Scheme 13. In contrast, an SNAr2 mechanism

was proposed in the defluorination of fluorobenzene (eq b inScheme 12). In this case, the faster reaction observed for the morehindered 1-fluoronaphthalene compared to that for fluorobenzenesuggests the formation of an intermediate or TS, like that depictedin Scheme 13, where the resonance has decreased. A nucleophilicaromatic substitution mechanism has been also proposed for the

Scheme 12. Hydrodefluorination Reactions of Aromatic and Olefinic Substrates with [Cp2ZrH2]2 and [Cp*2ZrH2] Complexes

Scheme 13. Schematic Representation of the TransitionStates Proposed for the Defluorination Reactions ofAromatic and Olefinic Substrates by Zr Complexes



defluorination of B(C6F5)3 by [{rac-(ebthi)ZrH(μ-H)}2] (ebthi =1,2-ethylene-1,1′-bis(η5-tetrahydroindenyl)).44

In reactions a and b in Scheme 12, formation of [Cp2Zr(C6F5)F]or [Cp*2Zr(C6H5)F] could follow an oxidative addition path-way by [Cp2Zr] or [Cp*2Zr] intermediates. However, H2 doesnot alter the rate of the reaction. In addition, the hexafluoro-benzene and fluorobenzene do not react with sources of Zr(II),as has been observed with Zr(II) and Ti(II) sources with penta-fluoropyridine.45 This lack of reactivity makes it difficult toexplain the formation of [Cp2Zr(C6F5)F] or [Cp*2Zr(C6H5)F]products.With olefinic substrates, the mechanisms normally proposed

are insertion/β-elimination and σ-bond metathesis processes.In order to differentiate between these two pathways, theo-retical calculations are crucial in many cases, due to the highreactivity of the insertion intermediates. Some of the reactionsthat have been experimentally and computationally studied areshowed in Scheme 12, eqs c−e.In the defluorination of perfluoropropene by [Cp*2ZrH2]

(eq c, Scheme 12) internal and external σ-bond metathesis andhydride insertion were considered by DFT methods using[Cp2ZrH2] as a model system (Scheme 13).46 In this case, theTS for the internal and external metathesis pathways were locatedat 2.2 and 6.3 kcal mol−1, respectively, above the separated reac-tants. Although these energies are very low, that for the internalhydride insertion is lower, with a potential energy of −3.7 kcalmol−1 with respect to the separated reactants. The reactant in thiscase is not a η2 complex but an adduct formed by the two sub-strates, which is 5 kcal mol−1 below the reactants. This impliesan energy barrier for the internal insertion of only 1.3 kcalmol−1. This process is also highly exothermic, with an energyfor the inserted intermediate of −48.6 kcal mol−1. Then, theβ-fluoride elimination takes place with an energy barrier of8.9 kcal/mol, which explains why the reaction intermediate isnot observed. Overall, the mechanism proposed for the hydro-genation of perfluoropropene by [Cp*2ZrH2] is an insertion/β-elimination process. This mechanism has been also proposedfor the hydrogenation of CH2CHF with [Cp2ZrHCl] studiedby Caulton and co-workers.47

Preference for an insertion/β-elimination process changeswhen the substrate is a cycloalkene, instead of perfluoropro-pene, as has been demonstrated in a recent work by Jones andEisenstein.48 In this case, hydrogenation of perfluorocyclopen-tene and perfluorocyclobutene with [Cp*2ZrH2] yields theproducts shown respectively in eqs d and e in Scheme 12. Theproduct observed in the latter reaction clearly shows that aninsertion/β-elimination pathway cannot take place in this case.As shown in Scheme 14, this pathway would imply the observa-tion of a product with the hydrogen in an sp3 carbon. Instead,the product observed has the hydrogen atom on an sp2 carbon,which is only possible by a metathesis pathway. Theoreticalcalculations were performed in order to explain this preference.Comparing the results obtained with perfluoropropene withthose obtained with perfluorocyclobutene, it was found thatthe preference for σ-bond metathesis in the latter case was theresult of a greater reactivity of perfluorocyclobutane towardhydride nucleophilic attack and a greater influence of steric bulkin the insertion process, which is associated with the presenceof the saturated part of the cyclobutene. Indeed, the use of Cp*in the calculations is necessary in order to obtain a clear pre-ference for the σ-bond metathesis process.

Other group 4 transition metals such as Ti49 and Hf50 alsolead to hydrodefluorination catalysis. In both cases the mecha-nisms proposed are the same as those observed with Zr.With late-transition-metal systems, the reactions where a

nucleophilic addition of hydride (or σ-bond metathesis path-ways) is proposed are rare, due to their ability to undergo oxidativeaddition reactions and formation of M−C intermediates. However,a recent computational study has shown that the formation of anM−C bond is not in contradiction with a nucleophilic additionpathway.51 This study was carried out for the catalytic hydrogena-tion of pentafluorobenzene by [Ru(NHC)(PPh3)2(CO)H2](NHC = N-heterocyclic carbenes) shown in Scheme 15.52

Some features of this reaction are high regioselectivity for theortho-hydrodefluorination of pentafluorobenzene (92−98%)and a drop in activity when the solvent is changed from THF tobenzene. The formation of 1,2-C6F4H2 rather than the 1,4-isomer led the researchers to discard, in the first experimentalstudy,52 nucleophilic substitution and electron transferreactions where normally the activation of the C−F bond isobtained para to the electron-withdrawing group. Instead, themechanism initially proposed consisted of several steps,including the formation of a benzyne intermediate, in orderto account for the ortho regioselectivity. Benzyne formation hasbeen observed in the dehydrofluorination of fluorobenzene byTi alkylidynes.53 However, an ulterior theoretical study usingthe Ru catalyst [Ru(IMes)(PPh3)2(CO)H2] (IMes = 1,3-bis-(2,4,6-trimethylphenyl)imidazol-2-ylidene) showed that forma-tion of benzyne lies almost 50 kcal mol−1 above the reactants.

Scheme 14. Expected Products for the Reaction of[Cp*2ZrH2] with Perfluorocyclobutene

Scheme 15. Hydrogenation Reaction of PentafluorobenzeneCatalyzed by [Ru(NHC)(PPh3)2(CO)H2] Complexes



In contrast to this pathway, different alternatives based onnucleophilic addition of the Ru hydride were found to be morefavorable and consistent with the experimental observation.The lowest energy pathway is shown in Figure 4 with thepotential energies (in kcal mol−1) obtained in the gas phase.The hydrogenation of pentafluorobenzene by [Ru(IMes)-

(PPh3)2(CO)H2] starts by the substitution of PPh3 by thefluorinated substrate, which coordinated the metal in an η2

fashion. From this intermediate takes place the nucleophilicaddition of the hydride to the C−F bond ortho to C−H,yielding a {C6F5H2}

− moiety that resembles a Meisenheimerintermediate. This species is able to deliver fluoride easily,which instead of being stabilized by the media or the metalcenter, abstracts a proton from C−H, leading to HF.Concomitant with this transformation, the {C6F4H2} ring isstabilized by the metal center, leading to a Ru−R intermediate.The highest TS for this nucleophilic addition pathway isassociated with the elimination of fluoride and has an energy of25.1 kcal mol−1. This energy is reduced to 20.1 kcal mol−1 byincluding THF solvent in the calculation, in agreement with thesolvent effects observed experimentally. In order to get the finalproduct, HF is able to protonate the Ru−C bond, formingRu−F and C−H in a concerted manner with a low energy barrier(ΔE⧧ = 5.4 kcal mol−1). This mechanism was also calculated forthe activation of the C−F bonds meta and para to C−H, and in

both cases higher energy barriers were obtained, in agreementwith the ortho regioselectivity observed in this reaction.Overall, this mechanism shows that ortho C−F bond

activation and formation of M−C intermediates are not alwaysassociated with oxidative addition pathways or nucleophilicaddition processes where the metal acts as the nucleophile.10

Taking this into account, some other systems that have beendescribed with Rh14a,54 or Fe14b could follow a nucleophilicaddition by the hydride, similar to the process depicted inFigure 4.In addition to these mononuclear systems, a σ-bond metathesis

has been proposed for the hydrodefluorination of pentafluoro-pyridine by [M3S4H3(dmpe)3]

+ (M = Mo, W) clusters that takesplace under microwave radiation (Scheme 16).55 As in the case ofRu represented in Scheme 15, this reaction takes place in the pre-sence of silanes, which are responsible for recovering the hydridecatalyst, and is regioselective, yielding exclusively 2,3,5,6-tetra-fluoropyridine. In addition, for this reaction, the σ-bond metath-esis mechanism has been proposed on the basis of theoreticalcalculations. This study has shown that the C−F bond activationrequires a previous dissociation of phosphine to create a vacantside followed by the metathesis process. The energy barriersobtained for the Mo and W systems are 38.6 and 41.4 kcal mol−1,respectively. Although there is a small difference in energy be-tween these two TSs (2.8 kcal mol−1), the lower energy obtained

Figure 4. Potential energy profile (in kcal mol−1) obtained for the reaction of [Ru(IMes)(PPh3)2(CO)H2] with pentafluorobenzene. [Ru] denotes[Ru(IMes)(PPh3)(CO)H].

Scheme 16. Hydrogenation Reaction of Perfluoropyridine Catalyzed by [M3S4H3(dmpe)3]+ (M = Mo, W) with a Representation

of the TS Proposed for the Hydrodefluorination Process



for Mo is consistent with the faster reaction observed with thissystem.Overall these theoretical studies suggest that nucleophilic

addition processes by hydride ligands could be more commonthan expected, especially for reactions with aromatic substrateswhere the nucleophilic substitution is much easier than anoxidative addition process.

5. CONCLUSIONS AND PERSPECTIVESC−F bond activation processes facilitated by transition-metalcomplexes have been usually analyzed from the perspective ofthe metal or substrate nature. However, as has become moreand more apparent for an increasing number of processes,56

ligands can play a very active role also in C−F bond activationreactions. The high polarity of carbon−fluorine bonds makesthem prone to nucleophilic attack at the electrophilic carbon.This weakness of a very strong bond has been largely exploitedby reacting fluorinated compounds with organic nucleophiles.However, despite the fact that metal−ligand bonds offer attrac-tive possibilities for such reactivity, this strategy has been muchless utilized with transition-metal complexes. A metal−ligandbond is also usually a polar bond, with two different charge dis-tributions depending on the metal and ligand natures. Anelectron-rich metal can behave as a nucleophile, attacking theelectrophilic carbon of the C−F bond with concomitantrupture of the C−F bond and release of a fluoride. Con-currently, the electrophilic ligand can trap the fluoride anion. Ina different situation, the ligand can play the role of nucleophileand an electrophilic metal (or also external electrophiles) canbehave as fluoride trapping. In this contribution we have revisedC−F bond activations from this perspective. This article attemptsto rationalize the somehow disperse information that can befound at the literature on C−F bond activation reactions trig-gered by nucleophilic attack of a coordinated ligand. Thesereactions are reminiscent of the fluoride elimination by organicnucleophiles, but the presence of the metal introduces newfeatures in this process, both in the selectivity (it can direct theattack toward a specific position of a fluoroaromatic ring) andin the thermodynamics (the leaving fluoride can end upcoordinated to the metal center). Transformations of C−F toC−X bonds are of definite interest in the search for syntheticroutes to valuable materials and fine chemicals. The role of metalcomplexes as catalysts adds an appealing feature to these pro-cesses. However, much work has to be done to make this dreamcome true. On one hand, strong M−XR bonds can be an in-convenience for release of the organic product. On the otherhand, poisoning of metal centers by formation of stable M−F is adrawback that in some cases can be solved by the concurrence ofexternal electrophiles, as shown in this review. This compilationof reactions, mechanisms, and concepts discussed herein, focusedon the role of coordinated ligands as nucleophiles, offers a valuabletool in the further design of synthetically useful processes entailingC−F bond activation.

■ AUTHOR INFORMATION

Corresponding Author*E-mail: [email protected].

■ ACKNOWLEDGMENTSFinancial support from the Spanish MICINN (projectsCTQ2011-23336 and ORFEO Consolider-Ingenio 2010CSD2007-00006, “Ramon y Cajal” contract to R.M.-B. and

“Juan de la Cierva” contract to A.N.) is gratefully acknowl-edged. R.M.-B. thanks the Comunidad de Madrid for fundingthrough the CCG10-UAM/MAT-588 project.

■ DEDICATIONThis article is dedicated to Professor Pilar Gonzalez-Duarte, onthe occasion of her retirement.

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breaking c–f bonds via nucleophilic attack of coordinated ligands: transformations from c–f to...

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