Stuart A. Macgregor

C-F and C-H bond activation of fluorobenzenes and fluoropyridines at transition metal centers: How fluorine tips the scales

In this Account, we describe the transition metal-mediated cleavage of C-F and C-H bonds in fluoroaromatic and fluoroheteroaromatic molecules. The simplest reactions of perfluoroarenes result in C-F oxida tive addition, but C-H activation competes with C-F activation for partially fluorinated molecules. We first consider the reactivity of the fluoroaromatics toward nickel and platinum complexes, but extend to rhenium and rhodium where they give special insight. Sections on spectroscopy and molecular structure are followed by discussions of energetics and mechanism that incorporate experimental and computational results. We highlight special characteristics of the metal-fluorine bond and the influence of the fluorine substituents on energetics and mechanism. Fluoroaromatics reacting at an ML(2) center initially yield η(2)-arene complexes, followed usually by oxidative addition to generate MF(Ar(F))(L)(2) or MH(Ar(F))(L)(2) (M is Ni, Pd, or Pt; L is trialkylphosphine). The outcome of competition between C-F and C-H bond activation is strongly metal dependent and regioselective. When C-H bonds of fluoroaromatics are activated, there is a preference for the remaining C-F bonds to lie ortho to the metal. An unusual feature of metal-fluorine bonds is their response to replacement of nickel by platinum. The Pt-F bonds are weaker than their nickel counterparts; the opposite is true for M-H bonds. Metal-fluorine bonds are sufficiently polar to form M-F···H-X hydrogen bonds and M-F···I-C(6)F(5) halogen bonds. In the competition between C-F and C-H activation, the thermodynamic product is always the metal fluoride, but marked differences emerge between metals in the energetics of C-H activation. In metal-fluoroaryl bonds, ortho-fluorine substituents generally control regioselectivity and make C-H activation more energetically favorable. The role of fluorine substituents in directing C-H activation is traced to their effect on bond energies. Correlations between M-C and H-C bond energies demonstrate that M-C bond energies increase far more on ortho-fluorine substitution than do H-C bonds. Conventional oxidative addition reactions involve a three-center triangular transition state between the carbon, metal, and X, where X is hydrogen or fluorine, but M(d)-F(2p) repulsion raises the activation energies when X is fluorine. Platinum complexes exhibit an alternative set of reactions involving rearrangement of the phosphine and the fluoroaromatics to a metal(alkyl)(fluorophosphine), M(R)(Ar(F))(PR(3))(PR(2)F). In these phosphine-assisted C-F activation reactions, the phosphine is no spectator but rather is intimately involved as a fluorine acceptor. Addition of the C-F bond across the M-PR(3) bond leads to a metallophosphorane four-center transition state; subsequent transfer of the R group to the metal generates the fluorophosphine product. We find evidence that a phosphine-assisted pathway may even be significant in some apparently simple oxidative addition reactions. While transition metal catalysis has revolutionized hydrocarbon chemistry, its impact on fluorocarbon chemistry has been more limited. Recent developments have changed the outlook as catalytic reactions involving C-F or C-H bond activation of fluorocarbons have emerged. The principles established here have several implications for catalysis, including the regioselectivity of C-H activation and the unfavorable energetics of C-F reductive elimination. Palladium-catalyzed C-H arylation is analyzed to illustrate how ortho-fluorine substituents influence thermodynamics, kinetics, and regioselectivity.

Synthesis, Electronic Structure, and Magnetism of (Ni(6-Mes) 2 ) + :A Two-Coordinate Nickel(I) Complex Stabilized by Bulky N‑Heterocyclic Carbenes

The two-coordinate cationic Ni(I) bis-N-heterocyclic carbene complex [Ni(6-Mes)2]Br (1) [6-Mes =1,3-bis(2,4,6-trimethylphenyl)-3,4,5,6-tetrahydropyrimidin-2-ylidene] has been structurally characterized and displays a highly linear geometry with a C-Ni-C angle of 179.27(13)°. Density functional theory calculations revealed that the five occupied metal-based orbitals are split in an approximate 2:1:2 pattern. Significant magnetic anisotropy results from this orbital degeneracy, leading to single-ion magnet (SIM) behavior.

Mechanisms of Catalyst Poisoning in Palladium-Catalyzed Cyanation of Haloarenes. Remarkably Facile C−N Bond Activation in the [(Ph3P)4Pd]/[Bu4N]+ CN- System

Reaction paths leading to palladium catalyst deactivation during cyanation of haloarenes (eq 1) have been identified and studied. Each key step of the catalytic loop (Scheme 1) can be disrupted by excess cyanide, including ArX oxidative addition, X/CN exchange, and ArCN reductive elimination. The catalytic reaction is terminated via the facile formation of inactive [(CN)4Pd]2-, [(CN)3PdH]2-, and [(CN)3PdAr]2-. Moisture is particularly harmful to the catalysis because of facile CN- hydrolysis to HCN that is highly reactive toward Pd(0). Depending on conditions, the reaction of [(Ph3P)4Pd] with HCN in the presence of extra CN- can give rise to [(CN)4Pd]2- and/or the remarkably stable new hydride [(CN)3PdH]2- (NMR, X-ray). The X/CN exchange and reductive elimination steps are vulnerable to excess CN- because of facile phosphine displacement leading to stable [(CN)3PdAr]2- that can undergo ArCN reductive elimination only in the absence of extra CN-. When a quaternary ammonium cation such as [Bu4N]+ is used as a phase-transfer agent for the cyanation reaction, C-N bond cleavage in the cation can occur via two different processes. In the presence of trace water, CN- hydrolysis yields HCN that reacts with Pd(0) to give [(CN)3PdH]2-. This also releases highly active OH- that causes Hofmann elimination of [Bu4N]+ to give Bu3N, 1-butene, and water. This decomposition mode is therefore catalytic in H2O. Under anhydrous conditions, the formation of a new species, [(CN)3PdBu]2-, is observed, and experimental studies suggest that electron-rich mixed cyano phosphine Pd(0) species are responsible for this unusual reaction. A combination of experimental (kinetics, labeling) and computational studies demonstrate that in this case C-N activation occurs via an S(N)2-type displacement of amine and rule out alternative 3-center C-N oxidative addition or Hofmann elimination processes.

[Ir(PCy3)2(H)2(H2BNMe2)]+ as a Latent Source of Aminoborane: Probing the Role of Metal in the Dehydrocoupling of H3B⋅NMe2H and Retrodimerisation of [H2BNMe2]2

The Ir(III) fragment {Ir(PCy(3))(2)(H)(2)}(+) has been used to probe the role of the metal centre in the catalytic dehydrocoupling of H(3)B⋅NMe(2)H (A) to ultimately give dimeric aminoborane [H(2)BNMe(2)](2) (D). Addition of A to [Ir(PCy(3))(2)(H)(2)(H(2))(2)][BAr(F)(4)] (1; Ar(F) = (C(6)H(3)(CF(3))(2)), gives the amine-borane complex [Ir(PCy(3))(2)(H)(2)(H(3)B⋅NMe(2)H)][BAr(F)(4)] (2 a), which slowly dehydrogenates to afford the aminoborane complex [Ir(PCy(3))(2)(H)(2)(H(2)B-NMe(2))][BAr(F)(4)] (3). DFT calculations have been used to probe the mechanism of dehydrogenation and show a pathway featuring sequential BH activation/H(2) loss/NH activation. Addition of D to 1 results in retrodimerisation of D to afford 3. DFT calculations indicate that this involves metal trapping of the monomer-dimer equilibrium, 2 H(2)BNMe(2) ⇌ [H(2)BNMe(2)](2). Ruthenium and rhodium analogues also promote this reaction. Addition of MeCN to 3 affords [Ir(PCy(3))(2)(H)(2)(NCMe)(2)][BAr(F)(4)] (6) liberating H(2)B-NMe(2) (B), which then dimerises to give D. This is shown to be a second-order process. It also allows on- and off-metal coupling processes to be probed. Addition of MeCN to 3 followed by A gives D with no amine-borane intermediates observed. Addition of A to 3 results in the formation of significant amounts of oligomeric H(3)B⋅NMe(2)BH(2)⋅NMe(2)H (C), which ultimately was converted to D. These results indicate that the metal is involved in both the dehydrogenation of A, to give B, and the oligomerisation reaction to afford C. A mechanism is suggested for this latter process. The reactivity of oligomer C with the Ir complexes is also reported. Addition of excess C to 1 promotes its transformation into D, with 3 observed as the final organometallic product, suggesting a B-N bond cleavage mechanism. Complex 6 does not react with C, but in combination with B oligomer C is consumed to eventually give D, suggesting an additional role for free aminoborane in the formation of D from C.

Transition metal-mediated P–C/X exchange at bound phosphine ligands (X = aryl, alkyl, NR2, OR and F): scope and mechanisms

The range of transition metal-mediated P-C/X exchange reactions that result in the replacement of a phosphine substituent with another group, X, are categorised according to the nature of the replacing group (X=aryl or alkyl, N- and O-based species and fluoride). Proposed mechanisms for P-C/X exchange are described and the factors promoting these unusual-and often undesirable-reactions are discussed. This tutorial review should be of relevance for those engaged in homogeneous catalysis, C-F activation and the synthesis of complexes combining soft metal centres and hard donor ligands.

Competing C−F Activation Pathways in the Reaction of Pt(0) with Fluoropyridines: Phosphine-Assistance versus Oxidative Addition

A survey of computed mechanisms for C-F bond activation at the 4-position of pentafluoropyridine by the model zero-valent bis-phosphine complex, [Pt(PH3)(PH2Me)], reveals three quite distinct pathways leading to square-planar Pt(II) products. Direct oxidative addition leads to cis-[Pt(F)(4-C5NF4)(PH3)(PH2Me)] via a conventional 3-center transition state. This process competes with two different phosphine-assisted mechanisms in which C-F activation involves fluorine transfer to a phosphorus center via novel 4-center transition states. The more accessible of the two phosphine-assisted processes involves concerted transfer of an alkyl group from phosphorus to the metal to give a platinum(alkyl)(fluorophosphine), trans-[Pt(Me)(4-C5NF4)(PH3)(PH2F)], analogues of which have been observed experimentally. The second phosphine-assisted pathway sees fluorine transfer to one of the phosphine ligands with formation of a metastable metallophosphorane intermediate from which either alkyl or fluorine transfer to the metal is possible. Both Pt-fluoride and Pt(alkyl)(fluorophosphine) products are therefore accessible via this route. Our calculations highlight the central role of metallophosphorane species, either as intermediates or transition states, in aromatic C-F bond activation. In addition, the similar computed barriers for all three processes suggest that Pt-fluoride species should be accessible. This is confirmed experimentally by the reaction of [Pt(PR3)2] species (R = isopropyl (iPr), cyclohexyl (Cy), and cyclopentyl (Cyp)) with 2,3,5-trifluoro-4-(trifluoromethyl)pyridine to give cis-[Pt(F){2-C5NHF2(CF3)}(PR3)2]. These species subsequently convert to the trans-isomers, either thermally or photochemically. The crystal structure of cis-[Pt(F){2-C5NHF2(CF3)}(P iPr3)2] shows planar coordination at Pt with r(F-Pt) = 2.029(3) A and P(1)-Pt-P(2) = 109.10(3) degrees. The crystal structure of trans-[Pt(F){2-C5NHF2(CF3)}(PCyp3)2] shows standard square-planar coordination at Pt with r(F-Pt) = 2.040(19) A.

Synthesis and Characterization of a Rhodium(I) σ-Alkane Complex in the Solid State

Solid View of a Sigma Complex For decades, it has been clear from kinetic studies that saturated hydrocarbons can also act as weak ligands, often just prior to bond cleavage reactions. These short-lived intermediates—termed “σ complexes” because the donated electrons reside in single (sigma symmetry) C-H bonds—have been glimpsed spectroscopically but have largely eluded full structural characterization. Pike et al. (p. 1648, published online 23 August) now present the crystallographic characterization of an alkane bound to rhodium, which they captured by direct hydrogenation of a more stable crystalline precursor incorporating an alkene. Hydrogenation of a crystalline precursor enables structural characterization of a commonly evoked reaction intermediate. Transition metal–alkane complexes—termed σ-complexes because the alkane donates electron density to the metal from a σ-symmetry carbon–hydrogen (C–H) orbital—are key intermediates in catalytic C–H activation processes, yet these complexes remain tantalizingly elusive to characterization in the solid state by single-crystal x-ray diffraction techniques. Here, we report an approach to the synthesis and characterization of transition metal–alkane complexes in the solid state by a simple gas-solid reaction to produce an alkane σ-complex directly. This strategy enables the structural determination, by x-ray diffraction, of an alkane (norbornane) σ-bound to a d8–rhodium(I) metal center, in which the chelating alkane ligand is coordinated to the pseudosquare planar metal center through two σ-C–H bonds.

Three-coordinate nickel(I) complexes stabilised by six-, seven- and eight-membered ring n-heterocyclic carbenes: synthesis, EPR/DFT studies and catalytic activity.

Comproportionation of [Ni(cod)(2)] (cod = cyclooctadiene) and [Ni(PPh(3))(2)X(2)] (X = Br, Cl) in the presence of six-, seven- and eight-membered ring N-aryl-substituted heterocyclic carbenes (NHCs) provides a route to a series of isostructural three-coordinate Ni(I) complexes [Ni(NHC)(PPh(3))X] (X = Br, Cl; NHC = 6-Mes 1, 6-Anis 2, 6-AnisMes 3, 7-o-Tol 4, 8-Mes 5, 8-o-Tol 6, O-8-o-Tol 7). Continuous wave (CW) and pulsed EPR measurements on 1, 4, 5, 6 and 7 reveal that the spin Hamiltonian parameters are particularly sensitive to changes in NHC ring size, N substituents and halide. In combination with DFT calculations, a mixed SOMO of ∣3d z 2〉 and ∣3d x 2-y 2〉 character, which was found to be dependent on the complex geometry, was observed and this was compared to the experimental g values obtained from the EPR spectra. A pronounced (31)P superhyperfine coupling to the PPh(3) group was also identified, consistent with the large spin density on the phosphorus, along with partially resolved bromine couplings. The use of 1, 4, 5 and 6 as pre-catalysts for the Kumada coupling of aryl chlorides and fluorides with ArMgY (Ar = Ph, Mes) showed the highest activity for the smaller ring systems and/or smaller substituents (i.e., 1>4≈6≫5).

Activation of an Alkyl C−H Bond Geminal to an Agostic Interaction: An Unusual Mode of Base-Induced C−H Activation

Deuterium labeling studies indicate that base-induced intramolecular C-H activation in the agostic complex 2-D proceeds with exclusive removal of a proton from the methyl arm of an (i)Pr substituent on the N-heterocyclic carbene (NHC) ligand. Computational studies show that this alkyl C-H bond activation reaction involves deprotonation of one of the C-H bonds that is geminal to the agostic interaction, rather than the agostic C-H bond itself. The reaction is readily accessible at room temperature, and a computed activation barrier of DeltaE (double dagger)(calcd) = +11.8 kcal/mol is found when the NHC 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene is employed as the external base. Charge analysis reveals that the geminal hydrogens are in fact more acidic than the agostic proton, consistent with their more facile deprotonation.

Catalytic Hydrodefluorination of Pentafluorobenzene by [Ru(NHC)(PPh3)2(CO)H2]: A Nucleophilic Attack by a Metal-Bound Hydride Ligand Explains an Unusual ortho-Regioselectivity†

The selective synthesis of fluoroarene compounds is a subject of intense current interest, driven by the prominent role such species play in many pharmaceuticals, agrochemicals, and other industrially important products. One attractive route to selectively substituted fluoroarenes involves the activation and functionalization of aromatic C F bonds derived from readily available perfluoroarenes. The simplest example of such a process is the hydrodefluorination reaction (HDF), in which fluorine is substituted for hydrogen. Catalytic HDF of C6F6 and C6F5H has been reported by Milstein et al. [3] and Holland et al. using Rh and Fe catalysts. However, both these systems exhibit practical problems that limit the mechanistic understanding of the HDF cycle. For example the Rh system requires high pressures of H2 as well as a sacrificial amine to remove HF, while with Fe no C F activation is observed in the absence of a reductant. As a consequence, the development of more active Rh or Fe catalysts has not been forthcoming. We recently reported the HDF of C6F6 and C6F5H using the ruthenium N-heterocyclic carbene (NHC) dihydride complex 1 (NHC = IMes, SIMes, IPr, SIPr; see Scheme 1 a) in the presence of trialkylsilanes at 70 8C in THF. Isolation and characterization of 1 allowed detailed kinetic studies to be undertaken, and these supported a mechanism involving initial phosphine dissociation to form 2 followed by HDF of the substrate to give the Ru F species, 3. Isolation of this 16e complex allowed us to demonstrate its reaction with trialkylsilane in the presence of PPh3 to regenerate catalyst 1. The most unusual feature of this system was the high regioselectivity for the formation of 1,2,3,4-C6F4H2 upon HDF of C6F5H, in complete contrast to the Milstein and Holland systems where the 1,2,4,5-isomer dominated. To account for the unusual ortho-regioselectivity we postulated the involvement of a tetrafluorobenzyne intermediate (Scheme 1b). Such species have been reported previously and could be formed here from 2 by successive C H and ortho-C F activation of C6F5H. However, density functional theory (DFT) calculations (with NHC = IMes) have now shown that this species lies more than 200 kJmol 1 above the reactants, effectively ruling it out as a viable intermediate under the conditions used experimentally. Further calculations, however, have now allowed us to define a series of alternative pathways which are based on a novel nucleophilic attack mechanism whereby a hydride ligand reacts directly with C6F5H. [10] These processes produced significantly lower barriers and, moreover, the lowestenergy pathway was found to be consistent with the unusual ortho-regioselectivity observed experimentally. Our calculations have shown that, after initial phosphine loss from 1, nucleophilic attack of hydride at C6F5H can occur through two different pathways (Scheme 2). In the concerted pathway I, the hydride is transfered from the metal onto the arene ring and the displaced fluorine migrates directly onto the metal center. In the alternative stepwise pathway II, an harene adduct, 4, is formed prior to the hydride attack. In this case the different orientation of the arene precludes direct transfer of fluorine onto the metal. Instead an intermediate is formed, 5, from which HF can be lost to form a s-aryl species, 6. Protonolysis by HF with concomitant F transfer to metal then yields 1,2,3,4-C6F4H2 and the M F species 3. The lowest-energy reaction profile for the HDF of C6F5H by 1 to give 1,2,3,4-C6F4H2 is computed to proceed through pathway II, and full details are shown in Figure 1. Initial Scheme 1. a) Catalytic hydrodefluorination (HDF) of C6F5H to 1,2,3,4C6F4H2 by 1; b) postulated tetrafluorobenzyne intermediate.