Robin N. Perutz

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.

Routes to fluorinated organic derivatives by nickel mediated C-F activation of heteroaromatics

New fluorinated azaheterocycles can be synthesised regio- and chemo-selectively via C-F activation of fluorinated precursors at nickel, with subsequent functionalisation and release from the coordination sphere of the metal; the requirements for productive C-F activation are significantly different from those for C-H bond activation.

Metal Fluorides Form Strong Hydrogen Bonds and Halogen Bonds : Measuring Interaction Enthalpies and Entropies in Solution

The organometallic compound trans-(tetrafluoropyrid-2-yl)bis(triethylphosphine)-fluoronickel(II) (NiF) is shown to serve as a strong hydrogen bond and halogen bond acceptor in solution via intermolecular interactions with the fluoride ligand. The nature of the interactions has been confirmed by multinuclear NMR spectroscopy. Experimental binding constants, enthalpies, and entropies of interaction with hydrogen-bond-donor indole and halogen-bond-donor iodopentafluorobenzene have been determined by 19F NMR titration. In toluene-d8 solution indole forms a 1:1 and 2:1 complex with NiF (K1 = 57.9(3), K2 = 0.58(4)). Interaction enthalpies and entropies are -23.4(2) kJ mol-1 and -44.5(8) J mol-1 K-1, respectively, for the 1:1 complex; -14.8(8) kJ mol-1 and -53(3) J mol-1 K-1, respectively, for the 2:1 complex. In toluene-d8 solution iodopentafluorobenzene forms only a 1:1 complex (K1 = 3.41(9)) with enthalpy and entropy of interaction of -16(1) kJ mol-1 and -42(4) J mol-1 K-1, respectively. A marked solvent effect was observed for the halogen bond interaction. NMR titrations in heptane solution indicated formation of both 1:1 and 2:1 complexes of iodopentafluorobenzene with NiF (K1 = 21.8(2), K2 = 0.22(4)). Interaction enthalpies and entropies are -26(1) kJ mol-1 and -63(4) J mol-1 K-1, respectively, for the 1:1 complex; -21(1) kJ mol-1 and -83(5) J mol-1 K-1, respectively, for the 2:1 complex. There is a paucity of such experimental energetic data particularly for halogen bonds despite substantial structural data. These measurements demonstrate that halogen bonds are competitive with hydrogen bonds as intermolecular interactions and provide a suitable benchmark for theoretical calculations and quantitative input into design efforts in supramolecular chemistry and crystal engineering.

Exceptional sensitivity of metal-aryl bond energies to ortho-fluorine substituents: influence of the metal, the coordination sphere, and the spectator ligands on M-C/H-C bond energy correlations.

DFT calculations are reported of the energetics of C-H oxidative addition of benzene and fluorinated benzenes, Ar(F)H (Ar(F) = C(6)F(n)H(5-n), n = 0-5) at ZrCp(2) (Cp = eta(5)-C(5)H(5)), TaCp(2)H, TaCp(2)Cl, WCp(2), ReCp(CO)(2), ReCp(CO)(PH(3)), ReCp(PH(3))(2), RhCp(PH(3)), RhCp(CO), IrCp(PH(3)), IrCp(CO), Ni(H(2)PCH(2)CH(2)PH(2)), Pt(H(2)PCH(2)CH(2)PH(2)). The change in M-C bond energy of the products fits a linear function of the number of fluorine substituents, with different coefficients corresponding to ortho-, meta-, and para-fluorine. The values of the ortho-coefficient range from 20 to 32 kJ mol(-1), greatly exceeding the values for the meta- and para-coefficients (2.0-4.5 kJ mol(-1)). Similarly, the H-C bond energies of Ar(F)H yield ortho- and para-coefficients of 10.4 and 3.4 kJ mol(-1), respectively, and a negligible meta-coefficient. These results indicate a large increase in the M-C bond energy with ortho-fluorine substitution on the aryl ring. Plots of D(M-C) vs D(H-C) yield slopes R(M-C/H-C) that vary from 1.93 to 3.05 with metal fragment, all in excess of values of 1.1-1.3 reported with other hydrocarbyl groups. Replacement of PH(3) by CO decreases R(M-C/H-C) significantly. For a given ligand set and metals in the same group of the periodic table, the value of R(M-C/H-C) does not increase with the strength of the M-C bond. Calculations of the charge on the aryl ring show that variations in ionicity of the M-C bonds correlate with variations in M-C bond energy. This strengthening of metal-aryl bonds accounts for numerous experimental results that indicate a preference for ortho-fluorine substituents.

Nickel‐Assisted Carbon–Fluorine Bond Activation of 2,4,6‐Trifluoropyrimidine: Synthesis of New Pyrimidine and Pyrimidinone Derivatives

Rapid and regioselective activation of the C-F bond of 2,4,6-trifluoropyrimidine occurs on reaction with [Ni(cod)(2)] (cod=1,5-cyclooctadiene) in the presence of PEt(3) to give 1, which can be converted into complex 2, containing a further N(3)-metalated pyrimidin-4-one unit. The novel pyrimidin-4-one 3 is released on protonation of 2.

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.

A solvent-resistant halogen bond

The effect of solvent on the stabilities of complexes involving a single H-bond or halogen-bond (X-bond) has been quantified. Association constants for binary complexes of 4-(phenylazo)phenol, molecular iodine, tetramethylurea and tetramethylthiourea have been measured in fifteen different solvents by UV/vis absorption and 1H NMR titration experiments. The stabilities of the H-bonded complexes decrease by more than three orders of magnitude with increasing solvent polarity. In contrast, the X-bonded complex of molecular iodine with tetramethylthiourea is remarkably insensitive to the nature of the solvent (association constants measured in alkanes and alcohols are similar). The results suggest that, in contrast to H-bonds, where electrostatics determine thermodynamic stability, charge-transfer interactions make a major contribution to the stability of these X-bonded complexes rendering them resistant to increases in solvent polarity.

Theoretical study of reaction pathways for the rhodium phosphine-catalysed borylation of C-H bonds with pinacolborane

The reaction mechanism of the rhodium-phosphine catalysed borylation of methyl-substituted arenes using pinacolborane (HBpin) has been investigated theoretically using DFT calculations at the B3PW91 level. Factors affecting selectivity for benzylic vs. aromatic C-H bond activation have been examined. It was found that [Rh(PR3)2(H)] is the active species which oxidatively adds the C-H bond leading to an eta3-benzyl complex which is the key to determining the unusual benzylic regioselectivity observed experimentally for this catalyst system. Subsequent reaction with HBpin leads to a [Rh(PR3)2(eta3-benzyl)(H)(Bpin)] complex from which B-C reductive elimination provides product and regenerates the catalyst. The electrophilic nature of the boryl ligand assists in the reductive elimination process. In contrast to Ir(L)2(boryl)3-based catalysts, for which Ir(III)-Ir(V) cycles have been proposed, the Rh(I)-Rh(III) cycle is operating with the system addressed herein.

Manganese Alkane Complexes: An IR and NMR Spectroscopic Investigation

Manganese propane and manganese butane complexes derived from CpMn(CO)(3) were generated photochemically at 130-136 K with the alkane as solvent and characterized by FTIR spectroscopy and by (1)H NMR spectroscopy with in situ laser photolysis. Time-resolved IR spectroscopic measurements were performed at room temperature with the same laser wavelength. The ν(CO) bands in the IR spectra of the photoproducts in propane are shifted to low frequency with respect to CpMn(CO)(3), consistent with formation of CpMn(CO)(2)(propane). The (1)H NMR spectra conform to the criteria for alkane complexes: a high-field resonance for the η(2)-CH protons that shifts substantially on partial deuteration of the alkane and exhibits a coupling constant J(C-H) on (13)C-labeling of ca. 120 Hz. The NMR spectrum of each system exhibits two diagnostic product resonances in the high-field region for the η(2)-CH protons, corresponding to CpMn(CO)(2)(η(2)-C1-H-alkane) and CpMn(CO)(2)(η(2)-C2-H-alkane) isomers. Partial deuteration of the alkane at C1 results in characteristic strong isotopic perturbation of equilibrium of the η(2)-CH resonance of CpMn(CO)(2)(η(2)-C1-H-alkane). With propane-(13)C(1), the η(2)-CH resonance of CpMn(CO)(2)(η(2)-C1-H-alkane) isomer exhibits (13)C satellites with J(C-H) = 119 Hz. The corresponding resonance of CpMn(CO)(2)(η(2)-C2-H-alkane) is identified by use of propane-2,2-d(2). The lifetimes of the (η(2)-C1-H-alkane) isomers of the manganese complexes were determined by NMR spectroscopy as 22 ± 2 min at 134 K (propane) and 5.5 min at 136 K (butane). The corresponding spectra and lifetimes of the CpRe(CO)(2)(alkane) complexes were measured for reference (CpRe(CO)(2)(propane) lifetime ca. 60 min at 161 K; CpRe(CO)(2)(butane) 13 min at 171 K). The lifetimes determined by IR spectroscopy were similar to those determined by NMR spectroscopy, thereby supporting the assignments. These measurements extend the range of alkane complexes characterized by NMR spectroscopy from rhenium and rhodium derivatives to include less stable manganese derivatives.

Improving the photocatalytic reduction of CO2 to CO through immobilisation of a molecular Re catalyst on TiO2.

The photocatalytic activity of phosphonated Re complexes, [Re(2,2′-bipyridine-4,4′-bisphosphonic acid) (CO)3(L)] (ReP; L=3-picoline or bromide) immobilised on TiO2 nanoparticles is reported. The heterogenised Re catalyst on the semiconductor, ReP–TiO2 hybrid, displays an improvement in CO2 reduction photocatalysis. A high turnover number (TON) of 48 molCO molRe−1 is observed in DMF with the electron donor triethanolamine at λ>420 nm. ReP–TiO2 compares favourably to previously reported homogeneous systems and is the highest TON reported to date for a CO2-reducing Re photocatalyst under visible light irradiation. Photocatalytic CO2 reduction is even observed with ReP–TiO2 at wavelengths of λ>495 nm. Infrared and X-ray photoelectron spectroscopies confirm that an intact ReP catalyst is present on the TiO2 surface before and during catalysis. Transient absorption spectroscopy suggests that the high activity upon heterogenisation is due to an increase in the lifetime of the immobilised anionic Re intermediate (t50 %>1 s for ReP–TiO2 compared with t50 %=60 ms for ReP in solution) and immobilisation might also reduce the formation of inactive Re dimers. This study demonstrates that the activity of a homogeneous photocatalyst can be improved through immobilisation on a metal oxide surface by favourably modifying its photochemical kinetics.