C-F bond activation

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Introduction

C-F bond activation involves the breaking of the Carbon-Fluorine bond (513.8 kJ mol^-1) ^[1]. Activation of the C-F group present many challenges because of the strength of the C-F bond. The C-F bond is the strongest amongst the halogens, Ar-F has a bond energy of 127kcalmol^-1; compared to 97kcalmol^-1, 84kcalmol^-1, 67kcalmol^-1 for Ar-Cl, Ar-Br, and Ar-I, respectively. This presents an issue with selectively activating the Ar-F bond while leaving the other halogens intact and thus gained high interest in Organometallic chemistry. The major catalysts involved in C-F bond activation involve Ni, Pt, and Pd, with nickel catalysts identified as being the most reactive. Since nickel is the least electronegative of these elements, it is better able to push electron density onto carbon. Sterics have also been identified as to the better reactivity of nickel, since the nickel atom is smaller than palladium or platinum and thus suffers less steric repulsion from the ligands.^[2] The applications C-F activation allow for new routes where synthesis of some flourinated products were difficult. By starting with multiple C-F bonds and removing them, the desired product can be reached. Fluoroaromaic reactions have been classified and new mechanisms being recently suggested. The main classes are oxidative addition, M-C bond formation with H-F elimination, M-C bond formation with fluorosilane elimination, hydrodefluorination with M-F bond formation,and nucleophilic attack. Almost all C-F activation is a subgroup of these classes.

Mechanism

C-F activation Oxidative addition

Oxidative addition is a crucial step in several coupling reactions, and is often thought of as the rate determining step of these reactions.^[3]Activation of the C-F bond for oxidative addition remains an issue due to the large strength of these bonds (127kcalmol^-1). In many cases, C-H attack is preferred over the C-F bond unless the ligands are sterically hindered.^[4] Activation of C-F by oxidative addition involves using a metal catalyst for activation, while raising the oxidation state of the metal by two. Trialkylphosphines are often used as ligands because of their electron donating ability. It has been proven that halogenated pyridines are much more reactive than hexafluorobenzene. Pentafluoropyridine is able to act as a π acceptor ligand, increasing the strength of the Nickel-pentafluorpyridine bond and increasing the quality of oxidative addition.^[2] . (maybe rephrase) The product obtained from oxidative addition is ortho substituted, which is contrast to the product obtained from nucleophilic aromatic substitution, which is para substituted. Interactions between the nitrogen and nickel atoms stabilize the transition state by 7.2kcalmol^-1, thus making ortho substitution kinetically favourable when compared to para substitution..^[2]

Group assisted C-F activation

The C-F bond is able to be activated intramolecularly through a catalytic cycle. Aizenberg and Milstein ^[5] report using a Rhodium transition metal complex to catalyze the activation of the C-F bond through the following pathway:

File:Catalytic cycle C-F bond activation using a rhodium complex as a catlyst.png

The reaction proceeds by dissociation of the ligand L to create a 16 electron complex with the metal having an oxidation state of 1 (A). Ligand substitution of hydrogen with perfluorobenzene and a base then occurs (step B), with the Rh complex having the same electron count, and hydrogen fluoride gas being produced. Oxidative Addition of hydrogen gas than occurs (step C), raising the electron count to 18 and the oxidation state of Rh to 3. Reductive elimination (step D) yields the product, 1,2,3,4,5-pentafluorobenzene, and regenerates the catalyst, allowing it to undergo another cycle. The position of the hydrides after oxidative addition of hydrogen is of major importance: The hydride trans to the C6F5 ligand weakens the bond between Rh and C6F5 due to the trans effect. The hydride cis to the C6F5 ligand can than undergo reductive elimination more easily with C6F5. ^[5]

Electron transfer of C-F activation

By utilization of the LUMO orbitals of poly-fluorinated arenas with an addition of an electron, fragmentation occurs due an unstable radical anion^[2]. By this theory,many mechanisms and complexes have since been studied using electron transfer and some successful.

By decomposing^[6] Cp₂Zr(C₆F₅)₂ in tetrahydrofuran at 85 C with an initator sodium naphthalide,and 1,10-azobis. Cp₂Zr(C₆F₅)F and linear polyfluoroarenes are produced. The initiator transfers an electron to zirconocen, resulting in Zr (III) radical species and removal of the polyfluorarene. The Zr (III) species removes a fluorine from C₆F₆ and the hexafluorobenzene radical bonds with one C₆F₅ ligand on Zirconium which results in perfluorobiphenyl. Richmond^[7] has also shown hydrodefluorination reactions by using zirconium complexes as well as Cao^[8] with terminal acetylenes and aryl fluorides and a coupling reaction. Using sodiummetal, calciumhydroxide, and sodiummethoxide with a grignard reagent, cross-coupling occurs between substituted phenlacetylenes. an electron is transferred from the donor to arylfluoride, fragmentation occurs, resulting in a fluoride anion and aryl radical.

Other methods

C-F Activation of Aromatic Compounds by Rhodium (I) Silyl Complexes

C-F activation by a silyl ruthenium complex

Activation of C-F bonds of pentafluoropyridine by Rhodium (I) Silyl compelxes show a unique reaction^[9]. Using a silyl-assisted mechanism (and complex [Rh{Si(OMe)₃}{PMe₃}₃], C-F activation occurs over the Rh-Si bond. The resulting complex can either be ortho or para of the nitrogen, considering attack at the 2(favored) or 4 position . activation at the 2-posistion results in trigonal-bipramidal intermedate with Si(OMe)₃ in equatorial position and the C₅F₅N ligand with hapacity 2 and orientated in the equatorial plane (two mer and one fac intermediates are possible but mer is favoured). C-F activation occurs and results in a mer Oh complex however isomerization is required for the elimination of Si-F. also possible is the dissociation of PMe₃ trans to the 2-C₅F₅N ligand and movement of F into the vacated site. PMe₃ association than gives the mer complex and the Si-F bond occurs. Due to the accessibility of the isomerization and Si-F reduction elimination, the C-F oxidation step is rate determining. This deviation from the expected oxidative addition at a sq pl ML₄ is interesting. Phosphine dissociation is also very crucial to the mechanism.

Phosphine-Assisted C-F Activation Pathway

Nucleophilic attack of the electron rich Ir metal with C₆F₆ results with the displacement of F and its immediate attachment to a Phosphine ligand. These events occur through a single step and is more favorable^[10] than oxidation or electron transfer C-F activation.

Applications

Fluorinated complexes are heavily used in many industries including pharmaceuticals, agriculture chemicals, inhaler propellants, fluoro surfactants, solvents, organic reagents, refrigerants, anesthetics,oil and water reppalnts, transition metal chemistry organo ligands, and materials. Flourine is is a heavily used halogen of which use is critical to everyday life and of high importance. For more in depth information, see Organo Fluoro Applications

Tafinlar (Dabrafenib) is a recently (2013) approved drug by the FDA used to inhibit enzyme B-Raf for cancer treatment.

Adempas (Riociguat) is another aromatic fluoryl molecule used in the pharmaceutical sector for hypertension.

1,1,1,2-Tetrafluoroethane is a inert gas used as a refrigerant, and solvent used in the extraction of flavors and fragrances like vanillin. It was initially used to replace other solvents for their effect on climate change but it is now restricted for its contribution to climate change.

References

^ CRC handbook of chemistry and physics. 95ed. 2014-2015. page 9-66
^ ^a ^b ^c ^d Weaver, Jimmie, and Senaweera, Sameera, C-F activation and functionalization of perfluoro- and polyfluoroarenes, Tetrahedron 70 (2014): 7413-7428. DOI: 10.1016/j.tet.2014.06.004
^ Goossen, Lukas J., Koley, Debasis, Hermann, Holger L., and Thiel, Walter. Mechanistic Pathways for Oxidative Addition of Aryl Halides to Palladium(0) Complexes: A DFT Study.Organometallics 2005, 24, 2398-2410. DOI: 10.1021/om0500220
^ Bosque, Ramon, Clot, Eric, Fantacci, Simona, Maseras, Feliu, Eisenstein, Odile, Perutz, Robin N., Renkama, Kenton B., and Caulton, Kenneth G. Inertness of the Aryl-F Bond toward Oxidative Addition to Osmium and Rhodium Complexes: Thermodynamic or Kinetic Origin?. J. Am. Chem. Soc. 1998, 120, 12634-12640. DOI: 10.1021/ja9824573
^ ^a ^b Aizenberg, Michael, and Milstein, David. Homogeneous Metal-Catalyzed Hydrogenolysis of C-F Bonds. J. Am. Chem. SOC. 1995,117, 8674-8675.DOI:10.1021/ja00138a027 Cite error: The named reference "two" was defined multiple times with different content (see the help page).
^ Edelbach, B. L.; Kraft, B. M.; Jones, W. D. J. Am. Chem. Soc. 1999, 121, 10327. DOI: 10.1021/ja991805d
^ Kiplinger, J. L.; Richmond, T. G. J. Am. Chem. Soc. 1996, 118, 1805. DOI: 10.1021/ja952563u
^ Jin, G.; Zhang, X.; Cao, S. Org. Lett. 2013, 15, 3114. doi: 10.1021/ac402524e
^ Raza, A. Panetier, J. Teltewskoi, M. Macgregor, S. Braun, T. Rhodium (I) Silyl Complexes for C-F Bond Activation Reactions of Aromatic Compounds: Experimental and Computational Studies. Organometallics. 2013, 32, 3795-3807. DOI: 10/1021/om400150p
^ Stefan Erhardt, Stuart A. Macgregor. Computational Study of the Reaction of C6F6 with [IrMe(PEt3)3]: Identification of a Phosphine-Assisted C-F Activation Pathway via a Metallophosphorane Intermediate. American Chemical Society. School of Engineering and Physical Sciences, Heriot-Watt UniVersity, Edinburgh EH14 4AS, U.K. 2008. DOI: 10.1021/ja804622j

[1] CRC handbook of chemistry and physics. 95ed. 2014-2015. page 9-66

[one-2] Weaver, Jimmie, and Senaweera, Sameera, C-F activation and functionalization of perfluoro- and polyfluoroarenes, Tetrahedron 70 (2014): 7413-7428. DOI: 10.1016/j.tet.2014.06.004

[3] Goossen, Lukas J., Koley, Debasis, Hermann, Holger L., and Thiel, Walter. Mechanistic Pathways for Oxidative Addition of Aryl Halides to Palladium(0) Complexes: A DFT Study.Organometallics 2005, 24, 2398-2410. DOI: 10.1021/om0500220

[4] Bosque, Ramon, Clot, Eric, Fantacci, Simona, Maseras, Feliu, Eisenstein, Odile, Perutz, Robin N., Renkama, Kenton B., and Caulton, Kenneth G. Inertness of the Aryl-F Bond toward Oxidative Addition to Osmium and Rhodium Complexes: Thermodynamic or Kinetic Origin?. J. Am. Chem. Soc. 1998, 120, 12634-12640. DOI: 10.1021/ja9824573

[two-5] Aizenberg, Michael, and Milstein, David. Homogeneous Metal-Catalyzed Hydrogenolysis of C-F Bonds. J. Am. Chem. SOC. 1995,117, 8674-8675.DOI:10.1021/ja00138a027 Cite error: The named reference "two" was defined multiple times with different content (see the help page).

[6] Edelbach, B. L.; Kraft, B. M.; Jones, W. D. J. Am. Chem. Soc. 1999, 121, 10327. DOI: 10.1021/ja991805d

[7] Kiplinger, J. L.; Richmond, T. G. J. Am. Chem. Soc. 1996, 118, 1805. DOI: 10.1021/ja952563u

[8] Jin, G.; Zhang, X.; Cao, S. Org. Lett. 2013, 15, 3114. doi: 10.1021/ac402524e

[9] Raza, A. Panetier, J. Teltewskoi, M. Macgregor, S. Braun, T. Rhodium (I) Silyl Complexes for C-F Bond Activation Reactions of Aromatic Compounds: Experimental and Computational Studies. Organometallics. 2013, 32, 3795-3807. DOI: 10/1021/om400150p

[10] Stefan Erhardt, Stuart A. Macgregor. Computational Study of the Reaction of C6F6 with [IrMe(PEt3)3]: Identification of a Phosphine-Assisted C-F Activation Pathway via a Metallophosphorane Intermediate. American Chemical Society. School of Engineering and Physical Sciences, Heriot-Watt UniVersity, Edinburgh EH14 4AS, U.K. 2008. DOI: 10.1021/ja804622j

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