C−F Bond in Pentafluoropyridine by Zerovalent Nickel: Reaction

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Organometallics 2010, 29, 1824–1831 DOI: 10.1021/om100064z

Selective Activation of the ortho C-F Bond in Pentafluoropyridine by Zerovalent Nickel: Reaction via a Metallophosphorane Intermediate Stabilized by Neighboring Group Assistance from the Pyridyl Nitrogen Ainara Nova,† Meike Reinhold,† Robin N. Perutz,*,† Stuart A. Macgregor,‡ and John E. McGrady*,§ †

Department of Chemistry, University of York, Heslington, York, YO10 5DD, United Kingdom, ‡ School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, United Kingdom, and §Department of Chemistry, Inorganic Chemistry Laboratory, University of Oxford, South Parks Road, OX1 3QR, United Kingdom Received January 26, 2010

Density functional theory is used to explore the origins of the chemoselectivity and regioselectivity of activation of C-F bonds in pentafluoropyridine with [Ni(PR3)2] species. Experimentally, Ni-fluoride species are observed and activation occurs preferentially at the 2-position (i.e., the C-F bond ortho to the pyridyl nitrogen). This is in marked contrast to related platinum reagents, which form Pt-alkyl species featuring fluorophosphine ligands with activation occurring exclusively at the 4-position. Using a model nickel complex, [Ni(PMe3)2], computed potential energy surfaces reveal two distinct types of reaction pathways: conventional oxidative addition and phosphine-assisted C-F bond activation. In the latter, the activated fluorine is transferred first to the phosphine ligand before migrating to the metal center. The phosphine-assisted routes lie substantially above their oxidative addition counterparts unless activation occurs at the 2-position, where coordination of the pyridyl nitrogen stabilizes both the metallophosphorane intermediate and the preceding transition state. The result is a lowering of the barrier such that the phosphine-assisted route becomes competitive with conventional oxidative addition. This “neighboring group acceleration” is unique to the phosphine-assisted pathway and, moreover, is unique to activation at the 2-position because it depends on the ability of the nitrogen to participate in a benzyne-like, pyridin-1,2-diyl coordination mode.

Introduction The pervasive presence of aromatic C-F bonds in the chemistry of pharmaceuticals and materials1 makes the prospect of catalytic and selective C-F bond activation very attractive as a method of converting polyfluorinated compounds selectively. A recent comprehensive review of C-F activation in organic synthesis sets out comparisons between transition-metal-mediated methods and more traditional methods such as nucleophilic attack.2 The range of reaction types observed in metal-mediated C-F bond activation includes (a) oxidative addition and (b) M-C bond formation accompanied by elimination of either fluorosilane or HF.3 The behavior of different metals in C-F activation varies very significantly with the metal, with oxidative addition most prevalent at *Corresponding authors. E-mail: [email protected]. (1) (a) M€ uller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c) Smart, B. E. J. Fluorine Chem. 2001, 109, 3. (2) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119. (3) Braun, T.; Perutz, R. N. Transition-Metal Mediated C-F Bond Activation. In Comprehensive Organometallic Chemistry III; Crabtree, R. H., Mingos, D. M. P., Eds.; Elsevier: Amsterdam, 2006; Vol. 1, Chapter 26. (4) (a) Torrens, H. Coord. Chem. Rev. 2005, 249, 1957. (b) Perutz, R. N.; Braun, T. Chem. Commun. 2002, 2749. (c) Jones, W. D. Dalton Trans. 2003, 3991. pubs.acs.org/Organometallics

Published on Web 03/12/2010

group 10 metals.4,5 Considerable progress has been made on catalytic cross-coupling and hydrodefluorination, although turnovers and selectivity are not yet sufficient for general application.6,7 (5) (a) Burdeniuc, J.; Jedlicka, B.; Crabtree, R. H. Chem. Ber. 1997, 130, 145. (b) Murphy, E. F.; Murugavel, R.; Roesky, H. W. Chem. Rev. 1997, 97, 3425. (c) Kiplinger, J. L.; Richmond, T. G.; Osterberg, C. E. Chem. Rev. 1994, 94, 373. (6) (a) Braun, T.; Perutz, R. N.; Sladek, M. I. Chem. Commun. 2001, 2254. (b) Steffen, A.; Sladek, M. I.; Braun, T.; Neumann, B.; Stammler, H. G. Organometallics 2005, 24, 4057. (c) Kiso, Y.; Tamao, K.; Kumada, M. J. Organomet. Chem. 1973, 50, C12. (d) B€ohm, V. P. W.; Gst€ottmayr, C. W. K.; Weskamp, T.; Herrmann, W. A. Angew. Chem., Int. Ed. 2001, 40, 3387. (e) Dankwardt, J. W. J. Organomet. Chem. 2005, 690, 932. (f) Ackermann, L.; Born, R.; Spatz, J. H.; Meyer, D. Angew. Chem., Int. Ed. 2005, 44, 7216. (g) Lamm, K.; Stollenz, M.; Meier, M.; Gorls, H.; Walther, D. J. Organomet. Chem. 2003, 681, 24. (h) Mongin, F.; Mojovic, L.; Guillamet, B.; Trecourt, F.; Queguiner, G. J. Org. Chem. 2002, 67, 8991. (i) Widdowson, D. A.; Wilhelm, R. Chem. Commun. 2003, 578. (j) Widdowson, D. A.; Wilhelm, R. E. Chem. Commun. 1999, 2211. (k) Wilhelm, R.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1 2000, 3808. (l) Schaub, T.; Backes, M.; Radius, U. J. Am. Chem. Soc. 2006, 128, 15964. (7) (a) Aizenberg, M.; Milstein, D. Science 1994, 265, 359. (b) Aizenberg, M.; Milstein, D. J. Am. Chem. Soc. 1995, 117, 8674. (c) Vela, J.; Smith, J. M.; Yu, Y.; Ketterer, N. A.; Flaschenriem, C. J.; Lachicotte, R. J.; Holland, P. L. J. Am. Chem. Soc. 2005, 127, 7857. (d) Meier, G.; Braun, T. Angew. Chem., Int. Ed. 2009, 48, 1546. (e) Braun, T.; Noveski, D.; Ahijado, M.; Wehmeier, F. Dalton Trans. 2007, 3820. (f) Reade, S. P.; Mahon, M. F.; Whittlesey, M. K. J. Am. Chem. Soc. 2009, 131, 1861. (g) Fuchibe, K.; Ohshima, Y.; Mitomi, K.; Akiyama, T. J. Fluorine Chem. 2007, 128, 1158. r 2010 American Chemical Society

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Two key issues for applications are chemoselectivity and regioselectivity. Transition metal complexes are mostly selective for aromatic C-F bonds over aliphatic C-F bonds.3 The opposite selectivity was recently achieved by Ozerov in a major development using silylium ions as Lewis acid catalysts.8 Surprisingly, it has also proved possible to select C-F bonds over C-Cl bonds in appropriate circumstances.6b Chemoselection of aromatic (and heteroaromatic) C-F bonds in the presence of aromatic C-H bonds has been achieved at nickel phosphine and nickel carbene complexes.4b,9-16 The interplay of kinetic and thermodynamic products in selecting C-F or C-H bonds has been analyzed by DFT methods for phosphine complexes of nickel and platinum.17 The past few years have seen great advances in the direct catalytic functionalization of aromatic C-H bonds in the presence of C-F bonds using copper, palladium, and rhodium catalysts.18 This reverse selectivity clearly highlights the importance of understanding the basis of chemoselection. Remarkably, [Ni(PEt3)2] activates tetrafluorobenzene selectively at the C-F bond,9 whereas [Ni(COD)2] in the presence of PCyp3 (Cyp = cyclopentyl) catalyzes the coupling of pentafluorobenzene to alkynes by activating the C-H bond selectively.19 The regioselectivity of heteroaromatic C-F bond activation may differ from more conventional nucleophilic attack, as has been demonstrated in reactions of fluorinated pyridines. Pentafluoropyridine is such a weak base that it is not protonated by HCl and rarely coordinates to transition metals through nitrogen;20 notably, an η2-C3dC4 mode is preferred instead in a rhodium complex.21 With only a few exceptions, pentafluoropyridine undergoes nucleophilic attack at the (8) (a) Scott, V. J.; C-elenligil-C-etin, R.; Ozerov, O. V. J. Am. Chem. Soc. 2005, 127, 2852. (b) Douvris, C.; Ozerov, O. V. Science 2008, 321, 1188. (9) (a) Johnson, S. A.; Huff, C. W.; Mustafa, F.; Saliba, M. J. Am. Chem. Soc. 2008, 130, 17278. (b) Johnson, S. A.; Taylor, E T.; Cruise, S. J. Organometallics 2009, 28, 3842. (10) It is now clear that kinetic C-H activation products may also be formed on reaction of [Ni(PEt3)2] with tetrafluorobenzene, but these give way to the thermodynamic C-F activation products.9 (11) Cronin, L.; Higgitt, C. L.; Karch, R.; Perutz, R. N. Organometallics 1997, 16, 4920. (12) Archibald, S. J.; Braun, T.; Gaunt, J. F.; Hobson, J. E.; Perutz, R. N. J. Chem. Soc., Dalton Trans. 2000, 2013. (13) Braun, T.; Cronin, L.; Higgitt, C. L.; McGrady, J. E.; Perutz, R. N.; Reinhold, M. New J. Chem. 2001, 25, 19. (14) Burling, S.; Elliott, P. I. P.; Jasim, N. A.; Lindup, R. J.; McKenna, J.; Perutz, R. N.; Archibald, S. J.; Whitwood, A. C. Dalton Trans. 2005, 3686. (15) Schaub, T.; Fischer, P.; Steffen, A.; Braun, T.; Radius, U.; Mix., A. J. Am. Chem. Soc. 2008, 130, 9304. (16) (a) Schaub, T.; Radius, U. Chem. Eur. J. 2005, 11, 5024. (b) Doster, M. E.; Johnson, S. A. Angew. Chem., Int. Ed. 2009, 48, 2185. (17) Reinhold, M.; McGrady, J. E.; Perutz, R. N. J. Am. Chem. Soc. 2004, 126, 5268. (18) (a) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253. (b) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754. (c) Lafrance, M.; Shore, D.; Fagnou, K. Org. Lett. 2006, 8, 5097. (d) Bedford, R. B.; Betham, M.; Charmant, J. P. H.; Weeks, A. L. Tetrahedron 2008, 64, 6038. (e) Oi, S.; Funayama, R.; Hattori, T.; Inoue, Y. Tetrahedron 2008, 64, 6051. (f) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128. (19) Nakao, Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 16170. (20) (a) Holtcamp, M. W.; Labinger, J. A.; Bercaw, J. E. J. Am. Chem. Soc. 1997, 119, 848. (b) Holtcamp, M. W.; Henling, L. N.; Day, M. W.; Labinger, J. A.; Bercaw, J. E. Inorg. Chim. Acta 1998, 270, 467. (c) Huhmann-Vincent, J.; Scott, B. L.; Kubas, G. J. Inorg. Chem. 1999, 38, 115. (d) Basus, S.; Arulsamy, S.; Roddick, D. M. Organometallics 2008, 27, 3659. (21) Perutz, R. N.; Rendon, N. Unpublished. (22) Veits, Y. A.; Karlstedt, N. B.; Chuchuryukin, A. V.; Beletskaya, I. P. Russ. J. Org. Chem. 2000, 36, 750.

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4-position.22 In transition metal reactions, pentafluoropyridine has been found to undergo reaction at the 4-position with [Ni(iPr2Im)2] (iPr2Im=1,3-di(isopropyl)imidazol-2-ylidene),12 [Pd(PCy3)2], [Pt(PCy3)2],23 and [Zr(C5H5)2],24 while attack at the 2-position is dominant for [Ni(PEt3)2] and also [Ti(C5Me5)2].4b,11,12,14,25 One of the objectives of this paper is to establish the origin of the changes in regioselectivity of C-F bond activation in these systems. Oxidative addition of a C-F bond generates a metalfluorine bond in addition to a metal-carbon bond, and it is this mode of reaction that is dominant in nickel chemistry.4b,6,9,11,15,16,26 It is now established that certain complexes with M-F bonds, notably [RhF(PPh3)3], may undergo rearrangements involving phosphine ligands because of the accessibility of metallophosphorane species, while similar pathways are unavailable to M-H or M-Hal (Hal = Cl, Br, I) analogues.27 These reactions involving direct participation of the phosphines have influenced the development of mechanisms for unusual C-F activation reactions28,29 and the proposals put forward below. In a recent paper on the activation of aromatic C-F bonds by Pt(0),29 we showed that phosphine ligands, far from acting as spectators, function as fluorine atom acceptors. Thus pentafluoropyridine reacts with [Pt(PR3)2] (R = cyclohexyl, iPr), not via classic oxidative addition leading to platinum fluoride species such as [Pt(F)(4-C5NF4)(PR3)2], but via transfer of the fluoride to a phosphine ligand with concomitant migration of one of the alkyl groups to the metal, giving platinum alkyls, trans[Pt(R)(4-C5NF4)(PR3)(PR2F)] (Scheme 1a).23 Although hexafluorobenzene reacts similarly at [Pt(PR3)2],27a it is sometimes possible to direct the reaction of platinum phosphines to platinum fluoride formation. Thus Hoffman showed that the highly strained platinum phosphine [Pt(R2PCH2PR2)] (R = tBu) reacts with C6F6 to give [Pt(F)(C6F5)(R2PCH2PR2)2],30 while more recently we have shown that replacement of pentafluoropyridine by 2,3,5-trifluoro-4-(trifluoromethyl)pyridine can lead to formation of the platinum fluoride at [Pt(PR3)2] (Scheme 1b).29 DFT calculations have been employed to study several aspects of C-F bond activation.15,17,28,29,31,32 Of direct relevance to this paper is our comparison of C-F activation of C6F6 and C-H activation of C6H6 at [M(PH3)2] (M = Ni, Pt).17 A study of analogous reactions of nickel carbene complexes included calculations for several fluorinated benzenes.15 Both studies demonstrate oxidative addition via (23) Jasim, N. A.; Perutz, R. N.; Whitwood, A. C.; Braun, T.; Izundu, J.; Neumann, B.; Rothfeld, S.; Stammler, H. G. Organometallics 2004, 23, 6140. (24) J€ager-Fiedler, U.; Arndt, P.; Baumann, W.; Spannenberg, A.; Burlakov, V. V.; Rosenthal, U. Eur. J. Inorg. Chem. 2005, 2842. (25) Piglosiewicz, I. M.; Kraft, S.; Beckhaus, R.; Haase, D.; Saak, W. Eur. J. Inorg. Chem. 2005, 938. (26) Braun, T.; Cronin, L.; Higgitt, C. L.; McGrady, J. E.; Perutz, R. N.; Reinhold, M. New J. Chem. 2001, 25, 19. (27) (a) Macgregor, S. A.; Roe, D. C.; Marshall, W. J.; Bloch, K. M.; Bakhmutov, V. I.; Grushin, V. V. J. Am. Chem. Soc. 2005, 127, 15304. (b) Macgregor, S. A. Chem. Soc. Rev. 2007, 35, 67. (c) Macgregor, S. A.; Wondimagegn, T. Organometallics 2007, 26, 1143. (28) Erhardt, S.; Macgregor, S. A. J. Am. Chem. Soc. 2008, 130, 15490. (29) Nova, A.; Erhardt, S.; Jasim, N. A.; Perutz, R. N.; Macgregor, S. A.; McGrady, J. E.; Whitwood, A. C. J. Am. Chem. Soc. 2008, 130, 15499. (30) Hofmann, P.; Unfried, G. Chem. Ber. 1992, 125, 659. (31) Bosque, R.; Clot, E.; Fantacci, S.; Maseras, F.; Eisenstein, O.; Perutz, R. N.; Renkema, K. B.; Caulton, K. G. J. Am. Chem. Soc. 1998, 120, 12634. (32) Maron, L.; Werkema, E. L.; Perrin, L.; Eisenstein, O.; Andersen, R. A. J. Am. Chem. Soc. 2005, 127, 279.

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Scheme 1. C-F Bond Activation Chemistry at Zerovalent Platinum and Nickel Phosphine Complexes

η2-C,C-C6F6 precursor complexes. In comparing C-H and C-F activation pathways it is also important to stress the increase in M-C bond energy that accompanies substitution of ortho hydrogens by fluorine.33 This change stabilizes products with fluorines in the ortho positions over alternative isomers. Our DFT calculations on the reactions of the Pt(0) system, [Pt(PH3)(PH2Me)], with pentafluoropyridine show that the platinum alkyl is some 10 kcal/mol less stable than the isomeric trans fluoride, precluding a simple thermodynamic explanation for the observed formation of alkyls.29 These calculations reveal four distinct pathways for C-F bond activation at [Pt(PR3)2] (Scheme 2), one of which (pathway 1) is the well-established oxidative addition reaction that we had previously explored in the context of the reaction of hexafluorobenzene with [Pt(PH3)2] and [Ni(PH3)2].17 The other three, described as “phosphineassisted” in Scheme 2, involve metallophosphorane species, Pt-PR3F, and lead either to the trans isomer of the aryl fluoride, trans-[Pt(F)(4-C5NF4)(PR3)2] (pathway 4), or the metal alkyl, trans-[Pt(R)(4-C5NF4)(PR3)(PR2F)] (pathways 2 and 3). The early stages of the phosphine-assisted pathways can be viewed as a nucleophilic attack on the carbon by the electronrich metal center, as a result of which the C-F bond is almost entirely cleaved at the transition state. The fluorine atom therefore carries a significant negative charge, which is effectively stabilized by the low-lying vacant orbitals on carbon, platinum, and phosphorus. Our calculations suggested that pathway 2, a concerted phosphine-assisted C-F activation with a metallophosphorane transition state, is most favorable for the reaction of [Pt(PR3)2] with pentafluoropyridine, but all four pathways have similar barriers, consistent with our observation that rather subtle changes in structure of the phosphine or the substrate can have a major impact on the observed product distribution.29 In this paper, we focus on the corresponding chemistry of nickel, where the formation of metal fluorides appears to be the norm.4b,9,11,15 For example, the reaction of pentafluoropyridine with [Ni(PEt3)2] in alkane solvents (formed in situ from [Ni(COD)2] and PEt3) generates [Ni(2-C5NF4)(PEt3)2] (Scheme 1c).11 Although no intermediates have been identified in the reaction with pentafluoropyridine, (33) Clot, E.; Megret C.; Eisenstein, O.; Perutz, R. N. J. Am. Chem. Soc. 2009, 131, 7817.

Nova et al. Scheme 2. Four Reaction Pathways of Pentafluoropyridine with [Pt(PR3)2]

[{Ni(PEt3)2}2(μ-η2-η2-C6F6)] has been isolated very recently from the reaction of [Ni(PEt3)2(η2-anthracene)] with excess C6F6. A small amount of [Ni(PEt3)2(η2-C6F6)] was detected at equilibrium with this dinuclear complex and was shown to convert to [Ni(F)(C6F5)(PEt3)2]. Moreover, C-H oxidative addition has been proved to compete with C-F activation for pentafluorobenzene and tetrafluorobenzene.9 In contrast to platinum, there are still no examples of nickel-alkyl formation. In the context of the pathways shown in Scheme 2, the predominance of the metal fluoride products could indicate that the oxidative addition pathway is favored over the phosphine-assisted alternatives in nickel chemistry. We cannot, however, discount the possibility that the phosphine ligands still play a role in the reaction, because metallophosphorane formation followed by fluoride transfer from phosphorus to metal (Scheme 2, pathway 4) is indistinguishable from direct oxidative addition (pathway 1) followed by cis/trans isomerization of the fluoride product. A second striking feature of the nickel chemistry is the different regioselectivity from platinum: in the latter, C-F bond activation invariably occurs at the 4-position, and our calculations confirmed that this position is favored both thermodynamically and kinetically. The reaction of pentafluoropyridine with [Ni(PEt3)2], in contrast, leads to a mixture of regioisomers, but the dominant product is the 2-isomer (85%) (Scheme 1c); reaction at the C-F bond in the 2-position is also observed with 2,3,4,5-tetrafluoropyridine.12 Until now, no satisfactory explanation of this selectivity has emerged. We now use a DFT approach to show that despite its weak basicity, the lone pair on the pyridyl nitrogen can participate in the reaction at Ni(0), lowering the barrier to C-F bond activation at the 2-position, but only when the reaction proceeds through a metallophosphorane intermediate. Our analysis of this reaction provides further evidence that phosphines are more than mere spectators and that metallophosphoranes may feature more generally in C-F activation reactions of metal-phosphine complexes.27-29

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Computational Methods All calculations described in this paper were performed using the Gaussian0334 package. Calculations were performed using the BP8635b,c functional. Natural bond orbital (NBO) analysis was performed using NBO version 5.036 as implemented in Gaussian03. The ethyl groups on the phosphine ligands were in all cases replaced by more computationally tractable methyl groups. The SDD pseudopotential, along with its associated basis set, was used to describe the nickel centers, while the 6-31G(d,p) basis set was used for the main group atoms P, C, N, and H, augmented by a set of diffuse functions on the fluorine atoms (6-31Gþ(d,p)). Diffuse functions are generally important when atoms have significant anionic character (i.e., the phosphineassisted pathways), and indeed when these functions are removed we have been unable to locate either of the phosphineassisted transition states (vide infra); our calculations invariably converged on the alternative oxidative addition transition state. In our previous work on platinum we did not encounter similar basis-set dependencies, presumably because the Pt 5d orbitals occupy the same region of space as the diffuse functions and therefore play a similar role in stabilizing the negative charge on the fluoridic center in the transition state. Full geometry optimizations were performed without symmetry constraints, and stationary points were characterized as minima or transition states by vibrational analysis.

Results We report computed potential energy surfaces for activation of C-F bonds in pentafluoropyridine at both the 4- and 2positions. The results for activation at the 3-position are very similar to those for the 4-position and are summarized in the Supporting Information (Figure S1). We take the 14-electron species [Ni(PMe3)2] as the starting point for the reaction pathway because, as noted above, there is ample evidence that 16-electron complexes of the type NiL2(η2-arene) are formed prior to C-F bond activation.9,13 We have not, therefore, considered the possibility that C-F activation takes place at complexes where cyclooctadiene remains coordinated to the metal. The key features of the oxidative addition pathways for attack at both sites are presented first, before we turn to the phosphine-assisted pathways described in Scheme 2. Oxidative Addition Pathways (Phosphine As Spectator). Potential energy profiles for the direct oxidative addition mechanism at the 4- and 2-positions of pentafluoropyridine are presented in Figure 1, while optimized structures of the various stationary points are collected in Figure 2. The potential energy surfaces for the reactions at the 2- and 4-positions are strikingly similar: in both cases the reaction starts with the exothermic formation of approximately trigonal-planar η2-arene complexes (labeled πXY, where XY identifies the pair of atoms coordinated to the metal center) with P-Ni-P angles of ∼115° and coordinated CC or CN bonds somewhat longer than those in free pentafluoropyridine, consistent with the Dewar-Chatt-Duncanson (34) Frisch, M. J. et al. Gaussian 03, Revision B.03; Pittsburgh, PA, 2003. (35) (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 1372. (c) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (d) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200. (e) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. (f) Becke, A. D. J. Chem. Phys. 1986, 84, 4524. (g) Perdew, J. P. Phys. Rev. B 1986, 33, 8822. (36) (a) Glendenning, E. D.; Badenhoop, J. K.; Reed, A. E.; Carpenter, J. E.; Bohmann, J. A.; Morales, C. M.; Weinhold, F. NBO Version 5.0; Theoretical Chemistry Institute, University of Wisconsion: Madison, WI, 2001. (b) Bohmann, J. A.; Weinhold, F.; Farrar, T. C. J. Chem. Phys. 1997, 107, 1173.

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model. Coordination at C3dC4 is preferred to coordination at C2dN by 5.3 kcal/mol. From this point the Ni center migrates away from the aromatic π system along a C-F bond, leading to the C-F oxidative addition transition states OA-TS(4) and OA-TS(2) for activation at the 4- and 2positions, respectively. Both are three-center transition states where the C-F bond is substantially elongated: 1.50 and 1.53 A˚ in OA-TS(4) and OA-TS(2), respectively (vs 1.34-1.35 A˚ in C5NF5). The slightly more advanced C-F bond cleavage and Ni-F bond formation in the latter are consistent with the reduced exothermicity of the reaction at the 2-position (vide infra). These subtle structural differences are also reflected in a slightly lower transition state for activation at the 4-position (-3.3 kcal/mol) compared to that at the 2-position (-0.6 kcal/mol). The oxidative addition transition states then collapse to square-planar Ni(II) products cisF(4) and cisF(2), where the newly formed fluoride ligand lies cis to the pyridyl ligand. We have never detected these cis isomers of the Ni(II) complex experimentally: the fluoride products instead always have the fluoride and pyridyl ligands trans to each other, and indeed the corresponding isomers transF(4) and transF(2) lie ∼10 kcal/mol below their cis counterparts. In the corresponding platinum chemistry, we were able to detect the initially formed cis fluoride products and follow their conversion to the trans analogues, presumably either through a tetrahedral transition state or via a solventassisted pathway involving a five-coordinate intermediate. We have not explored this issue explicitly here, but we anticipate that the square-planar Ni(II) complexes would isomerize more readily than their Pt(II) counterparts, leading to rapid conversion to the more stable trans isomers. In our previous work on Pt(0) complexes we noted the strong thermodynamic preference for activation in the 4-position, and this is also apparent in the nickel chemistry, with cisF(4) and transF(4) lying ∼10 kcal/mol below their counterparts arising from activation in the 2-position. Thus if only the oxidative addition pathway were active, we would predict a strong thermodynamic preference as well as a small kinetic preference for activation at the 4-position, contrary to the experimentally observed product distribution. Phosphine-Assisted Pathways. As shown in Scheme 2, three different phosphine-assisted C-F bond activation mechanisms have been identified for Pt complexes, involving direct formation of the alkyl (pathway 2), formation of the alkyl via an intermediate metallophosphorane (pathway 3), and formation of the fluoride (in this case trans to the aryl) via an intermediate metallophosphorane (pathway 4). As Nifluorides are the only C-F activation products observed experimentally, our initial focus will be on pathway 4. Potential energy surfaces for pathway 4 for activation at both the 4- and 2-positions are compared in Figure 3. These phosphine-assisted reactions again start with formation of the π complexes, πC2N and πC3C4, discussed previously in the context of oxidative addition. For activation at the 4-position, the reaction proceeds via a four-centered transition state, PA-TS(4), which features a T-shaped Ni(II) center with a vacant site trans to the developing phosphoranide ligand. The reaction coordinate is highly asynchronous, with the Ni-C and C-F bonds almost fully formed (Ni-C = 1.84 A˚) and cleaved (C-F = 2.06 A˚), respectively, at the transition state, while the P-F distance remains rather long (2.32 A˚). These structural features suggest that the early part of the reaction coordinate involves nucleophilic attack by the metal, leading to a highly fluoridic fluorine center (natural

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Figure 1. Potential energy surface for the oxidative addition pathway (pathway 1) for activation of the C-F bonds in the 4- and 2positions. Energies are given in kcal/mol.

charge -0.63, cf. ∼-0.33 for the fluorines bonded to carbon). The role of the P-C σ* antibonding orbital in stabilizing the negative charge on the migrating fluoride ion is illustrated by the natural localized molecular orbitals (NLMOs) shown in Figure 4. Both orbitals are primarily (>88%) fluoride lone pairs, but have significant delocalization tails on both the P-C unit (orbitals a and b) and the ipso carbon of the aryl unit (orbital b). Collapse of the phosphine-assisted transition state PA-TS(4) leads to a metallophosphorane intermediate MP(4), where the phosphorus center has a trigonal-bipyramidal coordination environment. MP(4) corresponds to a very shallow minimum (so shallow that the intermediate will be at best transient), and subsequent transfer of the fluoride to the vacant site at the nickel to give transF(4) is almost barrierless. In comparison with the direct oxidative addition (pathway 1) discussed above, the phosphine-assisted route is highly unfavorable: PA-TS(4) lies 5.0 kcal/mol above the free reactants compared to -3.3 kcal/ mol for OA-TS(4). The contrast with the platinum systems, where the two pathways are energetically very close, can be traced to the greater strength of the Ni-F bond, which is partially formed in the oxidative addition transition state (Ni-F=2.22 A˚) but almost entirely absent in its phosphine-assisted counterpart (Ni-F = 2.81 A˚). In contrast to the oxidative addition pathways that are very similar for activation in the 2- and 4-positions, we find phosphine-assisted C-F activation via pathway 4 at the 2position to be substantially different from that for reaction at the 4-site. The metallophosphorane intermediate, MP(2), again features an approximately planar Ni(II) center, but the nitrogen of the pyridyl ring now occupies the fourth coordination site (Ni-N = 1.97 A˚), which was vacant in MP(4). The

η2-coordination mode of the pyridyl ligand in MP(2) is reminiscent of benzyne complexes,37 and a number of related pyridin-1,2-diyl complexes have been characterized experimentally with early transition metal centers,38 including one tetrafluoro example.38f Complexes of the all-carbon analogue, tetrafluorobenzyne, are also well established, and Jones and coworkers have postulated that a tetrafluorobenzyne complex of zirconium is an intermediate in the activation of aromatic C-F bonds.39 In the context of late transition metal chemistry, Hughes and co-workers have also shown that pentafluorophenyl complexes M(C6F5) (M = Rh, Ir) can be converted to M(tetrafluorobenzyne) complexes by reaction with BuLi.40 The potential well (37) (a) Buchwald, S. L.; Nielsen, R. B. Chem. Rev. 1988, 88, 1047. (b) Hughes, R. P.; Laritchev, R. B.; Williamson, A.; Incarvito, C. D.; Zakharov, L. N.; Rheingold, A. L. Organometallics 2002, 21, 4873. (c) Retbøll, M.; Edwards, A. J.; Rae, A. D.; Willis, A. C.; Bennett, M. A.; Wenger, E. J. Am. Chem. Soc. 2002, 124, 8348. (38) (a) Neithamer, D. R.; Parkanyi, L.; Mitchell, J. F.; Wolczanski, P. T. J. Am. Chem. Soc. 1988, 110, 4421. (b) Arndt, S.; Elvidge, B. R.; Zeimentz, P. M.; Spaniol, T. P.; Okuda, J. Organometallics 2006, 25, 793. (c) Krut'ko, D. P.; Kirsanov, R. S.; Belov, S. A.; Borzov, M. V.; Churakov, A. V.; Howard, J. A. K. Polyhedron 2007, 26, 2864. (d) Zhu, G.; Tanski, J. M.; Churchill, D. G.; Janak, K. E.; Parkin, G. J. Am. Chem. Soc. 2002, 124, 13658. (e) Bradley, C. A.; Lobkovsky, E.; Chirik, P. J. J. Am. Chem. Soc. 2003, 125, 8110. (f) Spannenberg, A.; Jager-Fiedler, U.; Arndt, P.; Rosenthal, U. Z. Kristallogr.-New Cryst. Struct. 2005, 220, 253. (g) Jordan, R. F.; Taylor, D. F.; Baenziger, N. C. Organometallics 1990, 9, 1546. (h) Scott, J.; Basuli, F.; Fout, A. R.; Huffman, J. C.; Mindiola, D. J. Angew. Chem., Int. Ed. 2008, 47, 8502. (i) Ozerov, O. V.; Pink, M.; Watson, L. A.; Caulton, K. G. J. Am. Chem. Soc. 2004, 126, 2105. (39) Kraft, B. M.; Lachicotte, R. J.; Jones, W. D. Organometallics 2002, 21, 727. (40) (a) Hughes, R. P.; Williamson, A.; Sommer, R. D.; Rheingold, A. L. J. Am. Chem. Soc. 2001, 123, 7443. (b) Hughes, R. P.; Laritchev, R. B.; Williamson, A.; Incarvito, C. D.; Zakharov, L. N.; Rheingold, A. L. Organometallics 2002, 21, 4873.

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Figure 2. Optimized geometries of stationary points for activation of the C-F bonds in the 4- and 2-positions . Hydrogen atoms have been removed for clarity.

for MP(2) is even shallower than that for MP(4), and indeed it is debatable whether this species would have even a transient existence before decomposing to the metal center (via FtransferTS(2)). In the context of the overall reaction mechanism, however, the most significant feature is that coordination of the nitrogen is already established in the preceding transition state, PA-TS(2) (Ni-N = 1.93 A˚). The NLMOs of PATS(2)

shown in Figure 4 confirm that the nitrogen-based lone pair features a substantial delocalization tail on the nickel center. In energetic terms, the neighboring group effect stabilizes the transition state such that it lies 7.2 kcal/mol below the reactants, some 12.2 kcal/mol below the corresponding transition state for activation at the 4-position. While the initial C-F activation step remains clearly rate-limiting, the gross effect

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Nova et al.

Figure 3. Potential energy surface for the phosphine-assisted pathway (pathway 4) for activation of the C-F bonds in the 4- and 2positions. Energies are given in kcal/mol.

of the neighboring group participation is to accelerate the phosphine-assisted C-F activation pathway such that is now favored over the oxidative addition pathways described above.41 Most pertinently, the neighboring group participation reduces the barrier to only 16.4 kcal/mol, consistent with a rapid reaction at room temperature. Our focus on pathway 4 in the preceding paragraphs was motivated by the fact that we have never observed nickel alkyls, which could in principle arise from the alternative phosphine-assisted pathways 2 and 3 shown in Scheme 2. There are both thermodynamic and kinetic reasons: the absence of nickel alkyl species compared to their platinum analogues can be traced to the more rapid increase in M-C bond strength relative to M-F bond strength as we descend the group, resulting in destabilization of the pathway 2.17 More specifically, pathways 2 and 3 are significantly less accessible than simple oxidative addition for activation at the 4-position. The transition state for pathway 2 (concerted C-F activation/Me transfer) lies at þ3.6 kcal/mol compared (41) The arguments put forward in the previous paragraphs suggest that the neighboring group effect should favor activation at the 2position if phosphine-assisted pathways prevail over oxidative addition. Why, then, do we observe activation at the 4- rather than 2-position for the corresponding reactions with platinum, where both computational and experimental evidence confirms a prominent role for metallophosphoranes? The transition-state structure for activation at the 2-position does indeed show evidence for neighboring group participation by nitrogen, albeit not as conspicuous as in the nickel analogue (Pt-N = 2.35 A˚, Ni-N 1.98 A˚), probably because the greater stability of the Pt(II) oxidation state reduces the need for donation of electron density from the pyridyl ligand. Moreover, the Pt-C bonds (which are fully formed at the transition state) are very strong, and this favors activation in the 4position. Thus the rather weak neighboring group effect in the platinum system is unable to overcome the intrinsic preference for activation at the 4-position dictated by the M-C bond strength.

Figure 4. Selected natural localized molecular orbitals (NLMOs) of PA-TS(4) (a and b) and PA-TS(2) (c, d, and e).

to -3.3 for pathway 1 (oxidative addition). The surface for pathway 3 is coincident with that for pathway 4 up to MP(4), which then decomposes via methyl, rather than fluoride, transfer. Although this methyl transfer proceeds via a relatively stable transition state at -13.3 kcal/mol, the overall barrier for this process would still reflect the high energy of PA-TS(4) (þ5.0 kcal/mol) associated with the initial C-F activation. For activation at the 2-position the situation is

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Scheme 3. Mechanism of Formation of Nickel 2-Tetrafluoropyridyl Complex

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the 2-product. Thus the observed regioselectivity can be explained only by invoking the phosphine-assisted pathway of Scheme 3, which leads exclusively to attack at the 2-position due to the neighboring group assistance by the pyridyl nitrogen. We therefore conclude that the phosphine-assisted pathway dominates the reaction chemistry in solution, giving rise to a preference for C-F activation at the 2-position, while the smaller quantities of products derived from activation at the 3- and 4-positions probably arise from conventional oxidative addition pathways.

Conclusions even more clear-cut because pathway 2 is absent entirely: all attempts to locate the appropriate transition state converged instead on PA-TS(2) (pathway 4). Thus any alkyl product could be formed only from decomposition of MP(2) via methyl, rather than fluoride, transfer. While MP(2) is accessible (via PATS(2)), its collapse via methyl transfer (transition state at -3.6 kcal/mol) is much less favorable than the corresponding fluoride transfer discussed above (FtransferTS(2), -15.5 kcal/mol). As a result, we can eliminate pathways 2 and 3 of Scheme 2, leaving us with pathway 4 as the only viable phosphine-assisted mechanism.

Discussion As a result of our detailed survey of the potential energy surfaces, we have been able to reduce the number of energetically accessible pathways for C-F activation by [Ni(PR3)2] species from 12 (the four pathways shown in Scheme 2 for each of three possible positions of attack) to just four: oxidative addition at the 4-, 3-, and 2-positions and a phosphine-assisted pathway that is effective only at the 2position, where neighboring group assistance from the pyridyl nitrogen can stabilize the relevant transition state (Scheme 3). Taking the isolated reactants as a common reference point, we find that the key transition states for the four surviving pathways lie within 2.5 kcal/mol of each other, which, given the simplicity of our computational model, precludes a definitive conclusion on the preferred pathway. We do not expect systematic errors associated with our choice of model phosphine, functional, or basis set to have a significant impact on the barriers to the three oxidative addition pathways, where the changes in structure and electron density along the reaction coordinate are very similar. It is not so clear, however, that the computational protocol will provide a balanced description of the energetics of the oxidative addition pathways relative to the phosphineassisted ones, where changes in geometry and electronic structure are more dramatic. Thus we need to interpret the relative heights of the barriers to oxidative addition and phosphine-assisted pathways with some caution. However, if the barrier on the phosphine-assisted pathway is underestimated by our chosen protocol, only the three competing oxidative addition pathways would be active, and the increase in barrier in the order 4- < 3- < 2- would leave us with no plausible explanation for the observed preference for

Our survey of the potential energy surfaces for C-F activation of pentafluoropyridine by [Ni(PR3)2] reveals that the observed regioselectivity has its origins in an entirely unexpected neighboring group effect involving the phosphine and the nitrogen of the attacking pentafluoropyridine. This neighboring group effect is active only when attack occurs at the C-F bond adjacent to the nitrogen center (i.e., at the 2-position of the pyridyl ring) such that the lone pair on nitrogen can coordinate to the nickel center. Moreover, it operates only when the reaction proceeds via a phosphineassisted pathway, in which the fluoride is initially passed from carbon to phosphorus to form a transient metallophosphorane intermediate before subsequently migrating to the metal center. This observation also explains why the regioselectivity reverts to attack at the 4-position when the phosphine ligands are replaced by carbenes, which cannot stabilize a migrating fluoride in the same way. At first glance, the chemistry of pentafluoropyridine with the platinum and nickel phosphines appears to be very different: the heavier congener attacks at the 4-position and forms metal alkyls, while the nickel substrate attacks at the 2-position and forms metal fluorides. Our investigation, however, suggests that a metallophosphorane intermediate is common to both metals, and the differences arise from the greater role of Ncoordination for nickel and the decomposition of this intermediate through alkyl transfer (Pt) or fluoride transfer (Ni) to the metal. Thus the preference for activation at the 2position observed in the experimental studies provides further compelling evidence that phosphine ligands, far from being mere spectators, play an active role in the chemistry of metal fluorides.

Acknowledgment. A.N.’s stay at the University of York was funded by the Ministerio de Ciencia y Tecnologia of Spain (Project BQU2002-04110-C02-02). M.R. acknowledges the award of a studentship from the University of York. Supporting Information Available: Potential energy surfaces for activation at the 3-position; optimized Cartesian coordinates and total energies of all stationary points for activation at the 2-, 4-, and 3-positions; optimized Cartesian coordinates and total energies of nickel alkyl complexes; full author list for ref 34. This material is available free of charge via the Internet at http:// pubs.acs.org.