CâN Bond Formation Reactions

Organometallics 2010, 29, 821–834 DOI: 10.1021/om900895t

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Palladium-Catalyzed C-H Activation/C-N Bond Formation Reactions: DFT Study of Reaction Mechanisms and Reactive Intermediates Zhuofeng Ke†,‡ and Thomas R. Cundari*,† †

Center for Advanced Scientific Computing and Modeling (CASCaM), Department of Chemistry, University of North Texas, Box 305070, Denton, Texas 76203-5070 and ‡School of Chemistry & Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, People’s Republic of China Received October 13, 2009

The mechanism and intermediates of palladium-catalyzed cascade C-H activation and C-N bond formation are investigated with density functional theory (DFT), modeling an experimental system, (benzo[h]quinoline)PdII(Cl)Py, and nitrogen source, PhINTs. For [PdCl4]2--catalyzed C-H activation, the reaction is predicted to proceed via a deprotonation mechanism induced by internal or external base; external base-induced deprotonation is suggested by calculations to be more favored in a water-assisted manner. The reaction barriers for the deprotonation pathways are ca. 12-16 kcal/mol. Electrophilic activation via an arenium intermediate and oxidative addition are less feasible. For the C-N bond formation process, a singlet Pd(IV) imido complex is revealed to be the key reactive intermediate. A concerted or dissociative imido transfer initiated from the Pd(IV) imido complex is the preferred mechanism (ΔHq = 10-13 kcal/mol). In contrast, another proposed intermediate, a triplet Pd(III) nitrene complex, is ∼15 kcal/mol higher in energy than the corresponding Pd(IV) imido complex. DFT studies indicate that triplet nitrene transfer is kinetically disfavored (ΔHq = ∼21 kcal/mol) versus imido transfer. Neither a concerted PhINTs transfer mechanism from a Pd-iminoiodinane intermediate nor a free nitrene insertion mechanism appears to be operative in the modeled system. Introduction Catalytic C-H bond functionalization by organometallic complexes is one of the most fundamental topics in modern *Corresponding author. E-mail: [email protected]. (1) Hartwig, J. F. Nature 2008, 455, 314–322. (2) (a) Godula, K.; Sames, D. Science 2006, 312, 67–72. (b) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417–424. (c) Bergman, R. G. Nature 2007, 446, 391–393. (d) Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507–514. (e) Herrerias, C. I.; Yao, X.; Li, Z.; Li, C. J. Chem. Rev. 2007, 107, 2546–2562. (f) M€ uller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905–2920. (g) Espino, C. G.; Du Bois, J. In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; p 379. (h) Johannsen, M.; Jorgensen, K. A. Chem. Rev. 1998, 98, 1689–1708. (3) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439–2463. (4) (a) Breslow, R.; Gellman, S. H. J. Chem. Soc., Chem. Commun. 1982, 1400–1401. (b) Breslow, R.; Gellman, S. H. J. Am. Chem. Soc. 1983, 105, 6728–6729. (5) (a) Zhang, J.; Chan, P. W. H.; Che, C. M. Tetrahedron Lett. 2005, 46, 5403–5408. (b) Mahy, J.-P.; Bedi, G.; Battioni, P.; Mansuy, D. Tetrahedron Lett. 1988, 29, 1927–1930. (c) Kohmura, Y.; Katsuki, T. Tetrahedron Lett. 2001, 42, 3339–3342. (d) Yang, J.; Weinberg, R.; Breslow, R. Chem. Commun. 2000, 531–532. (6) Liang, J. L.; Huang, J. S.; Yu, X. Q.; Zhu, N. Y.; Che, C. M. Chem.;Eur. J. 2002, 8, 1563–1572. (7) Mahy, J.-P.; Bedi, G.; Battioni, P.; Mansuy, D. New J. Chem. 1989, 13, 651–657. (8) Zhou, X. G.; Yu, X. Q.; Huang, J. S.; Che, C. M. Chem. Commun. 1999, 2377–2378. (9) (a) Au, S. M.; Huang, J. S.; Che, C. M.; Yu, W. Y. J. Org. Chem. 2000, 65, 7858–7864. (b) Liang, J. L.; Yuan, S. X.; Huang, J. S.; Yu, W. Y.; Che, C. M. Angew. Chem., Int. Ed. 2002, 41, 3465–3468. (c) Liang, J. L.; Yuan, S. X.; Huang, J. S.; Che, C. M. J. Org. Chem. 2004, 69, 3610–3619. (d) Au, S. M.; Zhang, S. B.; Fung, W. H.; Yu, W. Y.; Che, C. M.; Cheung, K. K. Chem. Commun. 1998, 2677–2678. (e) Yu, X. Q.; Huang, J. S.; Zhou, X. G.; Che, C. M. Org. Lett. 2000, 2, 2233–2236. (f) He, L.; Chan, P. W. H.; Tsui, W. M.; Yu, W. Y.; Che, C. M. Org. Lett. 2004, 6, 2405–2408. (g) Liang, J.-L.; Yu, X.-Q.; Che, C.-M. Chem. Commun. 2002, 124–125. r 2010 American Chemical Society

chemistry.1 C-H activation and C-N bond formation are widely used as synthetic tools to functionalize hydrocarbons to nitrogen-containing pharmaceuticals and bioactive molecules.2,3 Since early reports of amination of cyclohexane with Mn or Fe porphyrin catalysts,4 numerous metal catalysts have been developed, including Mn,5-8 Fe,4,7 Ru,6,8-10 Co,11 Rh,12 Pd,13-18 Cu,16,19 Ag,20 etc. In particular, recently reported Pd-catalyzed cascade C-H activation/C-N bond formation methods (Scheme 1) have attracted interest, as (10) Au, S. M.; Huang, J. S.; Yu, W. Y.; Fung, W. H.; Che, C. M. J. Am. Chem. Soc. 1999, 121, 9120–9132. (11) (a) Cenini, S.; Gallo, E.; Caselli, A.; Ragaini, F.; Fantauzzi, S.; Piangiolino, C. Coord. Chem. Rev. 2006, 250, 1234–1253. (b) Caselli, A.; Gallo, E.; Ragaini, F.; Ricatto, F.; Abbiati, G.; Cenini, S. Inorg. Chim. Acta 2006, 359, 2924–2932. (c) Ragaini, F.; Penoni, A.; Gallo, E.; Tollari, S.; Gotti, C. L.; Lapadula, M.; Mangioni, E.; Cenini, S. Chem.;Eur. J. 2003, 9, 249–259. (12) (a) M€ uller, P.; Baud, C.; N€ageli, I. J. Phys. Org. Chem. 1998, 11, 597–601. (b) Fruit, C.; Muller, P. Helv. Chim. Acta 2004, 87, 1607–1615. (c) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598–600. (d) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378–15379. (e) Liang, J. L.; Yuan, S. X.; Chan, P. W. H.; Che, C. M. Org. Lett. 2002, 4, 4507–4510. (f) Yamawaki, M.; Tsutsui, H.; Kitagaki, S.; Anada, M.; Hashimoto, S. Tetrahedron Lett. 2002, 43, 9561–9564. (13) Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800–5807. (14) (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560–14561. (b) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318–5365. (15) (a) Brice, J. L.; Harang, J. E.; Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 2868–2869. (b) Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2003, 125, 12996–12997. (16) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4, 4041–4047. (17) Dick, A. R.; Remy, M. S.; Kampf, J. W.; Sanford, M. S. Organometallics 2007, 26, 1365–1370. (18) Thu, H. Y.; Yu, W. Y.; Che, C. M. J. Am. Chem. Soc. 2006, 128, 9048–9049. Published on Web 01/28/2010

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Organometallics, Vol. 29, No. 4, 2010

Scheme 1. Cascade C-H Bond Activation and C-N Bond Formation Catalysis

they exhibit several novel characteristics. As compared with the widely utilized Pd-catalyzed amination of aryl halides, Pd-catalyzed cascade C-H activation/C-N bond formation is more atom economical, and synthetically convenient, as it does not require prefunctionalization of a substrate to form the halide coupling partner. Another intriguing merit is that the cascade method has novel regioand chemoselectivity.3,13,14,18 For example, aminations of unactivated aromatic and aliphatic 1° C-H bonds, which are rare in the literature, can be achieved with Pd-catalyzed cascade C-H activation and C-N bond formation methods.13,17,18 In contrast, typical nitrene insertion into C-H bonds has a selectivity paralleling the C-H bond dissociation enthalpy, preferring tertiary, allylic, benzylic, or C-H bonds R to heteroatoms.3,10,21,22 Despite increasing experimental investigations,3,13,14,17,18,23 reaction mechanisms of Pd-catalyzed cascade C-H activation and C-N bond formation remain elusive, in large part due to difficulties in experimental characterization of reactive intermediates. Several plausible mechanistic hypotheses have been proposed. As shown in Scheme 2, the first step was proposed to be formation of a palladacyclic intermediate via C-H bond activation.24-26 An electrophilic activation mechanism via metal arenium intermediates was proposed for this cyclopalladation process with aromatic substrates.26 In the electrophilic activation mechanism, C-H bond breaking was suggested to be rate-determining.27 However, it was suggested that the Pd(II) ion is not a typical electrophile in the reaction medium.27 An oxidative addition mechanism involving a Pd(IV) intermediate was also proposed,28 and a C-H 3 3 3 PdII agostic (19) (a) Albone, D. P.; Aujla, P. S.; Taylor, P. C. J. Org. Chem. 1998, 63, 9569–9571. (b) Hamilton, C. W.; Laitar, D. S.; Sadighi, J. P. Chem. Commun. 2004, 1628–1629. (c) Diaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.; Trofimenko, S.; Perez, P. J. J. Am. Chem. Soc. 2003, 125, 12078–12079. (d) Fructos, M. R.; Trofimenko, S.; Diaz-Requejo, M. M.; Perez, P. J. J. Am. Chem. Soc. 2006, 128, 11784–11791. (e) Chen, X.; Hao, X. S.; Goodhue, C. E.; Yu, J. Q. J. Am. Chem. Soc. 2006, 128, 6790–6791. (20) Cui, Y.; He, C. Angew. Chem., Int. Ed. 2004, 43, 4210–4212. (21) Lin, X. F.; Zhao, C. Y.; Che, C. M.; Ke, Z.; Phillips, D. L. Chem.-Asian J. 2007, 2, 1101–1108. (22) Lin, X.; Che, C.-M.; Phillips, D. L. J. Org. Chem. 2008, 73, 529– 537. (23) (a) Tsang, W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7603–7610. (b) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932–1934. (c) JordanHore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J . Am. Chem. Soc. 2008, 130, 16184–16186. (d) Tang, S.; Peng, P.; Pi, S. F.; Liang, Y.; Wang, N. X.; Li, J. H. Org. Lett. 2008, 10, 1179–1182. (e) Muniz, K.; Hovelmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130, 763–773. (f) Wasa, M.; Yu, J. Q. J. Am. Chem. Soc. 2008, 130, 14058–14059. (g) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9, 2931–2934. (h) Rogers, M. M.; Wendlandt, J. E.; Guzei, I. A.; Stahl, S. S. Org. Lett. 2006, 8, 2257–2260. (i) Beccalli, E. M.; Broggini, G.; Paladino, G.; Penoni, A.; Zoni, C. J. Org. Chem. 2004, 69, 5627–5630. (24) Cope, A. C.; Siekman, R. W. J. Am. Chem. Soc. 1965, 87, 3272– 3273. (25) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. Rev. 2005, 105, 2527–2572. (26) Ryabov, A. D. Chem. Rev. 1990, 90, 403–424. (27) Ryabov, A. D.; Sakodinskaya, I. K.; Yatsimirsky, A. K. J. Chem. Soc., Dalton Trans. 1985, 2629–2638. (28) Canty, A. J.; van Koten, G. Acc. Chem. Res. 1995, 28, 406–413.

Ke and Cundari

complex assumed to be a key intermediate.29 Recently, computational studies of Pd(OAc)2-promoted cyclopalladations suggested a mechanism involving intramolecular H-transfer via a six-membered cyclic transition state.30,31 These acetateassisted deprotonation processes are proposed to operate via a C-H agostic intermediate or a η2-arene complex. However, less attention has been paid to deprotonation mechanisms assisted by external base,32,33 although recent experiments observed that cyclometalation is sensitive to the nature of the external base for Os(II) systems.34 Therefore, it remains a challenge to determine the mechanism(s) of ligand-dependent cyclometalation.35 Upon reaction with nitrene sources, the palladacycle formed upon C-H activation was proposed to undergo a C-N bond formation reaction. There remains no direct experimental evidence as to reactive intermediates, if any, which directly precede nitrogen transfer and C-N bond formation. Metaliminoiodinane, metal-imido, or metal-nitrene (perhaps in singlet or triplet spin states) complexes that may result from the reaction of the metal catalyst with iminoiodinanes (ArIdNR) have been suggested as possible intermediates.17,18 Free nitrene (NR) derived from iminoiodinane decomposition was also proposed to have the possibility to directly insert into the Pd-C bond.18 The reactive intermediates remain unclear, thus leading to several plausible reaction mechanisms. For example, with a metal-iminoiodinane complex as an intermediate, C-N bond formation may proceed through the concerted transfer of the PhINTs into the Pd-C bond via a three-centered transition state accompanied by the dissociation of PhI.7,8,17 A metal-imido (formally [M]qþ2(NR)2-) would be expected to lead to an imido transfer reaction mechanism.17 A metal-nitrene ([M]q(NR)0) could prefer a reaction mechanism involving nitrene transfer into the Pd-C bond via a singlet or a triplet pathway.21,36 Since it is often extremely difficult to experimentally distinguish such possibilities, computational methods are necessary to provide deeper insight into reaction mechanisms. Via the analysis of plausible reactive intermediates and the comparison of proposed reaction mechanisms, this research aims to evaluate the catalytic cycle of cascade Pd-catalyzed C-H activation/C-N formation and provide information to advance the development of these catalysts and to further the goal of rational catalyst design.

Computational Methods Density functional theory (DFT),37 B3LYP (Becke’s three-parameter hybrid functional),38 the LYP correlation (29) Vigalok, A.; Uzan, O.; Shimon, L. J. W.; Ben-David, Y.; Martin, J. M. L.; Milstein, D. J. Am. Chem. Soc. 1998, 120, 12539–12544. (30) (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc. 2005, 127, 13754–13755. (b) Bielsa, R.; Navarro, R.; Urriolabeitia, E. P.; Lledos, A. Inorg. Chem. 2007, 46, 10133–10142. (31) (a) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066–1067. (b) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848–10849. (32) Lafrance, M.; Lapointe, D.; Fagnou, K. Tetrahedron 2008, 64, 6015–6020. (33) Pascual, S.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. Tetrahedron 2008, 64, 6021–6029. (34) Ceron-Camacho, R.; Morales-Morales, D.; Hernandez, S.; Le Lagadec, R.; Ryabov, A. D. Inorg. Chem. 2008, 47, 4988–4995. (35) Davies, D. L.; Donald, S. M. A.; Al-Duaij, O.; Macgregor, S. A.; Polleth, M. J. Am. Chem. Soc. 2006, 128, 4210–4211. (36) M€ uller, P.; Bolea, C. Helv. Chim. Acta 2002, 85, 483–494. (37) Parr, R. G.; Yang, W. Density-functional Theory of Atoms and Molecules; Oxford Univ. Press: Oxford, 1989. (38) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.

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Scheme 2. Reaction Mechanisms and the Catalytic Cycle Studied in This Researcha

a

The Roman numeral in each reaction step refers to the corresponding discussion section in the text.

functional,39 and VWN40 were utilized to fully optimize all the initial geometries on singlet or triplet potential energy surfaces without symmetry or geometric constraints, in conjunction with the Stevens (SBK) valence basis sets (valence triple-ξ for transition metals; valence double-ξ for main group elements) and effective core potentials (ECPs) for all heavy atoms and the -31G basis set for hydrogen. The basis sets of main group elements were augmented with a d-polarization function (i.e., ξd = 0.8 for C, N, and O; ξd = 0.75 for Cl; ξd = 0.65 for S; ξd = 0.302 for I). This basis set combination, termed BS1, has been found to be reliable in the computations of ground states, excited states, and transition states for many diverse organometallic systems (see the comparison with X-ray structure below).41 Frequency calculations at the B3LYP/BS1 level of theory have been carried out to confirm stationary points as minima (zero imaginary frequencies) or transition states (one imaginary frequency) and to obtain the zero-point energies and the thermal correction data in the gas phase at 1 atm and 298.15 K. Intrinsic reaction coordinates (IRC)42 were employed to verify the connection of the transition states to two relevant minima. The thermodynamic stability of singlet and triplet spin states of nitrenes is a long-standing issue.43 As compared with highlevel CCSD(T)44 calculations, the widely used B3LYP was reported to overestimate the singlet-triplet splitting (ΔEST) by (39) Lee, C. T.; Yang, W. T.; Parr, R. G. Phys. Rev. B 1988, 37, 785– 789. (40) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200– 1211. (41) See, for example: Cundari, T. R.; Dinescu, A.; Kazi, A. B. Inorg. Chem. 2008, 47, 10067–10072. (42) (a) Fukui, K. J. Phys. Chem. 1970, 74, 4161–4163. (b) Fukui, K. Acc. Chem. Res. 1981, 14, 363–368. (43) Gritsan, N. P.; Platz, M. S.; Borden, W. T. In Computational Methods in Photochemistry; Kutateladze, A. G., Ed.; Boca Raton: Talor & Francis, 2005; Vol. 13, p 235. (44) Raghavachari, K.; Trucks, G. W.; Pople, J. A.; Head-Gordon, M. Chem. Phys. Lett. 1989, 157, 479–483. (45) Pritchina, E. A.; Gritsan, N. P.; Bally, T.; Autrey, T.; Liu, Y.; Wang, Y.; Toscano, J. P. Phys. Chem. Chem. Phys. 2003, 5, 1010–1018. (46) Travers, M. J.; Cowles, D. C.; Clifford, E. P.; Eillison, G. P. J. Am. Chem. Soc. 1992, 114, 8699–8701.

8-10 kcal/mol for some nitrenes.45,46 On the contrary, GGA (generalized gradient approximation) and meta-GGA (mGGA) DFT functionals without Hartree-Fock (HF) exchange estimate the ΔEST more accurately; the resulting ΔEST are comparable to experimental results or CCSD(T) calculations.21,46 Since the B3LYP/BS1 optimized structures are deemed reliable, to evaluate appropriate DFT functionals to refine the energies of all the optimized species in different spin states, calculations were carried out with different functionals and the CCSD(T) method. The ECP basis sets augmented with additional p and f functions47 were used for palladium, SBK(p,2d) was used for iodine, and 6-31þG* was used for other elements (termed BS2) in these single-point energy calculations. To further validate the results, we also performed CCSD(T) single-point calculations with 6-311þþG** for main group elements and ECP basis sets augmented with additional p and f functions40 for palladium (termed BS3). Due to the expense of the CCSD(T) calculations, simplified models were used for the comparison of ΔEST (Chart 1) and fixed in geometry to assess the electronic structures of the full models. As shown in Table 1, CCSD(T)/BS3 predicts an ΔEST value of 18.3 kcal/mol for Pd4A0 and 14.4 kcal/mol for Pd4B0 . CCSD(T)/BS2 predicts similar values. Hybrid DFT functionals perform much worse than the DFT functionals without HF exchange, especially BHandHLYP, which contains a large (50%) contribution of HF exchange and yields a reverse prediction in thermodynamic stability for the singlet and triplet states. B3LYP also deviates significantly from the CCSD(T) results. Similar results were found in previous reports, i.e., that “B3” methods (B3LYP or B3PW91) underestimate ΔEST values for Rh2(II,II) nitrene complexes.21 GGA and m-GGA DFT functionals without HF exchange are seen to be more accurate insofar as ΔEST values are concerned (ranging from 11.5 to 16.4 kcal/mol for Pd4A0 and 8.7 to 12.8 kcal/mol for Pd4A0 ). Among the tested GGA and m-GGA DFT functionals, BP86 has the (47) (a) Couty, M.; Hall, M. B. J. Comput. Chem. 1996, 17, 1359– 1370. (b) Ehlers, A. W.; Biihme, M.; Dapprich, S.; Gobbi, A.; Hijllwarth, A.; Jonas, V.; Kiihler, K. F.; Stegmann, R.; Veldkamp, A.; Frenking, G. Chem. Phys. Lett. 1993, 208, 111–114.

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Table 1. Comparison of ΔEST (kcal/mol) for Pd-Nitrene/Imido Intermediates Calculated by Different Methods with BS2/BS3 Basis Sets (see Computational Methods)a

Pd4A Pd4B0 Pd4A Pd4B

0

BHandHLYP/BS2

B3LYP/BS2

BLYP/BS2

mPWKCIS/BS2

BPW91/BS2

BPBE/BS2

mPWPW91/BS2

-0.6 -5.3 -2.2 -5.2

9.0 5.4 7.9 5.4

11.5 8.7 10.6 8.6

14.8 11.4 14.4 12.0

15.3 12.0 14.7 12.5

15.7 12.4 15.1 12.9

15.9 12.4 15.6 13.1

B97D/BS2

M06L/BS2

BP86/BS2

MP2/BS2(BS3)

B2PLYPD/BS2(BS3)

CCSD(T)/BS2

Pd4A0 9.4 12.5 16.4 52.3(46.5) 20.0(19.6) 5.6 8.4 12.8 40.7(40.8) 15.1(14.6) Pd4B0 11.8 13.6 15.9 Pd4A 8.7 11.0 13.5 Pd4B a See Chart 1 for definitions of Pd4A0 and Pd4B0 (ΔEST = ET - ES; ET/S denotes energy of triplet/singlet state).

Chart 1. Pd4A and Pd4B and their Simplified Models (Pd4A0 and Pd4B0 )

most similar results as compared to CCSD(T) values, Table 1. We have considered DFT methods that are able to include middle/long-range noncovalent interactions, including Truhlar’s DFT and Grimme’s dispersion functionals.48,49 We also considered the performance of double hybrid methods, which include MP2-like correlation.50 As shown in Table 1, the DFT functionals with dispersion correction do not perform as well as BP86 for the Pd-nitrene/imido system, based on the CCSD(T) benchmark. It is interesting that both the double hybrid DFT and BP86 can provide ΔEST values close to CCSD(T) results. Considering the computational requirements, BP86 has been used for this study. Using BP86/BS2 to evaluate the ΔEST for full chemical models, calculated values of 15.9 kcal/mol for Pd4A and 13.5 kcal/mol for Pd4B are obtained. In this study, gasphase enthalpies are calculated from BP86/BS2//B3LYP/BS1 energies with thermal corrections obtained at the B3LYP/BS1 level of theory. All calculations were performed with the Gaussian 03 package.51 To consider solvation effects, the Integral Equation Formalism Polarization Continuum Model (IEFPCM; radii = Pauling)52 was applied with methanol and tetrahydrofuran (THF) as solvents for the cyclopalladation reaction and the C-N bond formation reaction, respectively, as per experimental conditions.17 The solvation free energies were obtained at the BP86/BS2/IEF-PCM level of theory by using B3LYP/BS1 gas-phase structures, unless stated otherwise.

Results and Discussion Inspired by discussions in the literature, we examined the detailed reaction mechanisms for Pd-catalyzed C-H activation/C-N bond formation reactions depicted in Scheme 2. A palladacyclic complex (Pd2A or Pd2B) of benzo[h]quinoline (48) Zhao, Y.; Truhlar, D. G. J. Chem. Phys. 2006, 125, 194101– 194118. (49) Grimme, S. J. Comput. Chem. 2006, 27, 17871–1799. (50) Schwabe, T.; Grimme, S. Phys. Chem. Chem. Phys. 2007, 9, 3397–3406. (51) Frisch, M. J.; et al. et al. Gaussian 03, Revision D.01; Gaussian, Inc.: Wallingford, CT, 2004. (52) (a) Cances, M. T.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107, 3032–3037. (b) Mennucci, B.; Cances, E.; Tomasi, J. J. Phys. Chem. B 1997, 101, 10506–10517. (c) Tomasi, J.; Mennucci, B.; Cances, E. J. Mol. Struct. (THEOCHEM) 1999, 464, 211–226. (d) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106, 5151–5158.

18.8 14.9

CCSD(T)/BS3 18.3 14.4

Chart 2. Proposed Transition States for Reaction Mechanisms of Cyclopalladation: Electrophilic Activation (via Metal Arenium), Oxidative Addition, and H-Transfer/Deprotonation (by Either Internal or External Base) Mechanisms

(Bzq) was chosen as a model system, which is representative of experiments.17 In this paper, the subscript A/B indicates that the pyridine (Py) is trans/cis to the nitrogen of Bzq in the complex. Such a palladacyclic complex is formed via a C-H activation process between the Pd(II) complex (Pd1) and Bzq. With [N-(p-tolylsulfonyl)imino]phenyliodinane (PhINTs) as the reagent, complex Pd2 subsequently undergoes a C-N bond formation reaction to form complex Pd5. It remains unclear which species (Pd3 or Pd4) is the most plausible reactive intermediate for this process. The electronic structures of intermediates Pd3 and Pd4, as well as the corresponding mechanisms, are also of interest with respect to further understanding the properties of the investigated catalysts, so as to improve their reactivity and selectivity, to expand their reaction scope, and to inspire new catalyst design. (i). Cyclopalladation of Benzo[h]quinoline. Palladium salts are widely used reagents for cyclopalladation.25,26 As compared with related systems, the mechanisms of [PdCl4]2-catalyzed cyclopalladation are less known. Cyclopalladation of Bzq by the [PdCl4]2- system to form the palladacyclic complexes17,53,54 is studied by DFT calculations in this paper. The examined mechanisms include electrophilic activation via a metal arenium intermediate, oxidative addition, and deprotonation (H-transfer) induced by either an internal or external base. The transition states for these possibilities are depicted in Chart 2. In the reaction system, the catalytic amount of K2PdCl4 reagent may be expected to mainly exist as [PdCl4]2- or [PdCl3(H2O)]- in solution (MeOH/H2O), according to the reported distribution of [PdCln(H2O)4-n]2-n as a function of chloride concentration.55 With respect to (53) (a) Bhawmick, R.; Biswas, H.; Bandyopadhyay, P. J. Organomet. Chem. 1995, 498, 81–83. (b) Cockburn, B. N.; Howe, D. V.; Keating, B. F.; Johnson, B. F. G.; Lewis, J. J. Chem. Soc., Dalton Trans. 1973, 404–410. (54) Dick, A. R.; Kampf, J. W.; Sanford, M. S. Organometallics 2005, 24, 482–485. (55) (a) Cruywagen, J. J.; Kriek, R. J. J. Coord. Chem. 2007, 60, 439– 447. (b) Boily, J. F.; Seward, T. M. Geochim. Cosmochim. Acta 2005, 69, 3773–3789.

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Figure 1. Energy profiles for the cyclopalladation of Bzq catalyzed by the [PdCl4]2- system. The relative enthalpies are given in kcal/ mol relative to Pd1 considering solvation effects (IEF-PCM; solvent = methanol; radii = Pauling). aThe relative enthalpies of C1 and C2 are obtained with BP86/BS1 optimized structures.

either [PdCl4]2- or [PdCl3(H2O)]- species, [PdCl3(Bzq)]- is a reasonable starting complex for the cyclopalladation. With [PdCl3(Bzq)]- as the starting material, different reaction pathways were studied (Figure 1). The energetic data quoted here include solvation effects via the IEF-PCM model with pure methanol as the solvent. The experimental media is a mixed MeOH/H2O solvent. Our calculations indicate that methanol and water have a similar solvation effect for the investigated reactions. The implicit continuum of methanol is thus assumed to be an appropriate model for the mixed solvent. Electrophilic activation involving an arenium intermediate is calculated to be less likely for cyclopalladation of Bzq by [PdCl4]2-. Although generally assumed as a key intermediate during cyclopalladation, areniums (C3 and C4) are highly thermodynamically unstable via DFT calculations.30 The instabilities of the arenium intermediates are mainly due to the high strain of sp3 hybridization at the nucleophilic carbon and the loss of aromatic character of the Bzq ligand. Thus, it seems that deprotonation occurs concertedly during the electrophilic attack of the Pd(II) center on the C-H bond of Bzq, without the formation of arenium intermediates. Deprotonation of Bzq can be induced by either an internal base (i.e., ligand) or external base. Our studies indicate that [PdCl3(Bzq)]-, Pd1, can undergo a direct deprotonation assisted by the internal base Cl- to form the palladacyclic intermediate, C6, via a four-membered ring transition state, TS(Pd1-C6). In TS(Pd1-C6), the Cl- (Pd 3 3 3 Cl, 3.31 A˚) abstracts a proton from the ortho-C-H bond of Bzq (H 3 3 3 Cl, 2.22 A˚), accompanied with a forming Pd-C bond (2.41 A˚), Figure 2. This intramolecular deprotonation has a barrier of 15.1 kcal/mol. IRC analysis found no C-H agostic

intermediate; the TS(Pd1-C6) directly connects to Pd1. In contrast, the external base-induced deprotonation pathway initiates from a C-H agostic intermediate, C1, formed by dissociation of a Cl- ligand from the Pd(II) center of Pd1. The dissociated Cl- intermolecularly deprotonates the ortho-C-H bond of Bzq to yield palladacyclic product via transition state TS(C1-C6). In TS(C1-C6), the H 3 3 3 Cl distance is calculated to be 2.93 A˚, and the forming Pd-C bond has a distance of 2.33 A˚. The reaction barrier for this intermolecular deprotonation pathway is calculated to be 15.6 kcal/ mol, quite similar to that of the intramolecular deprotonation pathway via TS(Pd1-C6). However, another possible intramolecular deprotonation pathway from the C-H agostic intermediate C2 is found to be kinetically much less feasible, with a calculated barrier of 32.0 kcal/mol relative to Pd1. The transition state TS(C2-C6) interestingly resembles the oxidative hydrogen migration.56 Pd1 may also undergo an oxidative addition mechanism to form an octahedral Pd(IV) intermediate, C5, which then leads to palladacyclic product via reductive elimination of HCl. DFT calculations found that the transition state TS(Pd1-C5) for this pathway has a barrier of 23.0 kcal/mol. Hence, as compared with intra/inter-deprotonation mechanisms, this oxidative addition mechanism seems to be less feasible. All of the C-H bond activation reaction pathways examined in this research are summarized in Figure 1. It is seen that the intra/inter-deprotonation pathways entail similar barriers (around 15.5 kcal/mol) and are more plausible for (56) Oxgaard, J.; Periana, R. A.; Goddard, W. A., III. J. Am. Chem. Soc. 2004, 126, 11658–11665.

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Figure 2. Energy profiles for the cyclopalladation of Bzq by [PdCl4]2- in the water-assisted inter-deprotonation reaction pathway. The relative enthalpies are given in kcal/mol considering solvation effects (IEF-PCM, solvent = methanol, radii = Pauling). aThe relative enthalpy of C9 is obtained with the BP86/BS1 optimized structure; C9 is lower in energy than TS(C9-C10) by 0.7 kcal/mol without considering the zero-point energy (ZPE) at the B3LYP/BS1 level of theory.

the cyclopalladation of Bzq by [PdCl4]2-. Both of these pathways have barriers consistent with the experimental values in the range 11-18 kcal/mol for Pd(II)-mediated cyclopalladation.25,26 Both TS(Pd1-C6) and TS(C1-C6) involve C-H bond making/breaking, suggesting that a significant kinetic isotope effect should be observed in KIE studies, which is found in related cyclopalladation systems.57 Although it is difficult to distinguish between intermolecular and intramolecular deprotonation mechanisms on the basis of energetic considerations, we currently prefer the former for several reasons. (1) Direct observation of the deprotonation of an aromatic C-H bond induced by external base has been reported in Ru and Co systems.58 (2) There is evidence suggesting that cyclopalladation should occur through a 14-electron intermediate with aromatic C-H bonds within the coordination plane of the palladium center.25,26,59 (3) Recent studies of cyclopalladation by a palladium complex bearing a bidentate diphospine implied deprotonation induced by external base.33 Experimentally, the cyclopalladation reaction is carried out in a protic solvent (MeOH/H2O). We hypothesized that solvent molecules may thus play an important role in baseinduced deprotonation, since protic solvents like water have been shown to be important for proton transfer processes.60 DFT studies of the inter-deprotonation reaction pathway with an assisting water molecule are depicted in Figure 2. The reactant complex C8, with a weak interacting water (57) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285–13293. (58) (a) Haller, L. J. L.; Page, M. J.; Macgregor, S. A.; Mahon, M. F.; Whittlesey, M. K. J. Am. Chem. Soc. 2009, 131, 4604–4605. (b) Kanamori, K.; Broderick, W. E.; Jordan, R. F.; Willett, R.; Legg, J. I. J. Am. Chem. Soc. 1986, 108, 7122–7124. (59) Deeming, A. J.; Rothwell, I. P.; Hursthouse, M. B.; New, L. J. Chem. Soc., Dalton Trans. 1978, 1490–1496. (60) Some recent examples: (a) Rossin, A.; Gonsalvi, L.; Phillips, A. D.; Maresca, O.; Lledos, A.; Peruzzini, M. Organometallics 2007, 26, 3289–3296. (b) Kamachi, T.; Yoshizawa, K. J. Am. Chem. Soc. 2005, 127, 10686–10692. (c) Phillips, D. L.; Zhao, C.; Wang, D. J. Phys. Chem. A 2005, 109, 9653–9673.

molecule, is calculated to be exergonic by 1.2 kcal/mol at the BP86/BS2//B3LYP/BS1 level of theory versus Pd1. C8 leads to a C-H agostic intermediate C9 with Cl- dissociation, uphill by 12.1 kcal/mol, which then goes through the transition state TS(C9-C10) to form the palladacyclic product C10. Unlike TS(C1-C6), TS(C9-C10) has a bridging water to help abstract the proton from the ortho-C-H of Bzq (H 3 3 3 O, 1.43 A˚), Figure 2. The bridging water donates another proton to connect with Cl- (H 3 3 3 Cl, 1.90 A˚), assisting the activation of the C-H bond by external Cl-. In contrast, DFT studies found no water-assisted intramolecular deprotonation, because the four-membered ring transition state, TS(Pd1-C6), has no room to incorporate a bridging water molecule. The water-assisted inter-deprotonation pathway has a barrier of only 11.9 kcal/mol, lower than calculated for the unassisted intra-deprotonation pathway (ΔHq = 15.1 kcal/mol). Therefore, our DFT calculations suggest that [PdCl4]2--catalyzed cyclopalladation proceeds more likely via deprotonation induced by an external base. In fact, the cyclometalation reactions have been reported to be sensitive to the nature of external bases for the related systems.34,61 The external base-induced deprotonation mechanism may also be practicable for other cyclopalladation systems. Recent experimental and computational studies also suggested an inter-deprotonation mechanism for Pd(OAc)2-promoted cyclopalladations.33 (ii). Palladacyclic PhINTs Complexes and Palladacyclic Nitrene/Imido Complexes. Transformation of Pd2 f Pd3 f Pd4. Despite increasing interest in Pd-catalyzed C-H activation and C-N bond formation reactions, it remains unclear which intermediates precede the formation of the C-N bond between the carbon of the C-Pd bond and the nitrene source. Computations were carried out for the transformations of Pd-PhINTs complexes and Pd-nitrene/ imido complexes, to reveal their electronic structures and to (61) (a) Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org. Chem. 2009, 74, 1826–1834. (b) Schipper, D. J.; Campeau, L. C.; Fagnou, K. Tetrahedron 2009, 65, 3155–3164.

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Scheme 3. Formation and Decomposition of Palladacyclic PhINTs Complexesa

a Superscript S refers to singlet species and T denotes triplet species. Enthalpy changes of Pd3 to triplet Pd4 are shown in blue. Enthalpies in parentheses (kcal/mol, considering solvation effects, IEF-PCM, solvent = THF, radii = Pauling) are relative to SPd4A. TPd3A and TPd3B are not stationary points on the global energy surface.

evaluate their thermodynamic and kinetic properties. According to the literature, the monomeric palladacyclic complex Pd2 can be generated in situ from dimeric C7 in pyridine (Py).17 The complex Pd2 then catalyzes the C-N bond formation reaction with a nitrogen source.17 There are two isomers (Pd2A, Py and N(Bzq) in trans positions; and Pd2B, Py and N(Bzq) in cis positions) for monomeric Pd2. Complex Pd2A is calculated to be more stable than Pd2B (lower in enthalpy by 3.0 kcal/mol). The energetic difference between Pd2A and Pd2B can be attributed to the transphobia effect62 or the antisymbiotic effect.63 According to these rules, a squareplanar Pd(II) complex should be more stable when the softer ligands are located in mutually cis positions (Csp2 and Py in our case). However, the difference in thermodynamic stability between Pd2A and Pd2B is quite small (only 3.0 kcal/mol). Thus, there will be facile equilibrium between them, assuming an accessible transition state for the process, in the reaction system. In fact, the coexistence of both cis and trans isomers was observed via NMR for a cyclopalladated imine.64 As shown in Scheme 3, upon treatment with PhINTs, Pd2A and Pd2B can bind the reagent to form SPd3A and S Pd3B with ΔH values of -5.0 and -5.6 kcal/mol, respectively. Superscript S refers to a singlet state and superscript T refers to a triplet state for stationary points that may have spin dichotomy in this paper. Several possible isomers of S Pd3 have been evaluated including trigonal-bipyramidal, square-pyramidal, and octahedral structures. Octahedral S Pd3A and SPd3B are the most stable isomers (Scheme 3). It is interesting that the PhI has a very weak interaction with NTs in the palladacyclic PhINTs complexes, with an I 3 3 3 N distance of 3.07/3.06 A˚ for SPd3A/SPd3B (shorter than the sum of van der Waals radii of N and I, 3.53 A˚). This is different from the previous DFT studies of Ru(II) and Rh2(II,II) phenyliodinane complexes, which have I-N distances of 2.08 and 2.10 A˚, respectively.21,22 The variations in I 3 3 3 N (62) (a) Vicente, J.; Abad, J. A.; Martı´ nez-Viviente, E.; Jones, P. G. Organometallics 2002, 21, 4454–4467. (b) Vicente, J.; Arcas, J. A.; Farkland, A. D.; Ramírez de Arellano, M. C. Chem.;Eur. J. 1999, 5, 3066– 3075. (63) (a) Pearson, R. G. Inorg. Chem. 1973, 12, 712–713. (b) Díez, A.; Fornies, J.; García, A.; Lalinde, C.; Moreno, M. T. Inorg. Chem. 2005, 44, 2443–2453. (64) Pregosin, P. S.; R€ uedi, R.; Anklin, C. Magn. Reson. Chem. 1986, 24, 255–258.

distance can be attributed to different electronic structures. As for the palladacyclic complex, the d8 metal center has no empty dz2 orbital to directly interact with the lone pair of nitrogen in PhINTs. The interaction of NTs and the metal center in SPd3 thus compels the breaking of the IdN bond. However, the (d7,d7) Rh2(II,II) and d6 Ru(II) do have empty dz2 orbitals with which to interact with the nitrogen lone pair, which should thus not affect the IdN bond too greatly (the original IdN bond length in PhINTs is calculated to be ∼2.05 A˚). A real transition state for PhI loss from PhINTs is not expected, as has been reported in the literature.65 Considering the very weak I 3 3 3 N interaction in SPd3, it is not surprising that the release of PhI from SPd3 to yield SPd4 is barrierless and thermodynamically favored (ΔH = -7.1 kcal/mol for SPd3A f SPd4A and -7.4 kcal/mol for SPd3B f SPd4B, respectively (Scheme 3)). Calculations reveal that a palladacyclic PhINTs complex in a triplet spin state is not a stationary point on the potential energy surface. The excitation of SPd3 to a triplet state, followed by geometry optimization, leads to triplet metal nitrene (TPd4) and the separate PhI (ΔH = 10.4 kcal/mol for S Pd3A f TPd4A and 6.2 kcal/mol for SPd3B f TPd4B). After geometric and conformational isomer searching, the most stable singlet or triplet Pd nitrene/imido complexes and their relative stabilities are shown in Scheme 3. SPd4A is the most stable structure among all Pd4 species. trans-SPd4B is close in energy to SPd4A (only higher by 2.0 kcal/mol in enthalpy). Triplet TPd4A and TPd4B are calculated to be much less stable than SPd4A, by 17.4 and 15.7 kcal/mol, respectively. However, triplet intermediates cannot yet be excluded from consideration, because the kinetic competence of triplet states is unknown (vide infra). Electronic Structure of Pd4. Electronic structure analysis is necessary to reveal the bonding in potential key intermediates that may directly precede the C-N bond formation step in the catalytic cycle. The optimized structures of SPd4A and T Pd4A and plausible valence bond descriptions are depicted in Figure 3. For singlet SPd4A, we envisage three possibilities: A, B, and C. In A, Pd remains in 2þ formal oxidation state and neutral nitrene coordinates to Pd with lone pairs. In B, (65) Brandt, P.; Sodergren, M. J.; Andersson, P. G.; Norrby, P. O. J. Am. Chem. Soc. 2000, 122, 8013–8020.

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Figure 3. Optimized structures of SPd4A and TPd4A with selected structural parameters (bond lengths in A˚) and the elucidation of their electronic structures. Hydrogen atoms are omitted for clarity.

the oxidation state of Pd is 4þ and the dianionic imido coordinates to Pd with lone pairs. In C, Pd also has an oxidation state of 4þ, and the imido nitrogen interacts with Pd with both a σ bond and a π bond. On the basis of our analysis of the electronic structure, we propose type B, a Pd(IV)-imido complex, as the most “correct” resonance structure for SPd4A for several reasons. First, SPd4A has an octahedral structure, which is the expected geometry for a Pd(IV) complex with its lowspin, d6 electronic configuration. However, the type A structure is formally a d8 complex, which is less likely to occupy an octahedral geometry (note the η2 coordination of NTs to Pd). In a d8 octahedral complex, in addition to the filled dxy, dyz, and dxz orbitals, one antibonding orbital (dx2-y2 or dz2) would be filled, which thus destabilizes the octahedral geometry. NBO analysis also revealed a higher oxidation state for the Pd center in SPd4A (NBO charge in Pd: þ1.04) than in Pd2A (NBO charge: þ0.63). Second, the π interaction between Pd and N(NTs) as illustrated in type C is indeed absent, or at least very weak, because both the d orbital of Pd and the p orbital of nitrogen are fully occupied. Evidence can also be seen from the bond length of Pd-N(NTs) in SPd4A (Figure 3). It is calculated to be 2.09 A˚, very close to the prototypical σ bonds, Pd-N(Py) (2.10 A˚) and Pd-N(Bzq) (2.06 A˚). Third, a more electron-rich nitrogen in NTs of SPd4A is indicated (NBO charge: -1.02) as compared with that in free NTs (NBO charge: -0.29). Interestingly, we can see evidence of π bonding between the sulfur and the nitrogen(NTs), because the sulfur, which has a relatively high energy 3d orbital, would prefer to form a π-type interaction with a more electron-rich oxygen or nitrogen that has more diffuse p orbitals.66 This delocalized interaction (N 3 3 3 S 3 3 3 O) results in a shortened SdN bond length (1.60 A˚) as compared with the S-N bond length (1.70 A˚) in PhINTs and an elongated SdO bond length (1.56 A˚) in SPd4A (cf. 1.48 A˚ in S Pd4B, Figure 3). Fourth, further analysis of the molecular orbital of SPd4A shows that the dx2-y2 and dz2 orbitals are empty (Figure 4). Unlike octahedral SPd4A, triplet TPd4A is found to be a square-pyramidal structure with NTs in the axial position. (66) (a) Oae, S.; Doi, J. Organic Sulfur Chemistry: Structure and Mechanism, 1st ed.; CRC: Boston, 1991. (b) Hamilton, C. W.; Sadighi, J. P.; Laitar, D. S., Synthesis and reactivity of monomeric sulfonylamido and sulfonylimido complexes of palladium. In 230th ACS National Meeting; ACS: Washington, DC, 2005.

The triplet nitrene may be depicted in two resonance structures, D (one unpaired electron on NTs with the other on Pd) and E (both unpaired electrons reside on NTs), Figure 3. Despite this dichotomy, our analysis suggests that TPd4A is best described as a triplet Pd(III) nitrene with a type D structure. As shown in Figure 4, plotting the spin density of TPd4A reveals that the unpaired electrons are primarily located on the metal center and on the nitrogen of NTs. The two SOMO orbitals of TPd4A can be easily recognized as a dz2 orbital of Pd and a p orbital of N(NTs). NBO analysis also suggests that the oxidation state of Pd in TPd4A (NBO charge in Pd: þ0.87) is between that in SPd4A (NBO charge: þ1.04) and in Pd2A (NBO charge: þ0.63). TPd4A has a less electronrich NTs nitrogen (NBO charge: -0.62) than SPd4A (NBO charge: -1.02). The N-S bond (1.68 A˚) in TPd4A is closer to a single bond, as compared with SPd4A, which has a N 3 3 3 S bond length of 1.60 A˚. A triplet Pd(III) nitrene has a formally d7 electronic configuration, and thus as expected, a strong Jahn-Teller distortion is found in TPd4A. The Pd-N(NTs) bond on the axial position has a much longer length (2.28 A˚) versus the Pd-N(Py) and Pd-N(Bzq) bonds (both 2.11 A˚) in the equatorial positions. We hypothesize that this distortion at the axial position may facilitate the transfer of the NTs to the Pd-C bond. The isomeric SPd4B and TPd4B are similar in bonding to SPd4A and TPd4A just discussed, and thus no elaboration will be given. The only point we mention here is that TPd4B adopts a square-pyramidal structure with the N(Bzq) in the axial position. This coordination isomer is more stable than the isomer with NTs in the axial position by 1.4 kcal/mol. (iii). Mechanisms for C-N Bond Formation. With a better understanding of bonding in key intermediates (i.e., palladacyclic PhINTs complexes, singlet Pd(IV)-imido complexes, and triplet Pd(III) nitrene complexes), we turn to the reaction mechanisms for the C-N bond formation. As shown in Chart 3, mechanisms deemed plausible from the experimental literature include (a) concerted transfer of PhINTs from Pd3 to form Pd5 via a transition state involving a three-centered interaction between the Pd center, the C(Pd-C), and the N(NTs), accompanied by the “PhI” leaving group; (b) a stepwise pathway Pd3 f Pd4 f Pd5 involving singlet/triplet nitrene/imido transfer (Scheme 2); and (c) free nitrene insertion into the Pd-C bond. As discussed above,

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Figure 4. Selected Kohn-Sham orbitals for SPd4A and TPd4A and spin density for TPd4A. (Orbitals for TPd4A are obtained from single-point RODFT calculation with unrestricted DFT optimized structures.) Hydrogen atoms are omitted for clarity. Chart 3. Proposed Transition States for Possible Reaction Mechanisms of C-N Bond Formation: Nitrene/Imido Transfer, Concerted PhINTs Transfer, and Free Nitrene Insertion

S

Pd4 is described as a singlet Pd(IV)-imido complex. In contrast, a singlet Pd(II) nitrene does not appear to be an intermediate in this catalyst system. Furthermore, a free nitrene insertion mechanism is found to be implausible. Calculations indicate that a free nitrene is thermodynamically unstable and tends to interact with metal complexes. Intrinsic reaction coordinate (IRC) calculations verify that the transition states for free nitrene insertion actually connect to metal-nitrene/imido complexes instead of separate palladacyclic complexes and free nitrene. As for the mechanism of the concerted transfer of PhINTs, we anticipate that the I 3 3 3 N interaction is too weak in SPd3 and the PhI will detach from NTs immediately prior to NTs transfer. In fact, our computations found no three-centered transition states with PhI 3 3 3 NTs interaction. In the located transition states (resembling those for imido transfer, discussed below), the PhI has dissociated and only interacts with oxygen in NTs by way of hydrogen bonding. Therefore, the calculations implicate singlet imido transfer or triplet nitrene transfer initiated from SPd4 or TPd4, respectively, as the most plausible reaction mechanisms for the C-N bond formation. Hence, the analysis will concentrate on these mechanisms.

The calculated enthalpy profiles for these mechanisms are summarized in Figures 5 and 7. Imido Transfer from the Pd(IV) Imido Complex SPd4. The concerted transfer of the imido group from SPd4A yields Pd5A via the three-membered ring transition state TS1, where the C-N(NTs) bond (2.21 A˚) is forming and the Pd-C bond is breaking (2.08 A˚), Figure 6. This imido transfer is highly exothermic (ΔH = -43.0 kcal/mol). The barrier of TS1 is calculated to be 11.8 kcal/mol relative to SPd4A, implying that the transfer is highly feasible both kinetically and thermodynamically under mild reaction conditions. The concerted imido transfer from SPd4B to yield Pd5B proceeds via transition state TS2, with the reaction barrier calculated to be 18.0 kcal/mol relative to SPd4A. It is interesting that the concerted imido transfer step from SPd4B to Pd5B has a higher barrier (by 6.2 kcal/mol) than that from SPd4A to Pd5A. Structural analysis gives more insight into the energetic difference between TS1 and TS2. Both TS1 and TS2 represent the transition from an octahedral Pd(IV) complex to a square-planar Pd(II) complex. Considering the transition-state structure from the viewpoint of a pseudo-squareplanar geometry (see the gray plane in Figure 6), it can be seen that the coordinated oxygen has been detached from the metal center in TS1. Thus, TS1 will simultaneously change into a square-planar structure during the formation of the C-N(NTs) bond and the breaking of the Pd-C bond. However, in TS2, the Py ligand is located in the axial position (see the gray plane in Figure 6), preventing the formation of square-planar Pd5B. Note also the significant elongation of the Pd-N(Py) bond (2.51 A˚) in TS2, which is weakened by the filling of the Pd dz2 during the breaking of the Pd-C bond in the transition state. The transition between six-coordinate M(IV) and four-coordinate M(II) complexes often assumes preliminary ligand dissociation to form a five-coordinate

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Figure 5. Energy profiles for the reaction mechanisms of the C-N bond formation from Pd(IV) imido intermediates, SPd4. The enthalpies considering solvation effects (IEF-PCM, solvent = THF, radii = Pauling) are given in kcal/mol relative to SPd4A.

Figure 6. Optimized structures of TS1-4 with selected structural parameters (bond lengths in A˚). Hydrogen atoms are omitted for clarity. The reaction barriers corrected with solvation effects (IEF-PCM, solvent = THF, radii = Pauling) are reported in kcal/mol.

intermediate for the coupling reaction from a group 10 M(IV) complex.67,68 Inspired by this, we hypothesize that the imido transfer may also proceed via dissociative pathways. With Py as the dissociating ligand, SPd4B can first form intermediate Pd6Py, uphill by 4.6 kcal/mol. Pd6Py then promotes the imido transfer to yield intermediate Pd8, via a three-membered ring transition state, TS3. Without a ligating Py, TS3 more resembles a square-planar geometry. In TS3, the forming C-N(NTs) bond length is calculated to be 2.21 A˚ and the breaking Pd-C bond is 2.09 A˚, implying an earlier transition state as compared with TS2. The reaction (67) Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 12790–12791. (68) (a) Smythe, N. A.; Grice, K. A.; Williams, B. S.; Goldberg, K. I. Organometallics 2009, 28, 277–288. (b) Williams, B. S.; Goldberg, K. I. J. Am. Chem. Soc. 2001, 123, 2576–2587. (c) Byers, P. K.; Canty, A. J.; Crespo, M.; Puddephatt, R. J.; Scott, J. D. Organometallics 1988, 7, 1363– 1367.

barrier of TS3 (12.8 kcal/mol) is thus lower than that of TS2 (18.0 kcal/mol). For SPd4A, the dissociation of Py from S Pd4A leads to five-coordinate intermediate Pd7Py, which is uphill by 15.7 kcal/mol. This enthalpy change is greater than the reaction barrier of the concerted imido transfer pathway (TS1, ΔHq = 11.8 kcal/mol), indicating that the dissociative pathway with pyridine as the detached ligand is less feasible for SPd4A. Another possible dissociative pathway via detaching the oxygen arm of NTs is also considered. The dissociation of O(NTs) from SPd4B leads to intermediate Pd6O, with a squarepyramid geometry. Isomerization of Pd6O yields another square-pyramid structure, Pd6O0 , with NTs in the axial position. The subsequent imido transfer from Pd6O0 to produce Pd5B proceeds via transition state TS5, which is calculated to have a relatively high reaction barrier (ΔHq = 20.5 kcal/mol), implying a less feasible pathway. On the other hand, the dissociation of O(NTs) from SPd4A leads to intermediate Pd7O (uphill by 3.3 kcal/mol), followed by a

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Figure 8. Selected computational and experimental (in parentheses) structural parameters for Pd5A (bond length in A˚). Hydrogen atoms are omitted for clarity.

Figure 7. Energy profiles for the reaction mechanisms of the C-N bond formation from Pd(III) nitrene intermediates, TPd4. The enthalpies considering solvation effects (IEF-PCM, solvent = THF, radii = Pauling) are given in kcal/mol relative to S Pd4A.

subsequent imido transfer to form Pd5A via transition state TS4. The structure of TS4 is quite similar to TS1, except that the Cl- ligand is located nearly perpendicular to the Bzq plane in TS4. In contrast, the Cl- ligand lies closer to the Bzq plane in TS1. These two transition states have quite similar barriers to each other. The calculated ΔHq values in solution are 11.8 and 10.0 kcal/mol for TS1 and TS4, respectively, and the calculated ΔHq values in the gas phase are 9.5 and 11.7 kcal/mol for TS1 and TS4, respectively, indicating that these two reaction pathways may both be practical for C-N bond formation reactions from SPd4A. Other dissociative reaction pathways were also considered, including the dissociation of the Bzq ligand or the Clligand. However these dissociation pathways have to overcome high dissociation energies (>25 kcal/mol, see discussion below), which are much higher than the reaction barriers for the imido transfer pathways just discussed above. Thus, a dissociative pathway with a detached Bzq or Cl- ligand seems less likely. Triplet Nitrene Transfer from the Pd(III) Nitrene Complex T Pd4. Calculations show that the triplet Pd(III) nitrene complexes TPd4A and TPd4B are thermodynamically unstable with respect to SPd4A by ∼15 kcal/mol. Triplet nitrene transfer pathways from TPd4 to TPd6 were studied with DFT to assess their kinetic competence. The enthalpy profiles are depicted in Figure 7. Nitrene transfer from TPd4A to TPd6A via the three-membered-ring transition state TS6 needs to overcome a barrier of only 4.0 kcal/mol. A similar step from T Pd4B to TPd6B via TS7 has a barrier of 5.1 kcal/mol. These two transition states both form a C-N bond and break a C-Pd bond and do not differ much in a structural sense from their corresponding reactive intermediates. Along the energy profiles, the formed triplet intermediate TPd6 has a quasisawhorse structure, with one unpaired electron in the dx2-y2 orbital and the other in the dz2 orbital. The quasi-sawhorse structure allows the single occupied dx2-y2 and dz2 to be (69) Lee, J. P.; Ke, Z. F.; Ramirez, M. A.; Gunnoe, T. B.; Cundari, T. R.; Boyle, P. D.; Petersen, J. L. Organometallics 2009, 28, 1758–1775.

stabilized by the mixing with p orbitals of Pd.69 The geometric relaxation of TPd6A from triplet state to singlet state leads to formation of the final product, Pd5A. Relaxation of T Pd6B to the singlet state leads to Pd8, releasing the Py ligand. Recombination of Pd8 and Py then yields final product Pd5A. Although triplet nitrene transfer from TPd4 to form the C-N bond is kinetically facile, the reaction barriers for TS6 and TS7 are quite high (21.4 and 20.8 kcal/ mol for TS6 and TS7, respectively) relative to the most stable intermediate, SPd4A, as compared with the reaction barriers for the singlet imido transfer pathways (∼10 kcal/mol). Our studies show that C-N bond formation occurs via either a concerted or a dissociative mechanism (highlighted in blue, Figure 6) to selectively produce a single product Pd5A, consistent with the experimental observation that Pd5A is the single major product.17 The X-ray structure of Pd5A has been reported. Comparison of the key parameters of the Pd5A structure between computational and experiment data is shown in Figure 8. Computational results are in good agreement with experimental data. In addition to the bond lengths and bond angles, the calculated dihedral angle (τ = 14.1°) of the twisting rigid Bzq is consistent with the experimental data (τ = 14.9 ( 0.7°). The twisting feature for the Pd5A structure was proposed to be caused by the face-toface interaction between the aryl ring and the NTs group.17 Computations suggest that the sp3 hybridization of the nitrogen of NTs plays a more important role in this twisting feature. Calculation of a simplified model, where an H atom replaces the p-Tol group of NTs to obviate the π face-to-face interaction, also leads to a structure with a twisted Bzq (τ = 14.2°). This twisting motion is also found in the C-H agostic intermediate of the cyclopalladation process: C2 also has a twisted Bzq (τ = 12.0°). C-Cl Reductive Elimination. Calculations favor C-N bond formation initiated from a Pd(IV)-imido intermediate via imido transfer mechanisms. Considering the debate of the key intermediate as either a Pd nitrene or a Pd imido species, further evidence to support the latter is that this high formal oxidation state intermediate may promote reductive elimination side reactions. In reported cases of Pd-catalyzed C-H activation/C-N bond formation reactions, side products resulting from C-Cl reductive elimination were indeed observed.17 To give more insight into possible side reactions, C-Cl reductive elimination has also been evaluated by computations taking the most stable intermediate SPd4A as the starting point. The C-Cl reductive elimination has

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Scheme 4. Evaluation of Possible Mechanisms of C-Cl Reductive Elimination from Pd(IV)-Imido Intermediate SPd4Aa

a

The enthalpies corrected with solvation effects (IEF-PCM, solvent = THF, radii = Pauling) are given in kcal/mol relative to SPd4A.

several probable mechanisms, as suggested by similar reductive elimination processes in Pd(IV) systems.54,67 As shown in Scheme 4, the reductive elimination may undergo either concerted or stepwise dissociative pathways to form a C-Cl bond. Calculations indicate that a concerted pathway via transition state TS8 has a barrier of 27.2 kcal/mol. As for the dissociative pathways, the chlorine anion, the pyridine, the nitrogen arm of Bzq, or the oxygen arm of NTs can dissociate from Pd to form a five-coordinate intermediate, followed by C-Cl coupling. Computations suggest that the dissociative pathway with Py or O(NTs) as the detached ligand is the most energetically feasible mechanism. In contrast, the dissociation of Cl- (ΔH = 26.0 kcal/mol) or N(Bzq) (ΔH = 34.4 kcal/ mol) is highly endothermic. As expected, the chloride anion and the positively charged metal center have a strong interaction. The consequent external nucleophilic attack of the chlorine anion on the carbon of the Pd-C bond via TS8Cl has a barrier of 29.7 kcal/mol relative to SPd4A. Although “ionic” reductive elimination was suggested to be possible for other Pd(IV) and Pt(IV) systems,68 it seems less probable in the present case. The dissociation of N(Bzq) is highly endothermic probably due to the rigid structure of the Bzq. Dissociation of Py is calculated to be endothermic by ∼16 kcal/mol. The subsequent C-Cl bond coupling step through

transition state TS8Py has a reaction barrier of 26.0 kcal/mol, comparable to that of the concerted pathway. As for the dissociation pathway with detached O(NTs), both the dissociation and C-Cl coupling steps are feasible. The dissociation of O(NTs) is uphill by only 3.3 kcal/mol, and the ensuing C-Cl bond coupling via the three-membered ring transition state TS8O has the lowest barrier among all the investigated pathways (ΔHq = 24.3 kcal/mol). Neutral ligands, ionic ligands, or one arm of polydentate ligands are all reported to be preliminary dissociative ligands.54,67,68 Since TS8, TS8Py, and TS8O have very similar energies, it is difficult to definitively distinguish these possibilities. Note that the oxygen arm of NTs has actually detached from the metal center (Pd 3 3 3 O distance = 2.95 A˚) in TS8. The concerted pathway can be taken as a quasidissociative pathway with a detached O(NTS). Therefore, the investigated Pd(IV) imido complex seems to prefer the detachment of the neutral Py ligand or the oxygen arm of NTs. The calculated reaction barriers for the C-Cl coupling from Pd(IV)-imido intermediate are ∼25 kcal/mol, implying a feasible process under mild reaction conditions. In fact, C-X reductive elimination was observed in other palladacyclic systems, e.g., (Bzq)Pd(OAc)Py or (8-ethylquinoline)Pd(OAc)Py,17 although C-Cl coupling cannot compete with

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the C-N bond formation for the investigated monomeric palladacyclic complex Pd2. Studies of Pd(IV) complexes with 2-phenylpyridine ligands also suggested that there are competing C-X reductive eliminations in the reaction system, including C-N, C-Cl, and C-C couplings.70 Those experimental results further support the inference that a Pd(IV) imido complex is the key reactive intermediate that effects the NTs insertion into the Pd-C bond and that imido transfer is the preferred reaction mechanism for the C-N bond formation reaction.

Concluding Remarks Detailed reaction mechanisms for Pd-catalyzed C-H activation/C-N bond formation have been investigated with the aid of density functional theory, to expand and deepen insights into this cascade process. Considering the experimental proposals as to the reaction mechanism(s) and the reactive intermediate(s) (Scheme 2), (Bzq)PdII(Cl)Py and nitrogen source, PhINTs, were chosen as the targeted systems.17 The key findings of this research are summarized as follows. (1) Previously proposed mechanisms including electrophilic activation via a metal arenium intermediate, oxidative addition, and deprotonation (H-transfer) induced by internal base or external base have been examined for the cyclopalladation process. Our research suggests that [PdCl4]2--catalyzed cyclopalladation should proceed via a deprotonation mechanism induced by an internal or external base. The external base-induced deprotonation mechanism is suggested to be more favored in a water-assisted manner in a protic solvent, suggesting that the nature of external base, as well as the solvent, will play an important role in optimizing cyclometalation processes. The calculated reaction barriers for the deprotonation reactions are in the range 12-16 kcal/mol, consistent with experimental values. Electrophilic activation involving an arenium intermediate is predicted to be less likely. The oxidative addition mechanism is also found to be less likely due to its higher calculated reaction barrier (ΔHq = 23.0 kcal/mol). (2) Electronic structure analysis of various suggested intermediates (metal-iminoiodinane, metal-imido, and metal-nitrenes in singlet or triplet spin states) reveals that a Pd(IV) imido complex, SPd4, is the most plausible reactive intermediate for the subsequent C-N bond formation reaction. Both the formation and the decomposition of metal-iminoiodinane complex SPd3 are found to be thermodynamically and kinetically facile. No triplet metal-iminoiodinane intermediate is located. The PhI spontaneously dissociates during the optimization of triplet metal-iminoiodinane. The singlet metaliminoiodinane complex has a very weak I 3 3 3 N interaction. The Pd(IV) imido complex SPd4, which can be regarded as a formally [M]qþ2(NR)2- intermediate, is the key intermediate in the reaction system with an octahedral geometry and a d6 electronic configuration. A triplet Pd(III) nitrene complex is found to be about 15 kcal/mol higher in enthalpy. Unpaired electrons of the triplet Pd(III) nitrene are primarily located on the metal center (dz2 orbital) and on the nitrogen of NTs (p orbital). Unlike the (d7, d7) Rh2(II,II)21 and d6 Ru(II)22 systems, a singlet Pd(II) nitrene intermediate was not implicated, presumably because the d8 metal center cannot serve as (70) Whitfield, S. R.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 15142–15143.

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a Lewis acid to accept the lone pair density from the nitrene in neutral NTs. Our research indicates that the character of the metal-heteroatom bond highly depends on the d electronic configuration for late transition metal complexes. (3) Mechanistic study of the C-N bond formation reveals that a concerted or a dissociative imido transfer initiated from a Pd(IV) imido complex is the most favored mechanism for the studied system. SPd4A prefers a concerted (ΔHq = 11.8 kcal/mol) or a dissociative pathway (ΔHq = 10.0 kcal/ mol, oxygen arm of NTs is the dissociating ligand) to produce product Pd5A. SPd4B tends to undergo a dissociative pathway (ΔHq = 12.8 kcal/mol) with Py as the detached ligand to yield a single product, Pd5A. The triplet nitrene transfer pathways from Pd(III) nitrene complexes, TPd4A and TPd4B, are suggested to be less plausible due to their relatively higher barriers (∼21 kcal/mol). Both a free nitrene insertion mechanism and a mechanism of concerted transfer of PhINTs are also suggested to be less likely in the investigated catalytic system. (4) Pd(IV) imido complex SPd4A can also undergo reductive elimination side reactions. This investigated Pd(IV) imido complex is suggested to undergo a C-Cl coupling side reaction via dissociative mechanisms with the detachment of the neutral Py ligand or the oxygen arm of NTs. The C-Cl coupling from the Pd(IV)-imido intermediate is calculated to have reaction barriers of around 25 kcal/mol, implying that it is a feasible process under mild reaction conditions. In fact, various C-X reductive elimination reactions have been observed for Pd(IV) complexes.17,70,71 Therefore, the Pd(IV) imido complexes are potentially versatile active species for C-N bond formation and also have the potential for reductive coupling (C-C, C-O, C-halogen, C-P, etc.), although the challenge remains in the control of the various pathways, which may be close in energy. In addition to “inner-sphere” C-H bond functionalizations (e.g., the cascade C-H activation/C-N bond formation system studied in this paper) of ligated substrates, “outer-sphere” type C-H bond functionalizations are also an intriguing way to produce C-N bonds,3 because the latter require no premetalation of the substrates and no protonolysis of the M-N bonds to release the functionalized products. Additionally, such pathways could open the door to a wider array of potential hydrocarbon substrates for amination. The low reaction barrier of the imido transfer indicates that the Pd(IV) imido complex is a highly reactive intermediate for C-N bond formation reactions. Hopefully, the Pd(IV) imido complex may also have the potential to functionalize external inert C-H bonds by “outer-sphere” type insertion. In order to expand the scope of this catalysis, research exploring the potential for intermolecular amination of C-H bonds by Pd-imido catalysts is in progress in our laboratories.

Acknowledgment. T.R.C. and Z.K. acknowledge numerous helpful discussions with Professor Weston T. Borden (Chemistry, UNT). T.R.C. acknowledges the NSF for partial support through grant CHE-0701247 and for the facilities (CHE-0342824 and CHE-0741936) (71) (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300–2301. (b) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134–7135. (c) Kalek, M.; Stawinski, J. Organometallics 2008, 27, 5876–5888.

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that made this work possible. Z.K. acknowledges the State Scholarship Fund of CSC (No. 2007102840) for support of his visit to UNT and a Sun Yat-sen University fellowship for their excellent doctoral program. The authors thank Matt Remy and Brannon Gary (Chemistry, U. Michigan) for helpful comments. Partial financial support for Z.K. was provided by the NSFsponsored Center for Enabling New Technologies through Catalysis (CENTC; CHE-0650456). Some SP

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calculations were performed at the Fukui Institute for Fundamental Chemistry, Kyoto University. Their computational resources are also acknowledged. Supporting Information Available: Complete citation for ref 51, Cartesian coordinates for all calculated structures, and background calculations pertinent to the employed level of theory are available free of charge via the Internet at http:// pubs.acs.org.

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