Theoretical Study on Mechanism of Copper(I)-Catalyzed Cross

Organometallics 2011, 30, 633–641 DOI: 10.1021/om100996e

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Theoretical Study on Mechanism of Copper(I)-Catalyzed Cross-Coupling between Aryl Halides and Alkylamines Songlin Zhang and Yuqiang Ding* School of Chemical and Material Engineering, Jiangnan University, Wuxi 224161, Jiangsu Province, People’s Republic of China Received October 20, 2010

Density functional theory method B3LYP was used to study the mechanism of amination reactions between aryl bromides and alkylamines catalyzed by Cu(I) species with 1,3-diketone ligands. Through systematic evaluation of the relative concentrations of possible copper species in solution and oxidative addition of these species with aryl bromide, we propose that the active catalyst is a neutral threecoordinate 1,3-diketonate-ligated Cu(I)(amine) complex. Oxidative addition of aryl bromide to this species is the rate-limiting step of the catalytic cycle. These results explain why for basic alkylamine substrates, diamine ligands are ineffective, because for diamine ligands, formation of such a neutral Cu(I) complex containing both ligand and nucleophile is thermodynamically unfavorable. Interestingly, the active catalyst Cu(I)(diketonate)(amine) complex is essentially akin to the active catalyst Cu(I)(diamine)(amidate) proposed in copper-catalyzed coupling of amides with aryl halides. Therefore, this implies that for an acidic substrate a neutral ligand is preferred, while for basic substrate an acidic ligand is necessary to achieve high efficiency. Our results also show that anionic copper(I) complexes with two molecules of deprotonated necleophiles or ligands are not reactive. Therefore, the wise selection of appropriate ligand and base combinations for a specific nucleophile to generate a neutral copper(I) complex containing both ligand and nucleophile is the key point to the success of these copper-catalyzed cross-coupling reactions. These insights should be helpful for our understanding and further development of more efficient reaction protocols for copper-catalyzed coupling of more challenging electrophiles such as aryl chlorides and tosylates and other types of nucleophiles. 1. Introduction C-N bond formation reactions are powerful tools for preparing many important compounds widely used in organic synthesis, pharmaceuticals, and polymer science.1 Traditional methods for forming C-N bonds, such as the coppermediated Ullmann reaction2 and Goldberg reaction,3 always suffer from limitations such as the use of high temperature, stoichiometric amounts of copper reagents, long reaction times, and strong bases. Alternatively, palladium-catalyzed C-N bond formation reactions provide an efficient method

for forming C-N bonds and have found numerous applications in synthesis.4 However, due to the high price of palladium metal and the difficulty in product separation, Pd-catalyzed C-N bond formation reactions have been limited in some cases for large-scale applications and for synthesis of pharmaceuticals. Less costly and more environmentally benign alternatives remain highly desirable. In recent years, a revisit of the classical Ullmann and Goldberg reactions has led to a number of efficient copper-catalyzed C-N bond formation protocols when appropriate ligands are used.5 Various ligands, especially some bidentate ligands,

*To whom correspondence should be addressed. E-mail: yding@ jiangnan.edu.cn. (1) (a) Negwer, M. Organic-Chemical Drugs and Their Synonyms: An International Survey, 7th ed.; Akademie Verlag: Berlin, 1994. (b) MacDiarmid, A. G.; Epstein, A. J. In Science and Applications of Conducting Polymers; Salaneck, W. R.; Clark, D. T.; Samuelsen, E. J., Eds.; Hilger: New York, 1991. (c) Hartwig, J. F.; Shekhar, S.; Shen, Q.; Barrios-Landeros, F. In Chemistry of Anilines; Rappoport, Z., Ed.; Wiley-Interscience: New York, 2007; Vol. 1, p 455. (2) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. (b) Lindley, J. Tetrahedron 1984, 40, 1433. (c) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359. (3) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691. (4) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (c) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125. (d) Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.; WileyVCH: Weinheim, Germany, 2000. (e) Jiang, L.; Buchwald, S. L. In MetalCatalyzed Cross-Coupling Reactions; De Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, p 699.

(5) For recent reviews on copper-catalyzed C-N, C-O, and C-S bond formation reactions, see: (a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 15, 2428. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (c) Deng, W.; Liu, L.; Guo, Q.-X. Chin. J. Org. Chem. 2004, 24, 150. (d) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337. (e) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054–3131. (f) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954. (g) Sperotto, E.; van Klink, G. P. M.; van Koten, G.; de Vries, J. G. Dalton Trans. 2010, 39, 10338. (6) (a) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315. (b) Goodbrand, H. B.; Hu, N. X. J. Org. Chem. 1999, 64, 670. (c) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657. (7) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120, 12459. (b) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583. (c) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (d) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164. (e) Deng, W.; Wang, Y.-F.; Zou, Y.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2004, 45, 2311. (f) Deng, W.; Zou, Y.; Wang, Y.-F.; Liu, L.; Guo, Q.-X. Synlett 2004, 1254. (g) Deng, W.; Liu, L.; Zhang, C.; Liu, M.; Guo, Q.-X. Tetrahedron Lett. 2005, 46, 7295.

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have been employed to facilitate these transformations, such as phenanthroline,6 amino acids,7 glycol,8 beta-amino alcohol,9 bis-pyridylimines,10 1,2-diamine,11 1,3-diketones,12 and others.13 Although much effort has been made toward developing milder reaction conditions and broadening the substrate scope, a convincing mechanistic foundation concerning the relevant intermediates in the catalytic cycle and their reactivity has not yet been established for copper-catalyzed C-N bond-forming reactions. Moreover, the specific roles of ligand and base have not been well understood. Nevertheless, previous studies have shown that the active catalyst involved in the catalytic cycle should be a Cu(I) species.14 Precursor Cu(II) salts are proposed to be reduced to the active Cu(I) species by amines or alcohols in the reaction solution, which is supported by the EPR observation that Cu(II) species decay over time in the presence of amine, generating Cu(I),15 and confirmed recently by Jutand et al. through compelling evidence from UV-vis spectra and NMR studies.16 As to the conversion of Cu(0) to Cu(I) in coppercatalyzed coupling of aryl halides, Jutand et al. suggested through a cyclic volammetry study that one-electron transfer from Cu(0) to aryl halide generates the active Cu(I).17 Additionally, early SEM imaging observation by Paine et al. that the surface of Cu(0) is covered with a thin layer of Cu2O lends further support for the validity of conversion of Cu(0) to Cu(I) in copper catalysis.14a Yamamoto et al. and Whitesides et al. showed that a 1:1 ratio of Cu(I) amidate or alkoxide complexes can react stoichiometrically with aryl halides to generate C-N or C-O coupling products, albeit in low yields.18,19 Later, Buchwald et al. reported the characterization of a copper(I)(pyrrolidin2-onyl) N,N0 -dimethyl cyclohexanediamine complex in solution phase and found that the stoichiometric reaction of this complex toward aryl iodide was faster than the catalytic process, demonstrating the competence of this complex as an intermediate in the catalytic cycle of copper-catalyzed amidation reactions. Consequently, they suggested that the (8) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581. (9) (a) Lu, Z.; Twieg, R. J. Tetrahedron 2005, 61, 903. (b) Lu, Z.; Twieg, R. J.; Huang, S. D. Tetrahedron Lett. 2003, 44, 6289. (10) (a) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.;Eur. J. 2004, 10, 5607. (b) Xia, N.; Taillefer, M. Chem.;Eur. J. 2008, 14, 6037. (11) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727–7729. (b) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421. (c) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. (12) (a) de Lange, B.; Lambers-Verstappen, M. H.; Schmieder-van de Vondervoort, L.; Sereinig, N.; de Rijk, R.; de Vries, A. H. M.; de Vries, J. G. Synlett 2006, 3105. (b) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742. (13) (a) Zhang, Z.; Mao, J.; Zhu, D.; Wu, F.; Chen, H.; Wan, B. Tetrahedron 2006, 62, 4435. (b) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.;Eur. J. 2006, 3636. (c) Tao, C.-Z.; Li, J.; Fu, Y.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2008, 49, 70. (d) Yang, C.-T.; Fu, Y.; Huang, Y.-B.; Yi, J.; Guo, Q.-X.; Liu, L. Angew. Chem., Int. Ed. 2009, 48, 7398. (14) (a) Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496. (b) Weingarten, H. J. Org. Chem. 1964, 29, 3624. (c) Aalten, H. L.; van Koten, G.; Grove, D. M.; Kuilman, T.; Piekstra, O. G.; Hulshof, L. A.; Sheldon, R. A. Tetrahedron 1989, 45, 5565. (d) Resnik, R.; Cohen, T.; Fernando, Q. J. Am. Chem. Soc. 1961, 83, 3344. (15) Kondratov, S. A.; Shein, S. M. Zh. Org. Khim. 1979, 15, 2160. (16) Franc, G.; Jutand, A. Dalton Trans. 2010, 39, 7873. (17) Mansour, M.; Giacovazzi, R.; Quali, A.; Taillefer, M.; Jutand, A. Chem. Commun. 2008, 6051. (18) Yamamoto, T.; Ehara, Y.; Kubota, M.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1980, 53, 1299. (19) Whitesides, G. M.; Sadowski, J. S.; Lilburn, J. J. Am. Chem. Soc. 1974, 96, 2829.

Zhang and Ding Scheme 1. Proposed Catalytic Cycle for Copper-Catalyzed Amidation Reactions

active catalyst of the amidation reaction is the Cu(amidate)(diamine) species.20 Recently through DFT calculations, we evaluated the relative concentrations of possible copper species in the reaction solution of copper-catalyzed amidation reactions and oxidative addition of these species with aryl bromides. Our results did demonstrate that the neutral Cu(amidate)(diamine) species is the most active copper species.21 Oxidative addition of this species to aryl halides is the rate- and turnover-determining step of the catalytic cycle as shown in Scheme 1. The relative activities of some common N,N-bidentate ligands predicted on the basis of our proposed pathway are consistent with experimental findings. To our delight, Tye and Hartwig et al. recently prepared, isolated, and characterized by X-ray crystallographic and solution-phase NMR studies Cu(I)(amidate)(diamine) complexes and several other related complexes and studied their reactivity with aryl iodides and bromides.22 It was found that copper(I) amidate and imidate ligated by ancillary ligands such as 1,2-diamines underwent cross-coupling reactions at a similar selectivity and faster rate compared to the corresponding catalytic process, indicating the competence of these species as possible intermediates in the catalytic cycle. Similar observations were later reported by Buchwald et al. during their kinetic studies of a diamine-ligated Cu(I) amidate complex with aryl halides.23 All these results strongly indicate the active catalyst for copper-catalyzed amidation reactions is a neutral Cu(I)(amidate)(diamine) species and substantiate the mechanistic proposal in Scheme 1. Despite the above mechanistic insights, it is quite surprising that the trans-1,2-diamine ligands, which are good ligands for copper-catalyzed amidation reactions, are ineffective in copper-catalyzed amination reactions between aryl halides and alkylamines. For coupling of alkylamines, 1,3-diketones and amino acids are currently the best choices.7,12 Using amino acid ligands, Ma et al. developed a versatile method for coupling of aryl halides with alkylamines (Scheme 2a).7c,d Buchwald and Lange and their co-workers independently (20) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4120. (21) Zhang, S. -L.; Liu, L.; Fu, Y.; Guo, Q.-X. Organometallics 2007, 26, 4546–4554. (22) Tye, J. W.; Weng, Z.; Johns, A. M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 9971–9983. (23) Strieter, E. R.; Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 78–88.

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Scheme 2. Copper-Catalyzed Cross-Coupling of Alkylamines with Aryl Halides Using Amino Acids or Diketones As Ligands

reported efficient protocols for coupling of alkylamines using 1,3-diketones as ligands (Scheme 2b).12 The remarkable difference of ligand performance in coppercatalyzed amidation reactions and amination reactions greatly intrigued us. Since alkylamines differ from amides only in that they are much less acidic, with pKa values higher than 40,24 how does the acidity of the substrates affect their reactivity and the overall catalytic behavior? Because the reaction pathway of amidation reactions has been systematically investigated in our previous theoretical work and later evaluated by Hartwig and Buchwald through stoichiometric reactivity study and kinetic study,21-23 we are eager to extend our research to the mechanism of coppercatalyzed amination reactions. Herein, we report our systematic DFT study on this interesting topic through evaluation of relative concentrations of possible copper species in reaction solution and oxidative addition of these species with aryl halides. The role of ligand and base, the relationship to the mechanism of copper-catalyzed amidation reactions, and consequent mechanistic implications are discussed. We believe that these results can be helpful for developing more efficient and mild protocols for copper-catalyzed C-X (X = C, N, O, etc.) bond-forming reactions.

2. Method All calculations were performed with the Gaussian03 suite of programs.25 The density functional theory method with the B3LYP functional was used,26 which has been demonstrated in many previous studies to be a reliable method for dealing with transition metal complexes.27 All the geometries were fully optimized employing the standard 6-31G(d) basis set21,27d,28 for all the atoms, without any structural constraints. Harmonic force (24) In DMSO, the pKa of acetylacetone is 13.3, while those of alkylamines are more than 40. For these pKa values, see: (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463. (b) Fu, Y.; Liu, L.; Li, R.-Q.; Liu, R.; Guo, Q.-X. J. Am. Chem. Soc. 2004, 126, 814. (25) Frisch, M. J.; et al. et al. Gaussian 03 (Revision D.01 and B.05); Gaussian, Inc.: Wallingford, CT, and Pittsburgh, PA, 2004. (26) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (b) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789. (27) (a) Yamanaka, M.; Nakamura, E. Organometallics 2001, 20, 5675–5681. (b) Dunbar, R. C. J. Phys. Chem. A 2002, 106, 9809–9819. (c) Yamanaka, M.; Inagaki, A.; Nakamura, E. J. Comput. Chem. 2003, 24, 1401–1409. (d) Holland, J. P.; Green, J. C.; Dilworth, J. R. Dalton Trans. 2006, 783–794. (e) Yoshizawa, K.; Shiota, Y. J. Am. Chem. Soc. 2006, 128, 9873–9881. (28) (a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210–216. (b) Zhang, S.-L.; Liu, L.; Fu, Y.; Guo, Q.-X. J. Mol. Struct. (THEOCHEM) 2005, 757, 37–46. (c) Shang, R.; Fu, Y.; Wang, Y.; Xu, Q.; Yu, H.-Z.; Liu, L. Angew. Chem., Int. Ed. 2009, 48, 9350.

constants were computed for the optimized geometries to characterize the stationary points as real minima or saddle points on the potential energy surface. Transition states were optimized using the default Berny algorithm implemented in Gaussian03 and further analyzed by intrinsic reaction coordinate (IRC) computations29 to verify that they connect the right reactants and products. Single-point energy calculations were performed for the optimized geometries with the B3LYP/6-311þG(d,p) method.21,22 Zero-point vibrational corrections and thermal corrections to the Gibbs free energy were determined by the harmonic vibrational frequencies. To take the solvent effect into account, single-point solvation energy calculations were performed at the optimized gas-phase geometries for all species involved by using the selfconsistent reaction field method (SCRF)30 with the CPCM solvation model.31 Acetonitrile. with a similar dielectric constant to dimethylformamide (DMF), which was the frequently used solvent in copper-catalyzed amination reactions, was chosen as solvent in the CPCM calculations. The UAHF (united atom Hartree-Fock) radii were used for all the atoms.

3. Results and Discussions 3.1. Model Reaction and Possible Copper Complexes. The reaction between bromobenzene (1) and methylamine (2) was chosen as the model reaction (eq 1). The 1,3-diketone ligand was modeled by acetylacetone. This model reaction was devised on the basis of reaction protocols reported by Buchwald et al.12b

Although some evidence concerning the involvement of radical species has appeared in the literature, those systems investigated were quite different from what we are discussing now.32 In addition, strong evidence against radical mechanisms has been reported recently by Hartwig et al. in a closely (29) (a) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154– 2161. (b) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523–5527. (30) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. J. Comput. Chem. 2003, 24, 669. (31) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105, 2999. (32) For proposals of radical mechanisms, see: (a) Aalten, H. L.; van Koten, G.; Grove, D. M.; Kuilman, T.; Piekstra, O. G.; Hulshof, L. A.; Sheldon, R. A. Tetrahedron 1989, 45, 5565. (b) Couture, C.; Paine, A. J. Can. J. Chem. 1985, 63, 111. (c) Arai, S.; Hida, M.; Yamagishi, T. Bull. Chem. Soc. Jpn. 1978, 51, 277.

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Scheme 3. Equilibria of Possible Copper Species in Solutiona

a

All the values on the arrows are Gibbs free energy changes in kcal/mol.

related C-N coupling reaction. Aryl chlorides with favorable reduction potentials, which are expected to react faster toward Cu(I) amidate complexes in the context of electron-transfer mechanisms, in fact reacted slower than aryl bromides, with less favorable reduction potentials, thus excluding such radical mechanisms.22,33 Therefore, in this work radical mechanisms were not taken into account. Equilibriums between different copper complexes in the reaction solution have been envisaged as in Scheme 3. An assumption has been made that amines all exist in their neutral form due to high pKa values of alkylamines and the relatively weak base used. The Cu(acac)2 anion (acac denotes acetylacetonate) represents a dead-end in the reaction solution because there is no vacant site for coordination of the reactants due to coordination saturation and the high energy required to liberate one mole of acac ligand from the Cu(acac)2 anion (26.6 kcal/mol) (Scheme 3). Thus, complexes A, B, C, D, and E are possible starting species that would undergo oxidative addition with phenyl bromide. Complex A is a two-coordinate, unsaturated neutral species, which would combine with amine or halide anion generated during the reaction (or from the precatalyst) to form complex B or C, respectively. Calculation results show that coordination of one mole of CH3NH2 or Br anion to complex A is exothermic by 18.1 and 21.0 kcal/mol, respectively. Thus it is expected that the concentration of complex A is very low in reaction solution. Complex C is reminiscent of the active species in Pd-catalyzed cross-coupling and Heck reactions, where the halide anion exerts a profound effect on the reaction kinetics and has been suggested to participate in the oxidative addition step.34 Precatalyst CuBr may also combine with one or two molecules of amine to form D or E, respectively. Complex D is more stable than E thermodynamically since coordination of a second amine to complex D results in an increase of 10.3 kcal/mol in free energy. As separated by a red dotted line in Scheme 3, those species above the line involve the participation of ancillary ligand such as complex A, B, and C, whereas species below do not contain ligand acac, such as D and E. Comparison of the reactivity of these two series of complexes can therefore highlight the effect of ancillary ligands. (33) Enemaerke, R. J.; Christensen, T. B.; Jensen, H.; Daasbjerg, K. J. Chem. Soc., Perkin Trans. 2 2001, 1620. (34) For halide effects in Pd-catalyzed cross-coupling and Heck reactions, see: (a) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314. (b) Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576, 254. (c) Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26.

Zhang and Ding

Precatalyst CuBr is more prone to bind acac ligand than to bind amine, as can be indicated by a much larger binding energy with acetylacetonate than with methylamine (-40.0 vs -30.1 kcal/mol). Additionally, displacement of the bromide anion ligand in CuBr or complex D by the acac ligand would generate favorably complex A or B, respectively, as indicated by the large exothermicity of these substitution reactions (-19.0 and -7.0 kcal/mol, refer to Scheme 3). These results indicate that ancillary ligand should be favorably involved in these equilibriums and would further enter into the catalytic cycle. From the above results, complexes B and C are likely to be the most abundant species among the five complexes.35 In principle, the relative concentrations of A, B, C, D, and E can be deduced provided that the concentrations of bromide anion and acetylacetonate ligand anion are known. To provide more information for determining the active catalyst, oxidative addition reactions of phenyl bromide to these five species were examined. Detailed results are shown below. 3.2. Oxidative Addition Reaction of Each Complex with Phenyl Bromide. 3.2.1. Oxidative Addition of A, B, C, D, and E with Phenyl Bromide. Oxidative Addition of Complex A. Coordination of phenyl bromide to complex A results in the formation of complex CPa (Figure 1). This coordination is slightly exothermic by 3.1 kcal/mol. Oxidative cleavage of the C-Br bond in CPa leads to the formation of PDa through transition state TSa. Apparently, this process is reversible and in fast equlilibrium, as reflected by the small barrier and positive reaction thermodynamics. Oxidative Addition of Complex B. Figure 2 shows the optimized structures and the energetics in the oxidative addition initiated by complex B. Complex B is appropriately a T-shaped complex. The Cu-O bond trans to the amine ligand is significantly shorter than the other Cu-O bond, as reflected by the bond length of 1.83 and 2.04 A˚, respectively. A precomplex CPb with the phenyl bromide coordinated to complex B was located, which is high-lying on the energy surface, endothermic by 24.2 kcal/mol. Cleavage of the C-Br bond in complex CPb through transition state TSb leads to oxidative addition product PDb. The cleavage of the C-Br bond is facile once complex CPb is formed, as reflected by the small activation barrier (6.6 kcal/mol) and the slightly elongated C-Br bond length from CPb to TSb (1.96 vs 2.05 A˚). In oxidative addition product PDb, the C-Br bond is completely broken, with a bond distance of 2.78 A˚. PDb is a square pyramidal Cu(III) complex, with the amine ligand occupying the apical position. Noteworthy, during the oxidative addition process, the coordination of the acetylacetonate ligand is strengthened, while the coordination of the amine ligand is weakened, as reflected by the shortening of the Cu-O bonds and the elongation of the Cu-N bond from CPb to TSb to PDb. The energy profile of this process is similar to that of coppercatalyzed amidation reactions where the overall activation barrier largely comes from the unfavorable formation of the precomplex for the oxidative addition.21 The magnitude of the activation free energy (30.8 kcal/mol) is reasonable (35) Provided that the concentrations of acac anion and bromide anion is known, it is possible for us to obtain the relative concentrations of complexes A, B, C, D, and E in solution. For example, if we assume that [PhBr] and [MeNH2] are equal to 1.0 mol/L, [Cu]tot = 0.1 mol/L, [acac]= 0.05 mol/L, [Br-]=0.1 mol/L, then we get [A]:[B]:[C]:[D]:[E] ≈ 2 10-12:0.2:1:2 10-5:1 10-11. Apparently, complexes B and C constitute the most abundant existing forms of copper catalyst.

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Figure 1. Oxidative addition of phenyl bromide to complex A.

Figure 2. Oxidative addition of phenyl bromide to complex B.

considering that the reaction was conducted at 90 °C for aryl bromides. Tye and Hartwig et al. recently reported a similar activation free energy through kinetic data and DFT predictions for copper-catalyzed amidation reactions.22 Oxidative Addition of Complex C. Oxidative addition of phenyl bromide to complex C, where the bromide anion directly participates in this step, leads to a pentacoordinated trigonal bipyramidal Cu(III) complex PDc with the two bromide ligands occupying the axial positions (Figure 3). The transition state for this step, with an activation energy of 38.9 kcal/mol relative to separated reactants, clearly makes this process kinetically unfavorable. This is in significant contrast to palladium-catalyzed cross-coupling reactions where halide anions are proposed to play a positive effect in the oxidative addition step.34 This is possibly due to the increased repulsion effect between anionic complex C and the π electrons and/or the C-Br σ bond of phenyl bromide. Oxidative Addition of Complex D. As for complex D, the initial dicoordinated copper(I) complex is found to have a

linear Br-Cu-N arrangement (Figure 4). This copper species can form a η2 complex with PhBr, which results in an increase of 28.6 kcal/mol in free energy, possibly due to the significant bend of the Br-Cu-N moiety during this process. Subsequent migration of the copper from the top of the phenyl CdC double bond to the C-Br bond provides the transition state of the oxidative addition (i.e., TSd). This step costs a free energy of 7.5 kcal/mol calculated from the precursor η2 complex. Finally, cleavage of the C-Br bond takes place, leading to a tetracoordinated Cu(III) complex as the product of oxidative addition. Overall, the activation barrier for complex D is 36.1 kcal/mol, which is kinetically unfavorable. Oxidative Addition of Complex E. For the tricoordinate planar complex E, formation of a η2 complex coordinated by phenyl bromide costs a free energy of 28.4 kcal/mol (Figure 5). Migration of the copper atom from the CdC double bond to the phenyl C-Br bond forms a transition state TSe, from which a pentacoordinate square pyramidal complex PDe is formed. The overall activation free energy is 35.8 kcal/mol.

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Figure 3. Oxidative addition of phenyl bromide to complex C.

The high activation energy for the oxidative addition of complex E with aryl bromide explains why neutral diamine ligands are not effective for copper-catalyzed coupling of alkylamines with aryl halides, because using diamine ligands, an analogous complex with a diamine ligand replacing the two amine ligands in complex E would form, which makes the reaction kinetically unfavorable. 3.2.2. Comparing Different Copper Species. With the equilibria between these copper complexes and detailed oxidative addition reaction of each copper complex in hand, it is possible for us to determine which complex contributes most to the overall reaction kinetics according to the Curtin-Hammett principle.36 As deduced from the equilibria shown in Scheme 3, concentrations of D and E are very low. Combining with their high activation barriers (36.1 and 35.8 kcal/mol, respectively), complexes D and E are unlikely to be reactive species in this copper-catalyzed amination reaction. These results highlight the crucial role of the diketone ligand, which is overviewed in the oxidative addition of complex D and E. Complex C is a thermodynamically favored copper species. However, the dramatically large barrier for reaction of complex C (38.9 kcal/mol) makes it kinetically unfavorable. Complex B represents a thermodynamically favored and kinetically competent copper species initiating this crosscoupling reaction. Noteworthy, complex B is a neutral species containing both an ancillary ligand and a nucleophilic substrate. The magnitude of the activation barrier for the oxidative addition is reasonably consistent with the reaction conditions. Additionally, the presence of base would promote the reaction to the right through favorable deprotonation of the oxidative addition product PDb, acting as a driving force for the reaction of complex B (vide infra). Complex A is very reactive, with an activation energy of only 7.2 kcal/mol, but its concentration is negligibly low.35 Oxidative addition of complex A with PhBr is reversible and in fast equilibrium. After oxidative addition of A with PhBr, the amine would bind to the copper center to continue the reaction to form the desired coupling product. In principle, (36) For books and reviews on the Curtin-Hammett principle, see: (a) Advanced Organic Chemistry: Part A: Structure and Mechanisms, 4th ed.; Carey, F. A.; Sundberg, R. J., Eds.; Springer: Berlin, 2004; pp 25-261. (b) Seeman, J. I. Chem. Rev. 1983, 83, 83.

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dissociative and associative binding of amine are both possible (Figure 6). However, due to the strong Cu-Br bond strength in PDa, dissociative binding of amine in which PDa dissociates the Br anion ligand before binding amine is strongly disfavored (32.6 kcal/mol, Figure 6). In contrast, associative binding in which amine directly binds to PDa results in an increase of free energy by only 9.6 kcal/mol (Figure 6, associative path). Therefore, associative binding of amine is favored, thus converging the pathway initiated by complex B at intermediate PDb. According to transition-state theory,37 the overall activation barrier for the path initiated by complex A should be larger than the energy of intermediate PDb, 29.6 kcal/mol, comparable to or larger than that of complex B. In combination with the fact that the concentration of complex A is negligibly low, it is more likely that kinetically competent and thermodynamically stable complex B is the active copper catalyst initiating the catalytic cycle.38 Therefore, in the following discussions, only steps following the oxidative addition of complex B (i.e., PDb) are taken into account. 3.3. Deprotonation. After oxidative addition of complex B, the base reacts with the oxidative addition complex PDb to form the complex CPrd for reductive elimination. This deprotonation process is exothermic by 25.5 kcal/mol (eq 2).

CuðacacÞðNH2 CH3 ÞðPhÞðBrÞ þ Cs2 CO3 PDb - 25:5 kcal=mol CuðacacÞðNHCH3 ÞðPhÞ s F s R CPrd

þ CsBr þ CsHCO3

ð2Þ

Although the detailed mechanism for this step is elusive due to its heterogeneous nature39 and much research work is still needed to finally elucidate this issue, the large exothermic feature of this step clearly indicates that this step is thermodynamically favorable and irreversible.40 Thus, the base acts as the driving force for this cross-coupling reaction by sequestering the proton of the coordinated substrate amine and pushing the oxidative addition complex to the desired coupling product,41 as well as facilitating the formation of the active copper species B through deprotonation of the ancillary ligand. 3.4. Reductive Elimination. Once complex CPrd is generated, facile reductive elimination occurs to produce the coupling (37) Laidler, K.; King, C. J. Phys. Chem. 1983, 87, 2657. (38) However, from the present data, we cannot exclude a path initiated by complex A completely. It may represent a minor kinetically competing pathway. (39) Typically, base cannot dissolve completely in the solvent, and some remains undissolved in many of these copper-catalyzed coupling reactions, making the reaction solution heterogeneous in nature. Refer to some discussions in refs 5b 5c, and 5e. (40) Relatively few studies have been performed on the transmetalation step in transition metal catalysis. For some limited examples relevant to Pd catalysis, refer to: (a) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.; Maseras, F. J. Am. Chem. Soc. 2005, 127, 9298. (b) Nova, A.; Ujaque, G.; Maseras, F.; Lledos, A.; Espinet, P. J. Am. Chem. Soc. 2006, 128, 14571. (c) Liu, Q.; Lan, Y.; Liu, J.; Li, G.; Wu, Y. D.; Lei, A. J. Am. Chem. Soc. 2009, 131, 10201. However, there are no precedents of such studies for copper-catalyzed C-X (X = C, N, O, etc.) bond formation reactions. It seems that deprotonation of complex PDb by base is a stepwise process since concerted extrusion of HBr from PDb possesses a very high activation barrier (more than 30 kcal/mol). (41) For an example of base acting as reaction driving force, see: Rousseaux, S.; ; Gorelsky, S. I.; Chung, B. K. W.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 10692.

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Figure 4. Oxidative addition of phenyl bromide to complex D.

Figure 5. Oxidative addition of phenyl bromide to complex E.

Figure 6. Dissociative and associatve binding of amine to PDa.

The strong trans influence of the phenyl group makes the trans Cu-O bond distance longer than that of the cis one by 0.07 A˚.42 In transition state TSrd, the C-N bond is shortened to 1.97 A˚. Meanwhile both Cu-C and Cu-N bond distances are elongated from 1.88 and 1.82 A˚ to 1.90 and 1.83 A˚, respectively. Another remarkable change is the C-Cu-N bond angle, from 85.9° in CPrd to 63.9° in TSrd. All these structural changes imply the formation of a C-N bond and simultaneous weakening of relevant Cu-C and Cu-N bonds. In reductive elimination product PDrd, the C-N bond is further shortened to 1.45 A˚. Cu-C and Cu-N bond distances are further elongated to 2.64 and 1.90 A˚, respectively. Now, the product methyl aniline is formed, with the lone pair of nitrogen atom coordinating to copper.

product. Relevant optimized structures and energy changes are demonstrated in Figure 7. Complex CPrd is of square-planar geometry with phenyl and amide ligands appropriately perpendicular to each other.

(42) For reviews on the trans effect, see: (a) Quagliano, J. V.; Schubert, L. Chem. Rev. 1952, 50, 201–260. (b) Basolo, F. Prog. Inorg. Chem. 1962, 4, 381–453. (c) Coe, B. J.; Glenwright, S. J. Coord. Chem. Rev. 2000, 203, 5–80.

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Figure 7. Reductive elimination step.

The reductive elimination step is very facile, with an activation energy of only 1.4 kcal/mol. Additionally, this process is highly exothermic by 40.1 kcal/mol. So this process is both kinetically and thermodynamically favored. And this is probably why Cu(III) intermediates are difficult to characterize and isolate experimentally.43 Finally, ligand exchange between Pdrd and reactant methylamine occurs to liberate the coupling product methyl aniline and regenerate the active copper complex B. This process is exothermic by 9.0 kcal/mol. Thus, the catalytic cycle is completed. The energy diagram of a catalytic cycle is shown in Figure 8. 3.5. Discussions. 3.5.1. Acidity of the Nucleophile and Selection of Ancillary Ligand. From Figure 8, It is apparent that the rate-limiting step of the whole catalytic cycle is the oxidative addition step, where a neutral copper(I) species containing both an ancillary ligand and an alkylamine acts as the active catalyst to activate aryl bromide. In view of copper-catalyzed amidation reactions where the active species participating in the ratelimiting oxidative addition step is the Cu(diamine)(amidate) neutral species,21-23 this strongly indicates that copper-catalyzed amination and amidation reactions intrinsically follow the same mechanistic pathway. However, the acidity of the nucleophilic substrate plays a decisive role in the selection of reaction conditions, especially the ancillary ligand. Thus, for acidic substrates, neutral ancillary ligands are required to form the neutral Cu(I) species initiating the catalytic cycle. In contrast, for less acidic or basic substrates, acidic ligands are preferred. This can explain why diketones and amino acids are better ligands than basic diamine ligands in copper-catalyzed cross-coupling of alkylamines with aryl halides. (43) Cu(III) intermediates are only characterized very recently by solution NMR methods. See: (a) Bertz, S. H.; Cope, S.; Murphy, M.; Ogle, C. A.; Taylor, B. J. J. Am. Chem. Soc. 2007, 129, 7208–7209. (b) G€artner, T.; Henze, W.; Gschwind, R. M. J. Am. Chem. Soc. 2007, 129, 11362–11363. (c) Bartholomew, E. R.; Bertz, S. H.; Cope, S.; Murphy, M.; Ogle, C. A. J. Am. Chem. Soc. 2008, 130, 11244–11245.

3.5.2. The Role of the Base. It should be pointed out that appropriate selection of the base is also critical. Too weak a base would be unable to deprotonate the substrate or the ligand to form the active neutral Cu(nucleophile)(ligand) species, while too strong a base would lead to formation of unreactive Cu(amidate)221,22 or Cu(acac)2 anion. Additionally, base acts as the driving force for the coupling reaction because it pushes the reversible oxidative addition step to the direction of desired product formation through irreversible deprotonation of the oxidative addition complex. 3.5.3. Dichotomy of Copper Catalysis Compared to Pd Catalysis. One important feature of copper catalysis is that arylcopper(III) amide complexes are very reactive toward reductive elimination. This is in significant contrast to palladium catalysis, where much evidence has shown that arylpalladium(II) amides or alkoxides are quite stable toward reductive elimination and reductive elimination of these complexes even constitutes the rate-limiting step in some catalytic processes.44 This may account for the few examples of detection, characterization, and reactivity studies of copper(III) intermediates45 and the underdeveloped level of copper-catalyzed cross-coupling reactions compared to palladium-catalyzed analogues. The halide effect in copper-catalyzed cross-coupling and palladium-catalyzed cross-coupling deserves some discussion. (44) For reviews and examples of aryl-Pd(II) amides or alkoxides, see: (a) Widenhoefer, R. A.; Zhong, H. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 6787–6795. (b) Stambuli, J. P.; Weng, Z.; Incarvito, C. D.; Hartwig, J. F. Angew. Chem., Int. Ed. 2007, 46, 7674. (c) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7734. (d) Fulton, J. R.; Holland, A. W.; Fox, D. J.; Bergman, R. G. Acc. Chem. Res. 2002, 35, 44–56. (e) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (45) Examples of reactions of isolated aryl-Cu(III) complexes with nucleophiles: (a) Ribas, X.; Jackon, D. A.; Donnadieu, B.; Mahia, J.; Parella, T.; Xifra, R.; Hedman, B.; Hodgson, K. O.; Llobet, A.; Stack, T. D. P. Angew. Chem., Int. Ed. 2002, 41, 2991. (b) Xifra, R.; Ribas, X.; Llobet, A.; Poater, A.; Duran, M.; Sola, M.; Stack, T. D. P.; Benet-Buchholz, J.; Donnadieu, B.; Mahia, J.; Parella, T. Chem.;Eur. J. 2005, 11, 5146. (c) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196. (d) Yao, B.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Chem. Commun. 2009, 2899.

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Figure 8. Energy diagram of a catalytic cycle for copper-catalyzed amination reaction between phenyl bromide and methylamine.

Halides have been shown to play a positive role in some Pdcatalyzed cross-coupling reactions and have been suggested to participate in the oxidative addition step.34 However, our results here clearly show a detrimental effect of halide on the oxidative addition step. Complex A is very reactive toward aryl halides, while complex C, with an additional bromide anion ligand, possesses a much higher activation barrier. In solution, the halide anion may compete with the nucleophilic substrate to coordinate to the copper atom, thus depressing the formation of active Cu(I)(amine)(ketonate) species.

4. Conclusions In this study, the mechanism of copper-catalyzed crosscoupling of alkylamines with aryl bromides has been investigated in detail using the density functional method. Analogous to copper-catalyzed amidation reactions, copper-catalyzed amination reactions intrinsically follow the same mechanism, where the active copper species is a neutral copper(I) complex containing both ligand and nucleophilic substrate. Oxidative addition of phenyl halide to this species is the ratelimiting step of the catalytic cycle. To generate this active species, wise selection of ligand and base is critical to the success of such kind of cross-coupling. For acidic substrates such as amides, basic 1,2-diamine ligands are preferred, while for basic substrates such as alkylamines, acidic ligands are required. In both cases, base plays a critical role because too strong or too weak a base is detrimental to the formation of the neutral active copper species, instead generating unreactive

Cu(acac)2 or Cu(amidate)2 anions. In addition, significant mechanistic differences between copper- and palladiumcatalyzed cross-coupling reactions have been noted. Halide effect, which is proposed to be positive in some closely related Pd catalysis, is suggested to be negative in coppercatalyzed cross-coupling reactions. In addition, arylcopper(III) intermediates are shown to be too unstable toward reductive elimination, while a variety of arylPd(II) amides or alkoxides have been isolated and are indicated to be very stable. Reductive elimination of such Pd complexes even constitutes the rate-limiting step in some catalytic C-N or C-O bond formation reactions.44 These findings and insights should be valuable for the understanding of coppercatalyzed cross-coupling reactions and the development of more effective catalyst systems to encompass more challenging aryl chlorides and sulfonates and to realize selective or orthogonal reactions employing complex substrates containing multiple nucleophilic functional groups.

Acknowledgment. This work was supported by the National Natural Science Foundation of China (No. 20971058) and research funds granted for young chemists by the Ministry of Education, China (No. 2050205). Supporting Information Available: Detailed optimized geometries, free energies, and full citation of the Gaussian03 program. This material is available free of charge via the Internet at http:// pubs.acs.org.

Theoretical Study on Mechanism of Copper(I)-Catalyzed Cross

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