Enantioselectivity in the Iridium-Catalyzed Hydrogenation of

Organometallics 2010, 29, 6769–6781 DOI: 10.1021/om100899u

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Enantioselectivity in the Iridium-Catalyzed Hydrogenation of Unfunctionalized Olefins Tamara L. Church,† Torben Rasmussen,*,‡ and Pher G. Andersson*,† †

Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, 751 23 Uppsala, Sweden, and ‡National Supercomputer Centre, Link€ oping University, House G, SE-581 83 Link€ oping, Sweden Received September 17, 2010

The iridium-catalyzed asymmetric hydrogenation of largely unfunctionalized olefins has been studied by DFT calculations using a full, experimentally tested combination of ligand and substrate. All possible diastereomeric pathways were considered within four different hydrogenation mechanisms. The effect of a solvent continuum was also considered, and both the gas-phase and solventcontinuum calculations favored the same mechanism. This mechanism passed through IrIII and IrV intermediates and was consistent with the sense of stereoselection observed experimentally. Comparing the calculations to those performed on a model system permitted an evaluation of the model system’s utility in representing the full one. A simple, general method for predicting the sense of stereoselection in iridium-catalyzed olefin hydrogenation was developed and tested against published data.

Introduction Asymmetric hydrogenation is the atom-economical addition of H2 to a CdY (Y = C, N, or O) bond to obtain enantiomerically enriched compounds and was among the first reactions to be developed into a general method for producing these compounds.1 Early advances in asymmetric olefin hydrogenation were dominated by the introduction of rhodium-2 and ruthenium-diphosphine3 catalysts, and their success inspired the development of multitudinous chiral diphosphine ligands. Many of these have been used in highly *To whom correspondence should be addressed. E-mail: torbenr@ nsc.liu.se; [email protected] (1) (a) Asymmetric Catalysis in Industrial Scale: Challenges, Approaches and Solutions; Blaser, H. U., Schmidt, E., Eds.; Wiley: Weinheim, Germany, 2003. (b) Ojima, I., Ed. In Catalytic Asymmetric Synthesis; WileyVCH: New York, 2000. (c) Brown, J. M. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999; Vol. I, pp 121-182. (d) Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds. In Comprehensive Asymmetric Catalysis; Springer: Berlin, 1999; Vols. 1-3. (e) Ojima, I., Ed. In Catalytic Asymmetric Synthesis; VCH: New York, 1993. (f ) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994. (g) Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1998–2007. (h) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008–2022. (2) (a) Knowles, W. S.; Sabacky, M. J. J. Chem. Soc., Chem. Commun. 1968, 1445–1446. (b) Horner, L.; Siegel, H. Angew. Chem., Int. Ed. Engl. 1968, 7, 942. (c) Dang, T. P.; Kagan, H. B. J. Am. Chem. Soc. 1972, 94, 6429–6433. (3) Ikariya, T.; Ishii, Y.; Kawano, H.; Arai, T.; Saburi, M.; Yoshikawa, S.; Akutagawa, S. J. Chem. Soc., Chem. Commun. 1985, 922–924. (4) For some recent reviews, see: (a) Johnson, N. B.; Lennon, I. C.; Moran, P. H.; Ramsden, J. A. Acc. Chem. Res. 2007, 40, 1291–1299. (b) Zhang, W.; Chi, Y.; Zhang, X. Acc. Chem. Res. 2007, 40, 1278–1290. (c) Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de Vries, J. G. Acc. Chem. Res. 2007, 40, 1267–1277. (d) Chi, Y.; Tang, W.; Zhang, X. In Modern RhodiumCatalyzed Organic Reactions; Evans, P., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2005; pp 1-31. (e) Kitamura, M.; Noyori, Y. In Ruthenium in Organic Synthesis; Murahashi, S.-I., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2004; pp 3-52. (f ) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029–3069. r 2010 American Chemical Society

stereoselective hydrogenations of functionalized olefins.4 However, the high stereoselectivities of these catalysts rely upon the availability of a coordinating group, most often an amide, in the immediate vicinity of the CdC double bond. This group cooperates with the olefin double bond to chelate to the metal center, forming a cyclic structure that governs the stereochemical outcome of the hydrogenation reaction.5 Rhodium- and ruthenium-based catalysts are therefore less effective in the asymmetric hydrogenation of substrates without coordinating groups or with less-coordinating groups.6,7 A breakthrough in the hydrogenation of olefins without coordinating substituents came in 1997 when Pfaltz and coworkers used phosphinooxazoline ligands (1, Scheme 1)8 to design [(1)Ir(COD)]þ[PF6]- (COD = 1,5-cyclooctadiene), a chiral analogue of Crabtree’s catalyst ([(py)(PCy3 )Ir(COD)]þ[PF6]-)9 that enantioselectively hydrogenated prochiral imines.10 Although this catalyst also hydrogenated prochiral olefins highly enantioselectively, it was unstable to the reaction conditions. Pfaltz and co-workers overcame this (5) (a) Landis, C. R.; Halpern, J. J. Am. Chem. Soc. 1987, 109, 1746– 1754. (b) Landis, C. R.; Brauch, T. W. Inorg. Chim. Acta 1998, 270, 285–297. (6) See for example: (a) Ohta, T.; Ikegami, H.; Miyake, T.; Takaya, H. J. Organomet. Chem. 1995, 502, 169–176. (b) Bakos, J.; Toth, I.; Heil, B.; Marko, L. J. Organomet. Chem. 1985, 279, 23–29. (c) Hayashi, T.; Tanaka, M.; Ogata, I. Tetrahedron Lett. 1977, 18, 295–296. (d) Tanaka, M.; Ogata, I. J. Chem. Soc., Chem. Commun. 1975, 735. (7) The asymmetric hydrogenation of enamides by diphosphine-ligated rhodium catalysts has recently been the subject of highly predictive calculations. See: Donoghue, P. J.; Helquist, P.; Norrby, P.-O.; Wiest, O. J. Am. Chem. Soc. 2009, 131, 410–411. (8) For reviews on phosphinooxazoline ligands, see: (a) Pfaltz, A.; Drury, W. J., III. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5723–5726. (b) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–345. (c) Pfaltz, A. J. Heterocycl. Chem. 1999, 36, 1437–1451. (9) Crabtree, R. H. Acc. Chem. Res. 1979, 12, 331–338. (10) Schnider, P.; Koch, G.; Pret^ ot, R.; Wang, G.; Bohnen, F. M.; Kr€ uger, C.; Pfaltz, A. Chem.;Eur. J. 1997, 3, 887–892. Published on Web 11/17/2010

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Scheme 1. General Structure of a Chiral Phosphinooxazoline Ligand (1)8 and Pfaltz’s Phosphinooxazoline-Ligated Iridium Catalyst for Asymmetric Olefin Hydrogenation11

Church et al. Scheme 2. The Most Stable Isomers of [Ir(H)2(S)2]þ (3)25,27a

a

problem by changing the catalyst anion to [(3,5-(F3C)2-C6H3)4B]([BArF]-). The result was 2, an active, enantioselective, and stable catalyst for olefin hydrogenation (Scheme 1, R1 =Ph, o-tol; R2=iPr, tBu, Np).11 Since then, plentiful iridium-based catalysts for the reaction have been reported, and many of these employ chiral, chelating N,P donors as stereodirecting ligands.12 Chiral diphosphines have been used,13 and chelating oxazolinecarbene ligands have also been developed, primarily by Burgess and co-workers.12e The large arsenal of chiral, iridium-based hydrogenation catalysts has enabled the enantioselective reduction of unfunctionalized olefins,14 largely unfunctionalized olefins,12,15 vinyl phosphonates,16 vinyl fluorides,17 CF3-substituted olefins,18 vinyl silanes,19 enol phosphinate esters,20 enol ethers,12f,21 enamines,22 and even heteroaromatic rings.23 (11) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 2897–2899. (12) For reviews, see: (a) Church, T. L.; Andersson, P. G. Coord. Chem. Rev. 2008, 252, 513–531. (b) Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40, 1402–1411. (c) Roseblade, S. J.; Pfaltz, A. C. R. Chim. 2007, 10, 178–187. (d) K€allstr€ om, K.; Munslow, I.; Andersson, P. G. Chem.;Eur. J. 2006, 12, 3194–3200. (e) Cui, X.; Burgess, K. Chem. Rev. 2005, 105, 3272–3296. (f ) Valla, C.; Pfaltz, A. Chim. Oggi 2004, 22, 4–7. (g) Pfaltz, A.; Blankenstein, J.; Hilgraf, R.; H€ormann, E.; McIntyre, S.; Menges, F.; Sch€ onleber, M.; Smidt, S. P.; W€ustenberg, B.; Zimmermann, N. Adv. Synth. Catal. 2003, 345, 33–43. (13) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029–3069. (14) Bell, S.; W€ ustenberg, B.; Kaiser, S.; Menges, F.; Netscher, T.; Pfaltz, A. Science 2006, 311, 642–644. (15) Tolstoy, P.; Engman, M.; Paptchikhine, A.; Bergquist, J.; Church, T. L.; Leung, A. W.-M.; Andersson, P. G. J. Am. Chem. Soc. 2009, 131, 8855–8860. (16) (a) Cheruku, P.; Paptchikhine, A.; Church, T. L.; Andersson, P. G. J. Am. Chem. Soc. 2009, 131, 8285–8289. (b) Wang, D.-Y.; Hu, X.-P.; Deng, J.; Yu, S.-B.; Duan, Z.-C.; Zheng, Z. J. Org. Chem. 2009, 74, 4408– 4410. (c) Huang, Y.; Berthiol, F.; Stegink, B.; Pollard, M. M.; Minnaard, A. J. Adv. Synth. Catal. 2009, 351, 1423-1430. (d) Goulioukina, N. S.; Dolgina, T. M.; Bondarenko, G. N.; Beletskaya, I. P.; Ilyin, M. M.; Davankov, V. A.; Pfaltz, A. Tetrahedron: Asymmetry 2003, 14, 1397–1401. (17) (a) Engman, M.; Diesen, J. S.; Paptchikhine, A.; Andersson, P. G. J. Am. Chem. Soc. 2007, 129, 4536–4537. (b) Kaukoranta, P.; Engman, M.; Hedberg, C.; Bergquist, J.; Andersson, P. G. Adv. Synth. Catal. 2008, 350, 1168–1176. (18) Engman, M.; Cheruku, P.; Tolstoy, P.; Bergquist, J.; V€ olker, S.; Andersson, P. G. Adv. Synth. Catal. 2009, 351, 375–378. (19) K€ allstr€ om, K.; Munslow, I. J.; Hedberg, C.; Andersson, P. G. Adv. Synth. Catal. 2006, 348, 2575–2578. (20) (a) Cheruku, P.; Diesen, J.; Andersson, P. G. J. Am. Chem. Soc. 2008, 130, 5595–5599. (b) Cheruku, P.; Gohil, S.; Andersson, P. G. Org. Lett. 2007, 9, 1659–1661. (21) (a) Zhu, Y.; Burgess, K. Adv. Synth. Catal. 2008, 350, 979–983. (b) Zhou, J.; Ogle, J. W.; Fan, Y.; Banphavichit(Bee), V.; Zhu, Y.; Burgess, K. Chem.;Eur. J. 2007, 13, 7162–7170. (22) (a) Cheruku, P.; Church, T. L.; Trifonova, A.; Wartmann, T.; Andersson, P. G. Tetrahedron Lett. 2008, 49, 7290–7293. (b) Hou, G.-H.; Xie, J.-H.; Yan, P.-C.; Zhou, Q.-L. J. Am. Chem. Soc. 2009, 131, 1366– 1367. (c) Baeza, A.; Pfaltz, A. Chem.;Eur. J. 2009, 15, 2266–2269. (23) Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357–1366.

In the third case, which has a planar ligand, 3a = 3b.

Contrary to the case for rhodium catalysts, there is little consensus regarding the mechanism of olefin hydrogenation (and consequently of stereocontrol) by chiral iridium catalysts, despite that the reaction has been investigated both experimentally and computationally. One largely understood facet of the reaction is the role of the catalyst anion. Pfaltz and co-workers demonstrated that the catalyst anion strongly affects the rate and stability, but not the enantioselectivity, of these reactions.11,24 The hydrogenation is most effective in the presence of very weakly coordinating anions such as [BArF]-, as these slow catalyst decomposition relative to olefin coordination. Thus most iridium-based catalysts for asymmetric olefin hydrogenation contain [BArF]-, and investigations of their mechanism(s) of stereoselection necessarily focus on events occurring at the cation. A variety of experiments have offered clues about the reactions that occur at iridium during the catalytic cycle. The first stage of the reaction, catalyst activation, has been examined using NMR spectroscopic studies and DFT calculations. Pfaltz and Meuwly25 and Burgess and Hall26 have combined their respective [L*Ir(COD)]þ[BArF]- catalysts with H2 in deuterated chloroalkane solution, which best mimics hydrogenation conditions, but both obtained complex mixtures of products. Pfaltz and co-workers obtained a much cleaner reaction between catalyst 2 (R1 = Ph, R2 = iPr) and H2 in THF-d8 solution;25 at -40 °C, H2 oxidatively added to the Ir center to produce a single diastereomeric product. When the solution was warmed to 0 °C, the COD ligand was hydrogenated and lost from the Ir center, which then took up another equivalent of H2 and two equivalents of solvent to form two isomers of [(N∩P)Ir(H)2(S)2]þ, 3 (R1 = Ph, R2 = iPr). 2D NMR spectroscopy was used to assign these as the diastereomeric pair having the two hydride ligands cis to each other and to the P terminus of the ligand (3a and 3b, Scheme 2; N∩P = 1 (R1 = Ph, R2 = iPr), S = THF-d8). The ratio of diastereomers was not reproducible, although the same diastereomer was always favored. Pfaltz and co-workers’ calculations on the cation [(1)Ir(H)2(CH3Cl)2]þ corroborated their experimental findings, with 3a and 3b (S = CH3Cl) being the most stable isomers.25 In an earlier computational study, Brandt and co-workers used a truncated ligand set (N∩P = MeNdCHCHdCHPMe2) to (24) (a) Smidt, S. P.; Zimmermann, N.; Studer, M.; Pfaltz, A. Chem.;Eur. J. 2004, 10, 4685–4693. (b) Drago, D.; Pregosin, P. S.; Pfaltz, A. Chem. Commun. 2002, 286–287. (c) Blackmond, D. G.; Lightfoot, A.; Pfaltz, A.; Rosner, T.; Schnider, P.; Zimmermann, N. Chirality 2000, 12, 442–449. (25) Mazet, C.; Smidt, S. P.; Meuwly, M.; Pfaltz, A. J. Am. Chem. Soc. 2004, 126, 14176–14181. (26) Cui, X.; Fan, Y.; Hall, M. B.; Burgess, K. Chem.;Eur. J. 2005, 11, 6859–6868.

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Scheme 3. The Four Reaction Pathways Investigated in This Study, Each Shown from a Single Starting Configuration: (1) 1/3-MI-Solv, Which Proceeds through Migratory Insertion/Reductive Elimination to Give IrI and IrIII Intermediates That Have a Coordinated Solvent Molecule; (2) 1/3-MI, Which Proceeds through Migratory Insertion/Reductive Elimination to Give IrI and IrIII Intermediates That Lack Coordinated Solvent Molecules; (3) 3/5-MI, Which Proceeds through IrIII and IrV Intermediates in a Migratory-Insertion/ Reductive-Elimination Sequence; and (4) 3/5-Meta, Which Proceeds through IrIII and IrV Intermediates in a Metathesis/ Reductive-Elimination Sequencea

a

Reaction steps shown in gray are not discussed.

explore the course of iridium-catalyzed asymmetric hydrogenation and also found 3 (S = CH2Cl2) to be the most stable isomers of [(N∩P)Ir(H)2(CH2Cl2)2]þ.27,28 An [L*Ir(H)2(S)2]þ cation, formed from an [L*Ir(COD)]þ precatalyst via the hydrogenation and dissociation of the COD ligand, must coordinate an olefin in order to catalyze asymmetric olefin hydrogenation. If the olefin replaces a solvent molecule in a simple substitution reaction, [L*Ir(H)2(S)(olefin)]þ is formed. The most straightforward olefin hydrogenation sequence from [L*Ir(H)2(S)(olefin)]þ involves standard migratory-insertion and reductive-elimination steps. This pathway is illustrated in Scheme 3 (1) for one isomer of an olefin-bearing cation of the form [(N∩P)Ir(H)2(S)(olefin)]þ having olefin trans to P (though we have considered all of its isomers, including those with the olefin axial or trans to N, in our calculations). In the first step, a hydride ligand migrates from the IrIII center to the olefin, forming an (alkyl)IrIII species. The alkyl group and remaining hydride ligand can then reductively eliminate to form an IrI species with a weakly bound alkane. Dissociation of the alkane, oxidative addition of H2, and coordination of another olefin molecule complete the catalytic cycle. This type of mechanism, in which an [(N∩P)Ir(H)2(S)(olefin)]þ cation undergoes migratory insertion and reductive elimination through IrI (27) Brandt, P.; Hedberg, C.; Andersson, P. G. Chem.;Eur. J. 2003, 9, 339–347. (28) Structures 3a and 3b are identical in Brandt’s system because the N∩P ligand considered in that case possesses a mirror plane.

and IrIII species with coordinated solvent molecules, is labeled 1/3-MI-Solv and has been suggested as a possibility by Pfaltz.12c A related mechanism was proposed by Dieteker and Chen, who performed gas-phase MS studies of the reactions of 2 (R1 = Ph, R2 = iPr) and related olefin complexes with H2 and D2.29 Their data supported the intermediacy of IrI and IrIII species without coordinated solvent molecules, possibly because the reactions were studied in the gas phase. Thus the authors proposed an IrI/IrIII cycle based on five-coordinate intermediates. Buriak and co-workers proposed a similar mechanism for the hydrogenation of olefins using achiral [(PR3)(NHC)Ir(COD)]þ[PF6]- (NHC = N-heterocyclic carbene) catalysts.30 Upon studying that reaction using parahydrogen-induced polarization (PHIP) 1H NMR spectroscopy, they found peak enhancements that were consistent with the transfer of two hydrides from the same molecule of H2 to a single olefin, suggesting that a pathway with IrI and IrIII intermediates was operative.31 The authors noted, however, that PHIP does not exclude the participation of other, parallel pathways. In the present study, the iridium-catalyzed olefin hydrogenation mechanism passing through migratory (29) Dietiker, R; Chen., P. Angew. Chem., Int. Ed. 2004, 43, 5513– 5516. (30) Vazquez-Serrano, L. D.; Owens, B. T.; Buriak, J. M. Inorg. Chim. Acta 2006, 359, 2786–2797. (31) Vazquez-Serrano, L. D.; Owens, B. T.; Buriak, J. M. Chem. Commun. 2002, 2518–2519.

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insertion and reductive elimination steps to give IrI and IrIII intermediates that have no coordinated solvent molecules is labeled 1/3-MI (see Scheme 3 (2)). There has also been evidence to suggest that iridiumcatalyzed olefin hydrogenation passes through IrIII and IrV intermediates. Though this is contrary to the case in rhodiumcatalyzed asymmetric hydrogenation,32 the concept of IrV complexes as catalytic intermediates is well precedented. Experimental and theoretical studies have provided convincing evidence for the intermediacy of pentavalent species in iridium-catalyzed C-H33 and H-H34 activation reactions. There are also multiple examples of discrete, isolable IrV polyhydrides.35 Though Brandt and co-workers calculated that 3 was the most stable isomer of [(L)Ir(H)2(S)2]þ (L = MeNdCHCHd CHPMe2, S = CH2Cl2; vide supra), they found that the lowest-energy olefin-hydrogenation cycle did not include this species.27 Rather, they calculated that 3 could react with olefin and another equivalent of H2 to form a dihydride/ dihydrogen complex of the formula [(L)Ir(H)2(H2)(olefin)]þ. In this complex, migration of one hydride ligand onto the olefin (i.e., migratory insertion) was accompanied by simultaneous cleavage of the H-H bond to form an IrV trihydride, [(L)Ir(H)3(alkyl)]þ. The alkyl group was then reductively eliminated with one of the hydrides formed from the H2 cleavage. Dissociation of the alkane and coordination of both H2 and olefin regenerated the IrIII species [(L)Ir(H)2(H2)(olefin)]þ. This IrIII/IrV, migratory-insertion/reductiveelimination pathway is labeled 3/5-MI and shown in Scheme 3 (3). In 2004, Burgess, Hall, and co-workers used DFT calculations with the PBE functional to examine the mechanism of asymmetric olefin hydrogenation by their [(oxazolineNHC)Ir(COD)]þ[BArF]- catalysts.36 The lowest-energy pathway calculated in that study also passed through IrIII and IrV intermediates, including the dihydride/dihydrogen complex [(L)Ir(H)2(H2)(olefin)]þ, but followed a different mechanism (3/5-Meta, Scheme 3 (4)). They calculated that the first H transfer to olefin occurred via a metathesis reaction with the bound H2 molecule. This reaction produced an IrV trihydride, [(L)Ir(H)3(alkyl)]þ, related to the one calculated by Brandt. Reductive elimination of alkane (32) For a review on the mechanism of stereoselection in rhodiumcatalyzed asymmetric hydrogenation, see: Gridnev, I. D.; Imamoto, T. Acc. Chem. Res. 2004, 37, 633–644. (33) (a) Appelhans, L. N.; Zuccaccia, D.; Kovacevic, A.; Chianese, A. R.; Miecznikowski, J. R.; Macchioni, A.; Clot, E.; Eisenstein, O.; Crabtree, R. H. J. Am. Chem. Soc. 2005, 127, 16299–16311. (b) Oxgaard, J.; Muller, R. P.; Goddard, W. A., III; Periana, R. A. J. Am. Chem. Soc. 2004, 126, 352–363. (c) Webster, C. E.; Hall, M. B. Coord. Chem. Rev. 2003, 238-239, 315–331. (d) Tamura, H.; Yamazaki, H.; Sato, H.; Sakaki, S. J. Am. Chem. Soc. 2003, 125, 16114–16126. (e) Klei, S. R.; Tilley, T. D.; Bergman, R. G. J. Am. Chem. Soc. 2000, 122, 1816–1817. (34) Li, S.; Hall, M. B.; Eckert, J.; Jensen, C. M.; Albinati, A. J. Am. Chem. Soc. 2000, 122, 2903–2910. (35) (a) Bernskoetter, W. H.; Lobkovsky, E.; Chirik, P. J. Chem. Commun. 2004, 764–765. (b) Alaimo, P. J.; Bergman, R. G. Organometallics 1999, 18, 2707–2717. (c) Loza, M.; Faller, J. W.; Crabtree, R. H. Inorg. Chem. 1995, 34, 2937–2941. (d) McLoughlin, M. A.; Flescher, R. J.; Kaska, W. C.; Mayer, H. A. Organometallics 1994, 13, 3816–3822. (e) Goldman, A. S.; Halpern, J. J. Organomet. Chem. 1990, 382, 237–253. (f ) Goldman, A. S.; Halpern, J. J. Am. Chem. Soc. 1987, 109, 7537–7539. (g) Garlaschelli, L.; Khan, S. I.; Bau, R.; Longoni, G.; Koetzle, T. F. J. Am. Chem. Soc. 1985, 107, 7212–7213. (h) Gilbert, T. M.; Hollander, F. J.; Bergman, R. G. J. Am. Chem. Soc. 1985, 107, 3508–3516. (i) Gilbert, T. M.; Bergman, R. G. J. Am. Chem. Soc. 1985, 107, 3502–3507. (36) Fan, Y.; Cui, X.; Burgess, K.; Hall, M. B. J. Am. Chem. Soc. 2004, 126, 16688–16689.

Church et al.

from the trihydride and subsequent coordination of one equivalent each of H2 and olefin completed the catalytic cycle. Burgess and Hall also calculated that a 3/5-Meta mechanism was operative in the asymmetric hydrogenation of a 1,3-diene by an [(oxazoline-NHC)Ir(COD)]þ[BArF]catalyst.26 Despite that many studies have addressed the mechanism of iridium-catalyzed asymmetric olefin hydrogenation, none of the pathways described above (Scheme 3 (1)-(4)) can be eliminated as a possible mechanistic route for the reaction. To date, experimental data have been gathered from various systems and under various conditions, so the results are difficult to compare. Different results have been obtained even with very similar catalyst/substrate pairs. For example, kinetic studies on the hydrogenation of R-methylstilbene by [(1)Ir(COD)]þ[BArF]- complexes have shown the reaction to be either diffusion-limited24c or first-order in H2 pressure,27 depending on the reaction conditions. Further, Burgess has shown that the asymmetric hydrogenations of some olefins by a [(phosphine-NHC)Ir(COD)]þ[BArF]catalyst are independent of hydrogen pressure, whereas both the conversion and enantioselectivity of the reaction were pressure-dependent when other substrates were used.37,38 Additionally, though we27 and others21b,25,26,36 have conducted computational studies aimed at understanding the reaction, these have been carried out on truncated model systems and/or on a limited number of diastereomeric pathways and mechanisms. As a result, the mechanism of iridiumcatalyzed asymmetric olefin hydrogenation remains poorly understood. This is contrary to the case of rhodiumcatalyzed asymmetric olefin hydrogenation, where NMR, kinetic, and isotope-labeling studies have provided significant support to a RhI/RhIII mechanism in which substrate chelation to metal plays a pivotal role in hydrogenation and stereodiscrimination.32,39

Computational Details Geometries of all substrates were optimized using the Jaguar program40 by applying the B3LYP hybrid density functional41 together with the LACVP** basis sets. The complexes were treated with charge = þ1 and in the singlet state. In some cases, structures were first optimized using geometric constraints in order to generate starting structures that were subsequently optimized without geometric constraints. No symmetry constraints were applied. Normal-mode analysis of stable structures (37) Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D.-R.; Reibenspies, J. H.; Burgess, K. J. Am. Chem. Soc. 2003, 125, 113–123. (38) The difference in the H2 pressure dependence observed in refs 24c and 27 could be explained by mass transfer effects, as the reactions were performed at different stirring rates (2000 vs 700 rpm, respectively). However, this would not account for the observations in ref 37, as the hydrogenations of different substrates showed different pressure dependences in that article. The effects of mass transfer on hydrogenation reactions are discussed in: (a) Sun, Y.; Wang, J.; LeBlond, C.; Reamer, R. A.; Laquidara, J.; Sowa, J. R., Jr.; Blackmond, D. G. J. Organomet. Chem. 1997, 548, 65–72. (b) Sun, Y.; Landau, R. N.; Wang, J.; LeBlond, C.; Blackmond, D. G. J. Am. Chem. Soc. 1996, 118, 1348– 1353. (39) (a) Landis, C. R.; Brausch, T. W. Inorg. Chim. Acta 1998, 270, 285–297. (b) Brown, J. M. Chem. Soc. Rev. 1993, 25–41. (c) Brown, J. M.; Chaloner, P. A.; Morris, G. A. J. Chem. Soc., Perkin Trans. 2 1987, 1583– 1588. (d) Landis, C. R.; Halpern, J. J. Am. Chem. Soc. 1987, 109, 1746– 1754. (e) Halpern, J. Science 1982, 217, 401–407. (40) (a) Jaguar 4.2; Schr€odinger, Inc.: Portland, OR, 1991-2000. (b) Jaguar 6.0; Schrodinger, LLC,: Portland, OR, 2005. (41) (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.

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revealed no imaginary frequencies or a single imaginary frequency with negligibly low frequency (ν < 100 cm-1); those of transition states had a single imaginary frequency of higher frequency (usually ν > 500 cm-1). LACVP in Jaguar defines a combination of the LANL2DZ basis set42 for iridium and the 6-31G basis set for other atoms. Final energies were retrieved from single-point calculations at the B3LYP/LACV3pþþ** level of theory. LACV3pþþ** differs from LACVP** by using the 6-311þþG** basis set in place of 6-31G** as well as using one additional p function and two additional d functions on Ir. Energies in CH2Cl2 solution were calculated as single-point energies from optimized structures at the B3LYP/LACVP** level of theory using a continuous field with ε = 9.08 and F = 1.3266 g/mL to calculate the solvent radius (2.33 A˚). All energies are reported as electronic energies. Although frequency calculations were performed on all stable species and transition states, so free energies could technically be calculated, these are not reported here for two reasons. First, the free energies calculated from vibrational data are valid only at the standard state, i.e., P(H2)=1 atm and [CH2Cl2]= [catalyst 3 substrate]=1 M. Given that iridium-catalyzed asymmetric hydrogenation reactions are typically performed under 10-50 bar of H2, free energies calculated from vibrational data are not expected to be accurate. Second, the species calculated generally had several low-frequency vibrations, which can introduce significant error into free-energy calculations.43

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Scheme 4. (a) Experimental Result Obtained in the Hydrogenation of Substrate 5 by Catalyst Precursor [(4)Ir(COD)]þ[BArF]-;44 (b) Skeletal Structures Used to Illustrate the Cations A-Ca

Results and Discussion The main aims of this study were (i) to investigate all possible catalyst isomers (coordination isomers and diastereomers) in each of the mechanistic proposals in Scheme 3 using DFT calculations on an experimentally relevant system and (ii) to evaluate the utility of sterically truncated models in understanding iridium-catalyzed asymmetric olefin hydrogenation. Thus, the mechanisms in Scheme 3 have been evaluated using both a model catalyst and substrate, and an experimentally tested catalyst and substrate. To enable comparisons between the mechanisms in Scheme 3, each was tested with the same two catalyst/substrate combinations. The first system studied (eq 1) was based on the Crabtree catalyst, but with a PMe3 ligand in ½ðpyÞðPMe3 ÞIrðHÞ2 ðH2 CdCH2 ÞYþ f

½ðpyÞðPMe3 ÞIrðH3 C- CH3 ÞYþ Y ¼ H2, CH2 Cl2, empty coordination site ð1Þ place of PCy3 and ethylene as the substrate. Though this system is achiral and therefore gave no information regarding stereoselection, it was useful in evaluating the utility of small model systems in calculations on iridium-catalyzed asymmetric hydrogenations. Data for the model system and the related discussion can be found in the Supporting Information. The second, full system we studied was a complete catalyst cation and substrate combination that had already been examined experimentally. We compared the results of these calculations to those on the model system to evaluate the utility of the latter. Finally, we used the results of our calculations to produce a simple, reliable method for predicting the stereochemical outcome of asymmetric, iridium-catalyzed hydrogenation of olefins without coordinating groups. (42) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299–310. (43) Cramer, C. J. Essentials of Computational Chemistry; John Wiley & Sons, Ltd.: West Sussex, 2002.

a

Aref was chosen as the reference; A0 is the most stable isomer of A.

2. Comparison of Different Mechanisms on an Experimentally Relevant System. We calculated each of the mechanisms in Scheme 3 using the full structures of an experimentally examined substrate and catalyst cation pair. All isomeric pathways were considered, allowing each of the proposed mechanisms to be evaluated fully. Additionally, we calculated single-point energies for each species both in the gas phase and in CH2Cl2 solution in order to examine the effect of the solvent medium on the reaction pathways. We chose to study the catalyst precursor [(4)Ir(COD)]þ[BArF]because it has been tested in the reduction of a wide range of substrates and gives high ee values for many of these.44 As a substrate, we selected 3,4-dihydro-1-methylnaphthalene (5), which has proven difficult to hydrogenate highly stereoselectively.44,45 In the laboratory, [(4)Ir(COD)]þ[BArF]hydrogenates 5 to (R)-1,2,3,4-tetrahydro-1-methylnaphthalene ((R)-6) in 55% ee (Scheme 4a). By studying a catalyst/ substrate combination that gives only modest stereoselectivity, we hoped to locate the most energetically accessible reaction paths to both the R and S enantiomers of the product. 2.1. Starting Structures. We began by calculating energies for the cations that may be formed upon addition of H2 and (44) Hedberg, C.; K€allstr€ om, K.; Brandt, P.; Hansen, L. K.; Andersson, P. G. J. Am. Chem. Soc. 2006, 128, 2995–3001. (45) (a) Cheruku, P.; Paptchikhine, A.; Ali, M.; Neudoerfl, J.-M.; Andersson, P. G. Org. Biomol. Chem. 2008, 6, 366–373. (b) Verendel, J. J.; Andersson, P. G. Dalton Trans. 2007, 5603–5610. (c) K€allstr€om, K.; Andersson, P. G. Tetrahedron Lett. 2006, 47, 7477–7480. (d) Trifonova, A.; Diesen, J. S.; Andersson, P. G. Chem.;Eur. J. 2006, 12, 2318–2328. (e) Xu, G.; Gilbertson, S. R. Tetrahedron Lett. 2003, 44, 953–955. (f ) Broene, R. D.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115, 12569– 12570.

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Table 1. The Most Stable Isomers of Each of the Ir(III) Dihydride Olefin Complexes A, B, and Ca

a Energies are reported relative to compound Aref. b S = CH2Cl2, E(given) = [E(structure) þ E(H2)] - [E(Aref) þ E(CH2Cl2)]. c E(given) = [E(structure) þ E(H2)] - E(Aref).

olefin 5 to [(4)Ir(COD)]þ[BArF]- in CH2Cl2 solution. These are labeled A ([(4)Ir(H)2(H2)(5)]þ), B ([(4)Ir(H)2(CH2Cl2)(5)]þ), and C ([(4)Ir(H)2(5)]þ) and are visually simplified as shown in Scheme 4b. Olefins coordinated on the si face are shown in green and are hydrogenated to (R)-6, whereas those coordinated on the re face are shown in red and are hydrogenated to (S)-6. All isomers of A, B, and C that had geometrically accessible H atoms were considered.46 Upon calculating optimized structures for A, B, and C, it was clear that isomers with axial olefin ligands were unstable and generally underwent olefin dissociation. This effect has also been observed by Burgess for calculations on a full ligand set36 and is attributed to the bulk of the ligand above and below the N-Ir-P plane (N-Ir-C plane in Burgess’s case). Thus ligand 4 and olefin 5 are restricted to the equatorial plane. The most stable isomer of each cation is shown in Table 1, and the other stable isomers are shown in Tables 2-4, Table S5, or Figures S4-S8.47,48 The re coordination of the olefins in A0, B0, and C0 suggested that none of these were involved in the lowest-energy hydrogenation pathway, because they should form (S)-6 rather than the major product observed in experimental studies, (R)-6. Overall, A0 was the most stable cation of the type [(4)Ir(H)2(Y)(5)]þ (Y = CH2Cl2, H2, or empty coordination site). The pentacoordinate C0 was more stable than the solvent-coordinated B0 at the standard state, both in the gas phase and in CH2Cl2 solution, though the difference was smaller when the solvent model was applied. In the actual reaction, entropic factors will destabilize the A and C cations to some degree, whereas they will be favored (46) To be accessible for hydrogen transfer, a hydride or hydrogen ligand had to be positioned cis to the olefin ligand, which had to be oriented parallel to the Ir-H or Ir-H2 bond. To be accessible for reductive elimination, a hydride or hydrogen ligand had to be cis to the alkyl ligand. The alkyl group could rotate prior to elimination. Cations in which neither migratory insertion of H nor metathesis with H2 could occur without being preceded by olefin rotation were omitted from the study because they necessarily pass through another cation isomer and are therefore already considered. (47) Most of the “unstable” isomers relaxed to stable ones via olefin rotation during optimization, although a few instances of olefin dissociation or hydride/hydrogen exchange were observed. When these olefin rotations were blocked by constraining the structure during the calculation, the resulting structures were very high in energy. (48) Cations that were “dead ends” for hydrogenation (i.e., for which no stable intermediates could be found from the geometrically accessible migratory insertions and/or metatheses) are shown in Figures S4, S6, and S8.

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by the high pressure of H2 and high concentration of CH2Cl2, respectively. 2.2. Mechanisms. For each pathway, we calculated optimized structures and energies for (refer to Scheme 3) (i) the transition state for the first hydrogen transfer (via metathesis for 3/5-Meta or via migratory insertion for the other three pathways); (ii) the intermediate formed from this hydrogen transfer; and (iii) the transition state for reductive elimination from this intermediate. The energies of the reductiveelimination products are not needed to identify the lowestenergy pathway and were not calculated. Only the lowestenergy pathways to (S)- and (R)-6 within each mechanism type will be discussed here; higher-energy routes are discussed in the Supporting Information. 2.2.1. Gas Phase. Computational investigations of model systems and of some pathways on full systems have suggested that the 3/5 pathways are low in energy.27,36 We were thus interested in whether these pathways were low in energy for the full catalyst/substrate pair and whether they correctly predicted the stereochemical outcome of the hydrogenation of 5 by [(4)Ir(COD)]þ (Scheme 4a). The energies relevant to the lowest-energy 3/5-MI mechanisms are shown in Table 2; less favorable mechanisms of this type are shown in Table S5. The productive 3/5-Meta mechanisms are shown in Table 3. A0 (Table 2, entry 1 and Table 3, entry 1) was the most stable isomer of A and, because it had a re-coordinated olefin, produced (S)-6 upon hydrogenation. Hydrogenations from A0 were the lowest-energy 3/5 migratory-insertion and metathesis routes to (S)-6 and are therefore labeled 3/5-MIS0 and 3/5-MetaS0, respectively. The migratory insertion reaction of 3/5-MIS0 (Table 2, entry 1) was 3.6 kcal/mol lower in energy than the metathesis reaction of 3/5-MetaS0 (Table 3, entry 1), making it the preferred route to (S)-6. The most stable isomer of A that had a si-bound olefin was Aref (Table 2, entry 2 and Table 3, entry 2), which is related to A0 by a simple “vertical flip” of the olefin. Aref proceeded to the R alkane along the most favored 3/5 migratory-insertion (3/5-MIR0) and metathesis (3/5-MetaR0) pathways. The former was 4.0 kcal/mol lower in energy, making the migratory insertion pathways preferred for the formation of both (R)- and (S)-6. In all four preferred IrIII/IrV pathways (3/5-MIS0, 3/5-MetaS0, 3/5-MIR0, and 3/5-MetaR0), the first H transfer was rate-determining and endothermic and was followed by a nearly barrierless reductive elimination. The most-favored IrIII/IrV pathway to (R)-6 (3/5-MIR0, Table 2, entry 2) was 2.9 kcal/mol lower in energy than the most stable IrIII/IrV pathway to (S)-6 (3/5-MIS0, Table 3, entry 1), so the 3/5-MI mechanism correctly predicts the stereochemical outcome of the hydrogenation of 5 by [(4)Ir(COD)]þ. The same is true when the 3/5-Meta routes are considered. The calculations on the IrIII/IrV mechanisms allowed some pathways through IrI/IrIII mechanisms to be discarded on the basis of very high starting energies. No reaction data were computed starting from isomers of B and C whose energy exceeded that of the highest barriers in 3/5-MIR0 and 3/5-MIS0 by g10 kcal/mol. Practically, this meant that isomers of B and C with E > 25 kcal/mol were considered kinetically inaccessible in the reaction mixture. These cations are shown in Figures S5 and S7. Calculations on the IrI/IrIII mechanism without coordinated solvent molecules (the 1/3-MI mechanism) gave inauspicious results (Table S6). The energies calculated for both insertion and reductive elimination were higher than those for the 3/5 pathways in all cases (g18.9 and g29.4 kcal/mol).

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Table 2. Energies of the Transition States and Intermediates along the 3/5-MI Pathway for Olefin Hydrogenation Starting from Complexes of the Form [(4)Ir(H)2(H2)(5)]þ (A)a

a Energies are given relative to Aref. Only the lowest-energy pathways of this type are shown; see Table S5 for remaining pathways. Gas-phase energies are given in normal text, and solution-phase energies are given in italics. The lowest-energy pathway to the R alkane is shown in green, and the lowestenergy pathway to the S alkane is shown in red. b Intermediate formed from migratory insertion. c Migratory insertion onto the monosubstituted carbon atom of the olefin. d Migratory insertion onto the disubstituted carbon atom of the olefin.

The highest barriers in the 1/3-MIR0 and 1/3-MIS0 pathways were very similar, but the one in 1/3-MIS0 was lower, so the 1/3-MI mechanism for iridium-catalyzed hydrogenation predicts that the hydrogenation of 5 by [(4)Ir(COD)]þ will produce a small excess of (S)-6. Experimentally, the reaction produces a significant excess of (R)-6. The high barriers involved in the 1/3-MI mechanism and its incorrect stereochemical prediction indicate that the 1/3-MI mechanism is not important in the reduction of 5 by [(4)Ir(COD)]þ. None of the stable cations B could traverse the 1/3-MISolv cycle shown in Scheme 3 (1) to provide the alkane product (Table 4). Seven isomers of B could undergo migratory insertion; however, attempts to model reductive elimination following these insertions resulted in solvent loss to yield the analogous five-coordinate intermediates. We thus examined the possibility that the cations B could participate in the first step of the hydrogenation reaction before losing CH2Cl2 and continuing along another pathway. However, the migratory insertions from B6 and B8, which have the lowest barriers among the 1/3-MI-Solv pathways, form alkyliridium hydrides whose corresponding pentacoordinate complexes and H2 adducts (intermediates from C14 and A11 for B6; from C13 and A10 for B8) also have high barriers to reductive elimination. Thus all of the hydrogenation pathways from B6 and B8 are high in energy compared to

3/5-MIR0 and 3/5-MetaR0. Additionally, pathways beginning from B6 and B8 fail to predict the stereochemistry of the experimental product. Hydrogenations that began with migratory insertions from B6 or B8 before losing solvent to undergo reductive elimination through the C13 and C14 pathways would produce (S)-6 as the major product. If they instead bound H2 to undergo reductive elimination through the A10 and A11 pathways, the product should be nearracemic. Thus partial hydrogenation through the 1/3-MISolv pathways cannot account for the observed reaction outcome, so the 1/3-MI-Solv mechanism is not important in iridium-catalyzed asymmetric olefin hydrogenation.49 Overall, both the 3/5-MI and 3/5-Meta mechanisms correctly predict the stereochemical outcome of the studied reaction. The most favorable pathways to (R)- and (S)-6 proceeded through the 3/5-MI mechanism and began from Aref, and A0, respectively. The latter was calculated to be 2.9 kcal/mol lower in energy in the gas phase. 2.2.1. In CH2Cl2 Solution. Energies for all of the stable cations A, B, and C, as well as the relevant transition states and intermediates, were evaluated using a solvent-continuum (49) This analysis is also valid when less-stable isomers of B are included, as the barriers to reductive elimination are similar for the corresponding A and C analogues.

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Table 3. Energies of the Transition States and Intermediates along the 3/5-Meta Pathway for Olefin Hydrogenation Starting from Complexes of the Form [(4)Ir(H)2(H2)(5)]þ (A)a

a Energies are given relative to Aref. Only stable isomers of A that form stable products from metathesis are displayed in the table. Gas-phase energies are given in normal text, and solution-phase energies are given in italics. The lowest-energy pathway to the R alkane is shown in green, and the lowestenergy pathway to the S alkane is shown in red. b Intermediate formed from metathesis. c The migratory insertion transition state relaxed directly to the bound-alkane product (E = 10.3 kcal/mol). d Not applicable.

model to approximate CH2Cl2 solution. The data from these calculations are shown along with the gas-phase data in Tables 2-4 and S6. The inclusion of solvent in the calculations had little effect on the 3/5-MI and 3/5-Meta mechanisms; only minor adjustments in the relative energy of each species were observed, and the same pathways that were favored in the gas phase remained favored in CH2Cl2 solvent. The 3/5-MI pathways remained the preferred route to both (R)- and (S)-6, and the former was lower in energy by 4.1 kcal/mol (cf. 2.9 kcal/mol in the gas-phase calculations). Thus the calculations in CH2Cl2 solvent predicted a greater degree of stereoselectivity. The 3/5-Meta mechanism still predicted the preferred formation of (R)-6, and 3/5-MetaR0 was 5.0 kcal/mol higher in energy than 3/5-MIR0. The cations, transition states, and intermediates in the 1/3-MI pathways (Table S6) had slightly higher relative energies in CH2Cl2 than in the gas phase, but the effect was small. In the presence of solvent, the pathways shown in Table S6, entries 5 and 6, were the lowest routes through pentacoordinate intermediates to (S)- and (R)-6, respectively (cf. entries 8 and 9 in the gas phase), but these pathways were all very close in energy in both cases. The calculations in CH2Cl2 solvent predicted that 1/3-MIS0 would be 1.7 kcal/ mol lower in energy than 1/3-MIR0 (cf. 1.5 kcal/mol in the gas phase); thus both predicted (S)-6 to be the major product.

The inclusion of a CH2Cl2 solvent continuum impacted the 1/3-MI-Solv mechanism most strongly. The structures associated with this pathway had considerably higher relative energies in solution than in the gas phase. On average, a given species in the 1/3-MI-Solv mechanism was 5.7 kcal/mol less stable (relative to Aref) in CH2Cl2 than in the gas phase. Thus the 1/3-MI-Solv mechanism, which was already disfavored compared to the other three mechanisms in the hydrogenation of 5 by [(4)Ir(COD)]þ[BArF]-, is more disfavored when the calculations include a CH2Cl2 solvent field. 3. Predictive Value and Limitations of the Small Model System. The model system shown in eq 1 is a good electronic approximation of the full system shown in Scheme 4, and we therefore expected it to offer a realistic representation of the electronic factors that guide the reaction. Sterically, however, the small model system is quite different from the full system. Nevertheless, the model system was remarkably accurate in evaluating many aspects of the reaction mechanism. It accurately identified starting cations that could not participate in feasible hydrogenation routes; if a stable smallsystem cation had no routes to bound alkane, the analogous full-system cations with the same arrangement of ligands about the metal were also “dead ends” for migratory insertion and metathesis. The two systems also agreed that the 3/5 mechanisms were lower in energy than the 1/3 mechanisms,

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Table 4. Energies of the Transition States and Intermediates along the IrI/IrIII Pathway for Olefin Hydrogenation, 1/3-MI-Solv, Starting from Complexes of the Form [(4)Ir(H)2(S)(5)]þ (S = CH2Cl2; B)a

a Egiven = [Estructure þ E(H2)] - [E(Aref) þ E(CH2Cl2)]. Gas-phase energies are shown in normal font, whereas energies calculated in CH2Cl2 solvent are italicized. Only stable isomers of B with E < 25.0 kcal/mol that have a stable migratory insertion intermediate are displayed in the table. b Intermediate formed from migratory insertion. c No transition state with a bound CH2Cl2 could be found.

and in general the reaction profile (i.e., the relationship between the energies of all the steps within a given pathway) of a model-system pathway accurately predicted the reaction profiles of its full-system analogues. In the mechanisms passing through IrI and IrIII intermediates without bound solvent molecules, the lowest-energy pathways calculated for the model (1/3-mi0, see Supporting Information) and full (1/3-MI0) systems began from analogous cations, and the relative energies of the intermediates and transition states in 1/3-MIS0 and 1/3-mi0 corresponded extremely well. The model system was least predictive within the 1/3-MI-Solv reaction pathway, as it overestimated the stability of most species. The binding of CH2Cl2 to the starting cations (evaluated by comparing a pair of corresponding B and C cations) was less favorable in the full system, and the CH2Cl2 ligand was problematic during the reaction. Thus, though the model and full systems agreed that the 1/3-MI-Solv mechanism is less favorable than the 3/ 5 mechanisms and not experimentally relevant, the degree to which it is disfavored was underestimated by the model system. This effect was amplified when the calculations were performed using a CH2Cl2 solvent-continuum model. Although both the small and full systems predicted that a mechanism passing through IrIII and IrV intermediates should predominate in the iridium-catalyzed hydrogenation of olefins, calculations on the small system could not distinguish between the migratory-insertion and metathesis mechanisms. Studies of the full system, on the other hand, found that the 3/5-MIR0 pathway was overall the most favored pathway, requiring 4.0 kcal/mol less energy than the corresponding 3/5-MetaR0 mechanism. That the full

system could distinguish the 3/5 pathways, but the small system could not, suggests that the 3/5-MI mechanism is favored over the 3/5-Meta mechanism in the hydrogenation of 5 by [(4)Ir(COD)]þ, but that this conclusion may not necessarily extend to other full ligand/substrate combinations. Notably, the two mechanisms predicted the same stereochemical outcome. The model system, despite being severely truncated compared to the full system, models the lowest-energy, experimentally relevant pathways in that system very well. We attribute this to the correspondence in electronic properties between the two systems. These appear to be most important in steering the reaction, as they set the energy profiles of each pathway, whereas steric effects increase the energy of all steps in some pathways. The agreement between the results calculated for the two systems is striking. The model system likely has predictive value for the reactions of other catalyst/ substrate combinations with similar electronic characteristics, namely, the hydrogenations of unfunctionalized, nonpolar or weakly polar olefins by [(N∩P)Ir(COD)]þ cations.50 The mechanistic results calculated on the model system may not, on the other hand, apply to catalyst/substrate combinations that diverge substantially from it electronically. The large difference in trans-effect/trans-influence strength of the phosphorus and nitrogen termini of the ligand was significant in determining the relative energies of isomeric cations; a ligand with termini that resemble each other, such as a (50) Because we did not consider pathways in which the nitrogen and phosphorus ligands were trans to one another, we cannot draw conclusions regarding cations with nonchelating ligands.

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Figure 1. The major enantiomer from hydrogenation of a trisubstituted olefin can be predicted from examining the general cation [(N∩P)Ir(H)2(H2)(olefin)]þ.

diphosphine, could produce a different result. The model may also be inadequate to describe substrates having substituents that can coordinate to the metal or that strongly polarize the double bond. For example, Burgess and co-workers have described a system in which a functional group R to an olefin interacts with an iridium catalyst, altering the course of its hydrogenation.21b 4. Stereocontrol in the Iridium-Catalyzed Hydrogenation of Unfunctionalized Olefins. In the hydrogenation of 5 by [(4)Ir(COD)]þ, the most stable reaction pathways to (S)- and (R)-6 began from A0 and Aref, respectively, and these were therefore key to determining the stereoselectivity of the reaction. We therefore examined the structures of A0 and Aref in the hope of developing a general model of stereoselection for the iridium-catalyzed hydrogenation of olefins. Notably, these cations were quite similar, differing only by a vertical flip of the olefin ligand. Chiral [(N∩P)Ir(COD)]þ catalysts are usually most selective for the asymmetric hydrogenation of trisubstituted olefins and much less selective for tetrasubstituted or 1,1-disubstituted olefins; this suggests that the placement of the hydrogen substituent plays a crucial role in stereodiscrimination. The olefin in A0 and Aref is oriented perpendicular to the equatorial plane. In both structures, the H atom on the olefin is directed toward the N terminus of the ligand, with the more bulky olefin substituents pointing toward the equatorial hydride ligand. In Aref, which formed the major stereoisomer, the hydrogen substituent was directed toward the greatest steric bulk of the ligand, minimizing the interactions between the ligand and the non-hydrogen olefin substituents. According to the calculations, this configuration yielded the lowest-energy transition states for migratory insertion (and metathesis) and therefore produced the major product; this is consistent with the experimental result. Notably, this configuration did not produce the most stable starting cation, as Aref was not the most stable isomer of A. Apparently, pointing the hydrogen substituent of the olefin toward the ligand bulk is more important in the TS for migratory insertion than it is in the coordinated olefin complex. An interesting consequence of this analysis is that, in the asymmetric hydrogenation of a nonchelating trisubstituted

Figure 2. The quasi-dihedral angle θ is defined by the lines shown in purple: an extension of the Ir-P bond, the distance from the Ir center to the atom next to the coordinated nitrogen, and the distance from that atom to the adjacent atom that lies closest to Ir. For θ < 0, the ligand bulk lies below the equatorial plane; for θ > 0, it lies below the plane. 0=H or H2 coordination sites; 9 = substrate coordination site.

olefin by a chiral [(N∩P)Ir(COD)]þ cation, the major enantiomeric product should be predicted by simply drawing the cation [(N∩P)Ir(H)2(H2)(olefin)]þ in the configuration adopted by A0 and Aref and then determining whether the ligand N terminus has greater steric bulk “above” or “below” the equatorial plane (Figure 1). We tested the accuracy of predictions made this way using hydrogenations reported in the literature. Because each cation had to be in its most stable conformation when the ligand position was analyzed, geometry optimizations were performed; however, sufficiently accurate ligand conformations could be calculated by optimizing the simplified IrV cation [(N∩P)Ir(H)4]þ (instead of [(N∩P)Ir(H)2(H2)(olefin)]þ) using the MM2 force field as implemented in Spartan 02.51 Manual searches were used to locate the most stable ligand conformations. Upon finding an optimized structure for a cation [(N∩P)Ir(H)4]þ, we found it convenient to quantify the position of the ligand bulk by defining the quasi-dihedral angle θ as shown in Figure 2.52 A positive value of θ indicates that the bulk near the N terminus of the ligand lies above the equatorial plane, whereas it is below this plane for θ < 0. Thus the absolute configuration of the major product (51) Spartan 02; Wavefunction, Inc.: Irvine, CA, 2002. (52) [(N∩P)Ir(COD)]þ catalysts for asymmetric hydrogenation generally contain an sp2-hybridized N atom. In most cases, this atom is part of a five- or six-membered ring.

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Table 5. Predicted and Observed Product Configurations in the Hydrogenation of Alkenes 7-11 by Catalysts of the Type [(L)Ir(COD)]þa

a The expected configurations for hydrogenations by catalysts with θ values greater or less than zero are shown for each substrate. Configurations that were not correctly predicted by the model described in Figures 1 and 2 are shown in red. In most cases, ee values were determined using chiral GC-MS or HPLC. Most absolute configurations were determined by comparing their GC-MS or HPLC retention times to literature values. In some cases, we have derived absolute configurations from reported optical rotations. See individual publications for details. b Absolute configuration of the product alkane. c Data not available. d Neither absolute configuration nor relevant experimental details (sign of optical rotation, HPLC elution order, etc.) were given. e Ar = o-Et-C6H4. f X∩X = N,N0 -[(1S,2S)-1,2-diphenyl-1,2-ethanediyl] bis(4-methylbenzyl)sulfonamidyl. g X∩X = 3,30 -Bis(trimethylsilyl)biphenyl2,20 -dioxyl. h Ar = 2,6-Me2-C6H3.

formed from the hydrogenation of a trisubstituted olefin by [(N∩P)Ir(COD)]þ could be predicted from the sign of an easily determined parameter.

Table 5 shows results from the reductions of some common olefin substrates (7-11) by iridium catalysts with a wide variety of ligands53 and compares these results to the θ values

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calculated for each complex. (This analysis assumes that absolute configurations were always reported correctly. Although mistakes can occur quite easily when reporting absolute configurations, most are presumably correctly assigned.) In most cases, the sign of θ correctly predicted the major enantiomers in the hydrogenations of 7-11, although the magnitude of θ did not correlate with the ee values. The ligands studied had N termini that were part of oxazoline (entries 2-4, 6, 7, 9, 19, and 21-23), imidazole (entries 11 and 24), pyridine (entries 12, 14, and 16-19), quinoline (entry 13), and thiazole (entries 25 and 26) rings or that were acyclic (entry 15). The P termini of these ligands were most often phosphines, but could also be phosphinites (entries 16-18 and 23), phosphites (entry 22), and azaphosphinites (entries 4 and 7). Notably, the analysis was useful even when chirality at phosphorus (entry 6), multiple stereocenters (entries 6, 7, 12-14, and 22), and planar chirality (entry 9) were present in the ligands. In fact, the sign of θ also predicted the major products in hydrogenations by Burgess’s catalyst,53r which bears a chiral N∩C ligand (38, entry 27). That the present analysis, which was based on calculations on a [(N∩P)Ir(H)2(H2)(olefin)]þ system, is useful for a [(N∩C)Ir(H)2(H2)(olefin)]þ system suggests that the configuration of the latter cation is also determined in large part by the trans influence and can be compared to [(4)Ir(H)2(H2)(olefin)]þ. Indeed, DFT calculations performed by Burgess, Hall, and co-workers on olefin hydrogenation by [(38)Ir(COD)]þ found that the cation [(38)Ir(H)2(H2)(olefin)]þ, which produced the major enantiomer, had a coordination geometry analogous to that in A0 and Aref, but with the carbene moiety, which exerts a strong trans influence, taking the place of the phosphine.36 In that system, the reaction was predicted to occur via a 3/5-Meta pathway. The analysis presented here is based on the 3/5-MI mechanism but is equally valid for the reaction via 3/5-Meta because the same cation produces the major product in both mechanisms. For three ligands (entries 1, 8, and 20),53a predictions based on the sign of θ failed only for substrate 10, but were correct for the other five substrates. In these cases, the allylic alcohol of the substrate may be influencing the stereoselection by coordinating to the iridium metal, though this would be somewhat surprising in light of a report by Burgess that examined the hydrogenation of aliphatic olefins by [(12)Ir(COD)]þ[BArF]-.21b Burgess and co-workers found that the (53) (a) Smidt, S. P.; Menges, F.; Pfaltz, A. Org. Lett. 2004, 6, 2023– 2026. Org. Lett. 2004, 6, 3653. (b) Cozzi, P. G.; Menges, F.; Kaiser, S. Synlett 2003, 833–836. (c) Cozzi, P. G.; Zimmermann, N.; Hilgraf, R.; Schaffner, S.; Pfaltz, A. Adv. Synth. Catal. 2001, 343, 450–454. (d) Tang, W.; Wang, W.; Zhang, X. Angew. Chem., Int. Ed. 2003, 42, 943–946. (e) Li, X.; Li, Q.; Wu, X.; Gao, Y.; Xu, D.; Kong, L. Tetrahedron: Asymmetry 2007, 18, 629–634. (f ) Hilgraf, R.; Pfaltz, A. Adv. Synth. Catal. 2005, 347, 61–77. (g) Menges, F.; Neuburger, M.; Pfaltz, A. Org. Lett. 2002, 4, 4713– 4716. (h) Bunlaksananusorn, T.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 3941–3943. (i) Schenkel, L. B.; Ellman, J. A. J. Org. Chem. 2004, 69, 1800–1802. ( j) Kaiser, S.; Smidt, S. P.; Pfaltz, A. Angew. Chem., Int. Ed. 2006, 45, 5194–5200. (k) Liu, Q.-B.; Yu, C.-B.; Zhou, Y.-G. Tetrahedron Lett. 2006, 47, 4733–4736. (l) Drury, W. J., III; Zimmermann, N.; Keenan, M.; Hayashi, M.; Kaiser, S.; Goddard, R.; Pfaltz, A. Angew. Chem., Int. Ed. 2004, 43, 70–74. (m) Liu, D.; Tang, W.; Zhang, X. Org. Lett. 2004, 6, 513–516. (n) Liu, D.; Dai, Q.; Zhang, X. Tetrahedron 2005, 61, 6460–6471. (o) Hou, D.-R.; Reibenspies, J.; Colacot, T. J.; Burgess, K. Chem.;Eur. J. 2001, 7, 5391–5400. (p) Dieguez, M.; Mazuela, J.; Pamies, O.; Verendel, J. J.; Andersson, P. G. J. Am. Chem. Soc. 2008, 130, 7208– 7209. (q) K€allstr€ om, K.; Hedberg, C.; Brandt, P.; Bayer, A.; Andersson, P. G. J. Am. Chem. Soc. 2004, 126, 14308–14309. (r) Powell, M. T.; Hou, D.-R.; Perry, M. C.; Cui, X.; Burgess, K. J. Am. Chem. Soc. 2001, 123, 8878–8879.

Church et al.

catalyst added H2 to one face of the olefin 2-X-2-butene for X = Ph, CH2OH, or CH2OR, but to the opposite face when X = C(O)O-, C(O)OH, or C(O)OR. They combined these results with computational studies and concluded that transient functional-group coordination was important in the hydrogenation of 2-methyl-2-butenoic esters but not of the corresponding allylic alcohols. Factors not yet understood may be responsible for the surprising selectivity in Table 5, entries 1, 8, and 20. As all of these ligands were reported in the same article, this effect has been documented only once,53a although it may be more common; the configuration of the major product in the asymmetric hydrogenation of 10 often goes unreported. However, all other catalysts for which data were available (see entries 14, 16, and 22-26) hydrogenated 10 to the predicted enantiomer. There were two additional unexpected results. One catalyst (based on the ligand in entry 10) hydrogenated E- and Z8 to the same major product, although with very different enantioselectivities.53f The former substrate was hydrogenated to the expected product, (R)-2-(4-methoxyphenyl)butane, in 85% ee, and the latter was hydrogenated to the same product in 35% ee. Strong secondary interactions may be present in that catalyst, making the olefin’s non-hydrogen substituents more important in determining the sense of selectivity. In another case (entry 5), substrates 8-11 were hydrogenated to the product predicted by θ, but 7 was not.45e The use of the parameter θ is based upon considering only the position of the hydrogen substituent. Nevertheless, it was very useful in predicting the direction of stereoselection in the iridium-catalyzed hydrogenation of trisubstituted olefins. Because this method generally allows the accurate prediction of the major product of such hydrogenations based on a single parameter obtained from a molecular-mechanics calculation, we hope that it will find use in the design of new ligand structures for iridium-catalyzed asymmetric olefin hydrogenation.

Conclusions The iridium-catalyzed hydrogenation of unsubstituted olefins is a powerful method in asymmetric synthesis. In this study, we have used DFT calculations to consider all of the possible diastereomeric routes through four different mechanisms for converting an iridium-bound alkene/dihydride complex to a hydrogenated-alkane complex. By considering these routes on both a small, model system and a full, experimentally tested system, we were able to evaluate the validity of using model systems to study this reaction. The correspondences between the model and full systems were striking. The model system predicted the energy profiles of each of the diastereomeric pathways from [(N∩P)Ir(H)2 (Y)(olefin)]þ (Y = H2, CH2Cl2, or empty coordination site) and was useful in identifying the low-energy pathways within each cation type. The ability of the model system to predict the behavior of a full system with a real ligand and cation was encouraging, and we hope that it will provide a solid foundation for the use of model systems in future computational investigations of other iridium-catalyzed asymmetric hydrogenations, such as those of imines or coordinating substrates. The model system failed, however, to distinguish the two 3/5 mechanisms, though the stereochemical outcome is the same in either case. Thus although the hydrogenation of olefin 5 by [(4)Ir(COD)]þ likely follows the 3/5-MI mechanism, reactions between other substrate/catalyst combinations may occur via a 3/5-Meta pathway.

Article

A very simple model was produced to predict the major enantiomer formed from the iridium-catalyzed asymmetric hydrogenation of an olefin, regardless of the specific ligand and olefin involved. This model relies upon a single parameter that can be measured from a molecular mechanics calculation and was quite accurate in predicting the stereochemical outcome of asymmetric olefin hydrogenations using a wide variety of catalysts. Thus it provides an efficient tool in the design of new ligands for this reaction.

Acknowledgment. The authors are grateful to Prof. P.-O. Norrby (G€ oteborgs Universitet, Sweden) and Mr. J. J. Verendel for helpful discussions and advice.


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This work was supported by grants from AstraZeneca, The Swedish Research Council (VR), and Ligbank. T.L.C. thanks Wenner-Gren Stiftelserna for a Postdoctoral Fellowship. Supporting Information Available: Comparison of mechanisms on a model system, basis set effects in the model system, nonproductive isomers of A, B, and C, high-energy isomers of B and C, higher-energy pathways from A, pathways from C, absolute energies, input coordinates for the most favorable mechanisms, and output coordinates for all species in productive reaction pathways. This material is available free of charge via the Internet at http://pubs.acs.org.

Enantioselectivity in the Iridium-Catalyzed Hydrogenation of

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