ARTICLE pubs.acs.org/Organometallics
On the Mechanism of Iridium-Catalyzed Asymmetric Hydrogenation of Imines and Alkenes: A Theoretical Study Kathrin Helen Hopmann*,†,‡ and Annette Bayer† † ‡
Department of Chemistry, University of Tromsø, N-9037 Tromsø, Norway Centre for Theoretical and Computational Chemistry, University of Tromsø, N-9037 Tromsø, Norway
bS Supporting Information ABSTRACT: Phosphine-oxazoline (PHOX)-based iridium complexes have emerged as useful tools for enantioselective hydrogenation of unfunctionalized alkenes and imines. The mechanistic details of the asymmetric hydrogenation process, however, are poorly understood. Several different mechanisms have been put forward for hydrogenation of unfunctionalized alkenes, but it remains unclear which of these provide an accurate description of the hydrogenation reaction. The mechanistic aspects of Ir-(PHOX)-mediated hydrogenation of imines are little explored, and no detailed mechanism has been formulated to date. Here we provide a comprehensive quantum mechanical study of Ir-(PHOX)-mediated hydrogenation of both alkene and imine substrates. Our results support previous findings by Brandt et al., clearly favoring an Ir(III)/ Ir(V) reaction cycle for Ir-(PHOX)-mediated hydrogenation of unfunctionalized alkenes. An important aspect of this reaction mechanism is the orientation of the metal-coordinated alkene substrate, which determines the stereochemistry of the resulting product. Our analysis further shows that none of the proposed alkene hydrogenation mechanisms are applicable for imines. For Ir-(PHOX)-mediated imine hydrogenation, we suggest a fundamentally different catalytic cycle involving dissociation of the imine substrate. The suggested mechanism correctly reproduces the stereoselectivity of imine reduction, but indicates that the enantioselectivity should be more sensitive to the reaction conditions and less controllable than the enantioselectivity of alkene hydrogenations.
’ INTRODUCTION Asymmetric hydrogenation of alkenes and imines is of importance for generation of chiral building blocks from prochiral precursors. Enantioselective conversion is achieved by transition metal-based catalysts (typically Ir, Rh, or Ru complexes) modified with chiral organic ligands.1,2 Whereas the applicability of Rh and Ru catalysts often depends on the presence of a functional group in the substrate, Ir complexes with N,P-ligands can be applied for efficient asymmetric conversion of unfunctionalized substrates.1,2 Chiral analogues of Crabtree’s catalyst3 such as phosphine-oxazoline (PHOX)-type complexes (Figure 1) are successful examples, providing enantioselective conversion of unfunctionalized alkenes (up to 99% enantiomeric excess, ee) and imines (up to 96% ee).2,47 Rational improvement of chiral hydrogenation catalysts requires detailed knowledge about the reaction pathway. For Ir-(PHOX)-mediated hydrogenations, however, the mechanistic details remain controversial. On the basis of mass spectrometry studies on Ir-(PHOX)-mediated hydrogenation of styrene, Dietiker and Chen suggested an Ir(I)/Ir(III) cycle (mechanism A, Scheme 1-I).8 The catalytic species is a dihydride-Ir(III) complex formed after oxidative addition of H2. Migratory insertion of the substrate into a metalhydride bond is followed by reductive elimination of the product and regeneration of Ir(I).8 DFT studies by Brandt et al., however, indicated that a Ir(I)/Ir(III) cycle is unlikely,9 and instead, an Ir(III)/Ir(V) cycle (mechanism B, r 2011 American Chemical Society
Scheme 1-II) was put forward. Migratory insertion of the substrate occurs simultaneously with oxidative addition of a second H2 molecule, resulting in an Ir(V) intermediate. Proton transfer to the substrate is accompanied with regeneration of Ir(III).9 The computational results by Brandt et al. have been questioned by several groups, who pointed out that the heavily truncated achiral model of Ir-(PHOX) employed in calculations (the catalyst was modeled as CH3-N-(CH)3-P-(CH3)2)9 is unable to describe the steric and electronic properties of the real system correctly.5,8,10 DFT calculations by Burgess and co-workers on a full iridiumcarbene oxazoline complex support an Ir(III)/Ir(V) cycle for iridium-mediated alkene hydrogenation, but suggest a slightly different reaction pathway, in which the substrate does not insert into an Irhydride bond, but into the Ir-coordinated H2 molecule (mechanism C, Scheme 1-III).10 Burgess and co-workers also reported a comparison of mechanism B and C on a full Ir-(PHOX) complex with the simple substrate ethene, indicating an energy difference of only 0.3 kcal mol1 between these two pathways.10 Clearly, in order to establish which of the proposed mechanisms is employed by Ir-(PHOX) catalysts, it is necessary to evaluate all proposals with the same model complex of a full Ir-(PHOX) complex and a realistic substrate. Interestingly, concurrently with our study, Andersson and co-workers have performed DFT studies Received: October 1, 2010 Published: April 05, 2011 2483
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Organometallics on a full model of a thiazole derivative of Ir-(PHOX), showing that mechanism B is the preferred mechanism for alkene hydrogenation.11 For hydrogenation of unfunctionalized imines, Ir-(PHOX) catalysts have been shown to provide very good yields and selectivities.6,7 Nevertheless, the mechanistic details of Ir-(PHOX)-catalyzed imine hydrogenation are little explored, and to our knowledge, a reaction mechanism has not been put forward. It is possible that Ir-(PHOX)mediated imine hydrogenation utilizes the same mechanism as alkene hydrogenation (Scheme 1) or that it occurs through one of the reaction mechanisms proposed for various achiral Ir complexes.1218 The latter, however, differ widely, involving various mechanistic strategies, ranging from stepwise hydride and proton transfer from a dihydride-Ir complex to a bound imine substrate,1315 to concerted proton and hydride transfer from a trihydride-Ir complex to an
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unbound substrate.17 Ir-(PHOX)-mediated imine hydrogenation could also occur through a hitherto unknown mechanism. Given the controversial mechanistic results on Ir-(PHOX)mediated alkene hydrogenation and the limited knowledge about Ir-(PHOX)-mediated imine hydrogenation, we decided to investigate the reactions of Ir-(PHOX) with alkenes and imines in more detail. Quantum chemical methods are applied to analyze the mechanisms of both alkene and imine hydrogenation with full catalyst and substrate models. Initially, we focus on the three proposed alkene hydrogenation mechanisms (Scheme 1) to establish the energetically preferred pathway. Analysis of the enantioselectivity of the most feasible alkene hydrogenation mechanism is performed to ensure reproduction of the experimentally observed product stereochemistry. The proposed alkene and imine hydrogenation mechanisms then serve as a starting point for analysis of Ir-(PHOX)-mediated imine hydrogenation and enantioselectivity.
’ COMPUTATIONAL DETAILS
Figure 1. Crabtree’s catalyst and the chiral phosphine-oxazoline (PHOX) derivatives.
All studies were performed on the full PHOX catalyst (C1) and the substrates trans-stilbene (S1), E-1,2-diphenylpropene (S2), and N-(1phenylethylidene)aniline (S3) (Figure 2). The density functional B3LYP,19,20 as implemented in the Gaussian 03 package,21 was employed for calculations. All computational models have a charge of þ1 and were computed in the closed-shell singlet state (test calculations show that the triplet state is ∼18 kcal mol1 higher in energy). Geometries were optimized in vacuum with the triple-ζ basis set
Scheme 1. Proposed Alkene Hydrogenation Mechanisms Mediated by Iridium Phosphine-Oxazoline (PHOX) or CarbeneOxazoline Catalysts:a (I) Ir(I)/Ir(III) Cycle by Dietiker and Chen,8 (II) Ir(III)/Ir(V) Cycle by Brandt et al.,9 (III) Ir(III)/Ir(V) Cycle by Burgess and Co-workers10
a
Ligands abbreviated as N,P or N,C; COD = 1,5-cyclooctadiene, Sol = solvent. 2484
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Figure 2. Catalyst (C1) and substrates (S1S3) employed in this study.
Figure 3. Quantum chemical model of catalyst C1 with substrate S1 (corresponding to the energetic reference, ReacA-si,a). 6-311G(d,p) (as implemented in Gaussian 03) on all atoms except iridium. For iridium, the double-ζ basis set LANL2DZ was employed (corresponding to the Los Alamos Effective Core Potential plus DZ22), which was augmented with an extra f polarization basis function (exponent 0.65). Frequency calculations were performed on all optimized geometries to ensure only positive eigenvalues for minima and one negative imaginary frequency for transition states. Thermochemical data and temperature corrections were computed at 298.15 K for all optimized geometries. The effect of the surrounding solvent was accounted for by performing single-point calculations with the IEFPCM23 model, employing CH2Cl2 as the solvent (dielectric constant = 8.93), which is the solvent used in reported experimental studies.7 The radii employed for cavity generation were taken from the UFF force field (scaled by 1.1).24 Reported energies (in kcal mol1) are the Gibbs free energies including solvent corrections (ΔG298K,sol) unless otherwise noted. To evaluate the effect of dispersion effects, we additionally performed single-point calculations on selected geometries employing the DFT-D3 empirical dispersion correction by Stefan Grimme,25 as implemented in GAMESS.26 The dispersion-corrected energies are given as ΔG298K,sol,dis. To test the effect of the employed functional, we also performed single-point calculations on selected optimized geometries with the B3LYP* functional (with 15% HF exchange).27 The obtained results are very close to the B3LYP results (see Supporting Information).
’ RESULTS AND DISCUSSION The mechanistic studies were performed using a full model of the Ir-(iPr-PHOX) catalyst C1 and the alkene and imine substrates S1, S2, and S3 (Figure 2). The PHOX ligand was chosen with S-configuration, which according to experiment results in formation of the R-products for hydrogenation of S2 and S3.47 The feasibilities of mechanisms A through C (Scheme 1) were tested with the olefin substrate S1. The model employed in these studies is shown in Figure 3. Alkene Hydrogenation Based on Mechanism A. Chen and Dietiker have proposed an Ir(I)/Ir(III) cycle for Ir-(PHOX)mediated alkene hydrogenation (mechanism A, Scheme 1).8 We have evaluated mechanism A using a dihydride complex as starting point (Figure 4, Scheme 2). Experimental studies of
oxidative addition of H2 to C1 have shown formation of two dihydride stereoisomers, with one hydride coordinated trans to the oxazoline ring and the other hydride bound either below or above the basal plane.28 Four different isomers of ReacA are considered here, originating from the two dihydride isomers and with re- or si-face coordination of the substrate (Figure 4). The preferred isomer is ReacA-si,a, whereas the others are 0.9 to 1.6 kcal mol1 higher in energy. For the various mechanisms analyzed below, studies were performed on the different reactant isomers, but only the lowest energy pathway is discussed in detail. The preferred reaction pathway for mechanism A originates from reactant ReacA-si,a (Scheme 2; for optimized geometries see Supporting Information Figure S1). The first step involves transfer of the hydride above the equatorial plane to the substrate, with a barrier of 19.2 kcal mol1 (TS1A, Table 1). The formed intermediate (InterA) exhibits an agostic bond between iridium and the reduced carbon center. The adjacent carbon is formally anionic and coordinates to iridium through its lone pair. The second reaction step involves transfer of a proton to the anionic carbon, with simultaneous reduction of Ir(III) to Ir(I) (TS2A). The barrier for this step is 24.0 kcal mol1. The product complex exhibits two agostic bonds to the metal center (AlkaneA). The reaction energy (24.0 kcal mol1) indicates a highly endothermic reaction. An alternative binding mode for the product involves one agostic bond and one η2-interaction of a phenyl substituent, with a relative energy of 15.6 kcal mol1. The computed enthalpies (ΔH298K,sol) provide a similar picture of the reaction mechanism (Table 1). Calculations with S1 coordinated through the re-face (ReacA-re,a, Figure 4B) result in a similar overall barrier of 23.5 kcal mol1. DFT calculations by Brandt et al. on the simplified CH3N-(CH)3-P-(CH3)2 complex and ethene as substrate yielded relative energies for mechanism A of 8.0 kcal mol1 for TS1, 15.3 kcal mol1 for TS2, and 7.0 kcal mol1 for the product (electronic energies, B3LYP/LANL2DZ).9,30 Thus, the overall shape of the potential energy surfaces is similar for the two models, although a direct comparison to the results obtained here is not possible due to the large differences in model size. On the basis of the same truncated model, it was shown that a more feasible reaction mechanism can be obtained if an additional H2 molecule coordinates to iridium, giving rise to mechanism B.9 Alkene Hydrogenation Based on Mechanism B. Binding of H2 to the empty coordination site of the dihydride isomers of ReacA (Figure 4) gives rise to four six-coordinated isomers of ReacB (Figure 5AD). H2 coordination has a cost of 5.7 to 7.2 kcal mol1, which is entirely due to loss of entropy (ΔH298K,sol = 1.1 to 2.7 kcal mol1). The most feasible reaction pathway for mechanism B (Scheme 3) originates from ReacB-si,b (Figure 5C; for optimized geometries see Supporting Information Figure S2). The first step involves substrate insertion into the Irhydride below the basal plane, simultaneously with oxidative addition of H2 (TS1B). 2485
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Figure 4. Isomers of ReacA (a = hydride above basal plane, b = hydride below basal plane).29
Scheme 2. Computed Reaction Pathway for Mechanism A (Substrate S1 and Catalyst C1)
Table 1. Computed Energies (kcal mol1) for Mechanism A (Figure S1, Scheme 2, S1 and C1) ΔE ReacA-si,a
a
ΔG298K
ΔH298K,sola
ΔG298K,sola
0.0
0.0
0.0
0.0
TS1A
22.0
18.4
21.1
19.2
InterA
11.8
11.5
13.5
12.0
TS2A AlkaneA
23.0 22.2
22.6 22.5
24.2 25.3
24.0 24.0
η2-AlkaneA
10.8
12.3
16.5
15.6
Includes effect of CH2Cl2 solvent.
This step has a barrier of 18.6 kcal mol1 (Table 2). At the TS, the substrate has rotated so that the double bond is aligned parallel with the axial ligands. The formed Ir(V) intermediate is seven-coordinated and exhibits an agostic bond to the hydrogenated carbon center (InterB). Proton transfer to the substrate occurs simultaneously with reduction of Ir(V) to Ir(III) (TS2B), which has a barrier of 16.2 kcal mol1 (Table 2). Two product conformations were tested, involving either two agostic bonds (AlkaneB) or an η2interaction through a phenyl substituent (η2-AlkaneB) with respective relative energies of 5.2 and 5.7 kcal mol1. Calculations on the alternative reactant isomers (Figure 5) give slightly higher overall barriers of 19.4 to 23.5 kcal mol1. Calculations by Brandt et al. with the truncated Ir-(PHOX) model and ethane as substrate gave respective activation enthalpies for the first and second step of mechanism B of 9.0 and 5.8 kcal mol1,9,31 which are similar to the values computed here (10.5 and 8.2 kcal mol1, Table 2). Alkene Hydrogenation Based on Mechanism C. Burgess and co-workers have proposed a slightly different Ir(III)/Ir(V) cycle, in which the alkene in the first reaction step inserts into the coordinating H2 molecule (mechanism C, Scheme 1-III). We have tested mechanism C with the different ReacB isomers (Figure 5). The preferred pathway originates from ReacB-si,b (Scheme 4, Supporting Information Figure S3). The first step (TS1C) involves transfer of a hydride from the coordinated H2 to the substrate with a barrier of 22.7 kcal mol1 (Table 3).
The resulting seven-coordinated intermediate (InterC) has a relative energy of 22.6 kcal mol1. At TS2C, the proton below the basal plane is transferred to the formally anionic substrate, resulting in the alkane product. The barrier for this step is 23.2 kcal mol1 (Table 3). The barriers for the other reactant isomers (Figure 5) are slightly higher, 23.8 to 27.7 kcal mol1. Comparison of Alkene Hydrogenation Mechanisms. The computed Gibbs free energies for mechanisms AC are compared in Figure 6. The first reaction steps have comparable barriers, whereas the second step is ∼7 kcal mol1 lower in energy for mechanism B than for mechanisms A and C. The computed enthalpies provide a similar picture (Supporting Information Figure S4). Also single-point calculations with the B3LYP* functional on the optimized geometries provide very similar relative energies (Supporting Information Table S1). Standard DFT functionals such as B3LYP fail to describe van der Waals interactions correctly. Here we have tested the effect of van der Waals interactions on the energetics for mechanisms A, B, and C by computing the DFT-D3 empirical dispersion corrections (Supporting Information, Table S2).25 The computed dispersion effects increase the overall barrier for mechanism A by 3.4 kcal/mol, resulting in a barrier of ΔG298K,sol,dis = 27.4 kcal mol1. For mechanisms B and C, the relative dispersion effects are somewhat less, reducing the overall barriers by respectively 0.1 and 0.9 kcal mol1 to ΔG298K,sol,dis = 18.5 kcal mol1 for mechanism B and ΔG298K,sol,dis = 22.3 kcal mol1 for mechanism C. The computed dispersion effects thus increase the preference for mechanism B over mechanism A from ΔΔG298K,sol = 5.4 kcal mol1 to ΔΔG298K,sol,dis = 8.9 kcal mol1. The preference for mechanism B over mechanism C is slightly reduced by the dispersion corrections, from ΔΔG298K,sol = 4.6 kcal mol1 to ΔΔG298K,sol,dis = 3.8 kcal mol1. The presented results, which have been obtained from calculations on the full catalyst and substrate complex and which include corrections for solvent effects (CH2Cl2), temperature (298 K), and dispersion effects, show that mechanism B provides the most feasible pathway for alkene hydrogenation with the Ir-(PHOX) catalyst C1. Interestingly, the very recent study by Andersson and 2486
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Figure 5. Isomers of ReacB (a = hydride above, b = hydride below).
Scheme 3. Computed Reaction Pathway for Mechanism B (Substrate S1 and Catalyst C1)
Table 2. Computed Energies (kcal mol1) for Mechanism B (Figure S2, Scheme 3, S1 and C1)a ΔE
ΔG298K
ΔH298K,solb
ΔG298K,solb
ReacB-si,b
1.6
8.9
1.1
6.6
TS1B
11.3
20.2
10.5
18.6
InterB TS2B
5.5 6.6
16.5 17.3
8.1 8.2
15.7 16.2
AlkaneB η2-AlkaneB
5.9
4.6
0.1
5.2
16.3
4.1
11.7
5.7
a The energetic reference is ReacA-si,a þ free H2. b Includes effect of CH2Cl2 solvent.
co-workers on a thiazole derivative of Ir-(PHOX) also provided a clear preference for mechanism B, with mechanism C exhibiting a 5 kcal mol1 higher barrier (electronic energies including solvent corrections).11 It is noteworthy, however, that the overall barriers computed here for mechanisms A and C do not exclude these pathways per se. Thus, a change of mechanism might occur with a different catalyst or substrate, or under different reaction conditions. Burgess and Cui have suggested that for diene substrates (such as COD), mechanism A should operate, because the additional H2 molecule required for an Ir(III)/Ir(V) cycle cannot bind to the Ir center if two coordination sites are occupied by the substrate.32 It has also been proposed that the H2 pressure might influence whether an additional H2 molecule coordinates to iridium,33 which then could be the factor determining through which route alkene hydrogenation takes place. Enantioselectivity of Alkene Hydrogenation. We have tested if mechanism B provides the expected enantioselectivity for hydrogenation of S2. For this substrate, experimental studies with different Ir-(PHOX) catalysts have shown 70% to 99% ee of the R-enantiomer.9,28,34,35 Binding of S2 to C1 can occur in four different binding modes, two that involve binding through the si-face and give rise to the R-product and two that involve binding
through the re-face and give rise to the S-product (Figure 7). Thus, the face through which binding occurs determines the enantioselectivity. For each binding mode, both dihydride isomers were analyzed (coordination of the apical hydride below or above the basal plane), resulting in eight reaction pathways (Table 4). Brandt et al. have suggested that the preferred S2 binding mode has the unsubstituted alkene position pointing toward the oxazoline substituent.9 In agreement with this, we find that the preferred reaction pathway, 1si,b, involves coordination of S2 to C1 through the si-face, with the unsubstituted alkene position pointing toward the isopropyl group (Figure 8A and B). This pathway has an overall barrier of 18.2 kcal mol1 (Table 4) and gives rise to the R-product. The reaction energy is positive (5.4 kcal mol1) but, as shown for S1, can be lowered by differential binding of the product. The second best pathway, 2re,b, involves substrate binding through the re-face (Figure 8C and D), resulting in formation of the S-product (overall barrier of 21.7 kcal mol1, Table 4). Formation of the R-alkane is thus favored, in agreement with experimental results (the computed enthalpies yield the same picture, Supporting Information Table S3).9,28,34,35 Note that for 2re,b, a phenyl substituent of the substrate is pointing toward the isopropyl group. It appears surprising that this orientation is favored over the sibinding mode 2si,b, which has a smaller methyl substituent pointing toward the isopropyl group (Figure 7). The optimized geometries show that for 2re,b a favorable CH/π-interaction occurs between CH of the oxazoline ring and the phenyl group, which lowers the energy (Figure 8C and D, dashed line). Such an interaction is not possible with a methyl group. Thus, the orientation of the alkene substrate (and the resulting enantioselectivity) will be influenced by both steric and electronic factors. Analysis of the effect of dispersion corrections on the overall barriers for conversion of S2 in the different binding modes results in the same relative ordering of transition states (Supporting Information, Table S4), with a small change in the barriers for the eight pathways of 0.0 to 1.3 kcal mol1. This 2487
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Scheme 4. Computed Reaction Pathway for Mechanism C (Substrate S1 and Catalyst C1)
Table 3. Computed Energies (kcal mol1) for Mechanism C (Figure S3, Scheme 4, S1 and C1)a ΔE
ΔG298K
ΔH298K,solb
ΔG298K,solb
ReacB-si,b
1.6
8.9
1.1
6.6
TS1C
14.7
24.0
13.8
22.7
InterC
14.0
24.4
14.2
22.6
TS2C AlkaneB/C
15.0 5.9
25.1 4.6
14.7 0.1
23.2 5.2
16.3
4.1
11.7
5.7
η2-AlkaneB/C
The energetic reference is ReacA-si,a þ free H2. b Includes effect of CH2Cl2 solvent. a
Figure 6. Computed Gibbs free energies (kcal mol1, corrected for solvent effects) for mechanisms A, B, and C (Schemes 2, 3, and 4, catalyst C1 and substrate S1).
results in an overall barrier of ΔG298K,sol,dis = 18.2 kcal mol1 for the preferred pathway 1si,b (yielding the R-alkane) and ΔG298K,sol,dis = 20.4 kcal mol1 for 2re,b (yielding the S-alkane). The dispersion effects thus reduce the preference for formation of the R-product from 3.5 kcal mol1 (ΔΔG298K,sol) to 2.2 kcal mol1 (ΔΔG298K,sol,dis). The latter difference translates into an enantiomeric excess of the R-product of 95%, in good agreement with experimental values.9,28,34,35 Our results are in line with the very recent DFT analysis of Andersson and co-workers on the stereocontrol in Ir-(PHOX) catalysts and their derivatives.11 On the basis of an extensive comparison to available experimental data, they developed a predictive scheme indicating that the orientation of the substituent on the nitrogen-containing ring of the catalyst (here oxazoline) relative to the ligand plane (defined by the IrP bond and the distance from Ir to the atom next to the coordinating nitrogen) defines the stereochemical outcome.11
If the substituent is above the ligand plane, as is the case for the isopropyl group in catalyst C1, conversion of S2 is predicted to result in R-stereochemistry, which is in agreement with our computed results. Imine Hydrogenation. A mechanism for Ir-(PHOX)mediated imine hydrogenation has to our knowledge not been put forward. In order to improve the efficiency and selectivity of imine hydrogenation, however, it is of importance to establish the mechanistic pathway through which Ir-(PHOX) catalysts reduce imine substrates. One possibility is that imines are converted in a fashion similar to alkenes. Therefore, first attempts to study a possible reaction pathway can be based on the proposed alkene hydrogenation mechanisms, mechanisms A to C (Scheme 1). Further, a number of imine hydrogenation mechanisms have been suggested for various achiral Ir catalysts (mechanisms DH, Scheme 5), for which Ir-(PHOX)-adapted variants can be considered. For example, for [Ir(COD)(PPh3)2]þ-mediated imine hydrogenation, Herrera et al. have suggested the Ir(I)/ Ir(III) cycle mechanism D (Scheme 5-I).1315 Hydride transfer from the dihydride-Ir(III) center to the imine carbon of the η2coordinated substrate is followed by reductive elimination of the amine product.13 Mechanism D is thus the imine analogue of mechanism A. Eisenstein and co-workers have put forward a similar mechanism for reduction of an imine intermediate formed during Ir-catalyzed alkylation of primary amines with primary alcohols (mechanism E, Scheme 5-II).12 Hydride transfer from the monohydride-Ir(III) complex to the carbon center of the η2-coordinated imine is followed by proton transfer from a hydrogen-carbonate ligand.12 Fabrello et al. recently proposed a general Ir-mediated imine hydrogenation mechanism (mechanism F, Scheme 5-III).16 Proton transfer to the nitrogen atom of the η1-coordinated imine results in a cationic η2-bound iminium and a monohydride Ir(I) complex, which is proposed to constitute a key intermediate in Ir-mediated hydrogenations.16 Hydride transfer to the imine carbon yields the amine product.16 For [IrH2(η6-C6H6)(PiPr3)]þ-mediated hydrogenation of Nbenzylidene aniline, Oro and co-workers have suggested a conceptually different mechanism (mechanism G, Scheme 5-IV).17 Generation of the active catalyst involves replacement of a ligand by a product molecule. Proton transfer from the dihydride-Ir(III) complex to the product ligand (mediated by another product molecule) and oxidative addition of H2 results in a trihydrideIr(III) complex, which mediates hydrogenation of an unbound imine molecule through concerted transfer of the ligand proton and a metal-bound hydride.17 For a dinuclear trihydride iridium complex, [Ir2(μ-H)(μ-Pz)2H2-(η2-H2)(NCMe)(PiPr3)2]þ, Oro and co-workers have suggested a slightly different mechanism for imine hydrogenation, involving stepwise proton and hydride transfer to a free imine substrate (mechanism H, Scheme 5-V).18 2488
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Figure 7. Coordination of S2 to C1 can occur from two faces (si or re), with two different orientations (1 or 2), and with coordination of hydride below (b) or above (a) the basal plane.
Table 4. Computed Energies (kcal mol1, ΔG298K,sol) for Hydrogenation of Substrate S2 (Catalyst C1, Figure 8) with Different Substrate Orientationsa coordination through si-face 1si,b
1si,a
2si,b
2si,a
coordination through re-face 1re,b 1re,a 2re,b 2re,a
Reac
7.7
7.9
10.2
10.6
8.6
11.6
9.9
12.6
TS1 Inter
18.2 15.4
22.6 19.5
23.6 18.0
27.0 25.5
23.2 20.8
28.9 24.4
21.7 17.5
24.1 19.7
TS2
16.3
20.8
19.9
25.2
21.6
24.8
18.1
21.2
Alkane
5.4
2.8
5.0
0.4
5.3
0.9
6.2
1.2
configuration
R
R
R
R
S
S
S
S
a
Energies are relative to the S2-coordinated dihydride reactant (with H bound above the basal plane) þ free H2.
The above discussion illustrates that iridium-mediated imine hydrogenation may occur through a variety of different mechanisms, making it exceedingly difficult to predict the mechanistic steps employed by Ir-(PHOX) catalysts. We have therefore computed imine-adapted variants of mechanisms A through C (Scheme 1) and Ir-(PHOX)-adapted variants of mechanisms D through H (Scheme 5) in order to obtain a detailed understanding of Ir-(PHOX)-mediated imine hydrogenation. All mechanisms were computed with the imine S3 (Figure 2). S3 can in principle exist in both E- and Z-conformations; however, NMR studies have shown that it exists as a pure E-isomer in solution.7 In our calculations, free E-S3 is 3.7 kcal mol1 lower in energy than free Z-S3, and we have therefore performed the mechanistic analyses with E-S3. Ir-(PHOX)-Mediated Imine Hydrogenation Based on Mechanisms A to C. The optimized S3-coordinated dihydride complex ReacA-IM (Supporting Information Figure S5A) shows that imine binding occurs in a η1-fashion, which generally is preferred over η2-binding.13,14 For each imine-adapted variant of mechanisms A to C (Scheme 1-I), two different pathways were computed here, with initial hydride transfer to the imine carbon (mechanisms A1IM, B1IM, and C1IM) or to the nitrogen (mechanisms A2IM, B2IM, and C2IM, Scheme 6). Optimized geometries and energetic details are given in the Supporting Information, Figures S5 to S10 and Tables S5 to S7. The first step of mechanism A1IM (Scheme 6A and Figure S5) involves insertion of the imine carbon into the equatorial Irhydride bond (TS1A1-IM). This mechanism can be considered an Ir-(PHOX)-adapted analogue of mechanisms D and E (Scheme 5-I and II). The resulting anionic intermediate is bound to the Ir center through the nitrogen lone pair and through one agostic bond. In the second reaction step (TS2A1-IM), transfer of a proton from iridium to nitrogen results in formation of the
amine product ((R)-ProdA1-IM). The computed energies reveal an overall barrier of 55.9 kcal mol1, rendering mechanism A1IM nonfeasible (Scheme 6 and Table S5). If initial hydride transfer instead occurs to the nitrogen center (mechanism A2IM, Scheme 6D), a similar overall barrier of 51.3 kcal mol1 is obtained (Table S5 and Figure S6). The reactant species for the imine variants of mechanisms B and C are formed through coordination of an additional H2 molecule to the S3-coordinated dihydride ReacA-IM, giving rise to the six-coordinated complexes ReacIM,a and ReacIM,b (Scheme 6B and C). Addition of H2 is endothermic by 8.4 and 9.6 kcal mol1, respectively, which is almost entirely due to a loss of entropy (ΔH298K,sol = 1.1 to 1.4 kcal mol1, Table S6). The first step of mechanism B1IM involves migratory insertion of the imine carbon into an Irhydride bond of ReacIM,b (Scheme 6B, Figure S7). At TS1, the substrate S3 can adopt different orientations, which are analogues of the four conformations of S2 (Figure 7). The favored pathway has the nitrogen lone pair pointing toward the isopropyl substituent of the catalyst, which is analogous to the favored alkene orientation. Insertion into the IrH bond below the basal plane occurs simultaneously with oxidative addition of the H2 molecule coordinated above the plane (TS1B1-IM). The resulting anionic substrate coordinates to the Ir(V) center through the nitrogen lone pair (InterB1-IM). At the intermediate, one of the hydrides above the basal plane has moved to an equatorial position, giving two equatorial hydrogens. Various attempts to obtain a different hydride configuration always converted back to the shown complex. The two hydrogens exhibit IrH bonds of 1.68 Å and a HH distance of 0.90 Å, which is in between the computed bond distances for a true H2 ligand and a true dihydride (a configuration that is referred to as “compressed dihydride” or “elongated dihydrogen”).36,37 The second reaction step (TS2B1-IM) involves proton transfer to nitrogen, which has a barrier of 43.5 kcal mol1. Coordination of S3 through the si-face at TS1 and formation of the experimentally observed R-product has an overall barrier of 48.2 kcal mol1. Mechanism B2IM involves initial hydride transfer to the nitrogen center of the substrate (Scheme 6E, Figure S8, Table S7). In the first step of mechanism B2IM, the hydride above the basal plane is transferred to the nitrogen center (TS1B2-IM). Proton transfer to the carbon center leads to formation of the product ((S)-ProdB2-IM). The overall computed barrier is 57.5 kcal mol1. The corresponding imine analogues of mechanism C, mechanism C1IM and C2IM, involve initial hydride transfer from the coordinated H2 molecule to the substrate (Scheme 6C and E, Figures S9 and S10). The intermediate formed after hydride transfer to the carbon center (mechanism C1IM) is identical to the intermediate of mechanism B1IM (Inter1B/C-IM), and the reaction proceeds in an identical manner from there on, leading 2489
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Figure 8. TS structures for the two most feasible routes (1si,b and 2re,b) for C1-mediated hydrogenation of S2 (mechanism B). (A) TS11si,b, (B) TS21si,b, (C) TS12re,b, (D) TS22re,b.
to formation of the S-product. The overall barrier is 47.8 kcal mol1 (TS1C1-IM, Table S6). Formation of the R-product has a barrier of 51.5 kcal mol1. Mechanism C2IM (Scheme 6D), involving hydride transfer from the coordinated H2 to the nitrogen center, has a barrier of 49.9 kcal mol1 (TS1C2-IM, Table S7). On the basis of the computed energies, the imine analogues of mechanisms AE are not considered feasible for Ir-(PHOX)mediated hydrogenation. Attempts to compute an analogue of mechanism F (Scheme 5-III), involving proton transfer to the substrate and resulting in an η2-coordinated iminium, did not succeed. Transfer of a proton to the imine nitrogen resulted in dissociation of the substrate. A η2-coordinated iminium intermediate as suggested by Fabrello et al.16 is thus not supported by our calculations. Imine Hydrogenation Involving a Dissociated Substrate. The different imine hydrogenation mechanisms computed above involve coordination of the substrate to the iridium center throughout the hydrogenation process. Oro and co-workers have suggested that for different achiral mononucelar and dinuclear iridium complexes, imine hydrogenation occurs through an outer-sphere mechanism, in which the substrate is unbound during the hydrogenation (mechanisms G and H, Scheme 5-IV and V).17,18 Here we have studied different Ir-(PHOX)-adapated mechanisms, involving partial or complete dissociation of the imine substrate. Mechanism G involves a concerted transfer of a ligand proton and a metal-coordinated hydride to the unbound imine substrate (Scheme 5-IV). The Ir-(PHOX) complex does not have a suitable ligand for protonation, and therefore we instead analyzed transfer of a proton from the Ir-coordinated H2 or H to the substrate, in analogy to mechanism H (Scheme 5-V). A concerted proton and hydride transfer was not achievable; however, stepwise transfer to a dissociated substrate appears far more feasible than the imine mechanisms studied above. We have here analyzed three Ir-(PHOX) adapted variants of mechanism
H (Scheme 7): (i) mechanism H1IM, involving proton transfer to a dissociated substrate, followed by recoordination prior to hydride transfer, (ii) mechanism H2IM, involving stepwise proton and hydride transfer to a dissociated substrate, (iii) mechanism H3IM, involving binding of an additional ligand to the Ir complex prior to stepwise proton and hydride transfer to a dissociated substrate. Optimized geometries and energetic details are found in the Supporting Information (Figures S11S14 and Tables S8, S9). The computed mechanism H1IM involves transfer of a proton from a coordinated H2 molecule to the nitrogen center of the dissociated imine substrate (TS1H1-IM, Scheme 7A, Figure S11), which has a barrier of 30.8 kcal mol1 (Table S8). The resulting intermediate exhibits a free iminium and a trihydride Ir(III) center (Inter1H1-IM), similar to the trihydride intermediate formed in mechanism G (Scheme 5-IV). Moving the hydride below the equatorial plane to an equatorial position lowers the energy of the intermediate from 28.9 to 15.6 kcal mol1 (Inter2H1-IM). Following iminium formation, the substrate might recoordinate to the iridium center prior to reduction to the amine. We have located a transition state for substrate recoordination (TS2H1-IM, Figure S12), which has a barrier of 32.8 kcal mol1 (Table S8). Binding is accompanied with electron transfer to the substrate, resulting in a formally anionic substrate (Inter3H1-IM). This highlights the inability of the positively charged iminium to coordinate to the iridum center; that is, recoordination can occur only if the substrate is reduced. Subsequent proton transfer to the carbon center yields the R-amine, with a barrier of 23.2 kcal mol1 (TS3H1-IM). For the alternative mechanism H2IM (Scheme 7B), the first reaction steps are identical to mechanism H1IM, involving proton transfer to a free substrate. The substrate remains unbound, however, and the second reaction step (TS2H2-IM) involves hydride transfer to the carbon center of the free iminium (Figure S13), which has a barrier of 25.4 kcal mol1 (Table S8). Thus, stepwise proton and hydride transfer to an unbound imine substrate has an overall barrier of 30.8 kcal mol1, which 2490
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Scheme 5. Imine Hydrogenation Mechanisms Proposed for Various Achiral Ir Catalystsa
a (I) [Ir(COD)(PPh3)2]þ catalyst (Herrera et al.13), (II) [IrHCpCO3H] catalyst (Eisenstein and co-workers12), (III) general iridium-based catalyst (L = phosphine, L0 = phosphine/amine, Fabrello et al.16), (IV) [IrH2(η6-C6H6)(PiPr3)]þ catalyst (Oro and co-workers17), (V) [Ir2(μ-H)(μ-Pz)2 H2-(η2-H2)(NCMe)(PiPr3)2]þ catalyst (Oro and co-workers18).
can be considered feasible (for example, [Ir(COD)(PBenzyl3) (py)]þ-mediated hydrogenation of N-(β-naphthylmethylene) aniline has an experimentally determined barrier of ΔGq,298K = 31 ( 2 kcal mol1).15 Formation of the unbound amine product ((R)-ProdH2-IM) is rather endothermic, however, with a reaction energy of 18.5 kcal mol1 (Table S8). Binding of H2 to the free coordination site reduces the reaction energy to 5.9 kcal mol1 ((R)-ProdH2-IM-H2 bound, Table S8), which indicates that the high endothermicity is caused by the unsaturated iridium center.
On the basis of the above results, we have tested the effect of coordinating an additional ligand (CH2Cl2 or H2) to the iridium center throughout the catalytic cycle. The resulting reaction pathway (mechanism H3IM, Scheme 7C) displays considerably reduced barriers and reaction energies (Table 5). The S3coordinated reactant complex with a bound CH2Cl2 molecule is shown in Figure 9A (ReacIM,CH2Cl2). Replacement of the equatorially coordinated substrate with an H2 molecule (Inter1H3-IM,CH2Cl2, Figure 9B) has a cost of 10.1 kcal mol1 relative to the reactant (Table 5). Subsequently, the equatorially 2491
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Scheme 6. Computed Reaction Pathways for Analogues of Mechanisms A, B, and C for C1-Mediated Hydrogenation of Imine S3: (A) Mechanism A1IM, (B) Mechanism B1IM, (C) Mechanism C1IM, (D) Mechanism A2IM, (E) Mechanism B2IM, (F) Mechanism C2IM
coordinated H2 molecule transfers a proton to the free substrate (TS1H3-IM,CH2Cl2, Figure 9C), with a barrier of 12.3 kcal mol1. The second reaction step involves transfer of a hydride to the free iminium (TS2H3-IM,CH2Cl2, Figure 9D). Of the three available hydrides, transfer of the equatorial hydride trans to the phosphine ligand is preferred, with a barrier of 17.7 kcal mol1 (transfer of one of the other hydrides has barriers that are ∼5 to ∼8 kcal mol1 higher). Product formation is still endothermic, but considerably less than for mechanism H2IM (8.0 kcal mol1,
ProdH3-IM,CH2Cl2, Table 5). Following hydride transfer, the empty coordination site is likely to bind a new ligand. This might initially be the amine product (ProdH3-IM-bound,CH2Cl2), which then is replaced by a new substrate. If the additional axial ligand is a H2 molecule instead of CH2Cl2, the energy surface looks similar, with an overall barrier of 17.7 kcal mol1 (Table S9, Figure S14). The results indicate that the iridium center adopts a Ir(III) oxidation state throughout the catalytic cycle (Scheme 7C); however, it is possible that the dihydride dihydrogen intermediate (Inter1H3-IM,L) 2492
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Scheme 7. Computed Reaction Pathways for C1-Mediated Hydrogenations of Imine S3 Involving a Dissociated Substrate: (A) Mechanism H1IM, (B) Mechanism H2IM, (C) Mechanism H3IM (L = CH2Cl2 or H2)
is in equilibrium with the corresponding tetrahydride Ir(V) complex, as suggested by Burgess and co-workers,38 and therefore has some Ir(V) character. Calculations of empirical dispersion corrections to the overall barrier for mechanism H3IM result in a barrier increase from ΔG298K,sol = 17.7 kcal mol1 to ΔG298K,sol,dis = 21.2 kcal mol1, which nonetheless still can be considered feasible. The results for mechanism H3IM indicate that this mechanism constitutes a feasible pathway for Ir-(PHOX)-mediated imine hydrogenation. The computed mechanism (Scheme 7C) bears interesting similarities to the imine-reduction mechanism suggested by Oro and co-workers for the dinuclear iridium complex [Ir2(μ-H)(μ-Pz)2H2-(η2-H2)(NCMe)(PiPr3)2]þ (mechanism H, Scheme 5-V).18 Both mechanisms display a stepwise proton
and hydride transfer from an Ir-coordinated H2 molecule to a free imine substrate. The results also bear some similarity to the mechanism suggested by Norton and co-workers for hydrogenation of iminium ions with the ruthenium complex [CpRu (diphosphine)H].39 In the suggested ruthenium mechanism, the unbound iminium ions are reduced through a hydride transfer from the metal center, in analogy to the mechanism computed here. The proton transfer necessary to restore the catalyst, however, occurs in a subsequent step, leading to formation of ammonium cations.39 The computed mechanism for Ir-(PHOX)-mediated imine hydrogenation can also be evaluated in light of recent results by Burgess and co-workers, which conclude that the acidity of N,P-type iridium complexes might 2493
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imply a release of protons to the medium, resulting in protonation of substrates prior to the catalytic hydride transfer step.38 Although this would result in a conceptually similar mechanism to the one computed here (involving proton transfer from the iridium complex to the imine substrate in the first step, but mediated by the solvent), such a scenario could explain Table 5. Computed Energies (kcal mol1) for Mechanism H3IM with CH2Cl2 as Ligand (Figure 9, Scheme 7C, Substrate S3 and Catalyst C1) ΔE
ΔH298K,sola
ΔG298K,sola
ReacIM,CH2Cl2 (þ free H2)
0.0
0.0
0.0
0.0
Inter1H3-IM,CH2Cl2
2.7
9.0
5.9
10.1 12.3
7.6
11.7
8.7
Inter2H3-IM,CH2Cl2
0.7
9.2
0.6
7.3
TS2H3-IM,CH2Cl2
10.0
20.1
10.6
17.7
TS1H3-IM,CH2Cl2
ProdH3-IM,CH2Cl2 ProdH3-IM-bound,CH2Cl2 a
ΔG298K
Includes solvent effects.
3.3
9.1
1.2
8.0
17.6
2.2
12.7
4.5
unexpected deuterium labeling results that have been observed for acid-sensitive substrates such as enol ethers.38 Enantioselectivity of Imine Hydrogenation. C1-catalyzed hydrogenation of S3 gives rise to the R-product (7090% ee, depending on reaction conditions).6,7 In the computed mechanism H3IM (Scheme 7C), the stereoselective (and rate-limiting) step is hydride transfer to the iminium carbon at TS2. Hydride transfer preferably occurs from the position trans to the phosphine group, that is, the hydride close to the oxazoline ring. Therefore, just as for alkene hydrogenation, steric interactions between the substrate and the oxazoline substituent are likely to influence the stereoselectivity. In analogy to the four substrate orientations of the alkene substrate S2 (binding through the re/ si-face in orientation 1 or 2, Figure 7), four different transition states for hydride transfer to the iminium are considered here (Figure 10; for optimized geometries, see Supporting Information Figure S15). The iminium is not bound at this stage, however, and can therefore adopt slightly different orientations than the bound alkene. The two transition states for formation of the S-amine, 1reIM and 2reIM (Figure 10A and B), are direct analogues of the corresponding si-face-bound alkene orientations (Figure 7).
Figure 9. Optimized geometries for mechanism H3IM with CH2Cl2 as ligand (C1, S3): (A) ReacIM,CH2Cl2, (B) Inter1H3-IM,CH2Cl2, (C) TS1H3-IM, CH2Cl2, (D) Inter2H3-IM,CH2Cl2, (E) TS2H3-IM,CH2Cl2, (F) (R)-ProdH3-IM,CH2Cl2.
Figure 10. Transition states for hydride transfer to the free iminium (mechanism H3IM) leading to formation of the S-amine (A and B), or the R-amine (C and D, only the reactive hydride is shown for clarity). 2494
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1reIM has the NH bond of the iminium pointing toward the isopropyl substituent and is the preferred TS for formation of the S-amine. The computed barriers with CH2Cl2 as ligand are 19.4 kcal mol1 for 1reIM and 19.5 kcal mol1 for 2reIM (Table 6). The two transition states for formation of the R-amine, 1siIM and 2siIM (Figure 10C and D), display a tilted substrate compared to the re-bound alkene analogues (Figure 7). The tilted orientation implies that the smaller imine substituents are pointing toward the isopropyl group, NH in 1siIM and CH3 in 2siIM (Figure 10C and D). The computed barriers with CH2Cl2 as ligand are 17.7 kcal mol1 for 1siIM and 18.1 kcal mol1 for 2siIM (Table 6). Thus, the two energetically preferred transition states both lead to formation of the R-amine, in agreement with experiment.6,7 With H2 as apical ligand instead of CH2Cl2, the results also show preferred formation of the R-amine, although less pronounced (Supporting Information, Table S10, Figure S15). Addition of empirical dispersion corrections to the relative barriers results in a barrier increase of 3.5 to 4.5 kcal mol1; however, the ordering of transition states remains the same (Supporting Information Table S11). The computed energy differences between the stereoselective transition states indicate an enantiomeric excess of the R-amine of 87% without dispersion corrections and 92% with dispersion corrections, in good agreement with experimental results.6,7 Table 6. Computed Energies (kcal mol1) for Hydrogenation of Substrate S3 (Catalyst C1) with Different Substrate Orientations at TS2 (Mechanism H3IM, CH2Cl2 above, Figure 10 and S15)a
a
orientation
ΔE
ΔG298K
ΔH298K,solb
ΔG298K,solb
configuration
1reIM
10.7
21.6
11.5
19.4
S
2reIM 1siIM
11.0 10.0
21.0 20.1
12.2 10.6
19.5 17.7
S R
2siIM
11.3
20.5
11.8
18.1
R
ReacIM-CH2Cl2 (with free H2) as energetic reference. b Includes solvent effect.
In summary, we conclude that (i) the unbound iminium is able to adopt a tilted orientation not accessible for the bound alkene substrate (thus favoring hydrogenation of imines from the opposite side than alkenes), (ii) the oxazoline substituent directs the substrate orientations (i.e., the most favorable S3 conformations have NH or CH3 pointing toward the isopropyl substituent), and (iii) due to the flexibility of the unbound substrate, imine enantioselectivity is expected to be more sensitive to the reaction conditions (such as solvent composition and temperature) and less controllable than alkene enantioselectivity.
’ CONCLUSIONS A comprehensive quantum chemical study was performed to establish the preferred Ir-(PHOX)-mediated alkene and imine hydrogenation mechanisms. Calculations on the full catalyst (C1) and substrate (S1) reveal that of the three suggested alkene mechanisms (mechanisms AC, Scheme 1), the Ir(III)/Ir(V) cycle suggested by Brandt et al. (mechanism B9) is energetically favored. A final general mechanism for Ir-(PHOX)-mediated alkene hydrogenation is shown in Scheme 8A. The active species is the alkene-coordinated dihydride-Ir(III) complex formed after COD hydrogenation and release. Two cis-hydride isomers of the dihydride species exist, as has been shown in NMR experiments.28 The first reaction step is rate-limiting and involves hydride transfer to the alkene and oxidative addition of H2 to give an Ir(V) species. The second step involves proton transfer to the substrate to form the alkane product and reduction of the metal to Ir(III). The enantioselectivity of alkene hydrogenation is determined by the orientation of the substrate, that is, if binding occurs through the si- or re-face of the alkene. Calculations of C1mediated hydrogenations of substrate S2 show that the preferred binding mode has the unsubstituted carbon pointing toward the oxazoline isopropyl substituent. This binding mode correctly predicts the R-enantiomer as the favored product. The computed barriers for the alternative Ir(I)/Ir(III) cycle mechanism A (Table 1) indicate that such a mechanism could be feasible under conditions where coordination of a second H2 molecule is
Scheme 8. Ir-(PHOX)-Mediated Hydrogenation Mechanisms: (A) Hydrogenation of Unfunctionalized Alkenes (Based on Calculations in This Study and the Ir(III)/Ir(V) Cycle Proposed by Brandt et al.9); (B) Hydrogenation of Unfunctionalized Imines (Based on Calculations in This Study, L = Solvent; Catalyst and Substrates Are Drawn Simplified)
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Organometallics not possible (under low hydrogen pressure or if the substrate is bidentate). On basis of the computed alkene pathways and different imine mechanisms proposed in the literature (Scheme 5), several Ir-(PHOX)-adapted mechanisms for imine hydrogenation were evaluated computationally. The imine analogues of mechanisms AC and Ir-(PHOX)-adapted analogues of mechanisms D and E involve Ir coordination of the imine substrate and exhibit computed barriers of ∼40 to ∼60 kcal mol1. Hydrogenation of a free imine substrate instead exhibits much more feasible barriers. On the basis of our results, we propose that Ir-(PHOX)-mediated imine hydrogenation occurs through the mechanism shown in Scheme 8B. Given the high affinity of the substrate for the iridium center, it is assumed that initial Ir coordination of the imine will occur. Binding of an additional ligand (a solvent molecule such as CH2Cl2 or H2) to the iridium center results in formation of a six-coordinated dihydride-Ir(III) species, which is considered the energetic reference of the catalytic cycle. The substrate is then replaced by an H2 molecule, followed by proton transfer from the equatorial H2 to the nitrogen of the free imine. In the second reaction step, the hydride trans to the phosphine ligand is transferred from the trihydride-Ir(III) center to the iminium carbon, resulting in formation of the amine product. This step is stereoselective and rate-limiting. Analysis of the enantioselectivity of imine hydrogenation of the substrate S3 shows that the unbound imine is able to adopt a tilted orientation that favors formation of the Ramine (implying hydrogenation from the opposite side than for alkenes), in agreement with experimental results. Due to the flexibility of the unbound imine substrate, however, imine enantioselectivity is expected to be more sensitive to the reaction conditions than alkene enantioselectivity.
’ ASSOCIATED CONTENT
bS
Supporting Information. Additional optimized geometries (Figure S1S15) and computed energies (Table S1S8), as discussed in the text. This material is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected].
’ ACKNOWLEDGMENT This work was supported by the Norwegian Research Council through a Center of Excellence (179568/V30) and by a grant of computer time from the Norwegian Supercomputing Program (Notur). We also wish to thank Dr. Adam Chamberlin for technical assistance with computation of dispersion effects. ’ REFERENCES (1) Cui, X.; Burgess, K. Chem. Rev. 2005, 105, 3272. (2) 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, No. 1 þ 2, 33. (3) Crabtree, R. Acc. Chem. Res. 1979, 12, 331. (4) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336. (5) Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40, 1402.
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(30) The energies are given relative to the substrate-coordinated dihydride species. (31) Enthalpies were computed at B3LYP/LANL2DZ geometries with 6-311þG(d,p) on all atoms except Ir, for which SDD augmented by a polarization function (0.65) was employed.9 (32) Cui, X.; Burgess, K. J. Am. Chem. Soc. 2003, 125, 14212. (33) Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D.-R.; Reibenspies, J. H.; Burgess, K. J. Am. Chem. Soc. 2003, 125, 113. (34) Cozzi, P. G.; Menges, F.; Kaiser, S. Synlett 2003, 6, 833. (35) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 2897. (36) Heinekey, D. M.; Lledos, A.; Lluch, J. M. Chem. Soc. Rev. 2004, 33, 175. (37) A true dihydrogen ligand can for example be seen in ReacIM,b (0.82 Å for HH and 1.831.86 Å for IrH2, Supporting Information Figure S7), whereas a true dihydride is seen in InterB, Supporting Information Figure S2 (1.66 Å for HH and 1.56 and 1.57 Å for IrH). (38) Zhu, Y.; Fan, Y.; Burgess, K. J. Am. Chem. Soc. 2010, 132, 6249. (39) Guan, H.; Iimura, M.; Magee, M. P.; Norton, J. R.; Zhu, G. J. Am. Chem. Soc. 2005, 127, 7805.
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