ARTICLE pubs.acs.org/JPCA
Concerted or Stepwise Hydrogen Transfer in the Transfer Hydrogenation of Acetophenone Catalyzed by Ruthenium Acetamido Complex: A Theoretical Mechanistic Investigation Xiaojia Guo,†,‡ Yanhui Tang,§ Xin Zhang,†,‡ and Ming Lei*,†,‡ †
State Key Laboratory of Chemical Resource Engineering, Institute of Materia Medica, College of Science, Beijing University of Chemical Technology, Beijing, 100029, People's Republic of China ‡ State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, People's Republic of China § School of Materials Science and Engineering, Beijing Institute of Fashion Technology, Beijing, 100029, People's Republic of China
bS Supporting Information ABSTRACT: In this paper, the mechanism of transfer hydrogenation of acetophenone catalyzed by rutheniumacetamido complex was studied using density function theory (DFT) method. The catalytic cycle of transfer hydrogenation consists of hydrogen transfer (HT) step and dehydrogenation (DH) step of isopropanol (IPA). Inner sphere mechanism (paths 1 and 7) and outer sphere mechanism (paths 26) in HT step are fully investigated. Calculated results indicate that DH step of IPA (from i1 to i2) is the rate-determining step in the whole catalytic cycle, which has a potential energy barrier of 16.2 kcal/ mol. On the other hand, the maximum potential energy barriers of paths 17 in the HT step are 5.9, 12.7, 24.4, 16.8, 23.7, 7.2, and 6.1 kcal/mol, respectively. The inner sphere pathways (paths 1 and 7) are favorable hydrogen transfer modes compared with outer sphere pathways, and the proton transferred to the oxygen atom of acetophenone comes from the hydroxyl group but not from amino group of acetamido ligand. Those theoretical results are in agreement with experimental report. However, in view of this DFT study in the inner sphere mechanism of HT step, hydride transfer and proton transfer are concerted and asynchronous hydrogen transfer but not a stepwise one, and hydride transfer precedes proton transfer in this case.
’ INTRODUCTION Catalytic hydrogenation of ketones is one of the most important methods to produce chiral alcohols. Many transition metal (TM) or non-TM complexes could be employed as catalysts in fine chemical and pharmaceutical industries.19 Ruthenium complexes bearing 1,2-diamines designed by Noyori’s group created a new era of high efficient asymmetric hydrogenation of CdO and CdN polar bonds.57 The concept of a novel metalligand bifunctional mechanism proposed by Noyori et al. has been extended to other catalytic reactions. In the past decades, progresses in TM-catalyzed hydrogenation, including mechanistic understanding and greener TM catalyst design, have been extensively reviewed.1012 Mechanisms of ketone or imine hydrogenation were described by both experimental and theoretical studies.1318 According to the usage of hydrogen source to regenerate active catalytic species, the hydrogenation could be divided into H2-hydrogenation and transfer hydrogenation from H2 or organic hydrogen donors like isopropanol (IPA), HCOOH/Et3N azeotrope. On the other hand, the mechanism could be classified as inner sphere mechanism and outer sphere mechanism according to direct/indirect interaction between ketone substrate and TM catalyst (see left catalytic cycle and r 2011 American Chemical Society
right catalytic cycle in Scheme 1). It is inner sphere mechanism if the substrate coordinates with TM center or outer sphere mechanism if not.10,19 In the later one, hydrogen is directly transferred to ketone substrate without coordination of ketone to TM center of catalyst. As shown in Scheme 1, an inner sphere or outer sphere mechanism could be carried out with H2 or organic hydrogen source. As shown in Figure 1, Yi et al. reported a ruthenium acetamido complex RuH(NHCOMe)(OHiPr)(PCy3)2CO (Ru acetamido), which is an efficient precatalyst for transfer hydrogenation of aryl- and alkyl-substituted ketones and imines at 80 °C using IPA as hydrogen source.20 The alcohol hydrogenated from acetophenone was produced in more than 95% isolated yield. They pointed out that (1) the hydrogenation of acetophenone follows an inner sphere HT mode; (2) hydrogen transfer from Ruacetamido catalyst to ketone in the HT step is a stepwise mechanism involving a rapid and reversible proton transfer followed by a rate-determining step of hydride transfer; Received: May 19, 2011 Revised: October 5, 2011 Published: October 05, 2011 12321
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Scheme 1. General Representation of Inner Sphere Mechanism and Outer Sphere Mechanism in Ketone Hydrogenation Catalyzed by Transition-Metal Complex
Figure 1. Target reaction of acetophenone hydrogenation catalyzed by the precatalyst Ruacetamido.
(3) in experiment, IPA is zero-order in kinetics. However, these results are all from experiments and the details for the mechanism are still unclear. We will further discuss it in Hydride Transfer and Proton Transfer. So, verifying some conclusions in this experiment at computational level is very necessary. To clearly describe the mechanism of ketone hydrogenation, some symbols are used along the reaction pathways. In Figure 2A, is41 means 4 along the inner sphere pathway, resulting in the S-alcohol product in path 1, and os 41 means that intermediate 4 along the outer sphere pathway results in the S-alcohol product in path 1. The is47a means intermediate 4 along the inner sphere pathway results in the S-alcohol product with assistance of IPA solvent in path 7. The left superscript i/o denotes inner sphere/outer sphere, the left subscript r/s denotes R/S chirality, the right superscript denotes pathway number, and the right
Figure 2. (A) Descriptions of the symbols used in this paper. (B) Atomic labels.
subscript denotes that the reaction proceeds with the assistance of IPA. Serial numbers of key atoms related to stationary points of the catalytic cycle are shown in Figure 2B. Scheme 1 demonstrates a general inner- and outer-sphere mechanism in catalytic cycles of ketone hydrogenation, and the case of inner sphere via a decoordination of ligand from TM center is not included here.21 In Scheme 1, catalytic cycle starts with the active catalytic species, 3. In the inner-sphere mechanism, 3 is a coordinately unsaturated Ru hydride species. Coordination of ketone substrate with 3 gives the intermediate i4, 12322
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Figure 3. Inner-sphere mechanism of the catalytic cycle
and then it forms an alkoxide intermediate i5 via a hydride migration. Another hydrogen from the ligand or Ru could transfer to the alkoxide moiety leading to i6 in stepwise or concerted mode. By means of obtaining the hydrogen from H2 or IPA, 3 could be regenerated. In the outer-sphere mechanism, for 3, the “L” ligand could be the group with “NH” or “OH” moiety such as Noyori’s catalysts and Shvo’s catalysts.2229 The hydride and proton of Ru catalyst are transferred to the carbonyl group (CdO) of ketone substrate, affording the hydrogenated product and coordinately unsaturated species o6. In the hydrogenation catalyzed by Rudiamine complex, the 16-electron Ruamido complex is usually stabilized by π-back-donation from the ligand. In the case of H2 hydrogenation, dihydrogen could coordinate with Ruamido complex along the vacant site of Ruamido and it could be heterolytically split and regenerate 3. In the case of transfer hydrogenation, o3 could be regenerated through the reduction of o6 with organic alcohol and so on. In this paper, based on the target reaction catalyzed by an Ruacetamido complex shown in Figure 1, the DH step of IPA and HT step involving seven possible pathways of catalytic cycles of acetophenone hydrogenation were studied using the DFT
method. It will shed light on understanding the difference between the inner-sphere mechanism, outer-sphere mechanism, and the role of alcohol solvent in the catalytic cycle. In the HT step, paths 1 and 7 were classified as an inner-sphere mechanism (see Figure 3), while paths 26 were classified as an outer-sphere mechanism or bifunctional mechanism (see Figure 4). Paths 6 and 7 considered the involvement of the alcohol solvent, which may assist hydrogen transfer. This theoretical study will clarify the preference of the inner- and outer-sphere mechanisms, the preference of hydride and proton transfer, the preference of proton transfer from the hydroxyl or amino group of the acetamido ligand, and the role of solvent alcohol in acetophenone hydrogenation catalyzed by the Ruacetamido catalyst.
’ COMPUTATIONAL DETAILS Geometries of transition states (TSs), intermediates (INTs) and separated reactants were optimized using Gaussian 03 program package with B3LYP hybrid density functional.30 LANL2DZ basis set was used for Ru atom and 631+G** basis set for the other atoms.31 We denote this calculation level as B3LYP/BSI. The hybrid density functional B3LYP method 12323
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Figure 4. Outer-sphere mechanism of the catalytic cycle.
Table 1. Bond Lengthsa of Ru1H4 and C8O9, Changesa of Corresponding Bond Lengths between 4 and TS4-5 (CBL), and Hydrogen Transfer Potential Energy Barriers in Paths 17 of the HT Stepb
4 TS45 CBL potential energy barriers a
Ru H C8O9 Ru1H4 C8O9 Ru1H4 C8O9 1
4
path 1
path 2
path 3
path 4
path 5
path 6
path 7
1.601 1.299 1.656 1.313 0.055 0.014 5.9
1.648 1.225 1.688 1.278 0.040 0.053 12.7
1.650 1.229 1.881 1.338 0.231 0.109 24.4
1.581 1.227 1.693 1.302 0.112 0.075 16.8
1.627 1.232 1.920 1.342 0.293 0.110 23.7
1.625 1.233 1.696 1.272 0.071 0.039 7.2
1.607 1.288 1.671 1.299 0.064 0.011 6.1
Unit: Å. b Unit: kcal/mol.
and basis sets are reliable and were used in our previous works.16,17,32,33 All of the TSs were further confirmed by the vibrational analysis and characterized by only one imaginary vibrational mode. The value of the S2 of every stationary structure in the catalytic cycle is zero, which means none of spin-contamination. The PPh3 ligand of the complex was simplified to PH3. In these calculations, energies discussed below were values without zero-point vibrational energy correction (ZPE) in order to perform an effective comparison with our previous calculations. Atomic polar tensor (APT) charge and Natural Population Analysis (NPA) charge were used for charge population, because the commonly used Mulliken charge analysis was generally deficient.34 Solvent effects (ethanol) were evaluated using the polarizable continuum model (PCM)
performing single-point calculations on gas phase optimized geometries.35 By means of TheRate (THEoretical RATEs) program, the rate constants under 273.15 K for key reaction steps (DH and HT steps) are evaluated by using the conventional transition state theory (TST) and conventional transition-state theory with Eckart tunneling correction (TST/ Eckart).3638
’ RESULTS AND DISCUSSION Structural Details of Intermediates and Transitional States. Here S-phenylethanol is used as a default alcohol product
after acetophenone hydrogenation in this study. Table 1 presents Ru1H4 and C8O9 bond lengths, corresponding bond length 12324
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Table 2. APT Chargesa and NPA Chargesb of Key Atoms in Paths 17 of the HT Step path 1
H4 H5 C8 O9
path 2
H4 H5 C8 O9
path 3
H4 H7 C8 O9
path 4
H4 H5 C8 O9
path 5
H4 H7 C8 O9
path 6
H4 H13 C8 O9
path 7
H4 H13 C8 O9
a
4
TS45
5
0.017 0.132 0.476 0.546 0.966 0.455 0.607 0.621 0.236 0.065 0.459 0.529 0.956 0.569 0.749 0.570 0.200 -0.025 0.199 0.432 1.007 0.579 0.773 0.591 0.140 0.130 0.427 0.530 0.947 0.570 0.758 0.578 0.162 0.125 0.300 0.442 1.040 0.591 0.860 0.609 0.204 0.032 0.510 0.559 1.127 0.608 0.958 0.624 0.004 0.116 0.440 0.552 1.009 0.468 0.661 0.640
0.152 0.133 0.520 0.545 1.068 0.412 0.783 0.665 0.659 0.012 0.762 0.538 1.696 0.475 1.136 0.708 0.518 0.116 0.445 0.481 1.231 0.237 0.979 0.796 0.571 0.117 0.684 0.533 1.423 0.375 1.046 0.756 0.502 0.126 0.494 0.488 1.152 0.231 0.978 0.802 0.575 0.039 0.385 0.556 1.579 0.474 1.022 0.742 0.226 0.118 0.443 0.554 1.158 0.420 0.851 0.694
0.084 0.216 0.504 0.544 0. 641 0.072 0.913 0.781 0.570 0.127 0.505 0.544 0.113 0.200 0.822 0.778 0.079 0.219 0.396 0.548 0.643 0.068 0.841 0.762 0.094 0.150 0.455 0.539 0.559 0.237 0.479 0.775 0.349 0.166 0.452 0.527 0.799 0.148 0.799 0.803 0.342 0.177 0.374 0.526 0.811 0.136 0.713 0.791 0.050 0.238 0.473 0.550 0.561 0.070 0.875 0.770
In normal font. b In italics.
changes between 4 and TS45 in HT step and HT energy barriers for paths 17. Table 2 lists APT charges of C8, O9, H4, and transferred proton atom (H5 in paths 1, 2, and 4, H7 in paths 3 and 5, H13 in paths 6 and 7) in HT step. Compared with the crystal structure of Ruacetamido reported by Yi et al.,20 calculated geometries are almost the same not only using the simplified model but also the full model, as shown in Figure 5.
Figure 5. Structural comparison of crystal structure, full model, and simplified model.
The CN2 bond lengths are 1.322(5), 1.326, and 1.331 Å for the crystal structure, full model, and simplified model, respectively. The OO distances are also almost the same. The precatalyst, Ruacetamido, owns an octahedral structure, and the oxygen atom of IPA coordinates with Ru center. The hydrogen atom of hydroxyl group of IPA points to oxygen of carbonyl group of acetamido ligand, which makes Ruacetamido more stable. Figures 3 and 4 show the inner-sphere mechanism (paths 1 and 7) and outer-sphere mechanism (paths 26) in the HT step, respectively. In paths 1, 2, 3, and 7, as acetophenone approaches the active species 3, INTs (is41,os 42,os 43,is47a) are located, respectively. In path 7, is47a involves with IPA solvent’s assistance, two hydrogen bonds of O12H13 3 3 3 O9 and O3H5 3 3 3 O12 in this structure contribute to proton transfer. In path 4, because of the flexibility of two hydrides (H4 and H6) of Ru center of 3, the coordination of alcohol could form INTA1, acetophenone then interacts with INTA1 giving the intermediate os 44. In paths 5 and 6, IPA could first coordinate with the vacant site of the Ru center of 3 forming INTA1’s enantiomer, INTA10 , then acetophenone approaches in two ways, giving the intermediate os 45 and os 46a, respectively. Weak interaction between H5 and H6 turns out to be a slightly different configuration of the acetamido ligand between INTA1 and INTA10 . Ru intermediates with phenylethanol, 5 (is51, os 52, os 53, os 54, os 55, os 56a, and is57a), could be obtained through the TS45s (TSis41is51, TSos 42os 52, TSos 43os 53, TSos 44os 54, TSos 45os 55, TSos 46aos 56a, and TSis47ais57a) from their corresponding INTs 4 (is41, os 42, os 43, o 4 o 5 o 6 i 7 1 4 s 4 , s 4 , s 4 a, s4 a). The bond lengths of Ru H of 4 are 1.601, 1.648, 1.650, 1.581, 1.627, 1.625, and 1.607 Å for paths 17, respectively. Charges of H4 are 0.017, 0.236, 0.200, 0.140, 0.162, 0.204, and 0.004, respectively. The bond lengths of Ru1H4 of TS45 are elongated to 1.656, 1.688, 1.881, 1.693, 1.920, 1.696, and 1.671 Å, respectively. In paths 14, intermediate 6 is formed after the removal of phenylethanol product, which contains a four-membered ring of Ru and acetamido ligand (see Figure 3). With the coordination of IPA solvent with 6, active species i1 is formed. The O3 atom of the acetamido ligand takes a rotation to form a hydrogen bond of O3H13 3 3 3 O12 in i1. In path 4, there is a hydrogen migration from RuNOA to RuNO. 12325
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Figure 6. Potential energy profiles, free energies, and solvation energies of catalytic cycles of paths 17 at the B3LYP/BSI Level (potential energy in italic and solvation energy in bold).
For paths 57, the leave of alcohol product from os 55, os 56a, and i i 7 s5 a lead to catalytic species 1. Altogether with the HT step, the DH step involving the dehydrogenation of IPA constructs the whole catalytic cycle, which could regenerate active species, 3. Similar to the HT step, the DH step could also process in inner-sphere mechanism (i1 to i2) or outer-sphere mechanism (o1 to o2) according to the coordination of the oxygen (O12) of IPA with the Ru center in the DH step (see Figure 3 and 4). In inner- or outer-sphere mechanism, IPA delivers two hydrogens to the Ru and acetamido ligand, respectively. But the inner-sphere mechanism of IPA dehydrogenation is regarded as a dominant DH pathway, because the DH energy barrier for the outer-sphere mechanism is too high (more than 40 kcal/mol). It will be discussed in the following part. Potential Energy Profiles of Catalytic Cycles. The potential energy profile of the whole catalytic cycle is shown in Figure 6 (potential energy in normal font, free energy in italic, and solvation energy in bold). The potential, free, and solvation energies of each stationary point are summarized in Table 3. The unsaturated intermediate i1 is formed from the 18-electron Ru complex Ruacetamido after losing a PH3 ligand. In the HT step, the removal of acetone from the Ru complex results in the regeneration of the catalytic species 3, which is 15.0 kcal/mol higher in potential energy than that of 2. It should be noticed that the regeneration of 3 is 1.7 kcal/mol lower than that of 2 in free energy, which is due to a large entropy effect of 3 + acetone. Intermediates INTA1 and INTA10 are more stable than the others owing to the coordination of IPA with Ru center, and intermediates 4 are more stable than 3 due to coordination of acetophenone with the Ru center. Especially, the potential energy of is47a is 4.4 kcal/mol less than that of is41 owing to the presence of O9 3 3 3 H13O12 and O12 3 3 3 H5O3 hydrogen bonding interactions in is47a. Acetophenone hydrogenation occurs from intermediates 4 to 5 via transition states TS45 in paths 17. The corresponding energy barriers in HT step are 5.9, 12.7, 24.4, 16.8, 23.7, 7.2, and 6.1 kcal/mol, respectively. The hydrogenation processes of paths 25 are endothermic by 2.0, 12.4, 14.8, and 20.8 kcal/mol, respectively. And the hydrogenation processes are exothermic by 9.8, 8.1, and 10.0 kcal/mol for paths 1, 6, and 7, respectively. The HT free energy barriers for paths 1, 6, and 7 are 5.4, 9.9, and 5.3 kcal/mol,
respectively. Therefore, paths 1 and 7 are more favorable in the HT step than the other pathways in both thermodynamics and kinetics. Release of alcohol products causes a sharp decrease in energies in paths 2, 3, and 5. In path 1, the energy slightly increases by 2.5 kcal/mol from is51 to 6. In path 4, the energy barrier of hydrogen migration from RuNOA to RuNO is 18.0 kcal/mol. In paths 6 and 7, there are little changes in energy from os 56a and is57a to i1. From 6 to i1, the energy decreases by 8.6 kcal/mol. In the DH step, the inner-sphere DH barrier of IPA from i1 to i 2 via TSi1i2 is 16.2 kcal/mol. The outer-sphere DH barrier of IPA from o1 to o2 via TSo1o2 is 41.3 kcal/mol. It is obvious that the inner-sphere DH pathway is the favorable DH step. Based on calculated energy profiles discussed above, the inner-sphere DH step of IPA to regenerate 3 is the rate-determining step in the whole catalytic cycle. Relationship between Structures and HT Energy Barriers. In our previous works,33 it is suggested that the longer the Ru1H4 distance of the Ru catalyst is, the lower the HT energy barrier is. In the HT step, the Ru1H4 distances of INTs are slightly different (see Table 1). However, those of TSs are quite different. The changes of bond lengths (CBLs) in Ru1H4 from 4 to TS45 are found to be related with the corresponding HT barriers of paths 17, as shown in Figure 7A. In paths 1, 2, 6, and 7, which have smaller CBLs in Ru1H4 bond length, corresponding CBLs are 0.06, 0.04, 0.07, and 0.06 Å, respectively, HT barriers are 5.9, 12.7, 7.2, and 6.1 kcal/mol, respectively. On the contrary, higher HT barriers of paths 3, 4, and 5 (24.4, 16.8, and 23.7 kcal/mol) own larger CBLs in Ru1H4 bond lengths (0.231, 0.112, 0.293 Å). Meanwhile, CBLs in C8O9 bond lengths from 4 to TS45 have a close relationship with HT barriers (see Figure 7B). A larger CBL implies a higher energy barrier. Charges of transferred hydrogens (hydride/H4, proton/H5 in paths 1, 2, and 4, H7 in paths 3 and 5, H13 in path 6 and 7) also affect HT energy barriers (see Table 2). These results have similar tendency using NPA charge compared with those using APT. In paths 2 and 4, which both proceed bifunctional mechanism and have similar charges of H5 in 4, the APT charges on H5 are 0.459 and 0.427 in paths 2 and 4, respectively (0.529 and 0.530 for NPA charges in paths 2 and 4, respectively). The more negative charges on H4 in path 2 (0.236 for APT charge 12326
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Table 3. Calculated Relative Energies at B3LYP/BSI Level of Stationary Points including Potential, Free, and Solvation Energya i
Ruacetamido 56.8 44.2 53.7
potential energy free energy potential energy with solvent effect path 1
path 2
1
TSi1-i2
0 0 0
16.2 14.5 15.7
path 3
path 4
i
2
3
6
10.8 9.4 11.0
25.8 7.7 18.7
8.6 5.2 1.9
path 5
path 6
path 7
10.6 10.3 34.0 31.1
7.4 14.6 0.7
11.5 17.6 1.5
5.2 15.6 42.0 40.6
14.5 24.4 10.8
21.5 26.8 12.7
8.9 15.2 37.1 34.3
10.9 20.7 5.2
18.5 24.1 7.1
Potential Energy INTA1 INTA10 4 TS45 5 RuNOA RuNO TSRuNO-6
9.6 15.9 21.8 6.1
20.4 33.1 22.4
17.2 41.6 29.6
10.6 27.4 25.4 16.0 34.0 48.1
Free Energy INTA1 INTA10 4 TS45 5 RuNOA RuNO TSRuNO-6
4.5 13.6 19.0 4.4
9.6 26.4 18.7
10.7 34.6 27.1
14.0 35.6 37.7 5.2 18.9 32.1
Solvation Energy INTA1 INTA10 4 TS45 5 RuNOA RuNO TSRuNO-6 a
7.9 16.0 21.4 4.1
17.9 33.2 20.1
17.8 41.9 29.9
12.2 30.8 28.4 10.5 23.9 40.6
Unit: kcal/mol.
and 0.065 for NPA charge) result in lower energy than that of path 4 (0.140 for APT charge and 0.130 for NPA charge). This is due to a higher trans effect of PH3 ligand than IPA. In paths 3 and 5, which also proceed bifunctional mechanism, the HT step with a higher HT barrier (compared to paths 2 and 4) owns a less positive charge on H7. In general, the H4 of 4 in paths 1 and 7 possesses more positive charges than those of 4 in the other paths, while the energy barriers of paths 1 and 7 are lower than those of the others. This situation is due to the C8dO9 bond is activated by the Ru center before hydrogen transfer through the inner sphere mechanism (paths 1 and 7). Differences between Inner- and Outer-Sphere Mecha nism. It is obvious the inner- and outer-sphere mechanisms in this study are different. Hydrogenation via the inner-sphere mechanism involves coordination of the carbonyl group of ketones with a Ru center, while hydrogenation via outer-sphere mechanism
does not. The preference of inner- or outer-sphere mechanism in the HT or DH step does depend on the molecular orbital overlap of substrate and TM catalyst. It is in no doubt that ketone hydrogenation prefers the outer-sphere mechanism if the HT or DH step took place for ketone with saturated 18e Ru catalyst like diphosphine diamine Ru catalysts proposed by Noyori et al.,19,39 unless the 18e Ru catalyst involves a decoordination of ligands from Ru catalyst like Ru complex with N-heterocyclic carbine ligand reported by Morris et al.21 Even alcohol dehydrogenation for the 16e unsaturated complex, like the Ruamido complex, will adopt an outer-sphere mechanism because of an overlap of π-orbital between the ketone substrate and the Ruamido complex. Both Noyori and Shov’s catalysts, as we know, proceed the HT step through the outer-sphere mechanism,2229 and this mode will benefit a high efficiency of hydrogenation. The innersphere mechanism will be taken for ketone hydrogenation 12327
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Figure 7. (A) Relationship between the CBL of Ru1H4 and the HT barrier. (B) Relationship between the CBL of C8O9 and the HT barrier.
Figure 8. (A) IRC analysis along the HT step of path 1 from is41 to is51. (B) Interaction between frontier molecular orbitals (FMOs) of acetophenone and 3.
catalyzed by a 16e unsaturated Ru catalyst lacking an appropriate π orbital like Ruacetamido complex. Interestingly, in this study, it is clear that hydrogenation catalyzed by the Ruacetamido catalyst prefers inner-sphere mechanism (paths 1 and 7). Hydride Transfer and Proton Transfer. In Yi’s experimental study on ketone hydrogenation catalyzed by the Ruacetamido complex, the reaction rate was found to be first order in acetophenone with the IPA solvent and zero order in IPA with the C6D6 solvent.20 However, according to our computational results, the energy barrier of DH step of IPA regenerating active species 3 is the rate-determining step. Thus, the concentration of IPA is a nonignorable factor on the reaction rate. We believe the mechanism proposed by Yi et al. did not take this factor into account. In Yi’s experimental research, an inverse deuterium isotope effect was observed from both (CH3)2CHOH/ (CH3)2CHOD and (CH3)2CHOH/(CD3)2CDOD for the hydrogenation of acetophenone in the presence of 1.0 mol % of i1 (kOH/kOD = 0.7 ( 0.1 and kCHOH/kCDOD = 0.7 ( 0.2). Under the competitive reaction conditions, a normal deuterium isotope effect was observed for a 1:1 mixture of (CH3)2CHOH and (CH3)2CDOH (kCH/kCD = 1.9 ( 0.2). Yi et al. deduced that the HT step is a stepwise mechanism involving a rapid and reversible proton transfer followed by a rate-determining step of hydride
transfer. Interestingly, this theoretical study reveals that the HT step is a concerted but asynchronous one and that the hydride transfer precedes the proton transfer. IRC analysis along the HT step of path 1 from si41 to si51 has been done to verify this observation (see Figure 8A). It is clear that the C8H4 distance is shortened first and the O3H5 bond length is little changed, then O9H5 distance decreases, while the C8H4 distance is little changed. These data support that the HT step is indeed a concerted but asynchronous mechanism as well as the DH step. In contrast, proton transfer precedes the hydride transfer from the IPA ligand to the Ru center and oxygen atom of i1. Calculated results about the interaction of the frontier molecular orbitals (FMOs) between acetophenone and 3 show that the energy gap between the LUMO of acetophenone and the HOMO of 3 is 0.186 au, while that between the HOMO of acetophenone and LUMO of 3 is 0.193 au (see Figure 8B). It also proves that the hydride transfer is prior to proton transfer in the HT step, which is consistent with our previous works.16 By means of TheRate program, TST and TST/Eckart methods were used for the rate constant calculation. In the DH step, a deuterium isotope effect was observed from both (CH3)2CHOH/(CH3)2CDOH (kCH/ kCD = 6.32 for TST and kCH/kCD = 7.42 for TST/Eckart). In the HT step from is41 to TSis41is51, we calculated the rate constants 12328
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revealed in the free and solvation energy (see Table 3). It could predict that the Ruacetamido catalyst could not do well in enantioselectivity of catalytic hydrogenation because of only 0.5 kcal/mol energy gap.
Figure 9. HT potential energy barriers resulting in R-phenylethanol and S-phenylethanol products.
of the unmarked reactant (RuH4) and the reactant marked by deuterium (RuD4). The ratio values of the rate constants are 1.61 for TST and 1.94 for TST/Eckart. Obviously, the DH step with larger rate ratios that are inconsistent with the experimental results is the rate-determining step. Reaction Activities of Hydrogen Transfer. In the HT step, it is found in this study that the activity of the HT in a different pathway changes a lot with the different transferred hydrogens. Proton transfer could come from hydroxyl group (OH5; paths 1, 2, and 4), amine group (NH7) of acetamido ligand (paths 3 and 5), or hydroxyl group (OH13) of IPA (paths 6 and 7). Compared with the HT barrier in path 3, the lower HT barrier in path 4 demonstrates that the transfer of H4 and H5 are easier than H4 and H7. These results are because H5 owns a more positive charge than H7. The difference in charges could be explained by the higher electronegativity of oxygen atom than nitrogen atom in acetamido ligand. Even for the same proton transfer, the energy barrier of path 4 is higher than that of path 2. This situation could be explained by the high trans effect of the phosphine ligand than IPA. Alcohol-Assisted Effects. Subsequent computational studies have pointed out the possibility of alcohol assistance in ketone hydrogenation catalyzed by the TM complex.17,33,4042 In path 7, the potential energy of si4a7 is 4.4 kcal/mol lower than that of i 1 s4 in path 1 because of the involvement of IPA. In path 6, a more stable intermediateos 46a can be obtained when IPA as a ligand coordinating to the Ru center. In paths 6 and 7, IPA assists facile proton transfer (H13) to acetophenone and obtains another proton (H5) from the acetamido ligand at the same time. The energy barriers of the HT step in these two paths are quite low (7.2 kcal/mol for path 6 and 6.1 kcal/mol for path 7). The HT free energy barriers are 9.9 and 5.3 kcal/mol. Thus, path 7 is a competitive HT pathway compared to path 1. Steric Effects. Enantioselectivity was also taken into consideration along path 1, which was not mentioned in the experimental report.20 Acetophenone approaches the active catalytic species 3 with two prochiral faces resulting in two intermediates with pro-S and pro-R chiral ketone (is41 and ir41). Their electronic potential energies are 15.9 and 14.5 kcal/mol, respectively. Figure 9 shows the energy profiles of the HT step leading to R and S chiral alcohol. The red dashed line leading to the R configuration has the energy barrier of 6.4 kcal/mol, while the red plain line leading to the S configuration has the energy barrier of 5.9 kcal/mol. Similar energy barrier differences are
’ CONCLUSION In summary, the mechanism of acetophenone hydrogenation catalyzed by the Ruacetamido complex has been studied using the DFT method. In both the HT and DH steps, the hydrogenation prefers an inner-sphere mechanism instead of an outersphere mechanism. The energy barriers o f HT and DH steps are 5.9 and 16.2 kcal/mol, respectively. The DH step of IPA is the rate-determining step in the whole catalytic cycle. On the other hand, path 7 in the HT step is competitive compared with path 1, considering the assistance of the alcohol solvent. The calculated results demonstrate that the hydrogenation proceeds a concerted but asynchronous mechanism instead of a stepwise one, that the hydride transfer is prior to proton transfer, and that proton transferred to the oxygen atom of ketone substrate is from hydroxyl group but not from amine group of acetamido ligand. ’ ASSOCIATED CONTENT
bS
Supporting Information. Optimized geometries and Cartesian coordinates of stationary points along each path. This material is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*Phone: 86-10-6444-6598. Fax: 86-10-6444-6598. E-mail: leim@ mail.buct.edu.cn.
’ ACKNOWLEDGMENT This work was in part supported the National Natural Science Foundation of China (Grant Nos. 21072018 and 20703003), the Fundamental Research Funds for the Central Universities (Program No. ZZ1020), the National Basic Research 973 Program of China (Grant 2007CB714304). We also thank Chemical Grid Project at Beijing University of Chemical Technology (BUCT) for providing part of the computational resources. ’ REFERENCES (1) Zhao, L. L.; Li, H. X.; Lu, G.; Wang, Z. X. Dalton Trans. 2010, 39, 4038–4047. (2) Yang, X. H.; Zhao, L. L.; Fox, T.; Wang, Z. X.; Berke, H. Angew. Chem., Int. Ed. 2010, 49, 2058–2062. (3) Wang, Z. X.; Lu, G.; Li, H.; Zhao, L. Chem.—Eur. J. 2010, 55, 239–245. (4) Lu, G.; Li, H.; Zhao, L.; Huang, F.; Wang, Z. X. Inorg. Chem. 2010, 49, 295–301. (5) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 2675–2676. (6) Ohkuma, T.; Doucet, H.; Pham, T.; Mikami, K.; Korenaga, T.; Terada, M.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 1086–1087. (7) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008–2022. (8) Zhang, H.; Chen, D.; Zhang, Y.; Zhang, G.; Liu, J. Dalton Trans. 2010, 39, 1972–1978. (9) Baratta, W.; Barbato, C.; Magnolia, S.; Siega, K.; Rigo, P. Chem.— Eur. J. 2010, 16, 3201–3206. 12329
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