Note pubs.acs.org/Organometallics
Asymmetric Transfer Hydrogenation of Acetophenone N‑Benzylimine Using [RuIICl((S,S)‑TsDPEN)(η6‑p‑cymene)]: A DFT Study Petr Šot,*,† Marek Kuzma,*,‡ Jiří Václavík,† Jan Pechácě k,† Jan Přech,† Jakub Janušcǎ ḱ ,† and Petr Kačer† †
Department of Organic Technology, Institute of Chemical Technology, Technická 5, 166 28 Prague, Czech Republic Laboratory of Molecular Structure Characterization, Institute of Microbiology, v.v.i., Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20 Prague 4, Czech Republic
‡
S Supporting Information *
ABSTRACT: Asymmetric transfer hydrogenation of the acyclic imine acetophenone N-benzylimine was studied by means of computational chemistry. Calculated transition states offer an explanation of why this prochiral imine leads to the delivery of (S)-amine (when using (S,S)-TsDPEN ligand) rather than (R)-amine, which is common for endocyclic imines (e.g., substituted 3,4-dihydroisoquinolines or 3,4-dihydro-β-carbolines). This study extends our previous investigation of the so-called ionic mechanism.
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RESULTS AND DISCUSSION The phenomena associated with ATH of acetophenone N-benzylimine using the [RuIICl((S,S)-TsDPEN)(η6-p-cymene)] catalyst were investigated by means of computational chemistry. Optimization of the structures and frequency analyses were carried out employing density functional theory (DFT) at the B3LYP level. Single-point energies were computed using DFT and second-order Møller−Plesset perturbation theory (MP2). Our calculations include the substrate and catalyst. The structure of the catalyst is based on single-crystal XRD data,14 as in our previous study.12 Since no structural simplifications were applied, the calculations were very demanding of the hardware. Also for this reason, the solvation effects were mostly neglected and nearly all calculations were performed in vacuo. We simulated the solvation effects (CH2Cl2) using IEFPCM only in the case of transition states with the lowest energy. The molecules of acyclic imines such as acetophenone N-benzylimine are very flexible in conformation, and in addition, they can undergo isomerization between their Z and E isomers. Each isomer can interact with the catalyst in a different way, which can affect the enantioselectivity of the whole reaction. The equilibrium ratio of the isomers, readily established by acid-catalyzed E/Z interconversion, is reported to be 94:6 (E:Z)2 (Scheme 2). Protonation of the imine nitrogen by formic acid results in a dramatic change in molecular geometry, which can hinder an effective interaction between the active site of the catalyst and substrate. For example, the neutral molecule of the E isomer of acetophenone N-benzylimine is nearly planar, but the protonated molecule is clearly more sterically demanding (see Figure 4 in the Supporting Information).
hiral amines and alcohols play a significant role, especially in pharmaceutical chemistry. Asymmetric transfer hydrogenation (ATH) allows us to prepare those substances with great purity and under mild conditions (room temperature and atmospheric pressure). The landmark catalytic system capable of highly efficient ATH of imines and ketones was reported by Noyori in 1995.1,2 It consists of a chiral N-p-toluenesulfonyl-1,2diphenylethylenediamine (abbreviated TsDPEN) ligand and a η6-arene (e.g., benzene, p-cymene, 1,2,3,4,5,6-hexamethylbenzene, etc.) coordinated to the ruthenium atom. Over the years, many structural modifications of these complexes have been developed.3−6 In the case of imine hydrogenation, the HCOOH/ triethylamine mixture serves as a hydrogen donor for the reaction. The first proposed mechanism of hydrogenation predicted that both CO and CN bonds are hydrogenated in the same fashion via six-membered transition states.7 This mechanism was extensively studied (Andersson,8 Noyori9) and confirmed for ketone substrates, but on the other hand, imines exhibited entirely different behavior than expected and the mechanism is less well understood. Bäckvall10 pointed out that it was impossible to hydrogenate imines without acidic conditions, which is possible for ketones. Wills11 showed that if a six-membered transition state occurred, there would be two possible outcomesthe reaction would deliver the wrong isomer of product, which would contradict experimental observation (a catalyst with the (S,S)-TsDPEN ligand delivers (R)-1-methyltetrahydroisoquinoline), or a CH/π interaction (which is deemed crucial for the enantioselectivity of this ATH system12) would not take place. We examined this pathway extensively in our previous paper,13 which was focused on endocyclic imines (1-methyl-3,4dihydroisoquinolines). In this work, we wish to supplement the recent results by the first evaluation of hydrogenation of acyclic imines with respect to the suggested pathway (Scheme 1). © 2012 American Chemical Society
Received: May 15, 2012 Published: August 8, 2012 6496
dx.doi.org/10.1021/om300413n | Organometallics 2012, 31, 6496−6499
Organometallics
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Scheme 1. Proposed Catalytic Cycle for the Hydrogenation of Acetophenone N-Benzyliminea
a
Structure 1 represents the Ru−Cl precatalyst, 2 is a cationic intermediate, and 3 is the catalytically active hydride.
Scheme 2. Isomerization of Acetophenone N-Benzyliminea
a
The equilibrium is shifted towards the E isomer, 94:6 (E:Z).2
We examined the so-called ionic pathway,10,11 as it seems to be the most probable way that imines are hydrogenated. Using the QST3 algorithm, we obtained 22 conformationally different transition states (TSs)10 for E and 12 for Z. Computed structures of transition states show that the hydrogen bond between the protonated nitrogen of the substrate and the sulfonyl group of the catalyst significantly contributes to the stabilization of TSs.13 Nevertheless, the whole system also has to employ weak hydrogen bonds to ensure the enantioselective progress of the reaction (typically, it is a CH/π bond between the η6-arene and the aromatic cycle of the substrate). The p-cymene ligand offers four possible sites for CH/π bond formation. Our calculations show that, in the case of acetophenone N-benzylimine, even multiple CH/π bonds can existthe first via the η6-arene and the second via one of the aromatic rings in the DPEN ligand. The amino group (−NH2) of the catalyst can contribute to the stabilization via an NH/π bond as well (e.g., in fav-E, Figure 1). An NH/π bond or multiple CH/π bonds are not formed in the case of 3,4-dihydroisoquinolines (DHIQs). The substrate conformational flexibility (different for cyclic and acyclic imines) is thus decisive for the possible structures of TSs, which strongly complicates the efforts to describe the reaction mechanism.
Figure 1. Geometry of fav-E calculated in vacuo. All possible noncovalent bonds are highlighted. These bonds noticeably help to stabilize the whole structure. Unimportant hydrogen atoms are omitted for clarity.
Four transition states with the lowest energy were selected for further consideration for every combination of the substrate and product isomers (E/Z and R/S). On this basis, the structures were labeled fav-E-1, dis-E-1, fav-Z-1, and dis-Z-1, where “fav” and “dis” represent favorable and disfavorable TSs. However, the difference in the free energies of dis-E-1 and favE-1 was unrealistically high (see Table 1), which led us to recalculate the TSs with respect to the solvation effects. The obtained structures had geometries nearly identical with those calculated in vacuo, as can be seen in Table 2, where the characteristic noncovalent bonds are compared for both cases. 6497
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Organometallics
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Table 1. Relative Energies of the Optimized Transition States fav-E-1/dis-E-1 fav-Z-1/dis-Z-1 fav-E-1/dis-E-1 fav-Z-1/dis-Z-1
isomer of substrate
isomer of product
solvation model
ΔG⧧RB3LYP (kJ/mol)
ΔERB3LYP (kJ/mol)
ΔERMP2 (kJ/mol)
E Z E Z
S R S R
none none IEFPCM IEFPCM
15.48 −4.25 8.56 −5.40
18.19 −4.55 14.34 −4.30
25.59 −0.35 21.01 −0.15
Figure 2. Comparison of optimized transition states with respect to the solvation effect (IEFPCM) together with their DFT//MP2 (DFT//DFT) single-point energies. Unimportant hydrogen atoms are omitted for clarity.
The difference in free energy decreased significantly (Table 1), which showed that the consideration of solvation effects was essential. Energy barriers for each solvated TS were computed as well (see Table 3). For this purpose the sum of energies of noninteracting substrate and catalyst was used as a global minimum. Furthermore, a comparison of dis-E-1 and fav-E-1 supports the experimental data published by Noyori2 and Bäckvall:10 the (major) E isomer of acetophenone N-benzylimine is preferentially reduced to (S)-amine. Surprisingly, the (minor) Z isomer is reduced with significantly lower enantioselectivity (compare dis-Z-1 and fav-Z-1 in Table 1), and its presence lowers the enantiomeric excess of the overall reaction. The lower enantioselectivity can be a result of the structural difference, which makes it harder for the Z isomer to realize both of the stabilizing noncovalent interactions. When the geometries of the substrates were compared with respect to the solvation effects, no striking differences appeared. In summary, the ATH of an acyclic imine was examined in great detail and the computed transition states allowed us to
study key aspects of the reaction and explain the observed phenomena with respect to the newest findings concerning the ionic mechanism. Transition states are stabilized via noncovalent bonds: e.g. hydrogen bonds between the protonated substrate and the sulfonyl group of the catalyst. The calculations also revealed that multiple CH/π bonds or NH/π bonds are possible as well (see Figure 2). The exocyclic CN bond of acetophenone N-benzylimine allows for the existence of two isomers, and our study confirms that they can interact with the catalyst in a different manner. The E isomer of the substrate leads to the delivery of (S)-amine, and in contrast, the Z isomer is reduced with much lower enantioselectivity to (R)-amine. This is assumed to be due to the structural differences between the two isomers. We compared the differences between the behaviors of cyclic and acyclic imines. Cyclic imines such as 3,4dihydroisoquinolines have restricted structural opportunities the NH2 group of the catalyst cannot form an NH/π interaction and a multiple CH/π interaction is also not possible. Thanks to the endocyclic CN bond, DHIQs cannot isomerize. 6498
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ACKNOWLEDGMENTS This work has been financially supported by the Grant Agency of the Czech Republic (Grants GACR 104/09/1497 and P106/ 12/1276) and by a grant for long-term conceptual development from the Institute of Microbiology (RVO: 61388971). Access to computing and storage facilities owned by parties and projects contributing to the National Grid Infrastructure MetaCentrum, provided under the program “Projects of Large Infrastructure for Research, Development, and Innovations” (No. LM2010005), is highly appreciated.
Table 2. Differences in Non-Covalent Bonding of the Optimized Transition States
fav-E-1 dis-E-1 fav-Z-1 dis-Z-1
solvation model
H bond NH+−O(30)/NH+− O(40) a (Å)
CH/π bond (Å)
none IEFPCM none IEFPCM none IEFPCM none IEFPCM
2.83596/1.91815 2.86751/1.95325 3.24056/2.93979 3.23559/3.13991 3.06302/2.00671 2.62661/2.46266 2.90127/2.00569 2.90117/2.05063
3.09364/3.30786b 3.11057/3.33601b 3.02072/3.26215c 3.06325/3.28200c d d d d
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b
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Table 3. Energy Barriers of Solvated Transition States
fav-E-1 dis-E-1 fav-Z-1 dis-Z-1
isomer of substrate
isomer of product
solvation model
ΔG⧧RB3LYP (kJ/mol)
ΔERMP2 (kJ/mol)
E E Z Z
S S R R
IEFPCM IEFPCM IEFPCM IEFPCM
115.10 123.66 128.46 123.06
10.86 31.94 24.50 24.65
It is worth noting that DHIQs lead to the delivery of (R)-amine (when using the (S,S)-TsDPEN ligand) but acetophenone N-benzylimine leads to the delivery of (S)-amine.2,13
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EXPERIMENTAL SECTION
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
REFERENCES
(1) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562. (2) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916. (3) Blackmond, D. G.; Ropic, M.; Stefinovic, M. Org. Process Res. Dev. 2006, 10, 457. (4) Václavík, J.; Kačer, P.; Kuzma, M.; Č ervený, L. Molecules 2011, 16, 5460. (5) Cheung, F. K. K.; Hayes, A. M.; Hannedouche, J.; Yim, A. S. Y.; Wills, M. J. Org. Chem. 2005, 70, 3188. (6) Morris, D. J.; Hayes, A. M.; Wills, M. J. Org. Chem. 2006, 71, 7035. (7) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (8) Alonso, D. A.; Brandt, P.; Nordin, S. J. M.; Andersson, P. G. J. Am. Chem. Soc. 1999, 121, 9580. (9) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466. (10) Å berg, J. B.; Samec, J. S. M.; Bäckvall, J. E. Chem. Commun. 2006, 70, 2771. (11) Martins, J. E. D.; Clarkson, G. J.; Wills, M. Org. Lett. 2009, 11, 847. (12) Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem., Int. Ed. 2001, 40, 2818. (13) Václavík, J.; Kuzma, M.; Přech, J.; Kačer, P. Organometallics 2011, 30, 4822. (14) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285. (15) Frisch, M. J.; et al. Gaussian 03, revision E.01; Gaussian, Inc., Wallingford, CT, 2004. (16) Frisch, M. J.; et al. Gaussian 09, revision A.02; Gaussian, Inc., Wallingford, CT, 2009. (17) Lee, C.; Yang, W.; Parr, R. Phys. Rev. B 1988, 37, 785−789. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (18) Head-Gordon, M.; Pople, J. A.; Frisch, M. J. Chem. Phys. Lett. 1988, 153, 503. (19) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270. (20) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105, 2999.
O(3) is proximal to the η -p-cymene, and O(4) is distal. C(61)− H(65)···C(79)/C(74). cC(10)−H(19)···C(79)/C(87). dNo CH/π bond. a
Note
We used the Gaussian0915 and Gaussian0316 software packages for our calculations. DFT employing the restricted B3LYP17 hybrid functional was used for frequency analyses and optimizations, and both DFT and MP218 were used to compute single-point energies. Calculations were conducted with the usage of Pople’s polarized 6-31g(d,p) basis set for all atoms, except for ruthenium. Ruthenium was described by LANL2DZ19 together with the LANL2DZ effective core potential (ECP). The whole approach can be described as DFT/6-31g(d,p)/ LANL2DZ//DFT/6-31g(d,p)/LANL2DZ and DFT/6-31g(d,p)/ LANL2DZ//MP2/6-31g(d,p)/LANL2DZusually abbreviated as DFT//DFT and DFT//MP2. Geometries of transition states were obtained using the QST3 algorithm (which is based on the STQN (synchronous transit-guided quasi-Newton) approach). All minima were verified to have no negative frequencies and all the transition states to have just one negative frequency. (Some of the optimizations (QST3) were completed on the basis of negligible forces.) Nearly all calculations were carried out in vacuo, with the exception of transition states with the lowest energy, which were recalculated using the integral equations formalism variant of the polarization continuum model (IEFPCM20) with UFF radii (i.e., the optimization process was redone with IEFPCM applied). Solvation was set up using an unmodified dielectric constant for dichloromethane (ε = 8.93). S Supporting Information *
Text giving the full refs 15and 16 and figures and tables giving computation data for each structure. This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding Author
*E-mail:
[email protected] (M.K.);
[email protected] (P.S.). Notes
The authors declare no competing financial interest. 6499
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