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Direct experimental and computational evidence for the dihydride pathway in TangPHOS-Rh catalysed asymmetric hydrogenation† Ilya D. Gridnev,*a Christina Kohrtb and Yuanyuan Liua DFT computations of various possible reaction pathways in asymmetric hydrogenation of methyl (Z-α) acetylaminocinnamate catalysed by Rh-TangPHOS complex revealed the clear preference of the dihy-
Received 29th August 2013, Accepted 15th October 2013
dride pathway. This conclusion was explicitly confirmed by the structure of the monohydride intermediate intercepted in the low temperature NMR hydrogenation experiments. DFT analysis of the origin of enan-
DOI: 10.1039/c3dt52383g
tioselection showed that it takes place via obstructing the proper coordination of the double bond in the
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S-enantioselective pathway.
Introduction Asymmetric hydrogenation catalysed by chiral soluble complexes of Rh is among the brightest examples of a successful reaction both from the point of view of synthetic or industrial applications1 and the intensity of the mechanistic and theoretical studies.2 Despite the fact that rigorous research in this field has been carried out for several decades, the interest of the chemical community to the mechanism of enantioselection in the asymmetric hydrogenation continues to be extremely high in view of the importance of achieving definite conclusions on the exact reasons for the utmost enantioselectivity observed in some reactions of this type, for the conscious catalysts design and for development of the general concept of selectivity in synthetic and catalytic chemistry. The initially suggested unsaturated mechanism (Scheme 1) of enantioselection in the Rh-catalyzed asymmetric hydrogenation via the difference in the rates of oxidative addition of dihydrogen to diastereomeric square planar Rh(I) complexes3 is questioned in view of the numerous recent experimental and computational results rather suggesting that stereoselection takes place via a dihydride mechanism (Scheme 1) in octahedral Rh(III) complexes that are formed by initial hydrogen
a Department of Chemistry, Graduate School of Science, 6-3 Aramaki, Aoba-ku, 980-8578 Sendai, Japan. E-mail: [email protected]; Fax: +81 22 795 6602; Tel: +81 22 795 6603 b Leibniz-InstitutfürKatalyse e. V., Albert Einstein Strasse 29a, 18059 Rostock, Germany. E-mail: [email protected]; Fax: +49 0381-1281-50183; Tel: +49 0381-1281-50183 † Electronic supplementary information (ESI) available: Additional computational details, NMR charts and Cartesian coordinates of all optimized structures. See DOI: 10.1039/c3dt52383g
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Scheme 1 Two possible mechanisms in Rh-catalyzed asymmetric hydrogenation.
activation by Rh(I) solvates or non-chelating catalyst–substrate complexes.2,4 Recently we have computed all possible reaction pathways leading to the R-enantiomer of phenylalanine in the asymmetric hydrogenation of methyl Z-α-acetlylamidocinnamate (MAC) catalysed by Rh complex of R,R-1,2-bis(tert-butylmethylphosphino)benzene (BenzP*).5 The computations showed clearly that the pathways involving the hydrogenation of the species with non-coordinated double bond are 10–15 kcal mol−1 lower in energy than the most favourable pathway involving hydrogenation of the chelate catalyst–substrate complexes. However, this conclusion was not proved experimentally, since no late intermediates could be observed
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in the low-temperature hydrogenation of the catalyst–substrate complexes. Here we report the results of combined computational and experimental study of the mechanism of asymmetric hydrogenation of MAC catalysed by TangPHOS-Rh complex. This catalyst is one of the most versatile and is widely used for asymmetric hydrogenation of various activated prochiral olefins.6 Catalytic hydrogenation of MAC with RhTangPHOS is very fast and yields the hydrogenation product with >99% ee.6a Hence, it is important to understand the intrinsic mechanism of enantioselection in this highly effective catalytic reaction.
Results and discussion The catalyst–substrate complex of Rh-TangPHOS and MAC has been characterized in solution and in the solid state.7 Only one isomer with re-coordinated substrate has been intercepted so far. In order to compare the relative stabilities of the catalyst–substrate complexes, we have optimized their structures on the B3LYP/6-31+G(2d,2p)/CPCM(methanol) level of theory with additional diffuse function for phosphorus (Fig. 1).‡ The catalyst–substrate complex 1b with si-coordinated substrate was computed to be 2.6 kcal mol−1 less stable than its analog with re-coordinated olefin 1a at 298 K. This means that the equilibrium concentration of 1b is too low for its detection with the means of NMR spectroscopy. Nevertheless, MAC can use a different mode of si-coordination,5 utilizing the non-hindered quadrant of the catalyst for the almost coplanar coordination of the double bond with respect to the chelate cycle of the catalyst, yielding catalyst–substrate complex 1c, which was computed to be only 1.5 kcal mol−1 less stable than 1a at 298 K (Fig. 1). We attempted to detect the relatively less concentrated 1c in the NMR spectra. Although we failed to obtain absolutely neat spectra of the catalyst–substrate complexes,§ the 1H–31P HMBC spectrum recorded at 203 K had only two cross-peaks in the region δ1H 4.5–6.5, which is characteristic for the CH = signal of the coordinated double bond (Fig. S1†). The more intensive signal belonged to 1a, whereas an approximately ten times less intensive signal correlated to the broad double doublet at δ31P 105.2 (1JPRh = 139 Hz). In order to determine the structure of the less populated species we have recorded a phase-sensitive 1H–1H ROESY spectrum at the same temperature. From the section plot of this spectrum shown in the Fig. S2† one can see that the CH = proton of the coordinated double bond in 1a has a very intensive ROE with one of the CH2 groups protons and much less intensive ROE with the tert-Bu group, in accordance with the computed interatomic distances shown in Fig. 1. On the other Fig. 1 ‡ Prompted by the reviewer’s suggestion we checked a newer functional TPSS with same basis set. However, B3LYP described the equilibria between MAC, 2, and 1a–c more accurately. See ESI† for details. § Upon storage, even at decreased temperatures the samples become contaminated with the complexes with one of the phosphorus atom dissociated from Rh. These complexes, however are silent in the hydrogenation, so their presence did not affect our conclusions.
1786 | Dalton Trans., 2014, 43, 1785–1790
Computed structures of the catalyst–substrate complexes 1a–c.
hand, the CH = proton of the less concentrated complex has comparable in intensity ROE’s with the CH2 and C(CH3)3 groups, that according to the interatomic distances shown in the Fig. 1 identifies it as 1c.
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Scheme 2 Four catalytic pathways of the asymmetric hydrogenation of MAC catalysed by Rh-TangPHOS complex computed on the B3LYP/SDD(Rh)/6-31+G(2d,2p)(all others)/CPCM(methanol) level of theory with additional diffuse function for phosphorus.
Double bond similar to that in 1c is known to be significantly more reactive towards hydrogen than the normal catalyst–substrate complexes like 1a and 1b with orthogonal orientation of the coordinated double bond relative to the chelate cycle of the catalyst.5,8 Hence, it was important to compare the feasibility of different reaction pathways in order to draw conclusions on the mechanism of enantioselection in this case. To do this we have computed various catalytic cycles of the hydrogenation of MAC with [Rh(R,R,S,S)TangPHOS(CH3OH)2]+ (2) leading to R-phenylalanine (3) (Scheme 2, Fig. 2). Hydrogenation of catalyst 2 can produce solvate hydride 5 via intermediate formation of molecular hydrogen complex 4 with very low activation barrier. On the other hand, the catalyst can coordinate the substrate via the oxygen atom of amido carbonyl yielding a non-chelating catalyst–substrate complex 6. Its hydrogenation would provide a non-chelating dihydride intermediate 8. However, computational results imply that 8 is likely to form via coordination of the substrate to the solvate dihydride 5, since this pathway is 5 kcal mol−1 lower in energy. The coordination of the double bond yielding the chelate catalyst–substrate complex 9 is the rate-limiting stage of the dihydride catalytic cycle, since the following migratory insertion affording the monohydride intermediate 10 proceeds with a very low activation barrier. Importantly, the monohydride 10 was computed to be quite stable, and the activation barrier of the reductive elimination (13.3 kcal mol−1) is high enough to allow its detection at decreased temperatures. To compare, the similar monohydride intermediate of the MAC hydrogenation
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Fig. 2 Computed profiles of the relative Gibbs free energies at 298 K along with four reaction pathways leading to R-3.
catalysed by BenP*-Rh complex was computed to undergo reductive elimination with only 4.3 kcal mol−1 activation barrier, accordingly all attempts to intercept it were not successful. If prior to hydrogenation the non-chelating catalyst–substrate complex 6 coordinated the double bond, it would result in the formation of chelate si-coordinated catalyst–substrate complexes 1b or 1c, either of which is expected to produce R-3 after oxidative addition. In the computation of a model system four possible ways of the approach of dihydrogen molecule to
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the chelating catalyst–substrate complex have been considered (see ESI†).8 However, our computations show that due to the significant steric hindrance from both the substituents on the phosphorus atoms of the catalyst and coordinated MAC, only one way of the productive approach of a dihydrogen molecule is possible for either 1b or 1c. In both cases the formation of a molecular hydrogen complex (11 or 14) requires significant energy. Moreover, in the case of 1b the following oxidative addition has unreasonably high activation barrier and leads to the practically uncoordinated bond in the dihydride intermediate 15. Three transition states for the oxidative addition are compared in Fig. 3. On the other hand, the consequence of the oxidative addition and migratory insertion steps starting from the molecular hydrogen complex 11 proceeds with very low activation barriers, and the free energy of the limiting stage (oxidative addition in 11) was computed to be only 3.4 kcal mol−1 higher than that in the hydride pathway (coordination of the double bond in 8). Taking into account possible inaccuracies in the computations, one should consider the competition of two pathways in the course of hydrogenation. In order to make a definite conclusion on the mechanism of hydrogenation of MAC catalysed with 2, we have carried out a low-temperature hydrogenation of the sample prepared by addition of 2 equivalents of MAC to a solution of 2 in deuteriomethanol. Monitoring the reaction mixture with 1H and 31P NMR taken at 193 K showed that after 10 min of hydrogenation at this temperature no more signals of 1a were observed in the NMR spectra. Instead, almost the same amount of a monohydride intermediate (δP1 98.6, 1JRhP 139 Hz, δP2 116.6, 1JRhP 139 Hz) was observed (Fig. S3†). The chemical shift of the hydride signal that correlated with the signal of P1, δ −22.46 in 1 H–31P HMBC (Fig. S4†) unequivocally testified for a strongly electronegative substituent in trans-position to this hydride, i.e. the experimental data are in accordance with the structure 10 and not 13. The ee of the samples obtained after the low temperature hydrogenation experiments was 99.9% (R) and 99.7% (R) in two independent experiments, of the same sign and value that is observed in the catalytic hydrogenation of MAC catalysed by TangPHOS-Rh complex.6a Thus, in view of combined experimental and computational evidence we concluded that the asymmetric hydrogenation of MAC catalysed by TangPHOS-Rh complex proceeds exclusively via the dihydride mechanism, and the stereoselective step is the coordination of the double bond. The corresponding TS3 is characterized by a relatively low value of the imaginary frequency (ν = 61.2i). Three largest displacement vectors in the TS3 correspond to the approach of CHvC unit to the H–Rh–H plane (see ESI† for a figure). Hence TS3 itself corresponds to the intramolecular motion that is followed by a barrierless formation of the coordination bond. The total free energy barrier can be estimated as 16.9 kcal mol−1 (relative free energy of TS3 with respect to 2 + MAC + H2), that corresponds to TOF 153 min−1. The catalytic
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Fig. 3 Structures of the oxidative addition transition states: in TS2 hydrogen is activated at the free coordination site that results in the relatively low activation barrier. The TS9 is very unstable, because the oxidative addition is accompanied by the movement of the substituted double bond towards bulky substituents on the phosphorus atoms. This effect is less pronounces in the TS6, because the double bond can keep orientation that is almost coplanar to the chelate cycle.
hydrogenation was too rapid for an accurate kinetic measurement at ambient temperature. A rough estimation of the pseudo rate constant from the hydrogen consumption curves at 273 K showed that it was larger than 100 min−1. In order to understand better the mechanism of generation of the extremely high optical yields characteristic for this
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Fig. 4 Scan of relative energies for the double bond replacing the MeOH molecule at the Rh coordination site. Computed at the B3LYP/ SDD(Rh)/6-31G(d,p)(all others)/CPCM(MeOH) level of theory with additional diffuse function for phosphorus.
Scheme 3 Enantioselection via the coordination of the prochiral double bond.
reaction, we analysed in more detail the coordination of the prochiral double bond in the octahedral Rh(III) complexes (Scheme 3). The opposite enantiomer 3(S) might be produced via the coordination of the double bond in the non-chelating complex 8′ that originates from alternative mode of the addition of dihydrogen via 4′ and 5′. It is evident from the computational data that 8·MeOH and 8′·MeOH can interconvert via the consequence of reversible steps with low activation barriers, hence either of them is accessible kinetically. But if in the case of 8·MeOH the substitution of the methanol molecule with the double bond takes place in the non-hindered quadrant, the same process in 8′·MeOH would require significant intramolecular movements in the hindered quadrant (Scheme 3). Fig. 4 displays a scan of the relative energies along the pathway approaching the tetra-substituted carbon atom of the double bond towards Rh in 8·MeOH and 8′·MeOH. In the case of 8 the scan proceeds via a single maximum at approximately 3 Å and results in the dihydride intermediate 9·MeOH. On the other hand, in the case of 8′ the maximum reached only at 2.5 Å has unreasonably high energy. The minimum reached upon further approach of the double bond has the
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double bond oriented coplanar to the Rh–H axial bond (transto the oxygen atom), and is therefore unlikely to undergo migratory insertion. Hence the practically perfect R-enantioselection in the asymmetric hydrogenation of MAC catalysed by Rh(1S,1S′,2R,2R′)-TangPHOS complex can be explained by the effective blockade of the S-enantioselective pathway on the stage of the double bond coordination in octahedral Rh(III) complex. Due to the steric hindrance created by the But group in the hindered quadrant, the substitution of the solvent molecule by the double bond becomes practically impossible. Therefore, the proper configuration for the occurrence of the migratory insertion can be only achieved for the R-enantioselective pathway. Noteworthy, this mechanism of enantioselection explains well the absence of the temperature effect on the optical yield. Indeed, in the case when the ee is determined by the difference in the free energies of the diastereomeric transition states, significant dependence of the optical yields on the temperature is usually observed due to the natural temperature variation of the rate constants. On the other hand, the structure of the catalyst implying facile transformation of 8·MeOH to 9·MeOH and impossibility of similar transformation in the case of 8′·MeOH, remains the same at any temperature. Hence, the almost perfect enantioselectivity can be observed either in catalytic or low-temperature stoichiometric reaction.
Conclusions Experimental NMR studies and DFT computations showed that highly enantioselective hydrogenation of MAC with RhTangPHOS complex follows the dihydride pathway. The enantioselection occurs via blockage of the S-enantioselective pathway on the stage of the double bond coordination in the octahedral Rh(III) non-chelating complex.
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Experimental section
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Instrumentation NMR experiments were carried out on JEOL ESX 400, Bruker Avance 500, Jeol ESX 600 and Bruker Avance 700 spectrometers. Computations were performed on Tsubame-2 Supercomputer of the Tokyo Institute of Technology. Materials Methanol-d4 of the grade “100%” (99.6% D) packed in sealed ampules was purchased from Cambridge Isotope Laboratories, Inc. Hydrogen of 99.9999% (Tanuma Sanso) was used for the mechanistic studies. Computational details All computations were carried out using the hybrid Becke functional (B3)9 for electron exchange and the correlation functional of Lee, Yang and Parr (LYP),10 as implemented in the GAUSSIAN 09 software package.11 For rhodium the SDD basis set with the associated effective core potential was employed.12 All other atoms were modeled at the 6-31G+(2d,2p) level of theory.13 The following additional diffuse function was applied for the phosphorus atom: P 0 D 1 1.0 0.55 0.100D+01 Geometry optimizations were performed with the account of the solvent effects (CPCM, methanol) without applying any geometry constraints (C1 symmetry). Starting geometries for the transition state search were located either by QST2 or QST3 procedures, or by the guess based on the structure of the previously found TS. The transition states were subsequently fully optimized as saddle points of first order, employing the Berny algorithm.14 Frequency calculations were carried out to confirm the nature of the stationary points, yielding zero imaginary frequencies for all Rh complexes and one imaginary frequency for all transition states, which represented the vector for the appropriate bond formation.
Acknowledgements This work was supported in part by Campus Asia Project of Tohoku University. The authors are grateful to Prof. Takao Ikaria (Tokyo Institute of Technology) for his kind help with the supercomputing facilities.
Notes and references 1 Recent review: P. Etayo and A. Vidal-Ferran, Chem. Soc. Rev., 2013, 42, 728–754 and references therein.
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2 Recent review: I. D. Gridnev and T. Imamoto, Chem. Commun., 2009, 7447–7465 and references therein. 3 (a) J. Halpern, Science, 1982, 217, 401; (b) J. M. Brown, Hydrogenation of Functionalized Carbon–Carbon Double Bonds, in Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfalz and H. Yamamoto, Springer, Berlin, 1999, vol. 1, pp. 119–182. 4 I. D. Gridnev and T. Imamoto, Acc. Chem. Res., 2004, 37, 633–644. 5 T. Imamoto, K. Tamura, Z. Zhang, Y. Horiuchi, M. Sugiya, K. Yoshida, A. Yanagisawa and I. D. Gridnev, J. Am. Chem. Soc., 2012, 134, 1754–1769. 6 (a) W. Tang and X. Zhang, Angew. Chem., Int. Ed., 2002, 41, 1612–1614; (b) W. Tang and X. Zhang, Org. Lett., 2002, 4, 4159–4161; (c) W. Tang, D. Liu and X. Zhang, Org. Lett., 2003, 5, 205–207. 7 C. Kohrt, W. Baumann, A. Spannenberg, H.-J. Drexler, I. D. Gridnev and D. Heller, Chem.–Eur. J., 2013, 19, 7443. 8 S. Feldgus and C. Landis, J. Am. Chem. Soc., 2000, 122, 12714–12727. 9 (a) A. D. Becke, J. Chem. Phys., 1993, 98, 1372; (b) A. D. Becke, J. Chem. Phys., 1993, 98, 5648. 10 C. Lee, W. Yang and R. G. Parr, Phys. Rev. B, 1988, 37, 785. 11 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski and D. J. Fox, GAUSSIAN 09 (Revision A.02), Gaussian, Inc., Wallingford CT, 2009. 12 D. Andrae, U. Haeussermann, M. Dolg, H. Stoll and H. Preuss, Theor. Chim. Acta, 1990, 77, 123. 13 (a) R. Ditchfield, W. J. Hehre and J. A. Pople, J. Chem. Phys., 1971, 54, 724; (b) W. J. Hehre, R. Ditchfield and J. A. Pople, J. Chem. Phys., 1972, 56, 2257; (c) P. C. Hariharan and J. A. Pople, Theor. Chim. Acta, 1973, 28, 213; (d) P. C. Hariharan and J. A. Pople, Mol. Phys., 1974, 27, 209; (e) M. S. Gordon, Chem. Phys. Lett., 1980, 76, 163. 14 C. Y. Peng and B. Schlegel, Isr. J. Chem., 1994, 34, 449.
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Direct experimental and computational evidence for the dihydride pathway in TangPHOS-Rh catalysed asymmetric hydrogenation† Ilya D. Gridnev,*a Christina Kohrtb and Yuanyuan Liua DFT computations of various possible reaction pathways in asymmetric hydrogenation of methyl (Z-α) acetylaminocinnamate catalysed by Rh-TangPHOS complex revealed the clear preference of the dihy-
Received 29th August 2013, Accepted 15th October 2013
dride pathway. This conclusion was explicitly confirmed by the structure of the monohydride intermediate intercepted in the low temperature NMR hydrogenation experiments. DFT analysis of the origin of enan-
DOI: 10.1039/c3dt52383g
tioselection showed that it takes place via obstructing the proper coordination of the double bond in the
www.rsc.org/dalton
S-enantioselective pathway.
Introduction Asymmetric hydrogenation catalysed by chiral soluble complexes of Rh is among the brightest examples of a successful reaction both from the point of view of synthetic or industrial applications1 and the intensity of the mechanistic and theoretical studies.2 Despite the fact that rigorous research in this field has been carried out for several decades, the interest of the chemical community to the mechanism of enantioselection in the asymmetric hydrogenation continues to be extremely high in view of the importance of achieving definite conclusions on the exact reasons for the utmost enantioselectivity observed in some reactions of this type, for the conscious catalysts design and for development of the general concept of selectivity in synthetic and catalytic chemistry. The initially suggested unsaturated mechanism (Scheme 1) of enantioselection in the Rh-catalyzed asymmetric hydrogenation via the difference in the rates of oxidative addition of dihydrogen to diastereomeric square planar Rh(I) complexes3 is questioned in view of the numerous recent experimental and computational results rather suggesting that stereoselection takes place via a dihydride mechanism (Scheme 1) in octahedral Rh(III) complexes that are formed by initial hydrogen
a Department of Chemistry, Graduate School of Science, 6-3 Aramaki, Aoba-ku, 980-8578 Sendai, Japan. E-mail: [email protected]; Fax: +81 22 795 6602; Tel: +81 22 795 6603 b Leibniz-InstitutfürKatalyse e. V., Albert Einstein Strasse 29a, 18059 Rostock, Germany. E-mail: [email protected]; Fax: +49 0381-1281-50183; Tel: +49 0381-1281-50183 † Electronic supplementary information (ESI) available: Additional computational details, NMR charts and Cartesian coordinates of all optimized structures. See DOI: 10.1039/c3dt52383g
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Scheme 1 Two possible mechanisms in Rh-catalyzed asymmetric hydrogenation.
activation by Rh(I) solvates or non-chelating catalyst–substrate complexes.2,4 Recently we have computed all possible reaction pathways leading to the R-enantiomer of phenylalanine in the asymmetric hydrogenation of methyl Z-α-acetlylamidocinnamate (MAC) catalysed by Rh complex of R,R-1,2-bis(tert-butylmethylphosphino)benzene (BenzP*).5 The computations showed clearly that the pathways involving the hydrogenation of the species with non-coordinated double bond are 10–15 kcal mol−1 lower in energy than the most favourable pathway involving hydrogenation of the chelate catalyst–substrate complexes. However, this conclusion was not proved experimentally, since no late intermediates could be observed
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in the low-temperature hydrogenation of the catalyst–substrate complexes. Here we report the results of combined computational and experimental study of the mechanism of asymmetric hydrogenation of MAC catalysed by TangPHOS-Rh complex. This catalyst is one of the most versatile and is widely used for asymmetric hydrogenation of various activated prochiral olefins.6 Catalytic hydrogenation of MAC with RhTangPHOS is very fast and yields the hydrogenation product with >99% ee.6a Hence, it is important to understand the intrinsic mechanism of enantioselection in this highly effective catalytic reaction.
Results and discussion The catalyst–substrate complex of Rh-TangPHOS and MAC has been characterized in solution and in the solid state.7 Only one isomer with re-coordinated substrate has been intercepted so far. In order to compare the relative stabilities of the catalyst–substrate complexes, we have optimized their structures on the B3LYP/6-31+G(2d,2p)/CPCM(methanol) level of theory with additional diffuse function for phosphorus (Fig. 1).‡ The catalyst–substrate complex 1b with si-coordinated substrate was computed to be 2.6 kcal mol−1 less stable than its analog with re-coordinated olefin 1a at 298 K. This means that the equilibrium concentration of 1b is too low for its detection with the means of NMR spectroscopy. Nevertheless, MAC can use a different mode of si-coordination,5 utilizing the non-hindered quadrant of the catalyst for the almost coplanar coordination of the double bond with respect to the chelate cycle of the catalyst, yielding catalyst–substrate complex 1c, which was computed to be only 1.5 kcal mol−1 less stable than 1a at 298 K (Fig. 1). We attempted to detect the relatively less concentrated 1c in the NMR spectra. Although we failed to obtain absolutely neat spectra of the catalyst–substrate complexes,§ the 1H–31P HMBC spectrum recorded at 203 K had only two cross-peaks in the region δ1H 4.5–6.5, which is characteristic for the CH = signal of the coordinated double bond (Fig. S1†). The more intensive signal belonged to 1a, whereas an approximately ten times less intensive signal correlated to the broad double doublet at δ31P 105.2 (1JPRh = 139 Hz). In order to determine the structure of the less populated species we have recorded a phase-sensitive 1H–1H ROESY spectrum at the same temperature. From the section plot of this spectrum shown in the Fig. S2† one can see that the CH = proton of the coordinated double bond in 1a has a very intensive ROE with one of the CH2 groups protons and much less intensive ROE with the tert-Bu group, in accordance with the computed interatomic distances shown in Fig. 1. On the other Fig. 1 ‡ Prompted by the reviewer’s suggestion we checked a newer functional TPSS with same basis set. However, B3LYP described the equilibria between MAC, 2, and 1a–c more accurately. See ESI† for details. § Upon storage, even at decreased temperatures the samples become contaminated with the complexes with one of the phosphorus atom dissociated from Rh. These complexes, however are silent in the hydrogenation, so their presence did not affect our conclusions.
1786 | Dalton Trans., 2014, 43, 1785–1790
Computed structures of the catalyst–substrate complexes 1a–c.
hand, the CH = proton of the less concentrated complex has comparable in intensity ROE’s with the CH2 and C(CH3)3 groups, that according to the interatomic distances shown in the Fig. 1 identifies it as 1c.
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Scheme 2 Four catalytic pathways of the asymmetric hydrogenation of MAC catalysed by Rh-TangPHOS complex computed on the B3LYP/SDD(Rh)/6-31+G(2d,2p)(all others)/CPCM(methanol) level of theory with additional diffuse function for phosphorus.
Double bond similar to that in 1c is known to be significantly more reactive towards hydrogen than the normal catalyst–substrate complexes like 1a and 1b with orthogonal orientation of the coordinated double bond relative to the chelate cycle of the catalyst.5,8 Hence, it was important to compare the feasibility of different reaction pathways in order to draw conclusions on the mechanism of enantioselection in this case. To do this we have computed various catalytic cycles of the hydrogenation of MAC with [Rh(R,R,S,S)TangPHOS(CH3OH)2]+ (2) leading to R-phenylalanine (3) (Scheme 2, Fig. 2). Hydrogenation of catalyst 2 can produce solvate hydride 5 via intermediate formation of molecular hydrogen complex 4 with very low activation barrier. On the other hand, the catalyst can coordinate the substrate via the oxygen atom of amido carbonyl yielding a non-chelating catalyst–substrate complex 6. Its hydrogenation would provide a non-chelating dihydride intermediate 8. However, computational results imply that 8 is likely to form via coordination of the substrate to the solvate dihydride 5, since this pathway is 5 kcal mol−1 lower in energy. The coordination of the double bond yielding the chelate catalyst–substrate complex 9 is the rate-limiting stage of the dihydride catalytic cycle, since the following migratory insertion affording the monohydride intermediate 10 proceeds with a very low activation barrier. Importantly, the monohydride 10 was computed to be quite stable, and the activation barrier of the reductive elimination (13.3 kcal mol−1) is high enough to allow its detection at decreased temperatures. To compare, the similar monohydride intermediate of the MAC hydrogenation
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Fig. 2 Computed profiles of the relative Gibbs free energies at 298 K along with four reaction pathways leading to R-3.
catalysed by BenP*-Rh complex was computed to undergo reductive elimination with only 4.3 kcal mol−1 activation barrier, accordingly all attempts to intercept it were not successful. If prior to hydrogenation the non-chelating catalyst–substrate complex 6 coordinated the double bond, it would result in the formation of chelate si-coordinated catalyst–substrate complexes 1b or 1c, either of which is expected to produce R-3 after oxidative addition. In the computation of a model system four possible ways of the approach of dihydrogen molecule to
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the chelating catalyst–substrate complex have been considered (see ESI†).8 However, our computations show that due to the significant steric hindrance from both the substituents on the phosphorus atoms of the catalyst and coordinated MAC, only one way of the productive approach of a dihydrogen molecule is possible for either 1b or 1c. In both cases the formation of a molecular hydrogen complex (11 or 14) requires significant energy. Moreover, in the case of 1b the following oxidative addition has unreasonably high activation barrier and leads to the practically uncoordinated bond in the dihydride intermediate 15. Three transition states for the oxidative addition are compared in Fig. 3. On the other hand, the consequence of the oxidative addition and migratory insertion steps starting from the molecular hydrogen complex 11 proceeds with very low activation barriers, and the free energy of the limiting stage (oxidative addition in 11) was computed to be only 3.4 kcal mol−1 higher than that in the hydride pathway (coordination of the double bond in 8). Taking into account possible inaccuracies in the computations, one should consider the competition of two pathways in the course of hydrogenation. In order to make a definite conclusion on the mechanism of hydrogenation of MAC catalysed with 2, we have carried out a low-temperature hydrogenation of the sample prepared by addition of 2 equivalents of MAC to a solution of 2 in deuteriomethanol. Monitoring the reaction mixture with 1H and 31P NMR taken at 193 K showed that after 10 min of hydrogenation at this temperature no more signals of 1a were observed in the NMR spectra. Instead, almost the same amount of a monohydride intermediate (δP1 98.6, 1JRhP 139 Hz, δP2 116.6, 1JRhP 139 Hz) was observed (Fig. S3†). The chemical shift of the hydride signal that correlated with the signal of P1, δ −22.46 in 1 H–31P HMBC (Fig. S4†) unequivocally testified for a strongly electronegative substituent in trans-position to this hydride, i.e. the experimental data are in accordance with the structure 10 and not 13. The ee of the samples obtained after the low temperature hydrogenation experiments was 99.9% (R) and 99.7% (R) in two independent experiments, of the same sign and value that is observed in the catalytic hydrogenation of MAC catalysed by TangPHOS-Rh complex.6a Thus, in view of combined experimental and computational evidence we concluded that the asymmetric hydrogenation of MAC catalysed by TangPHOS-Rh complex proceeds exclusively via the dihydride mechanism, and the stereoselective step is the coordination of the double bond. The corresponding TS3 is characterized by a relatively low value of the imaginary frequency (ν = 61.2i). Three largest displacement vectors in the TS3 correspond to the approach of CHvC unit to the H–Rh–H plane (see ESI† for a figure). Hence TS3 itself corresponds to the intramolecular motion that is followed by a barrierless formation of the coordination bond. The total free energy barrier can be estimated as 16.9 kcal mol−1 (relative free energy of TS3 with respect to 2 + MAC + H2), that corresponds to TOF 153 min−1. The catalytic
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Fig. 3 Structures of the oxidative addition transition states: in TS2 hydrogen is activated at the free coordination site that results in the relatively low activation barrier. The TS9 is very unstable, because the oxidative addition is accompanied by the movement of the substituted double bond towards bulky substituents on the phosphorus atoms. This effect is less pronounces in the TS6, because the double bond can keep orientation that is almost coplanar to the chelate cycle.
hydrogenation was too rapid for an accurate kinetic measurement at ambient temperature. A rough estimation of the pseudo rate constant from the hydrogen consumption curves at 273 K showed that it was larger than 100 min−1. In order to understand better the mechanism of generation of the extremely high optical yields characteristic for this
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Fig. 4 Scan of relative energies for the double bond replacing the MeOH molecule at the Rh coordination site. Computed at the B3LYP/ SDD(Rh)/6-31G(d,p)(all others)/CPCM(MeOH) level of theory with additional diffuse function for phosphorus.
Scheme 3 Enantioselection via the coordination of the prochiral double bond.
reaction, we analysed in more detail the coordination of the prochiral double bond in the octahedral Rh(III) complexes (Scheme 3). The opposite enantiomer 3(S) might be produced via the coordination of the double bond in the non-chelating complex 8′ that originates from alternative mode of the addition of dihydrogen via 4′ and 5′. It is evident from the computational data that 8·MeOH and 8′·MeOH can interconvert via the consequence of reversible steps with low activation barriers, hence either of them is accessible kinetically. But if in the case of 8·MeOH the substitution of the methanol molecule with the double bond takes place in the non-hindered quadrant, the same process in 8′·MeOH would require significant intramolecular movements in the hindered quadrant (Scheme 3). Fig. 4 displays a scan of the relative energies along the pathway approaching the tetra-substituted carbon atom of the double bond towards Rh in 8·MeOH and 8′·MeOH. In the case of 8 the scan proceeds via a single maximum at approximately 3 Å and results in the dihydride intermediate 9·MeOH. On the other hand, in the case of 8′ the maximum reached only at 2.5 Å has unreasonably high energy. The minimum reached upon further approach of the double bond has the
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double bond oriented coplanar to the Rh–H axial bond (transto the oxygen atom), and is therefore unlikely to undergo migratory insertion. Hence the practically perfect R-enantioselection in the asymmetric hydrogenation of MAC catalysed by Rh(1S,1S′,2R,2R′)-TangPHOS complex can be explained by the effective blockade of the S-enantioselective pathway on the stage of the double bond coordination in octahedral Rh(III) complex. Due to the steric hindrance created by the But group in the hindered quadrant, the substitution of the solvent molecule by the double bond becomes practically impossible. Therefore, the proper configuration for the occurrence of the migratory insertion can be only achieved for the R-enantioselective pathway. Noteworthy, this mechanism of enantioselection explains well the absence of the temperature effect on the optical yield. Indeed, in the case when the ee is determined by the difference in the free energies of the diastereomeric transition states, significant dependence of the optical yields on the temperature is usually observed due to the natural temperature variation of the rate constants. On the other hand, the structure of the catalyst implying facile transformation of 8·MeOH to 9·MeOH and impossibility of similar transformation in the case of 8′·MeOH, remains the same at any temperature. Hence, the almost perfect enantioselectivity can be observed either in catalytic or low-temperature stoichiometric reaction.
Conclusions Experimental NMR studies and DFT computations showed that highly enantioselective hydrogenation of MAC with RhTangPHOS complex follows the dihydride pathway. The enantioselection occurs via blockage of the S-enantioselective pathway on the stage of the double bond coordination in the octahedral Rh(III) non-chelating complex.
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Experimental section
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Instrumentation NMR experiments were carried out on JEOL ESX 400, Bruker Avance 500, Jeol ESX 600 and Bruker Avance 700 spectrometers. Computations were performed on Tsubame-2 Supercomputer of the Tokyo Institute of Technology. Materials Methanol-d4 of the grade “100%” (99.6% D) packed in sealed ampules was purchased from Cambridge Isotope Laboratories, Inc. Hydrogen of 99.9999% (Tanuma Sanso) was used for the mechanistic studies. Computational details All computations were carried out using the hybrid Becke functional (B3)9 for electron exchange and the correlation functional of Lee, Yang and Parr (LYP),10 as implemented in the GAUSSIAN 09 software package.11 For rhodium the SDD basis set with the associated effective core potential was employed.12 All other atoms were modeled at the 6-31G+(2d,2p) level of theory.13 The following additional diffuse function was applied for the phosphorus atom: P 0 D 1 1.0 0.55 0.100D+01 Geometry optimizations were performed with the account of the solvent effects (CPCM, methanol) without applying any geometry constraints (C1 symmetry). Starting geometries for the transition state search were located either by QST2 or QST3 procedures, or by the guess based on the structure of the previously found TS. The transition states were subsequently fully optimized as saddle points of first order, employing the Berny algorithm.14 Frequency calculations were carried out to confirm the nature of the stationary points, yielding zero imaginary frequencies for all Rh complexes and one imaginary frequency for all transition states, which represented the vector for the appropriate bond formation.
Acknowledgements This work was supported in part by Campus Asia Project of Tohoku University. The authors are grateful to Prof. Takao Ikaria (Tokyo Institute of Technology) for his kind help with the supercomputing facilities.
Notes and references 1 Recent review: P. Etayo and A. Vidal-Ferran, Chem. Soc. Rev., 2013, 42, 728–754 and references therein.
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