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. 2022 May 20;12(10):5961-5969.
doi: 10.1021/acscatal.2c00231. Epub 2022 May 5.

Kinetic and Thermodynamic Considerations in the Rh-Catalyzed Enantioselective Hydrogenation of 2-Pyridyl-Substituted Alkenes

Wei Hao  1 , Candice L Joe  2 , Andrea Darù  1 , Sloan Ayers  2 , Antonio Ramirez  2 , Bhupinder Sandhu  2 , Ryan A Daley  1 , Jason S Chen  3 , Michael A Schmidt  2 , Donna G Blackmond  1
Affiliations

Kinetic and Thermodynamic Considerations in the Rh-Catalyzed Enantioselective Hydrogenation of 2-Pyridyl-Substituted Alkenes

Wei Hao et al. ACS Catal. .

Abstract

The mechanism of asymmetric hydrogenation of 2-pyridyl alkenes catalyzed by chiral Rh-phosphine complexes at ambient temperature is examined using kinetic, spectroscopic, and computational tools. The reaction proceeds with reversible substrate binding followed by rate-determining addition of hydrogen. Substrate binding occurs only through the pyridine nitrogen in contrast to other substrate classes exhibiting stronger substrate direction. The lack of influence of hydrogen pressure on the product enantiomeric excess suggests that a pre-equilibrium in substrate binding is maintained across the pressure range investigated. An off-cycle Rh-hydride species is implicated in the mild catalyst deactivation observed. In contrast to Ru-phosphine-catalyzed reactions of the same substrate class, the stereochemical outcome in this system correlates generally with the relative stability of the E and Z rotamers of the substrate.

Keywords: asymmetric hydrogenation; kinetics; reaction progress kinetic analysis; transition metal catalysis; trisubstituted olefins.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Effect of hydrogen pressure and catalyst loading on the reaction rate, final yield, and enantiomeric excess in the reaction of substrate 1a using Rh(cod)2BF4/L1 at 25 °C. All reactions employed 0.2 M 1a except the run at 250 psi, which used 0.1 mM. [Rh] = 1 mM except where noted.
Figure 2.
Figure 2.
Reaction progress kinetics with VTNA for the reaction in Scheme 1 using 1a at ambient temperature. Top: H2 as noted in legend, [Rh] = 0.001 M, [1a]0 = 0.2 M; middle: [1a]0 as noted in legend, [Rh] = 0.001 M, H2 = 25 psi; bottom: [Rh] as noted in legend, [1a]0 = 0.2 M, H2 = 25 psi.
Figure 3.
Figure 3.
General comparison of power law kinetics to the Michaelis–Menten rate expression giving a correlation between order, x = 0.75, and substrate binding constant, Keq = 3.3 M−1, over the concentration range of the experiments in Figure 2.
Figure 4.
Figure 4.
Separate and competitive reaction of 0.2 M substrates 1d and 1k in the reaction of Scheme 1 using 0.001 M Rh with ligand L1 and 10 psi H2. Competitive reaction data taken after 10 min reaction time.
Figure 5.
Figure 5.
Time-adjusted reaction progress kinetics for the reaction in Scheme 1 using 1a and Rh-L1 at ambient temperature with [1a]0 and [2a]0 as noted in the legend. [Rh] = 0.001 M, H2 = 25 psi. Lack of overlay in the time-shifted curve blue, along with the overlay between the blue curve and the open circle points, implicates catalyst deactivation rather than product inhibition.
Figure 6.
Figure 6.
31P NMR studies of Rh-L1 under hydrogen in the absence (bottom spectrum) and presence (top spectrum) of 1d.
Figure 7.
Figure 7.
Computational equilibrium constant for relative stability of the E and Z conformers of substrates 1 vs the experimental ratios for products 2 [S]/[R]. Structures are shown for E-1e and E-1k, which follow the trend, and for E-1g and E-1h, which give identical experimental ee values but very different computed stabilities outside the trend. Calculations by three different functionals as noted in the legend. Shaded area shows ca. ±0.5 kcal/mol from the trend.
Scheme 1.
Scheme 1.
Asymmetric Hydrogenation of 2-Pyridyl-Substituted Olefins
Scheme 2.
Scheme 2.
Ligand Screening for the Reaction of Scheme 1
Scheme 3.
Scheme 3.
Substrate Variation Effects of Scheme 1 Run at 25 psi, 0.2 M Substrate, 0.5 mol % Rh-L1 for 1 h
Scheme 4.
Scheme 4.
Rh-L1-H Hydride Complex Characterized by 1H, 13C, and 31P NMR Spectroscopy
Scheme 5.
Scheme 5.
Calculated Structures of Substrate Rotamers Bound to Rh-L1 with Pyrroline Double Bond Positioned in Optimal Proximity to Rh for Hydrogenation
Scheme 6.
Scheme 6.
Curtin–Hammett Description of the Role of Equilibrium and Kinetic Constants in Product Enantioselectivity
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