An Amino-trans-Dihydrido Cobalt(III) Catalyst for Asymmetric Hydrogenation Reactions

The development and fundamental chemistry of an amino-trans-dihydrido Co(III) catalyst for asymmetric hydrogenation (AH) reactions are described in this work. With an enantiopure tetradentate (S,S)-amino-ene(amido)diphosphine ligand defining the equatorial plane, axial trans-dihydrido coordination donors are incorporated into a cobalt(III) center with an octahedral coordination geometry. This cobalt complex serves as a novel amino-trans-dihydrido cobalt(III) catalyst (C1) for AH of ketones and esters. The introduction of these dihydrido ligands to C1 occurs in the precatalyst activation process, which involved substituting the bidentate acetylacetonato (acac) ligand in the amino-ene(amido)diphosphine Co(III) acac precatalyst (PC1) with trans-located dihydride ligands derived from dihydrogen gas. The molecular structure of C1 was characterized using ¹H and ³¹P{¹H} nuclear magnetic resonance (NMR) spectroscopy, and a comparative analysis of calculated ³¹P NMR chemical shifts versus the experimental values was conducted to further confirm the molecular structure of C1. C1 exhibited an unexpectedly high turnover frequency (TOF) of up to 9.9 s^-1 and an enantiomeric excess (e.e.) of up to 99% in the AH of a wide range of ketone substrates under mild conditions. This efficiency, particularly for diaryl ketone substrates, was 66-90 times greater than those achieved with precious metal (ruthenium and iridium) catalysts and 8 503 times greater than those reported for cobalt catalysts chelated with other chiral ligands. The practical synthetic application of this cobalt catalyst was demonstrated through the synthesis of (R)-inabenfide, a plant growth regulator, with 95% e.e., at the 50 g scale. Kinetic studies determined that the H₂ activation by a cobalt catalyst was the turnover-limiting step. For reactions conducted in toluene at 303 K, with [C1] = (0.36-1.52) × 10^-4 M, [ketone] = (0.95-1.89) M, and H₂ pressure = 50-70 bar, the rate law was rate = k[C1][H₂], with k = (0.74-3.84) × 10⁵ M^-1 h^-1, ΔH^⧧ = 7.8 kcal mol^-1, and ΔS^⧧ = -35.9 cal mol^-1 K^-1. Density functional theory (DFT) calculations revealed that the enantio-determining step of the ketone reduction by C1 has a minimum energy barrier of 7.0 kcal mol^-1. Analysis of the catalyst structure and performance revealed that the trans-located hydride ligand at C1 activates the catalyst for the hydrogenation of ketone substrates, while the NH functionality enables an outer-sphere H₂ heterolytic splitting pathway that proceeds through a low-energy barrier. This active catalyst also catalyzed the hydrogenation of more challenging esters under mild conditions.