An Amino-<i>trans</i>-Dihydrido Cobalt(III) Catalyst for Asymmetric Hydrogenation Reactions

The development and fundamental chemistry of an amino-<i>trans</i>-dihydrido Co(III) catalyst for asymmetric hydrogenation (AH) reactions are described in this work. With an enantiopure tetradentate (<i>S,S</i>)-amino-ene(amido)diphosphine ligand defining the equatorial plane, axial <i>trans</i>-dihydrido coordination donors are incorporated into a cobalt(III) center with an octahedral coordination geometry. This cobalt complex serves as a novel amino-<i>trans</i>-dihydrido cobalt(III) catalyst (<b>C1</b>) for AH of ketones and esters. The introduction of these dihydrido ligands to <b>C1</b> occurs in the precatalyst activation process, which involved substituting the bidentate acetylacetonato (<i>acac</i>) ligand in the amino-ene(amido)diphosphine Co(III) <i>acac</i> precatalyst (<b>PC1</b>) with <i>trans</i>-located dihydride ligands derived from dihydrogen gas. The molecular structure of <b>C1</b> 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 <b>C1</b>. <b>C1</b> 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 (<i>R</i>)-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 [<b>C1</b>] = (0.36-1.52) × 10^-4 M, [ketone] = (0.95-1.89) M, and H₂ pressure = 50-70 bar, the rate law was rate = <i>k</i>[<b>C1</b>][H₂], with <i>k</i> = (0.74-3.84) × 10⁵ M^-1 h^-1, Δ<i>H</i>^⧧ = 7.8 kcal mol^-1, and Δ<i>S</i>^⧧ = -35.9 cal mol^-1 K^-1. Density functional theory (DFT) calculations revealed that the enantio-determining step of the ketone reduction by <b>C1</b> has a minimum energy barrier of 7.0 kcal mol^-1. Analysis of the catalyst structure and performance revealed that the <i>trans</i>-located hydride ligand at <b>C1</b> 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.