Understanding the influence of hydrogen pressure on the enantioselectivity of hydrogenation: A combined theory-experiment approach

Abstract

Why would the pressure of hydrogen affect the enantioselectivity of hydrogenation in an opposite way for two enamide reactants, M-acrylate (methyl 2-acetamidoacrylate) and E-emap (ethyl 4-methyl-3-acetamido-2-pentanoate), with rhodium (I) complexes coordinated to a diphosphine ligand? This question was answered by a combination of experiments and DFT calculations. The activation free energies, the kinetic constants and the enantiomeric excess ee have been calculated. In the static pathways, the two substrates show significant differences. From the square-planar substrate-metal complex, M-acrylate (resp. E-emap) prefers the attack of the hydrogen on the side opposite to (resp. of) the amide group. Both substrates however show lower transition states on the pathway starting from the minor stereoisomer of the substrate-metal complex. The turnover-limiting step for M-acrylate is the oxidative addition of hydrogen on the substrate-metal complex, while it is the migratory insertion of the substrate in the Rh-H bond for E-emap. However, the energy profiles are not sufficient to understand the enantioselectivity of the reaction: the kinetic simulations lead to different conclusions and show a marked influence of the hydrogen pressure. For both substrates, the R isomer is obtained in the realistic pressure range, coming from the minor isomer for M-acrylate and from the major isomer for E-emap. Hence, depending on the reactant, the preferred pathway follows either the major/minor or the lock-and-key concept. The importance of combining DFT calculations with kinetic simulations in unraveling the mechanism is underlined. In particular, they reveal that the rate of formation of the metal-substrate complex plays a key role for the enantioselectivity.