DFT Mechanistic Study of RuII-Catalyzed Amide Synthesis from Alcohol and Nitrile Unveils a Different Mechanism for Borrowing Hydrogen

Using Ru-II complex as a mediator, Hong and coworkers recently developed a redox-neutral synthetic strategy to produce amide from primary alcohol and nitrile with complete atom economy. Intrigued by the novel strategy, we performed DFT computations to unravel the catalytic mechanism of the system. The transformation is catalyzed by (RuH2)-H-II(CO)(PPh3)((IPr)-Pr-i) ((IPr)-Pr-i = 1,2-diisopropylimidazol-2-ylidene) via four stages including nitrile reduction, alcohol dehydrogenation, C-N coupling, and amide production. Generally, alcohol dehydrogenation in dehydrogenative coupling (DHC) or borrowing hydrogen methodology (BHM) takes place separately, transferring the H-alpha and hydroxyl H-OH atoms of alcohol to the catalyst to form the catalyst-H-2 hydride. Differently, the alcohol dehydrogenation in the present system couples with nitrile hydrogenation; alcohol plays a reductant role to aid nitrile reduction by transferring its H-OH to nitrile N atom directly and H-alpha to the catalyst and meanwhile becomes partially oxidized. In our proposed preferred mechanism-B, the Ru-II state of the catalyst is retained in the whole catalytic cycle. Mechanism-A, postulated by experimentalists, involves Ru-II -> Ru-0 -> Ru-II oxidation state alternation, and the Ru-0 intermediate is used to dehydrogenate alcohol separately via oxidative addition, followed by beta-hydride elimination. As a result, mechanism-B is energetically more favorable than mechanism-A. In mechanism-B, the (N-)H atom of the amide bond exclusively originates from the hydroxyl H-OH of alcohol. In comparison, the (N-)H atom in mechanism-A stems from either H-OH or H-alpha of alcohol. The way of borrowing hydrogen that is used by nitrile is via participating in alcohol dehydrogenation, which is different from that in the conventional DHC/BHM reactions and may help expand the strategy and develop new routes for utilizing DHC and BHM strategies.