Asymmetric Transfer Hydrogenation of Aromatic Ketones : Catalyst Development and Mechanistic Studies

Abstract: This thesis describes the development and evaluation of new chiral Ru(arene)(amino alcohol) catalysts for the transfer hydrogenation of aromatic ketones using isopropanol as the hydrogen source. Two mechanistic studies of the Ru(arene)(amino alcohol) catalyzed transfer hydrogenation of acetophenone were also conducted. The Ru(arene)[(1S,3R,4R)-3.(Hydroxymethyl)-2-azabicyclo[2.2.1]heptane] catalyst was optimized for catalytic asymmetric transfer hydrogenation of aromatic ketones. The effect of substituents on the arene ligand on both selectivity and reactivity was investigated. The performance of the catalyst was also optimized by altering the structure of the chiral amino alcohol ligand. These optimizations resulted in a highly active and selective catalyst, Ru(p-cymene)[(R)-1-[(1S,2R,6S,7R,9R)-4,4-Dimethyl-3,5-dioxa-8-aza-tricyclo[5.2.1.00,0]dec-9-yl]-ethanol], for asymmetric transfer hydrogenation of aromatic ketones. This catalyst was capable of reducing acetophenone in 96% ee in 4 minutes at room temperature at a substrate to catalyst ratio of 200. Full conversion was reached even at a substrate to catalyst ratio of 5000 and the high enantioselectivity of 96% ee was maintained. A range of prochiral aromatic ketones with electron withdrawing or electron donating substituents in any position on the aromatic ring were reduced in short reaction times and with high enantioselectivity, up to 99% ee. Bulky aryl alkyl ketones were also reduced with high enantioselectivity.A combined quantum chemical and kinetic investigation of the Ru(arene)(amino alcohol) catalyzed transfer hydrogenation of acetophenone was conducted. Three possible mechanisms were studied and the quantum chemical calculations indicated that the mechanism was concerted. In addition, a kinetic isotope study for the Ru(arene)(amino alcohol) catalyzed transfer hydrogenation of acetophenone was conducted. The determination of the kinetic isotope effect of the proton and hydride transfer showed that the proton and the hydride transfer were both rate-limiting and occurred in the same step. This result supports the proposed concerted mechanism.