Theoretical Study On Several Asymmetry Addition Reactions Catalyzed By The Cinchona Alkaloid Catalyst

Recently, the organocatalysts have been developed with high efficiency and highselectivity. Among them, the asymmetry reactions catalyzed by the cinchona alkaloidcatalyst play an important role in organocatalysis chemistry. In this paper, the reactionmechanisms of several asymmetry addition reactions catalyzed by cinchona alkaloidcatalyst have been investigated using density functional theory and ab initiocalculations. The investigation on the activation of different organocatalysts couldfacilitate understanding of catalytic reaction mechanism, some important informationsuch as geometries and energies of the reactant, intermediates, transition states andproducts are obtained. On the basis of the relation of the reactant, intermediates,transition states and products, the possible reaction channels as well as theenantioselectivity also were provided. All the results obtained in this paper can shedsome light on the future experimental investigations of these kinds of reactions. Themain results are summarized as follows:1. Asymmetric Michael addition of trans-1-nitro-2-phenylethylene to2-methylpropionaldehyde catalyzed by a Cinchona Alkaloid Derived Primary Amine.At present，using cinchona alkaloid-derived primary amine as catalyst and benzoicacid as co-catalyst, Michael-type addition reactions between enolizable carbonylcompounds and nitroalkenes have been extensively studied, however, ourunderstanding of the mechanism is far from complete. A theoretical study is presentedfor the Michael addition reaction between trans-1-nitro-2-phenylethylene and2-methylpropionaldehyde catalyzed by9-epi-QDA and benzoic acid. By performingDFT and ab initio calculations, we have identified a detailed mechanism. Thecalculations indicated that four continuous steps are involved in the overall reaction:1)the formation of an iminium intermediate,2) an addition reaction between theiminium and trans-1-nitro-2-phenylethylene,3) the proton transfer process, and4)hydrolysis and regeneration of the catalyst. The rate determining step is the proton transfer from the amine group to β-carbon of trans-1-nitro-2-phenylethylene, and theenantioselectivity is also controlled by this step. The calculated results provide ageneral model that explains the mechanism and enantioselectivity of the title reaction.2. Theoretical Study on Mechanism of Cinchona alkaloids catalyzed asymmetricconjugate addition of dimethyl malonate to β-nitrostyrene. The mechanism andenantioselectivity of the asymmetric conjugate addition of dimethyl malonate toβ-nitrostyrene catalyzed by cinchona alkaloid QD-4as organic catalyst areinvestigated using DFT and ab initio methods. Six different reaction pathways,corresponding to the different approach modes of β-nitrostyrene to dimethyl malonateare considered. Calculations indicate that the reaction process through a dualactivation mechanism, in which the tertiary amine of cinchona alkaloid QD-4firstworks as a Br nsted base to promote the activation of the dimethyl malonate bydeprotonation, and then the hydroxyl group of QD-4acts as Br nsted acid to activatethe β-nitrostyrene. The rate determining step is the proton transfer process from thetertiary amine of QD-4to α-carbon of β-nitrostyrene. The comparison of themechanisms and energies of the six reaction channels enable us to learn the fact thatQD-4has good catalytic activities for the system, and implies C9-OH in QD-4maynot be involved in the activation. These calculation results accounts well for theobservations in experiments.3. The conjugate addition of1-bromonitromethane to benzylidene acetonecatalyzed by9-amino-9-deoxyepiquinine. Asymmetric conjugate addition of1-bromonitromethane to benzylidene acetone catalyzed by9-amino-9-deoxyepiquinine as organic catalyst and benzoic acid as co-catalyst has beenextensively studied. However, in-depth understanding of the detailed mechanism is farfrom complete. By performing density functional theory (B3LYP and M062X) and abinitio calculations (MP2), we have identified a detailed mechanism of the title reaction.The reaction process includes three major stages:(I) the formation of an iminium ionintermediate;(II) the nucleophilic addition between the iminium and1-bromonitromethane; and (III) hydrolysis and recovery of catalyst. The calculatedresults not only explain benzoic acid as acidic additive plays an important role in the formation of the key reaction iminium intermediate, but also provide a general modelto help explain the mechanism and enantioselectivity of the conjugate additionreaction.