Mechanistic insights into bicyclic guanidine-catalyzed reactions from microscopic and macroscopic perspectives

• Main Author: Xue, Hansong
• Other Authors: Wong Ming Wah
• Format: Theses and Dissertations
• Language: English
• Published: 2015
• Subjects: DRNTU::Science::Chemistry
• Online Access: http://hdl.handle.net/10356/65453
• Institution: Nanyang Technological University

In recent decades, the development and application of chiral bicyclic guanidine-catalyzed enantioselective reactions have grasped much attention. This is because chiral bicyclic guanidine can act as an efficient chiral Broensted base catalyst in enantioselective reactions, delivering good yields with high enantioselectivities. There is also much interest in understanding the detailed mechanisms of these guanidine-catalyzedreactions. The first goal of this work is to examine guanidine-catalyzed phospha-Michael reaction of beta-nitrostyrene and addition reaction of fluorocarbon nucleophiles from both the microscopic and macroscopic perspectives by using a combination of kinetic and computational methods. Although the proposed catalytic cycle for these two reactions are the same, their overall kinetic rate equations are significantly different from each other because of the difference in the rate-determining step in the catalytic cycle. The theoretical rate expression derived from computational results provides kinetic behavior at a microscopic level, while the experimental kinetic result gives insight into kinetic behavior at a macroscopic level. These two support each other in our study of these two reactions as we show here that the theoretical rate expression for each reaction agrees well with the corresponding experimentally observed rate equation. Subsequently we evaluate the bifunctionality of guanidine catalyst in guanidine-catalyzed isomerization reaction of alk-3-ynoate and guanidine-catalyzed asymmetric Strecker reaction of N-benzhydryl imine. In the former reaction, the reaction initiated at a higher alk-3-ynoate concentration follows a bifunctional Broensted-Lewis acid activation mechanism in which the key transition state consists of the coordination of guanidinium ion and two alk-3-ynoates in a side-on manner. However in the second reaction, bifunctional Broensted acid activation is dominated and the key transition state consists of the coordination of guanidinium ion and cyanide and N-benzhydryl imine in a side-on manner. The C-H pi interactions are responsible for its high enantioselectivity and our predicted enantioselectivity is in good accord with the experimentally observed results.