Discovery and Synthesis of Novel, Porous Organic Cages via Dynamic Imine Chemistry in Continuous Flow

In recent years, Porous Organic Cages (POCs) have gained widespread research interest owing to the well-defined porosity and solution dispersity, which have given rise to various applications, such as molecular encapsulation and catalysis. A common synthetic strategy for POCs, Dynamic Covalent Chemistry (DCvC) exploits the reversibility of certain covalent reactions and allows for facile discovery and synthesis of well-defined macromolecules through error-correction mechanisms. Thermodynamic effects of DCvC systems have been widely studied via structure-focused strategies along with empirical methods. More recently, researchers have begun to incorporate kinetic factors in DCvC systems to discover and synthesise new macromolecular structures. However, thermodynamic and kinetic effects are often studied in isolated contexts. The combination of both thermodynamic and kinetic effects, which define energy landscapes of DCvC systems, has been scarcely investigated. As a result, there is a lack of sustainable methods to navigate the energy landscapes of DCvC reactions in general. Addressing the issue will allow for fine tuning of product distribution in a DCvC system, which will in turn promote our understanding of the corresponding DCvC system through exploring new reaction pathways. This thesis demonstrates the possibility of using continuous flow chemistry as a sustainable method to navigate energy landscapes of DCvC reactions. A trialdehyde building block with alternating “up-down” substitution pattern was designed to guide the dynamic assembly pathways to potentially form [2+3] and [4+6] imine cages with commercially available diamine building blocks. Structures of all monomers and their corresponding molecular cages were modelled and optimised at their local minima with ab initio methods. Then, syntheses in both batch and continuous flow conditions were carried out. The product distributions were characterised by Gel Permeation Chromatography (GPC) and 1H Nuclear Magnetic Resonance (1H NMR). The results revealed that in continuous flow, the imine condensation reaction quickly reaches equilibrium, but imine exchange keeps taking place rapidly. Both retention time and temperature can systematically affect product distribution.