Continuous Flow Aminolysis of RAFT Polymers Using Multistep Processing and Inline Analysis

The reversible addition-fragmentation chain transfer (RAFT) method enables the synthesis of polymers with well-defined architecture and narrow molar mass distribution. Simple postpolymerization reactions using amines and Michael acceptors make it possible to conjugate RAFT polymers to a variety of active small molecules and macromolecules. Herein we demonstrate an efficient continuous flow process for aminolysis of RAFT polymers and subsequent Michael addition reactions, using continuous flow reactors, resulting in either thiol- or thioether-terminated polymer chains. After initial reaction optimization we managed to achieve the following: (1) establishment of an integrated flow process, which is capable of producing free thiol containing polymer without the formation of disulfide byproduct; this was achieved by means of an inline, amine scavenging process post-aminolysis using a polymer supported column; (2) the application of UV spectroscopy for inline monitoring of the continuous flow aminolysis reaction; (3) establishment of a simple two-step flow process for the polymerization and subsequent end-group removal by aminolysis; this was achieved by using two continuous reactor units in series in which the residual monomer from the polymerization acted as the Michael acceptor to cap the thiol after aminolysis.