From monomer to micelle: a facile approach to the multi-step synthesis of block copolymers via inline purification

A one-pass continuous flow strategy to form block copolymer nanoaggregates directly from monomers is presented. A key development towards such a sophisticated continuous flow setup is a significant improvement in continuous flow dialysis. Often impurities or solvent residues from polymerizations must be removed before block extensions or nanoaggregate formation can be carried out, typically disrupting the workflow. Hence, inline purification systems are required for fully continuous operation and eventual high throughput operation. An inline dialysis purification system is developed and exemplified for amphiphilic block copolymer synthesis from thermal and photoiniferter reversible addition fragmentation chain transfer (RAFT) polymerization. The inline dialysis system is found to be significantly faster than conventional batch dialysis and the kinetics are found to be very predictable with a diffusion velocity coefficient of 4.1 × 10^-4 s^-1. This is at least 4-5 times faster than conventional dialysis. Moreover, the newly developed setup uses only 57 mL of solvent for purification per gram of polymer, again reducing the required amount by almost an order of magnitude compared to conventional methods. Methyl methacrylate (MMA) or butyl acrylate (BA) was polymerized in a traditional flow reactor as the first block via RAFT polymerization, followed by a 'dialysis loop', which contains a custom-built inline dialysis device. Clearance of residual monomers is monitored via in-line NMR. The purified reaction mixture can then be chain extended in a second reactor stage to obtain block copolymers using poly(ethylene glycol) methyl ether acrylate (PEGMEA) as the second monomer. In the last step, nano-objects are created, again from flow processes. The process is highly tuneable, showing for the chosen model system a variation in nanoaggregate size from 34 nm to 188 nm.