Macro-RAFT Synthesis by Single Unit Monomer Insertion (SUMI) into Dithiobenzoate RAFT Agents – Towards Biological Precision

Achieving well defined control over the monomer sequence in polymers, as e.g. biopolymers do in nature, remains a long standing challenge in polymer chemistry. Sequence control by single unit monomer insertion (SUMI), ‘one at a time’, into dithiobenzoate RAFT agents has been explored. Critical factors for success are a high chain transfer constant for the RAFT agent and addition of the radical (R^.) to monomer should be fast relative to further propagation. Macro-RAFT [(CH₃)₃C(CN)-(M)-SC(=S)-phenyl] synthesis by SUMI of styrene and N-isopropylacrylamide (NIPAm) into 2-cyano-2-propyl dithiobenzoate was successful. However, attempted SUMI of maleic anhydride (MAH) gave low yield consistent with the low reactivity of MAH towards 2-cyano-2-propyl radicals. Insertion of methyl methacrylate (MMA) provided an oligomeric insertion product due to the low transfer constant of the dithiobenzoate in MMA polymerization. Kinetic aspects for the synthesis of macro-RAFT agents by SUMI were investigated with real time ¹H-NMR experiments and byproducts were identified. Next, A step towards the controlled synthesis of macro-RAFT [(CH₃)₃C(CN)-(M₁)-(M₂)-SC(=S)-phenyl] was taken. The insertion of MAH, styrene and NIPAm into the styrene SUMI product has been investigated. Insertion of MAH into the macro-RAFT was fast, however, reactions with styrene and NIPAm were slow attributed both to the low concentration of monomer used to favor SUMI and the poor leaving group ability of the propagating species compared to the 2-cyano-2-propyl radical. This study demonstrates the potential of RAFT for the synthesis of a new generation of synthetic polymers.