(649i) 2-Methyltetrahydrofuran (2-MeTHF) As a Versatile Green Solvent for the Synthesis of Amphiphilic Copolymers Via ROP, FRP and RAFT Tandem Polymerizations.

Introduction: The widespread adoption of bio-sourced polymer feedstocks has led to scale-up challenges in the sourcing of equally green solvent, initiators, and catalysts. Petrochemical solvents such as dichloromethane (DCM) and tetrahydrofuran (THF) are generally chosen for a variety of polymerization processes because they are relatively inexpensive. These conventional solvents dissolve a wide range of monomer precursors and the resulting polymer products, making them ideal solvents for homogeneous polymerizations; however, they pose environmental and health risks [1]. Economic pressure to use greener solvents in the chemistry sector is driving the substitution of petrochemicals with those produced from renewable bio-based feedstocks [2], [3]. 2-methyltetrahydrofuran (2-MeTHF) has been proposed as a suitable biologically produced alternative to petrochemical solvents.

2-MeTHF is a volatile cyclic ether generated by the chemo-catalytic treatment of biomass and has been touted as the most successful neoteric bio-based solvent [4], [5]. The cost is comparable to that of similar petrochemical solvents and the Hildebrand solubility parameter is within 20% of the values for THF and DCM, suggesting similar solvency [6]. This work examines the suitability of 2-MeTHF for a range of polymerization reactions, including nucleophilic ring-opening polymerization (ROP), reversible addition-fragmentation chain-transfer (RAFT), and free-radical polymerization (FRP). Similarly, a range of bio-sourced or biodegradable monomers were selected along with two different low-temperature, metal-free catalysts and four different initiators.

Methods and Materials: Ten amphiphilic block (co)polymers were synthesized, as detailed in Table 1.

Table 1: Synopsis of the block (co)polymers synthesized

Linear (co)polymers: Hydrophilic methyl-polyethylene glycol 5000 Da (mPEG) was used as the macroinitiator for ROP synthesis of linear block (co)polymers using either lactide (LA) catalysed by DBU or ε-caprolactone (ε-CL) catalysed by Nomozym 435 as the second block. One of the synthesized mPEG-CL₅₀ diblock (co)polymers was further extended to a linear triblock (co)polymer via the addition of LA monomer catalysed by DBU. The linear block (co)polymers synthesis schematic is represented in Figure 1.

Figure 1: Reaction schematic for the synthesis of the linear block (co)polymers.

Branched block (co)polymers: The constructed linear block (co)polymers of polyethylene glycol methacrylate 300 Da and lactide (PEGMA-LA) and hydroxyethyl methacrylate and lactide (HEMA-LA) were initiated by the radical initiator azobisisobutyronitrile (AIBN). The RAFT reactions were conducted in the presence of a RAFT agent, 4-Cyano-4-(phenylcarbonothioylthio) pentanoic acid (CPAB). The radical polymerizations resulted in grafted block (co)polymers. The branched block (co)polymers synthesis schematic is represented in Figure 2.

Figure 2: Reaction schematic for the synthesis of the grafted block (co)polymers.

Nanoprecipitation: Both linear and grafted block (co)polymer architectures enabled the resulting polymers to self-assemble into nanostructures in aqueous environments. The polymers were purified and nanoprecipitated to investigate their self-assembling behaviour into nanoparticles (NPs). Finally, the formulated nanoparticles were tested for their cytocompatibility in three model cell lines to evaluate their future use as drug delivery carrier-systems.

Results and conclusions: We have demonstrated that 2-MeTHF is effective as a reaction solvent for lactide, caprolactone, block (co)polymers, macroinitiators, and hybrid methacrylate-ester macro-initiators in ROP, eROP, FRP, and RAFT polymerizations as both a single process and in tandem. The use of 2-MeTHF also allowed for a sequential one-pot ROP of ε-CL and LA, crucial to producing a material with tunable biodegradability, and circumventing the limitations of DBU and lipase in the ROP of lactones and lactide respectively.

Labile-ester ROP initiators HEMA and PEGMA were used to initiate LA macromonomers. For both methacrylate initiators, no transesterification occurred in the reaction time frame and a quantitative conversion of monomer into polymer was observed. To further demonstrate the versatility of 2-MeTHF as “multipolymerization” green solvent the produced macromonomers were tested in FRP and RAFT tandem polymerization. Keeping the reaction temperature at 65 ^oC as for the ROP stage, both FRP and RAFT model reactions yielded grafted amphiphilic biodegradable hybrid-polymers. Due to the temperature requirements for many radical processes to allow for adequate radical initiation, the use of 2-MeTHF clearly showed the potential to conduct a wider range of polymerizations compared to solvent free conditions.

We confirmed the ability of all the amphiphilic materials produced, linear block and hybrid-grafted (co)polymers, to self-assemble into NPs without the use of any stabilizer. Moreover, in vitro toxicity testing demonstrated that the produced polymers in nanoparticle formulation are non-toxic and appropriate vehicles for future investigation in oral, inhalation and systemic drug delivery studies.

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