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

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


Englezou, G. - Presenter, University of Sheffield
Kortsen, K., University of Nottingham
Pacheco, A. A. C., University of Nottingham
Cavanagh, R., University of Nottingham
Lentz, J. C., University of Nottingham
Krumins, E., University of Nottingham
Sanders-Velez, C., University of Nottingham
Howdle, S. M., University of Nottingham
Nedoma, A., The University of Sheffield
Taresco, V., University of Nottingham
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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