Cu(0)-RDRP of 2-hydroxyethyl methacrylate in a non-polar solvent enables rapid synthesis of high-molecular weight homopolymers and direct access to amphiphilic copolymers
Graphical abstract
Introduction
Poly(2-hydroxyethyl methacrylate) (poly(HEMA)) is an important functional polymer with favorable properties such as biocompatibility and non-toxicity. Since Lím's and Wichterle's early work on poly(HEMA) hydrogels [1], poly(HEMA)-based materials have found numerous applications particularly in the biomedical field [2], including soft contact lenses [3,4], surgical implants [5], tissue engineering scaffolds [6], wound dressings [7], or drug delivery vehicles [8].
The development of reversible-deactivation radical polymerization (RDRP) techniques has allowed the synthesis of well-defined poly(HEMA)-based materials of diverse architectures [9]. Among these techniques, HEMA polymerization in polar solvents through various copper-mediated RDRP protocols (Cu-RDRP) was particularly thoroughly studied. Already in 1999, Matyjaszewski group reported the first successful atom transfer radical polymerization (ATRP) of HEMA in a methyl ethyl ketone (MEK)/1-propanol mixed solvent [10]. However, when high molecular weights (MWs) were targeted, the polymerization was plagued by limited conversion and increased dispersity (Ɖ), which was rectified only by protecting the monomer's hydroxyl function by a trimethylsilyl group. Later, Armes and coworkers prepared well-defined poly(HEMA) via ATRP in methanol or methanol/water mixtures [[11], [12], [13]], and in isopropanol/water mixtures [14]. Further, ATRP of HEMA was performed in ethylene glycol [15] and a MEK/methanol mixture [16]. The latter medium was employed also in activators generated by electron transfer (AGET) ATRP of HEMA [17] while methanol served as a solvent in activators regenerated by electron transfer (ARGET) ATRP of HEMA [18]. Nevertheless, the use of alcoholic solvents in ATRP of HEMA was later found to be problematic as monomer transesterification has been observed under standard ATRP conditions [19]. Finally, a polar aprotic solvent, dimethyl sulfoxide (DMSO), was utilized by Percec and coworkers in the synthesis of ultrahigh-MW poly(HEMA) via metallic copper-mediated RDRP (Cu(0)-RDRP) [20]. Nevertheless, it needs to be stressed that in these previous studies employing polar media only limited conversions were attained [10,[15], [16], [17],20] and/or the polymerization control deteriorated (Ɖ > 1.3) [10,15,16,18,20] when targeting poly(HEMA) of MW higher than several tens of thousands. Therefore, the field currently lacks a reliable method for well-controlled polymerization of HEMA in a broad range of MWs.
Due to the solubility reasons, non-polar solvents were not generally considered for HEMA homopolymerization; these media found use only when copolymerizing HEMA with an excess of a non-polar comonomer that ensured the solubility of the produced copolymer [21]. If this was not feasible, protected HEMA had to be used [22,23], which required an additional deprotection step. A development of an efficient and well-controlled method for direct HEMA homopolymerization and its copolymerization with nonpolar (lipophilic) comonomers via Cu-RDRP would therefore substantially increase the application potential of the monomer.
Cu(0)-RDRP, denoted also as single electron transfer living radical polymerization (SET-LRP) [24,25] or supplemental activators and reducing agents (SARA) ATRP [26] with reference to the proposed polymerization mechanism, is typically conducted in polar solvents, such as DMSO or alcohols [24,27,28], or in aqueous media [[29], [30], [31], [32]]. Nevertheless, in early works by the groups of Percec and Haddleton, Cu(0)-RDRP of methyl acrylate in non-polar solvents (neat or with additives) was also considered [[33], [34], [35]], and this approach was later successfully applied to other non-polar monomers, using toluene as a solvent [[36], [37], [38], [39]]. Additionally, our laboratory has also demonstrated the suitability of the method for the polymerization of a bulky, hydrophobic POSS-methacrylate monomer in benzene [40]. In relevance to the present study, Yuan et al. briefly reported on the preparation of the poly(HEMA) block in an amphiphilic triblock copolymer via Cu(0)-RDRP in toluene [21]. However, to the best of our knowledge, Cu(0)-RDRP and other Cu-RDRP methods have not been previously applied to the direct homopolymerization of unprotected HEMA in a non-polar solvent.
In this study, we investigated the applicability of copper wire-mediated Cu(0)-RDRP, conducted in 1,4-dioxane as a comparatively non-polar solvent, to HEMA (co)polymerization. We show that when chlorine-based initiation/catalytic system is used, unprecedently well-defined polymers can be rapidly obtained up to high MWs. In addition, we demonstrate the utility of the non-polar polymerization medium in the well-controlled copolymerization of HEMA with non-polar monomers, 2-ethylhexyl methacrylate (EHMA) and lauryl methacrylate (LMA), at the equimolar comonomer content.
Section snippets
Materials
α-Chlorophenylacetate (ECPA; Sigma-Aldrich, 97%), α-bromophenylacetate (EBPA; Acros, 97%), methyl α-bromophenylacetate (MBPA; Sigma-Aldrich, 97%), CuCl2 (Sigma-Aldrich, 99%), CuBr2 (Sigma-Aldrich, 98%) were used as received. Cu-wire (Sigma-Aldrich, diameter = 0.64 mm) was activated before each polymerization by conc. HCl using the procedure provided below. N,N,N′,N′′,N′′-Pentamethyldiethylenetriamine (PMDETA; Sigma-Aldrich, 99%) was vacuum distilled and stored under argon at 4 °C.
Optimization of conditions for HEMA homopolymerization
In our investigation, copper wire (5 cm) was conveniently employed as a catalyst source, activated by conc. HCl before each polymerization. Dioxane, used in this study as a reaction medium, is classified as a rather non-polar solvent, yet it is readily miscible with a range of both polar and non-polar compounds [43,44]. Importantly, we confirmed that, despite only limited solubility of poly(HEMA) in dioxane, the polymer prepared under the conditions of this study (monomer/solvent = 1:1 (v/v))
Conclusions
In conclusion, our data show that Cu(0)-RDRP in dioxane using a chlorine-based initiation/catalytic system is a method that is superior to the previous Cu-RDRP protocols applied to HEMA (co)polymerization. With purified HEMA, our method provides a rapid access to well-defined poly(HEMA) in an unprecedently wide range of MWs without the risk of solvent transesterification side-reactions. Additionally, we demonstrated that the developed conditions will be particularly useful for HEMA
CRediT authorship contribution statement
Sachin Gupta: Methodology, Validation, Formal analysis, Investigation, Data curation, Writing – review & editing, Visualization. Vladimír Raus: Conceptualization, Methodology, Writing – original draft, Writing – review & editing, Supervision, Project administration, Funding acquisition.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors thank Dr. Lívia Kanizsová for performing the GC analysis of HEMA monomers and to Ms. Eva Čadová for performing the SEC analysis in THF. Sachin Gupta is a PhD student at Charles University, Prague, Czech Republic.
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