Controlled single polymer chain cyclization of fully synthetic macromolecules was investigated by using oxidative dynamic covalent bonds. In order to access new analytic tools and reveal the degree of structural control, cyclic polymers were transformed into cyclic brush macromolecules to enable direct molecular visualization by AFM analysis. The global synthetic concept was primarily established with intermediate molecular weight macromolecules and was subsequently transferred to high molecular weight polymer chains with related difficulties. First, single polymer chain folding was investigated by using positional diselenide bridge to trigger single chain compaction. Controlled radical copolymerization of styrene derivatives with precisely injected amounts of N-substituted maleimides bearing protected selenol pendent functions was used to prepare macromolecules, with moderate molecular weight (DPn = 50) and positioned selenol moieties. The oxidation of selenol groups into the diselenide bridge was exploited to induce controlled intramolecular crosslinking and generate chain cyclization. The ring-closure reaction was successfully characterized by SEC analysis, 1H and 2D NMR spectroscopies. To gain insight into the degree of structural control, a synthetic route consisting in the transformation of the cyclic polymers into cyclic molecular brushes was developed and allowed direct visualization and conformation analysis by AFM. The «grafting from» synthetic approach was initially targeted for the preparation of cyclic brush macromolecules. However, unexpected side reactions of the diselenide moieties got evident as those could not tolerate ATRP process. This was more closely analysed by carefully control reactions, using low molecular weight compounds. The outcome of such study required a modification of the brush synthesis strategy. A synthetic route toward cyclic brush polymers was established by using the «grafting onto» approach by exploiting triazolinedione (TAD) −diene cycloaddition to graft side chain polymers onto the styrenic polymer backbone. Cyclic molecular brushes with different side chains grafting densities were synthesized and AFM characterization was used to investigate the brush polymer morphologies. Round-shape nano-objects could be successfully observed and confirm the obtention of controlled cyclic topology. Nevertheless, the incompatibility of the diselenide formation which only tolerates grafting onto methods requiring intense purification, and the small size of cyclic nano-objects, remained an evident bottleneck toward AFM characterization with high resolution. Thus, a second study was investigated on larger synthetic polymers via positional disulfide bridge to induce single chain collapse. While diselenide bond appeared to be incompatible with ATRP process, disulfide group remained inherent to radical
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approach toward the preparation of brush macromolecules, which is a more straightforward method for subsequent AFM characterizations. Similarly, sequence-controlled polymer exhibiting thiol pendent function at specific positions among the polymer chains was successfully prepared. Thiol oxidation into disulfide bond was then investigated to induce single chain folding. While Ellman’s tests qualitatively indicated the substantial consumption of free thiol moieties, the SEC chromatograms could not give conclusive evidence of reduction in hydrodynamic volume that would be indicative of intramolecular cyclization. The potentially cyclic polymers were transformed into brush polymers via the «grafting from»
approach to allow AFM microscopy characterization. The brushes could be visualized in molecular resolution confirming a clean multi-step synthesis. Interestingly, only a small number of cyclic polymers were evidenced. Two different hypothesis were investigated. On one hand, going to larger molecular weight could increase statistically the risk that under the given conditions for sequence-controlled polymerizations, the degree of sequence control decreases and not all polymer chains might contain two thiol moieties at requested positions.
Thus, a first investigation based on the insertion of more equivalents of thiol fragments during the sequence-controlled polymerization was performed, to ensure the incorporation of thiol moieties at desired positions. The multi-step synthesis was then similarly reproduced but AFM characterization indicated only a slight improvement of cyclic polymer statistic. On the other hand, the thiol-thiol coupling reaction in high molecular weight polymer chains was evidently slower than expected and could be responsible of the obtained low yield of cyclic polymers.
Hence, time reaction of the crosslinking step was increased and indicated a clear improvement in the obtention of cyclic macromolecules. Moreover, it appeared that the solvent had a considerable effect on the reaction kinetic. While the linear polymer precursor was swelling and potentially immobilized in dimethylformamide, methanol enabled better diffusion of the thiol groups and a larger fraction of disulfide bridge could be formed. However, intermolecular disulfide bridges were essentially formed, instead of intramolecular disulfide bridges, resulting in the formation of chain dimers. Such investigations evidenced an unexpected bottleneck that could arise from the slow reaction rate of thiol oxidation into disulfide bridge and leading to the formation of competing intermolecular disulfide bridges for kinetic reasons. Nevertheless, the project was rather successful, as significant progress in understanding of both sequence-controlled polymerization for large macromolecules synthesis and crucial parameters impacting on the reactivity of high molecular weight entities have been made.
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5. OUTLOOK
With the final aim of fabricating macromolecules exhibiting as advanced functions as natural polymers, gaining insights into the formation and morphological characteristics of simplified folded synthetic systems are crucial steps to move forward. Cyclic polymers are the simplest class of folded macromolecules and should be considered as a first attempt to improve understanding for the production of advanced materials. In this study, a cyclic folded system, induced by the formation of one single positional intramolecular crosslink was targeted. This cyclic polymer was used to further gain in understanding in the developed synthetic approach, as well as into oxidative macromolecular folding and morphology characterization. While controlled single chain compaction with intermediate molecular weight macromolecules was successfully promoted, the attempts conducted with larger macromolecules illustrated that the folding process becomes more challenging as the molecular weight increases. The more distance between the reactive entities, the more intramolecular bond formation efficiency is compromised. It is reasonable to assume that such issue could be overcome in further investigations, by inducing a pre-organization of the linear macromolecules to force the reactive entities to be at required proximity, and form subsequently the desired intramolecular crosslinks. For example, the insertion of H-bond motifs within the polymer chain could be a potential alternative to pre-organize compaction prior to form intramolecular disulfide or diselenide bridges. Although this study primarily focused on the insertion of one single intramolecular crosslink for proof-of-concept, it is believed that such synthetic strategy could allow the controlled insertion of additional oxidative intramolecular bridges within the polymer chain, and lead to the elaboration and characterization of advanced and dynamic macromolecular structures.
Although the simplest folded macromolecular structure was targeted in this study, cyclic polymers are known to exhibit already considerable difference in macroscopic properties compared to their linear analogues. Furthermore, cyclic polymers are interesting candidates for the elaboration of advanced crosslinked network.272 Indeed, gels based on cyclic polymers often display good tensile strength and a large swelling capacity compared to the gels obtained from cross-linking linear polymers.272,273 The cyclic polymers obtained in this study could be potential candidates for the fabrication of novel cyclic gels, with possible subsequent photo-responsive degradation due to the presence of dynamic covalent bonds.274
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