Single chain compaction by intramolecular dynamic crosslinks

Dynamic folded macromolecules can be achieved by using supramolecular bonds or dynamic covalent bonds. Conversely to covalently folded macromolecules, exploiting intramolecular dynamic bonds generates compacted single chain nano-objects that are adaptive

19 to the environment and can respond to an external trigger, such as pH, solvent, light, heat, oxidation or metals. This responsiveness to external stimuli induces reversible transformation of the polymer random coil into a compact nano-object, which is an attractive feature since folding/unfolding of proteins is often directly associated with their functioning. ^134,135

 Supramolecular bond

Within the last decades, supramolecular chemistry has been widely explored to induce single polymer chain folding. Several synthetic methods have been reported for the preparation of single chain compaction by using non-covalent bonds such as hydrogen bond (H-bond), metal ligation,^136-138 host-guest interactions^139,140 and hydrophobic interactions.^4,141 Elegant synthetic approaches have been developed toward the preparation of synthetic folded macromolecules via H-bond interactions by using various motifs such as diamides,¹⁴² BTA bipyridines,¹⁴³ thymine-diaminopyridine,¹⁴⁴ six-point cyanuric acid-Hamilton wedge interactions.¹⁴⁵ Meijer and co-workers have reported an extremely mild method to induce single chain collapse by exploiting protected 2-ureidopyrimidinone (UPy) as H-bond motifs (Figure 4).¹⁴⁶ Controlled Cu-mediated radical polymerization was performed to synthesize alkyne-functionalized methacrylate-based polymers. Azide alkyne-functionalized UPy motives were incorporated on the alkyne methacrylate units by azide-alkyne 1,3-dipolar cycloaddition. The UPy motifs were protected with o-nitro benzyl ether photolabile protecting groups. The photolabile protecting groups were removed by photoirradiation, which triggered the folding process. Subsequently the UPy motifs could dimerize intramolecularly in highly diluted conditions, resulting in the formation of folded macromolecules. In a following work, it has been showed that the chiral hydrogen bond motif benzene- 1,3,5-tricarboxamides (BTAs) can be exploited to induce chain compaction and dimerize intramolecularly into helical stacks.¹⁴⁷

Figure 4. Single polymer chain compaction induced by UV irradiation via supramolecular cross-linking of UPy-motifs (Adapted from reference 146).

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 Dynamic covalent bond

Although supramolecular crosslinking bonds have been widely investigated for the preparation of folded macromolecules, the exploration via dynamic covalent bond has only emerged in the last years. Recently, polymers with intramolecular dynamic crosslinking bonds have become an important research focus due to their ability to reversibly assemble or disassemble in response to external environmental changes.^148,149 For example, the dynamic nature allows the incorporation and release of desired molecules inside the folded macromolecules and therefore, these polymeric materials are widely exploited for drug delivery systems involving the controlled loading and release of drug molecules.¹⁵⁰ Various types of dynamic covalent bonds have been successfully applied to generate intramolecular crosslinking, such as disulfides,¹⁵¹ reversible cycloadditions,¹⁵² acyl hydrazones,^153,154 or enamines.^155,156 Disulfides are a dynamic covalent bond of interest due to their crucial role in protein folding and sensitivity to redox chemistry. Following Nature’s systems, an interesting approach has exploited the formation of several disulfide bridges to induce reversible single-chain collapse.¹⁵⁷ In this work, oxidation of thiol groups by iron chloride (FeCl3) into disulfide bonds led to polymer chain compaction while subsequent reduction of disulfide bonds with dithiothreitol (DTT) resulted in the corresponding thiols and the random coil precursor was regenerated.

 Diselenide bond

Among the several types of dynamic covalent bonds, diselenide bridges have been less exploited in general in polymer science.¹⁵⁸Although organic selenium chemistry has been rising very fast, the introduction of selenium groups in macromolecular chemistry has only emerged recently. The development of selenium-based polymers was underexposed for mainly two reasons.¹⁵⁹ Firstly, the synthesized selenium-containing polymers often demonstrate poor solubility in common organic solvent, thus limiting their uses and applications. Secondly, macromolecules containing selenium group are not, in general, very stable due to the high reactivity of this element. However, for the last decade, diselenide-containing polymers has attracted considerable attention due to the unprecedented characteristic of diselenide bond. The selenium element (Se) is part of the chalcogen group in the periodic table of elements, like sulfur (S) and exhibits similar properties as its analogue. Indeed, selenium and sulfur display similar characteristics, such as electronegativity, atom size and accessible oxidation states. In contrast to the disulfide bond, the diselenide bond has a lower bond energy (Se-Se:

172 kJ.mol^-1) than disulfide bond (S-S: 240 kJ.mol^-1). Due to this inherent feature, the

21 diselenide bond are less stable and consequently more dynamic and responsive in mild conditions.^160,161 Diselenide containing polymers are sensitive to extremely mild external stimuli such as light, reducing agent (phosphine, DTT) or oxidizing agents (H2O2) and this property makes them promising biomaterials for synthetic enzyme mimics and drug delivery.158,159,162 Indeed, dynamic material containing diselenides are already established polymer class in the fields of drug delivery and self-healing materials. Recently, amphiphilic triblock copolymer containing an internal diselenide bond in the main chain could self-assemble into spherical micelles in water.¹⁶³ The self-organized structure showed very mild sensitive redox responsive property and disassembled under treatment of only 0.01% of oxidizing agent. Such unique property endows diselenide-containing polymers as promising candidates for smart drug delivery vehicles, which release the loading drug molecules in response to redox stimuli in the tumor microenvironment.¹⁵⁹ Besides the redox responsiveness, another exceptional feature displayed by diselenide-containing polymers is the responsiveness to light. Diselenide can undergo metathesis reaction under visible light, while disulfide bond undergo metathesis reaction under UV-light, which is more energy consuming and may cause unnecessary damage to the macromolecular system.¹⁵⁹ An elegant study have taken the advantage of the relatively mild diselenide metathesis reaction to fabricate self-healing materials.¹⁶⁴

Interestingly, the use of diselenide chemistry in the field of single chain folding has not been thoroughly explored and is still at his infancy. For instance, some studies have been focused on the preparation of simple topological polymers such as linear block copolymers,¹⁶³ cyclic,¹⁶⁵ and dendritic¹⁶⁶ polymers by exploiting diselenide bonds. Recently, a synthetic strategy based on the use of selenolactone as building block, has been reported for the straightforward and mild synthesis of branched, cyclic, and cross-linked polymers containing several diselenide moieties.¹⁶⁵ Moreover, a study provided an alternative approach to modulate topological transformation of macromolecules, by exploiting multiple diselenide groups in cyclic polymers (Scheme 8).¹⁶⁷ In this work, CRP of styrene was mediated by using a novel bifunctional diselenocarbonate chain transfer reagent, resulting in a linear polystyrene chain with protected selenols at both chain extremities. Then, diselenocarbonate groups were transformed into free selenols by aminolysis, followed by spontaneous oxidation by air of selenols into diselenide bridges. By tuning the concentration of α, ω-telechelic polystyrene for the one pot aminolysis/oxidation reaction, monoblock or multiblock cyclic copolymer linked by one or several diselenide bonds were obtained. Interestingly, the cyclic copolymers could

22 be then converted to each other under UV irradiation by adjusting the concentration. Besides, the reduction or oxidation of diselenide bonds both enable the conversion from cyclic to linear polymers. This work shows a straightforward approach for the preparation of cyclic polymers and evidences the unique stimuli-responsiveness behaviour of diselenide bond, which can be exploited to induce topological transformation under very mild conditions.

Scheme 8. Schematic illustration of the one-pot synthetic approach for the preparation of cyclic polymer by aminolysis of the linear RAFT polymer, the metathesis reaction for shuffling diselenide bonds, and ring-chain opening by hydrogen peroxide (Adapted from reference 167).