Next generation of folded single polymer chains

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).

2.3.3. Next generation of folded single polymer chains

Currently, a large chemical toolbox for intramolecular crosslink formations has been developed.⁴ However, such intramolecular bridges are mostly introduced randomly into the polymer chain and generate random single chain compaction.¹⁶⁸ Conversely in natural polymers, the primary sequence is the key parameter for controlling the formation of their complex and uniform 3D structures, which subsequently display biological functions. Thus, research focus is currently shifting to the preparation of folded macromolecules with complex and uniform structures which could mimic closer the complexity exhibited only by natural polymers.¹⁶⁹ Within the last years, different trends have emerged toward the preparation of more complex 3D structures or controlled folded macromolecules.¹⁶⁹ For example, multiple orthogonal crosslinking motifs have been exploited to generate complex synthetic polymers folding.^170,171 An elegant synthetic route has been described by using two orthogonal hydrogen-bond motifs to induce a stepwise folding process and access complex structural self-organization.¹⁷² An ABA triblock copolymer bearing chiral BTA motifs in the middle block (B) and UPy motifs in both end blocks (A) has been synthesized and exploited to induce a

23 stepwise orthogonal folding process (Figure 5a). Protected functionalized monomers such as propargyl methacrylate (PMA), hydroxyethyl methacrylate (HEMA), and isobornyl methacrylate (IBMA) were copolymerized by ATRP to form a triblock copolymer poly(IBMA-co-HEMA)-b-poly(IBMA-co-PMA)-b-poly(IBMA-co-HEMA). Subsequently, the alkyne groups were functionalized with BTA motifs via azide-alkyne cycloaddition, while hydroxyl side groups were post-modified by isocyanate conjugation reactions to introduce protected UPy motifs. Such synthesis enabled the elaboration of a ABA-type triblock copolymers, with the middle-block-containing BTAs and the two outer blocks o-nitrobenzyl protected UPy groups (Figure 5b). These complex copolymers were folded in an orthogonal stepwise manner. The ABA block copolymers could fold by thermal treatment through intramolecular H-bond of the BTAs motifs to generate helical stacks (Figure 5c). Then, the photolabile protecting groups of UPy moieties were removed by photoirradiation and intramolecular UPy motifs could dimerize (Figure 5d). This second reaction induced a further folding step to yield into more compact and stabilized conformation. An additional study showed that when the order of block was inverted, the BAB-type triblock copolymers were found to fold into a slightly less compacted nanoparticle than the ABA-type copolymers. These examples illustrate how the complexity and specificity of the internal structure of folded macromolecule can be tuned by using multiple orthogonal intrachain bonds.

Figure 5. (a) Triblock copolymer with BTA and UPy motifs that folds via orthogonal self-assembly.

(b) Chemical structure of the copolymers. (c) Helical self-assembly of chiral BTAs via H-bond. (d) Photoinduced dimerization of protected UPys via H-bond(Adapted from reference 172).

24 Besides, arising from their well-defined primary structures, biopolymers are capable to undergo guided folding in solution to complex structures.^123,173 Thus, research interest has grown toward the use of sequence-controlled polymers to induce single chain folding in a controlled manner and toward complex architectures. For instance, foldamers, which are synthetic sequence-defined oligomers, were extensively investigated to adopt well defined secondary structures.¹⁷⁴ In the contrary, progress in controlled folded macromolecules with high-molecular weight is less advanced compared to oligomers. Interestingly, an elegant method to generate controlled single polymer chain folding into a precise origami has been reported by exploiting sequence-controlled polymerization (Figure 6).¹⁷⁵ In this study, sequence-regulated polymerization based on the styrene/ maleimide platform with timed monomer additions was performed to form at desired position an intramolecular bridge within the macromolecule. Linear polymer precursors were synthesized by ATRP copolymerization of an excess of styrene with one equivalent of N-substituted maleimides bearing a protected alkyne group. The donor monomer is the main constituent of the chain, while the maleimide unit was precisely positioned within the polymer chain via timed injection during the polymerization. The bromine terminal group inherited from the ATRP process was exploited and transformed into azide group. After deprotection of the alkyne reactive groups located on the maleimide, copper-catalysed azide-alkyne “click” reaction was performed between the alkyne group and the azide terminal group to induce a controlled intramolecular cross linking.

Figure 6. Schematic illustration of the controlled shapes obtained by click reaction: tadpole (P-shaped), pseudocyclic (Q-shaped), bicyclic (8-shaped) and knotted (α-shaped). Experimental conditions: i) azide–alkyne 1,3-dipolar cycloaddition: CuBr, 2,2′-bipyridine, dimethylformamide, 80 °C. ii) Glaser coupling: CuBr,2,2′-bipyridine, O2, dimethylformamide, 80 °C (Adapted from reference 175).

This approach leads to a variety of tuneable cyclic shapes, commanded by the position maleimide units bearing the reactive groups. Inspired by this work, Lutz and co-workers have also described the fabrication of controlled folded macromolecules by forming one positional dynamic disulfide bridge.¹⁷⁶ The use of sequence-controlled multiblock copolymers has also been employed to induce controlled single polymer chain compartmentalization.^177-179

25 Exploiting such sequence-regulation techniques could potentially enable new designs of tailored polymer microstructures, in which the amount and positioning of cross-linking sites can be precisely controlled.¹⁶⁹ Hence, it is reasonable to assume that the use of sequence-controlled polymerizations is a major step to move forward the complexity and uniformity of folded macromolecules. Such current progress highly requires parallelly the development of analytic tools capable of characterizing this emerging class of synthetic of folded macromolecules. An overview of the typical analytic tools is discussed in the next section.