Controlled Supramolecular Polymerization via Bioinspired, Liquid-Liquid Phase Separation of Monomers.

Dynamic supramolecular assemblies, driven by noncovalent interactions, pervade the biological realm. In the synthetic domain, their counterparts, supramolecular polymers, endowed with remarkable self-repair and adaptive traits, are often realized through bioinspired designs. Recently, controlled supramolecular polymerization strategies have emerged, drawing inspiration from protein self-assembly. A burgeoning area of research involves mimicking the liquid-liquid phase separation (LLPS) observed in proteins to create coacervate droplets and recognizing their significance in cellular organization and diverse functions. Herein, we introduce a novel perspective on synthetic coacervates, extending beyond their established role in synthetic biology as dynamic, membraneless phases to enable structural control in synthetic supramolecular polymers. Drawing parallels with the cooperative growth of amyloid fibrils through LLPS, we present metastable coacervate droplets as dormant monomer phases for controlled supramolecular polymerization. This is achieved via a π-conjugated monomer design that combines structural characteristics for both coacervation through its terminal ionic groups and one-dimensional growth via a π-conjugated core. This design leads to a unique temporal LLPS, resulting in a metastable coacervate phase, which subsequently undergoes one-dimensional growth via nucleation within the droplets. In-depth spectroscopic and microscopic characterization provides insights into the temporal evolution of disordered and ordered phases. Furthermore, to modulate the kinetics of liquid-to-solid transformation and to achieve precise control over the structural characteristics of the resulting supramolecular polymers, we invoke seeding in the droplets, showcasing living growth characteristics. Our work thus opens up new avenues in the exciting field of supramolecular polymerization, offering general design principles and controlled synthesis of precision self-assembled structures in confined environments.

Enzymatic Reaction-Coupled, Cooperative Supramolecular Polymerization.

Nature employs sophisticated mechanisms to precisely regulate self-assembly and functions within biological systems, exemplified by the formation of cytoskeletal filaments. Various enzymatic reactions and auxiliary proteins couple with the self-assembly process, meticulously regulating the length and functions of resulting macromolecular structures. In this context, we present a bioinspired, reaction-coupled approach for the controlled supramolecular polymerization in synthetic systems. To achieve this, we employ an enzymatic reaction that interfaces with the adenosine triphosphate (ATP)-templated supramolecular polymerization of naphthalene diimide monomers (NSG). Notably, the enzymatic production of ATP (template) plays a pivotal role in facilitating reaction-controlled, cooperative growth of the NSG monomers. This growth process, in turn, provides positive feedback to the enzymatic production of ATP, creating an ideal reaction-coupled assembly process. The success of this approach is further evident in the living-growth characteristic observed during seeding experiments, marking this method as the pioneering instance where reaction-coupled self-assembly precisely controls the growth kinetics and structural aspects of supramolecular polymers in a predictive manner, akin to biological systems.

Tuning Supramolecular Polymer Assembly through Stereoelectronic Interactions.

The supramolecular polymerization of 2,11-dithia[3.3]paracyclophanes through self-complementary intermolecular and transannular amide hydrogen bonding is presented. An n → π* interaction between the amide hydrogen bonding units and the central bridging atom results from the single-point exchange of a carbon atom for a sulfur atom. This orbital donor-acceptor interaction can be strengthened by oxidizing the sulfide to a sulfone which acts to shorten the donor···acceptor distance and increase orbital overlap. Experimental signatures of the increased n → π* interaction include larger isodesmic polymerization elongation constants in solution, changes in characteristic bond stretching frequencies, and geometric/structural changes evaluated by X-ray crystallography. The experimental data are supported by extensive computational investigations of both assembling and nonassembling 2,11-dithia[3.3]paracyclophanes as well as a rationally designed model system to confirm the role of stereoelectronic effects on supramolecular polymer assembly.

Muscle-Mimetic Synergistic Covalent and Supramolecular Polymers: Phototriggered Formation Leads to Mechanical Performance Boost.

A thin filament stimulated by Ca2+ to combine with myosin is the structural basis to achieve filament sliding and muscle contraction. Though a large variety of artificial materials has been developed by mimicking muscle, the on-demand combination of the actin filament and myosin has never been precisely reproduced in polymeric systems. Herein, we show that both the combination process and the combined structure of actin filament and myosin have been mimicked to construct synergistic covalent and supramolecular polymers (CSPs). Specifically, photoirradiation as a stimulus induces the independently formed covalent polymers (CPs) and supramolecular polymers (SPs) to interact with each other through activated quadruple H-bonding. The resultant CSPs possess a unique network structure which not only facilitates the synergistic effect of CPs and SPs to afford stiff, strong, yet tough materials but also provides efficient pathways to dissipate energy with the damping capacity of the representative material being higher than 95%. Furthermore, muscle functions, for example, by becoming stiff during contraction and self-growth by training, are imitated well in our system via in situ phototriggered formation of CSP in the solid state. We hope that the fundamental understanding gained from this work will promote the development of synergistic CSP systems with emergent functions and applications by mimicking the principle of muscle movements.

Poly(peptide): Synthesis, Structure, and Function of Peptide-Polymer Amphiphiles and Protein-like Polymers.

In this Account, we describe the organization of functional peptides as densely arrayed side chains on polymer scaffolds which we introduce as a new class of material called poly(peptide). We describe two general classes of poly(peptide): (1) Peptide-Polymer Amphiphiles (PPAs), which consist of block copolymers with a dense grouping of peptides arrayed as the side chains of the hydrophilic block and connected to a hydrophobic block that drives micelle assembly, and (2) Protein-like Polymers (PLPs), wherein peptide-brush polymers are composed from monomers, each containing a peptide side chain. Peptides organized in this manner imbue polymers or polymeric nanoparticles with a range of functional qualities inherent to their specific sequence. Therefore, polymers or nanoparticles otherwise lacking bioactivity or responsiveness to stimuli, once linked to a peptide of choice, can now bind proteins, enter cells and tissues, have controlled and switchable biodistribution patterns, and be enzyme substrates (e.g., for kinases, phosphatases, proteases). Indeed, where peptide substrates are incorporated, kinetically or thermodynamically driven morphological transitions can be enzymatically induced in the polymeric material. Synergistically, the polymer enforces changes in peptide activity and function by virtue of packing and constraining the peptide. The scaffold can protect peptides from proteolysis, change the pharmacokinetic profile of an intravenously injected peptide, increase the cellular uptake of an otherwise cell impermeable therapeutic peptide, or change peptide substrate activity entirely. Moreover, in addition to the sequence-controlled peptides (generated by solid phase synthesis), the polymer can carry its own sequence-dependent information, especially through living polymerization strategies allowing well-defined blocks and terminal labels (e.g., dyes, contrast agents, charged moieties). Hence, the two elements, peptide and polymer, cooperate to yield materials with unique function and properties quite apart from each alone. Herein, we describe the development of synthetic strategies for accessing these classes of biomolecule polymer conjugates. We discuss the utility of poly(peptide)-based materials in a range of biomedical applications, including imaging of diseased tissues (myocardial infarction and cancer), delivering small molecule drugs to tumors with high specificity, imparting cell permeability to otherwise impermeable peptides, protecting bioactive peptides from proteolysis in harsh conditions (e.g., stomach acid and whole blood), and transporting proteins into traditionally difficult-to-transfect cell types, including stem cells. Poly(peptide) materials offer new properties to both the constituent peptides and to the polymers, which can be tuned by the design of the oligopeptide sequence, degree of polymerization, peptide arrangement on the polymer backbone, and polymer backbone chemistry. These properties establish this approach as valuable for the development of peptides as medicines and materials in a range of settings.

Thiosquaramide-Based Supramolecular Polymers: Aromaticity Gain in a Switched Mode of Self-Assembly.

Despite a growing understanding of factors that drive monomer self-assembly to form supramolecular polymers, the effects of aromaticity gain have been largely ignored. Herein, we document the aromaticity gain in two different self-assembly modes of squaramide-based bolaamphiphiles. Importantly, O → S substitution in squaramide synthons resulted in supramolecular polymers with increased fiber flexibility and lower degrees of polymerization. Computations and spectroscopic experiments suggest that the oxo- and thiosquaramide bolaamphiphiles self-assemble into "head-to-tail" versus "stacked" arrangements, respectively. Computed energetic and magnetic criteria of aromaticity reveal that both modes of self-assembly increase the aromatic character of the squaramide synthons, giving rise to stronger intermolecular interactions in the resultant supramolecular polymer structures. These examples suggest that both hydrogen-bonding and stacking interactions can result in increased aromaticity upon self-assembly, highlighting its relevance in monomer design.

Towards new nanoporous biomaterials: self-assembly of sulfopillar[5]arenes with vitamin D3 into supramolecular polymers.

Novel water-soluble, deca-substituted pillar[5]arenes containing thiasulfate and thiacarboxylate fragments were synthesized and characterized. UV-vis, 2D 1H-1H NOESY and DOSY NMR spectroscopy revealed the ability of pillar[5]arenes containing thiasulfate fragments to form an inclusion complex with cholecalciferol (vitamin D3) in a 1 : 2 ratio (lg Kass = 2.2). Using DLS and SEM it was found that upon concentration and/or evaporation of the solvent, the supramolecular polymer (pillar[5]arene/vitamin D3 (1 : 2)) forms a porous material with an average wall diameter of 53 nm. It was shown that the supramolecular polymer is stable during photolysis by UV radiation (k1 = 1.7 × 10-5 s-1).

Switching between Stacked Toroids and Helical Supramolecular Polymers in Aqueous Nanotubules.

Although significant advances have been made in supramolecular tubules, reversible polymerization in the tubular walls while maintaining their intact structure remains a great challenge. Here, reversible helical supramolecular polymerization of stacked toroids is reported, while maintaining tubular structures in aqueous solution. At room temperature, the tubules consist of discrete toroid stackings with hydrophobic interior. Upon heating, the tubules based on toroid stackings undergo a reversible helical supramolecular polymerization to transform into helical tubules by interconnecting between spirally open toroids. The helical polymerization arises from a tilting transition of the closed toroids that transform into spirally open toroids driven by the thermal dehydration of a hydrophilic oligoether dendron surrounding the toroid frameworks.

ß-Cyclodextrin-derived Room Temperature Macromolecular Ionic Liquids by PEGylated Anions.

A series of cyclodextrin-derived room temperature macromolecular ionic liquids carrying rather low glass transition temperatures of -20 to -40 °C are synthesized via sequential esterification, quaternization, and anion metathesis reactions. In addition to being ionic in nature, they are viscous liquids at room temperature with more fluidic behavior at elevated temperatures. They serve as a solvent for organic dyes or iodine separation via a liquid-liquid extraction approach. This strategy is useful for the development of various sugar (macro)molecule-based functional ionic liquids as well as macromolecular ionic liquids.

Isocyanoacetate-Aldehyde Polymerization: A Facile Tool toward Functional Oxazoline-Containing Polymers.

As an important nitrogen source, isocyanides have been involved in numerous organic reactions. As a result, many complicated compounds have been successfully synthesized through isocyanide chemistry. However, compared with its popular research in organic reactions, the application of isocyanides in polymerization is less investigated. In this work, a new polymerization based on isocyanide monomers is established. By simply mixing diisocyanoacetates and dialdehydes in the presence of a catalytic system of CuCl/PPh3 /organobase in dichloromethane at room temperature readily produces soluble and thermally stable oxazoline-containing polymers with moderate weight-averaged molecular weights (Mw up to 11 200) in excellent yields (up to 97%) after 6 h. Furthermore, introducing the tetraphenylethene moiety into the main chains endows the resultant polymers with aggregation-induced emission, which can function as fluorescent probes for Fe3+ ion detection with high sensitivity and selectivity. This work not only enriches the family of isocyanide-based polymerizations but also provides an efficient tool for the preparation of functional heterocycle-containing polymers.

Supramolecular Block Copolymers by Seeded Living Polymerization of Perylene Bisimides.

Living covalent polymerization has been a subject of intense research for many decades and has culminated in the synthesis of a large variety of block copolymers (BCPs) with structural and functional diversity. In contrast, the research on supramolecular BCPs is still in its infancy and their generation by living processes remains a challenge. Here we report the formation of supramolecular block copolymers by two-component seeded living polymerization of properly designed perylene bisimides (PBIs) under precise kinetic control. Our detailed studies on thermodynamically and kinetically controlled supramolecular polymerization of three investigated PBIs, which contain hydrogen-bonding amide side groups in imide position and chlorine, methoxy, or methylthio substituents in 1,7 bay-positions, revealed that these PBIs form kinetically metastable H-aggregates, which can be transformed into the thermodynamically favored J-aggregates by seed-induced living polymerization. We show here that copolymerization of kinetically trapped states of one PBI with seeds of another PBI leads to the formation of supramolecular block copolymers by chain-growth process from the seed termini as confirmed by UV/vis spectroscopy and atomic force microscopy (AFM). This work demonstrates for the first time the formation of triblock supramolecular polymer architectures with A-B-A and B-A-B block pattern by alternate two-component seeded polymerization in a living manner.

Supramolecular assembly of functional peptide-polymer conjugates.

The following review gives an overview about synthetic peptide-polymer conjugates as macromolecular building blocks and their self-assembly into a variety of supramolecular architectures, from supramolecular polymer chains, to anisotropic 1D arrays, 2D layers, and more complex 3D networks. A selection of recent literature examples using linear, coiled-coil and cyclic peptide motifs is provided. The reversible nature of the unimer-to-supramolecular polymer transition provides unique opportunities to investigate mechanistic aspects of the supramolecular assembly, with respect to the thermodynamic or kinetic parameters and furthermore provides exciting opportunities for non-equilibrium assembly strategies. Using specific examples we also highlight some of the biological or mechanical function that arises from this versatile class of supramolecular biomaterials.

Microfluidics for real-time direct monitoring of self- and co-assembly biomolecular processes.

Molecular self-assembly is a major approach for the fabrication of functional supramolecular nanomaterials. This dynamic, straightforward, bottom-up procedure may result in the formation of various architectures at the nano-scale, with remarkable physical and chemical characteristics. Biological and bio-inspired building blocks are especially attractive due to their intrinsic tendency to assemble into well-organized structures, as well as their inherent biocompatibility. To further expand the morphological diversity, co-assembly methods have been developed, allowing to produce alternative unique architectures, enhanced properties, and improved structural control. However, in many cases, mechanistic understanding of the self- and co-assembly processes is still lacking. Microfluidic techniques offer a set of exclusive tools for real-time monitoring of biomolecular self-organization, which is crucial for the study of such dynamic processes. Assembled nuclei, confined by micron-scale pillars, could be subjected to controlled environments aiming to assess the effect of different conditions on the assembly process. Other microfluidics setups can produce droplets at a rate of over 100 s-1, with volumes as small as several picoliters. Under these conditions, each droplet can serve as an individual pico/nano-reactor allowing nucleation and assembly. These processes can be monitored, analyzed and imaged, by various techniques including simple bright-field microscopy. Elucidating the mechanism of such molecular events may serve as a conceptual stepping-stone for the rational control of the resulting physicochemical properties.

The Past 40 Years of Macromolecular Sciences: Reflections on Challenges in Synthetic Polymer and Material Science.

Technology and science are often successful in discontinuities ("disruptive innovations" or "leapfrogging"), in turn allowing true, big societal development by entire changes in technology rather than by minuscule stepwise improvements. Examples are the emergence of modern computer science by inventing the field-effect transistor rather than further fine-tuning the "Röhrentransistor"; the development of (organic) light-emitting diodes in advance of the "Gasglühstrumpf"; CRISPR/Cas exceeding any previous genetic method or Ziegler-Natta polymerization enabling stereoregular polypropylene (PP) and high-density polyethylene (HDPE) in advance of free-radical polymerization. Where may the frogs in polymer science in the future "jump" to? Contemplating past achievements in (synthetic) polymer science, such as living polymerization, "click" chemistry, supramolecular chemistry, the potentially "leaping" areas of self-healing and (bio)degradable materials, amyloids, and biomaterials are reflected upon.

Supramolecular Assembly of Oriented Spherulitic Crystals of Conjugated Polymers Surrounding Carbon Nanotube Fibers.

The directed assembly of conjugated polymers into macroscopic organization with controlled orientation and placement is pivotal in improving device performance. Here, the supramolecular assembly of oriented spherulitic crystals of poly(3-butylthiophene) surrounding a single carbon nanotube fiber under controlled solvent evaporation of solution-cast films is reported. Oriented lamellar structures nucleate on the surface of the nanotube fiber in the form of a transcrystalline interphase. The factors influencing the formation of transcrystals are investigated in terms of chemical structure, crystallization temperature, and time. Dynamic process measurements exhibit the linear growth of transcrystals with time. Microstructural analysis of transcrystals reveals individual lamellar organization and crystal polymorphism. The form II modification occurs at low temperatures, while both form I and form II modifications coexist at high temperatures. A possible model is presented to interpret transcrystallization and polymorphism.

Engineering Redox Activity in Conjugated Microporous Polytriphenylamine Networks Using Pyridyl Building Blocks toward Efficient Supercapacitors.

Nitrogen-rich conjugated microporous polymers (CMPs) with tunable porosities and reversible redox properties have received increasing interest as electrode materials for supercapacitors. Herein, pyridyl building blocks with different substitutions are selected to synthesize four amine-linked conjugated microporous polytriphenylamine (PTPA) networks via Buchwald-Hartwig cross-coupling reaction engineering the redox activity of PTPAs. The structures, porosities, and redox activities of these four PTPAs are investigated. The electrochemical characterization results show that PTPA obtained using 2,5-diaminopyridine dihydrochloride (i.e., PTPA-25) displays the highest specific capacitances up to 335 F g-1 in 1.0 m H2 SO4 at a current density of 0.5 A g-1 . Upon 5000 cycles, PTPA-25 maintains good initial capacitances up to 65%, nearly 100% Coulombic efficiencies at a current density of 2 A g-1 , and high rate properties (remained a high capacitance of 250 F g-1 at 10 A g-1 ). The influence of different substitutions of pyridyl on the redox activities of the synthesized PTPA electrodes is further proposed, which would give insight into engineering the performance of CMPs-based supercapacitors.

Halogen-Bond-Mediated Self-Assembly of Polymer-Resorcinarene Complexes.

A new supramolecular system based on halogen-bonded macromolecular substances is presented. Binding and complex formation between a halogen bond acceptor N-benzyl ammonium resorcinarene bromide and a library of polymeric halogen bond donors based on iodotetrafluorophenoxy functionality is shown. The complex formation was confirmed in liquid state by dynamic light scattering and transmission electron microscopy. Spectroscopic measurements in the solid state verify the halogen bonding. In particular, the study shows that both homopolymers and polyethylene glycol block copolymers act as effective halogen bond donors leading to polymer-architecture-dependent complex morphologies.

A Mechanically Robust, Stiff, and Tough Hyperbranched Supramolecular Polymer Hydrogel.

In this study, a simple yet versatile method is introduced to prepare a hyperbranched supramolecular polymer hydrogel by utilizing Type II photoinitiated self-condensing vinyl polymerization of N-acryloyl glycinamide, which can serve not only as an inimer providing branching sites, but also as a hydrogen-bonding cross-linker. The hyperbranched poly(N-acryloyl glycinamide) (HB-PNAGA) hydrogels demonstrate excellent mechanical performances with a tensile strength of 0.793-2.724 MPa, elongation at break of 203-902%, Young's modulus of 0.450-1.172 MPa, and maximal fracture energy of 2200 J m-2 , which are all superior to those of linear PNAGA hydrogels. The results indicate that the HB-PNAGA hydrogel is very stiff and tough due to much higher H-bonding cross-linking density formed in hyperbranched architecture. The high stiffness, toughness, and ease of preparation make these hyperbranched supramolecular hydrogels very attractive for application as soft supporting tissue replacements.

Cylindrical Micelles by the Self-Assembly of Crystalline-b-Coil Polyphosphazene-b-P2VP Block Copolymers. Stabilization of Gold Nanoparticles.

During the last number of years a variety of crystallization-driven self-assembly (CDSA) processes based on semicrystalline block copolymers have been developed to prepare a number of different nanomorphologies in solution (micelles). We herein present a convenient synthetic methodology combining: (i) The anionic polymerization of 2-vinylpyridine initiated by organolithium functionalized phosphane initiators; (ii) the cationic polymerization of iminophosphoranes initiated by -PR2Cl2; and (iii) a macromolecular nucleophilic substitution step, to prepare the novel block copolymers poly(bistrifluoroethoxy phosphazene)-b-poly(2-vinylpyridine) (PTFEP-b-P2VP), having semicrystalline PTFEP core forming blocks. The self-assembly of these materials in mixtures of THF (tetrahydrofuran) and 2-propanol (selective solvent to P2VP), lead to a variety of cylindrical micelles of different lengths depending on the amount of 2-propanol added. We demonstrated that the crystallization of the PTFEP at the core of the micelles is the main factor controlling the self-assembly processes. The presence of pyridinyl moieties at the corona of the micelles was exploited to stabilize gold nanoparticles (AuNPs).

Quadruple H-Bonding Cross-Linked Supramolecular Polymeric Materials as Substrates for Stretchable, Antitearing, and Self-Healable Thin Film Electrodes.

Herein, we report a de novo chemical design of supramolecular polymer materials (SPMs-1-3) by condensation polymerization, consisting of (i) soft polymeric chains (polytetramethylene glycol and tetraethylene glycol) and (ii) strong and reversible quadruple H-bonding cross-linkers (from 0 to 30 mol %). The former contributes to the formation of the soft domain of the SPMs, and the latter furnishes the SPMs with desirable mechanical properties, thereby producing soft, stretchable, yet tough elastomers. The resulting SPM-2 was observed to be highly stretchable (up to 17 000% strain), tough (fracture energy ∼30 000 J/m2), and self-healing, which are highly desirable properties and are superior to previously reported elastomers and tough hydrogels. Furthermore, a gold, thin film electrode deposited on this SPM substrate retains its conductivity and combines high stretchability (∼400%), fracture/notch insensitivity, self-healing, and good interfacial adhesion with the gold film. Again, these properties are all highly complementary to commonly used polydimethylsiloxane-based thin film metal electrodes. Last, we proceed to demonstrate the practical utility of our fabricated electrode via both in vivo and in vitro measurements of electromyography signals. This fundamental understanding obtained from the investigation of these SPMs will facilitate the progress of intelligent soft materials and flexible electronics.