Polyrotaxanes and the pump paradigm.

The year 2022 marks the 30th anniversary of the first reports of polyrotaxanes in the scientific literature. During the past three decades, many combinations of molecular rings and polymer chains have been synthesised and characterised. Until recently, however, the permutations of polyrotaxanes available to researchers were limited by synthetic methods which typically relied on an innate affinity between the molecular rings and polymer chains. With the advent of oligorotaxane-forming molecular pumps in 2015, it has now become possible to pump multiple rings against their will onto oligomer and polymer chains which have little or no affinity for the rings. These molecular pumps, which can recruit rings actively from solution to form precise polyrotaxanes, represent a major breakthrough in the field. This Tutorial Review highlights key milestones in the synthesis and investigation of polyrotaxanes along with recent developments in the synthesis and theory relating to molecular pumps. Polyrotaxane properties, arising from their topologies, have allowed them to steal a march on traditional polymers in a wide range of applications in materials, electronic and biological science, from slide-ring gels to robust coatings on cell phones, from molecular wires to flexible binders for battery anodes, from efficient multivalent protein binders to bio-cleavable polyplexes for cellular DNA delivery. Molecular pumps have the potential to blaze a contemporary trail for the synthesis of precise mechanically interlocked materials, especially those dependent on non-equilibrium chemistry and those related to energy storage and nanomedicine.

Precise Non-Equilibrium Polypropylene Glycol Polyrotaxanes.

Traditionally, the synthesis of polyrotaxanes has been limited by synthetic methods that rely on an innate affinity between the rings and the polymer chains. The use of rotaxane-forming molecular pumps allows this limitation to be circumvented in the production of non-equilibrium polyrotaxanes in which rings are trapped on polymer chains for which they have little or no affinity. Pumping cassettes, each composed of a bipyridinium unit linked (i) by a bismethylene bridge to a terminal 2,6-dimethylpyridinium cationic unit and (ii) by a methylene group to an isopropylphenylene steric barrier, were attached using copper-catalyzed azide-alkyne cycloadditions to the ends of a polypropylene glycol (PPG) chain of number-average molecular weight Mn ≈ 2200. Using a one-pot electrosynthetic protocol, a series of PPG-based polyrotaxanes with cyclobis(paraquat-p-phenylene) as the rings were synthesized. Despite the steric bulk of the PPG backbone, it was found to be a suitable collecting chain for threading up to 10 rings. The pumping of two rings is sufficient to render these hydrophobic polymers soluble in aqueous solution. Their hydrodynamic diameters and diffusion constants vary according to the number of pumped rings. The non-equilibrium nature of these polyrotaxanes is manifested in their gradual degradation and dethreading at elevated temperatures.

Alkoxy-Substituted Quadrupolar Fluorescent Dyes.

Polar and polarizable π-conjugated organic molecules containing push-pull chromophores have been investigated extensively in the past. Identifying unique backbones and building blocks for fluorescent dyes is a timely exercise. Here, we report the synthesis and characterization of a series of fluorescent dyes containing quadrupolar A-D-A constitutions (where A = acceptor and D = donor), which exhibit fluorescence emission at a variety of different wavelengths. We have investigated the effects of different electron-withdrawing groups, located at both termini of a para-terphenylene backbone, by steady-state UV/vis and fluorescence spectroscopy. Pyridine and substituted pyridinium units are also introduced during the construction of the quadrupolar backbones. Depending on the quadrupolarity, fluorescence emission wavelengths cover from 380 to 557 nm. Time-resolved absorption and emission spectroscopy reveal that the photophysical properties of those quadrupolar dyes result from intramolecular charge transfer. One of the dyes we have investigated is a symmetrical box-like tetracationic cyclophane. Its water-soluble tetrachloride, which is non-cytotoxic to cells up to a loading concentration of 1 µM, has been employed in live-cell imaging. When taken up by cells, the tetrachloride emits a green fluorescence emission without any hint of photobleaching or disruption of normal cell behavior. We envision that our design strategy of modifying molecules through the functionalization of the quadrupolar building blocks as chromophores will lead to future generations of fluorescent dyes in which these A-D-A constitutional fragments are incorporated into more complex molecules and polymers for broader photophysical and biological applications.

Wholly Synthetic Molecular Machines.

The past quarter of a century has witnessed an increasing engagement on the part of physicists and chemists in the design and synthesis of molecular machines de novo. This minireview traces the development of artificial molecular machines from their prototypes in the form of shuttles and switches to their emergence as motors and pumps where supplies of energy in the form of chemical fuel, electrochemical potential and light activation become a minimum requirement for them to function away from equilibrium. The challenge facing this rapidly growing community of scientists and engineers today is one of putting wholly synthetic molecules to work, both individually and as collections. Here, we highlight some of the recent conceptual and practical advances relating to the operation of wholly synthetic rotary and linear motors.

Folding of oligoviologens induced by radical-radical interactions.

We report the synthesis of a series of homologous oligoviologens in which different numbers of 4,4'-bipyridinium (BIPY(2+)) subunits are linked by p-xylylene bridges, as a prelude to investigating how their radical cationic forms self-assemble both in solution and in the solid state. The strong radical-radical interactions between the radical cationic forms of the BIPY(2+) units-namely, BIPY(•+)-in these oligoviologens induce intra- or intermolecular folding of these homologues. UV/Vis/NIR spectroscopic studies and DFT quantum mechanics indicate that the folding of the shorter oligoviologens is dominated by intermolecular radical-radical interactions. In addition to intermolecular interactions, strong intramolecular radical-radical interactions, which give rise to an NIR absorption band at 900 nm, tend to play a crucial role in governing the folding of the longer oligoviologens. The solid-state superstructure of the oligoviologen with three BIPY(2+) units reveals that two intertwining chains fold together to form a dimer, stabilized by intermolecular radical-radical interactions. These dimers continue to stack in an infinite column through intermolecular radical-radical interactions between them. This research features an artificial biomimetic system which sustains delicate secondary and tertiary structures, reminiscent of those present in nucleic acids and proteins.

Acid-base actuation of [c2]daisy chains.

A versatile synthetic strategy, which was conceived and employed to prepare doubly threaded, bistable [c2]daisy chain compounds, is described. Propargyl and 1-pentenyl groups have been grafted onto the stoppers of [c2]daisy chain molecules obtained using a template-directed synthetic protocol. Such [c2]daisy chain molecules undergo reversible extension and contraction upon treatment with acid and base, respectively. The dialkyne-functionalized [c2]daisy chain (AA) was subjected to an [AA+BB] type polymerization with an appropriate diazide (BB) to afford a linear, mechanically interlocked, main-chain polymer. The macromolecular properties of this polymer were characterized by chronocoulometry, size exclusion chromatography, and static light-scattering analysis. The acid-base switching properties of both the monomers and the polymer have been studied in solution, using (1)H NMR spectroscopy, UV/vis absorption spectroscopy, and cyclic voltammetry. The experimental results demonstrate that the functionalized [c2]daisy chains, along with their polymeric derivatives, undergo quantitative, efficient, and fully reversible switching processes in solution. Kinetics measurements demonstrate that the acid/base-promoted extension/contraction movements of the polymeric [c2]daisy chain are actually faster than those of its monomeric counterpart. These observations open the door to correlated molecular motions and to changes in material properties.

Azobenzene-based light-responsive hydrogel system.

A deoxycholic acid-modified beta-cyclodextrin derivative (2) and an azobenzene-branched poly(acrylic acid) copolymer (3) were prepared, and the association and dissociation of 2 with the trans/cis-azobenzene units in 3 were characterized by UV/vis spectroscopy, induced circular dichroism, and 1H NMR spectroscopy. The experimental results indicate that the trans-azobenzene units are bound strongly within the cavities of 2 whereas the cis-azobenzene is not bound at all. A supramolecular inclusion complex (1), formed by 2 and 3, is accompanied by the formation of a hydrogel. The light-responsive gel-to-sol and sol-to-gel phase transitions of the hydrogel, induced by trans-cis photoisomerization of the azobenzene units, were investigated. In the hydrogel system, the trans-azobenzene units in 3 are included inside the hydrophobic cavity of 2. Upon photoirradiation with UV light of 355 nm, the hydrogel is converted efficiently to the sol phase because the trans-azobenzene units are converted photochemically to their cis configurations, whereupon the resulting cis-azobenzene units dissociate from 2. The hydrogel can be recovered from the sol phase by photoirradiation with visible light of 450 nm. The swelling ratio for fresh hydrogel samples, which was found to be 8.7 +/- 0.7, was measured for a number of gel-to-sol and sol-to-gel phase-transition cycles.

A bistable poly[2]catenane forms nanosuperstructures.

Side-chain poly[2]catenanes at the click of a switch! A bistable side-chain poly[2]catenane has been synthesized and found to form hierarchical self-assembled hollow superstructures of nanoscale dimensions in solution. Molecular electromechanical switching (see picture) of the material is demonstrated, and the ground-state equilibrium thermodynamics and switching kinetics are examined as the initial steps towards processible molecular-based electronic devices and nanoelectromechanical systems.

Multivalent interactions between lectins and supramolecular complexes: Galectin-1 and self-assembled pseudopolyrotaxanes.

Supramolecular chemistry has been employed to develop flexible and adaptable multivalent neoglycoconjugates for binding galectin-1 (Gal-1). Gal-1, a dimeric lectin with two galactoside-binding sites, regulates cancer progression and immune responses. Self-assembled pseudopolyrotaxanes consisting of lactoside-displaying cyclodextrin (LCD) "beads" threaded onto polyviologen "strings" display mobile ligands as a result of cyclodextrin rotation about, and limited translation along, the polymer chain. The pseudopolyrotaxanes rapidly and efficiently precipitate Gal-1 and provide valency-corrected enhancements of up to 30-fold compared to native lactose and 20-fold over free LCD in a T-cell agglutination assay. A supramolecular statistical effect was observed, wherein the efficacy of Gal-1 inhibition correlates with the number of ligands connected to each other solely through mechanical and noncovalent interactions. Such flexible and adaptable self-assembled pseudopolyrotaxanes show promise for the study of multivalent interactions and targeting of therapeutically relevant lectins.

Esterase- and pH-responsive poly(ß-amino ester)-capped mesoporous silica nanoparticles for drug delivery.

Gating of mesoporous silica nanoparticles (MSNs) with the stimuli-responsive poly(ß-amino ester) has been achieved. This hybrid nanocarrier releases doxorubicin (DOX) under acidic conditions or in the presence of porcine liver esterase. The DOX loaded poly(ß-amino ester)-capped MSNs reduce cell viability when tested on MDA-MB-231 human breast cancer cells.

Dynamic multivalent lactosides displayed on cyclodextrin beads dangling from polymer strings.

[reaction: see text] Lactose-appended cyclodextrin derivatives have been synthesized and threaded onto hydrophobic polymers in aqueous solution to form dynamic multivalent lactosides for binding to lectins. The threading process, which proceeds quickly, can be observed by one- and two-dimensional NMR spectroscopies.

High-contrast photopatterning of photoluminescence within quantum dot films through degradation of a charge-transfer quencher.

Diffraction-limited, high-contrast photopatterning of the photoluminescence of layer-by-layer films comprising CdSe@CdS@ZnS quantum dots and polyviologen is reported. The photoluminescence of the quantum dots is initially quantitatively quenched due to ultrafast photoinduced electron transfer to polyviologen. Photopatterning is achieved by high-power or prolonged illumination in air, which photochemically degrades the polyviologen and thereby restores the photoluminescence of the quantum dots.

Polyporous metal-coordination frameworks.

Starting from a chiral building block--α-cyclodextrin--and rubidium salts, the crystallization of a complex of chiral helices, which constitute a "green" porous coordination polymer, has been realized. Cyclodextrin molecules coordinated by rubidium ions form porous, infinitely long left-handed helical channels, interdigitated with each other. A theoretical examination of the potential of this new material to act as a medium for chiral separation is presented.

pH-responsive mechanised nanoparticles gated by semirotaxanes.

A [2]pseudorotaxane-based mechanised nanoparticle system, which operates within an aqueous acidic environment, has been prepared and characterised; this integrated system affords both water-soluble stalk and ring components in an effort to improve the biocompatibility of these promising new drug delivery vehicles.

Dynamic hook-and-eye nanoparticle sponges.

Systems in which nanoscale components of different types can be captured and/or released from organic scaffolds provide a fertile basis for the construction of dynamic, exchangeable functional materials. In such heterogeneous systems, the components interact with one another by means of programmable, noncovalent bonding interactions. Herein, we describe polymers that capture and release functionalized nanoparticles selectively during redox-controlled aggregation and disaggregation, respectively. The interactions between the polymer and the NPs are mediated by the reversible formation of polypseudorotaxanes, and give rise to architectures ranging from short chains composed of few nanoparticles to extended networks of nanoparticles crosslinked by the polymer. In the latter case, the polymer/nanoparticle aggregates precipitate from solution such that the polymer acts as a selective 'sponge' for the capture/release of the nanoparticles of different types.

Monitoring cyclodextrin-polyviologen pseudopolyrotaxanes with the Bradford assay.

Self-assembled multivalent pseudopolyrotaxanes, composed of lactoside-bearing cyclodextrin (CD) rings threaded on linear polyviologen polymers, have been introduced recently as flexible and dynamic neoglycoconjugates. In the course of this research, it was found that polyviologens are responsive to the Bradford assay, which is traditionally highly selective for proteins. The response of the pseudopolyrotaxanes to the Bradford assay was dependant on, and thus indicative of, the degree of threading of the CD rings onto the polyelectrolyte. The assay was then used to report on the threading and dethreading of native and lactoside-bearing alpha-CD rings onto and off of polyviologen chains, a phenomenon which demonstrates the utility of biochemical assays to address problems unique to supramolecular chemistry.

Template-directed one-step synthesis of cyclic trimers by ADMET.

A trifurcated template, containing three secondary dialkylammonium ion recognition sites for encirclement by a dibenzo [24]crown-8-containing acyclic diene, is used to promote acyclic diene metatheses (ADMET) catalyzed by ruthenium-alkylidene complexes, affording a cyclic trimer in 55% yield. Following this one-step, threefold ADMET reaction, the resulting cyclic trimer was isolated by preparative HPLC and characterized by NMR spectroscopy and mass spectrometry.

Molecular dynamics simulation of amphiphilic bistable [2]rotaxane langmuir monolayers at the air/water interface.

Bistable [2]rotaxanes display controllable switching properties in solution, on surfaces, and in devices. These phenomena are based on the electrochemically and electrically driven mechanical shuttling motion of the ring-shaped component, cyclobis(paraquat-p-phenylene) (CBPQT(4+)), between a monopyrrolotetrathiafulvalene (mpTTF) unit and a 1,5-dioxynaphthalene (DNP) unit located along a dumbbell component. The most stable state of the rotaxane (CBPQT(4+)@mpTTF) is that in which the CBPQT(4+) ring encircles the mpTTF unit, but a second less favored metastable co-conformation with the CBPQT(4+) ring surrounding the DNP (CBPQT(4+)@DNP) can be formed experimentally. For both co-conformations of an amphiphilic bistable [2]rotaxane, we report here the structure and surface pressure-area isotherm of a Langmuir monolayer (LM) on a water subphase as a function of the area per molecule. These results from atomistic molecular dynamics (MD) studies are validated by comparing with experiments based on similar amphiphilic rotaxanes. For both co-conformations, we found that as the area per molecule increases the thickness of the LM decreases while the molecular tilt increases. Both co-conformations led to similar LM thicknesses at the same packing area. From the simulated LM systems, we calculated the electron density profiles of the monolayer as a function of area per molecule, which show good agreement with experimental analyses from synchrotron X-ray reflectivity measurements of related systems. Decomposing the overall electron density profiles into component contributions, we found distinct differences in molecular packing in the film depending upon the co-conformation. Thus we find that the necessity of allowing the tetracationic ring to become solvated by water leads to differences in the structures for the two co-conformations in the LM. At the same packing area, the value of the overall tilt angle does not seem to be sensitive to whether the CBPQT(4+) ring is encircling the mpTTF or the DNP unit. However, the conformation of the dumbbell does depend on the location of the CBPQT(4+) ring, which is reflected in the segmental tilt angles of the mpTTF and DNP units. Using the Kirkwood-Buff formula in conjunction with MD calculations, we find the surface pressure-area isotherms for each co-conformation in which the CBPQT(4+)@mpTTF form has smaller surface tension and therefore larger surface pressure than the CBPQT(4+)@DNP at the same packing area, differences that decreases with increasing area per molecule, which is verified experimentally.