Dual-Readout of the Mechanical Response of a Bis-acridinium [2]Rotaxane

A [2]rotaxane built around a multi-responsive bis-acridinium macrocycle has been synthesized. Structural investigation has confirmed the interlocked nature of the molecule, and MD simulations illuminated its conformational dynamics with atomic resolution. Both halochromic and redox-switching properties were explored to shed light on the mechanical response and electronic changes that occur in the bis-acridinium [2]rotaxane. The topology of the rotaxane led to different mechanical behaviors upon addition of hydroxide ions or reduction that were easily detected by UV/Vis spectroscopy and electrochemistry.     

Bimodal dynamics of mechanically constrained hydrogen bonds revealed by vibrational photon echoes

We have investigated the dynamics of the hydrogen bonds that connect the components of a [2]rotaxane in solution. In this rotaxane, the amide groups in the benzylic-amide macrocycle and the succinamide thread are connected by four equivalent N-H???O=C hydrogen bonds. The fluctuations of these hydrogen bonds are mirrored by the frequency fluctuations of the NH-stretch modes, which are probed by means of three-pulse photon-echo peak shift spectroscopy. The hydrogen-bond fluctuations occur on three different time scales, with time constants of 0.1, 0.6, and ≥200 ps. Comparing these three time scales to the ones found in liquid formamide, which contains the same hydrogen-bonded amide motif but without mechanical constraints, we find that the faster two components, which are associated with small-amplitude fluctuations in the strength of the N-H???O=C hydrogen bonds, are very similar in the liquid and the rotaxane. However, the third component, which is associated with the breaking and subsequent reformation of hydrogen bonds, is found to be much slower in the rotaxane than in the liquid. It can be concluded that the mechanical bonding in a rotaxane does not influence the amplitude and time scale of the small-amplitude fluctuations of the hydrogen bonds, but strongly slows down the complete dissociation of these hydrogen bonds. This is probably because in a rotaxane breaking of the macrocycle-axle contacts is severely hindered by the mechanical constraints. The hydrogen-bond dynamics in rotaxane-based molecular machines can therefore be regarded as liquidlike on a time scale 1 ps and less, but structurally frozen on longer (up to at least 200 ps) time scales.     

Determining the intracellular transport mechanism of a cleft-[2]rotaxane

Rotaxanes are a class of interlocked compounds that have been extensively investigated for their potential utility as switches or sensors. We recently demonstrated that rotaxanes have further application as agents that transport material into cells. This novel finding prompted our investigation into the mechanism by which rotaxanes are involved in transmembrane transport. Two-dimensional NMR analysis showed that a cleft-containing rotaxane exists in two dominant conformations ("closed" and "open"). To determine the importance of conformational flexibility on the ability of the rotaxanes to bind guests and transport material into cells, the rotaxane was chemically modified to lock it in the closed conformation. Charged guests interact less favorably with the locked rotaxane, as compared to the unmodified rotaxane, both in an aqueous solution and in DMSO. In a chloroform solution, both rotaxanes bind the guests with similar affinities. The locked rotaxane exhibited a reduced capacity to transport a fluoresceinated peptide into cells, whereas the unmodified rotaxane efficiently delivers the peptide. Flow cytometry experiments demonstrated that a high percentage of the cells contained the delivered peptide (89-98%), the level of delivery is concentration dependent, and the rotaxanes and peptide have low toxicity. Cellular uptake of the peptide was largely temperature and ATP independent, suggesting that the rotaxane-peptide complex passes through the cellular membrane without requiring active cell-mediated processes. The results show that the sliding motion of the wheel is necessary for the delivery of materials into cells and can enhance the association of guests. These studies demonstrate the potential for rotaxanes as a new class of mechanical devices that deliver a variety of therapeutic agents into targeted cell populations.     

Mechanically Interlocked [2]Rotaxane Aerogels with Tunable Morphologies and Mechanical Properties

Mechanical bonds have been utilized as promising motifs to construct mechanically interlocked aerogels (MIAs) with mechanical adaptivity and multifunctionality. However, fabricating such aerogels with not only precise chemical structures but also dynamic features remains challenging. Herein, we present MIAs carrying dense [2]rotaxane units, which bestow both the stability and flexibility of the aerogel network. Owing to the stable chemical structure of a [2]rotaxane, MIAs possessing a precise and full-scale mechanically interlocked network could be fabricated with the aid of diverse solvents. In addition, the dynamic nature of the [2]rotaxane resulted in morphologies and mechanical performances of the MIAs that can be dramatically modulated under chemical stimuli. We hope that the structure–property relationship in MIAs will facilitate the development of mechanically interlocked materials and provide novel opportunities toward constructing smart materials with multifunctionalities.     

A redox-driven multicomponent molecular shuttle

A multicomponent [2]rotaxane designed to operate as a molecular shuttle driven by light energy has been constructed, and its properties have been investigated. The system is composed of (1) a light-fueled power station, capable of using the photon energy to create a charge-separated state, and (2) a mechanical switch, capable of utilizing such a photochemically generated driving force to bring about controllable molecular shuttling motions. The light-fueled power station is, in turn, a dyad comprising (i) a pi-electron-accepting fullerene (C60) component and (ii) a light-harvesting porphyrin (P) unit which acts as an electron donor in the excited state. The mechanical switch is a redox-active bistable [2]rotaxane moiety that consists of (i) a tetrathiafulvalene (TTF) unit as an efficient pi-electron-donor station, (ii) a dioxynaphthalene (DNP) unit as a second pi-electron-rich station, and (iii) a tetracationic cyclobis(paraquat-p-phenylene) (CBPQT4+) pi-electron-acceptor cyclophane, which encapsulates the better pi-electron-donating TTF station. Diethylene glycol spacers were conveniently introduced between the electroactive components in the dumbbell-shaped thread to facilitate the template-directed synthesis of the [2]rotaxane. A modular synthetic approach was undertaken for the overall synthesis of this multicomponent bistable [2]rotaxane, beginning with the syntheses of the P-C60 dyad unit and the two-station TTF-DNP-based [2]rotaxane separately, using conventional synthetic methodologies. These two components were finally stitched together by an esterification to afford the target rotaxane. Its structure was characterized by 1H NMR spectroscopy and mass spectrometry as well as by UV-vis-NIR absorption spectroscopy and voltammetry. The observations reflect remarkable electronic interactions between the various units, pointing to the existence of folded conformations in solution. The redox-driven shuttling process of the CBPQT4+ ring between the two competitive electron-rich recognition units, namely, TTF and DNP, was investigated by electrochemistry and spectroelectrochemistry as a means to verify its operational behavior prior to the photophysical studies related to light-driven operation. The oxidation process of the TTF unit is dramatically hampered in the rotaxane, thereby reducing the efficiency of the shuttling motion. These results confirm that, as the structural complexity increases, the overall function of the system no longer depends simply on its "primary" structure but also on higher-level effects which are reminiscent of the secondary and tertiary structures of biomolecules.     

Mechanical Bond Enhanced Lithium Halide Ion-Pair Binding by Halogen Bonding Heteroditopic Rotaxanes**

A family of novel halogen bonding (XB) and hydrogen bonding (HB) heteroditopic [2]rotaxane host systems constructed by active metal template (AMT) methodology, were studied for their ability to cooperatively recognise lithium halide (LiX) ion-pairs. ¹H NMR ion-pair titration experiments in CD₃CN:CDCl₃ solvent mixtures revealed a notable “switch-on“ of halide anion binding in the presence of a co-bound lithium cation, with rotaxane hosts demonstrating selectivity for LiBr over LiI. The strength of halide binding was shown to greatly increase with increasing number of halogen bond donors integrated into the interlocked cavity, where an all-XB rotaxane was found to be the most potent host for LiBr. DFT calculations corroborated these findings, determining the mode of LiX ion-pair binding. Notably, ion-pair binding was not observed with the corresponding XB/HB macrocycles alone, highlighting the cooperative, heteroditopic, rotaxane axle-macrocycle component mechanical bond effect as an efficient strategy for ion-pair recognition in general.     

Dendrimer with rotaxane-like mechanical branching

[reaction: see text] A dendrimer wherein the branching points are mechanical in nature has been synthesized. It contains two identical covalently linked bis-dendrons and a core unit fused to two rings that encircle the two bis-dendrons. A "threading-followed-by-stoppering" approach is used in the template-directed synthesis of a precursor bis[2]rotaxane, which undergoes stopper exchange four times to yield the dendrimer in which the two bis-dendrons act as stoppers within the two [2]rotaxane subunits.     

Macrocyclic Dinuclear Palladium Complex as a Novel Doubly Threaded [3]Rotaxane Scaffold and Its Application as a Rotaxane Cross-Linker

A dinuclear Pd^II complex possessing a cyclic ligand was developed as a novel doubly threaded [3]rotaxane scaffold and applied as a rotaxane cross-linker reagent. The dinuclear complex (PdMC)₂ was prepared by one-step macrocyclization followed by the double palladation reaction. ¹H NMR analysis and UV/Vis measurements revealed the formation of a doubly threaded pseudo[3]rotaxane by the complexation of (PdMC)₂ with 2 equivalents of 2,6-disubstituted pyridine 3 through double metal coordination. The treatment of (PdMC)₂ with 2 equivalents of 4-vinylpyridine (VP) afforded a doubly threaded [3]rotaxane cross-linker (PdMC-VP)₂ . Radical co-polymerization of VP and t-butylstyrene in the presence of (PdMC-VP)₂ afforded a stable rotaxane cross-linked polymer (RCP). An elastic RCP was also prepared by using n-butyl acrylate as a monomer. The obtained RCPs exhibited higher swelling ability and higher mechanical toughness compared with the corresponding covalent cross-linked polymers.     

Star/Linear Polymer Topology Transformation Facilitated by Mechanical Linking of Polymer Chains

Topology transformation of a star polymer to a linear polymer is demonstrated for the first time. A three‐armed star polymer possessing a mechanical linking of two polymer chains was synthesized by the living ring‐opening polymerization of δ‐valerolactone initiated by a pseudo[2]rotaxane having three hydroxy groups as the initiator sites on the wheel component and at both axle termini. The polymerization was followed by the propagation end‐capping reaction with a bulky isocyanate not only to prevent the wheel component deslippage but also to introduce the urethane moiety at the axle terminal. The resulting rotaxane‐linked star polymer with a fixed rotaxane linkage based on the ammonium/crown ether interaction was subjected to N‐acetylation of the ammonium moiety, which liberated the components from the interaction to move the wheel component to the urethane terminal as the interaction site, eventually affording the linear polymer. The physical property change caused by the present topology transformation was confirmed by the hydrodynamic volume and viscosity.     

Versatile Supramolecular Cross‐Linker: A Rotaxane Cross‐Linker That Directly Endows Vinyl Polymers with Movable Cross‐Links

A supramolecular cross‐linked cross‐linker, capable of introducing rotaxane cross‐links to vinyl polymers, has been developed for the rational synthesis of polyrotaxane networks. The experimental results reveal that the combination of an oligocyclodextrin (OCD) and a terminal bulky group‐tethering macromonomer (TBM) forms a polymer‐network structure having polymerizable moieties through supramolecular cross‐linking. Radical polymerization of a variety of typical vinyl monomers in the presence of the vinylic supramolecular cross‐linker (VSC) afforded the corresponding vinyl polymers cross‐linked through the rotaxane cross‐links (RCP) as transparent stable films in high yields under both photoinitiated and thermal polymerization conditions. A poly(N,N‐dimethylacrylamide)‐based hydrogel synthesized by using VSC, RCP_DMAAm, displayed a unique mechanical property. The small‐angle X‐ray scattering (SAXS) results, indicating patterns characteristic of a polyrotaxane network, clearly suggested the presence and role of the rotaxane cross‐links. The confirmation of the introduction of rotaxane‐cross‐links into vinyl polymers strongly reveals the significant usefulness of VSC.     

Efficient Synthesis of Cyclic Block Copolymers by Rotaxane Protocol by Linear/Cyclic Topology Transformation

High‐yielding synthesis of cyclic block copolymer (CBC) using the rotaxane protocol by linear‐cyclic polymer topology transformation was first demonstrated. Initial complexation of OH‐terminated sec‐ammonium salt and a crown ether was followed by the successive living ring‐opening polymerizations of two lactones to a linear block copolymer having a rotaxane structure by the final capping of the propagation end. CBC was obtained in a high yield by an exploitation of the mechanical linkage through the translational movement of the rotaxane component to transform polymer structure from linear to cyclic. Furthermore, the change of the polymer topology was translated into a macroscopic change in crystallinity of the block copolymer.     

A Guiding Principle for Strengthening Crosslinked Polymers: Synthesis and Application of Mobility‐Controlling Rotaxane Crosslinkers

Three component mobility controlling vinylic rotaxane crosslinkers with two radically polymerizable vinyl groups ( RC_R s) were synthesized to prove that the mobility of the components of the RC_R s plays a crucial role in determining the properties of rotaxane‐crosslinked polymers (RCPs). RC_R s (R=H, Me, or Et) were obtained from living ring‐opening polymerization. RCP_Et was prepared using RC_Et , which exhibits the lowest component mobility. The low component mobility is reflected in inferior mechanical strength and stretching ability in tensile stress tests compared to components with good (R=Me) and high (R=H) mobility. However, RCP_Et exhibited significantly higher stress and strain values than the corresponding covalently crosslinked polymers ( CCP_R s). These results indicate that a suitable component mobility substantially enhances the mechanical strength of RCPs. This behavior could serve as a guiding principle for the molecular design of advanced RCs.     

Macrocyclic Dinuclear Palladium Complex as a Novel Doubly Threaded [3]Rotaxane Scaffold and Its Application as a Rotaxane Cross‐Linker

A dinuclear Pd^II complex possessing a cyclic ligand was developed as a novel doubly threaded [3]rotaxane scaffold and applied as a rotaxane cross‐linker reagent. The dinuclear complex (PdMC)₂ was prepared by one‐step macrocyclization followed by the double palladation reaction. ¹H NMR analysis and UV/Vis measurements revealed the formation of a doubly threaded pseudo[3]rotaxane by the complexation of (PdMC)₂ with 2 equivalents of 2,6‐disubstituted pyridine 3 through double metal coordination. The treatment of (PdMC)₂ with 2 equivalents of 4‐vinylpyridine (VP) afforded a doubly threaded [3]rotaxane cross‐linker (PdMC‐VP)₂ . Radical co‐polymerization of VP and t‐butylstyrene in the presence of (PdMC‐VP)₂ afforded a stable rotaxane cross‐linked polymer (RCP). An elastic RCP was also prepared by using n‐butyl acrylate as a monomer. The obtained RCPs exhibited higher swelling ability and higher mechanical toughness compared with the corresponding covalent cross‐linked polymers.     

Olefin Cyclopropanation by Radical Carbene Transfer Reactions Promoted by Cobalt(II)/Porphyrinates: Active‐Metal‐Template Synthesis of [2]Rotaxanes

A Co^II/porphyrinate‐based macrocycle in the presence of a 3,5‐diphenylpyridine axial ligand functions as an endotopic ligand to direct the assembly of [2]rotaxanes from diazo and styrene half‐threads, by radical‐carbene‐transfer reactions, in excellent 95 % yield. The method reported herein applies the active‐metal‐template strategy to include radical‐type activation of ligands by the metal‐template ion during the organometallic process which ultimately yields the mechanical bond. A careful quantitative analysis of the product distribution afforded from the rotaxane self‐assembly reaction shows that the Co^II/porphyrinate subunit is still active after formation of the mechanical bond and, upon coordination of an additional diazo half‐thread derivative, promotes a novel intercomponent C?H insertion reaction to yield a new rotaxane‐like species. This unexpected intercomponent C?H insertion illustrates the distinct reactivity brought to the Co^II/porphyrinate catalyst by the mechanical bond.     

A Stimuli‐Responsive Rotaxane–Gold Catalyst: Regulation of Activity and Diastereoselectivity

A rotaxane‐based Au catalyst was developed and the effect of the mechanical bond on its behavior was studied. Unlike the non‐interlocked thread, the rotaxane requires a catalytically innocent cofactor, the identity of which significantly influences both the yield and diastereoselectivity of the reaction. Under optimized conditions, Au^I (the catalyst), Ag^I (to abstract the Cl^? ligand), and Cu^I (the cofactor) combine to produce a catalyst with excellent activity and selectivity.     

A photoswitchable rotaxane with a folded molecular thread

Novel [2]rotaxanes containing the tetracationic cyclophane cyclobis(paraquat-4,4-biphenylene) and a dumbbell-shaped molecular thread incorporating a photoactive diarylcycloheptatriene station as well as a photoinactive anisol station have been synthesized with yields of nearly 50 % by the alkylative endcapping method. The rotaxane was transformed into the related rotaxane incorporating a diaryl tropylium unit by electrochemical oxidation. The precursor of the cycloheptatrienyl rotaxane, the related pseudorotaxane, and the rotaxanes incorporating the diarylcycloheptatriene and the corresponding tropylium unit were characterized by (1)HNMR spectroscopy and UV/Vis spectroscopy. According to the NMR spectra, both the cycloheptatriene and the tropylium rotaxane possess a folded conformation enabling the tetracationic cyclophane to interact with two stations. The diarylcycloheptatriene station is incorporated inside the cavity of the cyclophane and the anisol station resides alongside the bipyridinium unit of the cyclophane. In contrast, the anisol station is inside the cyclophane in the tropylium rotaxane. The exchange between both conformations can be achieved by introducing the methoxy leaving group into the cycloheptatriene ring; the tropylium rotaxane is generated by photoheterolysis of this methoxy-substituted rotaxane, which reacts thermally back to the cycloheptatriene rotaxane, thus closing the switching cycle. These induced conformational changes achieve a so-called molecular machine.     

Neutralization of a sec-ammonium group unusually stabilized by the "rotaxane effect": synthesis, structure, and dynamic nature of a "free" sec-amine/crown ether-type rotaxane

A fifteen-year riddle has been settled: neutralization, the most popular chemical event, of a crown ether/sec-ammonium salt-type rotaxane has been achieved and a completely nonionic crown ether/sec-amine-type rotaxane isolated. A [2]rotaxane was prepared as a typical substrate from a mixture of dibenzo[24]crown-8 ether (DB24C8) and sec-ammonium hexafluorophosphate (PF(6)) with a terminal hydroxy group through end-capping with 3,5-dimethylbenzoic anhydride in the presence of tributylphosphane as a catalyst in 90% yield. A couple of approaches to the neutralization of the ammonium rotaxane were investigated to isolate the free sec-amine-type rotaxane by decreasing the degree of thermodynamic and kinetic stabilities. One approach was the counteranion-exchange method in which the soft counterion PF(6)(-) was replaced with the fluoride anion by mixing with tetrabutylammonium fluoride, thus decreasing the cationic character of the ammonium moiety. Subsequent simple washing with a base allowed us to isolate the free sec-amine-type rotaxane in a quantitative yield. The other approach was a synthesis based on a protection/deprotection protocol. The acylation of the sec-ammonium moiety with 2,2,2-trichloroethyl chloroformate gave an N-carbamated rotaxane that could be deprotected by treating with zinc in acetic acid to afford the corresponding free sec-amine-type rotaxane in a quantitative yield. The structure of the free sec-amine-type rotaxane was fully confirmed by spectral and analytical data. The generality of the counteranion-exchange method was also confirmed through the neutralization of a bisammonium-type [3]rotaxane. The mechanism was studied from the proposed potential-energy diagram of the rotaxanes with special emphasis on the role of the PF(6)(-) counterion.     

Synthesis of [1]rotaxane via covalent bond formation and its unique fluorescent response by energy transfer in the presence of lithium ion

Although there have been a lot of reports on the synthesis and properties of [n]rotaxanes (mainly n = 2), only a few reports on the synthesis of [1]rotaxane has been published by V?gtle's group and others (see ref 5). Generally speaking, [1]rotaxane might be expected to exhibit properties different from other rotaxanes, because the rotor and the axle in the [1]rotaxane is bound covalently and closely. We report on a novel method to make [1]rotaxanes via covalent bond formation from a macrocyclic compound. That is, we first prepared a bicyclic compound from macrocycle and then proceeded to [1]rotaxane by aminolysis. This is the first synthetic example of preparation of [1]rotaxane via covalent bond formation, not utilizing weak interactions such as hydrogen bonding, charge transfer, via metal complexation, etc. This method might provide a powerful and new tool for construction of [1]rotaxane as a new supramolecular system. In addition, we investigated energy transfer from rotor to axle using [1]rotaxane that we prepared. Energy transfer occurred perfectly from the naphthalene ring of the rotor to the anthracene ring of the axle. We found also that only lithium ion among alkali ions can drastically enhance the fluorescence intensity. This finding could be applicable to ion-sensing systems, switching devices, and so on.     

Linear artificial molecular muscles

Two switchable, palindromically constituted bistable [3]rotaxanes have been designed and synthesized with a pair of mechanically mobile rings encircling a single dumbbell. These designs are reminiscent of a "molecular muscle" for the purposes of amplifying and harnessing molecular mechanical motions. The location of the two cyclobis(paraquat-p-phenylene) (CBPQT(4+)) rings can be controlled to be on either tetrathiafulvalene (TTF) or naphthalene (NP) stations, either chemically ((1)H NMR spectroscopy) or electrochemically (cyclic voltammetry), such that switching of inter-ring distances from 4.2 to 1.4 nm mimics the contraction and extension of skeletal muscle, albeit on a shorter length scale. Fast scan-rate cyclic voltammetry at low temperatures reveals stepwise oxidations and movements of one-half of the [3]rotaxane and then of the other, a process that appears to be concerted at room temperature. The active form of the bistable [3]rotaxane bears disulfide tethers attached covalently to both of the CBPQT(4+) ring components for the purpose of its self-assembly onto a gold surface. An array of flexible microcantilever beams, each coated on one side with a monolayer of 6 billion of the active bistable [3]rotaxane molecules, undergoes controllable and reversible bending up and down when it is exposed to the synchronous addition of aqueous chemical oxidants and reductants. The beam bending is correlated with flexing of the surface-bound molecular muscles, whereas a monolayer of the dumbbell alone is inactive under the same conditions. This observation supports the hypothesis that the cumulative nanoscale movements within surface-bound "molecular muscles" can be harnessed to perform larger-scale mechanical work.     

Porphyrin-functionalised rotaxanes for anion recognition

The synthesis and anion-recognition properties of two new porphyrin-functionalised [2]rotaxane host molecules are described. The rotaxane compounds are prepared via a chloride-anion-templated clipping strategy. (1)H NMR titration experiments demonstrate that the rotaxane host systems exhibit high binding affinities and general selectivities for chloride anions in DMSO-d(6) or CDCl(3)/CD(3)OD solvent systems. UV-visible and fluorescence spectroscopy experiments reveal that the rotaxane receptors are ineffective as optical anion sensors. However, both receptors are shown to be capable of detecting chloride anions electrochemically via cathodic shifts in the porphyrin P/P(+) redox couples.