Macrocyclic Components Research Articles

Directional Ring Translocation in a pH‐ and Redox‐Driven Tristable [2]Rotaxane

AbstractWe describe the synthesis and characterization of a [2]rotaxane comprising a dibenzo‐24‐crown‐8 (DB24C8) macrocyclic component and a thread containing three recognition sites: ammonium (AmH+), bipyridinium (Bpy2+) and triazolium (Trz+). AmH+ and Bpy2+ are responsive to fully orthogonal stimuli, pH and electrochemical, which allows to precisely control the directional translation of the macrocycle along the axle. A better understanding of the processes driving the operation of the system was obtained thanks to an in‐depth thermodynamic characterization. Orthogonal stimuli responsive tristable rotaxanes represent the starting point for the creation of linear motors and the development of molecular logic gates.

Directional Ring Translocation in a pH- and Redox-Driven Tristable [2]Rotaxane.

We describe the synthesis and characterization of a [2]rotaxane comprising a dibenzo-24-crown-8 (DB24C8) macrocyclic component and a thread containing three recognition sites: ammonium (AmH+), bipyridinium (Bpy2+) and triazolium (Trz+). AmH+ and Bpy2+ are responsive to fully orthogonal stimuli, pH and electrochemical, which allows to precisely control the directional translation of the macrocycle along the axle. A better understanding of the processes driving the operation of the system was obtained thanks to an in-depth thermodynamic characterization. Orthogonal stimuli responsive tristable rotaxanes represent the starting point for the creation of linear motors and the development of molecular logic gates.

Bidirectional Molecular Motors by Controlling Threading and Dethreading Pathways of a Linked Rotaxane.

Artificial molecular motors have been presented as models for biological molecular motors. In contrast to the conventional artificial molecular motors that rely on covalent bond rotation, molecular motors with mechanically interlocked molecules (MIM) have attracted considerable attention owing to their ability to generate significant rotational motion by dynamically shuttling macrocyclic components. The topology of MIM-type rotational molecular motors is currently limited to catenane structures, which require intricate synthetic procedures that typically produce a low synthetic yield. In this study, we develop a novel class of MIM-type molecular motors with a rotaxane-type topology. The switching of the threading/dethreading pathways of the linked rotaxane by protecting/deprotecting the bulky stopper group and changing the solvent polarity enables a net unidirectional rotation of the molecular motor. The threading/dethreading reaction rates were quantitatively evaluated through detailed spectroscopic investigations. Repeated net unidirectional rotation and switching of the direction of rotation were also achieved. Our findings demonstrate that linked rotaxanes can serve as MIM-type molecular motors with reversible rotational direction controlled by threading/dethreading reactions. These motors hold potential as components of molecular machinery.

Bidirectional Molecular Motors by Controlling Threading and Dethreading Pathways of a Linked Rotaxane

AbstractArtificial molecular motors have been presented as models for biological molecular motors. In contrast to the conventional artificial molecular motors that rely on covalent bond rotation, molecular motors with mechanically interlocked molecules (MIMs) have attracted considerable attention owing to their ability to generate significant rotational motion by dynamically shuttling macrocyclic components. The topology of MIM‐type rotational molecular motors is currently limited to catenane structures, which require intricate synthetic procedures that typically produce a low synthetic yield. In this study, we develop a novel class of MIM‐type molecular motors with a rotaxane‐type topology. The switching of the threading/dethreading pathways of the linked rotaxane by protecting/deprotecting the bulky stopper group and changing the solvent polarity enables a net unidirectional rotation of the molecular motor. The threading/dethreading reaction rates were quantitatively evaluated through detailed spectroscopic investigations. Repeated net unidirectional rotation and switching of the direction of rotation were also achieved. Our findings demonstrate that linked rotaxanes can serve as MIM‐type molecular motors with reversible rotational direction controlled by threading/dethreading reactions. These motors hold potential as components of molecular machinery.

Rotational isomerism of amide units in the ring of rotaxanes in response to base/acid stimuli

Abstract Rotational isomerism of 4 amide moieties of the threaded macrocyclic component of [2]rotaxanes featuring mono- and bis-ammonium moieties in dumbbell-shaped axle components was investigated in response to base, and the rotational isomerization of both rotaxanes could be controlled reversibly through the addition of appropriate amounts of base and acids.

P.054 Long-term safety and efficacy of zilucoplan in myasthenia gravis: additional interim analyses of RAISE-XT

Background: Zilucoplan, a macrocyclic peptide complement component 5 inhibitor, sustained efficacy for up to 60 weeks of treatment, with a favourable safety profile in patients with acetylcholine receptor autoantibody-positive generalised myasthenia gravis in an interim analysis of RAISE-XT (NCT04225871). We evaluate the safety and efficacy of zilucoplan up to 96 weeks. Methods: RAISE-XT, a Phase 3, multicentre, open-label extension study, included patients who participated in the double-blind Phase 2 (NCT03315130) and Phase 3 (NCT04115293) zilucoplan studies. Patients self-administered daily subcutaneous zilucoplan 0.3mg/kg injections. Primary outcome was incidence of treatment-emergent adverse events (TEAEs). Secondary outcomes included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Results: At data cut-off (11 May 2023), median (range) exposure to zilucoplan was 1.8 (0.11–5.1) years (N=200). TEAEs occurred in 191 (95.5%) patients; the most common TEAE was COVID-19 (n=64; 32.0%). At Week 96, mean (standard error) change in MG-ADL score from double-blind study baseline was –6.33 (0.49) and –7.83 (0.60) for patients who received zilucoplan 0.3mg/kg and placebo in the double-blind studies, respectively. Conclusions: Zilucoplan demonstrated a favourable long-term safety profile. Efficacy was sustained for 96 weeks in patients who had previously received zilucoplan and who switched from placebo.

Lithium chloride selective ion-pair recognition by heteroditopic [2]rotaxanes.

The first heteroditopic [2]rotaxane host systems capable of strong and selective binding of lithium chloride ion-pair species are described. Importantly, a cooperative 'switch on' mechanism was found to operate, in which complexation of a lithium metal cation enhances the halide anion affinity of the rotaxanes via a combination of favourable proximal electrostatic and preorganised allosteric effects. The mechanically bonded rotaxane host design features a macrocycle component possessing a 2,6-dialkoxy pyridyl cation binding motif and an isophthalamide anion binding group, as well as an axle component functionalised with either a halogen bonding (XB) iodotriazole or hydrogen bonding (HB) prototriazole moiety. Extensive quantitative 1H NMR titration studies in CD3CN/CDCl3 solvent mixtures determined enhanced ion-pair binding affinities for lithium halides over the corresponding sodium or potassium halide salts, with the axle prototriazole-containing HB rotaxane in particular demonstrating a marked selectivity for lithium chloride. Solid-state X-ray crystallographic studies and computational DFT investigations provide evidence for a [2]rotaxane host axle-separated ion-pair binding mode, in which complementary cation and anion binding motifs from both the macrocycle and axle components act convergently to recognise each of the charged guest species.

Selective lithium halide ion-pair sensing by a dynamic metalloporphyrin [2]rotaxane.

A dynamic zinc(II) metalloporphyrin axle-containing [2]rotaxane with a heteroditopic macrocycle component is shown to selectively recognise and optically sense lithium halide (LiX) ion-pair species. 1H NMR and UV-visible absorption experiments demonstrate a strong macrocycle pyridyl⋯Zn(II) metalloporphyrin axle interaction which results in a marked co-conformational bias in the free [2]rotaxane host system. Extensive 1H NMR cation, anion and ion-pair titration experiments demonstrate the binding of lithium halide ion-pairs disrupts the inter-component mechanical bond interaction, wherein dynamic macrocycle shuttling to an axle triazole station enables co-operative axle-separated LiX ion-pair recognition and the selective optical sensing of lithium halide salts.

Liquid-crystalline pillar[5]arene-based [2]rotaxanes

ABSTRACT Liquid-crystalline mechanically interlocked molecules have been prepared from a clickable pillar[5]arene-containing [2]rotaxane building block incorporating ethynylated stoppers and dendritic mesogenic subunits of generation 0, 1 and 2 under copper-catalysed alkyne-azide cycloaddition conditions. The liquid-crystalline properties of the resulting pillar[5]arene-based rotaxanes bearing 4, 8 and 16 peripheral cyanobiphenyl units have been investigated and compared to those of corresponding model compounds lacking the macrocyclic component.

Monodirectional Photocycle Drives Proton Translocation.

Photoisomerization of retinal is pivotal to ion translocation across the bacterial membrane and has served as an inspiration for the development of artificial molecular switches and machines. Light-driven synthetic systems in which a macrocyclic component transits along a nonsymmetric axle in a specific direction have been reported; however, unidirectional and repetitive translocation of protons has not been achieved. Herein, we describe a unique protonation-controlled isomerization behavior for hemi-indigo dyes bearing N-heterocycles, featuring intramolecular hydrogen bonds. Light-induced isomerization from the Z to E isomer is unlocked when protonated, while reverse E → Z photoisomerization occurs in the neutral state. As a consequence, associated protons are displaced in a preferred direction with respect to the photoswitchable scaffold. These results will prove to be critical in developing artificial systems in which concentration gradients can be effectively generated using (solar) light energy.

Squaramide-Based Heteroditopic [2]Rotaxanes for Sodium Halide Ion-Pair Recognition.

A series of squaramide-based heteroditopic [2]rotaxanes consisting of isophthalamide macrocycle and squaramide axle components are synthesized using an alkali metal cation template-directed stoppering methodology. This work highlights the unprecedented sodium cation template coordination of the Lewis basic squaramide carbonyls for interlocked structure synthesis. Extensive quantitative 1 H NMR spectroscopic anion and ion-pair recognition studies reveal the [2]rotaxane hosts are capable of cooperative sodium halide ion-pair mechanical bond axle-macrocycle component recognition, eliciting up to 20-fold enhancements in binding strengths for bromide and iodide, wherein the Lewis basic carbonyls and Lewis acidic NH hydrogen bond donors of the squaramide axle motif operate as cation and anion receptive sites simultaneously in an ambidentate fashion. Notably, varying the length and nature of the polyether cation binding unit of the macrocycle component dramatically influences the ion-pair binding affinities of the [2]rotaxanes, even overcoming direct contact NaCl ion-pair binding modes in polar organic solvents. Furthermore, the cooperative ion-pair binding properties of the squaramide-based heteroditopic [2]rotaxanes are exploited to successfully extract solid sodium halide salts into organic media.

Dynamic Metalloporphyrin-Based [2]Rotaxane Molecular Shuttles Stimulated by Neutral Lewis Base and Anion Coordination.

A series of dynamic metalloporphyrin [2]rotaxane molecular shuttles comprising of bis-functionalised Zn(II) porphyrin axle and pyridyl functionalised macrocycle components are prepared in high yield via active metal template synthetic methodology. Extensive variable temperature 1 H NMR and quantitative UV-Vis spectroscopic titration studies demonstrate dynamic macrocycle translocation is governed by an inter-component co-ordination interaction between the macrocycle pyridyl and axle Zn(II) metalloporphyrin, which serves to bias a 'resting state' co-conformation. The dynamic shuttling behaviour of the interlocked structures is dramatically inhibited by the addition of a neutral Lewis base such as pyridine, but can also be tuned via post-synthetic rotaxane demetallation of the porphyrin axle core to give free-base, or upon subsequent metallation, Ni(II) [2]rotaxane analogues. Importantly, the Lewis acidic Zn(II) porphyrin axle component is also capable of coordinating anions which induces mechanical bond shuttling behaviour resulting in a novel optical sensing response.

Electrochemistry and electrochemical assessment of host–guest complexation of substituted pillar[m]arene[n]quinones

Electrochemical behavior of pillar[n]arene[m]quinone (n + m = 5, n = 2–4) has been for the first time investigated in aqueous media on the glassy carbon electrode. All the compounds studied showed quasi-reversible redox conversion to hydroquinone derivatives. The reaction was not complicated with ionization of hydroxy groups or by the formation of intramolecular hydrogen bonds. In the whole pH region tested (2.0 – 9.0) the stoichiometry of electron and hydrogen ions transfer was found the same (1:1). The peak currents changed with no respect of the number of quinone units in the macrocycle molecule and were probably more affected by steric factors and self-aggregation confirmed by scanning electron microscopy. Adsorption of the macrocycles on the electrode covered with carbon black resulted in remarkable improvement of the conditions of electron exchange and of the peak currents on voltammograms. Screening of possible guest molecules showed that among amino acids, tyrosine formed complexes with pillarquinones both in solution and on the electrode interface. Complexation resulted in decrease of the peak currents on voltammograms due to steric hindrance of electric wiring. This made it possible to determine 5–100 µM tyrosine in the solution and 1–100 µM tyrosine with pillar[3]arene[2]quinone adsorbed in the carbon black layer. No interferences were established in normal human serum and Ringer-Locke’s solution. The approach to supramolecular detection of small molecules by intrinsic redox activity of the macrocyclic hosts can be extended to other analytes by modification of the macrocyclic components of the reaction.

Diverse Self-Assembly and Xenon Binding from a Single Mesomeric Macrocycle Component

Xenon binding has received considerable interest, but effective hosts remain rare, and the majority of assembly-type hosts are barely explored. Here, we report the synthesis, self-assembly, and xenon inclusion behavior with a homemade mesomeric bisurea–bisthiourea macrocycle. Compared to its racemic counterparts as recently investigated, the single mesomeric macrocycle forms even more comprehensive dimerization assemblies. From the single macrocycle component, up to two pairs of enantiomeric homochiral dimeric assemblies are formed. In the presence of xenon, the assembly diversity was pushed further, and an additional pair of enantiomeric heterochiral assemblies is induced. The diverse assembly comes from the macrocycle component adopting a folded, dissymmetric chiral conformation and undergoing spontaneous symmetry breaking upon cross-buckling together. The formed capsular assemblies possess a sealed, adaptive cavity for accommodating xenon. The cumulative xenon binding constant with the induced heterochiral capsule is about two times higher than the prior one assembled from racemic counterparts. The xenon-induced heterochiral capsule formation with the mesomeric macrocycle again demonstrates that xenon can find its own preferred host from a dynamic self-assembly system and likes to be accommodated by a more spherical van der Waals surrounding.

Designs and Applications of Multi-stimuli Responsive FRET Processes in AIEgen-Functionalized and Bi-fluorophoric Supramolecular Materials

Materials capable of displaying strong ratiometric fluorescence with Förster resonance energy transfer (FRET) processes have attracted much research interest because of various chemosensor and biomedical applications. This review highlights several popular strategies in designing FRET-OFF/ON mechanisms of ratiometric fluorescence systems. In particular, the developments of organic and polymeric FRET materials featuring aggregation-induced emission-based luminogens (AIEgens), supramolecular assemblies, photochromic molecular switches and surfactant-induced AIE/FRET mechanisms are presented. AIEgens have been frequently employed as FRET donor and/or acceptor fluorophores to obtain enhanced ratiometric fluorescences in solution and solid states. Since AIE effects and FRET processes rely on controllable distances between fluorophores, many interesting fluorescent properties can be designed by regulating aggregation states in polymers and supramolecular systems. Photo-switchable fluorophores, such as spiropyran and diarylethene, provide drastic changes in fluorescence spectra upon photo-induced isomerizations, leading to photo-switching mechanisms to activate/deactivate FRET processes. Supramolecular assemblies offer versatile platforms to regulate responsive FRET processes effectively. In rotaxane structures, the donor-acceptor distance and FRET efficiency can be tuned by acid/base-controlled shuttling of the macrocycle component. The tunable supramolecular interactions are strongly influenced by external factors (such as pH values, temperatures, analytes, surfactants, UV-visible lights, etc.), which induce the assembly and disassembly of host-guest systems and thus their FRET-ON/FRET-OFF behavior. In addition, the changes in donor or acceptor fluorescence profiles upon detections of analytes can also sufficiently alter the FRET behavior and result in different ratiometric fluorescence outputs. The strategies and examples provided in this review offer the insights and toolkits for future FRET-based material developments.

Evidence for effect of macrocycle symmetry on radiation-induced ring opening in 18-crown-6 complexes with alkali-earth metal halogenides

The complexes of 18-crown-6 with alkali-earth metal halides were synthesized to simulate the macrocyclic component of crown-containing extractants selective for radionuclide 90Sr and to investigate the effect of cationic and anionic factors on its radiation destruction at low-temperature (77 K) irradiation. The halide anion was found to protect the complexes from ring opening at the initial stages of radiolysis due to positive charge transfer from the primary macrocyclic radical cation to anion. This effect was found in 18-crown-6 complexes with SrCl2, SrBr2 and BaCl2, where the macrocycle had D3d symmetry. In contrast, the anionic protection was less efficient when the 18-crown-6 conformation was measurably distorted, as illustrated by the examples of complexes with SrI2, CaCl2 and, especially, MgCl2 with folded C2 and D2 symmetries. Based on the results obtained, it was concluded that preliminary conformational analysis of a macrocyclic complex could be a useful way to predict its resistance to radiation-induced polyether ring cleavage.

Conformational Control of [2]Rotaxane by Hydrogen Bond.

A series of [2]rotaxanes with various functional groups in the axle component was synthesized by the oxidative dimerization of alkynes, which is mediated by a macrocyclic phenanthroline–Cu complex. The rotaxanes were fully characterized by spectroscopic methods, and the structure of a rotaxane was determined by X-ray crystallographic analysis. The interaction between the ring component and the axle component was studied in detail to understand the conformation of the rotaxanes. The presence of the hydrogen bond between the phenanthroline moiety in the macrocyclic component and the acidic proton in the axle component influenced the conformation of rotaxane.

Hydroxy Groups Enhance [2]Rotaxane Anion Binding Selectivity.

We report the synthesis of two [2]rotaxanes containing an interlocked three dimensional binding cavity formed from a pyridinium bis(amide) axle component containing two phenol donors, and an isophthalamide based macrocycle. In the competitive solvent mixture 1 : 1 CDCl3 : CD3OD, one of the receptors exhibits a much higher selectivity preference for chloride than an analogous rotaxane without the hydroxy groups. X‐ray crystal structures reveal the chloride anion guest encapsulated within the interlocked binding cavity, though not all of the hydrogen bond donors are utilised. Computational semi‐empirical simulations indicate that secondary intermolecular interactions occur between the axle hydroxy hydrogen bond donors and the [2]rotaxane macrocycle components, contributing to a more preorganised binding pocket, which may be responsible for the observed enhanced selectivity.

Ferrocene-Containing Pseudorotaxanes in Crystals: Aromatic Interactions with Hammett Correlation.

Single crystals of pseudorotaxanes, [(FcCH2NH2CH2Ar)(DB24C8)][PF6] (DB24C8 = dibenzo[24]crown-8, Fc = Fe(C5H4)(C5H5), Ar = -C6H3-3,4-Cl2, -C6H3-3,4-F2, -C6H4-4-F, -C6H4-4-Cl, -C6H4-4-Br, -C6H3-3-F-4-Me, -C6H4-4-I) and [(FcCH2NH2CH2C6H4-4-Me)(DB24C8)][Ni(dmit)2] (dmit = 1,3-dithiole-2,4,5-dithiolate), were obtained from solutions containing DB24C8 and ferrocenylmethyl(arylmethyl)ammonium. X-ray crystallographic analyses of the pseudorotaxanes revealed that the aryl ring of the axle moiety and the catechol ring of the macrocyclic component were at close centroid distances and parallel or tilted orientation. The structures with parallel aromatic rings showed correlation of the distances between the centroids to Hammett substituent constants of the aryl groups.

Selective photoinduced charge separation in perylenediimide-pillar[5]arene rotaxanes

The ability to control photoinduced charge transfer within molecules represents a major challenge requiring precise control of the relative positioning and orientation of donor and acceptor groups. Here we show that such photoinduced charge transfer processes within homo- and hetero-rotaxanes can be controlled through organisation of the components of the mechanically interlocked molecules, introducing alternative pathways for electron donation. Specifically, studies of two rotaxanes are described: a homo[3]rotaxane, built from a perylenediimide diimidazolium rod that threads two pillar[5]arene macrocycles, and a hetero[4]rotaxane in which an additional bis(1,5-naphtho)-38-crown-10 (BN38C10) macrocycle encircles the central perylenediimide. The two rotaxanes are characterised by a combination of techniques including electron diffraction crystallography in the case of the hetero[4]rotaxane. Cyclic voltammetry, spectroelectrochemistry, and EPR spectroscopy are employed to establish the behaviour of the redox states of both rotaxanes and these data are used to inform photophysical studies using time-resolved infra-red (TRIR) and transient absorption (TA) spectroscopies. The latter studies illustrate the formation of a symmetry-breaking charge-separated state in the case of the homo[3]rotaxane in which charge transfer between the pillar[5]arene and perylenediimide is observed involving only one of the two macrocyclic components. In the case of the hetero[4]rotaxane charge separation is observed involving only the BN38C10 macrocycle and the perylenediimide leaving the pillar[5]arene components unperturbed.