Introduction

The terminology “molecular tweezers” was first introduced by Chen and Whitlock in 1978 through a seminal paper , wherein they presented a water-soluble molecular receptor composed of two caffeine recognition units linked by a semi-rigid diyne spacer. This ingenious design enabled the tweezers to selectively bind aromatic guests within a cavity, utilizing an induced fit mechanism. Subsequently, with the emergence and advancement of supramolecular chemistry, the field of molecular tweezers experienced rapid expansion, witnessing the development of rigid clips by Klärner and Schrader , and more flexible variants by Rebek , Zimmerman , Bosnich and others . Initially serving as agents for guest binding and recognition, molecular tweezers have undergone a remarkable evolution, diversifying their applications into the realms of biology, catalysis, and molecular machines. In particular, the advent of artificial molecular machines , consisting of an assembly of molecular components that perform mechanical-like motions in response to specific stimuli, has inspired the development of stimuli-responsive molecular tweezers, which have flourished since the early 2000s. It is worth mentioning, as stated by Leigh in a comprehensive review , that a pioneering example of a molecular machine was the photoswitchable molecular tweezers developed by Shinkai in 1981 for photocontrolled cation binding. This novel class of tweezers represents prototypes of molecular machines in which guest binding is regulated by stimuli-induced conformational changes between open and closed states (Figure 1). This feature holds significant promise for applications in sensing, drug delivery, or membrane transport within biological systems. Moreover, the incorporation of responsive functionalities into molecular tweezers not only provides significant benefits in catalysis for the development of switchable catalysts but also extends their utility to molecular magnetism, where magnetic switches exploit mechanical motion, and to molecular electronics, enabling multilevel switches.

Figure 1: Principle of switchable molecular tweezers.

The stimuli applied to trigger these conformational changes can be categorized into three principal types: chemical, photochemical, and electrochemical. Chemical stimuli involve the introduction of small reactive molecules, such as reagents, ions, or pH changes, and are frequently employed in biological systems for communication and actuation (e.g., ATP). They, however, generate waste which is very well managed in biological systems by using compartmentalization strategies. Nonetheless, the challenge of waste management in artificial systems remains significant. On the other hand, photochemical stimuli offer cleaner alternatives, relying solely on a light source that can be focused on specific areas. However, they may be limited by photostationary states and penetration depth in absorbing media that might prevent full conversion and potential side photochemical reactions. Electrochemical stimuli, while generating no waste when employing electrodes, may face limitations due to the electroactive window of the solvent and require the incorporation of redox-active switching units, which can impose constraints on design and functionality. It is worth noting that the stimulus may affect either the spacer or the functional units, with the former being more commonly employed for the design of switchable molecular tweezers. In this review, we aim to present recent developments in switchable molecular tweezers, classified according to their principal type of stimulus, and explore their applications in various domains.

Switchable molecular tweezers as an emerging direction in supramolecular chemistry

Among the large variety of molecular machines capable of controlling mechanical motion in response to stimuli, we found switchable molecular tweezers particularly appealing because of the simple design and high potential for many applications. The drastic conformational change induced by the opening and closing of the tweezers attracted us as a straightforward method to control various properties. This change creates a cavity for guest binding, but tweezers have even greater potential if the arms exhibit additional properties such as luminescence, magnetism, catalysis, redox activity, or more. Such systems can also provide two orthogonal responses: the mechanical motion between the open and closed forms, and a potential new property that emerges when the arms are in spatial proximity, either by direct interaction or via a small intercalating molecule. Therefore, switchable molecular tweezers can be considered a prototype of a mechanical molecular device capable of allosteric regulation and dual control through switching and guest binding. While the primary application of molecular tweezers has been in molecular recognition with reversible guest binding, we believe that the scope of applications can be significantly broader. Recent examples have demonstrated their potential to regulate biological activity, facilitate transmembrane transport, enable switchable catalysis, influence magnetic interactions, or serve as multilevel switches. These new directions will be highlighted in the following.

Review Coordination-responsive tweezers

Coordination-responsive switchable systems hold great potential thanks to the tunability and dynamic nature of the coordination bond. This is particularly evident for metal complexes, where the system's geometry can be finely tuned to modulate its response based on the selection of metal and ligand components. This aspect has been extensively explored by Schmittel and co-workers in a recent review . Molecular tweezers have been developed in this direction since the beginning of the 21st century concomitantly with the growth of the field . Because of their ability to respond to chemical stimuli, coordination-responsive switchable tweezers have the potential to be used in many applications including but not limited to supramolecular sensors and drug delivery systems .

pH-Responsive molecular tweezers

A particular case of coordination-responsive systems is when a proton is used as a stimulus leading to pH-responsive systems with the protonation/deprotonation of the switchable moiety. The conformational switch in these systems is mainly driven by intramolecular hydrogen bonds.

The methoxyphenyl-pyridine-methoxyphenyl moiety, developed by Petitjean et al. , demonstrates conformational switching upon the addition of acid in aqueous media (Figure 2). The neutral tweezers adopt a "U"-shaped conformation with both arms pointing in a parallel direction, as the bulky -OMe groups are located outside the tweezer’s cavity to avoid steric hindrance with each other. When protonated, the pyridinium group acts as a hydrogen-bond donor for the two methoxy groups and triggers the rotation of the respective benzene rings along with the attached functional arms. The formation of new hydrogen bonds between -OMe groups and protonated pyridine stabilizes a "W"-shaped open conformation. The conformation switch can be easily followed by NMR spectroscopy in solution. Remarkably, the water-soluble tweezers 1, when functionalized with hydrophobic arms, can encapsulate planar aromatic molecules, making this system promising for drug delivery.

Figure 2: Principle of pH-switchable molecular tweezers 1 .

The advancement of pH-switchable molecular tweezers laid the groundwork for the development of switchable lipids . When such lipids are incorporated in lipid vesicles, they provide means for controlled release of siRNA or miRNA encapsulated within them into the solution in vitro and in vivo . The closed conformation of 2 with parallel alkyl chains acts as a building block of the bilayer membrane and is packed together with other lipids. When the surrounding medium becomes acidic, the tweezers adopt their open conformation. This causes fluctuations and local defects in the packing of a bilayer (Figure 3), leading to membrane disruption and release of active components from within the vesicles . Such concept makes these tweezers good candidates for controlled drug delivery.

Figure 3: a) pH-Switchable tweezers 2 substituted with alkyl chains as switchable lipids. b) Schematic depiction of the lipid bilayer disruption mechanism induced by 2. Figure 3b was reproduced from W. Viricel et al., “Switchable Lipids: Conformational Change for Fast pH-Triggered Cytoplasmic Delivery” Angew. Chem., Int Ed. with permission from John Wiley and Sons. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This content is not subject to CC BY 4.0.

The group of F. Wang et al. exploited the same scaffold to control the physical properties of materials. They incorporated planar terpyridine-alkyne Pt complexes as functional units and studied the intercalation of a Pt-complex guest in order to obtain Pt–Pt interactions in solution . In the native state of 3, both arms with planar Pt complexes are parallel and the distance between them allows for the intercalation of another terpy-Pt complex. The guest intercalation coupled with the induction of short-range Pt–Pt interactions was followed by UV–vis absorption and emission spectroscopies with characteristic MMLCT signals in the low-range visible/NIR region. Upon protonation of the pyridine, the conformation switch leads to a spatial separation of the active Pt moieties and a release of the guest (Figure 4). Also, the same group demonstrated the induction of chirality and fluorescence with chiral guest molecules using a similar principle . The protection from the solvent of the intercalated Pt guest enables its fluorescence emission and is accompanied by the induction of chirality in the resulting host–guest complex. A significant enhancement of the circular dichroism response of the chiral guest is observed confirming the formation of the host–guest complex. Again, protonation of the pyridine results in a guest release and a loss of the CD signal. Thus, this system provides a peculiar example of the control of chirality by a pH stimulus.

Figure 4: Modification of spectral properties of 3 by controlled induction of Pt–Pt interactions.

A similar moiety employed for acid–base-triggered conformational switching is di(hydroxyphenyl)pyrimidine which was developed by Osakada et al. (Figure 5). By default, this moiety adopts a U-shaped conformation stabilized by OH···N hydrogen bonds. In this conformation, tweezers 4 with two 9-ethynylanthryl arms form a 1:1 complex with 2,4,7-trinitrofluorenone (TNF) with a good association constant of 2100 M−1. Upon protonation of the pyrimidine nitrogen atom the hydrogen bond is disturbed, which should result in a conformational change to an open W-shaped form. Even though an acid-mediated hydrogen bond disruption was expected, no clear experimental evidence was reported. Nevertheless, conformational changes were obtained from two other stimuli: (i) alkylation of phenolic OH groups that leads to the disappearance of the hydrogen bonds and a more stable W-shaped conformation; (ii) addition of F− anion as a competitive hydrogen-bond acceptor that binds to the OH groups instead of the pyrimidine nitrogen atoms.

Figure 5: Conformational switching of di(hydroxyphenyl)pyrimidine-based tweezer 4 upon alkylation or fluoride anion addition.

The group of Aprahamian has developed hydrazone-based molecular switches that can be controlled by photochemical or chemical stimuli such as pH . They reported mesogenic tweezers-like compound 5 composed of a hydrazone switch substituted by two mesogenic cholesteryl groups (Figure 6) . Due to strong hydrogen bonding between the pyridyl moiety and the N–H of the hydrazone, tweezers 5 predominantly exist in the closed E-form in a CD2Cl2 solution (E/Z-isomer ratio of 91:9). Upon protonation of the pyridyl group, a complete conversion to the Z open form is achieved, in which the cholesteryl units are oriented in an anti-fashion. This conformational change results in a significant increase in the solvent-accessible surface area. Tweezers 5 were utilized as a dopant for the achiral liquid crystalline material nematic phase 5 (NP5) to produce a chiral nematic phase, whose reflected color can change from green to purple under cross-polarized view upon protonation. This system serves as an elegant example of a macroscopic effect induced by a conformational change at the molecular level.

Figure 6: Hydrazone-based pH-responsive tweezers 5 for mesogenic modulation.

In a different approach where the stimuli affect the recognition unit, pH-switchable molecular tweezers with acridinium functional units have been recently reported by de Rouville et al. . The acridinium moiety is a planar electron-poor aromatic system that can form π–π interactions with electron-rich molecules . The particularity of acridinium is that it can undergo the addition of a nucleophile like HO− or RO− forming an acridane derivative having non-planar geometry and different electronic properties. Triphenylene tweezers 6 are able to intercalate planar electron-rich guest molecules like TTF and pyrene. Upon the addition of a nucleophile (MeO−) the acridinium moieties are modified to acridane which leads to the loss of affinity for the guests (Figure 7). This process is reversible as the addition of an acid restores the acridinium planar form. Thus, such molecular tweezers are also good candidates for controlled guest release in solution. This concept was further developed with a bis-acridinium cyclophane as a multiresponsive receptor for selective phase transfer. In organic media, this macrocyclic receptor presented an affinity for polyaromatic guests with strong selectivity for perylene. A reversible guest release was achieved by chemical (hydroxide/proton) or electrochemical (reduction/oxidation) stimuli allowing the enrichment of perylene from a mixture of polycyclic aromatic hydrocarbons (PAHs) in phase-transfer experiments into a perfluorocarbon phase.

Figure 7: pH-Switchable molecular tweezers 6 bearing acridinium moieties.

Metal cation responsive tweezers

In the early 2000s, Lehn and co-workers introduced a switchable system based on a terpyridine (terpy) ligand (Figure 8), which is structurally similar to the diphenylpyridine units used by Zimmerman in rigid clips, but can change their conformation upon complexation by a metal cation . When substituted at the 6 and 6" positions, the terpyridine adopts an open "W"-shaped conformation due to the s-trans-conformation between two pyridines forced by the repulsion of the nitrogen lone pairs. Upon metal coordination the pyridine units rotate to allow for a tridentate binding to the metal cation, thus inducing a molecular motion to a closed “U”-shaped conformation. This type of switch was first described with the molecular tweezers 7 bearing two pyrene chromophores on the position 6 and 6” of the terpyridine, resulting in an open “W” conformation . In this state, the system exhibits luminescence properties that are quenched when the tweezers are closed by the addition of a Zn2+ cation because of intramolecular π–π stacking interactions between the chromophores. The system can be reopened and its luminescence properties restored by introducing tris(2-aminoethyl)amine (TREN), which has a better affinity for Zn2+ and can abduct it from the terpyridine. The luminescence properties in the closed state can also be modulated by the formation of host–guest complexes. This happens with ligands complexing the metal center only, such as terpyridines and phenanthrolines. In fact, the counterions of the zinc2+ cation and their solvation sphere occupy part of the cavity and prevent non-coordinating guests from entering the binding cavity. By extending the spacer between the terpy and the arms from a single C–C bond to an amide functional group that also participates in the coordination of the Zn2+, non-coordinating guests such as trinitrofluorene (TNF) and tetracyanoquinodimethane (TCNQ) are complexed in the closed state .

Figure 8: a) Terpyridine and pyridine-hydrazone-pyridine analogs molecular tweezers and b) extended pyridine bishydrazone tweezers for guest binding.

Terpyridine-based switches have also been described with metalloporphyrin arms bearing metal ions such as Zn(II) and Au(III) . Terpyridine bisporphyrin tweezers have been synthesized as homometallic (Zn/Zn) and heterometallic (Zn/Au) compounds. In the open state, the porphyrins do not interact and the closing process allows the system to acquire distinct properties depending on the porphyrin. For the Zn/Zn system, guest binding abilities have been observed with diamines that can coordinate the two metallic centers in the tweezers cavity in a bridging mode. For the heterometallic Zn/Au system, luminescence quenching was observed in the closed state.

The pyridine-hydrazine-pyridine unit has been extensively studied by Lehn and co-workers in coordination-responsive supramolecular polymers as it is isomorphic to the terpyridine and presents similar metal coordination properties . Molecular tweezers 10 bearing 1,4,5,8-naphthalenediimide (NDI) luminescent arms have thus been developed. The system exhibits similar switching behavior as the terpyridine tweezers. In terms of host–guest complexation, it can also only bind to coordinating guests (terpyridine, bipyridine) due to the proximity of the coordination sphere with the binding pocket. Tweezers 11 with NDI arms and an extended pyridine-hydrazone-pyridine-hydrazone-pyridine switchable unit have thus been developed. This larger system adds two more chelating sites and moves farther the functional unit allowing the intercalation of electron-rich polyaromatic guests such as pyrene . In general, these hydrazone-based systems have the advantage of being more synthetically accessible than the terpyridine-based system and enable dynamic ligand formation due to the reversibility of the hydrazone bond formation .

More recently, Vives and co-workers have developed a family of terpyridine-based tweezers bearing metal–salphen complexes as functional units (Figure 9). Using metal complexes as arms brings modularity to the system and allows exploring applications beyond guest recognition for molecular tweezers. Indeed, with the same design of tweezers, their properties can be modified just by changing the complexed metal in the functional unit. Such tweezers were first described with 6,6”-substituted terpyridine-bearing platinum–salphen known for their luminescence properties . The closing process of the tweezers 12 was studied by NMR or UV–vis titrations with Zn2+ and other cations such as Pb2+, Fe2+, Cu2+, Eu3+, and Yb3+ indicating in all cases a 1:1 association model. The system can then be reversibly reopened by the addition of TREN as a competitive ligand. The authors reported a slight luminescence quenching in the zinc-closed state with a decrease in the quantum yield from 0.27 to 0.21. However, Hg2+ presented a special behavior with the formation of a 2:1 complex, the closing of the tweezers by the first equivalent generating an allosteric binding site specific to a second Hg2+ ion. While the addition of one equivalent of Hg2+ decreased the quantum yield to 0.09, the formation of a bis-coordinated [tweezers-Hg2]4+ complex resulted in a total luminescence quenching (quantum yield <10−3). The crystallographic structure of the closed form revealed a helicoidal folding of tweezers resulting in a stacking of the Pt–salphen moieties with a Pt–Pt distance of 3.75 Å slightly above the limit for Pt–Pt interactions. In order to enable better interactions in the closed form, modified Pt–salphen tweezers with tert-butyl groups positioned farther from the salphen via alkyne spacers were synthesized . While, like in the parent tweezers 12, no intercalation of aromatic guests was observed in the closed form, strong intramolecular and intermolecular Pt–Pt bonds were achieved in the solid state.

Figure 9: Terpyridine-based molecular tweezers with M–salphen arms and their field of application. Figure 9 was adapted with permission from , Copyright © 2017 American Chemical Society. This content is not subject to CC BY 4.0.”

Using the same architecture, the group explored the control of magnetic properties by the mechanical motion of the tweezers using Cu(II)–salphen complexes . The magnetic properties of tweezers 13 were studied by EPR spectroscopy and SQUID magnetometry. In the open state, the large intramolecular distance of 21 Å between the two Cu(II) complexes results in an independent paramagnetic behavior. However, in the closed form, the metal centers are much closer to each other (4.03 Å) resulting in a weak antiferromagnetic coupling via through-space exchange interaction. This demonstrates the value of coordination-switchable tweezers for switching between two magnetic states that are stable at room temperature . To increase the magnetic coupling between the metal center the group investigated the Mn(III)–salphen tweezers 14 that can coordinate in apical position to cyanide ions. The complexation of CN− anions to the open form unexpectedly resulted in the closing of the tweezers thanks to a Mn–CN–Mn bridging . An antiferromagnetic coupling between the two Mn(III) centers combined with a spin crossover from high spin to low spin Mn(III) was observed. Like in the other terpy-based tweezers, a reversible Zn-induced closing was also achieved. Despite the magnetic anisotropy of Mn(III), no single molecule magnet behavior was observed in either closed form. Nevertheless, this system constitutes a promising example of dual switchable molecular tweezers that can be addressed by two orthogonal stimuli.

Vives and co-workers then explored the redox non-innocent properties of Ni(II)–salphen moieties to achieve a multistate system with tweezers 15 . Indeed, Ni(II)–salphen complexes present two reversible oxidation waves with oxidation centered on the ligand. However, in the presence of a coordinating ligand (such as pyridine or pyrazine), valence tautomerism from ligand-centered oxidation to a metal-centered one is achieved due to the stabilization of an octahedral Ni(III). These properties allow the tweezers to reach six distinct and stable states by playing with three orthogonal stimuli that are: (i) metal coordination for closing/opening of the tweezers, (ii) reversible oxidation, (iii) pyrazine guest binding in the oxidized state. Such an example demonstrates the potential of the molecular tweezers architecture to go beyond simple two-level switches and access multilevel systems. Catalytic tweezers 16 were then synthetized by Vives and co-workers using a 6,6”-substituted terpyridine this time bearing zinc(II)–salphen complexes . The catalytic activity was evaluated in an acetyl transfer reaction between pyridinemethanol derivatives and anhydrides. For the ortho derivative, a rate increase was observed upon closing due to the spatial proximity in the cavity between the two substrates. In contrast, the open tweezers showed a higher rate for the acetylation of meta and para substrates as a result of substrate inhibition of the closed cavity. These tweezers constitute a remarkable substrate-dependent allosteric with potential applications for regulating cooperative catalytic reactions.

Terpyridine-based tweezers have also been developed by Bencini, Lippolis, and co-workers for the selective recognition of diphosphate with [9]aneN3 unit 17 . When closed with Zn(ClO4)2, the anion-binding moieties are preorganized for diphosphate binding, resulting in a 3-order of magnitude increase in affinity compared to the open form (log K = 6.9 vs 2.9). This positive allosteric response benefits from ion pairing with the metal cation in addition to the diphosphate interactions via hydrogen bonding with the two protonated [9]aneN3 units and two water molecules coordinated to the zinc center. More recently, terpyridine was also used by Crassous and co-workers to create a chiroptic switch (Figure 10) . They synthesized tweezers 18 bearing helicene moieties as functional groups. The two enantiomers (P,P) and (M,M) were separated by chiral HPLC and displayed opposite circularly polarized luminescence (CPL) and electronic circular dichroism (ECD) properties. The addition of ZnCl2 switched the system from a compact conformation to an extended conformation, resulting in a modulation of the chiroptical properties with a large change in the absorption spectra and a bathochromic shift in the emission maximum. This system represents a rare example of a multi-output readout system, showing responses in ECD, fluorescence, and CPL activity. The authors later reported a similar system with a bipyridine switching unit that exhibits similar chiroptical switching properties .

Figure 10: a) Terpyridine-based molecular tweezers for diphosphate recognition ; b) bishelicene chiroptical terpyridine-based switch .

During the writing of this review, Lee et al. reported molecular tweezers presenting an allosteric response with hard–soft cooperativity . Tweezers 19 is based on a terpyridine ligand substituted in a 6,6” position by azacrown macrocyclic units. As shown previously, the tweezers adopt an open “W” form that can be switched to a closed “U” form by Zn2+ complexation. However, in this system, depending on the zinc counter ions either a bis(terpy) 2:1 complex or a 1:1 complex is obtained (Figure 11). With non-coordinating triflate counter ions, the bis(terpy) complex is exclusively formed in CDCl3/CD3OD 4:1. This complex can be converted to the 1:1 species upon exchange of the triflate with more coordinating chloride anions or directly formed upon closing with ZnCl2. Interestingly, only the closed 1:1 form presents a selective allosteric binding to alkali K+ cations associated with a shift in the emission maxima. This system offers innovative exploitation of switchable molecular tweezers for allosteric ion recognition with a double selection (metallic ion and counter anion) of the closing stimulus.

Figure 11: Terpyridine-based molecular tweezers with allosteric cooperative binding.

Closed-by-default tweezers can be achieved by changing the substitution pattern of the terpyridine from 6,6” to 4,4” (Figure 12). Due to the repulsion between the nitrogen lone pairs, the 4,4”-substituted terpy adopts a “U” conformation in the non-complexed state and can be switched by metal coordinating to a “W” open conformation. Vives and co-workers reported bis(platinum–salphen)terpyridine tweezers 20 that can intercalate in the U form extended aromatic guests such as coronene and perylene . The opening of the tweezers with the addition of Zn2+ released the guest demonstrating an example of negative allosteric regulation with molecular tweezers. It should be noted that the coordination of Zn2+ resulted in a 2:1 bis(terpyridine) [Zn(19)2]2+ complex that was not observed in the analog 6,6” terpy-based tweezers 12.

Figure 12: Terpyridine-based molecular tweezers presenting closed by default conformation.

Wang and co-workers also reported closed-by-default molecular tweezers based on 4,4”-substituted terpyridine bearing this time alkynylplatinum(II)–terpyridine arms 21 . The intercalation of an alkynylplatinum(II)–terpyridine complex system results in a large absorption band in the visible domain (λmax,abs = 515 nm) and an enhanced emission band in the infrared (λmax,emission = 780 nm) attributed to the proximity of the metallic centers which allows MMLCT transitions. These properties have been used to generate reactive oxygen species (ROS) and efficient photocatalytic oxidative cyanation of N-phenyl-1,2,3,4-tetrahydroisoquinoline. The photocatalytic activity of the catalyst could be allosterically imbibed by the addition of zinc(II) which opens the tweezers, releasing the guest and leading to the disappearance of the photosensitizing properties of the system. In an extension of this work, discrete tetranuclear Pt complexes with Pt–Pt interaction were obtained by self-assembly between 21 and bisalkynylplatinum(II)–terpyridine clips . The dimer showed photocatalytic activity in the photooxidation of a secondary amine to the corresponding imine that could be deactivated and reactivated by opening or closing the tweezers.

Variations on multidentate N-donor ligands have also been developed by Lehn and co-workers to introduce new behaviors for cation-responsive systems. One of them is a pyridine-pyrimidine-pyridine (py-pym-py) moiety that, when substituted in 6,6” positions, adopts a “U” conformation due to the lone pairs repulsion between the central pyrimidine and side pyridine nitrogen (Figure 13) . Such moiety is able to complex two copper(I) cations, both sides of the system acting as independent bipyridine units, giving the possibility of sequential opening of the tweezers one arm at a time. Indeed, when only one copper(I) cation is complexed, tweezers 22a and 22b adopt an “S” intermediate conformation that is converted to a “W” conformation like the open terpyridine when complexed to a second Cu+ cation. While the “S” state is obtained with one equivalent of copper(I), the full conversion to the “W” state is more difficult to achieve and needs up to 8 equivalents. This is due to the reduced basicity of the second pyrimidine’s nitrogen when the first is already coordinated. The py-pym-py closed-by-default “U”-shaped systems form host–guest complexes with electron-poor guests such as TNF. These tweezers are thus a three-state system controlled by copper(I) with allosterically regulated guest binding.

Figure 13: Pyridine-pyrimidine-pyridine-based molecular tweezers.

Other groups developed coordination-switchable molecular tweezers with several ligands based on nitrogen coordination sites. Plante and Glass reported tweezers 23 using a bisimidazole-pyridine unit with anisole arms (Figure 14a) . This system can coordinate copper(II) in a square planar conformation giving an almost parallel arrangement of the aryl arms. This creates a cavity able to complex small coordinating guests that interact with the copper as ligands and also with the arms through π–π stacking. This system is selective towards flat aromatic guests and towards electron-rich coordinating guests. Detection by fluorescence was implemented using competition experiments with dimethylaminostyrylpyridine (DMASP). Intercalated DMASP is not emissive, but its displacement by a guest releases its free fluorescent form, which can be detected. The group of Nabeshima reported closely related tweezers based on a 2,6-bis(oxazolinyl)pyridine (Pybox) ligand with two 4-nitrophenylurea substituents as anion receptor 24 (Figure 14b) . This ligand presents a “W” to “U”-shaped conformational change upon metal coordination similar to terpyridine but displays additional chirality that enables monitoring by circular dichroism. Upon the addition of Ca(II), a large increase in the binding affinity for halide ions was observed due to the folding of the receptor in a helicoidal form that enabled cooperative interaction with both urea moieties.

Figure 14: Coordination-responsive molecular tweezers based on nitrogen-containing ligands.

More flexible coordination responsive units composed of two pyridine units linked with a propyldiamine spacer (tweezers 25, see Figure 14c) have been reported by Fuzukumi and co-workers . This unit has four coordination sites and can bind copper in a square planar geometry. The authors functionalized this spacer with two zinc–porphyrin arms. In the uncoordinated state, the conformation is not fixed so the porphyrins do not interact but when the tweezers are closed the porphyrins are facing each other and can interact. The closed and open states exhibit different electrochemical and photochemical properties. The porphyrin interaction in the closed state splits the second oxidation of the porphyrins from a two-electron process to two single-electron processes. This is due to the electrostatic repulsion between the two positively charged complexes that shift the second oxidation potential. The absorption bands of the closed state are redshifted with respect to the open state, demonstrating the porphyrin–porphyrin interactions. Along with Lehn’s and Vives’ work , this example opens the way for new electroactive systems with a cation-controlled electrochemical behavior.

The common bidentate 2,2’-bipyridine ligand has also been used as a switching unit for molecular tweezers. Like the terpyridine unit, substitution in 4 and 4’ or 6 and 6’ gives access to open or closed-by-default systems. An early example of allosterically regulated systems was reported by Fukazawa and co-workers. Their system 26 is composed of two bipyridine-calixarene units linked by a flexible spacer (Figure 15a) . In the non-complexed state, the system presents no cavity. But, when copper(I) is introduced, a complex is formed with the two bipyridine units bringing the two calixarenes close to each other and creating a cavity suitable for C60 complexation. Bipyridine was also used in fluorescence signal transduction systems to induce a conformational change by coordination stimuli (Figure 15b) . The tweezers-like system 27 is built around a tetrasubstituted cis-anti-cis-perhydroanthracene core functionalized at opposite ends with two bis-2,2’-bipyridyl ligands and bis-pyrene fluorescent units. The stable conformation of perhydroanthracene is with the two pyrene units in the equatorial position. Their close spatial proximity leads to the observation of an excimer emission. Upon Zn2+ coordination, the perhydroanthracene core undergoes a conformational change resulting in an axial position of the pyrene groups that are now far away and present monomeric emission properties. It should be noted that in both systems, the conformational change from s-trans to s-cis of the bipyridine unit is not directly responsible for the closing of the tweezers.

Figure 15: Molecular tweezers exploiting the remote bipyridine or pyridine binding to trigger the conformational change.

In a similar way but with monodentate pyridine moieties, Yamaguchi and co-workers described the bis zinc–porphyrin system 28 . By default, the 1,1′-(1,2-ethynediyl)bis[3-methoxybenzene] spacer adopts a trans-conformation due to the pyridine units that intramolecularly complex the zinc in the apical position of the porphyrins (Figure 15c). Upon the addition of Pd(II), the two pyridine moieties prefer to coordinate the palladium which leads to a 180° rotation motion and confers a cis-conformation to the system. This motion positions the porphyrin units face-to-face and allows fullerene complexation in the cavity, thus enabling an allosteric regulation of the complexation properties of the system by a Pd(II) stimulus.

An example of direct utilization of the rotation around the single bond of the bipyridine unit was reported by Caltagirone and co-workers in tweezers 29 (Figure 16a). They developed tweezers with carboxamidoindole units connected in 4 and 4’ positions to a 2,2’-bipyridine unit for switchable anion recognition . The uncomplexed open conformation displays a very low affinity for anions such as chloride, acetate, or diphosphate (log K < 2). The coordination of PtCl2 preorganizes the tweezers in a closed conformation with the two hydrogen-bonding-recognition sites in proximity. A significant increase in the binding affinity toward all anions and in particular for dihydrogen phosphate (log K = 3.5) was obtained. More recently, Álvarez and co-workers reported bipyridine-based molecular tweezers 30 (Figure 16b) with corannulene recognition units on positions 4 and 4’ (open-by-default) for fullerene complexation . The bipyridine can be switched from s-trans to s-cis-conformation by the addition of copper(II) and one equivalent of 1,2-bis(diphenylphosphino)ethane (dppe) ligand forming a square planar complex. This triggers the closing motion of the tweezers by rotation of one pyridine unit. The tweezers can be reversibly reopened by the addition of a second dppe equivalent that forms a more stable Cu(dppe)2 complex. The authors could successfully induce C60 and C70 complexation, with selectivity for C70 (log KC60 = 3.3 and log KC70 = 4.7).

Figure 16: Bipyridine-based molecular tweezers exploiting the direct s-trans to s-cis-switching for a) anion binding or b) fullerene recognition.

In a follow-up of this work, they reported a similar redox-switchable biscorannulene tweezers system with a bis(arylthiol) switching unit that can be locked in the cis-conformation by forming a disulfide S–S bridge upon oxidation. As expected, the preorganized rigid form presents stronger binding affinities to fullerenes than the freely rotating dithiol form .

Recently, similar bipyridine-based tweezers with Zn–porphyrin functional units for fullerene binding were reported, using different stimuli for switching . The Zn-closed tweezers were opened by adding H2PO4− to competitively complex the Zn2+ ions. Then, Ca2+ was added to precipitate the hydrogen phosphate adduct and release the Zn2+ ions, closing the tweezers again.

Another class of a coordination-responsive spacer using oxygen coordination sites was developed concomitantly to the nitrogen-based systems. In 1999, Boschi and co-workers reported the podand-based switchable tweezers 31 (Figure 17) . This kind of spacer is flexible due to the ethylene glycol chain but can complex alkali cations like crown ethers. Upon complexation, the podand unit adopts a cyclic conformation wrapping around the cation and brings the arms close to each other. The selectivity of the cation binding can be modulated by changing the chain length similarly to a crown ether (Figure 17). The cation can be removed by the addition of a better ligand such as a crown ether. The authors reported switchable tweezers bearing metalloporphyrin arms that can be switched by the addition of K+ and Na+ cations. The cation brings the porphyrins together and causes some dynamic fluorescence quenching from the iodine counter anion. The authors attributed the more efficient quenching using KI instead of NaI to the better size affinity of the podand with potassium.

Figure 17: a) Podand-based molecular tweezers . b) Application of tweezers 32 for the catalytic allosteric regulation of the Henry reaction between benzaldehyde derivatives and nitromethane.

Even though this system seemed promising, podand-based molecular tweezers have not attracted much interest for switchable molecular tweezers design until the work of Fan and co-workers in 2014 . They reported tweezers 32 (Figure 17) incorporating chiral Cr(III)–salen arms for the allosteric regulation of a Henry reaction between benzaldehyde derivatives and nitromethane. In the closed form induced by K+ binding, high enantiomeric excesses around 90% and yields (<70%) were obtained due to the cooperative catalytic effect of the two Cr(III) units. Control experiments without K+, or in the presence of competitive crown ether presented a reduced conversion rate and enantioselectivity, proving the conformation change in the reactivity of the system.

Anion responsive tweezers

The main types of anion-responsive switchable tweezers are based on an H-bonding motif that can establish recognition interactions with the anionic species. One of the first examples was developed by Sessler, Jeppesen, and co-workers with a calix[4]pyrrole switching unit . Calix[4]pyrrole tweezers 33 are functionalized by four tetrathiafulvalene (TTF) arms, adopting a 1,3-alternate conformation by default with two cavities for binding electron-poor guests between the TTFs (Figure 18). The authors demonstrated complexation with 1,3,5-trinitrobenzene and other electron-poor guests such as TCNQ. The N–H protons of the pyrrole subunits can form H-bonds with anions, causing the tweezers to switch to a cone conformation when Cl− is introduced. This alters the cavities, allowing for the release of guests bound in the alternate conformation. Such a system offers new approaches towards molecular electronics by generating multistate systems with electronically differentiated states using the tweezers' switching and modulation of host–guest complexes' electronic properties . Sessler also explored the host–guest properties of the cone conformation towards the complexation of fullerenes. Indeed, the large cavity of the cone-conformation calix[4]pyrrole and the electron-donating nature of TTFs allow the complexation of electron-poor C60 guests . A 2:1 complexation of C60 by TTF-functionalized calix[4]pyrrole 33 was observed for the Cl− bound cone conformation with each calix[4]pyrrole entrapping C60 on one side. The complex was easily detected by a large charge transfer absorption band (λmax = 725 nm) and a noticeable emission change (brown to green solution). This complexation happened only in the presence of Cl− and not with the tweezers in alternate conformation, demonstrating the allosteric regulation of the fullerene complexation. Other halides (Br− and F−) also allowed C60 and C70 complexation while tetrabutylammonium cations inhibited the fullerenes' complexation by competing for the cavity of the calix . These calixpyrrole-based tweezers provide a good example of ON/OFF molecular sensors for neutral guests with an anion-binding stimulus.

Figure 18: Anion-triggered molecular tweezers based on calix[4]pyrrole.

This system could further be tuned and adapted by increasing the macrocycle size or by modifying the TTF groups. Indeed, the authors later reported the allosterically regulated complexation of Li+ encapsulated C60 (Li+@C60) in TTF-calix[4]pyrroles and benzoTTF-calix[4]pyrroles . The electrochemical properties of the host–guest system are modulated by a thermally induced electron transfer (ET) that generates the charge separation state [PrS-TTF-C4P•+/Li+@C60•−]. This behavior was first reported with Cl− as an allosteric regulator but was then described with a porphyrin carboxylate anion as the effector. This allowed the generation of photoinduced charge-separated states with extended lifetimes in a supramolecular triad .

Another switching unit controlled by an anion-binding stimulus is bis-indole, reported by Jang and co-workers (Figure 19a) . In the