arene Cavitands: Switching, Halogen-Bonded Capsules, and

Perspective Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Molecular Recognition with Resorcin[4]arene Cavitands: Switching, Halogen-Bonded Capsules, and Enantioselective Complexation Cornelius Gropp,† Brendan L. Quigley,† and François Diederich* Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland ethers6 to cryptands7 to spherands,1c,d the degree of host preorganization increases and metal-ion complex stability and selectivity are greatly enhanced. The beginnings of anionrecognition studies also relied on complexation by macropolycyclic oligoammonium ions.7b,8 Later, anion and cation recognition were merged in macrocyclic systems capable of efficient ion-pair complexation.9 Various classes of preorganized macrocyclic receptors were also key in the early complexation studies with neutral organic molecules. Examples are cyclodextrins,10 cyclophanes,11 cryptophanes,12 carcerands,13 hemicarcerands,13a,14 and cucurbiturils.15 The transition to exploiting readily functionalizable macrocyclic platforms, such as calixarenes16 and resorcinarenes,17 allowed a more general approach for the construction of highly complex receptors, where selectivity was achieved by the incorporation of specific targeting groups. Today, systems for host−guest chemistry and molecular recognition have gained in complexity, including extended frameworks, such as metal−organic18 and covalent organic19 frameworks, selfassembled cages,20 and a variety of mechanically interlocked structures, such as rotaxanes and catenanes.21 New families of macrocyclic hosts have recently emerged, including cycloparaphenylenes22 and pillararenes.23 The latter exemplify the quick pace in this growing field, with their synthesis reported just under a decade ago and their functionalization, host−guest chemistry, and supramolecular assembly rapidly developing in the following years. In this Perspective, we focus on the utility of resorcin[4]arene cavitands in the design and application of model systems that advance the understanding of molecular recognition phenomena in chemistry and biology. First, we briefly illustrate the key properties of resorcin[4]arenes and describe their development into bistable molecular switches with only one state being capable of efficient guest binding. Subsequently, we summarize their use in the formation of halogen-bonded capsules and outline their utility in the generation of optically active receptors for enantioselective complexation.

ABSTRACT: The development of synthetic host−guest chemistry to investigate and quantify weak, non-covalent interactions has been key to unraveling the complexity of molecular recognition in chemical and biological systems. Macrocycles have shown great utility in the design of receptors, enabling the development of highly preorganized structures. Among macrocycles, resorcin[4]arenebased cavitands have become privileged scaffolds due to their synthetic tunability, which allows access to structures with precisely defined geometries, as well as receptors that display conformational switching between two distinct states with a large difference in guest-binding properties. Here, we highlight three case studies demonstrating redoxand photoredox-controlled switching of molecular recognition properties, the formation of guest-binding supramolecular capsules based solely on halogen-bonding interactions, and enantioselective encapsulation of chiral, substituted cyclohexanes by enantiopure cage compounds as a result of perfect shape complementarity, dispersion interactions, and halogen bonding. The high geometrical and conformational control that can be achieved with resorcin[4]arene-derived host systems will continue to be a powerful resource in future molecular recognition studies.

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INTRODUCTION In Cram’s historical definition of host−guest chemistry, hosts are defined as the synthetic equivalent of biological receptors and guests as their counterpart, such as substrates, inhibitors, or co-factors.1 As much as the design of synthetic host systems was inspired by natural receptors, the lessons learned from synthetic systems have contributed directly to elucidating the basic principles governing the function of their biological equivalents.2 In this regard, host−guest chemistry and the study of biological systems have developed an extraordinary symbiosis, helping to decipher phenomena observed in nature.1,2 The evolution of synthetic hosts for specific guest recognition has been closely tied to the development of highly preorganized structures.1,3 This rationalizes the ubiquitous occurrence of macrocycles in early molecular recognition studies, in particular in the development of macrocyclic hosts for alkali metal cations. Since the discovery of crown ethers by Pedersen in 1967,4 synthetic ionophores have experienced a rapid growth in complexity, spanning from acyclic, poorly preorganized polyethers (podands5) to two- and threedimensional macrocyclic hosts. Upon changing from crown © XXXX American Chemical Society

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KEY PROPERTIES OF RESORCIN[4]ARENE CAVITANDS The majority of research is centered around resorcin[4]arene derivatives,16b,24 as the higher homologues are more challenging to access and purify,25 with efforts ongoing to generate improved methods for their preparation and isolation.26 While the Brønsted-acid-catalyzed condensation of resorcinol and an aldehyde remains the most common method for the Received: December 6, 2017

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DOI: 10.1021/jacs.7b12894 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society

polar groups provide solubility in aqueous environments;33 terminal ester groups have been used to create amphiphilic molecules that form ordered Langmuir monolayers at the air− water interface.34 Additionally, through the incorporation of binding groups at the leg termini, resorcin[4]arene cavitands can be deposited on various surfaces, including metals and organic supports.35 While the parent octol compound is highly flexible and adopts multiple conformations,13a,27d,36 bridging of the adjacent phenolic groups by alkyl or aryl groups results in significantly rigidified structures, offering preorganized concave platforms amenable to the design of sophisticated receptor systems (Figure 1). The methylene-bridged compound is locked in a near-C4-symmetric concave conformation, where exit vectors depart from the aryl rings at an angle α of ∼30° with respect to the principal axis of the molecule.37 The more flexible, near-C2symmetric ethane-1,2-diyl-bridged compound can adopt conformations with exit vectors ranging from ∼30° to 50°.37 Bridging the phenolic OH groups with aryl substituents results in structures that can adopt one of two conformations, a vase form featuring a guest-binding cavity and a flat kite form lacking a defined guest binding site (see proceeding Section).17a,32a Both types of bridging enhance the conformational preorganization of the resulting cavitands. Synthetic strategies have been developed that exploit the reversibility of bridging reactions to selectively remove one or more bridging groups, which provide an efficient route to access cavitands bearing distinct wall flaps by subsequent functionalization.29a,b The increased preorganization as well as the ability to access differentially substituted cavitands has been key to their application in more complex host−guest systems.

Figure 1. Functionalization of the octol scaffold and geometrical considerations. (A) Alkyl bridging with n = 1 or 2; methylene bridging (n = 1) leads to rigid exit vectors of ∼30°; ethylene bridging (n = 2) leads to exit vectors of ∼30−50°. (B) Aryl bridging leads to variable exit vectors. The black arrows denote the direction of the exit vectors. R = leg groups; R′ = variable functionalities; LG = leaving group. Representative models from X-ray crystal structures (CCDC No. 1496457 (top) and 888613 (bottom)).13,37

preparation of octols (Figure 1),27 modular post-functionalization methods28 as well as alternative synthetic strategies27d,29 provide access to a diversity of resorcin[4]arene cavitands for widespread applications in host−guest chemistry.27d,29c,30 These synthetic protocols have been extensively reviewed elsewhere and only a few key structural aspects specifically relevant to the construction of resorcin[4]arene-based receptors are presented here. A major advantage of the macrocyclic scaffold is the ability to tune the solubility properties by varying the leg groups (Figure 1), which are typically introduced by the selection of the corresponding aldehyde in the octol synthesis.27d,30 Long alkyl chains, such as undecyl, render the resorcinarenes soluble in low-polarity solvents, such as hexane and benzene,31 whereas shorter alkyl chains aid solubility in more polar organic solvents and also facilitate crystallization.32 Incorporation of charged or

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FROM CONFORMATIONAL SWITCHING TO MOLECULAR SWITCHES Early studies on quinoxaline-bridged resorcin[4]arene cavitands demonstrated that they exist in one of two well-defined conformations, the open kite form (1-kite) or the closed vase form (1-vase), which differ in the orientation of the heteroaryl groups with respect to the bowl (Figure 2).17a,32a In the expanded kite form, these groups fold outward in an unsymmetrical fashion, creating two degenerate, equilibrating C2v-symmetric structures (kite 1 and kite 2).32a,38 In the C4vsymmetric vase form, the heteroaryl groups are oriented upward, forming an extended bowl-type structure with an

Figure 2. Strategies for achieving switchable host−guest complexation. Conformational switching between two conformers with different guestbinding properties (1).41a Changing the size of the cavity aperture by reversible gating (2).46c Switchable pendant guest which competes intramolecularly for external guest binding in the cis-azobenzene configuration (3).47b B


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Figure 3. Diquinone−diquinoxaline redox-active cavitands 4-Q and 5-Q.50 Lone-pair repulsion between the oxygen atoms destabilizes the vase form in 6-Q, while hydrogen bonding (dashed lines) stabilizes the vase form in 6-HQ.52

Figure 4. Cavitands 6-Q−10-Q with H-bond acceptor groups on the quinoxaline wall flaps to stabilize the vase form in the reduced dihydroquinone state.52,53 The triptycene moieties of cavitand 10-HQ efficiently close the cavity at the upper ring.53 Stabilization of the vase conformation in the semiquinone state (4-SQ).54

away from the cavity and intermolecular guest binding became possible (Figure 2).47 While these systems did achieve stimuluscontrolled guest binding and release that was reproducible over a number of cycles, the process relied on competitive binding and was thereby limited by the type of guests and incomplete switching. The vase−kite switching process represented a potentially more general approach to a molecular switch. However, in order for such a switch to be robust, it was desirable to prepare resorcinarene cavitands where the conformational switchingand, hence, guest binding and releasedepended primarily on a single stimulus and was largely independent of variation in other conditions, such as temperature or solvent effects. In addition, the molecular switch should be able to proceed through multiple cycles and ideally be addressable via a non-invasive stimulus. Incorporation of quinones (Q) as redox-active wall flaps48 into the cavitand was seen as an attractive method to achieve this, as they have the ability to be switched chemically, photochemically, or electrochemically to the reduced hydroquinone (HQ) state.49 Cavitand 4-Q bearing alternate quinone and quinoxaline walls was found to undergo solvent-dependent vase−kite switching that was, however, largely independent of the diquinone/dihydroquinone redox state (Figure 3).50 Incorporation of bulkier triptycene-derived quinone walls in 5-Q resulted in slower guest exchange, allowing quantification of the guest-induced conformational switching for a number of cycloalkane guests, in both the oxidized and reduced states of the cavitand. The measured association constants Ka (M−1) for binding to the oxidized cavitand were significantly higher than those for complexation to the reduced form. However, true redox-dependent molecular switching required improved discrimination in guest binding based on the redox state.

internal cavity. Switching between vase and kite conformations was originally observed in response to changes in temperature.17a,32a,39 The favorable solvation of the larger surface area makes the kite form predominant at low temperatures (≤213 K for 1), whereas this solvation becomes entropically disfavored at higher temperatures (≥293 K for 1), resulting in the transition to the more compact vase form.17a,32a,37,39c Many groups have focused on inducing conformational switching in response to a variety of other stimuli,40 including pH changes,41 metal ion concentration,34 solvent effects,41b,e,42 and the presence of guest molecules,37,38,43 as well as studying the kinetics and thermodynamics of the vase−kite switching process.38,42 Significantly, efficient guest binding occurs only in the vase conformation, whereas the kite form, which lacks a cavity, shows poor binding affinities for guests. The ability to access two stable conformational states with extremely different molecular geometries and guest-binding properties offered the potential to develop a molecular switch, which could bind a small molecule guest and release it ondemand in response to an external stimulus.44 This would represent a fundamentally different approach to that typically exploited,45 wherein guest binding and release was achieved by changing the pore size of capsular assemblies.46 This approach often led to poor control over the kinetics of the process. In 2, the pore size is modulated by the reversible, photochemical [4+4] cycloaddition of two anthracene flaps.46c,d An alternative strategy pursued by Rebek and co-workers produced two examples of resorcin[4]arene cavitands bearing a pendant covalently bonded guest functionality.47 In the study of 3,47b a photoswitchable azobenzene linker directed a pendant guest fragment into the cavity when in its cis configuration, thereby preventing intermolecular guest binding in this state. Upon switching to the trans geometry, the pendant guest is directed C


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high residency lifetimes of the guest in the reduced HQ cavitand.53 This is evident when comparing the association constants for cyclooctane binding by the two cavitands, Ka = 5300 M−1 was measured for 10-HQ, whereas the rim-open 6HQ binds this guest with a much lower Ka value (83 M−1, both in mesitylene-d12 at 298 K). In comparison, the oxidized kite form 10-Q shows a negligible binding affinity for cyclooctane (Ka ≈ 2 M−1). The first-order rate constant for decomplexation of 1,4-cyclohexanedione from 6-HQ is kout = (10.5 ± 0.2) s−1, whereas it is dramatically slowed down for the escape of cyclohexane from 10-HQ (kout = (5.3 ± 0.2) × 10−5 s−1). Triptycenes close the upper rim of the cavitands even more efficiently than covalent handles bridging the rim in related molecular baskets.46a,b,49 These experimental findings provide proof of principle that appropriately designed resorcin[4]arenebased cavitands represent a viable approach to molecular grippers that can pick up a small molecule, hold onto it for a significant period of time, and then release it on-demand. This offers the potential for use in nano-manipulation processes, such as ordered self-assembly on surfaces, by attaching such molecular grippers to the tip of a scanning microscope. A second strategy relied on the stabilization of the vase form in the bis-semiquinone (SQ) redox state of cavitands 4 and 5 (see Figure 3 and 4-SQ, Figure 4).54 While NMR spectroscopy had proved an extremely valuable technique in studying both the Q and HQ states in the previously described approach, the paramagnetic triplet SQ dianion state required the application of new analytical techniques for structural characterization and for the investigation of kite-to-vase switching and guest binding. Electrochemical reduction of both 4-Q and 5-Q demonstrated a first, fully reversible 2 e−-reduction, which produced the corresponding SQ compounds, 4-SQ and 5-SQ. EPR spectroscopy confirmed that 4-SQ and 5-SQ were predominantly formed as stable triplet bis-SQ diradical dianions, which were present in the vase conformation. This was further supported by UV/vis spectroelectrochemistry and transient absorption spectroscopy measurements, which demonstrated characteristic absorption bands associated with the bis-SQ triplet state, providing further evidence for its formation and electronic nature, as well as confirming the conformational preference for the vase form in the SQ state. Significantly, this state could also be accessed photochemically using [Ru(bpy)3]2+ as a photoreductant and Et3N as a sacrificial electron donor. Consistent with stabilization of the vase form in the SQ state, probably through the coupling of the two radicals and/or their stabilization by the neighboring quinoxalines and solvent molecules, the highest binding affinities for several smallmolecule guests were observed for the cavitands in the SQ state. For example, guest 1,4-dioxane bound with Ka = 4 M−1 to 5-Q and with Ka ≤ 0.1 M−1 to 5-HQ (mesitylene-d12, 293 K), but with Ka = 949 M−1 to the 5-SQ state (CH2Cl2, 293 K), largely due to the preorganized vase conformation of the latter. Reversibility of switching between the Q and SQ states is much better achieved than switching between the Q and HQ states, which includes a slow reoxidation step. Therefore, the development of this photoredox-switchable cavitand system represents a further advance toward functional molecular grippers and continues to be the subject of ongoing research. Recently, these systems were complemented by a thianthrene-based system from the groups of Dalcanale and Swager, which also demonstrated redox-dependent vase-to-kite switching upon oxidation, due to electrostatic repulsion between the four radical cations in the oxidized state.55d The manifold

Two strategies were explored to introduce intramolecular interactions that selectively stabilize the vase conformation of the cavitand in only one of its redox states. The first strategy was based on previous work by Rebek and co-workers, who demonstrated that the establishment of hydrogen-bonding (Hbonding) interactions between the aromatic cavitand wall flaps could stabilize the vase conformation.51 In the reduction of the diquinone−diquinoxaline cavitands, such as 4 and 5, the Q walls are reduced to the HQ state, converting a H-bondaccepting group into a H-bond-donor group. Therefore, the introduction of H-bond-accepting groups on the neighboring quinoxaline walls was targeted to selectively stabilize the vase conformation in the reduced state by direct H-bonding with the hydroquinone moieties. Conversely, the lone pairs of these Hbond-accepting groups would be repelled by the lone pairs of the quinone carbonyls in the oxidized state, further disfavoring the vase conformation. This is illustrated for the cavitand system 6-Q/6-HQ in Figure 3.52 Besides 6-Q, a series of other diquinone−diquinoxaline cavitands incorporating a variety of H-bond-accepting groups on the quinoxaline walls were prepared (including 7-Q−9-Q, Figure 4).52,53 The conformational behavior of the cavitands was then studied by 1H NMR spectroscopy in CDCl3, in both their oxidized and reduced forms. While all of the cavitands were present in the kite form in their oxidized state, the behavior of the reduced form varied strongly across the series. Insights into this behavior were gained by density functional theory (DFT) calculations, which revealed essential conformational criteria for redox-dependent molecular switching.53 As predicted in these calculations, the two carboxamide moieties on each quinoxaline wall flap in 6 and 10 (Figure 4) provided the highest degree of preorganization for H-bonding to the hydroquinone OH groups, and both cavitands underwent clean kite-to-vase switching upon reduction to the HQ state. Co-crystal structures of 6-HQ and 10-HQ with cavity-bound cyclooctane and chloroform, respectively, confirmed the predicted H-bonding stabilization between the carboxamide and hydroquinone moieties in the solid state (Figure 5). This

Figure 5. X-ray structures of cavitands 6-HQ and 10-HQ with encapsulated guests cyclooctane and chloroform, respectively.52 Guests are shown in the space-filling representation. Hydrogens as well as n-hexyl and n-butyl chains are omitted for clarity. The key Hbonds to the carboxamide moieties stabilizing the hydroquinone vases are shown as dashed lines.

crucial interaction was also demonstrated by IR and 1H NMR spectroscopies in solution studies. For solubility reasons, the di(n-butyl)carboxamide in 6 had to be exchanged for di(noctyl)carboxamide H-bond donor groups. The bulkier triptycene-quinone/hydroquinone flaps in 10 efficiently close the upper ring of the cavitand and lead to both enhanced binding and slower decomplexation rates, ensuring desirably D


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Figure 6. From hydrogen bonding and metal coordination to halogen bonding: examples of supramolecular assemblies employing various interactions, such as hydrogen bonding (11, 12),73 metal coordination (13),74 ion pairing (14),75a hydrophobic effects,75b−d and halogen bonding (15).76 Note the abundance of resorcin[4]arenes as platforms for the assembly of the cages. Counter ions and guest molecules omitted for clarity.

systems developed to provide insight into the conformation of small molecules in the confined space of receptor pockets.62 More recently, the field has progressed to the recognition of dispersion interactions63 and the interaction between dipoles, such as orthogonal dipolar, amide−π (arene/heteroarene), and halogen-bonding interactions in chemical and biological systems.2,64 Halogen bonds are a prominent example of a more subtle interaction,65 where model systems have contributed substantially to their quantification. As a result of these studies, halogen bonds have become an important tool in many areas of chemistry, including medicinal chemistry.66 Halogen bonding (XB) is defined, in analogy to hydrogen bonding, by a donor and an acceptor, where the halogen-containing part is the donor and the electron-donating part, usually a Lewis base (A), the acceptor.67 The increasing polarizability of the halogens from Cl to Br to I rationalizes their increasing strength in XB.65d,68 Important criteria for XB are the required precise orientation of the binding partners, with the CX···A angle approaching 180°, together with a sub-van-der-Waals distance between the interacting atoms of donor and acceptor.69 In this alignment, the lone pair of the Lewis base can interact with the σ*-orbital (electropositive “σ-hole”) of the C−X bond. The high geometrical constraints of this type of interaction are often challenging to be established in solution and explain its abundance in precisely aligned solid-state networks, where XB was first discovered.70 Extensive XB studies in solution started appearing around 2010.2,71 It was shown that the enthalpic gain for a single strong neutral halogen bond in non-competitive solvent environment is larger than the energy gain for a strong neutral hydrogen bond, but that most of it is compensated by large entropic costs due to the mentioned stringent geometrical requirements.71c In protein−ligand complexes, the entropic costs are largely paid by the binding of the entire ligand, which then orients an XB donor bond in precise direction to an XB acceptor site of the protein.66,72

techniques that can be applied to resorcinarene cavitands have allowed a clear picture of the structural changes, kinetics and thermodynamics of conformational switching and guest binding.49,54 While studies have mostly been in solution to date, the modularity of the resorcinarene cavitand systems can potentially provide access to molecules with improved characteristics for solid-state studies and interfacing with metal surfaces, allowing for a wide array of potential applications, such as molecular gripping in nano-manipulation.55

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NON-COVALENT INTERACTIONS STUDIED IN MODEL SYSTEMS Over the past 40 years, model systems have guided chemists through the ensemble of intermolecular interactions observed in natural systems, spanning from strong interactions, such as hydrogen bonding and Coulombic attraction, to more subtle contacts.2 With the observation of both π−π and edge-to-face aromatic interactions in biological systems by Burley and Petsko in the mid 1980s,56 various model systems followed, which allowed quantification of their energetics.57 Cyclophanes are prominent examples of early model systems which illustrate the achievements in the complexation of aromatic molecules and led to the discovery of cation−π interactions by Dougherty and co-workers in the late 1980s.11b,58 The preorganized nature of cyclophanes further enabled the investigation of enthalpically driven complexation (the non-classical hydrophobic effect) for the tight binding of apolar substrates in cavities, both in organic and aqueous media.15c,59 In the late 1990s, investigations with hydrogen-bonded supramolecular capsules, pioneered by Rebek and co-workers, allowed the determination of the optimal space occupancy of 55 ± 9% for lipophilic molecules in apolar confined binding sites.60 This rule became one of the guiding principles for optimal pocket filling in medicinal chemistry.61 From 2000 onward, there has been increased recognition of the importance of conformational analysis, with various model E


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Journal of the American Chemical Society Another approach to overcome large entropic costs for host− guest bonding in solution is the establishment of multidentate bonding. This is nicely illustrated by supramolecular capsular assemblies based on multiple hydrogen bonding (11, 12),20a,73 metal coordination (13),74 ion pairing (14),75a hydrophobic effects,75b,c and more recently halogen bonding (15, Figure 6).76 In all of these cases, stringent design criteria had to be applied in order to obtain the necessary balance between flexibility and preorganization. With decreasing interaction strength and increasing directionality, more rigorous geometrical requirements had to be met. Here, the design and evolution of a capsular assembly for the study of halogen bonding in the solid state, solution, and gas phase will be highlighted.76 The approach toward halogen-bonded capsules chosen by the group of Diederich and other researchers was the supramolecular assembly consisting of resorcin[4]arene-based XB donor and acceptor platforms.76a,77 The key design feature for the synthesis of the halogen-bonded capsule 15 (Figure 6) was the high preorganization of both XB donor and acceptor with the interacting atoms approaching each other in a perfect alignment, not requiring conformational adjustments in the hemispheres upon self-assembly. The hemispheres were functionalized by either n-undecyl chains (15a for solution studies) or n-hexyl chains (15b for crystallography) as legs. The top-rim functionalization with imidazole walls, first reported by Rebek and co-workers, allowed for the introduction of various donor and acceptor substituents in the direction of the principal axis of each hemisphere.78 Additional rigidification and preorganization of the flexible imidazole walls was achieved by adding small amounts of alcohol to bridge the benzimidazole walls in a cyclic hydrogen-bonding array, a protocol again previously introduced by Rebek and co-workers.78b The capsular assembly solely based on four neutral halogen bonds was established by halogen bonding between strong XB donors, tetrafluoroiodophenyls, and modest XB acceptors, lutidines. The assembly of the hemispheres in solution was determined by 19F NMR titrations at fast exchange in C6D6/(CD3)2CO/CD3OD 70:30:1, and the association constant for formation of 15a was determined as Ka = 5370 M−1 (283 K) in an enthalpycontrolled assembly process. Both hemispheres in the capsule tightly bound complementary guests, such as 1,4-dioxane or 1,4-dithiane, but the lutidine Me groups prevented communication between the bound species. Pyridines as XB acceptors, which would not prevent guest communication in the capsule, led to insoluble assemblies. Capsule formation was also demonstrated in the gas phase by electrospray-ionization mass spectrometry (ESI-MS).76b X-ray diffraction on single crystals obtained from MeOH/ benzene/CS2 revealed a 12-component assembly (Figure 7) consisting of the donor and acceptor hemispheres, solely held together by halogen bonding, with their cavities filled by benzene guests. In addition, eight MeOH molecules are clearly resolved and bridge the benzimidazoles of each hemisphere in a circular hydrogen-bonding array, preorganizing them for selfassembly.76b Structural modifications revealed important guidance to further enhance the association strength in solvent mixtures containing alcohols, such as MeOH, for preorganization. The exchange of the four modest lutidine by four strong quinuclidine XB acceptors only augmented the association strength by a factor of 2 (Ka = 10300 M−1) since halogen bonding for capsule formation competes with strong hydrogen

Figure 7. Single-crystal X-ray structure of the 12-component supramolecular assembly of 15b, featuring the halogen bonding as the sole intermolecular interaction between the two hemispheres, with two encapsulated benzene (space filling representation) and eight MeOH molecules (only 4 are shown) preorganizing the hemispheres by bridging the benzimidazole wall flaps in a circular hydrogenbonding array. Hydrogens and n-hexyl legs omitted for clarity.76b

bonding of the alcohol molecules to the highly basic quinuclidine moieties. Gratifyingly, this capsule formation occurred at slow exchange on the NMR time scale, with the capsular association rate constant (kon) strongly lowered due to the desolvation of the four quinuclidines in the acceptor hemisphere required in the assembly step.76b On the other hand, maintaining the lutidine acceptor hemisphere and exchanging the four fluoroiodophenyls by stronger XB donors, (iodoethynyl)tetrafluorophenyl moieties, raised the capsular association constant, now again at fast exchange, to Ka = (2.11 ± 0.39) × 105 M−1. In competitive protic solvent environments, the strength of halogen-bonding self-assembly is better enhanced by tuning the XB donor than by increasing the basicity of the XB acceptor76b New unusual interactions are continuously discovered, and, similar to halogen bonding, synthetic model systems will allow significant insight into their nature and strength. Chalcogen79 and pnictogen80 bonding have recently been added to the repertoire of unusual interactions, and multidentate systems promise to provide a useful tool for their quantification in solution.

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FROM OPTICALLY ACTIVE RECEPTORS TO ENANTIOSELECTIVE COMPLEXATION Early concepts, such as Fischer’s lock-and-key principle for shape complementarity81 and the three-point interaction model,82 eventually evolved to more complex multi-point interaction models,83 and guided chemists in their design of enantioselective substrates for synthetic and natural receptors and artificial enantiopure receptors for chiral ligands. The pioneering studies by Cram et al.1b,c,84 and Prelog et al.85 mainly focused on the enantioselective binding of chiral ammonium cations, α-amino acid esters, or α-aminoalcohols, by enantiopure crown ethers using strong interactions, such as hydrogen-bonding and ion−dipole interactions. With increasing variation of the cationic guest molecules, the development of more complex and highly preorganized optically active cage receptors, such as cryptophanes or hemicarcerand derivatives, was pursued to achieve enantioselective binding.13a,86 Examples of synthetic hosts enabling enantioselective complexation of chiral anionic guests emerged only recently due to the solvation-related challenges associated with anion complexation in protic environments.87 Anion complexation in F


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discrimination in solution study was achieved in most cases. In the solid state, co-crystallization in porous complexes and metal−organic frameworks have gained considerable interest, especially for the structural elucidation of small molecules.95 Also, the absorption and subsequent release of chiral small molecules by porous organic cage structures in the solid state enables their enantiomeric enrichment or even separation.96 Diederich and co-workers set out to construct enantiopure alleno-acetylenic cage (AAC) receptors, (P,P,P,P)-18 ((P)4-18) and (M,M,M,M)-18 ((M)4-18), consisting of four axially homochiral 1,3-diethynylallenes (DEAs) departing from the aryl rings of a tetra-methylene-bridged resorcin[4]arene platform (Figure 8).97 Axially chiral DEAs are optically and thermally stable building blocks featuring a lean all-carbon backbone.98 Both (P)- and (M)-configured enantiomers are available in multigram quantities by efficient synthesis99 and chiral HPLC separation.99d One of the signatures of enantiopure DEAs are their outstanding chiroptical properties.98 Since their first preparation,99a DEAs have been incorporated into various structures spanning from molecular material science to supramolecular and host−guest chemistry.92f,100 Enantiopure alleno-acetylenic oligomers featured high chiral amplification as a result of secondary helical structures with increasing number of monomers in the backbone.100b Shape-persistent macrocyclic oligomers100a enabled in-depth studies of the contribution of symmetry toward their exceptionally strong chiroptical properties.101 The subsequent incorporation of enantiopure DEAs into phenanthroline-based ligands led to the formation of triple helicates with interior cavities in between the lean, axially chiral elements for guest inclusion.92f,100g,i While strong guest-binding-induced circular dichroism was observed upon complexation of achiral nonchromophoric cycloalkanes and heterocyclic analogs (such as 1,4-dioxane), enantioselective complexation was not effective, due to lack of preorganization and insufficient confinement of the chiral cavities. Complete enantioselective and stereoselective narcissistic self-sorting was demonstrated in CH2Cl2 or C2H2Cl4 for racemic mixtures of shorter and longer allenoacetylenic phenanthroline strands, which in the presence of silver(I) salts assemble into dinuclear and trinuclear double helicates and, upon increasing solvent polarity to MeCN or MeOH, to [2]catenanes and bis[2]catenanes.93d,100g For AACs, rotation around a C−C bond in each DEA moiety of (P)4-18 and (M)4-18 resulted in solvent-controlled binary conformational switching between a closed cage conformation and an open state which were characterized both in solution and in the solid state (Figure 9). Small polar solvents such as tetrahydrofuran, acetonitrile, alcohols, and smaller halomethanes favor the open state, whereas the cage conformation is predominant in larger, less polar solvents, such as higher nalkanes, bulky tetrachloromethane, and cycloalkanes. In the closed conformation, the four tertiary alcohols at the termini of the DEAs converge and close the cage with the formation of a four-fold hydrogen-bonding array (Figure 9). While (P)4-18 shows a clockwise orientation of the H-bonding array in the solid state, a counterclockwise directionality is observed for the (M)4-18.97 This chirality of the H-bonding system, reminiscent of earlier work by the groups of Rebek,102 Atwood,20a,94e and Szumna,94e,103 is postulated to contribute to the strong enantioselective binding and chiroptical properties of the overall assembly. The introduction of a binary conformational switching mechanism, enabling guest uptake and release, circumvents the trade-off of confinement versus porosity

protic solvents requires strong Coulombic and hydrogenbonding interactions, compensating for the very high costs of desolvation. Additionally, both the protonation states of receptor and anion, as well as the influence of the counterions need to be considered.87a Similar to enantioselective cation recognition, enantioselective anion binders have evolved by increasing the degree of preorganization and sophistication of the artificial receptor systems.3b,87−89 Examples are the cyclic sapphyrin-based dimer for enantioselective dicarboxylate binding reported by Sessler and co-workers89a or the mechanically interlocked [2]rotaxanes reported by Beer and co-workers, which also take advantage of ionic halogen-bonding interactions in the recognition of guests such as N-Boc-protected amino acids.89d,e Conversely, enantioselective recognition of neutral small molecules often relies on a network of multiple weaker interactions. Early attempts at enantioselective binding of neutral molecules utilized confined molecular cage systems, such as hemicarcerands, constructed from resorcin[4]arene platforms and enantiopure 1,1′-binaphthyl linkers ((P)4-16, Figure 8).90 Another family of enantiopure cage receptors are

Figure 8. Enantiopure cage receptors: hemicarcerand (P)4-16,13a,90 cryptophane (M)2-17,12,86b,91 and alleno-acetylenic cage receptor (P)418.97

the cryptophanes, derived from cyclotriveratrylenes (CTVs, (M)2-17) and introduced by Collet and co-workers.12a,91 In the cryptophanes, chirality stems from the helical chirality of the bridged CTV platforms.86b Recently, metal-mediated (metal−organic cages),20b,c,92 dynamic covalent,93 and mainly hydrogen-bonded noncovalent20a,e,94 assemblies have emerged in the construction of enantiopure cage receptors featuring a wide variety of structural platforms. However, few have been applied to chiral recognition studies and only moderate enantiomeric guest G


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no residual electron density for the other enantiomer was detected) was observed in the X-ray co-crystal structures, with (P)4-18 exclusively complexing the (R,R)-guest and (M)4-18 the (S,S)-enantiomer (Figure 10).97 Remarkably, the guests were bound in their higher-energy diaxial conformation, as the lower-energy diequatorial conformer does not fit into the cavity. A second unexpected observation was the substantial deviation of the dihedral angles θa,a (Me−C(1)−C(2)−Me) from the commonly accepted value of 180° (Figure 10).104 This angle measures −146° for the (R,R)-guest and +144° for the (S,S)-guest. Exclusive binding in the (di)axial conformation was also observed for monohalo- and trans-1,2-dihalocyclohexanes.104 For the dihalo derivatives, torsional angles around 160°, decreasing to 147° for (±)-trans-1,2-bromofluorocyclohexane, were observed. Theoretical calculations on both the isolated guest molecules and their AAC complexes confirmed the substantial reduction of the dihedral angle from the expected 180°, demonstrating that the non-covalent interactions with the host hardly affect the guest conformation and validating the suitability of the interior of the host to capture and study elusive conformers.104 Chiral recognition of (±)-trans-dimethylcyclohexane is exclusively based on dispersion interactions and perfect shape complementarity, with a complete absence of any directional interaction. In the series of (±)-trans-1,2-dihalocyclohexanes, chiral recognition is less effective, reaching a ratio of 3:1 for the diastereoisomeric complexes formed by the (R,R)- and (S,S)enantiomers of the 1,2-dibromo derivative with (P)4-18 (Figure 10).104 Methyl groups, which are much harder and less polarizable than the higher halides Cl and Br are favorable for chiral recognition, as the methylated guests in the disfavored enantiomer cannot be well accommodated in the AAC cavity. Interestingly, even more directional halogen-bonding interactions in the complexes of the dihalo derivatives do not substantially enhance enantioselectivity in binding. In the cocrystal structures of both the (±)-trans-1,2-dichloro- and the (±)-trans-1,2-dibromocyclohexane complexes, short C−X···π and C−X···||| (acetylene) contacts are observed, with theoretical calculations validating the interesting halogen bonding to the DEA acetylene moieties.104 The enantioselectivities and host−guest binding modes deduced from the crystallographic work were fully confirmed in solution by NMR studies at slow host−guest exchange. The association constants

Figure 9. X-ray co-crystal structures of (P)4-18⊃cycloheptane in the closed cage form and (P)4-18⊃acetonitrile in the open conformation. Guests are shown in space-filling representation with carbons in green. Hydrogens and n-hexyl chains omitted for clarity.97 Also shown is the clockwise orientation of the four-fold hydrogen-bonding pattern that closes the top of the cage.

(Figure 9). Importantly, the binary switching is accompanied by strong changes in the chiroptical responses of the electronic circular dichroism (ECD) spectra enabling a sensitive readout for guest complexation in the cage form.97 In the ECD spectra, the longest-wavelength Cotton effect at 304 nm switches from Δε = +191 M−1 cm−1 for the open (P)4-18 in MeCN to Δε = −691 M−1 cm−1 (ΔΔε = 882 M−1 cm−1) for closed (P)4-18 in cyclohexane,97 an unprecedentedly large change in chiroptical properties upon conformational switching. The combination of a highly shape-persistent, confined chiral cavity together with the chiroptical readout for cage inclusion complexation make this receptor an ideal model system to study chiral recognition. A general method to obtain single crystals of the solid-state inclusion complexes was developed.104 It relies on the guestinduced switching of the receptor from the open state in MeCN/H2O 9:1 to the closed cage state upon encapsulation of the guest. Sparing solubility of the closed form in the selected solvent system facilitates the nucleation of crystalline host− guest complexes. A series of co-crystal structures of cycloheptane, cyclohexane, and mono- and trans-1,2-disubstituted cyclohexanes were obtained, enabling a study of the conformation of these guests and their interactions with the AAC.97,104 A highlight was the chiral recognition of (±)-trans1,2-dimethylcyclohexanes: complete optical resolution (>95:5,

Figure 10. Chiral recognition of trans-1,2-disubstituted cyclohexanes in the diaxial conformation bound to the interior of AAC 18. (Left) (P)4-18⊃ trans-1,2-dimethylcyclohexane ((R,R):(S,S) > 95:5). (Middle) (M)4-18⊃trans-1,2-dimethylcyclohexane ((S,S):(R,R) > 95:5). (Right) (P)4-18⊃trans1,2-dibromocyclohexane ((R,R):(S,S) = 3:1). Hydrogens and n-hexyl chains omitted for clarity. Halogen-bonding and selected dispersion contacts are depicted by dashed lines. Distances are given in angstroms.104 H


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Journal of the American Chemical Society measured for the 1:1 complexes in n-octane at 293 K by 1H NMR and ECD spectroscopies are in excellent agreement. (±)-trans-1,2-Dimethylcyclohexane forms a much weaker complex (Ka = 110 M−1) with (P)4-18 than (±)-trans-1,2dichloro- ((Ka = 3800 M−1) or (±)-trans-1,2-dibromocyclohexane (Ka = 29 000 M−1), due to the high energetic costs for accessing the bound diaxial conformation. Further chiral recognition studies with AAC receptors are ongoing.

sensors,111 where the high level of geometrical and conformational control over the resorcinarene scaffold continues to be exploited.

CONCLUDING REMARKS Over the past 50 years, the field of molecular recognition has evolved to achieving highly selective recognition of challenging small molecules and distinguishing complex mixtures of compounds. The fundamental principles governing noncovalent interactions that were determined from the study of synthetic host−guest systems have enhanced our understanding of both chemical and biological molecular recognition phenomena. For example, we had achieved large enhancement in biological affinity by properly establishing halogen-bonding interactions between proteins and designed ligands.2,66,70c The intrinsic strength of individual halogen bonds was subsequently established by study of model systems in solution.71,72 Resorcin[4]arene cavitands have played an enduring role in this development, with continuing studies on their synthesis and properties enabling them to become an even more powerful tool for the future construction of supramolecular receptors and in-depth molecular recognition studies. Routes to efficiently access and selectively functionalize higher resorcin[n]arenes (n > 4)26 would represent a considerable advance, allowing to study of cavitands with larger internal cavities, further broadening the scope of their applications. The selected case studies in this Perspective highlight how the modularity of the resorcin[4]arene scaffold allows precise control over geometry and degree of conformational flexibility. The redox- and photoredox-controlled switching between the bistable conformational states of quinone/quinoxaline-bridged resorcinarenes has enabled the controlled capture and release of small molecules for application as molecular grippers. Stabilization of the vase conformation can be used to access preorganized multidentate cavitands bearing precise exit vectors, which were exploited to form dimeric supramolecular capsules that allowed the study of weak halogen-bonding interactions, which have specific directional requirements. The rigid geometry and precise exit vectors associated with the methylene-bridged resorcin[4]arene were exploited to design chiral receptors that allowed the enantiodiscrimination of challenging hydrophobic small molecules. The ability to readily tune the solubility properties by varying the leg groups was key to carrying out these studies both in the solid state and in solution, allowing a comprehensive picture of the chiral recognition. While these examples (and the majority of examples today) are restricted to organic solvent systems, future studies in aqueous medium promise to offer further insight into the role of water in molecular recognition.2,75,105 Recently, several new branches of supramolecular chemistry have emerged, focusing on the translation of molecular recognition into the development of functional and robust assemblies and materials for applications, such as catalysis,62e,106 separation,107 and transport.108 While there have been some initial promising results for resorcinarenes in these areas,109 especially for self-assembled capsules in the context of catalysis,110 a particularly promising utility for resorcinarenes remains in the development of molecular switches and

François Diederich: 0000-0003-1947-6327

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AUTHOR INFORMATION

Corresponding Author

*[email protected]

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ORCID Author Contributions †

C.G. and B.L.Q. contributed equally to this Perspective article.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This article is dedicated to the memory of Prof. Ronald Breslow. We are grateful to the Swiss National Science Foundation (SNF 200020_159802), the ETH research council (ETH-01 13-2), and F. Hoffmann−La Roche, Basel, for their continued support of our research described in this Perspective article. The Studienstiftung des Deutschen Volkes is acknowledged for a fellowship to C.G. The corresponding author thanks all his co-workers who have contributed to this research over the past three decades; their names are given in the references.

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