Size-Induced Highly Selective Synthesis of Organometallic Rectangular Macrocycles and Heterometallic Cage Based on Half-Sandwich Rhodium Building Block

The controlled synthesis of organometallic supramolecular macrocycles cages remains interesting and challenging work in the field of supramolecular chemistry. Here, two tetranuclear rectangular macrocycles and an octuclear cage were designed and synthesized utilizing a rigid and functionalized pillar linker, 2,6-bis(pyridin-4-yl)-1,7-dihydrobenzo [1,2-d:4,5-d′]diimidazole (BBI4PY) based on three half-sandwich rhodium building blocks bearing different sizes. X-ray crystallography in combination with ¹H NMR spectroscopy elucidated that the two building blocks with shorter spacers only result in rectangular macrocycles. However, the building block of bulkier size to avoid the π-π stacking interactions between two ligands BBI4PY led to the formation of an octuclear cage complex. The latter cage contains two types of metal ions, namely Rh³⁺ and Cu²⁺, showing significant characteristics of heterogeneous metal-assembling compounds. In addition, the cage accommodates two free isopropyl ether solvent molecules, thus displaying host–guest behavior.     

A host–guest strategy for converting the photodynamic agents from a singlet oxygen generator to a superoxide radical generator

Type-I photosensitizers (PSs) generate cytotoxic oxygen radicals by electron transfer even in a hypoxic environment. Nevertheless, the preparation of type-I PSs remains a challenge due to the competition of triplet–triplet energy transfer with O₂ (type-II process). In this work, we report an effective strategy for converting the conventional type-II PS to a type-I PS by host–guest complexation. Electron-rich pillar[5]arenes are used as an electron donor and macrocyclic host to produce a host–guest complex with the traditional electron-deficient type-II PS, an iodide BODIPY-based guest. The host–guest complexation promotes intermolecular electron transfer from the pillar[5]arene moiety to BODIPY and then to O₂ by the type-I process upon light-irradiation, leading to efficient generation of the superoxide radical (O₂⁻˙). The results of anti-tumor studies indicate that this supramolecular PS demonstrates high photodynamic therapy efficacy even under hypoxic conditions. This work provides an efficient method to prepare type-I PSs from existing type-II PSs by using a supramolecular strategy.

A supramolecular strategy is reported for converting the conventional photodynamic agents from a singlet oxygen generator to a superoxide radical generator by the host–guest interaction enhanced electron transfer.     

Supramolecular free radicals: near-infrared organic materials with enhanced photothermal conversion

A novel kind of supramolecular free radical with significantly improved free radical yield and enhanced near-infrared (NIR) photothermal conversion has been fabricated. Perylene diimide (PDI) can undergo chemical reduction to generate PDI radical anions. Cucurbit[7]uril (CB[7]), a bulky hydrophilic head, was utilized to encapsulate the two end groups of the PDI derivative via host–guest interactions, thus hindering its aggregation and suppressing the dimerization and quenching of PDI radical anions in aqueous solution. Due to the increased concentration of radical anions and their absorption above 800 nm, the efficiency of NIR photothermal conversion was significantly improved. Compared with free radicals fabricated by covalent chemistry, the supramolecular free radicals established here could provide a facile approach for the promoted formation of aromatic free radicals, thus opening up a new strategy for the design of NIR photothermal materials with enhanced photothermal conversion.     

In situ reversible tuning of chemical interface damping in single gold nanorod-based recyclable platforms through manipulation of supramolecular host–guest interactions

Recently, chemical interface damping (CID) has been proposed as a new plasmon damping pathway based on interfacial hot-electron transfer from metal to adsorbate molecules. It has been considered essential, owing to its potential implications in efficient photochemical processes and sensing experiments. However, thus far, studies focusing on controlling CID in single gold nanoparticles have been very limited, and in situ reversible tuning has remained a considerable challenge. In these scanning electron microscopy-correlated dark-field spectroscopic measurements and density functional theory calculations, cucurbit[7]uril (CB[7])-based host–guest supramolecular interactions were employed to examine and control the CID process using monoamine-functionalized CB[7] (CB[7]-NH₂) attached to single gold nanorods (AuNRs). In situ tuning of CID through the CB[7]–oxaliplatin complexation, which can result in the variation of the chemical nature and electronic properties of adsorbates, was presented. In addition, in situ tuning of CID was demonstrated through the competitive release of the oxaliplatin guest from the oxaliplatin@CB[7] complex, which was then replaced by a competitor guest of spermine in sufficient amounts. Furthermore, nuclear magnetic resonance experiments confirmed that the release of the guest is the consequence of adding salt (NaCl). Thus, in situ reversible tuning of CID in single AuNRs was achieved through successive steps of encapsulation and release of the guest on the same AuNR in a flow cell. Finally, single CB[7]-NH₂@AuNRs were presented as a recyclable platform for CID investigations after the complete release of guest molecules from their host–guest inclusion complexes. Therefore, this study has paved a new route to achieve in situ reversible tuning of CID in the same AuNR and to investigate the CID process using CB-based host–guest chemistry with various guest molecules in single AuNRs for efficient hot-electron photochemistry and biosensing applications.

This study has paved a new route to achieve in situ reversible tuning of chemical interface damping (CID) in the same gold nanorod (AuNR) and to investigate the CID process using cucurbituril (CB)-based host–guest chemistry with various guest molecules in single AuNRs.     

Engineering living cells with cucurbit[7]uril-based supramolecular polymer chemistry: from cell surface engineering to manipulation of subcellular organelles

Supramolecular polymer chemistry, which closely integrates noncovalent interactions with polymeric structures, is a promising toolbox for living cell engineering. Here, we report our recent progress in exploring the applications of cucurbit[7]uril (CB[7])-based supramolecular polymer chemistry for engineering living cells. First, a modular polymer-analogous approach was established to prepare multifunctional polymers that contain CB[7]-based supramolecular recognition motifs. The supramolecular polymeric systems were successfully applied to cell surface engineering and subcellular organelle manipulation. By anchoring polymers on the cell membranes, cell–cell interactions were established by CB[7]-based host–guest recognition, which further facilitated heterogeneous cell fusion. In addition to cell surface engineering, placing the multifunctional polymers on specific subcellular organelles, including the mitochondria and endoplasmic reticulum, has led to enhanced physical contact between subcellular organelles. It is highly anticipated that the CB[7]-based supramolecular polymer chemistry will provide a new strategy for living cell engineering to advance the development of cell-based therapeutic materials.

Cucurbit[7]uril-based supramolecular polymer chemistry, which closely integrates host–guest recognition with multifunctional polymeric structures, is a promising toolbox for living cell engineering.     

Binding site exchange kinetics revealed through efficient spin–spin dephasing of hyperpolarized 129Xe

Spin exchange between different chemical environments is an important observable for characterizing chemical exchange kinetics in various contexts, including protein folding, chelation chemistry, and host–guest interactions. Such spins experience effective spin–spin relaxation rate, R_2,eff, that typically shows a dispersive behavior which requires detailed analysis. Here, we describe a class of highly simplified R_2,eff behavior by relying on hyperpolarized ¹²⁹Xe as a freely exchanging ligand reporter. It provides large chemical shift separations that yield reduced expressions of both the Swift–Connick and the Carver–Richards treatment of exchange-induced relaxation. Despite observing a diamagnetic system, R_2,eff is dominated by large Larmor frequency jumps and thus allows detection of otherwise inaccessible analyte concentrations with a single spin echo train (only 0.01% of the overall hyperpolarized spins need to be transiently bound to the molecule). The two Xe hosts cryptophane-A monoacid (CrA-ma) and cucurbit[6]uril (CB6) represent two exemplary families of container molecules (the latter one also serving as drug delivery vehicles) that act as highly efficient phase shifters for which we observed unprecedented exchange-induced relaxivity r₂ (up to 866 s⁻¹ mM⁻¹). By including methods of spatial encoding, multiple data points can be collected simultaneously to isolate the exchange contribution and determine the effective exchange rate in partially occupied binding sites with a single delivery of hyperpolarized nuclei. The relaxivity is directly related to the guest turnover in these systems and temperature-dependent measurements yield an activation energy of E_A = 41 kJ mol⁻¹ for Xe@CrA-ma from simple relaxometry analysis. The concept is transferable to many applications where Xe is known to exhibit large chemical shifts.

Localized detection of hyperpolarized, exchanging Xe spins enables quantitative insights at unprecedented sensitivity for characterizing chemical exchange kinetics in various contexts such as host–guest interactions and displacement assays.     

Chiroptical Sensing of Amino Acid Derivatives by Host–Guest Complexation with Cyclo[6]aramide

A hydrogen-bonded (H-bonded) amide macrocycle was found to serve as an effective component in the host–guest assembly for a supramolecular chirality transfer process. Circular dichroism (CD) spectroscopy studies showed that the near-planar macrocycle could produce a CD response when combined with three of the twelve L-α-amino acid esters (all cryptochiral molecules) tested as possible guests. The host–guest complexation between the macrocycle and cationic guests was explored using NMR, revealing the presence of a strong affinity involving the multi-point recognition of guests. This was further corroborated by density functional theory (DFT) calculations. The present work proposes a new strategy for amplifying the CD signals of cryptochiral molecules by means of H-bonded macrocycle-based host–guest association, and is expected to be useful in designing supramolecular chiroptical sensing materials.     

Biphen[n]arenes

To design and exploit novel macrocyclic synthetic receptors is a permanent and challenging topic in supramolecular chemistry. Here we describe the one-pot synthesis, unique geometries and intriguing host–guest properties of a new class of supramolecular macrocycles – biphen[n]arenes (n = 3, 4), which are made up of 4,4′-biphenol or 4,4′-biphenol ether units linked by methylene bridges at the 3- and 3′- positions. The biphenarene macrocycles are conveniently accessible/modifiable and extremely guest-friendly. Particularly, biphen[4]arene is capable of forming inclusion complexes with not only organic cationic guests but also neutral π-electron deficient molecules. Compared with calixarenes, resorcinarenes, cyclotriveratrylenes and pillararenes with substituted mono-benzene units, the biphen[n]arenes reported here possess significantly different characteristics in both their topologic structures and their recognition properties, and thus can find broad applications in supramolecular chemistry and other areas.     

Fluorescence detected circular dichroism (FDCD) for supramolecular host–guest complexes

Fluorescence-detected circular dichroism (FDCD) spectroscopy is applied for the first time to supramolecular host–guest and host–protein systems and compared to the more known electronic circular dichroism (ECD). We find that FDCD can be an excellent choice for common supramolecular applications, e.g. for the detection and chirality sensing of chiral organic analytes, as well as for reaction monitoring. Our comprehensive investigations demonstrate that FDCD can be conducted in favorable circumstances at much lower concentrations than ECD measurements, even in chromophoric and auto-emissive biofluids such as blood serum, overcoming the sensitivity limitation of absorbance-based chiroptical spectroscopy. Besides, the combined use of FDCD and ECD can provide additional valuable information about the system, e.g. the chemical identity of an analyte or hidden aggregation phenomena. We believe that simultaneous FDCD- and ECD-based chiroptical characterization of emissive supramolecular systems will be of general benefit for characterizing fluorescent, chiral supramolecular systems due to the higher information content obtained by their combined use.

Fluorescence-detected circular dichroism (FDCD) spectroscopy is applied for the first time to supramolecular host–guest and host–protein systems and compared to the more known electronic circular dichroism (ECD).     

Encapsulation of Pt(iv) prodrugs within a Pt(ii) cage for drug delivery

This report presents a novel strategy that facilitates delivery of multiple, specific payloads of Pt(iv) prodrugs using a well-defined supramolecular system. This delivery system comprises a hexanuclear Pt(ii) cage that can host four Pt(iv) prodrug guest molecules. Relying on host–guest interactions between adamantyl units tethered to the Pt(iv) molecules and the cage, four prodrugs could be encapsulated within one cage. This host–guest complex, exhibiting a diameter of about 3 nm, has been characterized by detailed NMR spectroscopic measurements. Owing to the high positive charge, this nanostructure exhibits high cellular uptake. Upon entering cells and reacting with biological reductants such as ascorbic acid, the host–guest complex releases cisplatin, which leads to cell cycle arrest and apoptosis. The fully assembled complex displays cytotoxicity comparable to that of cisplatin against a panel of human cancer cell lines, whereas the cage or the Pt(iv) guest alone exhibit lower cytotoxicity. These findings indicate the potential of utilising well-defined supramolecular constructs for the delivery of prodrug molecules.     

Tubular supramolecular alternating copolymers fabricated by cyclic peptide–polymer conjugates

Supramolecular copolymers are an emerging class of materials, which bring together different properties and functionalities of multiple components via noncovalent interactions. While it is widely acknowledged that the repeating unit sequence plays an essential role on the performance of these materials, mastering and tuning the supramolecular copolymer sequence is still an open challenge. To date, only statistical supramolecular copolymers have been reported using cyclic peptide–polymer conjugates as building blocks. To enrich the diversity of tubular supramolecular copolymers, we report here a strategy of controlling their sequences by introducing an extra complementary noncovalent interaction. Hence, two conjugates bearing one electron donor and one electron acceptor, respectively, are designed. The two conjugates can individually assemble into tubular supramolecular homopolymers driven by the multiple hydrogen bonding interactions between cyclic peptides. However, the complementary charge transfer interaction between the electron donor and acceptor makes each conjugate more favorable for complexing with its counterpart, resulting in an alternating sequence of the supramolecular copolymer. Following the same principle, more functional supramolecular alternating copolymers are expected to be designed and constructed via other complementary noncovalent interactions (electrostatic interactions, metal coordination interactions, and host–guest interactions, etc.).

Tubular supramolecular alternating copolymers using cyclic peptide–polymer conjugates are synthesized by the introduction of an extra complementary noncovalent interaction.     

Elucidating dissociation activation energies in host–guest assemblies featuring fast exchange dynamics

The ability to mediate the kinetic properties and dissociation activation energies (E_a) of bound guests by controlling the characteristics of “supramolecular lids” in host–guest molecular systems is essential for both their design and performance. While the synthesis of such systems is well advanced, the experimental quantification of their kinetic parameters, particularly in systems experiencing fast association and dissociation dynamics, has been very difficult or impossible with the established methods at hand. Here, we demonstrate the utility of the NMR-based guest exchange saturation transfer (GEST) approach for quantifying the dissociation exchange rates (k_out) and activation energy (E_a,out) in host–guest systems featuring fast dissociation dynamics. Our assessment of the effect of different monovalent cations on the extracted E_a,out in cucurbit[7]uril:guest systems with very fast k_out highlights their role as “supramolecular lids” in mediating a guest''s dissociation E_a. We envision that GEST could be further extended to study kinetic parameters in other supramolecular systems characterized by fast kinetic properties and to design novel switchable host–guest assemblies.

GEST-NMR is utilized for quantifying the dissociation activation energy (E_a,out) in host-guest systems featuring fast dissociation dynamics.     

Halogen bonding and chalcogen bonding mediated sensing

Sigma–hole interactions, in particular halogen bonding (XB) and chalcogen bonding (ChB), have become indispensable tools in supramolecular chemistry, with wide-ranging applications in crystal engineering, catalysis and materials chemistry as well as anion recognition, transport and sensing. The latter has very rapidly developed in recent years and is becoming a mature research area in its own right. This can be attributed to the numerous advantages sigma–hole interactions imbue in sensor design, in particular high degrees of selectivity, sensitivity and the capability for sensing in aqueous media. Herein, we provide the first detailed overview of all developments in the field of XB and ChB mediated sensing, in particular the detection of anions but also neutral (gaseous) Lewis bases. This includes a wide range of optical colorimetric and luminescent sensors as well as an array of electrochemical sensors, most notably redox-active host systems. In addition, we discuss a range of other sensor designs, including capacitive sensors and chemiresistors, and provide a detailed overview and outlook for future fundamental developments in the field. Importantly the sensing concepts and methodologies described herein for the XB and ChB mediated sensing of anions, are generically applicable for the development of supramolecular receptors and sensors in general, including those for cations and neutral molecules employing a wide array of non-covalent interactions. As such we believe this review to be a useful guide to both the supramolecular and general chemistry community with interests in the fields of host–guest recognition and small molecule sensing. Moreover, we also highlight the need for a broader integration of supramolecular chemistry, analytical chemistry, synthetic chemistry and materials science in the development of the next generation of potent sensors.

Sigma–hole mediated detection of anions is rapidly emerging as a new paradigm in supramolecular sensor chemistry. Herein, we provide an overview of this field including halogen bonding and chalcogen bonding optical, electrochemical and other sensors.     

Supramolecular Immobilization of Adamantyl and Carboxylate Modified N-Heterocyclic Carbene Ligand on Cucurbituril Substrates

Herein, the design, synthesis, supramolecular interactions and structural analysis of a novel bidentate carboxylate chelating N-heterocylic carbene (NHC) ligand is presented. The NHC structure was modified to strategically incorporate adamantyl moiety for the formation of a supramolecular complex with host molecules such as cucurbiturils. The adamantyl modified NHC ligand could potentially be used in recoverable homogeneous catalysts when Immobilized on a solid support via host–guest chemistry. As a versatile precursor, NHC ligand (8) was synthesized and characterized by ¹H-NMR, ¹³C-NMR, FTIR, single crystal x-ray crystallography and elemental analysis. A proof-of-principle non-covalent immobilization of the NHC ligand (8) with a Cucurbit[7]uril (CB7) host was demonstrated using ¹H-NMR titration.     

Modular and hierarchical self-assembly of siRNAs into supramolecular nanomaterials for soft and homogeneous siRNA loading and precise and visualized intracellular delivery

siRNA therapeutics are challenged by homogeneous and efficient loading, maintenance of biological activities, and precise, dynamic and monitorable site-release. Herein, supramolecular nanomaterials of WP5⊃G–siRNA were constructed by modular and hierarchical self-assembly of siRNA with guest (3,6-di(thiophen-2-yl)pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione derivative, G) and host (pillar[5]arene, WP5) molecules in the same system. Demonstrated by experiments and theoretical calculations, WP5⊃G–siRNA was constructed via comprehensive weak interactions including electrostatic, hydrophobic–hydrophilic, host–guest and π–π interactions. Therefore, siRNAs were efficiently loaded, maintaining good stability, bioactivities and biocompatibilities. At pH 6.8, G was protonated to give weak acidic-responsive “turn-on” fluorescent signals, which realized the precise location of cancer sites. This triggered a subsequent delivery and a dynamic release of siRNA in cancer cells under acidic conditions for the entire collapse of WP5⊃G–siRNA by the protonation of both WP5 and G. By both in vitro and in vivo experiments, precise and visualized delivery to cancer sites was achieved to exhibit effective tumour inhibition. This provided an efficient and soft strategy of siRNA therapies and expanded the application of supramolecular nanomaterials in diagnosis and treatment.

Supramolecular nanomaterials of WP5⊃G–siRNA were constructed by modular and hierarchical self-assembly of siRNA with guest and host molecules, initiating weak acidic-responsive, precise and visualized intracellular delivery for efficient therapies.     

Cucurbiturils brighten Au nanoclusters in water

Gold nanoclusters (AuNCs) with well-defined atomically precise structures present promising emissive prospects for excellent biocompatibility and optical properties. However, the relatively low luminescence efficiency in solutions for most AuNCs is still a perplexing issue to be resolved. In this study, a facile supramolecular strategy was developed to rigidify the surface of FGGC-AuNCs by modifying transition rates in excited states via host–guest self-assembly between cucurbiturils (CBs) and FGGC (Phe–Gly–Gly–Cys peptide). In aqueous solutions, CB/FGGC-AuNCs presented an extremely enhanced red phosphorescence emission with a quantum yield (QY) of 51% for CB[7] and 39% for CB[8], while simple FGGC-AuNCs only showed a weak emission with a QY of 7.5%. Furthermore, CB[7]/FGGC-AuNCs showed excellent results in live cell luminescence imaging for A549 cancer cells. Our study demonstrates that host–guest self-assembly assisted by macrocycles is a facile and effective tool to non-covalently modify and adjust optical properties of nanostructures on ultra-small scales.

A host–guest self-assembly approach was developed to brighten Au₂₂(FGGC)₁₈ nanoclusters between CB[n] (n = 7, 8) and FGGC peptide in aqueous solutions.     

Boosting purely organic room-temperature phosphorescence performance through a host–guest strategy

The host–guest doping system has aroused great attention due to its promising advantage in stimulating bright and persistent room-temperature phosphorescence (RTP). Currently, exploration of the explicit structure–property relationship of bicomponent systems has encountered obstacles. In this work, two sets of heterocyclic isomers showing promising RTP emissions in the solid state were designed and synthesized. By encapsulating these phosphors into a robust phosphorus-containing host, several host–guest cocrystalline systems were further developed, achieving highly efficient RTP performance with a phosphorescence quantum efficiency (ϕ_P) of ∼26% and lifetime (τ_P) of ∼32 ms. Detailed photophysical characterization and molecular dynamics (MD) simulation were conducted to reveal the structure–property relationships in such bicomponent systems. It was verified that other than restricting the molecular configuration, the host matrix could also dilute the guest to avoid concentration quenching and provide an external heavy atom effect for the population of triplet excitons, thus boosting the RTP performance of the guest.

Several host–guest cocrystal systems with bright and persistent room-temperature phosphorescence were developed by utilizing a phosphorus-containing material as a robust host and newly developed isomeric organic phosphors as guests.     

Photoregulated supramolecular hydrogels driven by polyradical interactions

Organic radical as a powerful tool has been extensively applied in synthetic chemistry. However, harnessing radical-mediated noncovalent interactions to fabricate soft materials remains elusive. Here we report a new category of supramolecular hydrogel system held by multiple radical-radical (polyradical) interactions, and its photosensitive cross-linking structure. A simple polyacrylamide with triarylamine (TAA) pendants is designed as the precursor. The TAA units in polymer can be converted into active TAA^•⁺ radical cations with light and further associate each other via TAA^•⁺‒TAA^•⁺ stacking interactions to form stable supramolecular network. Temporal control of the light irradiation dictates the degree of radical stacks, thus regulating the mechanical performance of the resulting hydrogel materials on-demand. Moreover, the reversible collapse of this hydrogels can be promoted by adding radical scavenger or exerting reduction voltage.     

Supramolecular Chemistry: Host–Guest Molecular Complexes

In recent times, researchers have emphasized practical approaches for capturing coordinated and selective guest entrap. The physisorbed nanoporous supramolecular complexes have been widely used to restrain various guest species on compact supporting surfaces. The host–guest (HG) interactions in two-dimensional (2D) permeable porous linkages are growing expeditiously due to their future applications in biocatalysis, separation technology, or nanoscale patterning. The different crystal-like nanoporous network has been acquired to enclose and trap guest molecules of various dimensions and contours. The host centers have been lumped together via noncovalent interactions (such as hydrogen bonds, van der Waals (vdW) interactions, or coordinate bonds). In this review article, we enlighten and elucidate recent progress in HG chemistry, explored via scanning tunneling microscopy (STM). We summarize the synthesis, design, and characterization of typical HG structural design examined on various substrates, under ambient surroundings at the liquid-solid (LS) interface, or during ultrahigh vacuum (UHV). We emphasize isoreticular complexes, vibrant HG coordination, or hosts functional cavities responsive to the applied stimulus. Finally, we critically discuss the significant challenges in advancing this developing electrochemical field.     

Selective adsorptive separation of cyclohexane over benzene using thienothiophene cages

The selective separation of benzene (Bz) and cyclohexane (Cy) is one of the most challenging chemical separations in the petrochemical and oil industries. In this work, we report an environmentally friendly and energy saving approach to separate Cy over Bz using thienothiophene cages (ThT-cages) with adaptive porosity. Interestingly, cyclohexane was readily captured selectively from an equimolar benzene/cyclohexane mixture with a purity of 94%. This high selectivity arises from the C–H⋯S, C–H⋯π and C–H⋯N interactions between Cy and the thienothiophene ligand. Reversible transformation between the nonporous guest-free structure and the host–guest assembly, endows this system with excellent recyclability with minimal energy requirements.

Selective adsorptive separation of cyclohexane was realized from an equimolar benzene and cyclohexane mixture via crystalline thienothiophene cages with a selectivity of 94%.