Supramolecular Host Research Articles

Enantioselective photochemical reactions within the confined cavities of supramolecular assemblies

Compared to bulk solvents, reactions in the confined spaces of supramolecular self-assemblies feature rate acceleration, high efficiency and substrate selectivity. These advantages lead to efficient catalytic efficiency and excellent selectivity in enantioselective supramolecular photochemical transformations. During the last few years, enantioselective supramolecular photocatalysis has developed into one of the most powerful strategies to construct enantioenriched chiral compounds. In this review, the recent advances of enantioselective photochemical reactions taking place within the confined spaces of supramolecular assemblies are summarized, with an emphasis on the specific catalytic modes and chemical transformations. Organization of the data follows a subdivision according to supramolecular host and reaction type. At last, the current limitations and the future research orientation of this research field are discussed.

Unusual Metal–organic Multicomponent Ni(II) and Mononuclear Zn(II) Compounds Involving Pyridine dicarboxylates: Supramolecular Assemblies and Theoretical Studies

In the present work, we reported the synthesis and characterization [single crystal X-ray diffraction technique, spectroscopic, etc.] of two new Ni(II) and Zn(II) coordination compounds, viz. [Ni(2,6-PDC)2]2[Ni(en)2(H2O)2]2[Ni(en)(H2O)4]·4H2O (1) and [Zn(2,6-PDC)(Hdmpz)2] (2) (where 2,6-PDC = 2,6-pyridinedicarboxylate, en = ethylene-1,2-diamine, and Hdmpz = 3,5-dimethyl pyrazole). Compound 1 is found to crystallize as a multicomponent Ni(II) compound with five discrete complex moieties, whereas compound 2 is isolated as a mononuclear Zn(II) compound. A deep analysis of the crystal structure of 1 unfolds unusual dual enclathration of guest complex cationic moieties within the supramolecular host cavity stabilized by anion–π, π-stacking, N–H⋯O, C–H⋯O, and O–H⋯O hydrogen bonding interactions. Again, the crystal structure of compound 2 is stabilized by the presence of unconventional C–H⋯π(chelate ring) interactions along with C–H⋯O, C–H⋯N hydrogen bonding, π-stacking, and C–H⋯π(pyridyl) interactions. These non-covalent interactions were further studied theoretically using density functional theory (DFT) calculations, molecular electrostatic potential (MEP) surfaces, non-covalent interaction (NCI) plot index, and quantum theory of atoms in molecules (QTAIM) computational tools. The computational study displays that π-stacking or H bonds greatly tune the directionality of compound 1, although non-directional electrostatic forces dominate energetically. For compound 2, a combined QTAIM/NCI plot analysis confirms the presence of unconventional C–H⋯π(chelate ring) interactions along with other weak interactions obtained from the crystal structure analysis. Further, the individual energy contributions of these weak yet significant non-covalent interactions have also been determined computationally.

Supramolecular Interfacial Assembly: Integrating Supramolecular Hosts into Polymeric Membranes through an Aqueous Interface.

Efficient incorporation of supramolecular hosts in polymeric membranes can impart the overall matrix with new properties for a range of cutting-edge applications. Here, we introduce a Supramolecular Interfacial Assembly (SIA) method for the fabrication of polymeric membranes featuring embedded macrocycles. Through harnessing the quasi-liquid nature of the concentrated polymer solution, SIA orchestrates the homogenous spreading of macrocycles in an aqueous layer on its surface, leading to the creation of an interface between "water/water" phases, subsequently forming a cross-linked membrane driven by supramolecular electrostatic interactions. Remarkably, compared to the traditional interfacial polymerization, SIA adheres to a "green" paradigm without the need for organic solvents. The resultant composite membrane exhibits superior performance in organic solvent nanofiltration (OSN), owing to the precise molecular sieving property provided by the macrocycles with well-defined permanent cavities. This fabrication method holds great promise for the innovative design of composite membranes, which can greatly impact the production of smart membrane materials for advanced technology applications in the future.

Supramolecular Interfacial Assembly: Integrating Supramolecular Hosts into Polymeric Membranes through an Aqueous Interface

Efficient incorporation of supramolecular hosts in polymeric membranes can impart the overall matrix with new properties for a range of cutting‐edge applications. Here, we introduce a Supramolecular Interfacial Assembly (SIA) method for the fabrication of polymeric membranes featuring embedded macrocycles. Through harnessing the quasi‐liquid nature of the concentrated polymer solution, SIA orchestrates the homogenous spreading of macrocycles in an aqueous layer on its surface, leading to the creation of an interface between “water/water” phases, subsequently forming a cross‐linked membrane driven by supramolecular electrostatic interactions. Remarkably, compared to the traditional interfacial polymerization, SIA adheres to a “green” paradigm without the need for organic solvents. The resultant composite membrane exhibits superior performance in organic solvent nanofiltration (OSN), owing to the precise molecular sieving property provided by the macrocycles with well‐defined permanent cavities. This fabrication method holds great promise for the innovative design of composite membranes, which can greatly impact the production of smart membrane materials for advanced technology applications in the future.

Advanced electrochemical detection of pyrophosphatase activity in LNCaP cells utilizing in-situ redox of copper

The necessity for precise delineation and quantitation of pyrophosphatase (PPase) activities is underscored, especially in aggressive prostate cancer, driving the demand for more refined analytical techniques due to challenges associated with inadequate sensitivity and poor signal amplification. In response, a novel electrochemical method utilizing in-situ copper(II) (Cu(II))-based Fast Scan Cyclic Voltammetry (FSCV) is introduced for the advanced detection of PPase in LNCaP prostate cancer cells. This technique is characterized by the exploitation of competitive binding between Cu(II) and L-Phenylalanine (L-Phe) versus pyrophosphate (PPi), with FSCV technology enhanced by ohmic drop compensation to improve detection sensitivity and signal reliability. Through the application of the FSCV technique transitioned to Current(I)-Voltage(V) analysis, the signal generation is facilitated by an L-Phe-Cu(II) complex, driven by the redox reaction of in-situ Cu(II), specifically its rapid transition from the Cu(0) state back to the Cu(II) state. When this complex is anchored onto a gold substrate modified with cucurbit[7]uril (CB[7]) through supramolecular host–guest interactions, a significant FSCV signal is elicited. A detection limit of 0.05 mU/mL (S/N = 3) is subsequently achieved when the method is applied to the quantification of PPase concentration. Leveraging the FSCV method, we have effectively analyzed PPase activity in LNCaP cells, offering a fresh perspective on tumor marker analysis and fostering advancements in drug development.

Guest‐Induced “Breathing‐Helical” Dynamic System of a Porphyrinic Metallo‐Organic Cage for Advanced Conformational Manipulation

Host‐guest dynamic systems in coordination‐driven metallo‐organic cages have gained significant attentions since their promising applications in chiral separation, drug delivery, and catalytical fields. To maximize guest‐binding affinity, hosts adopting multiple conformations are widely investigated on their structural flexibility for guest accommodation. In this study, a novel metallo‐organic cage S with breathing inner cavity and freely twisted side chains was proposed. Single‐crystal X‐ray diffraction analyses depicted a characteristic “breathing‐helical” dynamic system on the semiflexible framework, which led to an unprecedent co‐crystallisation of racemic and symmetric conformations via the encapsulation locking of C70 guests. By taking advantages of the high binding affinity, selective extraction of C70 was realized. This research provides new ideas for the modification on the helicities of metallo‐organic cages, which could pave a new way for advanced conformational manipulation of supramolecular host systems.

Guest-Induced "Breathing-Helical" Dynamic System of a Porphyrinic Metallo-Organic Cage for Advanced Conformational Manipulation.

Host-guest dynamic systems in coordination-driven metallo-organic cages have gained significant attentions since their promising applications in chiral separation, drug delivery, and catalytical fields. To maximize guest-binding affinity, hosts adopting multiple conformations are widely investigated on their structural flexibility for guest accommodation. In this study, a novel metallo-organic cage S with breathing inner cavity and freely twisted side chains was proposed. Single-crystal X-ray diffraction analyses depicted a characteristic "breathing-helical" dynamic system on the semiflexible framework, which led to an unprecedent co-crystallisation of racemic and symmetric conformations via the encapsulation locking of C70 guests. By taking advantages of the high binding affinity, selective extraction of C70 was realized. This research provides new ideas for the modification on the helicities of metallo-organic cages, which could pave a new way for advanced conformational manipulation of supramolecular host systems.

Expedient Decagram-Scale Synthesis of Robust Organic Cages That Bind Sulfate Strongly and Selectively in Water.

Selective anion recognition remains a key challenge in supramolecular chemistry: only a very small number of systems that can function in water are known, and these nearly always preferentially bind hydrophobic anions. In this work, we report three robust hexa-cationic cages that can be prepared on scales up to 14 g in two simple and high-yielding steps from commercially available materials. One of these cages displays unusually strong sulfate binding in water (Ka = 12,000 M-1), and demonstrates high selectivity for this anion over H2PO4-/HPO42- in DMSO/buffer mixtures. These results demonstrate that relatively large, three-dimensional supramolecular hosts can be prepared in high yields and on large scales, and can be highly potent receptors.

Reactivity Inside Molecular Flasks: Acceleration Modes and Types of Selectivity Obtainable.

There is increasing interest in the discovery and application of molecular flasks - supramolecular host structures capable of catalyzing organic reactions. Reminiscent of enzymes due to possessing a host cavity akin to an active site, molecular flasks can exhibit complex catalytic mechanisms and in many cases provide selectivity not achievable in bulk solvent. In this Review, we aim to organize the increasingly diverse examples through a two-part structure. In part one, we provide an overview of the different acceleration modes that operate within molecular flasks, while in part two we showcase, through selected examples, the different types of selectivity that are obtainable through the use of molecular flasks. Particular attention is given to examples that are relevant to current challenges in synthetic organic chemistry. We believe that this structure makes the field more approachable and thus will stimulate the development of novel applications of molecular flasks.

New methods of modification of α-cyclodextrin.

While being some of the oldest supramolecular hosts, cyclodextrins remain very popular as molecular binders in materials, devices, artificial enzymes and more. The popularity is undoubtedly connected to the ready availability, carbohydrate biomass origin, biodegradability and water solubility of the cyclodextrins. Many of these applications require synthetic modification of the cyclodextrin - at the simplest the attachment of a linker - but also often attachment of several functional groups, lids, bridges etc. Here we review state of the art methods of modifying α-cyclodextrin, which include direct modications of unprotected α-cyclodextrin and protection/deprotection method to partially modified cyclodextrins.

A Supramolecular Biosensor for Rapid and High-Throughput Quantification of a Disease-Associated Niacin Metabolite.

Metabolic abnormalities play a pivotal role in various pathological conditions, necessitating the quantification of specific metabolites for diagnosis. While mass spectrometry remains the primary method for metabolite measurement, its limited throughput underscores the need for biosensors capable of rapid detection. Previously, we reported that pillar[6]arene with 12 carboxylate groups (P6AC) forms host-guest complexes with 1-methylnicotinamide (1-MNA), which is produced in vivo by nicotinamide N-methyltransferase (NNMT). P6AC acts as a biosensor by measuring the fluorescence quenching caused by photoinduced electron transfer upon 1-MNA binding. However, the low sensitivity of P6AC makes it impractical for detecting 1-MNA in unpurified biological samples. In this study, we found that P6A with 12 sulfonate groups (P6AS) is a specific and potent supramolecular host for 1-MNA interactions even in biological samples. The 1-MNA binding affinity of P6AS in water was found to be (5.68 ± 1.02) × 106 M-1, which is approximately 700-fold higher than that of P6AC. Moreover, the 1-MNA detection limit of P6AS was determined to be 2.84 × 10-7 M, which is substantially lower than that of P6AC. Direct addition of P6AS to culture medium was sufficient to quantify 1-MNA produced by cancer cells. Furthermore, this sensor was able to specifically detect 1-MNA even in unpurified human urine. P6AS therefore enables rapid and high-throughput quantification of 1-MNA, and further improvement of our strategy will contribute to the establishment of high-throughput screening of NNMT inhibitors, diagnosis of liver diseases, and imaging of human cancer cells in vivo.

Cooperative Binding and Chirogenesis in an Expanded Perylene Bisimide Cyclophane.

The encapsulation of more than one guest molecule into a synthetic cavity is a highly desirable yet a highly challenging task to achieve for neutral supramolecular hosts in organic media. Herein, we report a neutral perylene bisimide cyclophane, which has a tailored chiral cavity with an interchromophoric distance of 11.2 Å, capable of binding two aromatic guests in a π-stacked fashion. Detailed host-guest binding studies with a series of aromatic guests revealed that the encapsulation of the second guest in this cyclophane is notably more favored than the first one. Accordingly, for the encapsulation of the coronene dimer, a cooperativity factor (α) as high as 485 was observed, which is remarkably high for neutral host-guest systems. Furthermore, a successful chirality transfer, from the chiral host to encapsulated coronenes, resulted in a chiral charge-transfer (CT) complex and the rare observation of circularly polarized emission originating from the CT state for a noncovalent donor-acceptor assembly in solution. The involvement of the CT state also afforded an enhancement in the luminescence dissymmetry factor (glum) value due to its relatively large magnetic transition dipole moment. The 1:2 binding pattern and chirality-transfer were unambiguously verified by single-crystal X-ray diffraction analysis of the host-guest superstructures.

Development of Cyclodextrin-Based Mono and Dual Encapsulated Powders by Spray Drying for Successful Preservation of Everlasting Flower Extract.

The study aimed to develop encapsulation systems to maintain the preservation of everlasting (Helichrysum plicatum) flower extract polyphenols. Spray-dried encapsulates were formulated using β-cyclodextrin (BCD) and 2-hydroxypropyl-β-cyclodextrin (HPBCD) as supramolecular hosts, and their macromolecule mixtures with the conventional carriers, maltodextrin (MD) and whey protein (WP). The obtained microparticles were comparatively assessed regarding technological, physicochemical, and phytochemical properties. The highest yields were achieved by combining cyclodextrins with whey protein (73.96% for WP+BCD and 75.50% for WP+HPBCD compared to 62.48% of pure extract). The extract-carrier interactions and thermal stability were evaluated by FTIR and DSC analysis, suggesting successful entrapment within the carriers. Carriers reduced the particle diameter (3.99 to 4.86 μm compared to 6.49 μm of pure extract), classifying all encapsulates as microsystems. Carrier blends made the particle size distribution uniform, while SEM analysis revealed the production of more spherical and less aggregated particles. The HPBCD provided the highest encapsulation efficiency, with the highest content of detected aglycones and slightly lower values of their glycosylated forms. An analysis of the dual macromolecule encapsulation systems revealed the highest bioactive preservation potential for SHE+MD+BCD and SHE+WP+HPBCD. Overall, macromolecule combinations of cyclodextrins and conventional biopolymers in the spray-drying process can enhance the functional properties of H. plicatum extract.

Room‐Temperature Near‐Infrared Phosphorescence from C64 Nanographene Tetraimide by π‐Stacking Complexation with Platinum Porphyrin

AbstractNear‐Infrared (NIR) phosphorescence at room temperature is challenging to achieve for organic molecules due to negligible spin–orbit coupling and a low energy gap leading to fast non‐radiative transitions. Here, we show a supramolecular host–guest strategy to harvest the energy from the low‐lying triplet state of C64 nanographene tetraimide 1. 1H NMR and X‐ray analysis confirmed the 1 : 2 stoichiometric binding of a Pt(II) porphyrin on the two π‐surfaces of 1. While the free 1 does not show emission in the NIR, the host–guest complex solution shows NIR phosphorescence at 77 K. Further, between 860–1100 nm, room temperature NIR phosphorescence (λmax=900 nm, τavg=142 μs) was observed for a solid‐state sample drop‐casted from a preformed complex in solution. Theoretical calculations reveal a non‐zero spin–orbit coupling between isoenergetic S1 and T3 of π‐stacked [1 ⋅ Pt(II) porphyrin] complex. External heavy‐atom‐induced spin–orbit coupling along with rigidification and protection from oxygen in the solid‐state promotes both the intersystem crossing from the first excited singlet state into the triplet manifold and the NIR phosphorescence from the lowest triplet state of 1.

Exploring the potential of supramolecular hydrogels as advanced bioinks for bioprinting and biomedical applications

Supramolecular hydrogels have emerged as versatile bioinks in tissue engineering, providing a promising avenue for constructing intricate and functional biological structures. This paper explores the significance of employing supramolecular hydrogels as advanced bioinks for three-dimensional bioprinting and various biomedical applications. Supramolecular hydrogels possess distinct and tunable characteristics attributed to the dynamic nature of supramolecular host–guest interactions alongside interactions based on DNA and peptides, which increases their significance in tissue engineering. These interactions are essential for enhancing the mechanical properties, injectability, printability, post-printing stability, and biocompatibility of hydrogels. Gelation kinetics and rheological properties can also be manipulated to suit specific printing techniques. Furthermore, these supramolecular interactions facilitate the incorporation of bioactive molecules to regulate cellular behavior and tissue development. These diverse interactions observed in supramolecular hydrogels underscore their ability to emulate the dynamic and responsive nature of the cell’s extracellular matrix, which fosters cell growth, adherence, and differentiation. This review specifically highlights the cucurbit[n]uril and cyclodextrin-based host–guest supramolecular hydrogels, as well as peptide and DNA-based supramolecular structures as advanced bioinks and brief examples of their applications in various biomedical fields. These advanced bioinks would drive the development of intricate tissue constructs with enhanced biomimicry and therapeutic potential in regenerative medicine.

Acyclic Cucurbit[n]uril Receptors Function as Solid State Sequestrants for Organic Micropollutants

AbstractThe accumulation of organic micropollutants (OMP) in aquatic systems is a major societal problem that can be addressed by approaches including nanofiltration, flocculation, reverse osmosis and adsorptive methods using insoluble materials (e.g. activated carbon, MOFs, nanocomposites). More recently, polymeric versions of supramolecular hosts (e.g. cyclodextrins, calixarenes, pillararenes) have been investigated as OMP sequestrants. Herein, we report our study of the use of water insoluble dimethylcatechol walled acyclic cucurbit[n]uril (CB[n]) hosts as solid state sequestrants for a panel of five OMPs. A series of hosts (H1–H4) were synthesized by reaction of glycoluril oligomer (monomer–tetramer) with 3,6‐dimethylcatechol and fully characterized by spectroscopic means and x‐ray crystallography. The solid hosts sequester OMPs from water with removal efficiencies exceeding 90 % in some cases. The removal efficiencies of the new hosts parallel the known molecular recognition properties of analogous water soluble acyclic CB[n]. OMP uptake by solid host occurs rapidly (≈120 seconds). Head‐to‐head comparison with CB[6] in batch‐mode separation and DARCO activated carbon in flow‐through separation mode show that tetramer derived host (H4) performs very well under identical conditions. The work establishes insoluble acyclic CB[n]‐type receptors as a promising new platform for OMP sequestration.

Acyclic Cucurbit[n]uril Receptors Function as Solid State Sequestrants for Organic Micropollutants.

The accumulation of organic micropollutants (OMP) in aquatic systems is a major societal problem that can be addressed by approaches including nanofiltration, flocculation, reverse osmosis and adsorptive methods using insoluble materials (e.g. activated carbon, MOFs, nanocomposites). More recently, polymeric versions of supramolecular hosts (e.g. cyclodextrins, calixarenes, pillararenes) have been investigated as OMP sequestrants. Herein, we report our study of the use of water insoluble dimethylcatechol walled acyclic cucurbit[n]uril (CB[n]) hosts as solid state sequestrants for a panel of five OMPs. A series of hosts (H1-H4) were synthesized by reaction of glycoluril oligomer (monomer-tetramer) with 3,6-dimethylcatechol and fully characterized by spectroscopic means and x-ray crystallography. The solid hosts sequester OMPs from water with removal efficiencies exceeding 90 % in some cases. The removal efficiencies of the new hosts parallel the known molecular recognition properties of analogous water soluble acyclic CB[n]. OMP uptake by solid host occurs rapidly (≈120 seconds). Head-to-head comparison with CB[6] in batch-mode separation and DARCO activated carbon in flow-through separation mode show that tetramer derived host (H4) performs very well under identical conditions. The work establishes insoluble acyclic CB[n]-type receptors as a promising new platform for OMP sequestration.

Supramolecular assemblies involving unusual N(nitrile)∙∙∙π(fum) and nitrile-nitrile non-covalent contacts in fumarato and succinato bridged polymers of Co(II) and Ni(II): Experimental and theoretical studies

Two new Co(II) and Ni(II) coordination polymers viz. [Co(H2O)2(μ-fum)(3-CNpy)2]n (1) and {[Ni(H2O)2(μ-succ)(4-CNpy)2]·2H2O}n (2) (where, fum= fumarate, CNpy = cyanopyridine, succ = succinate) have been synthesized and characterized using single crystal XRD, elemental analysis, spectroscopic (IR and electronic) techniques and TGA. Compound 1 crystallizes as a fumarato bridged Co(II) polymer; whereas, compound 2 is a succinato bridged Ni(II) polymer. The presence of various non-covalent interactions in the compounds stabilizes the layered assemblies of the compounds. Antiparallel nitrile∙∙∙nitrile interactions are observed in both the crystal structures involving the nitrile moieties of coordinated CNpy which provide rigidity to the compounds. Further analysis reveals that the N-atom of –CN group of 3-CNpy in 1 is involved in unusual N(nitrile)∙∙∙π(fum) interactions with the π-electrons of the C=C bond of fum. Enclathrated (H2O)2 cores within the supramolecular host cavity of compound 2 provides additional reinforcement to the crystal structure. We have also carried out theoretical studies to analyze the π-stacking and H-bonding interactions present in the crystal structure of compound 1 using quantum theory of atoms-in-molecules (QTAIM), non-covalent interaction plot (NCI plot) and molecular electrostatic potential (MEP) surface analysis. The MEP value at the N-atom of the cyano group of 1 is negative and the value is neutral over the double bond of the fum; indicating the possibilities of formation of N(nitrile)∙∙∙π(fum) interactions. Energetic analysis suggests that antiparallel π-stacking observed between the 3-CNpy moieties in 1 is the most dominating force followed by N(nitrile)∙∙∙π(fum) interaction and finally the H-bonds.

Colorimetric Detection of Fentanyl Powder on Surfaces Using a Supramolecular Displacement Assay.

Fentanyl is a potent synthetic opioid with an alarmingly low lethal dosage of 2 mg. The equipment necessary to detect fentanyl in field settings (e.g., hand-held spectrometers) is restricted to highly trained, well-funded, and specialized personnel. Established point-of-need technologies, such as lateral flow immunochromatographic strips, are available; however, they often involve multiple contact-based steps (e.g., collection, mixing) that pose a higher risk to users handling unknown substances. Herein, we developed a colorimetric displacement assay capable of contactless detection of fentanyl in liquid or solid samples. The basis of our assay relies on the presence of fentanyl to displace a redox mediator, ferrocene carboxylic acid, inclusively bound in the cavity of a supramolecular host, CB[7]. The displacement is only possible in the presence of high affinity binding guests, like fentanyl (KA ∼ 106 M-1). The liberated redox guest can then react with indicator reagents that are free in solution, producing either: (i) a distinct blue color to indicate the presence of fentanyl or (ii) a pale blue tint in the absence of fentanyl. We demonstrate rapid and specific detection of fentanyl free base and fentanyl derivatives (e.g., acetyl fentanyl and furanyl fentanyl) against a panel of 9 other common drugs of abuse (e.g., morphine, cocaine, and heroin). Furthermore, we highlight the intended use of this assay by testing grains of fentanyl derivatives on a surface with a drop (i.e., 25 μL) of the assay reagent. We anticipate that this approach can be applied broadly to identify the presence of fentanyl at the point of need.

Preparation of a Fluorescent Polymer Sensing System with an Oxidation-Electric Dual-Mode Response Based on the Supramolecular Host–Guest Interaction

Preparation of a Fluorescent Polymer Sensing System with an Oxidation-Electric Dual-Mode Response Based on the Supramolecular Host–Guest Interaction