Tracking water dimers in ambient nanocapsules by vibrational spectroscopy.

Nanoconfined few-molecule water clusters are invaluable systems to study fundamental aspects of hydrogen bonding. Unfortunately, most experiments on water clusters must be performed at cryogenic temperatures. Probing water clusters in noncryogenic systems is however crucial to understand the behavior of confined water in atmospheric or biological settings, but such systems usually require either complex synthesis and/or introduce many confounding external bonds to the clusters. Here, we show that combining Raman spectroscopy with the molecular nanocapsule cucurbituril is a powerful technique to sequester and analyze water clusters in ambient conditions. We observe sharp peaks in vibrational spectra arising from a single rigid confined water dimer. The high resolution and rich information in these vibrational spectra allow us to track specific isotopic exchanges inside the water dimer, verified with density-functional theory and kinetic population modeling. We showcase the versatility of such molecular nanocapsules by tracking water cluster vibrations through systematic changes in confinement size, in temperatures up to 120° C, and in their chemical environment.

Manipulating the Host-Guest Chemistry of Cucurbituril to Propel Highly Reversible Zinc Metal Anodes.

Rechargeable aqueous zinc-ion batteries are practically plagued by the short lifespan and low Coulombic efficiency (CE) of Zn anodes resulting from random dendrite deposition and parasitic reactions. Herein, the host-guest chemistry of cucurbituril additive with Zn2+ to achieve longstanding Zn anodes is manipulated. The macrocyclic molecule of cucurbit[5]uril (CB[5]) is delicately designed to reconstruct both the CB[5]-adsorbed electric-double layer (EDL) structure at the Zn interface and the hydrated sheath of Zn2+ ions. Especially benefiting from the desirable carbonyl rims and suitable hydrophobic cavities, the CB[5] has a strong host-guest interaction with Zn2+ ions, which exclusively permits rapid Zn2+ flux across the EDL interface but retards the H2O radicals and SO4 2-. Accordingly, such a unique particle redistributor warrants long-lasting dendrite-free deposition by homogenizing Zn nucleation/growth and significantly improved CE by inhibiting side reactions. The Zn anode can deliver superior reversibility in CB[5]-containing electrolyte with a ninefold increase of cycle lifetime and an elevated CE of 99.7% under harsh test conditions (10 mA cm-2/10 mA h cm-2). The work opens a new avenue from the perspective of host-guest chemistry to propel the development of rechargeable Zn metal batteries and beyond.

Insoluble Acyclic Cucurbit[n]uril-Type Receptors Capture Iodine from the Vapor Phase.

Nuclear energy makes large contributions toward meeting global energy needs, but societal concerns remain high given the impacts of the intended release of radioactive materials including 129I and 131I. In this paper we explore the use of a homologous series of acyclic CB[n] type hosts (H1 - H4) as adsorbents of iodine from the vapor phase. We find that H2 - H4, but not H1 - perform well in this application with uptake capacities of 2.2 g g-1, 1.5 g g-1, and 1.9 g g-1, respectively. The chemisorptive uptake process involves partial oxidation of catechol walled H2 to quinone walled host and capture of I3- and I5-. Solid H2 can be regenerated by treatment with Na2S2O4 and reused at least five times. The x-ray crystal structure of H2 is also reported.

Self-Assembly Strategy for Constructing Porous Boron and Nitrogen Co-Doped Carbon as an Efficient ORR Electrocatalyst toward Zinc-Air Battery.

Carbon nanomaterials doped with N and B could activate nearby carbon atoms to promote charge polarization through the synergistic coupling effect between N and B atoms, thus facilitating adsorption of O2 and weakening O-O bond to enhance oxygen reduction reaction. Herein, a simple and controllable self-assembly strategy is applied to synthesize porous B, N co-doped carbon-based catalysts (BCN-P), which employs the macrocyclic molecule cucurbit[7]uril (CB7) as nitrogen source, and 3D aromatic-like closo-[B12H12]2- as boron source. In addition, polystyrene microspheres are added to help introduce porous structure to expose more active sites. Benefitting from porous structures and the synergistic coupling effect between N and B atoms, BCN-P has a high onset potential (Eonset=0.846 V) and half-wave potential (E1/2=0.74 V) in alkaline media. The zinc-air battery assembled with BCN-P shows high operating voltage (1.42 V), peak power density (128.7 mW cm-2) and stable charge/discharge cycles, which is even comparable with Pt/C.

On the supramolecular interactions into a pH- and Metal-Actuated Molecular Shuttle: some insights from QTAIM modeling.

Supramolecular contacts responsible for chemical interaction of cucurbit[7]uril (CB[7]) macrocycle on a Tolyl-Viologen-Phenylene-Imidazole (T-VPI) molecular thread, at acid pH (T-VPI-H+) or after Ag+ cation addition (T-VPI-Ag+), are analytically addressed in a computational framework combining Quantum Theory of Atoms in Molecules (QTAIM) with Density Functional Theory (DFT). In this respect, the crystallographic structure (CCDC number 2217466) is taken as reference condition for addressing the nature of the chemical interactions driving the shuttling of the CB[7] between T and P stations recently observed in dilute water solutions. Beside the host(CB[7]) vs guest(T-VPI-H+ or T-VPI-Ag+) complexation, the coordination sphere of the Ag+ cation is also investigated by means of local electronic energy density - H(r) - descriptors. The derived non-covalent interaction patterns are found to support diagnostic 1H NMR signals used for detecting the mutual position of the CB[7] along the axle. This work highlights the potentialities of a QTAIM based approach in the characterization of supramolecular and metal-complexation effects in molecular aggregates such as not-interlocked synthetic molecular shuttles.

Uncovering the mechanism of selective stabilization of high-energy diastereoisomers via inclusion.

Supramolecular systems may be used to stabilize otherwise unstable isomers to find alternative synthetic pathways. It has been reported that cucurbit[8]uril can stabilize trans-I and trans-II CuII cyclam, whereas trans-III is the only non-substituted trans CuII cyclam diastereoisomer found outside of the host molecule experimentally. Quantum chemistry methods can provide valuable insight into the intermolecular interactions involved in these inclusion complexes. All five possible trans diastereoisomers of CuII cyclam were studied within the host molecule to calculate the interaction energy and free energy of association for each complex. The relative free energies of the five free cyclams confirm that trans-I and trans-II are the most energetically accessible diastereoisomers from the initial trans-III starting point. Energy decomposition analysis was used to identify the attractive and repulsive interactions between cyclam and cucurbit[8]uril and showed that trans-II encounters repulsive forces almost three times greater than trans-I, which may explain the 7:3 ratio of trans-I to trans-II within cucurbit[8]uril that occurs experimentally. Optimized complex geometries with trans-III, IV, and V show that the cyclams protrude out of cucurbit[8]uril, whereas trans-I and trans-II become more encapsulated and elongate the host, suggesting that the position of the cyclam is extremely important when forming non-covalent interactions. Our results agree with the experimental findings and provide greater insight into why the most stable isolated cyclam diastereoisomer, trans-III, does not form a complex. Supplementary Information: The online version contains supplementary material available at 10.1007/s00214-023-03077-7.

Internal Dynamics and Modular Peripheral Binding in Stimuli-Responsive 3 : 2 Host:Guest Complexes.

Now that the chemistry of 1 : 1 host:guest complexes is well-established, it is surprising to note that higher stoichiometry (oligomeric) complexes, especially those with excess host, remain largely unexplored. Yet, proteins tend to oligomerize, affording new functions for cell machinery. Here, we show that cucurbit[n]uril (CB[n]) macrocycles combined with symmetric, linear di-viologens form unusual 3 : 2 host:guest complexes exhibiting remarkable dynamic properties, host self-sorting, and external ring-translocation. These results highlight the structural tunability of cucurbit[8]uril (CB[8]) based 3 : 2 host:guest complexes in water and their responsiveness toward several stimuli (chemicals, pH, redox).

Supramolecular Complex of Cucurbit[7]uril with Diketopyrrolopyrole Dye: Fluorescence Boost, Biolabeling and Optical Microscopy.

New photostable and bright supramolecular complexes based on cucurbit[7]uril (CB7) host and diketopyrrolopyrole (DPP) guest dyes having two positively charged 4-(trimethylammonio)phenyl groups were prepared and characterized. The dye core displays large Stokes shift (in H2O, abs./emission max. 480/550 nm; ϵ~19 000, τfl>4 ns), strong binding with the host (~560 nM Kd) and a linker affording fluorescence detection of bioconjugates with antibody and nanobody. Combination of protein-functionalized DPP dye with CB7 improves photostability and affords up to 12-fold emission gain. Two-color confocal and stimulated emission depletion (STED) microscopy with 595 nm or 655 nm STED depletion lasers shows that the presence of CB7 not only leads to improved brightness and image quality, but also results in DPP becoming cell-permeable.

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.

A Strong Supramolecular Mechanophore with Controlled Mechanical Strength.

Supramolecular mechanophores typically exhibit much lower mechanical strengths than covalent counterparts, with strengths usually around 100 pN, which is significantly lower than the nN-scale strength of covalent bonds. Inspired by the slow dissociation kinetics of the cucurbit[7]uril (CB[7])-hexanoate-isoquinoline (HIQ) complex, we discovered that charge-dipole repulsion can be utilized to create strong supramolecular mechanophores. When activated at its -COO- state, the CB[7]-HIQ complex exhibits a high mechanical strength of ~700 pN, comparable to weak covalent bonds such as Au-S bonds or thiol-maleimide adducts. The strength of the CB[7]-HIQ complex can also be tuned with pH in a gradual manner, with a minimum value of ~150 pN at its -COOH state, similar to an ordinary supramolecular conjugate. This research may pave the way for the development of supramolecular architectures that combine the advantages of covalent and supramolecular systems.

Cage versus sheet: Probing the Determinants of Protein - Cucurbit[7]uril Crystalline Architectures.

The donut-shaped cucurbit[n]urils (Qn) are a class of rigid macrocyclic receptor with protein recognition capabilities. Qn encapsulation of amino acid side chains can enable protein assembly. Recently, cucurbit[7]uril (Q7) has been applied as a molecular glue for organizing protein building blocks into crystalline architectures. Q7 co-crystallization with dimethylated Ralstonia solanacearum lectin (RSL*) has yielded novel crystalline architectures. Co-crystallization of RSL* and Q7 yields either cage- or sheet-like architectures which may be modulated via protein engineering. However, questions remain as to the factors dictating the formation of one architecture over another (cage versus sheet). Here, we make use of an engineered RSL*-Q7 system which co-crystallizes as the cage or sheet assembly with easily-distinguished crystal morphologies. Using this model system, we probe how the crystallization conditions dictate which crystalline architecture is adopted. Protein-ligand ratios and the sodium concentration were identified as key determinants for the growth of the cage versus sheet assemblies.

The Diversity of Cucurbituril Molecular Switches and Shuttles.

Ring translocation switches and shuttles featuring a macrocycle (or a ring molecule) navigating between two or more stations continue to attract attention. While the vast majority of these systems are developed in organic solvents, the cucurbituril (CB) macrocycles are ideally suited to prepare such systems in water. Indeed, their stability and their relatively high affinity for relevant guest molecules are key attributes toward translating the progresses made in organic solvents, into water. This concept article summarizes the findings, key advances and multiple possibilities offered by CBs toward advanced molecular switches and shuttles in water.

A pH- and Metal-Actuated Molecular Shuttle in Water.

The structure of the Viologen-Phenylene-Imidazole (VPI) guest, previously shown to be bound by cucurbit[7]uril (CB[7]) with binding modes depending on pH and silver ions, has been extended by adding hydrophobic groups on the two extremities of VPI before investigations of CB[7] binding by NMR, ITC, X-ray diffraction, UV-vis and fluorescence spectroscopies. With an imidazole station extended by a naphthalene group (VPI-N), binding modes of CB[7] are similar to those previously observed. However, with the viologen extended by a tolyl group (T-VPI), CB[7] preferentially sits on station T, shuttling between the T and P stations at acid pH or after Ag+ addition. The CB[7] ⋅ T-VPI complex thus behaves as a metal-actuated thermodynamic stop-and-go molecular shuttle featured by fast and autonomous ring translocation between two stations and a continuum for fractional station occupancy solely and easily controlled by Ag+ concentration.

Metal-Assisted Complexation of Fluorogenic Dyes by Cucurbit[7]uril and Cucurbit[8]uril: A DFT Evaluation of the Key Factors Governing the Host-Guest Recognition.

With the emergence of host-guest systems, a novel branch of complexation chemistry has found wide application in industries such as food, pharmacy, medicine, environmental protection and cosmetics. Along with the extensively studied cyclodextrins and calixarenes, the innovative cucurbiturils (CB) have enjoyed increased popularity among the scientific community as they possess even better qualities as cavitands as compared to the former molecules. Moreover, their complexation abilities could further be enhanced with the assistance of metal cations, which can interestingly exert a dual effect on the complexation process: either by competitively binding to the host entity or cooperatively associating with the CB@guest structures. In our previous work, two metal species (Mg2+ and Ga3+) have been found to bind to CB molecules in the strongest fashion upon the formation of host-guest complexes. The current study focuses on their role in the complex formation with three dye molecules: thiazole orange, neutral red, and thioflavin T. Various key factors influencing the process have been recognized, such as pH and the dielectric constant of the medium, the cavity size of the host, Mn+ charge, and the presence/absence of hydration shell around the metal cation. A well-calibrated DFT methodology, solidly based and validated and presented in the literature experimental data, is applied. The obtained results shed new light on several aspects of the cucurbituril complexation chemistry.

Supramolecular Polymer Brushes Grown by Surface-Initiated Atom Transfer Radical Polymerization from Cucurbit[7]uril-based Non-Covalent Initiators.

Polymer brushes are densely grafted, chain end-tethered assemblies of polymers that can be produced via surface-initiated polymerization. Typically, this is accomplished using initiators or chain transfer agents that are covalently attached to the substrate. This manuscript reports an alternative route towards polymer brushes, which involves the use of non-covalent cucurbit[7]uril-adamantane host-guest interactions to surface-immobilize initiators for atom transfer radical polymerization. These non-covalent initiators can be used for the surface-initiated atom transfer radical polymerization of a variety of water-soluble methacrylate monomers to generate supramolecular polymer brushes with film thicknesses of more than 100 nm. The non-covalent nature of the initiator also allows facile access to patterned polymer brushes, which can be produced in straightforward fashion by drop-casting a solution of the initiator-modified guest molecules onto a substrate that presents the cucurbit[7]uril host.

Near-Infrared Phosphorescent Switch of Diarylethene Phenylpyridinium Derivative and Cucurbit[8]uril for Cell Imaging.

Near-infrared (NIR) pure organic room-temperature phosphorescence (RTP) materials have received growing research interest due to their wide application in the fields of high-resolution bioimaging and luminescent materials. In this work, the authors report a macrocycle-confined pure organic RTP supramolecular assembly, which is constructed by diarylethene phenylpyridinium derivative (DTE-TP) and cucurbit[8]uril (CB[8]). Compared with CB[6] and CB[7], the larger cavity of CB[8] induces molecular folding and enhances the intramolecular charge transfer interactions, which leads to the obtained assembly emitting efficient NIR phosphorescence at 700 nm. Due to the photochromism of the diarylethene core, the NIR phosphorescence is reversibly regulated by light irradiation at wavelengths of 365 and >600 nm. Furthermore, cell-based experiments show that this supramolecular assembly is located in the lysosomes and displays a NIR phosphorescence at 650-750 nm. In addition, by means of phosphorescence resonance energy transfer, the obtained assembly exhibits a red-shifted NIR emission at 817 nm. This supramolecular phosphorescent switch provides a convenient path for the modular design of water-soluble pure organic room-temperature NIR phosphorescent materials.

Spermine-Responsive Intracellular Self-Aggregation of Gold Nanocages for Enhanced Chemotherapy and Photothermal Therapy of Breast Cancer.

Improving the precise accumulation and retention of nanomedicines in tumor cells is one of the keys to effective therapy of tumors. Herein, supramolecular peptides capped Au nanocages (AuNCs) that may self-aggregate into micron-sized clusters intracellularly in response to spermine (SPM), leading to specific accumulation and retention of AuNCs in SPM-overexpressed tumor cells, are developed. In this design, polydopamine (PDA) is in situ coated on the surface of AuNCs with doxorubicin (DOX) encapsulated. A small peptide, Phe-Phe-Val-Leu-Lys (FFVLK), is conjugated with PDA via esterification, and cucurbit[7]uril (CB[7]) is threaded onto the N-terminal Phe via host-guest interactions. Once the supramolecular peptide (CB[7]-FFVLK) capped AuNCs are internalized in SPM-overexpressed breast cancer cells, CB[7] can be competitively removed from FFVLK by SPM, due to the much higher binding affinity between CB[7] and SPM than that between CB[7] and Phe, leading to exposure of free FFVLK, which can subsequently self-assemble and induce the aggregation of AuNCs to micron-sized clusters, resulting in the significantly enhanced accumulation and retention of DOX-loaded AuNCs in tumor cells. Under NIR laser irradiation, the enhanced photothermal conversion of AuNCs aggregates, together with photothermia-induced release of DOX leads to synergistic photothermal therapy and chemotherapy against breast cancer.

Sequential Formation of Heteroternary Cucurbit[10]uril (CB[10]) Complexes.

The globular and monocationic guest molecule trimethyl-azaphosphatrane (AZAP, a protonated Verkade superbase) was shown to form a host:guest 1 : 1 complex with the cucurbit[10]uril (CB[10]) macrocycle in water. Molecular dynamics calculations showed that CB[10] adopts an 8-shape with AZAP occupying the majority of the internal space, CB[10] contracting around AZAP and leaving a significant part of the cavity unoccupied. This residual space was used to co-include planar and monocationic co-guest (CG) molecules, affording heteroternary CB[10]⋅AZAP⋅CG complexes potentially opening new perspectives in supramolecular chemistry.

An overview of the SAMPL8 host-guest binding challenge.

The SAMPL series of challenges aim to focus the community on specific modeling challenges, while testing and hopefully driving progress of computational methods to help guide pharmaceutical drug discovery. In this study, we report on the results of the SAMPL8 host-guest blind challenge for predicting absolute binding affinities. SAMPL8 focused on two host-guest datasets, one involving the cucurbituril CB8 (with a series of common drugs of abuse) and another involving two different Gibb deep-cavity cavitands. The latter dataset involved a previously featured deep cavity cavitand (TEMOA) as well as a new variant (TEETOA), both binding to a series of relatively rigid fragment-like guests. Challenge participants employed a reasonably wide variety of methods, though many of these were based on molecular simulations, and predictive accuracy was mixed. As in some previous SAMPL iterations (SAMPL6 and SAMPL7), we found that one approach to achieve greater accuracy was to apply empirical corrections to the binding free energy predictions, taking advantage of prior data on binding to these hosts. Another approach which performed well was a hybrid MD-based approach with reweighting to a force matched QM potential. In the cavitand challenge, an alchemical method using the AMOEBA-polarizable force field achieved the best success with RMSE less than 1 kcal/mol, while another alchemical approach (ATM/GAFF2-AM1BCC/TIP3P/HREM) had RMSE less than 1.75 kcal/mol. The work discussed here also highlights several important lessons; for example, retrospective studies of reference calculations demonstrate the sensitivity of predicted binding free energies to ethyl group sampling and/or guest starting pose, providing guidance to help improve future studies on these systems.

Unravelling Supramolecular Photocycloaddition: Cavitand-Mediated Reactivity of 3-(Aryl)Acrylic Acids.

The supramolecular photocycloaddition (PCA) of 3-(phenyl)acrylic acid has been extensively pursued by chemists to study weak interactions and synthesize substituted cyclobutanes. The stereo- and regioselectivity of the products in a supramolecularly affected reaction are often used as a probe for assessing the nature of weak interactions and/or molecular ambience of the reactants. However, some crucial aspects of this chemistry have often remained underexplored in the past, especially within the context of interpreting strength and directionality of interactions based on reaction outcomes. We present a detailed study of the cavitand-mediated PCA of a new and suitable reactant (3-(naphthyl)acrylic acids) that exhibits labile photo-reversible chemistry, which is suitable for exploring previously un-explored aspects of the supramolecular PCA chemistry. Our studies afford important insights about this chemistry that should be considered while using product selectivity as a proxy for deducing intermolecular interactions.