Neutral Guest Molecules Research Articles

Host-Guest Interactions of Ruthenium(II) Arene Complexes with Cucurbit[7/8]uril.

Cucurbit[n]urils (CB[n]s) have been recognized for their chemical and thermal stability, and their ability to bind many neutral and cationic guest molecules makes them excellent hosts in a range of supramolecular applications. In drug delivery, CB[n]s can enhance drug solubility, improve chemical and physical drug stability, and allow for triggered and controlled release. This study aimed to investigate the ability of CB[7] and CB[8] as molecular hosts to bind ruthenium(II) arene complexes that are current anticancer lead structures in the area of metallodrugs. Both, experimental and computational methods, led to insights into the binding preferences and geometries of [RuII(cym)Cl2]2 (1; cym = η6-p-cymene), [RuII(cym)(dmb)Cl2]) (2; cym = η6-p-cymene; dmb = 1,3-dimethylbenzimidazol-2-ylidene), and [RuII(cym)(pta)Cl2] (3, RAPTA-C; cym = η6-p-cymene; pta = 1,3,5-triaza-7-phospha-adamantane) with CB[7] and CB[8]. Competition experiments by mass spectrometry revealed clear preferences of 2 for CB[8] and 3 for CB[7]. Based on a comparison of the associated interaction energies from quantum chemical calculations as well as experimental data, 3@CB[7] clearly prefers a binding mode, where the pta ligand is located inside the cavity of the host, and the metal ion interacts with two of the carbonyl groups on the rim of CB[7]. In contrast, complex 2 binds in two different orientations with interaction energies similar to those of both CB[n]s, with the cym ligand being either inside or outside of the cavity. These findings suggest that ruthenium(II) arene complexes are able to form stable host-guest interactions with CB[n]s, which can be exploited as drug delivery vehicles in further metallodrug development to improve their chemical stability.

Bidentate boron Lewis acids: synthesis by tin boron exchange reaction and host-guest complex formation.

Four bidentate boron Lewis acids based on the 1,8-diethynylanthracene backbone have been synthesized by a tin-boron exchange reaction with various chloroboranes, yielding the products in good to excellent yields. Complexation experiments of the host compounds with pyridine, pyrimidine and TMEDA demonstrated striking differences in terms of formation and solubility of the supramolecular adducts. The host-guest complexes were investigated by multinuclear NMR spectroscopy and structurally characterized by X-ray diffraction experiments, illustrating the adaptation of the host system upon adduct formation with different neutral guest molecules.

Contrasting complexation behaviour of zwitterionic amyloid probe, SYPRO orange with β-cyclodextrin and captisol

The differential complexation studies with cyclodextrins and their charged derivatives have been well studied using cationic, anionic, as well as neutral guest molecules. However, supramolecular complexation with zwitterionic guest molecules is quite limited. Zwitterions are overall neutral molecules with localized charges that can offer additional site-specific electrostatic interaction with cyclodextrins as compared to neutral guest molecules. There is no information on how the different intra- and intermolecular interactions can modulate the binding of a zwitterion with a macrocyclic host. Herein, the supramolecular interactions of biologically important zwitterionic amyloid probe, SYPRO Orange (SO) with β-cyclodextrin (β-CD) and sulfobutylether β-cyclodextrin (SBE-β-CD, Captisol®) have been evaluated and compared using different spectroscopic methods. SO forms inclusion complexes with both β-CD and SBE-β-CD which led to the enhanced fluorescence along with a hypsochromic shift in its emission spectra. It has been shown that the presence of segmental rotation in a guest molecule with charge transfer property favours its association with the macromolecules. The fluorescence enhancement and the binding affinities show contrasting behavior in these two types of host–guest complexes. Time-resolved emission measurements could disentangle the contribution from different inclusion complexes. Ionic strength and temperature variation in the photophysical properties helped to understand the molecular interactions involved in such contrasting behavior.

Stimuli-Responsive Cucurbit[n]uril-Based Supramolecular Nanocarriers for Delivery of Chemotherapeutics

Chemotherapeutics commonly exhibit low bioavailability and systemic adverse effects. Supramolecular nanovesicles, such as pillar[n]arenes, calix[n]arenes, cucurbit[n]urils (CBs), and cyclodextrins, have been introduced as promising nanocarriers due to their remarkable encapsulation capacity and ability to host hydro-philic/-phobic guest molecules. Additionally, such nanovesicles can be decorated with various stimuli-responsive entities to enable drug targeting and controlled drug release. Self-assembly of amphiphilic cavitands and host–guest complexation represent the two common approaches for preparation of supramolecular nanovesicles with customizable surfaces capable of accommodating different biologically active guest molecules. CBs have been used as smart and multifunctional host macromolecules in cancer therapy. CBs are fabricated via a condensation reaction between formaldehyde and glycoluril units generating barrel-shaped supramolecules with partially enclosed cavities. The unique structure of CBs surrounding an internal hydrophobic cavity allows them to accommodate cationic and neutral guest molecules via ion-dipole and hydrophobic interactions, respectively. Additionally, CBs are stable, safe, and biocompatible, and their surfaces can be decorated with various functional targeting moieties. These advantages have promoted CBs as promising candidates for stimuli-responsive targeted delivery of chemotherapeutics. This review presents the most recent advances in the design of stimuli-responsive nanosystems based on CBs for effective cancer treatment.

Multistep sequence-controlled supramolecular polymerization by the combination of multiple self-assembly motifs

The precise sequence control of polymer chain is an important research topic of polymer chemistry. Although some methods such as iterative synthesis and supramolecular polymerization have been developed to fabricate sequence-controllable polymer, it is still a great challenge to consecutively prepare multiple supramolecular polymers with different sequence structures. In this work, through the reasonable utilization of assembly motifs, we integrated multiple host-guest recognitions and metal coordination interactions to prepare different sequence-controlled supramolecular polymers by a multistep assembly strategy. This research provides inspiration for the design and preparation of supramolecular polymers with different sequence structures.

Aryl- and Superaryl-Extended Calix[4]pyrroles: From Syntheses to Potential Applications

The incorporation of aryl substituents at the meso-positions of calix[4]pyrrole (C4P) scaffolds produces aryl-extended (AE) and super-aryl-extended (SAE) calix[4]pyrroles. The cone conformation of the all-α isomers of "multi-wall" AE-C4Ps and SAE-C4Ps displays deep aromatic clefts or cavities. In particular, "four-wall" receptors feature an aromatic polar cavity closed at one end with four convergent pyrrole rings and fully open at the opposite end. This makes AE- and SAE-C4P scaffolds effective receptors for the molecular recognition of negatively charged ions and neutral guest molecules with donor-acceptor and hydrogen bonding motifs. In addition, adequately functionalized all-α isomers of multi wall AE- and SAE-C4P scaffolds self-assemble into uni-molecular and supra-molecular aggregates displaying capsular and cage-like structures. The self-assembly process requires the presence of template ions or molecules that lock the C4P cone conformation and complementing the inner polar functions and volumes of their cavities. We envisioned performing an in-depth revision of AE- and SAE-C4P scaffolds owing to their importance in different domains such as supramolecular chemistry, biology, material sciences and pharmaceutical chemistry. Herewith, besides the synthetic details on the elaboration of their structures, we also draw attention to their diverse applications. The organization of this review is mainly based on the number of "walls" present in the AE-C4P derivatives and their structural modifications. The sections are further divided based on the C4P functions and applications. The authors are convinced that this review will be of interest to researchers working in the general area of supramolecular chemistry as well as those involved in the study of the binding properties and applications of C4P derivatives.

Silicon‐Bridged Bi‐ and Tridentate Lewis Acidic Host Systems

AbstractConnecting multiple organic spacer functions via silicon core units leads to various organosilanes that are excellently suited as backbones for poly‐Lewis acids (PLAs). Using ethynyl spacer groups, rigid bis‐ and tris‐dioxabenzoborole (BCat)‐substituted PLAs were prepared. The fixed orientation of the Lewis acidic functions of the PLAs is reflected in their solid‐state structures. Further flexible PLAs were obtained by hydroboration of vinylsilanes using 9‐borabicyclo[3.3.1]nonane (9‐BBN), which shows the flexibility of the backbone motif. Host‐guest experiments of the bidentate representatives with pyridine demonstrate the ability of both PLA‐types (BCat or 9‐BBN) for complexing neutral guest molecules. The rigid host system shows additionally a 1 : 1 adduct formation using a bridged diamine as guest compound.

Partial Order–Disorder Transformation of Interpenetrated Porous Coordination Polymers

Controlling interpenetration and flexibility behaviors is intriguing and fundamental for porous coordination polymers. We report exceptional interpenetration behaviors involving controllable partia...

Host-aided intermolecular proton transfer in the inclusion complexes of imidazole ⊂ p-sulfonatocalix[4]arene

ABSTRACT Structural analysis of two multi-component complexes comprising p-sulfonatocalix[4]arene penta-anion as the host molecule and 1-methylimidazolium or 1-butylimidazolium monocation as the guest species, aquated gadolinium(III) ion along with tetraphenylphosphonium cation, is reported. An interesting process during the formation of these inclusion complexes was seen, in which a proton transfer from p-sulfonatocalix[4]arene to the neutral guest molecules took place via acid-base reaction. 1H NMR experiment confirms the formation of the host–guest complexes and the proton transfer between the calixarene and imidazolium species in solution. Careful analysis aided by CrystalExplorer, the dominant intermolecular interactions that contribute to the stabilisation of the host–guest complex formation were readily identified. Bilayer arrangement prevails in the extended structure for both complexes regardless of the type of guest species.

Cyclodextrin binding constants as a function of pH for compounds with multiple pKa values.

Complex formation between cyclodextrins and ionizable guest molecules depends on pH. In general, the neutral species of an ionizable guest molecule has the highest affinity for the cyclodextrin cavity, but ionized species will also be able to form complexes with cyclodextrins. This work presents a theoretical expression for the relationship between the stability constant and pH for interaction between neutral cyclodextrins and ionizable guest molecules with multiple pKa values. Input parameters for the theoretical expression are pKa values of the guest molecule and stability constants for the complex at specific pH values. The pH profile of the stability constant for a complex depends on the acid-base properties of the guest and the closeness of the pKa values, and examples of pH profiles for polyprotic acids, bases and amphoteric guests are shown. Empirical data sets from the literature were used to confirm the accuracy of the theoretical expression, and Monte Carlo simulations were used to validate that the theoretical expression yield a good fit to empirical data. Lastly, an experimental protocol was suggested, and a freely available graphical user interface was presented to facilitate easy use of the theoretical expression.

High-Affinity Binding of Metallacarborane Cobalt Bis(dicarbollide) Anions to Cyclodextrins and Application to Membrane Translocation.

Metallacarboranes are a class of inorganic boron clusters that have recently been recognized as biologically active compounds. Herein, we report on the host-guest complexation of several cobalt bis(1,2-dicarbollide) anions (COSANs) with cyclodextrins (CDs) in aqueous solution. The binding affinities reach micromolar values, which are among the highest known values for native CDs, and exceed those for neutral hydrophobic organic guest molecules. The entrapment of the COSANs inside the cavity of CDs was confirmed using NMR and UV-visible spectroscopy, mass spectrometry, cyclic voltammetry, and isothermal titration calorimetry. Complexation by CDs greatly influences the photophysical and electrochemical properties of COSANs. In combination with indicator displacement assays, a label-free fluorescence-based method was developed to allow real-time monitoring of the translocation of COSANs through lipid bilayer membranes.

Bambusuril analogs based on alternating glycoluril and xylylene units.

The glycoluril monomer is a popular building block in supramolecular chemistry as it is used for the synthesis of versatile host molecules which can interact with cationic, anionic or neutral guest molecules. Here we present the design and synthesis of a new hybrid macrocycle containing glycoluril and aromatic units. The reaction afforded a mixture of macrocyclic homologues from which a two-membered macrocycle was isolated as the main product. Two disastereomers of the macrocycle were separated and characterized by means of NMR spectroscopy and X-ray crystallography. Conformational changes of these diastereomers were investigated using DFT models and variable-temperature NMR.

Positive Allosteric Control of Guests Encapsulation by Metal Binding to Covalent Porphyrin Cages.

The allosteric control of the receptor properties of two flexible covalent cages is reported. These receptors consist of two zinc(II) porphyrins connected by four linkers of two different sizes, each incorporating two 1,2,3-triazolyl ligands. Silver(I) ions act as effectors, responsible for an on/off encapsulation mechanism of neutral guest molecules. Binding silver(I) ions to the triazoles opens the cages and triggers the coordination of pyrazine or the encapsulation of N,N'-dibutyl-1,4,5,8-naphthalene diimide. The X-ray structure of the silver(I)-complexed receptor with short connectors is reported, revealing the hollow structure with a cavity well-defined by two eclipsed porphyrins. Rather unexpectedly, the crystallographic structure of this receptor with pyrazine as a guest molecule showed that the cavity is occupied by two pyrazines, each binding to the zinc(II) porphyrin in a monotopic fashion.

Redox active [Pd2L4]4+ cages constructed from rotationally flexible 1,1'-disubstituted ferrocene ligands.

Two new ferrocene-containing [Pd2(LFc)4]4+(X-)4 (where X- = BF4- or SbF6-) self-assembled cages (C·BF4 and C·SbF6) were synthesised from the known, rotationally flexible, 1,1'-bis(3-pyridylethynyl)ferrocene ligand (LFc), and characterised by 1H, 13C and diffusion ordered (DOSY) NMR and UV-visible absorption spectroscopies, high resolution electrospray ionisation mass spectrometry (HR-ESI-MS), elemental analysis, X-ray crystallography and cyclic voltammetry (CV). The molecular structures confirmed that cage-like systems (C·BF4 and C·SbF6) were generated. Similar to related [Pd2L4]4+(X-)4, C·SbF6 was able to interact with a range of neutral and anionic guests, with p-toluenesulfonate showing the strongest association constant. Cyclic voltammetry studies revealed that the cage systems were redox active. However, the redox potential of the cage was unperturbed upon the addition of guests.

A dimethoxypillar[5]arene/azastilbene host-guest recognition motif and its applications in the fabrication of polypseudorotaxanes.

Pillar[n]arenes, known as the fifth generation of host macrocycles since 2008, have become a popular topic over the past ten years. Until now, the studies of pillar[n]arenes were mainly focused on pillar[5]arenes owing to their easy synthesis and high yields. In particular, 1,4-dimethoxypillar[5]arene (DMP5), which shows a simple structure, efficient synthesis and high yield, has played important roles in the construction of various advanced supramolecular architectures. However, DMP5 has only displayed host-guest binding properties towards some guests. Therefore, the investigation of the host-guest chemistry of DMP5 should be able to greatly promote the development of pillararene chemistry. Herein, a photosensitive azastilbene derivative was chosen as a neutral guest to study the host-guest binding and stimuli-responsive behavior with DMP5. In addition, the binding behavior of DMP5 towards a series of analogous neutral guest molecules was investigated to study the driving forces of the host-guest interaction between DMP5 and the azastilbene guest. Moreover, the [2]pseudorotaxane based on DMP5 and the azastilbene guest was used to construct a polypseudorotaxane via metal coordination.

Molecular Russian dolls

The host-guest recognition between two macrocycles to form hierarchical non-intertwined ring-in-ring assemblies remains an interesting and challenging target in noncovalent synthesis. Herein, we report the design and characterization of a box-in-box assembly on the basis of host-guest radical-pairing interactions between two rigid diradical dicationic cyclophanes. One striking feature of the box-in-box complex is its ability to host various 1,4-disubstituted benzene derivatives inside as a third component in the cavity of the smaller of the two diradical dicationic cyclophanes to produce hierarchical Russian doll like assemblies. These results highlight the utility of matching the dimensions of two different cyclophanes as an efficient approach for developing new hybrid supramolecular assemblies with radical-paired ring-in-ring complexes and smaller neutral guest molecules.

Induced-fit expansion and contraction of a self-assembled nanocube finely responding to neutral and anionic guests

Induced-fit or conformational selection is of profound significance in biological regulation. Biological receptors alter their conformation to respond to the shape and electrostatic surfaces of guest molecules. Here we report a water-soluble artificial molecular host that can sensitively respond to the size, shape, and charged state of guest molecules. The molecular host, i.e. nanocube, is an assembled structure consisting of six gear-shaped amphiphiles (GSAs). This nanocube can expand or contract its size upon the encapsulation of neutral and anionic guest molecules with a volume ranging from 74 to 535 Å3 by induced-fit. The responding property of this nanocube, reminiscent of a feature of biological molecules, arises from the fact that the GSAs in the nanocubes are connected to each other only through the hydrophobic effect and very weak intermolecular interactions such as van der Waals and cation-π interactions.

Construction of Metallacage-Cored Supramolecular Gel by Hierarchical Self-Assembly of Metal Coordination and Pillar[5]arene-Based Host-Guest Recognition.

In this work, a Pd2 L4 metallacage 2•([BF4 ]- )4 with four pillar[5]arene units is first prepared and characterized by 1D multinuclear NMR (1 H, 11 B, and 19 F NMR), 2D 1 H-1 H correlation spectra, 1 H-13 C heteronuclear single quantum coherence, and diffusion-ordered NMR spectroscopy, and electrospray ionization time-of-flight mass spectrometry. By the introduction of a ditopic guest molecule 3 into a chloroform solution of 2•([BF4 ]- )4 , a supramolecular polymer network gel is successfully constructed based on the metal coordination interactions and host-guest recognition between the pillar[5]arene units of 2•([BF4 ]- )4 and neutral ditopic guest molecule 3. The temperature and pH responsivenesses of the supramolecular gel are studied, which are further employed for the controlled release of different cargos. As a demonstration, emodin and methylene blue are trapped in the cavities of the metallacage and in the pores of the supramolecular gel, respectively. Methylene blue is first released along with the gel-sol transition while emodin is then released by the further addition of acid to destroy the metallacage. This study explores the use of metallacage-cored supramolecular network gels for sequential controlled release and contributes to the development of smart and adaptive materials.

Host-guest complexation behaviour of emissive calix[3]naphthobipyrrole toward aromatic guests

ABSTRACTA new hexapyrrolic macrocycle composed of three naphthobipyrrole units has been synthesized which exhibited different emission changes with hydrogen pyrophosphate and benzoate ions. Phosphate ions caused red shifting of the fluorescence band of calixnaphthobipyrrole while benzoate ions resulted in quenching of the same. The fluorescence quenching was further utilized for investigating binding preferences of the probe with neutral aromatic guest molecules substituted with groups having varied electron withdrawing abilities. The extent of quenching with the neutral guests increased with the increasing electron deficiency on the aromatic ring of the guest. The fluorescence quenching has been ascribed to electron transfer from the host to the guest species.

Synergistic host-guest hydrophobic and hydrogen bonding interactions in the complexation between endo-functionalized molecular tube and strongly hydrophilic guest molecules in aqueous solution.

The propensity of complex formation of a host, an endo-functionalized naphthotube that has bisnaphthalene cleft architecture (host-1b), with four different strongly neutral hydrophilic guest molecules, namely 1,4-dioxane (14D), acetone, DMSO and DMF, in water is examined using classical molecular dynamics simulations. This type of molecular tube has received significant attention recently due to its usefulness as a supramolecular catalyst and for its ability to selectively recognise biologically and environmentally important neutral molecules in aqueous solution. We sequentially address the role of the different guest molecules in the structural change of host-1b, the role of the host-inserted guest and the water-inserted guest hydrogen bond properties and the host-guest binding free energies in the complex. The derivatives of our findings are: (a) the host changes its shape upon the insertion of a guest molecule and the magnitude of the shape change depends on the type and the nature of the guest molecule; (b) the complete insertion of a guest into the cavity of host-1b is only observed for guest 14D; and (c) the complete removal of water molecules from the host cavity is observed for guest 14D and the presence of a single water molecule is observed for all other guest molecules. The PMF and MM-PBSA calculations reveal that host-1b/14D complexation is the most energetically stable and the synergistic host-guest hydrophobic and hydrogen bonding interactions play a profound role in the stability of these host-guest complexes. Specifically, as the host cavity contains a small hydrophilic part and a large hydrophobic part, guest molecules with both these parts can form hydrogen bonds with the hydrophilic part of the host as well as forming a favorable hydrophobic interaction with the hydrophobic part of the host at the time of complexation.