Simultaneous Organic and Inorganic Host-Guest Chemistry within Pillararene-Protein Cage Frameworks.

Supramolecular self-assembly of biomolecules provides a powerful bottom-up strategy to build functional nanostructures and materials. Among the different biomacromolecules, protein cages offer various advantages including uniform size, versatility, multi-modularity, and high stability. Additionally, protein cage crystals present confined microenvironments with well-defined dimensions. On the other hand, molecular hosts, such as cyclophanes, possess a defined cavity size and selective recognition of guest molecules. However, the successful combination of macrocycles and protein cages to achieve functional co-crystals has remained limited. In this study, we demonstrate electrostatic binding between cationic pillar[5]arenes and (apo)ferritin cages that results in porous and crystalline frameworks. The electrostatically assembled crystals present a face-centered cubic (FCC) lattice and have been characterized by means of small-angle X-ray scattering and cryo-TEM. These hierarchical structures result in a multiadsorbent framework capable of hosting both organic and inorganic pollutants, such as dyes and toxic metals, with potential application in water-remediation technologies.

Simultaneous Organic and Inorganic Host-Guest Chemistry within Pillararene-Protein Cage Frameworks.

Invited for the cover of this issue are Mauri A. Kostiainen and co-workers at Aalto and Oakland Universities. The image depicts two ferritin protein cages joined by a cationic pillararene hosting a guest dye. Read the full text of the article at 10.1002/chem.202104341.

Divalent Benzimidazolium-Based Axles for Self-Reporting Pseudorotaxanes.

Mono- and (bis)benzimidazoliums were evaluated both experimentally and computationally for their potential as pseudopolyrotaxane axle building blocks. Their aggregation and photophysical behavior, along with their potential to form a [2]pseudorotaxane with dibenzyl-24-crown-8, was studied through the synergistic application of 1D/2D and diffusion-ordered NMR spectroscopy, mass spectrometry, ultraviolet-visible and fluorescence spectroscopy, and time-dependent density functional theory. Their photophysical behavior was measured and modeled as a function of protonation state, solvent, and concentration. The axles show strong solvochromaticism and a very pronounced concentration-dependent optical profile, including self-quenching when a pseudorotaxane is formed. This axle with multiple recognition sites has the potential to form pseudorotaxanes with tunable optical behavior.

Naphthalene-functionalized resorcinarene as selective, fluorescent self-quenching sensor for kynurenic acid.

Kynurenic acid is a by-product of tryptophan metabolism in humans, with abnormal levels indicative of disease. There is a need for water-soluble receptors that selectively bind kynurenic acid, allowing for detection and quantification. We report here the high-affinity binding of kynurenic acid in aqueous media to a resorcinarene salt receptor decorated with four flexible naphthalene groups at the upper rim. Experimental results from 1H NMR, isothermal titration calorimetry, and electronic absorption and fluorescence spectroscopies all support high-affinity binding and selectivity for kynurenic acid over tryptophan. The measured binding constant (K = 1.46 ± 0.21 × 105 M-1) is one order of magnitude larger than that observed with other resorcinarene receptors. The present host-guest system can be employed for sensory recognition of kynurenic acid. Computational studies reveal the key role of a series of cooperative attractive intra- and inter-molecular interactions contributing to an optimal binding process in this system.

Recent Advances in Halogen Bonded Assemblies with Resorcin[4]arenes.

Resorcinarenes are cavity-containing compounds when in the crown conformation, from the calixarene family of concave compounds. These easy to synthesize macrocycles can be decorated at the upper rim through the eight hydroxyl groups and/or the 2-position of the aromatic ring. They are good synthons in supramolecular chemistry leading to appealing assemblies such as open-inclusion complexes, capsules and tubes through multiple weak interactions with various guests. Halogen bonding (XB) is a highly directional non-covalent interaction by an electron-deficient halogen atom as a donor that interacts with a Lewis base, the XB acceptor. This tutorial review provides an overview of recent advances in halogen-bonded assemblies based on resorcinarenes and their derivatives, specifically focusing on discrete and capsular assemblies.

Bringing a Molecular Plus One: Synergistic Binding Creates Guest-Mediated Three-Component Complexes.

Cethyl-2-methylresorcinarene (A), pyridine (B), and a set of 10 carboxylic acids (Cn) associate to form A·B·Cn ternary assemblies with 1:1:1 stoichiometry, representing a useful class of ternary systems where the guest mediates complex formation between the host and a third component. Although individually weak in solution, the combined strength of the multiple noncovalent interactions organizes the complexes even in a highly hydrogen-bond competing methanol solution, as explored by both experimental and computational methods. The interactions between A·B and Cn are dependent on the pKa values of carboxylic acids. The weak interactions between A and C further reinforce the interactions between A and B, demonstrating positive cooperativity. Our results reveal that the two-component system such as that formed by A and B can form the basis for the development of specific sensors for the molecular recognition of carboxylic acids.

Thermodynamically driven self-assembly of pyridinearene to hexameric capsules.

Pyridinearene macrocycles have previously shown unique host-guest properties in their capsular dimers including endo complexation of neutral molecules and exo complexation of anions. Here, we demonstrate for the first time the formation of hydrogen bonded hexamer of tetraisobutyl-octahydroxypyridinearene in all three states of matter - gas phase, solution and solid-state. Cationic tris(bipyridine)ruthenium(ii) template was found to stabilize the hexamer in gas phase, whereas solvent molecules do this in condensed phases. In solution, the capsular hexamer was found to be the thermodynamically favoured self-assembly product and transition from dimer to hexamer occurred in course of time. The crystal structure of hexamer revealed 24 N-HO direct intermolecular hydrogen bonds between the six pyridinearene macrocycles without any bridging solvent molecules. Hydrogen bond patterns correlate well with DFT computed structures. Thus, all structural chemistry methods (IM-MS, DOSY NMR, DFT, X-ray crystallography) support the same structure of the hexameric capsule that has a diameter of ca. 3 nm and volume of 1160 Å3.

Halogen-Bond-Mediated Self-Assembly of Polymer-Resorcinarene Complexes.

A new supramolecular system based on halogen-bonded macromolecular substances is presented. Binding and complex formation between a halogen bond acceptor N-benzyl ammonium resorcinarene bromide and a library of polymeric halogen bond donors based on iodotetrafluorophenoxy functionality is shown. The complex formation was confirmed in liquid state by dynamic light scattering and transmission electron microscopy. Spectroscopic measurements in the solid state verify the halogen bonding. In particular, the study shows that both homopolymers and polyethylene glycol block copolymers act as effective halogen bond donors leading to polymer-architecture-dependent complex morphologies.

Halogen bonding and host-guest chemistry between N-alkylammonium resorcinarene halides, diiodoperfluorobutane and neutral guests.

Single crystal X-ray structures of halogen-bonded assemblies formed between host N-hexylammonium resorcinarene bromide (1) or N-cyclohexylammonium resorcinarene chloride (2), and 1,4-diiodooctafluorobutane and accompanying small solvent guests (methanol, acetonitrile and water) are presented. The guests' inclusion affects the geometry of the cavity of the receptors 1 and 2, while the divalent halogen bond donor 1,4-diiodooctafluorobutane determines the overall nature of the halogen bond assembly. The crystal lattice of 1 contains two structurally different dimeric assemblies A and B, formally resulting in the mixture of a capsular dimer and a dimeric pseudo-capsule. 1H and 19F NMR analyses supports the existence of these halogen-bonded complexes and enhanced guest inclusion in solution.

Host-guest complexes of conformationally flexible C-hexyl-2-bromoresorcinarene and aromatic N-oxides: solid-state, solution and computational studies.

Host-guest complexes of C-hexyl-2-bromoresorcinarene (BrC6) with twelve potential aromatic N-oxide guests were studied using single crystal X-ray diffraction analysis and 1H NMR spectroscopy. In the solid state, of the nine obtained X-ray crystal structures, eight were consistent with the formation of BrC6-N-oxide endo complexes. The lone exception was from the association between 4-phenylpyridine N-oxide and BrC6, in that case the host forms a self-inclusion complex. BrC6, as opposed to more rigid previously studied C-ethyl-2-bromoresorcinarene and C-propyl-2-bromoresorcinarene, undergoes remarkable cavity conformational changes to host different N-oxide guests through C-H···π(host) interactions. In solution phase CD3OD/CDCl3 (1:1 v/v), all twelve N-oxide guests form endo complexes according to 1H NMR; however, in more polar CD3OD/DMSO-d6 (9:1 v/v), only three N-oxides with electron-donating groups form solution-phase endo complexes with BrC6. In solid-state studies, 3-methylpyridine N-oxide+BrC6 crystallises with both the upper- and lower-rim BrC6 cavities occupied by N-oxide guests. Computational DFT-based studies support that lower-rim long hexyl chains provide the additional stability required for this ditopic behaviour. The lower-rim cavity, far from being a neutral hydrophobic environment, is a highly polarizable electrostatically positive surface, aiding in the binding of polar guests such as N-oxides.

Recognition of Viologen Derivatives in Water by N-Alkyl Ammonium Resorcinarene Chlorides.

Three water-soluble N-alkyl ammonium resorcinarene chlorides decorated with terminal hydroxyl groups at the lower rims were synthesized and characterized. The receptors were decorated at the upper rim with either terminal hydroxyl, rigid cyclohexyl, or flexible benzyl groups. The binding affinities of these receptors toward three viologen derivatives, two of which possess an acetylmethyl group attached to one of the pyridine nitrogens, in water were investigated via 1H NMR spectroscopy, fluorescence spectroscopy, and isothermal titration calorimetry (ITC). ITC quantification of the binding process gave association constants of up to 103 M-1. Analyses reveal a spontaneous binding process which are all exothermic and are both enthalpy and entropy driven.

Simultaneous endo and exo†Complex Formation of Pyridine[4]arene Dimers with Neutral and Anionic Guests.

The formation of complexes between hexafluorophosphate (PF6- ) and tetraisobutyloctahydroxypyridine[4]arene has been thoroughly studied in the gas phase (ESI-QTOF-MS, IM-MS, DFT calculations), in the solid state (X-ray crystallography), and in chloroform solution (1 H, 19 F, and DOSY NMR spectroscopy). In all states of matter, simultaneous endo complexation of solvent molecules and exo complexation of a PF6- anion within a pyridine[4]arene dimer was observed. While similar ternary complexes are often observed in the solid state, this is a unique example of such behavior in the gas phase.

[N⋠⋠⋠I+ ⋠⋠⋠N] Halogen-Bonded Dimeric Capsules from Tetrakis(3-pyridyl)ethylene Cavitands.

Two [N⋅⋅⋅I+ ⋅⋅⋅N] halogen-bonded dimeric capsules using tetrakis(3-pyridyl)ethylene cavitands with different lower rim alkyl chains are synthesized and analyzed in solution and the gas phase. These first examples of symmetrical dimeric capsules making use of the iodonium ion (I+ ) as the main connecting module are characterized by 1 H NMR spectroscopy, diffusion ordered NMR spectroscopy (DOSY), electrospray ionization mass spectrometry (ESI-MS), and ion mobility-mass spectrometry (TW-IMS) experiments. The synthesis and effective halogen-bonded dimerization proceeds through analogous dimeric capsules with [N⋅⋅⋅Ag+ ⋅⋅⋅N] binding motifs as the intermediates as evidenced by the X-ray structures of (CH2 Cl2 )2 @[3 a2 ⋅Ag4 ⋅(H2 O)2 ⋅OTs4 ] and (CH2 Cl2 )2 @[3 a2 ⋅Ag4 ⋅(H2 O)4 ⋅OTs4 ], two structurally different capsules.

Concerted Halogen-Bonded Networks with N-Alkyl Ammonium Resorcinarene Bromides: From Dimeric Dumbbell to Capsular Architectures.

N-Alkyl ammonium resorcinarene bromides and 1,4-diiodooctafluorobutane via multiple intermolecular halogen bonds (XB) form different exotic supramolecular architectures through subtle changes of the upper rim substituents. Dimeric dumbbell-like assembly with encapsulated guest molecules is generated with N-benzyl substituents. The N-hexyl groups engender an XB-induced polymeric pseudocapsule and an XB-induced dimeric capsule with entrapped 1,4-dioxane guest molecules. The N-propyl and N-cyclohexyl groups generate deep cavity cavitands. The deep cavity cavitands possess cavities for self-inclusion leading to polymeric herringbone arrangement in one direction and that pack into 3D polymeric arrangement resembling egg crate-like supramolecular networks. These assemblies are studied in solution via NMR spectroscopy and in the solid state via X-ray crystallography.

A Halogen-Bonded Dimeric Resorcinarene Capsule.

Iodine (I2) acts as a bifunctional halogen-bond donor connecting two macrocyclic molecules of the bowl-shaped halogen-bond acceptor, N-cyclohexyl ammonium resorcinarene chloride 1, to form the dimeric capsule [(1,4-dioxane)3@1(2)(I2)2]. The dimeric capsule is constructed solely through halogen bonds and has a single cavity (V=511 Å(3)) large enough to encapsulate three 1,4-dioxane guest molecules.

The "Nitrogen Effect": Complexation with Macrocycles Potentiates Fused Heterocycles to Form Halogen Bonds in Competitive Solvents.

Weak intermolecular forces are typically very difficult to observe in highly competitive polar protic solvents as they are overwhelmed by the quantity of competing solvent. This is even more challenging for three-component ternary assemblies of pure organic compounds. In this work, we overcome these complications by leveraging the binding of fused aromatic N-heterocycles in an open resorcinarene cavity to template the formation of a three-component halogen-bonded ternary assembly in a protic polar solvent system.

Repurposing host-guest chemistry to sequester virulence and eradicate biofilms in multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii.

The limited diversity in targets of available antibiotic therapies has put tremendous pressure on the treatment of bacterial pathogens, where numerous resistance mechanisms that counteract their function are becoming increasingly prevalent. Here, we utilize an unconventional anti-virulence screen of host-guest interacting macrocycles, and identify a water-soluble synthetic macrocycle, Pillar[5]arene, that is non-bactericidal/bacteriostatic and has a mechanism of action that involves binding to both homoserine lactones and lipopolysaccharides, key virulence factors in Gram-negative pathogens. Pillar[5]arene is active against Top Priority carbapenem- and third/fourth-generation cephalosporin-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, suppressing toxins and biofilms and increasing the penetration and efficacy of standard-of-care antibiotics in combined administrations. The binding of homoserine lactones and lipopolysaccharides also sequesters their direct effects as toxins on eukaryotic membranes, neutralizing key tools that promote bacterial colonization and impede immune defenses, both in vitro and in vivo. Pillar[5]arene evades both existing antibiotic resistance mechanisms, as well as the build-up of rapid tolerance/resistance. The versatility of macrocyclic host-guest chemistry provides ample strategies for tailored targeting of virulence in a wide range of Gram-negative infectious diseases.