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Core-fluorescent cavitands based on 2-(2'-resorcinol)benzimidazole fluorophores (RBIs) merged with the resorcin[4]arene skeleton were designed and synthesized. The cavitands, due to the presence of intramolecular hydrogen bonds and increased acidity, show excited state intramolecular proton transfer (ESIPT) and readily undergo deprotonation to form dianionic cavitands, capable of strong binding to organic cations. The changes in fluorescence are induced by deprotonation and binding events and involve huge Stokes shifts (due to emission from anionic double keto tautomers) and cation-selective enhancement of emission originating from the restriction of intramolecular motion (RIR) upon recognition in the cavity. Ab initio calculations indicate that the macrocyclic scaffold stabilizes the ground state tautomeric forms of the fluorophores that are not observed for non-macrocyclic analogs. In the excited state, the emitting forms for both macrocyclic scaffolds and non-macrocyclic analogs are anionic double keto tautomers, which are the result of excited state intramolecular proton transfer (ESIPT) or excited state double proton transfer (ESDPT).

Spatial sequestration of molecules is a prerequisite for the complexity of biological systems, enabling the occurrence of numerous, often non-compatible chemical reactions and processes in one cell at the same time. Inspired by this compartmentalization concept, chemists design and synthesize artificial nanocontainers (capsules and cages) and use them to mimic the biological complexity and for new applications in recognition, separation, and catalysis. Here, we report the formation of large closed-shell species by interactions of well-known polyphenolic macrocycles with anions. It has been known since many years that C-alkyl resorcin[4]arenes (

We present the synthesis of new chiral water-soluble dimeric capsules by the multicomponent Mannich reaction between charged amino acids (glutamic acid or arginine), resorcinarene, and formaldehyde and by subsequent self-assembly. The zwitterionic character of the backbones enables electrostatic interactions between arms and induces self-assembly of dimeric capsules, namely, (L-ArgR)2 and (L-GluR)2, in water with a wide range of pH, as demonstrated by NMR, diffusion coefficient measurement, and circular dichroism. The assembly/disassembly processes are fast on the NMR timescale. This mode of dimerization leaves side chains available for additional interactions and creates chiral cavities of mixed hydrophobic/hydrophilic character. According to this characteristic, capsules do not bind fully nonpolar or fully polar guests but effectively encapsulate a variety of chiral molecules with mixed polar/apolar characters (aliphatic and aromatic aldehydes, epoxides, alcohols, carboxylic acids, amines, and amino acids) with moderate strength. We also demonstrate the formation of heterocapsules (GluR) (ArgR) (homo- and heterochiral) that utilize additional interactions between charged acidic and basic side chains and have better encapsulation properties than those of the homodimers.

Peptides are commonly perceived as inapplicable components for construction of porous structures. Due to their flexibility the design is difficult and shape persistence of such putative structures is diminished. Notwithstanding these limitations, the advantages of peptides as building blocks are numerous: they are functional and functionalizable, widely available, diverse and biocompatible. We aimed at the construction of discrete porous structures that exploit the inherent functionality of peptides by an approach that is inspired by nature: structural pockets are defined by the backbones of peptides while functionality is introduced by their side chains. In this work peptide ribbons were preorganized on a macrocyclic scaffold using azapeptide-aldehyde reactions. The resulting cavitands with semicarbazone linkers arrange the peptide backbones at positions that are suitable for self-assembly of dimeric capsules by formation of binding motifs that resemble eight-stranded β-barrels. Self-assembly properties and inside/outside positions of the side chains depend crucially on the chirality of peptides. By rational optimization of successive generations of capsules we have found that azapeptides containing three amino acids in a (l, d, d) sequence give well-defined dimeric capsules with side chains inside their cavities. Taking advantage of the reversibility of the reaction of semicarbazone formation we have also employed the dynamic covalent chemistry (DCC) for a combinatorial discovery of capsules that could not be rationally designed. Indeed, the results show that stable capsules with side chains positioned internally can be obtained even for shorter sequences but only for combination peptides of (l, l) and (d, l) chirality. The hybrid (l, l)(d, l) capsule is amplified directly from a reaction mixture containing two different peptides. All capsules gain substantial ordering upon self-assembly, which is manifested by a two orders of magnitude increase of the intensity of CD spectra of capsules compared with non-assembled analogs. Temperature-dependent CD measurements indicate that the capsules remain stable over the entire temperature range tested (20-100 °C). Circular dichroism coupled with TD DFT calculations, DOSY measurements and X-ray crystallography allow for elucidation of the structures in the solid state and in solution and guide their iterative evolution for the current goals.

Numerous applications of Stoddart's 'blue-box', a pyridinium containing macrocycle of rectangular shape, encouraged us to seek successors of this amazing molecule. Using a one-step cyclization reaction we synthesized a square-shaped cyclic tetramer consisting of 4-methylenepyridinium units - pillar[4]pyridinium (P[4]P). Pillar[4]pyridinium is a quadruply positively charged water-soluble macrocycle with a highly symmetric, strained structure and an electron-deficient cavity. These features impel the macrocycle to assemble into channel networks in the solid state and render it an effective fluoride receptor in water.

We present the synthesis of hybrid[4]arenes via a one-pot reaction of 1,4,5,8-tetramethoxyanthracene and 1,3-dimethoxybenzene with formaldehyde catalyzed by TFA. Two new C2h-symmetric macrocycles having different substitution patterns at anthracene units were obtained. Both X-ray structure analysis and molecular modelling reveal a parallel arrangement of the anthracene units with an interplane distance of 4.8 A. A comparison of UV and fluorescence spectra of hybrid[4]arene and a monomeric anthracene unit indicates that the energies and intensities of the absorption bands (scaled to the same number of chromophores) remain similar. However, for the macrocycle the quantum yield of emission is increased, which may originate from its rigid structure. Hybrid[4]arene was post-macrocyclization modified by the Diels–Alder reaction with benzyne and a macrocycle with an expanded cavity was obtained. The expanded cavity macrocycle is able to selectively complex and solubilize pyridinium iodide in chloroform.

Mechanical grinding/milling can be regarded as historically the first technology for changing the properties of matter. Mechanically activated molecular units (mechanophores) can be present in various structures: polymers, macromolecules, or small molecules. However, only polymers have been reported to effectively transduce energy to mechanophores, which induces breakage of covalent bonds. In this paper, a second possibility is presented-molecular capsules as stress-sensitive units. Mechanochemical encapsulation of fullerenes in cystine-based covalent capsules indicates that complexation takes place in the solid state, despite the fact that the capsules do not possess large enough entrance portals. By using a set of solvent-free MALDI (sf-MALDI) and solid-state NMR (ss-NMR) experiments, it has been proven that encapsulation proceeds during milling and in this process hydrazones and disulfides get activated for breakage, exchange, and re-forming. The capsules are porous and therefore prone to collapse under solvent-free conditions and their conformational rigidity promotes the collapse by the breaking of covalent bonds.

Directional self-assembly of uncharged molecules in water is a major challenge in supramolecular chemistry. Herein, it is demonstrated that peptide-based cavitands wrap around a hydrophobic core (fullerene C60 ) by a combination of the hydrophobic effect and hydrogen-bonding interactions to form highly ordered three-component complexes in water that resemble the molten-globule stage of protein folding. The complexes were characterized by DOSY NMR spectroscopy, small-angle X-ray scattering, and circular dichroism, and their structures were confirmed by X-ray crystallography. Enhancement of the CD signals by nearly one order of magnitude and increased hydrolytic stability of hydrazone bonds of the complexes relative to the nonassembled species were observed. In contrast, DMSO and DMSO/water mixtures were found to be highly disintegrative for these complexes. Interestingly, some cavitands can only be synthesized in the presence of the hydrophobic template followed by disassembly of the complexes.

This paper presents a novel approach to highly diastereoselective synthesis of resorcinarenes having enlarged cavities. Inherently chiral heterocyclic resorcinarenes have been obtained with unusually high diastereoselecivity by a “one pot” sequence involving thermal generation of o-quinomethide resorcinarene derivatives and the subsequent Diels–Alder reaction with dienophiles (exemplified by α-methylstyrene). The diastereoselectivity of this reaction is explained based on the thermodynamic stability of the products. The enantiomers of rac-4 have been separated by HPLC and their absolute configuration was assigned by comparison of their experimental and theoretical CD spectra.

Macrocycles consisting of naphthalene units connected via methylene bridges offer certain advantages as macrocylic scaffolds as compared with parent calixarenes. These advantages originate from their electron rich and enlarged cavities. Additionally, macrocycles containing 1,3-bridged naphthalene units are dissymmetric and therefore they present interesting stereochemical features, including inherent chirality. We describe here a facile, one-step synthesis of two new calix[4]naphthalenes, by the condensation of 1,6-dimethoxynaphthalene with formaldehyde catalyzed by Bronsted acid (TFA). Additionally, we show the first example of hybrid[n]arene containing a 1,6-dimethoxynaphthalene unit and 1,3-dimethoxybenzene units obtained by a simple, one-pot condensation. The conformational and complexation properties were also studied for the resulting hybrid macrocycles.

Sublimation of p-iso-propylcalix[4]arene under reduced pressure results in the concomitant formation of two new polymorphs (forms IIP and IIIP). Both forms consist of interdigitated dimers of calixarene molecules, as does the known form IP. Despite similar inclusion behaviour to that of p-tert-butylcalix[4]arene, p-iso-propylcalix[4]arene does not appear to favour the formation of a transiently porous material.

A cubic nanocage (O symmetry) that exhibits inherent chirality and has a covalent, rigid skeleton with molecule-sized entrance portals was obtained by means of dynamic covalent chemistry using a reaction between aldehyde-functionalized resorcin[4]arene and hydrazine.

This review discusses chiral self-sorting-the process of choosing an interaction partner with a given chirality from a complex mixture of many possible racemic partners. Chiral self-sorting (also known as chiral self-recognition or chiral self-discrimination) is fundamental for creating functional structures in nature and in the world of chemistry because interactions between molecules of the same or the opposite chirality are characterized by different interaction energies and intrinsically different resulting structures. However, due to the similarity between recognition sites of enantiomers and common conformational lability, high fidelity homochiral or heterochiral self-sorting poses a substantial challenge. Chiral self-sorting occurs among natural and synthetic molecules that leads to the amplification of discrete species. The review covers a variety of complex self-assembled structures ranging from aggregates made of natural and racemic peptides and DNA, through artificial functional receptors, macrocyles, and cages to catalytically active metal complexes and helix mimics. The examples involve a plethora of reversible interactions: electrostatic interactions, π-π stacking, hydrogen bonds, coordination bonds, and dynamic covalent bonds. A generalized view of the examples collected from different fields allows us to suggest suitable geometric models that enable a rationalization of the observed experimental preferences and establishment of the rules that can facilitate further design.

A strategy that utilizes macrocyclic resorcin[4]arenes for the pre-positioning of peptides to form cavitands that subsequently self-assemble through hydrogen bonds was used for the formation of molecular capsules. Hydrophobic tri- and tetrapeptides were attached via their C-termini to tetraformylresorcin[4]arene using acylhydrazone linkers. The resulting cavitands self-assemble in relatively non-polar environments (chloroform or chloroform-methanol) forming non-covalent dimers through hydrogen bonding motifs resembling beta-sheets. NMR studies (ROESY and DOSY) indicate that the binding motif involves C-terminal amino acids from the peptide strands, while the N-terminal parts are positioned outside of the cavity. The capsules possess stable porous structures and they are able to quantitatively complex fullerenes C60 and C70.

The complexation of chiral guests in the cavity of dimeric self-assembled chiral capsule 1(2) was studied by using NMR spectroscopy and X-ray crystallography. Capsule 1(2) has walls composed of amino acid backbones forming numerous directional binding sites that are arranged in a chiral manner. The polar character of the interior dictates the encapsulation preferences towards hydrophilic guests and the ability of the capsule to extract guests from water into an organic phase. Chiral discrimination towards hydroxy acids was evaluated by using association constants and competition experiments, and moderate de values were observed (up to 59 %). Complexes with one or two guest molecules in the cavity were formed. For 1:1 complexes, solvent molecules are coencapsulated; this influences guest dynamics and makes the chiral recognition solvent dependent. Reversal of the preferences can be induced by coencapsulation of a nonchiral solvent in the chiral internal environment. For complexes with two guests, filling of the capsule's internal space can be very effective and packing coefficients of up to 70 % can be reached. The X-ray crystal structure of complex 1(2) superset((S)-6)(2) with well-resolved guest molecules reveals a recognition motif that is based on an extensive system of hydrogen bonds. The optimal arrangement of interactions with the alternating positively and negatively charged groups of the capsule's walls is fulfilled by the guest carboxylic groups acting simultaneously as hydrogen-bond donors and acceptors. An additional guest molecule interacting externally with the capsule reveals a possible entrance mechanism involving a polar gate. In solution, the structural features and dynamic behavior of the D(4)-symmetric homochiral capsule were analyzed by variable-temperature NMR spectroscopy and the results were compared with those for the S(8)-symmetric heterochiral capsule.

Dynamic chirality of iminoresorcin[4]arenes that originates from regioselective and diastereoselective keto-enol tautomerisation was switched by non-covalent interactions with achiral molecules, as demonstrated by experimental electronic circular dichroism (ECD) spectra supported by TD DFT calculations.

The interaction of the neutral form of resorcin[4]arene 1 (R=i-Bu) with tetraalkylammonium cations (Me4N+, Et4N+, Pr4N+and Bu4N+) was analyzed in the solid state and in methanol solutions. In methanol, NMR titration results indicate almost no differentiation between Me4N+ and Et4N+ cations (Kass(Me4N+)=93 M−1 and Kass(Et4N+)=81 M−1) and a relatively low association constant for Pr4N+( Kass(Pr4N+)=25 M−1). In the solid state, for the Me4NCl complex, the resorcinarene assumes the C2v boat conformation and is surrounded by as many as four Me4NCl moieties. The structure of the Et4NCl complex indicates that ethyl group can be conveniently placed in the resocin[4]arene cavity. The larger Bu4N+ cation was found completely external to the cavity.

Owing to their versatility and biocompatibility, peptide-based self-assembled structures constitute valuable targets for complex functional designs. It is now shown that artificial capsules based on β-barrel binding motifs can be obtained by means of dynamic covalent chemistry (DCC) and self-assembly. Short peptides (up to tetrapeptides) are reversibly attached to resorcinarene scaffolds. Peptidic capsules are thus selectively formed in either a heterochiral or a homochiral way by simultaneous and spontaneous processes, involving chiral sorting, tautomerization, diastereoselective induction of inherent chirality, and chiral self-assembly. Self-assembly is shown to direct the regioselectivity of reversible chemical reactions. It is also responsible for shifting the tautomeric equilibrium for one of the homochiral capsules. Two different tautomers (keto-enamine hemisphere and enol-imine hemisphere) are observed in this capsule, allowing the structure to adapt for self-assembly.

Chiral capsules with polar interiors (reversed capsules) undergo heterochiral sorting and exhibit positive mutalism - both hemispheres mutually benefit from the association. This feature can be coupled with partial reversibility of the formation reaction and utilized to amplify synthesis of hybrid capsules made of hemispheres that cannot be formed independently.

Comparison of water-free and water-mediated recognition processes within a synthetic resorcinarene-based self-assembled capsule shows that water can change the stoichiometry of binding as well as the selectivity and it can substantially restrict guest dynamics within the binding site.

A charge transfer-type fluorescent molecular sensor consisting of a bisamidopyridine receptor and two styryl base chromophores shows H(2)PO(4)(-) and acetate-enhanced fluorescence due to the conversion of weak intramolecular hydrogen bonds into strong ones in the host-guest ensemble.

A new approach to anion recognition utilizing electrostatic and hydrogen bonding interactions has been demonstrated by placement of the whole ion-pair in a molecular capsule.

In the presence of methanol the tetrakis(benzoxazines) complex tetramethylammonium cation within the cavity, and the cavity is completely sealed by two intramolecular hydrogen bonds between amide groups. The Cl(-) anion is found external to the cavity. In CHCl(3), Me(4)N(+) is complexed within the cavity, but the Cl(-) anion acts as a stopper in the upper rim of the cavity, hydrogen-bonded to the amide groups. The solution results are supported by single-crystal X-ray structural studies of both the single-molecule molecular capsules, and those stoppered by Cl(-).

This tutorial review covers the recent development in the synthesis and application of molecules and finite assemblies that are chiral owing to their curvature. A modified definition of inherent chirality is provided. Various classes of chiral concave molecules are presented including salphen complexes, cyclic amides, derivatives of sumanene, trioxatricornan or subphthalocyanine, cyclotriveratrylenes, homooxacalix[3]arenes, calixarenes, resorcinarenes, phthalocyanines, corannulenes and cavitands. Some of these bowl shaped compounds exhibit high inversion barriers, comparable with the stability of classical carbon chirality centres, while the others (e.g. hydrogen bonded assemblies) can only be detected by NMR. This review is focused on practical aspects of synthesis, resolution and applications in chiral recognition and asymmetric synthesis.

Phenylalanine substituted resorcinarenes form self-complementary dimeric homo- or heterochiral capsules based on deeply buried electrostatic interactions (salt bridges) with numerous polar and non-polar functionalities in their interiors available for interactions with encapsulated polar molecules, as proved by X-ray analysis and diffusion NMR spectroscopy.