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Monopropargyloxy-tripropoxy-calix[4]arene 1 was subjected to a propargyl Claisen rearrangement to give unusual calix[3]arene[1]chromene and homocalix[3]arene[1]benzofuran macrocycles. Quantum mechanical density functional theory calculations indicated that an initial [3,3] sigmatropic reaction affords a highly reactive allene intermediate, stabilized by two main diradical pathways leading to six- and five-membered oxygenated rings. In the presence of a n-butylammonium guest, calix[3]-arene[1]chromane 6 forms two stereoisomeric complexes stabilized by +N−H···O and cation···π interactions.

The confused-prism[5]arene macrocycle (c-PrS[5](Me)) shows conformational adaptive behavior in the presence of ammonium guests. Upon guest inclusion, the 1,4-bridged naphthalene flap reverses its planar chirality from pS to pR (with reference to the pS(pR)(4) enantiomer). Stereoselective directional threading is also observed in the presence of directional axles, in which up/down stereoisomers of homochiral (pR)(5)-c-PrS[5](Me) pseudorotaxanes are formed.

Cone-shaped calix[4]arene-tetrol 3 has the ability to form open structures due to the presence of four OH groups at the upper rim, which allows the construction of H-bonded supramolecular organic frameworks (SOFs). In the presence of water, SOF-1 is formed, which contains hydrophilic channels (mean diameter of 8.5 Å) contoured by the p-phenolic OH groups. In the presence of acetonitrile, SOF-2 is formed, which contains smaller hydrophobic channels (mean diameter of 6.6 Å) delimited by aromatic walls. The Na+@3 complex, which hosts acetonitrile molecules in the calixarene cavities, and dibromo-calix[4]arene-diol 5 give rise to more compact SOFs not containing channels. The H-bond network formed by all four p-phenolic OH groups in a pinched cone conformation of the calixarene is a determinant for the porosity of SOFs based on calix[4]arene-tetrol.

Vitamin B

Chloroquine (CQ) is a first-choice drug against malaria and autoimmune diseases. It has been co-administered with zinc against SARS-CoV-2 and soon dismissed because of safety issues. The structural features of Zn-CQ complexes and the effect of CQ on zinc distribution in cells are poorly known. In this study, state-of-the-art computations combined with experiments were leveraged to solve the structural determinants of zinc-CQ interactions in solution and the solid state. NMR, ESI-MS, and X-ray absorption and diffraction methods were combined with ab initio molecular dynamics calculations to address the kinetic lability of this complex. Within the physiological pH range, CQ binds Zn2+ through the quinoline ring nitrogen, forming [Zn(CQH)Clx(H2O)3-x](3+)-x (x = 0, 1, 2, and 3) tetrahedral complexes. The Zn(CQH)Cl3 species is stable at neutral pH and at high chloride concentrations typical of the extracellular medium, but metal coordination is lost at a moderately low pH as in the lysosomal lumen. The pentacoordinate complex [Zn(CQH)(H2O)4]3+ may exist in the absence of chloride. This in vitro/in silico approach can be extended to other metal-targeting drugs and bioinorganic systems.

Diphenylalanine is an amyloidogenic building block that can form a versatile array of supramolecular materials. Its shortcomings, however, include the uncontrolled hierarchical assembly into microtubes of heterogeneous size distribution and well-known cytotoxicity. This study rationalized heterochirality as a successful strategy to address both of these pitfalls and it provided an unprotected heterochiral dipeptide that self-organized into a homogeneous and optically clear hydrogel with excellent ability to sustain fibroblast cell proliferation and viability. Substitution of one l-amino acid with its d-enantiomer preserved the ability of the dipeptide to self-organize into nanotubes, as shown by single-crystal XRD analysis, whereby the pattern of electrostatic and hydrogen bonding interactions of the backbone was unaltered. The effect of heterochirality was manifested in subtle changes in the positioning of the aromatic side chains, which resulted in weaker intermolecular interactions between nanotubes. As a result, d-Phe-l-Phe self-organized into homogeneous nanofibrils with a diameter of 4 nm, corresponding to two layers of peptides around a water channel, and yielded a transparent hydrogel. In contrast with homochiral Phe-Phe stereoisomer, it formed stable hydrogels thermoreversibly. d-Phe-l-Phe displayed no amyloid toxicity in cell cultures with fibroblast cells proliferating in high numbers and viability on this biomaterial, marking it as a preferred substrate over tissue-culture plastic. Halogenation also enabled the tailoring of d-Phe-l-Phe self-organization. Fluorination allowed analogous supramolecular packing as confirmed by XRD, thus nanotube formation, and gave intermediate levels of bundling. In contrast, iodination was the most effective strategy to augment the stability of the resulting hydrogel, although at the expense of optical transparency and biocompatibility. Interestingly, iodine presence hindered the supramolecular packing into nanotubes, resulting instead into amphipathic layers of stacked peptides without the occurrence of halogen bonding. By unravelling fine details to control these materials at the meso- and macro-scale, this study significantly advanced our understanding of these systems.

Dinuclear Cu-2(II,II)-cores stabilized by the N3O donorset of HL1 = (2-{[[di(2-pyridyl)methyl](methyl)amino]methyl}phenol), HL2 = 2-({[di(2-pyridyl)methyl] amino}methyl)phenol), and HL3 = 2-({[di(2-pyridyl)methyl]amino}methyl)-4-nitrophenol display a unique superoxide dismutase (SOD) combined with catalase (CAT)-like activity in water, at neutral pH. The Cu2L21 < Cu2L22 < Cu2L23 structure-reactivity trend puts a spotlight on the electron-deficient core of Cu2L23 that exhibits the highest SOD (log k(cat) (O-2(center dot-)) = 7.55) and CAT-like (k(H2O2) = 0.66 M(-1)s(-1)) performance. Time-lapse ESI-MS and EPR experiments indicate that a dimeric core is essential for oxygenic turnover upon H2O2 decomposition.

We here explore the soluble Human Leukocyte Antigen-G (sHLA-G) expression level as clinical biomarker in metastatic colorectal cancer (mCRC). To this aim the sHLA-G protein was measured in plasma samples of 40 patients with mCRC treated with the FOLFIRI (irinotecan (CPT-11) plus 5-fluorouracil (5-FU) and leucovorin (LV)) regimen. The results suggest a link between HLA-G levels and irinotecan (CPT-11) pharmacokinetic, leading to hypothesize a molecular interaction between sHLA-G and CPT-11. This interaction was confirmed experimentally by fluorescence spectroscopy. HLA-G is known to exist in a number of polymorphs that affect both the protein expression levels and its peptide-binding cleft. The interaction between HLA-G polymorphs and CPT-11 was explored by means of computational modelling, confirming the hypothesis that CPT-11 could actually target the peptide binding cleft of the most common HLA-G polymorphs.

Sulfonato-calix[n]arenes (sclxn) are promising tools to generate crystalline protein frameworks. We report, for the first time, a lower rim functionalised octa-anionic calix[4]arene (sclx4mc) in complex with proteins. Two crystal structures of sclx4mc bound to yeast or horse heart cytochrome c (cytc) are described. Highly porous honeycomb or tubular assemblies were obtained with yeast or horse cytc, respectively. Related frameworks were obtained previously with sclx8 and sclx6 but not with sclx4, suggesting that the ligand charge is a determining factor.

Inclusion of polymethine cyanine dyes in the cavity of macrocyclic receptors is an effective strategy to alter their absorption and emission behavior in aqueous solution. In this paper, the effect of the host-guest interaction between cucurbit[8]uril (CB[8]) and a model trimethine indocyanine (Cy3) on dye spectral properties and aggregation in water is investigated. Solution studies, performed by a combination of spectroscopic and calorimetric techniques, indicate that the addition of CB[8] disrupts Cy3 aggregates, leading to the formation of a 1 : 1 host-guest complex with an association constant of 1.5×106 M-1 . At concentrations suitable for NMR experiments, the slow formation of a supramolecular polymer was observed, followed by precipitation. Single crystals X-ray structure elucidation confirmed the formation of a polymer with 1 : 1 stoichiometry in the solid state.

Calix[6]arenes disubstituted at the methylene bridges, which are stable in the cone or 1, 2, 3- alternate conformation, form pseudorotaxanes with dialkylammonium axles. The cone-wheel based pseudorotaxanes are 10-100 times more stable than those obtained with the native conformationally- mobile calix[6]arene wheel, as a consequence of their higher degree of preorganization. The threading of conformationally stable 1, 2, 3- alternate-calix[6]arenes is unprecedented in the literature. Therefore, very peculiar NMR features are here evidenced for this threading process involving the less symmetrical 1, 2, 3-alternate calix[6]arene conformation, which implies a peculiar rototranslation motion of the axle.

A four component system consisting of two water-soluble calix[5]arenes (1 and 2) with differently substituted upper-rims and two α,ω-alkanediyldiammonium ions of different lengths (NC8N and NC10N) was found to assemble in a high-fidelity fashion providing exclusively the two homocalixarene capsules 1⊃NC8N⊂1 and 2⊃NC10N⊂2, irrespective of the order of guest addition. When the longer linker (NC10N) was left out from the mixture altogether, however, 1⊃NC8N⊂2 heterocapsules were formed.

Direct O-alkylation of p-tert-butyldihomooxacalix[4]arene (1) with N-(bromopropyl)- or N-(bromoethyl)phthalimides and K2CO3 in acetonitrile was conducted under conventional heating (reflux) and using microwave irradiation and ball milling methodologies. The reactions afforded mono- and mainly distal di-substituted derivatives in the cone conformation, in a total of eight compounds. They were isolated by column chromatography, and their conformations and the substitution patterns were established by NMR spectroscopy (1H, 13C, COSY and NOESY experiments). The X-ray structures of four dihomooxacalix[4]arene phthalimide derivatives (2a, 3a, 3b and 5a) are reported, as well as their photophysical properties. The microwave (MW)-assisted alkylations drastically reduced the reaction times (from days to less than 45 min) and produced higher yields of both 1,3-di-substituted phthalimides (3a and 6a) with higher selectivity. Ball milling did not reveal to be a good method for this kind of reaction.

The conformational changes of the homooxa adamantyl ketones 1 and 2, as well as of the calix[4]arene analogue derivative 3, all in the cone conformation, upon Pb2+ complexation were investigated by 1H, 13C, 207Pb NMR and proton spin-lattice relaxation times (T1) experiments. The X-ray crystal structures of ketones 1 and 3 were determined. The inclusion of an acetonitrile molecule in the hydrophobic cavity of the ligands was observed in the solid state. In solution, inclusion was observed only in the case of Pb2+ ⊂ ketone 3 complex. DFT calculations were also performed to complement the NMR conformational analysis and to bring further insights to the cation complexation. The data confirmed the formation of 1:1 complexes between Pb2+ and the ligands, and that the cation is located inside the cavity defined by the phenoxy and carbonyl oxygen atoms. In general, the ligand conformations became closer to a regular cone upon complexation, with the binding models found for the three ketones through the NMR studies corroborated by the DFT calculations.

The host-guest inclusion complexes of cucurbiturils with alkyl viologen have interesting architectures, chemical properties, and potential applications in sensors and nanotechnology. A highly hydrated triclinic crystal of cucurbit[8]uril (CB[8]) complexed by methyl hexadecyl viologen (MVC16) is characterized by the unprecedented coexistence in the crystal of three host-guest complexes with 3:2, 2:2, and 1:1 stoichiometries. In all these complexes, the hook-shaped alkyl chain of the MVC16 is hosted in the CB[8] macrocycles, while the methyl viologen moieties have various environments. In the Z-shaped 3:2 complex, a central CB[8] unit hosts two viologen heads in the cavity, while the 2:2 complex is held together by π-stacking interactions between two viologen units. In the square 2D tiling crystal packing of CB[8] macrocycles, the same site which favors the dimerization observed in the 2:2 complex is also statistically occupied by a single methyl viologen moiety of the 1:1 complex. The rational interpretation of the crystal structure represented an intriguing challenge, due to the complicated statistical disorder in the alkyl chains hosted in CB[8] units and in the methyl viologen moieties of 2:2 and 1:1 complexes. In contrast with the solution behavior dominated by the 2:1 complex, the coexistence of three host-guest complexes with 3:2, 2:2, and 1:1 ratios highlights the fundamental importance of packing effects in the crystallized supramolecular complexes. Therefore, the crystallization process has permitted us to capture different host-guest systems in a single crystal, revealing a supramolecular landscape in a single photo.

There is considerable interest in dynamic materials featuring modular components with nano-scale dimensions and controlled responsiveness to external stimuli. Supramolecular polymers are a class of materials that fulfil all these conditions well. Here, we present a family of host–guest supramolecular polymers that combine the outstanding complexing properties of tetraphosphonate cavitands toward N-methylpyridinium guests with molecular switching. The designed monomer is a cavitand featuring four inward facing PO groups at the upper rim and a single N-methylpyridinium unit at the lower rim, forming instantaneously a polymeric species in solution, thanks to the high complexation constants measured for these host–guest interactions. This system has been analyzed by NMR spectroscopy and electrochemical techniques. In order to interpret the results of diffusion-sensitive experiments, we took advantage of the X-ray crystal structure obtained for the polymeric species and developed an original treatment for the PGSE data by non-linear fitting. The analysis of the experimental data identified an isodesmic polymerization model at a monomer concentration below 20 mM, driven by intrachain host–guest interactions, and an additional level of tetrameric bundle aggregation above 20 mM, due to interchain dipolar and quadrupolar interactions. Two orthogonal disassembly procedures have been implemented: electrochemical reduction for the linear chains and solvent-driven dissolution for the bundles.

Ethyl- and propyl-prism[6]arenes are obtained in high yields and in short reaction times, independent of the nature and size of the solvent, in the cyclization of 2,6-dialkoxynaphthalene with paraformaldehyde. PrS[6]Et or PrS[6]nPr adopt, both in solution and in the solid state, a folded cuboid-shaped conformation, in which four inward oriented alkyl chains fill the cavity of the macrocycle. On these bases, we proposed that the cyclization of PrS[6]Et or PrS[6]nPr occurs through an intramolecular thermodynamic self-templating effect. In other words, the self-filling of the internal cavity of PrS[6]Et or PrS[6]nPr stabilizes their cuboid structure, driving the equilibrium toward their formation. Molecular recognition studies, both in solution and in the solid state, show that the introduction of guests into the macrocycle cavity forces the cuboid scaffold to open, through an induced-fit mechanism. An analogous conformational change from a closed to an open state occurs during the endo-cavity complexation process of the pentamer, PrS[5]. These results represent a rare example of a thermodynamically controlled cyclization process driven through an intramolecular self-template effect, which could be exploited in the synthesis of novel macrocycles., Ethyl- and propyl-prism[6]arenes are obtained by an intramolecular thermodynamic self-template effect: the self-filling of the internal cavity stabilizes their cuboid structure, driving the equilibrium toward their formation.

The chiral (R)-10-hydroxystearic acid ((R)-10-HSA) is a positional homologue of both (R)-12-HSA and (R)-9-HSA with the OH group in an intermediate position. While (R)-12-HSA is one of the best-known low-molecular-weight organogelators, (R)-9-HSA is not, but it forms crystals in several solvents. With the aim to gain information on the structural role of hydrogen-bonding interactions of the carbinol OH groups, we investigated the behavior of (R)-10-HSA in various solvents. This isomer displays an intermediate behavior between (R)-9 and (R)-12-HSA, producing a stable gel exclusively in paraffin oil, while it crystallizes in other organic solvents. Here, we report the X-ray structure of a single crystal of (R)-10-HSA as well as some structural information on its polymorphism, obtained through X-ray Powder Diffraction (XRPD) and Infrared Spectroscopy (IR). This case study provides new elements to elucidate the structural determinants of the microscopic architectures that lead to the formation of organogels of stearic acid derivatives.

Calix[6]arenes bearing adamantyl groups at the exo-rim form pseudorotaxanes with dialkylammonium axles paired to the weakly coordinating [B(ArF)4]− anion. The exo-adamantyl groups give rise to a more efficient threading with respect to the exo-tert-butyl ones, leading to apparent association constants more than one order of magnitude higher. This improved stability has been ascribed to the more favorable van der Waals interactions of exo-adamantyls versus exo-tert-butyls with the cationic axle. Calix[6]arenes bearing endo-OH functions give rise to a less efficient threading with respect to the endo-OR ones, in line with what was known from the complexation of alkali metal cations.

Amino acid stereoconfiguration has been shown to play a key role in the self-assembly of unprotected tripeptides into hydrogels under physiological conditions. Dramatic changes were noted for hydrophobic sequences based on the diphenylalanine motif from the formation of amorphous aggregates in the case of homochiral peptides to nanostructured and stable hydrogels in the case of heterochiral stereoisomers. Herein, we report that by further shortening the sequence to a dipeptide, the overall differences between isomers are less marked, with both homo- and hetero-chiral dipeptides forming gels, although with different stability over time. The soft materials are studied by a number of spectroscopic and microcopic techniques, and single-crystal X-ray diffraction to unveil the supramolecular interactions of these hydrogel building blocks.

Calix[6]arenes bearing adamantyl groups at the exo-rim form pseudorotaxanes with dialkylammonium axles paired to the weakly coordinating [B(ArF)4]- anion. The exo-adamantyl groups give rise to a more efficient threading with respect to the exo-tert-butyl ones, leading to apparent association constants more than one order of magnitude higher. This improved stability has been ascribed to the more favorable van der Waals interactions of exo-adamantyls versus exo-tert-butyls with the cationic axle. Calix[6]arenes bearing endo-OH functions give rise to a less efficient threading with respect to the endo-OR ones, in line with what was known from the complexation of alkali metal cations.

The novel title macrocycles, based on methylene-bridged 1,5-naphthalene units, have been obtained by template effect in a thermodynamically controlled synthesis. In detail, the prism[5]arene 1 or the prism[6]arene 3 was selectively removed from the equilibrium mixture by using the complementary ammonium-templating agent. When only the solvent 1,2-DCE was used, the 1,4-confused derivative 2 was obtained. The prism[5]arene here described shows a deep π-electron-rich aromatic cavity that exhibits a great affinity for the quaternary ammonium guests, originating from favorable cation···π and +NC-H···π interactions. This recognition motif is the basis of the templated synthesis of the prism[n]arenes here reported.

The reaction of cis-blocked, square-planar M-II complexes with tetratopic N-donor ligands is known to give metallasupramolecular assemblies of the formula M2nLn. These assemblies typically adopt barrel-like structures, with the ligands paneling the sides of the barrels. However, alternative structures are possible, as demonstrated by the recent discovery of a Pt8L4 cage with unusual gyrobifastigium-like geometry. To date, the factors that govern the assembly of (M2nLn)-L-II complexes are not well understood. Herein, we provide a geometric analysis of M2nLn complexes, and we discuss how size and geometry of the ligand is expected to influence the self-assembly process. The theoretical analysis is complemented by experimental studies using different cis-blocked Pt-II complexes and metalloligands with four divergent pyridyl groups. Mononuclear metalloligands gave mainly assemblies of type Pt8L4, which adopt barrel- or gyrobifastigium-like structures. Larger assemblies can also form, as evidenced by the crystallographic characterization of a Pt10L5 complex and a Pt16L8 complex. The former adopts a pentagonal barrel structure, whereas the latter displays a barrel structure with a distorted square orthobicupola geometry. The Pt16L8 complex has a molecular weight of more than 23 kDa and a diameter of 4.5 nm, making it the largest, structurally characterized M2nLn complex described to date. A dinuclear metalloligand was employed for the targeted synthesis of pentagonal Pt10L5 barrels, which are formed in nearly quantitative yields.

The supramolecular organization in the solid state of five novel gamma-hydroxybutenolides is described. The functionalities on their framework drive the construction of the crystalline packing through weak non-covalent forces such as H-bonds, CH-pi, pi-pi and CH center dot center dot center dot O interactions. Gamma-butenolides bearing an unsubstituted aromatic or heteroaromatic ring as the side arm exhibit a helical assembly, in which the helical sense is determined by the chirality of the molecule, promoted by a three-center, bifurcated intraintermolecular H-bond. In this assembly, the aromatic residues form an "aromatic zipper" between adjacent homochiral helices. Crystal structures of gamma-butenolide with p-substituted aromatic rings exhibit dimers, promoted by mutual O-H center dot center dot center dot O=C intermolecular hydrogen-bond interactions. Finally, when the p-position of the aromatic ring is occupied by a potential H-bond acceptor substituent, such as CN group, the aromatic substituent is involved in an exclusive intermolecular H-bond in the observed crystal packing. The ability of gamma-butenolides to control the type of packing induced by the substitution pattern of their side arm makes them interesting for the engineering of novel crystalline assemblies.

We report here the synthesis of two [8]cycloparaphenylenes ([8]CPP) derivatives, 1 and 2, bearing a monosubstituted benzene moiety. The presence of the substituent implies a planar chirality for the monosubstituted [8]CPP 1 and 2, whose configuration is here described by applying the chirality descriptors pR and pS. Experimental evidence of this planar chirality has been obtained through 1H VT NMR studies and by addition of Pirkle's reagent. This was confirmed by the X-ray crystal structure of 2, which represents an interesting example of solid-state structure of a monosubstituted [8]CPP derivative. Derivative 2 crystallizes in two monoclinic crystal forms (α and β), which show a herringbone motif. The [8]CPP ring of the α form encapsulates two dichloromethane molecules, held through C-H···π interactions, while in the β form, open channels are partially filled by highly disordered solvent molecules.

The preparation and characterisation of a novel three‐dimensional organic material consisting of porphyrin arrays on carbon nanotubes embedded in an organogel is reported. Firstly, the porphyrin array was prepared through metal‐ligand coordination of a ditopic ligand (1,2‐bis(4‐pyridyl)ethane) and two bis‐Zn(II) porphyrins, linked through a pyrene core, and was studied through UV‐Vis, NMR and diffusion spectroscopies. Secondly, the porphyrin supramolecular architecture was adsorbed on pristine carbon nanotubes, greatly improving the dispersibility of the latter in organic solvents. The hybrid material was characterised by means of UV‐Vis spectroscopy, microscopic techniques and thermogravimetric analysis. Finally, by exploiting the anisotropic magnetic susceptibility of carbon nanotubes, the hybrid material was aligned under a magnetic field, the organisation of which could be maintained by in situ gelation. The resultant hybrid organogel exhibited notable optical anisotropy, suggesting an anisotropic arrangement of the porphyrin‐CNTs architectures in the macroscopic material.

In this paper, we report the synthesis, structural characterization, and solvatochromic properties of a N-linked p-pyridiniumcalix[4]arenediol derivative 1. In the solid state, 1 forms a dimeric assembly stabilized by a network of weak H-bonding interactions involving acetonitrile solvent molecules. In solution, 1 shows a peculiar negative solvatochromism which was rationalized with the aid of TD-DFT calculations. The species responsible for this phenomenon is the monodeprotonated betainic form of 1 which is easily formed at pH close to neutrality.