Supramolecular Weaving by Halogen-Bonding in Functionality-Rich Hexasubstituted Aromatic Synthons.

Hexasubstituted benzenes are interesting platforms for the generation of functional materials, whose applications span from supramolecular recognition to organic electronics. Their synthesis is difficult to achieve by controlling multiple substitution steps of all hydrogen atoms on the aromatic benzene skeleton, so, often, cycloaddition reactions from disubsituted alkynes are used. In this work, we report a novel, straightforward route to C3-symmetrical hexasubstituted aromatic synthons with a diverse and rich pattern of functionalities, and we report about their packing mode in the crystals, in which, unprecedentedly, directional, strong halogen bonding interactions are capable of forming bidimensional supramolecular weaving.

CO2 Separation by Imide/Imine Organic Cages.

Invited for the cover of this issue are the groups of Valeria Amendola at the University of Pavia, Mariolino Carta at the University of Swansea, and Johannes C. Jansen at the CNR-ITM. The image depicts one of the novel imide/imine organic cages that were employed as fillers in mixed-matrix membranes for the selective separation of CO2 from N2 and CH4 . Read the full text of the article at 10.1002/chem.202201631.

CO2 Separation by Imide/Imine Organic Cages.

Two novel imide/imine-based organic cages have been prepared and studied as materials for the selective separation of CO2 from N2 and CH4 under vacuum swing adsorption conditions. Gas adsorption on the new compounds showed selectivity for CO2 over N2 and CH4 . The cages were also tested as fillers in mixed-matrix membranes for gas separation. Dense and robust membranes were obtained by loading the cages in either Matrimid® or PEEK-WC polymers. Improved gas-transport properties and selectivity for CO2 were achieved compared to the neat polymer membranes.

Fluorogenic Detection of Sulfite in Water by Using Copper(II) Azacyclam Complexes.

Copper(II) azacyclam complexes (azacyclam = 1,3,5,8,12-pentaazacyclotetradecane) containing naphthyl or dansyl subunits can be prepared by template synthesis involving proper sulfonamide derivatives as locking fragments. The macrocyclic complexes are very poorly emissive due to the fluorescence-quenching behavior displayed by Cu2+ ions. However, the fluorescence can be recovered as a result of the decomposition of the complexes, which induces the release of free light-emitting subunits to the solution. This reaction takes place very slowly in neutral water but its rate is increased by the presence of sulfite. Therefore, [Cu(azacyclam)]2+ derivatives have been investigated as simple chemical probes for the fluorogenic detection of sulfite both on laboratory and real samples. Preliminary tests performed on samples of white wine provided sulfite concentration values that are in agreement with those obtained by a standard analytical method.

Bitopic Sigma 1 Receptor Modulators to Shed Light on Molecular Mechanisms Underpinning Ligand Binding and Receptor Oligomerization.

The sigma 1 receptor (S1R) is an enigmatic ligand-operated chaperone involved in many important biological processes, and its functions are not fully understood yet. Herein, we developed a novel series of bitopic S1R ligands as versatile tools to investigate binding processes, allosteric modulation, and the oligomerization mechanism. These molecules have been prepared in the enantiopure form and subjected to a preliminary biological evaluation, while in silico investigations helped to rationalize the results. Compound 7 emerged as the first bitopic S1R ligand endowed with low nanomolar affinity (Ki = 2.6 nM) reported thus far. Computational analyses suggested that 7 may stabilize the open conformation of the S1R by simultaneously binding the occluded primary binding site and a peripheral site on the cytosol-exposed surface. These findings pave the way to new S1R ligands with enhanced activity and/or selectivity, which could also be used as probes for the identification of a potential allosteric site.

Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds.

During the past several years, the frequency of discovery of new molecular entities based on γ- or δ-lactam scaffolds has increased continuously. Most of them are characterized by the presence of at least one chiral center. Herein, we present the preparation, isolation and the absolute configuration assignment of enantiomeric 2-(4-bromophenyl)-1-isobutyl-6-oxopiperidin-3-carboxylic acid (trans-1). For the preparation of racemic trans-1, the Castagnoli-Cushman reaction was employed. (Semi)-preparative enantioselective HPLC allowed to obtain enantiomerically pure trans-1 whose absolute configuration was assigned by X-ray diffractometry. Compound (+)-(2R,3R)-1 represents a reference compound for the configurational study of structurally related lactams.

Sensing and Liquid-Liquid Extraction of Dicarboxylates Using Dicopper Cryptates.

We report the investigation of dicopper(II) bistren cryptate, containing naphthyl spacers between the tren subunits, as a receptor for polycarboxylates in neutral aqueous solution. An indicator displacement assay for dicarboxylates was also developed by mixing the azacryptate with the fluorescent indicator 5-carboxyfluorescein in a 50:1 molar ratio. Fluorimetric studies showed a significant restoration of fluorophore emission upon addition of fumarate anions followed by succinate and isophthalate. The introduction of hexyl chains on the naphthalene groups created a novel hydrophobic cage; the corresponding dicopper complex was investigated as an extractant for dicarboxylates from neutral water into dichloromethane. The liquid-liquid extraction of succinate-as a model anion-was successfully achieved by exploiting the high affinity of this anionic guest for the azacryptate cavity. Extraction was monitored through the changes in the UV-visible spectrum of the dicopper complex in dichloromethane and by measuring the residual concentration of succinate in the aqueous phase by HPLC-UV. The successful extraction was also confirmed by 1H-NMR spectroscopy. Considering the relevance of polycarboxylates in biochemistry and in the environmental field, e.g., as waste products of industrial processes, our results open new perspectives for research in all contexts where recognition, sensing, or extraction of polycarboxylates is required.

Anion Recognition in Water, Including Sulfate, by a Bicyclam Bimetallic Receptor: A Process Governed by the Enthalpy/Entropy Compensatory Relationship.

The dimetallic system [CuII2 (L)]4+ contains two facing equivalent metallocyclam subunits and incorporates ambidentate anions, mono- (halides) and poly-atomic (sulfate), which bridge the two CuII centres. Isothermal titration calorimetry (ITC) experiments in water showed that the log K values of the inclusion equilibria for halides and sulfate varied over a restricted interval (3.6±0.2), which indicated lack of selectivity and that similarity of ΔG° values resulted from the unbalanced contribution of the ΔH° and TΔS° terms: the more favourable the one, the less favourable the other. In particular, a linear dependence of ΔH° and TΔS° was observed (a typical enthalpy/entropy compensatory diagram), which assigned a major role to hydration terms: 1) a more hydrated anion resulted in a more endothermic dehydration process; and 2) a larger number of water molecules released to the solution resulted in a more positive TΔS°. Limiting cases refer to the complexation 1) of the poorly hydrated iodide (highly exothermic process, entropically disfavoured), and 2) of the highly hydrated sulfate (moderately endothermic process, entropically very favoured). Anion receptors operating in water belong to two main domains: 1) those exhibiting positive ΔH° and positive TΔS° (+/+ signature), and 2) those displaying the opposite behaviour: (-/- signature). The receptor investigated herein connects the two domains, along the ΔH°/TΔS° straight line, thanks to the hidden role of the versatile metal-anion interaction.

Bimacrocyclic Effect in Anion Recognition by a Copper(II) Bicyclam Complex.

The dicopper(II) complex of the bimacrocyclic ligand α,α'-bis(5,7-dimethyl-1,4,8,11-tetraazacyclotetradecan-6-yl)-o-xylene, 2, interacts with selected anions in dimethyl sulfoxide solution according to two different modes: (i) halides (Cl-, Br-, and I-) and N3 - coordinate the two metal centers at the same time between the two macrocyclic subunits that face each other and (ii) anionic species that do not fit the bridging coordination mode (e.g., NCO-, SCN-, CH3COO-, NO3 -, and H2PO4 -) interact with copper(II) ions only at the "external" positions or their interaction is too weak to be detected. Occurrence of the bridging interaction is demonstrated by X-ray crystallographic studies performed on the adduct formed by [Cu2(2)]4+ with azide and by electron paramagnetic resonance investigation, as the anion coordination between the two copper(II) centers induces spin-spin coupling. Isothermal titration calorimetry experiments performed on [Cu2(2)]4+ and, for comparison, on [(5,7-dimethyl-6-benzyl-1,4,8,11-tetraazacyclotetradecane)copper(II)], representing the mononuclear analogue, allowed determination of thermodynamic parameters (log K, ΔH, and TΔS) associated with the considered complex/anion equilibria. Thermodynamic data showed that adducts formed by [Cu2(2)]4+ with halides and azide benefit from an extra stability that can be explained on the basis of the anion advantage of simultaneously binding the two metal centers, i.e., in terms of the bimacrocyclic effect.

Structure-activity relationship for the solid state emission of a new family of "push-pull"π-extended chromophores.

We report the design, synthesis, molecular optical properties, and solid state emissive behaviour of a series of novel compounds, which, similar to the archetypal AIE luminogen tetraphenylethene, are formed of a central olefin stator and decorated with either three or four rotors. These rotors, being either electron-rich substituted benzenes, or electron-withdrawing functional groups (esters, ketones, cyano groups) confer a "push-pull" character to the overall molecular structure. Building on both new and already published contributions, a comprehensive picture of the properties and the potential of these compounds is provided.

Conjugated Thiophene-Fused Isatin Dyes through Intramolecular Direct Arylation.

We report on the design, synthesis, and properties of innovative, planar, π-conjugated compounds in which a thiophene ring is fused with the skeleton of the naturally occurring dye isatin. The synthesis is achieved in high yields making use of an intramolecular direct arylation reaction as the key step, making the overall process potentially scalable. The synthetic sequence has been demonstrated also for an isatin bearing fluorine substituents on the aromatic ring. NMR and X-ray studies demonstrate the crosstalk occurring between the fused, coplanar, and conjugated moieties, making these novel dyes with a donor-acceptor character. Cyclic voltammetry and UV-vis studies confirm very interesting HOMO-LUMO levels and energy gaps for the new compounds.

Chloride-binding in organic-water mixtures: the powerful synergy of C-H donor groups within a bowl-shaped cavity.

For the first time, the tetrafluorobenzyl unit has been considered as a C-Hanion binding motif. In synergy with imidazolium groups within a bowl-shaped receptor, it has allowed for the effective binding of chloride in solution. Remarkable affinity was observed in organic-water mixtures.

Anion Binding by Dimetallic Nickel(II) and Nickel(III) Complexes of a Face-to-Face Bicyclam: Looking for a Bimacrocyclic Effect.

The dinickel(II) complex of the face-to-face bicyclam ligand α,α'-bis(5,7-dimethyl-1,4,8,11-tetraazacyclotetradecan-6-yl)-o-xylene (L∩L) in a dimethyl sulfoxide solution exists as a mixture of high- and low-spin forms and uptakes up to three halide and pseudohalide ions (X(-)), according to stepwise equilibria, whose constants were determined through spectrophotometric titration experiments. In the case of halides, the first anion goes into the intermetallic cavity, whereas pseudohalides first coordinate the metal center from outside. Comparison with equilibrium data for the complex with the macrocycle 5,7-dimethyl-6-benzyl-1,4,8,11-tetraazacyclotetradecane (L) shows that the dinuclear complex [Ni(II)2(L∩L)](4+) displays an affinity for the first halide distinctly higher than the mononuclear complex [Ni(II)(L)](2+), thus disclosing the existence of a bimacrocyclic effect for anion binding. Differential pulse voltammetry studies typically showed a three-peak profile: the most anodic pertaining to the [Ni(II)2(L∩L)](4+) → Ni(III)2(L∩L)](6+) two-electron process, then one originating from the [Ni(II)2(L∩L)X](3+) → Ni(III)2(L∩L)X](5+) two-electron process, and one deriving from the two two-electron half reactions [Ni(II)2(L∩L)X2](2+) → Ni(III)2(L∩L)X2](4+) and [Ni(II)2(L∩L)X3](+) → Ni(III)2(L∩L)X3](3+), taking place at nearly the same potential. The crystal structure of the [Ni(II)2(L∩L)(µ-NCO)(NCO)2]ClO4·2.5H2O complex salt showed a caterpillar arrangement of the three metal-bound cyanate ions.

Copper(II) Complexes of Cyclams Containing Nitrophenyl Substituents: Push-Pull Behavior and Scorpionate Coordination of the Nitro Group.

The three nitrophenyl-cyclam derivatives (nitrocyclams): 1-(4-nitrophenyl)-1,4,8,11-tetraazacyclotetradecane (2), 1-(2-nitrophenyl)-1,4,8,11-tetraazacyclotetradecane (3), and 1-(2,4-dinitrophenyl)-1,4,8,11-tetraazacyclotetradecane (4), in an MeCN solution, specifically incorporate the Cu(II) ion according to an irreversible process signaled by disappearance of the yellow color for a concentration c < 1 × 10(-4) M and by a yellow-to-red color change for c ≥ 1 × 10(-3), and must be considered efficient and specific dosimeters of copper(II) salts. When present in the ortho position of the nitrophenyl substituent, the -NO2 group coordinates the Cu(II) according to a scorpionate mode, while the metallocyclam system exhibits a trans-I configuration. In an MeCN solution the red trans-I-[Cu(II)(3)](2+) and trans-I-[Cu(II)(4)](2+) scorpionate complexes slowly convert into the violet trans-III scorpionate complexes. Kinetic aspects of the trans-I-to-trans-III configurational rearrangement were investigated in detail for the [Cu(II)(4)](2+) system. In particular, the conversion is spectacularly accelerated by catalytic amounts of Cl(-), NCO(-), and F(-). While for Cl(-) and NCO(-) the effect can be associated with the capability of the anion to stabilize through coordination a possible dissociative intermediate, the amazingly powerful effect of F(-) must be related to the preliminary deprotonation of one N-H fragment of the macrocycle, driven by the formation of the HF2(-) ion. Most of the metal complex species studied in solution were isolated in a crystalline form, and their molecular structures were elucidated through X-ray diffraction studies. This study documents the first examples of effective metal coordination by the nitro group.

Oxo-anion recognition by mono- and bisurea pendant-arm macrocyclic complexes.

The novel macrocyclic copper(II) complexes [2](2+) and [3](2+), carrying one or two (nitrophenyl)urea fragments appended to an azacyclam or diazacyclam framework, exploit the hydrogen-bond-forming abilities of the urea subunits, along with the metal-ligand interaction, in the recognition of anionic species. Equilibrium studies in acetonitrile performed on [2](2+) and [3](2+) show that (nitrophenyl)urea pendant arms strongly interact with anionic species such as carboxylates and phosphates, which display both coordinating tendencies toward copper(II) and good affinity toward urea subunits. Stability constants of the adducts are considerably higher than those determined for the interaction of the same anions with a "plain urea" reference compound, confirming the synergistic action of metallomacrocyclic and urea subunits. Complex [2](2+) forms 1:1 adducts with acetate, benzoate, hydrogendiphosphate, and dihydrogen phosphate, while complex [3](2+) interacts with the same anions according to both 1:1 and 1:2 stoichiometries, with the exception of hydrogendiphosphate, which forms only the 1:1 adduct with a distinctly high association constant (log K > 7). Spectrophotometric investigations suggest that oxoanionic species interact with the complexes according to a "bridged" mode, inducing the macrocyclic systems to adopt a scorpionate-like conformation, as confirmed by crystallographic studies on the [3](2+)/succinate adduct.

The disproportionation of [Ni(tacn)]2+ in Ni2+ and [Ni(tacn)2]2+ crystallographically demonstrated (tacn = 1,4,7-triazacyclononane).

From an EtOH/H2O solution, 0.3 M each of Ni(2+) and cyclic triamine tacn (2; tacn = 1,4,7-triazacyclononane), after 10 min refluxing and cooling at room temperature, copious and comparable amounts of blue crystals (containing the complex [Ni(tacn)(H2O)3](2+)) and pink crystals (containing in the same cell both [Ni(H2O)6](2+) and [Ni(tacn)2](2+)) precipitated. This unusual behaviour is ascribed to the fact that at the refluxing temperature the three species are present at the equilibrium in similar concentrations, which are frozen on cooling, due to the inertness of the macrocyclic complexes [Ni(tacn)(H2O)3](2+) and [Ni(tacn)2](2+).

Mixing the spacers in azacryptands: effects on halide recognition.

In this work, we report on two new asymmetric dicopper cryptates, characterized by alternate furanyl and p-xylyl spacers. The results of the potentiometric, UV-vis and X-ray diffraction studies are discussed. In particular, for one of the cages in the octaprotonated form, the crystal structure of the complex with nitrate is described. From the point of view of the anion binding in water, the new dicopper cryptates display stronger similarities to each other than to the symmetric analogues (i.e. p-xylyl and furan cryptates). The substitution of even only one spacer modifies the distance between the metal ions. This prevents the development of the CT band, typically accompanying the binding of halides by the furan cryptate, and favors the formation of complexes of different stoichiometry with the linear azide anion, not observed for the symmetric cryptates. The obtained results may be very helpful in the design of new molecular receptors based on dimetallic cryptates, in particular for the tuning of the sensitivity towards specific anionic substrates.

Double-stranded dimetallic helicates: assembling-disassembling driven by the Cu(I)/Cu(II) redox change and the principle of homochiral recognition.

In the presence of d(10) metal ions, prone to tetrahedral coordination, ligands containing two bidentate subunits will give rise to double-stranded helical complexes (helicates). Upon electrochemical oxidation of Cu(I) to Cu(II), the helicate complex tends to disassemble, thus giving rise to two mononuclear Cu(II) complexes with tetragonal geometry. Upon subsequent Cu(II)-to-Cu(I) electrochemical reduction, two Cu(I) complexes instantaneously re-assemble to give the helicate complex. A helicand containing a chiral subunit (e.g. 1,2-substituted cyclohexanediamine) contains a racemic mixture of the R,R and S,S enantiomers. The racemic helicand, reacting with Cu(I), forms dimetallic helicates, in which the two strands show the same chirality, whether R,R or S,S, thus obeying the principle of homochiral recognition.

Dicopper double-strand helicates held together by additional π-π interactions.

The bis-bidentate ligand, obtained from Schiff base condensation of RR-1,2-cyclohexanediamine and 8-naphthylmethoxyquinoline-2-carbaldehyde (L-L), forms with [Cu(I)(MeCN)4]ClO4 a double strand helicate complex, made especially stable by the presence of four definite interstrand π-π interactions involving a quinoline subunit and a naphthylmethoxy substituent of the two strands. The [Cu(I)2(L-L)2](2+) complex, which does not decompose even on excess addition of either L-L or Cu(I), undergoes a two electron oxidation in MeCN, through two one-electron fully reversible steps, separated by 260 mV, as shown by cyclic voltammetry (CV) studies. The high stability of the mixed valence complex [Cu(I)Cu(II)(L-L)2](3+) with respect to disproportionation to [Cu(I)2(L-L)2](2+) and [Cu(II)2(L-L)2](4+) is essentially due to a favorable electrostatic term. Cu(II) forms with L-L a stable species, with a 1:1 stoichiometric ratio, but, in the absence of crystallographic data, it was impossible to assess whether it is of mono- or dinuclear nature. However, CV studies on an MeCN solution containing equimolar amounts of Cu(II) and L-L showed the presence in the reduction scan of two fully reversible waves, separated by about 250 mV, which indicated the presence in solution of a dicopper(II) double strand helicate complex, [Cu(II)2(L-L)2](4+). This work demonstrates that additional interstrand π-π interactions can favor the formation of unusually stable dicopper(I) and dicopper(II) helicate complexes.

Structure and properties of domperidone and its succinate salt.

This paper describes the structure and properties of the drug domperidone and a novel 1:1 domperidone succinate salt. The new salt is characterized by means of thermal, spectroscopic, microscopic and powder diffraction measurements. The crystal structures of the salt and, for the first time, of pure domperidone have been determined by means of single-crystal X-ray diffraction. In both structures, the piperidine ring of domperidone adopts the expected chair conformation, and supramolecular centrosymmetric R2(2)(8) motifs are formed by N-H...O hydrogen bonds between chlorine-substituted oxobenzimidazolyl groups. Further N-H...O hydrogen bonds occur between non-substituted oxobenzimidazolyl groups and the resulting C(4) motifs originates hydrogen-bonded chains, extending along the crystallographic b axis. In the salt, a single N-H...O hydrogen bond forms between the protonated nitrogen of the piperidine ring and the carboxylic O atom of the succinate ion. Two alternative and mutually exclusive positions for the nonsubstituted oxobenzimidazolyl group have also been observed; this disorder makes the hydrogen-bonded chains originating from the bicyclic group polar. The dissolution behaviour of the salt in dosage form is compared with two reference commercial products. The salt shows an increased solubility, a characteristic that could be of great advantage from a pharmaceutical view point.