A supramolecular assembly of sulfobutyl ether-ß-cyclodextrin and viologen calix[4]resorcinol as the master key to sustainable and eco-friendly catalyst for paraoxon hydrolysis.

The search for effective ways of paraoxon (POX) degradation becomes an extremely urgent problem, which can be solved by creating effective bioscavengers in the form of three-dimensional macrocycles. In this work, supramolecular interactions in an aqueous medium were studied between (4-sulfobutyl)-ß-cyclodextrin, the hydrophobic cavity of which is capable of binding POX, and viologen calix[4]resorcinol, the cationic groups of which are able to facilitate the nucleophilic attack on the phosphorus atom of the pesticide. A complex of physicochemical methods revealed the nature of the interactions between these cyclodextrin and calix[4]resorcinol, as a result of which the spontaneous formation of nanoparticles occurs. The kinetics of POX hydrolysis reaction using these nanoparticles was studied at room temperature in aqueous Tris-buffer medium by spectrophotometric method. Pure cyclodextrin does not exhibit catalytic activity in the POX hydrolysis, but its presence in a mixture with calix[4]resorcinol leads to a fivefold increase in the hydrolysis rate constant compared to pure calix[4]resorcinol.

Modeling Amine Methylation in Methyl Ester Cavitand.

Methylation of amines inside an introverted resorcinarene-based deep methyl ester cavitand is investigated by means of molecular dynamics simulations and quantum chemical calculations. Experimentally, the cavitand has been shown to bind a number of amines and accelerate the methylation reaction by more than four orders of magnitude for some of them. Eight different amines are considered in the present study, and the geometries and energies of their binding to the cavitand are first characterized and analyzed. Next, the methyl transfer reactions are investigated and the calculated barriers are found to be in generally good agreement with experimental results. In particular, the experimentally-observed rate acceleration in the cavitand as compared to the solution reaction is well reproduced by the calculations. The origins of this rate acceleration are analyzed by computational modifications made to the structure of the cavitand, and the role of the solvent is discussed.

A supramolecular catalyst based on sodium alginate and viologen calix[4]resorcinol for the room temperature hydrolysis of paraoxon.

Properties of paraoxon, such as poor water solubility, low rate of natural decomposition, ability to accumulate in soil and wastewater, lead to the fact that paraoxon is found in various agricultural products and textiles. In this regard, the search for effective ways of paraoxon degradation becomes an extremely urgent problem, which can be solved by creating catalysts by mimicking paraxonase. In this work, a complex of physicochemical methods was used to study the supramolecular interactions of sodium alginate, which has a calcium-binding ability similar to paraxonase, with viologen calix[4]resorcinol and to reveal the nature of the intermolecular interactions between them resulting in the spontaneous formation of nanoparticles. Before proceeding to the investigation of the binding ability of obtained nanoparticles to paraoxon, the encapsulating effect of nanoparticles on a number of model substrates of different solubility (doxorubicin hydrochloride, quercetin and oleic acid) was studied. The kinetics of paraoxon hydrolysis reaction using these nanoparticles was studied at room temperature in an aqueous medium by spectrophotometric method. The rate of this reaction increases with increasing concentration of stable nanoparticles having hydrophobic domains that ensure paraoxon immobilization. The results obtained allow considering the supramolecular polysaccharide/calixarene system as an effective biomimetic catalyst.

A New Application of Spin and Fluorescence Double-Sensor Molecules.

EPR imaging techniques are known to be successful tools for mapping living bodies, especially because of the high transparency of tissues in the microwave range. This technique assumes the presence of radicals whose in vivo transport is also controlled by serum albumins. Accordingly, in this study, the interactions between 3-hydroxymethyl-1-oxyl-4-(pyren-1-yl)-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole radical and the human serum albumin molecules were investigated. To clarify the adsorption processes of this radical onto the surface of human serum albumin (HSA), the interaction of the OMe derivative of the radical was also examined parallel with the studies on the radical-HSA interactions. Considering the solubility issues and also to modulate the transport, inclusion complexes of the radical with a cavitand derivative were also studied. The latter interactions were observed through fluorescence spectroscopy, fluorescence polarization, and by EPR spectroscopy. As a double-sensor molecule, we found that the fluorophore nitroxide is a good candidate as it gave further information about host-guest interactions (fluorescence, fluorescence polarization, and EPR). We also found that in the presence of a cavitand, a complex with greater stability was formed between the sensor molecule and the human serum albumin. Based on these observations, we can conclude that applying this double-sensor (spin, fluorescent) molecule is useful in cases when different interactions can affect the EPR measurements.

Synthesis of Novel Cavitand Host Molecules via Palladium-Catalyzed Aryloxy- and Azidocarbonylation.

Novel, elongated, resorcine[4]arene-based cavitands were synthesized via various consecutive reaction steps, including homogeneous catalytic aryloxy- and azidocarbonylation processes. The effects of carbon monoxide pressure and temperature on the conversion were examined in aryloxycarbonylation. It was revealed that a reaction temperature of 100 °C is required to achieve complete conversion both with monodentate (PPh3) and bidentate (Xantphos) phosphines at different carbon monoxide pressures (1-40 bar). Using ten different phenols as O-nucleophiles, partial hydrolysis of the esters to the corresponding carboxylic acids took place-i.e., 58-90% chemoselectivities toward esters were obtained. Moreover, the influences of temperature, reaction time and the catalyst ratio on the selectivity and conversion were described in the case of azidocarbonylation reaction. The formation of the acyl azide with high chemoselevtivity can be achieved at room temperature only. The higher reaction temperatures (50 °C) and higher catalyst loadings favor the formation of the primary amide. The characterization of the target compounds (esters and acyl azides) was carried out by IR and 1H and 13C NMR. The discussion of the influences of various parameters is based on in situ NMR investigations.

Smartphone-Based Dopamine Detection by Fluorescent Supramolecular Sensor.

Supramolecular recognition of dopamine by two quinoxaline cavitands was studied in solution by fluorescence titrations, ESI-MS and ROESY measurements. In addition, the tetraquinoxaline cavitand was dropped onto a siloxane-based polymeric solid support, obtaining a sensor able to detect dopamine in a linear range of concentrations 10 Mm-100 pM, with a detection limit of 1 pM, much lower than the normal concentration values in the common human fluids (plasma, urine and saliva), by using a simple smartphone as detector. This sensor shows also good selectivity for dopamine respect to the other common analytes contained in a saliva sample and can be reused after acid-base cycles, paving the way for the realization of real practical sensor for human dopamine detection.

Anodic Polymerization of Phenylphenols in Methyl Isobutyl Ketone and Mesityl Oxide: Incorporation of a Cavitand into the Layers Formed for Sensing Phenols in Organic Media.

The electropolymerization of three phenylphenol isomers was studied in methyl isobutyl ketone and mesityl oxide, and the remarkable differences highlighted the importance of the carbon-carbon double bond in mesityl oxide. In the case of each substrate, a brownish deposit formed during the electrooxidation. The obvious difference between the polymers formed from the two solvents was recognized via voltammetric signal enhancement of 4-methoxyphenol and 4-chlorophenol, and it was only observed in the case of mesityl oxide. The experiments highlighted that incorporation of a cavitand with biphenyl groups on the upper rim of the polymers of phenylphenols improved the results to a small extent. The cavitand was, itself, electroactive without any fouling effect. As 2-phenylphenol is by far the cheapest of the three isomers, a cavitand was incorporated into its polymer, which was exploited to solve analytical problems while mesityl oxide was used as solvent. Useful quantifications were achieved in organic solvents; however, it failed under aqueous conditions due to the high hydrophobicity of the deposit. Application of differential pulse voltammetry for 4-methoxyphenol and 4-chlorophenol gave detection limits of 9.28 and 50.8 µM in acetonitrile, respectively. This procedure resulted in the immobilization of cavitand derivatives onto the electrode's surface, and the layer formed offered selective sensing of phenols by electrochemical methods.

Cavitand Decorated Silica as a Selective Preconcentrator for BTEX Sensing in Air.

The monitoring of benzene and other carcinogenic aromatic volatile compounds at the ppb level requires boosting both the selectivity and sensitivity of the corresponding sensors. A workable solution is the introduction in the devices of preconcentrator units containing molecular receptors. In particular, quinoxaline cavitands (QxCav) resulted in very efficient preconcentrator materials for the BTEX in air to the point that they have been successfully implemented in a commercial sensor. In this work, we report a highly efficient quinoxaline-based preconcentrator material, in which the intrinsic adsorption capacity of the QxCav has been maximized. The new material consists of silica particles covalently coated with a suitable functionalized QxCav derivative (QxCav@SiO2). In this way, all the cavities are exposed to the analyte flux, boosting the performance of the resulting preconcentration cartridge well above that of the pure QxCav. It is noteworthy that the preconcentrator adsorption capacity is independent of the relative humidity of the incoming air.

Ultra-sensitive solid-phase Microextraction-Gas Chromatography-Mass spectrometry determination of polycyclic aromatic hydrocarbons in snow samples using a deep cavity BenzoQxCavitand.

A very sensitive and selective solid-phase microextraction-gas chromatography-mass spectrometry method based on the use of a deep cavity BenzoQxCavitand as innovative coating was developed and validated for the simultaneous determination of the 16 US-EPA priority pollutants polycyclic aromatic hydrocarbons (PAHs) in snow samples at ultra-trace levels. The presence of a 8.3 Å deep hydrophobic cavity allowed the engulfment of all the 16 PAHs, providing enhanced selectivity also in presence of interfering aromatic pollutants at high concentration levels. Validation proved the reliability of the method for the determination of the investigated compounds achieving detection limits in the 0.03-0.30 ng/L range, good precision, with relative standard deviations <18% and recovery rates in the 90.8(±2.1)%-109.6(±1.0)%. The detection of low-molecular weight PAHs in snow samples from Antarctica and Alps confirms the widespread occurrence of these compounds, thus assessing the impact of anthropogenic activities onto the environment.

Recent Advances in the Applications of Water-soluble Resorcinarene-based Deep Cavitands.

We review here the use of container molecules known as cavitands for performing organic reactions in water. Central to these endeavors are binding forces found in water, and among the strongest of these is the hydrophobic effect. We describe how the hydrophobic effect can be used to drive organic molecule guests into the confined space of cavitand hosts. Other forces participating in guest binding include cation-π interactions, chalcogen bonding and even hydrogen bonding to water involved in the host structure. The reactions of guests take advantage of their contortions in the limited space of the cavitands which enhance macrocyclic and site-selective processes. The cavitands are applied to the removal of organic pollutants from water and to the separation of isomeric guests. Progress is described on maneuvering the containers from stoichiometric participation to roles as catalysts.

Role of Rim Functions in Recognition and Selectivity of Small-Molecule Guests in Water-Soluble Cavitand Hosts.

Groups on the upper rim of cavitands can play major roles in the recognition of small molecules. Water-soluble deep cavitands 1, 2 or 3 bearing the walls upper rim of imidazole, urea, and methyl urea, respectively, were synthesized and characterized as hosts of small-molecule guests. The vase forms of 1 or 2 are stabilized through H-bonding to solvent water molecules between adjacent walls. Various small alkyl organic molecules - alcohols, halides, cycloalkane derivatives and heterocycles - are efficiently bound in 1. For n-alcohols (C5 to C12), the -OH end is fixed at the upper rim and the alkyl parts are in the hydrophobic cavity. The longer alcohol guests (C7-C12) show coiling. Cycloalkane guests rotate rapidly on all 3 axes within the host cavity, while heterocycles show orientations placing their heteroatoms near the cavitand rim. Competition studies between alkyl chlorides, bromides and iodides showed preference for binding of iodides in 1. Competition between cavitands for hexyl halide guests halide showed the order 2>1>3.

Voltammetric and Fluorimetric Studies of Dibenzoylmethane on Glassy Carbon Electrodes and Its Interaction with Tetrakis (3,5-Dicarboxyphenoxy) Cavitand Derivative.

Due to the medical importance of dibenzoylmethane, one of the aims of the study was to find an appropriate packing material and a biologically friendly co-solvent to help its introduction into living systems. Accordingly, redox properties of dibenzoylmethane were investigated on glassy carbon electrodes in acetonitrile and in 1-propanol with cyclic voltammetry, and showed a diffusion-controlled process. In the anodic window, an oxidation peak appeared at around 1.9 V in both solvents. Cycling repeatedly between 0 and 2 V, the reproducibility of this peak was acceptable, but when extending the window to higher potentials, the electrode deactivated, obviously due to electrode material. The addition of the investigated tetrakis(3,5-dicarboxyphenoxy) cavitand did not significantly change the voltammograms. Further electrochemical experiments showed that the coexistence of water in acetonitrile and 1-propanol drastically reduces the solubility of dibenzoylmethane. Moreover, very rapid electrode deactivation occurred and this fact made the use of electrochemical methods complicated. Considering that both the cavitand and dibenzoylmethane are soluble in dimethyl sulfoxide, the interaction of these species was investigated and formation of stable complexes was detected. This observation was verified with fluorescence quenching studies. The mixture of water and dimethyl sulphoxide also dramatically improved the solubility of the cavitand-dibenzoylmethane complex at high excess of water. The addition of cavitand improved the solubility of dibenzoylmethane, a property which supports the application of dibenzoylmethane in therapy.

Weak Interactions of the Isomers of Phototrexate and Two Cavitand Derivatives.

The interactions of two conformers of newly synthesized photoswitchable azobenzene analogue of methotrexate, called Phototrexate, with two cavitand derivatives, have been investigated in dimethyl sulfoxide medium. Photoluminescence methods have been applied to determine the complex stabilities and the related enthalpy and entropy changes associated to the complex formation around room temperature. Results show opposite temperature dependence of complex stabilities. The structure of the upper rims of the host molecules and the reordered solvent structure were identified as the background of the opposite tendencies of temperature dependence at molecular level. These results can support the therapeutic application of the photoswitchable phototrexate, because the formation of inclusion complexes is a promising method to regulate the pharmacokinetics of drug molecules.

Recognition of Hydrophilic Cyclic Compounds by a Water-Soluble Cavitand.

A water-soluble deep cavitand bearing amides on the upper rim and trimethyl ammonium groups on the feet was synthesized. The open-ended cavity is stabilized by the intramolecular hydrogen bonds formed between the adjacent amides, and the introduction of trimethylammonium imparts to the cavitand good solubility in water. The cavitand exhibits high binding affinity and selectivity to hydrophilic molecules in water. With certain guests, such as cyclohexyl alcohols, amines and acids, the recognition involves the synergistic action of hydrogen bonding with hydrophobic effects. The binding phenomena are interpreted in terms of a fixed solvent cage presented by the host to the guest.

Highly Selective Radical Monoreduction of Dihalides Confined to a Dynamic Supramolecular Host.

Reduction of alkyl dihalide guests (2-5 and 7) with trialkylsilanes (R3 SiH) was performed in water-soluble host 1 to investigate the effects of confinement on fast radical reactions (k≥103 m-1 s-1 ). High selectivity (>95 %) for mono-reduced products was observed for primary and secondary dihalide guests under mild conditions. The results highlight the importance of host-guest complexation rates to modulate the product selectivity in radical reactions.

Weak Interaction of the Antimetabolite Drug Methotrexate with a Cavitand Derivative.

Formation of inclusion complexes involving a cavitand derivative (as host) and an antimetabolite drug, methotrexate (as guest) was investigated by photoluminescence measurements in dimethyl sulfoxide solvent. Molecular modeling performed in gas phase reflects that, due to the structural reasons, the cavitand can include the methotrexate in two forms: either by its opened structure with free androsta-4-en-3-one-17α-ethinyl arms or by the closed form when all the androsta-4-en-3-one-17α-ethinyl arms play role in the complex formation. Experiments reflect enthalpy driven complex formation in higher temperature range while at lower temperature the complexes are stabilized by the entropy gain.

Solvent Switched Weak Interaction of a 4-Quinazolinone with a Cavitand Derivative.

Interaction of 4-quinazolinone with tetrakis (3,5-dicarboxylatophenoxy)-cavitand derivative has been studied in methanol and dimethylformamide media using fluorescence spectroscopy and molecular modeling methods. Results show temperature dependent complex formation: either the entropy gain or the high enthalpy changes are responsible for the formation of stable complexes in two separated temperature regions. However, different thermodynamic parameters are associated to different conformations of the complexes: while the high entropy gain associated to the formation of deeply included guest in methanol, the high entropy gain is associated with the formation of weakly included guest in dimethylformamide solvent. This finding highlights the importance of dynamic properties of the species interacted in different solvents.

Relative hydrophilicities of cis and trans formamides.

Secondary formamides are widely encountered in biology and exist as mixtures of both cis and trans isomers. Here, we assess hydrophilicity differences between isomeric formamides through direct competition experiments. Formamides bearing long aliphatic chains were sequestered in a water-soluble molecular container having a hydrophobic cavity with an end open to the aqueous medium. NMR spectroscopic experiments reveal a modest preference (<1 kcal/mol) for aqueous solvation of the trans formamide terminals over the cis isomers. With diformamides, the supramolecular approach allows staging of intramolecular competition between short-lived species with subtle differences in hydrophobic properties.

Recognition with metallo cavitands.

We describe here the effects of metal complexation on the molecular recognition behavior of cavitands with quinoxaline walls. The nitrogen atoms of the quinoxalines are near the upper rim of the vase-like shape and treatment with Pd(II) gave 2:1 metal:cavitand derivatives. Characterization by 1H, 13C NMR spectroscopy, HR ESI-MS, and computations showed that the metals bridged adjacent quinoxaline panels and gave cavitands with C2v symmetry. Both water-soluble and organic-soluble versions were prepared and their host/guest complexes with alkanes, alcohols, acids, and diols (up to C12) were studied by 1H NMR spectroscopy. Analysis of the binding behavior indicated that the metals rigidified the walls of the receptive vase conformation and enhanced the binding of hydrophobic and even water-soluble guests, compared to related cavitands reported previously. The results demonstrated that the conformational dynamics of the cavitand were slowed by the coordination of Pd(II) and stabilized the host's complexes.

Velcrand Functionalized Polyethylene.

Velcrands are a specific class of cavitands whose complementary surfaces induce self-dimerization. The insertion of a velcrand as physical cross-linking unit into a polymer is reported. To this purpose, the velcrand was functionalized at the lower rim with an isocyanate group. The functional velcrand was reacted with poly (ethylene-co-(2-hydroxethylmethacrylate)) (PE-HEMA), a polymer equipped with free hydroxyl groups suitable for reaction with the isocyanate group. The obtained functionalized polymer was characterized by nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR), proving the introduction of velcraplexes in the polymer. Films with varying amounts of velcrands were obtained by solution casting and slow evaporation, testifying the processability of the functionalized polymers. The obtained films were used to measure the oxygen barrier properties of the functionalized material.