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Iron dysregulation, dopamine depletion, cellular oxidative stress and α-synuclein protein mis-folding are key neuronal pathological features seen in the progression of Parkinson's disease. Iron chelators endowed with one or more therapeutic modes of action have long been suggested as disease modifying therapies for its treatment. In this study, novel 1-hydroxypyrazin-2(1

Two analogues of tolcapone where the nitrocatechol group has been replaced by a 1-hydroxy-2(1

Ubiquitin proteasome system (UPS) impairment, excessive cellular oxidative stress, and iron dyshomeostasis are key to substantia nigra dopaminergic neuronal degeneration in Parkinson's disease (PD); however, a link between these features remains unconfirmed. Using the proteasome inhibitor lactacystin we confirm that nigral injury via UPS impairment disrupts iron homeostasis, in turn increasing oxidative stress and promoting protein aggregation. We demonstrate the neuroprotective potential of two novel 1-hydroxy-2(1H)-pyridinone (1,2-HOPO) iron chelators, compounds C6 and C9, against lactacystin-induced cell death. We demonstrate that this cellular preservation relates to the compounds’ iron chelating capabilities and subsequent reduced capacity of iron to form reactive oxygen species (ROS), where we also show that the ligands act as antioxidant agents. Our results also demonstrate the ability of C6 and C9 to reduce intracellular lactacystin-induced α-synuclein burden. Stability constant measurements confirmed a high affinity of C6 and C9 for Fe3+ and display a 3:1 HOPO:Fe3+ complex formation at physiological pH. Reducing iron reactivity could prevent the demise of nigral dopaminergic neurons. We provide evidence that the lactacystin model presents with several neuropathological hallmarks of PD related to iron dyshomeostasis and that the novel chelating compounds C6 and C9 can protect against lactacystin-related neurotoxicity.

While the etiology of non-familial Parkinson’s disease (PD) remains unclear, there is evidence that increased levels of tissue iron may be a contributing factor. Moreover, exposure to some environmental toxicants is considered an additional risk factor. Therefore, brain-targeted iron chelators are of interest as antidotes for poisoning with dopaminergic toxicants, and as potential treatment of PD. We, therefore, designed a series of small molecules with high affinity for ferric iron and containing structural elements to allow their transport to the brain via the neutral amino acid transporter, LAT1 (SLC7A5). Five candidate molecules were synthesized and initially characterized for protection from ferroptosis in human neurons. The promising hydroxypyridinone SK4 was characterized further. Selective iron chelation within the physiological range of pH values and uptake by LAT1 were confirmed. Concentrations of 10–20 µM blocked neurite loss and cell demise triggered by the parkinsonian neurotoxicants, methyl-phenyl-pyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) in human dopaminergic neuronal cultures (LUHMES cells). Rescue was also observed when chelators were given after the toxicant. SK4 derivatives that either lacked LAT1 affinity or had reduced iron chelation potency showed altered activity in our assay panel, as expected. Thus, an iron chelator was developed that revealed neuroprotective properties, as assessed in several models. The data strongly support the role of iron in dopaminergic neurotoxicity and suggests further exploration of the proposed design strategy for improving brain iron chelation. Electronic supplementary material The online version of this article (10.1007/s00204-020-02826-y) contains supplementary material, which is available to authorized users.

International audience; Lanthanide cation binding by tetraketone derivatives of p-tert-butyldihomooxacalix[4]arene (methyl 1a, tert-butyl 1b, adamantyl 1c and phenyl 1d) and of p-tert-butylcalix[4]arene (methyl 2a, adamantyl 2c and phenyl 2d), in the cone conformation, was investigated. These properties were assessed by extraction experiments of the metal picrates from water to dichloromethane and by stability constant measurements in acetonitrile by UV-vis absorption spectrophotometry. Proton NMR titrations with La3+, Eu3+ and Yb3+ cations were also performed to obtain information on the binding sites. Molecular dynamics (MD) simulations and potential of mean force (PMF) free energy calculations were carried out for ligands 1d and 2d in pure solvents and at a CH2Cl2/water interface to add further information on the complexation and extraction processes. Comparison between dihomooxacalix[4]arene and calix[4]arene ketone derivatives showed that the former are better extractants, displaying the highest percentages of extraction for Gd3+ and Yb3+ cations. Concerning complexation, all ligands studied presented high affinities for the lanthanide ions. Ligands 1b and 1d showed preference for the light La3+, while 2d displayed the strongest affinity for the heavy and smaller Yb3+. These results were also corroborated by MD simulations, which revealed specificities of ligands 1d and 2d in the binding of lanthanide cations.

Pyridine-2,6-carboxamides bearing α- or β-naphthyl- and α- or β-anthryl residues were prepared using simple method from pyridine-2,6-carboxylic acid dichloride and the respective aromatic amines. For the obtained receptors, selective binding of lead(II) and copper(II) was found. Ion–receptor interactions were studied using UV–vis spectroscopy, spectrofluorimetry, 1H NMR and FTIR spectroscopy. The reversible lead(II) and copper(II) binding was discussed in regard of type of aromatic residue and amide bond localisation in aromatic ring, and binding model was proposed.

A family of 2,4-pyridyl-disubstituted bispidol derivatives bearing methylene carboxylic acid ethyl esters (L1-L3), methylene carboxylic acids (L4 and L5), or methylenethiophene (L6) groups were synthesized. In water, all ligands form rigid 1:1 complexes in the presence of Zn(II) in which the bicycle adopts a chair-chair conformation (cis isomer), as observed by (1)H NMR and, in the case of ligand L1, by an X-ray diffraction crystal structure. Interestingly, addition of Zn(II) ions on ligand L1 induces a metal-mediated selective hydrolysis of the ethyl esters. This selective hydrolysis was not observed upon addition of other cations such as Na(+), Mg(+), and Ca(2+). Reduction of the central ketone was achieved to prevent ring opening via retro Diels-Alder reactions and to afford highly stable and water-soluble ligands (L4, L5, L6). The complexation properties of L4 and L6 were studied in solution, with a particular interest for ligand L4. Fast complexation occurs in strongly acidic media (pH = 1), with a high affinity toward Cu(II) (log KCuL4 = 19.2(3), pCu = 17.0 at pH 7.4, pCu = -log[Cufree], [Cu] = 1 × 10(-6) M, [L] = 1 × 10(-5) M) and high selectivity versus Co(II), Ni(II), and Zn(II), as shown by the values of the binding constants obtained from potentiometric and spectrophotometric titrations. Reversible redox potential with E1/2 = -430 mV (vs normal hydrogen electrode) was measured. The complex was found to be fairly inert from acid-assisted dissociation experiments in 5 M HClO4 (t1/2 = 110 d at 25 °C).

The synthesis and characterization of four p-tert-butylcalix[4]arene-hydroxamic acids are reported. The dependence of the metal ion binding, assessed by liquid–liquid extraction of the metal nitrates from water into dichloromethane in individual and competitive experiments, on the ligand structure, is presented. The results showed that those ligands could be successfully used in separation process of transition and heavy metals often present together. Two of the ligands were used as active materials in Pb-ion-selective membrane electrodes. The characteristics of these electrodes, in particular their selectivity coefficients for Pb2+ over other metal ions, are discussed.

Three new bidentate ureidodihomooxacalix[4]arene derivatives (phenyl 5a, n-propyl 5b, and tert-butyl 5c) were synthesized in four steps from the parent compound p-tert-butyldihomooxacalix[4]arene and obtained in the cone conformation, as shown by NMR studies. The binding ability of these neutral receptors toward spherical, linear, trigonal planar, and tetrahedrical anions was assessed by (1)H NMR and UV-vis titrations. The structures and complexation energies of some complexes were also studied by DFT methods. The data showed that the association constants are strongly dependent on the nature of the substituent (aryl/alkyl) at the urea moiety. In general, for all the receptors, the association constants decrease with decrease of anion basicity. Ph-urea 5a is the best anion receptor, showing the strongest complexation for F(-) (log K(assoc) = 3.10 in CDCl3) and also high binding affinity for the carboxylates AcO(-) and BzO(-). Similar results were obtained by UV-vis studies and were also corroborated by DFT calculations.

The synthesis of ligand L(T)H8, based on a thiophene framework containing two bis(aminomethyldiphosphonate) functions in the ortho position to the central sulfur atom, is described, together with the characterization of the intermediate compounds. The physico-chemical properties of the ligand were first studied by means of potentiometry and UV-Vis absorption spectrophotometric titrations to determine its pK values. Six successive equilibrium constants were determined in aqueous solutions. The same means were then used to quantify the interactions of the ligand with Ni(II), Cu(II) and Zn(II). Following the conventional Irving-Williams trend, L(T) was shown to have the highest affinity towards Cu(II) (log K(CuL(T)) = 16.11(3)), while Zn(II) and Ni(II) showed similar values (log K(ML(T)) = 10.81(8) and 10.9(1), respectively), revealing a large selectivity of L(T) toward Cu(II). Based on a combination of UV-Vis absorption spectroscopy and EPR measurements as a function of pH, along with DFT calculations, the coordination behavior of the hard phosphonate, medium amino and soft thiophene entities are questioned regarding their coordination to the Cu atom.

Metal binding properties of a series of worm-like dendronized polymers bearing oxathiaether-based dendrons are reported. Extensive characterization of the complexation properties toward a large range of metal cations showed a high and selective affinity of the polymers for Ag+ and Hg2+ cations. Its origin is explained by the presence of specific M···S and M···O interactions (M = Ag+ or Hg2+) within a cage structure formed by the dendritic moiety. The stoichiometry of the complexation is found to be affected by the degree of steric constraints in the dendronized materials. The effect of Ag+ complexation leads to the appearance of polyelectrolyte/charged colloid properties which were intensively studied by SANS. A significant result is the absence of major modification of the (spherocylinder) shape of the polymers upon Ag+ sequestration which confirms the above mentioned complexation scenario. Another outstanding result of Ag+ complexation is the Coulombic stabilization of the charged denpols that drastical...

Diglycolamides (DGAs), and in particular N,N,N′,N′-tetraoctyl diglycolamide (TODGA), are well-known candidates for the co-extraction of trivalent actinides (An(III)) and lanthanides (Ln(III)) from highly acidic aqueous solutions of nuclear waste. A derivative of TODGA, the so-called Me-TODGA with the addition of a methyl-substituent on the central part of the TODGA molecule, has been proposed to improve its stability properties and extraction behaviour. This work describes the stability and viability of Me-TODGA by studying the properties of its degradation compounds formed upon gamma irradiation. The main degradation products have been synthesised and studied individually. Particular attention has been paid to their quantification, as well as their complexation and extraction properties, for a better understanding of the degradation pathways and the behaviour of the solvents upon gamma irradiation. The extraction behaviour of irradiated Me-TODGA solvents and their degradation compounds have been studied toward the fission products and lanthanides present in a highly active raffinate (HAR) solution. Binding properties of parent molecules (TODGA and Me-TODGA) and their main degradation compounds with Ln(III) have also been determined in a homogeneous phase. All the results obtained on degradation compounds are compared with those of the parent molecules in order to assess the effects of these compounds on the separation process. Among the radiolytic compounds, 2-hydroxyoctylamides are the most problematic compounds not only because of their high affinity for lanthanides but also for other fission products.

Six p-(1-adamantyl)calix[4]arenes 7, 8 with four differently attached diphenyl-carbamoylmethylphosphine oxide (CMPO) functions at the narrow rim were synthesized. This series was extended by adamantylcalix[4]arenes with two CMPO and two ester, acid or (diethylphosphono)acetylamino groups. Structures of new compounds were proved by NMR, mass-spectrometry and a single-crystal X-ray analysis for the intermediate di-phthalimide 103. The extraction studies towards selected lanthanides and thorium showed that the ligands 7 surpassed the corresponding p-H, p-tert-butyl and p-tert-octyl analogues 3–5 in lanthanide extraction while thorium was extracted with the same or lesser extent. For the lanthanide extraction DLn(74)>DLn(73)≈DLn(72), which follows the order established earlier for ligands 3–5. Among the tetra-CMPO derivatives of type 8, the ligand 83/4 was the best extractant for which the DLn and DTh values were comparable with those for 74.

The synthesis, characterisation and X-ray crystal structures of p-tert-butyl-calix[4]arene-thioamide L and its complex with lead L-Pb2+ is reported. The cation-binding properties in solution have been assessed by liquid–liquid extraction of the metal picrates from water into dichloromethane and by stability constants determination in acetonitrile using UV-absorption spectrophotometry or potentiometry. The compound was used as active material in Pb-ion-selective membrane electrodes. The characteristics of these electrodes as well as the selectivity coefficients for Pb2+ cation versus many metal ions tested were obtained. Complex formation constants within the electrode membranes were determined using the sandwich membrane method and were compared to those obtained in acetonitrile. The lead concentration in the scrap-lead was determined with the use of electrodes incorporating the ligand studied.

The binding properties of two homooxacalixarene diethylamides (1b and 2b) derived from p-tert-butyldihomooxacalix[4]arene and p-tert-butylhexahomotrioxacalix[3]arene, respectively, in the cone conformation, for lanthanide cations, were investigated. These properties were assessed by extraction studies of the metal picrates from water into dichloromethane and stability constant measurements in methanol, using spectrophotometric and potentiometric techniques. Microcalorimetric studies of La3+, Pr3+, Eu3+ and Gd3+ complexes in the same solvent were also performed. Proton NMR titrations with the representative lanthanides La3+, Eu3+ and Yb3+ were also carried out to establish the sites of interaction of the ligands with the cations. The analogous derivative (3b) of p-tert-butylcalix[4]arene was also studied and the results of the three compounds are compared. Diethylamide 1b is the strongest binder, showing some preference for the light lanthanides in extraction, but exhibiting practically no selectivity in c...

The effect of the presence of an additional ester or amide carboxy group in the 6-position of the pyridine nuclei of calixarene-based picolinamide ligands on the extraction and complexation properties of lanthanide(III) and actinide(III) metal ions was studied. For this purpose, six new ligands 1–6 were synthesized; their conformational properties were studied both in solution and in the solid state, and their binding properties towards lanthanide (LnIII) and actinide (AnIII) metal ions were determined under extracting conditions simulating those present in radioactive waste. In the presence of BrCosan as synergizer, a rather high efficiency in the extraction of trivalent metal ions by these ligands was observed even at [HNO3] > 2–3 M. Complexation of LnIII metal ions was also studied under homogeneous conditions (methanol solution), both in chloride and nitrate media, by using spectrophotometry and calorimetry. A comparison with the data obtained with ligands L1–L3, lacking the additional binding sites in the 6-position of the pyridine nuclei, is reported and the effects of the structure of the ligands on the stoichiometry of the complexes, coordination of the metal ions, basicity of the pyridine binding groups and efficiency and selectivity in the extractions are also discussed.

A number of p-tert-butylcalix[4]arene thioamides were synthesized and characterized by 1H-NMR and elemental analysis. Compounds 1–5 are O-substituted derivatives with –CH2–C(=S)–N–X groups, where NX = morpholidyl, NEt2, NHC2H4Ph, NHCH2Ph and NHEt, respectively. The X-ray structures of the ligands 1, 3, 5 and of the complex 3·Pb(ClO4)2, (compound 6), are presented and their slightly distorted cone conformation is established. The influence of the nature of the thioamide functions (secondary or tertiary) on the extractability of some selected metal cations was investigated. Whereas all these calixarenes show the highest extraction level for Ag+, tertiary thioamides are more efficient extractants for Pb2+ than secondary thioamides.

The remarkable actinide(III) selectivity of the polyaromatic N-donors bis-triazine-pyridines (BTPs), hemi-bis-triazine-pyridines (hemi-BTPs) and bis-triazine-bipyridines (BTBPs) make these ligands the most promising candidates in partitioning and transmutation processes developed so far to better manage nuclear waste. The interactions of n-Pr-BTP, C(5)-hemi-BTP, and the two most extensively investigated BTBPs (C(5)-BTBP and CyMe(4)-BTBP) have been studied with some representative lanthanide(III), uranyl, thorium, and transition- and other heavy-metal cations in methanol. The formation of complexes of different stoichiometries, the stability of which depended on both the ligands and the cations, was shown using UV absorption spectrophotometry. Study of the complexation reactions of La(3+), Eu(3+) and Yb(3+) with these four ligands by stopped-flow spectrophotometry allowed determination of the rate constants and postulation of possible complexation mechanisms.

The binding properties of three series of phosphorylated calixarene derivatives bearing phosphine oxide or phosphonate groups either at the wide or the narrow rims have been investigated towards some representative lanthanide and actinide ions using several approaches: (i) liquid–liquid extraction of europium, americium, thorium and uranyl ions from nitric acid solutions into the two diluents m-nitrobenzotrifluoride (m-NBTF) or dichloromethane; (ii) complexation in single media (methanol and acetonitrile) followed by UV-spectrophotometric and isoperibolic (micro)calorimetric titrations (ITC). The latter technique was found to be very useful for the determination of the stoichiometries of the complexes formed, in particular when the complexation did not induce significant spectral changes. It also provided a full thermodynamic characterization of these new systems. The influence of some structural features of the ligands as the nature of the substituents and the condensation degree of the calixarene moiety, on the distribution coefficients and on the complexation thermodynamic parameters has been established.

Calix[4]arene derivatives bearing two residues A(–) derived from cobalt bis(dicarbollide)(1–) (1) and two CMPO groups B at their narrow rim were synthesized from tBu-calix[4]arene in four steps. The first step involved the preparation of tBu-calix[4]arene diether derivatives with appropriate precursors for amino groups (mostly nitriles 3). These were O-alkylated through ring-opening reactions with the zwitterionic dioxane derivative [(8-O(CH2CH2)2O-1,2-C2B9H10)-(1′,2′-C2B9H11)-3,3′-Co]0 (10) to produce ionic nitrile derivatives 4. Reduction of the nitrile groups with BH3·SMe2 (or deprotection in the case of the corresponding phthalimido or Boc derivatives 8) led to a series of diamines 5a–f, which were subsequently converted into the corresponding CMPO derivatives 6a–f by acylation with p-nitrophenyl(diphenylphosphoryl) acetate. Pure cone conformers were isolated in moderate to excellent yields after the second or third reaction step, although the presence of other conformers in the reaction mixtures was sometimes observed by NMR spectroscopy and HPLC, and in one case a di-A(–)-di-B derivative 6c* in the 1,3-alternate conformation was prepared. The novel ionic ligands 6a–f showed dramatically enhanced extraction abilities for trivalent actinides and lanthanides in relation to the previously reported simple covalent combination of one A(–) with one B group or to various synergistic mixtures of calixarenes substituted exclusively with two A(–) or two B moieties. A 1:1 mixture of calix[4]arenes containing four A(–) anions (13) and four CMPO functions (14), however, showed similarly high extraction efficiency, comparable to that of the best calixarenes 6b–d with mixed substitution. Complexation studies with 6c for La3+, Eu3+ and Yb3+ in methanol carried out by UV spectrophotometry and microcalorimetry revealed the formation of 1:1 and 1:2 metal-to-ligand complexes with log β values ranging from 9.6 to 11.7.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Starting from p -adamantylcalix[4]- and [6]arenes functionalized with carboxylic acid or ester groups at the adamantane nuclei, carbamoylmethylphosphine oxide (CMPO)-containing ligands of a novel type were synthesized. They were studied as extractants for a series of f-block elements including radioactive 152 Eu(III), 241 Am(III), 233 U(VI), and 239 Pu(IV). Tetrameric ligand 4b in which CMPO residues are connected to adamantane nuclei through methylene groups gave the best extraction results for lanthanides and actinides. For all the ligands the extraction efficiency does not decrease at higher nitric acid concentration. Although the discrimination between trivalent actinides and lanthanides is not good, all ligands are highly selective for thorium(IV) with the best separation factor achieved in the case of hexameric ligand 5 ( D Th / D Ln >24).

The synthesis and characterization of p-tert-butylcalix[4]arene-crown-6 derivatives (compounds 2–9) are presented. Their ability to complex alkali, alkaline earth and some “softer” cations was investigated by using these compounds as ionophores in ion-selective membrane electrodes and determining the potentiometric selectivity coefficients and the complex stability constants in the membrane. The selectivities of these compounds depend on the size and nature of the substituents on the distal phenolic oxygens. The complexing properties of the two cone and partial cone conformers of compound 2 in the PVC membrane were compared with those in acetonitrile solution studied by UV absorption spectrophotometry and with alkali metal picrate liquid–liquid extraction.

Two members of the tetradentate N-donor ligand families 6,6'-bis(1,2,4-triazin-3-yl)-2,2'-bipyridine (BTBP) and 2,9-bis(1,2,4-triazin-3-yl)-1,10-phenanthroline (BTPhen) currently being developed for separating actinides from lanthanides have been studied. It has been confirmed that CyMe4-BTPhen 2 has faster complexation kinetics than CyMe4-BTBP 1. The values for the HOMO-LUMO gap of 2 are comparable with those of CyMe4-BTBP 1 for which the HOMO-LUMO gap was previously calculated to be 2.13 eV. The displacement of BTBP from its bis-lanthanum(III) complex by BTPhen was observed by NMR, and constitutes the only direct evidence for the greater thermodynamic stability of the complexes of BTPhen. NMR competition experiments suggest the following order of bis-complex stability: 1:2 bis-BTPhen complex ≥ heteroleptic BTBP/BTPhen 1:2 bis-complex > 1:2 bis-BTBP complex. Kinetics studies on some bis-triazine N-donor ligands using the stopped-flow technique showed a clear relationship between the rates of metal ion complexation and the degree to which the ligand is preorganized for metal binding. The BTBPs must overcome a significant (ca. 12 kcal mol(-1)) energy barrier to rotation about the central biaryl C-C axis in order to achieve the cis-cis conformation that is required to form a complex, whereas the cis-cis conformation is fixed in the BTPhens. Complexation thermodynamics and kinetics studies in acetonitrile show subtle differences between the thermodynamic stabilities of the complexes formed, with similar stability constants being found for both ligands. The first crystal structure of a 1:1 complex of CyMe4-BTPhen 2 with Y(NO3)3 is also reported. The metal ion is 10-coordinate being bonded to the tetradentate ligand 2 and three bidentate nitrate ions. The tetradentate ligand is nearly planar with angles between consecutive rings of 16.4(2)°, 6.4(2)°, 9.7(2)°, respectively.

Selectivity of new thioamide derivatives was assessed using those ligands as sensor materials in ion-selective membrane electrodes and tested towards Pb2+ - selectivity. The influence of the nature of the thioamide function (linear, branched or cyclic substituents) on their ionophoric properties was investigated. Electrodes based on cyclic thioamide moieties are promising analytical tools for monitoring Pb2+ concentration in natural and drinking waters.

The quadridentate N-heterocyclic ligand 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,2,4-benzotriazin-3-yl)-2,2′ : 6′,2′′-terpyridine (CyMe4-hemi-BTBP) has been synthesized and its interactions with Am(III), U(VI), Ln(III) and some transition metal cations have been evaluated by X-ray crystallographic analysis, Am(III)/Eu(III) solvent extraction experiments, UV absorption spectrophotometry, NMR studies and ESI-MS. Structures of 1 : 1 complexes with Eu(III), Ce(III) and the linear uranyl (UO22+) ion were obtained by X-ray crystallographic analysis, and they showed similar coordination behavior to related BTBP complexes. In methanol, the stability constants of the Ln(III) complexes are slightly lower than those of the analogous quadridentate bis-triazine BTBP ligands, while the stability constant for the Yb(III) complex is higher. 1H NMR titrations and ESI-MS with lanthanide nitrates showed that the ligand forms only 1 : 1 complexes with Eu(III), Ce(III) and Yb(III), while both 1 : 1 and 1 : 2 complexes were formed with La(III) and Y(III) in acetonitrile. A mixture of isomeric chiral 2 : 2 helical complexes was formed with Cu(I), with a slight preference (1.4 : 1) for a single directional isomer. In contrast, a 1 : 1 complex was observed with the larger Ag(I) ion. The ligand was unable to extract Am(III) or Eu(III) from nitric acid solutions into 1-octanol, except in the presence of a synergist at low acidity. The results show that the presence of two outer 1,2,4-triazine rings is required for the efficient extraction and separation of An(III) from Ln(III) by quadridentate N-donor ligands.

International audience; p-tert-Butylcalix[4]arenes, in the cone conformation, di- and tetrasubstituted at the narrow rim with charged phosphonium groups, have been synthesized and characterized. Their interactions with a wide range of anions have been investigated in solution in chloroform and acetonitrile by means of 1H and 31 P NMR and microcalorimetry (ITC). These compounds have also been incorporated as sensing material in PVC ion selective electrodes (ISE). The results showed that they interact strongly with the more lipophilic anions ClO4-, SCN- and I-, in solution as in the electrode membranes. The origin of this selectivity is discussed and, in particular, the role of the salt counterion is examined.

Synthesis and binding properties of a new hydrosoluble triphenylene 1b are reported. Selective recognition of acetylcholine (ACh) against other aliphatic ammoniums is achieved by this flat receptor, which also forms complexes with epibatidine and nicotine. Ionic pairing and hydrophobic effects between host 1b and ACh are studied by infrared spectroscopy.

Varied flexibility: Cyclic oligoureas are formed by using anions as templates. Linking of six xanthene and/or diphenyl ether fragments by urea groups leads to the formation of five macrocyclic compounds with a 48-membered ring with variable flexibility (see picture). Their interaction with anions shows a strong influence of acetate and chloride ions on the cyclization from four precursor molecules. Five macrocylic compounds XXXXXX, XXDXXD, XDXDXD, XDDXDD, and DDDDDD with 48-membered rings, in which six xanthene and/or diphenyl ether fragments are linked through six urea (-NH-C(O)-NH-) groups, have been synthesized. In the cyclization step, a linear diamine was allowed to react with the appropriate diisocyanate by using a [5+1] (i.e., “XDXDX+D” for XDXDXD), [4+2] (DDDDDD), or [3+3] (XDDXDD) procedure. Compounds XXXXXX and XXDXXD were prepared from two molecules of the dimeric amine XX and two molecules of the respective monomeric diisocyanate (X or D) in a [2+1+2+1] (or 2×[2+1]) reaction. The (nonoptimized) yields in the cyclization step ranged from 45 to 80 %. The linear precursor diamines or diisocyanates were obtained by analogous condensation reactions by using partial protection with a tert-butoxycarbonyl group. All the macrocyclic compounds and synthetic intermediates were characterized by 1H NMR and mass spectra. Three different crystal structures were obtained for XDDXDD, which show the molecule in a more or less strongly folded conformation determined by intramolecular hydrogen bonding. The interaction of the hexaureas with selected anions was studied by 1H NMR spectroscopy and UV absorption spectrophotometry.

Macrocyclic molecules containing several amide or urea functions may serve as anion receptors. We describe the synthesis of 32-membered macrocycles, in which four rigid xanthene units (X) and/or diphenyl ether units (D) as flexible analogues are linked via urea groups. All six possible combinations of these units (XXXX, XXXD, XXDD, XDXD, XDDD and DDDD) were synthesized and two examples were characterised by single-crystal X-ray analyses (DDDD and two structures for XXXD). Both macrocycles showed distinct differences in their overall conformation and consequently in their hydrogen-bonding pattern. Hydrogen-bonded solvent molecules are found for both compounds and intramolecular hydrogen bonds for the two structures of XXXD, but surprisingly no direct intermolecular hydrogen bonds between the macrocyclic tetraurea molecules. The interaction with various anions was studied by (1)H NMR spectroscopy. Stability constants for all tetramers were determined by UV spectroscopy for complexes with chloride, bromide, acetate and dihydrogenphosphate in acetonitrile-THF (3:1). The strongest binding was found for XXXD and acetate (log beta = 7.4 +/- 0.2), the weakest for XXXX and acetate (log beta = 5.1 +/- 0.5). MD simulations in chloroform and acetonitrile boxes show that all molecules except DDDD adopt very similar conformations characterized by an up-down-up-down arrangement of the spacer groups. Clustered solvation shells of acetonitrile molecules around XXXX and DDDD suggest their preorganization for spherical/planar and tetrahedral/bidentate anions, respectively, which in turn was corroborated by simulation of the corresponding complexes with chloride and dihydrogenphosphate.

International audience; Abstract The synthesis and characterisation of a new tetra (triphenylphosphonium) p-tert-butylcalix[4]arene 2 is presented. Its interactions with anions were studied by 1H and 31P NMR and UV absorption spectrophotometry, showing the biggest interaction with ClO4-, I- and SCN-. Anion selectivity in ion-selective PVC-membrane electrodes (ISEs) plasticized with o-NPOE containing ionophore 2 was also investigated. Compound 2 shows a potentiometric response for various anions with the following selectivity pattern: ClO4- > SCN- > I- > Cr2O72- > NO3- > Br- > Cl-.

The binding properties of three p-tert-butyldihomooxacalix[4]arene tetraketone derivatives (tert-butyl 2b, adamantyl 2c and phenyl 2d) in the cone conformation and one derivative (methyl 2a) in a partial cone conformation, towards alkali and alkaline earth metal cations have been established by extraction studies of metal picrates from water into dichloromethane, stability constant measurements in methanol and acetonitrile, and by H-1 NMR spectrometry. Transport experiments of metal picrates through a dichloromethane membrane were also performed. The results are compared to those obtained with closely-related calix[n]arene derivatives (n = 4 and 5) and discussed in terms of the substituents, size and conformational effects. Methylketone 2a is a poor binder for all the cations studied, due to its partial cone conformation. Ketones 2b, 2c and 2d show high extraction and complexation levels for the alkali cations, with similar profiles and preference for K+ and Na+ (plateau selectivity). Towards alkaline earth cations, these ketones show a strong peak selectivity for Ba2+ in extraction, but a plateau selectivity for Ca2+, Sr2+ and Ba2+ in complexation. The nature of the substituent attached to the ketone function has some influence on their binding properties, with phenylketone 2d being a slightly weaker binder than ketones 2b and 2c. H-1 NMR titrations confirm the formation of 1:1 complexes between the ketones and the cations studied, also indicating that they should be located inside the cavity defined by the phenoxy and carbonyl oxygen atoms. Ketones 2b, 2c and 2d show transport rates that do not follow, in general, the same trends observed in extraction and complexation.

Two different bridges were introduced at the 1,5:3,7-positions of p-tert-butylcalix[8]arene 1 using a two-step alkylation procedure. A probable cation template effect in the introduction of the second bridge was evidenced. The obtained bis-bridged derivatives 3 possess encapsulating properties toward alkali cations modulated by the length and nature of the bridges.

The binding properties of the tetra( diethyl) amide ( 2) derived from p-tert-butyldihomooxacalix[4]arene, in the cone conformation, towards alkali, alkaline earth, transition (Mn2+, Fe2+, Co2+, Ni2+, Cu2+ and Zn2+) and heavy (Ag+, Cd2+, Hg2+ and Pb2+) metal cations have been established by extraction studies of metal picrates from an aqueous solution into dichloromethane, transport experiments with the same salts through a dichloromethane membrane and stability constant measurements in methanol. Results concerning the calorimetric study of Na+ and K+ complexes in methanol are presented. The affinity of 2 for some cations (Na+, K+, Ba2+, Ag+ and Zn2+) has been investigated by H-1 NMR spectrometry, as well. The results are compared to those obtained with the analogous calix[4]arene tetraamide derivative 3. Amide 2 displays a preference for the alkali cations (mainly Na+ and K+) in contrast to amide 3 that prefers the alkaline earth cations. Ag+ and Cd2+ soft Lewis acids are also strongly bound by both amides. H-1 NMR titrations confirm the formation of 1: 1 complexes between 2 and all cations studied, also suggesting that they should be located inside the cavity defined by the phenoxy and carbonyl oxygen atoms. 2 shows transport rates that do not follow the same trends as the stability constants or extraction percentages; it can therefore be characterized as a selective receptor.

The synthesis of 24-membered macrocycles is described, in which rigid xanthene units (X) and/or diphenyl ether units (D) as flexible analogues are linked via urea groups. All four possible combinations (XXX, XXD, XDD, DDD) have been obtained with yields of 40-72% for the cyclisation step. In two cases, the respective cyclic hexamers (XXDXXD, XXXXXX) were also isolated. Two compounds have been characterised by a single crystal X-ray analysis of the free triurea (XXD, XDD) and one example (DDD) by its complex with tetrabutylammonium chloride. It shows the chloride anion in the centre of the macrocycle, held by six NH...Cl- hydrogen bonds. The interaction with various other anions has been studied by 1H NMR. Complexation constants for chloride, bromide and acetate have been measured for all trimers by UV spectrophotometry. Molecular dynamics simulations have been carried out to determine the conformation of the free receptors in chloroform and acetonitrile. They show that in chloroform, intramolecular hydrogen bonding occasionally facilitated by trans--cis isomerisation of an amide bond dominates the conformation of the macrocycles while in acetonitrile (the solvent used for complexation measurements), the ligating urea NH protons are properly arranged for the complexation of anions, however, their strong solvation is counteractive to the complexation.

The binding properties of three p-tert-butyldihomooxacalix[4]arene tetraketone derivatives ( tertbutyl 2b, adamantyl 2c and phenyl 2d) in the cone conformation and one derivative ( methyl 2a) in a partial cone conformation, towards transition ( Mn2+, Fe2+, Co2+, Ni2+, Cu2+ and Zn2+) and heavy (Ag+, Cd2+, Hg2+ and Pb2+) metal cations have been established by extraction studies of metal picrates from water into dichloromethane, transport experiments with the same salts through a dichloromethane membrane and stability constant measurements in methanol and acetonitrile. Results concerning the microcalorimetric study of Cu2+, Ag+ and Pb2+ complexes in methanol are presented. The affinity of the ligands for some cations ( Zn2+, Ag+, Pb2+ and Hg2+) has also been investigated by proton NMR spectrometry. The X-ray crystal structure of tert-butylketone 2b was determined. Towards transition metal cations, ketones 2b, 2c and 2d are reasonable binders, showing in general preference for Cu2+. Methylketone 2a is a poor binder for these cations, due to its partial cone conformation. The three ligands in the cone conformation present a high affinity for the heavy metal cations, with selectivities for Ag+ and Pb2+. This series of cations is even fairly well complexed by methylketone 2a, which presents high stability constants for Hg2+ and Pb2+. The cases studied by H-1 NMR titrations confirm the formation of 1 : 1 complexes between the ketones and the cations, also indicating that they should be located inside the cavity defined by the phenoxy and carbonyl oxygen atoms. Ketones 2b, 2c and 2d show transport rate sequences that follow, in general, the same trends observed in extraction and complexation for transition cations, but they are reversed for the heavy metal cations.

The binding properties of tetra(2-pyridylmethoxy) (2) derived from p-tert-butyldihomooxacalix[4]arene, in the cone conformation, towards alkali, alkaline earth, transition (Mn2+, Fe2+, Co2+, Ni2+, Cu2+ and Zn2+) and heavy (Ag+, Cd2+, Hg2+ and Pb2+) metal cations have been assessed by extraction studies of metal picrates from water into dichloromethane and stability constant measurements in methanol and acetonitrile. Results concerning the calorimetric study of K+, Ba2+, Cu2+ and Ag+ complexes in acetonitrile are presented. The affinity of 2 for some cations (K+, Ag+, Zn2+, Hg2+ and Pb2+) has also been investigated by proton NMR spectrometry. The analogous derivative (3) of p-tert-butylcalix[ 4] arene was also studied, and the results of both compounds are compared. Towards the hard alkali and alkaline earth metal cations ligands 2 and 3 display a low efficiency of extraction. The complexation levels are also low in methanol becoming, however, much higher in acetonitrile. The highest stability is found for Ca2+ with ligand 2 in this solvent. Both ligands show a very high affinity for the soft heavy metal ions with preference for Ag+, but other ions such as Hg2+, Pb2+ and Cu2+ are also well bound. Proton NMR titrations confirm the formation of 1 : 1 complexes between 2 and all the cations studied, also indicating that they should be located inside the cavity defined by the phenoxy oxygen and the pyridyl nitrogen atoms.

The binding of lanthanide cations by 2-pyridylmethoxy derivatives of p-tert-butyldihomooxacalix[4]arene (1b), in the cone conformation, and p-tert-butylhexahomotrioxacalix[3]arene (2b), in both cone and partial cone conformations, was studied. These properties were assessed by extraction studies of the metal picrates from water into dichloromethane and stability constant measurements in methanol and acetonitrile, using spectrophotometric and microcalorimetric techniques. Proton NMR titrations with La3+ and Yb3+ cations were done in order to get information on the binding sites. Computational methods (density functional theory (DFT) calculations) were also used to complement the NMR data. The p-tert-butylcalix[4]arene analogue (3b) was also studied, and the results of the four ligands were compared. Partial cone-2b is the best extractant for lanthanide ions, showing some preference for the heavy lanthanides. In complexation, all four ligands show the same trend and a high selectivity for Yb3+ (ML, log β ≥ ...