Polyaza Cryptand Receptor Selective for Dihydrogen Phosphate

A hexaamine cage with pyridyl spacers was synthesized in good yield by a [2+3] Schiff-base condensation followed by sodium borohydride reduction. The protonation constants of the receptor as well as its association constants with Cl−, NO3−, AcO−, ClO4−, SO42−, H2PO4−, and H2AsO4− were determined by potentiometry at 298.2 ± 0.1 K in H2O/MeOH (50:50 v/v) and at ionic strength 0.10 ± 0.01 M in KTsO. These studies revealed that although dihydrogen phosphate is less charged than sulfate, it is still appreciably bound by the receptor at low pH, suggesting that the pyridyl nitrogen is accepting hydrogen bonds from dihydrogen phosphate. It is also shown that dihydrogen phosphate is capable of effectively competing with sulfate for the receptor at higher pH, being selective for hydrogen phosphate at pH about 7.0. 31P NMR experiments supported these findings. The fact that the receptor shows such a marked preference for hydrogen phosphate based mainly in its hydrogen bond accepting/donating ability in a highly competitive medium such as water/methanol mixed solvent is quite remarkable. Single-crystal X-ray diffraction determinations of anion associations between H6pyr6+ receptor and nitrate, sulfate, and phosphate are consistent with the existence of [(H6pyr)(NO3)3(H2O)3]3+, [(H6pyr)(SO4)2(H2O)4]2+, and [(H6pyr)(HPO4)2(H2PO4)(H2O)2]+ cations. One nitrate anion is embedded into the H6pyr6+ cage of the first supermolecule whereas in the second and third ones the anions are located in the periphery of the macrobicycle

Dicarboxylate Recognition by Two Macrobicyclic Receptors: Selectivity for Fumarate over Maleate

Two ditopic polyamine macrobicyclic compounds have been studied as receptors for the recognition of dicarboxylate anions of varying chain length in aqueous solution. One of the receptors consists of two tris­(2-aminoethyl)­amine-derived binding subunits separated by <i>p</i>-xylyl spacers, while the other is a heteroditopic compound, combining two different head units, a tren-derived and a 2,4,6-triethylbenzene-derived one, also separated by <i>p</i>-xylyl spacers. The acid–base behavior of the compounds as well as their binding ability with oxalate (oxa^2–), malonate (mal^2–), succinate (suc^2–), glutarate (glu^2–), maleate (male^2–) and fumarate (fum^2–) anions were studied by potentiometry at 298.2 K in aqueous solution and at ionic strength 0.10 M in KTsO. NMR studies were also performed to obtain structural information in solution on the supermolecules formed by association of the protonated macrobicycles with the dicarboxylate substrates. The results revealed that both compounds are able to form stable associations with the dianionic substrates in competitive aqueous solution, with unprecedented selectivity for fum^2– over other dicarboxylate competitors, including its <i>cis</i> isomer male^2–. In addition it was found that although the selectivity pattern is unaffected by the introduction of the 2,4,6-triethylbenzene head unit, the affinity toward dicarboxylates is significantly reduced. Therefore, the comparison between the binding behavior of these two receptors showed the effect of the increased rigidity and lipophilicity of the receptor with the 2,4,6-triethylbenzene head unit in the binding properties and the selectivity pattern

Dicarboxylate Recognition by Two Macrobicyclic Receptors: Selectivity for Fumarate over Maleate

Two ditopic polyamine macrobicyclic compounds have been studied as receptors for the recognition of dicarboxylate anions of varying chain length in aqueous solution. One of the receptors consists of two tris­(2-aminoethyl)­amine-derived binding subunits separated by <i>p</i>-xylyl spacers, while the other is a heteroditopic compound, combining two different head units, a tren-derived and a 2,4,6-triethylbenzene-derived one, also separated by <i>p</i>-xylyl spacers. The acid–base behavior of the compounds as well as their binding ability with oxalate (oxa^2–), malonate (mal^2–), succinate (suc^2–), glutarate (glu^2–), maleate (male^2–) and fumarate (fum^2–) anions were studied by potentiometry at 298.2 K in aqueous solution and at ionic strength 0.10 M in KTsO. NMR studies were also performed to obtain structural information in solution on the supermolecules formed by association of the protonated macrobicycles with the dicarboxylate substrates. The results revealed that both compounds are able to form stable associations with the dianionic substrates in competitive aqueous solution, with unprecedented selectivity for fum^2– over other dicarboxylate competitors, including its <i>cis</i> isomer male^2–. In addition it was found that although the selectivity pattern is unaffected by the introduction of the 2,4,6-triethylbenzene head unit, the affinity toward dicarboxylates is significantly reduced. Therefore, the comparison between the binding behavior of these two receptors showed the effect of the increased rigidity and lipophilicity of the receptor with the 2,4,6-triethylbenzene head unit in the binding properties and the selectivity pattern

Dicarboxylate Recognition by Two Macrobicyclic Receptors: Selectivity for Fumarate over Maleate

Two ditopic polyamine macrobicyclic compounds have been studied as receptors for the recognition of dicarboxylate anions of varying chain length in aqueous solution. One of the receptors consists of two tris­(2-aminoethyl)­amine-derived binding subunits separated by <i>p</i>-xylyl spacers, while the other is a heteroditopic compound, combining two different head units, a tren-derived and a 2,4,6-triethylbenzene-derived one, also separated by <i>p</i>-xylyl spacers. The acid–base behavior of the compounds as well as their binding ability with oxalate (oxa^2–), malonate (mal^2–), succinate (suc^2–), glutarate (glu^2–), maleate (male^2–) and fumarate (fum^2–) anions were studied by potentiometry at 298.2 K in aqueous solution and at ionic strength 0.10 M in KTsO. NMR studies were also performed to obtain structural information in solution on the supermolecules formed by association of the protonated macrobicycles with the dicarboxylate substrates. The results revealed that both compounds are able to form stable associations with the dianionic substrates in competitive aqueous solution, with unprecedented selectivity for fum^2– over other dicarboxylate competitors, including its <i>cis</i> isomer male^2–. In addition it was found that although the selectivity pattern is unaffected by the introduction of the 2,4,6-triethylbenzene head unit, the affinity toward dicarboxylates is significantly reduced. Therefore, the comparison between the binding behavior of these two receptors showed the effect of the increased rigidity and lipophilicity of the receptor with the 2,4,6-triethylbenzene head unit in the binding properties and the selectivity pattern

Polyaza Cryptand Receptor Selective for Dihydrogen Phosphate

A hexaamine cage with pyridyl spacers was synthesized in good yield by a [2+3] Schiff-base condensation followed by sodium borohydride reduction. The protonation constants of the receptor as well as its association constants with Cl−, NO3−, AcO−, ClO4−, SO42−, H2PO4−, and H2AsO4− were determined by potentiometry at 298.2 ± 0.1 K in H2O/MeOH (50:50 v/v) and at ionic strength 0.10 ± 0.01 M in KTsO. These studies revealed that although dihydrogen phosphate is less charged than sulfate, it is still appreciably bound by the receptor at low pH, suggesting that the pyridyl nitrogen is accepting hydrogen bonds from dihydrogen phosphate. It is also shown that dihydrogen phosphate is capable of effectively competing with sulfate for the receptor at higher pH, being selective for hydrogen phosphate at pH about 7.0. 31P NMR experiments supported these findings. The fact that the receptor shows such a marked preference for hydrogen phosphate based mainly in its hydrogen bond accepting/donating ability in a highly competitive medium such as water/methanol mixed solvent is quite remarkable. Single-crystal X-ray diffraction determinations of anion associations between H6pyr6+ receptor and nitrate, sulfate, and phosphate are consistent with the existence of [(H6pyr)(NO3)3(H2O)3]3+, [(H6pyr)(SO4)2(H2O)4]2+, and [(H6pyr)(HPO4)2(H2PO4)(H2O)2]+ cations. One nitrate anion is embedded into the H6pyr6+ cage of the first supermolecule whereas in the second and third ones the anions are located in the periphery of the macrobicycle

Evaluation of the Binding Ability of a Novel Dioxatetraazamacrocyclic Receptor that Contains Two Phenanthroline Units: Selective Uptake of Carboxylate Anions

The novel dioxatetraaza macrocycle [26]phen2N4O2, which incorporates two phenanthroline units, has been synthesized, and its acid−base behavior has been evaluated by potentiometric and 1H NMR methods. Six protonation constants were determined, and the protonation sequence was established by NMR. The location of the fifth proton on the phen nitrogen was confirmed by X-ray determinations of the crystal structures of the receptor as bromide and chloride salts. The two compounds have the general molecular formula {(H5[26]phen2N4O2)Xn(H2O)5-n}Xn-1·mH2O, where X = Cl, n = 3, and m = 6 or X = Br, n = 4, and m = 5.5. In the solid state, the (H5[26]phen2N4O2)5+ cation adopts a “horseshoe” topology with sufficient room to encapsulate three or four halogen anions through the several N−H···X hydrogen-bonding interactions. Two supermolecules {(H5[26]phen2N4O2)Xn(H2O)5-n}(5-n)+ form an interpenetrating dimeric species, which was also found by ESI mass spectrum. Binding studies of the protonated macrocycle with aliphatic (ox2-, mal2-, suc2-, cit3-, cta3-) and aromatic (bzc-, naphc-, anthc-, pyrc-, ph2-, iph2-, tph2-, btc3-) anions were determined in water by potentiometric methods. These studies were complemented by 1H NMR titrations in D2O of the receptor with selected anions. The Hi[26]phen2N4O2i+ receptor can selectively uptake highly charged or extended aromatic carboxylate anions, such as btc3- and pyrc-, in the pH ranges of 4.0−8.5 and <4.0, respectively, from aqueous solution that contain the remaining anions as pollutants or contaminants. To obtain further insight into these structural and experimental findings, molecular dynamics (MD) simulations were carried out in water solution

Evaluation of the Binding Ability of a Novel Dioxatetraazamacrocyclic Receptor that Contains Two Phenanthroline Units: Selective Uptake of Carboxylate Anions

The novel dioxatetraaza macrocycle [26]phen2N4O2, which incorporates two phenanthroline units, has been synthesized, and its acid−base behavior has been evaluated by potentiometric and 1H NMR methods. Six protonation constants were determined, and the protonation sequence was established by NMR. The location of the fifth proton on the phen nitrogen was confirmed by X-ray determinations of the crystal structures of the receptor as bromide and chloride salts. The two compounds have the general molecular formula {(H5[26]phen2N4O2)Xn(H2O)5-n}Xn-1·mH2O, where X = Cl, n = 3, and m = 6 or X = Br, n = 4, and m = 5.5. In the solid state, the (H5[26]phen2N4O2)5+ cation adopts a “horseshoe” topology with sufficient room to encapsulate three or four halogen anions through the several N−H···X hydrogen-bonding interactions. Two supermolecules {(H5[26]phen2N4O2)Xn(H2O)5-n}(5-n)+ form an interpenetrating dimeric species, which was also found by ESI mass spectrum. Binding studies of the protonated macrocycle with aliphatic (ox2-, mal2-, suc2-, cit3-, cta3-) and aromatic (bzc-, naphc-, anthc-, pyrc-, ph2-, iph2-, tph2-, btc3-) anions were determined in water by potentiometric methods. These studies were complemented by 1H NMR titrations in D2O of the receptor with selected anions. The Hi[26]phen2N4O2i+ receptor can selectively uptake highly charged or extended aromatic carboxylate anions, such as btc3- and pyrc-, in the pH ranges of 4.0−8.5 and <4.0, respectively, from aqueous solution that contain the remaining anions as pollutants or contaminants. To obtain further insight into these structural and experimental findings, molecular dynamics (MD) simulations were carried out in water solution

Dicarboxylate Recognition Properties of a Dinuclear Copper(II) Cryptate

A ditopic polyamine macrobicyclic compound with biphenylmethane spacers was prepared, and its dinuclear copper­(II) complex was studied as a receptor for the recognition of dicarboxylate anions of varying chain length in H₂O/MeOH (50:50 (v/v)) solution. The acid–base behavior of the compound, the stability constants of its complexes with Cu²⁺ ion, and the association constants of the copper­(II) cryptate with succinate (suc^2–), glutarate (glu^2–), adipate (adi^2–), and pimelate (pim^2–) were determined by potentiometry at 298.2 ± 0.1 K in H₂O/MeOH (50:50 (v/v)) and at ionic strength 0.10 ± 0.01 M in KNO₃. The association constants of the same cryptate as receptor for aromatic dicarboxylate substrates, such as phthalate (ph^2–), isophthalate (iph^2–), and terephthalate (tph^2–), were determined through competition experiments by spectrophotometry in the UV region. Remarkably high values of association constants in the range of 7.34–10.01 log units were found that are, to the best of our knowledge, the highest values of association constants reported for the binding of dicarboxylate anions in aqueous solution. A very well defined peak of selectivity was observed with the binding constant values increasing with the chain length and reaching the maximum for substrates with four carbon atoms between the carboxylate groups. Single-crystal X-ray diffraction determinations of the cascade complexes with adi^2– and tph^2– assisted in the understanding of the selectivity of the cryptate toward these substrates. The Hirshfeld surface analyses of both cascade complexes suggest that the establishment of several van der Waals interactions between the substrates and the walls of the receptor also contributes to the stability of the associations

Anion Recognition by a Macrobicycle Based on a Tetraoxadiaza Macrocycle and an Isophthalamide Head Unit

A macrobicycle formed by a tetraoxadiaza macrocycle containing a dibenzofuran (DBF) spacer and an isophthalamide head unit, named DBF-bz, was used as receptor for anion recognition. The molecular structure of DBF-bz was established in solution by NMR and ESI-MS spectroscopies and in single crystal by X-ray diffraction analysis. The X-ray structure showed a water molecule encapsulated into the macrobicyclic cavity by four hydrogen bonds, two of them involving the two N−H amide binding sites and the oxygen of the water molecule (N−H···O hydrogen bonds) and the other two (O−H···N) involving the amine groups as hydrogen bonding acceptors. 1H NMR temperature dependence studies demonstrated that the same structure exists in solution. The ability of this ditopic receptor to recognize alkali halide salts was evaluated by extraction studies followed by 1H NMR and ESI-MS spectroscopies. The macrobicycle showed a capacity to extract halide salts from aqueous solutions into organic phases. The binding ability of this macrobicycle for halides was also quantitatively investigated using 1H NMR titrations in CDCl3 (and DMSO-d6) solution, and in acidic D2O solution. The largest binding association constant was found for the chloride anion and the completely protonated receptor. The results suggest that the diammonium-diamide unit of the receptor strongly bind the anionic substrate via multiple N−H···Cl− hydrogen bonds and electrostatic interactions. The binding trend follows the order Cl− > Br− > I− ≈ F− established from the best fit between the size of the anion and the cavity size of the protonated macrobicycle. Molecular dynamics (MD) simulations of the DBF-bz in CHCl3 solution allowed a detailed insight into the structural and binding properties of the receptor

Copper Complexes of New Benzodioxotetraaza Macrocycles with Potential Applications in Nuclear Medicine

Two novel benzodioxotetraaza macrocycles [2,9-dioxo-1,4,7,10-tetraazabicyclo[10.4.0]1,11-hexadeca-1(11),13,15-triene (H2L1) and 2,10-dioxo-1,4,8,11-tetraazabicyclo[11.4.0]1,12-heptadeca-1(12),14,16-triene (H2L2)] were synthesized by a [1 + 1] crablike cyclization. The protonation constants of both ligands were determined by 1H NMR titration and by potentiometry at 25.0 °C in 0.10 M ionic strength in KNO3. The latter method was also used to ascertain the stability constants of their copper(II) complexes. These studies showed that the CuL1 complex has a much lower thermodynamic stability than the CuL2, and the H2L2 displays an excellent affinity for copper(II), due to the good fit of copper(II) into its cavity. The copper complexes of the novel ligands were characterized by electronic spectroscopy in solution and by crystal X-ray diffraction. These studies indicated that the copper center in the CuL1 complex adopts a square−pyramidal geometry with the four nitrogen atoms of the macrocycle forming the equatorial plane and a water molecule at axial position, and the copper in the CuL2 complex is square−planar. Several labeling conditions were tested, and only H2L2 could be labeled with 67Cu efficiently (>98%) in mild conditions (39 °C, 15 min) to provide a slightly hydrophilic radioligand (log D = −0.19 ±0.03 at pH 7.4). The in vitro stability was studied in the presence of different buffers or with an excess of diethylenetriamine-pentaethanoic acid. Very high stability was shown under these conditions for over 5 days. The incubation of the radiocopper complex in human serum showed 6% protein binding