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The crystal structure of a hexaprotonated octaaza macrocycle, 1,4,7,10,13,16,19,21-octaazacyclotetracosane, has been obtained as the nitrate complex, H81·8NO3. The complex crystallizes in the monoclinic space group P21/c with unit cell parameters a=14.43(2), b=8.36(1), c=15.9(1) A, β=110.8(2)° and U=1793(12) A3. The macrocycle crystallizes in a relatively flat elliptical conformation with dimensions of 11.9 and 7.2 A, and a depth of 1.8 A. The crystallographic coordinates formed the basis for molecular dynamics simulations over a 400 ps timeframe using the all-atom CHARMM version 25 package. The major change in the conformational structure of the macrocycle during the simulations was the shifting of all NCCN dihedral angles to a trans conformation. Also, each conformational transition in CNCC and CCNC angles flanking a central CC bond was found to be correlated. The macrocycle remained relatively flat throughout the simulation, resulting in essentially complete hydration within the first 100 ps of the simulation. Extensive water relay networks could be identified throughout the simulation, which are attributed to maintaining and stabilizing anion/cation interactions in solution.

The new compounds 1,4,10,13-tetrakis(2,3-dihydroxybenzoyl)-7,16-dimethyl-1,4,7,10,13,16-hexaazacyclooctadecane (H8L1) and 1,4,7,10,13,16-hexakis(2,3-dihydroxybenzoyl)-1,4,7,10,13,16-hexaazacyclooctadecane (H12L2), having macrocyclic skeletons bearing four and six catechol hanging groups, respectively, have been synthesized and characterised. The crystal structure of H8L1·2dmso·2H2O (dmso = dimethyl sulfoxide), has been solved by single-crystal X-ray analysis. The equilibrium constants for protonation of the macrocycles and complexation of Fe3+ have been studied by potentiometric procedures in water–dmso (50∶50 v/v), 0.1 mol dm–3 NMe4Cl, at 298.1 ± 0.1 K. Both compounds are able to form mono- and di-nuclear iron(III) complexes of very high stability. These results indicate that the two compounds are thermodynamically able to scavenge Fe3+ from iron(III) transferrin. Their effectiveness as scavengers has been demonstrated by spectrophotometric measurements on the transmetallation reactions occurring in the presence of diiron(III) transferrin in aqueous solution. For comparison, the drug desferrioxamine B (DFB) has been also considered under the same experimental conditions. In 0.1 mol dm–3 phosphate buffer, at pH 7.4, both H8L1 and H12L2 remove iron from diiron(III) transferrin, the transmetallation reactions being much faster for H12L2 than for DFB which is slightly more effective than H8L1.

The ligand [30]aneN6O4 (L1) binds two Zn(II) in aqueous solution. The stability constants of the L1 complexes have been determined at 308.1 K by means of potentiometric measurements. Dinuclear monohydroxo [Zn2L1OH]3+ and dihydroxo [Zn2L1(OH)2]2+ complexes are formed in aqueous solution from neutral to alkaline pH. The kinetics of promoted hydrolysis of p-nitrophenyl acetate (NA) was studied. Both hydroxo species promote p-nitrophenyl acetate (NA) hydrolysis at 298.1 K with second-order kinetics. The activity of these species in NA hydrolysis is similar to that found for the mononuclear L2−Zn-OH+ complex (L2 = [15]aneN3O2), indicating that the hydrolytic process takes place via a simple bimolecular mechanism. The hydrolysis rate of bis(p-nitrophenyl) phosphate (BNP) was measured in aqueous solution at 308.1 K in the presence of the L1 and L2 zinc complexes. The hydrolysis rate of BNP is increased almost 10-fold by the dinuclear [Zn2L1(OH)2]2+ complex with respect to the mononuclear L2−Zn-OH+ one. This resu...

The stability constants of the Cu(II) complex of Me 6 tren (Me 6 tren=tris-(2-dimethylaminoethyl)amine) were determined. The axial binding constants of F − , Br − , I − and N 3 − to Cu(tren) 2+ and Cu(Me 6 tren) 2+ (tren=tris-(2-aminoethyl)amine) were measured. The results obtained are compared with those of the axial binding constants of the isomers, i.e. the complexes Cu(trien) 2+ and Cu(Me 6 trien) 2+ (trien=1,4,7,10-tetraazadecane; Me 6 trien=2,5,8,11-tetramethyl-2,5,8,11-tetraazadodecane). The results point out that N-methylation transforms the Cu(II)L complexes into stronger and harder acids. Properties of the copper complexes with TMC (1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane) and with Me 6 trpn (tris-(3-dimethylaminopropyl)amine) are also reported.

A new OFF-ON fluorescent chemosensor (L(1)) for Cd(2+) recognition based on a 5-chloro-8-hydroxyquinoline pendant arm derivative of 1,4,7-triazacyclononane ([9]aneN3) will be presented and its photochemical features in an MeCN-H2O 1 : 1 (v/v) mixture, in pure water, after inclusion within catanionic vesicles, and in living cells will be discussed. The coordination properties of L(1) both in solution and in the solid state were preliminarily studied and its selectivity towards Cd(2+)versus a set of different metal ions (Cu(2+), Zn(2+), Cd(2+), Pb(2+), Al(3+), Hg(2+), Co(2+), Ni(2+), Mn(2+), Mg(2+), K(+), Ca(2+), Ag(+), and Na(+)) was verified in MeCN-H2O 1 : 1 (v/v). In water, upon addition of increasing amounts of Cd(2+) to L(1) an enhancement of the fluorescence emission was detected. To overcome this serious drawback, L(1) was dissolved in an innovative catanionic vesicular solution based on sodium bis(2-ethylhexyl) sulfosuccinate, a traditional surfactant, and 1-dodecyl-3-methylimidazolium bromide, an ionic liquid. When enclosed within the vesicle bilayers in water, L(1) restored its fluorescence emission property upon addition of Cd(2+). Remarkably, L(1) enters the cellular membrane of living cells thus allowing the detection of intracellular Cd(2+). These findings encourage the application of this new fluorescent chemosensor in real samples for histological and environmental analyses.

Synthesis and characterization of a new macrocyclic compound, composed by a triethylentetraamine chain linking the 4 and 5 positions of an acridine moiety, are reported. The molecule, devised as a fluorescent chemosensor for anions, has revealed an intriguing pH-dependent spectroscopic behavior, whose features are the specific object of this article. Ligand protonation in aqueous solution has been analyzed by means of potentiometric, (1)H NMR, UV-vis, and fluorescence emission measurements. The molecule binds up to four protons in the pH range 2-11. Protonation takes place on the aliphatic tetraamine chain, while the acridine nitrogen does not participate to proton binding even at very low pH. Differently from acridine, the UV-vis spectra are almost unaffected by the pH. On the opposite, the emission spectra are strongly pH-dependent. In fact, at low pH values, the spectra show a blue-shifted emission, resembling that of unprotonated acridine, while at slightly acidic and alkaline pH the fluorescence features a red-shifted band similar to that of acridinium cation. This unusual behavior occurs in the mono-, bi-, and triprotonated forms of the compound and is interpreted as due to an excited state proton transfer from an aliphatic ammonium group adjacent to the acridine moiety to the acridine nitrogen. In the fully protonated state, this process is prevented owing to unfavorable molecular arrangements mainly determined by electrostatic repulsions. This interpretation is supported by quantum mechanical calculations as well as molecular dynamics simulations.

The [Cu2(dap)5] (ClO4)4 complex (dap = 1,3-diaminopropane) crystallizes, in almost quantitative yield, from alcoholic solutions containing the ligand and Cu(II) in a 5:2 molar ratio. Crystals of [Cu2(dap)5] (ClO4)4 are orthorhombic, space group Pbca, a = 14.737(7), b = 15.710(4), c = 39.995(9) A, Z = 8. As revealed by the crystal structure a dap molecule bridges two Cu(dap)22+ units. Each copper atom is five-coordinated in a rather regular square-pyramidal environment, the two nitrogen atoms of the bridging dap occupying the apical positions. The basal planes of the square pyramids form a dihedral angle of 61.7(2)°.

2,5,8,11-Tetramethyl-2,5,8,11-tetraazadodecane, 2,5,8,11,14-pentamethyl-2,5,8,11,14-pentaazapentadecane, and 2,5,8,11,14,17-hexamethyl-2,5,8,11,14,17-hexaazaoctadecane, form stable complexes with CuI in aqueous solutions. On the other hand 2,5,8-trimethyl-2,5,8-triazanonane, does not. This indicates that the stabilization of CuI by tertiary amine ligands in aqueous solutions requires at least four nitrogens. The electronic spectra and the electrochemical properties of the [CuLi]2+ complexes over a wide pH range were studied and potentiometric titrations were made of solutions containing equimolar concentrations of CuII and Li. The nature of the complexes present in these solutions is discussed.

International audience; Binding of Zn(II) by the ditopic ligands L1py, L2py and L1para, composed of a cyclam unit linked to the linear polyamines 1,4,8,11-tetraazaundecane (L1py and L2para) and 1,4,7-triazaheptane (L2py) via a 2,6-dimethylpyridinyl (L1py and L2py) or a 1,4-dimethylbenzyl spacer (L2para), has been analyzed by means of potentiometric and 1H and 13C NMR measurements. All ligands form stable mononuclear Zn(II) complexes in a wide pH range, featuring the metal ion bound to the macrocyclic unit. The open-chain polyamine unit can easily bind several protons in aqueous solution affording protonated metal complexes at neutral and acidic pH values. These complexes behave as bifunctional receptors for the anionic substrates N-(phosphonomethyl)glycine (glyphosate or PMG) and ATP. Potentiometric, 1H and 31P NMR measurements show that the Zn(II) complex with L1py is the better receptor for both substrates, thanks to the simultaneous presence of a pyridine linker functionalized at its 2,6 positions and of a flexible linear tetraamine chain. In fact, these structural features allow a stronger interaction of PMG and ATP with both the protonated tetraamine moiety and the Zn(II)–cyclam core.

A chiral ditopic polyammonium receptor featuring two [9]aneN3 moieties separated by a (S)-BINOL linker is able to selectively bind and sense in water (S,S)-tartaric acid over its (R,R)/meso forms. © 2012 The Royal Society of Chemistry.

The synthesis of 1,4,7-trimethyl-1,7-bis(p-(α-chloromethyl)benzyl)-1,4,7-triazaeptane is reported. This compound behaves as a versatile building block for the assembly of 1,4-dibenzo aza or oxa-aza macrocycles.

The small macrobicyclic cage (5,12,17-trimethyl-1,5,9,12,17-pentaazobicyclo[7.5.5]nonadecane, CESTO), which can selectively encapsulate lithium ions, has been studied in the presence of micellar solutions of 0.037 M lithium dodecyl sulfate (LDS). The CESTO cage behaves as a fairly strong base in the first protonation step (log K 1 =11.83 where K 1 is the equilibrium constant) and exhibits two different behaviors in LDS micellar solutions. Surface tension, electron spin echo modulation (ESEM), 7 Li NMR and small-angle neutron scattering (SANS) measurements show that the macrocyclic cage at about pH 10.2 behaves as a bulkier counterion, while at about pH 12.7 it complexes selectively lithium counterions at the micellar surface. Furthermore, ESEM studies show that CESTO encapsulates lithium ions at the micellar surface by reducing the amount of water at the surfactant polar head groups. SANS results show that, at about pH 12.5, LDS molecules form micelles of quasi-spherical shape with an average aggregation number of 90. The effective ionization of the micelles is about 20%. The addition of CESTO leads to lithium ion complexation with a drastic reduction of the micellar surface charge, and of the hydration number. This is accompanied by the growth of the aggregation number and the micelles become more elongated.

We study the effects of addition of the macrocyclic cage CESTO (5,12,17-trimethyl-1,5,9,12,17-pentaazabicyclo (7.5.5)nonadecane) on the aggregation behaviour of lithium dodecylsulphate (LDS) in aqueous solution at a pH approximately=12.7. At this pH CESTO is neutral and binds selectively Li counter-ion. Electron spin-echo modulation results show that CESTO interacts with LDS micelles by decreasing the amount of water at the LDS polar headgroups region. Small-angle neutron scattering shows that LDS forms micelles of quasi-spherical shape. Upon addition of CESTO to 1% LDS micellar solution (1/1 mole ratio) we observed a dramatic lowering of the micellar charge, a small growth of the aggregation number, and increased elongation of micelles.

Macrocyclic compounds have been extensively investigated, the interest for this huge class of compounds spans from fundamental research to specific industrial applications. 1 – 8 We have recently published a few papers on small macrocycles having cage-like molecular topology.9 – 19 They present special proton-transfer properties and in few cases they are strong, selective lithium binders in aqueous solution.14,15,17 The three-dimensional cavity present in these compounds is achieved by connecting two secondary nitrogen atoms of a tetraazamacrocycle with different bridging groups (see Fig 1). Molecular topology and nature of donor atoms are the most important elements influencing the chemical properties of this class of compounds. For these reasons we are continuing our investigations on these compounds by systematically changing the bridging unit; we report here the synthesis and chemical properties of the new cage 4,10-dimethyl-1,4,7,10-tetraazabicyclo[5.5.2]-tetradecane, abbreviated as L.

The synthesis and characterization of the two new oxa-aza macrobicycles 16,21 -dimethyl-4,7,10-trioxa-1,13,16,21-tetraazabicyclo[11.5.5]tricosane (C1) and 19,24-dimethyl-4,7,10,13-tetraoxa-1,16,19,24-tetraazabicyclo[14.5.5] hexacosane (C2) have been reported. Their proton transfer behaviour has been studied in aqueous solution by potentiometry (298.1 ± 0.1 K, I= 0.15 mol dm–3), microcalorimetry and 1H and 13C NMR spectroscopy. Both of them behave as diprotic bases. C1 and C2 behave as strong bases in the first protonation step and as moderate bases in the second one. Their basicity is due to a main enthalpic contribution. NMR experiments indicate that the nitrogen atoms involved in the protonation steps are the methylated ones. The crystal structure of [H2C2·H2O][ClO4]2[space group P21, a= 10.450(2), b= 11.391(2), c= 12.666(3)A, β= 100.21(2)°, V= 1483.8(5)A3, Z= 2, R= 0.059 and Rw= 0.052] gives confidence to NMR results, confirming that in the [H2C2·H2O]2+ cation the protons are localized on the methylated nitrogen atoms. Furthermore, a water molecule is enclosed into the macrocyclic cavity, interacting via hydrogen bonds with both protonated nitrogens and three oxygens of the macrocyclic framework and originating a ‘water cryptate’.

The synthesis of two new methylated ligands 1,10-dimethyl-1,4,7,10,13,16-hexaazacyclooctadecane L and 1,4,7-trimethyl-1,4,7,10,13,16,19-heptaazacyclohenicosane L1 is described. Basicity constants and protonation enthalpies of both ligands have been determined by potentiometric and microcalorimetric measurements in 0.15 mol dm–3 NaClO4 at 298.1 K. The protonated forms of these cyclic polyamines bind ATP in solution. The equilibrium constants of the species formed have been determined (0.15 mol dm–3 NaClO4, 298.1 K). The results presented for L and L1 are compared with those previously obtained for the related ligands 1,4,7,10,13,16-hexaazacyclooctadecane, 1,4,7,10,13,16,19-heptaazacyclohenicosane and 1,4,7,13-tetramethyl-1,4,7,10,13,16-hexaazacyclooctadecane. Among these macrocycles Lis a selective receptor for ATP binding.The crystal structure of the compound (H4L)(ClO4)4[space group P21/c, a= 9.257(4), b= 8.600(2). c= 17.990(10)A, β= 101.74(4)°, V= 1402(1)A3, Z= 2] shows that the four charged ammonium groups point inside the macrocyclic cavity.

International audience; This paper reports a study of the interaction between a ditopic cyclic–open-chain polyazaligand L1py and the herbicide glyphosate [N-(phosphonomethyl)glycine or PMG] by potentiometric titrations as well as calorimetry and NMR measurements. This nonsymmetrical ligand is composed of a cyclam unit (1,4,8,11-tetraazacyclotetradecane) and the linear tetraamine 1,4,8,11-tetraazaundecane linked by a 2,6-dimethylpyridine spacer. This ligand forms stable adducts with PMG. For comparison, two analogous symmetrical ditopic ligands, a bis-macrocycle L4py and a bis-tetraamine L5py, and two related anions, iminodiacetic acid (IDA) and iminobis(methylphosphonic acid) (IDP), were also investigated. The results unambiguously show that L1py selectively binds PMG, especially around neutral pH, whereas L4py and L5py exhibit a weaker affinity for this substrate. Calorimetic and 1H NMR measurements showed that the host–guest adducts are mainly stabilized by charge–charge interactions and hydrogen bonds involving the ammonium function of PMG and the nonprotonated nitrogen atom of the pyridine linker.

Binding of mono-, di-, and triphosphate, adenosine diphosphate (ADP), and adenosine triphosphatase (ATP) with receptors L1-L3, composed of two [9]aneN(3) units separated by a 2,9-dimethylene-1,10-phenanthroline (L1), a 2,6-dimethylenepyridine (L2), or a 2,3-dimethylenequinoxaline (L3) spacer, has been studied by means of potentiometric titrations, (1)H and (31)P NMR measurements in aqueous solutions, and molecular modeling calculations. In the case of inorganic phosphates, the binding properties of the receptors appear to be determined by their geometrical features, in particular the distance between the two [9]aneN(3) units imposed by the spacer separating the two macrocyclic units. While L1 is able to selectively bind triphosphate over di- and monophosphate, L3 selectively coordinates the smaller monophosphate anion. Finally, L2 shows preferential binding of diphosphate. (1)H and (31)P NMR measurements show that the complexes are essentially stabilized by charge-charge and hydrogen-bonding interactions between the anion and the protonated amine groups of the macrocyclic subunits of the receptors. Molecular dynamics simulations suggest that the larger distance between the two macrocyclic units of L1 allows this receptor to form a larger number of hydrogen-bonding contacts with triphosphate, justifying its selectivity toward this anion. Conversely, in the case of L3, the two facing [9]aneN3 units give rise to a cleft of appropriate dimensions where the small monophosphate anion can be conveniently hosted. Considering nucleotide coordination, L1 is a better receptor for ATP and ADP than L2, thanks to the higher ability of phenanthroline to establish stabilizing π stacking and hydrophobic interactions with the adenine units of the guests.

The 1:1 complex [Cu(L)](BF4)2·MeCN (1) of the tetradentate ligand 1-(2-quinolinylmethyl)-1,4,7-triazacyclononane (L) selectively changes its colour in the presence of CN- in H 2O and MeCN (without undergoing decomplexation from the macrocyclic ligand). The same complex in MeCN assumes different colours in the presence of CN- or I-. © The Royal Society of Chemistry., We thank the Università di Cagliari (Fondo 5%) (C.C.) and the MEC-ES (CTQ2010-20500-C02-01) (A.L.) for funding.

The interaction of adenosine 5'-triphosphate, pyrophosphate, and hexacyanoferrate(II) anions with the cyclic polyamines 1,4,7,10,13,16-hexaazacyclooctadecane ([18]aneN 6 ) and 1,4,7,13-tetramethyl-1,4,7,10,13,16-hexaazacyclooctadecane (Me 4 [18]aneN 6 ) and with the open-chain polyamine 1,14-bis(methylamino)-3,6,9,12-tetraazatetradecane (Mezpentaen) has been studied in the pH range 3-10 by potentiometry and cyclic voltammetry

Complexation equilibria between the open-chain terminally methylated polyamines 1,14-bis(methylamino)-3,6,9,12- tetraazatetradecane (L1), 1,17-bis(methylamino)-3,6,9,12,15-pentaazaheptadecane (L2), 1,20-bis(methylamino)- 3,6,9,12,15,18-hexaazaicosane (L3) and 1,23-bis(methylamino)-3,6,9,12,15,18,21-heptaazatricosane (L4) with Co2+ and Ni2+ have been studied by means of potentiometric and spectrophotometric methods in 0.15 mol dm−3 NaClO4 aqueous solution at 298.15 K The stability constants for the complexes formed have been determined from e.m.f, data. All these ligands form mononuclear ML2+ complexes of similar stability with Co2+ and Ni2+. Binuclear Co2L44+, Ni2L34+ and Ni2L44+ are also formed. The equilibrium constants of the complexes of L1–L4, which are the open-chain counterparts of the macrocyclic ligands [3k]aneNk (k=6−9), reveal that only [18]aneN6 with Co2+ and Ni2+, and [21]aneN7 with Co2+. present enhanced stability (macrocyclic effect) with respect to L1–L4. However this effect has not been observed for binuclear complexes.

The interaction of Pb2+ with the macrocyclic amines 1,4,7,10,13,16-hexaazacyclooctadecane (L1), 1,4,7,10,13,16,19-heptaazacyclohenicosane (L2), 1,4,7,10,13,16,19,22-octaazacyclotetracosane (L3), 1,4,7,10,13,16,19,22,25-nonaazacycloheptacosane (L4), 1,4,7,10,13,16,19,22,25,28-decaazacyclotriacontane (L5), 1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane (L6) and 1,4,7,10,13,16,19,22,25,28,31,34-dodecaazacyclohexatriacontane (L7) belonging to the [3k]aneNg series and with their related open-chain, terminally methylated polyamines 1,14-bis(methylamino)-3,6,9,12-tetraazatetra-decane (L8), 1,17-bis(methylamino)-3,6,9,12,15-pentaazaheptadecane (L9), 1,20-bis(methylamino)-3,6,9,12,15,18-hexaazaicosane (L10) and 1,23-bis(methylamino)-3,6,9,12,15,18,21-heptaazatricosane (L11) has been studied by potentiometry at 298.1 K in 0.15 mol dm–3 NaClO4. The cyclic amines L1 and L2 form only mononuclear complexes, while L3–L5 can form both mono- and bi-nuclear species. The largest amines of this series L6 and L7 form bi- and tri-nuclear lead(II) complexes. Of the open-chain ligands, L8 forms only mononuclear complexes, while L9–L11 form both mono- and bi-nuclear species. The crystal structure of the solid compound [Pb2L5][ClO4]4 has been solved by X-ray diffraction analysis [space group P21/n, Z= 2, a= 9.052(9), b= 11.400(9), c= 18.689(8)A, β= 94.42(6)°, R= 0.082 and R′= 0.068]. It shows that both Pb2+ ions are tightly co-ordinated to four nitrogens of the macrocycle (Pb–N ranging from 2.27 to 2.71 A). A fifth nitrogen and three oxygens of two perchlorate anions are weakly interacting at much larger distances (Pb–N 3.04; Pb–O 2.98, 3.38, 3.41 A). The complex cation is situated around a crystallographic symmetry centre. The arrangement of the eight atoms around the lead ion is rather asymmetric leaving a zone free from co-ordinated donor atoms which is believed to be occupied by a lone pair of electrons.

The behavior of Co(NO3)2 and 1,4,7,10,13,16,19,22,25,28-decaazacyclotriacontane aqueous solutions towards molecular dioxygen has been examined over a large range of ratios R between the ligand and cobalt(II) concentrations and in the presence of different types of anions at high concentrations. Both binuclear, Co2L(O2)(OH), and mononuclear, Co(HmL)(O2), peroxo complexes are formed depending on the value of R. The formation of the binuclear species is rapid, while that of the mononuclear complexes is slow. Phosphate anions (Y) enter into the bi- and mono-nuclear peroxo complexes, giving Co2L(O2)Y and CoL(O2)Y species. The kinetics of dioxygen uptake under various experimental conditions has been studied and reaction schemes are proposed.

The synthesis and characterization of the new macrobicyclic cage 4,10-dimethyl-1,4,7,10-tetraazabicyclo[5.5.4]hexadecane L is reported. Its basicity behaviour in aqueous solution has been investigated by potentiometric (25 °C, I= 0.15 mol dm–3) and NMR (1H and 13C) techniques. It behaves as a very strong base (proton sponge) in the first protonation step, and as a moderate base in the second step (log K2= 7.8). 1H–1H and 1H–13C two-dimensional NMR experiments permitted the unequivocal assignment of all 1H proton and 13C resonances of both species HL+ and H2L2+. Furthermore NMR experiments indicate that the first protonation involves the bridgehead nitrogens. Crystals of [HL][ClO4] are orthorhombic, space group P21cn, with a= 9.044(2), b= 12.573(2), c= 16.126(3)A, and Z= 4; final R value of 0.089 (Rw= 0.086) for 1267 unique observed reflections with I > 3σ(I). X-Ray analysis shows that protonation occurs on the bridgehead nitrogen N(2) and an overall macrocyclic conformation with the all nitrogen atoms in the endoconfiguration. The short H(2)⋯(4)[1.69(1)A] and N(2)⋯ N(4)[2.75(1)A] distances indicate a strong hydrogen bond. H(2) further interacts with the other two tertiary nitrogens: H(2)⋯ N(1)[2.53(1)A] and H(2)⋯ N(3)[2.46(1)A]. This arrangement makes the monoprotonated species very stable from the thermodynamic point of view and explains the high basicity of L. Crystals of [H3L][ClO4]3 are tetragonal, space group P43212, with a= 8.498(2), b= 8.498(2), c= 32.855(8)A, and Z= 4; final R value of 0.083 (Rw= 0.093) for 1076 unique observed reflections with I > 3σ(I). The X-ray analysis shows an overall macrocyclic conformation with two nitrogen atoms in the endoconfiguration and two in exo configuration.

The ligands in the series (3k)aneNk (k=6-12), when neutral or partially protonated, can form complexes with many cations, and when extensively protonated they can form adducts with polycharged anions. We shall report some general trends in both cation and anion coordination. In particular thermodynamic and structural parameters obtained for cation and anion complexes will be considered in this paper. The analysis of such parameters enables some characteristics in the molecular recognition of both metal cations and anions to be outlined.

In this tutorial review, we will discuss the most significant achievements in the structure-based design of cyclic receptors containing mainly aliphatic amine groups as metal-free hosts for phosphate-based guests in aqueous environment; in particular, inorganic phosphates and mononucleotide anions. The bulk of our attention will be devoted to show how this class of receptors has structurally evolved following the attempts by chemists to optimize all factors indicated by Nature as necessary to achieve the best possible binding of phosphates via non-covalent interactions.

The basicity properties of the two cryptands L1 and L2, featuring, respectively, a dibenzofuran or a diphenyl ether moiety bridging the 1,7 positions of a 1,4,7,10-tetraazacyclododecane macrocycle (cyclen) have been studied by means of potentiometric, UV-vis and fluorescence emission measurements. Both ligands show a high basicity in the first protonation step, the first basicity constant of L1 being too high to be measured in aqueous solution. The crystal structure of {[HL1]L1}(+) shows that the NH(2)(+) group is involved in an intramolecular hydrogen bonding network, which justifies the observed high basicity in solution. (1)H, (13)C NMR, UV-vis and fluorescence emission measurements show that, among first row divalent metal cations, both L1 and L2 selectively bind in acetonitrile Cu(II) and Zn(II), which are encapsulated within the ligand cavities. Zn(II) coordination is accompanied by a remarkable increase of the fluorescence emission of the ligands, pointing out that the molecular architecture displayed by L1 and L2 can be used to develop new OFF/ON chemosensors for this metal cation.

Three novel 2,7-substituted acridine derivatives were designed and synthesized to investigate the effect of this functionalization on their interaction with double-stranded and G-quadruplex DNA. Detailed investigations of their ability to bind both forms of DNA were carried out by using spectrophotometric, electrophoretic, and computational approaches. The ligands in this study are characterized by an open-chain (L1) or a macrocyclic (L2, L3) framework. The aliphatic amine groups in the macrocycles are joined by ethylene (L2) or propylene chains (L3). L1 behaved similarly to the lead compound m-AMSA, efficiently intercalating into dsDNA, but stabilizing G-quadruplex structures poorly, probably due to the modest stabilization effect exerted by its protonated polyamine chains. L2 and L3, containing small polyamine macrocyclic frameworks, are known to adopt a rather bent and rigid conformation; thus they are generally expected to be sterically impeded from recognizing dsDNA according to an intercalative binding mode. This was confirmed to be true for L3. Nevertheless, we show that L2 can give rise to efficient π-π and H-bonding interactions with dsDNA. Additionally, stacking interactions allowed L2 to stabilize the G-quadruplex structure: using the human telomeric sequence, we observed the preferential induction of tetrameric G-quadruplex forms. Thus, the presence of short ethylene spacers seems to be essential for obtaining a correct match between the binding sites of L2 and the nucleobases on both DNA forms investigated. Furthermore, current modeling methodologies, including docking and MD simulations and free energy calculations, provide structural evidence of an interaction mode for L2 that is different from that of L3; this could explain the unusual stabilizing ability of the ligands (L2 > L3 > L1 ) toward G-quadruplex that was observed in this study.

The synthesis and characterization of the small, new benzyl aza-cage 4-benzyl-10,15-dimethyl-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane (L) are reported. The basicity constants have been determined in aqueous solution by potentiometry (25 °C, [NaCl] 0.15 mol dm–3). L behaves as a biprotic base: log K1= 11.8, log K2= 8.3. The crystal structure of the monoprotonated salt [HL][BPh4] has been determined by single-crystal X-ray analysis. The compound crystallizes in an orthorhombic unit cell (space group Pc21n, Z= 4) with lattice constants a= 11.400(4), b= 16.893(3), c= 20.537(6)A. Least-squares refinement converged at R= 0.078 (Rw= 0.056) for 1290 unique reflections with I > 3σ(I). The structure of [HL]+ shows the five nitrogens atoms in an endo configuration, indicating that the proton is inside the cage cavity. The cage L encapsulate Li+ and the complex formation equilibrium for [LiL]+ has been investigated by potentiometry [log K= 3.0(1)] and 7Li NMR techniques.

The synthesis and characterization of the new azamacrocycle 4,10,15-trimethyl-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane (L) are reported. The stepwise basicity constants have been determined by potentiometry (25C, NaCl 0.15 mol dm[sup [minus]3]). L behaves as biprotic base: log K[sub 1] = 11.8; log K[sub 2] = 10.0. The molecular structure of the monoprotonated salt [HL][BPh[sub 4]] has been determined by single-crystal X-ray analysis. The structure of [HL]+ shows the five nitrogen atoms in endo configuration, indicating that the proton is inside the cage cavity. Geometrical considerations indicate that the proton is bound to the bridgehead nitrogen atom N(2). The cage L selectivity encapsulates Li+, and the equilibrium for the formation of the inclusion complex [LiL]+ has been investigated by potentiometry (log K = 5.5) and [sup 7]Li NMR techniques. The molecular structure of the complex [LiL][BPh[sub 4]] has been determined by single-crystal X-ray analysis. Li+ is wholly enclosed in the cage cavity adopting a regular bipyramidal geometry with the Li-N distances for the 2.01-2.08-[angstrom] range. Cu(II) is also encapsulated by L; the electronic spectra of the complex show essentially the same features in the solid state and in solution and are diagnostic of a five-coordinate trigonal-bipyramidal structure.

The synthesis and characterization of the new macrotricycle 10,22,28,32-tetraoxa-1,4,7,13,16,18-hexaazatricyclo[17.5.5.57,13]tetratriacontane L is reported. Its basicity in aqueous solution has been investigated by potentiometric and spectroscopic (1H, 13C NMR) techniques. The basicity constants have been determined (25 °C, I= 0.15 mol dm–3) in two ionic media. Macrotricycle L behaves as a hexaprotic base: log K1= 10.27(3), log K2= 9.52(3), log K3= 7.12(3), log K4= 4.62(3), log K5= 2.80(3), log K6= 2.27(3) in NaClO4 and log K1= 10.09(3), log K2= 9.27(3), log K3= 6.54(3), log K4= 4.88(3), log K5= 3.75(3), log K6= 3.07(3) in NaCl. The constants relative to the equilibrium Cl–+ HnLn+⇌ HnLCl(n–1)+ have been measured: n= 5, log K= 2.48(3); n= 6, log K= 3.59(3). The crystal structure of L has been determined by single-crystal X-ray analysis. The compound crystallizes in a triclinic unit cell (space group P, Z= 2) with lattice constants a= 8.984(5), b= 12.122(2), c= 14.667(3)A, α= 109.52(2), β= 105.47(3), γ= 95.24(3)°. Least-squares refinement converged at R= 0.088 (R′= 0.075) for 3198 unique reflections with I > 4σ(I). The structure shows that the molecule has a skewed cylindrical shape, the bases being formed by the two N2O2 macrocycles with the N(CH2CH2)2 chains constituting the walls. The cylindrane L binds two Li+ ions and the resulting complex has been studied by 7Li NMR spectroscopy. Copper(II) and cadmium(II) complexes with L have been investigated in aqueous solution and their stability constants determined by potentiometric techniques. For both metals the following species have been found: [ML]2+, [MLH]3+, [ML(OH)]+ and [ML(OH)2].

The interaction of adenosine 5'-triphosphate, pyrophosphate, and hexacyanoferrate(II) anions with the cyclic polyamines 1,4,7,10,13,16-hexaazacyclooctadecane ([18]aneN 6 ) and 1,4,7,13-tetramethyl-1,4,7,10,13,16-hexaazacyclooctadecane (Me 4 [18]aneN 6 ) and with the open-chain polyamine 1,14-bis(methylamino)-3,6,9,12-tetraazatetradecane (Mezpentaen) has been studied in the pH range 3-10 by potentiometry and cyclic voltammetry

The synthesis of a giant-size polyazamacrocycle 4,34-dimethyl-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46,49,52,55,58-icosaazapentacyclo[56.2.2.27,10.228,31.237,40]octahexacontane (L) is reported together with the crystal structure of its dinuclear cadmium(II) complex [Cd2(H2L)][ClO4]65H2O.

The protonation behaviour of the aza-cyclophane receptor 6,13,15,18-tetramethyl-6,13,15,18-tetraaza-1(1,4),11(1,4)-dibenzena-3(1 ,4),9(1,4)-dipiperazina-cyclodecanonaphane (L2) has been studied in aqueous solution by means of potentiometric and 1H and 13C NMR techniques. L2 behaves as a hexaprotic base and NMR experiments allow the determination of the stepwise protonation sites. Considering the [H5L2]5+ species, the acidic protons occupy alternate positions in the macrocycle, separated by an unprotonated amino group or by a p-phenylene moiety. The crystal structure of [H5L2](ClO4)5·1.5H2O (space group P, a = 8.87(1), b = 15.388(6), c = 20.476(7) A, α = 102.80(3)°, β = 93.43(5)°, γ = 101.41(6)°, V = 2656(3) A3, Z = 2, R = 0.0803) confirms the NMR data, showing one proton located on the N(1) methylated nitrogen and four protons on the amino groups adjacent to the aromatic rings. These features are analogous to those found in the paracyclophane L1, which shows a similar molecular architecture. Binding of ATP and ADP by L1 and L2 was studied by means of potentiometry and 31P NMR in aqueous solution. Although the [H4L1]4+ and the [H5L2]5+ species show a similar charge distribution, [H4L1]4+ forms stable complexes with ATP and ADP, while [H5L2]5+ does not bind such nucleotides. These results may be explained considering the different orientation of the N–H+ bonds in the two receptors.

Proton and Cu(II), Zn(II), Cd(II) and Pb(II) binding by ligand H(2)L, containing two bis(aminoethyl)amine (dien) units connected by a 2',7'-dichlorofluorescein (DCF) unit has been analyzed by means of potentiometric, UV-vis and fluorescence emission measurements. Considering proton binding, the ligand in its fully deprotonated form, L(2-), binds up to four acidic protons in the alkaline pH region. These protonation steps occur on the amine groups, whereas protonation of DCF takes place only below pH 4. In metal complexation, the ligand displays a marked selectivity for Zn(II) over Cd(II) and Pb(II), due to the better accommodation of the smaller and harder Zn(II) ion within the binding pocket generated by a dien unit and the adjacent deprotonated oxygen. The fluorescence emission study points out that Zn(II) binding is accompanied by a marked increase of the DCF emission from neutral to slightly alkaline pH values, where protonated forms of the complex are present in solution. The system is weakly emissive at slightly acidic pH values, where Zn(II) is essentially not bound to the receptor and above pH 9.5, probably due to the formation of the not protonated [ZnL] complex. Cd(II) binding gives rise to a much less intense increase of the emission only above pH 8.5, whereas Cu(II) and Pb(II) complexation leads to fluorescence quenching. Furthermore, the interaction of H(2)L with cells was investigated to explore its application as a new sensor for the evaluation of cellular Zn(II) content and distribution.

Reactive oxygen species produced during allergic inflammation are key players of the pathophysiology of asthma, leading to oxidative tissue injury and inactivation of endogenous manganese superoxide dismutase (MnSOD). On this ground, removal of excess superoxide anion by scavenger molecules would be beneficial and protective. Here we show that a novel manganese(II)-containing polyamine-polycarboxylic compound, termed Mn(II)(Me(2)DO2A), with potent superoxide dismuting properties decreases the respiratory and histopathological lung abnormalities due to allergen inhalation in a model of ovalbumin (OA)-induced allergic asthma-like reaction in sensitized guinea pigs. Severe respiratory dysfunction in response to OA aerosolic challenge arose rapidly in the sensitized animals and was accompanied by bronchoconstriction, alveolar hyperinflation, mast cell activation, increased leukocyte infiltration (evaluated by myeloperoxidase assay), oxidative lung tissue injury (evaluated by the thiobarbituric-acid-reactive substances and nitrotyrosine immunostaining), decay of endogenous MnSOD activity, production of pro-inflammatory prostaglandins, and lung cell apoptosis. Treatment with Mn(II)(Me(2)DO2A) (15mg/kg, given 1h before allergen challenge), but not the inactive congener Zn(II)(Me(2)DO2A) lacking redox-active metal site, significantly attenuated all the above functional, histopathological and biochemical parameters of allergic inflammation and restored the levels of MnSOD activity. In conclusion, our findings support the potential therapeutic use of Mn(II)(Me(2)DO2A) as novel superoxide scavenger drug in asthma and anaphylactic reactions.

A. Introduction 51 B. Macrocycles and macrobicycles able to incorporate several metal ions 52 C. Bis(macrocycles) 71 D. Bridged macrocyclic metal complexes 73 Acknowledgements 83 References 83

The effects of polyammonium macrocycles on the spectroscopic and photochemical properties of the Co(EDTA)−·I− ion-pair have been investigated. The addition of a macrocycle to aqueous solutions containing Co(EDTA)− and I− causes an increase of the absorbance in the region of the ion-pair charge-transfer band, as well as an increase of the quantum yield for the intramolecular photooxidation reduction of the ion-pair. Both these effects are mainly, if not only, due to an increase of the association constant between Co(EDTA)− and I−, caused by the positive charge of the macrocycle bound to the complex. On the contrary no change was observed on the intrinsic photoreactivity of the excited ion-pair. This last result is discussed in comparison with the effects already observed on the ligand photodissociation of MC excited states of Co(III) cyanide complexes.

A series of polyammonium macrocycles, ranging in size from the 18-membered ring [18]aneN6 to the 36-membered [36]aneN12 were examined as potential ATPase mimics. The rates of hydrolysis of ATP were followed at pH 3.0 and 7.0 using 31P NMR and HPLC techniques. Stability constants as a function of degree of protonation, distribution curves for the ligands as a function of pH, and distribution curves for the mixed species of nucleotides, inorganic phosphate, and macrocycle were also determined. All of the macrocycles catalyzed the hydrolysis of ATP to some extent compared to noncatalyzed hydrolysis. A critical dependence on macrocyclic ring size was observed, with [21]aneN7 being the best catalyst at both pHs. Stability constants of the complexes formed between the phosphate species and macrocycle increase with increasing degree of protonation and decreasing ring size. The trend in stability constants for phosphate species was found to be PO43− > P2O74− > ATP4− > ADP3− > AMP2− for a given degree of protonation. The crystal structure of tetraprotonated [21]aneN7 was determined. The compound N7C14Cl4H41O crystallizes in the monoclinic space group P21 (#4) with unit cell dimensions a = 7.472(1), b = 19.480(2), c = 8.3638(9) A , β = 100.38(1)o, and V = 1197.4(3) A 3 . The structure was solved by direct methods and refined using full-matrix least-squares techniques to give a final R = 0.041 and Rw = 0.055.

The interactions of the cyclic polyazaalkanes 1,4,7,10,13,16,19-heptaazacyclohenicosane, 1,4,7,10,13,16,19,22-octaazacyclotetracosane and of the open-chain counterparts 1,17-bis(methylamino)-3,6,9,12,15-pentaazaheptadecane and 1,20-bis(methylamino)-3,6,9,12,15,18-hexaazaicosane with the complex anions hexacyanoferrate(II) and hexacyanocobaltate(III) have been studied at 298.15 K in 0.15 mol dm–3 NaClO4 by using potentiometric and electrochemical techniques. Both types of polyamines, cyclic and linear, form stable complexes with 1 : 1 anion : receptor stoichiometry. This result has been obtained either by treatment of electromotive force data with the computer program SUPERQUAD or by analysing the variations of [Fe(CN)6]3––[Fe(CN)6]4– voltammograms with the ratio [Fe(CN)6]4– : polyamine. A macrocyclic effect for anion binding is observed, namely the stability of the ‘super-complexes’ of the cyclic ligands is higher than those formed by their open-chain counterparts. Both types of ligands interact more strongly with [Fe(CN)6]4– than with [Co(CN)6]3–. From the electrochemical measurements it has been estimated that the affinity of [Fe(CN)6]3– for these polyammonium receptors is similar to that presented by the equally charged complex anion [Co(CN)6]3–.

International audience; Synthesis, characterisation and proton-sponge behaviour of a new linear constrained tris-macrocycle (L), containing three cyclen (cyclen = 1,4,7,10-tetraazacyclododecane) reinforced macrocycles connected by two 2,6-pyridinediylbis(methylene) linkers, is reported. Protonated forms of L are efficient receptors for inorganic phosphate and nucleotide anions (ATP and ADP). The binding properties of L toward these substrates have been investigated in aqueous solution by means of potentiometric titrations, determining the stability constants of the adducts. The interaction mode was clarified by using 1H and 31P NMR measurements in aqueous solution and by means of molecular modelling calculations carried out on differently protonated species of L as well as on several nucleotide-receptor adducts. The stability of the adducts is mainly due to charge-charge and hydrogen bonding interactions between the polyphosphate chain of nucleotides and the ammonium groups of L.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)