Eleonora Macedi

A Macrocyclic Ligand as Receptor and ZnII‐Complex Receptor for Anions in Water: Binding Properties and Crystal Structures

Binding properties of 24,29-dimethyl-6,7,15,16-tetraoxotetracyclo[19.5.5.0(5,8).0(14,17)]-1,4,9,13,18,21,24,29-octaazaenatriaconta-Δ(5,8),Δ(14,17)-diene ligand L towards Zn(II) and anions, such as the halide series and inorganic oxoanions (phosphate (Pi), sulfate, pyrophosphate (PPi), and others), were investigated in aqueous solution; in addition, the Zn(II)/L system was tested as a metal-ion-based receptor for the halide series. Ligand L is a cryptand receptor incorporating two squaramide functions in an over-structured chain that connects two opposite nitrogen atoms of the Me(2)[12]aneN(4) polyaza macrocyclic base. It binds Zn(II) to form mononuclear species in which the metal ion, coordinated by the Me(2)[12]aneN(4) moiety, lodges inside the three-dimensional cavity. Zn(II)-containing species are able to bind chloride and fluoride at the physiologically important pH value of 7.4; the anion is coordinated to the metal center but the squaramide units play the key role in stabilizing the anion through a hydrogen-bonding network; two crystal structures reported here clearly show this aspect. Free L is able to bind fluoride, chloride, bromide, sulfate, Pi, and PPi in aqueous solution. The halides are bound at acidic pH, whereas the oxoanions are bound in a wide range of pH values ranging from acidic to basic. The cryptand cavity, abundant in hydrogen-bonding sites at all pH values, allows excellent selectivity towards Pi to be achieved mainly at physiological pH 7.4. By joining amine and squaramide moieties and using this preorganized topology, it was possible, with preservation of the solubility of the receptor, to achieve a very wide pH range in which oxoanions can be bound. The good selectivity towards Pi allows its discrimination in a manner not easily obtainable with nonmetallic systems in aqueous environment.

Efficient fluorescent sensors based on 2,5-diphenyl[1,3,4]oxadiazole: a case of specific response to Zn(II) at physiological pH.

The coordination properties and photochemical responses of three fluorescent polyamine macrocycles, 9,12,15,24,25-pentaaza-26-oxatetracyclo[21.2.1.0(2,7).0(17,22)]hexaicosa-2,4,6,17,19,21,23,25(1)-octaene (L1), 9,12,15,18,27,28-hexaaza-29-oxatetracyclo[24.2.1.0(2,7).0(20,25)]enneicosa-2,4,6,20,22,24,26,28(1)-octaene (L2), and 9,12,15,18,21,30,31-heptaaza-32-oxatetracyclo[27.2.1.0(2,7).0(23,28)]diatriconta-2,4,6,23,25,27,29,31(1)-octaene (L3), toward Cu(II), Zn(II), Cd(II), and Pb(II) are reported. Each ligand contains the 2,5-diphenyl[1,3,4]oxadiazole (PPD) moiety inserted in a polyamine macrocycle skeleton. The stability constants were determined by means of potentiometric measurements in aqueous solution. L1 forms mononuclear complexes only with Cu(II). L2 and L3 form stable mononuclear species with all of the metals, while L3 is able to form dinuclear Cu(II) species. The fluorescence of all ligands was totally quenched by the presence of Cu(II). L2 behaves as an OFF-ON sensor for Zn(II) under physiological conditions, even in the presence of interfering species such as Cd(II) and Pb(II). This ligand combines selective binding of Zn(II) with a highly specific fluorescent response to Zn(II) due to the chelating enhancement of fluorescence (CHEF) effect. The interaction of Zn(II), Cd(II), and Pb(II) with L3 does not produce an appreciable enhancement of fluorescence at the same pH. The different behavior is attributed to the cavity size of the macrocycle and to the number of amine functions. L2 possesses the best arrangement of these two characteristics, allowing a full participation of all of the amine functions in metal coordination, as shown by the crystal structures of [CuL2(ClO(4))](ClO(4))·H(2)O and [ZnL2Br]Br·H(2)O species; this prevents the PET effect and supplies the higher CHEF effect. The interaction between L2 and Zn(II) can also be observed with the naked eye as an intense sky blue emission.

A new versatile solvatochromic amino-macrocycle. From metal ions to cell sensing in solution and in the solid state

A new fluorescent NBD-polyaza-macrocycle sensor (L) was synthesized. The coordination of Cu(ii) and Zn(ii) in acetonitrile switches on the fluorescence with different emission wavelengths. Cu(ii) complexes showed solid-state fluorescence. Both L and Cu-complex interact with human cell line (U937) highlighting the cell membrane by fluorescence microscopy.

New branched macrocyclic ligand and its side-arm, two urea-based receptors for anions: synthesis, binding studies and crystal structure

The synthesis and characterization of the two new hosting molecules for anions 4(N),10(N)-bis-[2-(4-nitrophenylureido)acetamido]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane (L1) and 1-((diethylcarbamoyl)methyl)-3-(4-nitrophenyl)urea (L2) are reported. L1 is a branched tetraazamacrocycle bearing two p-nitrophenylureido groups as side-arms, whereas L2 has the same linear chain and binding moiety of L1 side-arm. The best synthetic routes for use in obtaining L1 were explored, affording the synthesis of the new intermediate 4, a versatile building block for further functionalized branched macrocyclic hosts. The binding properties of both ligands towards the halides series and acetate anions (G) were investigated by NMR and UV-Vis spectroscopy in a dimethyl sulfoxide–0.5% water solution. Both ligands interact with F−, Cl− and AcO− while Br− and I− did not. The NMR experiments proved that the binding occurs via H-bond to the ureido fragments. Fluoride anion is basic enough to deprotonate the ureido group of both ligands, thus preventing the determination of the addition constants to both ligands; this was instead possible for Cl− and AcO−. L1 forms G–L species of 1 : 1 ([GL1]) and 2 : 1 ([G2L1]) stoichiometry while L2 forms only the 1 : 1 [GL2] species. The higher value of the formation constant of the [AcOL1]−vs. the [AcOL2]− species (log K = 5.5 vs. 2.8 for the reaction AcO− + L = AcOL−) suggested that both side-arms of L1 cooperate in binding acetate; this does not occur with Cl−. The results confirmed that this tetraaza-macrocyclic base acts as a preorganizing scaffold for side-arms when they are linked to it via an amide function. The crystal structure of L2·H2O is also reported.

Multi-use NBD-based tetra-amino macrocycle: fluorescent probe for metals and anions and live cell marker.

Ligand L (4-(7-nitrobenzo[1,2,5]oxadiazole-4-yl)-1,7-dimethyl-1,4,7,10-tetra-azacyclododecane) is a versatile fluorescent sensor useful for Cu(II), Zn(II) and Cd(II) metal detection, as a building block of fluorescent metallo-receptor for halide detection, and as an organelle marker inside live cells. Ligand L undergoes a chelation-enhanced fluorescence (CHEF) effect upon metal coordination in acetonitrile solution. In all three complexes investigated the metal cation is coordinatively unsaturated; thus, it can bind secondary ligands as anionic species. The crystal structure of [ZnLCl](ClO(4)) is discussed. Cu(II) and Zn(II) complexes are quenched upon halide interaction, whereas the [CdL](2+) species behaves as an OFF-ON sensor for halide anions in acetonitrile solution. The mechanism of the fluorescence response in the presence of the anion depends on the nature of the metal ion employed and has been studied by spectroscopic methods, such as NMR spectroscopy, UV/Vis and fluorescence techniques and by computational methods. Subcellular localization experiments performed on HeLa cells show that L mainly localizes in spot-like structures in a polarized portion of the cytosol that is occupied by the Golgi apparatus to give a green fluorescence signal.

Polynuclear Complexes: Two Amino−Phenol Macrocycles Spaced by Several Linear Polyamines; Synthesis, Binding Properties, and Crystal Structure

The synthesis and characterization of the new polytopic ligands 1,14-bis(3,6,9-triaza-15-hydroxybicyclo[9.3.1]pentadeca-11,13,1(15)-trien-6-yl)-3,6,9,12-tetraazatetradecane L1, 1,15-bis(3,6,9-triaza-15-hydroxybicyclo[9.3.1]pentadeca-11,13,1(15)-trien-6-yl)-3,6,10,13-tetraazapentadecane L2, and 1,16-bis(3,6,9-triaza-15-hydroxybicyclo[9.3.1]pentadeca-11,13,1(15)-trien-6-yl)-3,7,10,14-tetraazahexadecane L3, containing two equal amino-phenol macrocycles spaced by several linear tetraamines, are reported. The basicity and coordination behavior toward the Cu(II) ion were potentiometrically determined in aqueous solution at 298.1 K. All the ligands show similar acid-base properties behaving as octaprotic bases in the examined pH range (pH = 2-12). The acid protons of L1-L3 cannot be removed under the experimental conditions used; thus, the main deprotonated species obtainable in aqueous solution are the neutral ligands, having amphionic character as demonstrated by UV-vis experiments. These species are able to form mono-, di-, and trinuclear Cu(II) complexes having stoichiometry [CuL](2+), [Cu(2)L](4+), and [Cu(3)L](6+), respectively, that can lose one or two protons giving rise to [CuH(-1)L](+), [Cu(2)H(-2)L](2+), and [Cu(3)H(-2)L](4+). Depending on the used ligand to metal molar ratio, the mono-, di-, or trinuclear species prevail over the others in solution. Both di- and trinuclear complexes are able to add secondary ligands (such as OH(-)), and in some cases two Cu(II) can cooperate to stabilize them by coordinating the guest in a bridged conformation. The structure of the [Cu(2)L3](4+) cation was resolved by X-ray analysis of the {[Cu(2)L3](ClO(4))(4) x 3 H(2)O}(2) x H(2)O crystalline complex. It shows that each Cu(II) is penta-coordinated by one phenolate oxygen, two amine functions, belonging to one macrocyclic unit, and two amine functions of the spacer; in this species the distance between the two Cu(II) is about 5.3 A.

Modulating the Sensor Response to Halide Using NBD-Based Azamacrocycles

Ligand L (2,6-bis{[7-(7-nitrobenzo[1,2,5]oxadiazole-4-yl)-3,10-dimethyl-1,4,7,10-tetraazacyclododeca-1-yl]methyl}phenol) is a fluorescent sensor that is useful for detecting Cu(II), Zn(II), and Cd(II). Some of the complexes formed are able to sense the presence of halides in solution. L passes through the cellular membrane, becoming fluorescent inside cells. The H(-1)L- species is able to form dinuclear complexes with [M(2)H(-1)L]3+ stoichiometry with Cu(II), Zn(II), and Cd(II) ions, experiencing a CHEF effect upon metal coordination in an acetonitrile/water 95:5 (v/v) solution. In all three of the complexes investigated, the metal cations are coordinatively unsaturated and can therefore bind secondary ligands as anionic species. The crystal structure of [Cd(2)(H(-1)L)Cl(2)](ClO(4))·4H(2)O is discussed. The Zn(II) complex behaves as an OFF-ON sensor for fluoride and chloride anions.

New family of polyamine macrocycles containing 2,5-diphenyl[1,3,4]oxadiazole as a signaling unit. Synthesis, acid-base and spectrophotometric properties.

Synthesis and acid-base properties for three fluorescent polyamine macrocycles 9,12,15,24,25-pentaaza-26-oxatetracyclo[21.2.1.0(2,7).0(17,22)]hexaicosa-2,4,6,17,19,21,23,25(1)-octaene (L1), 9,12,15,18,27,28-hexaaza-29-oxatetracyclo[24.2.1.0(2,7).0(20,25)]enneicosa-2,4,6,20,22,24,26,28(1)-octaene (L2) and 9,12,15,18,21,30,31-heptaaza-32-oxatetracyclo[27.2.1.0(2,7).0(23,28)]diatriconta-2,4,6,23,25,27,29,31(1)-octaene (L3) are reported. Each ligand contains the 2,5-diphenyl[1,3,4]oxadiazole (PPD) unit incorporated in the polyamine macrocycle. The protonation constants of L1-L3 were determined by means of potentiometric measurements in 0.15 mol dm(-3) NaCl aqueous solution at 298.1 K. All the ligands are highly fluorescent in aqueous solution under acidic conditions (pH < 2) and their emission drastically decreases when the pH is increased. At pH > 8, a total quenching of fluorescence is observable in all the ligands. The fluorescence is given by the PPD unit, while the behavior as a function of pH can be rationalized on the basis of photoinduced intramolecular electron transfer (PET) from the HOMO of the donor macrocycle nitrogen atoms to the excited fluorophore unit. The insertion of PPD in a polyamine skeleton strongly improves the fluorescence quantum yield of this class of ligands with respect to those already known.

Two polyaminophenolic fluorescent chemosensors for H+ and Zn(II). Spectroscopic behaviour of free ligands and of their dinuclear Zn(II) complexes

The UV-Vis and fluorescence optical properties of the two polyamino-phenolic ligands 3,3′-bis[N,N-bis(2-aminoethyl)aminomethyl]-2,2′-dihydroxybiphenyl (L1) and 2,6-bis{[bis(2-aminoethyl)amino]methyl}phenol (L2) were investigated in aqueous solution at different pH values as well as in the presence of Zn(II) metal ion. Both ligands show two diethylenetriamine units separated by the 1,1′-bis(2-phenol) (BPH) or the phenol (PH) for L1 and L2, respectively. Both ligands are fluorescence-emitting systems in all fields of pH examined, with L1 showing a higher fluorescence emission than L2. In particular, the emission of fluorescence mainly depends on the protonation state of the phenolic functions and thus on pH. The highest emitting species is H3L3+ for both systems, where the BPH is monodeprotonated (in L1) and the PH is in the phenolate form (in L2). On the contrary, when BPH and PH are in their neutral form both ligands show the lowest fluorescence, since H-bonds occurring between the phenol and the closest tertiary amine functions decrease fluorescence. The Zn(II)-dinuclear species are also fluorescent in the pH range where they exist; the highest emitting species being [Zn2(H−2L1)]2+ and [Zn2(H−1L2)]3+ which are present in a wide range of pH including the physiological one. Fluorescence experiments carried out at physiological pH highlighted that, in the case of L1, the presence of Zn(II) ion in solution produces a simultaneous change in λem with a drop in fluorescence due to the formation of the [Zn2(H−2L1)]2+ species, while, in the case of L2, it gives rise to a strong CHEF effect (a twenty-fold enhancement was observed) due to the formation of the [Zn2(H−1L2)]3+ species. These results, supported by potentiometric, 1H and 13C NMR experiments, are of value for the design of new efficient fluorescent chemosensors for both H+ and Zn(II) ions.

Pd(II) and Pt(II) complexes with a thio-aza macrocycle ligand containing an intercalating fragment: Structural and antitumor activity studies.

Two new PtII and PdII complexes of formula [LMCl2] (M=Pt, Pd) were synthesized and characterized both in solution and solid state. They were obtained using the thio-aza macrocycle 9,18-dimethyl-12,17dithia-9,18,27,28-tetraaaza-29-oxatetracyclo[24.2.1.02,7.020,25]enneicosa-2,4,6,20,22,24,26,281-octaene (L) containing the 2,5-diphenyl [1, 3, 4]oxadiazole as intercalating fragment. MII is coordinated in cis-position by the two S atoms of L. The two crystal structures of [LPtCl2] and [LPdCl2] complexes showed that the MII ion is located outside the macrocyclic cavity. The square planar coordination sphere is fulfilled by two chloride anions in a cisplatin-like arrangement with the chloride leaving groups exposed to the environment. The biological activity of both [LPtCl2] and [LPdCl2], monitored towards a leukemic cellular model (U937), is coherent with their ability to interfere, at different levels, with the DNA structure.