Luís M. P. Lima

Monopicolinate cyclen and cyclam derivatives for stable copper(II) complexation.

The syntheses of a new 1,4,7,10-tetraazacyclododecane (cyclen) derivative bearing a picolinate pendant arm (HL1), and its 1,4,8,11-tetraazacyclotetradecane (cyclam) analogue HL2, were achieved by using two different selective-protection methods involving the preparation of cyclen-bisaminal or phosphoryl cyclam derivatives. The acid-base properties of both compounds were investigated as well as their coordination chemistry, especially with Cu(2+), in aqueous solution and in solid state. The copper(II) complexes were synthesized, and the single crystal X-ray diffraction structures of compounds of formula [Cu(HL)](ClO(4))(2)·H(2)O (L = L1 or L2), [CuL1](ClO(4)) and [CuL2]Cl·2H(2)O, were determined. These studies revealed that protonation of the complexes occurs on the carboxylate group of the picolinate moiety. Stability constants of the complexes were determined at 25.0 °C and ionic strength 0.10 M in KNO(3) using potentiometric titrations. Both ligands form complexes with Cu(2+) that are thermodynamically very stable. Additionally, both HL1 and HL2 exhibit an important selectivity for Cu(2+) over Zn(2+). The kinetic inertness in acidic medium of both complexes of Cu(2+) was evaluated by spectrophotometry revealing that [CuL2](+) is much more inert than [CuL1](+). The determined half-life values also demonstrate the very high kinetic inertness of [CuL2](+) when compared to a list of copper(II) complexes of other macrocyclic ligands. The coordination geometry of the copper center in the complexes was established in aqueous solution from UV-visible and electron paramagnetic resonance (EPR) spectroscopy, showing that the solution structures of both complexes are in excellent agreement with those of crystallographic data. Cyclic voltammetry experiments point to a good stability of the complexes with respect to metal ion dissociation upon reduction of the metal ion to Cu(+) at about neutral pH. Our results revealed that the cyclam-based ligand HL2 is a very attractive receptor for copper(II), presenting a fast complexation process, a high kinetic inertness, and important thermodynamic and electrochemical stability.

Positively Charged Lanthanide Complexes with Cyclen-Based Ligands: Synthesis, Solid-State and Solution Structure, and Fluoride Interaction

The syntheses of a new cyclen-based ligand L(2) containing four N-[2-(2-hydroxyethoxy)ethyl]acetamide pendant arms and of its lanthanide(III) complexes [LnL(2)(H(2)O)]Cl(3) (Ln = La, Eu, Tb, Yb, or Lu) are reported, together with a comparison with some Ln(III) complexes of a previously reported analogue L(1) in which two opposite amide arms have been replaced by coordinating pyridyl units. The structure and dynamics of the La(III), Lu(III), and Yb(III) complexes in solution were studied by using multinuclear NMR investigations and density functional theory calculations. Luminescence lifetime measurements in H(2)O and D(2)O solutions of the [Ln(L(2))(H(2)O)](3+) complexes (Ln = Eu or Tb) were used to investigate the number of H(2)O molecules coordinated to the metal ion, pointing to the presence of an inner-sphere H(2)O molecule in a buffered aqueous solution. Fluoride binding to the latter complexes was investigated using a combination of absorption spectroscopy and steady-state and time-resolved luminescence spectroscopy, pointing to a surprisingly weak interaction in the case of L(2) (log K = 1.4 ± 0.1). In contrast to the results in solution, the X-ray crystal structure of the lanthanide complex showed the ninth coordination position occupied by a chloride anion. In the case of L(1), the X-ray structure of the [(EuL(1))(2)F] complex features a bridging fluoride donor with an uncommon linear Eu-F-Eu entity connecting two almost identical [Eu(L(1))](3+) units. Encapsulation of the F(-) anion within the two complexes is assisted by π-π stacking between the pyridyl rings of two complexes and C-H···F hydrogen-bonding interactions involving the anion and the pyridyl units.

Monopicolinate-dipicolyl derivative of triazacyclononane for stable complexation of Cu2+ and 64Cu2+.

The synthesis and characterization of Hno1pa2py, a new tacn-based ligand, is reported. The complexation process with Cu(2+) was proved to be very fast even in acidic medium. Potentiometric titrations allowed us to establish that Hno1pa2py exhibits an overall low basicity as well as a high selectivity for Cu(2+) over Zn(2+) cations. The copper(II) complex was synthesized and characterized using UV-vis and EPR spectroscopies and density functional theory (DFT) calculations. The studies clearly showed that the [Cu(no1pa2py)](+) complex is present in solution as a mixture of two isomers in which the ligand is coordinated to the metal center using a N5O donor set with the metal center in a distorted octahedral geometry. The very high kinetic inertness of the [Cu(no1pa2py)](+) complex was demonstrated by using acid-assisted dissociation assays as well as cyclic voltammetry. Preliminary investigations of (64)Cu complexation were performed to validate the potential use of such chelating agent for further application in nuclear medicine. The X-ray crystal structures of copper(II) complexes of L1, the ester derivative of Hno1pa2py, have been determined.

Lanthanide complexes of macrocyclic derivatives useful for medical applications

The protonation constants of two series of tetraazamacrocyclic ligands with acetate and methylphosphonate pendant arms, as well as their stability constants with Cu2+, La3+, Sm3+, and Ho3+, were determined. All the values were determined in aqueous solution at 298.0 K and 0.10 mol dm–3 in N(CH3)4NO3. In the first series, the effect of both types of pendant arms was observed by appending them in the same macrocyclic backbone, a 14-membered tetraazamacrocycle containing pyridine (ac3py14, p2py14, and p3py14). In the second series, two effects were taken into account, the increase of the cavity size of the macrocycle, from 12- to 14-membered, and the appending of acetate (dota, trita, and teta) or methylphosphonate (dotp, tritp, and tetp) arms. The ligands containing methylphosphonate arms have higher thermodynamic stability compared to the corresponding ones with acetate arms, especially in the series of compounds containing pyridine, even upon correction of the different basicity values of the ligands. On the other hand, the ligands with smaller macrocyclic cavity size, namely, dota and dotp, exhibit the largest values of stability constants. In contrast, ac3py14 presents low stability constants with lanthanides. An interpretation of these features based on the known adopted arrangement of dota and teta when free or coordinated with lanthanides is evaluated.

Monopicolinate Cross-Bridged Cyclam Combining Very Fast Complexation with Very High Stability and Inertness of Its Copper(II) Complex

The synthesis of a new cross-bridged 1,4,8,11-tetraazacyclotetradecane (cb-cyclam) derivative bearing a picolinate arm (Hcb-te1pa) was achieved by taking advantage of the proton sponge properties of the starting constrained macrocycle. The structure of the reinforced ligand as well as its acid-base properties and coordination properties with Cu(2+) and Zn(2+) was investigated. The X-ray structure of the free ligand showed a completely preorganized conformation that lead to very fast copper(II) complexation under mild conditions (instantaneous at pH 7.4) or even in acidic pH (3 min at pH 5) at room temperature and that demonstrated high thermodynamic stability, which was measured by potentiometry (at 25 °C and 0.10 M in KNO3). The results also revealed that the complex exists as a monopositive copper(II) species in the intermediate pH range. A comparative study highlighted the important selectivity for Cu(2+) over Zn(2+). The copper(II) complex was synthesized and investigated in solution using different spectroscopic techniques and DFT calculations. The kinetic inertness of the copper(II) complex in acidic medium was evaluated by spectrophotometry, revealing the very slow dissociation of the complex. The half-life of 96 days, in 5 M HClO4, and 465 min, in 5 M HCl at 25 °C, show the high kinetic stability of the copper(II) chelate compared to that of the corresponding complexes of other macrocyclic ligands. Additionally, cyclic voltammetry experiments underlined the perfect electrochemical inertness of the complex as well as the quasi-reversible Cu(2+)/Cu(+) redox system. The coordination geometry of the copper center in the complex was established in aqueous solution from UV-vis and EPR spectroscopies.

Cyclam derivatives containing three acetate pendant arms: synthesis, acid–base, metal complexation and structural studies

The ligands 1,4,8,11-tetraazacyclotetradecane-1,4,8-triacetic-11-methylphosphonic acid (H5te3a1p) and 1,4,8,11-tetraazacyclotetradecane-1,4,8-triacetic acid (H3te3a) were synthesized, the former one for the first time. The syntheses of these ligands were achieved from reactions on 1,4,8,11-tetraazacyclotetradecane-1,4,8-tris(carbamoylmethyl) hydroiodide (te3am x HI), and compounds (Hte3am)+, 1, and (H7te3a1p)2+, 4, were characterized by X-ray diffraction. Structures of two other compounds resulting from side-reactions, (H2te2lac)2+, 2, and (H4te2a2pOEt2)2+, 4, were also determined by X-ray diffraction. Potentiometric titrations of H5te3a1p and H3te3a were performed at 298.2 K and ionic strength 0.10 mol dm(-3) in NMe4NO3 to determine their protonation constants. 1H and 31P NMR titrations of H5te3a1p were carried out in order to determine the very high first protonation constant of this ligand and to elucidate the sequence of protonation. Potentiometric studies of the two ligands with Ca2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+ and Pb2+ metal ions performed in the same experimental conditions showed that the complexes of H5te3a1p present very high thermodynamic stability while complexes of H3te3a, particularly Co2+ and Zn2+, are even more stable. 31P NMR spectra of the cadmium(II) complex of H5te3a1p showed that the phosphonate moiety was coordinated to the metal ion. The UV-vis-NIR spectroscopic data and magnetic moment values of Co2+ and Ni2+ complexes of H5te3a1p and H3te3a together with the EPR of the corresponding Cu2+ complexes indicated that all these complexes adopt distorted octahedral coordination geometries in solution. This was confirmed by the single crystal structure of [Cu2(Hte3a)(H2O)3Cl]Cl0.5(ClO4)0.5 x 2H2O that showed two distorted octahedral copper centres bridged by a N-acetate pendant arm with a CuCu distance of 4.890(1) A. The first one is encapsulated into the macrocyclic cavity surrounded by four nitrogen and two oxygen donors from the macrocycle, whereas the second one is on the periphery of the macrocycle and is coordinated to two oxygen atoms of one acetate pendant arm in chelating fashion, one chloride and three water molecules.

Bis- and tris-(methylphosphonic) acid derivatives of a 14-membered tetraazamacrocycle containing pyridine: synthesis, protonation and complexation studies

Two N-methylphosphonic acid derivatives of a 14-membered tetraazamacrocycle containing pyridine have been synthesized, H(4)L(1) and H(6)L(2). The protonation constants of these compounds and the stability constants of complexes of both ligands with Ni(2+), Cu(2+) and Zn(2+) were determined by potentiometric methods at 298 K and ionic strength 0.10 mol dm(-3) in NMe(4)NO(3). The high overall basicity of both compounds is ascribed to the presence of the phosphonate arms. (1)H and (31)P NMR spectroscopic titrations were performed to elucidate the sequence of protonation, which were complemented by conformational analysis studies. The complexes of these ligands have stability constants of the order of or higher than those formed with ligands having the same macrocyclic backbone but acetate arms. At pH = 7 the highest pM values were found for solutions containing the compound with three acetate groups, followed immediately by those of H(6)L(2), however, as expected, the increasing pH favours the complexes of ligands containing phosphonate groups. The single-crystal structure of Na(2)[Cu(HL(1))]NO(3)x8H(2)O has shown that the coordination geometry around the copper atom is a distorted square pyramid. Three nitrogen atoms of the macrocyclic backbone and one oxygen atom from one methylphosphonate arm define the basal plane, and the apical coordination is accomplished via the nitrogen atom trans to the pyridine ring of the macrocycle. To achieve this geometric arrangement, the macrocycle adopts a folded conformation. This structure seems consistent with Uv-vis-NIR spectroscopy for the Ni(2+) and the Cu(2+) complexes and with the EPR for the latter.

TETA analogue containing one methylenephosphonate pendant arm: Lanthanide complexes and biological evaluation of its 153Sm and 166Ho complexes.

The thermodynamic stability constants of complexes of 1,4,8,11-tetraazacyclotetradecane-1,4,8-triacetic-11-methylphosphonic acid (H5te3a1p) with La3+, Sm3+, Gd3+, Ho3+ and Lu3+ metal ions were determined by potentiometric titrations at 298.2 K and with ionic strength 0.10 M in N(CH3)4NO3. The complexes are formed relatively fast and the stability constants exhibited are good although lower than those found for the related ligands H4teta and H8tetp. At physiological pH the completely deprotonated complex species predominate, unlike what happens with the other mentioned ligands. The 153Sm and 166Ho complexes, 153Sm/166Ho-te3a1p, were synthesised quantitatively at pH 9 and 70 °C, and have shown good in vitro stability in human serum and physiological solutions except phosphate buffer (pH 7.4). The in vivo behaviour indicated that both complexes have a similar biological pattern, showing a slow tissue clearance, slow rate of total radioactivity excretion and some in vivo instability, although with some differences in their extend. These results indicate that the replacement of one acetate pendant arm of H4teta by a methylphosphonate one does not provide promising chelators to stabilize radiolanthanides for in vivo application.

Cyclen derivatives with two trans-methylnitrophenolic pendant arms: a structural study of their copper(II) and zinc(II) complexes

Two new cyclen derivatives, H(2)do2nph and H(2)cb-do2nph, containing two trans-2-methyl-4-nitrophenol pendant arms and the latter including also an ethylene cross-bridge, were prepared in good yields using the bisaminal synthetic route. The two ligands were studied comparatively regarding their metal complexation behaviour. The copper(II) and zinc(II) complexes of H(2)do2nph and H(2)cb-do2nph were studied in dimethylsulfoxide-water (9 : 1 v/v) solution by a range of spectroscopic techniques. Copper(II) complexes were also studied in solid state by X-ray single crystal diffraction. These studies showed that the copper(II) and zinc(II) complexes of H(2)do2nph exhibited a distorted square pyramidal coordination environment with the four nitrogen atoms of the cyclen ring defining the basal plane, and that one of the nitrophenolate arms did not coordinate to the metal, independently of its protonation state. On the other hand, depending on the protonation state of one of the nitrophenolic arms, the cross-bridged derivative forms copper(II) complexes with distorted square pyramidal or octahedral geometries with one or two arms coordinated to the metal centre, respectively. In the complex with distorted octahedral geometry, the two phenolic oxygen atoms are coordinated to the metal centre in a cis-fashion. Acid-assisted dissociation assays in 1 mol dm(-3) HCl DMSO-H(2)O (9 : 1 v/v) solution at 298.2 K allowed one to determine the half-life of both copper(II) complexes, which is lower for the derivative without a cross-bridge as expected, while for the other one it is quite high and in line with similar cross-bridged cyclen derivatives from the literature.

Cyclams with Ambidentate Methylthiazolyl Pendants for Stable, Inert, and Selective Cu(II) Coordination

Aiming to develop new copper chelates for application in nuclear medicine we report two new chelators, te1th and te2th, based on a cyclam backbone mono-N- or di-N1,N8-functionalized by methylthiazolyl arms. The acid-base properties of both ligands were investigated as well as their coordination chemistry, especially with Cu(2+), when possible in aqueous solution and in the solid state. Single-crystal X-ray diffraction structures of complexes were determined. Stability constants of the copper(II) and zinc(II) complexes showed that the complexes of both ligands with Cu(2+) are thermodynamically very stable, and they exhibit an important selectivity for Cu(2+) over Zn(2+). The kinetic inertness in acidic medium of both copper(II) complexes was evaluated revealing a quite good resistance to dissociation (the half-life times of complexes with te1th and te2th are 50.8 and 5.8 min, respectively, in 5 M HCl and 30 °C). The coordination geometry of the metal center in the complexes was established in aqueous solution based on UV-visible, electron paramagnetic resonance (EPR) spectroscopy, DFT studies, and NMR by using the zinc(II) complex analogues. The [Cu(te1th)](2+) and [Cu(te2th)](2+) complexes adopt trans-I and trans-III configurations both in the solid state and in solution, while the [Zn(te2th)](2+) complex crystallizes as the cis-V isomer but exists in solution as a mixture of trans-III and cis-V forms. Cyclic voltammetry experiments in acetonitrile point to a relatively easy reduction of [Cu(te2th)](2+) in acetonitrile solution (Epc = -0.41 V vs NHE), but the reduced complex does not undergo dissociation in the time scale of our electrochemical experiments. The results obtained in these studies revealed that despite the limited solubility of its copper(II) chelate, te2th is an attractive chelator for Cu(2+) that provides a fast complexation process while forming a complex with a rather high thermodynamic stability and kinetic inertness with respect to dissociation even upon electrochemical reduction.