João D. G. Correia

Multiple bonds between main-group elements and transition metals. Part 133. Methyltrioxorhenium as a catalyst of the Baeyer-Villiger oxidation☆

Methyltrioxorhenium CH3ReO3 (MTO, 1) is one of the most active catalysts of the Baeyer-Villiger oxidation of cyclic ketones by use of H2O2 as oxidant. In contrast to the chemistry of established molybdenum and tungsten peroxo complexes, the bis(peroxo) complex [CH3ReO(O2)2·H2O] reacts stoichiometrically with ketones. The electronic character of the active species was determined by spectroscopy and by application of an oxygen transfer probe.

MULTIPLE BONDS BETWEEN TRANSITION METALS AND MAIN-GROUP ELEMENTS, 163. NITROGEN-DONOR ADDUCTS OF ORGANORHENIUM(VII) OXIDES : STRUCTURAL AND CATALYTIC ASPECTS

Abstract N-base adducts of methyltrioxorhenium(VII) (1), characterized by their structural and spectroscopic data, are compared with respect to the influence of the pKb values of the N-bases. The crystal structure of one of these derivatives, namely the adduct of Trogers base ((5R,11R)-(+)−2,8-dimethyl-6H,12H-5,11-methanodibenzo[b,f]-[1,5]diazocine) with compound 1 (2a) is reported. The cell constants are as follows: a = 1281.6(2)pm, b = 833.9(1)pm, c = 1705.5(2)pm, β = 106.09(1)°, V = 1751.2(4) × 106 pm3. Derivative 2a exhibits the longest Re(VII)-N bond distance known to date. Furthermore, 2a is the first adduct of Trogers base whose structure has been examined by X-ray crystallography. Epoxidation and sulfoxidation catalysis with N-base adducts of 1 is described, the influence of the Re-N bond strength on the catalytic processes is discussed.

Bisphosphonates as radionuclide carriers for imaging or systemic therapy

Bisphosphonates (BPs), biologically stable analogs of naturally occurring pyrophosphates, became the treatment of choice for pathologic conditions characterized by increased osteoclast-mediated bone resorption, namely Pagets disease, osteoporosis and tumor bone disease. Moreover, the clinical success of BPs is also associated with their use in (99m)Tc-based radiopharmaceuticals for bone imaging. In addition to the successful delivery of (99m)Tc (γ-emitter) to bone, BPs have also been used to deliver β(-)-particle emitting radiometals (e.g.(153)Sm, (186/188)Re) for bone-pain palliation. The main goal of this Review is to update the most recent research efforts toward the synthesis, characterization and biological evaluation of novel BP-containing radiometal complexes and radiohalogenated compounds for diagnostic or therapeutic purposes. The structure and in vivo properties of those compounds will be discussed and compared to the clinically available ones, namely in terms of image quality and therapeutic effect. We will also mention briefly the use of BPs as carriers of multimodal nuclear and optical imaging probes.

Multiple bonds between transition metals and main-group elements: Part 161 Oxygen-donor adducts of organorhenium(VII) oxides: syntheses, structures and catalytic properties

Abstract N-Oxide adducts of methyltrioxorhenium(VII) (1) are characterized and their catalytic properties in the epoxidation of olefins with hydrogen peroxide are examined. The crystal structure of one of these derivatives is described. Whereas aliphatic N-oxides form temperature-sensitive adducts with 1 and are inactive in the catalytic epoxidation of olefins, aromatic N-oxides adducts of 1 are both stable and catalytically active. The latter complexes show lower activity than 1, but in some cases the selectivity is even higher than that of the N-base adducts of 1. The catalytic active species are of similar type in all examined cases. The structure of the oxo-functionalized complex [O3Re(CH2)2CH(CH3)OCH3] as well as its catalytic properties in the olefin epoxidation with hydrogen peroxide are reported. The deactivation process of this catalyst is also examined.

Multiple bonds between main group elements and transition metals, 155. (Hexamethylphosphoramide) methyl(oxo) bis(η2-peroxo)rhenium(VII), the first example of an anhydrous rhenium peroxo complex: crystal structure and catalytic properties

Abstract Methyl(oxo)bis(η2-peroxo)rhenium(VII)1, the active species of the system CH3ReO3/H2O2 in the catalytic oxidation of different organic and organometallic compounds, is stabilized by a water molecule attached to the rhenium center. This water molecule can be removed and substituted by hexamethylphosphoramide (HMPA) to yield (hexamethylphosphoramide)methyl(oxo)bis(η2-peroxo rhenium(VII) (3). The synthesis, crystal structure (X-ray difraction study), and catalytic properties of which compound are reported. Crystal data are as follows: monoclinic, space group P21/n, a = 900.76(7) pm, b = 1229.80(11) pm, c = 1318.57(11) pm, β = 90.251(7)°, Rw = 0.034 for 1878 reflections. The catalytic properties of compound 3 in the oxidation of olefins with H2O2 are similar to those of 1.

Re and Tc Tricarbonyl Complexes: From the Suppression of NO Biosynthesis in Macrophages to in Vivo Targeting of Inducible Nitric Oxide Synthase

The in vivo molecular imaging of nitric oxide synthase (NOS), the enzyme responsible for the catalytic oxidation of l-arginine to citrulline and nitric oxide (NO), by noninvasive modalities could provide valuable insights into NO/NOS-related diseases. Aiming at the design of innovative (⁹⁹m)Tc(I) complexes for targeting inducible NOS (iNOS) in vivo by SPECT imaging, herein we describe a set of novel (⁹⁹m)Tc(CO)₃ complexes (2-5) and the corresponding rhenium surrogates (2a-5a) containing the NOS inhibitor N(ω)-nitro-l-arginine. The latter is linked through its α-NH₂ or α-COOH group and an alkyl spacer of variable length to the metal center. The complexes 2a (propyl spacer) and 3a (hexyl spacer), in which the α-NH₂ group of the inhibitor is involved in the conjugation to the metal center, presented remarkable affinity for purified iNOS, being similar to that of the free nonconjugated inhibitor (K(i) = 3-8 μM) in the case of 3a (K(i) = 6 μM). 2a and 3a are the first examples of organometallic complexes that permeate through RAW 264.7 macrophage cell membranes, interacting specifically with the target enzyme, as confirmed by the suppression of NO biosynthesis in LPS-treated macrophages (2a, ca. 30% inhibition; 3a, ca. 50% inhibition). The (⁹⁹m)Tc(I)-complexes 2 and 3, stable both in vitro and in vivo, also presented the ability to cross cell membranes, as demonstrated by internalization studies in the same cell model. The biodistribution studies in LPS-pretreated mature female C57BL6 mice have shown that 2 presented an overall higher uptake in most tissues of the LPS-treated mice compared to the control group (30 min postinjection). This increase is significant in lung (3.98 ± 0.63 vs to 0.99 ± 0.13%ID/g), which is known to be the organ with the highest iNOS expression after LPS treatment. These results suggest that the higher uptake in that organ may be related to iNOS upregulation.

Insights into the structural determinants for selective inhibition of nitric oxide synthase isoforms

AbstractSelective inhibition of the nitric oxide synthase isoforms (NOS) is a promising approach for the treatment of various disorders. However, given the high active site conservation among all NOS isoforms, the design of selective inhibitors is a challenging task. Analysis of the X-ray crystal structures of the NOS isoforms complexed with known inhibitors most often gives no clues about the structural determinants behind the selective inhibition since the inhibitors share the same binding conformation. Aimed at a better understanding of the structural factors responsible for selective inhibition of NOS isoforms we have performed MD simulations for iNOS, nNOS and eNOS complexed with Nω-NO2-L-Arg (1), and with the aminopyridine derivatives 2 and 3. The slightly better selectivity of 1 for nNOS may be assigned to the presence of extra charge–charge interactions due to its “extended” conformation. While the high affinity of 2 for iNOS can be explained by the formation of an iNOS-specific subpocket upon binding, the lack of affinity for eNOS is associated to a conformational change in Glu363. The strong van der Waals and electrostatic interactions between 3 and the active site of nNOS are most likely responsible for its higher affinity for this isoform. Owing to the elongated and narrow binding pocket of iNOS, the correct positioning of 3 over the heme group is difficult, which may account for its lower affinity toward this isoform. Brought together, our results might help to rationalize the design of selective NOS inhibitors. FigureOverall RMSD of the protein backbone over 8 ns simulation is shown for the complexes 3:eNOSmonomer and 3:eNOSdimer

Syntheses of bifunctional 2,3-diamino propionic acid-based chelators as small and strong tripod ligands for the labelling of biomolecules with 99mTc

The labelling of targeting biomolecules requires small and hydrophilic complexes in order to not affect the binding properties of the vectors. 2,3-Diamino propionic acid (dap) is a small and strong, albeit scarcely used, tripod ligand for the fac-[(99m)Tc(CO)(3)](+) moiety. We have introduced at the alpha-carbon atom in the basic dap structure various second functionalities such as carboxylato, amino and alpha-amino acid groups via various spacers in order to yield bifunctional chelators. These dap derivatives can be coupled to targeting molecules for application in molecular imaging. Full characterizations of the bifunctional chelators, X-ray structures of intermediates and of one rhenium complex, as well as labelling studies with (99m)Tc, are presented.

Coordination capabilities of pyrazolyl containing ligands towards the fac-[Re(CO)3]+ moiety

The coordination capabilities of the pyrazolyl containing ligands pz*(CH2)2NH(CH2)2pz*, pz*(CH2)2NH(CH2)2NH2, pz*(CH2)2S(CH2)2pz* and pz*(CH2)2S(CH2)2NH2 (pz* = 3,5-Me2pz) towards the synthon (NEt4)2[ReBr3(CO)3] (1) were studied. Depending on the reaction conditions, neutral or cationic Re(I) tricarbonyl complexes have been isolated: [ReBr(CO)3(κ2-pz*(CH2)2NH(CH2)2pz*)] (2), [ReBr(CO)3(κ2-pz*(CH2)2S(CH2)2pz*)] (3) [Re(CO)3(κ3-pz*(CH2)2NH(CH2)2pz*)]Br (4), [Re(CO)3(κ2-pz*(CH2)2S(CH2)2pz*)MeOH]Br (5), [Re(CO)3(κ3-pz*(CH2)2NH(CH2)2NH2)]Br (6) and [Re(CO)3(κ3-pz*(CH2)2S(CH2)2NH2)]Br (7). Complexes 2–7 have been characterized by the normal techniques, including X-ray crystallographic analysis in the case of 3, 4, 6 and 7. In these complexes the Re atom adopts a distorted octahedral coordination, being one of the triangular faces defined by the three carbonyl groups and the other three remaining coordination positions by the bidentate and the bromide ligands (3), or by the tridentate and neutral pyrazolyl containing ligands (4, 6, 7). Complexes 2–4, 6 and 7 are static in solution and the 1H NMR data indicate clearly a κ2-coordination mode of the ligand in 2 and 3 and a κ3-coordination in 4, 6 and 7, which agrees with the coordination mode found in the solid state. Compound 5 displays a fluxional behaviour in solution as shown by variable temperature 1H NMR studies. No X-ray data exists for this complex but the pattern obtained for the NMR spectrum at 215 K indicates a κ2-coordination mode for the pyrazolyl containing ligand.

Neutral Trichlorooxorhenium(V) Complexes Containing New Heterofunctionalized Phosphane Ligands of the Type PN2 and PNO

The new heterofunctionalized phosphane [(1R,2R)-N-(2-aminocyclohexyl)]-2-(diphenylphosphanyl)benzamide (L1), N-(2-aminoethyl)-2-(diphenylphosphanyl)benzamide (L2) and 2-(diphenylphosphanyl)-N-(2-hydroxyethyl)benzamide (L3) were synthesized by reaction of N-[2-(diphenylphosphanyl)benzoyloxy]succinimide (3) in dichloromethane with (1R,2R)-(−)-diaminocyclohexane, ethylenediamine and ethanolamine, respectively. Reactions of [Re(O)Cl4]− with L1, L2and L3, at a 1:1 metal/ligand molar ratio gave neutral trichlorooxorhenium(V) complexes of the type [Re(O)Cl3{κ2-L}] [L = L1 (4), L2 (5), L3 (6)]. The characterization of the compounds involved IR, 1H- and 31P-NMR spectroscopy, and X-ray crystallographic analysis for L1, 5 and 6. The Re atom is sixcoordinate in complexes 4−6, with an oxo ligand, three chloride ligands and a neutral bidentate heterofunctionalized phosphane ligand.