Synthesis of some mixed seven-coordinate complexes of the type [MI2(CO)3LL′] (M = Mo or W;L = pyridine or substituted pyridines; L′ = PPh3, AsPh3 or SbPh3)

The seven-coordinate bisacetonitrile complexes [MI₂(CO)₃(NCMe)₂] (M = Mo or W) react with L′ (L′ = PPh₃, AsPh₃ or SbPh₃) in CH₂Cl₂ at room temperature to give [MI₂(CO)₃(NCMe)L′] which when reacted in situ with L (L = pyridine or substituted pyridines) affords good yields of 28 mixed seven-coordinate complexes [MI₂(CO)₃LL′]. It is likely these reactions occur via successive dissociative displacements of two acetonitrile ligands.     

Binuclear rhodium carbonyl halide complexes containing the 1,1-bis(diphenylphosphino)ethene ligand,and the crystal structure of [Rh2Cl2(μ-CO){Ph2PC(CH2)PPh2}2]

Treatment of [RhCl(CO)₂]₂ with 1,1-bis(diphenylphosphino)ethene (dppee) yields the cationic binuclear rhodium complex [Rh₂(μ-Cl)(CO)₂(μ-CO)(dppee)₂]⁺ which may be isolated as the [RhCl₂(CO)₂]⁻ salt at low temperature (230 K) but which readily forms the Cl⁻ salt on allowing the solution to warm to room temperature. On bubbling nitrogen through a solution of this cationic complex at room temperature, the monocarbonyl species, [Rh₂Cl₂(μ-CO)(dppee)₂] is obtained. The crystal structure of this complex has been determined. The crystals are orthorhombic, space group Pnca, a = 29.98(3), b = 23.70(2), c = 14.78(3) Å, Z = 8. Using 3019 unique reflections the structure was refined to R = 0.091. The rhodium-rhodium distance is 2.650(14) Å. Direct rhodium NMR data are reported for these complexes.     

Synthesis and characterization of [Pt(COD)Cl(NO3)] and [Pt(COD)(NO3)2] and the use of [Pt(COD)Clx(NO3)2−x] in the preparation of cis[Pt(PPh3)2Clx(NO3)2−x] (x=0, 1, 2) and [Pt(PPh3)3L](NO3) (L=Cl,NO3)

[Pt(COD)Cl₂] (COD=1,5-cyclooctadiene) is a versatile starting material for the synthesis of Pt(II) compounds. The preparations of the new compounds [Pt(COD)Cl(NO₃)], [Pt(COD)(NO₃)₂] and [Pt(PPh₃)₃(NO₃)](NO₃) and also of the known compounds cis[Pt(PPh₃)₂Cl₂], cis [Pt(PPh₃)₂Cl(NO₃)], cis[Pt(PPh₃)₂(NO₃)₂] and [Pt(PPh₃)₃Cl](NO₃)are reported. The compounds are characterized by elemental analysis, ³¹P{¹H} NMR spectroscopy and IR spectroscopy.     

Haloalkyl complexes of the transition metals. Part 5. The synthesis and reactions of some new pentamethylcyclopentadienyl halomethyl and methoxymethyl complexes of molybdenum(II) and tungsten(II) and the X-ray crystal structure of the cationic ylide complex [η-C5Me5W(CO)3CH2PPh3]I

Synthetic routes are described for the new halo- methyl complexes of the type [η-C₅Me₅M(CO)₃- CH₂X]. The complexes where M = Mo, X = Cl or OMe and M = W, X = Cl, I, OMe have been fully characterized. Reaction of [η-C₅Me₅Mo(CO)₃CH₂Cl] with PPh₃ in methanol under reflux or acetonitrile at room temperature gives [η-C₅Me₅Mo(CO)₂(PPh₃)- Cl], whereas reaction of [η-C₅Me₅W(CO)₃CH₂I] with PPh₃ under similar conditions gives the cationic phosphorus ylide complex [η-C₅Me₅W(CO)₃CH₂- PPh₃]I. The structure of this ylide complex has been determined by X-ray crystallography. The complex crystallizes with half a molecule of CH₂Cl₂ in the monoclinic space group P2₁/n with a = 16.616- (8), b = 11.738(6), c = 18.126(9) Å, β = 101.74(2)° and Z = 4. The structure was solved and refined to R = 0.076. It confirms the formulation of the compound and the presence of the ylide ligand, WC_ylide 2.34(2) Å, PC_ylide 1.82(2) Å and the WC_ylideP angle of 119(1)°.     

Models of the pharmacophoric pattern and affinity trend of methyl 2-(aminomethyl)-1-phenylcyclopropane-1-carboxylate derivatives as σ1 ligands

Sigma-1 (σ₁) affinities of methyl 2-(aminomethyl)-1-phenylcyclopropane-1-carboxylate (MAPCC) derivatives were modelled by the genetic algorithm with linear assignment of hypermolecular alignment of datasets (GALAHAD) and the comparative molecular field analysis (CoMFA)/comparative molecular similarity indices analysis (CoMSIA) methods. GALAHAD was used for deriving the 3D pharmacophore pattern that encompasses the most potent σ₁ ligands within this series. Five MAPCC derivatives with a high σ₁ affinity were used for deriving this model. The obtained model included a nitrogen atom, the hydrophobes and the hydrogen bond acceptor features; it was able to identify other potent σ₁ ligands. On the other hand, CoMFA and CoMSIA methods were used for deriving quantitative structure–activity relationship (QSAR) models. All QSAR models were trained with 17 compounds, after which they were evaluated for predictive ability with additional five compounds. The best QSAR model was obtained by using CoMSIA, including steric, electrostatic and hydrophobic fields, and had a good predictive quality according to both internal and external validation criteria. In general, the models described herein provide meaningful information relevant for the rational design of new σ₁ ligands.     

Spectroscopic studies of metal complexes containing π-delocalized sulfur ligands. The pre-resonance Raman spectra of the antitumor agent 2-formylpyridine thiosemicarbazone and its Cu(II) and Zn(II) complexes

The pre-resonance Raman spectra of 2-formylpyridine thiosemicarbazone have been measured at three pH values corresponding to the fully protonated (H₂FPT⁺), half protonated (HFPT) and deprotonated (FPT⁻) forms of the ligand. Assignments of the vibrations coupled with the π→π^* transition have been made by comparison with the spectrum of the deuterated form (DFPT). The pre-resonance Raman spectra of the Zn(II) and Cu(II) complexes, [ZnFPT]⁺, [CuFPT]⁺ and [CuHFPT]²⁺, have also been measured. The spectral pattern of the Cu(II) complexes shows resonance enhancement of vibrations coupled with the π→π^*, as well as with the ligand to metal charge transfer transitions. In addition, it is consistent with coordination through thiolate sulfur in [CuFPT]⁺ and thione sulfur in [CuHFPT]²⁺.     

Solution behaviour and relative stability of the complexes [MCl2(RNCHCHNR)] and [MCl2(py-2-CHNR)] (M=Pd,Pt;R=C6H4OMe-p)

Even though the α-diimino complexes [MCl₂(RNCHCHNR)] and [MCl₂(py-2-CHNR)] (M=Pd, Pt;R=C₆H₄OMe-p) are poorly soluble in chlorinated solvents, such as chloroform and 1,2-dichloroethane, or in acetonitrile, the electronic and ¹H NMR spectra indicate that these compounds are generally present as undissociate monomers with σ, σ′-N,N′ chelate N-ligands in dilute solutions. Only for [PdCl₂(RNCHCHNR)], some dissociation of the α-diimine occurs in acetonitrile. In dimethylsulfoxide, where the solubility is much higher, no dissociation is observed for the pyridine-2-carbaldimine complexes [MCl₂(py-2-CHNR)], whereas the 1,2-bis(imino) ethane derivatives [MCl₂(RNCHCHNR)] are extensively dissociated through a step-wise process involving intermediates with a σ-N monodentate α-diimino group. As is shown by the course of substitution reactions with 2,2′-bipyridine, the higher stability of [MCl₂(py-2-CHNR)] in dimethylsulfoxide is mainly due to thermodynamic factors (ground state stabilization for the presence of stronger MN bonds) rather than by kinetic factors (higher activation energy for steric strain in the activation states or transients).     

Trinuclear palladium complexes containing terminal nitrosyl ligands: Behavior in solid state and in solution. X-ray structures of Pd3(NO)2(μ-OCOCX3)4(η2-ArH)2 (X = F,Cl; ArH = toluene or benzene)

Two trinuclear Pd(II) nitrosyl carboxylate complexes Pd₃(NO)₂(μ-OCOCX₃)₄(η²-ArH)₂ (X = F, ArH = toluene, 3a; X = Cl, ArH = benzene, 3b) have been prepared and structurally characterized. These display a linear Pd₃ array capped by terminal bent NO ligands and η²-coordinated molecules of aromatic molecules. Solution IR and NMR measurements indicate that the solid state structure of 3a is partially maintained in solution, while 3b loses benzene when dissolved in dichloromethane.     

MonodentateN coordination of 1aza4oxo1,3butadienes [R1NC(R2)C(R3)O] to platinum(II). X-ray structure of trans-[PtCl2(PEt3){σ-N-(t-BuNCHC(Me)O)}]

Reaction of dimeric trans-[PtCl₂(PR₃)]₂ with 1-aza-4-oxo-1,3-butadienes [R¹NC(R²)C(R³)O, R³ = Me, Ph, OMe, NEt₂] in a 1:2 molar ratio results in almost quantitative formation of mononuclear complexes trans·[PtCl₂(PR₃){σ-N-(R¹NC(R²)C(R³)O)}]. The ligands are bonded in the monodentate σ-N bonding mode to the platinum(II) centre. This has been established by an X-ray structure determination of trans-[PtCl₂(PEt₃){σ-N-(t-BuNCHC(Me)O)}]. Crystals of the latter compound are orthorhombic with space group Pc2₁n; cell constants are a = 14.712(3), b = 15.053(2), c = 9.025(5) Å, Z= 4 and R_w = 0.056 for 3281 reflections. The 1aza4oxol,3butadiene (α-iminoketone for R³ is alkyl or aryl) has the E-configuration about the imine bond (CN 1.34(4) Å), with a C(5)C(6) distance of 1.44(5) Å and a NC(5)/ C(6)O torsion angle of 89(4)°. As a result of this ligand conformation, the acetyl hydrogen atoms are positioned (on average) into the neighbourhood of the Pt-atom above the Pt-coordination plane. Infrared and NMR (¹H, ¹³C, ³¹p) data show that these structural features are also predominant in solution.     

Cyclopentadienyl iron xanthate complexes. Crystal and molecular structure and electrochemical reduction of η-C5R5Fe(CO)2(η1-SC(S)OEt) (RH or CH3)

Complexes η-C₅R₅Fe(CO)₂(η¹-SC(S)OEt) (RH, (1) and RCH₃ (2)) have been analysed by X-ray diffraction techniques. 1: P2₁2₁2₁ 11.3560(5), 10.8595(4), 10.1158(3) Å, Z=4; 1023 observed reflexions, R and R_w 0.069 and 0.073. 2: Pbca, 15.6907(11), 15.4566(13), 14.3083(11) Å, Z=8; 2271 observed reflexions, R and R_w being 0.071, 0.073. The coordination is quite similar for both compounds with the xanthate monodentate ligand almost perpendicular to the ring planes and a relative twist, one from each other of about 10°. The reductive electrochemistry of both complexes has been examined by cyclic voltammetry and coulometry. In a carbon electrode the first-one electron reduction step can be ascribed to the formation of corresponding carbonyl dimers. In a mercury electrode, the first reduction step of 1 leads to a bond rupture process with formation of a mercury compound [CpFe(CO)₂]₂Hg and further reduction to the anion CpFe(CO)₂⁻. However, the behaviour of the pentamethylcyclopentadienyl complex (2) is quite different, and it is reduced in a three step process.     

New synthesis of seven-coordinate complexes of molybdenum(II) and tungsten(II) containing bidentate phosphorus ligands, [MI2(CO)3{Ph2P(CH2)nPPh2}] (n = 1–6)

A new high yielding synthesis of the seven-coordinate complexes [MI₂(CO)₃{Ph₂P(CH₂)_nPPh₂}] (M = Mo and W; n = 1–6) is described. The procedure involves reacting the complexes [MI₂(CO)₃(NCMe)₂] in CH₂Cl₂ with an equimolar amount of the bidentate phosphorus ligand. The low temperature (−70 °C) ¹³C NMR spectra of the complexes [Wl₂(CO)₃{Ph₂P(CH₂)_nPPh₂}] (n = 3 and 5) indicates that the geometry is capped octahedral with a carbonyl ligand in the unique capping position.     

Uncoupling Protein 2 (UCP2) Function in the Brain as Revealed by the Cerebral Metabolism of (1–<Superscript>13</Superscript>C)-Glucose

The mitochondrial aspartate/glutamate transporter Aralar/AGC1/Slc25a12 is critically involved in brain aspartate synthesis, and AGC1 deficiency results in a drastic fall of brain aspartate levels in humans and mice. It has recently been described that the uncoupling protein UCP2 transports four carbon metabolites including aspartate. Since UCP2 is expressed in several brain cell types and AGC1 is mainly neuronal, we set to test whether UCP2 could be a mitochondrial aspartate carrier in the brain glial compartment. The study of the cerebral metabolism of (1–¹³C)-glucose in vivo in wild type and UCP2-knockout mice showed no differences in C3 or C2 labeling of aspartate, suggesting that UCP2 does not function as a mitochondrial aspartate carrier in brain. However, surprisingly, a clear decrease (of about 30–35?%) in the fractional enrichment of glutamate, glutamine and GABA was observed in the brains of UCP2-KO mice which was not associated with differences in either glucose or lactate enrichments. The results suggest that the dilution in the labeling of glutamate and its downstream metabolites could originate from the uptake of an unlabeled substrate that could not leave the matrix via UCP2 becoming trapped in the matrix. Understanding the nature of the unlabeled substrate and its precursor(s) as alternative substrates to glucose is of interest in the context of neurological diseases associated with UCP2.     

CoX2(NO)(PMe3)2 Complexes: an example of the influence of X (X = CI,Br, I,NO2) on the stereochemistry and electronic structure of the five-coordinate {CoNO}8 complexes

CoX₂(NO)(PMe₃)₂ complexes (X = Cl, Br, I, NO₂) exhibit markedly different ν(NO) stretching frequencies and different geometries. The structure of CoI₂(NO)(PMe₃)₂ (1) and CoCl₂(NO)(PMe₃)₂ (2) have been determined by X-ray diffraction. Both crystallize in the orthorhombic system, Pnma space group with four molecules in a cell of the following dimensions: for 1, a = 10.497(2), b = 10.694(2), c = 13.975(2) Å, ν= 1568.8, ų; for 2, a = 9.607(2), b = 10.689(2), c = 13.512(3) Å, ν= 1387.5 ų. The structures were refined to conventional R values of R = 0.040 from 1630 reflections for 1 and R = 0.033 from 976 reflections for 2. In both cases, the coordination geometry about the five-coordinate cobalt atom is approximately trigonal bipyramidal, with the NO group sharing the equatorial positions with the halide ligands. Structure 2 is disordered, which prevents any precise structural characterization. In (1), the CoNO angle is 179.2(19)° and the Co NO distance is 1.728(23) Å; v(NO) is 1753 cm⁻¹. CoCl₂(NO)(PMe₃)₃ shows a v(NO) vibration at 1637 cm⁻¹. Co(NO₂)₂(NO)(PMe₃)₂ with v(NO) = 1658 cm⁻¹ has been proposed as a square pyramidal structure with a bent apical CoNO. These differences in NO stretching frequencies and geometries are discussed.     

Discovery of novel α1-adrenoceptor ligands based on the antipsychotic sertindole suitable for labeling as PET ligands

The synthesis and in vitro preclinical profile of a series of 5-heteroaryl substituted analogs of the antipsychotic drug sertindole are presented. Compounds 1-(4-fluorophenyl)-3-(1-methylpiperidin-4-yl)-5-(pyrimidin-5-yl)-1H-indole (Lu AA27122, 3i) and 1-(4-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-3-(1-methylpiperidin-4-yl)-1H-indole (3l) were identified as high affinity α_1A-adrenoceptor ligands with K_i values of 0.52 and 0.16 nM, respectively, and with a >100-fold selectivity versus dopamine D₂ receptors. Compound 3i showed almost equal affinity for α_1B- (K_i = 1.9 nM) and α_1D-adrenoceptors (K_i = 2.5 nM) as for α_1A, as well as moderate affinity for 5-HT_1B (K_i = 13 nM) and 5-HT₆ (K_i = 16 nM) receptors, whereas 3l showed >40-fold selectivity toward all other targets tested. Based on in vitro assays for assessment of permeability rates and extent, it is predicted that both compounds enter the brain of rats, non-human primates, as well as humans, and as such are good candidates to be carried forward for further evaluation as positron emission tomography (PET) ligands.     

Syntheses and michael additions to vinylidene diphosphine complexes of type [M(CO)4{(Ph2P)2CCH2}] (MCr,Mo or W)

Treatment of [M(CO)₄Ph₂PCHPPh₂]⁻ with CH₃- OCH₂Cl at 20 °C gave the methoxymethyl derivations [M(CO)₄{Ph₂PCH(CH₂OCH₃)PPh₂}] (MCr or W), but a similar treatment at 80 °C gave derivatives of a vinylidene diphosphine [M(CO)₄(Ph₂P)₂C CH₂]. Treatment of [M(CO)₄Ph₂PCHPPh₂]⁻with CH₃CHClOCH₃ at 20 or 80 °C gave only [M(CO)₄- (Ph₂P)₂CHCH(CH₃)OCH₃] (MCr or W). The vinylidene diphosphine complexes [M(CO)₄(Ph₂P)2- CCH₂] (MCr, Mo or W) were even more easily prepared by treating [M(CO)₆] with (Ph₂P)₂CCH₂ (vdpp) in hot solvents such as CH₃OCH₂CH₂OCH₂- CH₂OCH₃.Treatment of [W(CO)₄vdpp] with LiBuⁿ followed by methanol gave [W(CO)₄(Ph₂P)₂CHCH₂Buⁿ] (1c), i.e. conjugate addition to the CCH₂ occurs. 1c was also made by treating [W(CO)₄(Ph₂P)₂CH]⁻ with n-pentyl-iodide. Similarly LiMe was added to [W(CO)₄(Ph₂P)₂CCH₂]. Treatment of [M(CO)₄- vdpp] with NaCH(COOEt)₂ gave [M(CO)₄(Ph₂- P)₂CHCH₂CH(COOEt)₂] (MW or Mo). Pyrrolidine added to the CCH₂ bonds of [M(CO)₄vddp] to give [M(CO)₄(Ph₂P)₂CHCH₂NC₄H₈]. ³¹p and ¹H NMR and IR data are given.