Synthesis and reactivity of rhodium(III) pentamethylcyclopentadienyl complexes of N-B-PTA(BH3): X-ray crystal structures of [CpRhCl2{N-B}-PTA(BH3)] and [CpRh{N-B-PTA(BH3)}(η-CH2 = CHPh)]

The reaction between 1-boranyl-1,3,5-triaza-7-phosphaadamantane ligand N-B-PTA(BH₃) and [Cp^∗RhCl(μ-Cl)]₂ affords [Cp^∗Rh{N-B-PTA(BH₃)}Cl₂] (3) or [Cp_∗Rh{N-B-PTA(BH₃)}₂Cl]Cl (5) containing one or two P-bonded boronated PTA ligands. The hydride [Cp_∗Rh{N-B-PTA(BH₃)}H₂] (8) was also obtained by reaction of 3 with NaBH₄ and alternatively by direct hydroboration of [Cp^∗Rh(PTA)Cl₂] with excess NaBH₄. Moderately slow hydrolysis of the N-boranyl rhodium complexes affords dihydrogen, H₃BO₃ and the corresponding PTA derivatives, including the water-soluble dihydride [Cp^∗Rh(PTA)H₂] (9). Finally, the reaction of 8 with electron poor alkynes gives the alkene complexes [Cp^∗Rh{N-B-PTA(BH₃)}(η²-CH₂ = CHR)] (R = Ph, 10; C(O)OEt, 11) as a mixture of rotamers η²-coordinated to rhodium without affecting the N-BH₃ moiety. The X-ray crystal structures of 3 and 10 were also obtained and are here discussed.     

Rearrangement, nucleophilic substitution, and halogen switch reactions of alkyl halides over NaY Zeolite: formation of the bicyclobutonium cation inside the zeolite cavity

Rearrangement and nucleophilic substitution of cyclopropylcarbinyl bromide over NaY and NaY impregnated with NaCl was observed at room temperature. The first-order kinetics are consistent with ionization to the bicyclobutonium cation, followed by internal return of the bromide anion or nucleophilic attack by impregnated NaCl to form cyclopropylcarbinyl, cyclobutyl, and allylcarbinyl chlorides. The product distribution analysis revealed that neither a purely kinetic distribution, similar to what is found in solution, nor the thermodynamic ratio, which favors the allylcarbinyl halide, was observed. Calculations showed that bicyclobutonium and cyclopropylcarbinyl carbocations are minimal over the zeolite structure, and stabilized by hydrogen bonding with the framework structure. A new process of nucleophilic substitution is reported, namely halogen switch, involving alkyl chlorides and bromides of different structures. The reaction occurs inside the zeolite pores, due to the confinement effects and is an additional proof of carbocation formation on zeolites. The results support the idea that zeolites act as solid solvents, permitting ionization and solvation of ionic species.     

Solution [Cu(amm)]2+ is a strongly solvated square pyramid: a full account of the copper K-edge XAS spectrum within single-electron theory

The solution structure of Cu(II) in 4 M aqueous ammonia, [Cu(amm)](2+), was assessed using copper K-edge extended X-ray absorption fine structure (EXAFS) and Minuit XANes (MXAN) analyses. Tested structures included trigonal planar, planar and D2d -tetragonal, regular and distorted square pyramids, trigonal bipyramids, and Jahn-Teller distorted octahedra. Each approach converged to the same axially elongated square pyramid, 4 x Cu-Neq=2.00+/-0.02 A and 1 x Cu-Nax=2.16+/-0.02 A (EXAFS) or 2.20+/-0.07 A (MXAN), with strongly localized solvation shells. In the MXAN model, four equatorial ammonias averaged 13 degrees below the Cu(II) xy-plane, which was 0.45+/-0.1 A above the mean N4 plane. When the axial ligand equilibrium partial occupancies of about 0.65 ammonia and 0.35 water were included, EXAFS modeling found Cu-Lax distances of 2.16 and 2.31 A, respectively, reproducing the distances found in the crystal structures of [Cu(NH3)5](2+) and [Cu(NH3)4(H2O)](2+). A transverse axially localized solvent molecule was found at 2.8 A (EXAFS) or 3.1 A (MXAN). Six second-shell solvent molecules were also found at about 3.4+/-0.01 (EXAFS) or 3.8+/-0.2 A (MXAN). The structure of Cu(II) in 4 M pH 10 aqueous NH 3 may be notationally described as {[Cu(NH 3)4.62(H2O)0.38](solv)}(2+).6solv, solv=H2O, NH 3. The prominent shoulder and duplexed maximum of the rising K-edge XAS of [Cu(amm)](2+) primarily reflect the durable and well-organized solvation shells, not found around [Cu(H2O)5](2+), rather than two-electron shakedown transitions. Not accounting for solvent scattering thus may confound XAS-based estimates of metal-ligand covalency. [Cu(amm)](2+) continues the dissymmetry previously found for the solution structure of [Cu(H2O)5](2+), again contradicting the rack-bonding theory of blue copper proteins.     

Diastereomerically enriched analogues of the water-soluble phosphine PTA. Synthesis of phenyl(1,3,5-triaza-7-phosphatricyclo[3.3.1.1(3,7)]dec-6-yl)methanol (PZA) and the sulfide PZA(S) and X-ray crystal structures of the oxide PZA(O) and [Cp*IrCl(2)(PZA)

A diastereomerically enriched analogue of 1,3,5-triaza-7-phosphaadamantane (PTA) was obtained by the reaction of PTA lithium salt with benzaldehyde to give the water-soluble derivative phenyl(1,3,5-triaza-7-phosphatricyclo[3.3.1.13,7]dec-6-yl)methanol (PZA, 1) as a mixture of two diastereoisomers. PZA derivatives phenyl(1,3,5-triaza-7-phospha-tricyclo[3.3.1.13,7]dec-6-yl)methanol sulfide [PZA(S), 2] and oxide [PZA(O), 3] were also synthesized. The latter was isolated in the solid state, and the X-ray crystal structure of a single diastereoisomer was obtained. Compound 1 was used as a k1-P monodentate ligand toward iridium(III) moieties, and the piano-stool complex [Cp*IrCl2(PZA)] (4) was obtained as a mixture of diastereoisomers both in solution and in the solid state.     

CuI complexes with N,N',S,S' scorpionate ligands: evidence for dimer-monomer equilibria

The heteroscorpionate N, N', S, S' donor ligands 4-methoxy-3,5-dimethyl-2-(3-(methylthio)-1-(3-(2-(methylthio)phenyl)-1H-pyrazol-1-yl)propyl)pyridine (L(a)) and 4-methoxy-3,5-dimethyl-2-(2-(methylthio)-1-(3-(2-(methylthio)phenyl)-1H-pyrazol-1-yl)ethyl)pyridine (L(b)) were prepared. The Cu(I) complexes [Cu(L(a))]2(BF4)2 (a2(BF4)2) and [Cu(L(b))]2(BF4)2 (b2(BF4)2) were synthesized and characterized by X-ray crystallography. Both compounds exhibit a dinuclear structure, presenting each Cu(I) center in a distorted N, N', S, S' tetrahedral environment. On the basis of nuclear magnetic resonance (NMR) and ESI-mass data, the presence of a mononuclear complex in equilibrium with the dimer was hypothesized for both complexes. The dimerization constants of the processes, 2a(+) = a2(2+) and 2b(+) = b2(2+) , were obtained by (1)H NMR dilution experiments (fast-exchange regime) in CD 3CN: log K(a2(2+)) = 3.55(6) and log K(b2(2+)) = 3.23(5) at 300 K. Thermodynamic parameters were determined by a van't Hoff analysis (280-310 K temperature range): DeltaH(0)(a2(2+)) = -12(1) kJ mol (-1), DeltaH(0)(b2(2+)) = -10(1) kJ mol(-1), DeltaS(0)(a2(2+)) = +27(4) kJ mol (-1), and DeltaS(0)(b2(2+)) = +28(4) kJ mol (-1). Pulsed gradient spin-echo (PGSE) NMR experiments provided the weighted-average hydrodynamic volume (VH) of the species present in CD 3CN solution at different copper concentrations (CCu). Nonlinear interpolation of VH as a function of C Cu for a dimer-monomer equilibrium led to the hydrodynamic volumes of both monomers (VH(0)(M)) and dimers (VH(0)(D)): VH(0)(a(+)) = 620(40) A(3), VH(0)(b(+)) = 550(10) A(3), VH(0)(a2(2+)) = 950(20) A(3), and VH(0)(b2(2+)) = 900(10) A(3). Cyclic voltammetry experiments performed in CH3CN and CH2Cl2 showed a quasi-reversible to irreversible behavior of the Cu(I)/Cu(II) redox couple for both complexes.     

X-ray absorption spectroscopy of hemes and hemeproteins in solution: multiple scattering analysis

A full quantitative analysis of Fe K-edge X-ray absorption spectra has been performed for hemes in two porphynato complexes, that is, iron(III) tetraphenylporphyrin chloride (Fe(III)TPPCl) and iron(III) tetraphenylporphyrin bis(imidazole) (Fe(III)TPP(Imid)2), in two protein complexes whose X-ray structure is known at atomic resolution (1.0 A), that is, ferrous deoxy-myoglobin (Fe(II)Mb) and ferric aquo-myoglobin (Fe(III)MbH2O), and in ferric cyano-myoglobin (Fe(III)MbCN), whose X-ray structure is known at lower resolution (1.4 A). The analysis has been performed via the multiple scattering approach, starting from a muffin tin approximation of the molecular potential. The Fe-heme structure has been obtained by analyzing independently the Extended X-ray Absorption Fine Structure (EXAFS) region and the X-ray Absorption Near Edge Structure (XANES) region. The EXAFS structural results are in full agreement with the crystallographic values of the models, with an accuracy of +/- 0.02 A for Fe-ligand distances, and +/-6 degrees for angular parameters. All the XANES features above the theoretical zero energy (in the lower rising edge) are well accounted for by single-channel calculations, for both Fe(II) and Fe(III) hemes, and the Fe-N p distance is determined with the same accuracy as EXAFS. XANES evaluations of Fe-5th and Fe-6th ligand distances are determined with 0.04-0.07 A accuracy; a small discrepancy with EXAFS (0.01 to 0.05 A beyond the statistical error), is found for protein compounds. Concerns from statistical correlation among parameters and multiple minima in the parameter space are discussed. As expected, the XANES accuracy is slightly lower than what was found for polarized XANES on Fe(III)MbCN single crystal (0.03-0.04 A), and states the actual state-of-the-art of XANES analysis when used to extract heme-normal parameters in a solution spectrum dominated by heme-plane scattering.     

Simultaneous determination of gemcitabine and its main metabolite, dFdU, in plasma of patients with advanced non-small-cell lung cancer by high-performance liquid chromatography-tandem mass spectrometry

Gemcitabine, 2',2'-difluoro-2'-deoxycytidine (dFdC) is a pyrimidine antimetabolite employed against several human malignancies. It undergoes intracellular activation to the pharmacologically active triphosphate form (dFdCTP) and metabolic inactivation to the metabolite 2',2'-difluorodeoxyuridine (dFdU). In order to investigate the human plasma pharmacokinetics of dFdC and dFdU, we developed and validated an HPLC-MS/MS method, adding 2'-deoxycytidine as internal standard and simply precipitating the protein with acetonitrile. The method requires a small sample (125 microl), and it is rapid and selective, allowing good resolution of peaks from the plasma matrix in only 7 min. It is sensitive, precise and accurate, with overall precision, expressed as CV%, always less than 10.0% for both analytes and high recovery: > or = 80%. The limits of detection for dFdC and dFdU were 0.1 and 1.1 ng/ml, but considering the high concentrations in the plasma of patients investigated, we set the limit of quantitation at 20 ng/ml (0.08 microM) for dFdC and 250 ng/ml for dFdU, and validated the assay up to the dFdC concentration of 6.0 microg/ml (22.8 microM). The method was successfully used to study the drug pharmacokinetics in patients with advanced non-small-cell lung cancer in a phase II trial with gemcitabine administered as a fixed dose-rate infusion.