Metabolization of [Ru(η6-C6H5CF3)(pta)Cl2]: a cytotoxic RAPTA-type complex with a strongly electron withdrawing arene ligand

Abstract  

The anticancer ruthenium–arene compound [Ru(η⁶-C₆H₅CF₃)(pta)Cl₂] (where pta is 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane), termed RAPTA-CF3, with the electron-withdrawing α,α,α-trifluorotoluene ligand, is one of the most cytotoxic RAPTA compounds known. To rationalize the high observed cytotoxicity, the hydrolysis of RAPTA-CF3 in water and brine (100 mM sodium chloride) and its reactions with the protein ubiquitin and a double-stranded oligonucleotide (5′-GTATTGGCACGTA-3′) were studied using NMR spectroscopy, high-resolution Fourier transform ion cyclotron resonance mass spectrometry, and gel electrophoresis. The aquation of the ruthenium–chlorido complex was accompanied by a loss of the arene ligand, independent of the chloride concentration, which is a special property of the compound not observed for other ruthenium–arene complexes with relatively stable ruthenium–arene bonds. Accordingly, the mass spectra of the biomolecule reaction mixtures contained mostly [Ru(pta)]–biomolecule adducts, whereas [Ru(pta)(arene)] adducts typical of other RAPTA compounds were not observed in the protein or DNA binding studies. Gel electrophoresis experiments revealed a significant degree of decomposition of the oligonucleotide, which was more pronounced in the case of RAPTA-CF3 compared with RAPTA-C. Consequently, facile arene loss appears to be responsible for the increased cytotoxicity of RAPTA-CF3.     

Reactions of the cationic monobut-2-yne complex [WI(CO)(NCMe)(dppm)(η2-MeC2Me)][BF4] {dppm = Ph2P(CH2)PPh2} with carbon monoxide and tButylisonitrile

The compound [WI(CO)(NCMe)(dppm)(η²-MeC₂Me)][BF₄] reacts with carbon monoxide and ^tbutylisonitrile in CH₂Cl₂ at room temperature to give the substituted products [WI(CO)₂(dppm)(η²-MeC₂Me)][BF₄] (1) and [WI(CO)(CN^tBu)(dppm)(η²-MeC₂Me)][BF₄] (2) in good yield. The new complexes were fully characterised by elemental analysis, infrared, ¹H and ¹³C NMR spectroscopy. ¹³C NMR spectroscopy suggests that the but-2-yne ligand is donating four electrons to the tungsten in these complexes.     

The synthesis and structural properties of [M(dippe)(η2-C4H4S)] complexes of Pd and Pt and comparison with their Ni analog

X-ray structural and NMR spectroscopic data for the ring-opened thiophene complexes [Pd(dippe)(T)] (2), and [Pt(dippe)(T)] (3) are now presented. The complex [Ni(dippe)(T)] (1), where T = (η²-C,S-C₄H₄S), was reported by our group, previously.The structural and bonding properties of complexes 2 and 3 were compared with those of complex 1. DFT calculations were carried out to rationalize their relative stabilities and structural properties. Compound 1 loses thiophene at ambient temperature in solution, while compound 2 decomposes rapidly in both acetone-d₆ and THF-d₈ with k_obs = 7.15(9) × 10⁻⁵ and 7.7(3) × 10⁻⁵ s⁻¹, respectively, to give products that varied by solvent. Complex 3 does not lose thiophene at temperatures below 100 °C. The ΔG⁰ values determined from DFT calculations are consistent with the observed stabilities of the complexes. The single crystal X-ray structures of all three complexes contain a disordered thienyl fragment in the asymmetric unit due to the interchange of the position of sulfur in the metal-inserted thiophenic ring. The thiophenic moiety is relatively flat in 1, 2 and 3, which is attributed to the open ligand environment at the M(dippe) fragment. All three complexes possess square-planar geometry around the metal center and have bond-length alternation among the thiophenic carbons, which indicates double bond localization. The calculated bond lengths are in good agreement with experimental data. Molecular orbital (MO) and natural bonding orbital (NBO) analyses were carried out to rationalize the results.     

Oxidation of [Ir(η-C5Me5)(C3S5)] [C3S5 = 4,5-disulfanyl-1,3-dithiole-2-thionate(2−)] and X-ray crystal structure of [IrBr(η-C5Me5)(μ-C2S4)IrBr(η-C5Me5)]

[Ir(η⁵-C₅Me₅)(C₃S₅)] [C₃S₅²⁻ = 4,5-disulfanyl-1,3-dithiole-2-thionate(2−)] was prepared by a reaction of [NMe₄]₂[C₃S₅] with [Ir(η⁵- C₅Me₅)Cl₂]₂ in ethanol. It was reacted with bromine to afford a paramagnetic species [IrBr(η⁵-C₅Me₅)(C₃S₅)] with the Ir-Br bond and in the one-electron-oxidized state, and a diamagnetic dinuclear species [IrBr(η⁵-C₅Me₅)(μ-C₂S₄)IrBr(η⁵-C₅Me₅)]. ESR spectra for the one-electron-oxidized species in solution are discussed. The X-ray crystal structural analysis for the latter complex revealed the geometry consisting of dinuclear IrBr(η⁵-C₅Me₅) moieties bridged by the C₂S₄²⁻ ligand.     

Mixed-bridged bimetallic d8 complexes. Crystal and molecular structure of (η3-C3H5)Pd(μ-pz)(μ-N3)Rh(CO)2, heterobinuclear complex with extended Rh⋯Rh interactions

The preparation and properties of binuclear complexes containing the pyrazolate and azide groups as bridging ligands are reported. Representative formulae are: M₂(μ-pz)(μ-N₃)(CO)₄, M₂(μ-pz)(μ-N₃)- (COD)₂ (M = Rh or Ir), (CO)₂Rh(μ-pz)(μ-N₃)ML₂ (M = Rh, L₂ = COD, M = Ir, L = CO) and (η³-C₃H₅)- Pd(μ-pz)(μ-N₃)Rh(CO)₂. The crystal and molecular structure of the latter complex has been determined by single-crystal X-ray methods. Crystals are monoclinic, space group C₂/c with cell constants a = 18.4750(10), b = 10.0351(3), c = 13.6399(6) Å, α = 90, β = 100.022(4), γ = 90°, and Z = 8. The final R and R_w values were 0.051 and 0.062 for 1417 observed reflexions. This binuclear compound packs in the crystal zig-zag chains of rhodium atoms, along the c axis, wtth intermolecular Rh···Rh contacts of 3.290(1) and 3.604(1) Å. The Rh···Rh···Rh angle is 163.16(4)°.     

Syntheses and characterization of Cp2Ce[η3-N(QPPh2)2] (Q = S,Se) and Cp2Ce[η3-N(SPiPr2)(SePPh2)]

The compounds Cp₂Ce[η³-N(QPPh₂)₂] (Q = S (1), Se (2)) and Cp₂Ce[η³-N(SPⁱPr₂)(SePPh₂)] (3) have been synthesized from the protonolysis reactions between Cp₃Ce and HN(QPPh₂)₂ or HN(SPⁱPr₂)(SePPh₂) in THF. The structures of these compounds have been determined by X-ray crystallographic methods. The three compounds have similar structures in which the ligands are coordinated to Cp₂Ce moiety in an η³ fashion through the two chalcogen atoms and an N atom. Whereas the ⁷⁷Se NMR resonances are normal the ³¹P NMR resonances are shifted to much lower frequencies than in similar rare-earth compounds.     

Crystal Structure of Organolanthanide Complexes [Li(THF)2]2 (μt-Cl)4(η5-C5 H5 )Ln·THF (Ln = La,Nd)

The crystal and molecular structures of the title compounds have been determined from single crystal X-ray diffraction. The two complexes crystallize in the orthorhombic space group Pna2₁ with Z = 4. Lattice parameters are: a = 10.504(2) [10.522(2)], ¹b = 16.816(4) [16.927(3)] and c = 18.931(4) [18.969(3)] Å. The two crystals are isomorphous. The structures were solved by Patterson and Fourier techniques and refined by least-squares techniques to R = 0.0430 for 1508 reflections. The Nd³⁺. ion is eight-coordinate, being bonded to five carbons of the cyclopentadiene ring, to four chloride atoms and to the one oxygen atom of the THF ring. The NdC distances are in the range 2.67–2.85 Å (average: 2.77 Å) and Nd-Cl distances are in the range 2.76–2.80 Å (average: 2.78 Å). The Nd-O distance is 2.52 A. The Li⁺ ion is four-coordinate, being bonded to the two chloride atoms and to the two oxygen atoms of the two THF rings. The other Li⁺ ion is the same as the above. The Li-Cl distances are in the range 2.17– 2.55 Å (average: 2.35 A) and LiO distances are in the range 1.89–1.98 Å (average: 1.91 Å). The Nd atom and the two Li atoms are bridged asymmetrically by the chloride ions, respectively.     

Protonation,alkylation, addition and redox reactions of 16, 17 and 18 valence electron [Mo(L)(NO)('S4')] complexes [L = SPh,PMe3, NO; 'S4'2– = 1,2-Bis-(2-mercaptophenylthio)ethane(2-)]

In the quest for complexes modelling functional characteristics of metal sulfur oxidoreductases, a series of molybdenum nitrosyl complexes with sulfur-dominated coordination sphere was synthesized. Treatment of the 16, 17 and 18 valence electron (VE) complexes [Mo(L)(NO)('S₄')] (1–3) [L?=?SPh (1), PMe₃ (2), NO (3), 'S₄'^2–?=?1,2-bis-(2-mercaptophenylthio) ethane(2-)] with the Brönsted acid HBF₄ resulted in formation of different types of products. 1 and 3 were reversibly protonated at one thiolate atom of the 'S₄'^2– ligand;2, however, yielded the phosphonium salt [HPMe₃]BF₄ and the dinuclear [Mo(NO)('S₄')]₂. Alkylation of 1, 2 and 3 by Me₃OBF₄ or Et₃OBF₄ uniformly resulted in high yields of [Mo(L)(NO)(R-'S₄')]BF₄ complexes [L?=?SPh: R?=?Me (5), Et (6); L?=?PMe₃: R?=?Me (7); L?=?NO: R?=?Me (8), Et (9)] in which one thiolate atom of the 'S₄'^2– ligand had become alkylated; the NMR spectra of 5, 6, 8 and 9 indicated that only one out of four theoretically possible diastereoisomers had formed. 5 and 6 were characterized also by single-crystal X-ray structure analyses. A comparison of ν(NO) bands and redox potentials (cyclic voltammetry) of parent complexes and alkylated derivatives showed that alkylation leads to a decrease in electron density at the molybdenum center and to a positive shift in redox potentials. The 16 VE complex 1 could be reduced, also chemically, to give the corresponding 17 VE anion [1]^–, and inserted elemental sulfur into the Mo-SPh bond, forming the 18 VE phenylperthio complex [Mo(η²–SSPh)(NO)('S₄')] (11) which, upon reaction with PPh₃, gave SPPh₃ and regenerated the parent complex 1. These results are discussed with regard to the sequence of proton and electron transfer steps occurring in substrate conversions catalyzed by metal sulfur oxidoreductases.     

Synthesis of 5′-deoxy-5′-ethoxycarbonylmethyl nucleosides,the precursors of oligonucleotides with the amide internucleoside bond C3′-NH-C(O)-CH<Subscript>2</Subscript>-C5′

A method for the synthesis of 5′-deoxy-5′-ethoxycarbonylmethyl nucleosides has been developed. 3-O-benzyloxymethyl-1,2-O-isopropylidene-α-D-allofuranose was oxidized by sodium periodate to form a 5′-aldo derivative, which was converted by the reaction with triethylphosphonoacetate in the presence of sodium hydride into a 5-deoxy-5-ethoxycarbonylmethylene derivative. The hydration of the unsaturated compound gave 5-deoxy-5-ethoxycarbonylmethyl-1,2-O-isopropylidene-α-D-ribofuranose. After the benzylation of 3-hydroxyl, the removal of the isopropylidene group by heating with acetic acid, and the subsequent acetylation, 1,2-di-O-acetyl-3-O-benzyl-5-deoxy-5-ethoxycarbonylmethyl-D-ribofuranose was obtained, which reacted with persilylated nucleic acid bases to form 5′-deoxy-5′-ethoxycarbonylmethyl nucleosides.     

Ligand induced PH bond formation and a comparison of the reactivity of two isomers of the carbonyl hydride [Pt2(μ-PBu2)2(H)(CO)(PBu2H)]CF3SO3

The Pt₂ ^(II) isomeric terminal hydrides [(CO)(H)Pt(μ-PBu^t ₂)₂Pt(PBu^t ₂H)]CF₃SO₃ (1a), and [(CO)Pt(μ-PBu^t ₂)₂Pt(PBu^t ₂H)(H)]CF₃SO₃ (1b), react rapidly with 1 atm of carbon monoxide to give the same mixture of two isomers of the Pt₂ ^(I) dicarbonyl [Pt₂(μ-PBu^t ₂)(CO)₂(PBu^t ₂H)₂]CF₃SO₃ (3-Pt); the solid state structure of the isomer bearing the carbonyl ligands pseudo-trans to the bridging phosphide was solved by X-ray diffraction. A remarkable difference was instead found between the reactivity of 1a and 1b towards carbon disulfide or isoprene. In both cases 1b reacts slowly to afford [Pt₂(μ-PBu^t ₂)(μ,η²,η²-CS₂)(PBu^t ₂H)₂]CF₃SO₃ (4-Pt), and [Pt₂(μ-PBu^t ₂)(μ,η²,η²-isoprene) (PBu^t ₂H)₂]CF₃SO₃ (6-Pt), respectively. In the same experimental conditions, 1a is totally inert. A common mechanism, proceeding through the preassociation of the incoming ligand followed by the PH bond formation between one of the bridging P atoms and the hydride ligand, has been suggested for these reactions.     

Iridium(I) dimers with bridging N,N′-di-p-tolylformamidine. X-ray molecular structure of Ir2(μ-p-CH3C6H4NCHN-p-C6H4CH3)(μ-NH-p-C6H4CH3)(C8H14)2

The reaction of [IrCl(COD)]₂ with K[CH(N-p- C₆H₄CH₃)₂] (K⁺form⁻) has been carried out in both neat toluene and in the presence of Bu^tOH. In the first case [Ir(form)(COD)]₂ (1) was obtained in good yields. The other reaction follows a somewhat different course with partial alcoholysis of the formamidine ligand and formation of Ir₂(μ-form)(μ-NH-p-C₆H₄CH₃)(COD)₂ (2). Crystal data for compound 2: space group P2₁/c, a = 9.389(2), b = 21.083(4), c = 16.810(2) Å, β = 91.54(1)° V=3326(2) ų, Z = 4, R = 0.0343 for 3707 data with F_o² > 3σ(F_o²).     

DFT study on the reactions of ClO–/BrO– with RCl (R = CH3, C2H5, and C3H7) in gas phase

Gas-phase reactions of ClO^–/BrO^– with RCl (R = CH₃, C₂H₅, and C₃H₇) have been investigated in detail using the popular DFT functional BHandHLYP/aug-cc-pVDZ level of theory. As a result, our findings strongly suggest that the type of reaction is firstly initiated by a typical S_N2 fashion. Subsequently, two competitive substitution steps, named as S_N2-induced substitution and S_N2-induced elimination, respectively, would proceed before the initial S_N2 product ion-dipole complex separates, in which the former exhibits less reactivity than the latter. Those are consistent with relevant experimental results. Moreover, we have also explored reactivity difference for the title reactions in term of some factors derived from methyl group, p-π electronic conjugation, ionization energy (IE), as well as molecular orbital (MO) analysis.

A 31P1H NMR study of the reactions of [Rh2(μ-Cl)2(cod)2] with unsymmetrical,bidentate ligands and hydrogen

[Rh₂(μ-Cl)₂(cod)₂] reacts with Ph₂PCH₂CH₂OMe (PC₂O), Ph₂P(CH₂)₃NMe₂ (PC₃N), PBuⁿPh₂ or PPh₃ to give [Rh(cod)L₂]Cl (L = PC₂O, PC₃N, PBuⁿPh₂, PPh₃). In the presence of hydrogen, [Rh(cod)L₂]Cl is converted to [RhClH₂L₃]. In contrast, [Rh(cod)(PC₂O)₂]BPh₄ reacts with H₂ to give [RhH₂(PC₂O)₂S₂]BPh₄ (S = solvent). With Ph₂PCH₂CH₂NMe₂ (PC₂N) or Ph₂PCH₂CH₂SMe (PC₂S), [Rh₂(μ-Cl)₂(cod)₂] reacts to form the chelate complexes cis- [Rh(PC₂N)₂]⁺ or cis-[Rh(PC₂S)₂]⁺, neither of which reacts with hydrogen under ambient conditions. The products of the reactions are characterized in situ by ³¹P¹H NMR spectroscopy.     

Synthesis, characterization and molecular structures of the trichloro-η-benzoyldiazenido [ReCl3{η-NNC(O)Ph}(PPh3)2] and oxorhenium [ReOCl2(OMe)(PPh3)2] complexes derived from reactions of [ReCl2{η-NNC(O)Ph}(PPh3)2] with a peroxide or dioxygen

The reactions of [ReCl₂{η²-NNC(O)Ph}(PPh₃)₂] (1) with t-BuOOH, in C₆H₆ or chlorinated solvents, at room temperature or with MeOH upon reflux in air lead to the trichloro-η¹-benzoyldiazenido [ReCl₃{η¹-NNC(O)Ph}(PPh₃)₂] (2) or the methoxy-oxo [ReOCl₂(OMe)(PPh₃)₂] (3) compound, respectively, which have been characterized by spectroscopic and FAB⁺-MS methods, elemental and single crystal X-ray diffraction analyses. They show distorted octahedral coordinaiton geometries with trans triphenylphosphine ligands, an essentially linear η¹-diazenido moiety in 2 and the methoxy group in 3 in trans position to the oxo ligand.