Organometallic ruthenium(II)-arene complexes with triphenylphosphine amino acid bioconjugates: Synthesis,characterization and biological properties

(p-Cymene)-ruthenium bioconjugates ML (1) and ML₂ (2), bearing phosphane ligands substituted with chiral or non-chiral amino acid esters, L, were synthetized and characterized by instrumental methods (NMR, CD, MS) and DFT calculations (using the wB97xD functional). Cytotoxic activity of complexes 1 and 2 was investigated by using human cervical carcinoma cell line (HeLa) and MTT assay. Four (2_pG, 2_pA, 2_mG and 2_mA) out of ten synthesized ruthenium complexes showed significant toxicity, with IC₅₀ values of 5–30 μM. Evaluation of the potential biomolecular targets of bioconjugates 2 by UV–Vis, fluorescence and CD spectroscopy revealed no measurable interaction with DNA, but micromolar affinity for proteins. The cytotoxicity of bioconjugates 2 is in correlation with their BSA binding constants, i. e. bioconjugates with lower IC₅₀ values show higher binding affinities towards BSA. Compound 2_mG with value of IC₅₀ 16 μM was selected for further biological characterization. The higher level of toxicity towards tumor compared to normal cell lines indicates its selective activity, important characteristic for potential medical use. It was detected 2_mG caused increase of cells in the S phase of cell cycle and consequential decrease of cells in G0/G1 phase. Additionally, 2_mG caused dose- and time-dependent increase of SubG0/G1 cell population, suggesting its ability to induce programmed cell death. Further investigation determined autophagy as the mode of cell death. The role of GSH in HeLa cells response to investigated organometallic ruthenium complexes was confirmed using specific regulators of GSH synthesis, buthionine sulfoximine and N-acetyl-cysteine. Pre-treatment of cells with ethacrynic acid and probenecid emphasized the role of GSH in detoxification of 2_mG compound. The amount of total ruthenium accumulation in the cell did not correlate with toxicity of 2_pG, 2_pA, 2_mG and 2_mA, suggesting structure dependent differences in either cell uptake or kinetics of ruthenium complexes detoxification. We speculate that ruthenium complexes bind protein-based biomolecules further triggering cell death. Based on the gained knowledge, the synthesis and development of more tumor-specific ruthenium-based complexes as potential anticancer drugs can be expected.     

Synthesis and isomerisation of two metallated N,O-complexes of ruthenium: Models for the Murai reaction

Two isomers of the N,O-coordinated acetylpyrrolyl complex [Ru(PPh₃)₂(CO)(NC₄H₃C(O)CH₃)H] {cis-N,H (1) and trans-N,H (2)} have been prepared as models for catalytic intermediates in the Murai reaction. Complex 2 isomerises to 1 upon heating via a dissociative pathway (ΔH^‡ = 195 ± 41 kJ mol⁻¹; ΔS^‡ = 232 ± 62 J mol⁻¹ K⁻¹); the mechanism of this process has been modeled using density functional calculations. Complex 2 displays moderate catalytic activity for the Murai coupling of 2′-methylacetophenone with trimethylvinylsilane, but 1 proved to be catalytically inactive under the same conditions.     

Preparation and structural characterization of group 1 metal complexes containing a chelating biphenolato phosphine ligand

The coordination chemistry of a potentially tridentate, dianionic biphenolato phosphine ligand with respect to group 1 metals is described. Deprotonation of bis-(3,5-di-tert-butyl-2-hydroxyphenyl)phenylphosphine (H₂[OPO]) with two equivalents of n-BuLi, NaH, or KH in dimethoxyethane (DME) solutions produces the corresponding dinuclear alkali metal complexes [OPO]M₂(DME)₂ (M = Li, Na, K). The X-ray structure of [OPO]Li₂(DME)₂ reveals that the two lithium atoms are bridged by both phenolato oxygen donors with only one lithium being coordinated to the phosphorus donor. Consistently, variable-temperature ³¹P{¹H} and ⁷Li{¹H} NMR spectroscopic studies elucidate the coordination of the phosphorus donor in [OPO]Li₂(DME)₂ to one of the lithium atoms in solution. Interestingly, an X-ray diffraction study of the potassium complex indicates a dimeric structure with S₂ symmetry for this species in which the four potassium atoms are bridged by both phosphorus and oxygen donors of the biphenolato phosphine ligands. These alkali metal complexes are active initiators for catalytic ring-opening polymerization of ε-caprolactone.     

Reactions of 1,8-bis(diphenylphosphino)naphthalene with ruthenium cluster carbonyls: C-H and C-P bond cleavage reactions

Reactions between Ru₃(CO)₁₂ and 1,8-bis(diphenylphosphino)naphthalene (dppn) have given the four complexes Ru₃(μ-H){μ₃-PPh₂(nap)PPh(C₆H₄)}(CO)₈ (1), Ru₄(μ-H){μ₃-PPh₂(nap)PPh(C₆H₄)}(μ-CO)₃(CO)₇ (2) and Ru₄(μ-H)(μ₃-C₆H₄){μ-PPh(nap)PPh₂}(CO)₁₁ (3) (in refluxing thf), and Ru₄{μ₄-P(nap)PPh₂}(μ₄-C₆H₄)(μ-CO)(CO)₉ (4) (in refluxing toluene) which have been characterised by single crystal X-ray studies. They have been formed by aryl C-H and aryl C-P bond cleavage reactions, presumably from an initial (unobserved) chelate dppn complex. The unchanged chelating ligand is found in Ru₃(μ-dppm)(CO)₈(dppn) (5), obtained from Ru₃(μ-dppm)(CO)₁₀ and dppn in refluxing thf.     

Synthesis and structures of aryl-substituted tetramethylcyclopentadienyl dinuclear metal carbonyl complexes

A series of 14 aryl-substituted tetramethylcyclopentadienyl dinuclear metal carbonyl complexes have been synthesized by treating the corresponding ligands (C₅Me₄C₆H₄X-4) (X = H, Me, Cl, OMe) with Ru₃(CO)₁₂, Fe(CO)₅, or Mo(CO)₃(MeCN)₃, respectively in refluxing xylene. It showed that the electronic effects of the substituents had influence on the molecular structures and reactions of the complexes, especially for the ruthenium and molybdenum complexes. In the reactions of aryl-substituted tetramethylcyclopentadiene with Mo(CO)₃(MeCN)₃, the electron-withdrawing effect of the substituent in the para position of benzene ring is favorable to produce the Mo-Mo triple bonded complexes, but the electron-donor effect of the substituent in the para position of benzene ring is favorable to produce the Mo-Mo single bonded complexes. In a given condition, the Mo-Mo single bonded complex could be transformed into the corresponding Mo-Mo triple bonded complex. The structures of nine complexes were determined by single crystal X-ray diffraction.     

Syntheses and molecular structures of ruthenium(II) complexes of the atropisomeric ligands 1,1′-biphenyl-2,2′-diamine and 3,3′-diamino-2,2′-bipyridine

The unique ligands of [Ru(bipy)₂(bpda)](PF₆)₂ (1, BPDA=1,1′-biphenyl-2,2′-diamine) and [Ru(bipy)₂(dabipy)](PF₆)₂ (2, DABIPY=3,3′-diamino-2,2′-bipyridine) are atropisomeric (exhibit hindered rotation about the sigma bonds that connect the two aromatic groups), so the complexes are diasteromeric with conformation isomers possible for the atropisomeric ligands and configurational isomers possible at the metal centers. Only one diastereomer is observed in the solid-state in both cases. The seven- (1) and five-membered (2) chelate ring of dabipy and bpda (the ligand is bound through its pyridyl groups) ligands are δ when the configuration at the metal is Δ. No evidence for atropisomerization is found in solution. For 1, we conclude bpda binds stereospecifically; however, the atropisomerization barrier of dabipy may be sufficiently low for 2 to preclude the observation of diastereomers by low-temperature NMR spectroscopy.     

Preparation of benzophenone imine complexes of transition metals

Benzophenone imine [M(η¹-NHCPh₂)(CO)_nP_5-n]BPh₄ [M = Mn, Re; n = 2, 3; P = P(OEt)₃, PPh(OEt)₂, PPh₂OEt, PPh₃] complexes were prepared by allowing triflate M(κ¹-OTf)(CO)_nP_5-n compounds to react with an excess of the imine. Hydride-imine [MH(η¹-NHCPh₂)P₄]BPh₄ (M = Ru, Os), triflate-imine [Os(κ¹-OTf)(η¹-NHCPh₂)P₄]BPh₄ and bis(imine) [Ru(η¹-NHCPh₂)₂P₄](BPh₄)₂ [P = P(OEt)₃] derivatives were also prepared. The complexes were characterized spectroscopically (IR, ¹H, ³¹P, ¹³C NMR) and a geometry in solution was also established. Hydride-benzophenone imine [IrHCl(η¹-NHCPh₂)L(PPh₃)₂]BPh₄and [IrHCl(η¹-NHCPh₂)L(AsPh₃)₂]BPh₄ [L = P(OEt)₃ and PPh(OEt)₂] complexes were prepared by reacting hydride IrHCl₂L(PPh₃)₂ and IrHCl₂L(AsPh₃)₂ precursors with an excess of imine. Dihydride IrH₂(η¹-NHCPh₂)(PPh₃)₃ complex was also obtained and a geometry in solution was proposed.     

Supported organometallic complexes part 39: cationic diamine(ether-phosphine)ruthenium(II) complexes as precursors for the hydrogenation of trans-4-phenyl-3-butene-2-one

Treatment of RuCl₂(η¹-Ph₂PCH₂CH₂OCH₃)₂(diamine) (1L₁-1L₇) with one equivalent of AgX (X=OTf, BF₄) in CH₂Cl₂ results in the formation of the monocationic ruthenium(II) complexes [RuCl(η¹-Ph₂PCH₂CH₂OCH₃)(η²-Ph₂PCH₂CH₂OCH₃)(diamine)]⁺X⁻ (2L₁-2L₇). These complexes were characterized by NMR, and mass spectroscopy as well as by elemental analyses, 2L₁ additionally by an X-ray structural analysis. Complex 2L₁ crystallizes in the monoclinic space group C2/c with Z=8. The monocationic and neutral complexes were applied as catalysts in the selective hydrogenation of trans-4-phenyl-3-butene-2-one. With the exception of 1L₃/1L₇ and 2L₃/2L₇ all catalysts showed high activities and selectivities toward the hydrogenation of the carbonyl group under mild conditions. However, the activity of the cationic catalysts is only half of that of their neutral congeners.     

Syntheses, characterization and luminescence of Pt-M (M = Re, Ru, Gd) heteronuclear complexes with 5-ethynyl-2,2′-bipyridine

Incorporation of diplatinum component [Pt₂(μ-dppm)₂(CCbpy)₄] (1, dppm = Ph₂PCH₂PPh₂, CCbpy = 2,2′-dipyridyl-5-acetylide) with Re(CO)₅Cl, Ru(bpy)₂Cl₂ (bpy = 2,2′-bipyridine) and Gd(hfac)₃(H₂O)₂ (Hhfac = hexafluoroacetylacetone) via 2,2′-dipyridyl chelating induced isolation of (2), (3), and (4) complexes, respectively. The structures of 2 and 4 were determined by X-ray single crystal diffraction. Intense low-energy absorptions occur in the range 360-510 nm originating from metal-to-ligand charge transfer (MLCT) transitions. These compounds display photoluminescence in both solid states and dichloromethane at room temperature with emissive lifetimes in the range of microseconds.     

Reaction of iron and ruthenium halogenide complexes with GaCp and AlCp: Insertion, Cp transfer reactions and orthometallation

The reactions of the Fe(II) and Ru(II) halogenide complexes [Fe(PPh₃)₂Br₂], [Fe(NCCH₃)₂Br₂], [Ru(PPh₃)₃Cl₂], and [Ru(dmso)₄Cl₂] with GaCp^∗ and AlCp^∗, respectively, are investigated. The reactions of [FeBr₂L₂] with ECp^∗ exclusively proceed via Cp^∗ transfer, leading to [FeCp^∗(GaCp^∗)(GaBr₂)(PPh₃)] (1) (L = PPh₃, E = Ga), [FeCp^∗(GaCp^∗)₂ (GaBr₂)] (2) (L = NCCH₃, E = Ga) and [FeCp^∗(μ³-H)(κ²-(C₆H₄)PPh₂)(AlCp^∗)(AlBr₂)] (3) (L = PPh₃, E = Al), the latter of which is formed via orthometallation of one PPh₃ ligand. The reaction of [Ru(dmso)₄Cl₂] leads to the homoleptic complex [Ru(GaCp^∗)₆Cl₂] (4) in high yields, while [Ru(PPh₃)₃Cl₂] gives 4 in rather low yields. The reason for this difference in reactivity is investigated and it is shown that Cp^∗ transfer and orthometallation are the limiting side reactions of the reaction of [Ru(PPh₃)₃Cl₂] with GaCp^∗. All compounds were characterized by NMR spectroscopy, and single crystal X-ray diffraction studies were performed for 1, 3, and 4.     

Reactions of nitrones with transition metal nitrile complexes: cycloaddition, ligand substitution, or hydrolysis

The reaction of nitrones with transition metal nitrile complexes of the type [MCl₂(PhCN)₂] and [MCl₄(MeCN)₂] leads to different products, depending on the metal. Reaction of [PdCl₂(PhCN)₂] with RCHN(Me)O (R=Ph, p-C₆H₄Me) afford Δ⁴-1,2,4-oxadiazoline complexes as products of [2 + 3] cycloaddition of the nitrone across the C≡N bond of the nitrile. The oxophilic transition metal compounds [TiCl₄(MeCN)₂] and [ZrCl₄(MeCN)₂] undergo rapid ligand exchange to form nitrone complexes from which the nitrone can be released without decomposition. The closely related compounds [MoCl₄(MeCN)₂] and [WCl₄(MeCN)₂] mediate the hydrolysis of nitrones to the corresponding aldehydes.     

Molecular structures and redox properties of oxorhenium(V) ‘3+1’ mixed ligand complexes with heterocyclic thiolates containing nitrogen

Reactions of chloro(3-thiapentane-1,5-dithiolato)oxorhenium(V) [ReO(SSS)Cl] with N-methyl-1H-imidazole-2-thiol (HL¹) and 2-pyrimidinethiol (HL²) have been studied to form ‘3+1’ oxorhenium(V) complexes. In the absence of triethylamine, [Re(SSS)(HL¹)]Cl (1a) was formed, while in the presence of triethylamine [Re(SSS)L¹] (1b) and [Re(SSS)L²] (2) were produced. Molecular structures of complexes 1a and 2 were determined to be distorted square pyramidal by single crystal X-ray analytical method. From cyclic voltammetric studies, furthermore, it was proposed that complexes 1b and 2 are irreversibly oxidized to Re(VI) at around 0.84 and 1.01 V versus Ag/AgNO₃, respectively, and are reduced to Re(IV) at −1.55 and −1.51 V with the dissociation of L¹ or L², followed by the quasi-reversible reductions to Re(III) at around −1.69 V, respectively.     

Reactions of captopril and epicaptopril with transition metal ions and hydroxyl radicals: An EPR spectroscopy study

In the present study, using the technique of EPR spin trapping with DMPO a spin trap, we demonstrated formation of thiyl radicals from thiol-containing angiotensin converting enzyme (ACE) inhibitor captopril (CAP) and from its stereoisomer epicaptopril (EPICAP), a non-ACE inhibitor, in the process of ^.OH radical scavenging. Splitting constants of DMPO/thiyl radical adducts were identical for both thiols and were a_N = 15.3 G, and a_H = 16.2 G. Bimolecular rate constants for the reaction of CAP and EPICAP with ^.OH radicals were close to a diffusion-controlled rate (≈ 2 × 10¹⁰ M⁻¹s⁻¹). Our data also show that both CAP and EPICAP reduce Fe(III) ions and that their respective thiyl radicals are formed in this reaction. In the presence of Fe(III), H₂O₂, and CAP, or EPICAP, ^.OH radicals were produced by a thiol-driven Fenton mechanism. Copper(II) ions were also reduced by these thiols, but no thiyl radicals could be detected in these reactions, and no ^.OH or other Fenton oxidants were observed in the presence of H₂O₂. Our data show direct evidence that thiol groups of CAP and EPICAP are involved in scavenging of ^.OH radicals. The direct ^.OH radical scavenging, together with the reductive “repair” of other sites of ^.OH radical attack, may contribute to the known protective effect of CAP against ischemia/reperfusion-induced arrhythmias. The formation of reactive thiyl radicals in the reactions of the studied compounds with ^.OH radicals and with Fe(III) ions may play a role in some of the known adverse effects of CAP.     

Addition compounds of MoO2Cl2 with chiral sulfoxides. First molecular structures of dioxomolybdenum complexes bearing chiral non-racemic sulfoxide as ligand

MoO₂Cl₂(L)₂ [L = (R)-(+)-methyl-p-tolylsulfoxide (R-MeTolSO) (1), methyl-p-tolylsulfoxide (MeTolSO) (2), 2-benzenesulfinyl-1,1-diphenylethanol (BSDPE) (3), 1-benzenesulfinyl-2-methyl-2-propanol (BSMP) (4), benzenesulfinylmethyl 4-methylphenyl ketone (BSMMPK) (5)], and MoO₂Cl₂(L) [L = BSDPE (6), BSMP (7), BSMMPK (8), (S,S)-bis(p-tolylsulfinyl)methane (S,S-TolSOCH₂SOTol) (9), bis(methylsulfinyl)methane (MeSOCH₂SOMe) (10), bis(phenylsulfinyl)methane (PhSOCH₂SOPh) (11)] have been synthesized by reacting a solution of MoO₂Cl₂(H₂O)₂ in diethyl ether with the corresponding ligand. The crystal and molecular structures of 1, 2, and 9 have been established by X-ray diffraction analysis. The ability of 1 and 9 as catalysts for the enantioselective reduction of sulfoxides to sulphides and the oxidation of sulphides to sulfoxides has been examined.     

Carbonylmolybdenum complexes with di(imino)pyridine and related ligands: Reduction of a di(imino)pyridine to an aminoiminopyridine system under mild conditions

The reactions of [Mo(CO)₆] towards a 2,6-di(imino)pyridine L¹ and related ligands were studied. The reaction with L¹ afforded two new complexes, [Mo(CO)₄L¹] (1) and [Mo(CO)₄L²] (2), where L² is the 2-amino-6-iminopyridine ligand arising from the hydrogenation of one imine function of L¹; similar reaction with a 2-acetyl-6-iminopyridine ligand L³ afforded [Mo(CO)₄L³] (3). Compounds 1, 2 and 3 have been fully characterised by IR, ¹H NMR and X-ray crystallography; they present a metal ion in a pseudo-octahedral environment, the three organic ligands acting with bidentate N₂ coordination modes. One of the imine functions in 1, the amine function in 2, and the ketone function in 3 are uncoordinated.     

Synthesis and characterization of Ru(II), Rh(III) and Ir(III) complexes of the “Daniphos” ligands and their application in the hydrogen transfer catalysis

The synthesis of arene-ruthenium(II) and C₅Me₅-rhodium(III) and -iridium(III) complexes of chiral arene-chromium-tricarbonyl-based P^∧P and P^∧N ligands is described. Three complexes were characterized in the solid state by X-ray structural analysis. The complexes were tested in the catalytic hydrogen transfer reactions as well as in the kinetic resolution of racemic alcohols, where some complexes showed good conversion, but low enantioselectivity.     

Multinucleating ligands from multiple palladium(0)-catalysed cross-coupling reactions — synthesis and characterisation of a trinuclear cyclometallated ruthenium(II) complex and a hexanuclear EPR-active molybdenum complex

Two multinucleating ligands have been prepared from 1,3,5-tris(3,5-dibromophenyl)benzene by multiple Pd(0)-catalysed cross-coupling reactions. 1,3,5-Tris[3,5-bis(4-pyridylethenyl)phenyl]benzene (L¹) has six remote pyridyl moieties, each of which can coordinate a 17 valence-electron Mo(tp^*)(NO)Cl fragment (tp^* = hydrotris(3,5-dimethylpyrazolyl)borate), affording the hexanuclear complex [Cl(NO)(tp^*)Mo₆(L¹) (1). 1,3,5-Tris[3,5-bis(2-pyridyl)phenyl]benzene (L²) incorporates three potentially terdentate, cyclometallating N,C,N-donor sets, and can coordinate three Ru(tpy)²⁺ fragments (tpy = 2,2′:6′,2″-terpyridine) giving the trinuclear complex [(tpy)Ru₃(L²)][PF₆]₃ (2). Complex 1 is EPR active, with nearest-neighbour pairs of molybdenum centres displaying magnetic exchange interactions. Electrochemical studies of the two complexes suggest that there is little ground-state interaction between the metal centres in either case.     

Early transition metal complexes of dinucleating Pacman ligands: X-ray crystal structures of mixed-valence V/V complexes

The use of a Schiff-base calixpyrrole (L) as a dinucleating ligand for early transition metals is described. Salt elimination reactions between the crystallographically-characterised [K₄(THF)₃(PhMe)(L)] and titanium(III) and vanadium(III) halides form the new dinuclear complexes [(MCl)₂(L)] (M = Ti, V). Adventitious, and partial, oxidation of [(VCl)₂(L)] resulted in the formation of the unusual mixed-valence vanadyl complexes [(VO)(S)(VCl)(L)] (S = THF or pyridine), which both adopt desired Pacman geometries in the solid state in which the oxo ligand is accommodated within the dinuclear molecular cleft.     

Application of the non-isothermal approach to the kinetics of organometallic reactions: the substitution of (η-pentamethylcyclopentadienyl)dicarbonylrhodium(I)

A non-isothermal method for determining the rate constant for a solution phase reaction as a function of temperature, and the quasithermodynamic parameters, are described. Non-isothermal methods for studying the kinetics of reactions offer several advantages, including savings in time and materials, and enhanced accuracy. The method is demonstrated by a study of the reactions of (η⁵-pentamethylcyclopentadienyl)dicarbonylrhodium with P(OMe)₃, P(n-Bu)₃, PPh₃ and P(i-Pr)₃.