Vadim Yu. Kukushkin

Oxime and oximate metal complexes: unconventional synthesis and reactivity

Abstract The chemistry of oxime/oximato metal complexes has been investigated actively since the beginning of 20th century and aspects such as traditional synthetic routes leading to oxime/oximato complexes, structural and solution chemistry and analytical applications of oxime species have been reviewed extensively. Despite a fairly large number of reviews and books on different aspects of the chemistry of oxime/oximato metal compounds, data on their metal-mediated reactions are just beginning to actively emerge. Apparently, our review (V.Yu. Kukushkin, D. Tudela, A.J.L. Pombeiro, Coord. Chem. Rev. 156 (1996) 333) published in this journal in 1996 was the first attempt for classification of such reactions. In this article we carry on the description, systematization and analysis of metal-mediated reactions of oxime species with special emphasis on research of the last few years and also work produced in our group. In addition, data on unconventional routes for preparation of oxime/oximato complexes are also included and ascribed to certain reaction modes.

Metal-ion mediated deoxygenation of sulfoxides

Abstract Over the past two decades, the deoxygenation (i.e. the reduction of the sulfinyl group) of free sulfoxides, R2SO, has been extensively studied and described in a number of reviews. However, the deoxygenation of coordinated sulfoxide ligands and metal-ion mediated deoxygenation of sulfoxides has received much less attention and no general overview of these processes has been presented. Correcting that omission is the major goal of this review. Although details of syntheses that involve the deoxygenation of sulfoxide ligands are presented, particular emphasis is placed on discussion of both the common features and differences in the reactions of S- and O-bonded sulfoxides. Along with general consideration of experimental results, an attempt is made to show that most of the methods for the reduction of the very strong SO bond in S-coordinated R2SO ligands are based on an initial activation of the sulfinyl oxygen by a reagent having a highly reactive electrophilic center. In contrast, in the case of O-bound sulfoxides, the metal ion itself plays the role of the electrophilic reagent and thus promotes the deoxygenation reaction. In order to provide a clearer picture of sulfoxide deoxygenation reactions, possible reaction pathways are discussed and evidence for these mechanisms is provided.

Reversion of Structure-Activity Relationships of Antitumor Platinum Complexes by Acetoxime but Not Hydroxylamine Ligands

The presence of cis-configured exchangeable ligands has long been considered a prerequisite for antitumor activity of platinum complexes, but over the past few years, several examples violating this structure-activity relationship have been recognized. We report here on studies with the geometric isomers of [PtCl2(acetoxime)2], cis-[dichlorobis(acetoxime)platinum(II)] [1 (cis)] and trans-[dichlorobis(acetoxime)platinum(II)] [2 (trans)], as well as those of [PtCl2(hydroxylamine)2], cis-[dichlorobis(hydroxylamine)platinum(II)] [3 (cis)] and trans-[dichlorobis(hydroxylamine)platinum(II)] [4 (trans)]. We found that 2 (trans)is 16 times more cytotoxic than 1 (cis) and as cytotoxic as cisplatin in cisplatin-sensitive ovarian carcinoma cells (CH1). Moreover, 2 (trans) is 15 times more cytotoxic than either cisplatin or 1 (cis) in intrinsically cisplatin-resistant colon carcinoma cells (SW480). Thus, compound 2 (trans) represents a novel type of active platinum(II) complexes of the trans geometry, whereas the hydroxylamine-containing complexes conform to the classic structure-activity relationships. The reactivity of the compounds toward dGMP and DNA and their capacity to alter the structure of double-stranded DNA and form interstrand cross-links were studied by capillary electrophoresis and gel electrophoresis. The slow binding of 2 (trans) to dGMP (τ½ = 50 h versus 8.9 h in the case of cisplatin), the low reactivity toward DNA, the comparatively small impact on DNA secondary structure, and the lack of detectable interstrand cross-linking suggest a mode of action fundamentally different from that of cisplatin. Implications of our findings for the minimal structural requirements (e.g., planarity around the nitrogen donor atom and/or ramified aliphatic moiety attached to the latter) of active trans-configured platinum complexes are discussed.

Novel Cis- and Trans-Configured Bis(oxime)platinum(II) Complexes: Synthesis, Characterization, and Cytotoxic Activity

Novel cis- and trans-configured bis(oxime)platinum(II) complexes have been synthesized and characterized by elemental analyses, IR, electrospray ionization mass spectrometry, multinuclear ((1)H, (13)C, and (195)Pt) NMR spectroscopy, and, in five cases, by X-ray diffraction. Their cytotoxicity was studied in the cisplatin-sensitive CH1 cell line as well as in inherently cisplatin-resistant SW480 cancer cells. Remarkably, every single dihalidobis(oxime)platinum(II) complex (with either a cis or trans configuration) shows a comparable cytotoxic potency in both cell lines, indicating a capacity of overcoming cisplatin resistance. Particularly strong cytotoxicities were observed in the case of trans-[PtCl(2)(R(2)C=NOH)(2)] (R = Me, n-Pr, i-Pr) with IC(50) values in the high nanomolar concentration range in both CH1 and SW480 cancer cells. These complexes are as potent as cisplatin in CH1 cells and up to 20 times more potent than cisplatin in SW480 cells. In comparison to transplatin, the novel compounds are up to 90 (CH1) and 120 times (SW480) more cytotoxic. The previously reported observation that the trans geometry yields a more active complex in the case of [PtCl(2)(Me(2)C=NOH)(2)] could be confirmed for at least two structural analogues.

A new family of luminescent compounds: platinum(II) imidoylamidinates exhibiting pH-dependent room temperature luminescence

The imidoylamidinate platinum(II) compounds [Pt{NH=C(R)NC(Ph)NPh}2] (R = CH2Ph 2, p-ClC6H43, Ph 4) were prepared by the reaction of the appropriate trans-[PtCl2(RCN)2] with 4 equiv of the amidine PhC(NH)NHPh giving 2-4 and 2 equivs of the salt PhC(=NH)NHPh.HCl. We also synthesized, by the double alkylation of 4 with MeOSO2CF3, complex [Pt{NH=C(Ph)N(Me)C(Ph)=NPh}2][CF3SO3]2 (5) which models the bis-protonated form of 4. The complexes were characterized by 1H, 13C NMR, and IR spectroscopies, FAB-MS and by C, H, N elemental analysis. The X-ray crystallography of 4.2CH2Cl2 enables the confirmation of the square planar coordination geometry of the metal center with almost planar imidoylamidine ligands, while in 5.2CHCl3 the planarity of the metallacycles is lost and and the central N atom is sp3-hybridized. The imidoylamidinate complexes represent a new family of Pt(II)-based luminescent complexes and they are emissive at room temperature both in solution and in the solid state, with an emission quantum yield ranging from 3.7 x 10(-4) to 6.2 x 10(-2) in methanol solution; the emission intensity is pH-dependent, being quenched at low pH. UV-visible and luminescence spectroscopies indicate that the lowest excited state of these compounds is 3MLCT or 3IL with significant MLCT character, with emission lifetimes of a few micros. A blue shift of both the absorption and emission with increasing solvent polarity and with decreasing pi-electron withdrawing properties of the ligand substituent was observed.

Metal-Mediated [2+3] Cycloaddition of Nitrones to Palladium-Bound Isonitriles

The reactions between equimolar amounts of cis-[PdCl(2)(C[triple bond]NR)(2)] (R = cyclohexyl (Cy) 1, tBu 2, 2,6-Me(2)C(6)H(3) (Xyl) 3) and the acyclic nitrones O(+)N(R(2))=C(H)R(3) (R(2) = Me 5, R(2) = CH(2)Ph 6, R(3) = 4-MeC(6)H(4)) proceeded in C(6)H(6) at 5 degrees C for around 4 h and then the reaction systems were maintained at 20-25 degrees C for 20 h to provide the carbene complexes [PdCl(2){C(ONR(2)C(c)HR(3)) = N(d)R}(C[triple bond]NR)(C(c)-N(d))] (8-13) in good yields (54-70%). The latter species originated from the previously unreported metal-mediated [2+3] cycloaddition of nitrones to coordinated isonitriles. For the reactions of cis-[PdCl(2)(C[triple bond]NR)(2)] (1-3) and 5 or 6 performed in C(6)H(6) at 20-25 degrees C, the selectivity of the cycloaddition was lost, and the reactions gave mixtures of 8-13 and the complexes [PdCl(2){N(R(2))=CHR(3)}(C[triple bond]NR)] (14-19, ca. 75%) derived from intramolecular deoxygenation of the nitrones. The reactions of equimolar amounts of cis-[PdCl(2)(C[triple bond]NR)(2)] (1-3 and R = 4-MeOC(6)H(4) 4) and the nonaromatic cyclic nitrone (-)O(+)N(a)=CHCH(2)CH(2)C(b)Me(2)(N(a)-C(b)) (7) in CHCl(3) at 5 degrees C for around 2 h led to the carbene species [PdCl(2){C(ON(a)CMe(2)CH(2)CH(2)C(b)H) = N(e)R}(C[triple bond]NR)(N(a)-C(b))(C(b)-N(e))] (21-24), isolated in yields of 78-92%. When the reactions of cis-[PdCl(2)(C[triple bond]NR)(2)] (1-4) and 7 (1:1 molar ratio) were performed in CHCl(3) at 20-25 degrees C for around 1 h, the carbenes 21-24 and the complexes [PdCl(2){N(f)CMe(2)CH(2)CH(2)C(g)H}(C[triple bond]NR)(N(f)-C(g))] (25-28, ca. 35%), derived from the deoxygenation of 7, were identified by ESI(+)-MS and (1)H NMR analysis (after redissolution in CDCl(3)). The reactions of cis-[PdCl(2)(C[triple bond]NR)(2)] (1-4) and 7 (1:2 molar ratio) in CHCl(3) at 5 degrees C furnished mixtures of [PdCl(2){C(ON(a)CMe(2)CH(2)CH(2)C(b)H)=N(e)R}(N(f)CMe(2)CH(2)CH(2)C(g)H)(N(a)-C(b))(C(b)-N(e))(N(f)-C(g))] (29-32; ca. 25-30%), 25-28 (ca. 10-15%), and [PdCl(2)(ON(a)CMe(2)CH(2)CH(2)C(b)H)(2)(N(a)-C(b))]. The same reactions at room temperature afforded the complex [PdCl(2)(N(f)CMe(2)CH(2)CH(2)C(g)H)(2)(N(f)-C(g))] (33; ca. 20 %) in a mixture with 29-32 (ca. 5-10%) and 25-28.

Difference in Energy between Two Distinct Types of Chalcogen Bonds Drives Regioisomerization of Binuclear (Diaminocarbene)PdII Complexes

The reaction of cis-[PdCl2(CNXyl)2] (Xyl = 2,6-Me2C6H3) with various 1,3-thiazol- and 1,3,4-thiadiazol-2-amines in chloroform gives a mixture of two regioisomeric binuclear diaminocarbene complexes. For 1,3-thiazol-2-amines the isomeric ratio depends on the reaction conditions and kinetically (KRs) or thermodynamically (TRs) controlled regioisomers were obtained at room temperature and on heating, respectively. In CHCl3 solutions, the isomers are subject to reversible isomerization accompanied by the cleavage of Pd-N and C-N bonds in the carbene fragment XylNCN(R)Xyl. Results of DFT calculations followed by the topological analysis of the electron density distribution within the formalism of Baders theory (AIM method) reveal that in CHCl3 solution the relative stability of the regioisomers (ΔGexp = 1.2 kcal/mol; ΔGcalcd = 3.2 kcal/mol) is determined by the energy difference between two types of the intramolecular chalcogen bonds, viz. S···Cl in KRs (2.8-3.0 kcal/mol) and S···N in TRs (4.6-5.3 kcal/mol). In the case of the 1,3,4-thiadiazol-2-amines, the regioisomers are formed in approximately equal amounts and, accordingly, the energy difference between these species is only 0.1 kcal/mol in terms of ΔGexp (ΔGcalcd = 2.1 kcal/mol). The regioisomers were characterized by elemental analyses (C, H, N), HRESI+-MS and FTIR, 1D (1H, 13C{1H}) and 2D (1H,1H-COSY, 1H,1H-NOESY, 1H,13C-HSQC, 1H,13C-HMBC) NMR spectroscopies, and structures of six complexes (three KRs and three TRs) were elucidated by single-crystal X-ray diffraction.

Fine-tuning halogen bonding properties of diiodine through halogen–halogen charge transfer – extended [Ru(2,2′-bipyridine)(CO)2X2]·I2 systems (X = Cl, Br, I)

The current paper introduces the use of carbonyl containing ruthenium complexes, [Ru(bpy)(CO)2X2] (X = Cl, Br, I), as halogen bond acceptors for a I2 halogen bond donor. In all structures, the metal coordinated halogenido ligand acts as the actual halogen bond acceptor. Diiodine, I2, molecules are connected to the metal complexes through both ends of the molecule forming bridges between the complexes. Due to the charge transfer from Ru–X to I2, formation of the first Ru–X⋯I2 contact tends to generate a negative charge on I2 and redistribute the electron density anisotropically. If the initial Ru–X⋯IA–IB interaction causes a notable change in the electron density of I2, the increased negative charge accumulates on the second iodine, IB. The increased negative charge on IB reduces its ability to act as a halogen bond donor. With the [Ru(bpy)(CO)2Cl2] complex, the electron density of the I2 molecule remains isotropic and it acts as a symmetrical halogen bond donor for two metal complexes. With [Ru(bpy)(CO)2Br2] and [Ru(bpy)(CO)2I2], the Ru–X⋯IA–IB⋯X–Ru bridges are unsymmetrical with a stronger and shorter Ru–X⋯IA contact and a weaker and longer Ru–X⋯IB contact. In these cases, the negative charge is accumulated on the more weakly bonded IB atoms. QTAIM calculations were used to analyze the strength of the interactions and charge distribution in the metal complex and I2 molecule in detail. In accordance with the experimental data, the QTAIM analyses show that the charge difference between the two ends of the I2 molecule is increased in the order Ru–Cl⋯I2 < Ru–Br⋯I2 < Ru–I⋯I2.

cis-Influence determination of ethylene and benzyl cyanide ligands in the complexes cis-[Pt(Me2SO)(C2H4)Cl2] and cis-[Pt(Me2SO)-(PhCH2CN)Cl2] on the basis of X-ray structure data. IR and 1H, 13C and 195Pt NMR characterization of the cis-[Pt(Me2SO)LCl2] series

Complexes of the cis-[Pt(Me2SO)LCl2] series (L=Me2SO, Me2S, C2H4, MeCN, PhCH2CN, PhCN, C5H5N, 2Me-C5H4N and NH3) were prepared by known methods and characterized by IR and 1H, 13C{1H}, 195Pt{1H} NMR spectra. Structures of cis-[Pt(Me2SO)(C2H4)Cl2] and cis-[Pt(Me2SO)- (PhCH2CN)Cl2] were determined by X-ray analysis, cis-[Pt(Me2SO)(C2H4)Cl2] crystallizes in the orthorhombic space group Pmnb. The unit cell parameters are a=8.200(1), b=12.924(3), c=8.574(1) A, V=908.7(3) A3, ρcalc=2.72 g cm−3, Z=4. cis-[Pt(Me2SO)(PhCH2CN)Cl2] crystallizes in the monoclinic space group P21/n. The unit cell parameters are: a=12.223(4), b=16.605(4), c=6.779(2) A, γ=91.10(2)°, V=1375.6(7) A3, ρcalc=2.23 g cm−3, Z=4. On the basis of the X-ray structure data cis- and trans- influence of C2H4 and PhCH2CN ligands were determined.

X-ray structure determination of cis-dichloro(dimethyl sulfoxide)(acetonitrile)platinum(II) and cis-dibromo(dimethyl sulfoxide)(acetonitrile)platinum(II). cis-influence of ligands in the complexes cis-[Pt(Me2SO)(ligand)Cl2]

Abstract The reaction of the complexes K[Pt(Me2SO)X3] (X  Cl, Br) with MeCN in water results in the isolation of solid cis-[Pt(Me2SO)(MeCN)X2] complexes. The latter complexes were characterized by the elemental analysis, IR and 1H NMR spectra and their structure was determined by the X-ray analysis. The complexes cis-[Pt(Me2SO)(MeCN)X2] are isostructural. cis-[Pt(Me2SO)(MeCN)Cl2] crystallizes in the triclinic space group P 1 . The unit cell parameters are: a = 7.346(1), b = 8.865(1), c = 14.886(2) A, α = 90.58(1), β = 96.10(1), γ = 87.44(2)°, V = 962.9(3) A3, ϱcalc = 2.65 g cm−3, Z = 4; bond lengths in two crystallographically independent molecules (A): PtCl (trans to N) 2.278(2), 2.278(2); PtCl (trans to S) 2.310(3), 2.322(3), PtN 1.977(8), 1.956(8); PtS 2.216(2), 2.224(3). cis-[Pt(Me2SO)(MeCN)Br2] crystallizes in the triclinic space group P 1 . The unit cell parameters are: a = 7.569(1), b = 9.053(2), c = 15.014(3) A, α = 90.33(1), β = 95.20(1), γ = 87.12(1)°, V = 1023.3(4) A3, ϱcalc = 3.08 g cm−3, Z = 4; bond lengths in two crystallographically independent molecules (A) are: PtBr (trans to N) 2.397(2), 2.394(2), PtBr (trans to S) 2.429(2), 2.427(2), PtN 1.983(13), 1.986(14), PtS 2.228(4), 2.233(5). Comparison of the data with those known from the literature suggests a mutual ligands influence in the cis-[Pt(Me2SO)(ligand)X2] complexes.