Lanthanoid Biphenolates as a Rich Source of Lanthanoid-Main Group Heterobimetallic Complexes.

Several new trivalent dinuclear rare earth 2,2'-methylenebis(6-tert-butyl-4-methylphenolate) (mbmp2- ) complexes with the general form [Ln2 (mbmp)3 (thf)n ] (Ln=Sm 1, Tb 2 (n=3), and Ho 3, Yb 4 (n=2), and a tetravalent cerium complex [Ce(mbmp)2 (thf)2 ] (5) have been synthesised by RTP (redox transmetallation/protolysis) reactions from lanthanoid metals, Hg(C6 F5 )2 and the biphenol mbmpH2 . These new complexes and some previously reported partially protonated rare earth biphenolate complexes [Ln(mbmp)(mbmpH)(thf)n ] react with lithium, aluminium, potassium and zinc organometallic reagents to form lanthanoid-main group heterobimetallic species. When reaction mixtures containing the Ln biphenolate complexes were treated with n-butyllithium, both molecular ([Li(thf)2 Ln(mbmp)2 (thf)n ] (Ln=La 6, Pr 7 (n=2) and Er 8, Yb 9, and Lu 10 (n=1)) and charge separated ([Li(thf)4 ][Ln(mbmp)2 (thf)2 ] (Ln=Y 11, Sm 12, Dy 13, and Ho 14) complexes were isolated. Treatment with trimethylaluminium also led to isolation of molecular ([AlMe2 Ln(mbmp)2 (thf)2 ] (Ln=Pr 15, Sm 16, and Tb 17)) and ionic [La(mbmp)(thf)5 ][AlMe2 (mbmp)] (18) complexes. One gadolinium-potassium ([K(thf)3 Gd(mbmp)2 (thf)2 ] (19)), and one ytterbium-zinc species ([ZnEtYb(mbmp)2 (thf)] (20)) were isolated from treatment of reaction mixtures with potassium bis(trimethylsilyl)amide and diethylzinc respectively.

New lanthanoid biphenolate complexes, their further reactivity with trimethylaluminium and catalytic activity for the polymerisation of rac-lactide.

A series of rare earth biphenolate complexes of the general form [Ln(mbmp)(mbmpH)(thf)3] (Ln = Y (1), Nd (2), Gd (3), Dy (4), Er (5), Tm (6) and Lu (7)) have been synthesised by redox transmetallation/protolysis (RTP) from the free rare earth metal, Hg(C6F5)2 and 2,2'-methylenebis(6-tert-butyl-4-methylphenol) (mbmpH2). The rare earth metal is six coordinate with one chelating biphenolate mbmp2- ligand and one unidentate monophenolate mbmpH- ligand. The yttrium complex, when crystallised from hot toluene or deuterated benzene, loses a coordinated thf and exhibits coordination through all three phenolate oxygen atoms, as well as the oxygen of the phenol, yielding two solvates [Y(mbmp)(mbmpH)(thf)2]·nsolv (solv = PhMe, n = 1 (8a) or C6D6, n = 2 (8b)). Of these rare earth complexes, the yttrium derivative (1) yielded the heterobimetallic complex [AlMe2Y(mbmp)2(thf)2] (9) when treated with trimethylaluminium, whereas all other complexes produced the transmetallation product [AlMe(mbmp)(thf)] (11). The dinuclear dysprosium complex [Dy2(mbmp)3(thf)3] (10) was isolated alongside 11 from the reaction of 4 with trimethylaluminium, suggesting trimethylaluminium instigates a redistribution reaction. The ROP activity of the mononuclear neodymium, dysprosium, lutetium, and aluminium complexes towards rac-lactide in toluene at 70 °C was found to be poor compared to rare earth complexes of monodentate aryloxides, but increased with increased rare earth ion size.

Competitive formation of DNA linkage isomers by a trinuclear platinum complex and the influence of pre-association.

2D [(1)H, (15)N] HSQC NMR spectroscopy has been used to monitor the reaction of fully (15)N-labelled [{trans-PtCl(NH3)2}2(µ-trans-Pt(NH3)2{NH2(CH2)6NH2}2)](4+) (BBR3464 ((15)N-1)) with the 14-mer duplex (5'-{d(ATACATG(7)G(8)TACATA)}-3'·5'-{d(TATG(18)TACCATG(25)TAT)}-3' or I) at pH 5.4 and 298 K, to examine the possible formation of 1,4 and 1,5-GG adducts in both 5'-5' and 3'-3' directions. In a previous study, the binding of the dinuclear 1,1/t,t to I showed specific formation of the 5'-5' 1,4 G(8)G(18) cross-link, whereas in this case a mixture of adducts were formed. Initial (1)H NMR spectra suggested the presence of two pre-associated states aligned in both directions along the DNA. The pre-association was studied in the absence of covalent binding, by use of the "non-covalent" analog [{trans-Pt(NH3)3}2(µ-trans-Pt(NH3)2{NH2(CH2)6NH2}2)](6+) (AH44, 0). Chemical shift changes of DNA protons combined with NOE connectivities between CH2 and NH3 protons of 0 and the adenine H2 protons on I show that two different molecules of 0 are bound in the minor groove. Molecular dynamic simulations were performed to study the interaction of 0 at the two pre-association sites using charges derived from density functional theory (DFT) calculations. Structures where the central platinum is located in the minor groove and the aliphatic linkers extend into the major groove, in opposite directions, often represent the lowest energy structures of the snapshots selected. In the reaction of (15)N-1 and I, following the pre-association step, aquation occurs to give the mono aqua monochloro species 2, with a rate constant of 3.43 ± 0.03 × 10(-5) s(-1). There was evidence for two monofunctional adducts (3, 4) bound to the 3' (G8) and 5' (G7) residues and the asymmetry of the (1)H,(15)N peak for 3 suggested two conformers of the 3' adduct, aligned in different directions along the DNA. The rate constant for combined monofunctional adduct formation (0.6 ± 0.1 M(-1)) is ca. 2-fold lower for 1 compared to 1,1/t,t, whereas the rate constant for conversion of the combined monofunctional species to combined bifunctional adducts (5) (8.0 ± 0.2 × 10(-5) s(-1)) is two-fold higher.

[1H, 15N] heteronuclear single quantum coherence NMR study of the mechanism of aquation of platinum(IV) ammine complexes.

The aquation and hydrolysis of a series of platinum(IV) complexes of the general form cis, trans, cis-[PtCl 2(X) 2( (15)NH 3) 2] (X = Cl (-), O 2CCH 3 (-), OH (-)) have been followed by [ (1)H, (15)N] Heteronuclear Single Quantum Coherence NMR spectroscopy. Negligible aquation (<5%) is observed for the complexes where X = O 2CCH 3 (-) or OH (-) over 3-4 weeks. Aquation of cis-[PtCl 4( (15)NH 3) 2] ( 1) is observed, and the rate of aquation increases with increasing pH and upon the addition of 0.01 mol equiv of the platinum(II) complex cis-[PtCl 2( (15)NH 3) 2] (cisplatin). The first aquated species formed from cis-[PtCl 4(NH 3) 2] has one of the axial chloro groups (relative to the equatorial NH 3 ligands) replaced by an aqua/hydroxo ligand. The second observed substitution occurs in an equatorial position. Peaks that are consistent with five of the eight possible aquation species were observed in the NMR spectra.

5,5'-Bis[(trimethyl-silyl)meth-yl]-2,2'-bipyridine.

The mol-ecule of the title compound, C(18)H(28)N(2)Si(2), occupies a special position on an inversion centre. The Si-CH(2)-C(ipso) plane is approximately orthogonal to the plane of the pyridine rings, the corresponding dihedral angle being 82.0 (2)°.

Underlying spin-orbit coupling structure of intervalence charge transfer bands in dinuclear polypyridyl complexes of ruthenium and osmium.

The mixed-valence systems meso- and rac-[{M(bpy)2}2(mu-BL)]5+ {M = Ru, Os; BL = a series of polypyridyl bridging ligands such as 2,3-bis(2-pyridyl)benzoquinoxaline (dpb)} are characterized by multiple intervalence charge transfer (IVCT) and interconfigurational (IC) bands in the mid-infrared and near-infrared (NIR) regions. Differences in the relative energies of the IC transitions for the fully oxidized (+6) states of the osmium systems demonstrate that stereochemical effects lead to fundamental changes in the energy levels of the metal-based dpi orbitals, which are split by spin-orbit coupling and ligand-field asymmetry. An increase in the separation between the IC bands as BL is varied reflects the increase in the degree of electronic coupling through the series of ruthenium and osmium complexes. The increase in the IVCT bandwidths for the former is therefore attributed to the increase in the separation of the three underlying components of the bands. Stark effect measurements reveal small dipole moment changes accompanying IVCT excitation in support of the localized-to-delocalized or delocalized classification for the dinuclear ruthenium and osmium systems.

Probing the transition between the localised (class II) and localised-to-delocalised (class II-III) regimes by using intervalence charge-transfer solvatochromism in a series of mixed-valence dinuclear ruthenium complexes.

Intervalence charge-transfer (IVCT) solvatochromism studies on the diastereoisomeric forms of [{Ru(bpy)(2)}(2)(mu-BL)](5+) (bpy=2,2'-bipyridine; BL=a series of di-bidentate polypyridyl bridging ligands) reveal that the solvent dependencies of the IVCT transitions decrease as the "tail" of the bridging ligand is extended, and the extent of delocalisation increases. Utilising a classical theoretical approach for the analysis of the intervalence charge-transfer (IVCT) solvatochromism data, the subtle and systematic variation in the electronic properties of the bridging ligands can be correlated with the shift between the localised (class II) and localised-to-delocalised (class II-III) regimes. The investigation of the diastereoisomeric forms of two series of complexes incorporating analogous structurally rigid (fused) and nonrigid (unfused) bridging ligands demonstrates that the differences in the IVCT characteristics of the diastereoisomers of a given complex are accentuated in the latter case, due to a stereochemically induced redox asymmetry contribution. The marked dependence of the IVCT transitions on the stereochemical identity of the complexes provides a quantitative measure of the fundamental contributions of the reorganisational energy and redox asymmetry to the intramolecular electron-transfer barrier at the molecular level.

Multisite effects on intervalence charge transfer in a clusterlike trinuclear assembly containing ruthenium and osmium.

The intervalence charge transfer (IVCT) properties of the mixed-valence forms of the diastereoisomers of the dinuclear [[Ru(bpy)2](mu-HAT)[M(bpy)2]]5+ (M = Ru or Os) complexes and the trinuclear heterochiral [[Ru(bpy)2]2[Os(bpy)2](mu-HAT)]n+ (n = 7, 8; HAT = 1,4,5,8,9,12-hexaazatriphenylene; bpy = 2,2'-bipyridine) species display a marked dependence on the nuclearity and extent of oxidation of the assemblies, while small differences are also observed for the diastereoisomers of the same complex in the dinuclear cases. The mixed-valence heterochiral [[Ru(bpy)2]2[Os(bpy)2](mu-HAT)]n+ (n = 7, 8) forms exhibit IVCT properties that are intermediate between those of the diastereoisomeric forms of the localized hetero-dinuclear complex [[Ru(bpy)2](mu-HAT)[Os(bpy)2]]5+ and the borderline localized-to-delocalized homo-trinuclear complex [[Ru(bpy)2]3(mu-HAT)]n+ (n = 7, 8). The near-infrared (NIR) spectrum of the +7 mixed-valence species exhibits both interconfigurational (IC) and IVCT transitions which are quantitatively similar to those in [[Ru(bpy)2](mu-HAT)[Os(bpy)2]]5+ and are indicative of the localized mixed-valence formulation [[Ru(II)(bpy)2]2[Os(III)(bpy)2](mu-HAT)]7+. The +8 state exhibits a new band attributable to an IVCT transition in the near-infrared region.

Effects of geometric isomerism in dinuclear platinum antitumor complexes on aquation reactions in the presence of perchlorate, acetate and phosphate.

The aquation and subsequent reactions of the dinuclear Pt antitumor complexes [{trans-PtCl(NH(3))(2)}(2)(mu-NH(2)(CH(2))(6)NH(2))](2+) (1,1/t,t) and [{cis-PtCl(NH(3))(2)}(2)(mu-NH(2)(CH(2))(6)NH(2))](2+) (1,1/c,c) in 15 mM perchlorate, acetate or phosphate solutions were followed at 298 K by [(1)H,(15)N] HSQC 2D NMR spectroscopy. Rate and equilibrium constants for the initial reversible aquation and the subsequent reversible reaction with phosphate or acetate are reported. The rate constant for the first aquation step is two-fold lower for 1,1/c,c than 1,1/t,t but the anation rate constants are similar so that the equilibrium lies further towards the chloro form for the 1,1/c,c compound. A pK (a) value of 6.01+/-0.03 was determined for the diaquated species [{cis-Pt(NH(3))(2)(H(2)O)}(2)(mu-NH(2)(CH(2))(6)NH(2))](4+) (1,1/c,c-3) which is 0.4 units higher than that of the 1,1/t,t compound. The rate constants for the binding of acetate and phosphate to 1,1/t,t are similar, but the rate constant for the reverse reaction is close to ten-fold higher in the case of phosphate so that equilibrium conditions are attained more rapidly (12 h compared with 64 h). On the other hand, for 1,1/c,c the rate constants for the forward and reverse reactions with acetate and phosphate are quite similar so that equilibrium conditions are reached very slowly (80-100 h) and a greater proportion of phosphate-bound species are present. The reduced lability of the bound phosphate for 1,1/c,c is attributed to the formation of a macrochelate phosphate-bridged species which was characterized by (31)P NMR and ESI-MS. The speciation profiles of 1,1/t,t and 1,1/c,c under physiological conditions are explored.

Long range 1,4 and 1,6-interstrand cross-links formed by a trinuclear platinum complex. Minor groove preassociation affects kinetics and mechanism of cross-link formation as well as adduct structure.

Reported here is a comparison of the kinetics of the stepwise formation of 1,4- and 1,6-GG interstrand cross-links by the trinuclear platinum anticancer compound (15)N-[[trans-PtCl(NH(3))(2)](2)[mu-trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)NH(2))(2)]](4+), (1,0,1/t,t,t (1) or BBR3464). The reactions of (15)N-1 with the self-complementary 12-mer duplexes 5'-[d(ATATGTACATAT)(2)] (I) and 5'-[d(TATGTATACATA)(2)] (II) have been studied at 298 K, pH 5.3 by [(1)H,(15)N] HSQC 2D NMR spectroscopy. The kinetic profiles for the two reactions are similar. For both sequences initial electrostatic interactions with the DNA are observed for 1 and the monoaqua monochloro species (2) and changes in the chemical shifts of certain DNA (1)H resonances are consistent with binding of the central charged [PtN(4)] linker unit in the minor groove. The pseudo first-order rate constants for the aquation of 1 to 2 in the presence of duplex I (3.94 +/- 0.03 x 10(-5) s(-1)), or II(4.17 +/- 0.03 x 10(-5) s(-1)) are ca. 40% of the value obtained for aquation of 1 under similar conditions in the absence of DNA. Monofunctional binding to the guanine N7 of the duplex occurs with rate constants of 0.25 +/- 0.02 M(-1) s(-1) (I) and 0.34 +/- 0.02 M(-1) s(-1) (II), respectively. Closure to form the 1,4- or 1,6-interstrand cross-links (5) was treated as direct from 3 with similar rate constants of 4.21 +/- 0.06 x 10(-5) s(-1) (I) and 4.32 +/- 0.04 x 10(-5) s(-1) (II), respectively. Whereas there is only one predominant conformer of the 1,6 cross-link, evidence from both the (1)H and [(1)H,(15)N] NMR spectra show formation of two distinct conformers of the 1,4 cross-link, which are not interconvertible. Closure to give the major conformer occurs 2.5-fold faster than for the minor conformer. The differences are attributed to the initial preassociation of the central linker of 1 in the minor groove and subsequently during formation of both the monofunctional and bifunctional adducts. For duplex I, molecular models indicate two distinct pathways for the terminal [PtN(3)Cl] groups to approach and bind the guanine N7 in the major groove with the central linker anchored in the minor groove. To achieve platination of the guanine residues in duplex II the central linker remains in the minor groove but 1 must diffuse off the DNA for covalent binding to occur. Clear evidence for movement of the linker group is seen at the monofunctional binding step from changes of chemical shifts of certain CH(2) linker protons as well as the Pt-NH(3) and Pt-NH(2) groups. Consideration of the (1)H and (15)N shifts of peaks in the Pt-NH(2) region show that for both the 1,4 and 1,6 interstrand cross-links there is a gradual and irreversible transformation from an initially formed conformer(s) to product conformer(s) in which the amine protons of the two bound [PtN(3)] groups exist in a number of different environments. The behavior is similar to that observed for the 1,4-interstrand cross-link of the dinuclear 1,1/t,t compound. The potential significance of preassociation in determining kinetics of formation and structure of the adducts is discussed. The conformational flexibility of the cross-links is discussed in relation to their biological processing, especially protein recognition and repair, which are critical determinants of the cytotoxicity of these unique DNA-binding agents.

The nature of the DNA template (single- versus double-stranded) affects the rate of aquation of a dinuclear Pt anticancer drug.

The rate of aquation of a dinuclear platinum anticancer agent is altered in the presence of template DNA with enhancement of hydrolysis in the presence of single-stranded over double-stranded DNA, emphasising how the alteration of chemical properties of small molecules in the presence of large host interactions is also dependent on the conformation and nature of that host.

Competitive reactions of interstrand and intrastrand DNA-Pt adducts: A dinuclear-platinum complex preferentially forms a 1,4-interstrand cross-link rather than a 1,2 intrastrand cross-link on binding to a GG 14-mer duplex.

A study of the kinetics and mechanism of the reaction between the dinuclear Pt complex [(trans-PtCl(NH(3))(2))(2)(mu-NH(2)(CH(2))(6)NH(2))](2+) (1) and the 14-mer duplex 5'-d(ATACATG(7)G(8)TACATA)-3'.5'-d(TATG(25)TACCATG(18)TAT)-3' is reported. [(1)H,(15)N]-HSQC NMR was used to follow the reaction at 298 K, pH 5.4. The product is primarily the 5'-5' 1,4-interstrand cross-link between G(8) and G(18) bases and exists in two conformational forms. No evidence for the possible 1,2-intrastrand G(7)G(8) adduct was seen, confirming the preferential formation of interstrand cross-links by these dinuclear complexes. An initial electrostatic association of (15)N-1 with the duplex is indicated by changes in its (1)H/(15)N chemical shifts, followed by aquation of 1 to form the monoaqua monochloro species 2, with a rate constant of 4.00+/-0.03x10(-5) s(-1). Monofunctional binding to the duplex occurs primarily at G(8), the 3' base of the nucleophilic GG grouping, with a rate constant of 1.5+/-0.7 M(-1) s(-1). Changes in the (1)H/(15)N shifts indicate there is an electrostatic interaction between the unbound (PtN(3)Cl) group of the monofunctional adduct and the duplex. No peaks for a transient aquated monofunctional species are seen and closure of 3 to form the 1,4-G(8)G(18) interstrand cross-link (5) was treated as direct, with a rate constant of 4.47+/-0.06x10(-5) s(-1). The G(8)G(18) cross-link was confirmed from analysis of the NOESY NMR spectrum of the final product. Structural perturbations for the 1,4-interstrand cross-link extend over approximately four base-pairs and are similar to those found for a 1,4-interstrand cross-link with a shorter 8-mer -GTAC- sequence. A major distortion was evident for the 5'T (T(17)) adjacent to the platinated G(18), consistent with the findings from the use of chemical probes to investigate the conformation of 1,4-interstrand cross-links.

Examination of the effects of oxidation and ring closure on the cytotoxicities of the platinum complexes of N-(2-hydroxyethyl)ethane-1,2-diamine and ethane-1,2-diamine-N,N'-diacetic acid.

The crystal structures, electrochemical properties and cytotoxicities of platinum(II) and platinum(IV) complexes of the multidentate ligands N-(2-hydroxyethyl)ethane-1,2-diamine (NNOH) and ethane-1,2-diamine-N,N'-diacetic acid (H(2)enda) are reported. In the platinum(II) state the NNOH and H(2)enda ligands act as bidentate ligands, coordinating through the two amine groups with the hydroxyethyl and carboxylate groups remaining uncoordinated. Oxidation with hydrogen peroxide followed by refluxing yields the ring closed Pt(IV) complexes in which the NNOH and H(2)enda ligands are deprotonated and coordinate via the two amine groups and either the deprotonated alcohol group in the case of NNO or both carboxylato groups in the case of enda. The platinum(IV) complex of NNO is 2- to 5-fold more active against a panel of cisplatin sensitive and resistant human tumour cell lines than is the platinum(II) complex, whereas in the case of enda, the reverse is true. Ring closure to occupy both axial sites apparently leads to deactivation of platinum(IV) complexes, but a single closure does not necessarily do so.

Kinetic and equilibria studies of the aquation of the trinuclear platinum phase II anticancer agent [(trans-PtCl(NH(3))(2))(2)(mu-trans-Pt(NH(3))(2)(NH(2)(CH(2))(6)NH(2))(2))](4+) (BBR3464).

The hydrolysis profile of the bifunctional trinuclear phase II clinical agent [(trans-PtCl(NH(3))(2))(2)(mu-trans-Pt(NH(3))(2)(NH(2)(CH(2))(6)NH(2))(2))](4+) (BBR3464, 1) has been examined using [(1)H,(15)N] heteronuclear single quantum coherence (HSQC) 2D NMR spectroscopy. Reported are estimates of the rate and equilibrium constants for the first and second aquation steps, together with the acid dissociation constant (pK(a1) approximately equal to pK(a2) approximately equal to pK(a3)). The equilibrium constants for the aquation determined by NMR at 298 and 310 K (I = 0.1 M, pH 5.3) are similar, pK(1) = pK(2) = 3.35 +/- 0.04 and 3.42 +/- 0.04, respectively. At lower ionic strength (I = 0.015 M, pH 5.3) the values at 288, 293, and 298 K are pK(1) = pK(2) = 3.63 +/- 0.05. This indicates that the equilibrium is not strongly ionic strength or temperature dependent. The aquation and anation rate constants for the two-step aquation model at 298 K in 0.1 M NaClO(4) (pH 5.3) are k(1) = (7.1 +/- 0.2) x 10(-5) s(-1), k(-1) = 0.158 +/- 0.013 M(-1) s(-1), k(2) = (7.1 +/- 1.5) x 10(-5) s(-1), and k(-2) = 0.16 +/- 0.05 M(-1) s(-1). The rate constants in both directions increase 2-fold with an increase in temperature of 5 K, and rate constants increase with a decrease in solution ionic strength. A pK(a) value of 5.62 plus minus 0.04 was determined for the diaqua species [(trans-Pt(NH(3))(2)(OH(2)))(2)(mu-trans-Pt(NH(3))(2)(NH(2)(CH(2))(6)-NH(2))(2))](6+) (3). The speciation profile of 1 under physiological conditions is explored and suggests that the dichloro form predominates. The aquation of 1 in 15 mM phosphate was also examined. No slowing of the initial aquation was observed, but reversible reaction between aquated species and phosphate does occur.