Transition metal clusters supported by multinucleating ligand frameworks as models of biological active sites

This dissertation describes efforts to model biological active sites with small molecule clusters. The approach used took advantage of a multinucleating ligand to control the structure and nuclearity of the product complexes, allowing the study of many different homo- and heterometallic clusters. Chapter 2 describes the synthesis of the multinucleating hexapyridyl trialkoxy ligand used throughout this thesis and the synthesis of trinuclear first row transition metal complexes supported by this framework, with an emphasis on tricopper systems as models of biological multicopper oxidases. The magnetic susceptibility of these complexes were studied, and a linear relation was found between the Cu-O(alkoxide)-Cu angles and the antiferromagnetic coupling between copper centers. The triiron(II) and trizinc(II) complexes of the ligand were also isolated and structurally characterized.

Chapter 3 describes the synthesis of a series of heterometallic tetranuclear manganese dioxido complexes with various incorporated apical redox-inactive metal cations (M = Na⁺, Ca²⁺, Sr²⁺, Zn²⁺, Y³⁺). Chapter 4 presents the synthesis of heterometallic trimanganese(IV) tetraoxido complexes structurally related to the CaMn₃ subsite of the oxygen-evolving complex (OEC) of Photosystem II. The reduction potentials of these complexes were studied, and it was found that each isostructural series displays a linear correlation between the reduction potentials and the Lewis acidities of the incorporated redox-inactive metals. The slopes of the plotted lines for both the dioxido and tetraoxido clusters are the same, suggesting a more general relationship between the electrochemical potentials of heterometallic manganese oxido clusters and their “spectator” cations. Additionally, these studies suggest that Ca²⁺ plays a role in modulating the redox potential of the OEC for water oxidation.

Chapter 5 presents studies of the effects of the redox-inactive metals on the reactivities of the heterometallic manganese complexes discussed in Chapters 3 and 4. Oxygen atom transfer from the clusters to phosphines is studied; although the reactivity is kinetically controlled in the tetraoxido clusters, the dioxido clusters with more Lewis acidic metal ions (Y³⁺ vs. Ca²⁺) appear to be more reactive. Investigations of hydrogen atom transfer and electron transfer rates are also discussed.

Appendix A describes the synthesis, and metallation reactions of a new dinucleating bis(N-heterocyclic carbene)ligand framework. Dicopper(I) and dicobalt(II) complexes of this ligand were prepared and structurally characterized. A dinickel(I) dichloride complex was synthesized, reduced, and found to activate carbon dioxide. Appendix B describes preliminary efforts to desymmetrize the manganese oxido clusters via functionalization of the basal multinucleating ligand used in the preceding sections of this dissertation. Finally, Appendix C presents some partially characterized side products and unexpected structures that were isolated throughout the course of these studies.

RESONANCE RAMAN INVESTIGATION OF PH-DEPENDENT EQUILIBRIA OF WATER-SOLUBLE IRON PORPHYRINS

Resonance Raman spectroscopy has been used to probe the structures of; tetrakis(1-methylpyridinium-4-yl)-porphinatoiron(III), FeIII (T4MPyP); tetrakis(1-methylpyridium-2-yl)porphinatoiron(III), FeIII (T2MPyP); tetrakis(4-sulphonatophkenyl)porphinatoir(III), FeIII(TSPP); and tetrakis(4-carboxylatophenyl)porphinatoiron(III), FeIII(TCPP), over a wide pH range. The anionic complexes FeIII (TSPP) and FeIII (TCPP) contain high-spin iron(III) at all pHs. Both these complexes exhibit marked spectral changes at ca. pH 6 which correspond to conversion from the diaquo species, in acid solution, to hydroxy- or mu-oxo dimer complexes. Both cationic complexes show similar diaquo to high-spin hydroxy, or mu-oxo dimer, transitions at ca. pH 6. However, at pH > 11.5 for FeIII (T4MPyP) and pH > 9 for FeIII (T2MPyP) a second equilibrium process is observed, leading to two new species. One of these is readily assigned as the low-spin iron(III) dihydroxy complex by analogy with spectra of the dicyano complex. The second species is assigned to the hydroxy iron(II) complex by comparison with photo-chemically generated FeII (T4MPyP) (OH). The formation of iron(II) species in alkaline solutions of FeIII (T4MPyP) and FeIII (T2MPyP) is entirely unexpected and the significance of the observation to previous investigations of the pH-dependent behaviour of these complexes is discussed.

Fluorimetric study of the pro-oxidant activity of EUK8 in the presence of hydrogen peroxide

The catalase mimetic complex Mn(III)-salen chloride (EUK8) was found to be pro-oxidant under low hydrogen peroxide concentrations. The increase in the fluorescence rate of the probe 1,2,3-dihydrorhodamine (DHR) in solution, as well as the carbonyl content of human serum albumin were found to be maximum at H(2)O(2):EUK8 molar ratios ranging from 0 to 2, supporting previous findings regarding the mechanism of EUK8 catalase activity and the formation of highly oxidative Mn(V)-O(2-) species. This pro-oxidant effect is precluded by the presence of glutathione. Cytotoxicity to HeLa cells, as probed by increased rate of oxidation of intracellular DHR, was not observed. Our findings suggest that the combination of H(2)O(2) and EUK8 at specific molar ratios, in the absence of reductants/antioxidants, induces the oxidation of organic molecules. It is shown that the fluorimetric determination of pro-oxidant activity of metal complexes is more sensitive than the colorimetric quantification of protein carbonyl content. The implications of our findings with respect to the somewhat confusing results arising from in vivo studies of EUK8 and other Mn(III) anti-oxidant metal complexes are discussed.

Screening da atividade antiproliferativa e investigação toxicológica in vitro e in vivo de compostos de coordenação

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Modellkomplexe zur Untersuchung der Radikal-Metall-Wechselwirkung innerhalb des wasseroxidierenden Zentrums im Photosystem II

Im Rahmen dieser Arbeit wurden zweikernige Modellkomplexe zur Untersuchung der Radikal-Metallwechselwirkung innerhalb des wasseroxidierenden Zentrums des Photo¬systems II synthetisiert und eine magneto-strukturelle Korrelation dieser Komplexe erstellt. Als Liganden wurden diverse sechs- bis siebenzähnige Chelatliganden verwendet, welche über zwei Koordinationstaschen und eine verbrückende Phenolatgruppe verfügen. Zwei daran gebundene Manganionen liegen in einer wohl definierten Umgebung nicht koordinativ gesättigt vor. An die freien Koordinationsstellen können weitere ein bis zwei Brückenliganden binden, bei denen es sich in dieser Arbeit hauptsächlich um Carboxylate handelt. Durch die Verwendung eines diamagnetischen Brückenliganden konnte die magnetische Spin-Spin-Austauschwechselwirkung zwischen den spintragenden Manganionen über die verbrücken¬de Phenolatgruppe bestimmt werden. Komplexe, welche über Manganionen in den gleichen Oxidationsstufen, aber über unterschiedliche Carboxylatbrückenliganden verfügen, weisen ähnliche magnetische Austauschwechselwirkungen zwischen den Metallzentren auf. Diese Beobachtung konnte durch eine strukturelle Ähnlichkeit dieser Komplexe erklärt werden. Mittels Aufsummieren der Bindungslängen der verbrückenden Phenolateinheit zu beiden Zentralionen kann innerhalb dieser Komplexe jeweils die Länge des Wechselwirkungspfades erhalten werden, welcher die magnetische Austauschwechselwirkung maßgeblich beein¬flusst. Je länger der Wechselwirkungspfad ist, desto kleiner ist die Austausch¬wechsel¬wirkung. Durch Austausch der diamagnetischen Carboxylate durch paramagnetische benzoat¬substituierte Nitronyl Nitroxid Radikale wurden den Komplexen ein bis zwei weitere Spinzentren hinzugefügt, welche mit den Spins der Zentralionen wechselwirken können. Simulationen der magnetischen Suszeptibilitätsmessungen liefern Werte für die magneti¬schen Austausch¬wechselwirkungen zwischen den Nitronyl Nitroxid Radikalen und den Manganionen, die in allen Fällen schwach ferromagnetisch zwischen 0 und 4,7 cm-1 sind. In einer Auftragung dieser Austauschwechselwirkungen gegen die Mangan-Carboxylat-Bindungs¬längen von strukturell charakterisierten äquivalenten acetatverbrückten Komplexen, kann eine lineare Abhängigkeit gezeigt werden.

Functional model for catecholase-like activity: A mechanistic approach with manganese(III) complexes of salen type Schiff base ligands

Three new Mn(III) complexes [MnL1(OOCH)(OH2)] (1), [MnL2(OH2)(2)][Mn2L22(NO2)(3)] (2) and [Mn2L21(NO2)(2)] (3) (where H2L1 = H(2)Me(2)Salen = 2,7-bis(2-hydroxyphenyl)-2,6-diazaocta-2,6-diene and H2L2 = H(2)Salpn = 1,7-bis(2-hydroxyphenyl)-2,6-diazahepta-1,6-diene) have been synthesized. X-ray crystal structure analysis reveals that 1 is a mononuclear species whereas 2 contains a mononuclear cationic and a dinuclear nitrite bridged (mu-1 kappa O:2 kappa O') anionic unit. Complex 3 is a phenoxido bridged dimer containing terminally coordinated nitrite. Complexes 1-3 show excellent catecholase-like activity with 3,5-di-tert-butylcatechol (3,5-DTBC) as the substrate. Kinetic measurements suggest that the rate of catechol oxidation follows saturation kinetics with respect to the substrate and first order kinetics with respect to the catalyst. Formation of bis(mu-oxo)dimanganese(III,III) as an intermediate during the course of reaction is identified from ESI-MS spectra. The characteristic six line EPR spectra of complex 2 in the presence of 3,5-DTBC supports the formation of manganese(II)-semiquinonate as an intermediate species during the catalytic oxidation of 3,5-DTBC.

Synthesis, X-ray structures, and spectroscopic and electrochemical properties of (mu-oxo)bis(mu-carboxylato)diruthenium complexes having six imidazole bases as terminal ligands

Complexes [Ru2O(O2CR)(2)(1-MeIm)(6)](ClO4)(2) (la-c), [Ru2O(O2CR)(2)(ImH)(6)](ClO4)(2) (2a,b), and [Ru2O(O2CR)(2)(4-MeImH)(6)](ClO4)(2) (3a,b) with a (mu-oxo)bis(mu-carboxylato)diruthenium(III) core have been prepared by reacting Ru2Cl(O2CR)(4) with the corresponding imidazole base, viz. 1-methylimidazole (1-MeIm), imidazole (ImH), and 4-methylimidazole (4-MeImH) in methanol, followed by treatment with NaClO4 in water (R: Me, a; C6H4-p-OMe, b; C6H4-p-Me, c). Diruthenium(III,IV) complexes [Ru2O(O2CR)(2)(1-MeIm)(6)](ClO4)(3) (R: Me, 4a; C6H4-p-OMe, 4b; C6H4-p-Me, 4c) have been prepared by one-electron oxidation of 1 in MeCN with K2S2O8 in water. Complexes la, 2a . 3H(2)O, and 4a . 1.5H(2)O have been structurally characterized. Crystal data for the complexes are as follows: la, orthorhombic, P2(1)2(1)2(1), a = 7.659(3) Angstrom, b = 22.366(3) Angstrom, c = 23.688(2) Angstrom, V = 4058(2) Angstrom(3), Z = 4, R = 0.0475, and R-w = 0.0467 for 2669 reflections with F-o > 2 sigma(F-o); 2a . 3H(2)O, triclinic, , a = 13.735(3) Angstrom, b = 14.428(4) Angstrom, c = 20.515(8) Angstrom, alpha = 87.13(3)degrees, beta = 87.61(3)degrees, gamma = 63.92(2)degrees, V = 3646(2) Angstrom(3), Z = 4, R = 0.0485 and R-w = 0.0583 for 10 594 reflections with F-o > 6 sigma(F-o); 4a . 1.5H(2)O triclinic, , a = 11.969(3) Angstrom, b = 12.090(6) Angstrom, c = 17.421(3) Angstrom, alpha = 108.93(2)degrees, beta = 84.42(2)degrees, gamma = 105.97(2)degrees, V = 2292(1) Angstrom(3), Z = 2, R = 0.0567, and R-w = 0.0705 for 6775 reflections with F-o > 6 sigma(F-o). The complexes have a diruthenium unit held by an oxo and two carboxylate ligands, and the imidazole ligands occupy the terminal sites of the core. The Ru-Ru distance and the Ru-O-oxo-Ru angle in la and 2a . 3H(2)O are 3.266(1), 3.272(1) Angstrom and 122.4(4), 120.5(2)degrees, while in 4a . 1.5H(2)O these values are 3.327(1) Angstrom and 133.6(2)degrees. The diruthenium(III) complexes 1-3 are blue in color and they exhibit an intense visible band in the range 560-575 nm. The absorption is charge transfer in nature involving the Ru(III)-d pi and O-oxo-p pi orbitals. The diruthenium(III,IV) complexes are red in color and show an intense band near 500 nm. The diruthenium(III) core readily gets oxidized with K2S2O8 forming quantitatively the diruthenium(III,IV) complex. The visible spectral record of the conversion shows an isosbestic point at 545 nm for 1 and at 535 nm for 2 and 3. Protonation of the oxide bridge by HClO4 in methanol yields the [Ru-2(mu-OH)(mu-O2CR)(2)](3+) core. The hydroxo species shows a visible band al 550 nm. The pK(a) value for la is 2.45. The protonated species are unstable. The 1-MeIm species converts to the diruthenium(III,IV) core, while the imidazole complex converts to [Ru(ImH)(6)](3+) and some uncharacterized products. Complex [Ru(ImH)(6)](ClO4)(3) has been structurally characterized. The diruthenium(III) complexes are essentially diamagnetic and show characteristic H-1 NMR spectra indicating the presence of the dimeric structure in solution. The diruthenium(III,IV) complexes are paramagnetic and display rhombic EPR spectral features. Complexes 1-3 are redox active. Complex 1 shows the one-electron reversible Ru-2(III)/(RuRuIV)-Ru-III, one-electron quasireversible (RuRuIV)-Ru-III/Ru-2(IV), and two-electron quasireversible Ru-2(III)/Ru-2(II) couples near 0.4, 1.5, and -1.0 V vs SCE In MeCN-0.1 M TBAP, respectively, in the cyclic and differential pulse voltammetric studies. Complexes 2 and 3 exhibit only reversible Ru-2(III)/(RuRuIV)-Ru-III and the quasireversible (RuRuIV)-Ru-III/Ru-2(IV) couples near 0.4 and 1.6 V vs SCE, respectively, The observation of a quasireversible one-step two-electron transfer reduction process in 1 is significant considering its relevance to the rapid and reversible Fe-2(III)/Fe-2(II) redox process known for the tribridged diiron core in the oxy and deoxy forms of hemerythrin.

Photo-induced double-strand DNA and site-specific protein cleavage activity of L-histidine (mu-oxo)diiron(III) complexes of heterocyclic bases

Three oxo-bridged diiron(III) complexes of L-histidine and heterocyclic bases [Fe-2(mu-O)(L-his)(2)(B)(2)](ClO4)(2) (1-3), where B is 2,2'-bipyridine (bpy),1,10-phenanthroline (phen), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq), were prepared and characterized. The bpy complex 1 was structurally characterized by X-ray crystallography. The molecular structure showed a {Fe-2(mu-O)} core in which iron(III) in a FeN4O2 coordination is bound to tridentate monoanionic L-histidine and bidentate bpy ligands. The Fe center dot center dot center dot Fe distance is similar to 3.5 angstrom. The Fe-O-Fe unit is essentially linear, giving a bond angle of similar to 172 degrees. The complexes showed irreversible cyclic voltammetric cathodic response near -0.1 V vs. SCE in H2O-0.1 M KCl. The binuclear units displayed antiferromagnetic interaction between two high-spin (S = 5/2) iron(III) centers giving a -J value of -110 cm(-1). The complexes showed good DNA binding propensity giving a binding constant value of similar to 10(5) M-1. Isothermal titration calorimetric data indicated single binding mode to the DNA. The binding was found to be driven by negative free energy change and enthalpy. The dpq complex 3 showed oxidative double-strand DNA cleavage on exposure to UV-A and visible light. The phen complex 2 displayed single-strand photocleavage of DNA. The DNA double-strand breaks were rationalized from theoretical molecular docking calculations. Mechanistic investigations showed formation of hydroxyl radicals as the reactive species through photodecarboxylation of the L-histidine ligand. The complexes exhibited good binding propensity to bovine serum albumin (BSA) protein in Tris-HCl/NaCl buffer medium. The dpq complex 3 showed UV-A light-induced site-specific oxidative BSA cleavage forming fragments of similar to 45 kDa and similar to 20 kDa molecular weights via SOH pathway.

Interaction of manganese(II) with valinomycin: Observation of mixed complexes

The interaction of antibiotic valinomycin with manganese (II) has been studied using circular dichroism, electron spin resonance and infrared techniques. Results show that Mn(II) forms complexes with valinomycin in both 2:1 (valinomycin-ion-valinomycin sandwich) and 1:1 (equimolar) stoichiometries. The 1:1 type observed here is very different from the well known K+-valinomycin bracelet conformation.

Synthesis, structure and electrochemical properties of complexes with a (μ-oxo)bis-(μ-carboxylato)diruthenium(III) core

Reaction of [Ru2O(O2CR)2(MeCN)4(PPh3)2](ClO4)2 (1) with 1,2-diaminoethane (em) in MeOH---H2O yielded a mixture of products, from which a purple diamagnetic and 1:2 electrolytic diruthenium(III) complex, [Ru2O(O2CR)2(en)2(PPh3)2](ClO4)2 (2), was isolated along with a trace by-product of [Ru2O(O2CR)2(en)2(PPh3)2](ClO4)(MeCONH) (3) (R = C6H4-p-X : X = H, a; OMe, b; Me, c). Complex 3b has been characterized by X-ray diffraction analysis. The structure shows the presence of a (Ru2(?-O)(?-O2CR)22+)_core, with the metal centre bonded to an unidentate PPh3 and a bidentate chelating en terminal ligand. The Ru�Ru distance and the Ru�O�Ru angle in the core are 3.255(3) Å and 119.1(4)°. The amidate anion, formed presumably by nucleophilic attack of OH? on the MeCN ligand in complex 1, remains uncoordinated to the metal. In MeCN/0.1 M [NBun4]ClO4 complex 2 exhibits a nearly reversible Ru2III,III?Ru2III,IV couple near 0.9 V and an irreversible Ru2III,III?Ru2III,II process at ?0.6 V (vs S.C.E.). The mechanistic aspects of the substitution and nucleophilic reactions in the formation of complexes 2 and 3 are discussed. References

Synthesis, structure and redox properties of (?-oxo)bis(?-carboxylato)diruthenium(III) complexes containing three different terminal ligands

Blue coloured, unstable, essentially diamagnetic and non-electrolytic diruthenium(III) complexes of the formation [Ru2O(O2CR)4(en)2(PPh3)2] were prepared by reacting [Ru2O(O2CR)4(PPh3)2] with 1,2-diaminoethane (en) in CH2Cl2 (R = C6H4-p-X; X = H, Me and OMe). The molecular structure of the complexes is proposed as [{(?1-O2CR)(?1-en)(PPH3)Ru}2(?-O)(?-O2CR)2] based on the 1H NMR spectral data. The electronic spectra of the complexes display a band near 569 nm with a shoulder at 630 nm. In CH2Cl2-0.1 M [Bun4N]ClO4, the complexes exhibit redox couples Ru2III,III/Ru2III,IV and Ru2III,IV/Ru2IV,IV near 0.1 and 1.2 V (vs SCE), respectively. The potentials are the lowest among diruthenium(III) complexes with a similar core structure.