<p> A new rigid, dianionic ligand, 4,5-bis(2,6-diisopropylanilido)-2,7-di-tert-butyl-9,9-dimethylxanthene {[XA₂]}, has been designed for use in the chemistry of the actinides. Pro-ligand H2[XA₂] (1) was synthesized by the Hartwig-Buchwald coupling of 4,5-dibromo-2,7-di-tert-butyl-9,9-dimethylxanthene with 2,6-diisopropylaniline. </p> <p> Stable alkali metal salts of the [XA₂] ligand, K₂(dme)₂[XA₂] (2) and Na₂[XA₂] (3), were accessible by deprotonation of H₂[XA₂] with KH or NaH in dme or toluene, respectively. The thermally unstable lithium salt of McConville's 2,6-bis(2,6diisopropylanilidomethyl)pyridine {Li₂[BDPP], 4} was isolated by deprotonation of pro-ligand H₂[BDPP] with nBuLi or LiCH₂SiMe₃ in hexanes at low temperature. Reaction of [ThCl₄(dme)₂] with Li₂[BDPP] or M₂(dme)_n[XA₂] (M = K, n = 2; M = Na, n = 0) resulted in the formation of pentagonal bipyramidal [LThCl₂(dme)] complexes {L = [BDPP], 5; [XA₂], 6}. Subsequent reaction of the dichloride complexes with LiCH₂SiMe₃ gave base-and salt-free dialkyl complexes [LTh(CH₂SiMe₃)₂] {L = [BDPP], 9; [XA₂], 10}, which are stable for days in solution at 90 and 70 °C, respectively. Reaction of 5 with LiNEt₂ or 10 with H₂NPh provided [(BDPP)Th(NEt₂)₂] (11) and [(XA₂)Th(NHPh)₂] (28), respectively. </p> <p> An alternative route to [(BDPP)ThCl₂(dme)] (5) and [LTh(CH₂SiMe₃)₂] (9 and 10) involved combination of two or four equivalents of LiCH₂SiMe₃ with [ThCl₄(dme)₂], followed by addition of H₂L. These reactions likely proceed by alkane elimination from dialkyl or tetraalkyl thorium intermediates. The solid-state structure of [(BDPP)Th(CH₂SiMe₃)₂] (9) suggests the presence of α-agostic C-H-Th interactions for both alkyl groups. In solution, 9 and 10 exhibit temperature-dependent ¹J_C-H coupling constants for ThCH₂, consistent with an equilibrium between products participating in aagostic C-H-Th bonding to a greater or lesser extent, with more agostic products favored at lower temperatures. Reaction of Li₂[BDPP] (4) with [(BDPP)ThCl₂(dme)] (5) at 0 °C, or the reaction of [(BDPP)Th(CH₂SiMe₃)₂] (9) with H₂[BDPP] at 100 °C resulted in the formation of extremely sterically encumbered [Th(BDPP)₂] (8), which adopts a highly distorted six-coordinate geometry with the four anilido groups arranged in an approximate tetrahedron around thorium. A his-ligand complex was not accessible with the [XA₂] ancillary ligand, presumably due to increased ligand rigidity. </p> <p> Addition of two equivalents of PhCH₂MgCl to [LThCl₂(dme)] yielded solvent-free [LTh(CH₂Ph)₂] {L = [XA₂] (12) and [BDPP] (13)]. The ¹J_C-H coupling constants in both complexes {120 and 139 Hz for 12; 127 and 138 Hz for 13} are indicative of η¹- and η²- or η³-coordinated benzyl ligands in solution; polyhapto benzyl coordination was also observed in the solid state. </p> <p> Reaction of [LThCl₂(dme)] with two equivalents of nBuLi provided highly soluble [LTh(nBu)₂] {L = [BDPP] (14), [XA₂] (15)]. These β-hydrogen-containing compounds are remarkably thermally stable, showing no sign of decomposition after days at 60 and 80 °C, respectively. Combination of [(BDPP)ThCl₂(dme)] (5) with three equivalents of MeLi yielded the thorium trimethyl 'ate' complex [(BDPP)ThMe₃{Li(dme)}] (16), which underwent thermal decomposition over 3 days at room temperature to produce the metalated complex [(BDPP*)Th(µ-Me)₂Li(dme)] (17) {BDPP* = 2,6-{NC₅H₃(CH₃NAr)(CH₂N {C₆H₃iPr(CMe₂)-2,6})}; Ar = 2,6-diisopropylphenyl; donor atoms in BDPP* are underlined}. Reaction of two equivalents of complex 16 with one equivalent of [(BDPP)ThCl₂(dme)] (5) yielded the dimethyl complex [(BDPP)ThMe₂] (18) which decomposes rapidly at room temperature to form a mixture of unidentified products. Labeling studies using ¹³CD₃ groups revealed that thermal decomposition of 16 and 18 occurs via a straightforward a-bond metathesis pathway. </p> <p> Reaction of [LThCl₂(dme)] with Grignard reagents {MeMgBr, L = [BDPP]; PhCH₂MgCl, L = [XA₂]} resulted, under certain conditions, in halide exhange and adduct formation as evidenced by the solid state structure of [{Th(BDPP)Br(µ-Br)₂Mg(µ-Me)(OEt₂)}₂] (19), or ancillary ligand transfer to magnesium to produce [(XA₂)Mg(dme)] (20). Complex 19 provides insight into the type of intermediates likely involved in undesired halide exchange reactions between d-or f-element halide complexes and Grignard reagents. </p> <p> Reaction of [(XA₂)Th(CH₂Ph)₂] (12) with either one or two equivalents of B(C₆F₅)₃ afforded the first non-carbocyclic actinide alkyl cation, [(XA₂)Th(CH₂Ph)][PhCH₂B(C₆F₅)₃] (21), and a rare example of an actinide dication, [(XA₂)Th][PhCH₂B(C₆F₅)₃]₂ (27). In both 21 and 27 the PhCH₂B(C₆F₅)₃⁻ anion is η⁶-coordinated to thorium. Reaction of neutral dialkyl complex [(XA₂)Th(CH₂SiMe₃)₂] (9) with [Ph₃C][B(C₆F₅)₄] in benzene or toluene at room temperature resulted in the formation of [(XA₂)Th(CH₂SiMe₃)(η⁶-arene)][B(C₆F₅)₄] (arene = C₆H₆, 22; arene = C₇H₈, 23). These complexes were characterized in solution by NMR spectroscopy (21, 22 and 23) and/or in the solid state by X-ray crystallography (22 and 27). In close analogy, [(XA₂)Th(CH₂Ph)₂] (12) reacted with [Ph₃C][B(C₆F₅)₄] in toluene at room temperature to form [(XA₂)Th(η²-CH₂Ph)(η⁶-C₇H₈)][B(C₆F₅)₄] (24). In contrast, related [(BDPP)Th(CH₂Ph)₂] (13) reacted with [Ph₃C][B(C₆F₅)₄] to precipitate a mixture of mononuclear and a dinuclear cations; the dinuclear cation was identified as [(BDPP)Th(η²-CH₂Ph)(µ-η¹:η⁶-CH₂Ph)Th(η¹-CH₂Ph)(BDPP)][B(C₆F₅)₄] (25) by X-ray crystallography. Complexes 22, 23, and 24 are rare examples of arene solvent-separated ion pairs, while complex 21 exists as a tight contact ion pair, and dinuclear 25 exhibits a unique benzyl ligand bridging mode. Cations 21-25 and 27 highlight a pronounced tendency for these systems to engage in arene π-coordination. </p> <p> Preliminary reaction studies with both neutral and cationic thorium complexes supported by the [BDPP] and [XA₂] ancillary ligands demonstrated significant activity for olefin polymerization and hydroamination catalysis. Reactions of 9 and 10 with 4 atm. of hydrogen also suggest that the [BDPP] and [XA₂] ligand frameworks may be suitable for the stabilization of thorium hydride complexes. </p> / Thesis / Doctor of Philosophy (PhD)

Os complexos do tipo [RuCl2(PPh3)2amina], amina = pip (1) ou pep (2), foram estudados como iniciadores catalíticos para reações de ROMP de NBE, NBD e oxaNBE-OMe e na ROMCP de NBE com NBD e oxaNBE-OMe com NBE. O complexo [RuCl2(PPh3)(pep)(isn)] (3) foi estudado na ROMP de NBE e NBD. Os complexos 2 e 3 são inéditos e suas caracterizações são discutidas e correlacionadas com o complexo com 1. As reações de catálises foram realizadas com variações de tempo, volume de solvente e temperatura, em atmosfera de Ar ou ar e na presença de EDA. <br />O rendimento foi quantitativo na ROMP de NBE com o complexo 1 em 2 mL de CHCl3, por 5 min a 25 &deg;C em Ar, com IPD de 1,9 e Mw na ordem de 106 g mol-1. Com o complexo 2, os rendimentos foram quantitativos (IPD ~ 3 e Mw na ordem de 104 g mol-1) e independentes do tempo (5 -120 min) e volume de solvente (2 - 8 mL). Com 3, os rendimentos diminuíram com o aumento do volume de solvente, mas com IPD ~ 2 e Mw na ordem de 104 g mol-1. Em todos os casos os rendimentos diminuíram em atmosfera de ar e com polímeros polimodais. <br />Rendimentos quantitativos de poliNBD foram obtidos com 1 a 40 &deg;C e com 2 a 25 &deg;C na faixa de volume de solvente estudada, por 60 e 120 min, em Ar. Os rendimentos com 3 foram inferiores a 35%. Foram também obtidos rendimentos quantitativos em atmosfera de ar em certas combinações de tempo e volume de solvente, indicando que os complexos são robustos para atividades em soluções contendo O2. Todos os polímeros de NBD foram insolúveis. <br />Obteve-se até 70% de poli(NBE-co-NBD) isolado a partir de reações com 1 e reações quantitativas com 2, dependendo da fração molar NBE:NBD usada, indicando as razões de reatividades do complexos. <br />A ROMP de oxaNBE-OMe com 1 ou com 2 formou 15 a 30% de rendimento, a 40 &deg;C por 24 h em Ar. Na ROMCP desse monômero com NBE obteve-se de 5 a 30% de rendimento, dependendo da fração molar. Os rendimentos são maiores nas frações molares com maior quantidade de NBE. Poli(oxaNBE-OMe) foi solúvel, enquanto que seus copolímeros foram pouco solúveis. <br />São realizadas discussões quantos às características eletrônicas e de impedimentos estéricos nos complexos estudados nas polimerizações via metátese, selecionando-se os ligantes ancilares frente às condições de reações para obtenções de bons rendimentos e características dos polímeros isolados. / The complexes of type [RuCl2(PPh3)2amina], amine = pip (1) or pep (2), were studied as catalytic initiators for ROMP of NBE, NBD and oxaNBE-OMe and for ROMCP of NBE with NBD and oxaNBE-OMe with NBE. The complex [RuCl2(PPh3)(pep)(isn)] (3) was studied for ROMP of NBE and NBD. The complexes 2 and 3 are novels and their characterizations are discussed and correlated with the complex 1. The catalysis reactions were performed with variations of time, volume of solvent and temperature, either in Ar or air atmosphere, in the presence of EDA. <br />The yield was quantitative for ROMP of NBE with complex 1 in 2 mL of CHCl3 for 5 min at 25 &deg;C in Ar, with PDI of 1.9 and Mw in the order of 106 g mol-1. With the complex 2, the yields were quantitatives (PDI ~ 3 and Mw in the order of 104 g mol-1) and independent of time (5 - 120 min) and volume of solvent (2 - 8 mL). With 3, the yields decreased when increasing the volume of solvent, but with PDI ~ 2 and Mw in the order of 104 g mol-1. In all the cases, the yields decreased in air atmosphere with polymodal polymers. <br />Quantitative yields of poliNBD were obtained with 1 at 40 &deg;C and with 2 at 25 &deg;C in the range of the studied volume of solvent, for 60 and 120 min, in Ar. The yields with 3 were less than 35%. Quantitative yields were also obtained in air atmosphere in some combinations of time and volume of solvent, indicating that the complexes are robust for activities in solutions containing O2. All polyNBD were insoluble. <br />It was obtained up to 70% of poly(NBE-co-NBD) isolated from reactions with 1 and quantitative reactions were obtained with 2, depending on the NBE:NBD molar fraction used, indicating the reactivity ratios for the complexes. <br />The ROMP of oxaNBE-OMe with 1 or with 2 yielded 15 to 30% at 40 &deg;C for 24h in Ar. In the ROMCP of this monomer with NBE, it was obtained from 5 to 30% yield, depending on the molar fraction. Yields are higher in molar fractions with higher amount of NBE. Poly(oxaNBE-OMe) was soluble, while its copolymers were poorly soluble. <br />Discussions are held on the electronic characteristics and steric hindrances in the studied complexes for the metathesis polymerization, selecting the ancillary ligands as a function of the reaction conditions to obtain good yields and to improve the characteristics of the isolated polymers.

Os complexos do tipo [RuCl2(PPh3)2amina], amina = pip (1) ou pep (2), foram estudados como iniciadores catalíticos para reações de ROMP de NBE, NBD e oxaNBE-OMe e na ROMCP de NBE com NBD e oxaNBE-OMe com NBE. O complexo [RuCl2(PPh3)(pep)(isn)] (3) foi estudado na ROMP de NBE e NBD. Os complexos 2 e 3 são inéditos e suas caracterizações são discutidas e correlacionadas com o complexo com 1. As reações de catálises foram realizadas com variações de tempo, volume de solvente e temperatura, em atmosfera de Ar ou ar e na presença de EDA. <br />O rendimento foi quantitativo na ROMP de NBE com o complexo 1 em 2 mL de CHCl3, por 5 min a 25 &deg;C em Ar, com IPD de 1,9 e Mw na ordem de 106 g mol-1. Com o complexo 2, os rendimentos foram quantitativos (IPD ~ 3 e Mw na ordem de 104 g mol-1) e independentes do tempo (5 -120 min) e volume de solvente (2 - 8 mL). Com 3, os rendimentos diminuíram com o aumento do volume de solvente, mas com IPD ~ 2 e Mw na ordem de 104 g mol-1. Em todos os casos os rendimentos diminuíram em atmosfera de ar e com polímeros polimodais. <br />Rendimentos quantitativos de poliNBD foram obtidos com 1 a 40 &deg;C e com 2 a 25 &deg;C na faixa de volume de solvente estudada, por 60 e 120 min, em Ar. Os rendimentos com 3 foram inferiores a 35%. Foram também obtidos rendimentos quantitativos em atmosfera de ar em certas combinações de tempo e volume de solvente, indicando que os complexos são robustos para atividades em soluções contendo O2. Todos os polímeros de NBD foram insolúveis. <br />Obteve-se até 70% de poli(NBE-co-NBD) isolado a partir de reações com 1 e reações quantitativas com 2, dependendo da fração molar NBE:NBD usada, indicando as razões de reatividades do complexos. <br />A ROMP de oxaNBE-OMe com 1 ou com 2 formou 15 a 30% de rendimento, a 40 &deg;C por 24 h em Ar. Na ROMCP desse monômero com NBE obteve-se de 5 a 30% de rendimento, dependendo da fração molar. Os rendimentos são maiores nas frações molares com maior quantidade de NBE. Poli(oxaNBE-OMe) foi solúvel, enquanto que seus copolímeros foram pouco solúveis. <br />São realizadas discussões quantos às características eletrônicas e de impedimentos estéricos nos complexos estudados nas polimerizações via metátese, selecionando-se os ligantes ancilares frente às condições de reações para obtenções de bons rendimentos e características dos polímeros isolados. / The complexes of type [RuCl2(PPh3)2amina], amine = pip (1) or pep (2), were studied as catalytic initiators for ROMP of NBE, NBD and oxaNBE-OMe and for ROMCP of NBE with NBD and oxaNBE-OMe with NBE. The complex [RuCl2(PPh3)(pep)(isn)] (3) was studied for ROMP of NBE and NBD. The complexes 2 and 3 are novels and their characterizations are discussed and correlated with the complex 1. The catalysis reactions were performed with variations of time, volume of solvent and temperature, either in Ar or air atmosphere, in the presence of EDA. <br />The yield was quantitative for ROMP of NBE with complex 1 in 2 mL of CHCl3 for 5 min at 25 &deg;C in Ar, with PDI of 1.9 and Mw in the order of 106 g mol-1. With the complex 2, the yields were quantitatives (PDI ~ 3 and Mw in the order of 104 g mol-1) and independent of time (5 - 120 min) and volume of solvent (2 - 8 mL). With 3, the yields decreased when increasing the volume of solvent, but with PDI ~ 2 and Mw in the order of 104 g mol-1. In all the cases, the yields decreased in air atmosphere with polymodal polymers. <br />Quantitative yields of poliNBD were obtained with 1 at 40 &deg;C and with 2 at 25 &deg;C in the range of the studied volume of solvent, for 60 and 120 min, in Ar. The yields with 3 were less than 35%. Quantitative yields were also obtained in air atmosphere in some combinations of time and volume of solvent, indicating that the complexes are robust for activities in solutions containing O2. All polyNBD were insoluble. <br />It was obtained up to 70% of poly(NBE-co-NBD) isolated from reactions with 1 and quantitative reactions were obtained with 2, depending on the NBE:NBD molar fraction used, indicating the reactivity ratios for the complexes. <br />The ROMP of oxaNBE-OMe with 1 or with 2 yielded 15 to 30% at 40 &deg;C for 24h in Ar. In the ROMCP of this monomer with NBE, it was obtained from 5 to 30% yield, depending on the molar fraction. Yields are higher in molar fractions with higher amount of NBE. Poly(oxaNBE-OMe) was soluble, while its copolymers were poorly soluble. <br />Discussions are held on the electronic characteristics and steric hindrances in the studied complexes for the metathesis polymerization, selecting the ancillary ligands as a function of the reaction conditions to obtain good yields and to improve the characteristics of the isolated polymers.

The thesis “Ancillary Ligand Effects on the Anticancer Activity of Ruthenium (II) Piano Stool Complexes” is an effort to design better antitumor metallodrugs based on ruthenium(II) complexes with various H-bond donor/acceptor ligands and to understand their mechanism of action. Chapter 1 presents a brief review of metallodrugs and their mechanism of action. Different classes of metallodrugs are discussed. A short discussion on ruthenium based anticancer drugs and their established mechanism of action is also included in this chapter. Chapter 2 deals with the synthesis, characterization and anticancer activity of Ru(II) complexes with P(III) and P(V) ligands. The effect of a strong hydrogen bond acceptor on the cytotoxicity of the complexes has been investigated which allows comparison of complexes with ligands possessing a strong hydrogen bond donor or hydrogen bond acceptor. Partial oxidation of the tertiary phosphine ligands leads to a decrease in cytotoxicity of the ligand, while coordination to ruthenium resulted in a significant increase in the cytotoxicity. A molecular mechanism of action for these complexes was suggested on the basis of various biophysical studies. These complexes bind DNA through non-intercalative interactions which lead to the destabilization of the double helix of the DNA and also unwinding of the negatively supercoiled DNA. Results show that the presence of a hydrogen bond acceptor on the ligand is not capable of enhancing interactions with DNA in comparison with hydrogen bond donor groups. Cellular studies of these complexes showed that inhibition of DNA synthesis and apoptosis occur on treatment with these complexes. Interestingly, these complexes are found to be not only cytotoxic but also antimetastatic. Chapter 3 deals with the synthesis, characterization and anticancer activity of Ru(II) complexes with biologically active S containing heterocyclic ligands and their mechanistic study. Complexation of ruthenium with mercaptobenzothiazole (MBT) gave the most cytotoxic complex (H3) in the series. Heterocyclic Ru(II) complexes behave differently as evidenced by cellular and biophysical studies. Unlike phosphine complexes, H3 shows biphasic melting of DNA at higher concentrations which suggests two different types of interaction with DNA. Chapter 4 deals with synthesis and characterization of water soluble multiruthenated hydrophilic ruthenium(II) complexes with urotropine. An increase in cytotoxicity and binding affinity has been observed with increase in the number of ruthenium atoms per molecule. The complex with three ruthenium atoms showed the best activity. However cytotoxicity of the complexes decreases with decrease in the lipophilicity of the complexes. Chapter 5 describes studies on the interaction of Ru complexes with water, ss-DNA, AMP, GMP and GSH by various spectroscopic techniques. Hydrolysis of Ru-Cl bond in the complexes correlates with the cytotoxicity. Chapter 6 reports the summary of the observations of the thesis and the future prospects of metallodrugs.