This thesis is based on the past three years of research work including synthesis, characterization of three series of iridium(III) complexes and one series of ruthenium(II) complexes, and their comparative bio-applications of DNA-binding, cell morphology, cytotoxicity, mitochondrial membrane potential, cellular uptake and distribution. Chapter 1 introduces the background and recent studies of transition-metal complexes as biosensors and anti-tumor medicines. Their structure related properties of cytotoxicities, cellular uptake and distributions were also discussed. In chapter 2, five iridium(III) complexes Ir4: [Ir(4-mpp)2DPPZ]+, Ir7: [Ir(4-mpp)2BDPPZ]+, Ir8: [Ir(4-mpp)2MDPPZ]+, Ir115: [Ir(pp)2DBDPPZ]+ and Ir139: [Ir(dpapp)2DBDPPZ]+ were synthesized and characterized. The crystals of complex Ir139 were successfully cultured and analyzed by X-ray crystallography. The HOMO and LUMO energy gaps of complexes Ir4, Ir7 and Ir8 were obtained. The smaller the energy gap is the larger the Stokes shift will be. The DNA binding properties of Ir4, Ir7 and Ir8 were studied to acquire their binding constants and quenching constants. All the five complexes were cultured with hepatocellular carcinoma cell (hep-G2) in different concentrations for cell morphologies and MTT assays. The IC50 values were calculated and the structure-activity relationship (SAR) was discussed. Properties of Ir115 and Ir139 for photodynamic therapy under the visible light were studied, and moderate light-enhanced cytotoxicities were discovered. The live and dead cell assay and mitochondrial transmembrane potential (ΔΨM) testing were performed and a similar cytotoxicity order to IC50 values was obtained. Some interesting interactions between complex and calcein or propidium iodide (PI) dye were observed and discussed. Cellular uptake and distribution assay showed that the fluorescence of iridium complex was closely related to its toxicity. The obvious cellular uptake at 4 ℃ indicated that all the complexes could transfer into cell through a passive transport mode of facilitated diffusion without the consumption of ATP. The greatest change in uptake intensity of Ir115 implied that the ATP could assist the transport of Ir115 at 37.5 ℃. The efficiency of uptake and distribution of complexes in paraformaldehyde (PFA) fixed cells was found to be strictly related to their size and the hydrophobicity. The rigidity of dipyrido[3,​2-​a:2',​3'-​c]phenazine based bipyridine ligands in this chapter contributed to the main cytotoxcities of those iridium complexes. Most of the iridium complexes in chapter 2 have similar structures to their classic ruthenium analogues while their activities have largely improved due to the higher cellular uptake and more biocompatibility. Chapter 3 presented five iridium complexes with rotatable 1H-imidazo [4,5-f] [1,10] (phenanthroline) based bipyridine ligands, which are Ir79: [Ir(pp)2MTPIP]+, Ir80: [Ir(pp)2EIPP]+, Ir116: [Ir(piq)2APIP]+, Ir119: [Ir(piq)2PPIP]+ and Ir134: [Ir(iqdpba)2PPIP]+. Cell morphology and proliferation assay, MTT assay indicated that most of them were not quite toxic for hep-G2 cell lines except for Ir116 which contained an amino group and was assumed to be very active to the carboxyl group in the protein residues in cells. Under the irradiation of visible light, Ir80 and the Ir119 were found to be quite photo-toxic with the light IC50 value of 8.08 μM and 6.14 μM respectively. They could become the potential candidates for the promising drugs of photo-dynamic therapy. The cytotoxicities of those five complexes were further investigated by the live and dead assay using calcein AM (acetoxymethyl) and propidium iodide (PI) double stain method. JC-1 aggregates observation and analysis in the mitochondrial transmembrane potential (ΔΨM) testing proved the lower cytotoxicities of those five complexes than those in chapter 2. Fluorescence and cytotoxicity relationship (FCR) was also uncovered in chapter 3 in which the stronger macromolecular binding to complex could lead to its higher fluorescence intensity. Without the metabolic activity and the assistance of ATP at low temperature of 4 ℃, little Ir80 and Ir134 were found in cells, and the moderate uptake for Ir79 and higher volume of Ir116 and Ir119 were detected. A novel strategy of cold-shock enhanced cellular uptake pathway was discovered in Ir119 and its cold-shock caused cytotoxicity would be further evaluated. The volumes of uptake for those complexes in paraformaldehyde fixed cells were all very low due to their higher hydrophilicity and lower structural rigidity than those in chapter 2. Chapter 4 reported the investigation of six iridium complexes of Ir105: [Ir(4-mpp)2CDYP]+, Ir107: [Ir(piq)2CDYP]+, Ir108: [Ir(3-mpp)2CDYP]+, Ir123: [Ir(4-mpp)2CDYMB]+, Ir125: [Ir(piq)2CDYMB]+ and Ir133: [Ir(dpapp)2CDYMB]+ with rotatable 5H-cyclopenta[2,1-b:3,4-b']dipyridin Schiff-base ligands. Most of them were rather toxic to hep-G2 cell lines from the MTT assay, cell morphology and proliferation assay due to the Schiff-base N^N ligands. Those rotatable Schiff-base ligands seemed to have more cytotoxicity than the flexible 1H-imidazo[4, 5-f] [1, 10](phenanthroline) ligands in chapter 3. The planar and rigid structure of piq C^N ligands in Ir107 and Ir125 were supposed to contribute to the highest cytotoxicity in chapter 4. The dead (red PI) to live (green calcein) cell area ratios and the ΔΨM assay were in accordance with the cytotoxocity sequence in MTT assay. Most of the complexes in chapter 4 demonstrated characteristics of one kind of programmed cell death (PCD), namely apoptosis and the typical features of another cell death mode of oncosis including cellular dwelling and cytoplasm vacuolation have been discovered from Hep-G2 cell lines in the incubation with Ir107. The JC-1 aggregates have disappeared when the two most toxic complexes Ir107 and Ir125 were cultured with the cells at 5 μmol/L, indicating the ΔΨM lost repidly under the damage of iridium complexes. All the complexes were distributed in the cellular nuclei when the incubation time reached 120 minutes at the concentration of 20 and 40 μmol/L. The positive correlation in the fluorescence and cytotoxicity relationship (FCR) were also discovered in chapter 4. The luminescence intensity sequence of the complexes from the cellular uptake and distribution has almost the same order as the previous toxicity results. The two most toxic complexes of Ir107 and Ir125 were found to have the two highest fluorescent intensities inside cells at 4 ℃. Most complexes in this chapter could easily distribute in the fixed cellular nuclei except for Ir125 and Ir133 owing to their large and hydrophobic structures. Generally, the uptake of complexes in paraformaldehyde fixed cells was higher than the live cells at 4 ℃ according to their passive transport mode. Although the simple Schiff base ligands of CDYP and CDYMB in this chapter were rotatable and flexible similar to the 1H-imidazo[4, 5-f][1, 10](phenanthroline) based bipyridine ligands in chapter 3, the cytotoxicities of complexes were much higher than those in chapter 3. The former chapters implied that effective uptake of complexes in nuclei were the results of the cytotoxicities which damaged the integrity of nuclear envelope and leaked into the nucleoplasm. We assumed that there could be another explanation in chapter 4 that the complexes transferred into the nuclei through the nuclear pore on the nuclear envelope and accumulated in the nucleolus, and therefore, triggered the apoptosis of cells. This kind of evidence was discovered for the two most toxic complexes Ir107 and Ir125 that could enter into cellular nuclei when the cell looked quite healthy. There would be another possiblilty that the Schiff base could interrupt the function of intracellular hydrolase enzymes. Chapter 5 compared the properties of five ruthenium(II) complexes of Ru2: [Ru(bpy)2DBDPPZ]2+, Ru7: [Ru(bpy)2MTPIP]2+, Ru8: [Ru(bpy)2EIPP]2+, Ru15: [Ru(phen)2BPDC]2+ and Ru24: [Ru(phen)2CDYMB]2+ with the ligand DBDPPZ from chapter 2, MTPIP and EIPP from chapter 3, CDYMB from chapter 4 and BPDC with two carboxyl groups. Those two positively charged ruthenium complexes indicated very low cytotoxicities from the cell morphology assay and MTT assay. No typical features of cellular apoptosis such as round and shrank cells were observed. However, the light IC50 value of Ru8 was excitingly obtained to be 2.33 μM upon the irradiation of 465 nm which was found to be one of the most promising drugs for photodynamic therapy (PDT) in his thesis. Charge and property relationship (CPR) was discovered to be the most decisive factor in the cytotoxicities of iridium and ruthenium complexes in this thesis which was also supported by a few of the independent literature papers mentioning high cytotoxicity of one positively charged ruthenium complex or low toxicity of two positively charged iridium complex. The DBDPPZ and CDYMB ligands in the ruthenium complexes Ru2 and Ru24 did not add into their cytotoxicity but those ligands greatly enhanced the toxicities of iridium complexes. The calculation of both area and number ratios of dead to live cells stained by the PI and calcein dyes indicated the lowest dark cytotoxicity among the ruthenium complexes could be Ru8 while the Ru24 and Ru7 were more toxic than others. Active JC-1 aggregates were maintained in the cell mitochondria and did not greatly diminish with the increasing concentration of ruthenium complexes. The two positive charges were found to play the important role in the poor cellular uptake of all the ruthenium complexes and the large size of phen ligand further prevented the uptake of Ru24 and reduced its toxicity. The Ru2, Ru7 and Ru8 were found to distribute in fixed cells with much higher luminescence intensities than their corresponding iridium complexes of Ir115, Ir79 and Ir80 with the same N^N ligand respectively which were assigned to be the two positive charges in those ruthenium complexes. The facilitated diffusion was found to be the main passive transport for the five ruthenium complexes in HepG2 cells at 4 ℃ when the ATP functions were considered to be largely inhibited. The low temperature cellular uptake has the similar trend of the cytotoxicities of the five complexes, indicating the structures of complexes were decisive in the process of facilitated diffusion. The enormous difference of cellular uptake and distribution in the fixes cells remind us the normal protocol before the cell-image pictures of fluorescence inverse microscopes (FIM) or confocal laser scanning microscope (CLSM) should be cancelled or very cautiously handled when the luminescent metal complexes were applied. In chapter 6, the further structure-activity relationship (SAR) was discussed based on the different C^N, N^N ligands and metal cores from the previous chapters. The overall research scheme, results and significance were summarized. Highlights were listed and future research plan was also proposed. At last, Chapter 7 described briefly the experiment protocols and supplementary information for the former chapters.

Les 2,2´-bipyridines et leurs homologues, les N,N´-dioxydes, appartiennent à une classe de composés hétéroaromatiques très importante ayant montré de nombreuses applications dans le domaine de la chimie et principalement en synthèse asymétrique. Une des méthodes les plus performantes pour leurs synthèses s´est révélée être une réaction de cocyclotrimérisation d´alcynes en présence de dérivés nitriles.Une nouvelle variante de la réaction de cyclotrimérisation – cocyclotrimérisation de diynes halogénés avec des dérivés nitriles – permettant la formation de composés 2- et3-halogéno-pyridines a ainsi été développée. La réaction a été étudiée sur une large gamme de substrats permettant l´accès à une librairie de pyridines avec de bons rendements. La formation d´un sous-produit, issu d´un échange d´halogène, a été approfondie au cours de l´étude et son origine a été élucidée grâce à différentes expériences.Les 2-halogéno-pyridines ont été utilisées comme réactifs de départ pour la synthèse de ligands chiraux de type 2,2´-bipyridines. L´étape problématique s´est avérée être la réaction de dimérisation réductrice des 2-halogéno-pyridines donnant accès aux2,2-bipyridines correspondantes. L´efficacité de ces ligands chiraux de type 2,2´-bipyridinea été évaluée dans différentes réactions asymétriques catalysées par des métaux de transition telles que l´aldolisation de Mukaiyama, l´hydroxyméthylation, l´addition conjuguée, l´activation C–H d´indoles mais aussi la désymmétrisation d´époxydes meso, dans laquelle un des ligands bipyridines a montré une extraordinaire activité et robustesse. Ensuite, basées sur des analyses RMN, des calculs DFT et des analyses par diffraction des rayons X, les propriétés structurales de ce ligand ont été étudiées.De plus, une nouvelle famille de catalyseurs à chiralité axiale de type 2,2´-bipyridines N,N´-dioxydes a pu être synthétisée via 2 différentes approches, où seule l´étape clé de dimérisation diffère. La première approche, basée sur la réaction de dimérisation réductrice des 2-halogéno-pyridines, permet l´obtention d´un seul atropoisomère du N,N´-dioxydes cible après une séquence réactionnelle de 8 étapes tandis que la seconde approche, basée sur la réaction de dimérisation oxydante de pyridines N-oxydes, donne l´accès aux 2 atropoisomères en seulement 5 étapes. Le champs d´application de ces nouveaux catalyseurs de typeN,N´-dioxydes, en tant que base de Lewis, a été examiné dans l´allylation énantiosélective du benzaldéhyde ainsi que dans l´aldolisation de l´acétal de cétène trichlorosilylé en présence de l´acétophénone. / 2,2'-Bipyridines and their appropriate N,N'-dioxides form a significant class of heteroaromatic compounds, which has found application in various fields of chemistry and predominantly in asymmetric catalysis. One of the most powerful methods for their synthesis is cocyclotrimerization of alkynes with nitriles.A new variant of cyclotrimerization reaction – cocyclotrimerization of halodiynes with nitriles, which results in the formation of 2- and 3-halopyridines, has been developed. The reaction was studied on a wide range of substrates providing the pyridine products in good isolated yields. Formation of an unexpected product of halogen exchange reaction was observed during the course of the study and its origin was elucidated by experimental studies.The prepared 2-halopyridines were used as starting materials for syntheses of new chiral 2,2'-bipyridine ligands. The crucial step of their synthesis turned out to be the reductive dimerization of 2-halopyridines to the corresponding 2,2'-bipyridines. Application of the formed bipyridine ligands was then tested in various metal-catalyzed asymmetric reactions, namely Mukaiyama aldol reaction, hydroxymethylation, conjugate addition, C–H activation of indole and desymmetrization of meso-epoxides, in which one of the bipyridine ligands showed extraordinary activity and robustness. The structural properties of this ligand were then studied based on the NMR analyses, DFT calculations and single crystal X-ray analyses.New axially chiral 2,2'-bipyridine N,N'-dioxides were synthesized via two approaches, which differed in the type of the key dimerization step. While the first approach, based on the reductive dimerization of 2-halopyridines, furnished only one atropoisomer of the target N,N'-dioxide by an eight-step reaction sequence, the second approach, based on oxidative dimerization of pyridine-N-oxides, provided both atropoisomers in only five steps. The applicability of these novel N,N'-dioxides as Lewis base catalysts were then examined in the enantioselective allylation of benzaldehyde and aldol reaction of trichlorosilyl ketene acetal with acetophenone.

The thesis can be divided into two chapters: synthesis and application. The first chapter presents the basis of synthesis. Generally, electronic-deficient aromatic molecules require activation before reacting with metal reagents and then can go coupling reaction. Our lab has developed a new bipyridine coupling method without pre-functionalization of pyridines to the corresponding activated halide or metal forms or using of transition metal catalysts. This new method is quite efficient and advantageous for environmental protection. In second chapter, we synthesized 3,3¡¦-dihydroxy-2,2¡¦-bipyridine -based molecules and the functional groups were modified to investigate its liquid crystal properties. According to analyzing data of differential scanning calorimetry (DSC), polarized optical microscope (POM) and powder x-ray diffraction (XRD), we found that a-3 may possess cubic mesophaes with Im3m symmetry, and a series of d-1~d-3 compounds exhibit mesophase and may be further identified as smectic phase.

Reproduction de : Thèse d'Etat : Sciences physiques : Toulouse, INPT : 1980. / Titre provenant de l'écran-titre. Bibliogr. 83 réf.

Thèse doctorat : Chimie Organo-Minérale : Strasbourg 1 : 2007. / Titre provenant de l'écran-titre. Bibliogr. 5 p.

Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2008. / Includes bibliographical references.

Th.--Sci. phys.--Toulouse--I.N.P., 1980. N°: 46.

Asymmetric catalysis is vitally important for modern organic chemistry. However, many chiral catalysts are readily available only in a single absolute configuration. This often prevents practical access to both enantiomers of a product. To address this shortcoming, we propose a novel type of accessible ligands based on the structure of trans-5,6-disubstituted-5,6-dihydro-1,10-phenanthroline. Conformers of this molecule have opposite twist in the bipyridine fragment (opposite helicity or axial chirality). Thus, a relative stabilization of one or the other conformer of the same chiral precursor could potentially give access to two ligands with opposite axial chirality and hence to two catalysts with opposite enantioselectivity. We proposed structural modifications of substituents attached to 5,6-dihydro-1,10- phenanthroline as a convenient and reliable approach for stabilization of one or another conformer. To validate this strategy, multiple oxygen- and sulfur-substituted ligands were synthesized and fully characterized. In particular, their conformational behavior was studied by 1H NMR. Some ligands and their metal complexes were designed and proved to be conformationally (axially) constrained. Chiral resolution of these ligands through separation of their diastereomeric derivatives was accomplished, resulting in material of high optical purity. The absolute configuration of chiral elements (centers and axis) were established by 1H NMR, CD and X-ray analysis. Metal complexes with a range of novel chiral 5,6-dihydro-1,10-phenanthrolines were assessed as chiral catalysts for the asymmetric alkylation of aldehydes, Henry reaction and allylic substitution. Moderate to high activities were achieved in all catalytic transformations while low to moderate degree of enantioselectivity was observed. The results of asymmetric catalysis confirmed the crucial role of the twist in the ligand’s bipyridine moiety (of its sign and magnitude) in the induction of stereoselectivity. Exploring an undesired aromatization of products in cleavage of 5,6-epoxy-5,6- dihydro-1,10-phenanthroline with various thiols in presence of base, we developed a new simple procedure and synthesized a broad library of novel valuable ligands: 5-aryl(alkyl)sulfanyl-1,10-phenanthrolines and bis(1,10-phenanthrolines). Other functional groups attached to the thiol moiety allow using these products as building blocks for versatile ligands and in functionalization of surfaces. Besides, the new sulfur- substituted derivatives were found to be potent modulators of fungal glycosidases.

Ce manuscrit de thèse décrit la conception, l’élaboration et l’étude de complexes organofers électro-actifs dans lesquels deux unités terminales Cp*(dppe)FeII/III sont reliés par un pont fonctionnel. Dans le premier chapitre, nous avons présenté une réaction à la fois originale et efficace catalysée par le Pd(0) qui permet d’accèder à la [5,5’-{(Cp*(dppe)Fe–C≡C}2-(μ-2,2’-bipy)]. Le deuxième chapitre porte sur la présentation d’une voie de synthèse rapide et efficace du métallo-ligand [6,6’-{Cp*(dppe)Fe–C≡C}2-(μ-2,2’-bipy)]. Le troisième chapitre de ce mémoire est consacré à l’utilisation du ligand 1’,1’’’-bis(éthynyle)biferrocényle comme pont entre deux terminaisons électroactives Cp*(dppe)FeII/III. L’espaceur électro-actif joue le rôle de relais moléculaire favorisant le transfert électronique d’une terminaison à l’autre par sauts successifs. Afin d’ajuster les potentiels redox des terminaisons par rapport à ceux du biferrocényle, les terminaisons Cp(PPh3)2M (M = Ru, Os) ont également été utilisées pour substituer un ou deux sites organofers. Le chapitre quatre est dédié aux travaux réalisés sur le système hybride Cp*(dppe)Fe-C≡C-TTMe3. Dans cette molécule, le site Cp*(dppe)FeII/III interagit à travers le pont acétylure avec le fragment tétrathiafulvalényle. La nouvelle molécule est stable sous trois degrés d’oxydation. L’espèce monocationique se comporte comme un composé à valence mixte de classe II et le couplage électronique entre les deux électrophores a été déterminé (Hab = 320 cm-1). Dans le cinquième et dernier chapitre nous mettrons à profit la découverte d’une réaction d’activation de la liaison C-H du groupement méthyle situé sur le même cycle du TTF et de l’acétylure de fer dans le composé [Cp*(dppe)Fe-C≡C-TTMe3](PF6)3. Cette réaction permet la synthèse du complexe moléculaire multifonctionnel [Cp*(dppe)Fe=C=C=TTFMe2=CH-CH=TTFMe2=C=C=Fe(dppe)Cp*][PF6]2 avec de très bon rendement. Les propriétés physicochimiques de ce nouveau complexe analysées avec le support de la chimie quantique permettent de révéler les caractéristiques originales de ce composé inédit. / This thesis highlights the conception, synthesis and studies of redox-active organoiron complexes in which the two termini Cp*(dppe)FeII/III are linked by a functional bridge. In chapter I, an original and efficient synthetic Pd(0) catalysed homocoupling procedure is reported involving mononuclear organoiron(II) intermediates allowing us to isolate [5,5’-{Cp*(dppe)Fe–C≡C}2-(μ-2,2’-bipy)]. In chapter II, a rapid and efficient synthetic access to the redox-active metallo-ligand [6,6’-{cp*(dppe)Fe–C≡C}2-(μ-2,2’-bipy)] is described. In chapter III, the synthesis and properties of a series of complexes containing bis(ethynyl)biferrocene as a bridge between different redoxactive groups is pointed out. The redox bridge acts as a molecular relay for the electronic exchange between the termini via an electron hopping pathway. In order to tune the redox potential compared with those of biferrocene, one or two organoiron groups have been substituted by the Cp(PPh3)2M (M = Ru, Os) groups. In chapter IV, works are dedicated to the hybrid system Cp*(dppe)Fe-C≡C-TTMe3. In this molecule, electronic interactions take place between the Cp*(dppe)FeII/III center and the tetrathiafulvalene core through the ethynyl bridge. The new molecule is stable under three redox states. The mono-oxidized species behaves as a mixed valence species with an electronic coupling Hab = 320 cm-1 between the two electrophores. In the fifth and final chapter, the discovery of a CH bond activation of a methyl group located on the same cycle of the TTF core and the iron acetylide for the compound [Cp*(dppe)Fe-C≡C-TTMe3](PF6)3 is reported. This new reaction allows the synthesis of the multicomponent molecule [Cp*(dppe)Fe=C=C=TTFMe2=CH-CH=TTFMe2=C=C=Fe(dppe)Cp*][PF6]2 in good yield. The resulting device displays specific properties analysed with the support of the quantum chemistry.

The interest in biosensors can be attributed to the first described enzyme containing sensor used to detect levels of glucose in 1962. Although research into biosensors was initially slow to pick up, the field has become increasingly popular and research has been widespread for the last 20 years. The continuing research into biosensors is crucial as this will improve current devices to become smaller, faster and more economical and yield new biosensors. This thesis is mostly concerned with the development of an integral component of a biosensor, the redox mediator. Complexes of ruthenium incorporating electron rich sulfur-donor ligands such as naphthalenedithiol should possess interesting redox qualities which could be used to produce better mediators. A second area covered in this thesis is in the structural studies of a series of iridium and rhodium complexes. Two classes of ruthenium complexes with sulfur-donor ligands have been prepared. The first class incorporates the ruthenium bis-bipyridine moiety while the second contains pentamethylcyclopentadienyl ruthenium. Most complexes synthesised exhibited reversible oxidation waves in the region of -0.1 to 0.2 V vs. Ag/Ag⁺. Their possible use as redox mediators was hindered by several factors, particularly difficulties in purification. They also exhibited oxygen sensitivity and low stability when in solution.The second area covered in this thesis is to further understand the bonding of the ligands used in the above study. A series of pentamethylcyclopentadienyl iridium and rhodium complexes were synthesised with three different dithiolato ligands. Two of the three ligands studies produced structures that included more than one metal centre leading to straining of the ligand. In order to study the monomeric form, the clusters were opened with a neutral phosphine ligand. Both the Ir…S and Rh…S bond lengths of all the complexes were within expected parameters.