Development of CO-releasing molecular for the treatment of inflammatory diseases

Dissertation presented to obtain a Ph.D. degree (Doutoramento) in Chemistry at the Instituto de Tecnologia Quimica e Biol6gica da Universidade Nova de LisboaCarbon Monoxide, CO, has been recognized as an endogenously produced, potent biological mediator involved in many defense mechanisms both in physiologic and pathologic situations. As a result of these signaling processes, CO possesses a strong therapeutic potential on a wide range of disease indications. However, the hardly avoidable safety and practical problems associated with therapeutic inhalation of toxic CO gas, led to the search for molecules capable of delivering CO to tissues in a living organism in a controlled and therapeutically useful manner. From all the areas of the chemical space where such CO-Releasing Molecules (CO-RMs) can be found, Metal Carbonyls Complexes (MCCs) seems to be the most versatile. It is the purpose of this Thesis to provide an extensive characterization of the behavior of MCCs in the presence of biological molecules and media, in order to identify the chemical and structural parameters that are more relevant to define the profile of a therapeutically effective metal-based CO-RM drug.(...)This Thesis was financially supported by Fundacao para a Ciencia e Tecnologia, European Social Fund grant number SFRH/BDE/15501/2004 and ALFAMAResearch and Development of Pharmaceutical Drugs Lt

The effect of Mo(CO)₆ as a catalyst in the carbonylation of methanol to methyl formate catalyzed by potassium methoxide under CO, syngas and H₂ atmospheres.

Ph. D. University of KwaZulu-Natal, Westville 2010In patents describing the low temperature production of methanol from syngas catalysed by the Ni(CO)₄/KOCH₃ system, Mo(CO)₆ was claimed to enhance the catalytic activity of the system. However, there has been no clarity on the effect of Mo(CO)₆ and KOCH₃ in the activation of the catalyst. Work reported in this thesis showed that most of the methyl formate is produced via a normal KOCH₃ catalyzed process under a CO atm. When the KOCH₃ system is compared with the Mo(CO)₆/KOCH₃ catalyzed system, it is noted that the amount of methyl formate increases very slightly due to the addition of molybdenum hexacarbonyl. The experiments were also performed under H₂ and synags (1:1) atm in different solvents. In all cases dimethyl ether was produced with methyl formate. Preliminary carbonylation studies performed at a syngas ratio of 1:2 showed an increase in the amount of methanol produced. Increasing the amount of Mo(CO)₆ in the Mo(CO)₆/KOCH₃ reaction under syngas (1:1) increases the production of methyl formate. High Pressure infrared (HPIR) studies for Mo(CO)₆/KOCH₃ were carried out under H₂, CO, syngas (1:1) and N₂ atmospheres. The alkoxycarbonyl complex (Mo(CO)₅(COOCH₃)⁻) was observed as an intermediate in all reactions involving Mo(CO)₆ and KOCH₃. Under a hydrogen atmosphere, the metalloester (Mo(CO)₅(COOCH₃)⁻) intermediate diminished to form a bridged molybdenum hydride (µ-HMo₂(CO)₁₀⁻) species as a stable intermediate. In contrast, under syngas atmosphere, the metallloester diminished in concentration to form the bridged hydride (µ-HMo₂(CO)₁₀⁻), which also disappeared to form the molybdenum alkoxide complex (Mo(CO)₅OCH₃⁻). The role of methanol in the formation of methyl formate is also discussed. Based on the HPIR studies, different types of metalloesters (alkoxycarbonyl complexes) were synthesized by nucleophilic reactions of alkoxides with Mo(CO)₆. Reactions of potassium alkoxides (KOR, R = -CH₃, -C(CH₃)₃, -C(CH₃)₂CH₂CH₃) with Mo(CO)₆ in THF produced water soluble alkoxycarbonyl complexes (K[Mo(CO)₅(COOR)]). The reaction of KOCPh₃ with Mo(CO)₆ yielded what is believed to be the metalloester as an insoluble compound. Attempts to improve the solubility of the formed alkoxycarbonyl complexes, K[Mo(CO)₅(COOR)], by metathesis with bulkier counter ions (PPNCl, Et₄NCl and n-Bu₄NI) was not successful. The reaction of K[Mo(CO)₅(COOCH₃)] with 18-crown-6 ether produced [K(18-crown-6)][Mo(CO)₅(COOCH₃)] which was more soluble in organic solvents. The reactions of [PPN][OCH₃] and [n-Bu₄N][OCH₃] with Mo(CO)₆ produced [PPN][Mo(CO)₅(COOCH₃)] and [n-Bu₄N][Mo(CO)₅(COOCH₃)], respectively. The reactions of [K(18-crown-6)][OCH₃] and [K(15-crown-5)₂][OCH₃] with Mo(CO)₆ under reflux gave the [K(18-crown-6)][Mo(CO)₅(COOCH₃)] and [K(15-crown- 5)₂][Mo(CO)₅(COOCH₃)] complexes. Reactions of Ph₃PMo(CO)₅ with KOCH₃ and [PPN][OCH₃] yielded K[Ph₃PMo(CO)₄(COOCH₃)] and [PPN][Ph₃PMo(CO)₄(COOCH₃)]. Other alkoxycarbonyl complexes were synthesized by an alternative approach using alcohols as solvent. For example, [PPN][Mo(CO)₅(COOCH₂CH₃)] was synthesized by refluxing [PPN][OEt] with Mo(CO)₆ in ethanol. The isopropyl derivative [PPN][Mo(CO)₅(COOCH(CH₃)₂)] was synthesized by refluxing [PPN][OCH(CH₃)₂] with Mo(CO)₆ in isopropanol. Two methyl derivatives were also synthesized in methanol as Et₄N and PPN derivatives. A crystal structure of the [PPN]₂[Mo₆O₁₉] oxo cluster, obtained from the decomposition of [PPN][Mo(CO)₅(COOCH(CH₃)₂)] in acetonitrile was solved. The crystal crystallized in the monoclinic form with a space group of P-1. Another oxo cluster, [Et₄N]₂[Mo₄O₁₃], formed from the decomposition of the [Et₄N][Mo(CO)₅(COOCH₃)] derivative. The structure was solved in the monoclinic form with a space group of P 2₁/n. The alkoxycarbonyl complex, [PPN][Mo(CO)₅(COOCH₃)], was tested for catalytic behaviour under hydrogen and syngas to determine its role in the production of methyl formate. No methyl formate was produced under hydrogen, but methyl formate was produced under syngas (1:1). HPIR studies of [PPN][Mo(CO)₅(COOCH₃)] under syngas (1:1) showed that methyl formate is formed via the decomposition of [PPN][Mo(CO)₅(COOCH₃)] to Mo(CO)₆. Interesting results for the reaction of Mo(CO)₆ with KOCH₃ under syngas (1:1) were obtained in triglyme. Here longer carbon chain alcohols were produced and identified by GC and GC-MS. These alcohols include ethanol, 2-propanol, 2-butanol, 3-methyl-2-butanol, 3-pentanol, 2-methyl- 3-pentanol and 2,4-dimethyl-3-pentanol

The chemistry of group-VIb metal carbonyls

The special interest attached to the chemistry of metal carbonyls arises from several causes. While quite distinct from the metal carbonyls in the organometallic compounds, they differ in physical properties (e.g., their volatility) from all other compounds of the transition metals. Chemically, they constitute a group of compounds in which the formal valency of the metal atoms is zero, and in this respect (apart, perhaps, from the ammoniates of the alkali metals) they are comparable only with the recently discovered compounds. As a class, the carbonyls are reactive compounds, and a number of new types of inorganic compounds have been discovered. In the concepts for new products, performance, product safety, and product economy criteria are equally important. They are taken into account already when the raw material base for a new industrial product development is defined. Since the discovery of nickel carbonyl by Mond and Langer in 1888, the carbonyls of the iron group and of chromium, molybdenum and tungsten have found important technical applications, e.g., in the Mond nickel process, and for the preparation of the metals in a state of subdivision and of purity suitable for powder metallurgy, for catalysts, etc. The reaction mechanism of the processes developed for producing the carbonyls technically has only recently received its interpretations. Within the space of review it is necessary to limit discussion to a few topics. Particular stress has accordingly laid upon (a) the chemical bonding in metal carbonyls, (b) importance of IR and NMR spectroscopy in characterization of metal carbonyls, (c) substitution reactions of G-VIb metal carbonyls, (d) kinetics and mechanism of substitution reactions in metal carbonyls, (e) substituted complexes of G-VIb metal carbonyl, (f) chelate complexes of G-VIb metal carbonyls, (g) uses of G-VIb metal carbonyl complexes and (h) studies done on G-VIb metal carbonyls

Primary Processes of Free Radical Formation in Pharmaceutical Formulations of Therapeutic Proteins

Oxidation represents a major pathway for the chemical degradation of pharmaceutical formulations. Few specific details are available on the mechanisms that trigger oxidation reactions in these formulations, specifically with respect to the formation of free radicals. Hence, these mechanisms must be formulated based on information on impurities and stress factors resulting from manufacturing, transportation and storage. In more detail, this article focusses on autoxidation, metal-catalyzed oxidation, photo-degradation and radicals generated from cavitation as a result of mechanical stress. Emphasis is placed on probable rather than theoretically possible pathways

Bimetallic complexes of d- and f-block metals with pentalene ligands

The focus of this thesis is the synthesis and characterisation of organometallic complexes incorporating the silylated pentalene ligand, [C8H4{SiiPr3-1,4}2]2- (= Pn†), bound to more than one metal centre. In general, metals in low oxidation states from the d- and f-block of the periodic table have been selected for these bimetallic complexes, as they are potentially reactive with small molecule substrates. Chapter One introduces the pentalene molecule and its derivatives, and discusses their use as ligands in organometallic chemistry. Particular emphasis is given to the application of organometallic pentalene complexes, ranging from conducting polymers in materials chemistry to small molecule activation and catalysis. In Chapter Two the silylated pentalene ligand Pn† is used to bridge two lanthanide(II) centres in anti-bimetallic sandwich complexes of the type [Cp*Ln]2(μ-Pn†) (Ln = Yb, Eu and Sm). Magnetic measurements and electrochemical methods are used to investigate the extent of intermetallic communication in some of these systems, which show potential for the design of organometallic 'molecular-wires'. Chemical oxidation of [Cp*Yb]2(μ-Pn†) leads to dissociation into mononuclear fragments (η8-Pn†)YbCp* and [Cp*Yb]+, and reaction of [Cp*Sm]2(μ-Pn†) with CO yields (η8-Pn†)SmCp*. Rational synthetic routes to mononuclear mixed-sandwich Pn†/Cp* compounds with trivalent f-block ions (Dy, Tb and U) are also developed, and their magnetic properties are studied by SQUID magnetometry including variable-frequency ac susceptibility measurements. These studies identified (η8-Pn†)DyCp* as the first known example of a pentalene based single molecule magnet, with a closed-waist hysteresis loop observed up to 2 K. Chapter Three describes the synthesis of iron(II) complexes with silylated pentalene ligands, and efforts towards incorporating them into extended organometallic arrays and heteronuclear anti-bimetallic complexes. Six complexes have been structurally characterised including the triple-decker homobimetallic [Cp*Fe]2(μ-Pn†), and the potassium salt [Cp*Fe(η5-Pn†)][K] which is an organometallic polymer in the solid state. Chapter Four documents efforts towards the synthesis of syn-bimetallic pentalene complexes, including the first row d-block metals V, Ti and Sc. A novel synthetic route to the di-titanium bis(pentalene) 'double-sandwich' complex (Pn†)2Ti2 is developed, via chloride-bridged dimers [(η8-Pn†)Ti]2(μ-Cl)x (x = 2 and 3). The electronic and magnetic properties of the latter are investigated using EPR spectroscopy and SQUID magnetometry, and the structure and bonding in (Pn†)2Ti2 is examined using spectroscopic, crystallographic, electrochemical and computational techniques. Preliminary studies toward the synthesis of an analogous di-scandium complex were unsuccessful, however three novel complexes have been synthesised including (η8- Pn†)ScCp* which is first example of a Sc complex bearing a Pn† ligand to be characterised by X-ray diffraction. Chapter Five explores the reactivity of the double-sandwich compound (Pn†)2Ti2 prepared in Chapter Four, with small molecules which are of industrial and environmental importance. The relatively open structure of (Pn†)2Ti2 allows the formation of adducts with unsaturated small molecules CO, MeNC and CO2. In the latter case the adduct formed is unstable at room temperature and the coordinated CO2 molecule is reduced to give a bis(oxo) bridged dimer and a di-carbonyl complex. This provides the first example of small molecule activation by a di-metal bis(pentalene) double-sandwich complex. The reactivity survey of (Pn†)2Ti2 is extended in Chapter Six to other substrates; including unsaturated heteroallenes as model molecules for CO2. In the case of nonpolar heteroallenes CS2 and carbodiimide, thermally stable adducts are isolated and have been structurally characterised. Polar heteroallenes COS and organic isocyanates undergo reductive transformations to give sulfide- and carbonimidate-bridged complexes respectively. The reactivity of (Pn†)2Ti2 with organic molecules containing heteroatom-heteroatom bonds is also described; the reactions with diphenyldichalcogenides and azobenzene show the ability of the double-sandwich complex to act as a 2e- and 4e- reducing agent respectively. The rich and varied chemistry shown by (Pn†)2Ti2 is evaluated and future work is suggested

Synthesis, characterization and reactivity of transition metal clusters and their role towards organic transformation

Transition metal cluster containing main group atoms as bridging ligands have drawn increased attention in recent years, mainly because of their unusual structures and novel chemical reactivity, as well as for their potential in the field of material science and catalysis. In the last three decades, varieties of synthetic methodologies have been developed for the synthesis of metal clusters containing chalcogens with unique structural features and properties. The chalcogen ligands have been known to act as bridging units and support the metal fragments in various cluster growth reactions. Designing of systematic synthetic routes to clusters containing metal-chalcogen bonds with new geometries and coordination modes led to the development of models and precursors for the synthesis of new materials. Some of these metal-chalcogen containing building blocks have been of great interest due to their unusual structural features and tunable opto-eletronic properties. Moreover, mixed-metal clusters have also been of tremendous importance due to their use as valuable precursors for the preparation of supported bimetallic and multimetallic heterogenous catalysts. In view of the enormous potential of transition metal clusters, we started our investigation to synthesise novel chalcogenide transition metal clusters containing ligands like phosphines, carbonyls, acetylides, alkynes etc. and understand their role in supporting cluster molecules and to explore the reactivity of metal clusters towards cluster growth reactions. Structural diversity of transition metal clusters can be achieved by using different types of ligands that play an important role to support the cluster framework and assist in the tuning of the cluster behaviour. This has prompted us to design transition metal cluster containing diphosphine groups of varied chain length and understand their potential in linking cluster cluster molecule. Furthermore, phosphines are one of the most widely utilized ligands in transition metal complex chemistry due to their extreme versatility in bonding and reactivity. Most of these diphosphine ligands have been found to adopt a variety of bonding modes on the cluster framework, including monodentate with a pendant phosphine center, chelating a single metal atom in the multimetallic cluster, bridging across a metal-metal bond and forming an intermolecular link across two clusters. The bonding modes adopted by these diphosphine ligands are influenced by the flexibility and length of the organic or organometallic backbone. In an effort to prepare novel clusters with structural identity, we sought to explore the possibility of incorporating both diphosphine ligands and chalcogen atoms in the cluster framework and study 3 their combined effect. We have been able to synthesize several homo- and hetero-metallic transition metal clusters containing chalcogens and diphosphines as supporting ligands. To understand the influence of different diphosphine ligands towards metal chalcogenide clusters we studied the reaction of triiron ditelluride carbonyl cluster and triironditelluride phosphine cluster with two different diphosphine ligands, bis(diphenylphosphino)methane and bis(diphenylphosphino)ethane. Synthesis and characterization of four new iron-palladium mixed metal clusters containing diphosphine ligand have been carried out and shows interesting bonding features and coordination modes. The contrasting results show the difference in reactivity between the cluster species and the influence of phosphines in controlling the cluster synthesis. Our aim has also been to synthesize complexes containing several metal binding sites for the synthesis of multimetallic system. In an effort to synthesize such molecules we have focussed our study on the preparation of dithiocarboxylate-alkyne metal complexes by sunlight mediated reaction process and use them to obtain mutimetallic complexes. A variety of organic transformations are supported and catalysed by metal complexes, wherein the necessary steric and electronic requirements for such transformations are offered by the metal centres and ligands. To understand the exact behaviour of the synthesized molecule on this front some investigation on the metal mediated transformation of different alkynes was undertaken

Photoredox Catalysts Based on Earth-abundant Metal Complexes

We would like to thank the Engineering and Physical Sciences Research Council and CRITICAT Centre for Doctoral Training for financial support [Ph.D. studentship to B.H.; Grant code: EP/L016419/1]. C.L thanks the Prof. & Mrs Purdie Bequests Scholarship and AstraZeneca for his PhD Studentship.Over the last decade, visible light photoredox catalysis has exploded into the consciousness of the synthetic chemist. The principal photocatalysts used are based on rare and toxic ruthenium(II) and iridium(III) complexes. This critical review focusses on Earth-abundant metal complexes as potential replacement photocatalysts and summarizes the use of photoactive Cu(I), Zn(II), Ni(0), V(V), Zr(IV), W(0), W(VI), Mo(0), Cr(III) , Co(III) and Fe(II) complexes in photoredox reactions. The optoelectronic properties of these complexes and relevant structurally related analogs, not yet used for photoredox catalysis, are disccussed in combination with the reaction scope reported for each photocatalyst. Prospects for the future of photocatalyst design are considered.PostprintPeer reviewe

An Investigation of the Photochemistry and Structures of Selected Second and Third Row Transition Metal Complexes

Examination of the electronic spectrum of IrCl3-6 has led to a reassignment of the electronic transitions involved. The band at 206 nm, formerly assigned as the spin allowed πL to metal eg transition, is shown to be 1t1u (σ) → 2eg(z2, x2 - y2) [1A1g → 1T1u]. Low temperature spectra revealed the presence of additional features at 250 and 278 nm. These are ascribed to the 1t2u (π) → 2eg(z2, x2 - y2) [1A1g → 1T1u] and 1t2u (π) → 2eg(z2, x2 - y2) [1A1g → 3T1u] transitions, respectively. Irradiation (λ = 254 nm) of 1-12 M HCl solutions of IrCl3-6 yields IrCl2-6 and H2. Since the excited state populated at this wavelength has been shown to be ligand to metal charge transfer in nature, the reactive intermediate is proposed to he an Ir(II) species with a chlorine atom still formally bound. Photolysis of the reaction product, IrCl2-6 in HCl results in the formation of IrCl3-6 and Cl2. This reaction prevails regardless of wavelength of excitation. The reactive state is again LMCT in nature. Coupling of these reactions effects a reversible photochemical hydrohalic acid splitting catalyst. The photochemistry of Mo(III), Mo(IV), Mo(V) in aqueous solution was investigated, and these ions were shown to be photochemically inert. Structural characterizations via Raman spectroscopy and X-ray ahsorption edge and EXAFS were undertaken. The Mo(II) structure is shown to be q quadruply bound dinuclear species. The Mo(III) is singly bonded with hydroxy bridges. Data for the Mo(V) ion are typical for oxobridged dinuclear compounds. In strong acid, Mo(IV) is shown to exist as a trinuclear species. As the pH of the medium is increased, the Mo-Mo amplitude decreased, indicating possible cluster fragmentation. In basic solution, a major structural change occurs. The presence of halide ions had no effect on the spectra. Ru3(CO)12 reacts photochemically in the presence of olefins, CO, and H2 to catalyze the hydroformylation reaction. Typical yields are 1.5 x 10-3 moles of aldehydes in a 2:1 linear to branched chain ratio. A heterogeneous catalyst can also be effected by photoinduced fragmentation of the cluster in the presence of PV4P. Attachment of a Ru-CO moiety was confirmed by IR and elemental analysis. The first step in catalyst activation was shown to be formation of Ru(CO)4 olefin with a quantum yield of 0.03 for 1-pentene. Subsequent steps involved formation of a hydride-olefin complex, rearrangement to a hydride alkyl, "CO insertion," and reductive elimination of aldehyde. Olefin isomerization and alkane production are also seen under reaction conditions. Formation of larger ruthenium carbonyl clusters led to catalyst deactivation. Photolysis of Ru3(CO)12 in the presence of H2 led to the formation of αH4-Ru4(CO)12. This molecule can also effect catalysis of the hydroformylation reaction, although yields are an order of magnitude less than for the parent cluster.</p