In medicinal chemistry, there is a constant need for new preparative methods, both to make the synthesis process more effective, and to increase the accessibility to a wide variety of compounds. A number of different approaches can be used to attain these goals. Transition metal catalysis is generally performed under mild conditions, providing both regio- and chemoselective reactions. Thus, it offers an attractive means of preparation of complex drug candidates. Two additional methodologies used to increase the preparative efficiency are one-pot protocols and controlled microwave heating. One-pot and multi-component reactions are less time consuming than step-by-step reactions, and microwave heating has been used to considerably shorten the reaction times. This thesis describes a new palladium-catalyzed, one-pot reaction producing racemic acetal-protected 3-hydroxy-1-indanones from ethylene glycol vinyl ether and triflates of salicylic aldehydes. The triflates were prepared using controlled microwave heating. The reaction sequence starts with a regioselective internal Heck coupling, followed by an annulation cascade. By including secondary amines in the reaction mixture, the reaction was further developed into a three-component reaction delivering racemic acetal-protected 3-amino-1-indanones. This new method was utilized for the synthesis of primary, secondary and tertiary aminoindanones. Finally, by using enantiopure t-butyl sulfinyl imines, derived from salicylic aldehyde triflates and ethylene glycol vinyl ether as starting materials in a closely related type of palladium coupling–annulation sequence, a stereoselective protocol providing enantiomerically pure 3-amino-1-indanones was developed. To demonstrate an application in medicinal chemistry, the enantiopure 3-amino-1-indanones were incorporated as P2 and/or P2´ substituents into active HIV-1 protease inhibitors.

A wide variety of computational methods are available for exploring molecular structures and reactivity in chemistry. These range from molecular mechanics calculations allowing determination of the geometry of a molecule to ab initio calculations for the electronic structure of compounds. Electronic structure calculations can be carried out with sufficient rigor so that the results are now comparable with experimental results in many cases. Density Functional Theory (DFT) with hybrid functional like B3LYP, for example, is very popular especially for studies on organometallic molecules and their reactions. Traditional ab initio approaches including Hartree-Fock (HF) and post-HF methods that include configuration interaction, such as MP2 and MP4 continue to be used, often for comparison with DFT based methods. Semi-empirical methods now appear to have only limited use except in large systems, in combination with molecular mechanics (MM) calculations. A relatively new use of MM for large systems is in hybrid calculations where the reactive center of the system is treated at a higher level leaving the remainder to be treated at the MM level. These hybrid QM/MM (quantum mechanics/molecular mechanics) calculations, such as ONIOM (our own n-layered integrated molecular orbital and molecular mechanics developed by Morokuma and co-workers) enable one to treat the steric bulk of the big system effectively and computationally efficiently. They appear to be very standard methods particularly in studies relating to reactions of organometallic systems and structures of large biomolecules. A short description of these methods is given below. • ab initio: a wide variety of programs that calculate the electronic structure of molecules using the Schrödinger equation, the values of the fundamental constants and the atomic numbers of the atoms present (Atkins, 1991). Molecular structures, optimized as a function of the electronic structure, are valuable starting points for many studies. • Density Functional Theory (DFT): a theoretical model in which the energy of an N-electron system is described as a functional of the density. • Semi-empirical techniques use approximations to evaluate the overlap, repulsion and exchange integrals in solving the Schrodinger equation. Often, these integrals are not evaluated but estimated to reproduce experimental data. • Molecular mechanics uses classical physics to explain and interpret the behavior of atoms and molecules. • Molecular dynamics (MD): Newton’s laws of motion are used to examine the time-dependent behavior of systems, including vibrations and Brownian motion, using a classical mechanical description. When combined with DFT, it leads to the Car-Parrinello method. • QM/MM method: It is a molecular simulation method that combines the strength of both QM (accuracy) and MM (speed) calculations, thus resulting in an extremely powerful tool for the study of bigger systems like chemical process in solution, interaction of drugs with biomolecules etc. Several commercial and educational packages in computational chemistry include a suite of programs that enable study of organic and organometallic molecules in an integrated fashion. While no list can be comprehensive, those that are more popular and useful are listed in several websites URL (http://www.ccl.net/chemistry/links/software/index.shtml). In the early days of computational chemistry up to 1980's, detailed studies were only carried out on small organic compounds or empirical studies were carried out on transition metal containing organometallics. However, in recent times, significant advancements in theoretical methods and computer capability (hardware and software), have led to the acceleration of theoretical and computational studies of complex systems including compounds containing transition metal elements. Computational and theoretical studies of organometallic complexes and their reactions have gained immense popularity and the numbers of papers including theoretical studies are dramatically increasing. One reason for this popularity is that organometallic complexes exhibit unusual geometries, bonding, and reactivity which often do not fall into the domain of inorganic or organic chemistry making them difficult to understand. Catalysis is one of the most extensively studied areas in organometallic chemistry where computational studies already make a real and valuable contribution to the analysis and interpretation of experimental data. However, what might be called ‘in silico’ catalyst screening and design, has rarely been achieved. One might say that successful prediction of catalyst performance is still a dream. A recent review summarizes the current state of the art in computational chemistry as applied to organometallic catalysis, covering both calculated ligand property descriptors and mechanistic studies of catalytic cycles.1 Some of the widely studied catalytic reactions of current interest, that provide huge scope for computational and theoretical analysis, are allylic alkylation (Pd),2 hydrogenation (Rh),3 hydroformylation (Rh),4 alkene metathesis (Ru),5 cross-coupling (Pd),6 C–H activation (Pd)7 and amination (Pd).8 There are many more examples where computational studies appear to be very useful for analysis of crystal structures and NMR structures or prediction of structures where no experimental data are available for complicated organometallic systems. There are a number of studies on drug-DNA/nucleobases interactions using QM/MM-MD simulations where people have investigated the interactions of metal complexes with double stranded (ds) DNA/nucleobases and the effects of their binding on the local and the global structure of DNA. QM/MM methods are also very helpful for studying catalytic reactions, interpretation of structure of large systems (proteins) and understanding reactions in biological systems. Scope of the Thesis In this thesis an attempt is made to use computational chemistry to understand organometallic reactions that are of significance from biological and synthetic view points, such as the action of organometallic complexes on DNA and the mechanism of some catalytic reactions. In many of these cases, the key step involved a nucleophillic attack. Specifically four such problems have been addressed where experimental results are not sufficient to provide a complete mechanistic picture of the reaction. Hence, the thesis contains four chapters with each having an independent brief introduction. The first chapter deals with the substitution reaction where water replaces chloride ion in the piano stool type ruthenium (II)-arene complexes and subsequently coordination of Ru to guanine/adenine occurs in these complexes. These steps have been studied using density functional theory at the B3LYP level. The complexes have promising anticancer activity. These nucleophilic substitution reactions are very important for activating these complexes so that they can interact with DNA, because DNA is thought to be primary target for their anticancer activity. In this chapter, both associative and dissociative pathways have been explored in the gas phase, as well as in the presence of other solvents for substitution reactions. Among the associative paths, a variety of possibilities can exist for the hydrolysis based on the direction of the nucleophilic attack by a water molecule. The proposed theoretical model for hydrolysis provides new insight into the hydrolysis process in half sandwich ruthenium complexes. The second chapter deals with the QM/MM calculations to investigate the structural and electronic properties of drug-DNA interactions, where DNA acts as nucleophile towards the metal complex. A series of piano-stool type ruthenium (II)-arene complexes were selected for the present study. These interactions were analyzed using the two layer ONIOM method. The importance of this study lies in the detailed understanding of factors that govern DNA binding and reactivity which is clearly of great pharmacological interest, as it may provide the basis for designing better anticancer agents. Experimental results that explore the structural feature of DNA-metal complexes at a molecular level are very limited. Thus theoretical calculations of molecular and electronic structure represent a valuable complement to experiments. They provide an alternative way to explore structure-activity relationships, and the drug binding mechanism, in detail. The third chapter reports the use of QM/MM methods in understanding the reaction mechanism and enantioselectivity in an organic transformation. In this section, a computational investigation of the enantioselectivity observed in the allylation of cinnamaldehyde, catalyzed by chiral platinum phosphinite complexes, have been carried out. The catalysts are ascorbic acid based phosphinite complexes where enantioselectivity depends on the substitution of benzyl groups on the chiral phosphinite ligands. From the experiment, it is not clear how the effect of an ancillary ligand can make such a big impact on enantioselectivity. To find out the origin of stereoselectivity, a computational study was taken up. A reaction mechanism was established where the nucleophilic attack determines the rate of the reaction and the corresponding enantioselectivity. A screening process has been utilized to select relevant reactant adducts and corresponding transition states from approximately 200 theoretically possible conformers using MM calculations. Finally with the help of QM/MM calculations, the numbers of contributions of these conformers were estimated. This approach correctly predicts the enantioselectivity in these reactions catalyzed by these complexes especially when the experimental enantioselectivity is very high. The fourth chapter of the thesis discusses the use of computational techniques to study the nucleophilic attack of an imine on a Ti-olefin complex. The reaction of Grignard reagents with imines mediated by stoichiometric amounts of titanium isopropoxide has been reported recently. On the basis of deuterium labeling experiments, nucleophilic attack of an imine on a Ti-olefin complex was believed to be a key step. Effect of deuterium labeling on the ratio of products formed is not easy to understand from experiments. Hence a computational study was performed using the DFT method to establish the mechanism of substitution and to understand the role of deuterium labeling. The thesis also includes a study of Cu-Cu interactions using Atoms in Molecules (AIM) theory in copper complexes with reasonably short Cu-Cu distances. The concept of bond critical points (BCP) from AIM analysis is employed to investigate the CuI-CuI bonding interactions in ligand unsupported copper complexes where the CuI-CuI contacts are shorter than the sum of their van der Waals radii. There is extensive debate about the nature of interactions between d10 "closed shell" systems in copper (CuI) complexes, which is known as cuprophilicity. In this study, an attempt has been made to compute the electron density between the two CuI centers and examine the nature of this “interaction”. As this falls outside the main theme of nucleophilic interactions in metal complexes, it has been relegated to an appendix.

Dendrimers are synthetic macromolecules with branches-upon-branches structures, nanoscale dimensions and a high density of surface groups. Presence of multiple cationic sites in dendrimers permits their efficient nucleic acid complexation and cellular internalization through endocytic pathways. PETIM dendrimers of are characterized by tertiary amine branch points, and ether linkages. A third generation PETIM dendrimer, G3(NH2)24, with nitrogen at the core and twenty four peripheral primary amines was synthesized through alternate Michael addition and reduction reactions. The ability of G3(NH2)24 to interact with DNA was ascertained by spectroscopic and bio-physical techniques. These studies established the formation of dendrimer-DNA, and complex formation was also shown to protect the plasmid DNA from nucleases. Toxicity studies in cell culture, as well as, in female Balb/c mice established the non-toxic properties of the dendrimer. G3(NH2)24 was able to mediate efficient transfection in mammalian cells and in vivo. Targeted delivery of small interfering RNA (siRNA) to hepatocytes, in order to combat hepatitis C virus (HCV) infection was undertaken to expand the scope of PETIM dendrimer based gene delivery. Functionalization of the dendrimer periphery with galactose units ensured preferential delivery to the liver through multivalent interactions with the asialoglycoprotein receptors on the liver cell surface. The delivery of siRNA to the perinuclear region, in close proximity to the HCV RNA replication site resulted in ~75% decrease in viral RNA levels in replicon containing cells, as well as, JFH-1 infectious virus systems. The dendrimer-siRNA complexes were preferentially delivered to mice liver and were active in vivo. Physico-chemical studies of the protonation pattern of PETIM dendrimer indicated that the protonation of the dendrimer amines proceeded in a shell-wise pattern from the periphery to the core. The primary amines of the dendrimer as well as the outer shell tertiary amines with pKa values ~7-10 were protonated at physiological pH and were cationic sites for nucleic acid condensation. The inner shell tertiary amines with a pKa of ~4-6 were protonated at endosomal pH and aided ‘endosomal escape’ due to the high buffering capacity of 3.5. Work described in the Thesis establish a new synthetic dendrimer vector, namely, the series of PETIM dendrimers, as a high value gene delivery vector, making in-roads towards pre-clinical and possible clinical trials in future studies.

No description available.

The synthesis of a rigid 4,5-bis(triphenylphosphinimino)-2,7-di-tert-butyl-9,9-dimethylxanthene (Ph3PN)2XT (1) ligand is outlined, along with a modified synthesis for previously reported 1,8-bis(triphenylphosphinimino)naphthalene (Ph3PN)2NAP (3). Reaction of neutral (Ph3PN)2XT with [Y(CH2SiMe3)3(THF)2] resulted in double cyclometallation, yielding the base-free monoalkyl complex, [({Ph2(C6H4)PN}2XT)Y(CH2SiMe3)] (2). Layering a concentrated THF solution of 2 with hexanes at −28 °C afforded THF-coordinated [({Ph2(C6H4)PN}2XT) Y(CH2SiMe3)(THF)]·2THF (2-THF·2THF), with a distorted pentagonal bipyramidal geometry and approximately meridional coordination of the pentadentate {Ph2(C6H4)PN}2XT dianion. Similarly, (Ph3PN)2NAP reacted with [Y(CH2SiMe3)3(THF)2] to afford a THF-coordinated monoalkyl complex, [{(Ph2(C6H4)PN)2NAP}Y(CH2SiMe3)(THF)] (4-THF). Layering a DME solution of 4-THF with hexanes at −28 °C afforded X-ray quality crystals of [{(Ph2(C6H4)PN)2NAP}Y(CH2SiMe3)(κ2-DME)]·hexane (4-DME·hexane), with a highly distorted pentagonal bipyramidal geometry and a facial coordination mode of the tetradentate {Ph2(C6H4)PN}2NAP dianion The synthesis of a rigid 4,5-bis(1,3-diisopropylimidazol-2-imine)-2,7,9,9-tetramethylacridan H(AII2) ligand (5) was achieved via a Buchwald-Hartwig cross-coupling reaction. Reaction of the proligand H(AII2) with [M(CH2SiMe3)3(THF)2] (M = Y(6), Sc(8)) yielded the base free dialkyl complexes [(AII2)Y(CH2SiMe3)2] (6) and [(AII2)Sc(CH2SiMe3)2] (8). The reaction of 6 with one equivalent of [CPh3][B(C6F5)4] yielded [(AII2)Y(CH2SiMe3)][B(C6F5)4] (7) in-situ. Complex 7 proved to be a potent intramolecular hydroamination catalyst for a variety of aminoalkane substrates. The attempted synthesis of 4,5-bis(1,3-diisopropylimidazol-2-imine)-2,7-di-tert-butyl-9,9-dimethylxanthene (XII2) via the Staudinger reaction resulted in the isolation of the triazene intermediate 4,5-bis(1,3-diisopropylimidazol-2-yliedene{triazene})-2,7-di-tert-butyl-9,9-dimethylxanthene XIA2 (9). Reaction of XIA2 with one equivalent of [Y(CH2SiMe3)3(THF)2] led to the isolation of [(XIA2)Y(CH2SiMe3)3] (10). Synthesis of XII2 (11) was achieved via a Buchwald-Hartwig cross-coupling reaction. Reaction of XII2 with one equivalent of YCl3(THF)3.5 resulted in the isolation of [(XII2)YCl3] (12). In contrast, the reaction of XII2 with one equivalent of [Y(CH2SiMe3)3(THF)2] led to several unidentified products. Reaction of XII2 with 1 equivalent of [H(Et2O)2][B(C6F5)4] led to the isolation of the precursor [H(XII)2][B(C6F5)4] (13). The reaction of 13 with 1.1 equivalents of [M(CH2SiMe3)3(THF)2] (M = {Y(14), Sc(15)} led to the isolation of the monocationic [(XII)2M(CH2SiMe3)2][B(C6F5)4] complexes. The reaction of [(XII)2Sc(CH2SiMe3)2][B(C6F5)4] with 1.1 equivalents of B(C6F5)3 led to the abstraction of a methyl anion from the silicon center, with concomitant migration of the remaining alkyl group to the positively charged silicon, forming a new CH2SiMe2CH2SiMe3 alkyl group. This process is accompanied by MeB(C6F5)3 anion formation, forming a contact ion pair to afford the dicationic species [(XII)2Sc(CH2SiMe3)][MeB(C6F5)3][B(C6F5)4] 16. In contrast, the reaction of 15 with 1.3 equivalents of [CPh3][B(C6F5)4] in the presence of 5 equivalents of toluene resulted in the synthesis of [(XII)2Sc(CH2SiMe3)(ɳx-toluene)][B(C6F5)4]2 17 in-situ. Complex 17 is a highly potent ethylene polymerization catalyst with an activity of 868 kg/mol·atm·h. The reaction of 15 with [HNMe2Ph][B(C6F5)4] led to the cyclometallation of the resulting NMe2Ph byproduct to yield [(XII2)Sc(C6H4NMe2)][B(C6F5)4]2 (18) in-situ. The synthesis of a rigid, asymmetric 4-(1,3-diisopropylimidazol-2-imine)-5-(2,6-diisopropylanilido)- 2,7-di-tert-butyl-9,9-dimethylxanthene XAI (19) ligand was achieved by a two step Buchwald-Hartwig cross-coupling reaction with initial cross coupling of 1,3-diisopropylimidazol-2-imine followed by the cross-coupling of 2,6-diisoproylaniline. The reaction of XAI with 1.1 equivalents of [Y(CH2SiMe3)3(THF)2] yielded [(XAI)Y(CH2SiMe3)2] (20). Subsequent reaction of [(XAI)Y(CH2SiMe3)2] with 1 equivalent of [CPh3][B(C6F5)4] in the presence of 10 equivalents of toluene resulted in the synthesis of the toluene coordinated [(XAI)Y(CH2SiMe3)(ɳx-toluene)][B(C6F5)4] (21) complex. Similar to 7, complex 21 was highly active for intramolecular hydroamination of various substrates. / Dissertation / Doctor of Philosophy (PhD) / Cationic group 3 alkyl complexes are underreported in comparison to analogous group 4 complexes. The scarcity of these complexes can be attributed to their propensity to engage in undesirable reactions such as ligand redistribution and cyclometallation. To increase the thermal stability of such complexes, design features, such as carefully positioned steric bulk and ligand rigidity are beneficial. Additionally, such ligands must also have considerable donor ability, in order to stabilize inherently electron deficient cationic metal centers. This work details the synthesis of a variety of neutral and monoanionic ligands that incorporate the aforementioned design features, which were utilized in the successful synthesis of a variety of neutral, monocationic and extremely rare dicationic group 3 alkyl complexes. The cationic monoalkyl complex in this work proved to be a highly potent intramolecular hydroamination catalyst. Furthermore, a rare dicationic scandium complex was highly active for ethylene polymerization

Di-tert-butyl N,N′-{[13,15,28,30,31,33-hexa­ethyl-3,10,18,25,32,34-hexa­aza­penta­cyclo­[25.3.1.15,8.112,16.120,23]tetra­triaconta-1(31),3,5,7,9,12(33),13,15,18,20,22,24,27,29-tetra­deca­ene-14,29-di­yl]bis­(methyl­ene)}dicarbamate methanol disolvate, C52H72N8O4·2CH3OH, was found to crystallize in the space group P21/c with one half of the macrocycle (host) and one mol­ecule of solvent (guest) in the asymmetric unit of the cell, i.e. the host mol­ecule is located on a crystallographic symmetry center. Within the 1:2 host–guest complex, the solvent mol­ecules are accommodated in the host cavity and held in their positions by O—H⋯N and N—H⋯O bonds, thus forming ring synthons of graph set R22(7). The connection of the 1:2 host-guest complexes is accomplished by C—H⋯O, C—H⋯N and C—H⋯π inter­actions, which create a three-dimensional supra­molecular network.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

The object of this work is to obtain a fundamentalunderstanding of the principal issues concerning the handlingof an aqueous WC-Co powder suspension. The WO3 surface layer on the oxidised tungsten carbidepowder dissolves at pH&gt;3 with the tungsten concentrationincreasing linearly with time. Adding cobalt powder to thetungsten carbide suspension resulted in a significant reductionof the dissolution rate at pH&lt;10. Electrokinetic studiesindicated that the reduced dissolution rate may be related tothe formation of surface complexes; the experiments showed thatCo species in solution adsorb on the oxidised tungsten carbidepowder. The surface forces of oxidised tungsten and cobalt surfaceswere investigated using the atomic force microscope (AFM)colloidal probe technique. The interactions at various ionicstrengths and pH values are well described by DLVO theory. Theadsorption of cobalt ions to tungsten oxide surfaces resultedin an additional non-DLVO force and a reduced absolute value ofthe surface potential. It was shown that the adsorption ofpoly(ethylene imine) (PEI) to the WO3 surfaces induces anelectrosteric repulsion. The properties of spray-dried WC-Co granules were related tothe WC primary particle size, and the poly(ethylene glycol)(PEG) binder and PEI dispersant content in aqueous WC-Cosuspensions. The granule characterisation includes a new methodfor measuring the density of single granules. The increase inthe fracture strength of granules produced from suspensionsthat were stabilised with PEI was related to a more densepacking of the WC-Co particles. The AFM was used to study the friction and adhesion ofsingle spray-dried WC-Co granules containing various amounts ofPEG binder. The adhesion and friction force between two singlegranules (intergranular friction) and between a granule and ahard metal substrate (die-wall friction) have been determinedas a function of relative humidity. The granule-wall frictionincreases with binder content and relative humidity, whereasthe granule-granule friction is essentially independent of therelative humidity and substantially lower than the granule-wallfriction at all PEG contents. Key words:Hard Metal, Cemented Carbide, WC-Co, TungstenCarbide, Cobalt, Oxidation, Dissolution, Surface Complexation,XPS, AFM, Colloidal Probe, Hamaker Constant, Cauchy, WO3,CoOOH, ESCA, Zeta-Potential, Surface Potential, Poly(ethyleneimine), PEI, Suspension, van der Waals, Steric, Spray-Dried,Poly(ethylene glycol), Strength, Density, Friction, Adhesion,Granule, PEG, Pressing, FFM. / <p>QC 20161027</p>

Aufgrund ihrer Eigenschaften und möglicher Anwendungen werden Siliciumkomplexe mit O,N,O´-Ligandsystemen in der Literatur beschrieben. Jedoch fehlen bisher Untersuchungen zur Strukturaufklärung. Im Rahmen dieser Arbeit wurden zahlreiche Silicium-, Germanium- und Zinnkomplexe mit chiralen O,N,O´-Liganden synthetisiert und strukturanalytisch charakterisiert. Dazu wurden die Liganden durch Kondensationsreaktionen von enantiomerenreinen Aminosäuren mit aromatischen ortho-Hydroxyaldehyden bzw. Acetylaceton hergestellt. Die weitere Umsetzung der Liganden mit Elementhalogeniden der Gruppe 14 führte zu den angestrebten Komplexverbindungen. Alle hergestellten Verbindungen wurden umfassend charakterisiert (NMR-, UV/Vis-, IR-Spektroskopie, Elementaranalyse, Einkristallstrukturanalyse, Drehwert). Quantenchemische Berechnungen an einfachen Modellverbindungen sowie an hergestellten Silicium- und Zinnkomplexen führten zu einem grundlegenden Verständnis der Festkörper-NMR-Parameter dieser Verbindungsklasse.