Free radical cyclization methodology has been used extensively in synthesis for manipulation of complex molecules such as alkaloids, terpenes, carbohydrates, peptides and nucleic acids. The methodology has emerged as a result of work by physical organic chemists who determined rate constants for the most common radical reactions used in organic synthesis. A novel route to cyclic imines based on 5-exo radical cyclization was explored. The radical precursors were imines prepared from allylamine and readily available a-phenylselenenyl ketones. The synthesis of conformationally constrained bicyclic nucleosides is also reported using 5-exo and 6-exo cyclizations of hexenyl and heptenyl radicals in thymidine nucleosides. The nucleosides were incorporated in a 15mer antisense oligonucleotide via solid-phase oligonucleotide synthesis. The AONs with the modifications were tested for target affinity and stability and compared with the well known LNA modified AONs. The thesis discusses the unique qualities of these novel molecules and presents them as potential candidates for antisense therapeutic agents. Keeping up with the theme of intramolecular carbon-carbon bond formation, microwave induced carbodechalcogenation of chalcogenoanhydrides was explored. Poor generality in these reactions made us turn to transition metal catalysis for Sonogashira cross-coupling reactions using alkyl aryl and diaryl tellurides as coupling partners.

The present project is related to two aspects of research (i) to develop a new technique to synthesize fine nano-size polymer particles with unique and controllable properties; (ii) to synthesize novel functional polymer nanoparticles aiming to overcome the central challenge that has limited the commercialization of green latex hydrogenation, i.e. the optimal interplay of accelerating the hydrogenation rate, decreasing the required quantity of catalyst, and eliminating the need for an organic solvent. Focusing on these two objectives stated above, the following studies were carried out. (1) Development of Micellar Nucleation Mechanism for Preparation of Fine Polymer Nanoparticles. Polymer nanoparticles below 20 nm with a solid content of more than 13 wt% and a narrow molecular weight polydispersity (~1.1) were prepared using a micellar nucleation semibatch microemulsion polymerization system emulsified by sodium dodecyl sulfate (SDS), with SDS/monomer (methyl methacrylate) and SDS/H2O weight ratios of up to 1:16 and 1:100, respectively. It was found that for benzoyl peroxide (BPO), micellar nucleation is more favorable for the synthesis of smaller polymer nanoparticles than ammonium persulfate (APS), which gives rise to homogeneous nucleation and 2,2'-azobisisobutyronitrile (AIBN), which involves partially heterogeneous nucleation. In the polymerization process, there exists a critical stability concentration (CSC) for SDS, above which the size of the nanoparticles is to be minimized and stabilized. With an increase in the monomer addition rate, the polymerization system changes from a microemulsion system to an emulsion system. A mechanism was proposed to describe the micellar nucleation process of semibatch microemulsion polymerization. This technique will pioneer a significant new way to use a simple but practical method to synthesize narrow PDI polymers, which is a very meaningful new development. (2) Diene-Based Polymer Nanoparticles: Preparation and Direct Catalytic Latex Hydrogenation. At the first stage of this study, poly(butadiene-co-acrylonitrile) nanoparticles were synthesized in a semibatch microemulsion polymerization system using Gemini surfactant trimethylene-1,3-bis (dodecyldimethylammonium bromide), referred to as GS 12-3-12, as the emulsifier. The main characteristic of this GS emulsified system lies in that the decomposition rate of initiator was increased considerably at a low reaction temperature of 50 °C because of the acidic initiation environment induced by GS 12-3-12. The particle size can be controlled by the surfactant concentration and monomer/water ratio and a particle size below 20 nm can be realized. The obtained latex particles exhibit a spherical morphology. The microstructure and copolymer composition of the polymer nanoparticles was characterized by FT-IR and 1H NMR spectroscopy. The effects of the surfactant concentration on the particle size, Zeta-potential, polymerization conversion, copolymer composition, molecular weight, and glass transition temperature (Tg) were investigated. The kinetic study of the copolymerization reaction was carried out, which indicated that an azeotropic composition was produced. The relationship between Tg and number-average molecular weight can be well represented by the Fox-Flory equation. Finally, the semibatch process using conventional single-tail surfactant SDS was compared. In the second stage of this study, the prepared unsaturated nanoparticles were employed as the substrates for latex hydrogenation in the presence of Wilkinson’s catalyst, i.e., RhCl(P(C6H5)3)3. The direct catalytic hydrogenation of poly(butadiene-co-acrylonitrile) nanoparticles in latex form was carried out under various experimental conditions in the presence of Wilkinson’s catalyst without the addition of any organic solvents. In order to appreciate the important factors which influence the nature and extent of this type of hydrogenation, the effects of particle size within the range from 17.5 to 42.2 nm, temperature from 90 to 130 °C, and catalyst concentration from 0.1 to 1.0 wt% (based on the weight of polymer) on the hydrogenation rate were fully investigated. The kinetics study shows that the reaction is chemically controlled with a fairly high apparent activation energy, which is calculated to be between 100 and 110 kJ/mol under the experimental conditions employed. Mass transfer of both hydrogen and catalyst involved in the reaction system was discussed. The analysis of mass transfer of reactants coupled with the reaction kinetics indicated that the catalysis of hydrogenation proceeds at the molecular level. The competitive coordination of the active catalyst species RhH2Cl(PPh3)2 between the carbon-carbon unsaturation and the acrylonitrile moiety within the copolymer was elucidated based on the reaction kinetics of the hydrogenation. (3) Poly(methyl methacrylate)-poly(acrylonitrile-co-butadiene) (PMMA-NBR) Core-Shell Polymer Nanoparticles: Preparation and Direct Catalytic Latex Hydrogenation. PMMA-NBR core-shell structured nanoparticles were prepared using a two stage semibatch microemulsion polymerization system with PMMA and NBR as the core and shell respectively. The GS 12-3-12 was employed as the emulsifier and found to impose a pronounced influence on the formation of the core-shell nanoparticles. A spherical morphology of the core-shell nanoparticles was observed. It was found that there exists an optimal MMA addition amount which can result in the minimized size of PMMA-NBR core-shell nanoparticles. The formation mechanism of the core-shell structure and the interaction between the core and shell domains was illustrated. The PMMA-NBR nano-size latex can be used as the substrate for the following direct latex hydrogenation catalyzed by Wilkinson’s catalyst to prepare the PMMA-HNBR core-shell nanoparticles. The hydrogenation rate is rapid. In the absence of any organic solvent, the PMMA-HNBR nanoparticles with a size of 30.6 nm were obtained within 3 h using 0.9 wt% Wilkinson’s catalyst at 130 °C under 1000 psi of H2. This study provides a new perspective in the chemical modification of NBR and shows promise in the realization of a "green" process for the commercial hydrogenation of unsaturated elastomers.

The regioselectivity in Pd(0)-catalyzed direct arylation of pyrrole, thiophene, and indole can be improved by blocking some of the reactive sites with a chloride group, leading to increased yields of the desired regioisomers. Competition experiments and computational studies show that the blocking group also activates the substrates toward arylation. Due to the activated nature of chlorinated heteroaromatics, rare and sought after regioisomers, such as 3-arylthiophenes, can be obtained under mild conditions in good yields. Chlorine-bearing thiophenes arylated at C3 and C4 have the potential to undergo controlled regioregular polymerization under conditions developed in the field of polythiophene chemistry. Mechanistic studies support the hypothesis that the arylation of the substrates under investigation likely proceeds via the CMD transition state.

Fluorocarbons (FCs) and their derivatives (FCDs) are heavily relied on due to their wide range of uses (e.g. solvents, surfactants, refrigerants, and pharmaceuticals). Currently, FCs and FCDs are produced on an industrial scale via energy-intensive processes, using hazardous materials. Hence, new catalytic chemical technologies are required to provide cleaner and greener synthetic routes to partially fluorinated materials. The exploration of fundamental organofluorometallic chemistry of base metals, such as nickel, has potential to advance the development of novel catalytic processes towards this end. It has been established previously that zero-valent nickel complexes have the ability to efficiently catalyze the hydrodimerization of polyfluoroalkenes. The reactivity of the intermediate polyfluoronickelacycles was found to be influenced by modifications in the ligand sphere. Furthermore, an increase in oxidation state of the central metal atom was proposed as an additional strategy to increase the reactivity of the M-RF bond. In this thesis, through variation of the ligand environment and oxidation state of nickel, we have further developed the chemistry of high-valent polyfluoronickelacycles. Synthesis and characterization (NMR, EPR, UV/Vis, IR spectroscopy and electrochemistry) of new trivalent polyfluoronickelacycles are described as well as attempts to generate the corresponding tetravalent cations. Attempts to induce nucleophilic insertion of acetonitrile into the Ni-RF bond were also investigated herein. Challenges were encountered with the isolation of the tetravalent cations due to decomposition to the corresponding divalent nickelacycle.

The ever-worsening environmental crisis has stimulated development of less wasteful “green” technologies. To this end, tandem catalysis enables multiple catalytic cycles to be performed within a single reaction vessel, thereby eliminating intermediate processing steps and reducing solvent waste. Assisted tandem catalysis employs suitable chemical triggers to transform the initial catalyst into new species, thereby providing a mechanism for “switching on” secondary catalytic activity. This thesis demonstrates the importance of highly productive secondary catalysts through a comparative hydrogenation study involving prominent hydrogenation catalysts of tandem ring-opening metathesis polymerization (ROMP)-hydrogenation, of which hydridocarbonyl species were proved superior. This thesis illuminates optimal routes to hydridocarbonyls under conditions relevant to our ROMP-hydrogenation protocol, using Grubbs benzylidenes as isolable proxies for ROMP-propagating alkylidene species. Analogous studies of ruthenium methylidenes and ethoxylidenes illuminate optimal routes to hydridocarbonyls following ring-closing metathesis (RCM) and metathesis quenching, respectively. The formation of unexpected side products using aggressive chemical triggers is also discussed, and emphasizes the need for cautious design of the post-metathesis trigger phase.

This research is focused on development of routes towards the rational design of nanoparticle catalysts. Primarily, it is focused on two main projects; (1) the use of imidazolium-based ionic liquids (ILs) as greener media for the design of quasi-homogeneous nanoparticle catalysts and (2) the rational design of heterogeneous-supported nanoparticle catalysts from structured nanoparticle precursors. Each project has different studies associated with the main objective of the design of nanoparticle catalysts.<p> In the first project, imidazolium-based ionic liquids have been used for the synthesis of nanoparticle catalysts. In particular, studies on recyclability, reuse, mode-of-stability, and long-term stability of these ionic-liquid supported nanoparticle catalysts have been done; all of which are important factors in determining the overall greenness of such synthetic routes. Three papers have been published/submitted for this project. In the first publication, highly stable polymer-stabilized Au, Pd and bimetallic Au-Pd nanoparticle catalysts have been synthesized in imidazolium-based 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM]PF6) ionic liquid (Journal of Molecular Catalysis A: Chemical, 2008, 286, 114). The resulting nanoparticles were found to be effective and selective quasi-homogeneous catalysts towards a wide-range of hydrogenation reactions and the catalyst solution was reused for further catalytic reactions with minimal loss in activity. The synthesis of very pure and clean ILs has allowed a platform to study the effects of impurities in the imidazolium ILs on nanoparticle stability. In a later study, a new mode of stabilization was postulated where the presence of low amounts of 1-methylimidazole has substantial effects on the resulting stability of Au and Pd-Au nanoparticles in these ILs (Chemical Communications, 2009, 812). In further continuation of this study, a comparative study involving four stabilization protocols for nanoparticle stabilization in BMIMPF6 IL is described, and have shown that nanoparticle stability and catalytic activity of nanoparticles is dependent on the overall stability of the nanoparticles towards aggregation (manuscript submitted).<p> The second major project is focused on synthesizing structurally well-defined supported catalysts by incorporating the nanoparticle precursors (both alloy and core shell) into oxide frameworks (TiO2 and Al2O3), and examining their structure-property relationships and catalytic activity. a full article has been published on this project (Journal of Physical Chemistry C, 2009, 113, 12719) in which a route to rationally design supported catalysts from structured nanoparticle precursors with precise control over size, composition, and internal structure of the nanoparticles has been shown. In a continuation of this methodology for the synthesis of heterogeneous catalysts, efforts were carried out to apply the same methodology in imidazolium-based ILs as a one-pot media for the synthesis of supported-nanoparticle heterogeneous catalysts via the trapping of pre-synthesized nanoparticles into porous inorganic oxide materials. Nanoparticle catalysts in highly porous titania supports were synthesized using this methodology (manuscript to be submitted).

The development of new, improved methods for forming carbon–carbon and carbon–heteroatom bonds is the basic goal in synthetic organic chemistry. In the Lautens group, many recent advances have been made using late transition metals such as rhodium and palladium. One such research project involves the synthesis of indoles through tandem C–N and C–C coupling reactions using gem-dibromoolefin starting materials, and this area serves as a starting point for the research described. Chapter 1 describes a method by which the tandem use of gem-dibromoolefins can be halted to give intramolecular monocoupling reactions, maintaining one of the carbon–bromine bonds which can serve as a useful handle for further functionalization. The use of copper as a catalyst is key to this reaction, as it features a unique mechanism for carbon–heteroatom bond formation. Benzofurans and benzothiophenes can be prepared by this method. Chapter 2 describes the synthesis of 2-bromoindoles using an intramolecular Buchwald–Hartwig amination of gem-dibromoolefins. It is found that the products are more reactive towards palladium(0) than the starting material, and the use of a bulky phosphine ligand which facilitates reversible oxidative addition is required. This represents one of the first catalytic applications of this step in synthesis. Chapter 3 further explores the concept of reversible oxidative addition in a novel carbohalogenation reaction of alkenes. Aryl iodides tethered to alkenes are treated with a palladium(0) catalysts, which can undergo the basic steps of oxidative addition, carbopalladation, and novel sp2 carbon–iodine reductive elimination. This process is remarkably simple in concept, and is a waste-free, atom economically method for preparing new carbon–carbon bonds. Chapter 4 discusses various limitations to the carbohalogenation methodology, and seeks to overcome these problems. The use of aryl bromide starting materials can be accomplished by adding an iodide source to the reaction, allowing halide exchange of palladium(II) intermediates to occur. Intermolecular and asymmetric variants are also explored. Computational studies are discussed which reveal useful mechanistic details of the catalytic cycle, and this information is used in the development of novel phosphine ligands.

The development of a palladium-catalyzed intramolecular carboesterification of unactivated olefins is described. Olefin difunctionalization is a powerful tool for adding complexity to a molecule, and this formal [3+2] cycloaddition generates highly functionalized fused ring systems. Initially discovered by Dr. Yang Li in our group, it was found that when propiolic acids with a pendant terminal olefin were treated with 1 mol % Pd(MeCN)2Cl2, 3 equivalents of copper (II) chloride, and 3 equivalents of lithium chloride in acetonitrile at 50 °C, cyclization occurred in up to 90% yield. The optimization of this reaction and the extension to propiolamides and propargyl alcohols is described in this thesis. A mechanism involving a novel palladium-carboxylate species is proposed. Preliminary investigations into the synthesis of chiral sulfoxide pincer ligands are also described. The nucleophilic aromatic substitution of 1,3-dibromobenzene and 2,6-dichloropyridine with various thiols, followed by oxidation of the sulfides to sulfoxides is investigated as a route to the desired proligands.

The selective manipulation of hydroxyl groups in di- and polyols is a frequently encountered problem in organic synthesis. Such processes are often tedious and/or moderate yielding, and often necessitate multistep protection / deprotection sequences. Applying boron–diol interactions previously exploited in molecular recognition and based on methods previously developed in our research group, we have developed two classes of chemical transformations: 1. Regioselective sulfonylations of carbohydrate derivatives catalyzed by a borinic ester, providing access to the corresponding mono-tosylates in high yields; 2. Selective monoalkylations and monosulfonylations of structurally diverse 1,2- and 1,3-diol substrates.

Since recognizing the significance of reversible oxidative addition of palladium into aryl halides in the synthesis of 2-bromo-indoles, the Lautens group has focused on unusual carbon-halogen reductive eliminations. These efforts led to the discovery of the novel palladium-catalyzed inter- and intramolecular carbohalogenation reaction – the formal addition of an sp2 carbon–iodide bond across an alkene. One current research direction is utilizing a range of aryl halides and pseudohalides as starting materials for carbohalogenation chemistry. This thesis describes complementary research, focusing on the expansion of functional group scope. Carbohalogenation has been developed to synthesize novel products including heteroaromatic compounds and 7-membered rings. Polyunsaturated aryl iodide substrates were investigated with the goal of performing domino carbohalogenation. Ultimately, the successful halogen exchange process was combined with domino carbohalogenation in an efficient halogen-exchange domino reaction. Additionally, preliminary studies on enantioselective carbohalogenation, and functionalization of the neopentyl iodide products are also discussed.