The essential questions of the dissertation research described here address concepts in homogeneous catalysis and organometallic chemistry, with a focus on method development for catalytic reaction applications in organic synthesis. The unifying theme throughout the research is the development of rational design principles for cooperative catalysis through both mechanistic and empirical study. Cooperative catalysis – in which multiple catalysts enable increased activity or selectivity versus a single catalyst system – can involve some combination of a transition metal, Lewis acid, and Brønsted acid. Chapter 1 reviews the literature regarding the cooperativity of transition metal and Lewis acid catalysis, and discusses four main areas in organic synthesis and the facilitation of these trnasformations by Lewis acids: (a) C-C bond and C-H activation, (b) hydrogenolysis of carboxylic acid derivates and ethers, (c) Au catalyzed alkyne activation and cyclization reactions, and related reactions, and (d) Pd catalyzed C-C and C-N bond forming reactions. These different topics are selected based on the mechanistic insight provided into the nature of transition metal-Lewis acid cooperativity. Chapter 2 describes the observation of Lewis acid acceleration of a Pd catalyzed C-N bond coupling. The synthetic methodology is elaborated using metal triflates as cocatalysts, and Lewis acid acceleration is observed for a variety of different N-nucleophiles. Qualitative mechanistic study implicates the role of halide anions in inhibiting this catalytic reaction, and it is proposed that metal triflates are competent to accelerate catalysis by binding halide anions, and therefore attenuating halide inhibition. This hypothesis is supported by initial rate measurements and 31P NMR experiments. Rationalizing trends observed in the reactivity of Lewis acids in the cooperative reactions described in Chapters 1 and 2 is challenging. Therefore, our goal was to provide further insight into the behavior or Lewis acids in complex reaction settings. Inspired by 31P NMR experiments from Chapter 2, a next generation NMR probe to observe anion exchange reactions of metal triflate Lewis acids is developed. Metal-ligand titrations are performed for a variety of metal triflates with complexes of the type (POCOP)Pd(X) (X = Cl, Br, I, OAc) to observe a variety of different X anion affinities for metal triflates. The determined parameters are discussed within the context of Lewis acid catalyzed reactions, along with other Lewis acidity parameters, such as hydrolysis constants and effective charge density. The data suggest that the chloride and iodide anion affinities of a Lewis acid represent a continuum of π-acidity (high anion affinity) and propensity to dissociate into cationic Mz+ species (low anion affinity). The anion affinities do not correlate with the tendency of a metal salt to release Brønsted acids or their respective effective charge densities. Based on the insight into Lewis acidity from Chapters 1 and 3, the parallel between Brønsted and Lewis acids is realized, and the role of both Brønsted and Lewis acids in mediating organic reactions is often related. In Chapter 4, further questions into the cooperativity of π-acids and Brønsted acids is explored. It is demonstrated that selectivity of alkene isomerization can be controlled through a cooperative system. A series of Mo(0) complexes are prepared and explored in their ability to mediate the conversion of terminal alkenes to internal alkenes, and the reaction is found to be promoted by Brønsted acid (TsOH) cocatalyst. Rational design principles are developed to maximize selectivity for (Z)-2-alkenes in this catalyst system. It is proposed that TsOH acts to generate a catalytic MoH species which mediates catalysis, and the role of phosphine ligands is critical in inhibiting the formation of less selective isomerization catalysts. Chapter 5 and 6 entail further method development for catalytic reactions based on the mechanistic wisdom described in previous chapters. High throughput experimentation is employed to rapidly assess conceptual aspects of Pd catalysis, such as ligand and additive effects, and facilitate catalyst discovery and optimization. Based on the substrate scope performed in Chapter 2, it was realized there is a knowledge gap in the ability to synthesize tertiary sulfonamides, both in terms of conventional methods, or modern Pd-catalyzed methods. A significant advance in organic reaction methodology is described: a new Pd catalyst featuring the AdBippyPhos ligand is discovered to be apt for the coupling of secondary sulfonamides with heteroaryl halides to yield tertiary N-heteroarylhalides. Using high throughput experimentation, 24 diverse heterocycles are screened with 12 sulfonamide variants to prepare >100 new products on microscale. Computational modelling reveals the unique steric parameters of the AdBippyPhos ligand, and a mechanistic rationale for its success in catalysis is provided. Lastly, Chapter 6 describes the use of a LiOTf additive to control the selectivity of Pd-catalyzed C-C bond forming reactions. In the presence of LiOTf, a Mizoroki-Heck type reaction, the alkenylation of an aryl halide with a vinyl ether, proceeds with regioselectivity. In the absence of LiOTf, a solvent (CH3CN) activation pathway proceeds to give benzyl nitrile products. High throughput microscale reactions discovered that the Pd/xantphos catalyst is uniquely selective to provide branched styrenes when using the Cs2CO3/CH3CN base/solvent combination. However, reaction performance differed on large scale reactions, where LiOTf was necessary to observe the Mizoroki-Heck reaction pathway. Mechanistic study, in the form of kinetic experiments and 31P NMR experiments, focused on the role of LiOTf in affecting chemoselectivity. It is proposed that xantphos oxidation is responsible for mediating the Mizoroki-Heck reaction pathway, whereas in the absence of xantphos oxidation, CH3CN α-arylation ensues. Due to the insoluble nature of the catalyst materials, xantphos oxidation is ordinarily slow under anaerobic conditions due to mass transfer limitation. LiOTf generates a soluble [(xantphos)Pd(NCCH3)2][OTf]2 and potentially mediates the formation of xantphos-monoxide catalyst which is competent for alkenylation. / Chemistry

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A number of privileged starting materials based on aryl halide frameworks have emerged that allow access to a variety of different heterocyclic scaffolds through judicious choice of reaction conditions. This work describes efforts to develop and extend the utility of two of these general heterocycle precursors - ortho-(haloalkenyl)aryl halides A and α-(ortho-haloaryl) ketones B - in conjunction with cascade reactions involving the construction of key carbon-heteroatom bonds via palladium or copper catalysis. Chapter 1 entails an overview of the development of palladium- and copper-catalysed carbon-heteroatom bond forming processes. The application of these processes in heterocycle synthesis using ortho-(haloalkenyl)aryl halide and ortho-haloacetanilides/ α-(ortho-haloaryl) ketone precursors is also described. Chapter 2 focuses on the development of a two-step synthesis of cinnolines using ortho-(haloalkenyl)aryl halides via intermediate protected dihydrocinnoline derivatives C. Chapter 3 demonstrates how the inherent reactivity of protected dihydrocinnoline derivatives C can be harnessed to provide access to functionalised products. A brief target synthesis of a pharmaceutically-relevent cinnoline is also described. Chapter 4 details attempts to develop a novel synthesis of benzothiophenes D from both ortho-(haloalkenyl)aryl halide and α-(ortho-haloaryl) ketone precursors.

The development of new methods for carbon-carbon bond formation is a challenging topic at the heart of organic chemistry. Over the past ten years a number of methods for the catalytic asymmetric 1,4-addition of organometallic reagents such as Grignard, organozinc and organoaluminium reagents have been reported. However these reagents suffer from many limitations, including the need for cryogenic temperatures, which prevent their widespread use. Here we have developed a new asymmetric method: the copper-catalysed enantioselective 1,4-addition of alkylzirconium compounds, generated in situM/em>, from alkenes. A general introduction into the formation of carbon-carbon bonds and catalytic asymmetric 1,4-addition reactions is first given. We then focus our attention on hydrometallation reactions and their current use in the addition of alkenyl and alkyl groups in asymmetric 1,4-addition reactions. In Chapter two, we introduce the development of our methodology. We found that by using copper complex <b>(S,S,S)-A</b>, high enantioselectivities can be achieved (up to 96% ee), in the presence of a broad range of functional groups which are often not compatible with comparable methods using pre-made organometallic reagents. The method gives good enantioselectivity at room temperature, in a wide range of solvents, using readily available alkenes. Chapter three discusses the expansion of our method to the 1,4- and 1,6-addition to complex steroids. Modified conditions were then found to enable the addition to &beta;-substituted enones, to form quaternary centres. This is followed by the successful addition to &alpha;,&beta;-unsaturated lactones, another difficult substrate class. All these results gave excellent selectivity. In summary, we have developed a new reaction which offers an alternative to current methods reported in the literature. This robust reaction can tolerate a variety of functional groups and we hope that this will aid in the synthesis of important molecules.

Gold catalysis has become an important tool to achieve highly chemoselective p-acid activation. Exceptional reactivity and selectivity are often encountered under mild reaction conditions. These properties have made gold(I) complexes suitable catalysts for tremendous applications in the total synthesis of natural products. The first chapter will highlight a number of total syntheses using gold catalysis as a key step. The second chapter will cover our application of the gold(I)-catalyzed 6-endo-dig carbocyclization for the synthesis of bridgehead-substituted scaffolds and its use toward the synthesis of PPAP natural products. This research has opened our eyes to the utility of biphenylphosphine ligands, particularly JohnPhos, in gold(I)-catalysis. The reactivity and selectivity exhibited by gold(I) complexes is modulated by the nature of the ancillary ligand. Recent research rationalizes the impact of these ligands on the divergent reactivity observed between cationic and carbenoid intermediates. Our desire to favor the 6-endo-dig pathway has led us toward the discovery of another example of the diagonal reactivity that NHC carbene and biphenylphosphine ligands can bring to gold(I)-catalysis. Chapter three will explain the development of a selective gold-catalyzed synthesis of fused carbocycles . Our selective divergent synthesis of fused carbocycles, combined with the Diels–Alder reaction, has brought new synthetic opportunities. Chapter four will describe our approach toward the synthesis of various polycyclic diterpene-related frameworks. Starting with a unique linear precursor, we have developed a new “one-pot” process for the synthesis of three different polycyclic compounds related to the terpenoid family. The facile modulation of the linear precursor and the use of different dienophiles during the Diels–Alder reaction could enable the synthesis of diverse polycyclic analogues based on three principal frameworks. The gold(I)-catalyzed synthesis of fused carbocycles reached some limitations during our study. Regioselective control was found to be substantially more challenging, with terminal alkynes or alkynes bearing a sterically and electronically neutral methyl substituent. In chapter five, we will discuss how the complementarity of silver(I) catalysis to gold(I) catalysis enabled the selective divergent synthesis of three different fused carbocycles from a unique precursor. Moreover, copper(I) catalysis has given access to the 6-endo-dig pathway on terminal alkynes without the formation of a vinylidene intermediate.

This work focuses on understanding the heterogeneous/homogeneous nature of the catalytic species for a variety of immobilized metal precatalysts used for C-C coupling reactions. These precatalysts include: (i) tethered organometallic palladium pincer complexes, (ii) an encapsulated small molecule palladium complex in a polymer matrix, (iii) mercapto-modified mesoporous silica metalated with palladium acetate, and (iv) amino-functionalized mesoporous silicas metalated with Ni(II). As part of this investigation, the use of metal scavengers as selective poisons of homogeneous catalysis is introduced and investigated as a test for distinguishing heterogeneous from homogeneous catalysis. The premise of this test is that insoluble materials functionalized with metal binding sites can be used to selectively remove soluble metal, but will not interfere with catalysis from immobilized metal. In this way the test can definitely distinguish between surface and solution catalysis of immobilized metal precatalysts. This work investigates three different C-C coupling reactions catalyzed by the immobilized metal precatalysts mentioned above. These reactions include the Heck, Suzuki, and Kumada reactions. In all cases it is found that catalysis is solely from leached metal. Three different metal scavenging materials are presented as selective poisons that can be used to determine solution vs. surface catalysis. These selective poisons include poly(vinylpyridine), QuadrapureTM TU, and thiol-functionalized mesoporous silica. The results are contrasted against the current understanding of this field of research and subtleties of tests for distinguishing homogeneous from heterogeneous catalysis are presented and discussed.

Gold catalysis has become an important tool to achieve highly chemoselective p-acid activation. Exceptional reactivity and selectivity are often encountered under mild reaction conditions. These properties have made gold(I) complexes suitable catalysts for tremendous applications in the total synthesis of natural products. The first chapter will highlight a number of total syntheses using gold catalysis as a key step. The second chapter will cover our application of the gold(I)-catalyzed 6-endo-dig carbocyclization for the synthesis of bridgehead-substituted scaffolds and its use toward the synthesis of PPAP natural products. This research has opened our eyes to the utility of biphenylphosphine ligands, particularly JohnPhos, in gold(I)-catalysis. The reactivity and selectivity exhibited by gold(I) complexes is modulated by the nature of the ancillary ligand. Recent research rationalizes the impact of these ligands on the divergent reactivity observed between cationic and carbenoid intermediates. Our desire to favor the 6-endo-dig pathway has led us toward the discovery of another example of the diagonal reactivity that NHC carbene and biphenylphosphine ligands can bring to gold(I)-catalysis. Chapter three will explain the development of a selective gold-catalyzed synthesis of fused carbocycles . Our selective divergent synthesis of fused carbocycles, combined with the Diels–Alder reaction, has brought new synthetic opportunities. Chapter four will describe our approach toward the synthesis of various polycyclic diterpene-related frameworks. Starting with a unique linear precursor, we have developed a new “one-pot” process for the synthesis of three different polycyclic compounds related to the terpenoid family. The facile modulation of the linear precursor and the use of different dienophiles during the Diels–Alder reaction could enable the synthesis of diverse polycyclic analogues based on three principal frameworks. The gold(I)-catalyzed synthesis of fused carbocycles reached some limitations during our study. Regioselective control was found to be substantially more challenging, with terminal alkynes or alkynes bearing a sterically and electronically neutral methyl substituent. In chapter five, we will discuss how the complementarity of silver(I) catalysis to gold(I) catalysis enabled the selective divergent synthesis of three different fused carbocycles from a unique precursor. Moreover, copper(I) catalysis has given access to the 6-endo-dig pathway on terminal alkynes without the formation of a vinylidene intermediate.

<p>Cyclopropanes are found in an array of synthetic and natural products. The Simmons–Smith reaction has been one of the most common methods used to synthesize cyclopropanes since it was first discovered in the 1950s. The Simmons–Smith reaction entails the transfer of a carbene (:CH2) from a zinc carbenoid to an alkene, forming a cyclopropane. However, there are still many limitations to the Simmons–Smith method, including poor functional group tolerance and poor regioselectivity in polyalkene substrates. </p> <p>To address the weaknesses in the Simmons–Smith reactions, we have pursued a transition metal-catalyzed method. Our group has reported a cobalt pyridinediimine (PDI) catalyst system to carry out cyclopropanation reactions using gem-dichloroalkanes and gem-dibromoalkanes in order to access nonstabilized carbenes. This method also offers an advantage over diazo transfer chemistry since diazo chemistry requires a stabilizing group to be present in most cases.  This established work has demonstrated a complimentary reactivity to the Simmons–Smith reaction.</p> <p>In this work, we demonstrate that we could expand upon the existing methods of dimethylcyclopropanation to access spirocyclopropanated products by changing the identity of the dichloroalkane. In addition to this reactivity, an enantiopure catalyst that is able to catalyze an enantioselective cyclopropanation was found. We were able to show a broad scope of this new reaction, and mechanistic experiments are carried out in order to probe the mechanism of this reaction. Overall, this thesis offers a new way to access enantiopure dimethylcyclopropane and spirocyclopropanated products.</p>

Fuel processing is one of the essential parts for development of intermediate solid oxide fuel cells (IT-SOFC). Natural gas (methane) is considered as the most abundant and cost effective fuel for the production of hydrogen for IT-SOFC. The primary aim of this thesis is to use a novel precursor material—layered double hydroxide (LDH) – for developing a new type of cost effective, highly active and long lasting catalyst which can reform natural gas in IT-SOFC anode environment. Small amount of noble metals Pd, Rh and Pt are used as promoters to enhance the catalyst’s performance as while maintaining the cost relatively low. The research objectives are achieved by a series of studies including catalysts synthesis, characterisation and the catalytic activities. The thesis initially gives a comprehensive review on fuel cell and SOFC technology, steam methane reforming and reforming catalyst to provide better understanding of the research. Experimental studies include the effects of the synthetic conditions of the LDH precursors and thermal treatments on the physical, chemical behaviours and catalytic activities of the catalysts and promotional effects by noble metals. The LDH derived catalysts compositions, promoter quantities and operating conditions are optimised for the best performance in the IT-SOFC anode environment. A new method for the development of precursor sol for easy coating of the anode is developed and studied. The sol preparation is achieved by acid attack. The sol developed is found to produce better coating and has very high catalytic properties after activation. The catalysts developed were tested for their stability and self-activation ability to ensure its use in the commercial cells. The findings of the present study indicate that the catalysts developed show excellent catalytic performance and these catalysts have very high potential for further commercialisation in IT-SOFC.

In this thesis, C-F bond activation and C-F bond construction under platinum and iridium catalysis is described. Chapter 1 provides a general introduction on the use of transition metal catalysis for the formation and activation of Csp³-F bonds in organofluorine compounds. In Chapter 2, an investigation on the reactivity of allylic fluorides, under platinum and palladium catalysed alkylation conditions, is presented. The relative reactivity of fluoride versus other commonly used leaving groups was compared via internal competition experiments. Fluoride showed a different reactivity profile, when subjected to Pt and Pd catalytic systems. Based on the observed reactivity trend, a Pd-catalysed fluorination reaction of allylic alcohol derivatives was successfully developed, within the group. In Chapter 3, a new iridium catalysed fluorination using branched, E- or Z-linear allylic carbonates is described. The catalyst [Ir(COD)Cl]₂ leads to an unexpected regio- and stereoretentive selectivity, affording fluorinated products not accessible via palladium catalysis. The effect of a fluoride additive on the selectivity of the Ir-catalysed alkylation reaction is also presented. A highly efficient ¹⁸F-fluorination variant for this new catalytic transformation is reported. Chapter 4 gives full experimental procedures and characterisation data for all compounds.