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<p>The objective for this work is to identify and develop an intramuscularly delivered cyanide scavenger. This dissertation outlines in vitro methods which are used to evaluate platinum-based complexes for the potential to scavenge cyanide. Examples of the in vitro techniques used are HPLC, UV-Vis and an ion-selective electrode as orthogonal strategies to monitor cyanide scavenging. Intramuscular formulations for the active platinum-based scavengers are prepared and evaluated for stability. Subsequently, the formulations are tested by collaborating labs for in vivo efficacy. In addition, Sprague Dawley rat studies are employed to investigate the potential toxicity for several platinum complexes. Taken together, this dissertation outlines a short list of novel platinum-based cyanide scavengers as potential alternatives to legacy cobalt-based scavengers. </p>

Contemporary challenges in synthetic organic chemistry require innovative solutions. The discovery of highly-effective and readily accessible scaffolds drives the ever expanding scope of catalytic transformations. This dissertation outlines the repurposing of 1,5-Diaza-3,7-diphosphacyclooctanes (P₂N₂) ligands, commonly employed in inorganic or coordination chemistry, towards organic cross-coupling reactions. Despite their prominence in energy-storage applications, P₂N₂ ligands have been underexplored in catalytic C-C bond formation reactions. Chapter 1 provides a detailed introduction to late transition metal catalysis and the history of P₂N₂ ligands. Chapter 2 outlines the discovery of P^(Cy)₂N^(ArCF3)₂ as a powerful P₂N₂ ligand for the Ni-catalyzed reductive cross-coupling of aryl iodides with aldehydes. Chapter 3 details the extrapolation of the Ni/P^(Cy)₂N^(ArCF3)₂ catalyst system to the related, but less established, redox-neutral α-arylation of primary alcohols. Chapter 4 highlights the applicability of P₂N₂ ligands towards Ni- and Pd-catalyzed Mizoroki-Heck reactions. High-throughput experimentation (HTE) indicated a range of hits with P₂N₂ ligands compared to established ligands in Heck-type couplings. We discovered that absolute site selectivity of C-C bond formation could be controlled by simply altering the phosphorus substituent on the P₂N₂ ligand for the coupling of aryl triflates with styrenes. Notably, this degree of selectivity was not observed with conventional ligands. Chapter 5 focuses on the preparation of the P₂N₂ ligands. Finally, chapter 6 offers a perspective on future developments of P₂N₂ ligands and the prospective directions of their application in transition metal-catalyzed transformations.

<p>Thorium complexes primarily exist in the thermodynamically stable (IV) oxidation state with only a few low-valent thorium(III) and thorium(II) complexes having been isolated. As a result, redox chemistry with thorium at the metal center is synthetically challenging without carefully selected ligand systems. This redox-restricted nature of thorium(IV) makes redox-active ligands (RALs) an attractive option to facilitate multi-electron redox chemistry with thorium. In this work, first, a series of thorium(IV) complexes featuring the redox-active iminoquinone ligand and its derivatives, including the iminosemiquinone and amidophenolate species, were synthesized and characterized. Rare thorium oxygen multiple bonds were then accessed by exploiting the RALs on the thorium center and using dioxygen in dry air. Other oxidation chemistry was attempted with the thorium amidophenolate complexes as well. Second, armed with the knowledge of synthesizing multiple bonds with thorium(IV) complexes, similar chemistry was explored with cerium as it is in the same group as thorium. A series of cerium(III) and cerium(IV) complexes featuring the redox-active iminoquinone ligand and its derivatives were synthesized. Oxidation chemistry was explored with the cerium amidophenolate complexes and a rare cerium oxo was isolated. Finally, with interest in expanding and addressing a gap in the literature related to the synthesis, characterization, and utility of thorium alkyls, several tetrabenzylthorium complexes were synthesized, characterized, and some reactivity was explored. A highlight of this work involved the isolation of the first crystal structure of ligand and solvent free tetrabenzylthorium since its first synthesis in 1974. Full spectroscopic and structural characterization of the complexes was performed via ¹H NMR spectroscopy, X-ray crystallography, EPR spectroscopy, electronic absorption spectroscopy, and SQUID magnetometry, which all confirmed the identity and electronic structure of these complexes. </p>

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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 &gt;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

<p dir="ltr">The use of redox non-innocent ligands to imbue third-row transition metal complexes with properties emulating those of their fourth- and fifth-row congeners has become an attractive strategy to overcome the limited resources and environmental implications associated with the latter class of metals. The tetra-imine macrocycle, TIM (2,3,9,10-tetramethyl-1,4,8,11-tetraza-cyclotetradeca-1,3,8,10-tetraene), which bears two sets of potentially redox-active α-diimine units, therefore, has been targeted as the ligand scaffold to investigate the structural and electronic properties of various organocobalt(III) complexes within this work.</p><p dir="ltr">First, the reaction between <i>trans</i>-[Co(TIM)Cl₂]⁺ and terminal alkynes (HC₂Ar), in the presence of triethylamine, yielded a series of mono- and bis-alkynyl Co^III(TIM) complexes, as discussed in Chapters 1 and 2. Interestingly, the use of electron-rich terminal alkynes (HC₂Y) favors the formation of products featuring a 1-aza-2-cobalt-cyclobutene unit. As detailed in Chapter 3, the <i>trans</i>-[Co(TIM')(HC=C)Y)Cl]⁺-type complexes (TIM' = the resulting derivative of TIM) were prepared through the addition of HC₂Y to <i>trans</i>-[Co(TIM)Cl₂]⁺ in the presence of KOH. The unprecedented involvement of the TIM ligand was verified crystallographically and through ¹H NMR and FT-IR spectroscopies. In Chapter 4, the properties and influences of the aza-cobalt-cyclobutene are further explored through UV-vis spectroelectrochemical studies on the constitutional isomers, <i>trans</i>-[Co(TIM)(C₂Fc)Cl]⁺ and <i>trans</i>-[Co(TIM')((HC=C)Fc)Cl]⁺ (Fc = ferrocene). Moreover, the reactivity of the Co^III center in the latter complexes is investigated via the reaction with KCN and AgOTf in CH₃CN.</p><p dir="ltr">In Chapter 5, a new facet of Co^III(TIM) reactivity is revealed through the reaction between <i>trans</i>-[Co(TIM)Cl₂]⁺ and HC₂Ar, in the presence of NaBH₄. The reaction generates both mono- and bis-alkenyl complexes along with products containing a 1-aza-2-cobalt-cyclopropane unit. The formation of the former class of products is postulated to proceed through a transient H-Co^III(TIM) intermediate, while the latter is believed to be accessed upon the reduction of an imine moiety within the TIM ligand. Moreover, the generation of the three-membered ring showcases another example of the non-innocent nature of the TIM ligand.</p>

This dissertation focuses on the computational investigation of gold(I) acyclic diaminocarbene (ADC) complexes and their application in homogeneous gold(I) catalysis. Chapter 2 is an in-depth computational investigation of the σ- and π-bonding interactions that make up the gold-carbene bond. Due to the inherent conformation flexibility of ADC ligands, distortions of the carbene plane can arise that disrupt orbital overlap between the lone pairs on the adjacent nitrogen atoms and the empty p-orbital of the carbene. This study investigated the affect these distortions have on the strength of the σ- and π-bonding interactions. This investigation demonstrated that while these distortions can affect the σ- and π-bonding interactions, the ADC ligand have to become highly distorted before any significant change in energy of either the σ- or π-bonding interactions occurs. Chapter 3 is a collaborative investigation between experimental and computational methods, DFT calculations were employed to support the experimental catalytic results and determine the role that steric effects have in controlling the regioselectivity of a long-standing electronically controlled gold(I)-catalyzed tandem 1,6-enyne cyclization/hydroarylation reaction with indole. This study demonstrated that by sterically hindering nucleophilic attack of indole at the favored position, nucleophilic attack would occur at a secondary position leading to the selective formation of the electronically unfavored product. Chapter 4 is a collaborative investigation between experimental and computational methods. DFT calculations were employed to investigate and rationalize the importance of secondary non-covalent interactions and their influence on the enantioselectivity of a gold(I)-catalyzed intramolecular hydroamination of allene reaction. Through computational investigation of the enantiodetermining step, and the non-covalent interactions present between 2′-aryl substituent and the rest of the catalyst, it was determined that the presence of CF3 group on the 3,5-position of the 2′-aryl ring is crucial to maintaining a more rigid chiral pocket leading to higher enantiomeric excesses in this dynamic system. This increased rigidity is believed to be attributable to the several weak non-covalent interactions that arise between the allene substrate or diisopropyl N-substituent and the fluorine atoms of the CF3 groups.

This work describes developments in new azetidine and azetine chemistry; specifically, methods developed for the introduction of functionality α- to nitrogen in both ring systems, with additionally in situ formation of the latter system, from azetidine substrates. Chapter 1 discusses the growing importance of azetidines, and the current methods available for making substituted azetidines by ring formation. Further discussion comprises of current sp³ C–H activation approaches α- to nitrogen in heterocyclic compounds as potential methods for sp³ C–H activation on azetidines to give substituted azetidines. Previous work by the Hodgson group in this area is detailed. Chapter 2 describes the advance made towards 2,3-disubstituted azetidines using the thiopivaloyl protecting/activating group, where the latter plays a key role. Optimisation, scope, selectivity and mechanistic insight into the α-deprotonation–electrophile trapping of a 3-hydroxy azetidine system is discussed, which successfully gives access to a range of 3-hydroxy-2-substituted azetidines. Preliminary investigations with 3-alkyl-2-substituted azetidines are also described. Chapter 3 describes the development of a straightforward protocol to make 2-substituted-2- azetines, a rarely studied and difficult to access 4-membered azacycle subclass, from readily accessible azetidine starting materials using α-deprotonation–in situ elimination followed by further α-lithiation–electrophile trapping. Extension of this methodology by transmetallation from the intermediate organolithium to the organocuprate, resulting in greater electrophile scope, is also described.

Benzylic fluorides are attractive target molecules for medicinal chemistry, agrochemicals and materials chemistry. The enantioselective synthesis of benzylic fluorides is challenging and few general methods exist. This thesis describes several approaches to the synthesis of benzylic fluoride targets, including enantioselective processes. Chapter 1: Reviews the properties, uses and synthetic approaches to fluorinated molecules, with a particular focus on benzylic fluorides and enantioselective syntheses. Chapter 2: Describes the fluorination cyclisation of prochiral indole precursors. The use of catalytic amounts of a bis-cinchona alkaloid gave good enantioselectivities for the cyclisation. Alcohol, tosylamine, amide and carbamate pendant nucleophiles all cyclised successfully to give quaternary benzylic fluorides in moderate yields and with enantioselectivities up to 92%. The substrate scope of the reaction is described, as well as methodology for deprotection of cyclised nitrogen nucleophiles. Chapter 3: Details an investigation of the Pd catalysed substitution of polycyclic benzylic fluorides by a range of nucleophiles and their relative reactivity in comparison to oxygen leaving groups. Modification of the methodology to enable reaction of monocyclic substrate substitution was enabled by the use of a protic solvent. Chemoselective reaction conditions were identified for selective reaction of Bn-F or Ar-Cl bonds and comparative reactivity studies were undertaken. The feasibility of Pd(0)/(II) catalysed nucleophilic C-F bond formation was examined. Chapter 4: The development of the defluorination methodology from Chapter 3 for secondary substrates is described. The stereochemical course of defluorination was probed, showing that displacement of fluoride is mechanistically similar to that of oxygen leaving groups. A kinetic resolution with a low selectivity was developed for access to enantioenriched benzylic fluorides.