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This thesis describes the use of C(1) ammonium enolate chemistry with Lewis base isothiourea catalysis in Michael addition-lactonization/lactamization between 2-pyrrolyl acetic acid derivatives and various Michael acceptors. Chapter 2 proved the principle that amino esters protected as benzophenone Schiff base could be α-functionalized using Lewis base catalysis. Chapter 3 described the use of 2-pyrrolyl acetic acid in enantioselective Michael addition-lactonization with CCl3 enone. After in situ ring-opening, a range of 30 diesters and diamides in up to 98% yield, >95:5 dr and >99:1 er. Further demonstration of the synthetic utility of these ring-opening derivatives was achieved with an intramolecular Friedel-Crafts acylation utilizing the electron-rich nature of pyrrole to afforded dihydroindolizinone derivatives in up to 90% yield with no erosion in stereoselectivity. Chapter 4 described the use of either α,β-unsaturated trifluoromethyl ketones or α-keto-β,γ-unsaturated esters with 2-pyrrolyl acetic acid to synthesize tetrahydroindolizine derivatives in one-pot, with up to 98% yield, >95:5 dr and >99:1 er. Chapter 5 described the synthesis of dihydropyridinones from chalcone-derived N-Ts ketimine and unsaturated cyclic sulfonamide derived from saccharin in up to 97% yield, >95:5 dr and >99:1 er. Chapter 6 described the synthesis of tetrasubstituted pyridines using a variety of unsaturated ketimines bearing esters with DHPB catalyst in up to 66% yield. Further derivatization was demonstrated via transforming 2-pivaloyloxy group into 2-OTs group in a two-step process, enabling the Pd-catalyzed cross coupling and reduction.

Hexagonal boron nitride nanosheets (BNNSs) are thin-layer lattices of alternating boron and nitrogen atoms. They are structurally analogous to graphene, a single layer of graphite, which has exhibited remarkable mechanical and electronic properties. However, unlike graphene which is black and a well-known electrical conductor, boron nitride is white and is an electrical insulator. To fully realise the potential of BNNSs, they are integrated into epoxy matrices to form epoxy nanocomposites. Efforts were made to improve, explore and characterise exfoliated BN from different commercial suppliers, with Alfa Aesar revealed to be most useful commercial source for the purposes of improving polymer properties. The yields of liquid phase exfoliation of bulk boron nitride were slightly improved by applying increased concentrations and by adopting a recycling methodology. Organic solvents tetrahydrofuran, dichloromethane and ethyl acetate were investigated as potential solvents, with ethyl acetate exhibiting good quality flakes. Atomic force microscopy (AFM) was used to analyse the exfoliation efficiency and lateral dimensions, while Raman spectroscopy proved an insight about the quality of the boron nitride flakes. Dynamic light scattering was used as a method to estimating the lateral sizes of boron nitride flakes. To fully facilitate dispersion and better interfacial interactions with the epoxy polymers, attempts to functionalise the BN flakes were made. A direct covalent method utilising the Suzuki Palladium catalyzed cross coupling reaction was attempted on hydroxylated BN flakes. The reaction was unsuccessful due to the formation of palladium salts. Inspired by layer-by-layer processes, polymer-adsorption techniques were adopted by adsorbing PEI onto BN flakes. The functionalisation strategy was successful and the subsequent PEI@OH-BN was characterised using several unique methods to investigate the surface properties such as zeta potential, wettability, AFM pull-off test, solvent dispersion, Raman, AFM, XRD, TGA, DSC. Fluorescence methods were also applied during the project as a potential method to monitor flake dispersion. Thermomechanical tests of BNNS/epoxy composites reveal that the BNNS, as well other boron containing compounds interferes with epoxy curing. This was validated by tests with other boron-containing molecules. The Tg of the resulting badly cured composites were found to decrease. Various surface coatings tests (adhesion pull-off tests, solvent uptake) were performed to analyse and compare BNNS/Macropoxy M922 composites with formulations with the PEI@OH-BN flakes. Electrical Impedance Spectroscopy measurements were also conducted on samples of graphene and BNNS within commercial Araldite 2954 Araldur LY564 and Macropoxy M922 epoxies. BNNS was found to be substantially improved compared to the graphene equivalents. These were also tested with the formulations of the PEI@OH-BN flakes but was found that PEI was detrimental within the Macropoxy formulations.

In recent years, photoredox catalysis emerged as a privileged tool for small molecules activation via single-electron transfer mechanisms. Despite their ubiquity as reagents in organic synthesis, the use of boronic acid derivatives to generate carbon-centred radicals remains elusive. This dissertation explores the utilisation of photoredox catalysis to generate carbon radicals from boronic acid derivatives and subsequently engage them in C–C cross-coupling reactions. In the first chapter, an introduction to photoredox catalysis and organoboron reagents is provided, as well as a discussion on the key mechanistic aspects of photoredox catalysed C–C cross-coupling reactions. The second chapter presents our initial coupling strategy and how it evolved in understanding that pinacol boronic ester species can be used as a source of carbon radicals via single-electron oxidation from a photoredox catalyst. Coordination of the boronic esters with Lewis basic species was identified as a fundamental activating interaction. The synthetic utility of this discovery was highlighted by performing a wide range of photoredox catalysed arylations of pinacol boronic esters. The third chapter builds on our mechanistic understanding to identify a set of Lewis base catalysts that conveniently activates boronic esters and acids towards single-electron oxidation. The usefulness of this improved set of conditions was demonstrated by alkylating a wide range of boronic acid derivatives. The fourth chapter describes the application of this methodology in synthesising four active pharmaceutical ingredients from the GABA family. An emphasis was made on developing an efficient flow process and “transition metal free” conditions to survey the attractiveness of the method for the pharmaceutical industry. Finally, the fifth chapter describes the experimental procedures relevant to the results described in chapters 2 to 4.

This thesis describes investigations into the ability of isothioureas to act as organocatalysts in formal [4+2] cycloadditions between carboxylic acids and various Michael acceptors via C1-ammonium enolate intermediates. Initial research focused upon establishing optimal reaction conditions to affect the asymmetric intermolecular formal [4+2] cycloaddition between a range of arylacetic acids and α-keto-β,γ-unsaturated esters, giving anti-dihydropyranones in high yield (49-87%) and with excellent diastereo- and enantioselectivity (up to 98:2 dr, up to 99% ee). This represented the first time that carboxylic acid derived ammonium enolates have been successfully applied towards an intermolecular reaction process. Subsequent studies utilised trifluoromethyl enones as Michael acceptors, forming a range of C(6)-trifluoromethyl anti-dihydropyranones with good diastereoselectivity (up to 95:5 dr) and enantioselectivity (up to >99% ee). Detailed mechanistic studies were carried out, revealing that the process was stereospecific, with the diastereoisomer of product formed dependent upon the configuration of trifluoromethyl enone used. A variety of product derivatisations were demonstrated including those which introduce additional trifluoromethyl-bearing stereogenic centres with high diastereoselectivity. Kinetic studies indicated that this Michael addition-lactonisation process is first order with respect to both in situ formed anhydride and catalyst concentration, with a primary kinetic isotope effect observed using α,α-di-deuterio 4-fluorophenylacetic acid. DFT computational studies support a rate-determining formation of a reactive ammonium enolate prior to a stereochemistry-determining enone conjugate-addition step. The isothiourea-catalysed α-amination of carboxylic acids with low catalyst loadings (as low as 0.25 mol%) using N-aryl-N-aroyl Michael acceptors was demonstrated, forming a range of 1,3,4-oxadiazin-6(5H)-ones or hydrazide products with excellent enantiocontrol (typically >99% ee). Notably, the scope of this methodology was expanded to allow the direct functionalisation of carboxylic acids bearing α-heteroatom and alkyl substitution for the first time. The synthetic utility of the hydrazide products was demonstrated through their derivatisation into a range of bespoke functionalised N-aryl-α-arylglycine derivatives in high enantiopurity (up to 99% ee). Isothiourea-mediated functionalisation of 3-alkenoic acids was shown to occur regioselectively, giving products derived from α-functionalisation of an intermediate C1-ammonium dienolate in a range of formal [2+2] and [4+2] cycloadditions. Formal [4+2] cycloadditions with either trifluoromethyl enones of N-aryl-N-aroyl diazenes allow access to products in high diastereo- and enantiocontrol (up to 95:5 dr, up to 99% ee). The simple, two-step elaboration of stereodefined hydrazides into aza-sugar analogues without erosion of enantiopurity has also been demonstrated. 2-Arylacetic anhydrides were also demonstrated as useful precursors for the formation of C1-ammonium enolates in isothiourea-mediated Michael addition-lactonisation processes. Trifluoromethylenones,α-keto-β,γ-unsaturated esters and N-aryl-N-aroyldiazenes are reactive Michael accceptors in this process, with HBTM-2.1 (5 mol%) readily promoting heterocycle formation with high diastereo- and enantiocontrol (up to 95:5 dr, up to >99% ee). This protocol offered a useful and practical alternative to the in situ carboxylic acid activation method, in which by-product formation and the amount of sacrificial base used is minimised. DHPB was shown to promote the one-pot synthesis of 2,4,6-subsituted pyridines bearing a readily derivatised 2-sulfonate functionality from (phenylthio)acetic acid and a range of α,β-unsaturated ketimines in moderate yields (40-66%). Functionalisation of the 2-sulfonate group via various methodologies allowed the rapid assembly of both novel and biologically relevant pyridines.

This thesis describes our physical organic and mechanistic investigations into N Heterocyclic Carbene (NHC) mediated organocatalytic transformations, through a collaboration with the research group of Dr AnnMarie O'Donoghue and PhD student Richard Massey at Durham University. Initial research focused upon the determination of kinetic acidities and associated pKₐ values for a range of triazolium salts using C(3) H/D exchange, monitored by ¹H NMR spectroscopy. Estimates for pKₐ values in the range 16.6 17.4 were obtained, which are some ~2 and ~3 5 pK units lower than analogous imidazolium and thiazolium species respectively, with modest N substituent (0.3 pK units) effects observed. At lower pD values, an altered pD dependence indicates a dicationic triazolium species is formed (through N(1) protonation) with an estimated pKₐᴺ¹ of -0.2-0.5 and C(3) H pKₐ values at least 2 units lower than their monocationic analogues. This methodology was subsequently extended to mesoionic NHCs, where pKa values of 23.0 27.1 for a range of triazolium and 30.2 31.0 for a range of imidazolium salts were estimated. A detailed study of the NHC catalysed intramolecular Stetter reaction was also undertaken using ¹H NMR spectroscopy. A range of 3 (hydroxybenzyl)azolium salts (adducts), formed from the addition of NHC to aldehyde were isolated, enabling the generation of reaction profiles and the determination of rate constants. The reaction proceeds via rapid and reversible adduct generation, followed by rate limiting Breslow intermediate formation, with electron withdrawing N aryl substituents increasing the rate of product formation. Consistent with rate limiting deprotonation, deuterium exchange studies of O methylated adduct analogues found electron withdrawing N-aryl units gave faster exchange. Examination of the equilibrium constants for adduct formation revealed that both in the case of NHCs bearing 2,6 disubstituted N aryl units and aldehydes bearing a 2 ether substituent, the equilibrium position is significantly shifted towards adduct. Finally, studies at sub-stoichiometric NHC concentrations, monitored by HPLC, imply the reaction is first order with respect to NHC precursor, but zero order in aldehyde, again indicative of rate limiting deprotonation.

This work describes the application of a variety of Lewis bases, encompassing predominantly N-heterocyclic carbenes (NHCs), but also the use of imidazoles, aminopyridines, amidines and isothioureas, as effective catalysts in the dearomatisation of heterocyclic carbonates, predominantly the rearrangement of oxazolyl carbonates to their C-carboxyazlactone isomers by means of the Steglich rearrangement. This rearrangement reaction has been investigated extensively, with the development of simplified reaction procedures and the invention of domino cascade protocols incorporating this transformation. In an attempt to understand the mechanism of this O- to C-carboxylation process, a number of interesting observations have been made. Firstly, the class of NHC has an important factor in promoting the rearrangement, with triazolinylidenes being the most effective. Secondly, an interesting chemoselectivity has been delineated using triazolium-derived NHCs, prepared using weak bases (typically Et₃N) or strong metallated bases; both alkyl and aryl oxazolyl carbonates undergo smooth rearrangement with triazolinylidenes derived from strong metallated bases such as KHMDS, while only aryl oxazolyl carbonates undergo rearrangement using Et₃N. Extensive effort has focused towards the development of asymmetric variants of these protocols, primarily towards the design, synthesis and evaluation of chiral NHC precatalysts. To this end, a number of chiral azolium salts have been prepared, encompassing a number of different NHC classes, including C₁- and C₂-imidazolinium salts, C₂-imidazolium salts and a range of triazolium salts. Efforts towards the asymmetric catalysis of the Steglich rearrangement of oxazolyl carbonate substrates have given an optimal 66% ee. Similar rearrangements have been demonstrated with the related furanyl heterocyclic substrate class, producing a mixture of α- and γ-carboxybutenolides. In contrast to the analogous oxazolyl carbonates, the regioselectivity of this rearrangement is dependent upon the nature of the Lewis base employed. Amidines and aminopyridines give a mixture of the α- and γ- regioisomers with generally the α-regioisomer being preferred, while a triazolium-derived NHC gives rise to predominantly the thermodynamically more stable γ-carboxybutenolide. Using amidines or aminopyridines, this rearrangement has been shown to proceed via an irreversible C-C bond-forming process, but in contrast, the rearrangement using the NHC proceeds via an equilibrium process with an optimised regioselectivity of >98:2 for the γ-carboxybutenolide regioisomer over the α-regioisomer. Whilst the asymmetric variant using chiral NHCs has proven unfruitful, rearrangements using a chiral isothiourea have given high levels of regioselectivity towards the α- regioisomer and with excellent levels of enantiodiscrimination (77–95% ee).

Interfacial interactions govern phenomena such as adsorption, wetting, and adhesion. These interactions can be broken down into two categories: van der Waals and polar interactions. A subset of polar interactions is acid-base interaction. Here, I continue to expand on Drago-Wayland and Badger-Bauer framework demonstrated in previous literature to a planar silicon dioxide surface. Sum frequency generation spectroscopy is used to determine the frequency shift between the acid (silicon dioxide) and a series of bases in the pursuit of determining the Ea and Ca parameter for the planar silicon dioxide surface. These parameters are juxtaposed with previously reported Drago-Wayland values for silicon dioxide and sapphire. Additionally, competitive adsorption of a binary mixture on silicon dioxide is examined by SFG. The interfacial composition is used to calculate an adsorption isotherm and the resultant interfacial energy is compared to the interfacial energy calculated by a thermodynamic approach. Additionally, interfacial interactions between water and polymers can affect the polymers interfacial structure which can result in product failure like biomedical incompatibility, adhesive failure and delamination of coatings. Contact angle has been used since the 18th century to probe interfacial information between liquids and substrates. Here, I propose that additional measurements taken in tandem with contact angle enable a better understanding of interfacial rearrangement and simultaneously reveal an interesting phenomena due to annealing temperature of polymer films.

Chapter 1. Review of concept and methodology development for asymmetric allylation of carbonyls and imines. Chapter 2. Description of the catalytic asymmetric addition of allyltrichlorosilane to aldehydes catalyzed by a proline-based N-oxide catalyst. Chapter 3. Introduction of the first catalytic asymmetric silylation of alcohols for desymmetrization of meso-diols. Chapter 4. Presentation of asymmetric silylation for synthesis of chiral syn-1,2-diols by kinetic resolution or divergent reaction on a racemic mixture.