The effect of scale on the conversion to products in flash vacuum pyrolysis experiments was studied using four model reactions. Overall, conversion was dependent on rection scale up to 0.5 g, but above 0.5 g, the effect was minimal and within experimental error. This effect was shown to be due to variations in contact time of the molecules in the furnace tube. Altering the furnace tube diameter had the effect of increasing the conversion to product. The pyrolysis of ortho-anilinomethylene Meldrum’s acid derivatives was investigated. Typically the 8-substituted quinolin-4-one was obtained as the major product, with a few exceptions. Certain substituents (such as nitro) were found to react with the ketene produced in the reaction to give alternative products, while others (such as chloro- and N-unsubstituted amides) gave the 3-substituted quinolin-4- ones via ipso-cyclisation and migration of the substituent. The regioselectivity of the pyrolysis of meta-anilinomethylene Meldrum’s acid derivatives, to give 5- and 7-substituted quinolin-4-ones, was studied. In general a 3:1 – 4:1 ratio of regioisomers was obtained, in favour of the 7-substituted quinolin-4-one. Substituents capable of hydrogen bonding, such as hydroxy-, were shown to give the 5-substituted quinolin-4-one exclusively and DFT calculations were employed to show that, in these examples, the 5-substituted product was favoured energetically. The pyrolysis of the methylene Meldrum’s acid derivative of 3-aminophenol gave 8-hydroxyquinolizinone as the sole product at low temperatures, with 5- hydroxyquinolinone as the major product formed at higher temperatures. The mechanism involves a regioselective electrocyclisation, followed by a hydrogen transfer and generation of a new ketene. Cyclisation of this ketene gives the quinolizinone. The scope of this reaction was explored, with a number of derivatives synthesised, and substitution on the aminophenol and the ketene generator was tolerated. The reactivity of the quinolizinones was also explored. The hydroxygroup was found to be phenol-like and underwent similar reactions, such as alkylations and acetylations. The compound was found to be highly reactive towards electrophiles, reacting in the 1- and 3- positions of the ring system, often in both positions. The pyrolysis of the aminomethylene Meldrum’s acid derivatives of certain pyridazinones was shown to give pyridopyrazidinediones. In some examples, a 4 second product based on a pyrrolopyridazine ring system was observed and DFT calculations show that the mechanism involves probably an electrocyclisation, followed by a decarboxylation reaction. Pyrolysis of amino acid ester derivatives of methylene Meldrum’s acid were shown to give N-unsubstituted 3-hydroxypyrroles and 1H-pyrrol-3(2H)-ones. Different amino acids were tolerated in the reaction, as were different electronwithdrawing groups in place of the amino acid ester. DFT calculations were employed to explore the mechanism of the reaction. 3-Hydroxypyrrole was also synthesised from the pyrolysis of Meldrum’s acid derivative of glycine tert-butyl ester, and the reactivity of the compound explored for the first time. The compound was found to be reactive towards electrophiles, such as diazonium salts, and could be O-acetylated under appropriate conditions.

Highly conjugated, extended heterocycles are recognized as important materials for use in electronic applications, and therefore the synthesis and characterization of new molecules of this type are necessary. One method of forming extended heterocycles relies on the dual cyclizations of the hetero-ene-ene-yne motif. By controlling the reaction conditions, these systems can be made to selectively undergo either a pericyclic reaction to form a cinnoline or a coarctate cyclization to form an isoindazole. The ability of the hetero-ene-ene-yne motif to produce two different heterocycles with distinct properties makes it an attractive system to study. Another method of forming extended heterocycles with tunable properties is by fusing aromatic hydrocarbons with aromatic heterocycles such as thiophene. Chapter I introduces the coarctate reaction and gives an overview of the Haley lab's work in this area. Chapter II explores the dual cyclizations of a phenanthrene-based system. In Chapter III an anthraquinone-based cyclization precursor is used to make diazaheterocycle analogs of tetracene. In Chapter IV isoindazoles were joined by an ethynyl linker to either phenyltriazenes and phenyldiazenes to yield molecules that could undergo both coarctate ring-forming and coarcate ring-opening reactions. Chapter V presents the synthesis and characterization of a series of indacenedithiophenes. Chapter VI advances the synthetic methodology of making larger heteroacenes by presenting work toward heterocyclic pentacene analogs. This dissertation includes both previously published and unpublished co-authored material. / 10000-01-01

Polymers with star shaped architectures represent an interesting class of macromolecule. Core cross-linked star (CCS) polymers in particular have shown potential for use in various fields of application including drug delivery, paint additives and membrane formation. The work presented in this thesis is directed towards investigating the synthesis of CCS polymers, looking at various ways of modifying the structural design to further expand the potential range of applications as well as develop a deeper understanding of this unique class of macromolecule. This was achieved through the incorporation of labile functional groups such that specific regions of the CCS polymer could be selectively targeted for degradation, thereby altering the structure and consequentially the properties in a controlled fashion. (For complete abstract open document)

Flow chemistry and continuous processing techniques are now frequently used in synthetic laboratories, taking advantage of the ability to contain reactive or hazardous intermediates and to perform moderate scale-up processes for important compounds. However, only a limited number of methods and tools for connecting flow synthesis steps into a single protocol have been described, and as a result manual interventions are frequently required between consecutive stages. There are two main challenges to overcome. Work-up operations such as solvent extractions and filtrations are invariably needed to ensure high purity of the intermediates. Solutions for achieving this are well established within industrial facilities for continuous production, but adapting such machinery for laboratory use is rarely straightforward. Secondly, the combination of multiple steps tends to result in a more elaborate reactor configuration. The control procedures required to achieve optimum performance may then be beyond the capabilities of a single researcher. Computer control and remote monitoring can help to make such experiments more practical; but commercially-available systems are often highly specialised, and purpose-built at high cost for a particular system, and so are not suitable for laboratory scientists to use routinely. This work describes the development of software tools to enable rapid prototyping of control systems that can integrate multiple instruments and devices (in Chapter 2). These are applied to three multi-step synthesis projects, which also make use of enabling technologies such as heterogeneous reagents and in-line work-up techniques so that material can be passed directly from one stage to the next: In Chapter 1, a series of analogues of a precursor to imatinib, a tyrosine kinase inhibitor used for the treatment of chronic myeloid leukaemia, are prepared. A “catch-react-release” technique for solid-phase synthesis is used, with computer-controlled operation of the reactors. In Chapter 3, a two-step procedure for the synthesis of piperazine-2-carboxamide, a valuable 3D building block, is developed. A computer control system enabled extended running and the integration of several machines to perform optimisation experiments. In Chapter 4, improvements to the continuous synthesis of 2-aminoadamantane-2-carboxylic acid are discussed. This includes an integrated sequence of three reactions and three workup operations. The final chapter describes a project to evaluate the application of control techniques to a medicinal chemistry project. New ligands for BRD9 and CECR2, proteins involved in the recognition of acetylated histone proteins, are produced. A number of triazolopyridazine compounds were synthesised and tested using a number of assay techniques, including a frontal-affinity chromatography system under development within our group. Pleasingly, the qualitative FAC data showed a good correlation with biological assessments made using established assay techniques. Further work using the FAC method is ongoing.

A novel approach to access N-Aryl nitrones via copper catalyzed coupling of benzyl alcohols with nitrosobenzenes is described. The results of mechanistic studies are conflicting but suggest this reaction proceeds through either redox process or a nucleophilic nitroso hydrate intermediate formed in situ, which was previously unprecedented. The unique electronics of this process allow access to nitrones with excellent step and atom economy, which are otherwise difficult to make using conventional methods. In this work, a total of 22 nitrones have been made. 15 of which from pure starting materials with yields ranging from 26 - 89 % and another 7 from two step, one pot reactions where the nitrosobenzenes were made in situ from commercially available anilines and reacted in a subsequent step to produce the nitrone in 8 - 46 % yield. In addition to the nitrone forming reaction occurring in the second step of a two-step sequence, we have also shown that subsequent reactions can be done on newly formed nitrones in one pot. This was demonstrated with a newly synthesized nitrone and a donor-acceptor cyclopropane in a [3+3] annulation reaction forming the cycloadduct in 90% yield. / Thesis / Master of Science (MSc) / With over 250 000 cases of resistant bacterial infections reported, and more than 5 400 directly causing Canadian deaths in 2018, we are currently facing an antibiotic crisis[67]. A particularly worrying class of resistance involves Gram-negative bacteria, as their highly impermeable outer membrane poses added complexity to their evolved resistance mechanisms[68]. The outer membrane restricts the chemical matter able to cross, making the bacteria intrinsically resistant to small molecule antibiotics and other compounds which may have intracellular targets[69],[70]. This barrier is therefore a major bottleneck for cellular mechanistic studies and compound mechanism of action, as these small molecules cannot gain entry to the cell. To circumvent this issue, outer membrane permeabilizing compounds must be discovered so that these systems can be more effectively studied. Commonly used membrane active compounds such as colistin and its derivatives, interact with both the outer and inner membranes of Gram-negative bacteria, and are toxic to cells[71]. Therefore, molecules that are outer membrane selective and nontoxic to Gram negative bacteria would be useful tools to expedite the study of biological systems.

Conjugated macrocycles have emerged as novel structural motifs that modulate the electronic properties of organic molecules because of their strained and contorted structures. Cycloparaphenylenes, known as nanohoops, are a particularly attractive scaffold for the design of new types of carbon nanomaterials because of their size-selective synthesis, radially oriented π-systems and tunable electronic properties. The development of modular syntheses of nanohoops over the past decade should enable the preparation of substituted derivatives that can be tuned for applications in biology and materials science. Chapter I provides a brief overview of conjugated macrocycles recently reported in the literature with a discussion of the structural effects that are responsible for the remarkable properties of this class of molecules. Chapter II highlights a scalable and mild synthetic approach developed in our lab to prepare nanohoop conjugated macrocycles and expands the generality of this methodology with the formal synthesis of natural product Acerogenin E. Chapter III describes the synthesis of cycloparaphenylenes with versatile functional handles and uncovers the reactivity of the strain nanohoop backbone under reaction conditions that promote the formation of radical cations. Chapter IV takes advantage of the functional groups described in chapter III to develop the first example of nanohoops as a new class of biocompatible fluorophores. Chapter V details a novel synthetic approach that enables the incorporation of the linear acene pentacene into the nanohoop backbone and reports our findings on the impact that the macrocyclic structure has on the properties of this organic semiconductor. In summary, the findings discussed in this dissertation provide synthetic strategies for the selective functionalization of nanohoops and highlight this class of molecules as a novel scaffold for the design of new types of carbon nanomaterials. This dissertation includes previously published and unpublished co-authored material.

The reactions of carboxylic acids with organoaluminium reagents were studied, which led to the formation of novel aluminium compounds. The reactions of orthofunctionalised derivatives of benzoic acid with trivalent aluminium organyls AlR3, led to the formation of different Al-based molecular clusters, depending on the nature of R, the reaction stoichiometry and the character of the benzoic acid derivative. The obtained compounds were characterised in the solid state by X-ray diffraction methods and two main motifs were observed. When the acid and AlR3 reacted in a one-to-two stoichiometry the obtained products, [iBu4Al2(μ-O2CC6H4-2-μ- O)]2, [(Me2Al)2(μ-O2CC6H4-2-μ-NH)]2, [(iBu2Al)2(μ-O2CC6H4-2-μ-NH)]2, [(Me2Al)2(μ- O2CC6H4-2-μ-NMe)]2 and [(iBu2Al)2(μ-O2CC6H4-2-μ-NMe)]2, consisted of a central distorted 12-membered macrocycle, formed by two [Al-O-C-O-Al-X] units (X= O,N) and was found to be dimeric. The reaction between anthranilic acid derivatives and AlR3 could also take place in a one-to-one ratio. For anthranilic acid and Nmethylanthranilic acid the obtained crystals only allowed a qualitative analysis and showed the structure of the products, [MeAl(μ-O2CC6H4-2-μ-NH)]4, [iBuAl(μ-O2CC6H4- 2-μ-NMe)]4 to be tetrameric and each consisting of a distorted 16-membered ring formed by four [O-C-O-Al] units. With the reaction of N-phenylanthranilic acid it was possible to isolate a structural analogous product [iBuAl(μ-O2CC6H4-2-μ-NPh)]4 which could be fully characterised by x-ray crystallography and NMR spectroscopy. Where the quantity and quality of the obtained product was sufficient, the solution behaviour of the compounds was elucidated by multinuclear and multidimensional NMR spectroscopic techniques. The 27Al NMR showed that the aforementioned aggregates are maintained in solution, which for the 12-membered [Al-O-C-O-Al-N] macrocycle of [(iBu2Al)2(μ-O2CC6H4-2-μ-NH)]2 was confirmed by a NOESY spectrum. The second part of this project focused on the preliminary studies towards the application of aluminium compounds in the crosslinking of guar and carboxymethyl hydroxypropyl guar, which are common additives in hydraulic fracturing. Different commercially available aluminium compounds were tested for their general ability to crosslink the aforementioned polysaccharides, yielding promising results for aluminium lactate, aluminium acetylacetonate and aluminium isopropoxide. For the system comprising aluminium lactate in combination with CMHPG, rheological studies were carried out to determine the viscosity, the viscoelasticity, the shear recovery and the stability towards high temperatures. These sought to evaluate the crosslinking properties of the aluminium additive and to optimise the required conditions of the different system components. Finally, it was possible to obtain first proof-of-concept data suggesting that synthetically obtained aluminium compounds such as [Me2Al(μ- O2CPh)]2 and Al[MeC(CH2O)3]2(AlMe2)3 can be employed for the crosslinking of guar and CMHPG.

Yes / Marrying synthetic biology with synthetic chemistry provides a powerful approach toward natural product diversification, combining the best of both worlds: expediency and synthetic capability of biogenic pathways and chemical diversity enabled by organic synthesis. Biosynthetic pathway engineering can be employed to insert a chemically orthogonal tag into a complex natural scaffold affording the possibility of site-selective modification without employing protecting group strategies. Here we show that, by installing a sufficiently reactive handle (e.g., a C–Br bond) and developing compatible mild aqueous chemistries, synchronous biosynthesis of the tagged metabolite and its subsequent chemical modification in living culture can be achieved. This approach can potentially enable many new applications: for example, assay of directed evolution of enzymes catalyzing halo-metabolite biosynthesis in living cells or generating and following the fate of tagged metabolites and biomolecules in living systems. We report synthetic biological access to new-to-nature bromo-metabolites and the concomitant biorthogonal cross-coupling of halo-metabolites in living cultures. / European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013/ERC consolidator grant GCGXC grant agreement no 614779) and ERAIB (Grant no. 031A338A) and H2020-MSCA-IF-2014 Grant no. 659399

No description available.

Carbon and phosphorus have often been compared owing to their diagonal relationship on the periodic table. However, relative to carbon, there remains an enormous breadth of polyphosphorus chemistry that is unexplored, particularly in the area of cationic phosphorus. A key step in the systematic and rational development of larger catenated organo-polyphosphorus cations is a fundamental understanding of the reactivity of small cationic building blocks. The smallest catenated framework in this context is the phosphinophosphonium monocation [R3P-PR2]+ (or phosphine-stabilized phosphenium cation), which can be prepared with a variety of functional groups at either phosphorus centre. This dissertation explores the diverse reactivity of chloro-substituted phosphinophosphonium cations, with a particular focus on reductive coupling as a synthetic route to novel catena-phosphorus systems. The resulting cationic frameworks are comprehensively described in terms of their diasteroisomerism, solution dynamics, and solid-state structural features. Additionally, fundamental electrochemical investigations of these diphosphorus cations are outlined as a tool for understanding and quantifying the reactivity of phosphenium cations. Finally, extension of reductive coupling methodology to the first chlorostibinophosphonium cations presents a promising outlook towards the catenation of the heavier pnictogen cations.