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Organic azides are important in the synthesis of many target molecules of great use in fine chemical and pharmaceutical production. The use of this class of compounds is however limited due to their hazardous nature and many safety concerns, as they are highly exothermic. Micro reactors can handle exotherms extremely well, due to the inherent high surface area to volume ratio, unlike the conventional batch process. This dissertation therefore aims to investigate the safe application of micro reactors in acyl azide chemistry.With this in mind, Chapter 1 provides a comprehensive background on organic azides, reaction calorimetric studies, flow chemistry technology (micro reactors) and their theoretical advantages. This chapter also discusses the preparation of organic azides in continuous flow systems and scaling up in continuous flow systems. Chapter 2 illustrates and discusses multivariate optimisation of benzoyl azide synthesis as a model reaction, synthesis of other acyl azides using the model reaction optimised conditions and multistep synthesis of carbamates, amides and amines in continuous flow systems via the Curtius rearrangement of benzoyl azide formed in situ from benzoyl chloride and sodium azide. The chapter also discusses process hazards analysis and evaluation of benzoyl azide synthesis and decomposition using calorimetric studies. It also investigates and discusses the effects of different mixing regimes and channel sizes on scale up. Chapter 3 has comprehensive experimental details for the whole dissertation with Chapter 4 providing the concluding remarks and future work recommendations.

Flow chemistry can be characterized as a continuous chemical reaction system performed in solution in connecting tubing and flow reactors which is efficient. Photochemistry is the chemical reaction initiated by light, and is the result of the absorption of photon by a reagent or starting material. Poly (ADP-ribose) polymerase is a big family of proteins related to cellular repair and death. Phenanthridinones have been shown to exhibit PARP inhibitory potency as competitive inhibitors. Instead of using conventional costly and low-efficiency coupling reactions, we have managed to develop a method to synthesize phenanthridinone-type compounds by photo-cyclization under flow conditions for the purposes of generating novel PARP inhibitors. In total, we have generated a series of phenanthridinones in yields ranging from 13 % to 99%, 18 examples. Additionally, we have also developed a flow photocyclization method for the synthesis of complex heterocycles, naphthyridinones (5 examples, yields ranging from 24-52%) and thieno-quinolinones (18 examples, yields ranging from 23-90%), molecules that would be much more difficult to construct using conventional batch methods. Overall, we have demonstrated that a flow photocyclization pathway is a robust synthesis route for producing phenanthridinone-type compounds for the purposes of developing novel PARP inhibitors. / October 2016

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.

This thesis presents an integrated study of nanocatalysts for heterogenous catalytic and electrochemical processes using pure ruthenium (Ru) with mixed-phase and platinum-based nanomaterials synthesized by continuous-flow chemistry. There are three major challenges to the application of nanomaterials in heterogenous catalytic reactions and electrocatalytic processes in acidic solution. These challenges are the following: (i) controlling the size, shape and crystallography of nanoparticles to give the best catalytic properties, (ii) scaling these nanoparticles up to a commercial quantity (kg per day) and (iii) making stable nanoparticles that can be used catalytically without degrading in acidic electrolytes. Some crucial limitations of these nanostructured materials in energy conversion and storage applications were overcome by continuous-flow chemistry. By using a continuous-flow reactor, the creation of scalable nanoparticle systems was achieved and their functionality was modified to control the nanoparticles’ physical and chemical characteristics. The nanoparticles were also tested for long-term stability, to make sure these nanoparticles were feasible under realistic working conditions. These nanoparticles are (1) shape- and crystallography-controlled ruthenium (Ru) nanoparticles, (2) size-controlled platinum-metal (Pt-M= nickel (Ni) & copper (Cu)) nanooctahedra (while maintaining morphology) and (3) core-shell platinum@ruthenium (Pt@Ru) nanoparticles where an ultrathin ruthenium shell was templated onto the platinum core. Thus, a complete experimental validation of the formation of a scalable amount of these nanoparticles and their catalytic activity and stability towards the oxygen evolution reaction (OER) in acid medium, hydrolysis of ammonia borane (AB) along with plausible explanations were provided.

Chemical processes and reactions are never perfect; there are always some problems in scope, scalability, applicability or safety. Sometimes, if these limitations pose a seemingly insurmountable barrier to the chemistry’s overall usefulness, decades can go by without a single new development even in fields that were initially very promising or popular in their infancy. By looking back on these forgotten topics through the lens of modern technology, new cutting-edge materials and methods can be applied to solve the problems that posed too great a challenge in previous decades. In this thesis, two such examples of reactions initially discovered and developed around the late 1960’s and remained largely untouched ever since will be explored. Chapter 1 will describe the use of ozone as an oxidant to transform amines into the corresponding alkyl nitro species. Ozone is a very powerful oxidant but tends to overreact with most organic substrates, which significantly reduces its potential as a commonplace synthetic tool. These limitations in applicability stem from an inherent lack of control over the reaction, which is the issue that we sought out to address. By applying modern principles of flow chemistry, the functional group tolerance of this oxidation reaction has been drastically increased from its initial state of simple small hydrocarbons. Chapter 2 will follow a similar narrative involving the use of ‘super-bases’ to activate benzylic C-H bonds and generate a variety of benzyllithium species. Organolithiums have also had historic issues with tolerance in transition metal-catalyzed cross coupling reactions. With a surge of new publications addressing this issue by using principles of flow chemistry, there remains a lack of easy methods to generate organolithium nucleophiles as coupling partners. Generation of benzyllithiums from toluene derivatives has historically been limited to require solvent quantities of substrate, along with unreasonably long reaction times at cryogenic temperatures. By utilizing modern tools and synthetic strategies, an easy and streamlined path from toluene derivatives to organolithiums for direct use in cross coupling has been developed.

In recent years, research has focused on reducing the cost of catalysts in a variety of ways including using less expensive materials, improving the synthetic method, and increasing the catalytic activity, recovery, and recyclability. Typically with nanoparticles, the size, shape, composition, and surface coating have an effect on catalytic activity.1-2 In this work, we focused on reducing the cost of precious metal based catalysts by altering the synthetic methods. One way to lower the cost of synthesizing precious metal nanoparticles is by debasing the precious metal with a second cheaper more abundant metal. CuPd nanoparticles were synthesized in oleylamine and displayed catalytic activity in several cross-coupling reactions. Due to copper being present in the nanoparticle, a copper halide co-catalyst was not needed for Sonogashira cross coupling to be successful.3 While this method produced reactive catalysts, low product yield hinders its application for industry. Solution based synthesis of metallic nanoparticles typically require long reaction times and high temperatures, which make large scale production of nanoparticles on an industrial scale difficult.4-5 The use of continuous flow microreactors provides greater control of synthetic parameters, leading to lower batch-to-batch variability and increasing the efficient of heat and mass transfer and have been applied to the synthesis of metals, semiconductors, zeolites, organic compounds, and semiconductors.5-7 To compare continuous flow methods to benchtop reactions, a well-characterized benchtop reaction synthesizing Cu@Ni core/shell nanoparticles was successfully transferred to a flow reactor set-up. Cu@Ni nanoparticles were synthesized using a capillary microreactor in under 1 minute compared to the 1 hour reaction on benchtop with similar properties in a green solvent.2 The Cu@Ni nanocomposites were active towards the Fischer Tropsch reaction.8 2 nm platinum nanoparticles and platinum bimetallic alloys were synthesized in water using a capillary microwave flow reactor. Investigations showed the nanoparticles were activity toward hydrogenation of octene. With further development, continuous flow synthesis of metallic nanoparticles can be applied to the synthesis of a wide variety of catalysts on an industrial scale. Continuous flow methods provide greater control of reaction parameters, increased safety by reacting smaller volumes of chemicals at a given time, and decreasing the batch-to-batch variability.

A direct and highly efficient synthesis has been developed for telmisartan, the active ingredient in the widely prescribed antihypertensive drug Micardis®. This approach brings together two functionalized benzimidazoles using a high-yielding Suzuki reaction that can be catalyzed by a homogeneous palladium source or palladium on a solid support. The ability to perform the cross-coupling reaction was facilitated by the regio-controlled preparation of a 2-bromo-1-methylbenzimidazole precursor. The method developed is the first reported selective bromination at the 2-position of a benzimidazole and produces the first major precursor in high yield (93%). The second precursor, potassium (4-methyl-2-propylbenzimidazol-6-yl) trifluoroborate, was prepared from commercially available 4-bromo-2-methyl-6-nitroaniline. An optimized preparation is described that provides a direct three-step process to prepare the benzimidazole and install the borate; this synthetic sequence yields the second precursor with a 90% yield and no isolated intermediates. The two prepared precursors were combined with a third, commercially available methyl-4’-(bromomethyl)-[1,1’-biphenyl]-2-carboxylate, utilizing a short sequence of high yielding reactions to produce the telmisartan with an 83% yield from these advanced intermediates. This new convergent approach provides the active drug ingredient with an overall yield of 74% while circumventing many issues associated with the previously reported processes. Additionally, a flow-based synthesis of telmisartan was achieved with no intermediate purifications or solvent exchanges. The continuous process utilizes a tubular reactor system coupled with a plug flow cartridge, ultimately delivering telmisartan in an 86% isolated yield.

This thesis describes the application of flow chemistry to discovery and development of medicinal compound synthesis and new chemical methodologies respectively. It is divided into three distinct sections. The first section addresses a brief introduction to flow chemistry, highlighting the advantages and challenges that have been faced in the past and present and also the outlook to the future. The second section reports the integration of machine-assisted methods with batch processes to produce two medicinal compounds, a precursor to the sacubitril and OZ439 respectively. In the respect to the precursor to sacubritil, a flow-batch integrated synthesis is developed to provide the desired product in 54% yield over 7 steps from commercially available 4-iodophenyl. In particular, a tube-in-tube gas flow reactor was employed in three gas-liquid reactions without the need for installing a costly highpressure autoclave. These gas-lquid reactions were an ethylene Heck coupling reaction, an anti-Markovnikov Wacker oxidation and a rhodium-catalysed stereoselective hydrogenation respectively. In addition, a diastereoselective Reformatsky-type carbethoxyallylation using zinc metal was also highlighted in this synthesis to install an important stereocentre. A new antimalarial agent, OZ439 containing a trioxolane unit as the main structural feature, has the unique property of providing a single-dose cure for malaria in humans and has recently completed phase IIb trials. A machine-enabled process for the preparation of OZ439 was developed in 33% overall yield over 5 steps without the need of column chromatography purification. This preparation features a selective continuous hydrogrenation, Griesbaum ozonlysis and a Zn-catalysed amide reduction in the present of triethoxylsilane. The third section contains the development of two new methodologies of diazo compounds with organoboron compounds. The first methodology involves an in situ generation of transient allylic boronic species by reacting TMSCHN2 and E-vinyl boronic acids in flow, followed by subsequent trapping with a range of aldehydes (15 examples, 55-97% yield) and on a large scale (10 mmol) to provide homoallylic alcohols with high diastereoselectivity (>20:1 dr confirmed by 1H NMR). This multicomponent metal-free reaction could also be applied under batch conditions (20 further examples, 60-82% yield). The second methodology involves the preparation of an organodimetallic compound, α-trimethylsilyl benzylboronic acid pinacol esters, by reacting TMSCHN2 and phenylboronic anhydrides (21 examples, 60-91% yield), and the development of their applications as bifunctional building blocks to complex structures.

This thesis investigates the application of online monitoring for the optimisation of flow chemistry, as well as how additive manufacturing can aid the integration of analysis and confer new functionality to flow reactors. The additive manufacturing (AM) processes used were stereolithography (SL) and the metal printing techniques selective laser melting (SLM) and ultrasonic consolidation (UC). Chapter 1 contains a short literature review, intended to give a clear background to the work contained herein. The literature reported gives a brief introduction to flow chemistry and some of the instrumentation used to perform it. Additionally, the evolution of reactor design is investigated leading to an overview of the use of AM for custom reactors. The subsequent use of online analytical technologies and how they relate to the enhancement of flow chemistry is discussed, as well as some of the protocols that have been employed to date to facilitate automated reaction optimisation. Chapter 2 investigates the design and manufacture of flow cells capable of online spectroscopy, as well as the integration of spectroscopic monitoring capability directly into reactors. In addition, the use of AM to produce accessories, not necessarily part of the wetted flow path, was investigated and showed that many useful parts such as fibre optic holders and screws could be produced. The capability of these flow cells was assessed through standard material analysis as well as through the online analysis of flow chemistry. In particular, the use of SL has enabled the production of flow cells with features smaller than 100 microns. This allowed in situ spectroscopy to be performed by embedding fibre optics directly adjacent to the flow channel, offering a new way for reaction monitoring by ultraviolet (UV) spectroscopy to be performed cheaply, and with full user control over the flow cell specification. No additional quartz features were required for these cheap and highly customisable parts. Flow cells of larger path lengths were also produced, and their performance tested, identifying designs and materials suitable for the inline analysis of flow chemistry. These designs were then successfully incorporated directly within the flow channels of larger scale reactors, tailored specifically to commercial flow equipment, for true inline analysis of flow chemistry. Chapter 3 examines the use of metal reactors formed through more expensive printing processes, SLM and UC. As the parts these techniques produce are fully dense, chemically resistant and thermally stable, they were used to perform high temperature chemistry, taking solvents substantially above their boiling points to accelerate reactions and perform them in a fraction of the time of the batch process. UC was also used to produce a reactor with a copper flow path and the possibility of reaction catalysis performed with active metal sections was investigated, revealing that chemical modification of the reactor surface greatly improved the reaction yield. UC was also utilised to produce a flow reactor incorporating a thermocouple in the main body, close to the flow channel to enable accurate reaction temperatures to be measured, a significant improvement over the temperature control offered through the flow instrument. This represents the first use of UC for the production of complicated geometry flow reactors and this work has shown that many more applications of the technique for flow chemistry should be investigated. The ability to perform light mediated coupling reactions in AM produced reactors was also demonstrated successfully for the first time, and further to this that the extended UV curing of SL reactors is crucial for improved robustness of these parts. Chapter 4 centres on the use of online analytical methods to provide rapid, selective, and quantitative online analysis of flow chemistry. This chapter also outlines some of the steps required for automation to be possible, including equipment specifications and the coding approach undertaken to integrate multiple different instruments. A combination of online nuclear magnetic resonance (NMR) spectroscopy analysis and automated experiment selection was then used to optimise a pharmaceutically relevant, photoredox catalysed, C-N coupling reaction between amines and aryl halides, performed under continuous flow conditions for the first time. This optimisation required minimal user input, operating completely unattended, and revealed that lower concentrations of catalyst could be employed than previously identified, reducing the amount of toxic and expensive metal salts required, while achieving high conversion of the starting material. In summary, this thesis has demonstrated that AM, in particular SL, can be used for the production of new high resolution microfluidic flow cells, as well as larger scale flow cell designs which can be integrated into the body of large reactors, not easily performed with other manufacturing methods. SL has also been used to produce reactors capable of performing light catalysed reactions directly, with no further modifications. The use of metal printing AM techniques has allowed in situ catalysis and high temperature, high pressure reactions to be carried out with ease. Finally, the use of online NMR with computer control and experiment automation has allowed the rapid optimisation of a pharmaceutically important C-N coupling reaction.