Flinn, Amy
(2021)
Towards Continuous Organic Photochemistry.
PhD thesis, University of Nottingham.
Abstract
The work presented in this Thesis is motivated by an increasing interest in approaching Chemistry from a greener standpoint. This work is focused on improving reaction credentials through a photochemical and/or flow approach, which despite the increasing uptake of these methods in academia is still limited in industry. This is, in part, due to misconceptions around the ease, applicability and scalability of these methods. This Thesis describes the investigation of various chemical transformations to continuous photochemical approaches, including exploiting unique reactors and flow equipment available at Nottingham. The reactions investigated include photoborylation, the Fries rearrangement and ozonolysis, which were selected due to their widespread use in drug synthesis.
Chapter 1 introduces the background of photochemical research, with a summary of important technological advances in both academia and industry with regards to photochemical and flow approaches. For comparison and information, the equipment used within this Thesis and developed at Nottingham are summarised within Chapter 2.
Several photochemical reactions are then tackled sequentially by Chapter. Within Chapter 3, the direct photo-induced borylation of bromobenzene was investigated using standard UV photochemical equipment. Borylation was chosen as it is a pre-requisite for Suzuki-Miyaura coupling, which remains one of the most common C-C bond forming reactions. This research provided further insight into UV induced borylation as well as identifying several challenges for the scale-up of this reaction, which led to consideration of an alternative route to borylation.
Chapter 4 developed this alternative borylation approach, relying on a decarboxylative borylation methodology using N-phthalimido ‘activated’ esters. This reaction was explored using various photochemical equipment at Nottingham, with significant advances made through the use of targeted UV irradiation. This work illustrates the value of a photochemical approach for improving reaction efficiency, with the optimised conditions an improvement on the pre-existing literature. The optimised reaction conditions were then expanded to a wider substrate scope.
Subsequently, the photo-induced Fries rearrangement was investigated in Chapter 5, through the application of a long-established rearrangement of phenyl acetate to new reactor set-ups. The Fries rearrangement is having its own renaissance, as the reaction products are otherwise difficult to produce through other routes. This specific reaction was chosen to confirm whether increases in productivity could be achieved relative to the initial work published in the 1960s, as the photochemical route has largely been abandoned in the literature.
The experience gained following the previously described work was then applied to a new challenge: the development of a flow reactor for ozonolysis, the focus of Chapter 6. Ozonolysis poses various safety issues and is typically limited to small-scale batch work, with relatively new interest in a flow approach for synthetic purposes. Initially, the ozone-producing capacity of a KrBr excimer lamp was established as a potential component of a larger flow reactor. The design of an ambient flow ozonolysis reactor was then applied to a commercial ozone generator. Further testing and application to model reactions was prevented by COVID-19, but the future direction of this project is outlined.
Following this research, working methodologies have been established for the above reactions across several photochemical approaches in both batch and flow, with a greater understanding achieved for the application of photochemistry for ‘greener’ synthesis. Finally, the work outlined in this Thesis is summarised in Chapter 7.
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