Computational Investigations into the Generation of Reactive Intermediates for Organic Synthesis
Creators: name: Blyth, Mitchell
Publisher: name: The Australian National University
Year: 2023

description: Chemical catalysis, the process by which reactions are accelerated via the addition of reagents which are not consumed throughout the course of the reaction, is one of the most significant areas of chemistry, by any measure. Through catalysis, we are able to access reactions that would otherwise proceed only on geological or universal timescales, or obtain molecules which by their very existence appear to defy Nature. Recent estimates suggest that greater than 80% of all industrial process globally utilise catalysts at some stage, representing a value of some USD $7 trillion in the European Union alone. These catalysts could be simple metal ions, surfaces with varying properties and composition, both simple and complex organic and inorganic molecules, or even enzymes and other biological machinery. In brief, this thesis concerns itself with the use of a broad variety of computational methods towards the development and understanding of a variety of catalysts, or processes which rely upon catalysts. Within this scope, our primary focus is toward the development of synthetically relevant electrostatic catalysts, and the creation and violation of rules which govern their design and implementation. As we shall see, recent research has demonstrated that appropriately oriented electric fields can be used as orthogonal catalysts in non-redox chemical reactions, albeit not without limitations. Given these as-yet-undefined limitations, the primary question is how we can introduce effective electric fields into chemical systems to perform this catalysis, circumvent the models which predict their effectiveness, and utilise them in an ever-growing number of realistic synthetic applications. To address these questions, we investigate the effect of electric fields upon a complex, multi-step reaction, the photo-enolisation/Diels-Alder (PEDA) sequence, and then question whether electric fields can be used to augment the existing catalytic activity of N-heterocyclic carbenes (NHCs). In the process, we critically evaluate a competing mechanistic proposition for the PEDA process, and perform the first broad-scope investigation into the effects of different substitution patterns upon PEDA reactivity. Later, we use computational chemical methods to simultaneously guide and rationalise a variety of experiments. In the first, we use mathematical models to understand the surprisingly complex kinetics of proline-catalysed intermolecular aldol reactions. These models were later employed by others to understand the varied role of electric fields upon these reactions. Then, we study an auto-tandem process which utilises a phosphine catalyst to link two mechanistically unrelated reactions, and explore how subtle changes in the structure of the phosphine catalyst produces dramatic changes in reactivity. Finally, we explore how subtle interactions and rapid conformational changes influence the stereochemical outcome of a intermolecular/transannular two-fold aza-Michael reaction in a natural product macrocycle.