Smallman, Harry R.; (2024) Enabling Technologies for Organic Synthesis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Within this thesis is described a series of studies into performing organic synthesis using different enabling technologies to help improve the safety, sustainability, and scalability of chemical reactions. Initially, A flow chemistry process for the generation and use of acylketene precursors through extrusion of nitrogen gas is reported. Key to the development of a suitable continuous protocol is the balance of reaction concentration against pressure in the flow reactor. The resulting process enables access to intercepted acylketene scaffolds using volatile amine nucleophiles and has been demonstrated on the gram scale. Thermal gravimetric analysis was used to guide the temperature set point of the reactor coils for a variety of acylketene precursors. The simultaneous generation and reaction of two reactive intermediates (both derived from nitrogen extrusion) is demonstrated. The nucleophilic aromatic substitution reaction (SNAr) was then explored via ball milling. Using mechanochemistry techniques a range of different nucleophiles were proven successful for this solvent-free process, giving access to a wide range of chemical structures. The addition of heat, through an internally developed jar heater gave access to higher yields across all nucleophile classes. The solvent minimised synthesis of 4CzIPN and related organic fluorophores was also demonstrated using ball milling. This process gave rapid access to a range of different photocatalysts which previously required long reaction times. Finally, the translation from ball milling to continuous twin screw extrusion and the challenges associated were examined and explored. Using the direct amidation of esters as an example reaction helped address all the issues encountered and the learnings were applied to a large-scale optimisation of a mechanochemical SNAr reaction.

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