Bolt, Robert RA; (2024) Exploring mechanochemistry for sustainable synthesis and pharmaceutical application. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis explores the application of mechanochemistry to organic synthesis and catalysis. A series of studies are presented, detailing the development of novel procedures and equipment specifically designed to enhance mechanochemical reactions. Initial investigations began with the optimisation of the nickel catalysed C-C Suzuki-Miyaura cross-coupling of pseudo halides under mechanochemical conditions. Initially finding the mechanochemical parameters developed a limited scope. Further investigations revealed thermal energy as a crucial factor for enhancing the reaction. A controllable heating device was designed and constructed enabling more translatable reaction conditions leading to the development of a broader substrates scope. These conditions were then translated from small batch mixer mill to large continuous twin-screw extrusion. Building upon the groups direct amidation of esters, this work addresses the limitation of scalability imposed by the ball mill. Twin-screw extrusion tackles this limitation but requires a re-evaluation of reaction protocol. Temperature control was incorporated to assess its impact on the small-scale reaction before scaling up to the extrusion process to ensure compatibility with the controlled thermal environment of twin-screw extrusion. The impact of temperature on the reaction was observed to result in increased reactivity at reduced base loadings. A broad scope was developed assessing morphology, followed by 50-fold scale-up reactions using twin-screw extrusion for each morphology environment. The reaction was scaled up and synthesised continuously for 7 hours to showcase the techniques versatility and capabilities. Finally, for the palladium catalysed C-S cross-coupling our group had previously observed that the reaction only proceeds when both reagents are in a liquid phase. Using precise temperature control, acoustic monitoring and the analytical analysis of the reaction mixture and reagents it was observed that there were three reaction influences: (1) transition to a melt phase, (2) a polymorphic transition, or (3) increased reaction kinetics.

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