To tackle the abovementioned challenge, I chose to take a gradual approach, adding layers of complexity one at a time to solve issues more efficiently and appreciate the added value that the 3 technologies (photochemistry, electrochemistry and flow chemistry) could bring to the table.
My investigation started by studying the C(sp3)-H to C(sp3)-N bond formation. This transformation can be easily achieved via photocatalyzed HAT, thus making it a useful starting point for HAT-TRICK; however, the previously established approaches mainly proceed via radical hydroalkylation of suitable Michael acceptor, e.g. diisopropyl azodicarboxylate (DIAD). Despite its synthetic utility, this approach remains fairly specific, atom-inefficient and limited to the strongly electrophilic N=N double bond present in DIAD. To expand the scope of C(sp3)−N bond forming reactions using HAT photocatalysis, I proposed to exploit an oxidative radical–polar crossover (RPC) process. Here, the intermediate generated via HAT can be subsequently oxidized with chemical oxidants to afford carbocations, paving the way to unprecedented C(sp3)−N bond forming reactions. Notably, as shown in the publication, the methodology was found to be amenable to the late-stage functionalization of complex organic molecules. Once the methodology was deemed to be reliable in batch, I focused my efforts on scaling it up using continuous-flow technology. The chemistry proved to be robust and of general applicability, including biorelevant scaffolds. These results were published in 2021 on Angewandte Chemie International Edition in collaboration with Eli Lilly and disseminated at the Merck Young Chemists' Symposium 2021 in Rimini (IT) and the NWO Chains 2021 (online symposium).
Afterwards, my attention shifted towards the substitution of the chemical oxidant utilized in the initial project with electrodes, functioning as both environmentally friendly and reusable oxidants. Firstly, I conducted a screening of conditions in a batch process, mainly focusing on optimizing the photocatalyst's nature, concentration, and electrode materials. Subsequently, in collaboration with a PhD from the Noël Research Group, I devised a continuous flow photoelectrochemical reactor for this reaction. We decided on a sandwich-type design, which was previously published by the NRG, where one of the electrodes allows for light to pass through and interact with the reacting mixture. The mixture flows through the cell and undergoes photoelectrolysis. The parameters optimized range from electrode materials to inter-electrode distance and residence time. The scope of the transformation is good even though some optimization is still required for future exploitation. The matching of electrolysis and photolysis rates remains an area for improvement, and the fine-tuning of these parameters must be evaluated on a case-by-case basis. However, the development of the flow photoelectrochemical cell is a significant step forward and serves as an excellent starting point for future endeavors. This cell stands as the first flow photoelectrochemical cell, the project is currently in its final phase and will soon be submitted for publication in a highly impactful journal.
