Periodic Reporting for period 1 - HAT-TRICK (Flow Photoelectrocatalysis via Hydrogen-Atom Transfer: net-oxidative C-H to C-C bond conversion)
Okres sprawozdawczy: 2021-04-01 do 2023-03-31
Currently, direct functionalization of C-H bonds via photocatalyzed Hydrogen Atom Transfer is mainly limited to redox neutral transformations, where the electrons in the reagents are preserved in the product of interest. The few non-redox neutral approaches reported are oxidative processes that require aggressive oxidants or fragile dual-catalytic systems to remove the extra electrons. HAT-TRICK combines photocatalyzed Hydrogen Atom Transfer (p-HAT), electrochemistry (e-chem) and flow chemistry (flow-chem) to deliver a game-changing and easy-to-use technology to drive these net-oxidative transformations sustainably. On one side, p-HAT will be used as the substrate activation manifold because it consists in the direct activation of a C-H bond in the substrate by the excited state of a photocatalyst to deliver an organoradical to be exploited for synthetic purposes. This methodology shows unrivalled atom-efficiency, step-economy and sustainability and waives chemists from installing activating groups in the molecule. On the other side, e-chem stands as a unique way to remove extra electrons from the reaction mixture, since an anode works as a recyclable, bottomless sink of electrons. This strategy outperforms those based on chemical oxidants as it allows to have absolute control on the applied potential, which is vital in the presence of the fleeting reactive intermediates that will be generated via p-HAT. Finally, flow-chem constitutes a godsend for this project: in a flow electrochemical cell the interelectrode distance can be reduced to micrometers, ensuring that radical intermediates are generated next to the anode to encourage the needed oxidation. On top of that, flow-chem innate modularity enables the possibility of performing tandem reactions.
Besides the intrinsic synthetic benefits, the approach proposed herein has important implications for society as it proves that complex organic synthesis can be carried out without environmentally harmful, explosive and flammable chemicals. Instead, photons and electrons will be used to achieve the desired transformation; our Star, the Sun, is an inexhaustible source of photons, while electrons can be easily produced from renewable sources. On top of that, one should not forget that the chemistry carried out during the project will benefit from the flow technology: this technique allows for the smooth scaling of chemical reactions, with the same reactor being used for both discovery and process chemistry. This means that the same reactor can produce a few milligrams of desired product, as well as larger quantities (up to several kilograms of material!). This approach is not only technically superior, but also provides a more sustainable and scalable solution for organic synthesis, benefiting both the scientific community and society at large.
In summary, the implications of this approach are significant, as it paves the way for a more sustainable synthesis and demonstrates that complex organic synthesis can be achieved without compromising the environment.
Besides the intrinsic synthetic benefits, the approach proposed herein has important implications for society as it proves that complex organic synthesis can be carried out without environmentally harmful, explosive and flammable chemicals. Instead, photons and electrons will be used to achieve the desired transformation; our Star, the Sun, is an inexhaustible source of photons, while electrons can be easily produced from renewable sources. On top of that, one should not forget that the chemistry carried out during the project will benefit from the flow technology: this technique allows for the smooth scaling of chemical reactions, with the same reactor being used for both discovery and process chemistry. This means that the same reactor can produce a few milligrams of desired product, as well as larger quantities (up to several kilograms of material!). This approach is not only technically superior, but also provides a more sustainable and scalable solution for organic synthesis, benefiting both the scientific community and society at large.
In summary, the implications of this approach are significant, as it paves the way for a more sustainable synthesis and demonstrates that complex organic synthesis can be achieved without compromising the environment.
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.
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.
The approach presented in this study significantly expands the state of the art in that it constitutes the first example of flow photoelectrochemical cell, where both light and electrodes are needed at the same time to forge new bonds. There are also significant societal implications, as it demonstrates that complex organic synthesis can be carried out without noxious reagents, using photons and electrons, which are readily available from renewable sources. Thanks to the flow technology, this approach not only provides a technically superior solution for organic synthesis via HAT but also offers a sustainable and scalable option for the scientific community and society as a whole.