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Functionalization of ethereal C-O Bonds Enabled by Metallaphotoredox Catalysis

Periodic Reporting for period 1 - ET-PHOTOX (Functionalization of ethereal C-O Bonds Enabled by Metallaphotoredox Catalysis)

Reporting period: 2018-07-01 to 2020-06-30

The direct utilization of native functional groups without the need for prefunctionalized holds considerable promise to revolutionize organic synthesis. While significant advances have been realized within the area of C-H activation, the functionalization of inert C-O bonds in aryl ethers is still at its infancy. Prompted by the natural abundance of aryl ethers in Lignin, the second most abundant biopolymer (30% of non-fossil organic carbon on earth), chemists have been challenged to devise, conceptuality and practicality aside, mild, general and widely applicable catalytic technologies for ethereal C-O functionalization. At present, however, these technologies remain confined to the use of rather activated extended p-systems, stoichiometric metal reagents and, in many instances, harsh conditions.

ET-PHOTOX aims at establishing a general platform that combines visible light photocatalysis with nickel catalysis for tackling the challenge of the functionalization of ubiquitous ethereal aryl C-OMe bonds via CT complexes. The successful accomplishment of this project will be of significant value for the synthetic community, as ethereal C–O bonds are commonly present in biomass-derived feedstocks such as Lignin, the second most abundant biopolymer on the earth. ET-PHOTOX has provided the fellow with new knowledge and skills to broaden his future career as an independent researcher at the European Community.

The main objective of ET-PHOTOX was to develop an efficient paradigm for forging C–C bonds via the functionalization of ethereal aryl C–OMe bonds by the merger of nickel catalysis and photocatalysis. The specific objectives were the following:
1. To synthesize a variety of π-acceptor catalysts that will form a CT complex with aryl ethers
2. To implement dual photochemical C–C bond-forming reactions of anisole derivatives with carbon-based nucleophiles
3. To develop a photocarboxylation technology of aryl ethers with CO2 en route to benzoic acids
Converting readily available feedstocks to value-added products, such as Wood-derived lignin-based C-O electrophiles and CO2 en route to carboxylic acids or other complex molecular architectures would be of prime interest. To tackle this down, we envisioned the utilization of metallaphotoredox catalysis to enable both C-O cleavage and the corresponding C–C bond-formation with CO2. Although we built up a series of photocatalysts and tried a wide variety of C-O electrophiles under a myriad of reaction conditions, all our attempts failed to provide the corresponding carboxylation event. Aimed at providing a metallaphotoredox solution to incorporate CO2 into organic molecules, we focused our attention on the utilization of organic halides, hoping that this will give us new knowledge to be implemented in the future for the utilization of C–O electrophiles as counterparts. Gratifyingly, it was possible to find reaction conditions for a metallaphotoredox strategy that allowed to obtain the targeted carboxylic acids in high regioselectivity and with an exquisite chemoselectivity profile. These findings provided us with a toolkit for introducing 13C-labels into organic molecules by using 13CO2, and for incorporating CO2 at either the initial reaction site or at remote positions within the alkyl chain via formal C-H functionalization. In addition, we have shown that such metallaphotoredox technologies allowed to convert alkane feedstocks into fatty acids of utmost synthetic relevance such as caprylic acid which is present in coconut oil and goat milk. Altogether, this has resulted in two publications in scientific journals (an additional one is currently being written and it is expected to be sent out for publication in the coming months) as well as presentations in three different international conferences, including appropriate dissemination in social media (twitter).
ET-PHOTOX is offering an innovative and challenging approach for functionalizing inert bonds by merging nickel catalysis and photoredox catalysis via electron donor-acceptor complexation events. Such synergistic catalysis will unlock unconceivable scenarios within the C-O bond-cleavage arena, including the use of non-extended p-systems, non-organometallic based nucleophiles or even carbon dioxide as coupling partner. Therefore, this project holds potential to change concepts in catalysis, allowing new tactics to be implemented in organic synthesis from ubiquitous feedstock materials, thus enhancing the ever-growing quality of the European research. The impact of ET-PHOTOX, together with the new scientific, technical training, competences and transferable skills received has positioned the candidate with a unique opportunity to start an independent career after the execution of the project. In fact, the fellow has accepted an Assistant Professor (Grade I) position at the Indian Institute of Science Education and Research (IISER), Thiruvananthapuram, India to start his independent research career along with teaching activity.
ET-PHOTOX Results