Periodic Reporting for period 5 - 2O2ACTIVATION (Development of Direct Dehydrogenative Couplings mediated by Dioxygen)
Reporting period: 2022-02-01 to 2022-08-31
The aim of 2O2ACTIVATION was to develop novel technologies utilizing O2 as sole terminal oxidant in order to allow useful, extremely sustainable, thermodynamically challenging, dehydrogenative C-N, C-C, C-O, and N-N bond forming coupling reactions. However, the moderate reactivity of O2 towards many catalysts constitutes a major challenge. 2O2ACTIVATION pioneered the design of new catalysts based on the ultra-simple propene motive, as well as on organo-tellurium scaffolds, capable of direct activation of O2 for C-H functionalization based cross-couplings. The project was divided into 3 major lines: O2 activation using propene and its analogues (propenoids), 1) without metal or halide, 2) with hypervalent halide catalysis, 3) with metal catalyzed C-H activation. In addition, Tellurium catalyzed methods, as well as electro-oxidative and photochemical methods were developed in the later stages of the project for the development of highly innovative and sustainable cross dehydrogenative coupling methods. These have delivered often unique scaffolds of moreover high value for the chemical industry in terms of bioactive structures as well as organic materials.
The philosophy of 2O2ACTIVATION was to focus C-H functionalization method development on the oxidative event. Consequently, 2O2ACTIVATION breakthroughs dramatically shortcut synthetic routes through the use of inactivated, unprotected, and readily available building blocks; and thus are or could become easily scalable. This will continue leading to a strong decrease in the costs related to the production of many essential chemicals, while preserving the environment (water as terminal by-product, or hydrogen). The resulting novels coupling methods will thus have a lasting impact on the chemical industry.
The original idea was to activate O2, one of the most sustainable oxidants possible as it delivers only water as terminal reduction byproduct, with alternative technologies compared to the state of the art. In particular, many synthetic methods utilizing O2, for example some of the valuable and frontier cross dehydrogenative coupling reactions, relied on high loadings of Cu salts, when possible at all. Indeed, while O2 is a sustainable oxidant, its activation is challenging because of its inherent chemical stability, and many oxidative synthetic methods were thus developed with far less sustainable oxidants such as stoichiometric Ag salts and related reagents. The main O2 alternative activation mode we started with was based on cumene. Cumene is a cheap commodity and hydrocarbon long known for its unique ability to activate O2 at moderate temperatures due to its structure, in particular its ability to stabilize its own oxidation intermediates. The plan was thus to develop the potential of cumene and its derivatives, with the aim of unlocking novel O2-mediated cross dehydrogenative reactivity. The first important result of this research, in the early phase of the project, was that plain unsubstituted cumene outperforms all of its derivatives that we tested (New J. Chem. 2017,41, 6981). While this may appear academically disappointing at first glance, it is certainly a key advantage for real life applications because cumene is by far the cheapest of its analogues. In many of our subsequent project publications, which were typically focused on the development of novel cross dehydrogenative coupling reactions, cumene turned out to be a key additive or solvent due to its unique radical properties and ability to activate oxidants such as O2 and similar (Angew. Chem. Int. Ed. 2018, 57, 11807; Chem. Eur. J. 2018, 24, 11936; Org. Lett. 2018, 20, 2884; Chem. Commun. 2019, 55, 13749). This part of the project was therefore a big success, as proof of principle of the concept was repeatedly demonstrated on multiple unrelated valuable and novel oxidative coupling reactions. The project then moved into a second phase, wherein we started to explore non-cumene, highly original organic and organometallic activators of O2. While these were not per say indicated as priority structures in the originally drawn project due to the fact that these correspond to serendipitous discoveries made en route, these structures do fall into the spirit of the unusual and innovative activation of O2. We were notably very successful with Te(II) ethers as catalytic O2 and related oxidant activators in cross dehydrogenative couplings, such as in Angew. Chem. Int. Ed. 2021, 60, 6451 and JACS Au 2022, 2, 1318. Several PhD students are now continuing on this very promising technology beyond this ERC project. A third phase should also be mentioned within this ERC project, in parallel to the second phase, wherein other sustainable alternatives to O2 activation were explored for cross dehydrogenative couplings, in particular electro-oxidative methods, and photochemical methods, respectively. These led to amazing results, which are very promising for the future, for example in Angew. Chem. Int. Ed. 2022, 61, e202201142, or ChemPhotoChem 2022, 6, e202200130. These research topics are also continuing beyond this ERC project.
For the time beyond this ERC project, we will continue expanding our new innovative oxidizing strategies, and thereby provide simple methods for the synthesis of valuable and complicated organic molecules for a moderate cost and moderate impact on the environment.