Periodic Reporting for period 4 - ELDORADO (Electrophilicity-Lifting Directed by Organochalcogen Redox-Auxiliaries and Diversiform Organocatalysis)
Reporting period: 2024-02-01 to 2024-07-31
Redox reactions, i.e. the alteration of the global oxidation state of a given molecule by any kind of chemical transformation, belong to the most important operations within chemical synthesis. Their paramount impact is, for instance, reflected in the large number of multi-ton-scale industrial processes through which certain commodity chemicals are produced by employment of selective reduction and/or oxidation reactions. Prominent examples include ammonia from dinitrogen (Haber-Bosch process), acetaldehyde from ethylene (Wacker process), and hydrocarbons from carbon monoxide and dihydrogen (Fischer-Tropsch process). An important feature characteristic to all of these processes is the use of oxidants/reductants that are low in molecular weight, cost, and waste production. In other words, these reagents are highly economic in virtually every respect. However, when looking at the development of new redox processes in the context of fundamental research, in particular concerning oxidation reactions, the aforesaid economic criteria are often not fulfilled. Considering the fact that the outcomes of such frontier scientific campaigns are intended to serve as potential starting points for the establishment of large-scale production lines of commodity and specialized chemicals (e.g. pharmaceuticals, functional materials, or crop protectants), the societal connotations of such activities and the pressing need for practical solutions become more apparent. Most frequently, oxidants are used that are similar or higher in molecular weight than the target compounds, produce polyatomic waste materials in (super)stoichiometric quantities (i.e. in direct proportion (or even disproportionate) to the number of substrate molecules), and are often characterized by very high cost/mass ratios. Against this background, the primary objective of this ERC grant was the development of oxidation reactions that primarily rely on the use of ambient air as a ubiquitous, gratuitous and environmentally benign oxidant and visible light as inexpensive source of energy. Results from this endeavor were meant to demonstrate that some of the most important oxidation reactions in organic chemistry, such as oxidative functionalizations of alkenes, allenes, and alkynes – including enantioselective reactions – are in fact compatible with the use of air and light to drive such processes.
Project ELDORADO was subdivided into three work packages focusing on 1,n-difunctionalizations (n ≥ 2) and asymmetric transformations of alkenes, including the design of chiral π-acidic catalysts, oxidative vinylations and allenylations of heteroatomic nucleophiles, and semipinacol reactions including the application in the synthesis of biologically active molecules. Key idea was to demonstrate that non-aromatic carbon–carbon π-bonds can be exploited as highly versatile building blocks in catalytic, photo-aerobic functionalization reactions. We intended to showcase the high expedience of this methodological concept through the selective formation of frequent and representative bonding motifs such as carbon–carbon, carbon–nitrogen, carbon–oxygen, and carbon–sulfur bonds. Prognostic outcomes of WPI revolve around the design of a new family of chiral selenium catalysts being employed, for instance, in asymmetric, photo-aerobic allylic functionalizations (ACS Catal. 2023, 13, 16240-16248; ACS Catal. 2024, 14, 9586-9593). Enantioselective photoredox catalytic reactions are still posing immense challenges to modern method-oriented research. Concretely, when looking at asymmetric photoredox catalysis in its current state, most protocols are predicated on the covalent or noncovalent binding of the photocatalysts or a co-catalysts to heteroatomic binding sites (e.g. possessing O- or N-atoms) within the substrates. In most cases, these coordinating groups are of no other use than directing the action of the catalysts, which can entail laborious operations for the removal of these directing groups. In addition, simple alkenes that are void of such heteroatomic binding sites were not sufficiently investigated in the context of such enantioselective reactions. During the ERC project, we were able to show that non-directed alkenes are indeed suitable substrates for asymmetric photo-aerobic functionalizations, as is exemplified, e.g. in enantioselective migratory Tsuji-Wacker oxidations and some total syntheses of biologically active compounds.
On the basis of mechanistic investigations, we were also able to develop oxidative allenylations (Eur. J. Org. Chem. 2021, 1720-1725), vinylations (ACS Catal. 2024, 14, 9586-9593), and photo-aerobic aminocyclizations (ACS Catal. 2023, 13, 16240-16248; ChemSusChem 2024, e202301518). The latter study included the first example of highly sought-after catalytic 5-endo-trig cyclizations to access 3-pyrroline derivatives, which are structurally related to important, pharmaceutically active agents. We could further elucidate the decisive role of H-bond interactions of selenium acceptors in photoredox catalytic semipinacol reactions (Angew. Chem. Int. Ed. 2022, e202208611, WPIII). The prevailing notion of such interactions prior to our study was that they are too feeble in nature to be of any significance in chemical reactions. This perception could be refuted by showing that they can be directive, e.g. in modulating the nucleofugality of selenium(III) species.
On the basis of mechanistic investigations, we were also able to develop oxidative allenylations (Eur. J. Org. Chem. 2021, 1720-1725), vinylations (ACS Catal. 2024, 14, 9586-9593), and photo-aerobic aminocyclizations (ACS Catal. 2023, 13, 16240-16248; ChemSusChem 2024, e202301518). The latter study included the first example of highly sought-after catalytic 5-endo-trig cyclizations to access 3-pyrroline derivatives, which are structurally related to important, pharmaceutically active agents. We could further elucidate the decisive role of H-bond interactions of selenium acceptors in photoredox catalytic semipinacol reactions (Angew. Chem. Int. Ed. 2022, e202208611, WPIII). The prevailing notion of such interactions prior to our study was that they are too feeble in nature to be of any significance in chemical reactions. This perception could be refuted by showing that they can be directive, e.g. in modulating the nucleofugality of selenium(III) species.
Results from the ELDORADO project have made two major contributions to the field of chemical synthesis that clearly go beyond the state of the art, and that are likely to have a resounding impact on many areas of chemistry and related disciplines. On the one hand, the compatibility of ambient air as a terminal oxidant and visible light as an expedient energy source with catalytic manifolds was shown for oxidative and, in part, asymmetric formations of carbon–element bonds from simple alkenes, allenes, and alkynes. On the other hand, we have developed an unprecedented mode of activation concerning the net heterolysis of symmetric and homopolar bonds (Nature 2024, 632, 550-556). According to valence bond theory, which is one of two fundamental theories to describe chemical behavior on the grounds of quantum mechanics, it is not possible to split symmetric bonds heterolytically (i.e. in such a way that a pair of opposingly charged ions is formed) from their electronic ground or lowest excited states in a unimolecular manner. In simple terms, it is neither possible to directly induce heterolysis of such bonds by heat nor by light. On the grounds of profound mechanistic investigations, we could finally show that such bond fissions are in fact feasible if the excitation occurs dissymmetrically (i.e. individual and unequal excitation of the two bond constituents). This discovery opens entirely new entryways to chemical space, as this mode of net heterolysis, which we have termed “internal poling”, is suspected to be universal in terms of bond constituents. This means, innumerate symmetric (and certain non-symmetric yet homopolar) bonding motifs might display a similar behavior, irrespective of the constituting elements. If true, internal poling is likely to have a paradigm-shifting impact on many areas within the chemical sciences such as target-oriented synthesis and catalysis with potential long-term implications for industrial settings (e.g. production of pharmaceuticals, materials as well as commodity and fine chemicals).