Iron Catalyzed Hydrogen Isotope Labelling

Isotopic labelling is a widely used technique in chemistry and biochemistry. By the selective incorporation of defined isotopes into a molecule, reaction mechanisms or metabolic pathways can be investigated and are thus frequently used for drug development and registration processes in the pharmaceutical industry. A common method is the exchange of hydrogen by its heavier isotopes deuterium or tritium. Since pharmaceutical substrates are often expensive compounds, labelling procedures are required that avoid multi-step reactions via several synthetic intermediates. Therefore, homogeneous transition metal catalysts are mainly used for hydrogen isotope exchange reactions as they provide a high degree of selectivity and operate under mild reaction conditions. In addition, hydrogen isotope labelling may also be used for the development of new catalysts. For example, catalytic hydrogen/deuterium provides a simple but powerful method to evaluate the potential of a catalyst for the activation and functionalization of CH bonds. Consequently, there is significant interest in mild and selective catalytic isotope exchange reactions from both fundamental and applied viewpoints. Polyhydride complexes, in which several hydrogen atoms are bound to a metal center, are excellently suited for this purpose. They exhibit a very dynamic behavior due to a fast exchange between the hydrogen atoms bound to the metal. Most polyhydride complexes are based on precious metals such as ruthenium, rhodium or iridium. The objective of this project, however, is the development of iron-based polyhydride complexes as new catalysts for hydrogen isotope labelling. On the one hand, iron appears as a cheap and environmental friendly alternative to expensive and often toxic precious metals commonly used in catalysis. On the other hand, the distinct properties of base metals might lead to the discovery of new selectivities and reactivities that are currently not accessible by traditional catalytic systems. A basic problem concerning the synthesis of iron-polyhydride complexes is the deficiency of convenient precursor compounds. This project aims to develop a novel family of such catalyst precursors that are readily accessible, tuneable and permit an operationally simple use of these compounds as catalysts in the selective isotope labelling reactions. Finally, the intended studies will help to explore the potential of these novel iron-based catalysts to promote C-H activation reactions paving the way for future applications in catalysis.

The concept of metal-ligand cooperativity has greatly enriched the chemistry and catalytic applications of transition metal complexes. Cooperative strategies that take advantage of the Lewis acidic nature of a transition metal center in combination with a Lewis basic ligand have become established features, frequently employed in the design of novel catalytic systems. Equally attractive but less common are transition metal complexes that bear a Lewis acidic functionality in the ligand. These new design principles offer an opportunity to overturn existing paradigms in transition metal chemistry. In this project, I successfully developed well-defined molecular Iron/Aluminium complexes and explored their reactivity brought about by cooperative effects between the two metals (bimetallic cooperativity). These complexes are easily accessible via a two-step synthesis and are best described as coordination of an Al(I) metalloligand to an Fe(II) dihydride fragment. Extensive analysis of the bonding situation suggests a highly polarised covalent bond between the two metals resulting in a highly negative charged Fe- and positive charged Al-centre. These compounds possess unusually distorted structures. This distortion was shown to result in the destabilisation of the electronic structure and is key to the reactivity of the bimetallic Fe/Al system. The reactivity has been demonstrated through intra- and intermolecular C-H bond activations. Through experimental and computational studies, I found that these reactions proceed via mechanism previously unknown for monometallic systems. I could show that the Fe/Al complexes can selectively break C-H bonds in pyridine substrates in a predictive manner (J. Am. Chem. Soc., 2022, 8770; Chem. Commun., 2022, 10849). Moreover, we discovered that these systems can also stabilise previously inaccessible species. This has been demonstrated though a double C-H bond activation of acetonitrile (Angew. Chem. Int. Ed., 2023, e202219212). The resulting product of this reaction features the first reported structure of an acetonitrile dianion stabilised through bonding between two Fe/Al fragments. Finally, I could also show that these Fe/Al systems can chemo- and stereo-selectively activate the C-H bond in the vinylic position of styrene substrates resulting in a rare (E)--metalation of the alkenes. (J. Am. Chem. Soc., 2024, 4252). In contrast to single-site systems, alkene binding appears to initiate C-H activation and is essential for the reaction to take place. Experimental and computational insights suggest an unusual reaction pathway in which a (2 + 2) cycloaddition intermediate is directly converted into the hydrido vinyl product via an intramolecular sp2 C-H bond activation across the two metals. The key C-H cleavage step proceeds through a highly asynchronous transition state near the boundary between a concerted and a stepwise mechanism influenced by the resonance stabilization ability of the aryl substituent. The metalated alkenes can be further functionalized, which has been demonstrated by the (E)-selective phosphination of the employed styrenes.