Amines are essential biological compounds whose synthesis is a major activity of the pharmaceutical industry. The efforts undertaken have led to the development of numerous methods, each adapted to a class of products and requiring multiple stages. Recent studies have identified nitrene transfer reactions as the most promising method for achieving this goal. However, so far, they use catalysts based on metals such as ruthenium, rhodium and palladium which are rare, expensive and toxic. In this context, the development of nitrene transfer catalysts based on iron and inspired by oxygenases appears to be a very attractive approach. As a result, the development of a direct, efficient and green method for synthesizing amines is both an issue and a challenge. Two new families of nitrene transfer catalysts have been developed based on oxygenase structures with one or two iron ions at their active sites.

Researchers from the Physicochemistry of Metals in Biologyteam [Chemistry and Biology of Metals laboratory] have shown ^[1] that two-iron catalysts have a very high activity and the very peculiar behavior of being able to adapt their redox activity to the difficulty of substrate transformation. Thus, while the amination of an easily transformable substrate involves a Fe^IIIFe^IV active species, that of a more recalcitrant substrate requires an active Fe^IIIFe^V species (Figure 1).


Figure 1. Auto-activation of the catalyst.

These two species have been highlightedd by chemical trapping reactions, detected by desorption electrospray ionization mass spectrometry. Their electronic structures have been characterized by researchers at Inac / SyMMES / CAMPE using DFT calculations which have shown that the high reactivity of these species is due in particular to their very great electronic affinity which quantifies the capacity of a species to remove an electron off the substrate.
To take advantage of this property, the researchers tested these two-iron catalysts and compared their activity to that of a new family of catalysts ^[2] with the advantage of being easily accessible and scalable.


Figure 2. The electronic affinity of the active species governs the transfer of nitrene to the substrate. These two-ion iron catalysts have been tested in the olefin aziridination reaction which provides access to compounds of high pharmaceutical interest.
TS = transition state.

The excellent yields obtained appear to a direct function of the electronic affinity of the active species (Figure 2). Moreover, the experimental and theoretical study of the mechanism of the reaction has shown that electronic affinity plays a major role in the stabilization of the transition state of the reaction, and ultimately governs its efficiency.

This mechanistic approach, which combines experimental studies and DFT calculations, allows to finely analyze the nitrene transfer reactions so that new catalysts can now be rationally designed. In addition, very recent studies have shown that this approach also applies to more complex reactions associating a nitrene to another component, which opens the way to the synthesis of polyfunctional complex molecules.