Remote functionalization of molecules with supramolecular catalysis – REMOTCAT

For overcoming the limitation of pyridine over-coordination to the metal catalyst, we molecularly engineered an iridium catalyst comprising a zinc-porphyrin platform that serves for molecular recognition to pyridines via Zn…N weak coordination. This interaction is labile enough to provide turnover during the catalysis at high temperatures in which the iridium site is catalytically productive. As such, the precise distance between the active site and the molecular recognition site made possible the functionalization to occur only in the C-H bond places at four chemical bond distance from the molecular recognition site. The reactions occurred at high temperature while keeping an excellent selectivity for pyridines and for other nitrogen-containing heterocycles such as imidazoles. In depth, mechanistic studies by means of experimental and theoretical studies led to identification of enzyme-like features but in a purely artificial system as well as fundamental changes in the elementary steps of the catalytic cycle thanks to the remote weak interaction taking place.

Supramolecular iridium catalysts have been developed enabling both fast and selective C-H bond borylations of pyridines and imidazoles via remote interactions. A wide spectrum of functional groups in the pyridine are tolerated, which is relevant for late-stage functionalization purposes. Mechanistic studies by means of experimental and theoretical analysis identified inhibiting processes that led to the design of a superior generation of supramolecular iridium catalysts that enabled the reactions to be done in a couple of hours using low catalyst loading at industrially-relevant temperatures.

The REMOTCAT has been a very successful project because it has demonstrated the benefits to exploit remote dynamic coordination chemistry (Zn…N interactions) in the rational design of supramolecular iridium catalysts to tackle a so far elusive reactivity for very demanding type of substrates, namely pyridines. With this approach, this strategy can be applicable to other type of challenging substrates and also applied to other type of functionalizations relevant for obtaining high-added value chemicals in a step- and atom-efficient manner.

Angew. Chem. Int. Ed. 2021, 60, 18006-18013. It shows that remote Zn…N interactions are relevant to achieve meta-selective C-H borylation of pyridines with enzyme-like behaviours.

Chem. Eur. J. 2022, 28, e202201970. This contribution describes a purely mechanistic study by means of state-of-the art computations to unravel unique features of our system.

ACS Catal. 2023, 13, 7715-7729. Here we describe the rational development of a new generation that outperforms the previous catalyst by circumventing unproductive pathways.

Chem. Soc. Rev. 2021, 50, 3565-3584. This work describes the state-of-the-art of the field of supramolecular catalysis using unconventional remote, weak interactions.

Pyridines are key molecules in biology and materials science. Unfortunately, they are highly difficult to functionalize by means of
transition metal (TM) catalysts as they displace the ligands of the metal active center via coordination of the nitrogen lone pair. This
inhibits the catalysis or, at best, leads to very low reactivity. To overcome this issue, a unique set of supramolecular catalysts will be
developed in this proposal. They are inspired by one of the most powerful action modes of enzymes: the highly selective molecular
recognition via weak interactions occurring during the catalysis. The supramolecular catalysts incorporate (1) a substrate recognition
site and (2) a catalytically active site with TM units. The substrate recognition site will fix the nitrogen lone pair of the pyridine
substrate via weak interactions, leaving the catalytically active TM available for turnover. This approach will be applied to the
directing-group-free C-H bond functionalization of pyridines.