Bio-inspired soft organocatalysis inaqueous coacervate droplets – CHEMinDROPS

Advances in modern synthetic chemistry must comply with the need for a lower environmental impact, which has led in recent years to the development of a softer chemistry drawing inspiration from Nature. The formation of C-C bonds, which often requires the use of metals and organic solvents, is a central issue in organic chemistry. We recently reported the creation of C-C bonds in water via the Stetter reaction; a bio-inspired organocatalyzed reaction using N-heterocyclic carbenes (NHCs), structural thiamin cofactor mimics. Due to their low water solubility, organic substrates form water-separated organic droplets and this hydrophobic environment promotes the Stetter reaction despite the NHC sensitivity to hydrolysis. The aim of this proposal is to study the Stetter reaction in polymer-rich aqueous microdroplets called “coacervates” and demonstrate the potential of these mildly hydrophobic environments to favourably combined organic and enzymatic catalysis. Coacervates form spontaneously in water without the need of organic solvents and can be recycled. This project will thus explore the potential of coacervate microenvironments for soft chemistry. We will first design new azolium-derived organocatalysts to study the influence of catalyst structure on the reactivity, kinetics and selectivity of the Stetter model reaction in presence of coacervates or within coacervates. We will then explore the “on-water”-like molecular mechanism of the reaction, and rationalize the impact of coacervates’ internal polarity on the kinetics, yield and selectivity of the Stetter reaction on model substrates. This project will last explore the potential of chemo-biocatalyzed tandem reactions within coacervates. These results will open new perspectives for a softer and more sustainable bio-inspired chemistry. Moreover, the chemical synthesis of molecules in coacervates, which represent primitive models of the first living cells, could also shed light on mechanisms at the origin of life. .