Water microdroplets are the latest addition to the skeletal editing toolbox. Powered by nothing more than a fine spray of water, researchers in India achieved a complex ring rearrangement with important implications for drug design and synthesis – the conversion of aniline to pyridine. The reagent-free process provides crucial insight into the fundamental mechanism of microdroplets’ unique reactivity and potentially opens the door to the green synthesis of other valuable heterocycles in future.
In recent years, microdroplet chemistry has emerged as a powerful alternative to standard solvated reactions, although exactly what is going on remains contentious. The unusual environment of each droplet is thought to play host to a surprising range of reactivity not normally observed in bulk solution. While researchers aren’t yet completely sure of the underlying mechanism, current thinking suggests that a combination of ionisation and electric field effects generate a high concentration of hydroxyl radicals at the surface of each droplet, although even this idea has recently been challenged. This constant supply of potently reactive intermediates then initiates a cascade of high-speed chemical transformations, ultimately forming products which would be otherwise inaccessible using conventional chemistry.
But knowing what to look for is its own challenge and it was thanks to a fortuitous experimental observation that Shibdas Banerjee and his team at the Indian Institute of Science Education and Research, Tirupati discovered their microdroplet-mediated atom swapping reaction. ‘We often use aniline as a nucleophile to drive microdroplet reactions. But my group found that instead of aniline straightforwardly attacking the electrophile, we got an unusual peak – pyridine,’ he explains.
Initially, the group presumed this was merely a contaminant in the starting material, but after a rigorous round of repeats with different materials, equipment and even working at a different site, they were sure: the microdroplets had induced a skeletal rearrangement of aniline into pyridine.
The team therefore sought to elucidate the mechanism behind the atom swapping reaction. They propose that, following an initial attack by a hydroxy radical, the aniline substrate undergoes a ring expansion to form a seven-membered lactone intermediate. Elimination of carbon monoxide then contracts this ring back down to six atoms, and a final oxidation step restores aromaticity to give pyridine.
In a final proof-of-concept, the team tested the reaction on three pharmaceutically relevant molecules, generating niacin, nicotinamide and isoniazid from their corresponding aniline substrates.
‘I find this publication to be a striking example of what can be achieved by microdroplet chemistry,’ says Richard Zare, a physical and analytical chemist at Stanford University. ‘One carbon atom has been removed from the aromatic ring of aniline and replaced by a nitrogen atom, which I regard as an amazing skeletal rearrangement. And, this has been accomplished in a most eco-friendly manner using water, room temperature, atmospheric pressure and no external applied electric field.’
For Banerjee, the focus is now upon making this powerful transformation both practical and scalable. The team’s isolated yields were substantially lower than those measured directly during the reaction and developing a procedure to efficiently generate and collect larger quantities of product will be a crucial next step. More broadly though, Banerjee hopes to use the mechanistic insight from this reaction to build a more detailed understanding of the fundamental principles governing microdroplet chemistry, and ultimately, to translate this to other heterocyclic systems.
