Carousel 12 used in one-pot ester and thioester formation mediated by pentafluoropyridine (PFP)

Acyl fluorides are useful intermediates in acyl nucleophilic substitution reactions. Reaction of an acyl fluoride with an alcohol or thiol can form an ester or thioester, respectively, both functional groups have widespread uses, with thioesters being used in medicinal chemistry. Acyl fluorides are difficult to isolate, due to their susceptibility to degradation, so methods to generate acyl fluorides in situ are popular. Most methods of in situ acyl fluoride generation require the use of harsh reagents, such as cyanuric fluoride or SeF₄, that are toxic and difficult to handle.

Researchers at Durham University have developed a one-pot acyl fluoride formation/acyl nucleophilic substitution combination using the bench-stable, commercially available and easy to handle, pentafluoropyridine. This new method allowed them to synthesise a range of esters, thioesters, diesters and amide esters in good yield, from the parent carboxylic acid.

¹⁹F NMR was used to monitor the first step of the reaction, and allowed the researchers to optimise the reaction protocol, and

 consequently improve yields, by allowing more time for the acyl fluoride to form. The reaction conditions were tolerated by a range of carboxylic acids, alcohols and thiols, with different aliphatic, aromatic, electron-withdrawing and electron-donating groups being tested.

All reactions were performed in a Radleys Carousel 12 Plus Reaction Station, which allowed them to synthesise a library of compounds more efficiently, as 12 reactions could be run at a time, on the same hotplate.