Optimisation and Scaling of an Efficient, Catalyst-free Condensation of Acid Chlorides and Alcohols using Continuous Flow

Esters are a synthetically important class of compound that find widespread application in the fine chemical industry as flavours and fragrances and afford protection of the carboxylic acid moiety within the pharmaceutical industry.
Whilst esterification reactions have been widely reported under continuous flow conditions using activated esters, acid, base or biocatalysts, or the use of super-heated alcohols, there have been no reports of the use of acid chlorides. Typically performed in the presence of a catalyst, the reaction of an acid chloride with an alcohol is a well-known strategy for the production of hydroxyl functionalities, catalysts include small organic bases such as pyridine, triethylamine, 4-dimethylaminopyridine, 1,4-diazabicyclo2.2.2octane and inorganic catalysts such as LiClO4, BiCl3 or TiO2. With a view to developing more sustainable, industrially relevant production methods, Steven and co-workers investigated the ability to perform the absence of a reaction solvent. In addition to reducing rocessing costs, removal of the catalyst also has the added advantage that product isolation is simplifield – with only alcohol removal required after reaction.