The efficacy of sodium hexafluoroaluminate (cryolite) for direct amidation of carboxylic acids

Direct amidation of carboxylic acids is a fundamental transformation in organic synthesis and plays a pivotal role in the construction of amide bonds that are ubiquitous in pharmaceuticals, natural products, and materials. Despite its importance, many of the reported catalytic methods rely on expensive, moisture-sensitive, or inefficient reagents, thereby limiting their practical utility. In this study, we introduce sodium hexafluoroaluminate (cryolite, Na₃AlF₆) as a cost-effective, recyclable, and environmentally benign catalyst for direct amidation. Using 10 mol% cryolite, a broad range of aromatic and aliphatic carboxylic acids were converted into the corresponding amides in moderate to high yields (46-97%). Notably, the method requires no specialized additives or chromatographic purification, further enhancing its synthetic practicality. Beyond amidation, cryolite also proved to be highly effective in esterification reactions, affording esters in up to 90-92% yield within 24 hours when employed in either toluene or the reacting alcohol as solvent. The catalyst is inexpensive on a per-mole basis, widely available, and easy to handle, and it can be recycled without significant loss of activity, underscoring its potential for sustainable applications. These attributes position cryolite as a robust and attractive alternative to conventional transition-metal-based catalysts. To the best of our knowledge, this work represents the first demonstration of cryolite as a catalyst in organic synthesis, providing a practical, scalable, and green approach to both amide and ester bond formation.