Synthesis of Amides from Amines and Esters Under Hydrothermal Conditions

Organic synthesis under hydrothermal conditions provides a green and environmentally friendly method that can minimize waste and avoid toxic byproducts. In this study, we investigate ester aminolysis in hydrothermal water at 250°C and P sat . Among the studied substrates, ethyl acetate with benzylamine yields the highest amide concentration, followed by ethyl acetate with cyclohexylamine and ethyl benzoate with benzylamine. Time‐series experiments reveal that a dominating pathway initiates with hydrolysis of ester to form carboxylic acid, followed by the condensation between the acid and amine. The reaction proceeds more efficiently under neutral and basic than acidic conditions, suggesting the protonation of amines at lower pH inhibits the amide formation. The effects of common metal salts, such as NaCl, FeCl 3 , FeCl 2 , CuCl 2 , and ZnCl 2 , on amide hydrothermal synthesis are also studied, in which all tested metal salts show an inhibition on the amide yield. In the phosphate‐buffered experiments, however, most of the metal salts show an increase in amide formation compared to the non‐buffered experiments, suggesting the inhibition from the metal salts is caused by the decrease of pH in dissolved metal solutions. These findings suggest another feasible synthetic pathway of amides under hydrothermal conditions, which is subject to the solution pH and complexation with metal ions.