# Synthesis of Amides from Amines and Esters Under Hydrothermal Conditions

## TL;DR

This study explores a green method to synthesize amides from amines and esters using high-temperature water, finding that pH and metal salts significantly affect the reaction.

## Contribution

The paper identifies a new hydrothermal pathway for amide synthesis influenced by pH and metal ion interactions.

## Key findings

- Ester hydrolysis followed by acid-amine condensation is the dominant amide formation pathway under hydrothermal conditions.
- Amide yield is higher under neutral/basic pH and is inhibited by acidic conditions due to amine protonation.
- Metal salts inhibit amide formation in non-buffered solutions but enhance it in phosphate-buffered experiments due to pH changes.

## Abstract

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, FeCl3, FeCl2, CuCl2, and ZnCl2, 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.

In this study, we explore the amide synthesis under hydrothermal conditions, using amines and esters as the starting materials. Proposed major pathway starts with ester hydrolysis, followed by condensation between carboxylic acids and amines. The amide yield is dependent on the substrate structure, solution pH, and the presence of dissolved metal salts.© 2026 WILEY‐VCH GmbH