Amide bonds are chemical linkages that are essential in biology, medicine and materials chemistry. Peptide bonds, a class of amide bonds, link amino acids together to form proteins. They are also important for medicines and making polymers. Efficient synthesis of amide bonds remains a major focus in green chemistry.
Most practical approaches for amide synthesis involve activation of carboxylic acids through suitable coupling reagents before they can react with amines to form amides. However, many commonly used reagents can be corrosive or toxic, can release hazardous byproducts, and generate substantial waste, creating challenges for large-scale synthesis. An ideal coupling reagent should be cost-effective, stable and produce only benign byproducts that can be easily eliminated.
In a breakthrough, a research team led by Professor Sunwoo Lee from the Department of Chemistry at Chonnam National University in South Korea, utilized dichloromethane as an effective coupling reagent for direct amide bond synthesis using carboxylic acids and amines. “ Dichloromethane is a commonly used solvent in many chemical processes, ” explains Prof. Lee. “ In this study, we present the successful application of this common solvent to facilitate efficient and scalable amide bond formation. ” The study was published online on July 6, 2026, and subsequently appeared in Volume 148, Issue 27 of the Journal of the American Chemical Society on July 15, 2026.
The researchers found that under basic conditions, carboxylates can attack dichloromethane through an S N 2 reaction to generate reactive chloromethyl ester intermediates. These intermediates can then undergo acyl substitution with amines to produce amides. Using benzoic acid and benzylamine as model substrates, the researchers optimized the reaction conditions.
Initial results showed that using sodium carbonate as the base, dichloromethane as the coupling reagent, and dimethyl sulfoxide as the solvent enabled the desired amide formation in good yield. Optimal efficiency and reproducibility required a combination of 80 °C, a 12-hour reaction time, and an excess of amine.
Further experiments demonstrated a broad substrate scope across a range of carboxylic acids and amines. Notably, the researchers were able to synthesize two key pharmaceutical amides using this approach, namely an antiarrhythmic agent called procainamide with 92% yield and an antidepressant called moclobemide with 76% yield. The team also achieved direct single-step amide synthesis using carboxylic acids and ammonium bicarbonate using this approach.
The researchers further demonstrated the scalability of the method in a 100 millimole level reaction of 4-chlorobenzoic acid and 2-morpholinoethanamine, producing more than 20 grams of moclobemide with greater than 99% purity.
Mechanistic studies revealed that the reaction primarily occurs when the intermediate carboxylate attacks dichloromethane, which produces an activated ester via S N 2 substitution. A competing pathway generates a methylene bis(carboxylate) intermediate, which can also undergo aminolysis and participate in further acyl transfer.
“By avoiding many conventional stoichiometric coupling reagents and reducing coupling-reagent-derived waste, our approach demonstrates that dichloromethane can provide a practical and scalable alternative for amide synthesis ,” concludes Prof. Lee.
Reference
Title of original paper: Reappraising Dichloromethane: Uncovering a Hidden Coupling Reagent for Activating Carboxylic Acids in Direct Amide Synthesis
Journal: Journal of the American Chemical Society
DOI: https://doi.org/10.1021/jacs.6c05971
About the institute
Chonnam National University (CNU), established in 1952, is one of South Korea's leading national universities located in Gwangju. Building on its founding commitment to cultivating leaders of integrity and professional excellence, CNU contributes to national development and global progress through the pursuit of knowledge, ethical responsibility, and inclusive excellence. Guided by the core motto “Truth, Creativity, and Service,” the university advances research, education, and public engagement that strengthen resilient societies, foster sustainable development, and promote the well-being of future generations. As a trusted partner in the global community, CNU remains dedicated to addressing complex challenges in an increasingly interconnected world.
Website: https://global.jnu.ac.kr/jnumain_en.aspx
About Professor Sunwoo Lee
Dr. Sunwoo Lee is currently a Professor at the Department of Chemistry at Chonnam National University. He received his master’s and Ph.D. degrees from the Department of Chemistry at Pohang University of Science and Technology in 1996 and 1999, respectively. His research focuses primarily on synthetic organic chemistry. His broader research areas include asymmetric catalysis, organometallic synthesis, and heterocyclic chemistry among others. He has published over 230 publications that have received over 7,500 citations to date.
Journal of the American Chemical Society
Experimental study
Not applicable
Reappraising Dichloromethane: Uncovering a Hidden Coupling Reagent for Activating Carboxylic Acids in Direct Amide Synthesis
15-Jul-2026
The authors declare no competing financial interest.