Reappraising Dichloromethane: Uncovering a Hidden Coupling Reagent for Activating Carboxylic Acids in Direct Amide Synthesis

Amide bonds are essential in biology and chemistry, yet their synthesis often requires expensive reagents or harsh conditions. We report that dichloromethane (CH 2 Cl 2 ), a commonly used solvent, can function as an effective coupling reagent for the direct amide bond formation between carboxylic acids and amines. Under mild basic and thermal conditions, CH 2 Cl 2 reacts in situ with acids to generate reactive intermediates, affording high yields (up to 92%) across a broad substrate scope while producing only benign byproducts. The reaction is scalable (over 20 g at a 100 mmol scale) and largely preserves the stereochemical integrity of chiral starting materials. Mechanistic studies support an S N 2/acyl substitution pathway via chloromethyl ester intermediates. This work introduces a practical and environmentally friendly strategy for amide synthesis by repurposing a ubiquitous solvent with an underappreciated reactivity.