康 · 学术 | Reaction of the Day No. 1701

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

NithinPootheri, Abbas Haruna Umar, and Sunwoo Lee*

Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea

Recommended by Bingbing Chang_MC5

KEY WORDS: SN2/acyl substitution, condensation (反应类型), C(sp2)–N(成键类型), amines, carboxylic acids (原料), amides (产物), dichloromethane (其他)

ABSTRACT: Amide bonds are essential in biology and chemistry, yet their synthesis often requires expensive reagents or harsh conditions. Prof.Sunwoo Lee et al. report that dichloromethane (CH2Cl2), 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, CH2Cl2 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 SN2/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.

Synthesizing Amides from Carboxylic Acids and Amines

Substrate Scope of the CH2Cl2-Mediated Amide Coupling Reaction

Synthesis of Sulfinic Amide

Large-Scale Application

Proposed Mechanism

Summary and Comments

Prof.Sunwoo Lee et al. report a new amide bond formation method using dichloromethane (CH?Cl?) as both solvent and coupling reagent, enabling direct carboxylic acid–amine coupling under mild, catalyst-free conditions. This approach offers operational simplicity, broad substrate scope, high efficiency, and low waste, aligning with green chemistry principles and scaling readily to 100 mmol with straightforward workups. Repurposing CH?Cl?—a common solvent—as a reactive partner highlights its latent reactivity and may inspire similar explorations in other solvents. While green metrics (AE, RME, PMI, E-factor) compare favorably with acid chloride and HATU methods, these comparisons are context-dependent due to formaldehyde-derived byproducts and are less favorable than boric-acid catalysis. However, their method offers much milder conditions, better functional-group tolerance, and preserved stereochemistry. Limitations include ongoing industrial efforts to reduce CH?Cl? use, particularly in SPPS, which may affect adoption in some settings.