Chonnam chemists put dichloromethane to work as an amide coupling reagent

"Dichloromethane is a commonly used solvent in many chemical processes," Lee said ^[11]. In the Chonnam work, published in the Journal of the American Chemical Society ^[2], it is a reactant. Under basic conditions a carboxylate attacks it by SN2 substitution to give a chloromethyl ester. An amine then turns that activated intermediate into the amide by acyl substitution ^[4].

Coupling reagents exist to activate the acid. According to the phys.org account, many of them are corrosive or toxic, release hazardous byproducts and generate substantial waste ^[3]. The same account describes the ideal reagent as cost-effective and stable, with only benign byproducts that are easy to remove ^[15]. Amide bonds link amino acids into proteins and are common in medicines and polymers, so the reaction is used widely ^[14].

The team worked out its conditions on a simple model pair, benzoic acid and benzylamine. Sodium carbonate was the base and dimethyl sulfoxide the solvent, so the usual solvent became a reagent and another liquid took its place ^[5]. The best and most reproducible yields came at 80 degrees Celsius over 12 hours, with the amine in excess ^[6]. I'd expect that excess to be the first condition a process chemist questions. When the amine is the more expensive half of the target, the surplus is material paid for that never ends up in the product.

According to the report, the method worked across a broad range of acids and amines ^[13]. It made the antiarrhythmic procainamide in 92% yield and the antidepressant moclobemide in 76% ^[7], a 16-point gap between two drug targets ^[16]. It also made amides in a single step from carboxylic acids and ammonium bicarbonate ^[10].

The scale-up used 100 millimoles of 4-chlorobenzoic acid with 2-morpholinoethanamine. It gave more than 20 grams of moclobemide at greater than 99% purity, and that run is the paper's evidence that the method scales ^[8]. Twenty grams is a bench quantity.

The mechanistic studies found that most of the reaction goes through the SN2 activation. A competing route forms a methylene bis(carboxylate) intermediate, and that intermediate can also react with the amine and pass its acyl group on ^[9]. So the side route also ends in amide.

"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," Lee said ^[12]. The waste he describes is the waste from the coupling reagent. The report does not say how many acid and amine pairs were tried or how many failed. Nor does it weigh the dichloromethane used up in each reaction against the reagents it would replace ^[4].