Enzyme and copper combo builds amide bonds

Even though amide bonds are everywhere—they hold proteins together and are essential components in many drugs—forging this molecular motif in a reaction flask can be challenging. For example, making amides by coupling amines and carboxylic acids may require expensive reagents and generates organic solvent waste.

Looking for an environmentally friendly alternative, chemists at the University of Manchester led by Jason Micklefield found that they could make amides by combining enzyme and copper catalysts (Nat. Commun. 2022, DOI: 10.1038/s41467-022-28005-4). Their method uses nitrile hydratase enzymes to transform aryl and alkyl nitriles into a primary amide intermediate. A catalyst, made from inexpensive, abundant copper, then tacks an aryl group onto the amide’s nitrogen. They used the reaction to create more than 50 amides, including a sodium channel inhibitor (shown).

The transformation takes place in a single reaction vessel using an environmentally benign aqueous buffer and a 2-propanol solvent system. The chemists found the reaction works best if they don’t purify the nitrile hydratase enzymes and instead add Escherichia coli cells containing the enzymes to the reaction flask. They speculate that this is because the cell membrane prevents the enzymes from interacting with the copper catalyst. They also discovered that adding surfactant to the reaction mixture boosted yields, particularly with aliphatic nitriles. This is probably because the surfactant creates organic microcompartments where the primary amide intermediate, iodoarene coupling partner, and copper catalyst can interact.