CLEAVER [+]Enlarge Credit: Courtesy of Neil Garg

Nature typically outdoes chemists when it comes to efficiently carrying out reactions. But for a nickel—or make that a simple nickel catalyst—a team of UCLA chemists has matched wits with enzymes on cleaving the C–N bond in amides. The achievement overcomes a classic problem of the low reactivity of amides and opens up this key family of compounds to broader use as synthetic building blocks.

Amides are the functional units that link amino acids together in proteins and are present in a range of natural and synthetic molecules. Some enzymes such as proteases have evolved to bind and cleave amide bonds, a process that governs many regulatory functions in cells and is responsible for degrading proteins to amino acids. But the double-bond resonance running through the O–C–N unit of amides makes the molecules poor electrophiles. They are therefore unreactive toward alcohol nucleophiles in all but the harshest conditions and with excessive amounts of reagents.

UCLA’s Kendall N. Houk, Neil K. Garg, and their coworkers, who carried out the research, say it’s surprising that chemists have never found a simple way to catalytically cleave amide acyl C–N bonds in the lab. That’s despite the fact that chemists carry out many precious-metal-catalyzed reactions on molecules containing amide linkages. To take a more focused look at the problem, the team used a combination of computational and experimental studies, allowing them to develop a nickel catalyst system that makes short work of amide bonds.

In a series of test cases, the researchers used the new methodology to combine a variety of amides and alcohols to make esters and amines, including tricky situations in which the reactants already contained potentially competing functional groups and stereocenters (Nature 2015, DOI: 10.1038/nature14615).

Houk’s group led computational studies to uncover the catalytic mechanism and the structures of key intermediates of the reaction pathway. The reaction first proceeds through oxidative addition of the amide to the nickel catalyst. The subsequent ligand-exchange step involves coordination and deprotonation of the alcohol, followed by the shedding of the unneeded amine. In the final step, a reductive elimination process releases the ester.

Taken together, the computational findings enabled Garg’s group to select the best ligand for the job and the optimal reaction conditions. The researchers zeroed in on using nickel cyclooctadiene with a bulky saturated N-heterocyclic carbene ligand. The reactions ran efficiently with only a slight excess of the alcohol nucleophile in toluene solvent at 80 °C.

“For more than a century, amide bonds have been considered inert substrates and a dead end due to their inherent stability toward other reactions,” notes Chris H. Senanayake, vice president of chemical development at Boehringer Ingelheim Pharmaceuticals. “In fact, most methods rely on amide construction rather than using amides as synthetic building blocks. This new chemistry has opened the door to use amides for constructing important molecules, including active pharmaceutical ingredients, in a cost-effective manner.” Senanayake adds that using nickel is especially advantageous nowadays, as there is a dramatic shift taking place in industrial process chemistry from palladium to non-precious-metal catalysis.