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Synthesis

Mimicking Enzyme Oxidation

Dimanganese catalyst targets specific C-H bonds using molecular recognition

by Bethany Halford
July 3, 2006 | A version of this story appeared in Volume 84, Issue 27

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Credit: Courtesy of Robert H. Crabtree
Hydrogen bonding between two carboxylic acid moieties holds ibuprofen adjacent to the catalyst's dimanganese core (purple) so that only one of the drug's benzylic C-H bonds is oxidized.
Credit: Courtesy of Robert H. Crabtree
Hydrogen bonding between two carboxylic acid moieties holds ibuprofen adjacent to the catalyst's dimanganese core (purple) so that only one of the drug's benzylic C-H bonds is oxidized.

If there's one area of chemistry where nature continues to humble even the most masterful synthetic chemists, it is the selective functionalization of C-H bonds. While chemists struggle to transform one hydrocarbon bond in a molecule without altering its similarly reactive neighbors, nature simply orients molecules over an enzyme's catalytic site in a manner that guarantees that the reaction will occur only at one particular spot.

Scientists have tried to construct systems that emulate enzymes, but because these systems have smaller, simpler scaffolds, they tend to be less selective than their biological counterparts and generally exhibit poor catalytic turnover rates. Now, Yale University chemists Robert H. Crabtree, Gary W. Brudvig, Siddhartha Das, and Christopher D. Incarvito have developed an enzyme-inspired catalyst that regioselectively oxidizes saturated C-H bonds in ibuprofen and 4-methylcyclohexylacetic acid (Science 2006, 312, 1941).

The system's innovative design features a dimanganese catalytic core coordinated to a rigid tridentate ligand. The ligand contains a carboxylic acid group that acts like a tweezer, holding onto the substrate's carboxylic acid group via hydrogen-bonding. According to the authors, this interaction orients the substrate so that the desired site of oxidation sits just above the catalytic core.

The oxidation proceeds with high regioselectivity for both substrates as well as excellent stereoselectivity for 4-methylcyclohexylacetic acid, which can adopt more than one conformation. By tinkering with the catalyst-substrate ratio, the Yale team observed up to 700 catalytic turnovers from the system.

"This is nice work, extending previous studies on geometric control of oxidations," Columbia University chemistry professor Ronald Breslow tells C&EN.

"I've been trying to get a catalytic system like this to work for quite a long time," Crabtree remarks. In the past, his group's efforts have been hampered by poor catalytic turnover. In previous systems, he explains, the products bound so well to the catalyst that no new substrate molecules could displace them.

Crabtree attributes the success of the new catalyst to a polar solvent system and a slight misfit between the substrate and the catalyst that allows products to dissociate from the catalyst more easily.

University of Minnesota chemists Rubén Mas-Ballesté and Lawrence Que Jr. note in a commentary that accompanies the report that the ligand's simple design "allows us to envisage a new horizon of modified ligands. By tuning the nature of the tweezer and the length of the tether, a whole family of catalysts could be tailored to accommodate a wide range of substrates."

Crabtree says the group is currently applying the catalyst's design principles to other systems. "Once you've got one system working, it's relatively straightforward to dream up others."

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