news of the week APRIL 5, 2010 EDITED BY WILLIAM G. SCHULZ & ALICIA J. CHAMBERS
SURVIVAL OF THE WEAKEST
reaction—with an overabundance of several organic ligands. In the equilibrium mixture, different ligands bind to Pd, forming catalysts that vary in their ability to accelerate alkylation of the substrate. The ligands that form the most stable Pd-ligand-substrate complexes CATALYST DISCOVERY: Least stable are most abundant in solution, and those that form unintermediates can lead to stable complexes are scarce. the best catalysts Using electrospray mass spectrometry (ESI/MS) to determine the least abundant and therefore least stable complexes, the researchers identified ligands that form VOLUTION MAY BE based on “survival of the the most active catalysts. The study thus evaluates fittest,” but when it comes to selecting the best catalysts not in the conventional way—by determining catalysts, that dictum doesn’t always hold. their ability to lower the activation barrier, the energy A research team has shown that one can select the required to make the reaction go—but instead by findbest catalysts from combinatorial libraries of candiing the least stable intermediates, which are closer dates by instead using the principle of “survival of the energetically to the top of the barrier and can therefore weakest”—that is, the most unstable catalytic interme- more easily traverse it. diates make for the best catalysts. The approach could The work “highlights the value of smart combinatomake it possible to discover catalysts more quickly for rial approaches for the development of highly efficient syntheses of drugs and other products. catalysts,” says catalysis specialist Helma Wennemers It has been difficult to find selection methods to sepaof the University of Basel, in Switzerland. rate the cream of the crop (the fastest catalysts) from the “This is a clever demonstration of successful catalyst screening using simple ESI/MS methodology,” says polymer chemist LIFTING THE VALLEY Krzysztof Matyjaszewski of Carnegie A Pd-ligand-substrate complex that is energetically less stable Mellon University. catalyzes allylic alkylation of a substrate more efficiently Groups such as Matyjaszewski’s and (dashed red coordinate)—that is, with a lower activation that of catalyst screening specialist Anenergy (Ea)—than a more stable complex (blue coordinate). L = dreas Pfaltz of the University of Basel have ligand, R = functional group, Nu = nucleophile. identified good catalysts from mixtures before. But the new study represents one Potential energy of the first screening examples in which “catalyst systems are in equilibrium and communicate,” Reek says. “It’s a Darwinian selection in which the weakest survive, whereas most others have monitored the Ea properties of mixtures of catalysts that L L L L Pd are not communicating.” Pd R R Dynamic combinatorial chemistry exL L pert Sijbren Otto of the University of GronPd X Nu ingen, in the Netherlands, says, “We underR stand initial states much better than transition states,” which are transient species at Reaction coordinate the tops of activation barriers. Manipulating the energies of reactant intermediates dross when screening libraries to identify highly active “may, for selected systems, be a much easier way to find catalysts. Now, theoretical chemist F. Matthias Bickelcatalysts than attempting to interact selectively with haupt of Free University of Amsterdam, catalysis specialmuch more elusive transition states,” Otto says. ist Joost N. H. Reek of the University of Amsterdam, and Using the new technique to detect least abundant coworkers have developed an innovative selection stratspecies in large libraries and screen substantially difegy for such experiments based on survival of the weakest ferent ligand classes in the same mixture, however, intermediates (Nat. Chem., DOI: 10.1038/nchem.614). could be difficult, Otto adds. Nevertheless, he says, The researchers mix limited amounts of palladi“the approach holds considerable promise for catalyst um—bound to the substrate of an allylic alkylation development and discovery.”—STU BORMAN
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O O Ph
Ph Pd-ligandsubstrate complex
O
O
CH3O Ph
OCH3 Ph
Ph = phenyl
The team applied their catalyst discovery approach to find the best of five ligands to accelerate this allylic alkylation of an acetate substrate.
