Catalysis of Organic..

Rothenberg et al. 26130. How to Find the Best Homogeneous CatalystGadi Rothenberg 1 , Jos A. Hageman 2 , Frédéric Clerc 3 , Hans-Werner Frühauf 1and Johan A. Westerhuis 21Van't Hoff Institute for Molecular Sciences and 2 Swammerdam Institute of LifeSciences, University of Amsterdam, Nieuwe Achtergracht 166, 1018 WV Amsterdam,The Netherlands. 3 Institut de Recherches sur la Catalyse, 2 Avenue Albert Einstein,69626 Villeurbanne Cedex, FranceAbstractgadi@science.uva.nlWe present in this communication an alternative concept for optimizinghomogeneous catalysts. With this method, one extracts and screens virtual catalystlibraries, indicating regions in the catalyst space where good catalysts are likely to befound. This automated screening is done in two stages: A ‘rough screening’ using 2Ddescriptors, followed by a “fine screening” using 3D descriptors. The model isdemonstrated for a set of Pd-catalyzed Heck reactions using bidentate ligands.IntroductionOne of the biggest challenges in chemistry is discovering new chemical reactionsthat will enable society to function in a sustainable manner. Atom economy andwaste minimization are at the heart of industrial policy, driven both by governmentalincentives and by market considerations. Homogeneous catalysis is a most promisingarea in this respect (1). The Nobel prizes (2, 3) awarded in 2001 (to Sharpless,Noyori and Knowles for their discovery of chirally-catalyzed oxidation andhydrogenation reactions), and in 2005 (to Chauvin, Grubbs, and Schrock for theirdiscovery of metathesis catalysts) exemplify how a new catalyst can cause aparadigm shift in the chemical industry (4).The last two decades have seen enormous developments in catalyst discoveryand optimization tools, notably in the area of high-throughput experimentation(HTE) and process optimization (5). However, the basic concept used for exploringthe catalyst space in homogeneous catalysis has not changed: Once an active catalystcomplex is discovered, small modifications are made on the structure to try andscreen the activity of neighboring complexes, covering the space much like an inkdrop spreads on a sheet of paper. This is not a bad method, but can we do better withthe new tools that are available today?Here we present an alternative concept for optimizing homogeneous catalysts.Using a “virtual synthesis” platform, we assemble large catalyst libraries (10 15 –10 17candidates) in silico, and use statistical models, molecular descriptors, and