Palladium Catalysis DOI: 10.1002/anie.200800153 Visual Observation of Redistribution and Dissolution of Palladium during the Suzuki–Miyaura Reaction** Stephanie MacQuarrie, J.Hugh Horton, Jack Barnes, Kevin McEleney, Hans-Peter Loock, and Cathleen M. Crudden* The use of Pd catalysts in cross-coupling reactions has revolutionized the way organic molecules are made. [1,2] Suzuki–Miyaura, Mizoroki–Heck, Kumada–Corriu, Stille, and Negishi couplings are but a few of the named reactions that provide versatile methods for the construction of organic frameworks. Although advances have been made in the use of alternative metals such as nickel or iron in cross-coupling reactions, palladium remains by far the catalyst of choice for these important reactions. With efficient ways of manufacturing molecules in hand, the main difficulty then becomes removing the catalyst at the completion of the reaction. [3,4] The strict controls regulatory agenciesplaceonthelevelsofheavymetalsinpharmaceutical and related products makes removal of metal catalysts after a reaction an even more serious issue in the pharmaceutical industry. An obvious approach to solving this problem is to use heterogeneous catalysts which should be removable by filtration. However, the groundbreaking studies of Arai and Kohler showed independently that even traditional hetero- geneous catalysts such as Pd/C act by releasing small amounts of soluble Pd, which then redeposit at the completion of the reaction. [5,6] Since this re-deposition removes Pd from solu- tion, understanding how this takes place is critical to developing effective catalysts that are removed after reaction. With this in mind, we embarked on a study of the Suzuki– Miyaura reaction using Pd foil as the catalyst, to permit the direct visualization of the changes that take place on the metal surface as a result of the Suzuki–Miyaura reaction, including the re-deposition phenomenon. In addition to bulk studies with Pd foil, we have employed a specially designed reactor that allows us to heat only a small portion of the surface to a temperature where reaction can take place, while exposing the entire surface of the foil to the reaction mixture. Using this technique, we demonstrate that both the Suzuki– Miyaura reaction itself and treatment with the aryl iodide alone cause changes in surface chemistry and morphology only where the temperature is sufficient to cause the coupling reaction to take place. In addition, we found that re- deposition of Pd occurs preferentially on the periphery of the reactive zone in cases when only a small portion of the surface is heated. As the catalyst, we employed 250 mm thick Pd foil. [7–11] Its surface was examined by scanning electron microscopy (SEM), optical microscopy, and X-ray photoelectron spec- troscopy(XPS)priortoreaction.Thefoilischaracterizedbya relatively smooth, pit-free surface that has ridges spaced at non-periodic distances presumably as a result of the rolling process used to generate the foil. Rather than anneal the foil, we employed these surface features as a frame of reference during the various treatments. For the Suzuki–Miyaura reaction, we employed the pinacol ester of phenyl boronic acid, and p-nitrophenyl iodide. An electron-deficient aryl iodide was chosen to facilitate the coupling reaction. The reaction was first carried outwiththeentirepieceofPdfoilimmersedinDMFat100 8C in a conventional reactor, without stirring, to prevent damage to the Pd surface. Figure 1A shows the Pd foil after treatment with DMF/ water at 100 8C, [12] which results in no visible change in the surface morphology. However under the reaction conditions, which gave the desired product in 45% yield, considerable pitting of the surface of the Pd was observed (Figure 1B). Exposure to the aryl iodide alone also led to considerable Figure 1. A)PdsurfaceafterexposuretoDMF/H 2 Oat100 8Cfor24h; B) Pd surface upon completion of successful Suzuki–Miyaura reaction; C)PdsurfaceafterexposuretothearyliodideinDMF/H 2 Oat100 8C for24h.Scalebar20 mm. [*] Dr. S. MacQuarrie, Prof. J.H. Horton, Dr. J. Barnes, K. McEleney, Prof.H.-P.Loock,Prof.C.M.Crudden Department of Chemistry, Queen’s University 90BaderLane,Kingston,ON,K7L3N6(Canada) Fax:(+ 1)613-533-6669 E-mail:cruddenc@chem.queensu.ca Homepage: http://www.chem.queensu.ca/people/faculty/Crudden/crudden.html [**] TheNaturalSciencesandEngineeringResearchCouncilofCanada is acknowledged for support of this research in terms of operating grantstoC.M.C.,H.P.L.,andJ.H.H.,andforscholarshipstoK.M. Queen’s University is acknowledged for support to K.M. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Angewandte Chemie 3279 Angew. Chem. Int. Ed. 2008, 47, 3279 –3282 # 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim