DOI: 10.1002/chem.200700105 Ion- and Atom-Leaching Mechanisms from Palladium Nanoparticles in Cross-Coupling Reactions Anil V. Gaikwad, [a] Alexandre Holuigue, [a] Mehul B. Thathagar, [b] Johan E. ten Elshof, [c] and Gadi Rothenberg* [a] Introduction Palladium-catalysed cross-coupling is a versatile synthetic protocol that is used to produce drugs, agrochemicals and fragrances. [1–3] The main reactions in this family are Heck, Suzuki-Miyaura, Negishi and Stille coupling reactions. [1] Tra- ditionally, such reactions are catalysed by Pd II /Pd 0 com- plexes in the presence of phosphines or other ligands. [4–6] However, these ligands are costly and require careful sepa- ration from the final product. Moreover, many ligands are air and moisture sensitive, which makes “ligand-free” Pd catalysis by using heterogeneous Pd/C [7] or suspensions of Pd colloids an attractive alternative. [8–10] Nanocolloids are at- tracting considerable attention as C  C coupling cata- lysts. [10, 11] They are not classical heterogeneous catalysts, but their dimensions (2–20 nm) are close to those of the crystal- lites that are used in traditional gas/solid hetACHTUNGTRENNUNGerogeneous cat- alysis reactions. [9, 12–14] Ligand-free Heck and Suzuki catalysis was reported by using Pd salt precursors, [15] nanocluster sus- pensions [16, 17] and supported nanoclusters. [14] In the last ex- ample different types of supports were used, which included carbon, [13] (thiol-functionalised) silica, [18] zeolites, [19] resins, [20] Abstract: Leaching of palladium spe- cies from Pd nanoparticles under CC coupling conditions was observed for both Heck and Suzuki reactions by using a special membrane reactor. The membrane allows the passage of palla- dium atoms and ions, but not of species larger than 5 nm. Three possible mech- anistic scenarios for palladium leaching were investigated with the aim of iden- tifying the true catalytic species. Firstly, we examined whether or not palladi- um(0) atoms could leach from clusters under non-oxidising conditions. By using our membrane reactor, we proved that this indeed happens. We then investigated whether or not small palladium(0) clusters could in fact be the active catalytic species by analysing the reaction composition and the palla- dium species that diffused through the membrane. Neither TEM nor ICP analysis supported this scenario. Final- ly, we tested whether or not palladi- ACHTUNGTRENNUNGum(II) ions could be leached in the presence of PhI by oxidative addition and the formation of [Pd II ArI] com- plexes. Using mass spectrometry, UV- visible spectroscopy and 13 C NMR spectroscopy, we observed and moni- tored the formation and diffusion of these complexes, which showed that the first and the third mechanistic sce- narios were both possible, and were likely to occur simultaneously. Based on these findings, we maintain that pal- ladium nanoparticles are not the true catalysts in CC coupling reactions. In- stead, catalysis is carried out by either palladium(0) atoms or palladium(II) ions that leach into solution. Keywords: catalysis · cross-cou- pling · Heck reaction · membranes · nanoparticles [a] A. V. Gaikwad, A. Holuigue, Dr. G. Rothenberg Van )t Hoff Institute for Molecular Sciences University of Amsterdam, Nieuwe Achtergracht 166 1018 WV Amsterdam (The Netherlands) Fax: (+ 31) 20-525-5604 E-mail: gadi@science.uva.nl [b] Dr. M. B. Thathagar DSM Pharma Chemicals, P.O. Box 18 6160 MD Geleen (The Netherlands) [c] Dr. J. E. ten Elshof MESA + Institute for Nanotechnology, University of Twente P.O. Box 217, 7500 AE Enschede (The Netherlands) Supporting information for this article is available on the WWW under http://www.chemeurj.org/ or from the author. It includes exper- imental procedures for Pd-species transport experiments, procedures for performing the cross-coupling reactions and UV-visible, 13 C NMR and FABMS spectra of the oxidative Pd/I complexes. # 2007 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim Chem. Eur. J. 2007, 13, 6908 – 6913 6908