We report that thiolate-protected Au-25(SR)(18) (R = CH2CH2Ph) nanoclusters supported on oxides (such as CeO2, TiO2, MgO, and SiO2) can catalyze Sonogashira cross-coupling reaction between phenylacetylene and p-iodoanisole with high conversion of p-iodoanisole (up to 96.1%) and excellent selectivity (up to 88.1%). The-well-defined structure of Au-25(SR)(18) provides an important clue as to the catalytically active sites: the sterically unhindered facets on the cluster surface allow easy reactant access; each facet comprises three surface gold atoms from three separate "staple"-like -S(R)-Au-S(R)-Au-S(R)- surface-protecting motifs. Density functional theory modeling of the reactant adsorption shows that both reactants prefer to adsorb on the open facet with the phenyl ring facing a surface gold atom. Each reactant has an adsorption energy of -0.40 to -0.48 eV. When they co-adsorb on the catalyst, the total adsorption energy reaches -0.90 eV (a relatively strong adsorption state); more interestingly, at this state the two reactants are well positioned to couple with their Ph-C CH and Ph-I groups pointing toward the third gold atom of the open facet. The combined experimental and DFT results suggest a great potential to correlate the atomic configuration of the active sites to the catalytic performance of an atomically precise nanocluster. (C) 2013 Elsevier Inc. All rights reserved.