The new approach for palladium-catalyzed cross-coupling of two non-activated aromatic compounds (D. R. Stuart, K. Fagnou, Science2007, 316, 1172) was studied theoretically. The energetic span model (S. Kozuch, S. Shaik, Acc. Chem. Res.2011, 44, 101, and references therein) was employed to analyze the kinetic behavior of the catalytic cycle. The computed energy profile, combined with the energetic span model, accounts for the experimental selectivity, which favors the hetero-coupling of benzene with indole. This selectivity is driven by a fine balance of the entropic contributions and the high ratio of concentrations used for benzene over indole. This analysis may allow future theoretical predictions of how different aromatic compounds can be effectively coupled.