Different Oxidative Addition Mechanisms for 12- and 14-Electron Palladium(0) Explain Ligand-Controlled Divergent Site Selectivity

In cross-coupling reactions, dihaloheteroarenes are usually most reactive at C–halide bonds adjacent to a heteroatom. This selectivity has been previously rationalized. However, no mechanistic explanation exists for anomalous reports in which specific ligands effect inverted selectivity with dihalopyridines and -pyridazines. Here we provide evidence that these ligands uniquely promote oxidative addition at 12e– Pd(0). Computations indicate that 12e– and 14e– Pd(0) can favor different mechanisms for oxidative addition due to differences in their HOMO symmetries. These mechanisms are shown to lead to different site preferences, where 12e– Pd(0) can favor oxidative addition at an atypical site distal to nitrogen.