Divergent Kinetic/Thermodynamic Selectivity in Palladium(II)-Mediated C–H Activation to Form 5- and 6-Membered Palladacycles

Palladium-catalyzed C–H functionalization proceeds via metallacycle formation and often favors 6-membered palladacycles, contrasting the typical preference for 5-membered chelates in transition-metal complexes. The present study probes the origin of this behavior by comparing the reactivity of benzoate and phenylacetate substrates in stoichiometric and catalytic reactions with MPAA-ligated Pd(OAc)2 (MPAA = mono-N-protected amino acid). Stoichiometric competition studies show that 6-membered palladacycle formation is kinetically favored, while the 5-membered palladacycle is thermodynamically favored. Density functional theory (DFT) calculations reveal that the transition state for 5-membered palladacycle formation is inhibited by a higher distortion energy. Replacement of the α-MPAA ligand with a more flexible β-MPAA derivative lowers the transition state energy of benzoate C–H activation and improves the catalytic performance.