Mechanisms and Site Selectivity of (Het)Ar–X Oxidative Addition to Pd(0) Are Controlled by Frontier Molecular Orbital Symmetry

Comparing oxidative addition rates for pairs of 2-chloro-3-EDG-pyridines/2-chloro-5-EDG-pyridines (EDG = electron-donating group: NH2, OMe, and F) to Pd(PCy3)2reveals the 3-EDG isomers undergo oxidative addition ∼100 times faster than their 5-EDG counterparts (ΔΔG‡OA= 10.4–11.6 kJ mol–1). Experimental and computational mechanistic studies reveal that the LUMO symmetries of the substrates control the oxidative addition mechanism. For the 3-EDG derivatives, high LUMO orbital coefficients at the reactive C2 position and antibonding LUMO symmetry through the C2═N bond of the pyridine lead to a nucleophilic displacement oxidative addition mechanism. Conversely, the LUMO of the 5-EDG derivatives has a node through the C5–C2 plane, leading to minimal orbital contribution at the reactive carbon. The higher energy LUMO+1 has substantial density at C2 but minimal orbital density at the nitrogen. This leads to 5-EDG substrates undergoing a three-centered insertion oxidative addition mechanism. These orbital symmetry effects also control site selectivity for multihalogenated pyridines, which we investigate for both electron-donating and electron-withdrawing substituents. Incorporating simple frontier orbital based molecular descriptors to a quantitative multivariate linear model for oxidative addition leads to improved prediction accuracy for both relative rates and site selectivity of substituted 2-halopyridine oxidative addition to L2Pd(0).