A general reactivity map for predicting outcomes in palladium-catalyzed cross-coupling

Making accurate, quantitative predictions of chemical reactivity based on molecular structure is an unsolved problem in chemical synthesis, particularly for complex molecules. We report a generally applicable and mechanistically based structure-reactivity model for the oxidative addition of (hetero)aryl halides to palladium(0), which is a key step in myriad catalytic processes. This model links simple molecular descriptors – electrostatic potential, steric parameters, and bond strengths – to relative rates of oxidative addition for 71 electrophile substrates. Because oxidative addition often controls the rate and/or selectivity of palladium-catalyzed cross-coupling reactions, this model can be used to make predictions about catalytic reaction outcomes. Demonstrated applications include a quantitative model for the rate of 410 different Sonogashira coupling reactions, and successful site-selectivity predictions for a series of multihalogenated substrates relevant to the synthesis of pharmaceuticals and natural products.