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

Abstract

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.

Quantitative Reactivity Models for Oxidative Addition to L2Pd(0): Additional Substrate Classes, Solvents, and Mechanistic Insights

“…A more comprehensive study of specific solvent effects and their origins is the subject of a contemporaneous follow-up paper. [60]…”

“…There are several instances where specific solvent effects are observed, and these are the subject of a contemporaneous follow-up study. [60] An unfortunate consequence of data aggregation is that phenomena affecting a small subset of the population can be obscured during a holistic analysis. As well, while the MAE values we obtain are generally very good (2-3 kJ mol -1 ), these do represent rate differences of approximately 2-3 fold at room temperature.…”

“…[53] The solvent effects on site-selectivity due to such mechanistic shifts are discussed in a follow-up paper. [60] The Relationship Between C-X Bond Strength and Oxidative Addition Rates…”

“…In a follow-up study, we further probe additional outlier substrates to elucidate specific explicit solvent effects on reactivity and selectivity. [60] Figure 1. Overview of prior quantitative model for Pd oxidative addition reactivity.…”