In the coupling of amines with aryl, vinyl, and heteroaryl halides, reductive elimination is a key step for the formation of new C-N bonds using Palladium-metal catalysis. Understanding what governs this key reaction provides the basis to predict reaction efficiency and achieve difficult C-N couplings. In this work, we studied the theory and mechanism of the Pd-catalytic cycle of pyridyl- and p-tolyl palladium complexes against reported experimental results to underly the overall rate-determining step. These mechanistic studies revealed relevant quantum mechanical molecular and steric descriptors to consider that captured the chemical space of this reaction. With a vast substrate scope of N-nucleophiles, aryl-, heteroaryl-electrophiles, and bidentate phosphine ligands, we report a multivariate-linear regression and random forest prediction models of the theoretical activation barriers with high prediction agreement.

Computer-assisted reaction prediction: Pd-catalyzed C-N cross-coupling reaction

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