DFT Insights into Suzuki–Miyaura Cross-Coupling: Mechanism, Metal Effects, and Computational Challenges

Abstract

Density Functional Theory (DFT) has been recognized as an essential theoretical tool for the mechanistic elucidation of transition metal-catalyzed cross-coupling reactions, especially for the Suzuki-Miyaura reaction (SMR). Experimental characterization of crucial reaction intermediates, for example, Pd-O-B pre-transmetalation complexes, has been an essential step in validating the theoretical models. Even though substantial progress has been made in the mechanistic elucidation of SMR catalyzed by transition metals, accurate characterization of the energy landscape of SMR remains a formidable challenge. This is largely due to the inherent functional dependence of Gaussian-based DFT calculations, poor treatment of dispersion forces, simplified treatment of solvation and bases, and difficulties in accurate description of transition metal energetics. In addition, static DFT calculations often fail to capture dynamic effects, branching in the reaction pathway, and catalyst deactivation routes that could play a crucial role in catalysis. This review aims to critically discuss recent developments and theoretical limitations of DFT calculations in the mechanistic elucidation of palladium and other earth-abundant metal-catalyzed Suzuki-Miyaura reactions. Emphasis will be given to recent developments in dispersion corrections, explicit and combined solvation approaches, conformational sampling approaches, molecular dynamics simulations, and machine learning-based quantum chemical calculations. The potential of machine learning-based quantum chemical calculations in catalysis and its integration with DFT calculations for efficient and chemically accurate catalyst design in Suzuki-Miyaura cross-coupling chemistry will be highlighted.