Application of Statistical Design of Experiment in the Screening of Carbon–Carbon Cross-Coupling Reactions

Abstract The statistical design of experiment (sDoE) enables efficient investigation of a large experimental space by screening multiple factors simultaneously, overcoming the limitations of the one-factor-at-a-time (OFAT) approaches. The Plackett-Burman design (PBD) was applied in screening four factors: electronic effect and Tolman's cone angle of phosphine ligands (4), catalyst loading (2), bases (2), and solvent polarity (2) across twelve (12) C–C cross-coupling reactions for the Mizoroki-Heck, Suzuki-Miyaura, and Sonogashira-Hagihara reactions. The main effects of the factors were used to identify optimal conditions. The preferred ligand for each reaction is tris(pentafluorophenyl)phosphine, tricyclohexylphosphine, and triphenylphosphite, respectively. Optimal catalyst loadings are 1 mol% K₂PdCl₄ (Mizoroki-Heck and Suzuki-Miyaura) and 5 mol% Pd(CH₃COO)₂ (Sonogashira-Hagihara reaction), with NaOH and DMSO as the optimal base and solvent, respectively. This study demonstrates the power of PBD in reaction screening and optimisation, providing an advantage in catalyst discovery, chemical synthesis, and process development.