Application of statistical design of experiment to identify key factors in cross coupling reactions

The statistical design of experiment (sDoE) enables efficient exploration of complex chemical space by screening multiple factors simultaneously, overcoming the limitations of the one-factor-at-a-time (OFAT) approaches. In this study, Plackett-Burman design (PBD) was applied to screen five 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. While the importance of these factors is well established in cross-coupling chemistry, this study aimed to demonstrate how statistical PBD can compare and rank factors' effect via high-throughput screening (HTS) context. The outcome identified influential factors for each reaction, indicating the efficiency of integrating HTS and sDoE. This proof-of-concept study demonstrates an initial screening approach for future optimisation using advanced designs such as response surface methodologies (RSM), providing a deeper understanding of complex chemical spaces by investigating factor interactions, catalyst design, and process development.