Mechanistic insights into palladium-catalyzed nucleophilic aromatic fluorination: From early discoveries to recent Design of new Ligands

The development of palladium-catalyzed nucleophilic aromatic fluorination is a noteworthy example of rational ligand design, with theoretical calculations playing a critical role throughout the process. This review presents the historical development of this catalysis, beginning with the first theoretical insights from Yandulov and Tran. In the sequence, the successful design of biaryl monophosphine ligands and experiments performed by Buchwald and coworkers are discussed. The last part is the recent new theoretical insights into the mechanism able to explain the formation of regioisomers, followed by in silico design of more powerful ligands. Along with the text, a close connection between theory and experiments is presented, providing a deep understanding of the mechanism. • Historical development of the palladium-catalyzed aromatic fluorination • Recent advances in the understanding of the mechanism of regioisomers formation • Discussion on new recent ligand design to boost reaction rate and selectivity