Free Energy Profile of a Model Palladium Catalyzed Fluorination of Aryl Bromide with Cesium Fluoride.

Addition of fluorine to aromatic rings has increased in importance in the past decade in view of the increased role of organofluorine compounds in the design of new pharmaceuticals. Palladium catalyzed nucleophilic fluorination of unactivated aryl halides using salts such as cesium fluoride was achieved with the use of bulky biaryl monophosphine ligand. Simple monophosphine palladium complexes were not able to promote this reaction, which is attributed to the difficult reductive elimination step and the formation of dimers of the PdL(Ph)(F) intermediate. The use of theoretical methods for reliable design of new ligands requires the knowledge of the complete free energy profile of the catalyzed reaction. Otherwise, predictions may not be observed. In this work, a complete free energy profile of a model palladium catalyzed fluorination (trimethyl phosphine ligand), including the precatalyst decomposition mechanism (allylpalladium chloride), was investigated using a reliable theoretical method, the mPW2-PLYP double-hybrid functional, which was compared with the DLPNO-CCSD(T) benchmark method. The results suggest that palladium(π-cinnamyl) chloride is not a good precatalyst, while the monophosphine palladium complex bonded to an alkene should work better. The transmetalation step raises the overall barrier for the reductive elimination by 4.3 kcal mol in the case of monophosphine catalyst, making the reaction difficult (Δ = 34.1 kcal mol), even in the case of no dimerization of the monophosphine palladium fluoride complex. Thus, success of a ligand to promote palladium catalysis requires not only a monophosphine ligand that avoids dimerization but also a strong repulsion to both phenyl and fluorine bonded to the palladium in the PdL(Ph)(F) complex.