Catalytic cycle and off-cycle steps in the palladium-catalyzed fluorination of aryl bromide with biaryl monophosphine ligands: Theoretical free energy profile

Abstract

• Accurate free energy profile including transmetalation step. • Unimolecular elimination of HF leads to regioisomers. • Located critical transition states for further ligand design. Palladium catalyzed fluorination of aryl halides with inorganic fluoride salts has been a challenge transformation during several decades. The successful catalysis came with the use of biaryl monophosphine ligand. However, the catalytic process suffers of the problem of off-cycle transformation as ligand modification and formation of regioisomers, which means that more ligand design is necessary. In this work, the complete free energy profile for the catalysis using t BuBrettPhos ligand was determined by reliable theoretical calculations, including the transmetalation step. The calculations have indicated that monocoordination by phosphine and the bulky groups in the t BuBrettPhos ligand, which has strong repulsion to the coordinating bromide ion, are critical to achieve low activation barriers for reductive elimination. The ligand modification transition state was found and involves migration of the coordinating aryl group. The mechanism of regioisomers formation, an important drawback of this methodology, was also found and corresponds to the elimination of HF without participation of CsF, forming a benzyne intermediate coordinating to the palladium. The return of the HF can take place by proton donation to any carbon of the benzyne, which produces the isomerization. These findings indicate that more rational ligand design can be done to produce more effective catalysis. The theoretically determined rate law and the overall ΔG ‡ are in excellent agreement with experimental data.