Mechanistic Insights into Chemoselectivity in Nickel-Catalyzed Arylation of Competitive Nucleophilic Systems: A DFT Perspective

Nickel-catalyzed cross-coupling of alcohols or amines with aryl electrophiles enables the selective arylation of complex substrates bearing competing nucleophilic groups without resorting to protective groups. In this study, the mechanisms underlying such competitive arylation reactions are investigated using DFT calculations to elucidate the origins of chemoselectivity. The results identify reductive elimination as the rate-limiting step, with chemoselectivity primarily governed by kinetic control. The dominant factor influencing the selectivity in various contending alcohols is the steric hindrance around the hydroxyl O atom. Diols exhibit selective primary O-arylation due to stronger d-p interactions between the alkoxide and the nickel-bisphosphine fragment in both reactant intermediates and transition states. Steric hindrance predominantly dictates O- versus N-arylation selectivity when alcohols and arylamines compete, whereas both steric and electronic effects collectively determine the preference for N-arylation when alcohols compete with alkylamines. Moreover, the selective O-arylation of amino alcohols is attributed to stronger noncovalent interactions between C and O. These mechanistic insights facilitate developing selective arylation methodologies for competitive nucleophilic systems.