Regioselective Lithium Diisopropylamide-Mediated Ortholithiation of 1-Chloro-3-(trifluoromethyl)benzene: Role of Autocatalysis Lithium Chloride Catalysis and Reversibility

摘要

Ortholithiation of 1-chloro-3-(trifluoromethyl)benzene with lithium diisopropylamide (LDA) in tetrahydrofuran at −78 °C displays characteristics of reactions in which aggregation events are rate limiting. Metalation with lithium chloride-free LDA involves a rate-limiting deaggregation via dimer-based transition structures. The post-rate-limiting proton transfers are suggested to involve highly solvated triple ions. Autocatalysis by the resulting aryllithiums or catalysis by traces (<100 ppm) of LiCl divert the reaction through di- and trisolvated monomer-based pathways for metalation at the two and six positions, respectively. The regiochemistry is dictated by a combination of kinetically controlled metalations overlayed by an equilibration involving diisopropylamine that is shown to occur by the microscopic reverse of the monomer-based metalations.