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

Ortholithiation of 1-chloro-3-(trifluoromethyl) benzene with lithium diisopropylamide (LDA) in tetrahydrofuran at -78 degrees 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 diverts the reaction through di- and trisolvated monomer-based pathways for metalation at the 2 and 6 positions, respectively. The regiochemistry is dictated by a combination of kinetically controlled metalations overlaid by an equilibration involving diisopropylamine that is shown to occur by the microscopic reverse of the monomer-based metalations.