title: Regioselective lithium diisopropylamide-mediated ortholithiation of 1-chloro-3-(trifluoromethyl)benzene: role of autocatalysis, lithium chloride catalysis, and reversibility.
abstract: 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 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.
authors.affiliation: Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, New York 14853-1301, USA.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Hoepker
authors.forename: Lekha
authors.initials: L
authors.lastname: Gupta
authors.forename: Yun
authors.initials: Y
authors.lastname: Ma
authors.forename: Marc F
authors.initials: MF
authors.lastname: Faggin
authors.forename: David B
authors.initials: DB
authors.lastname: Collum
mesh_terms: D001555:Benzene Derivatives / Q000737:chemistry*; D002384:Catalysis; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry*; D007700:Kinetics; D018021:Lithium Chloride / Q000737:chemistry*; D011437:Propylamines / Q000737:chemistry*
chemical_list: C560524:1-chloro-3-(trifluoromethyl)benzene; D001555:Benzene Derivatives; D006845:Hydrocarbons, Fluorinated; D011437:Propylamines; C007442:diisopropylamine; D018021:Lithium Chloride