title: Lithium diisopropylamide-mediated ortholithiation of 2-fluoropyridines: rates, mechanisms, and the role of autocatalysis.
abstract: Lithium diisopropylamide (LDA)-mediated ortholithiations of 2-fluoropyridine and 2,6-difluoropyridine in tetrahydrofuran at -78 °C were studied using a combination of IR and NMR spectroscopic and computational methods. Rate studies show that a substrate-assisted deaggregation of LDA dimer occurs parallel to an unprecedented tetramer-based pathway. Standard and competitive isotope effects confirm post-rate-limiting proton transfer. Autocatalysis stems from ArLi-catalyzed deaggregation of LDA proceeding via 2:2 LDA-ArLi mixed tetramers. A hypersensitivity of the ortholithiation rates to traces of LiCl derives from LiCl-catalyzed LDA dimer-monomer exchange and a subsequent monomer-based ortholithiation. Fleeting 2:2 LDA-LiCl mixed tetramers are suggested to be key intermediates. The mechanisms of both the uncatalyzed and catalyzed deaggregations are discussed. A general mechanistic paradigm is delineated to explain a number of seemingly disparate LDA-mediated reactions, all of which occur in tetrahydrofuran at -78 °C.
authors.affiliation: Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, New York 14853-1301, United States.
authors.forename: Lekha
authors.initials: L
authors.lastname: Gupta
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Hoepker
authors.forename: Yun
authors.initials: Y
authors.lastname: Ma
authors.forename: Mihai S
authors.initials: MS
authors.lastname: Viciu
authors.forename: Marc F
authors.initials: MF
authors.lastname: Faggin
authors.forename: David B
authors.initials: DB
authors.lastname: Collum
mesh_terms: D002384:Catalysis; D007700:Kinetics; D008094:Lithium / Q000737:chemistry*; D018021:Lithium Chloride / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D011437:Propylamines / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*
chemical_list: C521930:2-fluoropyridine; D009942:Organometallic Compounds; D011437:Propylamines; D011725:Pyridines; D008094:Lithium; C007442:diisopropylamine; D018021:Lithium Chloride