Rate Studies Of Organolithium-Mediated Reactions: Reaction Of Lithium Diisopropylamide With Fluoropyridines An D Reaction Of Lithium Diethylamide With An Alkyl Bromide And An Alkyl Sulfonate
Mechanistic studies of the lithium diisopropylamide (LDA)-mediated ortholithiation and subsequent aromatic nucleophilic substitution of fluoropyridines are described. 6Li, 15N, 13C and 19F NMR spectroscopic studies reveal the formation of monomeric aryllithium in THF solution at -78 oC. Computational studies support trisolvation state of the monomer. A combination of in situ IR and 19F NMR spectroscopic investigations provide the details of the rate-limiting step of the reaction. The dominant reaction pathway in ortholithiation involves substrate-assisted, rate-limiting deaggregation of LDA dimer. Standard and competitive isotope effects confirm post-rate-limiting proton transfer. Rate studies show a direct deaggregation of LDA dimer occurs parallel with an unprecedented tetramerbased pathway. Autocatalysis that emerges as the reaction proceeds originates from ArLi-catalyzed deaggregation of LDA that, paradoxically, proceeds through 2:2 LDA-ArLi mixed tetramers. A hypersensitivity of the ortholithiation rates to traces of LiCl derives from lithium chloride-catalyzed dimer-monomer exchange and a subsequent monomer-based ortholithiation. Once again, 2:2 LDA-LiCl mixed tetramers are suggested to be key intermediates. Ortholithiations of a range of other arenes mediated by lithium diisopropylamide (LDA) in THF at -78 oC also reveal substantial accelerations by as little as 0.5 mol % LiCl (relative to LDA). Warming the lithiated fluoropyridine solution to 0 oC converts the aryllithium to 2-fluoro-6(diisopropylamino)pyridine. Rate studies reveal evidence of a reversal of the ortholithiation and a subsequent 1,2-addition via two monomer-based pathways. Computational studies fill in the structural details and provide evidence of a direct substitution without the intermediacy of Meisenheimer complex. The last chapter describes the rate studies aimed at understanding the principles governing the selectivities in competing N-alkylation, elimination and sulfonation pathways, in the reactions of lithium diethylamide (Et2NLi) with n-dodecyl bromide and n-octyl benzenesulfonate. The alkyl bromide undergoes competitive SN2 substitution and E2 elimination via trisolvatedmonomer-based transition structures, in proportions that are insensitive to all concentrations except for a minor medium effect. The n-alkyl sulfonate undergoes competitive SN2 substitution (minor) and N-sulfonation (major). The SN2 substitution is shown to proceed via a disolvated monomer whereas; the dominant N-sulfonation follows a disolvated-dimer-based transition structure. The differential THF and Et2NLi orders explain the observed concentration-dependent chemoselectivities.
dissertation or thesis