Structure-Reactivity Principles of Alkali Metal Amides: Sodium Diisopropylamide, Lithium Hexamethyldisilazide, and Lithium Diisopropylamide

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Alkali metal amide structure-reactivity principles of foundational importance to synthetic chemists are described herein with an emphasis on sodium diisopropylamide (Chapters 1–4), lithium hexamethyldisilazide (Chapter 5), and lithium diisopropylamide (Chapter 6). Organosodium reagents are notably underdeveloped contrasting with the highly popular organolithium variants, which pervade the literature in capacities ranging from nucleophiles to strong non-nucleophilic bases. This is due in part to documented inferior solubility and stability of alkylsodiums and sodium amides. Nonetheless, scant reports on the reactivity of sodium diisopropylamide (NaDA)—primarily concerned with preparation and crystallography—suggested some regiochemical and reactivity advantages relative to LDA. NaDA in DMEA is highly soluble, stable, resistant to solvent decomposition, and easily prepared. The application of MCV afforded a uniform assignment of symmetric dimer in all solvents. Solvation of NaDA was addressed using a combination of solubility measurements, solvent exchanges, and DFT computations. NaDA/THF effectively metalates 1,4-dienes and isomerizes alkenes, and the corresponding mechanisms were ascertained, providing a glimpse into sodium coordination chemistry. Highly Z-selective isomerizations were observed for allyl ethers under conditions that compare favorably to those of existing protocols. NaDA/THF readily metalates a variety of arenes, and the mechanisms illuminate the influence of substituents on inductive, mesomeric, steric, and chelate effects. Lithium hexamethyldisilazide (LiHMDS)-mediated enolization of (+)-4-benzyl-3-propionyl-2-oxazolidinone is described in Chapter 5. This enolization shows unusual sensitivity to the choice of hydrocarbon cosolvent (hexane versus toluene) and to isotopic labeling, from which four distinct mechanisms were identified. The kinetics of lithium diisopropylamide (LDA) in tetrahydrofuran under non-equilibrium conditions are reviewed in Chapter 6. Three distinct topics include: (1) methods and strategies used to deconvolute complex reaction pathways, (2) conclusions about organolithium reaction mechanisms, and (3) perspectives on the concept of rate limitation.

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Organic chemistry


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Union Local


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Collum, David B.

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Fors, Brett P.
Coates, Geoffrey

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Chemistry and Chemical Biology

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Ph. D., Chemistry and Chemical Biology

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Doctor of Philosophy

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dissertation or thesis

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