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

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

Evans Enolates: Lithium Hexamethyldisilazide-Mediated Enolization of Acylated Oxazolidinones

Lithium hexamethyldisilazide (LiHMDS) is one of the most important bases in organic chemistry due to its prominence as a selective Brönsted base and its high thermal stability. Although the results of numerous crystallographic, spectroscopic, and computational studies have been published, chemists have assiduously avoided mechanistic studies due to the complexity stemming from a shifting dimer–monomer equilibrium of LiHMDS in THF– hydrocarbon mixtures. As part of our research program of oxazolidinone-based enolates, — the so-called Evans enolates that have appeared in more than 1600 patents and countless academic and industrial syntheses— we were drawn to the sequential enolization–aldol addition used by Pfizer that proved challenging during the kilogram scale-up of the hepatitis C drug filibuvir. LiHMDS-mediated enolization of (+)-4-benzyl-3-propionyl-2-oxazolidinone in THF−hydrocarbon mixtures showed unusual sensitivity to the choice of hydrocarbon cosolvent (hexane versus toluene) and to isotopic labeling. Four mechanisms corresponding to monosolvated monomers, trisolvated dimers, octasolvated monomers, and octasolvated dimers were identified by examining and quantitating complex reaction coordinates using FT-IR & NMR spectroscopy, mathematical software, and a unique combination of traditional kinetics with novel numerical integration and computational methods. Even under conditions in which the LiHMDS monomer was the dominant observable form, dimer-based metalation was shown to be significant. The mechanism-dependent isotope and cosolvent effects are discussed in the context of ground-state stabilization and transition-state tunneling. Finally, the LiHMDS mechanistic model developed to describe this complex scenario proves to be general and will enable the exploration of the indisputably important chemistry of LiHMDS and enolates — and many other substrates — to detailed mechanistic analysis

Sodium Diisopropylamide in Tetrahydrofuran: Selectivities, Rates, and Mechanisms of Arene Metalations

Sodium diisopropylamide (NaDA)-mediated metalations of arenes in tetrahydrofuran (THF)/hexane or THF/Me₂NEt solutions are described. A survey of >40 benzenoid- and pyridine-based arenes with a range of substituents demonstrates the efficacy and regioselectivity of metalation. Metalations of activated disubstituted arenes and selected monosubstituted arenes are rapid at −78 °C. Rate studies of 1,3-dimethoxybenzene and related methoxylated arenes show exclusively monomer-based orthometalations with two or three coordinated THF ligands. Rate studies of the isotopic exchange of benzene and monosubstituted arenes with weakly activating groups reveal analogous di- and trisolvated monomer-based metalations. Cooperative inductive, mesomeric, steric, and chelate effects are discussed

Sodium Diisopropylamide in Tetrahydrofuran: Selectivities, Rates, and Mechanisms of Alkene Isomerizations and Diene Metalations

Sodium diisopropylamide in tetrahydrofuran is an effective base for the metalation of 1,4-dienes and isomerization of alkenes. Dienes metalate via tetrasolvated sodium amide monomers, whereas 1-pentene is isomerized by trisolvated monomers. Facile, highly <i>Z</i>-selective isomerizations are observed for allyl ethers under conditions that compare favorably to those of existing protocols. The selectivity is independent of the substituents on the allyl ethers; rate and computational data show that the rates, mechanisms, and roles of sodium–oxygen contacts are substituent-dependent. The competing influences of substrate coordination and solvent coordination to sodium are discussed

Sodium Diisopropylamide: Aggregation, Solvation, and Stability

The solution structures, stabilities, physical properties, and reactivities of sodium diisopropyl­amide (NaDA) in a variety of coordinating solvents are described. NaDA is stable for months as a solid or as a 1.0 M solution in <i>N</i>,<i>N</i>-dimethyl­ethyl­amine (DMEA) at −20 °C. A combination of NMR spectroscopic and computational studies show that NaDA is a disolvated symmetric dimer in DMEA, <i>N,N</i>-dimethyl-<i>n</i>-butyl­amine, and <i>N</i>-methyl­pyrrolidine. Tetra­hydrofuran (THF) readily displaces DMEA, affording a tetra­solvated cyclic dimer at all THF concentrations. Dimethoxyethane (DME) and <i>N,N,N</i>′<i>,N</i>′-tetra­methyl­ethylene­diamine quantitatively displace DMEA, affording doubly chelated symmetric dimers. The trifunctional ligands <i>N,N,N</i>′<i>,N</i>″<i>,N</i>″-penta­methyl­diethylene­triamine and diglyme bind the dimer as bidentate rather than tridentate ligands. Relative rates of solvent decompositions are reported, and rate studies for the decomposition of THF and DME are consistent with monomer-based mechanisms

Lithium Hexamethyldisilazide-Mediated Enolization of Acylated Oxazolidinones: Solvent, Cosolvent, and Isotope Effects on Competing Monomer- and Dimer-Based Pathways

Lithium hexamethyldisilazide (LiHMDS)-mediated enolization of (+)-4-benzyl-3-propionyl-2-oxazolidinone in THF–hydrocarbon mixtures shows unusual sensitivity to the choice of hydrocarbon cosolvent (hexane versus toluene) and to isotopic labeling. Four mechanisms corresponding to monosolvated monomers, trisolvated dimers, octasolvated monomers, and octasolvated dimers were identified. Even under conditions in which the LiHMDS monomer was the dominant observable form, dimer-based metalation was significant. The mechanism-dependent isotope and cosolvent effects are discussed in the context of ground-state stabilization and transition-state tunneling

Mechanism of Lithium Diisopropylamide-Mediated Ortholithiation of 1,4-Bis(trifluoromethyl)benzene under Nonequilibrium Conditions: Condition-Dependent Rate Limitation and Lithium Chloride-Catalyzed Inhibition

Lithiation of 1,4-bis­(trifluoromethyl)­benzene with lithium diisopropylamide in tetrahydrofuran at −78 °C occurs under conditions at which the rates of aggregate exchanges are comparable to the rates of metalation. Under such nonequilibrium conditions, a substantial number of barriers compete to be rate limiting, making the reaction sensitive to trace impurities (LiCl), reactant concentrations, and isotopic substitution. Rate studies using the perdeuterated arene reveal odd effects of LiCl, including catalyzed rate acceleration at lower temperature and catalyzed rate inhibition at higher temperatures. The catalytic effects are accompanied by corresponding changes in the rate law. A kinetic model is presented that captures the critical features of the LiCl catalysis, focusing on the influence of LiCl-catalyzed re-aggregation of the fleeting monomer that can reside above, at, or below the equilibrium population without catalyst

Lithium Enolates Derived from Pyroglutaminol: Aggregation, Solvation, and Atropisomerism

Lithium enolates derived from protected pyroglutaminols were characterized by using ⁶Li, ¹³C, and ¹⁹F NMR spectroscopies in conjunction with the method of continuous variations. Mixtures of tetrasolvated dimers and tetrasolvated tetramers in different proportions depend on the steric demands of the hemiaminal protecting group, tetrahydrofuran concentration, and the presence or absence of an α-fluoro moiety. The high steric demands of the substituted bicyclo[3.3.0] ring system promote dimers to an unusual extent and allow solvents and atropisomers in cubic tetramers to be observed in the slow-exchange limit. Pyridine used as a ⁶Li chemical shift reagent proved useful in assigning solvation numbers