Structure Determination Using the Method of Continuous Variation: Lithium Phenolates Solvated by Protic and Dipolar Aprotic Ligands

The method of continuous variation (MCV) was used in conjunction with ⁶Li NMR spectroscopy to characterize four lithium phenolates solvated by a range of solvents, including <i>N</i>,<i>N</i>,<i>N</i>′,<i>N</i>′-tetramethylethylenediamine, Et₂O, pyridine, protic amines, alcohols, and highly dipolar aprotic solvents. Dimers, trimers, and tetramers were observed, depending on the precise lithium phenolate–solvent combinations. Competition experiments (solvent swaps) provide insights into the relative propensities toward mixed solvation

Solid-State and Solution Structures of Glycinimine-Derived Lithium Enolates

A combination of crystallographic, spectroscopic, and computational studies was applied to study the structures of lithium enolates derived from glycinimines of benzophenone and (+)-camphor. The solvents examined included toluene and toluene containing various concentrations of tetrahydrofuran, <i>N,N,N</i>′<i>,N</i>′-tetra­methyl­ethylene­diamine (TMEDA), (<i>R,R</i>)-<i>N,N,N</i>′<i>,N</i>′-tetra­methyl­cyclo­hexane­diamine [(<i>R,R</i>)<i>-</i>TMCDA], and (<i>S,S</i>)-<i>N,N,N</i>′<i>,N</i>′-tetra­methyl­cyclo­hexane­diamine [(<i>S,S</i>)<i>-</i>TMCDA]. Crystal structures show chelated monomers, symmetric disolvated dimers, <i>S</i>₄-symmetric tetramers, and both <i>S</i>₆- and <i>D</i>_3<i>d</i>-symmetric hexamers. ⁶Li NMR spectroscopic studies in conjunction with the method of continuous variations show how these species distribute in solution. Density functional theory computations offer insights into experimentally elusive details

Case for Lithium Tetramethylpiperidide-Mediated Ortholithiations: Reactivity and Mechanisms

Rate and mechanistic studies of ortholithiations by lithium 2,2,6,6-tetramethylpiperidide focus on four arenes: 1,4-bis­(trifluoromethyl)­benzene, 1,3-bis­(trifluoromethyl)­benzene, 1,3-dimethoxybenzene, and 4,4-dimethyl-2-phenyl-2-oxazoline. Metalations occur via substrate-dependent combinations of monosolvated monomer, disolvated monomer, and tetrasolvated dimer (triple ions). Density functional theory computational studies augment the experimental data. We discuss the challenges presented by shifting dimer–monomer proportions in determining the observable reaction orders and our mathematical treatment of such shifting in reactant structure

Evans Enolates: Solution Structures of Lithiated Oxazolidinone-Derived Enolates

The results of a combination of ⁶Li and ¹³C NMR spectroscopic and computational studies of oxazolidinone-based lithium enolatesEvans enolatesin tetrahydrofuran (THF) solution revealed a mixture of dimers, tetramers, and oligomers (possibly ladders). The distribution depended on the structure of the oxazolidinone auxiliary, substituent on the enolate, and THF concentration (in THF/toluene mixtures). The unsolvated tetrameric form contained a <i>D</i>_2<i>d</i>-symmetric core structure, whereas the dimers were determined experimentally and computationally to be trisolvates with several isomeric forms

Method of Continuous Variation: Characterization of Alkali Metal Enolates Using ¹H and ¹⁹F NMR Spectroscopies

The method of continuous variation in conjunction with ¹H and ¹⁹F NMR spectroscopies was used to characterize lithium and sodium enolates solvated by <i>N</i>,<i>N</i>,<i>N</i>′,<i>N</i>′-tetramethylethyldiamine (TMEDA) and tetrahydrofuran (THF). A strategy developed using lithium enolates was then applied to the more challenging sodium enolates. A number of sodium enolates solvated by TMEDA or THF afford exclusively tetramers. Evidence suggests that TMEDA chelates sodium on cubic tetramers

Lithium Enolates Derived from Weinreb Amides: Insights into Five-Membered Chelate Rings

Enolization of <i>O</i>-methyl hydroxamic acids (Weinreb amides) in tetrahydrofuran solution with lithium diisopropylamide affords predominantly tetrameric enolates. Aryl substituents on the enolates promote deaggregation. The aggregation states are assigned by using the method of continuous variation in conjunction with ⁶Li NMR spectroscopy. Decoalescence of the tetramer resonance below −100 °C shows considerable spectral complexity attributed to isomerism of the methoxy-based chelates. Density functional theory calculations were used to examine the consequences of the bite angle of five-membered chelates in cubic tetramers and resulting solvation numbers that were higher than anticipated

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

Structure–Reactivity Relationships in Lithiated Evans Enolates: Influence of Aggregation and Solvation on the Stereochemistry and Mechanism of Aldol Additions

Aldol additions to isobutyraldehyde and cyclohexanone with lithium enolates derived from acylated oxazolidinones (Evans enolates) are described. Previously characterized trisolvated dimeric enolates undergo rapid addition to isobutyraldehyde to give a 12:1 syn:syn selectivity in high yield along with small amounts of one anti isomer. The efficacy of the addition depends critically on aging effects and the reaction quench. Unsolvated tetrameric enolates that form on warming the solutions are unreactive toward isobutyraldehyde and undergo retroaldol reaction under forcing conditions. Additions to cyclohexanone are relatively slow but form a single isomeric adduct in >80% yield. The ketone-derived aldolates are robust. All attempts to control stereoselectivity by controlling aggregation failed. Rate studies of addition to cyclohexanone trace the lack of aggregation-dependent selectivities to a monomer-based mechanism. The synthetic implications and possible utility of lithium enolates in Evans aldol additions 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