15 research outputs found
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 1â4), 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)âprimarily concerned with preparation and crystallographyâsuggested 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 BrĂśnsted 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 dimerâmonomer equilibrium of LiHMDS in THFâ hydrocarbon mixtures. As part of our research program of oxazolidinone-based enolates, â the so-called Evans enolates that have appeared in more than 1600 patents and countless academic and industrial synthesesâ we were drawn to the sequential enolizationâaldol 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 THFâhydrocarbon 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 â and many other substrates â 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/Me<sub>2</sub>NEt 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 â78 °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 sodiumâoxygen
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 diisopropylÂamide (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>-dimethylÂethylÂamine (DMEA) at â20 °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>-butylÂamine, and <i>N</i>-methylÂpyrrolidine.
TetraÂhydrofuran (THF) readily displaces DMEA, affording a tetraÂsolvated
cyclic dimer at all THF concentrations. Dimethoxyethane (DME) and <i>N,N,N</i>â˛<i>,N</i>â˛-tetraÂmethylÂethyleneÂdiamine
quantitatively displace DMEA, affording doubly chelated symmetric
dimers. The trifunctional ligands <i>N,N,N</i>â˛<i>,N</i>âł<i>,N</i>âł-pentaÂmethylÂdiethyleneÂtriamine
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 THFâhydrocarbon 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-bisÂ(trifluoromethyl)Âbenzene with lithium diisopropylamide
in tetrahydrofuran at â78 °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 Pyroglutaminol: Aggregation, Solvation, and Atropisomerism
Lithium enolates derived from protected
pyroglutaminols were characterized
by using <sup>6</sup>Li, <sup>13</sup>C, and <sup>19</sup>F 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 Îą-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 <sup>6</sup>Li chemical shift reagent proved useful in assigning
solvation numbers