“…Zeroing the IR baseline and monitoring a second injection afford no significant change in the rate constant, showing that conversion-dependent autocatalysis or autoinhibition are unimportant under these conditions . Comparisons of 3 and 3- d 3 provided large kinetic isotope effects, confirming rate-limiting proton transfers. − 1 Relative Rate Constants ( k r el , in parentheses) for the Enolization of 2-Methylcyclohexanone (1) by LiHMDS (eq 1) in the Presence of 1.5 Equiv of Ethereal Ligand in Toluene at −78 °C a a The values are relative to enolizations in neat (ether-free) toluene ( k rel = 1). …”
Mechanistic studies of the enolization of 2-methylcyclohexanone mediated by lithium hexamethyldisilazide (LiHMDS; TMS(2)NLi) solvated by hindered dialkyl ethers (ROR') are described. Rate studies using in situ IR spectroscopy show that enolizations in the presence of i-Pr(2)O, 2,2,5,5-tetramethyltetrahydrofuran, and cineole proceed via dimer-based transition structures [(TMS(2)NLi)(2)(ROR')(ketone)]. Comparing the relative solvation energies and the corresponding solvent-dependent activation energies shows that the highly substituted ethers accelerate the enolizations by sterically destabilizing the reactants and stabilizing the transition structures. Comparisons of hindered dialkyl ethers with their isostructural dialkylamines reveal that the considerably higher rates elicited by the amines derive from an analogous relative destabilization of the reactants and relative stabilization of the transition structures.
“…Zeroing the IR baseline and monitoring a second injection afford no significant change in the rate constant, showing that conversion-dependent autocatalysis or autoinhibition are unimportant under these conditions . Comparisons of 3 and 3- d 3 provided large kinetic isotope effects, confirming rate-limiting proton transfers. − 1 Relative Rate Constants ( k r el , in parentheses) for the Enolization of 2-Methylcyclohexanone (1) by LiHMDS (eq 1) in the Presence of 1.5 Equiv of Ethereal Ligand in Toluene at −78 °C a a The values are relative to enolizations in neat (ether-free) toluene ( k rel = 1). …”
Mechanistic studies of the enolization of 2-methylcyclohexanone mediated by lithium hexamethyldisilazide (LiHMDS; TMS(2)NLi) solvated by hindered dialkyl ethers (ROR') are described. Rate studies using in situ IR spectroscopy show that enolizations in the presence of i-Pr(2)O, 2,2,5,5-tetramethyltetrahydrofuran, and cineole proceed via dimer-based transition structures [(TMS(2)NLi)(2)(ROR')(ketone)]. Comparing the relative solvation energies and the corresponding solvent-dependent activation energies shows that the highly substituted ethers accelerate the enolizations by sterically destabilizing the reactants and stabilizing the transition structures. Comparisons of hindered dialkyl ethers with their isostructural dialkylamines reveal that the considerably higher rates elicited by the amines derive from an analogous relative destabilization of the reactants and relative stabilization of the transition structures.
“…Very little is known about lithium amide enolization of unhindered ketones like 1-H . Isotope effects and Z / E ratios , based on product studies have provided only an indirect understanding of the role of aggregates.…”
Lithium enolates are widely used nucleophiles with a complicated and only partially understood solution chemistry. Deprotonation of 4-fluoroacetophenone in THF with lithium diisopropylamide occurs through direct reaction of the amide dimer to yield a mixed enolate-amide dimer (3), then an enolate homodimer (1-Li)(2), and finally an enolate tetramer (1-Li)(4), the equilibrium structure. Aldol reactions of both the metastable dimer and the stable tetramer of the enolate were investigated. Each reacted directly with the aldehyde to give a mixed enolate-aldolate aggregate, with the dimer only about 20 times as reactive as the tetramer at -120 °C.
“…Reestablishing the IR baseline and monitoring a second injection reveals no significant change in the rate constant, showing that conversion-dependent autocatalysis or autoinhibition is unimportant under these conditions . Comparisons of 3 versus 3- d 3 , and 4 versus 4- d 3 provided large kinetic isotope effects (see Supporting Information), confirming rate-limiting proton transfers. , …”
Mechanistic studies of the enolization of 2-methylcyclohexanone mediated by lithium hexamethyldisilazide (LiHMDS; TMS2NLi) in toluene and toluene/amine mixtures are described. NMR spectroscopic studies of LiHMDS/ketone mixtures in toluene reveal the ketone-complexed cyclic dimer (TMS2NLi)2(ketone). Rate studies using in situ IR spectroscopy show the enolization proceeds via a dimer-based transition structure, [(TMS2NLi)2(ketone)]++. NMR spectroscopic studies of LiHMDS/ketone mixtures in the presence of relatively unhindered trialkylamines such as Me2NEt reveal the quantitative formation of cyclic dimers of general structure (TMS2NLi)2(R3N)(ketone). Rate studies trace a >200-fold rate acceleration to a dimer-based transition structure, [(TMS2NLi)2(R3N)(ketone)]++. Amines of intermediate steric demand, such as Et3N, are characterized by recalcitrant solvation, saturation kinetics, and exceptional (>3000-fold) accelerations traced to the aforementioned dimer-based pathway. Amines of high steric demand, such as i-Pr2NEt, do not observably solvate (TMS2NLi)2(ketone) but mediate enolization via [(TMS2NLi)2(R3N)(ketone)]++ with muted accelerations. The most highly hindered amines, such as i-Bu3N, do not influence the LiHMDS structure or the enolization rate. Overall, surprisingly complex dependencies of the enolization rates on the structures and concentrations of the amines derive from unexpectedly simple steric effects. The consequences of aggregation, mixed aggregation, and substrate-base precomplexation are discussed.
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