Ketone Enolization by Lithium Hexamethyldisilazide:  Structural and Rate Studies of the Accelerating Effects of Trialkylamines

Abstract

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.

Lithium Diisopropylamide: Solution Kinetics and Implications for Organic Synthesis

“…The two models are mathematically indistinguishable, yet the latter is more probable within organolithium chemistry 10. 21 Such saturation is commonly observed in plots of k obs versus solvent concentration [Eq. (9)] owing to a solvent‐dependent change in aggregation31 or solvation number 10.…”

“…A zeroth‐order dependence (Figure 5, b =0) indicates that no additional solvent molecule is required beyond that already coordinated to the LDA ([AS(substrate)] ≠ or [A 2 S 2 (substrate)] ≠ ; Table 1, entries 2 and 8). In this instance, the coordinated solvent is still important (sometimes profoundly so),10, 21 but the existence and concentration of the uncoordinated solvent is not. An inverse solvent dependence (Figure 5, b =−1) is indicative of a mechanism demanding dissociation of one solvent ligand ([A(substrate)] ≠ or [A 2 S(substrate)] ≠ ).…”

“…Dimeric LDA–substrate complexes ( 4 ), most often detected by in situ IR spectroscopy,21, 24 typically form in weakly coordinating solvents 25. In contrast to the formation of transient complexes along the reaction coordinate, the formation of observable complexes significantly influences the concentration dependencies 25.…”

“…(9)] owing to a solvent‐dependent change in aggregation31 or solvation number 10. 21 Such saturation behavior usually results in an increase in rate to an asymptotic limit (Figure 8, curve A), but can result in a decrease to an asymptotic limit if the more solvated form is less reactive (Figure 8, curve B) 21 …”

Quenching of Singlet Oxygen by Tertiary Aliphatic Amines. Structural Effects on Rates and Products

“…The ring CÀH bonds in a-position to 2 ) A greater steric demand for 4 than for 5 has recently been suggested to explain the different catalytic effect of the two amines in ketone enolization [9]. 3 ) Clearly, dealing with a competition, it might also be suggested that the observed trend in the Q c values is due to a physical quenching that becomes less efficient as the oxidation potential of the amine decreases.…”