Lithium Diisopropylamide: Nonequilibrium Kinetics and Lessons Learned about Rate Limitation

Abstract

The kinetics of lithium diisopropylamide (LDA) in tetrahydrofuran under non-equilibrium conditions are reviewed. These conditions correspond to a class of substrates in which the rates of LDA aggregation and solvation events are comparable to the rates at which various fleeting intermediates react with substrate. Substrates displaying these reactivities, by coincidence, happen to be those that react at tractable rates on laboratory timescales at −78 °C. In this strange region of non-limiting behavior, rate-limiting steps are often poorly defined, sometimes involve deaggregation and at other times include reaction with substrate. Changes in conditions routinely cause shifts in the rate-limiting steps, and autocatalysis is prevalent and can be acute. The studies are described in three distinct portions: (1) methods and strategies used to deconvolute complex reaction pathways, (2) the resulting conclusions about organolithium reaction mechanisms, and (3) perspectives on the concept of rate limitation reinforced by studies of LDA in tetrahydrofuran at −78 °C under non-equilibrium conditions.

Case for Lithium Tetramethylpiperidide-Mediated Ortholithiations: Reactivity and Mechanisms

“…The metalation of 4 to form 4-Li at −40 °C shows a zeroth-order THF dependence (Figure ). The slight downward drift is too small to be relevant, particularly given subtle secondary-shell effects of similar magnitude; however, there is a subtle and pedagogical reason why it should be observable. The THF dependence in conjunction with a half-order LiTMP dependence (Figure ) are consistent with the monosolvated-monomer-based mechanism (eqs and ). …”

“…Arene 1 , which has para-disposed CF 3 moieties, proceeds via a transition structure of stoichiometry [A 2 S 4 (ArH)] ‡ . The high solvation numbers are incompatible with any form of cyclic- or open-dimer-based metalation and instead implicates triple ion 11 analogous to those invoked in a number of previous investigations. ,, DFT computations suggest a weak dipolar interaction between a fluorine and the lithium cation as evidenced by a minor distortion that does not rise to the level of a discrete contact.…”

Lithium Hexamethyldisilazide-Mediated Enolization of Highly Substituted Aryl Ketones: Structural and Mechanistic Basis of the E/Z Selectivities

“…10,11 Rate studies were undertaken using the tactics described in two reviews. 12 Density functional theory (DFT) computations were carried out at the B3LYP/6–31G(d) level of theory 13 with single-point MP2 calculations. …”

“…The notion that a monomer would reaggregate to react seems blasphemous, but evidence supporting such processes has begun to accumulate (including a LiHMDS/THF-mediated enolization). 12b,20,23 …”

Di-Palladium Complexes are Active Catalysts for Mono-N-Protected Amino Acid Accelerated Enantioselective C-H Functionalization

“…To gain insight into whether C-H activation contributes to the rate of Pd-MPAA turnover, we turned to a study of deuterium kinetic isotope effect (KIE) experiments. [73][74][75] In the absence of MPAA ligand, dmaf olefination revealed a primary KIE (kH/kD = 3.91 ± 0.40, Figure 8A). In the presence of MPAA ligand, on the other hand, a small KIE was observed in the rates of formation of both major and minor enantiomers (kH/kD = 1.17 ± 0.03 and 1.47 ± 0.20, respectively).…”