The reactivities and chemoselectivities of sodium diisopropylamide (NaDA) in N,N-dimethylethylamine (DMEA) are compared with those of lithium diisopropylamide (LDA) in tetrahydrofuran (THF). Metalations of arenes, epoxides, ketones, hydrazones, dienes, and alkyl and vinyl halides are represented. The positive attributes of NaDA–DMEA include high solubility, stability, resistance to solvent decomposition, and ease of preparation. The high reactivities and chemoselectivities often complement those of LDA–THF.

The solution structure, 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 N,N-dimethylethylamine (DMEA) at −20 °C. A combination of NMR spectroscopic and computational studies show that NaDA is a disolvated symmetric dimer in DMEA, N,N-dimethyl-n-butylamine, and N-methylpyrrolidine. Tetrahydrofuran (THF) readily displaces DMEA, affording a tetrasolvated cyclic dimer at all THF concentrations. Dimethoxyethane (DME) and N,N,N′,N′-tetramethylethylenediamine (TMEDA) quantitatively displace DMEA, affording doubly chelated symmetric dimers. The trifunctional ligands N,N,N′,N″,N″-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.

Generality in asymmetric catalysis can be manifested in dramatic and valuable ways, such as high enantioselectivity across a wide assortment of substrates in a given reaction (broad substrate scope) or as applicability of a given chiral framework across a variety of mechanistically distinct reactions (privileged catalysts). Reactions and catalysts that display such generality hold special utility, because they can be applied broadly and sometimes even predictably in new applications. Despite the great value of such systems, the factors that underlie generality are not well understood. Here, we report a detailed investigation of an asymmetric hydrogen-bond-donor catalyzed oxetane opening with TMSBr that is shown to possess unexpected mechanistic generality. Careful analysis of the role of adventitious protic impurities revealed the participation of competing pathways involving addition of either TMSBr or HBr in the enantiodetermining, ring-opening event. The optimal catalyst induces high enantioselectivity in both pathways, thereby achieving precise stereocontrol in fundamentally different mechanisms under the same conditions and with the same chiral framework. The basis for that generality is analyzed using a combination of experimental and computational methods, which indicate that proximally localized catalyst components cooperatively stabilize and precisely orient dipolar enantiodetermining transition states in both pathways. Generality across different mechanisms is rarely considered in catalyst discovery efforts, but we suggest that it may play a role in the identification of so-called privileged catalysts.

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.

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 Z-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.