What’s Going on with These Lithium Reagents?

Abstract

This Perspective describes a series of research projects that led the author from an interest in lithium reagents as synthetically valuable building blocks to studies aimed at understanding the science behind the empirical art developed by synthetic chemists trying to impose their will on these reactive species. Understanding lithium reagent behavior is not an easy task; since many are mixtures of aggregates, various solvates are present, and frequently new mixed aggregates are formed during their reactions with electrophiles. All of these species are typically in fast exchange at temperatures above -78 °C. Described are multinuclear NMR experiments at very low temperatures aimed at defining solution structures and dynamics and some kinetic studies, both using classic techniques as well as the rapid inject NMR (RINMR) technique, which can in favorable cases operate on multispecies solutions without the masking effect of the Curtin-Hammett principle.

Lithium Amino Alkoxide–Evans Enolate Mixed Aggregates: Aldol Addition with Matched and Mismatched Stereocontrol

“…22 In a second experiment, the addition of 2.0 equiv hexamethylphosphoramide (HMPA) per lithium to a THF solution afforded ( S )- 25a for which the most upfield resonance appeared as a doublet (0.26 ppm, J Li–P = 4.3 Hz) owing to 6 Li – 31 P coupling, but no change in the four 6 Li chemical shifts was observed. 32 …”

“…Coordination by external ligands was probed using pyridine as a 6 Li chemical shift reagent and HMPA to show specific solvent-lithium contacts through 6 Li– 31 P coupling. 32 The stereochemical assignments stem from the application of a battery of two-dimensional spectroscopic methods complemented by DFT computations. Several mixed aggregates received less scrutiny but are secure nonetheless.…”

Alkali-Controlled C–H Cleavage or N–C Bond Formation by N2-Derived Iron Nitrides and Imides

“…21 However, we know of no other examples where alkali chelation has been used to enhance the reactivity of N 2 reduction products. We anticipate that future ligand designs could encourage alkali metal binding that can be turned on and off to modulate the reactivity.…”

Azaaldol Condensation of a Lithium Enolate Solvated by N,N,N′,N′-Tetramethylethylenediamine: Dimer-Based 1,2-Addition to Imines

“…31,32,33,34 We modeled the tert -amyl group with a methyl. The reported energies correspond to the calculated free energies of activation at −60 °C and to fully balanced equilibria.…”

“…We hasten to add, however, that despite the enormous computed barrier for triple ion 5h —DFT is notoriously incapable of modeling ionization energies 38 —triple ion 5h has considerable appeal. Triple ions, including those derived from lithium enolates, 32 are well precedented 31,32 The (η 2 -TMEDA) 2 Li + counterion is well precedented 37 and the (η 2 -TMCDA) 2 Li + cation has been documented as well. 43 The bidentate interaction of the ester enolate in 5h also has structural precedent.…”