Mechanistic Studies of the Lithium Enolate of 4-Fluoroacetophenone: Rapid-Injection NMR Study of Enolate Formation, Dynamics, and Aldol Reactivity

Abstract

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.

Structure–Reactivity Relationships in Lithiated Evans Enolates: Influence of Aggregation and Solvation on the Stereochemistry and Mechanism of Aldol Additions

“…In the case of adding enolate 5 to cyclohexanone (Scheme 2), a rate law (eq 7) in conjunction with the assigned reactants as trisolvated dimers provided the generic mechanism involving a disolvated monomer intermediate (eqs 8 and 9). Despite speculation 34 and hard evidence 32 that the aldol addition occurs from aggregates, we found no support for aggregate-based Evans aldol additions. Of course, generalizing our results to other aldol additions is ill-advised.…”

“…8,10,32 That is not to say, however, that deaggregation necessarily occurs before aldol addition. The results of our previous studies showed that enolization with LDA forms isomeric trisolvated dimers 2a/b , which are kinetically stable at −78 °C.…”

“…This outcome is consistent with Reich’s observations that metastable dimers are more reactive than tetramers. 7,10,32 Attempts to force a tetramer-derived aldol addition, however, lead to debris and stereochemical erosion (Scheme 3) owing to the penchant of the aldolate to undergo retroaldol addition (eq 5). 6 …”

Three-Component Glycolate Michael Reactions of Enolates, Silyl Glyoxylates, and α,β-Enones

“…The addition of superstoichiometric lithium chloride provided optimal conversion and diastereoselectivity, which may be due to altered aggregation of the glycolate enolate or an increased degree of chelation during Michael addition. 30,31 …”

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

“…6 Most recently, Reich and coworkers have focused on measuring relative reactivities of aggregates and monomers under nonequilibrium conditions. 7 …”