Aggregation and Cooperative Effects in the Aldol Reactions of Lithium Enolates

Abstract

Density functional theory and Car-Parrinello molecular dynamics simulations have been carried out for model aldol reactions involving aggregates of lithium enolates derived from acetaldehyde and acetone. Formaldehyde and acetone have been used as electrophiles. It is found that the geometries of the enolate aggregates are in general determined by the most favorable arrangements of the point charges within the respective Lin On clusters. The reactivity of the enolates follows the sequence monomer≫dimer>tetramer. In lithium aggregates, the initially formed aldol adducts must rearrange to form more stable structures in which the enolate and alkoxide oxygen atoms are within the respective Lin On clusters. Positive cooperative effects, similar to allosteric effects found in several proteins, are found for the successive aldol reactions in aggregates. The corresponding transition structures show in general sofa geometries.

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

“…Moreover, favorable stereochemical influence was in doubt given that homotetrameric enolate 5 reacts sluggishly via a fleeting monomer rather than via a tetramer. 19 In short, we got lucky: tetrameric mixed aggregates form with excellent structural control and react rapidly without dissociation (Scheme 4). This success is by no means simple when viewed in detail.…”

Stereoselective Coupling of N-tert-Butanesulfinyl Aldimines and β-Keto Acids: Access to β-Amino Ketones

“…In the case of TS1­( R ) (Figure ), the S-Me group (S- t -Bu in the experiments) lies away of the cyclic structure and the proton migration from the starting enol to the carboxy moiety has been completed. The critical C···C bond distance is close to 2 Å, an expected value for aldol-like reactions involving complex lithium enolates . The chief geometric features of TS1­( S ) are similar to those of its ( R )-congener, with the exception of the steric clash generated by the S-Me group and the acetyl group coming from the 2-oxobutirate.…”

“…The critical C•••C bond distance is close to 2 Å, an expected value for aldol-like reactions involving complex lithium enolates. 23 The chief geometric features of TS1(S) are similar to those of its (R)-congener, with the exception of the steric clash generated by the S-Me group and the acetyl group coming from the 2-oxobutirate. As a consequence, TS1(S) lies 2.9 kcal/mol above TS1(R).…”

Structures and Reactivities of Sodiated Evans Enolates: Role of Solvation and Mixed Aggregation on the Stereochemistry and Mechanism of Alkylations

“…Mixed aggregates 5 – 7 could impose stereochemical control over the alkylations provided that the mixed aggregates react without dissociation to monomer 4 . , Although alkylations of 5 and 6 gave poor results presumably owing to the nefarious reactivities of the sodium amide fragments, the phenolate-derived mixed dimer 7 showed promise: it reacted cleanly and altered the product distribution, albeit in the wrong direction (eq ). Here is why we still find the experiment interesting.…”