Lithium enolates aggregation

Computational methods also indicate the stability of aggregated stmctures. Both ab initio and semiempirical calculations of the stmcture of the lithium enolate of methyl... 

Fig. 1.2. Unsolvated hexameric aggregate of lithium enolate of methyl r-butyl ketone the open circles represent oxygen and the small circles are lithium. Reproduced from J. Am. Chem. Soc., 108, 462 (1986), by permission of the American Chemical Society.

Experimentally, x values for gaseous lithium halides were determined as early as 1949 by molecular beam resonance experiments In solution, the quadrupolar interaction of ethyUithium and of t-butyllithium were investigated in 1964 . It was found that tetrameric and hexameric aggregates have different interactions. In the solid state x of tetrameric methyl- and ethyUithium was determined in 1965 and 1966 , and for lithium formate in 1972 . However, it was not untU Jackman started his investigations of lithium enolates and phenoxides in solution that the quadrupolar interaction was used in a systematic fashion to obtain structural information . 

Jackman and Szeverenyi were the first to systematically correlate the quadrupoiar interaction with molecular structure, i.e. with the aggregation of lithium enolates ". They noted that a tetrameric aggregate had a smaller QSC than a dimeric aggregate, ca 135 kHz compared to an estimate of 230 kHz for the dimer. The QSC of the tetramer was shown to be of the same magnitude in three different ethereal solvents. 

Wen and Grutzner used, among other NMR parameters, the QSC of the lithium enolate of acetaldehyde to deduce that it exists as tetramers of different solvation in THF and THF/n-hexane solvent systems . However, the most thorough study of Li QSC and the most interesting in the present context was reported by Jackman and coworkers in 1987167 -pjjg effects on the QSC values of both aggregation and solvation in a number of organolithium systems was studied in this paper, i.e. different arylamides, phenolates, enolates, substituted phenyllithium complexes and lithium phenylacetylide. 

Lithium enolates are the most studied lithium reagents because of their importance in synthetic chemistry. As in the cases of other lithium reagents, the state of aggregation... 

Wu and co-workers (Wu et al., 1999) have demonstrated a novel chiral lactone enolate-imine process to access 2-azetidinone diols such as 35 (Scheme 13.10). Treatment of 34 with LDA at — 25°C in THF followed by addition of imine 3, afforded only trace product. Addition of HMPA or the less toxic DMPU during the lithium enolate formation step improved the yield and the trans cis diastereoselectivity ( 90 10). Recrystallization improved the purity to >95 5 trans cis 2-azetidinone. Addition of an equivalent of lithium bromide accelerates the rate of ring closure, presumably by destabilizing the intermediate lithium aggregates. Side-chain manipulation of 35 was accomplished by sodium... 

Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on a,/S-unsaturated esters.27 Michael adducts have been obtained in ees up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction has been found to be determined by both the relative configuration of the stereogenic centres borne by the amide and the solvent. 

The low reactivity of glycine enolate with unactivated alkyl halides to form a-amino acids could be overcome by stabilizing the nucleophile using m-aminoindanol-derived hippuric acid 53. This key substrate was readily prepared from commercially available azalactone 54 by a one-pot operation (85% yield, 2 steps). The lithium enolate of amide acetonide 53 with a wide range of alkyl halides proceeded in moderate yields (>60%) and excellent diastereoselectivities (>95% de). Assuming that lithium halide would facilitate the dissociation of the amide enolate from the aggregated state and thus enhance its reactivity, 4 equivalents of lithium chloride were used as additive and resulted in a 25% increase in yield (Scheme 24.11). Reactions with secondary halides... 

It is not known whether lithium enolates exist in solution as homoaggregates or as mixed aggregates, nor is it known whether lithium enolates react as aggregates or via other species that might be present in low concentration. But it is certain that... 

After the proton transfer completion, the enolates tend to merge in (1 1) mixed aggregates with the excess lithium amide34. These species have so far been the object of relatively little attention48. Then, as the enolization proceeds to completion, the aggregated enolates form at the expense of the mixed dimers. Another aspect to be considered is the interaction between the lithium enolate and the amine released after protonation of the amide49. This phenomenon will be discussed in the section dedicated to the enantios-elective reactions of enolates. 

As most organometallic compounds, lithium enolates are highly polar entities susceptible to combine in various types of (eventually solvated) aggregates that undergo dynamic equilibria in solution. This phenomenon explains why enolate solutions are difficult to describe by the classical spectroscopic, physicochemical or theoretical methods, a difficulty enhanced by the sensitivity of these equilibria to many physicochemical factors such as the concentration, the temperature or the presence of complexing additives (lithium halides, amides, amines, HMPA,. ..). The problems due to dynamics are avoided in the solid state where many clusters of lithium enolates, alone or co-crystallized with exogenous partners, have been identified by X-ray crystallography. 

The structure of mixed aggregates involving ester enolates is also of major interest to macromolecular chemists, since ionic additives are often introduced in the polymerization medium. The more stable arrangement between lithium 2-methoxyethoxide and MIB lithium enolate was thus calculated (at the DFT level) to be a 5 1 hexagonal complex with similar O—Li lateral coordinations212. The same team has recently extended this study to complexes formed between the same enolate in THF and a-ligands such as TMEDA, DME, 12-crown-4 and cryptand-2,1,1213. Only in the case of the latter ligand could a separate ion pair [(MIB-Li-MIB),2 THF]-, Li(2,l,l)+ be found as stable, still at the DFT level, as the THF solvated dimer [(MIB-Li)2,4 THF]. 

SCHEME 57. Various types of solid-state aggregation of /3-ketocarbonyl compounds (A) unsolvated dimer [(CH3C(OLi)CH-COOEt]2]222 (B) unsolvated hexameric [(CH3C(OLi)CHCOOBu-t]6223 (C) tetrasolvated dimer of 1,3-cyclohexanedione lithium enolate exhibiting both O—Li and O—H coordinations224... 

SCHEME 59. Various types of solid-state mixed aggregates involving ketone lithium enolates (A) pinacolone enolate/lithium amide [LiHMDS/CH2C(OLi)Bu-i, 2 DME]230 (B) pentan-3-one enolate/2 chiral lithium amide232 (C) pinacolone enolate/lithium amide/LiBr [LiHMDS/2 Cl HCtOI.ijBu-f/LiBr, 2 TMEDA]235... 

SCHEME 60. Solid-state aggregation of (thio)ester lithium enolates (A) chelated dimer [(c-Pr= C(OLi)SBu-f)2, 2 TMEDA]236 (B) chelated hexamer of racemic (NH2CH(Me)CH2CH=C(OMe) OLi]6240... 

SCHEME 61. Solid-state aggregation of amide lithium enolates (A) tetrasolvated dimer [(C-C7H12C(OLi)NMe2)2, 4 THF]241 (B) intramolecular chelated [(PhC(OLi)=NPr- )6, 2 THF]243... 

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