Lithium hexamethyldisilylamide

LHMDs, lithium hexamethyldisilylamide LTMP, lithium 2,2,6,6-tetramethyl-piperidide. 

Deprotonation of carbonyl compounds by lithium dialkylamide bases is the single most common method of forming alkali enolates. Four excellent reviews have already been published. " Sterically hindered amide bases are employed to retard nucleophilic attack on the carbonyl group. The most common and generally useful bases are (i) lithium diisopropylamide (LDA 5) (ii) lithium isopropylcyclo-hexylamide (LICA 6) (iii) lithium 2,2,6,6-tetramethylpiperidide (LITMP 7) (iv) lithium hexamethyldisilylamide (LHMDS 8) and (v) lithium tetramethyldiphenyldisilylamide (LTDDS 9). Bases that are not amides include sodium hydride, potassium hydride and triphenylmethyllithium. 

Structural effects on the rates of deprotonation of ketones have also been studied using veiy strong bases under conditions where complete conversion to the enolate occurs. In solvents such as THF or DME, bases such as lithium di-/-propylamide (LDA) and potassium hexamethyldisilylamide (KHMDS) give solutions of the enolates in relative proportions that reflect the relative rates of removal of the different protons in the carbonyl compound (kinetic control). The least hindered proton is removed most rapidly under these... 

A quite consistent relationship is found in these and related data. Conditions of kinetic control usually favor the less substituted enolate. The principal reason for this result is that removal of the less hindered hydrogen is faster, for steric reasons, than removal of more hindered protons. Removal of the less hindered proton leads to the less substituted enolate. Steric factors in ketone deprotonation can be accentuated by using more highly hindered bases. The most widely used base is the hexamethyldisilylamide ion, as a lithium or sodium salt. Even more hindered disilylamides such as hexaethyldisilylamide7 and bis(dimethylphenylsilyl)amide8 may be useful for specific cases. On the other hand, at equilibrium the more substituted enolate is usually the dominant species. The stability of carbon-carbon double bonds increases with increasing substitution, and this effect leads to the greater stability of the more substituted enolate. 

To circumvent problems of nucleophilicity, lithium diisopropylamide (LDA), potassium hexamethyldisilylamide (KHMDS), and KH are often employed for proton removal since they are very strong bases (pKa > 35) but relatively poor nucleophiles. Hence they remove protons from acidic C-H bonds but normally do not attack carbonyl groups or other electrophilic centers. 

The pK measurements are nicely supported by efforts of Seebach and coworkers to get hold of the elusive nitrocyclopropyl anion . When nitrocyclopropane was treated at temperatures between —80 and — 110°C with bases such as butyllithium, LDA or potassium hexamethyldisilylamide in THF, yellow to red solutions have been obtained which were thought to contain the lithium salt of acinitrocyclopropane (267a). Workup after any amount of time, raising the temperature, or addition of any electrophile with or without oxidizing properties, always led to the isolation of mixtures of the colorless dinitro-compound 268, and of the deep-blue nitro-nitroso compound 269. 

By adjusting the conditions under which an enolate mixture is formed from a ketone, it is possible to establish either kinetic or thermodynamic control. Ideal conditions for kinetic control of enolate formation are those in which deprotonation is rapid, quantitative, and irreversible, This ideal is approached experimentally by using a very strong base such as lithium diisopropylamide or hexamethyldisilylamide in an aprotic solvent in the absence of excess ketone. Lithium as the counterion is better than sodium or potassium for regioselective generation of the kinetic enolate. Aprotic solvents are required because protic solvents permit enolate equilibration by allowing reversible protonation-deprotonation, which gives rise to the thermodynamically controlled enolate composition. Excess ketone also catalyzes the equilibration. 

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