Acidity of Aldehydes and Ketones
For alkylation reactions of enolate anions to be useful, these intermediates must be generated in high concentration in the absence of other strong nucleophiles and bases. The aqueous base conditions used for the aldol condensation are not suitable because the enolate anions of simple carbonyl compounds are formed in very low concentration, and hydroxide or alkoxide bases induce competing SN2 and E2 reactions of alkyl halides. It is necessary, therefore, to achieve complete conversion of aldehyde or ketone reactants to their enolate conjugate bases by treatment with a very strong base (pKa > 25) in a non-hydroxylic solvent before any alkyl halides are added to the reaction system. Some bases that have been used for enolate anion formation are: NaH (sodium hydride, pKa > 45), NaNH2 (sodium amide, pKa = 34), and LiN[CH(CH3)2]2 (lithium diisopropylamide, LDA, pKa 36). Ether solvents like tetrahydrofuran (THF) are commonly used for enolate anion formation. With the exception of sodium hydride and sodium amide, most of these bases are soluble in THF. Certain other strong bases, such as alkyl lithium and Grignard reagents, cannot be used to make enolate anions because they rapidly and irreversibly add to carbonyl groups. Nevertheless, these very strong bases are useful in making soluble amide bases. In the preparation of lithium diisopropylamide (LDA), for example, the only other product is the gaseous alkane butane.
