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Introduction to the Reactions of Enols and Enolates

Alkylation of the α Position of CH-acidic Compounds

Enolate anions are nucleophiles. Thus, they can participate in SN2 reactions. If alkyl halides are applied as electrophiles, alkylation of the enolate occurs. Due to the enolate's ambident character, O-alkylation or C-alkylation may take place. The practicality of the reaction therefore depends on the selectivity for one of the alkylation variations. The question is which position in the enolate displays the highest nucleophilicity. Nucelophilicity also depends on the electrophile. In alkylation with alkyl halides, the electrophile is a relatively soft Lewis acid. For that reason, C-alkylation of the enolate is favored, as, due to carbon's lower electronegativity, the enolate's carbon position is a much softer Lewis base than the oxygen position. According to the HSAB concept, a soft Lewis base tends to react with a soft Lewis acid, while a hard Lewis base tends to react with a hard Lewis acid. The fact that the enolate's carbon position is a softer base than the oxygen position may be illustrated by the graph of the enolate's HOMO. The larger orbital lobes at the carbon indicate that the electron density at the carbon is more nebulous than that at the oxygen, so, the carbon is a softer base than the oxygen.

C- and O-alkylation of enolates.
HOMO of the enolateC- and O-alkylation

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If a harder base is applied as an electrophile, O-alkylation may become considerably disturbing (aside from the case that O-alkylation is desired). In order to prevent O-alkylation in these cases, the carbonyl compound may, first of all, be converted to the corresponding enamine. After the enamine has been C-alkylated, hydrolysis then yields the C-alkylated carbonyl compound.

The possibility of a low selectivity between C- and O-alkylation is not the only problem of the alkylation of enolates. In addition, multiple alkylation may occur. As a result, a mixture of products is obtained.

Multiple alkylation.

In alkylation of carbonyl compounds, the enolate is actually the attacking nucleophile. Thus, if enolization cannot occur, alkylation cannot take place. Therefore, carbonyl compounds that contain only one α hydrogen atom (i.e. CR3COCHR2) can only be monoalkylated. Multiple alkylation is not an option. If the carbonyl compound possesses more than one α hydrogen atom, multiple alkylation can largely be prevented by applying a bulky, sterically demanding base, such as the widely used lithium diisopropylamide (LDA). In this case, further deprotonation and, thus, enolate formation of an existing monoalkylated carbonyl compound is hampered by additional steric interactions between the alkyl group and the bulky isopropyl substituents of LDA.

Exercise 1

Exercise 2

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