Enolate ion alkylation is a powerful tool for forming new carbon-carbon bonds. This process involves deprotonating carbonyl compounds to create nucleophilic enolate ions, which then attack electrophilic alkyl halides in SN2 reactions.

Malonic and acetoacetic ester syntheses are two key applications of enolate chemistry. These methods allow for the creation of substituted acetic acids and methyl ketones, respectively, through alkylation, hydrolysis, and decarboxylation steps.

Enolate Ion Alkylation and Synthesis

Mechanism of enolate ion alkylation

• Enolate ion formation occurs when a carbonyl compound (ketone or ester) is deprotonated by a strong base (LDA, NaH) at the α-carbon adjacent to the carbonyl group
• Resonance structures of the enolate ion delocalize the negative charge between the α-carbon and oxygen atom, increasing stability compared to a localized carbanion
• Alkylation reaction proceeds with the enolate ion acting as a nucleophile, attacking the electrophilic carbon of an alkyl halide (R-X) via an $S_N2$ reaction mechanism
  • Backside attack of the enolate ion on the alkyl halide causes inversion of stereochemistry at the electrophilic carbon
  • Forms a new C-C bond and regenerates the carbonyl group

Steps in malonic ester synthesis

1. Deprotonation of diethyl malonate by a strong base (NaOEt) forms a resonance-stabilized enolate ion
2. Alkylation of the enolate ion with an alkyl halide occurs via an $S_N2$ reaction mechanism, forming a new C-C bond
3. Hydrolysis of the alkylated malonic ester is achieved through acid-catalyzed hydrolysis of the ester groups, forming a dicarboxylic acid
4. Decarboxylation of the dicarboxylic acid by heating above its melting point results in loss of carbon dioxide ($CO_2$) and formation of the desired monocarboxylic acid

• Malonic ester synthesis is useful for preparing substituted acetic acids (alkyl halide determines α-carbon substituent) and synthesizing longer-chain carboxylic acids not readily available

Acetoacetic vs malonic ester synthesis

• Similarities: both involve alkylation of an enolate ion (formed by deprotonation of a β-ketoester or malonic ester) via an $S_N2$ reaction with an alkyl halide, followed by hydrolysis and decarboxylation steps
• Differences in reactants: acetoacetic ester synthesis uses ethyl acetoacetate, while malonic ester synthesis uses diethyl malonate
• Differences in products: acetoacetic ester synthesis yields methyl ketones, while malonic ester synthesis yields substituted acetic acids
• Mechanistic differences: in acetoacetic ester synthesis, alkylation occurs at the α-carbon between two carbonyl groups; in malonic ester synthesis, alkylation occurs at the α-carbon flanked by two ester groups
• Synthetic utility differs: acetoacetic ester synthesis prepares methyl ketones and derivatives, while malonic ester synthesis prepares substituted acetic acids and longer-chain carboxylic acids

Enolate formation and reactivity

• The pKa of the α-hydrogen affects the ease of enolate formation, with lower pKa values indicating greater acidity and easier deprotonation
• Kinetic vs. thermodynamic enolates: kinetic enolates form faster but may be less stable, while thermodynamic enolates are more stable but form more slowly
• The choice of base and reaction conditions can influence the formation of kinetic or thermodynamic enolates, affecting the regioselectivity of alkylation reactions