Dicarbonyl Compounds (Chapter 23)

Claisen Condensation Irreversible (Cannot Undergo Retro-Claisen Condensation)

Ester-Ester Mixed Claisen Condensation Irreversible

Ketone-Ester Mixed Claisen Condensation Irreversible

• NaOCH2CH3, HOCH2CH3 • H2O, H2SO4 The ester reagent must possess two α-Hydrogens. (Ester reagents with zero/one α-Hydrogen will not undergo Claisen Condensation.)

• One ester must possess no α-Hydrogens to ensure it is not deprotonated for form an ester enolate. • One ester must possess two α-Hydrogens to ensure it is deprotonated to form an ester enolate. Only one ester should become the ester enolate. The ester possessing no α-Hydrogens should be in large excess to ensure it is preferentially attacked by the ester enolate (in favor of self-Claisen Condenation).

The β-ketoester product will be the major product only if the non-α-Hydrogen ester is in large excess. Without large excess of the non-α-Hydrogen ester, the self-Claisen Condensation produce may become the major product.

• NaOCH2CH3 • H2O, H2SO4 • One ester must possess two α-Hydrogens, while the other ester must possess no α-Hydrogens. • The ester possessing no α-Hydrogens must be in large excess (to ensure that it is attacked by the ester enolate nucleophile).

• The hydride reagent deprotonates the α-Hydrogen of the ketone (to form an enolate). • The enolate nucleophile attacks the carbonyl Carbon of the ester (to form a tetrahedral intermediate). • Rearrangement of the oxide’s π-electrons forms a ketone and eliminates an alkoxide. • The intercarbonyl** α-Hydrogen is deprotonated** (to form the β-diketone enolate). • Acid workup protonates the intercarbonyl α-Carbon to yield the β-Diketone product.

The ketone α-Hydrogen is more acidic (than the ester α-Hydrogen) due to the ester’s electron-donating ether Oxygen. The ester’s ether Oxygen destabilizes the ester enolate (i.e. the conjugate base) due its electron-donating character.

• The alkoxide reagent/catalyst deprotonates the α-Hydrogen of one ester (to form an ester enolate). • The ester enolate nucleophile attacks the carbonyl Carbon of the other ester (to form a tetrahedral intermediate). • Rearrangement of the oxide’s π-electrons forms a ketone and eliminates an alkoxide. • The intercarbonyl α-Hydrogen is deprotonated (to form the β-ketoester enolate). • Acid workup protonates the intercarbonyl α-Carbon to yield the β-Ketoester product.

• NaH • H2O, H2SO4

• Deprotonation of Ester α-Hydrogen to Yield Ester Enolate • Nucleophilic Addition of Ester Enolate to Another Ester Carbonyl • π-Electron Rearrangement to Eliminate Alkoxide Group • Deprotonation of Intercarbonyl α-Hydrogen to Form β-Ketoester Enolate • Acid Workup to protonate Intercarbonyl α-Carbon. The final β-Ketoester product is stable under weakly acidic conditions (i.e. cannot under retro-Claisen Condensation).

Final Deprotonation to Yield β-Ketoester Enolate

The intercarbonyl α-Hydrogens are significanly more acidic than the hydroxyl Hydrogens (of the basic catalyst’s conjugate acid), so α-Hydrogen deprotonation (to form the hydroxyl group on the catalytic base) readily occurs.

The ester enolate (formed via or α-Hydrogen deprotonation) cannot be synthesized when no α-Hydrogen is present.

A second α-Hydrogen is required for the final/second deprotonation step that “drives” the Claisen Condensation reaction toward the β-Ketoester enolate product. WIthout a second α-Hydrogen, the formed β-Ketoester cannot be deprotonated within the basic Claisen Condensation conditions. (The non-deprotonated β-Ketoester is highly unstable under basic conditions, so the overall condensation reaction is thermodynamically unfavorable.)

Retro-Claisen Condensation Reversible Retro-Claisen Condensation must occur under basic conditions.

Retro-Claisen Condensation Reversible

NaOCH2CH3 • The reagent β-dicarbonyl can be either a β-Ketoester OR a β-Diketone. • No α-Hydrogens can be present on the reagent β-dicarbonyl to ensure alkoxide addition to a carbonyl Carbon. (f the reagent β-dicarbonyl possesses α-Hydrogens, the alkoxide will facilitate deprotonation to form a β-Dicarbonyl enolate.)

• The carbonyl Carbons of ketones are relatively stable (which decreases their susceptibility to nucleophilic attack by an enolate). • The carbonyl Carbons of ketones experience steric hindrance (which inhibits attack by the nucleophilic enolate). Self-Aldol Condensation of ketones does not occur.

Intramolecular Claisen Condensation Dieckmann Condensation The Intramolecular Claisen Condensation reaction is effective for forming five-membered/six-membered rings.

The ketone’s alkyl substituent cannot serve as a leaving group (following intramolecular attack of the ester enolate’s α-Carbon). Since the ketone’s alkyl substituent cannot leave, the reformation of the ketone group (C=O) cannot occur.

• The alkoxide reagent/catalyst deprotonates the α-Hydrogen of one ester (to form an ester enolate). • The ester enolate attacks the carbonyl Carbon of the other ester (to form a five-membered/six-membered ring). • Rearrangement of the oxide’s π-electrons forms a ketone and eliminates an alkoxide. • The intercarbonyl α-Hydrogen is deprotonated (to form the cyclic β-ketoester enolate). • Acid workup protonates the intercarbonyl α-Carbon to yield the cyclic β-Ketoester product.

• NaOCH2CH3 • H2O, H2SO4