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Chapter 18

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Reactions at the α Carbon

of Carbonyl Compounds

Enols and Enolates

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Reactions at the α Carbon of Carbonyl Compounds:�Enols and Enolates

α Hydrogens are weakly acidic (pK_a = 19 – 20)

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1. The Acidity of the α Hydrogens �of Carbonyl Compounds: �Enolate Anions

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Resonance structures for

the delocalized enolates

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2. Keto and Enol Tautomers

• Interconvertible keto and enol forms are called tautomers, and their interconversion is called tautomerization

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Resonance stabilization of the enol form

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3. Reactions via Enols & Enolates

3A. Racemization

Racemization at an α carbon takes place in the presence of acids or bases

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• Base-Catalyzed Enolization

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• Acid-Catalyzed Enolization

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3B. Halogenation at the α Carbon

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• Base-Promoted Halogenation

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• Acid-Promoted Halogenation

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3C. The Haloform Reaction

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• Mechanism

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• Acyl Substitution Step

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3D. α-Halo Carboxylic Acids: The �Hell–Volhard–Zelinski Reaction

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• Example

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4. Lithium Enolates

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• Preparation of lithium diisopropylamide (LDA)

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4A. Regioselective Formation of �Enolates

• Formation of a Kinetic Enolate

This enolate is formed faster because the hindered strong base removes the less hindered proton faster.

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• Formation of a Thermodynamic Enolate

This enolate is more stable because the double bond is more highly substituted. It is the predominant enolate at equilibrium.

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4B. Direct Alkylation of Ketones via �Lithium Enolates

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4C. Direct Alkylation of Esters

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• Examples

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5. Enolates of β-Dicarbonyl �Compounds

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• Recall

• α-hydrogens of β-dicarbonyl compounds are more acidic

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Contributing resonance structures

Resonance

hybrid

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6. Synthesis of Methyl Ketones: �The Acetoacetic Ester Synthesis

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• Synthesis of monosubstituted methyl ketones

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• Synthesis of disubstituted methyl ketones

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• Synthesis of γ-keto acids and γ-diketones

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6A. Acylation

• Synthesis β-diketones

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7. Synthesis of Substituted Acetic �Acids: The Malonic Ester Synthesis

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• Synthesis of monoalkylacetic acid

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• Synthesis of dialkylacetic acid

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• Example 1

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• Example 2

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8. Further Reactions of Active �Hydrogen Compounds

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• Example

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9. Synthesis of Enamines: �Stork Enamine Reactions

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• 2° amines most commonly used to prepare enamines

• e.g.

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(a)

(b)

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• Synthesis of β-diketones

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• Synthesis of γ-keto esters

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• Enamines can also be used in Michael additions

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10. Summary of Enolate Chemistry

1. Formation of an Enolate

Resonance-stabilized enolate

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2. Racemization

Enantiomers

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3. Halogenation of Aldehydes & Ketones

• Specific example: haloform reaction

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4. Halogenation of Carboxylic Acids: The HVZ Reaction

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5. Direct Alkylation via Lithium Enolates

• Specific example:

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6. Direct Alkylation of Esters

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7. Acetoacetic Ester Synthesis

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8. Malonic Ester Synthesis

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9. Stork Enamine Reaction