Chapter 13
Substitution Alpha to Carbonyl Groups
• Formation and Reactions of Enolate Anions and Enols
• Alkylation of Ketones and Esters: SN2 Reaction with Alkyl
Halides
• Aldol Reaction, Aldol Condensation and Related
Reactions: Nucleophilic Addition of Enolate Anions to
Carbonyl Groups
• The Claisen Condensation and Related Reactions:
Acylation of Esters
• Alkylation of -Dicarbonyl Compounds
• Synthetic Methods
• Spectroscopy
Chapter 13
Substitution Alpha to Carbonyl Groups
• Formation and Reactions of Enolate Anions and Enols
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Molecular Orbitals of Enolate Anions
Structure of Enolate Anions
Protonation of Enolate Anions
Halogenation Alpha to Carbonyl Groups
• Iodoform Test
– Kinetic versus Thermodynamic Deprotonation of Carbonyl Groups
• Kinetic Control with Lithium diisopropyl amide (LDA) strong Base,
poor Nucelophile
Chapter 13
Substitution Alpha to Carbonyl Groups
• Alkylation of Ketones and Esters: SN2 Reaction with Alkyl
Halides
– Works best with primary halide or secondary halide, but not tertiary
– More later in the chapter with -ketocarbonyls
Chapter 13
Substitution Alpha to Carbonyl Groups
• Aldol Reaction, Aldol Condensation and Related
Reactions: Nucleophilic Addition of Enolate Anions to
Carbonyl Groups.
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The Aldol Reaction (typically at low [base])
The Aldol Condensation (at high [base] and high temp)
Aldol Reaction and Aldol Condensation of Ketones
Intramolecular Aldol Reaction and Aldol Condensation
Crossed Aldol Reaction
Nucleophilic Addition of ,-Unsaturated Carbonyl Groups:
Conjugate Addition
• Michael addition (Enolate reacts with ,-unsaturated carbonyl)
• Robinson Annulation (two steps-Michael and Aldol condensation)
• “Fun in Bases”
Chapter 13
Substitution Alpha to Carbonyl Groups
• The Claisen Condensation and Related Reactions:
Acylation of Esters The Aldol Reaction
– The Claisen Condensation
• Enolate formation, addition, elimination, deprotonation, protonation
• forms -ketoester
– The Dieckmann Condensation
• Cyclic Claisen used to form 5 & 6 membered rings
• same 5 steps as Claisen
– Crossed Claisen Condensation
• Enolate anion reacts with ester or carbonate ester or oxalate ester or
benzoate ester
– The Reformatsky Reaction
• Enolate anion formed from -halo carbonyl followed by addition to
carbonyl and hydrolysis
Chapter 13
Substitution Alpha to Carbonyl Groups
• Alkylation of -Dicarbonyl Compounds
 -Dicarbonyl Compounds
• highly acidic, resonance stabilized
– Alkylation of -Ketoesters
• via SN2 displacement, can form mono and disubstituted
– Alkylation of Malonic Acid Diesters
• similar to -Ketoesters
– Hydrolysis and Decarboxylation of -Ketoesters and Malonic Acid
Diesters
• Ester hydrolyzed to carboxylic acid, heat to eliminate CO2
– Acetoacetic Ester and Malonic Ester Synthesis
• Synthetic utility: first do mono- or disubstituted alkylation, then
hydrolyze and decarboxylate to the more substituted ketone.
– Formation of Carbocyclic Rings using the Acetoacetic Ester and
Malonic Ester Syntheses
• with di-bromo alkyl, can form carbocyclic ring via intramolecular
closure
Chapter 13
Substitution Alpha to Carbonyl Groups
• Synthetic Methods
– Review Table 13.1 p 692-693
• Using Enolate Anions and Enols to Introduce Various Functional
Groups
• Spectroscopy
• Review of Reactions
• Summary
Chapter 13 Summary
• Carbonyl enhances the acidity of hydrogen on -carbon
• Treatment with base forms enolate anion, species with
significant nucleophilic character
• Under kinetic control conditions (e.g., LDA -Lithium diisopropyl amide) the less stable enolate forms
• Under thermodynamic equilibrium conditions (e.g., with
hydroxide) the more substituted enolate anion will form.
• Enolate anions (and enols) are nucleophiles which react
with electrophiles including halogen, alkyl halides,
ketones, aldehydes and esters
• Enolate intermediates in Aldol, Aldol condensation,
Michael reaction, Robinson Annulation, Claisen and
Dieckmann and Reformatsky reactions
Chapter 13 Summary
• Nucelophiles can add 1,2 or 1,4 to ,-unsaturated
carbonyls
– Grignard and alkyllithium reagents add 1,2
– Enolate anions add 1,4
• Aldol and Claisen are valuable synthetic tools for the
construction of carbon-carbon bonds between carbonyl
groups.
• Dieckmann condensation and Robinson annulation form 5
and 6 membered rings intramolecularly.
• Hydrolysis and Decarboxylation of corresponding
acetoacetic and malonic diesters are useful synthetic steps
for substituted ketones and carboxylic acids.