Chapter 13Substitution 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 13Substitution Alpha to Carbonyl Groups

• Formation and Reactions of Enolate Anions and Enols – 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 13Substitution 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 13Substitution Alpha to Carbonyl Groups

• Aldol Reaction, Aldol Condensation and Related Reactions: Nucleophilic Addition of Enolate Anions to Carbonyl Groups.– 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 13Substitution 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 13Substitution 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 13Substitution 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 di-isopropyl 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.