Chapter 13 Substitution Alpha to Carbonyl Groups Formation and Reactions of Enolate Anions and Enols Alkylation of Ketones and Esters: S N 2 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 –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: S N 2 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. –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 S N 2 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 CO 2 –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 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.