1 Nucleophilic reactions involving enolate anions (2) Aldehydes, Ketons and other carbonyl compounds having H on α-C -> in equilibrium (in solution) -> Keto-Enol tautomerization

2 Nucleophilic reactions involving enolate anions Acylation of enolate anions -> Claisen reaction (condensation) 2 mol ester - (base) -> β-ketoester

3 Nucleophilic reactions involving enolate anions Acylation of enolate anions -> Claisen reaction (condensation) OEt - -> is strong base rather than good leaving groupe reaction will run further -> anolate anion produced -> acid required to regenerate β-ketoester H + /acid If on α-C just one H -> no reaction under this condition -> no α-H left to produce anolate anion resonance structure

4 Nucleophilic reactions involving enolate anions Acylation of enolate anions -> Claisen reaction (condensation) Claisen and aldol in nature -> Cholesterol biosynthesis

5 Nucleophilic reactions involving enolate anions Intramolecular Claisen reaction -> Dieckman reaction

6 Nucleophilic reactions involving enolate anions Mixed Claisen reaction

7 Nucleophilic reactions involving enolate anions Mixed Claisen reaction Better synthesis approach !!!

8 Nucleophilic reactions involving enolate anions Aldol - Claisen reaction -> prediction of product Aldol -> Keton is electrophile Claisen -> Ester is electrophile

9 Nucleophilic reactions involving enolate anions Aldol - Claisen reaction -> prediction of product Aldol + Claisen reaction are in equilibria -> disturbing the equilibria -> product formation 1.Dehydration in aldol (slide 14) 2.Ionization in Claisen (slide 27) -> Ionization determinant -> Claisen reaction occurs Product from Claisen gives the more acidic product

10 Nucleophilic reactions involving enolate anions Reverse Claisen reaction Driving force for Claisen reaction -> formation of enolate anion of the β-ketoester product (ionization) If they cannot be formed -> reverse reaction controls equilibrium

11 Nucleophilic reactions involving enolate anions Decarboxylation reactions β-ketoesters + acid catalysed -> β-ketoacid -> loss of carbon dioxide -> decarboxylated

12 Nucleophilic reactions involving enolate anions Decarboxylation reactions β-ketoesters + acid catalysed -> β-ketoacid -> loss of carbon dioxide -> decarboxylated β-ketoesters are intermediates to obtain substituted ketons

13 Nucleophilic reactions involving enolate anions Decarboxylation reactions β-ketoesters + acid catalysed -> β-ketoacid -> loss of carbon dioxide -> decarboxylated β-ketoesters are intermediates to obtain substituted ketons

14 Nucleophilic reactions involving enolate anions Nucleophilic addition to conjugated systems

15 Nucleophilic reactions involving enolate anions Nucleophilic addition to conjugated systems

16 Nucleophilic reactions involving enolate anions Nucleophilic addition to conjugated systems 1,2 addition versus 1,4 addititon: -> Nu good leaving group -> 1,2 addition is reversible -> 1,4 product (thermodynamic control) -> Nu bad leaving group -> 1,2 addition irreversible -> 1,2 product (kinetic control) -> stereochemistry also important -> large Nu –> 1,4 addition preferred Except -> Grignard + LiAlH4 hydration -> 1,2 addition

17 Nucleophilic reactions involving enolate anions Nucleophilic addition to conjugated systems Grignard LiAlH4 Hydration

18 Nucleophilic reactions involving enolate anions Nucleophilic addition to conjugated systems – Michael reactions Enolate anion as nucleophile Production of Steroid hormones (Testosterone male sex hormone)

19 Nucleophilic reactions involving enolate anions Nucleophilic addition to conjugated systems – Michael reactions Michael acceptors can be carcinogenic Michael acceptors can also be utilized by the human body

20 Nucleophilic reactions involving enolate anions Nucleophilic addition to conjugated systems – Michael reactions Michael acceptors can also be utilized by the human body Interacts with proteins -> cell damage