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 reactionsMichael acceptors can also be utilized by the human body

Interacts with proteins -> cell damage