Chapter 22Alpha Substitution and

Condensations of Enolsand Enolate Ions

Organic Chemistry

Chapter 22 2

Alpha SubstitutionReplacement of a hydrogen on the carbon

adjacent to the carbonyl, C=O.

enolate ion

=>

Chapter 22 3

Condensation withAldehyde or Ketone

Enolate ion attacks a C=O and the alkoxide is protonated. The net result is addition.

C

O

C

_C

O

C

O

C

C

O_

ROHC

O

C

C

OH

=>

Chapter 22 4

Condensation with Esters

Loss of alkoxide ion results in nucleophilic acyl substitution.

=>

Chapter 22 5

Keto-Enol Tautomers

• Tautomers are isomers which differ in the placement of a hydrogen.

• One may be converted to the other.

• In base:

=>

Chapter 22 6

Keto-Enol Tautomers (2)

• Tautomerism is also catalyzed by acid.

• In acid:

=>

Chapter 22 7

Equilibrium Amounts• For aldehydes and ketones, the keto

form is greatly favored at equilibrium.

• An enantiomer with an enolizable hydrogen can form a racemic mixture.

=>

Chapter 22 8

Acidity of -Hydrogens

• pKa for -H of aldehyde or ketone ~20.

• Much more acidic than alkane or alkene (pKa > 40) or alkyne (pKa = 25).

• Less acidic than water (pKa = 15.7) or alcohol (pKa = 16-19).

• In the presence of hydroxide or alkoxide ions, only a small amount of enolate ion is present at equilibrium. =>

Chapter 22 9

Enolate Reaction

=>

As enolate ion reacts withthe electrophile, the equilibriumshifts to produce more.

Chapter 22 10

Acid-Base Reactionto Form Enolate

Very strong base is required for complete reaction.

Lithium diisopropylamide

N HHC

CH3

H3C

HCCH3H3C

n-BuLi NHC

CH3

H3C

HCCH3H3C

Li+

_

O

H

H

O- Li

+

HLDA+ C3H7)2N H(i-

pKa = 19 pKa = 40=>

Chapter 22 11

Halogenation• Base-promoted halogenation of ketone.• Base is consumed.• Other products are water and chloride ion.

OH_

O

H

HO

H

_O

H

ClCl Cl

=>

Chapter 22 12

Multiple Halogenations

• The -halo ketone produced is more reactive than ketone.

• Enolate ion stabilized by e--withdrawing halogen.

O

H

ClCl2

OH , H2O_

O

Cl

Cl

O

Cl

ClCl

O

Cl

ClClCl

=>

Chapter 22 13

Haloform Reaction

• Methyl ketones replace all three H’s with halogen.

• The trihalo ketone then reacts with hydroxide ion to give carboxylic acid.

Iodoform,yellow ppt. =>

C

O

CH3excess I2

OH-

C

O

CI3 OH-

C

O

OH

CI3-

C

O

O-

HCI3

Chapter 22 14

Positive Iodoformfor Alcohols

If the iodine oxidizes the alcohol to a methyl ketone, the alcohol will give a positive iodoform test.

=>

Chapter 22 15

Acid CatalyzedHalogenation of Ketones

• Can halogenate only one or two -H’s.

• Use acetic acid as solvent and catalyst.

C

O

CH3 + Br2CH3COOH

C

O

CH2Br

=>

Chapter 22 16

Aldehydes and Halogens

Halogens are good oxidizing agents and aldehydes are easily oxidized.

C

O

H + Br2 C

O

OHH2O

+ 2 HBr

=>

Chapter 22 17

The HVZ ReactionThe Hell-Volhard-Zelinsky reaction replaces

the -H of a carboxylic acid with Br.

=>

Chapter 22 18

Alkylation

• Enolate ion can be a nucleophile.

• Reacts with unhindered halide or tosylate via SN2 mechanism.

O

H

HO

H(i-Pr)2N-Li+

CH3 Br

O

H

CH3

=>

Chapter 22 19

Stork Reaction• Milder alkylation method than using LDA.

• Ketone + 2 amine enamine.

• Enamine is -alkylated, then hydrolyzed.

O

H

H NH

H+

H

HHON

H+

NH

H+

N

H

CH3 Br

+N

H

N

HCH3

H3O+

O

CH3

HBr

-

+ NH

H

+ =>

Chapter 22 20

Acylation via Enamines

Product is a -diketone.

=>

Chapter 22 21

Aldol Condensation

• Enolate ion adds to C=O of aldehyde or ketone.

• Product is a -hydroxy aldehyde or ketone.

• Aldol may lose water to form C=C.

=>

Chapter 22 22

Mechanism for Aldol Condensation

=>Also catalyzed by acid.

Chapter 22 23

Dehydration of Aldol

Creates a new C=C bond.

CO

H3CC H

H

CH3C

CH3

OH

H+ or OH

-

heat CO

H3CC

H

CH3C

CH3

=>

Chapter 22 24

Crossed AldolCondensations

• Two different carbonyl compounds.

• Only one should have an alpha H.

=>

Chapter 22 25

Aldol Cyclizations• 1,4-diketone forms cyclopentenone.

• 1,5-diketone forms cyclohexenone.

=>

Chapter 22 26

Planning Aldol Syntheses

=>

Chapter 22 27

Claisen CondensationTwo esters combine to form a -keto ester.

CH3 O C

O

CH R

CH3OC

O

CH2R

CH3 O C

O

CH R

CH3OC

O

CH2R

enolate ionpKa = 24

CH3 O C

O

CH Rbase

CH3 O C

O

CH2 R

=>

_

CH3 O C

O

C C

R

CH2R

O

pKa = 11

_OCH3

CH3 O C

O

CH C

R

CH2R

O

Chapter 22 28

Dieckmann Condensation• A 1,6 diester cyclic (5) -keto ester.

• A 1,7 diester cyclic (6) -keto ester.

=>

Chapter 22 29

Crossed Claisen

• Two different esters can be used, but one ester should have no hydrogens.

• Useful esters are benzoates, formates, carbonates, and oxalates.

• Ketones (pKa = 20) may also react with an ester to form a -diketone.

=>

Chapter 22 30

-Dicarbonyl Compounds

• More acidic than alcohols.

• Easily deprotonated by alkoxide ions and alkylated or acylated.

• At the end of the synthesis, hydrolysis removes one of the carboxyl groups.

CH3CH2O C

O

CH2 C

O

OCH2CH3

malonic ester, pKa = 13

CH3 C

O

CH2 C

O

OCH2CH3

acetoacetic ester, pKa =11=>

Chapter 22 31

Malonic Ester Synthesis• Deprotonate, then alkylate with good

SN2 substrate. (May do twice.)

• Decarboxylation then produces a mono- or di-substituted acetic acid.

=>

Chapter 22 32

Acetoacetic Acid SynthesisProduct is mono- or di-substituted ketone.

=>

Chapter 22 33

Conjugate Additions

• When C=C is conjugated with C=O, 1,2-addition or 1,4-addition may occur.

• A 1,4-addition of an enolate ion is called the Michael reaction.

=>

Chapter 22 34

Michael Reagents

• Michael donors: enolate ions stabilized by two electron-withdrawing groups.-diketone, -keto ester, enamine,

-keto nitrile, -nitro ketone.

• Michael acceptors: C=C conjugated with carbonyl, cyano, or nitro group.conjugated aldehyde, ketone, ester,

amide, nitrile, or a nitroethylene. =>

Chapter 22 35

A Michael Reaction

Enolates can react with ,-unsaturated compounds to give a 1,5-diketo product.

CH3CH2O C

O

CH

COOC2H5

_

CHH

C C

H O

CH3 CH3CH2O C

O

CH

COOC2H5

CH2C

H

C

O

CH3

_

H OC2H5

CH3CH2O C

O

CH

COOC2H5

CH2C

H

C

O

CH3

H

H3O+

heatHO C

O

CH CH2C

H

C

O

CH3

H

COOH

HO C

O

CH2 CH2C

H

C

O

CH3

H =>-keto acid

Chapter 22 36

Robinson Annulation

A Michael reaction to form a -diketone followed by an intramolecular aldol condensation to form a cyclohexenone.

CH3

H

O+

CH

H

C H

COH3C

_OH

CH3

O

=>

Chapter 22 37

Mechanism for Robinson Annulation (1)

=>

Chapter 22 38

Mechanism for Robinson Annulation (2)

=>

Chapter 22 39

End of Chapter 22