Organic Chemistry

Chapter 22 Alpha Substitution and Condensations of Enols and Enolate Ions

Alpha Substitution
Replacement of a hydrogen on the carbon adjacent to the carbonyl, C=O.

enolate ion

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Chapter 22 2

Condensation with Aldehyde or Ketone

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

OH ROH O C C C

Chapter 22

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Condensation with Esters

Loss of alkoxide ion results in nucleophilic acyl substitution.

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Chapter 22 4

Keto-Enol Tautomers
Tautomers are isomers which differ in the placement of a hydrogen. One may be converted to the other. In base:

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Chapter 22 5

Keto-Enol Tautomers (2)

Tautomerism is also catalyzed by acid. In acid:

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Chapter 22 6

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

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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 8

Enolate Reaction

As enolate ion reacts with the electrophile, the equilibrium shifts to produce more.
Chapter 22

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9

Acid-Base Reaction to Form Enolate

Very strong base is required for complete reaction.
CH3 HC H3C N H HC CH3 H3C n-BuLi CH3 HC _ + H3C N Li HC CH3 H3C
+

Lithium diisopropylamide

O H H LDA

O Li

H + (i- C3H7)2N H

pKa = 19
Chapter 22

pKa = 40
10

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 Halogenation
Base-promoted halogenation of ketone. Base is consumed. Other products are water and chloride ion.
O H H OH _ O _ H

O Cl Cl Cl H

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Chapter 22 11

Multiple Halogenations
The -halo ketone produced is more reactive than ketone. Enolate ion stabilized by e--withdrawing halogen.
O Cl H Cl2 _ OH , H 2O O Cl Cl Cl O Cl Cl Cl Cl O Cl Cl

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Chapter 22 12

Haloform Reaction
Methyl ketones replace all three Hs with halogen. The trihalo ketone then reacts with hydroxide ion to give carboxylic acid.
O C CH3 excess I2 OH
-

O C CI3

OH

O C OH CI3
-

O C O
-

HCI3

Iodoform, yellow ppt.

Chapter 22

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13

Positive Iodoform for Alcohols

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

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Chapter 22 14

Acid Catalyzed Halogenation of Ketones

Can halogenate only one or two -Hs. Use acetic acid as solvent and catalyst.
O C CH3 + Br2 O CH3COOH C CH2Br

Chapter 22

15

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Aldehydes and Halogens

Halogens are good oxidizing agents and aldehydes are easily oxidized.
O C H + Br2 O H2O C OH + 2 HBr

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Chapter 22 16

The HVZ Reaction

The Hell-Volhard-Zelinsky reaction replaces the -H of a carboxylic acid with Br.

Chapter 22

17

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Alkylation
Enolate ion can be a nucleophile. Reacts with unhindered halide or tosylate via SN2 mechanism.
O H H (i-Pr)2N Li
+

O H CH3 Br

O CH3 H

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Chapter 22 18

Stork Reaction
Milder alkylation method than using LDA. Ketone + 2 amine enamine. Enamine is -alkylated, then hydrolyzed.
O H H H
+

H H N HO + N H H

N H + H

N H

N H CH3 Br

+ N

Br

O H H3O
+

H + H N+
19

H CH3

CH3

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Chapter 22

Acylation via Enamines

Product is a -diketone.

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Chapter 22 20

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.

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Chapter 22 21

Mechanism for Aldol Condensation

Also catalyzed by acid.

Chapter 22 22

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Dehydration of Aldol
Creates a new C=C bond.
OH H3C C CH3 H3C C C H O H H3C H3C O

H or OH heat

C CH3 H

C C

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Chapter 22 23

Crossed Aldol Condensations

Two different carbonyl compounds. Only one should have an alpha H.

Chapter 22

24

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Aldol Cyclizations
1,4-diketone forms cyclopentenone. 1,5-diketone forms cyclohexenone.

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Chapter 22 25

Planning Aldol Syntheses

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Chapter 22 26

Claisen Condensation
Two esters combine to form a -keto ester.
O CH3 O C CH2 R pKa = 24
R CH3

O base
O R CH3 O O C CH R

CH3

O C CH R enolate ion

CH2 C O CH3 O O C CH R

CH2 C O CH3

O CH3

_ O C CH2R
Chapter 22

O CH3 R pKa = 11

O _

O C C R

O C CH C CH2R OCH3
27

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Dieckmann Condensation
A 1,6 diester cyclic (5) -keto ester. A 1,7 diester cyclic (6) -keto ester.

Chapter 22

28

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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.
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Chapter 22 29

-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.
O O

O CH3

CH3CH2O C CH2 C OCH2CH3

C CH2 C OCH2CH3

malonic ester, pKa = 13

acetoacetic ester, pKa =11 =>

Chapter 22 30

Malonic Ester Synthesis

Deprotonate, then alkylate with good SN2 substrate. (May do twice.) Decarboxylation then produces a monoor di-substituted acetic acid.

Chapter 22

31

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Acetoacetic Acid Synthesis

Product is mono- or di-substituted ketone.

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Chapter 22 32

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.

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Chapter 22 33

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 34

A Michael Reaction
Enolates can react with ,-unsaturated compounds to give a 1,5-diketo product.
COOC2H5 _ CH3CH2O C CH O H O H C H C C CH3 O CH3CH2O C CH CH2 COOC2H5 _ H O C C CH3
H OC2H5 COOC2H5 COOH O HO C CH CH2 H O C C CH3 H H O C C CH3 H H3O
+

O CH3CH2O C CH CH2

H O C C CH3 H

heat

O HO C CH2 CH2

-keto acid

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Chapter 22 35

Robinson Annulation
A Michael reaction to form a -diketone followed by an intramolecular aldol condensation to form a cyclohexenone.
H CH3 H O H + H3C C C H C O _ OH O CH3

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Chapter 22 36

Mechanism for Robinson Annulation (1)

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Chapter 22 37

Mechanism for Robinson Annulation (2)

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Chapter 22 38

End of Chapter 22

Chapter 22

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