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

=>
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 _
C O OH
O _ O C O C
ROH
C C C C C C

Chapter 22 3 =>
 Condensation with Esters
Loss of alkoxide ion results in nucleophilic
acyl substitution.

=>
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:

=>
Chapter 22 5
 Keto-Enol Tautomers (2)

• Tautomerism is also catalyzed by acid.

• In acid:

=>
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 7
=>
 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 9
 Acid-Base Reaction
to Form Enolate
Very strong base is required for complete
reaction.
CH3 CH3
HC HC _ +
H3C N H n-BuLi H3C N Li Lithium
HC HC
CH3 CH3 diisopropylamide
H3C H3C

- +
O O Li

H LDA H
+ (i-C3H7)2N H
H

pKa = 19 pKa = 40
Chapter 22 10
=>
  Halogenation
• Base-promoted halogenation of ketone.
• Base is consumed.
• Other products are water and chloride ion.
O O
O
H _ _
OH Cl
H H Cl Cl
H

=>
Chapter 22 11
 Multiple Halogenations
• The -halo ketone produced is more
reactive than ketone.
• Enolate ion stabilized by e--withdrawing
halogen.

O O O O
Cl Cl Cl Cl Cl Cl
Cl2 Cl Cl Cl Cl
H _
OH , H2O

=>
Chapter 22 12
 Haloform Reaction
• Methyl ketones replace all three H’s
with halogen.
• The trihalo ketone then reacts with
hydroxide ion to give carboxylic acid.
O O O
-
excess I2 C CI3 OH C OH
C CH3
-
OH
-
CI3

O
-
C O HCI3
Iodoform,
yellow ppt. =>
Chapter 22 13
 Positive Iodoform
for Alcohols
If the iodine oxidizes the alcohol to a
methyl ketone, the alcohol will give a
positive iodoform test.

=>
Chapter 22 14
 Acid Catalyzed
Halogenation of Ketones
• Can halogenate only one or two -H’s.
• Use acetic acid as solvent and catalyst.
O O
CH3COOH
C CH3 + Br2 C CH2Br

Chapter 22 15 =>
 Aldehydes and Halogens

Halogens are good oxidizing agents and

aldehydes are easily oxidized.

O O
H2O
C H + Br2 C OH + 2 HBr

=>
Chapter 22 16
 The HVZ Reaction
The Hell-Volhard-Zelinsky reaction replaces
the -H of a carboxylic acid with Br.

Chapter 22 17
=>
 Alkylation
• Enolate ion can be a nucleophile.
• Reacts with unhindered halide or
tosylate via SN2 mechanism.

O O O
H - + CH3
(i-Pr) 2N Li
H H CH3 Br H

=>
Chapter 22 18
 Stork Reaction
• Milder alkylation method than using LDA.
• Ketone + 2 amine  enamine.
• Enamine is -alkylated, then hydrolyzed.
H
O N N N
HO+ H H
H H N H
+
H H H
+
H

-
+ Br O
N N H H
H +
CH3 Br H
CH3
H3O CH3 + H N+ =>
Chapter 22 19
 Acylation via Enamines

Product is a -diketone.

=>
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.

=>
Chapter 22 21
 Mechanism for
Aldol Condensation

Also catalyzed by acid. =>

Chapter 22 22
 Dehydration of Aldol
Creates a new C=C bond.

OH
H3C H3C
C CH3 + - C CH3
H3C H or OH
H3C
C C H heat C C
O H O H

=>
Chapter 22 23
 Crossed Aldol
Condensations
• Two different carbonyl compounds.
• Only one should have an alpha H.

=>
Chapter 22 24
 Aldol Cyclizations
• 1,4-diketone forms cyclopentenone.
• 1,5-diketone forms cyclohexenone.

=>
Chapter 22 25
Planning Aldol Syntheses

=>
Chapter 22 26
 Claisen Condensation
Two esters combine to form a -keto ester.
O O
base
CH3 O C CH2 R CH3 O C CH R
pKa = 24 enolate ion
O O
R CH2 C O CH3 R CH2 C O CH3
O O
CH3 O C CH R CH3 O C CH R

O _ O O O
CH3 O C C C CH2R CH3 O C CH C CH2R
R R _
OCH3
=>
Chapter 22
pKa = 11 27
Dieckmann Condensation
• A 1,6 diester  cyclic (5) -keto ester.
• A 1,7 diester  cyclic (6) -keto ester.

Chapter 22 28 =>
 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 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 O
CH3CH2O C CH2 C OCH2CH3 CH3 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 mono-
or di-substituted acetic acid.

Chapter 22 31
=>
Acetoacetic Acid Synthesis
Product is mono- or di-substituted ketone.

=>
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.

=>
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 COOC2H5 _
H O
O H O O
_ C C CH3
CH3CH2O C CH C C CH3 CH3CH2O C CH CH2
H C H OC2H5
H
COOC2H5
COOH H O H O
O + O
C C CH3 H3O C C CH3
HO C CH CH2 CH3CH2O C CH CH2
H heat H

H O
O
C C CH3
HO C CH2 CH2
H =>
-keto acid Chapter 22 35
 Robinson Annulation
A Michael reaction to form a -diketone
followed by an intramolecular aldol
condensation to form a cyclohexenone.
H
C CH3
CH3 _
H C H OH
H
+
C
O H3C O O

=>
Chapter 22 36
 Mechanism for
Robinson Annulation (1)

=>
Chapter 22 37
 Mechanism for
Robinson Annulation (2)

=>
Chapter 22 38
End of Chapter 22

Chapter 22 39