Professional Documents
Culture Documents
Alpha Substitution and Condensations of Enols and Enolate Ions
Alpha Substitution and Condensations of Enols and Enolate Ions
Alpha Substitution and Condensations of Enols and Enolate Ions
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 =>
Soal
O
O
+ H3C CH3
O
O
CH3
+ H3C O
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)
=>
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
- +
O O Li
H LDA H
+ (i-C3H7)2N H
H
pKa = 19 pKa = 40
Chapter 22 11
=>
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 12
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 13
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 14
Positive Iodoform
for Alcohols
If the iodine oxidizes the alcohol to a
methyl ketone, the alcohol will give a
positive iodoform test.
=>
Chapter 22 15
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 16 =>
Aldehydes and Halogens
O O
H2O
C H + Br2 C OH + 2 HBr
=>
Chapter 22 17
The HVZ Reaction
The 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 O O
H - + CH3
(i-Pr) 2N Li
H H CH3 Br H
=>
Chapter 22 19
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 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
OH
H3C H3C
C CH3 + - C CH3
H3C H or OH
H3C
C C H heat C C
O H O H
=>
Chapter 22 24
Crossed Aldol
Condensations
• 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 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 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.
O O O O
CH3CH2O C CH2 C OCH2CH3 CH3 C CH2 C OCH2CH3
Chapter 22 32
=>
Acetoacetic Acid reaction
Product 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.
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 36
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 37
Mechanism for
Robinson Annulation (1)
=>
Chapter 22 38
Mechanism for
Robinson Annulation (2)
=>
Chapter 22 39
End of Chapter 22
Chapter 22 40