Transcript Chapter 22 Alpha Substitution and Condensations of Enols

Organic Chemistry, 6th Edition
L. G. Wade, Jr.
Chapter 22
Alpha Substitution and
Condensations of Enols
and Enolate Ions
Jo Blackburn
Richland College, Dallas, TX
Dallas County Community College District
2006, Prentice Hall
Alpha Substitution
Replacement of a hydrogen on the carbon
adjacent to the carbonyl, C=O.
=>
Chapter 22
2
Condensation with
Aldehyde or Ketone
Enolate ion attacks a C=O and the
alkoxide is protonated. The net result is
addition.
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. Example:
Chapter 22
=>
10
 Halogenation
• Base-promoted halogenation of ketone.
• Base is consumed.
• Other products are water and chloride ion.
O
O
H
H
_
OH
O
_
Cl
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.
Cl
Cl
H
Cl2
_
OH , H2O
O
O
O
O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
=>
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
C CH3
excess I2
C CI3
O
-
OH
C OH
-
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.
=>
Chapter 22
15
Aldehydes and Halogens
Halogens are good oxidizing agents and
aldehydes are easily oxidized.
O
O
C H
+ Br2
H2O
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
H
H
-
(i-Pr)2N Li
O
CH3
+
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
H
HO +
H N
N
N
N
H
H
+
H
H
H
H
+
H
+
N
N
H
CH3
Br
-
O
Br
H
H
CH3
+
H3O
Chapter 22
CH3
H
+
=>
H N+
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.
=>
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
CH3
O C CH2 R
pKa = 24
R
CH3
O
CH3
base
CH3
O C CH R
e nolate ion
O
O
R
CH2 C O CH3
O
O
CH3
O C CH R
O C CH R
O
_ O
O C C
CH3
C CH2R
R
Chapter 22
CH2 C O CH3
O C CH
R
pKa = 11
O
C CH2R
_
=>
OCH3
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
CH3CH2O C CH2 C OCH2CH3
malonic ester, pKa = 13
CH3
O
C CH2 C OCH2CH3
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
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
_
CH3CH2O C CH
H C
H
O
C C CH3
CH3CH2O C CH CH2
_
H O
C C CH3
H OC2H5
COOC2H5
COOH
O
HO C CH CH2
O
HO C CH2 CH2
H O
C C CH3
H
+
H3O
h e at
O
CH3CH2O C CH CH2
H O
C C CH3
H
H O
C C CH3
=>
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
CH3
H
O
H
C
+
H3C
CH3
_
C H
C
O
OH
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