Chapter 19: Carbonyl Compounds III
Learning Objectives:
1.
2.
3.
4.
5.
6.
Write the mechanism for keto-enol tautomerization and explain the consequence of such
tautomerizarion in the optical chiral of compound.
Remember the approximate pKa value for the -hydrogen of a carbonyl group.
Provide appropriate bases for the formation of enolate and use such enolate for halogenation and
alkylation.
Be able to write the general electron-pushing (arrow-pushing) mechanisms of Aldol reaction,
Michael reaction, Claisen condensation, and Dieckmann condensation.
Be able to write the general electron-pushing (arrow-pushing) mechanisms for decarboxylation
of 3-oxocarboxylic acids
Be able to employ the above-mentioned reaction for the formation of new carbon-carbon bond
Sections:
19.1
19.2
19.3
19.4
19.5
19.6
19.7
19.8
19.9
19.10
19.11
19.12
19.13
19.14
19.15
19.16
19.17
19.18
19.19
19.20
19.21
Acidity of -hydrogens*
Keto-Enol Tautomerism*
How Enols and Enolate Ions React*
Halogenation of the -Carbon of Aldehydes and Ketones*
Halogenation of the -Carbon of Carboxylic Acids: The Hell-Volhard-Zelinski (HVZ)
Reaction
-Halogenated Carbonyl Compounds in Synthesis*
Using LDA to form an Enolate*
Alkylation of the -Carbon of Carbonyl Compounds*
Alkylation and Acylation of the -Carbon via an Enamine Intermediate
Alkylation of the  -Carbon: the Michael Reaction*
The Aldol Reaction*
Dehydration of Aldol Addition Products: Formation of  -Unsaturated Aldehydes and
Ketones*
The Mixed Aldol Reaction
The Claisen Condensation*
The Mixed Claisen Condensation
Intramolecular Condensation and Addition Reactions*
Decarboxylation of 3-Oxocarboxylic Acids*
The Malonic Ester Synthesis: Synthesis of Carboxylic Acids
The Acetoacetic Ester Synthesis: Synthesis of Methyl Ketones
Designing a Synthesis VI: Making New Carbon-Carbon Bonds
Reactions at the -carbon in Biological Systems#
* Sections that will be focused
#
Sections that will be skipped
Recommended additional problems
19.44 – 19.52, 19.54 – 19.64, 19.66 – 19.80
1
Class Note
Acidity of -hydrogens
19.1
A. pKa of -hydrogen of carbonyl derivatives
O
O
R'

R'
H
H
O
OR
R'
H
H
O
O
O
H
R'
R
R'
H
H
B. Resonance effect
2
H
R
H
O
O
R'
R'
OR
NHR
O
O
19.2
Keto-Enol Tautomerism
O
R'
OH
R'
R
H
A. Mechanism in acidic condition
B. Mechanism in basic condition
3
R
19.3
How Enols and Enolate Ions React
A. Analysis of enols and enolates
4
19.4
Halogenation of the -Carbon of Aldehydes and Ketones
A. Acid-catalyzed halogenation
O
CH3
O
X2 (Cl2, Br2, I2)
H3O+
CH2
X
5
B. Base-promoted halogenation
X2 (Cl2, Br2, I2)
(excess)
HO-
O
R
CH2
O
R
CX2
C. Haloform reaction
O
CH3
O
X2 (Cl2, Br2, I2)
(excess)
HO-
O
6
+
CHX3
Halogenation of the -Carbon of Carboxylic Acids: The Hell-Volhard-Zelinski (HVZ)
Reaction
19.5
1) PBr3, Br2
2) H2O
O
R
OH
O
R
OH
Br
7
19.6
-Halogenated Carbonyl Compounds in Synthesis
A. Analysis of -halogenated carbonyl Compounds
B. Examples
8
19.7
Using LDA to form an Enolate
N
lithium diisopropylamide (LDA)
19.8
Alkylation of the -Carbon of Carbonyl Compounds
A. Analysis of the reaction
9
B. Examples
(i)
OCH3
1) LDA, THF
2) CH3I
O
(ii)
1) LDA, THF
2) CH3CH2I
CN
10
C. Potential problem in alkylation of the -carbon of carbonyl compounds
O
CH3
1) LDA, THF
2) CH3I
11
19.9
Alkylation and Acylation of the -Carbon via an Enamine Intermediate
O
N
catalytic H+
N
H
+
+
pyrrolidine
enamine
A. Examples
1) catalytic H+
O
N
H
2) CH3Br
3) H2O, H+
12
H2O
19.10
Alkylation of the  -Carbon: the Michael Reaction
A. Michael reaction
O
H3C
O
O
CH3OCH3
+
CH3
13
B. Examples
(i)
O
O
O
base (?)
+
OCH3
H3CO
(ii)
O
O
OCH2CH3
CN
+
H3C
14
base (?)
C. Stork enamine reaction
O
N
+
HCl
H2O
CH3
15
19.11
The Aldol Reaction
OH
O
base
O
R
R
H
H
R
A. Mechanism
16
19.12
Dehydration of Aldol Addition Products: Formation of  -Unsaturated Aldehydes and
Ketones
A. Aldol condensation
B. Examples
(i)
O
O
H
+
MeOMeOH
H
(ii)
O
EtO- Na+
EtOH
17
19.13
The Mixed Aldol Reaction
A. Potential problem in aldol reaction
(i)
O
EtO- Na+
EtOH
(ii)
O
O
MeO- Na+
+
MeOH
H
18
B. Solution
(i)
O
O
H
+
MeO- Na+
MeOH
H
19
19.14
The Claisen Condensation and 19.15
The Mixed Claisen Condensation
O
O
base
O
R
R
OR'
OR'
R
A. Mechanism
20
+
HOR'
B. Examples
(i)
O
base (?)
OCH2CH3
(ii)
O
O
base (?)
OCH3
OCH2CH3
+
21
19.16
Intramolecular Condensation and Addition Reactions
A. Intramolecular Claisen reaction (Dieckmann condensation)
(i)
H3CO
OCH3
MeO- Na+
MeOH
O
O
(ii)
O
EtO- Na+
H3CH2CO
OCH2CH3
O
22
EtOH
B. Intramolecular aldol reaction
(i)
H3C
CH3
MeO- Na+
MeOH
O
O
(ii)
O
EtO- Na+
H3C
CH3
O
23
EtOH
(iii)
O
EtO- Na+
H3C
H
EtOH
O
(iv) Robinson annulation
O
O
base
+
H+, heat
+
CH3
O
24
H2O
19.17
Decarboxylation of 3-Oxocarboxylic Acids
A. Easier in acidic condition: mechanism
O
O
R
O
OH
O
R
O
B. Examples of compounds containing 3-oxocarboxylic acid
O
O
O
HO
O
OH
OH
R
R
25
19.18 The Malonic Ester Synthesis: Synthesis of Carboxylic Acids and 19.19 The Acetoacetic
Ester Synthesis: Synthesis of Methyl Ketones
O
O
O
?
R
H3CH2CO
OCH2CH3
OH
26
A. Examples:
O
O
O
OH
OH
27
OH
19.20
Designing a Synthesis VI: Making New Carbon-Carbon Bonds
O
CO2H
synthesis of
O
from
H3CO
28
OCH3