Chapter 18: 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:
18.1
18.2
18.3
18.4
18.5
18.6
18.7
18.8
18.9
18.10
18.11
18.12
18.13
18.14
18.15
18.16
18.17
18.18
18.19
18.20
18.21
18.22
The Acidity of an -Hydrogens*
Keto-Enol Tautomers*
Enolization
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 Are Useful in Synthesis*
Using LDA to Form an Enolate*
Alkylation of the -Carbon of Carbonyl Compounds*
Alkylation and Acylation of the -Carbon Using an Enamine Intermediate
Alkylation of the  -Carbon: the Michael Reaction*
The Aldol Reaction Form -Hydroxyaldehydes or -Hydroxyketones*
Dehydration of Aldol Addition Products: Formation of  -Unsaturated Aldehydes and
Ketones*
The Mixed Aldol Reaction
The Claisen Condensation Forms a  -Keto Ester*
The Mixed Claisen Condensation
Intramolecular Condensation and Addition Reactions*
3-Oxocarboxylic Acids Can Be Decarboxylated*
The Malonic Ester Synthesis: A Way to Synthesize a Carboxylic Acids
The Acetoacetic Ester Synthesis: A Way to Synthesize Methyl Ketones
Designing a Synthesis VII: 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
18.48 – 18.58, 18.60 – 18.70, 18.72 – 18.85
1
Class Note
The Acidity of an -Hydrogens*
18.1
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
18.2
Keto-Enol Tautomers*
O
R'
OH
R'
R
H
A. Mechanism in acidic condition
B. Mechanism in basic condition
3
R
18.3
Enolization and 18.4
How Enols and Enolate Ions React*
A. Analysis of enols and enolates
4
18.5
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
18.6
1) PBr3, Br2
2) H2O
O
R
OH
O
R
OH
Br
7
18.7
-Halogenated Carbonyl Compounds Are Useful in Synthesis*
A. Analysis of -halogenated carbonyl Compounds
B. Examples
8
18.8
Using LDA to Form an Enolate*
N
lithium diisopropylamide (LDA)
18.9
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
18.10
Alkylation and Acylation of the -Carbon Using 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
18.11
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
18.12
The Aldol Reaction Form -Hydroxyaldehydes or -Hydroxyketones*
OH
O
base
O
R
R
H
H
R
A. Mechanism
16
18.13
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
18.14
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
18.15 The Claisen Condensation Forms a  -Keto Ester* and 18.16
Condensation
O
O
base
The Mixed Claisen
O
R
R
OR'
OR'
R
A. Mechanism
20
+
HOR'
B. Examples
(i)
O
base (?)
OCH2CH3
(ii)
O
O
base (?)
OCH3
OCH2CH3
+
21
18.17
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
18.18
3-Oxocarboxylic Acids Can Be Decarboxylated*
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
18.19 The Malonic Ester Synthesis: A Way to Synthesize a Carboxylic Acids and 18.20
Acetoacetic Ester Synthesis: A Way to Synthesize Methyl Ketones
O
O
O
?
R
H3CH2CO
OCH2CH3
OH
26
The
A. Examples:
O
O
O
OH
OH
27
OH
18.21
Designing a Synthesis VII: Making New Carbon-Carbon Bonds
O
CO2H
synthesis of
O
from
H3CO
28
OCH3