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Chapter 18: Carbonyl Compounds III
Learning Objectives:
1. Write the mechanism for keto-enol tautomerization and explain the consequence of such
tautomerizarion in the optical chiral of compound.
2. Remember the approximate pKa value for the α-hydrogen of a carbonyl group.
3. Provide appropriate bases for the formation of enolate and use such enolate for halogenation and
alkylation.
4. Be able to write the general electron-pushing (arrow-pushing) mechanisms of Aldol reaction,
Michael reaction, Claisen condensation, and Dieckmann condensation.
5. Be able to write the general electron-pushing (arrow-pushing) mechanisms for decarboxylation
of 3-oxocarboxylic acids
6. Be able to employ the above-mentioned reaction for the formation of new carbon-carbon bond
Sections:
18.1 The Acidity of an α-Hydrogens*
18.2 Keto-Enol Tautomers*
18.3 Enolization
18.4 How Enols and Enolate Ions React*
18.5 Halogenation of the α-Carbon of Aldehydes and Ketones*
18.6 Halogenation of the α-Carbon of Carboxylic Acids: The Hell-Volhard-Zelinski (HVZ)
Reaction
18.7 α-Halogenated Carbonyl Compounds Are Useful in Synthesis*
18.8 Using LDA to Form an Enolate*
18.9 Alkylation of the α-Carbon of Carbonyl Compounds*
18.10 Alkylation and Acylation of the α-Carbon Using an Enamine Intermediate
18.11 Alkylation of the β-Carbon: the Michael Reaction*
18.12 The Aldol Reaction Form β-Hydroxyaldehydes or β-Hydroxyketones*
18.13 Dehydration of Aldol Addition Products: Formation of α,β-Unsaturated Aldehydes and
Ketones*
18.14 The Mixed Aldol Reaction
18.15 The Claisen Condensation Forms a β-Keto Ester*
18.16 The Mixed Claisen Condensation
18.17 Intramolecular Condensation and Addition Reactions*
18.18 3-Oxocarboxylic Acids Can Be Decarboxylated*
18.19 The Malonic Ester Synthesis: A Way to Synthesize a Carboxylic Acids
18.20 The Acetoacetic Ester Synthesis: A Way to Synthesize Methyl Ketones
18.21 Designing a Synthesis VII: Making New Carbon-Carbon Bonds
18.22 Reactions at the α-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
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Class Note
18.1 The Acidity of an α-Hydrogens*
A. pKa of α-hydrogen of carbonyl derivatives
H
NHR
O
H
OR
O
H
R
O
H
H
O
R' R' R' R'α
H
OR
O
R'
O
H
R
O
R'
O
H
H
O
R'
O
B. Resonance effect
3
18.2 Keto-Enol Tautomers*
H
R
O
R'
R
OH
R'
A. Mechanism in acidic condition
B. Mechanism in basic condition
4
18.3 Enolization and 18.4 How Enols and Enolate Ions React*
A. Analysis of enols and enolates
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18.5 Halogenation of the α-Carbon of Aldehydes and Ketones*
A. Acid-catalyzed halogenation
CH3
OX2 (Cl2, Br2, I2)
H3O+
CH2
O
X
6
B. Base-promoted halogenation
CH2
O X2 (Cl2, Br2, I2)(excess)
HO-RCX2
O
R
C. Haloform reaction
CH3
O X2 (Cl2, Br2, I2)(excess)
HO-O
O
CHX3+
7
18.6 Halogenation of the α-Carbon of Carboxylic Acids: The Hell-Volhard-Zelinski (HVZ)
Reaction
OH
O
R
1) PBr3, Br22) H2O
OH
O
R
Br
8
18.7 α-Halogenated Carbonyl Compounds Are Useful in Synthesis*
A. Analysis of α-halogenated carbonyl Compounds
B. Examples
9
18.8 Using LDA to Form an Enolate*
N
lithium diisopropylamide (LDA)
18.9 Alkylation of the α-Carbon of Carbonyl Compounds*
A. Analysis of the reaction
10
B. Examples
(i)
O
OCH31) LDA, THF2) CH3I
(ii)
CN
1) LDA, THF2) CH3CH2I
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C. Potential problem in alkylation of the α-carbon of carbonyl compounds
O
CH31) LDA, THF2) CH3I
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18.10 Alkylation and Acylation of the α-Carbon Using an Enamine Intermediate
O
NH
pyrrolidine
+
N
enamine
+ H2O
catalytic H+
A. Examples
O
2) CH3Br3) H2O, H+
1) catalytic H+
NH
13
18.11 Alkylation of the β-Carbon: the Michael Reaction*
A. Michael reaction
CH3
O
CH3
O
H3C
O
+
CH3O-
14
B. Examples
(i)
O
OCH3
O
H3CO
O
+
base (?)
(ii)
OCH2CH3
O
+ CNH3C
Obase (?)
15
C. Stork enamine reaction
N
CH3
O
+
HClH2O
16
18.12 The Aldol Reaction Form β-Hydroxyaldehydes or β-Hydroxyketones*
H
O
Rbase
H
O
R
OH
R
A. Mechanism
17
18.13 Dehydration of Aldol Addition Products: Formation of α,β-Unsaturated Aldehydes and
Ketones*
A. Aldol condensation
B. Examples
(i)
H
O
H
O
+MeO-
MeOH
(ii)
O
EtO-
EtOH
Na+
18
18.14 The Mixed Aldol Reaction
A. Potential problem in aldol reaction
(i)
O
EtO-
EtOH
Na+
(ii)
H
O
+
O
MeO-
MeOH
Na+
19
B. Solution
(i)
H
O
H
O
+MeO-
MeOH
Na+
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18.15 The Claisen Condensation Forms a β-Keto Ester* and 18.16 The Mixed Claisen
Condensation
OR'
O
Rbase
OR'
O
R
O
R
+ HOR'
A. Mechanism
21
B. Examples
(i)
OCH2CH3
O
base (?)
(ii)
OCH3
O
OCH2CH3
O
+
base (?)
22
18.17 Intramolecular Condensation and Addition Reactions*
A. Intramolecular Claisen reaction (Dieckmann condensation)
(i)
H3CO OCH3
OO
MeO-
MeOH
Na+
(ii)
H3CH2CO
OCH2CH3
O
O
EtO-
EtOH
Na+
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B. Intramolecular aldol reaction
(i)
H3C CH3
OO
MeO-
MeOH
Na+
(ii)
H3C
CH3
O
O
EtO-
EtOH
Na+
24
(iii)
H3C
H
O
O
EtO-
EtOH
Na+
(iv) Robinson annulation
CH3
O
+
O
base H+, heat
O
+ H2O
25
18.18 3-Oxocarboxylic Acids Can Be Decarboxylated*
A. Easier in acidic condition: mechanism
R OH
OO
R O
OO
B. Examples of compounds containing 3-oxocarboxylic acid
HO OH
OO
R
OH
OO
R
26
18.19 The Malonic Ester Synthesis: A Way to Synthesize a Carboxylic Acids and 18.20 The
Acetoacetic Ester Synthesis: A Way to Synthesize Methyl Ketones
H3CH2CO OCH2CH3
OO?
R
OH
O
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A. Examples:
OH
O
OH
O
OH
O
28
18.21 Designing a Synthesis VII: Making New Carbon-Carbon Bonds
H3CO OCH3
OO
synthesis of
CO2H
from
