Chapter 19
Condensation and Conjugate
Addition Reactions of
Carbonyl Compounds
More Chemistry of Enolates
Created by
Professor William Tam & Dr. Phillis Chang
Ch. 19 - 1
About The Authors
These PowerPoint Lecture Slides were created and prepared by Professor
William Tam and his wife, Dr. Phillis Chang.
Professor William Tam received his B.Sc. at the University of Hong Kong in
1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an
NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard
University (USA). He joined the Department of Chemistry at the University of
Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and
Associate Chair in the department. Professor Tam has received several awards
in research and teaching, and according to Essential Science Indicators, he is
currently ranked as the Top 1% most cited Chemists worldwide. He has
published four books and over 80 scientific papers in top international journals
such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.
Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her
M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She
lives in Guelph with her husband, William, and their son, Matthew.
Ch. 19 - 2
https://www.concursolutions.com
1. Introduction

Carbonyl condensation reactions
● Claisen condensation
O
R'
O
OR
+
R'
OR
1. NaOR
2. H3O+
H
O
ROH
+
O
R'
OR
R'
Ch. 19 - 3
● Aldol addition and condensation
O
R'
O
H
+ R'
OH
Base
H
(addition)
O
R'
H
H
H
R'
"condensation"
O
H
O
H
+ R'
H
R'
Ch. 19 - 4

Conjugate addition reactions
● e.g.
O
O
1. Nu
R
2. H3O+
Nu
R
H
Ch. 19 - 5
2. The Claisen Condensation:
A Synthesis of b-Keto Esters
O
R'
O
OR
+
R'
H
1. NaOR
OR
2. H3O+
H
O
ROH
+
O
R'
OR
H
R'
Ch. 19 - 6

Mechanism
● Step 1
O
R'
H
O
OR
+
OR
R'
H
OR
+ ROH
H
O
R'
OR
H
Ch. 19 - 7

Mechanism
● Step 2
O
R'
O
OR
+
H
O
R'
OR
RO H
R'
R'
O
RO
O
+
OR
O
R'
OR
H R'
Ch. 19 - 8

Mechanism
● Step 3
O
O
O
R'
R'
OR
H R'
(pKa ~ 9)
O
OR
OR
R'
+
ROH
(pKa ~ 16)
Ch. 19 - 9
O
O
R'
OR
R'
O
O
R'
O
OR
R'
O
R'
OR
R'
Ch. 19 - 10

Mechanism
● Step 4
O
H
O
R'
OR
R'
OH
+
H
O
(rapid)
H
O
O
R'
OR
R'
(enol form)
O
R'
OR
H
R'
(keto form)
Ch. 19 - 11

Claisen condensation
● An Acyl Substitution
(nucleophilic addition-elimination
reaction)
● Useful for the synthesis of b-keto
esters
Ch. 19 - 12

Claisen condensation
● Esters that have only one a hydrogen
do not undergo the usual Claisen
condensation
e.g.
H
O
OMe
The a carbon has only
one a hydrogen
 does not undergo
Claisen condensation
This is because an ester with only one hydrogen
will not have an acidic hydrogen when step 3 is
reached, and step 3 promotes the favorable
equilibrium that ensures the forward reaction
Ch. 19 - 13

Examples of Claisen condensation
O
(1)
2
NaOMe
O
O
OMe
OMe
+ MeOH
O
O
H3O+
OMe
H
Ch. 19 - 14

Examples of Claisen condensation
O
(2)
2
O
NaOEt
OEt
O
OEt
+ EtOH
O
O
H3O+
OEt
H
Ch. 19 - 15
2A. Intramolecular Claisen Condensations:
The Diekmann Condensation
 Intramolecular Claisen condensation
● Diekmann condensation
● Useful for the synthesis of five- and
six-membered rings
MeO
7
4
6
5
2
1
OMe
3
O
O
O
1. NaOMe
6
2. H3O+
5
7
O
2
1
OMe
3
4
Ch. 19 - 16

MeO
Mechanism
7
H
4
6
5
3
2
O
O
H
O
7
1
OMe
OMe
O
6
7
5
(This
favorable
equilibrium
drives the
reaction)
2
4
OMe
OMe
6
5
O
O
OMe
OMe
1
3
O
OMe OMe
2
1
O
3
4
O
O
O
H
OMe
H
O
H
O
OMe
Ch. 19 - 17

Other examples
O
(1)
EtO
6
5
4
3
1
2
OEt
O
1. NaOEt
2. H3O
+
5
O
O
6
1
2
4
OEt
3
Ch. 19 - 18

Other examples
O
(2)
Me
OMe
MeO
1. NaOMe
O
O
2. H3O+
O
O
not
OMe
Me
O
OMe
Me
Why?
Ch. 19 - 19
2B. Crossed Claisen Condensations
 Crossed Claisen condensations are
possible when one ester
component has no a hydrogens
and, therefore, is unable to form an
enolate ion and undergo selfcondensation
O
O
OMe
+
1. NaOMe
OMe
2. H3O+
O
O
OMe
(no a-hydrogen)
Ch. 19 - 20

Mechanism
O
O
OMe
+ OMe
H
+ MeOH
OMe
O
OMe
O
O
OMe
H
O
O
OMe
OMe
Ch. 19 - 21

Mechanism
O
(This favorable
equilibrium
drives the
reaction)
O
O
O
OMe
OMe
H
H
OMe
O
H
O
O
H
OMe
Ch. 19 - 22

Other examples
(1)
O
O
OEt
O
+
O
OEt
1. NaOEt
OEt 2. H3O+
(no a hydrogen)
(2)
MeO
O
O
OMe
(no a carbon)
+
O
1. NaOMe
OMe
2. H3O+
MeO
O
OMe
Ch. 19 - 23

Recall: esters that have only one a
hydrogen cannot undergo
Claisen Condensation by using
sodium alkoxide
However, they can be converted to the
b-keto esters by reactions that use
very strong bases such as lithium
diisopropyamide (LDA)
Ch. 19 - 24
O
O
OMe
LDA
OMe
THF
O
O
Cl
O
OMe
Ch. 19 - 25
3.
b-Dicarbonyl Compounds by
Acylation of Ketone Enolates
O
NaNH2
O
O
Et2O
H
H
Ph
slightly
more
acidic
(kinetic
enolate)
O
O
OMe
O
Ch. 19 - 26

Intramolecular example
b
a
7
O
H
H
6
O
5
4
3
2
1
c
H
1. NaOMe
+
OMe 2. H3O
2
3
O
O
1
6
5
7
4
● The product was formed by
deprotonation of Hb, the enolate
formed at C5 and then adding to C1
Ch. 19 - 27
●
Questions
i.
Give the structure of the
product by deprotonation of
Ha, and adding the resulting
enolate (at C7) to C1. Explain
why this product is not formed.
ii. Give the structure of the
product by deprotonation of
Hc, and adding the resulting
enolate (at C2) to C6. Explain
why this product is not formed.
Ch. 19 - 28
4. Aldol Reactions: Addition of
Enolates and Enols to
Aldehydes and Ketones
O
10% NaOH
2
H
H2O, 5 oC
OH
O
H
 contains both an
aldehyde and an
alcohol functional
group
 aldol addition
Ch. 19 - 29
4A. Aldol Addition Reactions
 Mechanism of the aldol addition
O
H
O
H
O
H
H
+ H2O
O
HO
H
OH
O
HO
H
+ HO
H
O
O
H
Ch. 19 - 30
4B. The Retro-Aldol Reaction
OH
O
O
HO
2
H2O

Mechanism
H
O
O
O
O
O
HO
+
O
HO
HO
H
O
+
Ch. 19 - 31
4C. Aldol Condensation Reactions:
Dehydration of the Aldol Addition
Product

Dehydration of the aldol addition
product
● Aldol condensation
OH
O
O
H
H
H
+ H2O +
OH
OH
Ch. 19 - 32
4C. Acid-Catalyzed Aldol
Condensations
O
2
H3O
+
O
+ H2O
Ch. 19 - 33

Mechanism
O
+ H
O
O
H
H
O
OH2
H
H
H
O
O
O
+ H2O
+
+ H3O
H2O:
OH2
O
H
H
OH
H
Ch. 19 - 34
4E. Synthetic Applications of Aldol
Reactions

Aldol additions and aldol condensations
● Important methods for carboncarbon bond formation
● Useful synthesis for
 b-hydroxyl carbonyl compounds
 a,b-unsaturated carbon
compounds
Ch. 19 - 35
R
R
H
R
base
O
Aldehyde
R
NaBH4
OH
O
Aldol
R
OH
OH
1,3-diol
R
H LiAlH 4
R
a,b-unsaturated O
aldehyde
H2, Pd-C
R
H
HA, -H2O
H2/Ni
high
pressure
R
Saturated
alcohol
H
R
R
Allylic OH
alcohol
R
OH
H
R
O
Aldehyde
Ch. 19 - 36
5. Crossed Aldol Condensations
O
O
H
+
H
O
HO
H2O
OH
+
OH
+
O
H
+
H
OH
O
OH
O
H
Ch. 19 - 37
5A. Crossed Aldol Condensations
Using Weak Bases
O
O
+
H
HO
aldol
addition
OH
O
dehydration
O
H
Ch. 19 - 38
O
H
O
H
+
Na2CO3 (aq)
H
OH
H
H
O
H
Ch. 19 - 39
5B. Crossed Aldol Condensations Using
Strong Bases: Lithium Enolates and
Directed Aldol Reactions

Directed Aldol Synthesis using a strong
base, iPr2NLi (LDA)
O
LDA, THF
O
-78 oC
H
O
H
O
OH
H2O
O
O Li
Ch. 19 - 40

The use of a weaker base under protic
conditions
● Formation of both kinetic and
thermodynamic enolates
● Results in mixture of crossed aldol
products
Ch. 19 - 41
O
O
HO
O
+
protic
solvent
(Kinetic
enolate)
O
OH
O
1.
2. H2O
(Thermodynamic
enolate)
H
O
OH
Ch. 19 - 42

Suggest a synthesis of the following
compound using a directed aldol
O
OH
synthesis
● Retrosynthetic analysis
O
OH
O
O
disconnection
+
Ch. 19 - 43

Synthesis
O
O
O
Li
LDA
O
O
OH
1.
H
2. H2O
Ch. 19 - 44
6. Cyclizations via Aldol
Condensations

e.g.
Intramolecular Aldol condensation
● Useful for the synthesis of five- and
six-membered rings
● Using a dialdehyde, a keto
aldehyde, or a diketone
O
O
HO
H
O
Ch. 19 - 45
O
8
7
Ha
O
6
4
5
3
Hb
2
1
(Ha)
H
(path a)
Hc
O
H2O
8
O
6
7
5
4
3
2
1
H
OH
O
8
1
7
2
6
3
5
(-H2O)
O
4
(not formed)
Ch. 19 - 46
O
8
O
6
7
Ha
4
5
3
Hb
2
1
H
(path b)
Hc
O
H2O
8
7
O
6
5
4
3
2
1
H
O
O
8
(Hb)
OH
7
6
1
5
2
4
(-H2O)
3
Ch. 19 - 47
O
8
7
Ha
O
6
5
4
3
Hb
2
1
(Hc)
H
(path c)
Hc
O
H2O
8
8
HO
6
5
7
4
2
3
6
5
4
3
2
1
H
O
O
1
7
O
H
(-H2O)
H
(not formed)
Ch. 19 - 48
● Although three different enolates
are formed, cyclization usually
occurs with an enolate of the
ketone adding to the aldehyde
O

R  R
(Ketones are
less reactive
toward nucleophiles)
<
O

R  H
(Aldehydes are
more reactive
toward nucleophiles)
 Path c is least favorable
Ch. 19 - 49
● Path b is more favorable than path
a because six-membered rings are
thermodynamically more favorable
to form than eight-membered rings
● Likewise, five-membered rings form
far more readily than sevenmembered rings
Ch. 19 - 50
7. Additions to a,b-Unsaturated
Aldehydes and Ketones
O
OH
Nu H2O
Nu
O
simple addition
(1,2-addition)
+
Nu
O
Nu
conjugate addition
(1,4-addition)
O
H2O
Nu
H
Ch. 19 - 51
O
1. PhMgBr
Et2O
2. H3O+
OH
Ph
Ph
(82%)
(simple addition)
O
+
H
(18%)
(conjugate addition)
Ch. 19 - 52
O
O
b
b
a
O
b
a
a
nucleophiles attack
the carbonyl carbon
or the b carbon
Ch. 19 - 53

Conjugate addition of HCN
O
O
CN
CN
EtOH, AcOH
H
NC
CN
O
H+
Ch. 19 - 54

Conjugate addition of an amine
O
EtNH2
EtNH
O
(keto form)
H2O
H
EtNH2
H
Et
N
H O
EtNH
OH
(enol form)
Ch. 19 - 55
7A. Conjugate Additions of Enolates:
Michael Additions
1. NaOMe (cat.)
MeOH
O
2.
O
O
O
H
H
MeO
OMe
O
O
O
(Micheal
Addition)
O
Ch. 19 - 56

(1)
Other examples of Michael additions
MeOOC
1. NaOMe, MeOH
O
MeOOC
O
MeOOC
2.
OEt
COOMe
OEt
O
(2)
O
1. NaOMe, MeOH
OMe
2.
O
O
OMe
COOMe
COOMe
Ch. 19 - 57
7B. The Robinson Annulation
NaOH, MeOH
O
O
O
O
(Michael
conjugate
addition)
O
O
(Aldol
condensation)
O
O
Base
(-H2O)
Ch. 19 - 58

Mechanism of the Robinson Annulation
O
O
O
H
O
OH
O
O
O
(Micheal
addition)
O
MeO
H
O
O
O
O
O
HO
O
H
Ch. 19 - 59

Mechanism of the Robinson Annulation
O
O
O
O
(intramolecular
Aldol
condensation)
O
O
MeO
O
H
O
(dehydration)
O
HO
OH
O
H Ch. 19 - 60
8. The Mannich Reaction
O
O
+
H
+
H
Et2NH
HCl
O
H2O
+
NEt2
Ch. 19 - 61

Mechanism of the Mannich Reaction
O
H
H
OH
H
+ Et2NH
H
Et
N
OH
HCl
H
H
Et
Et
N
H
Et
(-HOH)
O
O
HCl
H
H
Et
H
N
Et
O
H
H
NEt2
Ch. 19 - 62

Other examples of the Mannich Reaction
O
O
+
(1)
H
H
+ Et2NH
O
HCl
NEt2
O
O
(2)
O
+
H
H
HCl
+
N
N
H
Ch. 19 - 63
9. Summary of Important Reactions

Claisen Condensations
O
R
O
[*]
OEt
O
O
[*]
OEt
H
OEt
EtO
[*] = 1. NaOEt,
OEt
[*]
O
R
EtO
Ph
OEt
O
[*]
OEt
O
2. H3O+
O
OEt
O
R
[*]
O
R
O
H
O
OEt
OEt
OEt
EtO
O
R
R
O
R
O
OEt
O
O
O
Ph
OEt
R
Ch. 19 - 64

Aldol Condensations
O
O
R
R
H
H
R
R
(-H2O)
O
O
R
R
H
R'
H
NaOH, H2O
1. LDA, THF, -78oC
O
2.
R'
R'
3. NH4Cl
R'
O
OH
H
R
OH
Ch. 19 - 65

Simple & Conjugate (Michael) additions
O
OH
O
(simple addition:
major product)
R
O
R
R'
1. R'MgBr, Et2O
MeOH, NaOMe
2. H3O+
O
R
R'
NH
R'NH2
O
R
H
NaCN
EtOH, AcOH
CN
O
R
H Ch. 19 - 66

Mannich reaction
O
R'
O
+
+
R
H
H
H
N
R''
H+
O
R
H
H
N
R'
R''
Ch. 19 - 67
 END OF CHAPTER 19 
Ch. 19 - 68