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 O
R' + R'
OR OR 1. NaOR
+
H 2. H3O

O O
ROH + R'
OR
R' Ch. 19 - 3
 ● Aldol addition and condensation
O O OH O
Base
R' + R' R'
H H (addition) H
H R'
H
"condensation"

O
O + R'
H H 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 O
R' + R'
OR OR 1. NaOR
H H 2. H3O+

O O
ROH + R'
OR
H R'
Ch. 19 - 6
  Mechanism
● Step 1
O O
R' + OR R' + ROH
OR OR
H H
H

O
R'
OR
H Ch. 19 - 7
  Mechanism
● Step 2
O O O O
R' + R'
OR OR OR
H RO H
R' R'

O O
RO + R'
OR
H R'
Ch. 19 - 8
 Mechanism
● Step 3
O O O O
R' R'
OR OR
H R' R'
+
OR
(pKa ~ 9) ROH
(pKa ~ 16)

Ch. 19 - 9
 O O
R'
OR
R'

O O O O
R' R'
OR OR
R' R'

Ch. 19 - 10
 Mechanism
● Step 4
O O H

R' + H O
OR
H (rapid)
R'

OH O O O
R' R'
OR OR
H R'
R'
(enol form) (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. O
H The a carbon has only
one a hydrogen
OMe  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 O O
NaOMe
(1) 2
OMe OMe

+ MeOH

O O
H3O+

OMe
H
Ch. 19 - 14
  Examples of Claisen condensation

O O O
NaOEt
(2) 2
OEt 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
6 4 2
MeO 7 1 OMe
5 3

O O O O

7 2 1
1. NaOMe 6 OMe
+
2. H3O 5 3

4 Ch. 19 - 16
  Mechanism O
H 7
OMe
MeO
6 4
OMe OMe 6
7 2 1
5 3 OMe
5 1
2
O O
4 3
O
O O OMe O
H OMe OMe
7 2 1
OMe 6

5 3
O
4
(This
favorable O O H O O
equilibrium H O H
drives the OMe OMe
reaction)
Ch. 19 - 17
  Other examples
O
(1) 6 5 4 3 2 1 OEt
EtO
O

O O
1. NaOEt
+ 6 1
2. H3O 5 2 OEt
4 3

Ch. 19 - 18
  Other examples
O Me
(2) OMe
MeO
1. NaOMe
O 2. H3O+

O O O O
not Me
OMe 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 self-
condensation
O O O O
1. NaOMe
+
OMe OMe 2. H3O+ OMe

(no a-hydrogen)
Ch. 19 - 20
 Mechanism
O O
+ OMe + MeOH
OMe OMe
H O

OMe

O O O O

OMe OMe
OMe
H
Ch. 19 - 21
 Mechanism
(This favorable
equilibrium
drives the
O O O O
reaction)

OMe OMe
H
OMe H
O O H O H

OMe
Ch. 19 - 22
  Other examples
(1) O O O
O
OEt 1. NaOEt OEt
+
OEt 2. H3O+

(no a hydrogen)

(2) O O O O
1. NaOMe
+
MeO OMe OMe 2. H3O+ MeO OMe
(no a carbon)

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

OMe

Ch. 19 - 25
3. b-Dicarbonyl Compounds by
Acylation of Ketone Enolates
O O O
NaNH2
Et2O
O (kinetic
H H enolate)
Ph OMe

slightly O O
more
acidic

Ch. 19 - 26
  Intramolecular example
a b O
H H O O
1. NaOMe
7 6 5 4 3 2 1 1 6
OMe 2. H3O + 2 5 7
c 3 4
O H

● 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 OH O
10% NaOH
2
H H2O, 5 oC 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 O O
H + H2O
H H H
HO O

OH O O O
HO H
H H
+ HO
Ch. 19 - 30
4B. The Retro-Aldol Reaction
OH O O
HO
2
H2O

 Mechanism
H
O O O O O
HO
+

O HO H O
HO +
Ch. 19 - 31
4C. Aldol Condensation Reactions:
Dehydration of the Aldol Addition
Product
 Dehydration of the aldol addition
product
● Aldol condensation
OH O O
+ H2O + OH
H H
H
OH
Ch. 19 - 32
4C. Acid-Catalyzed Aldol
Condensations

O + O
H3O
2 + H2O

Ch. 19 - 33
 Mechanism
H
H OH2 O
O O
+ H O H
H
H
H
O

H
O O OH2 O OH

+ H2O H2O:
H
+
+ H3O
Ch. 19 - 34
4E. Synthetic Applications of Aldol
Reactions

 Aldol additions and aldol condensations

● Important methods for carbon-
carbon bond formation
● Useful synthesis for
 b-hydroxyl carbonyl compounds
 a,b-unsaturated carbon
compounds

Ch. 19 - 35
 R R
H H H
R R R
base NaBH4
O OH O OH OH
Aldehyde Aldol 1,3-diol
HA, -H2O
H2/Ni
high R R
pressure
H LiAlH 4
R R
a,b-unsaturated O
R aldehyde Allylic OH
H2, Pd-C alcohol
R
R
Saturated OH
H
alcohol R
Aldehyde
O Ch. 19 - 36
5. Crossed Aldol Condensations

O O O OH
HO
+ + H
H H H2O

OH O

OH O OH O
+ +
H H

Ch. 19 - 37
5A. Crossed Aldol Condensations
Using Weak Bases
O O

H + HO

aldol
addition

OH O
O
dehydration

Ch. 19 - 38
 O O
Na2CO3 (aq)
+
H H H

OH O

H H
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 O
LDA, THF
-78 oC

H O

O OH O O Li
H2O

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 O
HO
+
protic
solvent
(Kinetic (Thermodynamic
enolate) enolate)
O

1. H O
O OH
2. H2O

OH
Ch. 19 - 42
 Suggest a synthesis of the following
compound using a directed aldol
synthesis O OH

● Retrosynthetic analysis
O OH O
O

+
disconnection
Ch. 19 - 43
 Synthesis

O O O Li

LDA

O OH O
1.
H

2. H2O
Ch. 19 - 44
 6. Cyclizations via Aldol
Condensations
 Intramolecular Aldol condensation
● Useful for the synthesis of five- and
six-membered rings
● Using a dialdehyde, a keto
aldehyde, or a diketone
e.g. O O
HO

H
O
Ch. 19 - 45
 O O
(Ha)
8 7 6 5 4 3 2 1
H
(path a)
Ha Hb Hc
O O
H2O
1
8 6 4 2
5 3
7 H

OH

O 8 1 O
7 2 (-H2O)
6 3
5 4

(not formed) Ch. 19 - 46

 O O
(Hb)
8 7 6 5 4 3 2 1
H
(path b)
Ha Hb Hc
O O
H2O 1
8 6 4 2
7 5 3
H

O O
8 7 OH
6 1 (-H2O)
5 2
4 3
Ch. 19 - 47
 O O
(Hc)
8 7 6 5 4 3 2 1
H
(path c)
Ha Hb Hc
O O
H2O 7
8 6 5 4 3 1
2 H

8 O O
HO
7 1
6 2 H (-H2O) H
5 3
4 (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 O
<
R  R R  H
(Ketones are (Aldehydes are
less reactive more reactive
toward nucleophiles) 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 seven-
membered rings

Ch. 19 - 50
7. Additions to a,b-Unsaturated
Aldehydes and Ketones
O OH
Nu H2O
O Nu
simple addition
(1,2-addition)
+
Nu
O O
Nu H2O

Nu
conjugate addition H
(1,4-addition)
Ch. 19 - 51
 O

1. PhMgBr
Et2O
2. H3O+
OH Ph O
+
Ph
H
(82%) (18%)
(simple addition) (conjugate addition)
Ch. 19 - 52
 O O O
b b b

a a a

nucleophiles attack
the carbonyl carbon
or the b carbon

Ch. 19 - 53
 Conjugate addition of HCN
O CN O
CN
EtOH, AcOH

NC
CN O

H+

Ch. 19 - 54
 Conjugate addition of an amine
O EtNH O
EtNH2
(keto form)
H2O

H
EtNH2

H
Et N H O EtNH OH
(enol form)

Ch. 19 - 55
7A. Conjugate Additions of Enolates:
Michael Additions
O 1. NaOMe (cat.) O O
MeOH
O
2.
H

MeO H OMe

O
O O O

(Micheal
Addition) Ch. 19 - 56
 Other examples of Michael additions
O
MeOOC 1. NaOMe, MeOH
(1) MeOOC
O OEt
MeOOC
2. COOMe
OEt

O O O O
1. NaOMe, MeOH
(2)
OMe 2. COOMe OMe

COOMe
Ch. 19 - 57
7B. The Robinson Annulation
NaOH, MeOH
O O O

(Michael O
O conjugate O
addition)

O Base
(Aldol (-H2O)
condensation)

O Ch. 19 - 58
 Mechanism of the Robinson Annulation
O O O O

H OH
O
(Micheal
O O addition) O

MeO H

O O

O O
O HO O
H
Ch. 19 - 59
 Mechanism of the Robinson Annulation
O O

O (intramolecular
O Aldol O
O
condensation)

MeO H

O O

(dehydration)

O HO O
OH
H Ch. 19 - 60
8. The Mannich Reaction

O O
+ + Et2NH
H H
HCl

O
H2O +
NEt2

Ch. 19 - 61
 Mechanism of the Mannich Reaction
H OH
O OH
HCl
+ Et2NH
H H H H
H H
N N
Et Et Et Et

(-HOH)

H H H
O O O H H
N
HCl Et Et NEt2

Ch. 19 - 62
  Other examples of the Mannich Reaction

O O O
HCl
(1) + + Et2NH
H H NEt2

O O
HCl N
(2) + +
H H
N
H

Ch. 19 - 63
9. Summary of Important Reactions
 Claisen Condensations O O
O
O R
R O R
OEt
OEt OEt OEt
EtO R
O O [*]
O [*] O [*] = 1. NaOEt,
OEt O
R O 2. H3O+
OEt
H OEt O Ph OEt
[*]
O [*] EtO OEt [*] O O
O
R
OEt R Ph OEt
OEt
R
O H
EtO O Ch. 19 - 64
  Aldol Condensations
O
O OH O
R
R H R
H NaOH, H2O H
R
1. LDA, THF, -78oC
O
2. (-H2O)
R' R'
3. NH4Cl
O
O
R
R H
H
R
R' OH
R' Ch. 19 - 65
 Simple & Conjugate (Michael) additions
OH
O O
R'
R (simple addition: R
O major product)

1. R'MgBr, Et2O
MeOH, NaOMe
O 2. H3O+

R NaCN
EtOH, AcOH
R'
NH O R'NH2 CN O

R R
H H Ch. 19 - 66
 Mannich reaction
O O R'
+ + H N
R H H R''

H+

O H H
R'
R N
R''
Ch. 19 - 67
 END OF CHAPTER 19 

Ch. 19 - 68