Chapter 18
Reactions at the a Carbon
of Carbonyl Compounds
Enols and Enolates
Created by
Professor William Tam & Dr. Phillis Chang
Ch. 18 - 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. 18 - 2
Reactions at the a Carbon of
Carbonyl Compounds:
Enols and Enolates
O

O
Nu
R
R'
R  R'
Nu
O
R'
R
H
a Hydrogens are weakly
acidic (pKa = 19 – 20)
Ch. 18 - 3
1. The Acidity of the a Hydrogens
of Carbonyl Compounds:
Enolate Anions
H
H
C
pKa
C
H
25
C
H
pKa
50
H
44
O
H
H3C
C
H2C
H
R'
R
H
19-20
Ch. 18 - 4
O
H
C
C
R
B:
O
O
C
R
C
C
C
R
Resonance structures for
the delocalized enolates
Ch. 18 - 5
O
H+
H+
C
C
R
Enolate
O
HO
C
C
R
Enol form
H
C
R
Keto form
Ch. 18 - 6
2. Keto and Enol Tautomers

Interconvertible keto and enol forms
are called tautomers, and their
interconversion is called
tautomerization
Ch. 18 - 7
Acetaldehyde
Keto form
O
Enol form
OH
H
(~100%)
H
(extremely small)
O
OH
Acetone
(>99%)
O
(1.5 X 10-4%)
OH
Cyclohexanone
(98.8%)
(1.2%)
Ch. 18 - 8
O
O
OH
Pentane-2,4-dione
(24%)
O
Enol form
(76%)
Hydrogen bond
O
Resonance stabilization
of the enol form
H
:
:O:
:
:
:O
H
:O:
Ch. 18 - 9
3. Reactions via Enols & Enolates
3A. Racemization
OH
O
t
Bu
Et
H Me
(chiral)
(s)
Racemization at
an a carbon
takes place in
the presence of
acids or bases
OH
or
H3O
t
Et
Bu
Enol
(achiral)
Me
H3O
O
t
O
Et
Bu
H
Me
+
t
Et
Bu
Me
( 1 : 1 ) racemate
H
Ch. 18 - 10

Base-Catalyzed Enolization
H
O
O
C
HO
C
C
OH
Enolate
(achiral)
C
H
O
HO
+
C
C
H
Enol
(achiral)
Ch. 18 - 11

Acid-Catalyzed Enolization
O
O
C
H
C
+ H
O
C
H
H
H
+
C
H
O
H
H
H
O
H
H +
O
C
H
C
Enol
(achiral)
Ch. 18 - 12
3B. Halogenation at the a Carbon
H
O
C
C
+ X2
acid
or base
X
O
C
C
+ HX
(racemic)
Ch. 18 - 13
 Base-Promoted
Step 1
:O:
H
B: +
C
Halogenation
slow
B:H +
C

C C

:O:
Enolate
fast
OH
B:
+ X
Step 2
:O:
C
C
Enolate anion
C
X
O
C
fast
+
C
X
C
Enol
:O:
+ X
Ch. 18 - 14

Acid-Promoted Halogenation
Step 1
:B
:O:
H
C
H
+ H:B
C
O
C
fast
H
C
O
C
slow
C
H
+ H:B
Enol
Step 2
X
X
O
+
C
C
H
X
fast
C
O
C
H
+ X
Step 3
X
C
O
C
H
+
X
fast
:O:
X
C
C
Racemic
+
HX
Ch. 18 - 15
3C. The Haloform Reaction
O
O
3 X2
CX3
3 OH
+ 3X
OH
O
+
CHX3
A haloform
(X = Cl, Br, I)
O
Ch. 18 - 16
O
R
A methyl
ketone
O
I2, HO
(Both in
excess)
+
R
O
CHI3
Iodoform
(a yellow
precepitate)
Ch. 18 - 17

Mechanism
O
O
H + B
R
O
X
Repeat
steps
O
R
CX3
twice
R
Enolate
R
X
O
R
X
+
X
Ch. 18 - 18
● Acyl Substitution Step
R
O
: :
O
:OH
CX3
R
O
CX3
OH
R
OH
+ :CX3
HO
O
A
haloform
+
R
: :
CHX3
O:
Carboxylate
anion
Ch. 18 - 19
3D. a-Halo Carboxylic Acids: The
Hell–Volhard–Zelinski Reaction
1. X2, P
O
R
OH
2. H2O
O
R
OH
X
Ch. 18 - 20

Example
O
O
OH
Br2
Br
P
Br
H2O
O
OH
Br
Ch. 18 - 21
O
R
O
P + Br2
OH
R
[PBr3]
:O
O
Br
R
Br
Br
R
Br
H
Br
Br
O
H2O
R
OH
Br
Ch. 18 - 22
O
N
Br
(NBS)
O
HBr, SOCl2
O
R
Br
O
R
Cl
Cl
O
I2
R
Cl
HI, SOCl2
I
Ch. 18 - 23
1. HO
2. H3O
R
OH
OH
a-Hydroxy acid
O
R
O
OH
X
O
NH3
R
O
NH3
a-Amino acid
Ch. 18 - 24
4. Lithium Enolates
O
O
+ EtO Na
H
weaker
acid
(pKa = 19)
weaker
base
O
+ EtOH
stronger
base
stronger
acid
(pKa = 16)
O
+ iPr2N Li
H
weaker
acid
(pKa = 19)
stronger
base
+ iPr2NH
weaker
base
weaker
acid
(pKa = 38)
Ch. 18 - 25

Preparation of lithium diisopropylamide
H
(LDA)
Li
Buyllithium
(BuLi)
+
Diisopropylamine
(pKa = 38)
THF
+
Butane
(pKa = 50)
N
Li
N
Lithium diisopropylamine
i
[LDA or LiN( Pr)2]
Ch. 18 - 26
4A. Regioselective Formation of
Enolates
 Formation of a Kinetic Enolate
O
H3C
O Li
H
H
Li
N(iPr)2
H3C
DME
This enolate is formed faster
because the hindered strong
base removes the less
hindered proton faster.
Kinetic
enolate
Ch. 18 - 27

Formation of a Thermodynamic Enolate
This enolate is more stable because
the double bond is more highly
substituted. It is the predominant
enolate at equilibrium.
B
H3C
H
O
Kinetic
(less stable)
enolate
H
H
H3C
O
O
H
H
2-Methylcyclohexanone
H3C
weak
base in
a protic Thermodynamic
solvent (more stable)
enolate
Ch. 18 - 28
4B. Direct Alkylation of Ketones via
Lithium Enolates
O
H3C
O
Li O
CH3
I
(- LiI)
(56%)
LDA
DME
O
Br
Ph
Ph
(- LiBr)
(42-45%)
Ch. 18 - 29
4C. Direct Alkylation of Esters
O
R
LDA
OR'
THF
O
R
OR'
H
E
O
R
OR'
E
Ch. 18 - 30

Examples
O
O
1. LDA, THF
OMe
2. MeI
OMe
Me
O
O
O
1. LDA, THF
2. Ph
O
Ph
Br
Ch. 18 - 31
5. Enolates of b-Dicarbonyl
Compounds
O
O
H
pKa = 9-11
(more acidic)
O
H
pKa = 18-20
Ch. 18 - 32

Recall
O
O
+ EtO
+ EtOH
H

a-hydrogens of b-dicarbonyl compounds
are more acidic
O
O
O
+ EtO
H
O
+ EtOH
Ch. 18 - 33
Contributing resonance structures
O
O
O
O
O
O
C
C
C
C
C
C
C


C
O
O
C
C
C

C
Resonance
hybrid

Ch. 18 - 34
6. Synthesis of Methyl Ketones:
The Acetoacetic Ester Synthesis
O
O
O
EtO Na
O
Na
OEt
O
O
OEt
t
O
BuO K
R
O
OEt
X
OEt
R
R
R'
X
O
O
(R, R' = 1o
OEt
R
R'
alkyl groups)
Ch. 18 - 35

Synthesis of monosubstituted methyl
ketones
O
O
O
1. EtO Na , EtOH
OEt
2. Ph
O
OEt
Br
Ph
1. NaOH
O
heat
O
(- CO2)
Ph (Decarboxylation
of b-keto acid)
2. H3O+
O
OH
Ph
Ch. 18 - 36

Synthesis of disubstituted methyl
ketones
O
O
O
1. EtO Na , EtOH
OEt
O
2. MeI
OEt
Me
1. tBuOK, tBuOH
O
O
1. NaOH
OH
Me
O
2. H3O+
2. Et-Br
OEt
Me
Et
heat
O
Et
O
Et
(- CO2)
Me
Ch. 18 - 37
O
O
Ethyl acetoacetate ion
is the synthetic
equivalent of
O
Acetate enolate
Ch. 18 - 38

O
Synthesis of g-keto acids and g-diketones
O
O
EtO Na
O
OEt
O
OEt
Br
O
O
1. NaOH (aq)
O
X
O
2. H3O+
OH
OEt
O
X
heat
(- CO2)
O
O
g
X
a
b
X
O
X=OH: g-keto acid
X=R: g-diketone
Ch. 18 - 39
6A. Acylation
 Synthesis b-diketones
O
NaH
DMF
O
O
O
OEt (cannot use EtOH
because it will react
with acid chloride)
O
O
R
R
1. NaOH (aq)
OH
O
heat
(- CO2)
O
OEt
O
Cl
O
2. H3O+
O
OEt
R
O
R
O
Ch. 18 - 40
7. Synthesis of Substituted Acetic
Acids: The Malonic Ester Synthesis
O
EtO
O
OEt
Diethyl malonate
O
EtO
O
OEt
is the synthetic
equivalent of:
O
O
and
OEt
O
Ch. 18 - 41
O
R
O
EtO
OH
O
OEt
O
R
OH
R'
Ch. 18 - 42

Synthesis of monoalkylacetic acid
O
O
O
OEt
EtO
O
EtO
OEt
OEt
R
H
O
O
HO
heat
1. NaOH (aq)
OH
2. H3O+
O
HO
OEt
R
O
OH
O
O
R
O
EtO
R
H
O
X
HO
R
HO
R
Ch. 18 - 43

Synthesis of dialkylacetic acid
O
O
EtO
O
1. EtONa
OEt
2. RX
O
EtO
OEt
R
1. tBuOK, tBuOH
2. R'X
O
O
HO
OH
R
O
1. NaOH (aq)
2. H3O+
EtO
R'
OEt
R
R'
O
heat
(- CO2)
O
R
HO
R'
Ch. 18 - 44

Example 1
O
EtO
O
O
1. EtONa, EtOH
OEt
2.
O
EtO
OEt
Br
1. 50% KOH, reflux
2. dil. H2SO4, reflux
O
HO
(Heptanoic acid)
O
(-CO2)
HO
O
OH
Ch. 18 - 45

Example 2
O
O
O
1. EtONa, EtOH
OEt 2. MeI
EtO
O
EtO
OEt
Me
1. tBuOK, tBuOH
2. Ph
O
HO
Me
O
O
1. NaOH (aq)
OH
Ph
2. H3O+
Me
O
OEt
Ph
O
180oC
(- CO2)
EtO
Br
HO
Ph
Me
Ch. 18 - 46
8. Further Reactions of Active
Hydrogen Compounds
Z
Z'
Active hydrogen compound
(Z and Z' are electron withdrawing groups)
Z, Z':
O
O
R
H
O
O
S
S
R
O
O
O
NR2
OR
O
R
S
O
N
NO2
O
OR
or
S
O
NR2
Ch. 18 - 47

Example
O
NC
O
1. EtONa, EtOH
OEt
2.
NC
Br
O
OEt
1. tBuOK, tBuOH
NC
OEt
2. Ph
Br
Ph
Ch. 18 - 48
9. Synthesis of Enamines:
Stork Enamine Reactions
O
C
C
H
Aldehyde
or ketone
OH
+ HN
R
C
R
C
R
N
R
H
2o Amine
R
N
C
C
R
+ H2O
Enamine
Ch. 18 - 49

2° amines most commonly used to
prepare enamines
O
N
H
Pyrrolidine
N
H
Piperidine
N
H
Morpholine
● e.g.
O
N
N
H
p-TsOH, H2O
Ch. 18 - 50
N
(a)
(a)
(b)
+X
N
+R
N
R
C-alkylated
product
+X
O
H
product
X
R = H2C CH
or Ph
+
N-alkylated
heat
(b)
N
R
R
H2O
Ch. 18 - 51

Synthesis of b-diketones
N
O
N
H
N
O
R
Cl
O
R
p-TsOH
Cl
(enamine)
O
N
O
R
H2O
O
R
Ch. 18 - 52

Synthesis of g-keto esters
N
O
N
H
OEt
Br
O
p-TsOH
(enamine)
N
O
OEt
O
OEt
H2O
O
Ch. 18 - 53

Enamines can also be used in Michael
additions
N
+
CN
EtOH
N
CN
reflux
O
CN
H2O
Ch. 18 - 54
10. Summary of Enolate Chemistry
1. Formation of an Enolate
O
O
+ :B
R
R
Resonancestabilized
enolate
H
O
H:B +
R
Ch. 18 - 55
2. Racemization
R'
R
H
O
OH
Ph or H3O
R'
R
OH
OH
Ph or H3O
R'
H
O
R
Ph
Enol
(achiral)
Enantiomers
Ch. 18 - 56
3. Halogenation of Aldehydes & Ketones
O
O
R'
R
+ X2
H

acid
or base
R'
R
X
Specific example: haloform reaction
O
O
H
Ph
H
H
OH
+ 3 X2
H2O
X
Ph
X
X
O
CHX3 +
Ph
O
Ch. 18 - 57
4. Halogenation of Carboxylic Acids: The
HVZ Reaction
O
O
R
1. X2, P
OH
2. H2O
R
OH
X
Ch. 18 - 58
5. Direct Alkylation via Lithium Enolates
O
R
O
LDA, THF
o
H(R') -78 C
R
R''
X
H(R')
(formation of the
kinetic enolate)

O
R
H(R')
R''
Specific example:
O
O Li
LDA, THF
O
CH3I
-78oC
Ch. 18 - 59
6. Direct Alkylation of Esters
O
O
LDA
R
OEt
THF
OEt
R'
O
R
R
Br
OEt
R'
Ch. 18 - 60
7. Acetoacetic Ester Synthesis
O
O
1. NaOEt
OEt
O
OEt
1. OH, heat
2. H3O+
R
1. BuOK
O
O
2. R'Br
OEt
R
O
R
R'
R
3. heat, ( CO2)
t
OEt
R
O
2. RBr
O
O
O
R'
1. OH, heat
2. H3O+
3. heat, ( CO2)
Ch. 18 - 61
8. Malonic Ester Synthesis
O
O
EtO
2. RBr
OEt
R
HO
O
EtO
R
2. R'Br
R
O
EtO
OEt
R
O
R'
R
O
1. BuOK
HO
OEt
3. heat, ( CO2)
t
OEt
O
EtO
1. OH, heat
2. H3O+
O
O
O
1. NaOEt
R'
1. OH, heat
2. H3O+
3. heat, ( CO2)
Ch. 18 - 62
9. Stork Enamine Reaction
O
R
NR'2
R + R' NH
2
R
Enamine
O
R
R
1. R''
R
Br
2. heat
3. H2O
R''
Ch. 18 - 63
 END OF CHAPTER 18 
Ch. 18 - 64