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Chapter 22
Alpha Carbon Chemistry: Enols and Enolates
Review of Concepts
Fill in the blanks below. To verify that your answers are correct, look in your textbook at
the end of Chapter 22. Each of the sentences below appears verbatim in the section
entitled Review of Concepts and Vocabulary.
• When an aldehyde is treated with sodium hydroxide, an aldol addition reaction
occurs, and the product is a ________________________________.
• For most simple aldehydes, the position of equilibrium favors the aldol product.
For most ketones, the reverse process, called a ______-aldol reaction is favored.
• When an aldehyde is heated in aqueous sodium hydroxide, an aldol ___________
reaction occurs, and the product is an ___________________________.
• For unsymmetrical ketones, reactions with _____ at low temperature favor
formation of the kinetic enolate, while reactions with ______ at room temperature
favor the thermodynamic enolate.
• When LDA is used with an unsymmetrical ketone, alkylation occurs at the
__________________ position.
552
CHAPTER 22
Review of Skills
Fill in the blanks and empty boxes below. To verify that your answers are correct, look
in your textbook at the end of Chapter 22. The answers appear in the section entitled
SkillBuilder Review.
22.1 Drawing Enolates
DRAW THE RESONANCE STRUCTURES OF THE ENOLATE THAT IS FORMED WHEN THE KETONE BELOW IS TREATED WITH A STRONG BASE:
Base
O
22.3 Drawing the Product of an Aldol Condensation
O
NaOH, heat
DRAW THE PRODUCT OF THE ALDOL CONDENSATION REACTION THAT OCCURS WHEN THE
FOLLOWING COMPOUND IS HEATED WITH SODIUM HYDROXIDE:
CHAPTER 22
553
22.5 Using the Malonic Ester Synthesis
22.6 Using the Acetoacetic Ester Synthesis
OEt
O O O
IDENTIFY REAGENTS THAT WILL ACHIEVE THE FOLLOWING TRANSFORMATION:
1)
2)
3)
4)
5)
22.7 Determining When to Use a Stork Enamine Synthesis
554
CHAPTER 22
22.8 Determining which Addition or Condensation Reaction to Use
22.9 Alkylating the Alpha and Beta Positions
O
R
R
O
IDENTIFY REAGENTS THAT WILL ACHIEVE THE FOLLOWING TRANSFORMATION:
1)
2)
Review of Reactions
Identify the reagents necessary to achieve each of the following transformations. To
verify that your answers are correct, look in your textbook at the end of Chapter 22. The
answers appear in the section entitled Review of Reactions.
Alpha Halogenation
O O
Br + HBr
CHAPTER 22
555
Aldol Reactions
H
O
H
O OH
H
O
H
O
H
2
O
+
+
Claisen Condensation
E
t
O
O
E
t
O
O O
Alkylation
O
O
R
R
O
R
RR
556
CHAPTER 22
Michael Additions
H
O
H
OR
O
OO
O
O
+
Solutions
22.1.
OH O
H
H
OHOH
HHOH
OH
CHAPTER 22
557
22.3.
O O O
HOH
OH
HOH
22.4.
a)
O O
d)
O O
558
CHAPTER 22
22.5.
O O
22.6.
a) This anion is a doubly stabilized enolate ion, so there will not be a substantial amount
of ketone present together with the enolate at equilibrium:
b) This anion is a regular enolate ion (not doubly stabilized), so there will be a substantial
amount of ketone present together with the enolate at equilibrium:
O O
O O
CHAPTER 22
559
22.7. This anion is highly stabilized by resonance. The negative charge is spread over
two oxygen atoms (just like a doubly stabilized enolate) and three carbon atoms:
O
O
O
O
O
O
22.8.
a) 2,4-dimethyl-3,5-heptanedione is more acidic because its conjugate base is a doubly
stabilized enolate. The other compound (4,4-dimethyl-3,5-heptanedione) cannot form a
22.9.
a)
OH O
H
HOHOH
H
HOHOH
Br
Br
560
CHAPTER 22
b)
OH O
H
HOHOH
H
HOHOH
c)
H
OH O
H
H
H
OH
H
OH
H
HOH
H
OH
22.10.
a)
OH O
1) Na
2
Cr
2
O
7
, H
2
SO
4
, H
2
O
2) Br
2
, [H
3
O
+
]
3) pyridine
CHAPTER 22
561
22.11.
a)
OH
O
1) Br
2
, PBr
3
2) H
2
O
OH
O
Br
22.12.
a)
Br
OH
O
1) NaCN
2) H
3
O
+
Br
OH
O
1) Br
2
, PBr
3
2) H
2
O
22.13.
a)
OH
O
b)
OH
O
c)
OH
O
22.14.
562
CHAPTER 22
b)
O O
OH
SOCl
2
O
Cl
1) O
3
2) DMS
1) Br
2
, NaOH
2) H
3
O
+
d)
NH
H
3
O
+
O
NH
2
O
1) SOCl
2
OH
O
1) Br
2
, NaOH
2) H
3
O
+
2) xs NH
3
22.15.
22.16.
a)
O O
HOH
OH
O
OO
H
OOH
CHAPTER 22
563
b)
O O
HOH
OH
O
OO
H
OOH
d)
O O
H
O
H
HOH
O
O O
564
CHAPTER 22
22.18.
OH
H
O
H
ONaOH, H
2
O
22.20.
a)
H
O
b)
H
O
c)
O
H
22.21.
a)
H
O
b)
H
O
c)
H
O
22.23.
a)
H H
O
1) LDA
O
2)
O
OH
3) H
2
O
CHAPTER 22
565
b)
O OH
1) LDA
2)
3) H
2
O
O
O
H
d)
O
1) LDA
2)
3) H
2
O
O
H
O
22.24.
a)
H
O1) LDA
2)
3) H
2
O
HH
OH
O OH 1) LAH
2) H
2
O
OH OH O O
-H
2
O
HH
OH H
[H
+
]
566
CHAPTER 22
b)
O
c)
H
O
HH
OH
O OH OH OH H
O
-H
2
O
[H
+
]
O O
1) LDA
2)
3) H
2
O
1) LAH
2) H
2
O
d)
O
22.25.
O
O
OH
H
O
OO
O
CHAPTER 22
567
22.26.
O
O
O
HOH
O
O
O
OH
OH OH
H
22.27.
O
OH
H
O
O
O O
O
H
22.28.
a) NaOEt b) t-BuOK
22.29.
568
CHAPTER 22
22.30.
a)
OEt
O
OEt
O
OEt
O O
1) LDA
2)
3) H
3
O
+
c)
O OMe
OMe
OO
O OMe
1) LDA
2)
3) H
3
O
+
e)
O
O
OMe
O
1) LDA
2)
3) H
3
O
+
O
OO
CHAPTER 22
569
22.31.
a)
O
OEt
O
b)
OEt
O
O
c)
EtO
O
O
22.33.
a)
ON
H
O
H
3
C
I
O
c)
O
N
H
O
O
I
H
570
CHAPTER 22
22.34.
OH OH
1) Na
2
Cr
2
O
7
, H
2
SO
4
, H
2
O
22.35.
a)
EtO OEt
O O 1) NaOEt / EtOH
3) H
3
O
+
, heat
2)
OH
O
Br
c)
COOH
EtO OEt
O O
1) NaOEt / EtOH
5) H
3
O
+
, heat
2)
3) NaOEt / EtOH
4)
Br
Br
CHAPTER 22
571
22.36.
a)
O
O
EtO OEt
O O 1) NaOEt / EtOH
3) H
3
O
+
, heat
2) Br
4) [H
+
], EtOH, (-H
2
O)
c)
O
NH
2
1) NaOEt / EtOH
2)
Br
EtO OEt
O O
22.37. Preparation of the desired compound requires the installation of three alkyl groups
572
CHAPTER 22
22.38.
OH
O
22.39.
a)
O
b)
OEt
O O
Br
O
1) NaOEt / EtOH
2) EtI
3) NaOEt / EtOH
4)
5) H
3
O
+
, heat
d)
OEt
O O
IO
1) NaOEt / EtOH
2) CH
3
I
3) NaOEt / EtOH
4)
5) H
3
O
+
, heat
CHAPTER 22
573
22.40.
O
22.41.
a)
b)
OH
OEt
OO
Br
1) NaOEt / EtOH
2)
c)
NH
OEt
OO
Br
1) NaOEt / EtOH
3) H
3
O
+
, heat
2)
4) [H
+
], NH
3
, (-H
2
O)
22.42. Preparation of the desired compound requires the installation of three alkyl groups
22.43.
OHHO
1) Na
2
Cr
2
O
7
, H
2
SO
4
, H
2
O
2) [H
+
], EtOH, (-H
O) OEtEtO
O O
574
CHAPTER 22
22.44.
a)
O
b)
CN
c)
OEt
O
OHO
O
OHO
O
O H
H
H
22.46.
a)
EtO OEt
O O
O
O O
HO
1) NaOEt / EtOH
3) H
3
O
+
, heat
2)
CHAPTER 22
575
b)
O O
O
1) NaOEt / EtOH
22.47.
a)
O O O
b)
O O
O
1) R
2
NH, [H
+
], (-H
2
O)
2)
3) H
3
O
+
O
576
CHAPTER 22
22.48.
NaOH, H
2
O, heat
(Aldol
O
22.49.
H
O
O
O
O
O
O
O
OH
O
O
H
22.50.
OH
O
H
H
O
OO
NaOH, heat
+
CHAPTER 22
577
22.51.
a)
OO
O
b)
OO
O
1) LDA
2) H
O
3) CH
3
I
22.52.
a)
OH PCC
H
ONaOH
CH
2
Cl
2
OH O
H
OH
OH
1) LAH
2) H
2
O
578
CHAPTER 22
b)
1) [H3O+], Br2
2) pyridine
c)
OH
PCC NaOH
CH
2
Cl
2
OHO
H
O
H
OO
H
PCC
CH
2
Cl
2
CHAPTER 22
579
22.53.
a)
OEt
O
OH
O
OH
Na
2
Cr
2
O
7
H
2
SO
4
, H
2
O
[H
+
]
EtOH
b)
NaOH , H
2
O, heat
22.54.
a)
O O
1) Me
2
CuLi
2)
I
580
CHAPTER 22
c)
H
O
Cl
O
1) Me
2
CuLi
2) MeI
3) Na
2
Cr
2
O
7
4) SOCl
2
H
2
SO
4
, H
2
O
e)
OH N
2) Me
2
CuLi
3) MeI
4) MeNH
2
1) PCC, CH
2
Cl
2
[H
+
], (-H
2
O)
CHAPTER 22
581
22.55.
O O
NaOH, H
2
O
heat
O
1) Me
2
CuLi
2) MeI
22.57.
OOOH
O O
HH
H
22.59.
a)
OEt
O O
OEt
O O
OEt
OO
582
CHAPTER 22
22.60.
O OO O O
O
O
OH
Increasing acidity
22.61.
a) This enol does not exhibit a significant presence at equilibrium:
OH
22.62.
E
t
O
OH O
E
t
O
O OH
E
t
O
O OH
CHAPTER 22
583
22.64. Deprotonation at the following γ-position results in an anion that has three
O
H
N
OO
O
22.65. Deprotonation at the α carbon changes the hybridization state of the α carbon
from sp
3
(tetrahedral) to sp
2
(planar). When the α position is protonated once
again, the proton can be placed on either side of the planar α carbon, resulting in
22.66.
O
Me
HH O
H
H
OH
Me
HHOH
OH
Me
22.67.
HO
H
O
H
O
HO
H
O
HOHO
H
O
HH
HH
584
CHAPTER 22
22.68.
HO
H
O
H HO
H
O
H
OH
O
HOH
H
HO
OH
H
HOH
OH
OH
H
22.70.
HO
O
H
O
H
O
OH
OH
HOH
O
H
22.71.
22.72. Trimethylacetaldehyde does not have any α protons.
H
O
22.73.
c)
H
O
NaOH
H
2
O
h
e
a
t
H
O
H
O
586
CHAPTER 22
22.74.
H
O
HOH
H
HOH
H
OH
H
OH
H
OH
22.75.
a)
EtO
O
B
r
OEt
O
b)
EtO
OH
H
OEt
O
EtO
OH
OEt
O
H O
H
H
EtO
O
OEt
O
c) The product should be more acidic than diethyl malonate because of the inductive
effect of the bromine atom.
CHAPTER 22
587
22.76.
H
O
H
O
NaOEt / EtOH
H
O
22.78.
a)
EtO OEt
O O 1) NaOEt / EtOH
3) H
3
O
+
, heat
2)
OH
O
Br
c)
COOH
PhPh
EtO OEt
O O
1) NaOEt / EtOH
5) H
3
O
+
, heat
2)
3) NaOEt / EtOH
4)
BrPh
BrPh
588
CHAPTER 22
b)
OEt
O O
1) NaOEt / EtOH
2) MeI
3) NaOEt / EtOH
4) MeI
5) H
3
O
+
, heat
O
22.80.
O
HOH
HO
HOH
O
CHAPTER 22
589
22.81.
O O
NaOH , H
2
O
heat
+ H
2
O
O
22.83.
O
OO
OEt
OLDA
1) Et
2
CuLi
2) H
3
O
+
NaOH, H
2
O
H H
O
h
e
a
t
590
CHAPTER 22
22.85.
O
OH
OOH
H
O
H
OO H
22.86.
a)
O
O
CO
2
Et
CO
2
Et
EtO
2
C
EtO
2
C
H
3
O
+
heat
O
O
+ 4 EtOH + 4 CO
2
CHAPTER 22
591
22.87.
a)
EtO
O
OEt
O
O
1) NaOEt
2) H
3
O
+
, heat
1) LDA
2) MeI
O
3) LDA
4) MeI
b)
c)
OEt
OO
1) H
3
O
+
2) SOCl
2
3) (CH
3
CH
2
CH
2
)
2
CuLi
592
CHAPTER 22
22.88.
HO
O
HO
H
O
1) TMSCl, Et
3
N
2) NaOH, H
2
O, heat,
O
3) H
2
, Pt
4) TBAF
b)
OO
1) Br
2
, [H
3
O
+
]
2) pyridine
3) Et
2
CuLi
4) H
3
O
+
d)
O
O
O
O
1) R
2
NH, [H
+
], (-H
2
O)
2)
3) H
3
O
+
CHAPTER 22
593
g)
O
O1) LDA
2) Me
I
3) LDA
4) Me
I
22.90. The driving force for this reaction is formation of a doubly stabilized enolate.
After the reaction is complete, an acid is required to protonate this anion.
594
CHAPTER 22
22.91.
O
H
NO
EtO OEt
O
O
OEt
OOEt
22.92.
EtO
O
H
N
EtO
OO
EtO
OO
CHAPTER 22
595
22.93.
a)
CN CN
R
N
H
CN R X
22.94.
a)
O
O
O
M
i
c
h
a
e
l
D
o
n
o
r
Michael Acceptor
c)
OEtEtO
O O
M
i
c
h
a
e
l
D
o
n
o
r
Michael Acceptor
NO
2
596
CHAPTER 22
e)
NO
2
Michael Donor Michael Acceptor
CH
2
O
2
N
22.95.
a)
OEt
EtO
O O
b)
OEtEtO
O O
OH
c)
OEt
EtO
O O
O
22.96.
O
OO
NaOH
O
OO
NaOH, heat
O
O
Michael
A
d
d
i
t
i
o
n
Aldol
Condensation
CHAPTER 22
597
22.98.
O
NO
2
HOH
NO
2
O
2
NO
H
O
22.99.
O
1) O
3
2) DMS
NaOH, H
2
O
H
OO
heat
O
1) Me
2
CuLi
2) H
3
O
+
598
CHAPTER 22
22.101.
OHHO
OH HOH
H
OO
H
H
HH H HOH
OHHO
O
H H
H
O
OHHO
HH
- H
2
O
a
c
r
o
l
e
i
n
22.103.
EtO OEt
O O 1) NaOEt
O
2)
O
O
CHAPTER 22
599
22.104.
O
O
O
OO CO
22.105.
When treated with aqueous acid, both compound A and compound B undergo
racemization at the α position (via the enol as an intermediate, see problem 22.65). Each
22.106.
HOH
H
Ph
O O
H H
Ph
O O
H H
Ph
O O H
600
CHAPTER 22
22.107.
O
O
O
HOH
O
O
O
OH
OH OH
H
CHAPTER 22
601
22.108.
a)
O
O
O
O
H H
OH
602
CHAPTER 22
b)
OO
H H
OEt
O
O
OO
22.109. Direct alkylation would require performing an S
N
2 reaction on a tertiary
substrate, which will not occur. Instead the enolate would function as a base and
