Professional Documents
Culture Documents
20-Carbonyl Reactions PDF
20-Carbonyl Reactions PDF
Daley
www.ochem4free.com
Organic
Chemistry
Chapter 20
Carbonyl Condensation Reactions
Chapter 20
Carbonyl Condensation
Reactions
Chapter Outline
20.1 The Carbonyl Condensation Mechanism
The general mechanism for the carbonyl condensation
reaction and an introduction to the aldol condensation
20.2 Carbonyl Condensation versus α
Substitution
Comparing the carbonyl condensation reaction with the
α substitution as discussed in Chapter 19
20.3 Mixed Aldol Condensations
Aldol condensations using two different carbonyl
compounds
20.4 Intramolecular Aldol Condensations
Aldol condensations involving different functional groups
in one molecule
20.5 The Claisen Condensation
An aldol type reaction using an ester as a substrate
20.6 The Dieckmann Cyclization
An intramolecular Claisen condensation
20.7 The Michael Addition Reaction
The addition of a nucleophile to the β carbon of an α,β-
unsaturated carbonyl compound
20.8 The Robinson Annulation Reaction
A two step ring forming reaction with a Michael reaction
followed by an aldol condensation
20.9 Carbonyl Condensations in Synthesis
A case study of the synthesis of jasmone
Objectives
O O O
C H Base C C
C C C
Enolate ion
In the next step, the nucleophilic enolate ion reacts with the
electrophilic carbonyl carbon of another carbonyl compound in a
nucleophilic addition reaction such as those you studied in Chapter 7.
••
•
• O•• •• ••
••
C C
•
• O ••
•
• O
•
• O •
•
••
O•• •
• OH
••
C RO H C
C C C
••
C C
(Solvent)
Carbonyl compound Alkoxide ion intermediate Aldol product
The reaction of the enolate ion and the carbonyl compound forms an
intermediate alkoxide ion. This alkoxide ion intermediate is then
protonated to form the aldol product. Usually carbonyl condensation
reactions involve the loss of a small molecule such as water or an
alcohol to form the α,β-unsaturated product.
••
••
•
• O
•
• OH O
C
C C Base C C
C
H
α,β-Unsaturated product
O OH O
OH, H2O
CH3CH CH3CHCH2CH
3-Hydroxybutanal
(50%)
O OH O
OH, H2O
CH3CCH3 CH3CCH2CCH3
CH3
4-Hydroxy-4-methyl-2-pentanone
(3%)
Chemists are not often able to isolate the aldol product because
it usually spontaneously dehydrates to the α,β-unsaturated aldehyde
or ketone product. The dehydration involves two steps. In the first
step, the base removes an α proton to form an enolate ion. Next, the
enolate ion intermediate loses the hydroxide group giving the α,β-
unsaturated aldehyde or ketone product. The —OH group is normally a
very poor leaving group, but in this reaction the enolate ion is a
stronger base so the —OH group readily leaves.
•• ••
• •
• OH • O
CH3CH CHCH
••
•• •• ••
• • •
• OH •O ••
• O
•
• OH
CH3CHCHCH ••
CH3CH CHCH
H
•• ••
•
•
• OH • O••
CH3CHCH CH
Exercise 20.1
The aldol condensation reaction also takes place with an acid catalyst.
The enol nucleophile first reacts with the protonated carbonyl. The
aldol product then loses water via an E2 elimination. Write a
mechanism for this reaction.
O O Li O
CH2CH3
LDA CH3CH2Br
••
•• •
H •• O • O •
••
••
• O
CHCH CH O•• •• CHCH
3•• CH2CH
CH3OH
•• •• ••
•• • •
•
• OH •
• O • O•• •O
CH2CHCHCH •• CH2CHCHCH
CH3••
O H
Exercise 20.2
[Sidebar]
O O2 OH
H
H2
NaOH
OH
O O
Na
H H
2-Propyl-2-heptenal
O OH O O
Na
CH3CH CH3CHCH2CH CH3CH CHCH
OH O OH O
CH3CH2CHCH2CH + CH3CHCH2CH
O O
Base
CH3CH + CH3CH2CH
OH O OH O
CH3CHCHCH + CH3CH2CHCHCH
CH3 CH3
CH3 O O CH3 OH O
OH
CH3 C CH + CH3CH CH3 C CH CH2CH
CH3 CH3
OH
CH3 O
CH3 C CH CHCH
CH3
4,4-Dimethyl-2-pentenal
(74%)
O O O
CH
CH3O
+
CH3OH
(81%)
O
O O
O O
EtO
CH3CCH2COEt + OEt
EtOH
Acetoacetic ester
(76%)
O O
COEt O COEt
EtO
CH2 + C
EtOH
COEt COEt
O O
(81%)
Malonic ester
The best method to use to ensure that you get the desired
product from a mixed aldol condensation is to form the enolate ion from
one of the carbonyl compounds before you add the other carbonyl
Formation of a silyl compound. An efficient technique for doing this is to first form a silyl
enol ether is discussed enol ether, a synthon of an enolate ion, then add the carbonyl
in Section 19.8. Note compound. This approach allows you to specifically form the desired
that a chemist can enolate ion, which then reacts with the other carbonyl compound. In
selectively form either
this reaction the titanium is a Lewis acid that forms a complex with
of the two possible silyl
enol ethers. the carbonyl oxygen. This complex makes the carbonyl carbon more
electrophilic and therefore more reactive.
OSi(CH3)3 O
CH3 O CH3 CHCH2CH3
1) TiCl4
+ CH3CH2CH
2) H3O
(84%)
Exercise 20.3
CH CHCH
Cinnamaldehyde
O O O
CH3
O OH OH
OH
CH3 CH3
CH3
2,6-Heptanedione 3-Methyl-2-cyclohexenone
(87%)
O O
OH
OH OH
O
CH3
CH3 CH3 3-Methyl-2-cyclohexenone
O
CH3
OH HO
2,6-Heptanedione CH3 CH3
OH
CH3 CH3
O O
Methyl (2-methyl-1-cyclobutenyl) ketone
O O O
O O
CH3
OH OH
CH3 CH3
Less stable product More stable product
O O O
OH
CH3 CH3
CH3
2,7-Octanedione Methyl (2-methylcyclopentenyl) ketone
(79%)
Synthesis of 1,5-Diphenyl-1,4-pentadien-3-one
O O O
H
NaOH, EtOH
Benzaldehyde 1,5-Diphenyl-1,4-pentadien-3-one
(45%)
Discussion Questions
1. Why is it necessary to cap the reaction vessel as soon as the reagents are added?
2. Besides the peaks for the benzene rings, the NMR spectrum of the product has a
pair of doublets at 7.1 and 7.7 ppm. The coupling constant for these peaks is 17 Hz.
These are typical peak positions for protons on conjugated double bonds. What
geometric isomers are formed in the reaction?
Exercise 20.4
Draw the structure of the products resulting from the reaction of each
of the following two cyclodecanediones with base.
O
a) b)
O O
The pKa for an ester is usually in the range of 23-25, whereas the pKa
for an aldehyde or ketone is 19-20. As a result an ester takes a
somewhat stronger base to deprotonate than does a ketone or an
aldehyde. Once the ester enolate ion forms, however, it is a stronger
nucleophile than a ketone or aldehyde enolate ion.
•• ••
•• •
•
• O ••
•
• O • O••
••
EtO
••
•
• •• ••
••
•
•O
•• •• •• •• ••
••
•
• O C C OEt
•
• O •• •
• O •
• O •
•O
•• ••
•• ••
H C
••
COEt
••
C C C COEt C C C COEt
•• ••
•
• OEt H
•• H
Ester enolate ion -Ketoester
Exercise 20.5
As a rule, the base used for a Claisen condensation is made from the
same alcohol as the one used in the synthesis of the ester itself. Thus,
O O
C C C COEt
O O O O O O
OEt H3O
C C C COEt C C C COEt C C C COEt
H H
O O
C C C COEt
O O O
1) EtO , EtOH
CH3COCH2CH3 CH3CCH2COCH2CH3
2) H3O
Ethyl acetoacetate
(77%)
O O
O
1) EtO , EtOH COCH2CH3
(CH3)3CCOCH2CH3 (CH3)3CC
C
2) H3O
H3C CH3
Ethyl 2,2,4,4-tetramethyl-3-oxopentanoate
(6%)
Draw the ester that would be used to synthesize the following product:
O O
OEt
Solution
In a Claisen condensation, a new carbon—carbon bond is formed between the
α carbon of one ester molecule and the carbonyl carbon of another ester
molecule.
O O
O
OEt
OEt
O O
O
O CCH2COEt
COEt
1) NaH, THF
+ CH3COEt
2) H3O
Ethyl 3-oxo-3-phenylpropanoate
(71%)
O O O
CH3 CH3
O CH
1) EtO , EtOH
CH3 + HCOEt CH3
2) H3O
2-Methanoyl-6,6-dimethylcyclohexanone
(94%)
Exercise 20.6
What product would you get from diethyl oxalate (CO2Et)2 in a mixed
Claisen reaction with ethyl acetate?
Exercise 20.7
Predict the products from the reaction of the following compounds with
ethoxide ion in ethanol.
Sample solution
b)
O O O
1) EtO , EtOH
CH3CH2CH2CH2COEt CH3CH2CH2CH2CCHCOEt
2) H3O
CH3CH2CH2
Ethyl pentanoate
[Sidebar]
NH2
CH3 O O N
N
HSCH2CH2NH C CH2CH2 NH C CH C CH2 O P O P O
CH2 N N
O O OH CH3 O O OH
H
H H
O OH
Coenzyme A O P O
O
CH3 C S CoA
Acetyl CoA
•
• Enzyme O
CH2 C S CoA
O
H CH2 C S CoA
Acetyl CoA O
CH2 C S CoA
O
CH3 C S CoA
O O O
O O O
CH3 C CH2 C S CoA CH3 CH2 CH2 C S CoA
O
CH3(CH2)nCOH
Fatty acid
(n > 10)
O O
CH3 C S CoA + CH3CH2CH2 C S CoA
or
O O O O
CH2CH3
None produced
O O O
O
2-Ethoxycarbonylcyclohexanone
(81%)
removed from the equilibrium. This step is also analogous to the final
step in the Claisen condensation. To recover the product, simply add
dilute acid.
O
O EtO O O
OEt OEt
OEt OEt
H OEt
OEt
O
O
O O O O O O
H
H2O H EtO
OEt OEt OEt
Exercise 20.8
O CH3 O O O
O O O H
C Nu C C H OH2 C C
C C Nu C Nu C
O H OH2
C C
Nu C
H
Michael donors are The best enolate nucleophiles, often called Michael donors,
nucleophiles that react
are those nucleophiles derived from β-dicarbonyl compounds. Other
in a Michael reaction
with α,β-unsaturated good nucleophiles are ones that contain an electron-withdrawing
carbonyl compounds. group, such as a nitrile or a nitro group instead of the carbonyl group of
a β-dicarbonyl compound. Table 20.1 lists some common Michael
Michael acceptors are donors. The electrophiles, often called Michael acceptors, contain
the α,β-unsaturated conjugated carbonyl, nitro, or nitrile groups.
carbonyl compounds
that react in a Michael Michael Donor Example
reaction.
Enamine
N
O O
EtOCCH2COEt
β-Dicarbonyl
Nitro alkane CH3NO2
O
N CCH2COEt
β-Cyanocarbonyl
Dialkylcuprates (CH3)2CuLi
O O O O
COEt COEt
O O
Michael donor Michael acceptor Ethyl 2-acetyl-5-oxohexanoate
91%
O1 2 3 O
CH3CCHCH2CH2CCH3
COEt
O
O N O O
O
NH CH2CH2CCH3
1) CH2 CHCCH3
H 2) H3O
1-Pyrrolidinocyclohexene 2-(3-Oxobutyl)cyclohexanone
An enamine (73%)
O O
OEt
Solution
There are three carbons between the two carbonyl groups. The best synthesis
is via an enamine.
O
Bond formed
O O N
O
OEt +
OEt
Exercise 20.9
a)
O O NH 1) O
H 2) H3O
b)
O O O
1) EtO , EtOH
CH3CCH2COEt + CH2 CHCCH3
2) H3O
c)
O O
OCH2CH3
?
O OCH2CH3
d)
O
? OEt
CN NO2
e)
O
(CH3)2CuLi
Sample Solution
a)
O
O
O N O
O NH 1)
O
H 2) H3O
EtO , EtOH
O
O CH3
CH3
–H2O
O
O OH
Annulation product Aldol intermediate
(68%)
enolate ions and the products that each would produce. As you examine
the relative stabilities of these three possible enolate ions, note that
enolate ion C, the enolate ion that produces the major product, is
actually the least stable intermediate.
O
CH3
O
O
O O
CH3 O
CH3 CH3
O O
O O O
O
A B C
OH O O
CH3 CH3 CH3
O
CH3 CH3
O
O O
Exercise 20.10
One other product could result from the enolate ion A above. However,
its elimination product violates Bredt's rule. Draw its structure. (Hint:
see Section 3.13, page 000.)
O O
O O
1,3-Cyclohexanedione
EtO , EtOH
O O
H
••
H3O
O O
O O
Most stable enolate ion
The only possible ring that could form from this enolate ion in a
Robinson annulation reaction is a four-membered ring. Because the
reaction is an equilibrium reaction with the outcome controlled by the
stability of the product, forming a four-membered ring is very unlikely.
Thus, no Robinson annulation reaction product forms.
The Robinson annulation has been used widely to synthesize
steroid molecules. The synthesis of the hormone estrone is particularly
O
CH3 CH3
O O
O O
O
Base
CH3O CH3O
O
CH3
CH3
O
O
HO CH3O
Estrone
Synthesis of 4,4-Dimethyl-2-cyclohexen-1-one
O O
O
H
H3O ,
2-Methylpropanal 4,4-Dimethyl-2-cyclohexen-1-one
(77%)
To a 100 mL round bottom flask, add 30 mL of toluene, 3.2 g (0.045 mol) of 3-buten-2-
one, and 4.2 g (0.058 mol) of 2-methylpropanal. Add 0.1 g of p-toluenesulfonic acid. Fit
the flask with a Dean-Stark trap and a reflux condenser. Reflux for at least 2.5 hours.
When the theoretical amount of water (0.8 mL) is collected, discontinue the reflux. Cool
the reaction mixture and transfer it to a separatory funnel. Wash with 25 mL of
saturated sodium bicarbonate solution. Separate the layers and dry the organic layer
over anhydrous sodium sulfate for at least 0.5 hour. Distill the solvent and unreacted
starting materials, then distill the product under reduced pressure. Yield of product is
4.3 g (77%), b.p. 75-78oC/15mm.
Discussion Question
Exercise 20.11
O
CH3
H3C
O
H3C
CH3
Jasmone
Exercise 20.12
O O
NaOH
O H2O, EtOH
Jasmone
(90%)
1) CH3COOH
2) H2O H O
OH
O OH O H
Furan
1,4-Butanedial
1) CH3COOH
2) H2O O
O
Z-8-Undecene-2,5-dione
(88%)
Ph3P CHCH2CH3
O O O
H (65%)
The other reaction places the aldehyde side chain on the furan via a
Michael addition of 2-methylfuran with propenal. 2-Methylfuran is
readily available commercially, so you don't need to synthesize it.
Because you go back no further than 2-methylfuran in your
retrosynthesis, 2-methylfuran is your beginning substrate for the
laboratory synthesis.
CH2 CHCH O
CH3OH
O O O
H
(65%)
••
•
•O
CH2 CHCH H
••
•
•• •• O •
O O ••
••
•• ••
•• O•• •• OH
O
••
O
••
••
CH2 CHCH O
CH3OH
O O O
H
Ph3P CHCH2CH3
1) CH3COOH
O 2) H2O
O O
NaOH
H2O, EtOH
S S S S
The synthetic uses for 1) C4H9Li
1,3-dithiane is 2) CH3Br
introduced in Section S S S S
(98%)
19.9, page 000.
1) C4H9Li
Br
O 2)
S S
1) HgCl2, CdCO3
O 2) KI
S S
Z-8-Undecene-2,5-dione (97%)
(85%)
S S
HS(CH2)3SH
HCl
CH3O O OCH3 S S
(83%)
Exercise 20.13