1 Carbonyl Condensation Reactions Carbonyl compounds are both the electrophile and nucleophile in carbonyl condensation reactions.
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Carbonyl Condensation Reactions Carbonyl compounds are both the electrophile and
nucleophile in carbonyl condensation reactions
2
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Condensations of Aldehydes and Ketones: The Aldol Reaction
Acetaldehyde reacts in basic solution (NaOEt, NaOH) with another molecule of acetaldhyde
The -hydroxy aldehyde product is aldol (aldehyde + alcohol) or a ketol (that name is never used though!)
This is a general reaction of aldehydes and ketones
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The aldol reaction is reversible, favoring the condensation product only for aldehydes with no α substituent.
Steric factors decrease the amount of the aldol product.
Aldehydes and the Aldol Equilibrium
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Mechanism of Aldol Reactions
H
O
HH
+ OH-
H
O
H
O
+
H
O
H
OO
H
OO
+
H2OH
OOH
+ OH
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Ketones and the Aldol Equilibrium
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Dehydration of Aldol Products to Enones
The β-hydroxy carbonyl products dehydrate to yield conjugated enones
The term “condensation” refers to the net loss of water and combination of 2 molecules
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Dehydration of β-Hydoxy Ketones and Aldehydes
The α hydrogen is removed by a base, yielding an enolate ion that expels the OH leaving group
Under acidic conditions the OH group is protonated and water is expelled
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CCH3
O
H
OH-
C
OH
H
CH3CH2
C
O
H-H2O CH3
C
H
C
H
C
O
H
Aldol
CH3
C
H
C
H
C
O
H
Dehydration of β-Hydoxy Ketones and Aldehydes
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Removal of water from the aldol reaction product can be used to drive the reaction toward completion.
Even if the initial aldol favors reactants, the subsequent dehydration step pushes the reaction to completion.
H
O
OH-
H
OHO
O
H
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Removal of water from the aldol reaction products drives the reaction toward products completely in case of the conjugation of the resultant double bond of the enone and the aromatic ring.
H
O
HCO3-
H
O
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Mixed Aldol Reactions A mixed aldol reaction between two similar aldehyde or
ketone partners leads to a mixture of four possible products.
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Mixed Aldol Reactions
H3C H
O
+ H3C
H2CC
O
H
OH-
H
OH O
+H
OH O
O
H
enol 1
+
H
O
enol 2
H
OH O
+H
OH O
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Practical Mixed Aldols If one of the carbonyl partners contains no α hydrogens, and
the carbonyl is unhindered (such as benzaldehyde and formaldehyde), it is a good electrophile and can react with enolates. In this case a mixed aldol reaction is likely to be successful.
C
O
H+
H
O
OH-
C
H
C
CH3
C
O
H
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Ethyl acetoacetate is completely converted into its enolate anion under less basic conditions than monocarbonyl compounds.
Therefore, in mixed aldol condensations with ethyl acetoacetate the latter acts preferentially as a nucleophile.
Practical Mixed Aldols
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Intramolecular Aldol Reactions Treatment of symmetrical dicarbonyl compounds with base
produces cyclic products by intramolecular reaction.
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Mechanism Both the nucleophilic carbonyl anion donor and the electrophilic carbonyl
acceptor are now in the same molecule, and the least strained product is formed because the reaction is reversible.
O O
' '
OEt-
OO-
1
2
3
4
5
6
H3O+
O
O-
O
OEt-O- O
1
2
3
4
O-
O
123
4
5
6
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Mechanism
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The Claisen Condensation Reaction Reaction of an ester having an α hydrogen with one
equivalent of a base to yield a β-keto ester.
Similar to aldol condensation: nucleophilic acyl substitution of an ester enolate anion on the carbonyl group of a second ester molecule.
Typically, the starting ester has more than one acidic hydrogen, abd the product β-keto ester has a doubly activated proton that can be abstracted by a base.
Requires a full equivalent of base rather than a catalytic amount. The deprotonation drives the reaction to the product.
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Mechanism of the Claisen Condensation
1.
O
O
pKa= 25
+ OH-
O
O
+ H2O
pKa= 16
2.
O
O
+
O
O
O
O
O
O
3.
O
O
O
O
O
O O
+O
O
O O
pKa= 11
+ OH-
O
O O
+ H2O
OorOH
pKa=16
Na4.
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Mixed Claisen Condensations Successful when one of the two ester act as the electrophilic
acceptor in reactions with other ester anions to give mixed β-keto esters.
O
O
+O
CO
O
no -H
OH-
+OH
O O
O O
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1.O
O
pKa= 25
+ OH-
O
O
+ H2O
pKa= 16
2.
O O
O
+
O
O
O O
O
O
O
3.
O O
O
O
O
O O
O O
+O
O O
O O
pKa= 13
+ OH-
O O
O O
+ H2O
OorOH
pKa=16
Na4.
Mechanism of the Mixed Claisen Condensation
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OEt
O ORXbase
R'Xbase
H3O+
heat R
R'
O
OEt
O
?
O
Synthesis of phenyl ketones
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OEt
O
+OEt
O1. LDA, THF
2. H3O+
O
OEt
O
O
OEt
O
H3O+
heat
O
O
OEt
H H
O
CH3IOH-
Br
OH-
O
OEt
O
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R1 C
O
R2
R3H
R1 OCH3
O
no -H's
START WITH
2. ALKYLATE TWICE
1. MIXED CLAISEN
3. DECARBOXYLATE
Generalization to the synthesis of any ketones
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Intramolecular Claisen Condensations: The Dieckmann Cyclization
Best with 1,6-diesters (product: 5-membered β-ketoester) and1,7-diesters (product: 6-membered β-ketoester).
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O
O
O
O
1
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4O
CO2Et
(even)
OO
O
O
12
3
45
O
CO2Et
(odd)
Claisen (Dieckmann) Diester
Aldol Diketone
Intramolecular Condensations
12
3 4
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BrBr
1
2
3
4 1. MgEt2O
2. CO2
H3O+1
2
3
4OH
HO
O
O
diester
O
CO2Et
O
H3O+
Dieckmann
Uses of the Dieckmann Cyclization:Synthesis of Cyclic Ketones.
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Uses of the Dieckmann Cyclization:Alkylation of Dieckmann Product
The cyclic β-keto ester can be further alkylated and decarboxylated as in the acetoacetic ester synthesis to give an alternative route to the α-alkylated cyclic ketones.
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O
CO2Et
O
C
R
OH
R
2 RMgX
[H]
O
CH2OH1
2
3
at C 1
at C 3
3 alcohol
PCC
O
CH
O
enolate
O
CO2Et
R
with protection/deprotection
Uses of the Dieckmann Cyclization:Generation of Cyclic Alcohols, Aldehydes
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O
CO2Et
O
C
OH
CH3
CH3
1. Protection
O
CO2Et
+
OHOHexcess
HCl
CO2Et
O
O
2. Product1. 2 CH3MgBr
2. H3O+
(H3C)2C
O
O
OH
3. De-protection
ProductExcess H2O
HClO
(H3C)2C OH
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