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Chemistry 328N
Lecture 20
March 31, 2016
Acetoacetic ester synthesis
&
Malonic ester synthesis
CH3 C
O
CH
R1
R2
HO C
O
CH
R1
R2
Chemistry 328N
Chemistry 328N
NH2
Br2, H2O
NH2
BrBr
BrStrong activator
NH2
HNO3
H2SO4, 20 oC
NH2
NO2
NH2
NO2
+
51% 47%
NH3
+
H+
nitration
Electrophilic reactions of aniline …the true story
Chemistry 328N
NH2 NH2
NO2
NH
O
?
Acylation
Nitration
Hydrolysis
NH
O
NO2a weak base
Protection-deprotection allows us to
synthesize p-nitroaniline in a high yield
Chemistry 328N
Two moles of ethyl acetate condense to give ethyl 3-oxobutanoate or … ethylacetoacetate aka acetoacetic ester
2CH3COCH2CH3
O1. NaOCH2CH3
2. H3O+
O O
CH3CCH2COCH2CH3
Classical Claisen CondensationAn excellent path to b-keto esters
Chemistry 328N
Crossed Claisen
Condensation -- An Example
C O
O
CH2 CH3
CH3 C O CH2 CH3
O
Base
C CH2
O
C O
O
CH2 CH3
+
acceptor
donor
Chemistry 328N
Lithium diisopropylamide (LDA)
Enolates generated from esters and LDA
can be alkylated.
CH3CH2CHCOCH3
O
••
–CH3CH2CHCOCH3
O
2. CH3CH2ICH2CH3
(92%)
1. LDA
Chemistry 328N
A versatile synthesis of b-ketoesters
and symmetrically substituted acetones
Acetone
CH2 C
O
OCH2CH3 CH2 C
O
CH C
O
OCH2CH3
H3O+
Heat
CH2 C
O
CH2 + CO2 + HOCH2CH3CH2 C
O
CH2
A AA
AAAA
Chemistry 328N
Alkylation of Acetoacetic Ester gives
unsymmetrically substituted acetone
Chemistry 328N
Ketone Synthesis
Let’s work some examples together
O O
CH3
CH3
O
CH3
Chemistry 328N
The Malonic Ester Synthesis
Versatile Synthesis of Carboxylic acids
CH
R '
R
CO
O H
Chemistry 328N
Malonic Ester
Malonic ester is another name for diethyl
malonate.
The "malonic ester synthesis" uses diethyl
malonate as a reactant for the preparation of
carboxylic acids.
CC
COCH2CH3
H H
O O
CH3CH2O
Chemistry 328N
Dialkylation
1. NaOCH2CH3
O O
CH3CH2OCCH2COCH2CH3
2. CH3Br
CH3
O O
CH3CH2OCCHCOCH2CH3
Chemistry 328N
1. NaOCH2CH3
2. CH3(CH2)8CH2Br
O O
CH3CH2OCCCOCH2CH3
CH3CH3(CH2)8CH2
CH3
O O
CH3CH2OCCHCOCH2CH3
Chemistry 328N
O O
CH3CH2OCCCOCH2CH3
CH3
O
CH3(CH2)8CH2CHCOH
CH3CH3(CH2)8CH2
1. NaOH, H2O
2. H+
3. heat, -CO2
Chemistry 328N
Malonic Ester Synthesis
??
O
O H
O
H
Chemistry 328N
H
O
O H
H
O
O H-
an Aldol!
{Aldehyde / Alcohol}
b
The product of an aldol condensation is
– a b-hydroxyaldehyde…nucleophilic acyl
substitution is not possibe here….why??
The Aldol Condensation
Chemistry 328N
Loss of water!
• Aldol products are easily dehydrated so the major
product is an ,b-unsaturated aldehyde or ketone
O H
H
O
H
O
D
O H-
b
Chemistry 328N
The reaction actually proceeds
via the resonance stabilized
enolate anion and unlike the
E2, it proceeds in a stepwise
fashion!
“E2 like” Elimination
OH O
H
H
OH
O
H
OH
H2O
OH O
H
Chemistry 328N
Crossed Aldol Reactions
In a “crossed aldol” reaction, one kind of
molecule provides the enolate anion and
another kind provides the carbonyl group
In most cases, this makes a big fat mess!!
O
CH3CH2CH
O
+ CH3CHCH2CH
CH3
HO-
Mess !!
Chemistry 328N
The Crossed Aldol Reaction
Chemistry 328N
Look…no a-hydrogens…. so no enolate anions!!
Crossed Aldol Reactions
Crossed aldol reactions only work if:– one of the reactants has no -hydrogen and,
therefore, cannot form an enolate anion and
– the other reactant has a very reactive carbonyl
group, namely an aldehyde
O
HCH
Formal-
dehyde
CHO CH
O O
Benzaldehyde Furfural
(CH 3 ) 3 CCH
O
2,2-Dimethyl-
propanal
Chemistry 328N
Let’s discuss a plan for actually
running a crossed aldol reaction
Does the addition sequence matter??
What goes into the pot first, second and third?
Chemistry 328N
The Signature Page
Claisen Condensation: b-ketoesters
Dieckmann: Cyclic b-ketoesters
Acetoacetic ester synthesis: decorated acetones
Malonic ester synthesis: decorated acetic acids
Aldol: , b-unsaturated aldehydes and ketones
Grignard Reaction: Alcohols…, etc.
Chemistry 328N
From what??
H
H
O
H3C
H3C
O
H
H
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