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Chemistry 328N
Lecture 23
April 12, 2018
H
O
O H
H
O
O H-
ab
an Aldol!
The Aldol Condensation
Chemistry 328N
Exam III - Wed April 18
• WEL 2.122
• 7-9 PM
• Covers thru today
• Homework
• Hydrolysis
• Reactions
• Synthesis
• Get an A!!!
Chemistry 328N
Lithium diisopropylamide (LDA)
LDA converts simple esters quantitatively
to the corresponding enolate.
CH3CH2CH2COCH3
O
+
pKa ~ 22I
CH3CH2CHCOCH3
O
+ HN[CH(CH3)2]2••
–Li
+
pKa ~ 36
Li +
C N C HH
CH3
CH3
CH3
CH3
••
••
–
Chemistry 328N
Lithium diisopropylamide (LDA)
Enolates generated from esters and LDA
can be alkylated.
CH3CH2CHCOCH3
O
••
–CH3CH2CHCOCH3
O
CH3CH2ICH2CH3
(92%)
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
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
Acetoacetic Ester Synthesis
??
O
CH3 C
O
CH
R1
R2
Chemistry 328N
Ketone Synthesis
Let’s work another example together
O O
CH3
CH3
O
CH3
Chemistry 328N
Intramolecular Claisen Condensation:The Dieckmann Reaction
Walter Dieckmann
1869 –1925
Chemistry 328N
CH3CH2OCCH2CH2CH2CH2COCH2CH3
O O
1. NaOCH2CH3
2. H3O+
Example
COCH2CH3
O O
Chemistry 328N
CH3CH2OCCH2CH2CH2CH2COCH2CH3
O O
NaOCH2CH3
via
CH3CH2OCCH2CH2CH2CHCOCH2CH3
O O
••
–
••••
••••
••••
Chemistry 328N
via
CH3CH2OCCH2CH2CH2CHCOCH2CH3
O O
••
–
••••
••••
Chemistry 328N
via
CH3CH2OCCH2CH2CH2CHCOCH2CH3
O O
••
–
••••
••••
CHCOCH2CH3
O
–••
••
CH2H2C
H2C
C
O••
••
••CH3CH2O
••
••
Chemistry 328N
via
CHCOCH2CH3
O
–••
••
CH2H2C
H2C
C
O••
••
••CH3CH2O
••
••
Chemistry 328N
via
CHCOCH2CH3
O
–••
••
CH2H2C
H2C
C
O••
••
••CH3CH2O
••
••
CH3CH2O••
••••–
••••
CHCOCH2CH3
O
CH2H2C
H2C
C
O••
••
+
This works well
for 5 and 6
membered rings
Chemistry 328N
via
CHCOCH2CH3
O
–••
••
CH2H2C
H2C
C
O••
••
••CH3CH2O
••
••
CH3CH2OH••
••
••••
C COCH2CH3
O
CH2H2C
H2C
C
O••
••
+–
The product is the
stable carbanion
prior to acidification
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}
ab
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 a,b-unsaturated aldehyde or ketone
O H
H
O
H
O
D
O H-
ab
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
A Note about Aldol Reactions
aldol reactions are reversible and,
particularly for ketones, there is often
little aldol present at equilibrium. Keq
for dehydration is generally large
and, if reaction conditions bring
about dehydration, good yields of
product can be obtained
It takes special efforts to isolate an Aldol…the product is
generally the a,b -unsaturated aldehyde or ketone
Chemistry 328N
Aldol condensation
H
OOH
H
O
H
O
H
OOH
H
O
H
O
H
OPh
OH
Ph
H
O
Ph
Ph
H
O
OH- D
OH-
OH-
D
D
Chemistry 328N
H
H
O
Ph
Ph
H
O
O
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 a-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: a, b-unsaturated aldehydes and ketones
Grignard Reaction: Alcohols…, etc.
Chemistry 328N
From what??
H
H
O
H3C
H3C
O
H
H
Chemistry 328N
Aldol reactions of ketones
the equilibrium constant for aldol addition reactions of ketones
is usually unfavorable but can be driven by dehydration
2%
98%
2CH3CCH3
O O
CH3CCH2CCH3
OH
CH3
O
CH3C=C CCH3
H
CH3
O
CH3CCH2CCH3
OH
CH3
OH-
Chemistry 328N
Aldol Reactions Intramolecular aldol reactions
(when the enolate anion and the
carbonyl acceptor are in the
same molecule) are most
successful for formation of five-
and six-membered rings
2,7-Octanedione
CH3
O
CH3OCH3
O
CH3
HO
CH3
O
CH3
a
KOH -H 2 Oa
Chemistry 328N
Intramolecular Aldol Condensation
ketones give very good yields of aldol
condensation products when the reaction is
intramolecular and driven by dehydration
Na2CO3, H2O
heat
O
O
O
(96%)