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7/28/2019 Aldol and Claisen Condensations
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REACTIONS OFa-HYDROGENS :ALDOL AND CLAISEN
CONDENSATION REACTIONS
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C CH
O
H
C CH
OH
H
C CH
O
NuNu:
:B
nucleophilic
addition
..-
removal
ofa-H
TYPES OF REACTIVITY FOR
ALDEHYDES AND KETONES
Good nucleophiles add. Strong bases removea-hydrogens.
Often, both processes compete.
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ALDOL CONDENSATION
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R CH2
C H
O
R CH2
C H
O
R CH2
C
OH
H
CH C H
O
R
+
R CH2
CH C C H
O
R
The Aldol Condensation
base
an aldol
(b-hydroxyaldehyde)
ald
+ol
H3O+ - H2O
a,b-unsaturated aldehyde
aldols easily lose
water to form a
double bond
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CH3C H
O: :
+ O H:.._
..
: : : :..
_.. _
CH3
C H
O: :
CH2
C H
O: :..
_
:
..
:
: :
: :..
: :
+ H2O
:..
: :
CH3
C
O
H
H
+ :OH..
..
_
CH2
C H
O
CH2
C H
O
CH2
C H
O
CH2
C H
O
_
_
CH3
CO
H
CH2
C H
O
CH3
C
O
H
Aldol Condensation -- Mechanism
fast
fast
slow
enolate ion
forms new
C-C bond
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+ _
CH3
C
H
O_
CH3
C
H
O
CH2
C
H
O
.. _
CH2
C
H
O
The Bond Forming Step
nucleophile
(donor)
carbonyl(acceptor)
enolate
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Ketones Also Give Aldol Condensations
C
O
CH3
C
OH
CH3
CH2
C OCH2
C O
..NaOH
C CH3
CH
C O
aldol
-H2O-
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CROSSED ALDOLCONDENSATIONS
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Crossed Aldol CondensationsKETONE + ALDEHYDE
C
O
H C
OH
H
CH2
C OCH2
C O
CH CH C
O
..
a chalcone
- H2O
NaOH
Works best to if an aldehyde isthe acceptor, since they are
more reactive; and works really
well if the aldehyde has no a-H.The ketone should have the a-H.
aldehyde
ketone
-
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IMPORTANT GUIDELINES
Aldehyde carbonyl groups are more reactive towardnucleophilic addition than ketone carbonyl groups.
OCR H
OCR R
d+d-
d+d-
+I +I
+I
Nu:
MORE
REACTIVE
Alkyl groupsdeactivate the
carbonyl ( +I )
to addition.
1.
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H-C-H CH3-C-H CH3-C-CH3
O O O
RELATIVE REACTIVITY OF C=O GROUPS
Density - LUMO plots ( color scale 0.000 to 0.030 )
MORE
REACTIVE
LESS
REACTIVE
THE EFFECT OF ALKYL SUBSTITUTION
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Ketones form enolate ions more easily than aldehydes.
O
CC
HR
R
O
CC
R
R
R
- -:: ::.. ..
More
substituents
on thedouble bond
more stable
Which enolate will
form fastest?
..
..
..: :
..: :
..:
..:
-
-
-
-CH3CH2 C
O
CH3
CH3CH
2C
O
CH2
CH3CH
2C
O
CH2
CH3CH C
O
CH3
C
O
CH3
CHCH3
disubstituted
monosubstituted
2.
aldehyde enolate ketone enolate
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In mixed reactions the ketone enolate
usually adds to the aldehyde.
ALDEHYDE + KETONE ?
The ketone forms the lower energy enolate (forms faster)
and it adds to the aldehyde (more reactive C=O).
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WHAT ABOUTTWO DIFFERENT KETONES ?
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HOW MANY PRODUCTS WITH THIS ONE ?
CH3
CO
CH2
CO
CH3
CH3CH
2+
x2 x2
8 POSSIBLE PRODUCTS !
two different self dimers two different self dimers
four mixed products
A B
a b c d
aB, bB, cA, dA
aA, bA cB, dB
.. which enolate do you think will form preferentially?
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FORMATION OF RINGS
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Formation of Rings
O
CH3
O
CH2
CH3
O
OH
O
CH3
CH3
C
O
CH2CH
2CH
2C
O
CH3
NaOH
:-
a1 a2
Why donta2 hydrogens react ?
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CH2
PhC
CH2
O
Ph
O O
PhPh
O
PhPh
Ph Ph
KOH
EtOH
TETRAPHENYLCYCLOPENTADIENONE
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O
O H H
OH
OO
1) O3
2) H3O+
KOH
Aldol
H2SO4
- H2O
OH-
An Interesting Sequence
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CLAISEN CONDENSATIONS
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CH2 C O CH2
O
R CH3
CH2C O CH
2
O
R CH3
CH2
C
O
R CH C
R
O
O CH2CH
3
+ NaOCH2CH3
+
CH3
CH2
O H
The Claisen Ester Condensation
a b-ketoesterCH3CH2OH
Notice that
the base, the solvent and the leaving group
CH3CH2O-Na+, CH3CH2OH, CH3CH2O
-
all match (this is required in most cases).
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1)
2)
+
:..
..
CH3C OC
2H
5
O
O C2H
5
_ :
_ : :.. _
CH3
C OC2H
5
O
:
_
CH2
C OC2H
5
O
: :
.. _
CH2C OC
2H
5
O
CH3
C OC2H
5
O
CH2
C OC2H
5
O
CH2
C
O
OC2H
5
Claisen Ester Condensation Mechanism
3)
: :.. _
CH3
C
O
CH2
C OC2H
5
O
: :
+ O C2H5:..
..
_
CH2
C OC2H
5
O
CH3
C OC2H
5
O
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Dieckmann Condensation
C
CH
O
O
CH3
C O
O
CH3
O
C
O
O CH3
CH2CH
2CH
2CH
2COOMeMeOOC
..
A CYCLIC CLAISEN CONDENSATION
NaOMe
MeOH
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PATTERNS
R CH2
COH
R
CH C RO
R
R CH2
C C C R
O
RR
3-hydroxyaldehyde or
3-hydroxyketone(H)
(H)
b-hydroxy to C=O
a,b-unsaturated C=O2-propen-1-al or
2-propen-1-one
ALDOL
ALDOL
CLAISENR CH2
C
O
CH C OR
O
R
b-keto ester
Type of
Condensation
Reaction
-H2O
(with loss of H2O)
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SYNTHESIS
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C
CH3
OCH2
CH2
CCH
2
O
CH2CH CH CH
2CH
3
C
CH3
CH2
CH2
CCH
O
CH2CH CH CH
2CH
3
OHKOH
O
CH3
CH2
C CCH2 CH3
H H
- H2O
Synthesis of a Perfumery Compound
Why dont the
other sets ofa-Hreact?
cis-Jasmone
Scent of Jasmine in perfumes.
Aldol Condensation
Dehydration
cis cis12
a3a4
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+CH2
CH C H
O
OHO
P
OH
OO
CH2
C CH2
O P OH
OH
O O
O
Glyceraldehyde-3-phosphate
CH2
CH C CH C CH2
O P OH
O
O
O
OH
OH
HOHO
P
OH
O O
Dihydroxyacetone phosphate
Fructose-1,6-diphosphate
a
ALDOLCONDENSATION
enzyme
Biological Synthesis of Fructose
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CH3
CH2
CH2
C H
O
CH3
CH2
CH2
C H
O
a
NaOH CH3 CH2 CH2 C
OH
CHCH2
CH3
C H
H
O
CH3
CH2
CH2
C
OH
CHCH2
CH3
C H
H
O
H2
Ni
CH3
CH2
CH2
C
OH
CHCH2
CH3
C H
O
HH
H
ALDOL
CONDENSATION
HYDROGENATION
2-Ethyl-3-hydroxyhexanal
2-Ethyl-1,3-hexanediol
--used in "6-12" insect repellent
Synthesis of an Insect Repellent