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REACTIONS OF REACTIONS OF -HYDROGENS :-HYDROGENS : ALDOL AND CLAISENALDOL AND CLAISEN CONDENSATION REACTIONSCONDENSATION REACTIONS
C CH
O
H
C CH
OH
H
C CH
O
NuNu::B
nucleophilicaddition
.. -
removalof -H
TYPES OF REACTIVITY FOR TYPES OF REACTIVITY FOR ALDEHYDES AND KETONESALDEHYDES AND KETONES
• Good nucleophiles add.• Strong bases remove -hydrogens.
Often, both processes compete.
ALDOL CONDENSATIONALDOL CONDENSATION
R CH2 C H
O
R CH2 C H
OR CH2 C
OH
H
CH C H
O
R
+
R CH2 CH C C H
O
R
The Aldol CondensationThe Aldol Condensation
base
an aldol(-hydroxyaldehyde)
ald+ol
H3O+ - H2O
,-unsaturated aldehyde
aldols easily losewater to form adouble bond
CH3 C 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 C
O
H
CH2 C H
O
CH3 C
O
H
Aldol Condensation -- MechanismAldol Condensation -- Mechanism
fast
fast
slow
enolate ion
forms new C-C bond
+ _CH3 C
H
O_
CH3 C
H
O
CH2
C
H
O
.._
CH2
C
H
O
The Bond Forming StepThe Bond Forming Step
nucleophile(donor)
carbonyl(acceptor)
enolate
Ketones Also Give Aldol CondensationsKetones Also Give Aldol Condensations
C
O
CH3C
OH
CH3
CH2
C OCH2
C O
..NaOH
C CH3
CH
C O
“aldol”
-H2O
-
““CROSSED” ALDOLCROSSED” ALDOL CONDENSATIONSCONDENSATIONS
Crossed Aldol CondensationsCrossed 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 aremore reactive; and works reallywell if the aldehyde has no -H.
The ketone should have the -H.
aldehyde
ketone
-
IMPORTANT GUIDELINESIMPORTANT GUIDELINES
Aldehyde carbonyl groups are more reactive towardnucleophilic addition than ketone carbonyl groups.
O
CR H
O
CR R+
-
+
-+I +I
+I
Nu:
MOREREACTIVE
Alkyl groupsdeactivate thecarbonyl ( +I )to addition.
1.
H-C-H CH3-C-H CH3-C-CH3
O O O
RELATIVE REACTIVITY OF C=O GROUPSRELATIVE REACTIVITY OF C=O GROUPS
Density - LUMO plots ( color scale 0.000 to 0.030 )
MOREREACTIVE
LESSREACTIVE
THE EFFECT OF ALKYL SUBSTITUTION
Ketones form enolate ions more easily than aldehydes.
O
CC HR
RO
CC RR
R
- -:: ::.. ..
More substituentson the double bond
more stable
Which enolate willform fastest?
..
..
..: :
..: :
..:
..:
-
-
-
-CH3CH2 C
O
CH3
CH3CH2 C
O
CH2 CH3CH2 C
O
CH2
CH3CH C
O
CH3 C
O
CH3CHCH3
disubstituted
monosubstituted
2.
aldehyde enolate ketone enolate
In “mixed” reactions the ketone enolate usually adds to the aldehyde.
ALDEHYDE + KETONE ?ALDEHYDE + KETONE ?
The ketone forms the lower energy enolate (forms faster)
and it adds to the aldehyde (more reactive C=O).
WHAT ABOUTWHAT ABOUTTWO DIFFERENT KETONES ?TWO DIFFERENT KETONES ?
HOW MANY PRODUCTS WITH THIS ONE ?HOW MANY PRODUCTS WITH THIS ONE ?
CH3 C
O
CH2 C
O
CH3CH3CH2+
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?
FORMATION OF RINGSFORMATION OF RINGS
Formation of RingsFormation of Rings
O
CH3
O
CH2
CH3
O
OH
O
CH3
CH3 C
O
CH2CH2CH2 C
O
CH3
NaOH
:-
1 2
Why don’t 2 hydrogens react ?
CH2PhC
CH2
O
Ph
O O
PhPh
O
PhPh
Ph Ph
KOH
EtOH
TETRAPHENYLCYCLOPENTADIENONETETRAPHENYLCYCLOPENTADIENONE
O
OH
H
OH
OO
1) O3
2) H3O+
KOHAldol
H2SO4
- H2O
OH-
An Interesting SequenceAn Interesting Sequence
CLAISEN CONDENSATIONSCLAISEN CONDENSATIONS
CH2 C O CH2
O
R CH3
CH2 C O CH2
O
R CH3
CH2 C
O
R CH C
R
O
O CH2 CH3
+ NaOCH2CH3
+
CH3 CH2 O H
The Claisen Ester CondensationThe Claisen Ester Condensation
a -ketoester
CH3CH2OH
Notice that the base, the solvent and the leaving group
CH3CH2O- Na+, CH3CH2OH, CH3CH2O
-
all match (this is required in most cases).
1)
2)
+
:..
..
CH3 C OC2H5
O
O C2H5
_ :_ : :
.. _
CH3 C OC2H5
O
:_
CH2 C OC2H5
O
: :.. _
CH2 C OC2H5
O
CH3 C OC2H5
O
CH2 C OC2H5
O
CH2 C
O
OC2H5
Claisen Ester Condensation MechanismClaisen Ester Condensation Mechanism
3)
: :.. _
CH3 C
O
CH2 C OC2H5
O
: :
+ O C2H5:
..
..
_
CH2 C OC2H5
O
CH3 C OC2H5
O
Dieckmann CondensationDieckmann Condensation
C
CH
O
O
CH3
C O
O
CH3
O
C
O
O CH3
CH2CH2CH2CH2 COOMeMeOOC
..
A CYCLIC CLAISEN CONDENSATION
NaOMe
MeOH
PATTERNSPATTERNS
R CH2 C
OH
R
CH C R
O
R
R CH2 C C C R
O
RR
3-hydroxyaldehyde or
3-hydroxyketone(H)
(H)
-hydroxy to C=O
,-unsaturated C=O
2-propen-1-al or
2-propen-1-one
ALDOL
ALDOL
CLAISENR CH2 C
O
CH C OR
O
R
-keto ester
Type of CondensationReaction
-H2O
(with loss of H2O)
SYNTHESISSYNTHESIS
C
CH3
OCH2
CH2
CCH2
O
CH2 CH CH CH2 CH3
C
CH3
CH2
CH2
CCH
O
CH2 CH CH CH2CH3
OHKOH
O
CH3
CH2
C C
CH2 CH3
H H
- H2O
Synthesis of a Perfumery CompoundSynthesis of a Perfumery Compound
Why don’t theother sets of -Hreact?
cis-JasmoneScent of Jasmine in perfumes.
Aldol Condensation
Dehydration
cis cis12
3
4
+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
ALDOLCONDENSATION
enzyme
Biological Synthesis of FructoseBiological Synthesis of Fructose
CH3 CH2 CH2 C H
O
CH3 CH2 CH2 C H
O
NaOH CH3 CH2 CH2 C
OH
CHCH2CH3 C H
H
O
CH3 CH2 CH2 C
OH
CHCH2CH3 C H
H
O
H2
Ni
CH3 CH2 CH2 C
OH
CHCH2CH3 C H
O
H H
H
ALDOLCONDENSATION
HYDROGENATION
2-Ethyl-3-hydroxyhexanal
2-Ethyl-1,3-hexanediol
--used in "6-12" insect repellent
Synthesis of an Insect RepellentSynthesis of an Insect Repellent