REACTIONS OF α -HYDROGENS :

ALDOL AND CLAISEN

CONDENSATION REACTIONS
 TYPES OF REACTIVITY FOR
ALDEHYDES AND KETONES

O nucleophilic OH
addition
C CH C CH

Nu:
H Nu H

:B
removal
of α -H O • Good nucleophiles add.
• Strong bases remove α -hydrogens.
C CH
.. Often, both processes compete.
-
ALDOL CONDENSATION
The Aldol Condensation
ald
O +
ol
R CH2 C H
OH O
+ base
R CH2 C CH C H
O H R an aldol
R CH2 C H (β -hydroxyaldehyde)

H 3O + - H 2O
O
aldols easily lose R CH2 CH C C H
water to form a
double bond R
α ,β -unsaturated aldehyde
Aldol Condensation -- Mechanism
:O : .. _
_ .. fast _ : O: : O:
CH3 C H ..
+ :O.. H CH2 C H H2C C H

: O: .. _ enolate ion
: O:
CH3 C H slow CH3 C H
:O: : O:
_ forms new
..
CH2 C H CH2 C H C-C bond

.. _ ..
: O: : O: :O H :O:
fast
CH3 C CH2 C H CH3 C CH2 C H
H H _ ..
+ H2O + :OH
..
 The Bond Forming Step
H carbonyl
H
(acceptor)
+ _ _
H3C C O H3C C O
_
.. CH2
CH2
C O
C O

nucleophile H
H (donor)

enolate
Ketones Also Give Aldol Condensations

O OH
C CH C CH3 C CH3
3
CH2 CH
..
- CH2 NaOH C O C O
C O -H2O

“aldol”
“CROSSED” ALDOL
CONDENSATIONS
 Crossed Aldol Condensations
KETONE + ALDEHYDE

O OH
C H C H

.. - CH2
aldehyde CH2 NaOH C O
C O

ketone

- H 2O
Works best to if an aldehyde is
the “acceptor”, since they are O
more reactive; and works really CH CH C
well if the aldehyde has no α -H.
The ketone should have the α -H. a “chalcone”
 IMPORTANT GUIDELINES
1. Aldehyde
carbonyl groups are more reactive toward
nucleophilic addition than ketone carbonyl groups.

Oδ - Oδ - Alkyl groups
+I δ +
C
+I
Cδ + deactivate the
R H R R +I carbonyl ( +I )
to addition.
Nu:

MORE
REACTIVE
RELATIVE REACTIVITY OF C=O GROUPS
THE EFFECT OF ALKYL SUBSTITUTION
Density - LUMO plots ( color scale 0.000 to 0.030 )

O O O
H-C-H CH3-C-H CH3-C-CH3

MORE LESS
REACTIVE REACTIVE
2.Ketones form enolate ions more easily than aldehydes.
.. ..
:O :- :O :-
R R More
C C H C C R substituents
R on the
R
double bond
aldehyde enolate ketone enolate
more stable

Which enolate will .. .. -

:O :O :
form fastest?
CH3CH2 C CH2 CH3CH2 C CH2
..
O -
monosubstituted
CH3CH2 C CH3
.. .. -
:O :O :
CH3CH C CH3 H3C CH C CH3
..
- disubstituted
 ALDEHYDE + KETONE ?

In “mixed” reactions the ketone enolate

usually adds to the aldehyde.

The ketone forms the lower energy enolate (forms faster)

and it adds to the aldehyde (more reactive C=O).
 WHAT ABOUT
TWO DIFFERENT KETONES ?
HOW MANY PRODUCTS WITH THIS ONE ?
A B
O O
a b c d
H3C C CH2 + CH3CH2 C CH3

x2 four mixed products x2

aB, bB, cA, dA

two different self dimers two different self dimers

aA, bA cB, dB

8 POSSIBLE PRODUCTS !
….. which enolate do you think will form preferentially?
FORMATION OF RINGS
 Formation of Rings
α 1 α 2
O O
H3C C CH2CH2CH2 C CH3

NaOH

CH3 CH3 CH3

OH
O

- : CH2 O O
O

Why don’t α 2 hydrogens react ?

TETRAPHENYLCYCLOPENTADIENONE

O
C O
Ph CH2 CH2 Ph
Ph Ph
KOH
O O EtOH
Ph Ph
Ph Ph
An Interesting Sequence

O
1) O3

2) H3O+
O H
H OH-
KOH
Aldol
OH
H2SO4
- H 2O

O O
CLAISEN CONDENSATIONS
 The Claisen Ester Condensation
O
R CH2 C O CH2 CH3

O O
+ NaOCH2CH3
R CH2 C CH C O CH2 CH3
CH3CH2OH
O R
a β -ketoester
R CH2 C O CH2 CH3 +

CH3 CH2 O H

Notice that
the base, the solvent and the leaving group

CH3CH2O- Na+, CH3CH2OH, CH3CH2O-

all match (this is required in most cases).
Claisen Ester Condensation Mechanism
1)
O
CH3 C OC2H5 .. _
_ O : O:
+
_ .. : CH2 C OC2H5 H2C C OC2H5
: O C2H5
..

2)
O .. _
:O :
CH3 C OC2H5
CH3 C OC2H5
_ O O
: CH2 C OC2H5 CH2 C OC2H5
3) .. _
: O: : O:
CH3 C OC2H5 CH3 C _ ..
O O + : O C2H5
..
CH2 C OC2H5 CH2 C OC2H5
Dieckmann Condensation
A CYCLIC CLAISEN CONDENSATION

MeOOC CH2CH2CH2CH2 COOMe

NaOMe
MeOH
O
O
C O CH O
3
C O CH3
..
CH C O CH3
O
 Type of
PATTERNS Condensation
Reaction

HO O
β -hydroxy to C=O
R CH2 C CH C R 3-hydroxyaldehyde or ALDOL
(H)
R R 3-hydroxyketone
(H)
-H2O

O α ,β -unsaturated C=O
R CH2 C C C R 2-propen-1-al or ALDOL
R R 2-propen-1-one (with loss of H2O)

O O β -keto ester
R CH2 C CH C OR CLAISEN
R
SYNTHESIS
Synthesis of a Perfumery Compound
O
α 2 α 1 cis O cis
C C
H2C CH2 CH2 CH CH CH2 CH3 H2C CH CH2 CH CH CH2 CH3
H2C O H2C
C C OH
α 3 KOH
CH3 Aldol Condensation CH3
α 4
Dehydration
- H2O
O
CH2 CH2 CH3
C C
H H Why don’t the
CH3 other sets of α -H
react?
cis-Jasmone
Scent of Jasmine in perfumes.
Biological Synthesis of Fructose
O O O
α
CH2 CH C H + CH2 C CH2 O P OH

O OH OH O

Dihydroxyacetone phosphate
O P O
enzyme ALDOL
OH CONDENSATION
Glyceraldehyde-3-phosphate
OH O O

CH2 CH C CH C CH2 O P OH

O OH H OH O

O P O Fructose-1,6-diphosphate

OH
Synthesis of an Insect Repellent
O
OH
CH3 CH2 CH2 C H
NaOH CH3 CH2 CH2 C H
O
CH3 CH2 CH C H
CH3 CH2 CH2 C H ALDOL
α CONDENSATION O
2-Ethyl-3-hydroxyhexanal

OH OH

CH3 CH2 CH2 C H H2 CH3 CH2 CH2 C H

H
Ni
CH3 CH2 CH C H CH3 CH2 CH C H

O HYDROGENATION O H
2-Ethyl-1,3-hexanediol
--used in "6-12" insect repellent