REACTIONS OF a-HYDROGENS :

1
REACTIONS OF a-HYDROGENS ALDOL AND
CLAISEN CONDENSATION REACTIONS
2
TYPES OF REACTIVITY FOR ALDEHYDES AND KETONES
nucleophilic addition
Nu
B
removal of a-H

• Good nucleophiles add.
• Strong bases remove a-hydrogens.

..
Often, both processes compete.
-
3
ALDOL CONDENSATION
4
The Aldol Condensation
base
H3O
- H2O
aldols easily lose water to form a double bond
a,b-unsaturated aldehyde
5
Aldol Condensation -- Mechanism
fast
enolate ion
slow
forms new C-C bond
fast
6
The Bond Forming Step
carbonyl (acceptor)
nucleophile
(donor)
enolate
7
Ketones Also Give Aldol Condensations
..
-
NaOH
-H2O
aldol
8
CROSSED ALDOL CONDENSATIONS
9
Crossed Aldol Condensations
KETONE ALDEHYDE
-
..
aldehyde
NaOH
ketone
- H2O
Works best to if an aldehyde is the acceptor,
since they are more reactive and works
really well if the aldehyde has no a-H.
a chalcone
The ketone should have the a-H.
10
IMPORTANT GUIDELINES
Aldehyde carbonyl groups are more reactive
toward nucleophilic addition than ketone carbonyl
groups.
1.
d-
d-
Alkyl groups deactivate the carbonyl ( I ) to
addition.
I
I
d
d
I
Nu
MORE REACTIVE
11
RELATIVE REACTIVITY OF CO GROUPS
THE EFFECT OF ALKYL SUBSTITUTION
Density - LUMO plots ( color scale 0.000 to
0.030 )
H-C-H
CH3-C-H
CH3-C-CH3
MORE REACTIVE
LESS REACTIVE
12
Ketones form enolate ions more easily than
aldehydes.
2.
..
..
-
-




More substituents on the double bond
aldehyde enolate
ketone enolate
more stable
-
..
..
Which enolate will form fastest?



..
-
monosubstituted
-
..
..



..
-
disubstituted
13
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 CO).
14
WHAT ABOUT TWO DIFFERENT KETONES ?
15
HOW MANY PRODUCTS WITH THIS ONE ?
A
B
a
b
c
d
x2
x2
four mixed products
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?
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FORMATION OF RINGS
17
Formation of Rings
a1
a2
NaOH

-
Why dont a2 hydrogens react ?
18
TETRAPHENYLCYCLOPENTADIENONE
KOH
EtOH
19
An Interesting Sequence
1) O3
2) H3O
OH-
KOH Aldol
H2SO4
- H2O
20
CLAISEN CONDENSATIONS
21
The Claisen Ester Condensation
CH3CH2OH
a b-ketoester
Notice that the base, the solvent and the
leaving group
CH3CH2O- Na, CH3CH2OH, CH3CH2O-
all match (this is required in most cases).
22
Claisen Ester Condensation Mechanism
23
Dieckmann Condensation
A CYCLIC CLAISEN CONDENSATION
NaOMe
MeOH
..
24
PATTERNS
Type of Condensation Reaction
b-hydroxy to CO
ALDOL
3-hydroxyaldehyde or
(H)
3-hydroxyketone
(H)
-H2O
a,b-unsaturated CO
ALDOL
2-propen-1-al or
(with loss of H2O)
2-propen-1-one
b-keto ester
CLAISEN
25
SYNTHESIS
26
Synthesis of a Perfumery Compound
cis
cis
a1
a2
a3
Aldol Condensation
a4
Dehydration
Why dont the other sets of a-H react?
cis-Jasmone
Scent of Jasmine in perfumes.
27
Biological Synthesis of Fructose
28
Synthesis of an Insect Repellent