1) The document discusses the acidity of α-hydrogens in enols and enolate ions. Strong bases will remove α-hydrogens to form resonance-stabilized enolate ions. 2) Enolate ions act as nucleophiles in reactions like alkylation, bromination, and the iodoform reaction. Catalytic bases like NaOH allow repeated reactions while non-catalytic bases like NaH and LDA only react once. 3) Important condensation reactions involving carbonyl compounds are the aldol and Claisen condensations. The aldol condensation forms β-hydroxycarbonyl products from carbonyl addition, while the Claisen forms β-keto

1. ACIDITY OFACIDITY OF αα-HYDROGENS-HYDROGENS
ENOLS and ENOLATE IONS

2. C C
H
O
C C
O
C C
O
..
..
..
..
:
:
::
-
-
α-hydrogen
base
“enolate
ion”
:B
However, the
ion is more
nucleophilic
at carbon.
acidic : pKa ~ 25
αα-- Hydrogens and Enolate IonsHydrogens and Enolate Ions
Strong bases will remove a hydrogen on the carbon next to a
carbonyl group (α-hydrogen) to make a resonance stabilized
conjugate base.
NaOH, KOH, NaOR, NaH, LDA, etc.
Major resonance
contributor:
charge is best
on oxygen =

3. ACETONE ENOLATE IONACETONE ENOLATE ION
density-
electrostatic
potential
HOMO
..
The nucleophilic electron pair is in the HOMO
major

4. C C
O
C C
O
..
..
..
:
::
-
-
I CH3
I CH3
Mechanisms are often drawn
from the enolate resonance
form like this:
Rather than from the
ketolate form like this:
Enolate Ions as NucleophilesEnolate Ions as Nucleophiles
MORE NUCLEOPHILIC AT CARBON, BUT BEST REPRESENTED AS THE ENOLATE
enolate
ketolate

5. αα-BROMINATION-BROMINATION
OF KETONESOF KETONES

6. BrominationBromination
O
O
Br
O
Br
Br
O
Br
Br
Br
O
Br
Br
Br
Br
KOH
Br2
O O
Br Br
:
: : :
::
..
.. ..
.. ..
..
Difficult to stop at monobromination
-
-
It just keeps
on going and
going …..

7. IODOFORM REACTIONIODOFORM REACTION

8. Iodoform ReactionIodoform Reaction
R C
CH3
O
R C
O
O
Na
CHI3
NaOH
I2
+ yellow
precipitate
R C
CH2
O
..
I I
R C
CH2
O
I
NaOH
I2
2x more R C
C
O
I
I
I
H O:
..-
..
R C
OH
O
C I
I
I
:
good
leaving
group
-
H2ONaOH
It just keeps
on going and
going …..

9. ALKYLATION OF KETONESALKYLATION OF KETONES
CATALYTIC BASES = NaOH, KOH, NaOR
NON-CATALYTIC BASES = NaH, LDA REACT ONCE
REACT REPEATEDLY

10. O
C CH3
THF
O
C CH2
..
_
O
C CH2
CH3
NaH
Alkylation of a KetoneAlkylation of a Ketone
α-hydrogens
CH3-I
one mole one mole
+ H2
one mole
NON-CATALYTIC BASES REACT ONCE
monoalkylation
CH3-I
O
C CH2
.. _
LDA
THF
N
CHCHCH3
CH3
CH3
CH3
: :
_
Li
+
“LDA”
Lithium Diisopropyl Amide
a strong base
Sodium Hydride
NaH

11. ALKYLATION OF CYCLOHEXANONEALKYLATION OF CYCLOHEXANONE
O O
O
CH3CH2 I O
CH2
CH3
:
::
:
..
..
-
-
:
..
NaOH
enolate
ion
O
CH2
CH3
CH2CH3
CH3
CH2
CH3
CH2
difficult to stop
at monoalkylation
with NaOH or KOH
(catalyst, not used up)
CATALYTIC BASES REACT REPEATEDLY
It just keeps
on going and
going …..

12. O
CH3
O
CH3
CH3
O
CH3
CH3
CH3
O
CH3
CH3
CH3
CH3
Alkylation follows the sequence
shown below.
Sequence of Alkylation - Cyclohexanone and BaseSequence of Alkylation - Cyclohexanone and Base
O
CH3
O
CH3
- -
It is difficult to stop at monoalkylation
even if one mole of CH3I is used.
This enolate has
lower energy -
the double bond is
more substituted.
Steric hindrance
is not a problem.
CH3-I This enolate has
higher energy.
O
KOH
CH3
I Large or bulky groups may follow a
different sequence than this one.
SAME
SIDE
FIRST

13. ALKYLATION OF KETONESALKYLATION OF KETONES
NON-CATALYTIC BASES = NaH, LDA

14. Monoalkylation is Obtained by UsingMonoalkylation is Obtained by Using
““Non-Catalytic Bases”Non-Catalytic Bases”
A “non-catalytic base” is used up, and not regenerated.
O
H
H
NaH
:H O
H
O
H
O
CH3
H
CH3
I
+ H2
Na+
:
: : :
+ NaI
.. ..
-
-
:
..
:
..
-
one
mole
gone
stoichiometric base

15. N
CHCHCH3
CH3
CH3
CH3
: :
_
Li
+
“LDA”
Lithium Diisopropyl Amide
a strong base
LDA is also a non-catalytic base.
It is too strong a base to be regenerated after it is
used to remove a proton from an aldehyde or ketone.
Lithium Diisopropyl AmideLithium Diisopropyl Amide
(iPr)2
N (iPr)2NH
..
:
..- (iPr)2
N
..
:
-
+ α-H Xdifficult
(need to add Lio
)

16. ALKYLATION OF KETONESALKYLATION OF KETONES
ENAMINES

17. ALKYLATION OF CYCLOHEXANONEALKYLATION OF CYCLOHEXANONE
ENAMINES ALSO GIVE MONOALKYLATION
O N CH3
CH2
I
O
CH2CH3
N
CH2
CH2
Alkylates once
and stops !
To perform a second alkylation
you must make the enamine all
over again!
+ I
-
..

18. N
CH3
N
CH3
Sequence of Alkylation: EnamineSequence of Alkylation: Enamine
Steric hindrance
yellow area
is planar
O O
CH3
O
CH3CH3
O
CH3
Difficult to go beyond dialkylation
because of steric hindrance.
Alkylations go one-at-a-time.
You must make a new enamine
each time.
first
time
second
time
Notice the different order of
methylation from that with base.
This enamine
is not favored.This enamine
is favored.
( pyrrolidine + CH( pyrrolidine + CH33I )I )

19. REACTIONS OFREACTIONS OF αα-HYDROGENS :-HYDROGENS :
ALDOL AND CLAISENALDOL AND CLAISEN
CONDENSATION REACTIONSCONDENSATION REACTIONS

20. C CH
O
H
C CH
OH
H
C CH
O
NuNu:
:B
nucleophilic
addition
..
-
removal
of α-H
TYPES OF REACTIVITY FORTYPES OF REACTIVITY FOR
ALDEHYDES AND KETONESALDEHYDES AND KETONES
• Good nucleophiles add.
• Strong bases remove α-hydrogens.
Often, both processes compete.

21. ALDOL CONDENSATIONALDOL CONDENSATION

22. 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 CondensationThe Aldol Condensation
base
an aldol
(β-hydroxyaldehyde)
ald
+
ol
H3O+
- H2O
α,β-unsaturated aldehyde
aldols easily lose
water to form a
double bond

23. 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

24. + _
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

25. Ketones Also Give Aldol CondensationsKetones Also Give Aldol Condensations
C
O
CH3
C
OH
CH3
CH2
C OCH2
C O
.. NaOH
C CH3
CH
C O
“aldol”
-H2O
-

26. ““CROSSED” ALDOLCROSSED” ALDOL
CONDENSATIONSCONDENSATIONS

27. Crossed Aldol CondensationsCrossed Aldol Condensations
KETONE + 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 is
the “acceptor”, since they are
more reactive; and works really
well if the aldehyde has no α-H.
The ketone should have the α-H.
aldehyde
ketone
-

28. IMPORTANT GUIDELINESIMPORTANT GUIDELINES
Aldehyde carbonyl groups are more reactive toward
nucleophilic addition than ketone carbonyl groups.
O
CR H
O
CR R
δ+
δ-
δ+
δ-
+I +I
+I
Nu:
MORE
REACTIVE
Alkyl groups
deactivate the
carbonyl ( +I )
to addition.
1.

29. 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 )
MORE
REACTIVE
LESS
REACTIVE
THE EFFECT OF ALKYL SUBSTITUTION

30. Ketones form enolate ions more easily than aldehydes.
O
CC H
R
R
O
CC R
R
R
- -:: ::
.. ..
More
substituents
on the
double bond
more stable
Which enolate will
form fastest?
..
..
..
: :
..
: :
..
:
..
:
-
-
-
-
CH3
CH2
C
O
CH3
CH3
CH2
C
O
CH2 CH3
CH2
C
O
CH2
CH3CH C
O
CH3
C
O
CH3
CHCH3
disubstituted
monosubstituted
2.
aldehyde enolate ketone enolate

31. 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).

32. WHAT ABOUTWHAT ABOUT
TWO DIFFERENT KETONES ?TWO DIFFERENT KETONES ?

33. 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?

34. FORMATION OF RINGSFORMATION OF RINGS

35. Formation of RingsFormation of Rings
O
CH3
O
CH2
CH3
O
OH
O
CH3
CH3
C
O
CH2
CH2
CH2
C
O
CH3
NaOH
:
-
α1 α2
Why don’t α2 hydrogens react ?

36. CH2
Ph
C
CH2
O
Ph
O O
PhPh
O
PhPh
Ph Ph
KOH
EtOH
TETRAPHENYLCYCLOPENTADIENONETETRAPHENYLCYCLOPENTADIENONE

37. O
O
H
H
OH
OO
1) O3
2) H3O+
KOH
Aldol
H2SO4
- H2O
OH-
An Interesting SequenceAn Interesting Sequence

38. CLAISEN CONDENSATIONSCLAISEN CONDENSATIONS

39. 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 β-ketoester
CH3CH2OH
Notice that
the base, the solvent and the leaving group
CH3CH2O-
Na+
, CH3CH2OH, CH3CH2O-
all match (this is required in most cases).

40. 1)
2)
+
:
..
..
CH3
C OC2
H5
O
O C2H5
_ :
_ : :
.. _
CH3
C OC2
H5
O
:
_
CH2
C OC2
H5
O
: :
.. _
CH2
C OC2
H5
O
CH3
C OC2
H5
O
CH2
C OC2
H5
O
CH2
C
O
OC2
H5
Claisen Ester Condensation MechanismClaisen Ester Condensation Mechanism
3)
: :
.. _
CH3
C
O
CH2
C OC2
H5
O
: :
+ O C2
H5
:
..
..
_
CH2
C OC2
H5
O
CH3
C OC2
H5
O

41. Dieckmann CondensationDieckmann Condensation
C
CH
O
O
CH3
C O
O
CH3
O
C
O
O CH3
CH2
CH2
CH2
CH2
COOMeMeOOC
..
A CYCLIC CLAISEN CONDENSATION
NaOMe
MeOH

42. 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)
β-hydroxy to C=O
α,β-unsaturated C=O
2-propen-1-al or
2-propen-1-one
ALDOL
ALDOL
CLAISENR CH2
C
O
CH C OR
O
R
β-keto ester
Type of
Condensation
Reaction
-H2O
(with loss of H2O)

43. SYNTHESISSYNTHESIS

44. C
CH3
OCH2
CH2
C
CH2
O
CH2 CH CH CH2 CH3
C
CH3
CH2
CH2
C
CH
O
CH2
CH CH CH2
CH3
OHKOH
O
CH3
CH2
C C
CH2
CH3
H H
- H2O
Synthesis of a Perfumery CompoundSynthesis of a Perfumery Compound
Why don’t the
other sets of α-H
react?
cis-Jasmone
Scent of Jasmine in perfumes.
Aldol Condensation
Dehydration
cis cisα1α2
α3
α4

45. +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
α
ALDOL
CONDENSATION
enzyme
Biological Synthesis of FructoseBiological Synthesis of Fructose

46. CH3
CH2
CH2
C H
O
CH3
CH2
CH2
C H
O
α
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
CHCH2
CH3
C H
O
H
H
H
ALDOL
CONDENSATION
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