REACTIONS OF a-HYDROGENS : ALDOL AND CLAISEN CONDENSATION REACTIONS

TYPES OF REACTIVITY FOR ALDEHYDES AND KETONES

O C CH
nucleophilic addition

OH C CH Nu H

Nu:
removal of a-H

:B
O C CH
Good nucleophiles add. Strong bases remove a-hydrogens. Often, both processes compete.

.. -

ALDOL CONDENSATION

The Aldol Condensation

O R CH2 C H + O R CH2 C H
H3O+ aldols easily lose water to form a double bond base ald + ol

OH H R

R CH2 C CH C H
an aldol (b-hydroxyaldehyde)

- H 2O

O R CH2 CH C C H R

a,b-unsaturated aldehyde

Aldol Condensation -- Mechanism

:O: CH3 C H : O: CH3 C H _ .. CH2 : O: C H : O: _ .. + :O .. H

fast

: O: _ .. CH2 C H .. _ : O: CH3 C H

.. _ : O: H2C C H

enolate ion
: O:

slow

CH2 C H .. :O H

forms new C-C bond

.. _ : O: H

CH3 C CH2 C H + H2O

fast

: O: H _ .. + :OH ..

CH3 C CH2 C H

The Bond Forming Step

H H3C + C .. CH2 C H
enolate

_ O _

carbonyl (acceptor)

H H3C C CH2 _ O

O
nucleophile (donor)

C H

Ketones Also Give Aldol Condensations

O C CH 3

OH C CH3
C CH3

- CH2
C O

..

NaOH

CH2 C O

CH C O

-H2O

aldol

CROSSED ALDOL CONDENSATIONS

Crossed Aldol Condensations

KETONE + ALDEHYDE
O C H OH C H

aldehyde

CH2 C O

.. -

CH2

NaOH

C O

ketone
- H 2O
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. The ketone should have the a-H.
O CH CH C

a chalcone

IMPORTANT GUIDELINES
1. Aldehyde carbonyl groups are more reactive toward

nucleophilic addition than ketone carbonyl groups. d+I

O
+I

R
Nu:

C d+

d+ C R R +I

d-

Alkyl groups deactivate the carbonyl ( +I ) to addition.

MORE REACTIVE

RELATIVE REACTIVITY OF C=O GROUPS

THE EFFECT OF ALKYL SUBSTITUTION
Density - LUMO plots ( color scale 0.000 to 0.030 )

O H-C-H
MORE REACTIVE

O CH3-C-H

O CH3-C-CH3
LESS REACTIVE

2. Ketones form enolate ions more easily than aldehydes. .. .. :O : :O : More R R substituents C C R C C H on the R R double bond aldehyde enolate ketone enolate more stable .. :O
CH3CH2 O CH3CH2 C CH3 C CH2 ..

Which enolate will form fastest?

.. :O :

CH3CH2

C CH2

monosubstituted

.. :O
CH3CH C CH3 ..

.. :O :
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 a

B d

H3C C CH2

CH3CH2

C CH3

x2

four mixed products aB, bB, cA, dA

x2

two different self dimers aA, bA

two different self dimers cB, dB

8 POSSIBLE PRODUCTS !
.. which enolate do you think will form preferentially?

FORMATION OF RINGS

Formation of Rings
a1
O

a2
O

H3C C CH2CH2CH2 C CH3

NaOH

CH3 O

CH3

OH

CH3

- :CH2
O

Why dont a2 hydrogens react ?

TETRAPHENYLCYCLOPENTADIENONE
O Ph CH2 O Ph C O CH2 Ph
KOH

Ph

Ph

O Ph

EtOH

Ph

Ph

An Interesting Sequence
O
1) O3
2) H3O+

O
KOH Aldol

OH-

OH
H2SO4 - H2O

CLAISEN CONDENSATIONS

The Claisen Ester Condensation

O R CH2 C O CH2 CH3 + O NaOCH2CH3
CH3CH2OH

O R +

R CH2 C CH C O CH2 CH3

a b-ketoester

R CH2 C O CH2 CH3

CH3 CH2 O H
Notice that the base, the solvent and the leaving group CH3CH2O- Na+, CH3CH2OH, CH3CH2Oall match (this is required in most cases).

Claisen Ester Condensation Mechanism

1) O CH3 C OC2H5 + _ .. : O C2H5 .. 2) O CH3 C OC2H5 O _ : CH2 C OC2H5
3) .. _ : O: CH3 C OC2H5 O CH2 C OC2H5

_ : CH2

O C OC2H5 H2C

.. _ : O: C OC2H5

.. _ :O : CH3 C OC2H5 O CH2 C OC2H5

: O: CH3 C O CH2 C OC2H5 + _ .. : O C2H5 ..

Dieckmann Condensation
A CYCLIC CLAISEN CONDENSATION
MeOOC CH2CH2CH2CH2 COOMe

NaOMe MeOH
O C O CH 3 CH C O CH3 O O O C O CH3

..

PATTERNS
HO R CH2 C R
-H2O

Type of Condensation Reaction

O CH C R R

b-hydroxy to C=O
(H)
3-hydroxyaldehyde or 3-hydroxyketone

ALDOL

(H)

O R CH2 C R C R C R

a,b-unsaturated C=O
2-propen-1-al or 2-propen-1-one

ALDOL
(with loss of H2O)

O R CH2 C R

O CH C OR

b-keto ester

CLAISEN

SYNTHESIS

Synthesis of a Perfumery Compound

a2
H2C H2C O C C

a1
O

cis
H2C H2C

O C

cis
CH CH2 CH CH CH2 CH3

CH2 CH2 CH CH CH2 CH3 KOH

Aldol Condensation

a3

C OH CH3

CH3

a4
O CH2 C H CH3 C H CH2 CH3

Dehydration

- H2O

cis-Jasmone
Scent of Jasmine in perfumes.

Why dont the other sets of a-H react?

Biological Synthesis of Fructose

O CH2 CH O O P OH O enzyme C H + a CH2 C OH O CH2 O O P O Dihydroxyacetone phosphate ALDOL CONDENSATION O CH OH C CH2 O O P O OH OH

OH Glyceraldehyde-3-phosphate

OH CH2 CH O O P OH OH O C H

Fructose-1,6-diphosphate

Synthesis of an Insect Repellent

O CH3 CH2 CH2 C H O CH3 CH2 CH2 C a H NaOH OH CH3 CH2 CH2 C CH3 CH2 CH ALDOL CONDENSATION H C H

O 2-Ethyl-3-hydroxyhexanal OH

OH CH3 CH2 CH2 C CH3 CH2 CH H C O H H2 Ni HYDROGENATION

CH3 CH2 CH2 C H CH3 CH2 CH

H C H

O H 2-Ethyl-1,3-hexanediol

--used in "6-12" insect repellent