CARBONYL CONDENSATION

REACTIONS

CARBONYL CONDENSATION
REACTIONS

Aldol Reaction
Dehydration of Aldol Products
Intramolecular Aldol Reaction
Claisen Condensation Reaction
Intramolecular Claisen
Condensation
Michael Reaction
Stork Enamine Reaction
Robinson Annulation Reaction

General Mechanism of Carbonyl

Condensation
O
C
R

H
C

OH
One carbonyl partner
with an alpha hydrogen
atom is converted by base
into its enolate ion.

OH2

Nucleophilic
Donor

C
R

This enolate ion acts as a

nucleophilic donor and
adds to the electrophilic
carbonyl group of the
acceptor partner

C:

Electrophilic
Acceptor

..

C
R

: O:

O
..

OH2

O
C
R

C
C

OH

New C-C Bond

Protonation of the tetrahedral alkoxide ion

intermediate gives the neutral condensation
product.

-OH

ALDOL REACTION
occurs between two aldehyde or ketone
molecules with a catalytic base
reaction can occur between two components
that have alpha hydrogens
reversible condensation reaction
two highlights: enolate formation and
nucleophilic attack at a carbonyl carbon
Aldol products are: alpha--unsaturated
aldehydes/ketones and -hydroxy
aldehydes/ketones

Mechanism of the Aldol Reaction

HO:
Base removes an
acidic alpha hydrogen
from one aldehyde
molecule, yielding
a resonancestabilized enolate ion.

O
H
H

C
H

: O:

O
H

C
CH3

.. C

+ H2O

H H

..
:O : -

O
CH3 C C C
H HH H H

The enolate ion attacks

a second aldehyde
molecule in a
nucleophilic addition
reaction to give a
tetrahedral alkoxide ion
intermediate.

H 2O

: OH

C
+
OH
C
C H3
HH H H
C

Protonation of the alkoxide ion intermediate yields

neutral aldol product and regenerates the base
catalyst.

Dehydration of Aldol Products:

Synthesis of Enones
-hydroxy aldehydes and -hydroxy ketones
formed in aldol reactions can be easily dehydrated
to yield conjugated enones
Dehydration is catalyzed by both acid and base
Reaction conditions for dehydration are only
slightly more severe than for condensation
Conjugated enones are more stable than
nonconjugated enones

Dehydration of Aldol Products

Base-catalyzed

OH

OH

.. :O :

OH

C
H

Enolate ion

O
C
C

OH-

Acid-catalyzed

OH

O
C

H
+

C
C
H

OH2+
C

Enol

O
C

O
C

H3O

Mixed Aldol Reaction

If two similar aldehydes/ketones react under
aldol conditions, 4 products may be formed
A single product can be formed from two
different components :
If one carbonyl component has no alphahydrogens or if one carbonyl compound is much
more acidic than the other.

Intramolecular Aldol Reaction:

Treatment of certain dicarbonyl compounds
with base can lead to cyclic products
A mixture of cyclic products may result ,
but the more strain-free ring is usually
formed

Intramolecular Aldol Reaction of 2, 5hexanedione yields 3-methyl-2cyclopentenone

O
C CH3
H b a
C
CH3
H C C
H H O

2,5- Hexanedione

Path A

-OH

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

H
C C H
H
C
CH3
C C
H
H
H
OH

NaOH, H2O

..
:O
H
..
O H
H C C H
HC
CH3
C
C
H
H
OH

O H O
+ 2

CH
3
3-Methyl-2-cyclopentenone

Path b
NaOH, H2O

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

..

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

..

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

..
:O
H
..

OH
H3 C

H3C

H
CH3

H3 C
+
H 2O

(2-Methylcyclopropenyl)ethanone
(NOT formed)

Claisen Condensation Reaction

Carbonyl condesation that occurs between two ester
components and gives a -keto ester product
Reaction is reversible and has a mechanism similar
to aldol reaction
Major difference from aldol condensation is the
expulsion of an alkoxide ion from the tetrahedral
intermediate of the initial Claisen adduct
1 equivalent of base is needed
to drive the reaction to completion because the
product is often acidic

Mechanism of Claisen Condensation:

involves nucleophilic acyl substitution of an ester
enolate ion on the carbonyl group of a second
ester molecule
tetrahedral intermediate expels an alkoxide leaving
group to yield an acyl substitution product

Mechanism of the Claisen

Condensation Reaction

O
Ethoxide base abstracts an
acidic alpha hydrogen
atom from an ester
molecule, yielding an ester
enolate ion

CH3COEt
- OEt

O
:CH2COEt

EtOH

Nucleophilic donor

:O:
CH3C OEt

..
:O: -

In a nucleophilic addition,
this ion adds to a second
ester molecule, giving a
tetrahedral intermediate.

Electrophilic
acceptor

CH3C CH2COEt
OEt

The tetrahedral intermediate

is not stable. It expels ethoxide
ion to yield the new carbonyl
compound, ethyl acetoacetate.

But ethoxide ion is basic enough

to convert the beta-keto ester
product into its enolate, thus
shifitng the equilibrium and driving
the reaction to completion.

O
O
CH3CCH2COEt + EtO-

O_ O
CH3CCHCOEt + EtOH
..

H3O+
Protonation by addition of acid
in a separate step yields the final
product.

O
CH3CCH2COEt + OH2

Mixed Claisen Condesation

occurs only when one of the two ester
components has no alpha-hydrogens, and
thus cant form enolate ion
can also be carried out between esters and
ketones resulting a synthesis of -diketones

Example of Mixed Claisen

Condensation
O
C OEt
Ethyl Benzoate

O
+

C H3 COEt
Ethyl Acetate
(Donor)

(Acceptor)

Ethyl benzoylacetate

C CH2 COEt
EtO H

1. NaH/THF
2. H30 +

Intramolecular Claisen Condensation:

Dieckmann Cyclization
can be carried out with diesters
works best on 1, 6-diesters and 1,7-diesters
5-membered cyclic -ketoesters result from
Dieckmann cyclization of 1,6-diesters
6-membered cyclic -keto esters result from
cyclization of 1,7-diesters

Examples of Intramolecular
Claisen Condensation
O

O
OEt

1. Na+ -OEt, ethanol

O
Diethyl hexanedioate
(a 1,6 -Diester)

O
OEt
EtOH

2. H3O+

Ethyl 2-oxocyclopentanecarboxylate
(82%)

OEt

O
1. Na+ -OEt, ethanol

OEt
O
OEt
Diethyl heptanediote
(a 1,7- Diester)

O
C

2. H3O+

OEt

+
Ethyl-2-oxocyclohexane carboxylate

Intramolecular Claisen Condensation

Mechanism
O
Base abstracts an acidic
alpha-proton from the
carbon atom next to one
of the ester groups,
yielding an enolote ion.

OEt
H
H

COOEt

Na + - OEt

..

tEO

EtOH

COOEt
Intramolecular nucleophilic addition of the ester enolate
ion to the carbonyl group of the second ester group at the
other end of the chain then gives a cyclic tetrahedral
intermediate.

tEO

H
COOEt

:
O
.
.

Loss of alkoxide ion from the tetrahedral

intermediate forms a cyclic beta-keto ester.

. .

Deprotonation of the
acidic beta-keto ester
gives an enolate
ion

H
COOEt

tEO
.

COOEt
O

EtOH

H 3O +

which is protonated
by addition of
aqueous acid at the
endoth the reaction to
generate the neutral
beta-keto ester
product.

+H

H
COOEt
O

O
2

Michael Reaction
Conjugate addition of a carbon nucleophile to an

alpha, -unsaturated acceptor

Best Michael Reactions:
Between unusually acidic donors (-ketoesters or diketones)
Unhindered alpha,-unsaturated acceptors

Stable enolates are Michael donors, and alpha,unsaturated compounds are Michael acceptors

The Michael Reaction

The base catalyst

removes an acidic alpha
proton from the starting
beta-keto ester to
generate a stabilized
enolate ion nucleophile.

O
C
EtO

O
C
CH3

C
H

H
+

Na - OEt

O O
C - C
The nucleophile adds
to the alpha,beta-keto
EtO ..C CH3
unsaturated ketone
H
O
H
electrophile in a
Michael reaction to
C
C
generate a new enolate
H
H
C
C
3
as product.
O

C ..
H3C C
H

+ EtOH

H HO
C C
C

CH3

H
CO2Et

The enolate product

abstracts an acidic
proton, either from
solvent or from starting
keto ester, to yield the
final addition product.

EtOH

O H H O
C C C
H3C C C CH3 + EtOH H
H
CO2Et

Some Michael Acceptors and

Michael Donors
Michael Acceptors
H2C CHCHO Propenol
H2C CHCO2Et Ethyl Propanoate
H2C CHC N Propenenitrile
H2C CHCOCH3 3-Buten-2-one
H2C CHNO2 Nitroethylene
H2C CHCONH2 Propenamide

Michael Donors
Beta-Diketone
RCOCH2COR'
RCOCH2CO2Et Beta-Keto Ester
EtO2 CCH2 CO2Et Malonic Ester
RCOCH2C N Beta-Keto nitrile
RCH2NO2
Nitro compound

Stork Enamine Reaction

enamine adds to an alpha,-unsaturated carbonyl

acceptor in a Michael- type process

Overall reaction is a three-step sequence:
Step 1: Enamine formation from a ketone
Step 2: Michael-type addition to an alpha, unsaturated carbonyl compound
Step 3: Enamine Hydrolysis back to ketone
net effect of Stork Enamine reaction sequence is the
Michael addition of a ketone to an alpha,unsaturated carbonyl compound

Example of Stork Enamine Reaction

O
N

N ..

H2C

-H2O
Cyclohexanone
O
N+
..
CH2CHCCH3

CHCCH3

An enamine

OH2

O
CH2CH2CCH3

CH2CH2CCH3

N
H

A 1,5-diketone

Robinson Annulation Reaction: Carbonyl

Condensation Reaction in Synthesis
leads to the formation of substituted cyclohexenones
2 step process:
Michael reaction
Intramolecular Aldol reaction
Treatment of a -diketone or -keto ester with an alpha, unsaturated ketone leads first to a Michael addition, which
is followed by intramolecular aldol cyclization