Transcript Document 7779374

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
OH
C
One carbonyl partner
with an alpha hydrogen
atom is converted by base
into its enolate ion.
O
OH2
Nucleophilic
Donor
C
R
C:
: O:
C
This enolate ion acts as a
nucleophilic donor and
adds to the electrophilic
carbonyl group of the
acceptor partner
O
..
C
C
R
Electrophilic
Acceptor
O:
..
C
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-ß-unsaturated
aldehydes/ketones and ß-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
C
C
H
H
H
O
: O:
H
C
C
CH3
+ H2O
.. C
H
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
O
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
• ß-hydroxy aldehydes and ß-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
O
OH
OH
C
C
.. :O:
OH
C
C
C
C
H
Enolate ion
O
C
C
C
+
OH-
Acid-catalyzed
H
OH
O
H
C
C
+
O
C
OH2+
C
C
C
H
Enol
O
C
C
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
H C
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
..
H
O H
H
C C H
H
C
CH3
H C C
H
O
O
..
H
O H
H
C C H
H
C
CH3
H C C
H
O
..
:O
H
..
OH
H3 C
O
H3C
H
CH3
O
H3 C
+
H 2O
(2-Methylcyclopropenyl)ethanone
(NOT formed)
Claisen Condensation Reaction
• Carbonyl condesation that occurs between two
ester components and gives a ß-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
O
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
O
CH3CCH2COEt + OH2
Mixed Claisen Condesation
•occurs only when one of the two ester
components has no alpha-hydrogens, and
thus can’t form enolate ion
•can also be carried out between esters and
ketones resulting a synthesis of ß-diketones
Example of Mixed Claisen
Condensation
O
C OEt
Ethyl Benzoate
O
1. NaH/THF
+
C H3 COEt
Ethyl Acetate
(Donor)
(Acceptor)
Ethyl benzoylacetate
O
O
C CH2 COEt
EtO H
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 ß-ketoesters result from
Dieckmann cyclization of 1,6-diesters
• 6-membered cyclic ß-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
C
OEt
EtOH
2. H3O+
Ethyl 2-oxocyclopentanecarboxylate
(82%)
OEt
O
O
1. Na+ -OEt, ethanol
OEt
O
O
C
2. H3O+
OEt
+
OEt
Diethyl heptanediote
(a 1,7- Diester)
Ethyl-2-oxocyclohexane carboxylate
Intramolecular Claisen Condensation
Mechanism
O
OEt
Base abstracts an acidic
alpha-proton from the
carbon atom next to one
of the ester groups,
yielding an enolote ion.
H
H
COOEt
Na + - OEt
..
:
O
tEO
+
H
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…
O
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
O
2
H
COOEt
O
Michael Reaction
• Conjugate addition of a carbon nucleophile to an
alpha, ß-unsaturated acceptor
Best Michael Reactions:
• Between unusually acidic donors (ß-ketoesters or ßdiketones)
• Unhindered alpha,ß-unsaturated acceptors
• Stable enolates are Michael donors, and alpha,ßunsaturated compounds are Michael acceptors
The Michael Reaction
O
C
The base catalyst
removes an acidic alpha
proton from the starting
beta-keto ester to
generate a stabilized
enolate ion nucleophile.
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,ß-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, ßunsaturated 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,ßunsaturated carbonyl compound
Example of Stork Enamine Reaction
O
N
O
N ..
H
H2C
-H2O
Cyclohexanone
O
N+
..
CH2CHCCH3
CHCCH3
An enamine
N
O
OH2
O
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 ß-diketone or ß-keto ester with an alpha, ßunsaturated ketone leads first to a Michael addition, which
is followed by intramolecular aldol cyclization