orgo ppt
TRANSCRIPT
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CARBONYL CONDENSATIONCONDENSATION
REACTIONS
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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
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General Mechanism of Carbonyl Condensation
One carbonyl partner with an alpha hydrogen atom is converted by base into its enolate ion.
O
CR C
HOH
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C
O
C
C O
R
:
..
..
R
C
O
C
OH2
C
O:: :
ElectrophilicAcceptor
NucleophilicDonor
This enolate ion acts as a nucleophilic donor and adds to the electrophilic carbonyl group of the acceptor partner
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Protonation of the tetrahedral alkoxide ion intermediate gives the neutral condensation product.
OH2
R
CC
C
OH -OH
O
+New C-C Bond
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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
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Mechanism of the Aldol Reaction
HO:
HC
H H
C
O
H
Base removes anacidic alpha hydrogenfrom one aldehydemolecule, yieldinga resonance-stabilized eno-late ion.
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C
O
CH3 H
: : OH+ 2
CH
H
CH
O
..
CH3 C
H
O
C
HH H
OC
H
: :-..
The enolate ion attacks a second aldehydemolecule in a nucleophilic addition reaction to give a tetrahedral alkoxide ion intermediate.
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H O2
C
O
C
HC C
HHHH
O H
HO3
+ -
:
Protonation of the alkoxide ion intermediate yields neutral aldol product and regenerates the base catalyst.
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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
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C
O
CH
C
OHOH
Base-catalyzed
C
O
CC
OH::-..
Enolate ion
C
O
CC OH-+
Dehydration of Aldol Products
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CC
C
O OH
H
H+
Acid-catalyzed
CC C
OHO
H
2+
Enol
C
O
CC H O+ 3
+
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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 alpha-hydrogens or if one carbonyl compound is much more acidic than the other.
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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
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Intramolecular Aldol Reaction of 2, 5-hexanedione yields 3-methyl-2-
cyclopentenone
aCH
HH H
C
O
H H OC
C
C
C 33 2,5- Hexanedione
b
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CH
HH
C
O
H HC
C
C
CH
H
O
3
-
-OHPath A
CH
HH
C
O
H HC
C
C
CH
H
OH
3
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CC
C
C C
C
HH
H
HH
H
O
H
H
O
HO
3
-:....
CH
O H O
3
2+
3-Methyl-2-cyclopentenone
NaOH, H2O
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Path b
NaOH, H2O
CH
HH H
C
O
H H OC
C
C
C 33
HO-
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CH
HH
C
O
HC
C
C
CH
H
O
H
3- CH
HH
C
O
HC
C
C
CH
HH
O
3
-
OHH
.. ..
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C
H
HCH
O
HH
O O
3
3
-:....
(2-Methylcyclopropenyl)ethanone(NOT formed)
CH O
CHH O
3
3+2
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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
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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
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Mechanism of the Claisen Condensation Reaction
CH3COEt
O
- OEt
Ethoxide base abstracts an acidic alpha hydrogen atom from an ester molecule, yielding an ester enolate ion
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:CH2COEt
O
EtOH
CH3C
:O:
OEt
+
Nucleophilic donor
Electrophilic acceptor
In a nucleophilic addition,this ion adds to a secondester molecule, giving a tetrahedral intermediate.
CH3C
:O: -
OEt
CH2COEt
O..
The tetrahedral intermediateis not stable. It expels ethoxideion to yield the new carbonyl compound, ethyl acetoacetate.
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But ethoxide ion is basic enoughto convert the beta-keto esterproduct into its enolate, thus shifitng the equilibrium and drivingthe reaction to completion.
CH3C
O
CH2COEt
O
EtO-+
CH3C
O
CHCOEt
O_
..EtOH+
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CH3C
O
CH2COEt
O
OH2+
Protonation by addition of acidin a separate step yields the finalproduct.
H3O+
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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
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Example of Mixed Claisen Condensation
1. NaH/THF
+2. H30
C
O
CH
O
C
H
2 OEt
EtO
Ethyl benzoylacetate
C
O
OEt
Ethyl Benzoate(Acceptor)
+
CH
O
COEt3Ethyl Acetate
(Donor)
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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
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Examples of Intramolecular Claisen Condensation
O
O
O
C
O
H
OEt
OEtDiethyl hexanedioate (a 1,6 -Diester)
1. Na+ -OEt, ethanol
2. H3O+OEt
EtO
Ethyl 2-oxocyclopentanecarboxylate (82%)
O
O
O
C
O
OEt
OEt
Diethyl heptanediote (a 1,7- Diester)
1. Na+ -OEt, ethanol
2. H3O+ OEt
+
Ethyl-2-oxocyclohexane carboxylate
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Intramolecular Claisen Condensation Mechanism
H
O
H
OEt
COOEt
+ OEtNa -
Base abstracts an acidic alpha-proton from the carbon atom next to one of the ester groups, yielding an enolote ion.
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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.
OH
H
tEOCOOEt
+ EtO:
. .
-
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H
OCOOEt
tEO : :. .
-
Loss of alkoxide ion from the tetrahedral intermediate forms a cyclic beta-keto ester.
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O
H
O
.
H
COOEt
+ tEO :.
. .
.
-
COOEt-
EtO+
Deprotonation of the acidic beta-keto ester gives an enolate ion…
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O
H
H O
+H3O
COOEt
+ 2
…which is protonated by addition of aqueous acid at the endoth the reaction to generate the neutral beta-keto ester product.
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Michael Reaction
• Conjugate addition of a carbon nucleophile to an alpha, ß-unsaturated acceptor
Best Michael Reactions:
• Between unusually acidic donors (ß-ketoesters or ß-diketones)
• Unhindered alpha,ß-unsaturated acceptors
• Stable enolates are Michael donors, and alpha,ß-unsaturated compounds are Michael acceptors
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The Michael Reaction
EtO
O
C
CC
O
CH3
HH
Na+
- OEt
The base catalyst removes an acidic alpha proton from the starting beta-keto ester to generate a stabilized enolate ion nucleophile.
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The nucleophile adds to the alpha,beta-keto unsaturated ketone electrophile in a Michael reaction to generate a new enolate as product.
EtO
C
O
CC
O
CH3
H
-
EtOH
C
H
CC
H3C H
O
C
H3C C
C
H H
CHH
CO2Et
C
CH3
OO
.. +
..
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O
EtOH
H3C
C
CC
H H
C
C
O
CH3H H
CO2EtH
EtO-+
The enolate product abstracts an acidic proton, either from solvent or from starting keto ester, to yield the final addition product.
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Some Michael Acceptors and Michael Donors
H2C CHCHO
H2C CHCO2Et
H2C CHC N
H2C CHCOCH3
H2C CHNO2
H2C CHCONH2
Propenol
Ethyl Propanoate
Propenenitrile
3-Buten-2-one
Nitroethylene
Propenamide
RCOCH2COR'RCOCH2CO2EtEtO2CCH2CO2Et
RCOCH2C NRCH2NO2
Beta-DiketoneBeta-Keto EsterMalonic Ester
Beta-Keto nitrile
Nitro compound
Michael Acceptors Michael Donors
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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, ß- 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,ß-unsaturated carbonyl compound
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Example of Stork Enamine Reaction
ON
H
-H2O
NH2C CHCCH3
O..
Cyclohexanone An enamine
NCH2CHCCH3
-..O
NCH2CH2CCH3
O+
OH2
OCH2CH2CCH3
O
N
H
+
A 1,5-diketone
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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, ß-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization