solomon organic chemistry chapter 19 slides
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8/11/2019 Solomon Organic Chemistry Chapter 19 Slides
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Chapter 19
Condensation and Conjugate Addition
Reaction of Carbonyl Compounds
- More Chemistry of Enolates -
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The Claisen Condensation: Formation of -Ketoestersfrom Esters with Enolizable Hydrogens
Esters with enolizable Hundergo a reaction similar to the aldolcondensation in the presence of alkoxide bases.
Alkoxide bases are used so that competing nucleophilic additiontothe acyl carbon does not destroy or change the ester function.
-C-C-OR
H
:O:=
pKa 25~~
+ B:- -C-C-OR
:O:=
:
--C=C-OR
:O:: -
enolate anion of ester
-C C OR
O
hybrid
-C-C-OR
O=
H
+ RO-
Na+
-C-C-OR
OR
O-
H
Na+
competing nucleophilic addition
-C-C-ORO=
H
+ RO- Na+
no change
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Condensation Step
The enolate anion of an ester reacts as a nucleophileby way of the
carbanion center in adding to the acyl carbon of a second ester:
-C-C-OR
H
:O:=
-C-C-OR
O=
:
-
+
enolate anion
-C C-OR
:O:
: -
H C-C-OR
O=
reversible nucleophilic addition
tetrahedral intermediate
-C C-OR
:O:
: -
HC-C-OR
O
=
cleavage
-C-C C-C-OR
O
=
O=
H
-keto ester
+ RO-
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Example: The Condensation of Ethyl Acetate.Ludwig Claisen (1851-1930)
The recommended procedure involves dissolving one equivalent ofsodium metal slowly in absolute (dry) ethanol. An immediate redoxreaction generates one equivalent of sodium ethoxide. Twoequivalents of ethyl acetate are added, and the mixture is heated forseveral hours. Acidification of the reaction mixture yields thecondensation product ethyl acetoacetate.
2 CH3COC2H5
O=
ethyl acetate pKa = 25
+ Na+ -OC2H5
overall reaction
CH3CCHCOC2H5
O= O=
:
-
Na++ C2H5O
sodium ethyl acetoacetate
CH3CCHCOC2H5
O=
:
-
Na+
workup
H+ CH3CCH2COC2H5
O= O=
ethyl acetoacetate pKa = 11
O=
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Some Observations
One full equivalent of base (NaOEt) is consumed in the reaction.
The product is the sodium salt of ethyl acetoacetate whichaccumulates as the condensation reaction proceeds.
The relative aciditiesof key compounds in this reaction are:
CH3CCH2COC2H5
O= O=
ethyl acetoacetate pKa = 11
> CH3CH2OH
ethyl alcohol pKa = 16
> CH3COC2H5
O=
ethyl acetate pKa = 25
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A Mechanism for the Claisen Condensation of Esters
formation of the enolate anion in low concentration
CH3COC2H5O=
pKa = 25
+ Na+ -OC2H5 :CH2COC2H5Na+ - + C2H5OH
pKa = 16
O=
addition to acyl carbon
:CH2COC2H5-CH3COC2H5
O=
+
O=
CH3C-OC2H5
O-
CH2CO2C2H5
Na+
cleavage and deprotonation
CH3C-OC
2H
5
O-
CH2CO2C2H5
Na+
CH3CCH2CO2C2H5
O=
pKa = 11
+ NaOC2H5
fast
CH3CCHCO2C2H5
O=
:
-Na+
+ C2H5O
pKa = 16
Although the Claisen condensation is areversible reaction, it is driven to completionby essentially irreversible formation of theanion of ethyl acetoacetate.
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The Claisen Condensation of Ethyl Propanoate
2 CH3CH2CO2C2H5NaOC2H5
ethanol, heat
CH3CH2CCCO2C2H5
O=
CH3
:-Na
+
+ C2H5O
CH3CH2CCCO2C2H5
O=
CH3
:-Na+
workup
H+
CH3CH2CCHCO2C2H5
CH3
O=
ethyl 3-oxo-2-methylpentanoate
Note the overall syntheticstrategy of the Claisencondensation of esters toyield ketoesters:
RCH2C CHCO2Et
R
O=
RCH2C CH2CO2Et
O=
OEt R
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Limitations of the Claisen Condensation
Esters with only one enolizable H do not give condensation
products under the usual conditions. Because the condensationproduct is not protected by deprotonation to the stable anion, a"reverse Claisen reaction" can occur thatlimits the amount ofproduct formed.
CH3CHCO2C2H5
CH3
+ CH3CCO2C2H5
CH3
:- Na+
CH3CHCO2C2H5
CH3ethyl 2-methylpropanoate
+ NaOEt CH3CCO2C2H5
CH3
:- Na+
+ EtOH
enolate anion
CH3CHC-C-CO2C2H5
O= CH3
CH3
+ NaOC2H5
CH3
reverse Claisen cleaves condensation product
CH3CHC-C-CO2C2H5
O= CH3
CH3
+-OC2H5
CH3
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Variations of the Claisen Condensation Reaction
The Dieckmann Condensation (1894): An IntramolecularClaisen Condensation
CH2
CH2
CH
CO2C2H5
CH2
C
OC2H5
O- Na
+
CH2CH2
CH2CO2C2H5
CH2CO2C2H5
diethyl adipate
+ NaOEtCH2
CH2
CHCO2C2H5
CH2CO2C2H5
:- Na+
+ EtOH
CH2
CH2
CHCO2C2H5
CH2C-OC2H5
:- Na+
intramolecular acyl addition
O
=
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CH2
CH2
CH
CO2C2H5
CH2
C
OC2H5
O- Na+
cleavage
CH2
CH2
CH
CO2C2H5
CH2
C=O + NaOEt
fast deprotonation
CH2
CH2
C:-
CO2C2H5
CH2
C=O
Na+
+ EtOH
workup
CH2
CH2
C:-
CO2C2H5
CH2
C=O
Na+
H+
CH2CH2
CHCO2C2H5
CH2
C=O
ethyl 2-oxocyclopentanecarboxylate10
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The Crossed Claisen Condensation
The condensation reaction of one ester with a second ester, orwith an aldehyde or ketone is called a crossed Claisen. As withthe crossed aldol condensation, it is a synthetically useful reactiononly when it is directedtowards one product.
The reaction may be directed by:
using two different esters where only onehas enolizable H.
reacting an an ester with aldehydes or ketones with enolizableH and exploiting the greater acidity of these compounds.
Examples of Crossed Claisen Reactions
COC2H5O=
+ CH3CO2C2H5
ethyl benzoate(no enolizable H)
(i) NaOEt/EtOH(ii) H+
C-CH2CO2C2H5
O=
ethyl 3-oxo-3-phenylpropanoate
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The Aldol Reaction: Addition of EnolateAnions to Aldehydes and Ketones
Aldehydes and ketones with enolizable hydrogens (
-H) undergo aself-reaction to give a -hydroxyaldehyde or -hydroxyketone in thepresence of base. This reaction is called the aldol condensation.
Requirements for an aldol reaction:
-H
Dilute solution of base-usually HO-
2 CH3CHO=
acetaldehyde
10% NaOH, H2O
5oCCH3CHCH2CH
O=OH
3-hydroxbutanal
an "aldol"
The aldol reaction does not occur with
ArCHO HCHO (CH3)3CCH
O=
ArCAr'
O=
ArCCR3
O=
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Aldol additon is reversible14
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Dehydration of Aldol Products
The -hydroxyaldehyde and-ketone aldol condensation products,when isolated, dehydrate very easily to
#
unsaturated carbonyl
compoundsbecause of the stability inherent in the conjugatedenone structures.
When R = aryl,dehydration occursduring the aldolcondensation:
RCCH3
O=
2
HO-
or RO-CH3CCH2CR
R
OH O=
-hydroxyaldehyde
or -ketone
dil. HCl
heat
fast(-H2O)
CH3C=CHCR
O=
R
#unsaturated
aldehyde or ketone
The dehydration yields an
extended system withresonance stabilization:
CH3C=CHCR
:O:=
R
CH3C-CH=CR
R
:O::
+-
acetophenone
C=C
CH3
H
C-O=
CCH3
O=
1,3-diphenyl-2-buten-1-one
NaOEt
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The Crossed Aldol Condensation
An aldol reaction using two different carbonyl compounds is acrossed aldol condensation. Because of the possibility of four
different condensation products, this reaction is not syntheticallyuseful unless it is carefully designed.
Directed Crossed Aldol Condensations
A simple designed synthesis includes one carbonyl compoundwith no -H, which eliminates two of the possible products. An
example is the crossed aldol condensation of benzaldehydeandacetaldehyde.
To minimize self-condensation of
acetaldehyde, the enolizable carbonyl
is slowly added to a mixture of
benzaldehyde and dilute HO-.
CH
O=
benzaldehyde
(no enolizable H)
+ CH3CHO= dil. HO-
CHCH2CH
O=OH
a directed aldol product
fast
(-H2O)
CH=CHCH
O=
cinnamaldehyde(3-phenyl-2-propen-1-one)
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Additional examples of directed crossed aldolreactions using benzaldehyde:
CH
O=
+ HO-
benzaldehyde(no enolizable H)
slowly add
CH3CCH3
O=
(-H2O)
CH=CHCCH3
O=
4-phenyl-3-buten-2-one
slowly add
C6H5CCH3
O=
(-H2O)
CH=CHC
O=
1,3-diphenyl-2-propenone
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The Acid-Catalyzed Aldol Condensation
The self-aldol reaction of aldehydes and ketones with enolizable-Halso occurs under acid-catalyzed conditions. The nucleophile in the
addition reaction is the enol (not the enolate anion), and the rate ofthe addition step is increased by acid catalysis, as shown below.
A Mechanism
acid-catalyzed enol formation
RCCH3
:O:=
+ H-B+ fast RCCH3
:O-H=
+ B:
+
While only a lowconcentration of enol ispresent under equilibriumconditions, it is a reactivenucleophile.
Overall Reaction
2 RCCH3
O= H+
heat RCCH2CCH3
O=
R
OH
(-H2O)RCCH=CCH3
O=
R
RCCH3
:O-H=
+ B:
+slow
RC=CH2
:O-H
:
+ H-B+
enol
low conc.
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In general the dehydration
product is formed in the acidcatalyzed mechanism
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A Directed Intramolecular Aldol Reaction
O
CH2CH2CCH3
O=
H+
O
To understand the selectivity of this reaction, the four possiblereaction pathways need to be evaluated. Also, favorableintramolecular reactions proceed much faster than comparableintermolecular reactions.
The acid-catalyzed intramolecular aldol reaction of the diketone
below yields a single product even though four different reactionpathways are possible.
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Four Intramolecular Aldol Pathways
OH
CH2CH
2CCH
3
O=O
CH3
OH
strained bicyclicring system
OH
CH2CH2CCH3
O=
O
CH2
CH2C
CH3
OH
highly strainedspiran system
O
CH2CH=CCH3
OH
CH2
CH
HO C=OCH3
highly strainedcyclobutane
O
CH2CHC=CH2
OH
OH O
stable product
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Claisen-Schmidt Reactions: -Unsaturated Ketones
Crossed aldol reactions where ketones are one component are called
Claisen-Schmidt reactions. These reactions were discovered anddeveloped by two Germans chemists in the 1880s: J.G. Schmidt andLudwig Claisen.
The crossed aldol product is favored over the self-reaction of theketones because of the irreversibility of the cross product (aconjugated enone), while the self-reaction of the ketones is
reversible.
C6H5CH
O=
benzaldehyde
+ CH3CCH3
O= HO-
100oCC6H5CH=CHCCH3
O=
4-phenyl-3-buten-2-one(benzalacetone) 70%
acetone
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A Mechanism for the Claisen-Schmidt Reaction ofBenzaldehyde and Acetone
enolate anion formation
CH3CCH3
O=
+ HO- :CH2CCH3
:O:=-
CH2=CCH3
:O:
:
-
+ H2O
C6H5CH
=
+ :CH2CCH3
:O:=-
:O:
nucleophilic addition
C6H5CH-CH2CCH3
:O:=:O:
: -
H2O
C6H
5CH-CH
2CCH
3
=OOH
+ HO-
aldoldehydration
C6H5CH-CHCCH3
=OOH
+ HO-
HC6H5CH=CHCCH3
O=+ H2O + HO
-
The dehydration step occurs readily.
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Additions to -Unsaturated Aldehydes and Ketones
C=C-C-
:O:=C=C-C-
:O:
:
+
-
C-C=C-
:O:
:
+
-
C C C
O!"
!+!+
Nu:-
modes of nucleophilic attack
-Unsaturated aldehydes and ketones react with nucleophiles bysimple(1,2) addition, and/or conjugate(1,4) addition. These twomodes of reaction are understandable from an examination of theresonance structures for a conjugated enone system that shows twoelectropositive carbon centers.
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Reaction Schemes for Simple and Conjugate Additions
C=C-C-O=
+ Nu:-
+H+simple addition
(1,2-addition)
+H+conjugate addition
(1,4-addition)
C=C-C-
O-H
Nu
C-C=C-
O-H
Nu enol
(initial product)
C-C-C-
Nu
O=H
ketone
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Examples
Often both modes of addition compete giving a mixture of 1,2-and 1,4-addition products.
CH3CH=CHCCH3
O= (i) CH3MgBr
(ii) H3O+
3-penten-2-one
CH3CH=CHCCH3CH3
OH
+ CH3CHCH2CCH3
O=
CH31,2-addition product
72%
1,4-addition product 20%
While Grignard reagents give mixtures from both addition modes,organocopper reagents tend to give conjugate addition products.
O=
CH3
4-methyl-2-cyclohexen-1-one
(i) (CH3)2CuLi
(ii) H3O+
O=
CH3
CH3
O=
CH3
CH3
+
98% 2%
(two diastereomers of 1,4-addition)
Only products from conjugate addition are found as a mixture ofdiastereomers. The dominant product results from addition fromthe less hindered side away from the methyl group in the
4-position.
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The Michael Addition of Diethyl Malonate to 3-Buten-2-one
H2C
CO2Et
CO2Et
diethyl malonate pKa = 12.9
+ CH2=CHCCH3
O=
3-buten-2-one(methyl vinyl ketone)
cat. NaOEt
EtOH CH2-CH2CCH3
O=
CH
EtOOC
EtOOC65%
A Mechanism
A catalytic amount of NaOEt produces a lowconcentration of the anion of diethyl malonate.
CH2(CO2Et)2 + NaOEt
pKa = 12.9
Na+ -CH(CO2Et)2 + HOEtpKa = 15.9
generation of nucleophile
CH2-CH-CCH3
O
CHEtOOC
EtOOC
-
simple enolate anion
conjugate addition
Na+ -CH(CO2Et)2 + CH2=CH-CCH3
O=
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The overall energetics for the Michael addition arefavorable, and the reaction goes to completion,because the carbon-carbon -bond formed isstronger than the carbon-carbon -bond that is lost.
protonation and regeneration of nucleophile
CH2-CH-CCH3
O
CHEtOOC
EtOOC
-
+ CH2(CO2Et)2
pKa = 12.9
CH2-CH=CCH3CHEtOOC
EtOOC
OH
enol+
Na+ -CH(CO2Et)2nucleophile regenerated
CH2-CH=CCH3CHEtOOC
EtOOC
OH
enol
ketone-enol equilibration
CH2-CH2CCH3O=
CHEtOOCEtOOC
ketone(stable product)
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The Robinson Annulation
CH3H
O=
2-methyl-1,3-cyclohexadione
+ CH2=CHCCH3O=
HO-
CH3OH
CH3O=
CH2CH2CCH3O=
Michael addition
O O
The addition product reacts further by way of anintramolecular aldol condensation:
CH3
O=
CH2CH2
C=O
CH3
+ HO-
O
CH3O=
CH2-CH2
C=O
CH2:-
enolate anion
O
CH3O=
O
CH2-CH2
C=OCH2-
CH3O=
O
CH2-CH2
C=OCH2H
CH3OH
(-H2O)
O=
CH3
65%
dehydrationO
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