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7/29/2019 3.Aldolica Claisen En
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Nucleophilic additions of enolates to carbonyl
compounds
The addition of nucleophiles based on oxygen, nitrogen, sulfur to carbonylcompounds is a reaction we met before. Carbon nucleophiles such as
carbanions (Grignard reagents, alkyl lithium) orenolates can also react with
carbonyl derivatives leading to a new C-C bond.
This class of reactions is called aldol condensation orClaisen
condensation according to whether the electrophile is a ketone/aldehyde or
an ester/thioester.
S Ch 21
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Apart from the diversity of products that are obtained w.r.t. the addition to C=O of
an alkyl lithium or Grignard reagent, what is the fundamental difference in enolate
additions?Enolates may also be formed in aqueous environment, unlike carbanions, and at
relatively high temperatures (r.t.).
Hence, enolates are the nucleophilic reagents present in nature, where the solvent
is H2O and reactions take place in narrow temperature ranges.
The aldol condensation is the self-condensation of an aldehyde
The reaction was so named by Charles Wurtz in 1872, who prepared 3-hydroxybutanal
(aldol) treating acetaldehyde with dilute HCl. The reaction was then studied by others,
including Hans Schmidt who was the first to employ basic, rather than acidic, conditions.
Aldol condensation
S1034
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Base-catalyzed aldol condensation
In basic environment the enolate is formed. In water the amount of enolate is
very low because carbonyl protons are less acidic than those of water by
several orders of magnitude.
Therefore in the reaction mixture there is a high amount of acetaldehyde
which may react with the enolate, forming the new C-C bond
S1034
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The -hydroxyaldehyde so produced has more acidic protons in to a
carbonyl: if OH- removes another proton, generating the corresponding
enolate, two reactions are possible:
Finally, the resulting alkoxide removes a proton from water, yielding a -
hydroxyaldehyde and regenerating the catalyst OH-
Condensation with another aldehyde molecule, leading to trimers or
oligomers
Elimination of H2O to an ,-unsaturated aldehyde
S1035
Base-catalyzed aldol condensation
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Dehydration of the product of the aldol condensation
A double bond conjugated with the carbonyl group is formed.
The elimination mechanism is different from the more common (E1 and E2) because theinitial event a carbanion is formed, which is allowed by the carbonyl function. Moreover,
the leaving group (OH-) is not particularly good.
The dehydration of the product of an aldol condensation occurs via an E1cb
mechanism
S1035
Unimolecular elimination, conjugate base (E1cb)
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Exercise: write the structures of the two products that are obtained from the
aldol condensation of propanal, catalyzed by OH-. Show the electron
movements that take place at every step.
S1036-7
H 3 CC
H
O
O H-
H 3 CC
H
O
+ H 2 O
C
H
O
HH
H
H
- O
H
C H O
H
O H
H
C H O+ H 2 O
+ O H -
H 3 C C H 2
O H
H
C H 3
H
C H O H 3 C C H 2
O H
H
C H 3
C H O
H 3 C C H 2
H
C H 3
C H O
- O H -
O H -
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In acidic environment an enol is formed, which is a much weaker nucleophile
than an enolate. However, the acid environment makes C=O a stronger
electrophile, owing to protonation at the carbonyl oxygen
Acid-catalyzed aldol condensation
S1036
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Deprotonation leads to the -hydroxyaldehyde
Stopping the process at the -hydroxyaldehyde is difficult. The acidic
environment favors elimination (E1 or E2)
S1036-7
Acid-catalyzed aldol condensation
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The aldol condensation, both acid- and base-catalyzed, is reversible. The
reverse process is called retroaldol reaction.
Retroaldol reaction
The ease with which this process occurs depends on steric effects at the and
positions.
S1037
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Aldol condensation of ketones
Enolizable and reactive ketones may undergo aldol condensation.
However, most often steric factors render the retroaldol reaction more
favorable.
The reaction can be displaced to the right if water is eliminated and the
,-unsaturated derivative is formed (acidic conditions).
The most important application of the aldol condensation of ketones is the
intramolecular Robinson annulation.
S1038
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Mixed aldol condensation
Using two enolizable
aldehydes leads to acomplex reaction
mixture deriving from
reaction of both
enolates with both
aldehydes (4 products)
and eliminationproducts the
corresponding ,-
unsaturated derivatives
(4 products).
S1039
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In order to make the mixed aldol condensation a useful process
we need to employ:
A non-enolizable aldehyde
A specific enolate
An enzymatic method
Non-enolizable aldehyde: benzaldehyde
S1040
Mixed aldol condensation
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How is the ,-unsaturated derivative formed?
S1040
Mixed aldol condensation
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If the ketone can form a single enolate, the reaction proceeds smoothlyand a single product is obtained in high yield.
S1041
Mixed aldol condensation
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Mixed aldol condensation promoted by Lewis acids
S1042
Using dialkylboron triflates (R2B-OTf), in the presence of a weak base
such as EtN(i-Pr)2 (DIEA) a boron enolate is obtained:
OTf = CF3SO
3
-
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The boron derivative, a Lewis
acid, coordinates to the
carbonyl oxygen
The base removes the acidic proton, generating the double bond with
loss of triflate ion
S1042
Mixed aldol condensation promoted by Lewis acids
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Then the boron enolate is added to an aldehyde and coordinates to it.
Thus boron acts both as carbonyl activator (Lewis acid) and as template,bringing the two reagents close to each other
The enolate now attacks the carbonyl and the new C-C bond is formed.
S1042-3
Mixed aldol condensation promoted by Lewis acids
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Oxidation with H2O2 in base leads to the -hydroxyaldehyde
Even if both carbonyl compounds are enolizable, self-condensation can be
avoided
S1043
Mixed aldol condensation promoted by Lewis acids
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Exercise: what is the major product expected for each of the following
reactions:
S1044
OBBu2
CHO
O
B-
O
H
+O
B-
O
H
H2O2 / OH-
O OH
O
HO
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A variant of aldol condensation assisted by a Lewis acid
Generation of the enolate,
nucleophilic addition to
carbonyl and protonation toalcohol
Addition of an ester enolate to an aldehyde or ketone
S1045
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Exercise. A carbanion derived from an imine or a tertiary amide may also
react with a carbonyl compound. What is the expected main product of
the following reactions?
S1046
CH C
O
NMe2 Ph C
Ph
CH
OH CH3
C
N
H
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The Claisen condensation
Besides aldehydes and ketones, esters can also generate enolates andbehave as electrophiles. When an ester is treated with a base a transformation
similar to the aldol condensation occurs the Claisen condensation.
The Claisen condensation leads to the formation of -ketoesters after acidic
workup.
S1060
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The Knoevenagel reaction
A variant of aldol condensation, in which the nucleophile is the
conjugate base of an active methylene compound
The product is an alkene containing two geminal acceptor groups
The reaction occurs under wakly basic (organic bases like piperidine)
or neutral (piperidinium acetate) conditions
S1091 (es. 21.27)
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C H O
+ C H 2 ( C O O E t ) 2
C O O E t
C O O E t
C H 2 ( C O O E t ) 2
NH 2
C H 3 C O O-
- C H ( C O O E t ) 2
C H O
- C H ( C O O E t ) 2
C
E t O O C C O O E t
H
OC
E t O O C C O O E t
H
O H
H +
C
E t O O C C O O E t
H
- O H -
H H
C
E t O O C C O O E t
H
O H
+ H 2 O
The Knoevenagel reaction: mechanism
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The Knoevenagel reaction: products
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Henry reaction
A variant of the aldol condensation in which the nucleophile is the
conjugate base of a nitroalkane (pKa < 10)
mechanism
S1091 (es. 21.26) es. nitroethane + PhCHO
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The mechanism is similar to that of the aldol condensations, with some
differences:
Low concentration of the enolate (pKa 24)
A stoichiometric (not catalytic) amount of base is needed
The enolate reacts with another ester molecule leading to a tetrahedral
intermediate:
S1060
The Claisen condensation
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The carbonyl function is regenerated with an ethoxide as leaving group
The reaction might stop here. However, since the newly formed compound has
an active methylene, in the reaction conditions the base can deprotonate itagain, generating a new stabilized enolate.
For this reaction to take place, at least 1 eq of base must be present. This is
another difference w.r.t. the aldol condensation, which requires only a catalytic
amount of base.
S1060
The Claisen condensation
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After acid workup the -ketoester is obtained:
If the reagent is ethyl acetate, this reaction is called acetoacetic
condensation or acetoacetic synthesis
In the Claisen condensation, formation of a resonance-stabilized enolate
shifts the equilibrium to the right
S1061
The deprotonation of the intermediate inthe basic environment is irreversible and
leads to complete conversion. The final
product can only be obtained in an acidic
environment.
The Claisen condensation
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Claisen condensation: retro Claisen
All steps of the Claisen condensation are reversible; the formation of a
dicarbonyl enolate brings the reaction to completion. If this process cannot
take place, the equilibrium favors the reactants.
ethyl isobutyrate vs. ethyl acetate
S1061-2
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In the presence of EtO- a further nucleophilic attack occurs at the carbonyl,
instead of deprotonation. The reaction reverts to the reactants
Retro Claisen
S1062
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A method to prevent retro Claisen from occurring is to use strong bases to
generate the enolate
The enolate is then treated with one equivalent of ester or, better, the
corresponding acyl chloride.
Avoiding retro Claisen
S1062-3
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Exercise. What is the main product of the following reaction?
S1063
H3
C C
O C H 3
C H 3
C O O E t
H 3 C C
O C H 3
C H 3
C O O E t
E t O -
( r e t r o - C l a i s e n )
C H 3 C O O E t + ( C H 3 ) 2 C H C O O E t
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The Dieckmann cyclization
The mechanism is fully analogous to that of the Claisen condensation: generation
of the enolate, formation of the tetrahedral intermediate, expulsion of the leavinggroup, formation of the stabilized carbanion
An intramolecular Claisen condensation
S1063
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Acidic workup allows to obtain the neutral product, in which the
carbonyl function is within the ring
S1064
The Dieckmann cyclization
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Since -ketoesters can be easily decarboxylated, this is a synthetic strategy
to obtain cycloalkanones.
S1064
E t O O C C O O E t
E t O - / E t O H
C O O E t
O E t
O
C O O E t
- O
E t O
C O O E t
O
+ E t O -
C O O E t
O
C O O E t
OH 3 O
+
The Dieckmann cyclization
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Mixed Claisen condensation
Like in the aldol condensation, two different esters can be used in the Claisen
condensation. The reaction works best when one of the esters does not have
hydrogens
S1064
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Mixed Claisen condensation
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An example of mixed Claisen condensation is a Dieckmann cyclization, when
one of the ester functions does not have protons. This allows for theformation of a single product.
A single product can be obtained even in the presence of two enolizable ester
functions, if the reaction is reversible.
Single product
S1065
Mixed Claisen condensation
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One of the two products does not have enolizable protons; therefore the
retro-Claisen is favored. The equilibrium is displaced towards the formationof the 2,6-disubstituted regioisomer.
S1066
Mixed Claisen condensation
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In the mixed Claisen condensation the enolizable partner may also be a
ketone. Ketones are 4 orders of magnitude more acidic than esters and will
preferentially form the enolate.A non-enolizable ester is preferred, even if ketones undergo self-condensation
slowly.
A common application of this reaction is the hydroxymethylenation of ketones
with ethyl formate:
Mixed Claisen condensation with ketones
S1067
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Acid workup yields theproduct, which exists
mainly as enol
Hydroxymethylenation of ketones
S1067-8
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Exercise. Explain the following
processes:
S1068
O
O
O
H
H C O O E t
O
O E t
O -
H
O
O
H
- E t O
-
O
H
H
O E t
- O
O
H
H
O
OH
O
OH
O
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Aldol condensation
Base-catalyzed aldol, possibly dehydration E1cbAcid-catalyzed: aldol dehydration E1/E2
Summary
H3C C
O
H2
cat. OH-
H3C CH
OH
CH2 CHO
cat. H+
H3C CH
CH CHOH3C CH
OH
CH2 CHO
H3C CH
CH CHOE1cb
E1 o E2
Condensation of ketones less favored
Mixed condensation requires a non-enolizable partner (e.g. PhCHO)
The enolizable component may be an ester, amide or imine
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Aldol condensation promoted by Lewis acids
Summary
R C
O
CH2 R'
n-Bu2BOTf / DIEA
R C
OBBu2
CHR'
+ DIEAH+
TfO-
R C
OBBu2
CHR'
PhCHO
R C
O
CH
B
O
Bu
Bu
R'
C
Ph
H
H2O2/OH-
R C
O
CH CH
OH
Ph
R'
No self-condensation
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Claisen condensation 2 mol. ester -ketoesterLow concentration of enolate, 1 equiv. base
Reversible reaction: equilibrium is displaced to the right by deprotonation,
otherwise retro Claisen
H 3 C C O O E t2E t O N a / E t O H
H 3 C C
O
C H C O O E t H 3 C C
O
C H 2 C O O E t
C C O O E t2E t O N a / E t O H
C C
O
C C O O E t
C H 3
C H 3
H
H
C H 3
C H 3 C H 3
C H 3
In such cases, use a strong base to generate the enolate with ester or
acyl halide
Dieckmann cyclization: intramolecular variant (cyclic -ketoester)
Summary
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Mixed Claisen condensation: to achieve regioselectivity, use a non-
enolizable component
ketone+HCOOEt hydroxymethylenationO
H C O O E t
O
H
C H O
O
C H O H
Carboxylatione of enolates: ketone-ketoacidwith CO2 reversible reactionPossible with equivalents such as ClCOOEt or CO(OEt)2
Summary
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Knoevenagel reaction: variant of aldol cond.
aldehyde + active methylene alkene with 2 geminal acceptor groups
C H O
+ C H 2 ( C O O E t ) 2
C O O E t
C O O E t
Henry reaction
aldehyde + nitroalkane nitroalkene
C H O
+ C H 3 N O 2
N O 2
Summary