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Chapter 23. Carbonyl Chapter 23. Carbonyl Condensation ReactionsCondensation Reactions
Why this Chapter?Why this Chapter?Carbonyl condensation reactions also occur often in metabolic pathways.Also one of the general methods used to form C-C bonds.
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Condensation ReactionsCondensation Reactions
Carbonyl compounds are both the electrophile and nucleophile in carbonyl condensation reactions
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23.1 Carbonyl Condensation: The Aldol 23.1 Carbonyl Condensation: The Aldol ReactionReaction
Acetaldehyde reacts in basic solution (NaOEt, NaOH) with another molecule of acetaldhyde
The -hydroxy aldehyde product is aldol (aldehyde + alcohol)
This is a general reaction of aldehydes and ketones
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General CondensationsGeneral Condensations
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Aldehydes & Ketones and Aldol EquilibriumAldehydes & Ketones and Aldol Equilibrium The aldol
reaction is reversible, favoring the condensation product only for aldehydes with no substituent
Steric factors are increased in the aldol product
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Mechanism of Aldol ReactionsMechanism of Aldol Reactions
Aldol reactions, like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule
The addition intermediate is protonated to give an alcohol product
Predicting Aldol ProductsPredicting Aldol ProductsThe product will have an alcohol and a carbonyl in a 1,3 relationship (a beta-hydroxy carbonyl)
Learning Check: Know how Learning Check: Know how to……to……Predict the aldol reaction products of:
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23.2 Carbonyl Condensation versus Alpha-23.2 Carbonyl Condensation versus Alpha-SubstitutionSubstitution
Carbonyl condensations and substitutions both involve formation of enolate ion intermediates
Alpha-substitution reactions are accomplished by converting all of the carbonyl compound to enolate form so it is not an electrophile
Immediate addition of an alkyl halide to completes the alkylation reaction
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Conditions for CondensationsConditions for CondensationsA small amount of base is used to generate a
small amount of enolate in the presence of unreacted carbonyl compound
After the condensation, the basic catalyst is regenerated
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23.3 Dehydration of Aldol Products: 23.3 Dehydration of Aldol Products: Synthesis of EnonesSynthesis of Enones
The -hydroxy carbonyl products dehydrate to yield conjugated enones
The term “condensation” refers to the net loss of water and combination of 2 molecules
Dehydration of Dehydration of -Hydroxy Ketones and -Hydroxy Ketones and AldehydesAldehydesThe hydrogen is removed by a base, yielding
an enolate ion that expels the OH leaving group
Under acidic conditions the OH group is protonated and water is expelled
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Driving the EquilibriumDriving the EquilibriumRemoval of water from the aldol reaction mixture
can be used to drive the reaction toward productsEven if the initial aldol favors reactants, the
subsequent dehydration step pushes the reaction to completion
Learning Check:Learning Check:What is the structure of the enone obtained from aldol condensation of acetaldehyde?
Solution:Solution:What is the structure of the enone obtained from aldol condensation of acetaldehyde?
Learning Check: Know Learning Check: Know how to…how to…
Predict the enone product from aldols of:
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23.4 Using Aldol Reactions in Synthesis23.4 Using Aldol Reactions in Synthesis
If a desired molecule contains either a -hydroxy carbonyl or a conjugated enone, it might come from an aldol reaction
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Extending the SynthesisExtending the SynthesisSubsequent transformations can be carried out on the
aldol products
A saturated ketone might be prepared by catalytic hydrogenation of the enone product
Learning Check: Know how Learning Check: Know how to…to…Prepare the following from an aldol condensation:
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23.5 Mixed Aldol Reactions23.5 Mixed Aldol ReactionsA mixed aldol reaction between two similar aldehyde or
ketone partners leads to a mixture of four possible products
This is not useful
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Practical Mixed AldolsPractical Mixed Aldols If one of the carbonyl partners contains no
hydrogens and the carbonyl is unhindered (such as benzaldehyde and formaldehyde) it is a good electrophile and can react with enolates, then a mixed aldol reaction is likely to be successful
2-methylcyclohexanone gives the mixed aldol product on reaction with benzaldehyde
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Mixed Aldols With Acidic Carbonyl Mixed Aldols With Acidic Carbonyl CompoundsCompounds
Ethyl acetoacetate is completely converted into its enolate ion under less basic conditions than monocarbonyl partners
Aldol condensations with ethyl acetoacetate occur preferentially to give the mixed product
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23.6 Intramolecular Aldol Reactions23.6 Intramolecular Aldol ReactionsTreatment of certain dicarbonyl compounds with base
produces cyclic products by intramolecular reaction
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Mechanism of Intramolecular Aldol ReactionsMechanism of Intramolecular Aldol ReactionsBoth the nucleophilic carbonyl anion donor and the electrophilic
carbonyl acceptor are now in the same molecule.The least strained product is formed because the reaction is
reversible
Learning Check:Learning Check:Which product would you expect to obtain from base treatment of the following?
Solution:Solution:Which product would you expect to obtain from base treatment of the following?
O
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23.7 The Claisen Condensation Reaction23.7 The Claisen Condensation Reaction
Reaction of an ester having an hydrogen with 1 equivalent of a base to yield a -keto ester
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Similar to aldol condensation: nucleophilic acyl substitution of an ester enolate ion on the carbonyl group of a second ester molecule
See the simulation at www.thomsonedu.com
Mechanism of the Claisen Mechanism of the Claisen CondensationCondensation
If the starting ester has more than one acidic a hydrogen, the product -keto ester has a doubly activated proton that can be abstracted by base
Requires a full equivalent of base rather than a catalytic amount
The deprotonation drives the reaction to the product
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Learning Check:Learning Check:
Predict the product of Claisen condensation of ethyl propanoate
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Solution:Solution:
Predict the product of Claisen condensation of ethyl propanoate
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23.8 Mixed Claisen Condensations23.8 Mixed Claisen Condensations
Successful when one of the two esters acts as the electrophilic acceptor in reactions with other ester anions to give mixed -keto esters
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Esters and KetonesEsters and KetonesReactions between esters and ketones, resulting in
-diketonesBest when the ester component has no
hydrogens and can't act as the nucleophilic donor
Learning Check: Know Learning Check: Know how to…how to…
Predict the product of the following reaction:
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23.9 Intramolecular Claisen Condensations: The 23.9 Intramolecular Claisen Condensations: The DieckmannDieckmann Cyclization Cyclization
Intramolecular Claisen condensation Best with 1,6-diesters (product: 5-membered
-ketoester) and 1,7-diesters (product: 6-membered -ketoester)
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Mechanism of the Dieckmann Mechanism of the Dieckmann CyclizationCyclization
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Alkylation of Dieckmann ProductAlkylation of Dieckmann Product
The cyclic -keto ester can be further alkylated and decarboxylated as in the acetoacetic ester synthesis
Learning Check: Know Learning Check: Know how to…how to…Predict the product:
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23.10 Conjugate Carbonyl Additions: The 23.10 Conjugate Carbonyl Additions: The Michael Michael ReactionReaction
Enolates can add as nucleophiles to ,-unsaturated aldehydes and ketones to give the conjugate addition product
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Best Conditions for the Michael ReactionBest Conditions for the Michael Reaction
When a particularly stable enolate ionExample: Enolate from a -keto ester or other
1,3-dicarbonyl compound adding to an unhindered ,-unsaturated ketone
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Mechanism of the MichaelMechanism of the Michael Nucleophilic
addition of a enolate ion donor to the carbon of an ,-unsaturated carbonyl acceptor
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Generality of the Michael ReactionGenerality of the Michael Reaction Occurs with a variety of ,-unsaturated carbonyl compounds
(aldehydes, esters, nitriles, amides, and nitro compounds)
Donors include -diketones, -keto esters, malonic esters, -keto nitriles, and nitro compounds
Learning Check:Learning Check:Make the following using a Michael Reaction:
Solution:Solution:Make the following using a Michael Reaction:
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23.11 Carbonyl Condensations with 23.11 Carbonyl Condensations with Enamines: The Stork ReactionEnamines: The Stork Reaction
Enamines are equivalent to enolates in their reactions and can be used to accomplish the transformations under milder conditions
Enamines are prepared from a ketone and a secondary amine
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Enamines Are NucleophilicEnamines Are NucleophilicOverlap of the nitrogen lone-pair orbital with the
double-bond π orbitals increases electron density on the carbon atom
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Enamine Addition and HydrolysisEnamine Addition and HydrolysisEnamine adds to an ,-unsaturated carbonyl acceptorThe product is hydrolyzed to a 1,5-dicarbonyl compound
Learning Check:Learning Check:Prepare Using a Stork Enamine Reaction
Solution:Solution:Prepare Using a Stork Enamine Reaction
Learning Check: Know Learning Check: Know how to…how to…Prepare Using a Stork Enamine Reaction
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23.12 The Robinson Annulation Reaction23.12 The Robinson Annulation Reaction
A two-step process: combines a ◦ Michael reaction with an ◦ intramolecular aldol reaction
The product is a substituted 2-cyclohexenone
Robinson Annulation Robinson Annulation ExampleExampleSynthesis of estrone
Learning Check: Know Learning Check: Know how to..how to..Prepare via a Robinson Annulation:
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23.13 Some Biological Carbonyl 23.13 Some Biological Carbonyl Condensation ReactionsCondensation ReactionsMalonyl ACP is decarboxylated and enolate is formedEnolate is added to the carbonyl group of another
acyl group through a thioester linkage to a synthaseTetrahedral intermediate gives acetoacetyl ACP
1. The benzene ring makes the carbonyl group unreactive towards aldol reactions.
2. A carbonyl group must be connected to two alkyl groups in order to undergo an aldol reaction.
3. The molecule does not possess any hydrogens α to the carbonyl group.
4. Electrophilic aromatic substitution competes favorably with the aldol reaction.
5. Nucleophilic acyl substitution competes favorably with the aldol reaction.
Which of the following statements explains why the Which of the following statements explains why the following aldehyde will not undergo an aldol reaction with following aldehyde will not undergo an aldol reaction with itself?itself?
Learning Check:Learning Check:
Which of the following statements explains why the Which of the following statements explains why the following aldehyde will not undergo an aldol reaction with following aldehyde will not undergo an aldol reaction with itself?itself?
1. The benzene ring makes the carbonyl group unreactive towards aldol reactions.
2. A carbonyl group must be connected to two alkyl groups in order to undergo an aldol reaction.
3. The molecule does not possess any hydrogens α to the carbonyl group.
4. Electrophilic aromatic substitution competes favorably with the aldol reaction.
5. Nucleophilic acyl substitution competes favorably with the aldol reaction.
Solution:Solution:
Predict the aldol reaction product of the Predict the aldol reaction product of the following following ketoneketone..
O OH
1.
O OH
2.O
HO
3.
O OH
4.
OH
O
5.
O NaOH
Ethanol
Learning Check:Learning Check:
Predict the aldol reaction product of the Predict the aldol reaction product of the following following ketoneketone..
O OH
1.
O OH
2.O
HO
3.
O OH
4.
OH
O
5.
O NaOH
Ethanol
Solution:Solution:
Which starting material(s) will produce the Which starting material(s) will produce the following aldol reaction product?following aldol reaction product?
1. 2. 3.
4. 5.
Learning Check:Learning Check:
Which starting material(s) will produce the Which starting material(s) will produce the following aldol reaction product?following aldol reaction product?
1. 2. 3.
4. 5.
Solution:Solution:
Select the correct aldol reaction product for the Select the correct aldol reaction product for the following reaction.following reaction.
1. 2.
3.
4. 5.
Solution:Solution:
Which pair of compounds would be required to Which pair of compounds would be required to prepare the following aldol product?prepare the following aldol product?
H
O
+O
1.
H
O
+O
O2.
H
O
+
O
3.
H
O
+O
4.H
O
+O
5.
O
Solution:Solution:
Learning Learning Check:Check:Which of the following reactions will yield the Which of the following reactions will yield the compound compound shownshown below? below?
1. 2.
3.
4. 5.
Solution:Solution:Which of the following reactions will yield the Which of the following reactions will yield the compound compound shownshown below? below?
1. 2.
3.
4. 5.
Which of the following would not be produced in the Which of the following would not be produced in the aldol reaction between 2-butanone and acetophenone?aldol reaction between 2-butanone and acetophenone?
O1.
O2.
O3.
O
4. O5.
NaOH
Ethanol
OO
+
Learning Learning Check:Check:
Which of the following would not be produced in the Which of the following would not be produced in the aldol reaction between 2-butanone and acetophenone?aldol reaction between 2-butanone and acetophenone?
O1.
O2.
O3.
O
4. O5.
NaOH
Ethanol
OO
+
Solution:Solution:
Predict the aldol reaction product(s) of the Predict the aldol reaction product(s) of the following ketone.following ketone.
OO
OOO NaOH
Ethanol
A B
C D
O
1. A2. B3. Both A and C4. Both B and D5. A, B, and C
Learning Learning Check:Check:
Predict the aldol reaction product(s) of the Predict the aldol reaction product(s) of the following ketone.following ketone.
OO
OOO NaOH
Ethanol
A B
C D
O
1. A2. B3. Both A and C4. Both B and D5. A, B, and C
Solution:Solution:
Which of the following is the best candidate for Which of the following is the best candidate for a crossed Claisen reaction with ethyl acetate?a crossed Claisen reaction with ethyl acetate?
CO2CH3
1.
OCH3
O2.
O
OCH3
3.
CH3O
O
Ph
4.
CH3O
O5.
Learning Learning Check:Check:
Which of the following is the best candidate for Which of the following is the best candidate for a crossed Claisen reaction with ethyl acetate?a crossed Claisen reaction with ethyl acetate?
CO2CH3
1.
OCH3
O2.
O
OCH3
3.
CH3O
O
Ph
4.
CH3O
O5.
Solution:Solution:
What type of reaction occurs in a Claisen What type of reaction occurs in a Claisen condensation?condensation?
1. electrophilic aromatic substitution
2. nucleophilic addition
3. hydrolysis4. nucleophilic acyl
substitution5. decarboxylation
Learning Learning Check:Check:
What type of reaction occurs in a Claisen What type of reaction occurs in a Claisen condensation?condensation?
1. electrophilic aromatic substitution
2. nucleophilic addition
3. hydrolysis4. nucleophilic acyl
substitution5. decarboxylation
Solution:Solution:
Select the correct Claisen condensation product Select the correct Claisen condensation product for the following reaction.for the following reaction.
1. 2. 3.
4. 5.
Learning Learning Check:Check:
Select the correct Claisen condensation product Select the correct Claisen condensation product for the following reaction.for the following reaction.
1. 2. 3.
4. 5.
Solution:Solution:
Predict the outcome of the following Predict the outcome of the following reaction.reaction.
1. 2. 3.
4. 5.
Learning Learning Check:Check:
Predict the outcome of the following Predict the outcome of the following reaction.reaction.
1. 2. 3.
4. 5.
Solution:Solution:
What is the expected major product of the What is the expected major product of the following reaction?following reaction?
O
1.
O
2.
HO
3.
O
O4.
O
5.
O
O
NaOH, EtOH
Learning Learning Check:Check:
What is the expected major product of the What is the expected major product of the following reaction?following reaction?
O
1.
O
2.
HO
3.
O
O4.
O
5.
O
O
NaOH, EtOH
Solution:Solution:
Predict the outcome of the following Predict the outcome of the following reaction.reaction.
1. 2. 3.
4. 5.
Learning Learning Check:Check:
Predict the outcome of the following Predict the outcome of the following reaction.reaction.
1. 2. 3.
4. 5.
Solution:Solution:
What type of reaction has occurred in the given What type of reaction has occurred in the given biological process?biological process?
1. Claisen condensation2. aldol reaction3. nucleophilic acyl substitution4. β-elimination5. both Claisen condensation and
nucleophilic acyl substitution
Learning Learning Check:Check:
What type of reaction has occurred in the given What type of reaction has occurred in the given biological process?biological process?
1. Claisen condensation2. aldol reaction3. nucleophilic acyl substitution4. β-elimination5. both Claisen condensation and
nucleophilic acyl substitution
Solution:Solution:
