Lecture 7
Carbonyl Condensation
Reactions
Organic chemistry, John McMurry
1
Lecture 7
CARBONYL CONDENSATION REACTIONS
•Carbonyl condensations: The aldol reaction
•The Claisen condensation reaction
•Intramolecular Claisen condensations: The Dieckmann cyclization
•Conjugate carbonyl additions: The Michael reaction
•Carbonyl condensations with enamines: The stork reaction
•The Robinson annulation reaction
•Some biological carbonyl condensation reactions
READING: Chapter 23
2
Condensation Reactions
• Carbonyl compounds are both the electrophile and
nucleophile in carbonyl condensation reactions
Carbonyl Condensations: The Aldol Reaction
• Carbonyl condensation reactions involve:
• Two carbonyl partners
• A series of nucleophilic addition and α-substitution steps
• In a carbonyl condensation reaction, one partner is
converted into an enolate-ion nucleophile and adds
to the electrophilic group of the second partner
The General Mechanism
of a Carbonyl Condensation Reaction
2
Carbonyl Condensations: The Aldol Reaction
• An aldol reaction is a base-catalysed carbonyl
condensation reaction that occurs in aldehydes and
ketones with an α- hydrogen atom
• The term aldol comes from the product formed, which
contains an aldehyde and an alcohol
Aldol Equilibrium
No α-substituent: product is favored
Disubstituted: reactant is favored (Steric factors)
Worked Example
• Predict the aldol reaction product in the compound below:
Worked Example
• Predict the aldol reaction product in the compound below:
• Solution:
• Forming the enolate of one molecule of the carbonyl
compound
Carbonyl Condensations vs Alpha Substitutions
• Similar experimental conditions
Carbonyl condensation: Relatively weak base
Alpha substitution: Strong base, a low temperature
Dehydration of Aldol Products: Synthesis of Enones
• The β-hydroxy carbonyl products dehydrate to yield
conjugated enones
• The term condensation is based on the fact that that water
condenses during the formation of an enone product
Dehydration of Aldol Products: Synthesis of Enones
• Dehydration in aldol products is due to their carbonyl group
• The α- hydrogen is removed by a base yielding an enolate ion that
expels the –OH leaving group
• In acidic conditions, the –OH group is protonated and water is
expelled
Dehydration of Aldol Products: Synthesis of Enones
• Conjugated enones (similar to dien) are more
stable than nonconjugated enones
Controlling Aldol Equilibrium
• Removal of water from the aldol reaction mixture can be
used to drive the aldol equilibrium toward the product
• Despite the unfavourable initial aldol step, the following
dehydration step results in the many aldol condensations
Worked Example
• Draw the two enone products, excluding double-
bond isomers, that result in the aldol condensation
of 3-methylcyclohexanone
Worked Example
• Draw the two enone products, excluding double-
bond isomers, that result in the aldol condensation
of 3-methylcyclohexanone
• Solution:
• Including double bond isomers, 4 products can be
formed
• The major product is formed by the reaction of the
enolate formed by abstraction of a proton at position
“a”
• Position “b” has more steric hindrance
Worked Example
Using Aldol Reactions in Synthesis
• Experimental conditions determine the product of
the aldol reaction
• Working backwards may help to foresee when the aldol
reaction may be useful in synthesis
• If a desired molecule contains either a β-hydroxy
carbonyl or a conjugated enone, it might come
from an aldol reaction
Extending the Synthesis
• Subsequent transformations can be carried out on
the aldol products
Mixed Aldol Reactions
• A mixed aldol reaction between two similar
aldehyde or ketone partners leads to a mixture of
four possible products
Practical Mixed Aldols
• A mixed aldol reaction is possible when:
• One of the carbonyl partners have no α- hydrogens
• An unhindered carbonyl group is present
• One of the carbonyl partners is more acidic ! transform
into its enolate ion
Worked Example
• Determine if the following compound can be
prepared by a mixed aldol reaction
• Show the reactant that can be used
• Solution:
• Benzaldehyde: good acceptor of nucleophiles, yet has
no α-hydrogen atoms
• Although it is possible for acetone to undergo self-
condensation, the mixed aldol reaction is favored more
Intramolecular Aldol Reactions
• Treatment of certain dicarbonyl compounds with base
produces cyclic products by intramolecular reaction
Intramolecular Aldol Reaction of 2,5-hexanedione
The characteristics of the enolate formed controls the end result
A mixture of products can be formed
Worked Example
• Determine the product from base
treatment of 1,6-cyclodecanedione
Worked Example
• Determine the product from base
treatment of 1,6-cyclodecanedione
• Solution:
• This intramolecular aldol condensation gives a product with
a seven-membered ring fused to a five-membered ring
Claisen Condensation Reaction
• Occurs between two ester molecules
• An ester with an α- hydrogen undergoes reversible
carbonyl condensation reaction when treated with 1
equivalent of a base resulting in a β-keto ester
Claisen Condensation Reaction Mechanism
3
Features of the Claisen Condensation
• If the starting ester has more than one acidic α-
hydrogen, the product β-keto ester has a doubly
activated hydrogen atom that can be abstracted by
base
• Requires a full equivalent of base rather than a catalytic
amount
• Deprotonation of the product causes a shic in
equilibrium over to the side of the product,
resulting in high yields
Worked Example
• Determine the product obtained by Claisen
condensation of (CH3)2CHCH2CO2Et
• Solution:
• Writing the two Claisen components in the correct
orientation makes it easier to predict the product
Mixed Claisen Condensations
• Successful when one of the two esters cannot form
an enolate ion as it does not possess α-hydrogens
Causing Claisen-like Reactions in Esters and Ketones
• Reactions between esters and ketones result in β-diketones
• An ester component with no α- hydrogens is favorable
Worked Example
• Predict the product in the following Claisen-like mixed
reaction
Worked Example
• Predict the product in the following Claisen-like mixed
reaction
• Solution:
• Dimethyl oxalate is a very efficient reagent in mixed Claisen
reactions
Intramolecular Claisen Condensations: The
Dieckmann Cyclization
• Occur in diketones; Effective in 1,6-diesters and 1,7-diesters
Mechanism of the Dieckmann Cyclization
Mechanism of the Dieckmann Cyclization
Alkylating the Product of the
Dieckmann Reaction
• The cyclic β-keto ester can be further alkylated and
decarboxylated as in the acetoacetic ester synthesis
Worked Example
• Determine the product of the reaction below
Worked Example
• Determine the product of the reaction below
• Solution:
Conjugate Carbonyl Additions: The
Michael Reaction
• Process in which a nucleophilic enolate ion reacts
with an α,β-unsaturated compound, producing a
conjugate addition product
Optimal Conditions for the Michael
Reaction
• Involve a particularly stable ion and an unhindered
α,β-unsaturated ketone
Mechanism of the Michael Reaction
Some Michael Acceptors and Donors
Worked Example
• Predict the product obtained from a base-catalysed
Michael reaction of 3-buten-2-one with the
nucleophilic donor below
Worked Example
• Predict the product obtained from a base-catalysed
Michael reaction of 3-buten-2-one with the
nucleophilic donor below
• Solution:
Carbonyl Condensations with Enamines: The
Stork Reaction
• Enamines are prepared from a ketone and a
secondary amine
Enamines Are Nucleophilic
• Overlap of the nitrogen lone-pair orbital with the
double-bond π orbitals increases electron density
on the carbon atom
Enamine Addition and Hydrolysis
• Enamine adds to an α,β-unsaturated carbonyl acceptor
• Product is hydrolyzed to a 1,5-dicarbonyl compound
Worked Example
• Use an enamine reaction to prepare the compound
below
Worked Example
• Use an enamine reaction to prepare the compound
below
• Solution:
• Analyze the product for the Michael acceptor and the
ketone
• The Michael acceptor is propenenitrile
• The ketone is cyclopentanone, which is treated with pyrrolidine to
form the enamine
Worked Example
The Robinson Annulation Reaction
• A two-step process
• It combines a Michael reaction with an intramolecular
aldol reaction
• The reactants required are a nucleophilic donor, an
enamine, and an α,β-unsaturated ketone acceptor
Synthesis of the Steroid Hormone Estrone
Some Biological Carbonyl Condensation Reactions
• Biological aldol reactions are widely found in
carbohydrate metabolism
• Type I aldolases are present mostly in animals and
higher plants
Some Biological Carbonyl Condensation Reactions
• Type II aldolases are present mostly in fungi and bacteria
• Aldolase-catalysed reactions are mixed aldol reactions
that occur between two different partners
Biological Claisen Condensations
• They are prevalent in many biological pathways
• Fa j y acid biosynthesis
Summary
• A carbonyl condensation reaction comprises two carbonyl
partners and involves nucleophilic and α- subtitution processes
• An aldol reaction is a reversible reaction that involves two aldehyde or
ketone molecules
• The Claisen condensation reaction is a carbonyl condensation that
produces a β-keto ester product
• Dieckmann cyclization reactions are intermolecular Claisen
condensations that yield five- and six- membered cyclic β-keto
esters
• The Michael reaction involves a conjugate addition of a carbon
nucleophile to an α,β-unsaturated acceptor
• The Robinson annulation reaction comprises a Michael addition and an
intramolecular aldol cyclization
