Organic Chemistry II / CHEM
252
Chapter 19 Synthesis and
Reactions of -Dicarbonyl
Compounds
Bela Torok
Department of Chemistry
University of Massachusetts Boston
Boston, MA
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Introduction
-Dicarbonyl compounds have two carbonyl groups separated by
a carbon
Protons on the -carbon of -dicarbonyl compounds are acidic
(pKa = 9-10)
The acidity can be explained by resonance stabilization of
the corresponding enolate by two carbonyl groups
Synthesis
Claisen condensation
The acetoacetic ester and malonic acid syntheses use -dicarbonyl
compounds for carbon-carbon bond forming reactions
The acetoacetic ester and malonic ester syntheses usually conclude with
decarboxylation of a -keto acid
Synthesis
The Claisen Condensation: Synthesis of -Keto Esters
Ethyl acetate undergoes a Claisen condensation when treated with
sodium ethoxide
The product is commonly called an acetoacetic ester
Ethyl pentanoate undergoes an analogous reaction
Synthesis
The overall reaction involves loss of an hydrogen from one ester and
loss of ethoxide from another
The mechanism is an example of the general process of nucleophilic
addition-elimination at an ester carbonyl
Synthesis
Synthesis
The alkoxide base must have the same alkyl group as the alkoxyl
group of the ester
The use of a different alkoxide would result in formation of some
transesterification products
Esters with only one hydrogen do not undergo Claisen condensation
A second hydrogen on the carbon is necessary so that it can be
deprotonated in Step 3
This deprotonation drives the reaction to completion
Synthesis
The Dieckmann condensation is an intramolecular Claisen
condensation
Only 5- and 6-membered rings may be prepared in this way
Synthesis
Crossed Claisen Condensations
Crossed Claisen condensations can lead to one major product when one
of the two esters has no hydrogen
Synthesis
Esters with one hydrogen can react in Claisen condensations if they
are deprotonated with a strong base and acylated with an acyl chloride
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Synthesis
Acylation of Other Carbanions
Ketone enolates formed with strong bases can also be acylated to form dicarbonyl compounds
Addition of strong base to 2-pentanone results in formation of the kinetic
enolate which can be acylated with an ester
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Reactions
The Acetoacetic Ester Synthesis: Synthesis of Methyl Ketones (Substituted
Acetones)
Alkylation
Alkylation of the enolate derived from acetoacetic ester is called the
acetoacetic ester synthesis
This is an SN2 reaction with the ethyl acetoacetate enolate acting as
the nucleophile
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Reactions
A second alkylation can be performed
A stronger base such as potassium tert-butoxide must be use to
deprotonate the monoalkyl ester
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Reactions
Hydrolysis of the ester and heating of the resultant -ketoacid causes
decarboxylation
The product is a substituted acetone derivative
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Reactions
Example:
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Reactions
Ethylacetoacetate serves as a synthetic equivalent of the acetone enolate
It is possible to use acetone enolate directly, but this would require a
much stronger base and special reaction conditions
If -halo esters are used to alkylate the enolate, -keto acids are obtained
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Reactions
Acylation
Acetoacetic ester anion can also by acylated with acyl halides or
anhydrides
The reaction is carried out in aprotic solvents such as DMF or
DMSO because these will not destroy the acylating reagents
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Reactions
Acetoacetic Ester Dianion: Alkylation at the Terminal Carbon
Treatment with two eq. of a very strong base produces the dianion
Alkylation of the dianion occurs first at the terminal carbon
The terminal carbanion is more nucleophilic and more basic because
it is stabilized by only one carbonyl group
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Reactions
The Malonic Ester Synthesis: Synthesis of Substituted Acetic Acids
Alkylation of diethylmalonate, hydrolysis of the diester to the dicarboxylic acid, and decarboxylation can be used to synthesize monoand disubstituted acetic acids
The mechanism is analogous to that for the acetoacetic ester synthesis
In step 1 the stabilized anion is formed
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Reactions
In step 2 the anion is mono- or dialkylated using SN2 reactions
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Reactions
In step 3 the product is hydrolyzed and decarboxylated
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Reactions
Diethylmalonate anion is the synthetic equivalent of acetic acid
dianion
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Reactions
Examples
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Reactions
By using two molar equivalents of malonate anion and a
dihalide, the dicarboxylic acid is obtained
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Reactions
C2 through C5 terminal dihalides can react to form rings by
dialkylation of one molar equivalent of malonate
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Reactions Other Active H Compounds
Reactions of Other Active Hydrogen Compounds
Compounds in which the hydrogen atoms of a methylene (CH2-) group are made acidic by two attached electronwithdrawing groups are called active hydrogen compounds or
active methylene compounds
A variety of electron-withdrawing groups can produce
enhanced hydrogen acidity
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Reactions Other Active H Compounds
Example: Deprotonation of ethyl cyanoacetate forms a
resonance-stabilized anion, which can then undergo alkylation
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Reactions Other Active H Compounds
Direct Alkylation of Esters and Nitriles
A strong and bulky base such as lithium diisopropyl amide (LDA) must
be used to directly alkylate esters and nitriles
A strong base rapidly converts all of the ester or nitrile molecules
into enolates so that they will not undergo Claisen condensation
A bulky base will not react as a nucleophile at the ester carbonyl
or nitrile carbon
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Reactions Other Active H Compounds
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Reactions Other Active H Compounds
Alkylation of 1,3-Dithianes
Protons on the carbon between the sulfur atoms of a 1,3-dithiane are
acidic
Strong bases convert the dithiane to its anion
Dithianes are 6-membered ring thioacetals
These can be prepared from an aldehyde and the 1,3- dithiol
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Reactions Other Active H Compounds
A dithioacetal anion is the synthetic equivalent of an aldehyde
An aldehyde can be converted to a ketone
The reversal of the polarity of the carbonyl carbon in this series of
reactions is called umpolung
An aldehyde carbonyl carbon normally + and is electrophilic
In dithioacetal alkylation, the equivalent of the aldeyhde carbon
is nucleophilic
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Reactions
Michael Additions
A Michael addition involves conjugate addition of the anion derived
from an active hydrogen compound (e.g., an enolate) to an ,unsaturated carbonyl compound (see next slide)
Michael additions take place with a wide variety of ,-unsaturated
compounds
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Reactions
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Reactions
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Reactions
The Mannich Reaction
Compounds which can form enols react with imines or iminium ions
derived from formaldehyde
Primary or secondary amines can be used to form the corresponding
formaldehyde imines or iminium ions
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Reactions
Synthesis of Enamines: The Stork Enamine Reactions
Aldehydes and ketones react with secondary amines to form enamines (see
Section 16.8C)
Cyclic amines are often used
The reaction is catalyzed by acid
Removal of water drives enamine formation to completion
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Reactions
Enamines have a nucleophilic carbon and are the equivalent of ketone
and aldehyde enolates
The nitrogen of enamines is also nucleophilic
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Reactions
Enamines can be acylated, alkylated, and used in Michael reactions
The iminium intermediate is hydrolyzed when water is added
C-Acylation leads to -diketones
N-acylated products can be formed, but they are unstable and act as
acylating agents themselves
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Reactions
Alkylation of enamines can lead to some N-alkylation
The N-alkylated product can often be converted to the Calkylated product by heating
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Reactions
Barbiturates
Reaction of diethyl malonate with urea in the presence of sodium
ethoxide produces barbituric acid
Barbiturates are substituted derivatives of barbituric acid
Barbiturates are used in medicine as soporifics ( sleep inducers)
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