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ALPHA HYDROGEN
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OBJECTIVES
1. Decsribe the acidity of-hydrogen of carbonyl compounds in the
form of enolate anions (page : 832)
2. Predict the products from alkylation and halogenation (-
bromination and haloform) reaction of -hydrogen of ketone
(page : 837, 842)3. Predict the product from the aldol condensation reaction and be
able to propose synthetic routes to get the target products. (page
: 876-889)
4. Predict the product from the Claisen condensation reaction
(Claisen ester condensation and Dieckmann condensation).(page : 870-874)
5. Predict the product from the addition to , unsaturated carbonyl
compounds and Michael addition. (page : 889, 892)
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1. Decsribe the acidity of-hydrogen of
carbonyl compounds in the form ofenolate anions (page : 832)
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The Acidity of the a Hydrogens of Carbonyl
Compounds: Enolate Anions Hydrogens on carbons a to carbonyls are unusually acidic The resulting anion is stabilized by resonance to the carbonyl
Chapter 17 5
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The enolate anion can be protonated at the carbon or
the oxygen
The resultant enol and keto forms of the carbonyl areformed reversibly and are interconvertible
Chapter 17 7
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REACTION OF -HYDROGEN
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2. Predict the products from alkylation
and halogenation (-bromination andhaloform) reaction of -hydrogen of
ketone (page : 837, 842)
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Direct Alkylation of Ketones via Lithium Enolates
Enolates can also be alkylated with primary alkyl halides via
an SN2 reaction Unsymmetrical ketones can be alkylated at the least substituted
position if LDA is used to form the kinetic enolate
Chapter 17 17
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The a-selenyl ketone is converted to the a,b-unsaturated
carbonyl compound by reaction with hydrogen peroxide
Elimination of the selenoxide produces the unsaturated carbonyl
Chapter 17 19
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Halogenation of Ketones
Ketones can be halogenated at the a position in the
presence of acid or base and X2 Base-promoted halogenation occurs via an enolate
Chapter 17 20
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Acid-catalyzed halogenation proceeds via the enol
Chapter 17 21
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Haloform Reaction
Reaction of methyl ketones with X2 in the presence of base
results in multiple halogenation at the methyl carbon Insert mechanism page 777
Chapter 17 22
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When methyl ketones react with X2 in aqueous hydroxide
the reaction gives a carboxylate anion and a haloform
(CX3H)
The trihalomethyl anion is a relatively good leaving group
because the negative charge is stabilized by the three halogen
atoms
Chapter 17 23
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3. Predict the product from the aldol
condensation reaction and be able topropose synthetic routes to get the target
products. (page : 876-889)
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Chapter 17 29
The Aldol Reaction: The Addition of Enolate
Anions to Aldehydes and Ketones
Acetaldehyde dimerizes in the presence of
dilute sodium hydroxide at room
temperature
The product is called an aldol because it
is both an aldehyde and an alcohol
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Chapter 17 30
The mechanism proceeds through the enolate anion
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Dehydration of the Aldol Product
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Dehydration of the Aldol Product
If the aldol reaction mixture is heated, dehydration to an a,b-
unsaturated carbonyl compound takes place
Dehydration is favorable because the product is stabilized by
conjugation of the alkene with the carbonyl group
In some aldol reactions, the aldol product cannot be isolated
because it is rapidly dehydrated to the a,b-unsaturated
compound
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Synthetic Applications
The aldol reaction links two smaller molecules and creates a new
carbon-carbon bond
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WWUWWU----ChemistryChemistry
Example
CH3 C H
O
CH3 C H
O
+NaOH
CH3 C CH2 C H
OOH
H"Aldol"
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WWUWWU----ChemistryChemistry
Another Example
CH3 CH2 C H
O
+ CH3 CH2 C H
O
NaOH
CH3 CH2 C CH C H
O
CH3
OH
H
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WWUWWU----ChemistryChemistry
One More:
CH3 C CH3
O
+ CH3 C CH3
O
NaOH
CH3 C CH2 C CH3
OOH
CH3
"Diacetone alcohol"
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WWUWWU----ChemistryChemistry
Synthesis Problem
CH3 CH2 CH CH C H
O
CH3
OH
Preparation via Aldol
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WWUWWU----ChemistryChemistry
Preparation viaAldolCondensation
CH3 CH CH CH2 OH
Preparation via Aldol
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WWUWWU----ChemistryChemistry
Preparation viaAldolCondensation
CH3 CH2 CH2 CH2 CH CH2 OH
CH2
CH3
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WWUWWU----ChemistryChemistry
Synthesis Problem
CH2 CH2 CH
OH
CH C
CH2
H
O
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WWUWWU----ChemistryChemistry
Chalcone Formation
C CH2
OH
H
C
O
CH CH C
O
"spontaneous"
a chalcone
(formed from an aldol
condensation)
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WWUWWU----ChemistryChemistry
Crossed Aldol Condensations
C H
O
+
CH3 C H
O
NaOHC CH2
OH
H
C H
O
- H2O(spontaneously)
CH CH C H
O
acceptor
donor
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Practical Crossed Aldol Reactions
Crossed aldol reactions give one predictable product when
one of the reaction partners has no ahydrogensThe carbonyl compound without any ahydrogens is put
in basic solution, and the carbonyl with one or two a
hydrogens is added slowly
Dehydration usually occurs immediately, especially if anextended conjugated system results
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Claisen-Schmidt Reactions
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Crossed-aldol reactions in which one partner is a ketone are called
Claisen-Schmidt reactions
The product of ketone self-condensation is not
obtained because the equilibrium is not favorable
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WWUWWU----ChemistryChemistry
From Experiment 35
C CH3
O
NO2
C H
O
NaOH
NO2
CH CH2
OH
C
O
+
- H2O
(spontaneous)
NO2
CH CH C
O
3-Nitrochalcone
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WWUWWU----ChemistryChemistry
Do the synthesis of:
CH C C
CH3
H
O
Cyclization via Aldol Condensations
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Cyclization via Aldol Condensations Intramolecular reaction of dicarbonyl compounds proceeds to form
five- and six-membered rings preferentially
In the following reaction the aldehyde carbonyl carbon is attacked
preferentially because an aldehyde is less sterically hindered and
more electrophilic than a ketone
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WWUWWU----ChemistryChemistry
Also:
CH2
CH2
C
C
CH3
O
CH3
O
NaOH
C2H5OH
25
O
CH3
a
a
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WWUWWU----ChemistryChemistry
Synthesis of:
C
H
O
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WWUWWU----ChemistryChemistry
Crossed Aldol Condensations
C H
O
+
CH3 C H
O
NaOHC CH2
OH
H
C H
O
- H2O(spontaneously)
CH CH C H
O
acceptor
donor
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f
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WWUWWU----ChemistryChemistry
Synthesis of an Insect Repellent
CH3
CH2
CH2
C H
O
CH3
CH2
CH2
C H
O
CH3
CH2
CH2
C
OH
CHCH2
CH3
C H
H
O
CH3
CH2
CH2
C
OH
CHCH2
CH3
C H
H
O
CH3
CH2
CH2
C
OH
CHCH2
CH3
C H
O
HH
H
a
NaOH
H2
Ni
ALDOL
CONDENSATION
HYDROGENATION
2-Ethyl-3-hydroxyhexanal
2-Ethyl-1,3-hexanediol
--used in "6-12" insect repellent
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WWUWWU----ChemistryChemistry
Synthesis of a Compound used in Perfumery
C
CH3
OCH2
CH2
C
CH2
O
CH2
CH CH CH2
CH3
C
CH3
CH2
CH2
CCH
O
CH2
CH CH CH2
CH3
OH
O
CH3
CH2
C C
CH2
CH3
H H
a cis
KOH
cis
ALDOLCONDENSATION
- H2O
DEHYDRATION
cis-Jasmone
--- used for the scent of jasmine
in perfumes
Biological Synthesis of Fructose
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WWUWWU----ChemistryChemistry
Biological Synthesis of Fructose
CH2 CH C H
O
OHO
P
OH
OO
CH2 C CH2 O P OH
OH
O O
O
CH2
CH C CH C CH2
O P OH
O
O
O
OH
OH
HOHO
P
OH
O O
+
Glyceraldehyde-3-phosphate
Dihydroxyacetone phosphate
Fructose-1,6-diphosphate
a
ALDOLCONDENSATION
enzyme
The Aldol Condensation Reaction: MechanismThe Aldol Condensation Reaction: Mechanism
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WWUWWU----ChemistryChemistry
The Aldol Condensation Reaction: MechanismThe Aldol Condensation Reaction: Mechanism
CH3 C H
O
O H OHH CH2 C H
O
CH2
C H
O
CH3
C H
O
CH2
C H
O
CH3
C
O
H
H
CH2
C H
O
CH2
C H
O
CH3
C
O
H
CH2
C H
O
CH3
C
O
H
1)
2)
3)
: :
+ :..
_
..
fast ..
.. +
: : : :
..
_
.. _
an enolate ion: :
: :
.._
slow
:..
:
: :
: :..
: :
+ H2O
fast
:..
: :
+ :OH..
..
_
acceptor
donor
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WWUWWU----ChemistryChemistry
The Heart of the Mechanism
CH3
C
H
O CH3
C
H
O
CH2
C
H
O
CH2
C
H
O
+ _ _
.._
acceptor
donor
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Chapter 19 69
b-Dicarbonyl compounds can be synthesized by the Claisen
condensation
The acetoacetic ester and malonic acid syntheses use b-
dicarbonyl compounds for carbon-carbon bond forming
reactions
The acetoacetic ester and malonic ester syntheses usually
conclude with decarboxylation of a b-keto acid
The Claisen Condensation: Synthesis of b Keto
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Chapter 19 70
The Claisen Condensation: Synthesis ofb-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
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Chapter 19 72
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Chapter 19 73
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 ahydrogen do not undergo Claisen
condensation
A second hydrogen on the a carbon is necessary so that it can
be deprotonated in Step 3
This deprotonation drives the reaction to completion
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Chapter 19 74
Crossed Claisen Condensations
Crossed Claisen condensations can lead to one major
product when one of the two esters has no ahydrogen
The Dieckmann condensation is an intramolecular Claisen
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Chapter 19 75
The Dieckmann condensation is an intramolecular Claisen
condensation
Only 5- and 6-membered rings may be prepared in this way
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5. Predict the product from the addition
to , unsaturated carbonyl
compounds and Michael addition.
(page : 889, 892)
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Stronger nucleophiles such as Grignard reagents favor 1,2 addition
h k l hil h id i f 1 4
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whereas weaker nucleophiles such as cyanide or amines favor 1,4
addition
Michael Additions
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Addition of an enolate to an a,b-unsaturated carbonyl compound
usually occurs by conjugate addition
This reaction is called a Michael addition
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6 Predict the products from the
Robinson annulation (ring forming)
(page : 893)
A Robinson annulation can be used to build a new six-membered ring
on an existing ring
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on an existing ring
Robinson annulation involves a Michael addition
followed by an aldol condensation to close the ring
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Chapter 19 84
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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Chapter 19 85
A second alkylation can be performed
A stronger base such as potassium tert-butoxide must be use to
deprotonate the monoalkyl ester
H d l i f h d h i f h l
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Chapter 19 86
Hydrolysis of the ester and heating of the resultant b-
ketoacid causes decarboxylation
The product is a substituted acetone derivative
E l
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Chapter 19 87
Example:
Ethylacetoacetate serves as a synthetic equivalent of the
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Chapter 19 88
Ethylacetoacetate serves as a synthetic equivalentof the
acetone enolate
It is possible to use acetone enolate directly, but this would require amuch stronger base and special reaction conditions
Ifa-halo esters are used to alkylate the enolate, g-keto acids
are obtained
A t ti E t Di i Alk l ti t th T i l
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Chapter 19 89
Acetoacetic Ester Dianion: Alkylation at the Terminal
Carbon
Treating acetoacetic ester with two equivalents 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 basicbecause it is stabilized by only one carbonyl group
Th M l i E t S th i S th i f
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Chapter 19 90
The Malonic Ester Synthesis: Synthesis of
Substituted Acetic Acids
Alkylation of diethylmalonate, hydrolysis of the diester to theb-dicarboxylic acid, and decarboxylation can be used to
synthesize mono- and disubstituted acetic acids The mechanism is analogous to that for the acetoacetic ester synthesis
In step 1 the stabilized anion is formed
I t 2 th i i di lk l t d i S 2
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Chapter 19 91
In step 2 the anion is mono- or dialkylated using SN2
reactions
In step 3 the mono or dialkylated product is hydrolyzed and
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Chapter 19 92
In step 3 the mono- or dialkylated product is hydrolyzed and
decarboxylated
Examples
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