Chapter 22Alpha Substitution and
Condensations of Enolsand Enolate Ions
Jo BlackburnRichland College, Dallas, TX
Dallas County Community College District2006,Prentice Hall
Organic Chemistry, 6th EditionL. G. Wade, Jr.
Chapter 22 2
Alpha SubstitutionReplacement of a hydrogen on the carbon
adjacent to the carbonyl, C=O.
=>
Chapter 22 3
Condensation withAldehyde or Ketone
Enolate ion attacks a C=O and the alkoxide is protonated. The net result is addition.
=>
Chapter 22 4
Condensation with Esters
Loss of alkoxide ion results in nucleophilic acyl substitution.
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Chapter 22 5
Keto-Enol Tautomers
• Tautomers are isomers which differ in the placement of a hydrogen.
• One may be converted to the other.
• In base:
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Chapter 22 6
Keto-Enol Tautomers (2)
• Tautomerism is also catalyzed by acid.
• In acid:
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Chapter 22 7
Equilibrium Amounts• For aldehydes and ketones, the keto
form is greatly favored at equilibrium.
• An enantiomer with an enolizable hydrogen can form a racemic mixture.
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Chapter 22 8
Acidity of -Hydrogens
• pKa for -H of aldehyde or ketone ~20.
• Much more acidic than alkane or alkene (pKa > 40) or alkyne (pKa = 25).
• Less acidic than water (pKa = 15.7) or alcohol (pKa = 16-19).
• In the presence of hydroxide or alkoxide ions, only a small amount of enolate ion is present at equilibrium. =>
Chapter 22 9
Enolate Reaction
=>
As enolate ion reacts withthe electrophile, the equilibriumshifts to produce more.
Chapter 22 10
Acid-Base Reactionto Form Enolate
Very strong base is required for complete reaction. Example:
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Chapter 22 11
Halogenation• Base-promoted halogenation of ketone.• Base is consumed.• Other products are water and chloride ion.
OH_
O
H
HO
H
_O
H
ClCl Cl
=>
Chapter 22 12
Multiple Halogenations
• The -halo ketone produced is more reactive than ketone.
• Enolate ion stabilized by e--withdrawing halogen.
O
H
ClCl2
OH , H2O_
O
Cl
Cl
O
Cl
ClCl
O
Cl
ClClCl
=>
Chapter 22 13
Haloform Reaction
• Methyl ketones replace all three H’s with halogen.
• The trihalo ketone then reacts with hydroxide ion to give carboxylic acid.
Iodoform,yellow ppt. =>
C
O
CH3excess I2
OH-
C
O
CI3 OH-
C
O
OH
CI3-
C
O
O-
HCI3
Chapter 22 14
Positive Iodoformfor Alcohols
If the iodine oxidizes the alcohol to a methyl ketone, the alcohol will give a positive iodoform test.
=>
Chapter 22 15
Acid CatalyzedHalogenation of Ketones
• Can halogenate only one or two -H’s.
• Use acetic acid as solvent and catalyst.
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Chapter 22 16
Aldehydes and Halogens
Halogens are good oxidizing agents and aldehydes are easily oxidized.
C
O
H + Br2 C
O
OHH2O
+ 2 HBr
=>
Chapter 22 17
The HVZ ReactionThe Hell-Volhard-Zelinsky reaction replaces
the -H of a carboxylic acid with Br.
=>
Chapter 22 18
Alkylation
• Enolate ion can be a nucleophile.
• Reacts with unhindered halide or tosylate via SN2 mechanism.
O
H
HO
H(i-Pr)2N-Li+
CH3 Br
O
H
CH3
=>
Chapter 22 19
Stork Reaction• Milder alkylation method than using LDA.
• Ketone + 2 amine enamine.
• Enamine is -alkylated, then hydrolyzed.
O
H
H NH
H+
H
HHON
H+
NH
H+
N
H
CH3 Br
+N
H
N
HCH3
H3O+
O
CH3
HBr
-
+ NH
H
+ =>
Chapter 22 20
Acylation via Enamines
Product is a -diketone.
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Chapter 22 21
Aldol Condensation
• Enolate ion adds to C=O of aldehyde or ketone.
• Product is a -hydroxy aldehyde or ketone.
• Aldol may lose water to form C=C.
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Chapter 22 22
Mechanism for Aldol Condensation
=>Also catalyzed by acid.
Chapter 22 23
Dehydration of Aldol
Creates a new C=C bond.
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Chapter 22 24
Crossed AldolCondensations
• Two different carbonyl compounds.
• Only one should have an alpha H.
=>
Chapter 22 25
Aldol Cyclizations• 1,4-diketone forms cyclopentenone.
• 1,5-diketone forms cyclohexenone.
=>
Chapter 22 26
Planning Aldol Syntheses
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Chapter 22 27
Claisen CondensationTwo esters combine to form a -keto ester.
CH3 O C
O
CH R
CH3OC
O
CH2R
CH3 O C
O
CH R
CH3OC
O
CH2R
enolate ionpKa = 24
CH3 O C
O
CH Rbase
CH3 O C
O
CH2 R
=>
_
CH3 O C
O
C C
R
CH2R
O
pKa = 11
_OCH3
CH3 O C
O
CH C
R
CH2R
O
Chapter 22 28
Dieckmann Condensation• A 1,6 diester cyclic (5) -keto ester.
• A 1,7 diester cyclic (6) -keto ester.
=>
Chapter 22 29
Crossed Claisen
• Two different esters can be used, but one ester should have no hydrogens.
• Useful esters are benzoates, formates, carbonates, and oxalates.
• Ketones (pKa = 20) may also react with an ester to form a -diketone.
=>
Chapter 22 30
-Dicarbonyl Compounds
• More acidic than alcohols.
• Easily deprotonated by alkoxide ions and alkylated or acylated.
• At the end of the synthesis, hydrolysis removes one of the carboxyl groups.
CH3CH2O C
O
CH2 C
O
OCH2CH3
malonic ester, pKa = 13
CH3 C
O
CH2 C
O
OCH2CH3
acetoacetic ester, pKa =11=>
Chapter 22 31
Malonic Ester Synthesis• Deprotonate, then alkylate with good
SN2 substrate. (May do twice.)
• Decarboxylation then produces a mono- or di-substituted acetic acid.
=>
Chapter 22 32
Acetoacetic Acid SynthesisProduct is mono- or di-substituted ketone.
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Chapter 22 33
Conjugate Additions
• When C=C is conjugated with C=O, 1,2-addition or 1,4-addition may occur.
• A 1,4-addition of an enolate ion is called the Michael reaction.
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Chapter 22 34
Michael Reagents
• Michael donors: enolate ions stabilized by two electron-withdrawing groups.-diketone, -keto ester, enamine,
-keto nitrile, -nitro ketone.
• Michael acceptors: C=C conjugated with carbonyl, cyano, or nitro group.conjugated aldehyde, ketone, ester,
amide, nitrile, or a nitroethylene. =>
Chapter 22 35
A Michael Reaction
Enolates can react with ,-unsaturated compounds to give a 1,5-diketo product.
CH3CH2O C
O
CH
COOC2H5
_
CHH
C C
H O
CH3 CH3CH2O C
O
CH
COOC2H5
CH2C
H
C
O
CH3
_
H OC2H5
CH3CH2O C
O
CH
COOC2H5
CH2C
H
C
O
CH3
H
H3O+
heatHO C
O
CH CH2C
H
C
O
CH3
H
COOH
HO C
O
CH2 CH2C
H
C
O
CH3
H =>-keto acid
Chapter 22 36
Robinson Annulation
A Michael reaction to form a -diketone followed by an intramolecular aldol condensation to form a cyclohexenone.
CH3
H
O+
CH
H
C H
COH3C
_OH
CH3
O
=>
Chapter 22 37
Mechanism for Robinson Annulation (1)
=>
Chapter 22 38
Mechanism for Robinson Annulation (2)
=>
Chapter 22 39
End of Chapter 22
