Beruflich Dokumente
Kultur Dokumente
Alpha Substitution
Replacement of a hydrogen on the carbon adjacent to the carbonyl, C=O.
enolate ion
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Chapter 22 2
OH ROH O C C C
Chapter 22
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Chapter 22 4
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 5
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Chapter 22 6
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.
Chapter 22
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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 8
Enolate Reaction
As enolate ion reacts with the electrophile, the equilibrium shifts to produce more.
Chapter 22
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9
Lithium diisopropylamide
O H H LDA
O Li
H + (i- C3H7)2N H
pKa = 19
Chapter 22
pKa = 40
10
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Halogenation
Base-promoted halogenation of ketone. Base is consumed. Other products are water and chloride ion.
O H H OH _ O _ H
O Cl Cl Cl H
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Chapter 22 11
Multiple Halogenations
The -halo ketone produced is more reactive than ketone. Enolate ion stabilized by e--withdrawing halogen.
O Cl H Cl2 _ OH , H 2O O Cl Cl Cl O Cl Cl Cl Cl O Cl Cl
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Chapter 22 12
Haloform Reaction
Methyl ketones replace all three Hs with halogen. The trihalo ketone then reacts with hydroxide ion to give carboxylic acid.
O C CH3 excess I2 OH
-
O C CI3
OH
O C OH CI3
-
O C O
-
HCI3
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13
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Chapter 22 14
Chapter 22
15
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Chapter 22 16
Chapter 22
17
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Alkylation
Enolate ion can be a nucleophile. Reacts with unhindered halide or tosylate via SN2 mechanism.
O H H (i-Pr)2N Li
+
O H CH3 Br
O CH3 H
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Chapter 22 18
Stork Reaction
Milder alkylation method than using LDA. Ketone + 2 amine enamine. Enamine is -alkylated, then hydrolyzed.
O H H H
+
H H N HO + N H H
N H + H
N H
N H CH3 Br
+ N
Br
O H H3O
+
H + H N+
19
H CH3
CH3
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Chapter 22
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Chapter 22 20
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 21
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Dehydration of Aldol
Creates a new C=C bond.
OH H3C C CH3 H3C C C H O H H3C H3C O
H or OH heat
C CH3 H
C C
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Chapter 22 23
Chapter 22
24
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Aldol Cyclizations
1,4-diketone forms cyclopentenone. 1,5-diketone forms cyclohexenone.
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Chapter 22 25
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Chapter 22 26
Claisen Condensation
Two esters combine to form a -keto ester.
O CH3 O C CH2 R pKa = 24
R CH3
O base
O R CH3 O O C CH R
CH3
O C CH R enolate ion
CH2 C O CH3 O O C CH R
CH2 C O CH3
O CH3
_ O C CH2R
Chapter 22
O CH3 R pKa = 11
O _
O C C R
O C CH C CH2R OCH3
27
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Dieckmann Condensation
A 1,6 diester cyclic (5) -keto ester. A 1,7 diester cyclic (6) -keto ester.
Chapter 22
28
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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.
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Chapter 22 29
-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.
O O
O CH3
C CH2 C OCH2CH3
Chapter 22
31
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Chapter 22 32
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 33
Michael Reagents
Michael donors: enolate ions stabilized by two electron-withdrawing groups.
-diketone, -keto ester, enamine, -keto nitrile, -nitro ketone.
A Michael Reaction
Enolates can react with ,-unsaturated compounds to give a 1,5-diketo product.
COOC2H5 _ CH3CH2O C CH O H O H C H C C CH3 O CH3CH2O C CH CH2 COOC2H5 _ H O C C CH3
H OC2H5 COOC2H5 COOH O HO C CH CH2 H O C C CH3 H H O C C CH3 H H3O
+
O CH3CH2O C CH CH2
H O C C CH3 H
heat
O HO C CH2 CH2
-keto acid
=>
Chapter 22 35
Robinson Annulation
A Michael reaction to form a -diketone followed by an intramolecular aldol condensation to form a cyclohexenone.
H CH3 H O H + H3C C C H C O _ OH O CH3
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Chapter 22 36
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Chapter 22 37
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Chapter 22 38
End of Chapter 22
Chapter 22
39