Transcript 19_Lecture - Ventura College

Organic Chemistry
6th Edition
Paula Yurkanis Bruice
Chapter 19
Carbonyl
Compounds III
Reactions at the
a-Carbon
1
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The a-Hydrogen Is Acidic
The anion is stabilized
by resonance
A carbon acid is a compound with a relatively acidic
hydrogen bonded to an sp3-hybridized carbon
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3
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Esters Are Less Acidic Than
Aldehydes and Ketones
The electrons are not as readily delocalized because of
resonance electron release by -OR (green arrows)
4
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In the following compounds, the anion resulting from
deprotonation can be delocalized into electronegative
atoms (oxygen and nitrogen):
5
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The acidity of the a-hydrogens is attributed to anion
stabilization by resonance:
6
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Keto–Enol Tautomerism
7
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The enol tautomer can be stabilized by intramolecular
hydrogen bonding:
In phenol, the enol tautomer predominates because it
is aromatic:
8
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Mechanism for base-catalyzed keto–enol
interconversion:
9
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Mechanism for acid-catalyzed keto–enol
interconversion:
10
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An Enol Is a Better Nucleophile
Than an Alkene
Carbonyl compounds that form enol undergo substitution
reactions at the a-carbon: an a-substitution reaction
11
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Mechanism for base-catalyzed a-substitution:
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Mechanism for acid-catalyzed a-substitution:
13
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An Enolate Is an Ambident Nucleophile
Reaction at the C or O site depends on the electrophile
and on the reaction condition
Protonation occurs preferentially on the O site
Otherwise, the C site is likely the nucleophile
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14
Acid-Catalyzed Halogenation
Under acidic conditions, one a-hydrogen is substituted
for a halogen
15
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Mechanism for acid-catalyzed halogenation:
16
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Base-Promoted Halogenation
Under basic conditions, all the a-hydrogens are
substituted for halogens
17
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Mechanism for base-promoted halogenation:
18
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Conversion of a Methyl Ketone to
a Carboxylic Acid
19
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Halogenation of the a-Carbon of
Carboxylic Acids
Mechanism for the Hell–Volhard–Zelinski reaction:
20
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a-Halogenated Carbonyl Compounds
Are Useful in Synthesis
Removing a proton from an a-carbon makes the acarbon a nucleophile:
21
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When the a-carbon is halogenated, it becomes
electrophilic:
An E2 elimination will occur if a bulky base is used:
22
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LDA is a strong base but a poor nucleophile
Why?
Because the steric bulk of the isopropyl groups
prevents an SN2 reaction
23
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Using LDA to Form an Enolate
24
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Keto–Enol Tautomerization
25
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Alkylation of the a-Carbon of
Carbonyl Compounds
This method can be used to alkylate ketones, esters, and
nitriles at the a-carbon; however, aldehydes give a poor
yield
26
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Enol and Enolate Reactions:
Halogenation and Alkylation
27
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Two different products can be formed if the ketone is not
symmetrical:
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The less substituted a-carbon can be alkylated if the
hydrazone is used:
29
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Alkylation and Acylation of the
a-Carbon Using an Enamine Intermediate
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The alkylation step is an SN2 reaction:
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Direct alkylation of a carbonyl compound yields several
products:
In contrast, alkylation of an aldehyde or a ketone using
an enamine intermediate yields the monoalkylated
product
32
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Aldehydes and ketones can be acylated via an enamine
intermediate:
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The a-carbon of an aldehyde or a ketone can be made to
react with an electrophile:
The a-carbon of an aldehyde or a ketone can also be
made to react with a nucleophile:
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The Michael Addition
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Michael reactions form 1,5-dicarbonyl compounds:
36
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Mechanism for the Michael
Addition Reaction
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The Stork Enamine Reaction
Enamines are used in place of enolates in these Michael
addition reactions:
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Aldol Addition Reaction
39
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One molecule of a carbonyl compound acts as a
nucleophile, and the other carbonyl compound acts as an
electrophile:
40
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Ketones are less susceptible than aldehydes to attack
by nucleophiles for steric reasons:
41
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An aldol addition product loses water to form an aldol
condensation product:
42
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Conjugation stabilizes the dehydrated product:
43
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The Mixed Aldol Addition
44
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One product will be formed if one of the carbonyl
compounds does not have any a-hydrogen:
45
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Primarily one product can be formed by using LDA to
deprotonate one of the carbonyl compounds:
46
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Condensation of Two Ester Molecules:
The Claisen Condensation
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The reaction can be driven to completion by removing a
proton from the b-keto ester:
Anion formation results in an
irreversible reaction
The Claisen condensation requires an ester with two
a-hydrogens and an equivalent amount of base
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The Crossed Claisen Condensation
The excess reactant has no a protons
51
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Because of the difference in the acidities of the
a-hydrogens in the two carbonyl compounds, primarily
one product is obtained
52
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Enolate Reactions of
Carboxylic Acids and Esters
No a protons
permitted in
this reactant
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Intramolecular Condensation
and Addition Reaction
The Dieckmann condensation:
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Intramolecular Aldol Additions
1,4-Diketones afford five-member rings:
55
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1,6-Diketones also afford five-member rings:
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1,5- and 1,7-diketones afford six-member rings:
57
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The Robinson Annulation
The Robinson annulation affords a product with a
fused 2-cyclohexenone ring:
Annulation: addition of a new ring
fused 2-cyclohexenone
ring
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Robinson annulation mechanism:
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Decarboxylation of
3-Oxocarboxylic Acids
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Acid catalyzes the intramolecular transfer of the proton:
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A malonic ester synthesis forms a carboxylic acid with
two more carbon atoms than the alkyl halide:
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Mechanism for the malonic ester synthesis:
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Preparation of Carboxylic Acids with Two
Substituents Bonded to the a-Carbon
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Synthesis of Methyl Ketone by
Acetoacetic Ester Synthesis
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Mechanism for the acetoacetic ester synthesis:
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Enolate
Reactions of
Carboxylic Acids
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Decarboxylation and Synthesis
68
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Designing a Synthesis to Make New
Carbon–Carbon Bonds
Synthetic goal:
Strategies:
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Solution:
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Synthetic goal:
Solution:
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Synthetic goal:
Solution:
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A Biological Aldol Condensation
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A Biological Claisen Condensation
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A Biological Decarboxylation
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