carbaniones...1,2-addition (direct addition) nucleophile attacks carbon of c=o 1,4-addition...
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CARBANIONES
1,2-addition (direct addition)
nucleophile attacks carbon of C=O
1,4-addition (conjugate addition)
nucleophile attacks -carbon
Nucleophilic Addition to
-Unsaturated Aldehydes and Ketones
H Y+C C
C
O
1,2-addition
C C
C
OH
Y
formed faster
major product under
conditions of kinetic
control (i.e. when
addition is not readily
reversible)
H Y+C C
C
O
1,4-addition
C C
C
OH
Y
- enol goes to keto form under
reaction conditions
- keto form is isolated product of
1,4-addition is more stable than
1,2-addition product
observed with strongly basic nucleophiles
Grignard reagents
LiAlH4
NaBH4
Sodium acetylide
strongly basic nucleophiles add irreversibly
1,2-Addition
Example
O
CH3CH CHCH + HC CMgBr
1. THF
2. H3O+
OH
CH3CH CHCHC CH
(84%)
observed with weakly basic nucleophiles
cyanide ion (CN–)
thiolate ions (RS–)
ammonia and amines
azide ion (N3–)
weakly basic nucleophiles add reversibly
1,4-Addition
Example
KCNethanol,
acetic acid
(93-96%)
O
C6H5CH CHCC6H5
O
C6H5CHCH2CC6H5
CN
via
C6H5CH CC6H5
CN
••
–
O••••
CH
C6H5CH CC6H5
CN
–O•••••
•
CH
Example
O
CH3
C6H5CH2SH HO–, H2O
(58%)
O
CH3
SCH2C6H5
via
–
O•••••
•
CH3
SCH2C6H5
CH3
SCH2C6H5
–
O••••
••
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The Michael AdditionThe Michael reaction is a useful method for forming C-C bonds.
It is also useful in that the product of the reaction can undergo
an intramolecular aldol condensation to form a six-membered
ring. One such application is called the Robinson annulation.
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Michael reactions form 1,5-dicarbonyl compounds:
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Mechanism for the Michael
Addition Reaction
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Example
O
H2C CHCCH3
CH3
O
O
KOH, methanol
+
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The Robinson Annulation
The Robinson annulation affords a product with a
fused 2-cyclohexenone ring:
Annulation: addition of a new ringfused 2-cyclohexenone
ring
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Robinson annulation mechanism:
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The Stork Enamine Reaction
Enamines are used in place of enolates in these Michael
addition reactions:
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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:
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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:
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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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The Malonic Ester Synthesis: preparation of
carboxylic acids.
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 -Carbon
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The Acetoacetic Ester Synthesis: preparation of
ketones
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
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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: