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Enols, enolates, aldol
• Problems
– 16.23, 16.25, 16.26, 16,27, 16,28, 16.31, 16.33,
16.35
– 17.20, 17.23, 17.25, 17.26, 17.27, 17.28, 17.29,
17.32, 17.34, 17.36, 17.39, 17.43
– 18.23, 18.25, 18.31, 18.32, 18.35, 18.37, 18.39
Recap
O
Nuc-H
OH
Nuc
if Nuc is strong base - not reversible
O
acid
H
if Nuc is weak base, may reverse, Drive to
O
completion by condensation
base
Nuc
O
Nuc
Strong bases
• Grignard
• Hydrides
• Alkynyl anions
• Additional – no need for acid or base
catalysis (reagents all strongly basic)
Weaker bases
• Water – hydration
• Alcohols – hemiacetal, reversible, acid
catalysis leads to loss of water, acetal
isolated if water removed (protecting group)
• Primary amines – imines if water removed
• Secondary amines – enamines if water
removed
This chapter
• Less basic sources of nucleophilic carbon
• Formation of C-C bonds but some chance of
reversibility
• Strategies for control of reversibility
• Use in synthesis
• Related reactions
Hydrocyanation
H
C
N
H
CN
Weak Acid
Cyanide anion can be a nucleophile, but addition to C=O reversible
Can't use acid catalysis, toxic gas
Reaction only favorable where steric effects make it favorable (recall hydration)
H
NaCN
N
H
N
acid
H
O
O
HO
OH
O
N
O
Poor yield
Carbonyl species
• We have seen as electrophile
• Also exists in a nucleophilic form
• These forms react with one another
– Enol
– Enolate anion
• Useful – adds much complexity
• Biomimetic
Enol Equilibrium
O
O
O
OH
H
O
OH
O
OH
O
Electron withdrawing groups
O
O
O
9
15.5
H
9.1
HCN
O
O
15.8
O
11
O
O
O
O
13
O
O
22
O
Acidic H is α hydrogen
O
O
O
H
O
H
O
H
O
O
H
α halogenation of carbonyls
Br
H
acid
H
Br2
O
O
O
O
acid
Br2
Br
Haloform test – methyl ketones
base
O
HO
+ CHBr3
Br2
O
base
O
HO
O
+ CHBr3
Br2
Aldol reaction – base catalyzed
H
H
O
O
O
O
H
H
OH
H
H
Aldol Reaction – acid catalyzed
H
H
O
OH
O
O
H
H
OH
H
H
Mixed Aldol reaction
O
O
H
H
O
H
OH
H
H
O
O
H
Consider α,β-unsaturated C=O
• Alkene now electron-poor, can react with
nucleophiles
• Thus two sites for nucleophilic attack
• Called 1,2 and 1,4 (or conjugate addition)
• 1,2 addition is kinetic
• Conjugate addition is thermodynamic
• Cuprates also do conjugate addition
O
O
O
Nuc
Nuc
Nuc
HO
1,2-addition
O
conjugate addition
Irreversible Additions
O
OH
CH3Li
H2O
or CH3MgCl
LiAlH4
or NaBH4
OH
examples of kinetic reaction, 1,2-addition
Conjugate Additions
•
•
•
•
Reversible nucleophiles
Cuprates
Enolate anions – Michael Addition
Robinson Annellation reaction
O
Nuc
OH
Nuc
fast but reversible for many nucleophiles
O
slower but more stable, actually isolated
Nuc
Examples
O
O
CH3NH2
N
H
O
O
CH3CH2OH
O
O
O
NaCN
NC
Cuprates
O
O
(CH3)2CuLi
mechanism complex
example above - prostaglandin synthesis
Enolates – Michael Addition
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Robinson Annelation
• Alternative method to form six member
rings
• Michael addition followed by aldol
condensation
• Often used in steroid syntheses – alternative
to Diels-Alder
O
O
O
O
O
O
HO
O
O
O
H
Alkylation of Enolates
• Use in Sn2 reactions to make C-C bonds
• Difficulty – competing aldol reaction
• Alkylation will only work where the enolate
can be formed in absence of starting C=O
• Thus only useful for highly acidic enolates
O
O
O
O
O
O
NaOCH 3
O
O
NaOCH 3
O
O
O
O
CH3-I
O
O
CH3-I
O
O
O
O
O
O
O
need strong enough base to prevent reverse reaction, but will not add to C=O
N
Li
LDA