Chapter 3 Reactions of Nucleophiles and Bases 1) Nucleophilic
Aldehyde & Ketone. Nucleophilic Addition to the Carbonyl Group Oxygen Nucleophiles Sulfur...
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Transcript of Aldehyde & Ketone. Nucleophilic Addition to the Carbonyl Group Oxygen Nucleophiles Sulfur...
Aldehyde & KetoneAldehyde & Ketone
Nucleophilic Addition Nucleophilic Addition to to the Carbonyl Groupthe Carbonyl Group
Oxygen NucleophilesOxygen Nucleophiles
Sulfur Sulfur NucleophilesNucleophiles
Carbon Carbon NucleophilesNucleophiles
Nitrogen Nitrogen NucleophilesNucleophiles
Reactions at the Reactions at the -Carbon of Aldeh-Carbon of Aldeh
yde & Ketoneyde & Ketone
Reactions at the Reactions at the -Carbon of Carbonyl Compounds-Carbon of Carbonyl Compounds
Acidity of the Acidity of the -hydrogens-hydrogens
Keto-Enol tautomerizationKeto-Enol tautomerization
ApplicationsApplications
Acidity of the -hydrogens
O C
C
O C
C
R C C C
H H
O
Hydrogens are unusually acidic
(pKa=19-20)
Hydrogens are not acidic(pKa=40-50)
pKpKaa
CC22HH66 5050
CC22HH44 4444
NHNH33 3434
CC22HH22 2525
CHCH33COCHCOCH33 2020
CC22HH55OHOH 15.915.9
HH22OO 15.7415.74
Ph-OHPh-OH 1010
HH22COCO33 6.56.5
Keto-Enol Tautomerization
KetoKeto EnolEnol
Which makes a greater contribution to the hybrid?
A. InterconversionA. Interconversion ::
B. Keto-enol tautomers B. Keto-enol tautomers
in equilibriumin equilibrium KK ==[enol[enol]]
[keto][keto]
Monocarbonyl compounds
C
O
H3C CH3
C
OH
H2C CH3
((99%) (1.5×1099%) (1.5×10-4-4%)%)
C
O
H3C HC
OH
H2C H
((100%) (extremely small)100%) (extremely small)
O OH
(98.8%) (1.2%)(98.8%) (1.2%)
-dicarbonyl compounds-dicarbonyl compounds
H3C
C
CH2
C
CH3
O O
H3C
C
CH
C
CH3
OH O
O
CC
C
OH
CH3H3C
H
O
CC
C
OH
CH3H3C
H
24%24% 76%76%
PhenolPhenol O OH
K K 10 101414
C. C. Detection:Detection:
H3C
C
CH
C
CH3
OH O
+ FeCl+ FeCl33
H3C
C
CH
C
CH3
O O
6
Fe
Purple or bluePurple or blue
D. Formation of enolate:D. Formation of enolate:
Which “Base”?Which “Base”?
C OH3C
H3C+ K+H-
H2C C
CH3
O-K+ + H2
enolateenolate
E. Regioselective Formation of Enolate Anions E. Regioselective Formation of Enolate Anions
?? ??Kinetic enolate
Thermodynamic enolate
Generally:Generally:
1. Low temperature gives the kinetic enolate.1. Low temperature gives the kinetic enolate.
2. High temperature, relatively weak base in a protic so2. High temperature, relatively weak base in a protic solvent gives the thermodynamic enolate.lvent gives the thermodynamic enolate.
LDA
Two special examples:Two special examples:
1. The kinetically favored enolate can be formed cl1. The kinetically favored enolate can be formed cleanly through the use of diisopropylamide (LDeanly through the use of diisopropylamide (LDA).A).
2. In acid condition, the thermodynamic 2. In acid condition, the thermodynamic enolenol is for is formed predominantly.med predominantly.
enolenolenolateenolate
F. Racemization:F. Racemization:
C CH
CH3
C2H5C C
CH3
C2H5BaseO O
a
b
b
C C CH3
C2H5O
H
(R-)
(S-)a
Application
Nucleophilic center
Nucleophilic center
Ambident nucleophileAmbident nucleophile
carbanion
alkoxide anions
React as an alkoxide anionsReact as an alkoxide anions
OH
NaOH
O
RI
O R
C
O
H3C CH2-
C
O
H3C CH2
(CH3)3Si-Cl
THFC
OSi(CH3)3
H3C CH2
trapped trapped
React as a carbanionReact as a carbanion
React as a carbanion 1: HalogenationReact as a carbanion 1: Halogenation
Haloform reactionHaloform reaction
iodoform reactioniodoform reaction
CH
OH
R CH3
C
O
R CH3
React as a carbanion 2: AlkylationReact as a carbanion 2: Alkylation
side reaction:side reaction:
solution:solution:
React as a carbanion 3: Aldol ReactionReact as a carbanion 3: Aldol Reaction
Reversible
easyeasy
difficultdifficult
Soxhlet ExtractorSoxhlet Extractorcatalyst
acetone
How does it work?How does it work?
Crossed Aldol ReactionCrossed Aldol Reaction
Practical Crossed Aldol Reaction
React as a carbanion 4: React as a carbanion 4:
Glucose
2 ATP
2 ADT
H
C OHH
C
C
O
OPO32-H
H
H
C OHH
C
C OPO32-H
H
OHH
DHAP GAP
C
C
H OH
2-O3POCH2 OH
Enediol Intermediate
glycolysisglycolysis