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台灣大學開放式課程
有機化學乙 蔡蘊明 教授
【本著作除另有註明，作者皆為蔡蘊明教授，所有內容皆採用 創用CC 姓名標示-非商業使用-相同方式分享 3.0 台灣 授權條款釋出】
Chapter 19 Condensation and conjugate addition reactions of carbonyl compounds
※ β-Dicarbonyl compounds
R R'
O O
R OR'
O O
RO OR
O O
β-dicarbonyl system β-keto ester malonic ester
O O
H
pKa~10-14
O OH
O O−
+ H+
O O OO−
a vinylougous acid resonance stabilized
★ The Claisen condensation
H3C OEt
O NaOEt
EtOH CH3CCH2COEtO O
2 + EtOH
NaOEt
CH3CCHCOEtO O
Na
HClCH3CCH2COEt
O O
ethyl acetoacetate(an acetoacetic ester)
75-76%
Mechanism:
RCH2COEtO
RCH COEtO−
+ EtO− + EtOH
RCH2COEtO
RCH COEtO−
RCH2CO
C CR H
OOEt+ + EtO−
RCH2CO
C CR
OOEt + EtOH
This step drives the equilibrium to the right
OEt
O
HOEt
O O
No Claisen condensation No available acidic hydrogen
OEt
O NaOEt
OEt
O O
OEt
O O
Na
AcOH
2 + EtOH
77%
例
Dieckmann condensation
EtOOEt
O
O
O
OEt
O1) NaOEt
2) H+
diethyl haxanedioate(diethyl adipate)
ethyl 2-oxocyclopentanecarboxylate
74-81%
Basically, this is an intramolecular Claisen condensation
◎ Crossed Claisen condensation
One component should have no α-hydrogen or be very reactive
O
OEt
O
OEtEtOO
OEt
OEtO
+
(excess)
1) NaOEt
2) H+
65%
CO2Et
CO2Et
O
OEtH
CO2Et
CO2Et
H
O
+1) NaH
2) H+
60-70%
Others:
OEt
ONa+ −CPh3
Et2O OEt
O+ HCPh3
O
Cl
Ph OEt
O O+ NaCl
◎ Acylation of ketones
O NaNH2 O− OEt
O
Et2O O O
1)
2) H3O+
76%
O
EtOOEt
O
O O OOEt
O+
1) NaOEt
2) H+
★ The aldol reaction
O
HH3C CH3CHCH2CHOH O
210% NaOH, H2O
5 oC3-hydroxybutanal
50%
an aldol product *Also called an aldol addition product
Mechanism: O
H+ OH− + H2O
O−
H
O
H
O−
H+
H
O− O
H
O− O+ H2O
H
OH O+ OH−
The aldol reaction is reversible For aldehydes, the equilibrium favors the aldol products
*The reverse of aldol reaction is called retro-aldol reaction
◎ Dehydration of aldol addition product
+ H2OH
OH O+ OH−
H
OH O−∆
H
OH O−
H
O+ OH−
crotonaldehyde (2-butenal)
an enal an aldol condensation product
This double bond is more stable due to conjugation
Aldol addition or condensation? depend on the reaction condition and substrate structure
◎ Acid-catalyzed aldol condensation
H+OO
H
OH OH
OH −H+ OH
OH
H+
OH
OH2O
Dehydration is easier under acidic condition
◎ Aldol reaction of ketones equilibrium favors starting materials
OH ONaOH
NaOH
OH
OO
O2
55%
2
22%
higher steric effect lower yield
◎ Synthetic application
2 RCH2CHO OH−
RCH2CHCHCHOH
R
O NaBH4
H2OR
OH
OH
R
a 1,3-diol
RCH2CH C CHR
O
H+, H2O
RCH2CH C CH2OHR
LAH
an allylic alcohol
H2
NiRCH2CH2CHCH2OH
R
RCH2CH2CHCHR
O
H2, Pd/C
◎ Crossed aldol reaction
O
H
O
H
NaOH
H2O H
OH O
H
OH O
H
OH O
H
OH O
+ +
+ +
A mixture is obtained Solutions:
H
O
+
O
HOH−
10 oCH
O
68%
has no α-hydrogen (non-enolizable)
adds slowly to avoid self condensation
an extended conjugate system: dehydrates very easily
O
HPh
O
HPhCH2
OH−PhCH CCH
Ph
O+
25 oC
O
HH+
O
Hdil. Na2CO3
40 oC
O
H
OH
> 64%
◎ The Claisen-Schmidt reactions condensation of non-enolizable aldehyde with ketone
O
HPh
O OH−
PhCH CHCCH3
O+
100 oC70%
slow addition not necessary self condensation is slow
O
HO NaOEt
O
+EtOH−5 oC
BF3HOAc
OO
+Vitamine A
β-ionone
◎ Condensation with nitroalkanes
RCH2 NO
O
−H+R-CH N
O
OR-CH N
O
Oresonance stabilizednitroalkane
pKa ~ 10
O
HPh
OH−
PhCH=CHNO2
PhCH2CH2NH2
+ CH3NO2
H2, Ni
◎ With nitriles
CH3CN pKa ~ 25
O
HPhPhCH2CN
NaOEt
EtOHPhCH C C
PhN+
◎ Application of aldol reaction: ring formation
HO
O
OH−O
HO−
O
O
−O
H2OO
HO
OH−
O−
HO
O
H
O−
cf.
※ α,β-Unsaturated aldehydes and ketones
O + H-Nu
O−
O−
OHNu
OHNu
ONu
an ambident electrophile
1,2-addition
1,4-addition or
conjugate addition
1,2-Addition is kinetic product
Oδ−
δ+
δ+ δ−
more positive: reacts faster
1,4-Addition is thermodynamically controlled
O−
NuO−
NuO
Nu
Resonance stabilized More stable
In general: highly reactive nucleophiles such as RLi, RMgBr 1,2-addition moderately reactive nucleophiles 1,4 addition Ex: RO−, ROH, RNH2,
−CN
O 1) CH3MgBr
2) H3O+
OH O+
1,2-addition 1,4-addition
72% 20%
例
PhCH=CHCPhO EtOH
AcOHPhCH-CH2CPh
CN
O+ −CN
95%
★ Michael addition
Addition of enolate to α,β-unsaturated carbonyl compounds
PhCH=CHCPhO
OOH−
O
Ph
Ph O
+
OOH−
O−
PhCH=CHCPhO
OH−
O
Ph
Ph O−
O
Ph
Ph O
H2O
+
Mechanism
OEt
O EtO OEt
O O NaOEtO OEt
OEt
O OEt
O
+EtOH25 oC
70%
NN
NCN+
EtOHreflux
H2O CNO
例
※ Robinson annulation
O
O
OOH−
CH3OH
O
OO
O
O
+
65%
a 1,3-dicarbonylcompound
methyl vinyl ketone(MVK)
OH−
O
O
O−
O
O
O−
very acidic
※ The Mannich reaction
O O
HH
HCl
NEt2
O+ + Et2NH + H2O
O
HH
H+ OH
NEt2+ Et2NH
H+ O
NEt2
H H
NEt2 + H2O
Mechanism:
An imminium ion (very reactive)
O H+ OH N
Et
Et
NEt2
O
◎ Directed aldol reaction
O O− Li+O
H O OLi
O OH
H2O
LDA, THF
−78 oC
75%cf. O O−
O
H
OO OH
+O−
O
H
HO
OH−
Obtain a mixture
※ The Knovenagel condensation
Condensation of active methylene compound with aldehyde or ketone
OEt
O OCl CHO
EtOH
NH
AcOH−H2O
Cl CH
C
OOEt
O
+
86%
※ Barbiturates (von Baeyer, 1863)
OEt
OEtO
O
OH2N
H2N NaOEt
NH
NHO
O
ON
N
HO
HO
OH+−EtOH
1
2
34
56
tautomerization
barbituric acid Stronger acid than acetic acid
Contains a pyrimidine ring
安眠藥用 HN
NH
O
O O
EtEt
Veronal (5,5-diethylbarbituric acid) pKa = 7.4
※ Biological chemistry
H3C SCoA
O
SCoA
O O2
acetoacetyl CoA thiolase
acetyl CoA
More acidic than ester
O
OHO
N
P O−OO−
N
N
N
NH2
OPO
O−OP
O
O−OC
H2CCH3
CH3
HCOH
CO
NH
CH2
CH2
CO
NH
CH2
CH2
SCO
H3C
Full structure of acetyl CoA
SCoA
O O
SCoA
O−O SCoA
O OH O+
HMG CoA synthase
β-hydroxy-β-methylglutaryl CoA
HMG CoA lyase
O−
O O
−CO2
O
acetone
β-hydroxybutyratedehydrogenase
O−
OHO H
ketone bodies
Diabetes or on starvation; No utilization of glucose Fat metabolism for energy Produce too much acetyl CoA Excess acetone is formed Ketosis Normal 3 mg/100 mL blood of ketone bodies Ketosis can be as high as 90 mg/100mL
