reactions at the αcarbon of carbonyl compounds enols and … · 2011. 6. 26. · stork enamine...
TRANSCRIPT
-
Chapter 18
Reactions at the α Carbon of Carbonyl CompoundsEnols and Enolates
Ch. 18 - 1
-
Ch. 18 - 2
O
RR'
Nu
Reactions at the α Carbon of Carbonyl Compounds:
Enols and Enolates
O
R R'δ+
δ−
O
RR'
Hα Hydrogens are weakly acidic (pKa = 19 – 20)
Nu
-
Ch. 18 - 3
1. The Acidity of the α Hydrogens of Carbonyl Compounds: Enolate Anions
H C C H H2C C H
H3C C
H
H
H
O
RR'
H
H
pKa 25 44
50 19-20pKa
-
Ch. 18 - 4
C C
O
R
H
Resonance structures forthe delocalized enolates
B:
C C
O
R
C C
R
O
-
Ch. 18 - 5
C C
R
O
Enolate
C CHO
R
Enol form
C
R
O H
Keto form
H+ H+
-
Ch. 18 - 6
2. Keto and Enol Tautomers
Interconvertible keto and enol forms are called tautomers, and their interconversion is called tautomerization
-
Ch. 18 - 7
O
H
OH
HAcetaldehyde
Keto form Enol form
(extremely small)(~100%)
O OHAcetone
(1.5 X 10-4%)(>99%)
O OH
Cyclohexanone
(1.2%)(98.8%)
-
Ch. 18 - 8
O OHO
Pentane-2,4-dione(24%)
O
Enol form(76%)
O OH
: ::
:
Resonance stabilization of the enol form
Hydrogen bond
O OH
: :
::
-
Ch. 18 - 9
3. Reactions via Enols & Enolates3A. Racemization
Racemization at an α carbon takes place in the presence of acids or bases
O
tBuEt
H Me
(chiral)(s)
OH
tBuEt
Me
OHor
H3O
Enol(achiral)
O
tBuEt
O
tBuEt
H MeMe H
+
H3O
( 1 : 1 ) racemate
-
Ch. 18 - 10
C C
H
O
HO
C C
O H+
Enol (achiral)HO
Base-Catalyzed Enolization
C C
OEnolate (achiral)
H OH
-
Ch. 18 - 11
C C
O
H
O HH
H
+ C C
O
H
H
O
H
H+
Acid-Catalyzed Enolization
C CO H
+O HH
HEnol
(achiral)
-
Ch. 18 - 12
3B. Halogenation at the α Carbon
C C
OH+ X2
acid
or baseC C
OX+ HX
(racemic)
-
Ch. 18 - 13
Base-Promoted Halogenation
C C
OHB: + + C C
Oδ−
δ−Step 1slow
C C
OH+
fast
Enolate
EnolB:
B:H: : : :
Step 2
C C
O
C C
O
+ X X
fast OX+ X
Enolate anion
: : : :
-
Ch. 18 - 14
Acid-Promoted Halogenation
C C
OH
C C
OH
fastC C
O H
Step 1
H+
Enol
+
:B
H:B H:B
: :
slow
Step 2fast
X X C C
O H+ C C
X O+ X
H
: :
C C
X O+ X
H fastC C
X O+ HX
Racemic
Step 3
-
Ch. 18 - 15
3C. The Haloform ReactionO
3 X2
3 OH
CX3
O
+ 3 X
OH
O
O
+CHX3A haloform
(X = Cl, Br, I)
-
Ch. 18 - 16
O
R
O
R O(Both in excess)
+ CHI3
A methylketone
Iodoform(a yellow
precepitate)
I2, HO
-
Ch. 18 - 17
O
RX + X
O
RH + B
Mechanism
O
R R
O
EnolateX X
Repeatsteps
twice
O
R CX3
-
Ch. 18 - 18
O
R CX3OH
O
R CX3
:OH
: :
● Acyl Substitution Step
O
R OH+ :CX3
O
R O:+CHX3
Ahaloform
Carboxylateanion
: :
HO
-
Ch. 18 - 19
3D. α-Halo Carboxylic Acids: The Hell–Volhard–Zelinski Reaction
O
OHR
O
OHR
X
1. X2, P
2. H2O
-
Ch. 18 - 20
OH
O
Br
O
OH
O
Br
Br
Br2
H2O
P
Example
-
Ch. 18 - 21
O
BrR
Br
O
OHR
P + Br2[PBr3]
O
BrR
O
BrR
H:Br Br
O
OHR
Br
H2O
-
Ch. 18 - 22
O
ClR
O
ClR
I
I2HI, SOCl2
O
ClR
Br
N
O
O
Br
HBr, SOCl2
(NBS)
-
Ch. 18 - 23
O
OHR
X O
OR
NH3α-Amino acid
NH3
O
OHR
OH
1. HO2. H3O
α-Hydroxy acid
-
Ch. 18 - 24
4. Lithium EnolatesO
H
O+ EtO Na
weakeracid
(pKa = 19)
weaker base
stronger base
strongeracid
(pKa = 16)
+ EtOH
O O+ iPr2N Li +
iPr2NH
H stronger base
weaker base
weakeracid
(pKa = 38)weaker
acid(pKa = 19)
-
Ch. 18 - 25
Preparation of lithium diisopropylamide (LDA)
Li N
H
+
N
THF
Li
Buyllithium(BuLi)
Diisopropylamine(pKa = 38)
Lithium diisopropylamine
[LDA or LiN(iPr)2]
Butane(pKa = 50)
+
-
Ch. 18 - 26
4A. Regioselective Formation of Enolates
O
H3CH3C
O
H
HLi N(iPr)2
DME
Li
Kineticenolate
Formation of a Kinetic Enolate
This enolate is formed faster because the hindered strong base removes the less hindered proton faster.
-
Ch. 18 - 27
Formation of a Thermodynamic Enolate
H3C
H
H
HO
2-Methylcyclo-hexanone
This enolate is more stable because the double bond is more highly substituted. It is the predominant enolate at equilibrium.
B
O
HH3CH
Kinetic(less stable)
enolate
O
H3C
Thermodynamic(more stable)
enolate
weak base in a protic solvent
-
Ch. 18 - 28
4B. Direct Alkylation of Ketones via Lithium Enolates
OO Li
LDA
DME
O
O
CH3
PhBr Ph
H3C I
(- LiI)
(- LiBr)
(56%)
(42-45%)
-
Ch. 18 - 29
4C. Direct Alkylation of Esters
O
OR'R
H
LDA
THF
O
OR'R
O
OR'R
E
E
-
Ch. 18 - 30
Examples
O
OMe
1. LDA, THF
2. MeI
O
OMe
Me
O
O
O
O
Ph1. LDA, THF
2. Ph Br
-
Ch. 18 - 31
5. Enolates of β-Dicarbonyl Compounds
O O
H
O
H
pKa = 9-11(more acidic)
pKa = 18-20
-
Ch. 18 - 32
Recall
O
H
O
+ + EtOHEtO
α-hydrogens of β-dicarbonyl compounds are more acidicO
H
+ + EtOHEtO
O O O
-
Ch. 18 - 33
O
CC
O
CC
C
O
C
O O
CC
C
O
Contributing resonance structures
Resonancehybrid
O
CC
C
O
δ−
δ−δ−
-
Ch. 18 - 34
6. Synthesis of Methyl Ketones: The Acetoacetic Ester Synthesis
O O
OEt
O O
OEt
EtO NaNa
O O
OEt
R X
R
O O
OEt
R
tBuO K
O O
OEt
R' X
R R'
(R, R' = 1o
alkyl groups)
-
Ch. 18 - 35
Synthesis of monosubstituted methyl ketones
O
OEt
O 1. EtO Na , EtOH O
OEt
O
2. Ph Br
Ph
O
OH
O1. NaOH
2. H3O+
Ph
heat
(- CO2)
O
Ph (Decarboxylationof β-keto acid)
-
Ch. 18 - 36
Synthesis of disubstituted methyl ketones
O
OEt
O1. EtO Na , EtOH O
OEt
O
Me
2. MeI
O
OEt
O1. tBuOK, tBuOH
2. Et-Br
Me Et
1. NaOH
2. H3O+
O
OH
O
Me EtO
Me
Etheat
(- CO2)
-
Ch. 18 - 37
O O O
Ethyl acetoacetate ion Acetate enolate
is the syntheticequivalent of
-
Ch. 18 - 38
Synthesis of γ-keto acids and γ-diketonesO
OEt
OEtO Na O
OEt
O
O
OEt
O
BrX
O
X
O
1. NaOH (aq)
2. H3O+
O
OH
O
O
X O
heat(- CO2)
X
O
α
βγ X=OH: γ-keto acid
X=R: γ-diketone
-
Ch. 18 - 39
6A. Acylation Synthesis β-diketones
O
OEt
O O
OEt
ONaHDMF
(cannot use EtOH because it will react with acid chloride)
O
OEt
O
R Cl
O
OR
1. NaOH (aq)
2. H3O+
O
OH
O
R O O
heat(- CO2)
R
O
-
Ch. 18 - 40
7. Synthesis of Substituted Acetic Acids: The Malonic Ester Synthesis
O
EtO
O
OEt
Diethyl malonate
O
EtO
O
OEt
is the synthetic equivalent of:
O
OEt
O
Oand
-
Ch. 18 - 41
O
EtO OEt
O
O
OHR
O
OHR
R'
-
Ch. 18 - 42
O
EtO OEt
O
R
Synthesis of monoalkylacetic acidO
EtO OEt
O
H
OEt O
EtO OEt
O
R X
1. NaOH (aq)
2. H3O+
O
HO OH
O
Rheat
O
HO O
O
R
H
HO
OH
RHO
O
R
-
Ch. 18 - 43
O
EtO OEt
O
R
1. tBuOK, tBuOH
2. R'X
R'
Synthesis of dialkylacetic acidO
EtO OEt
O
1. NaOH (aq)
2. H3O+
O
HO OH
O
R R'
heat
(- CO2)
O
HOR
R'
1. EtONa
2. RX
O
EtO OEt
O
R
-
Ch. 18 - 44
Example 1O
EtO OEt
O O
EtO OEt
O1. EtONa, EtOH
2.
Br
1. 50% KOH, reflux2. dil. H2SO4, reflux
O
HO OH
O(-CO2)
HO
O
(Heptanoic acid)
-
Ch. 18 - 45
Example 2
O
EtO OEt
O
Me
1. tBuOK, tBuOH
2. Ph Br
Ph
O
EtO OEt
O
1. NaOH (aq)
2. H3O+
O
HO OH
O
Me Ph
180oC
(- CO2)
O
HO
Me
Ph
1. EtONa, EtOH
2. MeI
O
EtO OEt
O
Me
-
Ch. 18 - 46
8. Further Reactions of Active Hydrogen Compounds
Z Z'
Active hydrogen compound
(Z and Z' are electron withdrawing groups)
Z, Z':O
R
O
H
O
OR
O
NR2
O
SR
S
O
O
R S OR
O
O
S NR2
O
O
N NO2
or
-
Ch. 18 - 47
Example
NCOEt
O
NCOEt
O1. EtONa, EtOH
2. Br
1. tBuOK, tBuOHNCOEt
O
Ph Br
Ph
2.
-
Ch. 18 - 48
O
CC
H
HN R
R
Aldehyde or ketone
2o Amine
+
9. Synthesis of Enamines: Stork Enamine Reactions
C C
H
N
OH R
R
C C
N
R
R
Enamine
+ H2O
-
Ch. 18 - 49
2° amines most commonly used to prepare enamines
NH
NH
NH
O
Pyrrolidine Piperidine Morpholine
N
H
O N
p-TsOH, −H2O
● e.g.
-
Ch. 18 - 50
NR X+
R = H2C CH
or Ph
N R
+ X
N-alkylated product
(a)
N
RC-alkylatedproduct
(b)
+ X
H2OO
R
H
N +
heat
(a)
(b)
-
Ch. 18 - 51
N O
ClR
Synthesis of β-diketones
O N
NH
p-TsOH(enamine)
O
R Cl
N O
R
O
R
O
H2O
-
Ch. 18 - 52
N
NH
p-TsOH(enamine)
BrOEt
O
Synthesis of γ-keto esters
O
N
OEt
O
O
H2OOEt
O
-
Ch. 18 - 53
Enamines can also be used in Michael additions
NCN+
N
CNEtOH
reflux
OH2OCN
-
Ch. 18 - 54
10. Summary of Enolate Chemistry1. Formation of an Enolate
O
R
H
+ :B
Resonance-stabilized enolate
O
R
O
RH:B +
-
Ch. 18 - 55
2. Racemization
Ph
OR'
HR
Enantiomers
Ph
OH
R
R'OH
or H3O
Enol(achiral)
Ph
OR'
RH
OH
or H3O
-
Ch. 18 - 56
3. Halogenation of Aldehydes & KetonesO
RR'
H
O
RR'
X
+ X2acid
or base
Specific example: haloform reactionO
PhH
H
O
Ph
X
+ 3 X2OH
H2O
X
X
O
Ph OCHX3 +
H
-
Ch. 18 - 57
4. Halogenation of Carboxylic Acids: The HVZ Reaction
O
OHR
O
OHR
X
1. X2, P
2. H2O
-
Ch. 18 - 58
5. Direct Alkylation via Lithium Enolates
Specific example:
O
H(R')
O
H(R')
LDA, THFR
(formation of thekinetic enolate)
RR'' X
O
H(R')R
-78oC
R''
O O Li O
CH3ILDA, THF
-78oC
-
Ch. 18 - 59
6. Direct Alkylation of Esters
O
OEtR
O
OEtR
LDA
THF
R' BrO
OEtR
R'
-
Ch. 18 - 60
7. Acetoacetic Ester SynthesisO
OEt
1. NaOEt
2. RBr
O O
OEt
O
RO
1. OH−, heat2. H3O
+
3. heat, (− CO2)R
O
OEt
1. tBuOK
2. R'Br
O O
OEt
O
O
R
RR R'
R'
1. OH−, heat
2. H3O+
3. heat, (− CO2)
-
Ch. 18 - 61
8. Malonic Ester SynthesisO
OEt
1. NaOEt
2. RBrEtO
O O
OEtEtO
O
R
HO
O1. OH−, heat2. H3O
+
3. heat, (− CO2)R
O
OEt
1. tBuOK
2. R'BrEtO
O O
OEtEtO
O
HO
O
R
RR R'
R'
1. OH−, heat
2. H3O+
3. heat, (− CO2)
-
Ch. 18 - 62
9. Stork Enamine Reaction
1.2. heat3. H2O
O
RR + R'2NH R
NR'2
R
R R
O
R''
R'' Br
Enamine
-
Ch. 18 - 63
END OF CHAPTER 18
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