chapter 18
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Created byProfessor William Tam & Dr. Phillis
Chang Ch. 18 - 1
Chapter 18
Reactions at the a Carbon
of Carbonyl CompoundsEnols and Enolates
Ch. 18 - 2
About The Authors
These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang.
Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.
Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.
Ch. 18 - 3
O
RR'
Nu
Reactions at the a Carbon of Carbonyl Compounds:
Enols and Enolates
O
R R'
O
RR'
Ha Hydrogens are weakly acidic (pKa = 19 – 20)
Nu
Ch. 18 - 4
1. The Acidity of the a 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 - 5
C C
O
R
H
Resonance structures forthe delocalized enolates
B:
C C
O
R
C C
R
O
Ch. 18 - 6
C C
R
O
Enolate
C CHO
R
Enol form
C
R
O H
Keto form
H+ H+
Ch. 18 - 7
2. Keto and Enol Tautomers
Interconvertible keto and enol forms are called tautomers, and their interconversion is called tautomerization
Ch. 18 - 8
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 - 9
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 - 10
3. Reactions via Enols & Enolates3A. Racemization
Racemization at an a 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 - 11
C C
H
O
HO
C C
O H
+Enol (achiral)HO
Base-Catalyzed Enolization
C C
OEnolate (achiral)
H OH
Ch. 18 - 12
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 - 13
3B.Halogenation at the a Carbon
C C
OH
+ X2acid
or baseC C
OX
+ HX
(racemic)
Ch. 18 - 14
Base-Promoted Halogenation
C C
OH
B: + + C C
O
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 - 15
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 - 16
3C. The Haloform ReactionO
3 X2
3 OH
CX3
O
+ 3 X
OH
O
O
+CHX3
A haloform(X = Cl, Br, I)
Ch. 18 - 17
O
R
O
R O(Both in excess)
+ CHI3
A methylketone
Iodoform(a yellow
precepitate)
I2, HO
Ch. 18 - 18
O
RX + X
O
RH + B
Mechanism
O
R R
O
EnolateX X
Repeatsteps
twice
O
R CX3
Ch. 18 - 19
O
R CX3OH
O
R CX3
:OH
: :
●Acyl Substitution Step
O
R OH+ :CX3
O
R O:+CHX3
Ahaloform
Carboxylateanion
: :
HO
Ch. 18 - 20
3D.a-Halo Carboxylic Acids: The Hell–Volhard–Zelinski Reaction
O
OHR
O
OHR
X
1. X2, P
2. H2O
Ch. 18 - 21
OH
O
Br
O
OH
O
Br
Br
Br2
H2O
P
Example
Ch. 18 - 22
O
BrR
Br
O
OHR
P + Br2
[PBr3]
O
BrR
O
BrR
H:Br Br
O
OHR
Br
H2O
Ch. 18 - 23
O
ClR
O
ClR
I
I2
HI, SOCl2
O
ClR
Br
N
O
O
Br
HBr, SOCl2
(NBS)
Ch. 18 - 24
O
OHR
X O
OR
NH3-Amino acid
NH3
O
OHR
OH
1. HO2. H3O
-Hydroxy acid
Ch. 18 - 25
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)
weakeracid
(pKa = 19)
Ch. 18 - 26
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 - 27
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 - 28
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 - 29
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 - 30
4C. Direct Alkylation of Esters
O
OR'R
H
LDA
THF
O
OR'R
O
OR'R
E
E
Ch. 18 - 31
Examples
O
OMe
1. LDA, THF
2. MeI
O
OMe
Me
O
O
O
O
Ph1. LDA, THF
2. Ph Br
Ch. 18 - 32
5. Enolates of b-Dicarbonyl Compounds
O O
H
O
H
pKa = 9-11(more acidic)
pKa = 18-20
Ch. 18 - 33
Recall
O
H
O
+ + EtOHEtO
a-hydrogens of b-dicarbonyl compounds are more acidicO
H
+ +EtOHEtO
O O O
Ch. 18 - 34
O
CC
O
CC
C
O
C
O O
CC
C
O
Contributing resonance structures
Resonancehybrid
O
CC
C
O
Ch. 18 - 35
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 - 36
Synthesis of monosubstituted methyl ketones
O
OEt
O1. EtO Na , EtOH
O
OEt
O
2. Ph Br
Ph
O
OH
O
1. NaOH
2. H3O+
Ph
heat
(- CO2)
O
Ph (Decarboxylationof -keto acid)
Ch. 18 - 37
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 Et
O
Me
Etheat
(- CO2)
Ch. 18 - 38
O O O
Ethyl acetoacetate ion Acetate enolate
is the syntheticequivalent of
Ch. 18 - 39
Synthesis of g-keto acids and g-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
X=OH: -keto acid
X=R: -diketone
Ch. 18 - 40
6A.Acylation Synthesis b-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 - 41
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 - 42
O
EtO OEt
O
O
OHR
O
OHR
R'
Ch. 18 - 43
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 - 44
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 - 45
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 - 46
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 - 47
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 - 48
Example
NCOEt
O
NCOEt
O1. EtONa, EtOH
2. Br
1. tBuOK, tBuOHNCOEt
O
Ph Br
Ph
2.
Ch. 18 - 49
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 - 50
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 - 51
N
R 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 - 52
N O
ClR
Synthesis of b-diketones
O N
NH
p-TsOH
(enamine)
O
R Cl
N O
R
O
R
O
H2O
Ch. 18 - 53
N
NH
p-TsOH
(enamine)
BrOEt
O
Synthesis of g-keto esters
O
N
OEt
O
O
H2OOEt
O
Ch. 18 - 54
Enamines can also be used in Michael additions
NCN+
N
CN
EtOH
reflux
OH2OCN
Ch. 18 - 55
10. Summary of Enolate Chemistry
1. Formation of an Enolate
O
R
H
+ :B
Resonance-stabilized enolate
O
R
O
RH:B +
Ch. 18 - 56
2. Racemization
Ph
OR'
HR
Enantiomers
Ph
OH
R
R'OH
or H3O
Enol(achiral)
Ph
OR'
RH
OH
or H3O
Ch. 18 - 57
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 - 58
4. Halogenation of Carboxylic Acids: The HVZ Reaction
O
OHR
O
OHR
X
1. X2, P
2. H2O
Ch. 18 - 59
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 - 60
6. Direct Alkylation of Esters
O
OEtR
O
OEtR
LDA
THF
R' BrO
OEtR
R'
Ch. 18 - 61
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 - 62
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 - 63
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 - 64
END OF CHAPTER 18
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