©Kevin Burgess, December 29, 2016
HalogenationOfEnolizableCarbonyl
Compounds
from chapter(s) ______ in the recommended text
A. Introduction
B. Halogenation Via Enols (Acidic Conditions)
AcidicConditionsGiveMonohalogenation
acidic conditions, whereas enolates form under basic
less
O
H
+H+,
-H+
O
Ph
Ph
Br
Br
-Br-,
-H+
Ph
less likely
less
Br +H+,
H
-H+
Ph
O
Br
Ph
bromoketone
enol
O
O
Br
O
Br
-HBr, -Br-,
Ph
Br
1
©Kevin Burgess, December 29, 2016
halide.
I2
O
O
H+
I
O
Cl2
H+
Cl
NOCl
monosubstitution
monosubstitution
O
O
N
N
O
nitroso form
OH
oxime tautomer
C. Halogenation Via Enolates (Basic Conditions)
BasicConditionsFacilitateSubstitutionOfMoreThanOneHalogen
different.
O-
O
O-
O
Br
-
- Br
Br
Br
3
O-
1
O-
O
O
- Br
Br
H
H
2
H
H
4
2
©Kevin Burgess, December 29, 2016
more
more
O
base
O-
Br
H
O
base
Br
O-
Br Br
Br
enolate
H
more likely to form enolate
than starting ketone
2,2-dimethylpentan-3-one
would
more
haloform reaction.
Br
Br 2
O
Br
Br
2,2-dibromo-4,4-dimethylpentan-3-one
3
©Kevin Burgess, December 29, 2016
O
O-
NaOH
Ph
Ph
-H2O
H
O
-NaBr
Br
NaOH
Br
Ph
Br
-H2O
H
HO -
HO -
monobromination
enolate
O-
O
-NaBr
Br
Ph
Br
Br
NaOH
Br
Br
Ph
-H2O
H
HO -
enolate
dibromination
O-
Br
O
-NaBr
Br
Ph
Br
Br
-OH
Br
Br
Ph
Br
HO -
enolate
tribromination
O-
Ph
CBr 3
OH
tetrahedral intermediate
could be
4
O
Ph
O
H + C- Br
3
O
Ph
O-
+
CHBr 3
©Kevin Burgess, December 29, 2016
H
NaOH
H
-NaI
-H2O
O
I
O-
I
H
I
-NaI
I
I
I
O
enolate
tetrahedral intermediate
slower
O-H
I
O-
OH
CI 3
O-
-H2O
I
O
I
NaOH
I
O-
I
I
triiodination
-CI3
CO2H
+
I 3C-
-H2O
O
-NaI
I
NaOH
I
I
5
-HI3C
CO2-
©Kevin Burgess, December 29, 2016
O
O
O
O
Ph
yes / no
yes / no
O
I
yes / no
O
Ph
CD 3
yes / no
yes / no
O
tBu
tBu
yes / no
yes / no
D. Choosing Acidic Or Basic Conditions For Halogenations
O
O
O
Br 2
Br 2
Br
H+
O
O
O
O
Br 2
O-
Br 2
Br
H+
HO -
O
O
O
Br
Br
HO -
O
O
Br 2
Br
H+
Br 2
HO -
Br
Br
6
Br
Br
©Kevin Burgess, December 29, 2016
O
O
I2
O
O
O-
HO -
O
O tBu
O-
HO -
Br 2
O
O
O
-O
HO -
O
O
I2
O
Br 2
7
O tBu
O
Br 2
Br
HO -
Br
Br 2
O
H+
O
HO -
Br
Br
Br
Br
Br
indicate
conditions
Br 2
Br 2
Ph
Ph
Br
Br
Ph
Br
Br
Br
Ph
Br
©Kevin Burgess, December 29, 2016
Br 2
Br 2
Br
CH2Cl2
8
Br
FeBr 3
Br
E1cb
O
i) Br 2
ii) base
i) Br 2
O
O
ii) base
Br
i) Br 2
O
O
ii) base
EtO
O
O
Br
EtO
(i) Br 2
(ii) base
O
O
Br
Br
O
©Kevin Burgess, December 29, 2016
E. a-Halogenation Of Carboxylic Acids
Mechanism
O
Ph
O
Ph
+ PBr 3
O-
O
Br
P
O
Ph
Br
H+
Br
Br -
acyl bromide
activated carbonyl
+OH
H+
Ph
O
-H+
Ph
Br
H
-H+
Br
Br
H
O
Ph
Br
enol
protonated carbonyl
acyl bromide
Br
CO2H
Br
Br
PBr 3, Br 2
H+
Cl
Cl
Br
Br
H 2O
OH
O
Cl
O
bromoacid bromide
Br
Ph
CO2H
PBr 3, Br 2
H+
Br
Ph
O
bromoacid bromide
Br
H 2O
OH
Ph
O
9
©Kevin Burgess, December 29, 2016
10
SynthesesFeaturinga-BromoAcids
S N2
NaN 3
OH
HO 2C
OH
O
-SMe
Br
HO 2C
SMe
O
Br
N3
indicate
nucleophile
-SMe
O
O
O
Br
-OPh
O
Br
OPh
SMe
Br
PhO
O
O
indicate
nucleophile
-OAc
O
Br
-CN
Br
O
O
AcO
CN
O
O
Br
PPh 3
O
P +Ph 3