Chemistry 206
Advanced Organic Chemistry
Handout–09A
Synthetic & Mechanistic Overview of
Electrophilic Halogenation
Matthew D. Shair Monday, October 7, 2002
Andy Ratz
Evans Group Seminar, May 7, 1992
Schmid, G. H.; Garratt, D.G.
The Chemistry of Double Bonded Functional Groups
, Wiley, Chichester 1977, pp. 765-789
Dubois, J.E.; Mouvier, G.
Bull. Soc. Chim. France
1968
, 765
The rate of addition is increased with increasing substitution on the double bond.Introduction of one bulky substituent (ie. t-Bu) retards the rate slightly.Cis olefins react faster the trans isomers
.. .
k
rel
Alkene
1
61705727
547026201700
130,000
1,800,000
CH
2
=CH
2
CH
3
CH=CH
2
n-PrCH=CH
2
i-PrCH=CH
2
t-BuCH=CH
2
(CH
3
)
2
C=CH
2
cis-CH
3
CH=CHCH
3
trans-CH
3
CH=CHCH
3
(CH
3
)
2
C=CHCH
3
(CH
3
)
2
C=C(CH
3
)
2
Substituent Effects on Bromination Rates
. .
Chlorination and iodination of olefins have similar kinetics and product stereochemistry to brominations. In synthesis, bromine and iodine have been used interchangebly. Conjugated olefins give a mixture of syn and anti products. The ratio of these products is highly dependent onalkene structure. Stereochemistry of addition to nonconjugated olefins is trans The rate of bromination is first order in alkene, but the order of bromine depends on how the reaction is run
..
General Aspects of Electrophilic Bromination
09A-Bromination 01
10/4/00
2:40
PM
δ
?
δ
+
.
de la Mare, P. B. D.; Bolton, R.
Electrophilic Additions to Unsaturated Systems
, 2nd Ed., Elsevier Publishing, New York 1982
Yates, K.
J. Org. Chem.
,
1973
38
, 2460
.. . ..
Reactions that are third order in Br
2
have been proposed, but there is no conclusive evidence for this
Iodination reactions have been shown to react with overall fourth order kinetics
III. Higher order reactions
Rate Law: -d[Br
2
]/dt = k[Olefin][Br
2
]
2
Reactions run with higher concentrations of Br
2
in aprotic solvents
Proposed that second molecule of Br
2
catalyzes the heterolytic bond cleavage in rate determining step
which forms Br
3
-
.
Alternatively, one Br
2
may be acting as the nucleophile and one acts as an electrophile (not as likely).
II. Third Order Reactions
.
Rate Law: -d[Br
2
]/dt = k[Olefin][Br
2
]
Reactions run with dilute bromine in water or alcohol solventsNo relationship between rate and product composition so the product forming stages follow the rate determining stepThere is a large solvent effect consistent with a highly polarized transition state, and a large solvent deuterium isotope effect k(Br
2
, MeOH)/k(Br
2
, MeOD) = 1.4.
. . .
I. Second order reactions:
Kinetics of Electrophilic Bromination
Br
Br
H
O
R
09A-Bromination 02
10/4/00
4:34
PM
Schmid, G. H.
The Chemistry of Double Bonded Functional Groups
, Wiley, New York 1990, p.699
. .
IR, Raman, and UV studies show the presence of a donor acceptor complexThe rate determining step is the disappearance of this donor-acceptor complex. Steps A and B have been considered irreversible in most kinetic analyses.The
σ
-complex may be a bromonium ion or bromocarbocations depending on the olefin used.
.
Products
Products
BSlow
ASlow
Br
-
+
+
Br
-.
HOR
σ
-complex
σ
-complex
charge transfer complex (
π
-complex)
Overall Reaction Mechanism
Br
2
Br
Br
Br
Br
Br
3
–
Br
3
–
Br
2
Br
2
Second Order Kinetics
Third Order Kinetics
09A-Bromination 03
10/4/00
5:23
PM
Olah, G. A.
J. Am. Chem. Soc.
1967
,
89
, 4744
Olah, G. A.
J. Am. Chem. Soc.
1968
,
90
, 947
Evidence for Cyclic Bromonium Ions
I. NMR Studies
i. Symmetrical Case:
SbF
5
SO
2
+
+
Not observed
+
SbF
5
SO
2
+
Dichloro and diiodo compounds behave much like the dibromideTwo distinct types of methyl groups for the fluoro compound indicates that a
β
-fluoro
carbocation is the major intermediate for this compound. The fluorine resonance is alsoindicative of an open carbocation.The bromo compound exhibits only one methyl resonance even when cooled to -120
°
C.
.. .
Me
F
Me
F
Me
Me
Me
Me
F
Me Me
F
Me
Me
Br
Me
Br
Me
MeMe
Br
Me
Me
Br
09A-Bromonium 04
10/5/00
6:46
PM
CH
3
CH
2
CH
3
CH
2
Olah, G. A.
J. Am. Chem. Soc.
1969
,
91
, 5801
Olah, G. A.
J. Am. Chem. Soc.
1974
,
96
, 3565
.
Open chlorocarbonium ion has long range coupling thru sp
2
cationic center
No long range coupling observed in the bromonium case implies a cyclic bridged intermediateNo
13
C data is given for the chloro-version
13
C data (variable temp.) for bromonium gives evidence for an equilibrium process. This low
temp. study suggests that the intermediate is mainly a static bridged ion in equilibrium with a small amount of
β
-haloalkyl carbonium ion.
Evidence for Cyclic Bromonium Ions
I. NMR Studies (cont'd)
ii. Unsymmetrical Case:
.. .
+
SbF
5
SO
2
+
Not observed
SbF
5
SO
2
+
+
Me
Cl
Me
Cl
Me
Me
Me
Me
Cl
H H
H
H
Cl
Me
Me
Br
H
Br
H
Br
Me
Me
Me
Me
Br
H
H
09A-Bromonium 05
10/4/00
2:44
PM
2 eq Br
2
-2 eq Br
2
II. Crystal Structure of Adamantylideneadamantane Bromonium Ion
Evidence for Cyclic Bromonium Ions
C-Br bond lengths are slightly longer than in normal alkyl bromides: 2.116 ? and 2.194 ? vs. 1.93-2.04 ? .C-C bond is 1.497 ? which is shorter than sp
3
hybridized C-C
bond (1.54 ?) but longer than C=C (1.336 ? in starting material).Br
3
-
counterion is linear but lengths are not symmetrical. Br-1
is interacting with Br-3 which causes an asymmetry in the molecule (accounts for different C-Br-1 bond lengths).Br-1 and Br-3 are within van der Waals distance (3.097 ? vs. 3.7 ? for van der Waals).
Slebocka-Tilk, H.; Ball, R. G.; Brown, R. S.
JACS
1985
,
107
. 4504
C
C
Br
Br
3
–
Br-1
Br-4
Br-2
Br-3
X-ray structure
2.116 ?
2.194 ?
1.497 ?
09A-Bromonium 06
10/4/00
3:01
PM
Brown, R. S.; Gedye, R.; Slebocka-Tilk, H.
J. Am. Chem. Soc.
1984
,
106
, 4515
.
Observed products have exclusively trans stereochemistryThe extent of reversibility most likely depends on the structure of the olefin used
.
Proposed Mechanism:
Crossover products
Br
2
+
Br
-
+
H
:
94.7
4.1
0.35
0.7
75
°
C
KBr, AcOH
1.3
5.2
2.4
91.7
KBr, AcOH
75
°
C
% Products
Reaction
Reversibility in the Formation of a Bromonium Ion
Br
Br
Br
Br
Br
Br
OBs
OAc
Br
OBs
OAc
Br
OBs
Br
Br
+
S OO
Br
= Bs
09A-Bromonium 07
10/4/00
4:09
PM
Reversibility cont'd
12
3
HBr (g)RT
Run
Solvent
12
3
1234
*
(CH
2
Cl)
2
CHCl
3
CCl
4
CHCl
3
254044
162439
362115
<1
50
Products
2
and
3
were quantitatively recovered when resubjected to the reaction conditions
Used the COCl protecting group on Nitrogen to prevent the stabilization of a benzylic carbocation.This was used in reactions involving the oxirane derivative of
1
where exclusive anti addition
products were formed. No ring restriction to acridane derivatives were found.Concerted elimination forming H
2
O and Br
2
have been excluded due to the reactions involving
BF
3
OEt
2
which cannot react thru a bromide assisted concerted elimination. A concerted
elimination was also ruled out in analogous reactions of HBr and 2-bromo-1,2-diphenyl-ethanol. When
3
was dissolved in CH
3
CN and cis-stilbene was added in the absence of acid, the
products obtained were
2
and dibromostilbene.
.. ..
* Reaction run with BF
3
OEt
2
instead of HBr and resorcinol added to scavenge
Bromine produced.
Bellucci, G.; Bianchini, R.
J. Am. Chem. Soc.
1988
,
110
, 546
Bellucci, G.; Chiappe, C.
J. Am. Chem. Soc.
1987
,
109
, 515
N
OH
Br
O
Cl
Cl
O
NN
Br
Br
O
Cl
09A-Bromonium 08
10/4/00
4:10
PM
k
y
k
x
k
Br
Bromonium vs
ββββ
-Bromocarbocation
Three reaction pathways for stilbenes:
The mode of reaction is strongly affected by solvent (polar sovents tend to accelerate the carbonium pathways while nonpolar solvents the bromonium pathway is predominent).The X and Y substiuents also greatly affect the reaction pathway (electron donating substituents favor k
x
and k
y
while electron withdrawing substituents favor k
Br
).
..
Schmid, G. H.; Garratt, D.G.
The Chemistry of Double Bonded Functional Groups
, Wiley, Chichester 1977, pp. 775-779
Bellucci, G.,
et al. J. Am. Chem. Soc.
1991
,
113
, 8012
X
Y
Y
X
X
Y
Y
acceptor
do
nor
X
acce
ptor
X
Y
donor
Br
2
Br
+
H
H
Br
Br
09A-Bromonium 09
10/4/00
4:13
PM
Bellucci, G.,
et al. J. Am. Chem. Soc.
1991
,
113
, 8012
.. ..
Only 4d was anti stereoselective which implies reaction thru an apparently symmetrically bridged bromonium ionReactions 4a and 5a give the same ratio of products. This implies that they are reacting thru essentially the
β
-bromo
carbonium ion. In the case of 5d, "the steric strain of a cis bromonium ion must be so high that isomerization to the trans ion occursdespite the destabilization of the open carbonium ion".Open or weakly bridged ions are attacked preferentially at carbon than are fully bridged bromonium ions which maybe attacked at bromine (reversibility!). This gives evidence for a mechanistic shift of the rate determining step from ionization to the product forming step.
Br
2
, RT
(CH
2
Cl)
2
Br
2
, RT
(CH
2
Cl)
2
Reactions with Cis and Trans Stilbenes
4
7
6
5
7
6
4
0.060.100.152.10
4/(6+7)
Entry
6
7
abcd
HH
CF
3
CF
3
CH
3
HH
CF
3
685573
>95
3245275
302815
2
707285
>98
CH
3
HH
CF
3
HH
CF
3
CF
3
abcd
7
6
Y
X
Entry
H
H
Y
X
X
Y
H
H
Br
Br
Br
Br
H
H
X
Y
Y
X
H
H
Br
Br
Br
Br
H
H
Y
X
X
Y
H
H
X
HH
Y
09A-Bromonium 10
10/4/00
4:18
PM
Marshall, D. R.; Warnhoff, E. W.
Can. J. Chem.
1971
,
49
, 885
Br
2
, 0
°
C
CCl
4
.. . .
All compunds are kinetically controlled addition products as shown by control experiments withHBr. They are not from secondary reactions or isomerizations.Products are not formed via radical chain processes as shown thru the use of radical scavengersCompound
9
is mainly formed thru HBr addition
Compound
11
is formed in equal amounts from two separate processes as shown by
14
C labelling
experiments.
27.330.731.822.8
1.90.61.31.5
3.11.73.03.2
12.4
9.7
12.113.5
3.01.13.13.6
34.445.536.042.2
16.710.211.4
2.4
Normal (0
°
C)
Low Temp (-78
°
C)
Radical ScavengerHBr Scavenger
15
14
13
12
11
10
9
Experiment
15
14
13
12
11
10
9
8
Bromonium Induced Rearrangement of Norbornene
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
09A-Bromonium 11
10/4/00
4:19
PM
+
+
+
13
14
15
11
12
6,2
6,1
2,1
Mechanism of the Rearrangement
Marshall, D. R.; Warnhoff, E. W.
Can. J. Chem.
1971
,
49
, 885
1
2
3
4
5
6
7
Br
+
Br
Br
H
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
09A-Bromonium 12
10/4/00
4:20
PM
Bartlett, P. A.; Richardson, D.; Myerson, J.
Tetrahedron
1984
,
12
, 2317
K= Kinetic Control: 3 eq. I
2
, MeCN, NaHCO
3
, 0
°
C
T= Thermodynamic Control: 3 eq. I
2
, MeCN, 0
°
C
69 9280 7868 9781
8377
T: 1 : 20 K: 1 : 20T: 1 : 20
K: 1 : 1.8T: 1 : 1.1 K: 1: 3T: 1: 6 K: 2.3 : 1T: 1 : 15
Selectivity
Yield
Products
Substrate
Selectivities in Iodolactonizations
HOOC
Me
Me
HOOCHOOC
Me
Me
HOOCHOOC
Me
Me
Me
O
O
I
I
O
OO
O
I
I
O
O
O
O
I
I
O
OO
O
O
OO
O
O
O
I
I
H
II
H
H
H
09A-Bromonium 13
10/4/00
4:20
PM
Iodolactonization in Synthesis of Monensin
1. O
3
, -78
°
C, acetone
Jones reagent -78
°
C
2. Pb(OAc)
4
, Cu(OAc)
2
C
6
H
6
, 80
°
C
73%
1. KOH, MeOH, H
2
O
2. I
2
, MeCN, -15
°
C
72h, 89 %
1.
THF, -20C
2. 10% Pd/C, H
2
, Et
2
O
84%
1. LAH, Et
2
O
2. Me
2
CO, CuSO
4
TsOH3. CrO
3
.
C
5
H
5
N
.
HCl
CH
2
Cl
2
80%
+
DMSO, RT, 18h 70%
KI
3
, NaHCO
3
H
2
O, 87%
AgO
2
CCF
3
CH
2
Cl
2
, 50%
1. Jones Reagent2. 2-PyrSH, (COCl)
2
Et
3
N
Collum, D. B.; McDonald, J. H.; Still, W. C.
J. Am. Chem. Soc.
1980
,
102, 2118
Me
COOBz
O
COOBz
Me
O
I
Me
H
H
Me
HO
O
O
O
-
K
+
O
O
CHO
Me
Ph
3
P
COOH
Me
Me
Me
O
O
Me
Me
HOOC
Me
Me
O
O
O
Me
I
O
O
O
O
Me
HO
H
Me
Me
Me
Me
O
H
PyrS
Me
O
O
O
diastereoselection: 20:1
09A-Bromonium 14
10/4/00
4:22 PM
Reaction conditions: I
2
, NaHCO
3
, 0
°
C to RT
Substrate
Products
Yield
Selectivity
91 : 998 : 293 : 7
1 : 6
1 : 4
1 : 2.5
949879828781
Selectivities in Iodoetherifications
Tamaru, Y.; Hojo, M.; Yoshida, Z.
J. Org. Chem.
1987
,
52
, 4062
OH
Me
HO
Ph
Me
OH
OH
HO
OHOH
OH
Me
Ph
OH
OH
Me
PhPh
Me
OH
OH
O
OH
I
Me
H
I
OH
O
H
Me
OH
O
O
OH
Me
H
PhPh
I
O
OH
Me
H
H
Me
OH
O
I
H
Ph
Ph
I
H
I
I
Ph
O
OH
Me
H
O
Ph
OH
IMe Me I
OH
Ph
O
09A-Bromonium 15
10/4/00
4:23
PM
Wiliams, D. R.; White, F. H.
J. Org. Chem.
1987
,
52
, 5067 Synthesis of Citreoviral
:
2
3
1. H
2
CCHMgBr, THF, 0
°
C
78%2. MEMCl, i-Pr
2
NEt
CH
2
Cl
2
, 82%
85% 1. O
3
, CH
2
Cl
2
, -78
°
C
2.
+
1. I
2
, MeCN, NaHCO
3
0
°
C, 80%
2. BzCl, DMAP 83%
1. DBU, o-DCB,
?
2. O
3
, CH
2
Cl
2
, -78
°
C
89%
1. Ph
3
P=CCH
3
COOEt
PhH, 80
°
C 93%
2. ZnBr
2
, CH
2
Cl
2
87%
3. DIBAL, CH
2
Cl
2
, -78
°
C
70%
MnO
2
, Et
2
O, 68%
Me
OP
h
O
Me
Me
Ph
O
OMEM
Me
MgBr
OBn OH
Me
MEMO
Me
Me
Me
Me
Me
Me
MEMO
Me
OHOBn
O
Me
Me
Me
OBz
OR
Me
I
Me
OR
OBz
CHO
Me
Me
O
O
Me
Me
OH
OH
Me
Me
OH
CHO
Me
Me
OH
OH
Me
Me
O
diastereoselection: 9.5 : 1
09A-Bromonium 16
10/4/00
4:24
PM
+
I
2
, CH
2
Cl
2
, Et
2
O
RT, 25%
1. Ph
3
P, THF, RT
2. NaBH
4
, MeOH
90%
Synthesis of (+)-Croomine
Williams, D. R.; Brown, D.; Benbow, J. W.
J. Am. Chem. Soc.
1989
,
111
, 1923
O
CHO
O
COOM
e
Me
Me
N
3
Me
COOM
e
NH
O
O
Me
H
H
N
Me
O
O
O
O
Me
H
H
IC
O
2
Me
Me
H
N
N
O
O
Me
H
Me
O
O
H
H
OMe
O
09A-Bromonium 17
10/4/00
4:25
PM
I
2
, THF
pH5 buffer, 0
°
C
R
1
R
2
R
3
R
4
Selectivity
Yield
n-Bu
t-Bu
MeMe
n-Bu
Me
n-Bun-Bun-Bu
MeMe
n-Bu
i-Pr
HH
MeMeMe
HHHH
Me
n-Bu
HHH
HHHHHH
Bn
TBS
Me
99: 01
97 : 0393 : 0788 : 1277 : 2397 : 0390 : 1088 : 1288 : 12
937293667772919985
1. HOAc, Bu
3
B,THF,
LiBH
4
, H
2
O
2
2. TIPSCl, DMAP, CH
2
Cl
2
71%
I
2
, THF
KH
2
PO
4
1. Bu
3
SnH
2. Me
2
C(OMe)
2
TsOH, 67%
Cytovaricin
Selective Formation of 2-Iodo-1,3-Diols
Chamberlin, A. R.; Mulholland, R.
Tetrahedron
1984
,
40
, 2297
Evans, D. A.; Kaldor, S. W.; Jones, T. K.
J. Am. Chem. Soc.
1990
,
112
, 7001
R
1
R
2
R
3
OR
4
R
4
O
R
3
R
2
R
1
OH
I
X
N
Me
O
Me
OH
OH
Me
TIPSO
Me
Me
TIPSO
Me
OH
I
OH
O
O
Me
TIPSO
Me
Me
Me
diastereoselection:
96 : 4
09A-Bromonium 18
10/4/00
4:28
PM