Bromination of Cyclohexa-1,3-diene and (R,S)-Cyclohexa-3,5-diene-1,2-diol

Article abstract of DOI:10.1021/jo990473s

The configuration of 1,2,3,4-tetrabromocyclohexane (mp 90°C), 5a, has been established as 1,2t,3t,4c by an X-ray crystallographic determination. The structures of two of three dibromocyclohexenes (3a, 3b, and 3c) have been reassigned on the basis of NMR e

Full text of DOI:10.1021/jo990473s

J . Org. Chem. 1999, 64, 5245-5250
5245
Br om in a tion of Cycloh exa -1,3-d ien e a n d
(
R,S)-Cycloh exa -3,5-d ien e-1,2-d iol
Xinghua Han, Rajashree N. Khedekar, J ohn Masnovi,* and Ronald J . Baker
Department of Chemistry, Cleveland State University, Cleveland, Ohio 44115
Received March 16, 1999
The configuration of 1,2,3,4-tetrabromocyclohexane (mp 90 °C), 5a , has been established as 1,2t,3t,4c
by an X-ray crystallographic determination. The structures of two of three dibromocyclohexenes
(3a , 3b, and 3c) have been reassigned on the basis of NMR evidence and an X-ray crystallographic
determination of the structure of 3b (trans-3,6-dibromocyclohexene). The structures of the two major
isomers of 3,4,5,6-tetrabromocyclohexane-1,2-diol obtained by bromination of cis-cyclohexa-3,5-diene-
1
,2-diol also were established by X-ray crystallographic determinations of their monobenzoate esters.
Studies of their formation indicate that the mechanism of bromination of 1,3-cyclohexadiene and
cis-cyclohexa-3,5-diene-1,2-diol are similar. Addition of 1 equiv of bromine occurs rapidly by anti
1
,2-addition, which is followed by rearrangements to form products of conjugation addition. A second
equivalent of bromine adds to afford mostly the 1,2t,3t,4c-tetrabromo compounds at -70 °C and,
with cyclohexadiene, the 1,2t,3c,4t-tetrabromo compound at higher temperature.
In tr od u ction
solution) was freed of ethyl acetate by careful concentration
under a stream of dry nitrogen and crystallization at -20 °C.
Pyridine (Aldrich), dichloromethane, and carbon tetrachloride
were reagent grade and were dried before use.
Our studies1,2 on the photochemistry of 1,3-cyclohexa-
diene (1) led to an interest in preparation of derivatives
starting with cyclohexa-3,5-diene-1,2-diol (2). Initial pro-
tection of the double bonds is helpful, as the diol readily
dehydrates to phenol. Bromination3 is one method of
protecting the double bonds of alkenes.5 However,
Dibr om in a tion of 1,3-Cycloh exa d ien e (1). A three-neck
round-bottom flask fitted with an addition funnel, CaCl drying
2
,4
tube, and magnetic stirbar was charged with 1 mL (10.5 mmol)
of 1,3-cyclohexadiene in 25 mL of carbon tetrachloride. The
flask was lowered into a dry ice-ethanol bath, and the
temperature was maintained at -15 to -20 °C. The flask was
protected from room light, the stirrer was started, and a
solution of 1 mL (21 mmol) of bromine in 10 mL of carbon
tetrachloride was added dropwise from the addition funnel.
When the addition of bromine was complete, the flask was
removed from the cooling bath and allowed to warm to room
temperature. The reaction was filtered by vacuum to afford
,6
reports of electrophilic bromination of 1 have led to
conflicting results concerning the products formed.7-9
Therefore, we have investigated the bromination of 1 and
in order to determine the usefulness of this reaction in
protecting the double bonds of these dienes.
2
We report here the results of our studies on the
electrophilic bromination of 2, including X-ray crystal-
lographic structure determinations of two tetrabromo-
cyclohexanediol derivatives in order to establish stereo-
chemistry. Reactions with 1 also were performed as a
model and to compare the effects of the hydroxyl groups
on the course of the reaction. X-ray determinations
establish the structures of the thermodynamic dibromo-
cyclohexene and the major tetrabromocyclohexane formed
at low temperature, the stereochemistry of which previ-
ously had been misassigned.10
1
.07 g of colorless product, and another 2.95 g of product was
obtained by evaporation of the filtrate under reduced pressure.
The solids were combined to afford 3.0 g of crude product.
Recrystallization from ethanol afforded 2.1 g (83% recovery)
of 5b as a colorless solid. Mp: 140 °C (lit.7 mp 141 °C).
1
H
NMR: 4.19 (dd, 2H, 7.7, 2.9 Hz), 4.07 (m, 2H), 2.5 (dd, 2H,
4.0,d 10.6 Hz), 2.0 (apparent dd, 2H, 2.8, 11.3 Hz). 13C NMR:
60.5, 51.9, 37.0.
Low -Tem p er a tu r e Dibr om in a tion of 1 Usin g Excess
Br om in e. The reaction apparatus was set up as described in
the preceding section. The flask was charged with 85 µL (0.89
mmol) of 1,3-cyclohexadiene and 67 µL of pyridine in 10 mL
of carbon tetrachloride and 10 mL of dichloromethane. The
flask was lowered into a dry ice-ethanol bath with a temper-
ature of -70 °C. The flask was carefully protected from
exposure to light. A solution of 0.30 mL (5.3 mmol) of bromine
in 5 mL of carbon tetrachloride and 5 mL of dichloromethane
was added dropwise from the addition funnel. A solid formed
in the bottom of the flask by the time the addition of bromine
was complete. The reaction was stirred for several hours at
Exp er im en ta l Section
Ch em ica ls. 1,3-Cyclohexadiene (Aldrich) was distilled be-
fore use. cis-3,5-Cyclohexadiene-1,2-diol (Aldrich, 20 wt %
(
1) Yang, N. C.; Gan, H.; Kim, S. S.; Masnovi, J . M.; Rafalko, P. W.;
Ezell, E. F.; Lenz, G. R. Tetrahedron Lett. 1990, 31, 3825.
2) J edrzejas, M. J .; Kingu, C. S.; Baker, R. J .; Towns, R. L. R.;
Masnovi, J . Acta Crystallogr. 1993, C49, 1963.
3) Bellucci, G.; Chiappe, C.; Bianchini, R. Ind. Chem. Libr. 1995,
, 128.
(
(
7
-
70 °C and then overnight, during which period it gradually
warmed to room temperature and the solid redissolved. The
solvent was stripped off under reduced pressure to afford an
(
(
(
4) Ruasse, M. F.; Motallebi, S. J . Phys. Org. Chem. 1991, 4, 527.
5) Fieser, L. F. J . Am. Chem. Soc. 1953, 75, 5421.
6) Organic Synthesis; Wiley: New York, 1963; Collect. Vol. IV, p
1
95.
oily residue, which was dissolved in CH
dilute hydrochloric acid and then water. The CH
dried over anhydrous MgSO , and the solvent was evaporated
2
Cl
2
and washed with
(
(
(
7) Hassel, O.; Lunde, K. Acta Chem. Scand. 1950, 4, 1597.
8) McMillen, D. W.; Grutzner, J . B. J . Org. Chem. 1994, 59, 4516.
9) Heasley, G. E.; Heasley, V. L.; Manatt, S. L.; Day, H. A.; Hodges,
2
2
Cl layer was
4
using a stream of dry nitrogen to afford 350 mg of a colorless
solid. The 1H NMR spectrum revealed the presence of two
isomers of 1,2,3,4-tetrabromocyclohexane, formed in about a
R. V.; Kroon, P. A.; Redfield, D. A.; Rold, T. L.; Williamson, D. E. J .
Org. Chem. 1973, 38, 4109.
(
10) Taken in part from: Khedekar, R. N. M.S. Thesis, Cleveland
8
State University, 1997.
60:40 ratio. These were identified previously as 5a and 5b.
1
0.1021/jo990473s CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/17/1999

5
246 J . Org. Chem., Vol. 64, No. 14, 1999
Han et al.
Ta ble 1. Yield s of Br om in a tion P r od u ctsa
dibromo-
alkenes
tetrabromo-
alkanes
starting
material conditions 3a 3b 3c
5a
5b
ref
1
1
1
1
3
-70 °C
kinetic
25 °C
thermodyn 25 59 16
25 °C
77b
0b 23
79
88
12
this work
9
this work
9
this work
18
3
c
c
c
18 64 18
b
8d
92d
dibromo-
alkenes
tetrabromo-
alkanes
starting
material conditions 4a 4b 4c 6a 6b
6c
ref
b
b
b
56 27 17e
2
2
-70 °C
25 °C
82 15
0
4
this work
this work
f
20f 80f 50 30 20
d
d
d,e
a
Relative NMR yields ((5%) in 1:1 CH2Cl2-CCl4 containing 1
equiv of pyridine for reactions in this work. See Experimental
3
F igu r e 1. Decay of 3a and 4a monitored by NMR in CDCl .
b
c
Section for specific conditions. Extrapolated. In addition to 10%
d
benzene in the absence of pyridine. Bromine in large excess.
e
Estimated from C spectrum. f After 1 day.
13
within the error of the measurement (about 5%), 3b is not
produced in the initial addition of bromine to 1 (Figure 1).
Br om in a tion of Dibr om ocycloh exen es (3). A small
excess of bromine was added immediately to a second fraction
of the reaction described in the preceding section. This reaction
was kept cold until the color of bromine had largely been
discharged. Afterward, volatile materials were removed by
evaporation under reduced pressure, and samples were re-
moved for NMR analysis. A third fraction was set aside in the
dark at room temperature and the solvent allowed to mostly
evaporate, during which time crystals of 3b grew spontane-
ously. The crystals (mp 95.6 °C) were harvested by filtration
The major isomer, 5a (mp 88-92 °C (lit.11 mp 90 °C)), was
isolated by chromatography on silica gel. The spectral proper-
ties of 5a were consistent with those reported (“broad unre-
1
solved peaks of the [ H] NMR” and “four peaks of comparable
1
3
8
1
intensity and one sharp line” for the C spectrum ). H NMR:
4
2
5
.81 (br s, 1H), 4.78 (s, 2H), 4.40 (br s, 1H), 2.66 (br s, 1H),
1
3
.50 (br m, 2H), 2.00 (br m, 1H). C NMR: 59.2 (br), 53.7 (br),
1.1, 33.2 (br), 29.0 (br). X-ray (from ether): space group P2
1
/
n, a ) 7.8644(7) Å, b ) 10.2295(9) Å, c ) 12.2478(12) Å, â )
9
3.064(8)°.
and then redissolved in CCl
4
. A large excess of bromine was
Stoich iom etr ic Br om in a tion of 1. A three-neck round-
added to the CCl solution; the reaction was virtually complete
4
bottom flask fitted with an addition funnel, CaCl
and magnetic stirbar was charged with 1.0 mL (10 mmol) of
,3-cyclohexadiene in 25 mL of carbon tetrachloride. The flask
2
drying tube,
within 30 min. The results for both of these reactions are given
in Table 1. The tetrabromides 5 were stable under the reaction
conditions.
1
was lowered into a dry ice-ethanol bath, and the temperature
was maintained at -70 °C. The flask was protected from room
light, the stirrer was started, and a solution of 0.55 mL (10
Low -Tem p er a tu r e Br om in a tion of (R,S)-Cycloh exa -
3,5-d ien e-1,2-d iol (2) Usin g Excess Br om in e. Initial at-
tempts to brominate cyclohexadienediol afforded mostly 2,4-
dibromophenol. The following conditions proved optimal. A
round-bottom flask equipped with magnetic stirbar and ad-
mmol) of Br
2
in 5 mL of carbon tetrachloride was added
dropwise from the addition funnel. When the addition of
bromine was complete, the crude material was partitioned into
three equal fractions. Two of these fractions were treated as
described in the following section. Volatile materials were
removed under reduced pressure from the third fraction, which
was used for NMR analysis as described next.
dition funnel with a CaCl drying tube was charged with 100
2
mg (0.89 mmol) of diol 2 and 67 µL (70 mg, 0.89 mmol) of
pyridine in 10 mL of carbon tetrachloride and 10 mL of
dichloromethane. The flask was lowered into a dry ice-ethanol
bath maintained at -70 °C and carefully protected from light.
A solution of 0.30 mL (5.3 mmol) of bromine in 5 mL of carbon
tetrachloride and 5 mL of dichloromethane was added drop-
wise from the addition funnel. The addition of bromine was
stopped when the color of bromine was no longer discharged.
NMR analysis of an aliquot indicated the formation of olefinic
products, as well as a small amount of pyridinium salts.
Therefore, the remaining bromine solution was added to the
reaction at -70 °C, and the reaction mixture was kept
overnight in a refrigerator (2 °C). Evaporation of the solvent
under reduced pressure afforded 530 mg of brown oil, which
was taken up in methylene chloride, filtered to remove 40 mg
of insoluble pyridinium hydrobromide, and washed with dilute
hydrochloric acid and then water. Analysis of the aqueous
layer revealed the presence of only pyridinium salts, which
were discarded. The methylene chloride layer was dried over
NMR analysis of the crude material revealed the presence
of three isomers of dibromocyclohexene, 3a , 3b, and 3c, in a
ratio 69:8:23, respectively. Similar results were obtained using
a 1:1 CH
2
Cl
2
4
-CCl solvent system in the presence of 10.5 mmol
of pyridine (Table 1). Isomer 3a rearranged to form 3b in the
NMR sample with a half-life of about 1 h to an equilibrium
ratio of 3a :3b of 18:64, whereas the amount of 3c remained
essentially constant at about 20% over a period of 2 days.
1
3
a . H NMR: 5.82 (m, 1H), 5.74 (m, 1H), 4.86 (dd, 1H, 4.2,
2
2
5
.3 Hz), 4.63 (dd, 1H, 4.1, 1.8 Hz), 2.49 (m, 1H), 2.44 (d, 1H,
.3 Hz), 2.15 (m, 1H), 1.95 (m, 1H). C NMR: 130.3, 124.2,
0.7, 48.5, 24.9, 21.3.
1
3
1
3
b. H NMR: 5.99 (d, 2H, 2.9 Hz), 4.90 (m, 2H), 2.46 (dt,
1
3
2
2
H, 11.1, 1.9 Hz), 2.16 (d, 2H, 11.1 Hz). C NMR: 129.9, 45.4,
7.2. X-ray (from carbon tetrachloride): P2
1
/n; a ) 7.0065(8)
4
anhydrous MgSO , and the solvent was evaporated at reduced
Å, b ) 5.6847(5) Å, c ) 10.2019(9) Å, â ) 109.641(9)°.
pressure to afford 310 mg (80%) of yellow oil. The ratio 6a :
6b:6c given in Table 1 was determined by careful integration
1
3
c. H NMR: 5.94 (d, 2H, 1.8 Hz), 4.77 (tt, 2H, 3.3, 1.7 Hz),
1
3
1
2
.35 (m, 2H), 2.20 (m, 2H). C NMR: 131.0, 44.7, 31.1.
of the H NMR of crude 6. Identical results were obtained using
1
14 µL of pyridine.
Due to overlap of H resonances, some of the assignments
The crude product was purified by column chromatography
on silica gel, eluting fractionally with dichloromethane and
methanol. Three isomers were obtained, identified as 6a , 6b,
and 6c. Isomer 6b eluted first (10 mg with 0.5-2% methanol).
The following three fractions with higher amounts of methanol
were enriched in 6a (126 mg), and later fractions contained
mixtures of 6a and 6c. The chromatography was repeated
twice more, each time on the fractions increasingly enriched
are tentative. The CHBr resonances at 4.6-4.9 ppm were most
resolved, and these were used for integration. The rate
constant for the 3a f 3b conversion in CDCl
3
is estimated to
for the reverse. Extrapola-
tion of the concentration of 3a to zero time indicates that,
-4
-1
-5 -1
be 1.6 × 10
s
and 4.7 × 10
s
(11) Cornubert, R.; Andre, R. Bull. Chem. Soc. Fr. 1955, 60.

Bromination of Cyclohexa-1,3-diene
J . Org. Chem., Vol. 64, No. 14, 1999 5247
in 6a to obtain 6a nearly free of the other isomers. Isomer 6a
was obtained nearly pure as a colorless oil. H NMR: 4.76
sure to obtain 53 mg (85%) of a light brown oil. The crude
materials were purified by column chromatography on silica
gel to afford two products, 7a or 7b, identified as monobenzoate
esters by their spectroscopic properties. The compound eluting
first (7b) was obtained as a colorless solid. Yield: 15 mg (15%).
1
(
broad m, 4H), 4.38 (broad d, 2H, 5.1 Hz), 2.98 (broad s, 2H).
1
3
C NMR: 72.7 (broad), 52.0 (very broad). IR (KBr): 3430
-
1
(broad, vs), 2931 (s), 1094 (s) cm . The 20 eV EI mass
1
3
1
spectrum of 6a (corrected for C isotope) exhibited isotopic
clusters as follows: [M] (RA 4%), [M - H] (3%), [M - Br]
Mp: 179-181 °C. H NMR: 8.09 (m, 2H), 7.62 (m, 1H), 7.48
2
+
+
+
(m, 2H), 5.23 (dd, 1H, 2.4, 11.1 Hz), 4.71 (t, 1H, 10.9 Hz), 4.51
(m, 2H), 4.32 (dd, 1H, 2.1, 11.2 Hz), 4.24 (t, 1H, 10.6 Hz), 2.63
2
+
+
(
H
-
26%), [M - HBr] (24%), [M - H OBr] (29%), [M -
2
2
+
+
2+
13
3
OBr] (28%), [M - HBr
2
] (79%), [M - H
2
Br
2
]
(20%), [M
(dd, 1H, 0.9, 3.2 Hz). C NMR: 165.2, 133.9, 130.0, 128.8,
+
+
+
3
H
3
OBr
2
]
(20%), [M - H
3
CO
2
Br
2
]
(100%), [M - H
2
Br
]
128.6, 74.3, 71.9, 56.8, 55.3, 51.4. IR (KBr): 3400 (broad, m),
+
2+
-1
(
52%), [M - H
2
COBr
3
] (18%), [M - H
3
CO
2
Br
3
]
(29%), [M -
Br
2981 (w), 1717 (s), 1453 (m), 1276 (m), 1116 (s), 708 (s) cm
.
+
2+
+
H
4
CO
M - H
Isomer 6b was obtained as a colorless oil (10 mg)., H NMR:
2
Br
3
]
(25%), [M - H
2
Br
4
]
(20%), [M - H
3
4
]
(29%),
X-ray (from xylene): space group P2 nb, a ) 8.6312(8) Å, b )
1
2
+
+
4
[
2
COBr
4
]
(21%), [M - H
3
COBr
] (47%), m/z 53 (23%).
14.8105(13) Å, c ) 25.650(8) Å. The compound eluting second
(7a ) was obtained as a colorless oil that solidified on standing.
1
1
4
1
.44 (m, 3H), 4.14 (m, 2H), 3.79 (m, 1H), 2.77 (dd, 2H, 5.5,
0.2 Hz). C NMR: 74.1, 73.0, 57.7, 56.7, 55.6, 55.1. The mass
Yield: 14 mg (14%). Mp: 148-150 °C. H NMR: 8.11 (m, 2H),
1
3
7.61 (m, 1H), 7.47 (m, 2H), 5.71 (s, 1H), 5.06 (s, 1H), 4.88 (dd,
1H, 3.1, 10.4 Hz), 4.76 (m, 2H), 4.60 (m, 1H), 2.67 (d, 1H, 5.3
Hz). 13C NMR: 165.3, 133.8, 130.2, 128.8, 128.6, 72.8, 70.8,
57.6, 52.5, 51.1, 46.2. IR (KBr): 3500 (s), 3000 (w), 2925 (w),
spectrum of 6b was essentially the same as that of 6a . Isomer
c was not obtained in pure form from this mixture, but
6
1
3
contained various amounts of 6a . The C NMR of 6c could be
obtained by subtraction of the peaks assigned to 6a : 73.9, 71.6,
-
1
1708 (s), 1601 (m), 1452 (m), 1274 (s), 1109 (s), 705 (s) cm
.
5
7.5, 52.3, 49.5, 46.9.
Stoich iom etr ic Br om in a tion of 2. Bromination of 2 at
70 °C was performed as described above except using 1 equiv
X-ray (from chloroform): space group P2 /a, a ) 7.1120(9) Å,
1
b ) 14.9248(19) Å, c ) 15.0591(13) Å, â ) 90.124(11)°.
-
of bromine. In this case, the reaction was partitioned into two
equal fractions. One of the fractions was treated as described
in the following section. Volatile materials were removed under
reduced pressure from the other fraction, which was used for
NMR analysis as described next.
Resu lts a n d Discu ssion
Bromination of conjugated dienes proceeds by both
direct and conjugate addition. Thus, bromination of 1,3-
cyclohexadiene affords three dibromocyclohexenes, trans-
,4-dibromocyclohexene 3a , trans-3,6-dibromocyclohex-
ene 3b, and cis-3,6-dibromocyclohexene 3c. The reported
NMR analysis of the crude material revealed the presence
of one dibromocyclohexenediol (4a ) in >80% yield, as deter-
3
1
13
1
mined by H and C NMR spectroscopy. H NMR (CDCl -
2
3
D
O): 5.90 (1H, br s), 5.89 (1H, br s), 4.75 (1H, d, 7.4 Hz),
9
kinetic yields are given in Table 1 and were essentially
the same in CCl as in CH Cl solvent. The relative
4 2 2
4
.43 (1H, dd, 10.0, 7.4 Hz), 4.38 (1H, m), 3.85 (1H, dd, 9.9, 4.0
1
3
Hz). C NMR: 130.4, 128.4. 71.4, 65.1, 57.0, 50.6.
Compound 4a was unstable and formed two other products
4b and 4c) with a half-life of about 3 h at room temperature.
thermodynamic yields reported for these isomers in CCl4
also are given in Table 1 and are virtually the same at
7
(
These secondary products were determined to be stereoisomers
8 °C as at 25 °C.9
1
13
of 4a by comparison of their H and C NMR spectra and
isolation of tetrabromocyclohexanediols produced by their
bromination (vide infra). Isomer 4b exhibited the following
With additional bromine, the remaining double bond
of the dibromocyclohexenes 3 adds bromine to afford the
8
7,12
1
tetrabromocyclohexanes 5. Two or three
been reported to form by addition of 0.4 mol of Br
mol of 1,3-cyclohexadiene in CHCl at room temperature.
isomers have
peaks. H NMR (CDCl
.76 (1H, br dd, 10.1, 2.4 Hz), 4.94 (1H, br sextet, 2 Hz), 4.75
1H, m), 4.23 (1H, br dd, 4.0, 2.4 Hz), 4.15 (1H, dd, 6.3, 2.2
3 2
-D O): 5.83 (1H, ddd, 10.1, 2.9, 1.7 Hz),
5
(
2
to 0.2
3
1
3
Hz). C NMR: 128.9, 128.1, 74.8, 69.0, 50.0, 49.8. Isomer 4c
exhibited the following peaks. H NMR (CDCl
2H, d, 1.5 Hz), 4.73 (2H, dd, 5.2, 1.4 Hz), 4.34 (2H, d, 5.2 Hz).
2
The first equivalent of Br is consumed rapidly, although
1
3
-D
2
O): 5.78
reaction of the second equivalent required 2-3 days. The
configuration of one of these isomers with mp 142 °C (5b)
has been established by an X-ray crystallographic deter-
(
1
3
C NMR: 128.6, 72.5, 49.1.
The initial ratio of 4b:4c was about 80:20, but after 22 h
a was essentially entirely depleted and the ratio 4b:4c was
1
2
mination to be all-equatorial (i.e., 1,2t,3c,4t). Early
disagreement7 concerning the configuration of one of
the other isomers, mp 156 °C, has recently been resolved
4
,12
about 20:80. The rate constant for the 4a f 4b + 4c conversion
-
5
-1
in CDCl
the concentration of 4a to zero time does not exclude 4b and
c from being produced in minor amounts as primary products
3
is estimated to be 5.9 × 10
s . Extrapolation of
8
by NMR evidence in favor of the 1,2c,3t,4c isomer, 5c.
4
The third isomer (mp 90 °C) has been proposed to be
in the initial addition of bromine to 2 (Figure 1).
1
,2c,3t,4t-tetrabromocyclohexane on the basis of its chemi-
Br om in a tion of Dibr om ocycloh exen ed iols (5). A small
excess of bromine was added immediately to the second
fraction of the reaction described in the preceding section. The
reaction was kept cold until the color of bromine had largely
been discharged. Afterward, volatile materials were removed
by evaporation under reduced pressure, and a sample was
removed for NMR analysis. The results are given in Table 1.
The tetrabromides 6 were stable under the reaction conditions.
Ben zoyla tion of Tetr a br om ocycloh exa d ien ed iol (6). A
1
1
cal reactivity. This is consistent with its NMR spectrum,
which indicates 2-fold symmetry at higher temperature.
8
The NMR spectra of this isomer exhibit broad peaks for
1
13
H and C resonances, indicative of conformational
changes that will occur with two bromines equatorial and
two bromines axial. However, because of the broadening
of the peaks, the NMR spectra do not allow unambiguous
structural assignment.
2
round-bottom flask equipped with CaCl drying tube was
Therefore, we undertook an X-ray crystallographic
investigation of the isomer with mp 90 °C. The structure
of the molecule, 5a , is shown in Figure 3. This established
the configuration of 5a to be 1,2t,3t,4c, with two axial
and two equatorial substituents. In solution at higher
temperature, dynamic conformational equilibration in
this molecule would give rise to an “average” structure
that possesses an internal plane of symmetry (rather
charged with 49 mg (0.11 mmol) of a fraction of 6 containing
mostly isomer 6a or isomer 6b and 0.25 mL of pyridine. The
flask was placed in an ice-water bath, and 17.5 µL (0.145
mmol) of benzoyl chloride was added slowly. The reaction
mixture was left at 0 °C for about 15 min, after which time
the reaction was diluted with 2 mL of dry dichloromethane.
The resulting solution was warmed to room temperature and
washed successively, twice with 3% hydrochloric acid, twice
with saturated aqueous sodium bicarbonate, and finally with
water. The organic layer was dried over anhydrous magnesium
sulfate, and the solvent was evaporated under reduced pres-
(12) Lund, E. W. Acta Chem. Scand. 1950, 4, 1109.

5
248 J . Org. Chem., Vol. 64, No. 14, 1999
Han et al.
As mentioned above, addition of a single equivalent of
Br to 1 has been shown to afford three dibromocyclo-
2
hexenes: a compound arising from anti 1,2-addition, 3a ,
which lacks internal symmetry, and two stereoisomers
arising from 1,4-addition, 3b and 3c, which exhibit higher
symmetry on the NMR time scale.9 At -70 °C, the
dibromocyclohexenes are insoluble in the solvent system
used (1:1 CH
formation. Under these conditions, we observed that the
2
Cl
2
4
-CCl ), and they precipitate upon
reaction afforded mostly the unsymmetrical isomer 3a
(
which must be the product of 1,2-addition), together with
a lesser amount of a symmetrical isomer, 3c. Addition of
an excess of Br at low temperature resulted in formation
2
of mostly 5a by a second anti 1,2-addition to the remain-
ing double bond of 3a (Table 1).13
At room temperature, 3a converted quickly to 3b, until
an equilibrium mixture favoring 3b was established. The
two more symmetrical isomers, 3b and 3c, must be the
products of formal anti and syn conjugate addition. The
F igu r e 2. ORTEP of 3b (30% probability elipsoids).
assignment of 3b as the product of anti 1,4-addition (C
2
symmetry) is confirmed by the result of an X-ray crystal-
lographic determination shown in Figure 2. Addition of
excess Br to 3b affords almost entirely 5b, in which Br1
2
and Br4 remain trans. In the bromination of 1, 5b
probably entirely results from rearrangement of the
initially formed 3a to 3b, which produces 5b by anti 1,2-
addition of bromine (1 f 3a f 3b f 5b, Scheme 1). At
2 2
high concentrations of Br , the addition of Br to 3b is
complete within about 30 min at 20 °C. However, it is
likely that, with a limited amount of bromine, the
1
4
reactions conform to the Curtin-Hammett principle,
since interconversion of 3a and 3b occurred relatively fast
(
(
half-life about 1 h) compared to the addition of bromine
which reportedly takes about 2 days9 under these
conditions).
F igu r e 3. ORTEP of 5a (30% probability elipsoids).
Our results would be consistent with the earlier reports
of product analyses9 if 5a is assigned as the 1,2t,3t,4c
isomer as shown in Figure 3 and if the original assign-
ment of the structures of 3a (established by NMR as
trans-3,4-dibromocyclohexene) and 3c is reversed (Table
1 and Scheme 1).
,11
than a 2-fold axis, as would be exhibited in the 1,2c,3t,4t
isomer proposed previously). Two bromines would be
equatorial and two axial, consistent with the substantial
line broadening observed in the NMR spectrum of this
stereoisomer attributed to the conformational exchange
at room temperature.
A similar mechanism is proposed for bromination of
diol 2 (Schemes 2 and 3). In this case, addition of 1 equiv
The structure shown in Figure 3 demonstrates that
Br2 and Br3 are cis to one another. Assuming that
addition to the remaining double bond of 3 must be anti,
this indicates that isomer 5a is formed by two consecutive
anti 1,2-additions of bromine (i.e., 1 f 3a f 5a , Scheme
of Br to 2 afforded a dibromocyclohexenediol 4a , which
lacks internal symmetry, as the major (>80%) product.
2
Compound 4a in time rearranged to two isomers, 4b and
4c, the latter of which exhibits higher symmetry on the
NMR time scale (Scheme 2).15 Although 4b initially was
formed from 4a in greater amount than 4c, 4b also
rearranged at longer times to form 4c. Addition of excess
bromine before extensive rearrangement could occur
afforded mostly a symmetrical tetrabromide, 6a , the
structure of which is assigned on the basis of an X-ray
crystallographic determination of its monobenzoate ester
7a (Figure 4).16 A smaller amount of 6b is formed, the
structure of which was assigned likewise from the
corresponding monobenzoate 7b (Figure 5). Isomer 6c,
the bromination product of 4c, was formed in the smallest
1
), as an initial conjugate addition would result in a trans
relationship between Br2 and Br3.
By the same argument, 5c (which we did not isolate)
should be formed by syn 1,4-addition followed by anti 1,2-
addition to the C3-C4 double bond (1 f 3c f 5c), since
syn 1,2-addition does not occur.9 Isomer 5b could be
formed by either two consecutive anti 1,2-additions (1 f
3
a f 5b) or alternatively by an anti 1,4-addition followed
by an anti 1,2-addition (1 f 3b f 5b).
Although the relative yields of 5 were reported not to
2 2 4
depend on whether the solvent was CH Cl or CCl , the
9
yields do depend on temperature. At -70 °C, the major
product is 5a , whereas at room temperature the product
is almost entirely 5b. Therefore, experiments involving
stoichiometric electrophilic bromination of 1, followed by
NMR analysis and further bromination, were performed
in order to obtain insight concerning the mechanism of
these reactions.
(13) An excess of Br2 was required to limit isomerization of 3 during
trapping with bromine. However, higher concentrations of bromide will
affect any equilibrium involving Br- and Br
-
.
3
(
14) Hammett, L. P. Physical Organic Chemistry, 2nd ed.; McGraw-
Hill: New York, 1970; p 119.
15) The presence of the hydroxyl groups slightly inhibits this
(
rearrangement, which has a half-life of about 3 h. This is reflected in
the similar product distributions of isomers 6 observed at -70 °C and
at 20 °C (Table 1).

Bromination of Cyclohexa-1,3-diene
J . Org. Chem., Vol. 64, No. 14, 1999 5249
Sch em e 1
Sch em e 2
amount and was not isolated. However, the dibromide
of highest symmetry, 4c, must result from formal syn
1
,4-addition, and its bromination would be expected to
afford a 3,4c,5t,6c-1,2-diol (Scheme 3). The relative stabil-
ity of 4c may be due to a thermodynamic preference for
adjacent bromine and hydroxyl groups to be anti, as
1
7
indicated by the structure of 7a . The preference of 4a
initially to form 4b (and of 3a to form 3b) may be
explained by a least motion 1,3-sigmatropic rearrange-
ment, in which bromide is more likely to reattach to the
same face from which it left.
Con clu sion
On the basis of X-ray crystallographic determinations
and NMR evidence, the configuration of 1,2,3,4-tetra-
F igu r e 4. ORTEP of 7a (30% probability elipsoids).
bromocyclohexane (mp 90 °C), 5a , has been established
as 1,2t,3t,4c, and the structures of dibromocyclohexene
intermediates 3a and 3c have been reassigned.
The mechanistic results are best explained as follows.
Bromine adds to 1,3-cyclohexadienes 1 and 2 similarly
(
16) The structure of 7a has two bromines and the hydroxyl group
equatorial, and the other two bromines and benzoate group are axial.
Benzoate is sterically bulkier than hydroxyl, and the unusual prefer-
ence is for bulkier groups to be situated equatorial. The axial
orientation of benzoate in crystalline 7a is supported by extensive
hydrogen bonding, both inter- and intramolecular, which is evident in
this structure. For example, the nonbonded contacts of the hydroxyl
hydrogen with O1 of the same molecule is 2.197 Å and with O7 of an
adjacent molecule is 1.998 Å.
2
at -70 °C. The first equivalent of Br affords predomi-
nantly or exclusively the anti 1,2-addition products 3a
or 4a . These kinetic products rearrange at room temper-
ature to form the anti conjugate addition products 3b or
4b. In the case of 4, a subsequent rearrangement of 4b
(
17) The structure for 6c in Scheme 3 was proposed as the 3,4c,5t,6c-
tetrabromo-1t, 2t-diol with this in mind; however, the alternative
,4c,5t,6c-tetrabromo-1c, 2c-diol cannot be ruled out.
3

5
250 J . Org. Chem., Vol. 64, No. 14, 1999
Han et al.
Sch em e 3
mechanistic details awaits explicit determination of the
kinetics and thermodynamics associated with the various
processes in Schemes 1-3 and further structural stud-
ies.13,17,18
Ack n ow led gm en t. The authors thank the CSU
College of Graduate Studies for financial support.
Su p p or tin g In for m a tion Ava ila ble: Tables of crystal-
lographic data, atomic coordinates, and bond distances and
angles for 3b, 5a , and 7a ,b. This material is available free of
charge via the Internet at http://pubs.acs.org.
F igu r e 5. ORTEP of 7b (molecula A, 30% probability elip-
soids).
J O990473S
ultimately affords the syn 1,4-addition product 4c as the
major thermodynamic product. At -70 °C in the presence
of excess bromine, the kinetic products 3a and 4a afford
predominantly or exclusively 5a and 6a , the 1,2t,3t,4c
isomers. At higher temperatures, the 1,2t,3c,4t isomer
(18) The reaction conditions play an important role in the mecha-
nism of addition. For example, additives such as pyridine, necessary
to prevent acid-catalyzed dehydration of 2, may lead to formation of
pyridine perbromide or addition compounds in brominations.
However, we note that bromination of 1 with or without pyridine
proceeds similarly.
19
20
(
(
19) McElvain, S. M.; Morris, L. R. J . Am. Chem. Soc. 1951, 73, 206.
20) Han, H.; Baker, R. J .; Masnovi, J . M. Acta Crystallogr. 1999,
5
b, formed by anti addition to 3b, becomes the major
tetrabromocyclohexane. More specific elucidation of the
C55, in press.