Regioselective monobromination of substituted phenols in the presence of β-cyclodextrin

Article abstract of DOI:10.1016/j.tet.2007.03.137

Cyclodextrin acts as a restricting nanovessel to enhance regioselectivity in bromination of substituted phenols such as 3-nitrophenol, 2-chlorophenol, 3-chlorophenol, and 4-chlorophenol. In contrast to solution bromination, cyclodextrin facilitates regioselective monobromination and formation of polybrominated products are substantially reduced. Selectivities in brominations are also observed in water and in the solid state. The observed results are rationalized on the basis of specific modes of inclusion of substituted phenols inside the cyclodextrin cavity and find strong support from energy minimization studies and ¹H-¹H NOESY.

Full text of DOI:10.1016/j.tet.2007.03.137

Tetrahedron 63 (2007) 4959–4967
Regioselective monobromination of substituted phenols in the
presence of b-cyclodextrin
*
Palaniswamy Suresh, Subramanian Annalakshmi and Kasi Pitchumani
School of Chemistry, Madurai Kamaraj University, Palkali Nagar, Madurai 625021, India
Received 20 December 2006; revised 27 February 2007; accepted 22 March 2007
Available online 27 March 2007
Abstract—Cyclodextrin acts as a restricting nanovessel to enhance regioselectivity in bromination of substituted phenols such as 3-nitro-
phenol, 2-chlorophenol, 3-chlorophenol, and 4-chlorophenol. In contrast to solution bromination, cyclodextrin facilitates regioselective
monobromination and formation of polybrominated products are substantially reduced. Selectivities in brominations are also observed in
water and in the solid state. The observed results are rationalized on the basis of specific modes of inclusion of substituted phenols inside
the cyclodextrin cavity and find strong support from energy minimization studies and 1H–1H NOESY.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
intermediates, and regulating the incoming reagents or reac-
tive intermediates toward limited accessible sites thus
improving the overall efficiency and selectivity.9–13
The bromination of arenes is a reaction of immense synthetic
and industrial importance, as the products are useful as
pharmaceuticals, flame retardants, agrochemicals, speciality
chemicals,1 and synthetic intermediates capable of under-
going carbon–carbon bond formation via transmetalation
reactions.2 Brominated phenols, in particular, have broad ap-
plications in many synthetic organic transformations as start-
ing precursors.3 However, bromination of phenols is often
unselective resulting in a mixture of mono- and polybromi-
nated derivatives. Therefore, regioselective monobromina-
tion of phenols has evoked great contemporary interest.
Although many reagents have been reported for selective
brominations, they are not readily available and need to be
freshly prepared. The reaction also requires harsh conditions.
In this study, readily available, non-selective molecular bro-
mine is used to achieve regioselective monobromination of
some substituted phenols inside the cyclodextrin cavity
both in organic as well as aqueous medium.
A pioneering work on the aromatic substitution reaction by
Breslow and Campbell14 has shown that CD alters the regio-
selectivity. Predominant para-chlorination of anisole14 has
been achieved in the presence of excess b-CD. Conse-
quently, halogenation reactions inside the CD cavity have
received extensive attention in recent years to achieve regio-
and stereoselectivities.15 Tee and Bennett16 have made
detailed and systematic studies on CD-mediated bromina-
tion of anisole and phenol and para-selectivity is achieved.
Bromination of several simple aromatic substrates such
as phenol,16 anisole,14,17 acetanilide,17 phenyl acetate,17
aniline, N-methylaniline, N,N-dimethylaniline, and N,N-di-
ethylaniline18 was studied inside CD cavity and appreciable
regioselective brominations are observed. In most of the
cases ortho/para-selectivity is altered and para-substituted
products are predominant.
Cyclodextrins (CDs) are unique reaction nanovessels, form-
ing inclusion complexes with many aromatic guest mole-
cules and resulting in modified reactivities and remarkable
selectivities.4 These unique features have facilitated the use
of CDs to mediate selective thermal5 and photochemical6 re-
actions. They also serve as enzyme models.7,8 In general, CD
functions by geometrically constraining the guest, stabilizing
However, not much attention has been given to bromination
of aromatic rings having more than one substituent. In an
earlier report, iodination of o-chlorophenol, o-iodophenol,
and p-iodophenol19 and its kinetics were studied in the pres-
ence of b-CD. The rate of iodination of the CD-complexed
substrate is faster than that of the free substrate and the
ortho/para ratio decreases in the presence of CD. Recently,
Easton et al.17 have extended the bromination of anisole
and acetanilide to derivatives having methyl groups in the
3-position. Both 3-methylanisole and 3-methylacetanilide
are more reactive toward aromatic substitution. In bromina-
tion of 3-methylanisole and 3-methylacetanilide in the
Keywords: b-Cyclodextrin;
Substituted phenols.
Regioselectivity;
Monobromination;
* Corresponding author. Tel.: +91 452 2456614; fax: +91 452 2459181;
e-mail: pit12399@yahoo.com
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.137

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P. Suresh et al. / Tetrahedron 63 (2007) 4959–4967
Table 1. Percentage conversion and product distribution in bromination of
3-nitrophenol 1 under various conditionsa
presence of a- and b-CD, the yield of monobromide in-
creases. These results can be attributed to inclusion of the
substrates within the CD cavity restricting access of the
reagent to the adjacent methoxy and acetamido groups.
Medium Br2/CCl4 Time Conversionb
Yield (%)
(h)
(%)
5
6+7+8
9
MeOH
MeOH
MeOH
MeOH
b-CDc
b-CDc
b-CDd
b-CDd
b-CDe
b-CDe
b-CDe
b-CDe
b-CDe
b-CDf
b-CDf
b-CDf
b-CDf
b-CDf
b-CDf
b-CDf
b-CDf
1.0
1.0
2.0
3.0
1.0
2.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
1.0
1.0
1.0
2.0
2.0
2.0
3.0
3.0
12
24
24
24
24
24
2
5
2
5
2
5
24
6
12
24
6
12
24
12
24
19.8
22.2
40.5
57.8
—
—
—
—
44.7
49.3
51.7
59.8
86.3
12.7 44.4
42.9
44.6
54.0
61.6
—
—
—
—
—
These interesting recent accounts prompted us to study the
bromination of disubstituted phenols such as 3-nitrophenol
1, 2-chlorophenol 2, 3-chlorophenol 3, and 4-chlorophenol
4 in the presence of b-CD. In these phenols, the phenolic hy-
droxy group strongly activates the aromatic ring while the
nitro/chloro groups deactivate it. These substrates are chosen
keeping in mind that an electron-releasing (–OH group) and
electron-withdrawing groups are present in the same ring
with their orientating influences opposing each other (1, 2,
and 4). For comparison, the reactivity of 3-chlorophenol 3
is also studied (wherein the orientating influence of substit-
uents reinforce each other).
11.7 43.7
11.1 34.9
10.0 28.4
—
—
—
—
100
100
100
100
—
—
—
—
—
—
—
—
—
—
—
78.0
5.60
8.50
9.80
100
100
100
—
—
—
—
—
—
—
—
—
—
—
14.2
63.2
25.2
78.2
80.7
93.8
94.1
80.8 19.2
94.5
91.9
96.3
95.4
5.50
2. Results and discussion
8.10
3.70
4.60
The structures of the various products obtained in the bromi-
nation of 1–4 using molecular bromine in different media are
given in Scheme 1. The percentage conversion and yields of
the various brominated products are presented in Tables 1–4.
a
Using Br2/CCl4 at room temperature. For structures of 5–9, refer
Scheme 1.
Determined by GC; error limit Æ3%.
Reactions carried out in methanol.
Reactions carried out in water.
b
c
d
e
f
Bromination of 1 in methanol was carried out with varying
amounts of Br2/CCl4. The percentage conversion increases
with an increase in bromine and polybrominated products
like dibromides 6–8 and tribromide 9 are formed more sig-
nificantly. In comparison, formation of monobromide 5 is
less favored. With an increase in the reaction time as well
as concentration of bromine, formation of tribromide 9 is
more pronounced. Formation of di- and polybrominated
Reactions carried out in CCl4.
Reactions carried out in solid state.
products is rationalized due to the presence of the activating
hydroxyl group. The observed results are in accordance with
a previous report,20 where NBS was used for bromination
of 1.
OH
OH
OH
OH
OH
Br
Br
Br
Br
Br
Br
Br
+
+
+
+
NO2
NO2
NO2
NO2
NO2
Br
9
Br
6
Br
8
5
7
Br2/CCl4
OH
OH
OH
OH
OH
OH
Br
Cl
Cl
Br
Br
Br
Br
Cl
Br2/CCl4
Br2/CCl4
+
+
+
R
Br
Cl
Cl
1 R= 3-NO2
2 R= 2-Cl
3 R= 3-Cl
4 R= 4-Cl
Br
11
21
20
10
12
Br2/CCl4
OH
OH
OH
OH
OH
OH
OH
Br
Br
Br
Cl
Br
Cl
Br
Cl
Br
+
Cl
Br
Cl
Br
+
+
+
+
+
Cl
Br
Cl
Br
Br
Br
13
14
15
16
17
18
19
Scheme 1. Products of bromination of 3-nitrophenol 1, 2-chlorophenol 2, 3-chlorophenol 3, and 4-chlorophenol 4 using Br2/CCl4.

P. Suresh et al. / Tetrahedron 63 (2007) 4959–4967
4961
Table 2. Percentage conversion and product distribution in bromination of
2-chlorophenol 2 under various conditionsa
Table 4. Percentage conversion and product distribution in bromination of
4-chlorophenol 4 under various conditionsa
Medium Br2/CCl4 Time (h) Conversionb (%)
Yield (%)
Medium Br2/CCl4 Time (h) Conversionb (%)
Yield (%)
10
11
12
20
21
MeOH
MeOH
b-CDc
b-CDc
b-CDc
b-CDd
b-CDd
b-CDe
b-CDe
b-CDe
1.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
5
5
2
98.7
100
16.4 61.8 21.6
30.3 69.7
MeOH
MeOH
MeOH
MeOH
b-CDc
b-CDc
b-CDc
b-CDc
b-CDd
b-CDd
b-CDe
b-CDe
b-CDe
b-CDe
1.0
1.0
2.0
2.0
1.0
1.0
2.0
2.0
1.0
1.0
1.0
1.0
2.0
2.0
2
5
2
5
2
5
2
5
2
5
6
12
6
12
71.1
58.7
100
100
27.9
47.9
85.7
100
60.3
63.1
53.6
82.0
42.4
89.5
62.3
22.7
10.4
—
100
100
37.7
77.3
89.6
100
—
—
6.00
5.70
2.60
2.80
—
20.9
72.6
91.9
17.2
35.4
13.3
33.4
37.7
15.7 84.3
20.3 79.6
20.6 79.4
—
—
—
5
12
12
12
6
12
24
11.6 39.6 48.8
7.20 27.2 65.6
94.0
—
22.5 77.5
80.3
97.3
97.1
8.60 20.0 71.2
8.20 22.2 75.0
100
—
a
Using Br2/CCl4 at room temperature. For structures of 10–12, refer
Scheme 1.
Determined by GC; error limit Æ3%.
Reactions carried out in methanol.
Reactions carried out in water.
94.1
75.6
89.6
5.90
21.9
9.30
b
c
d
e
a
Using Br2/CCl4 at room temperature. For structures of 20 and 21, refer
Scheme 1.
Determined by GC; error limit Æ3%.
Reactions carried out in methanol.
Reactions carried out in water.
Reactions carried out in solid state.
b
c
d
e
In contrast, monobromination is the predominant pathway
when bromination was studied in CD medium. A remarkable
selectivity is observed in solution and also in the solid state
bromination of 1 in the presence of b-CD. When CCl4 is
used, a significant regioselectivity toward monobromination
product 5 is observed. Polybrominated products 6–9 were
totally suppressed and monobromide 5 was formed as the ex-
clusive product. Bromination was also carried out in different
time intervals and with excess bromine (Table 1). In contrast
to solution bromination in the absence of CD, the rate of the
reaction is fairly enhanced with an increase in the concentra-
tion of CD. Even in the presence of excess bromine, 5 is
formed as the only product. In the solid state reaction, similar
selectivities were observed and the percentage conversion
also increases with an increase in the reaction time.
Reactions carried out in solid state.
mass spectra, M and M+2 peaks are observed (equal intensi-
ties) at 217 and 219 m/z values. However, when the 1H NMR
spectrum was recorded, peaks corresponding to the four aro-
matic protons of 1 were observed, ruling out the absence of
ring bromination. Very careful comparison showed that all
four aromatic protons are slightly shielded (DdH values for
the H2, H4, H5, and H6 protons of 1 and its bromo derivative
are only 0.013, 0.009, 0.010, and 0.016, respectively). These
interesting observations have prompted us to propose that the
hypobromide of 1 (Fig. 1) is formed as a stable isolable inter-
mediate and this is much more significant in polar solvents.
The observed regioselectivity in the presence of b-CD is
rationalized by proposing specific modes of inclusion of
1 inside the b-CD cavity. Schematic representation of vari-
ous possible modes of inclusion of 1 in b-CD is given in
Scheme 2 (modes 1a and 1b). In mode 1a (which is more
favored), the position ortho to the hydroxyl group is better
Bromination of b-CD complex of 1 was also studied in polar
solvents such as methanol and water. To our surprise, there
was no reaction even after 24 h. Actually in polar solvents
such as methanol and water a stable product was observed
by GC and we thought it was a monobromo derivative. In
Table 3. Percentage conversion and product distribution in bromination of 3-chlorophenol 3 under various conditionsa
Medium
Br2/CCl4
Time (h)
Conversionb (%)
Yield (%)
13
14
15
16
17
18
19
MeOH
MeOH
MeOH
MeOH
b-CDc
b-CDc
b-CDd
b-CDd
b-CDe
b-CDe
b-CDe
b-CDe
b-CDe
1.0
1.0
2.0
2.0
1.0
2.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2
5
2
5
2
2
2
5
6
62.1
98.7
100
32.2
28.9
22.1
—
1.70
6.50
9.20
10.9
7.60
2.70
—
0.70
—
6.10
8.90
—
7.60
7.40
56.2
49.9
41.9
—
—
5.90
—
—
—
3.90
42.3
0.30
4.70
8.80
—
—
—
—
—
4.40
11.8
22.7
—
8.00
9.20
5.70
—
—
—
31.5
31.6
3.30
6.40
—
—
—
2.20
2.60
—
—
—
11.2
27.9
—
—
12.4
100
7.10
96.2
80.0
65.2
80.1
13.1
77.3
88.1
29.5
44.5
97.3
80.8
52.0
56.0
80.2
76.0
73.0
19.8
17.6
18.9
7.90
19.8
16.4
19.6
48.7
36.5
—
—
—
—
12
24
6
—
—
—
—
12
5.10
9.20
a
Using Br2/CCl4 at room temperature. For structures of 13–19, refer Scheme 1.
Determined by GC; error limit Æ3%.
b
c
d
e
Reactions carried out in methanol.
Reactions carried out in water.
Reactions carried out in solid state.

4962
P. Suresh et al. / Tetrahedron 63 (2007) 4959–4967
Br
bromination was carried out in the solid state, the selectivity
O
was totally altered and dibromide 12 was formed as the ma-
jor product even in an equimolar concentration of bromine
and the yield of monobromides 10 and 11 decreased. This
may be attributed to the increase in the local concentration
of bromine around the b-CD complex of 2 in the solid state.
NO2
Figure 1. Hypobromite of 3-nitrophenol 1.
exposed for bromination and approaches to other sites are
sterically hindered by the CD cavity. The observed selectiv-
ity is also supported by molecular modeling data (Table 5),
where 1a has the minimum complexation energy than the
other mode of inclusion, 1b. This selectivity in bromination
effectively illustrates the utility of b-CD, which limits poly-
bromination, even in the presence of excess bromine.
The observed selectivity of bromination of 2 in the presence
of b-CD was also explained by the specific modes of inclu-
sionof2insidetheb-CDcavity(modes2aand2b, Scheme3).
Molecular modeling studies indicate that both modes are
probable with the former slightly more stable (Table 5). In
both modes of inclusion the para-position of the hydroxyl
group of 2 is readily available to bromine attack. The ortho-
position is hindered by the CD cavityand this causes predom-
inant formation of 11 along with a small amount of 10.
(a)
OH
NO2
(a)
OH
Cl
OH
mode 1b
NO2
Cl
mode 1a
OH
(b)
mode 2a
Br
Br
mode 2b
H
Br
(b)
OH
OH
OH
OH
OH
Br2/CCl4
r.t.
Cl
Cl
Br2/CCl4
r.t.
NO2
NO2
NO2
5
Br
Br
H
OH
Cl
Scheme 2. (a) Possible modes of inclusion of 1 inside b-CD cavity. (b)
Mechanism of bromination of 1 in the presence of b-CD.
(c)
Br
Br
H
Br
11
The above observed selectivity in the bromination of 1
prompted us to extend the studies to other substituted phe-
nols, namely 2-, 3-, and 4-chlorophenols. Solution bromina-
tion of 2-chlorophenol 2 was carried out in methanol
medium at various time intervals and with excess bromine.
A mixture of monobromides 10 and 11 along with dibromide
12 were obtained. With an increase in reaction time, mono-
bromides undergo further bromination and consequently the
yield of dibromide increases. In fact, dibromide 12 was
formed as the only product in the presence of excess bro-
mine. However, bromination of 2 in the presence of b-CD
in methanol resulted in selective bromination and 11 was
obtained as the major product (Table 2) along with a small
amount of 10 and formation of 12 was totally suppressed.
When the same bromination was carried out in water, a dra-
matic change in selectivity was observed. In contrast to
methanol, formation of monobromides 10 and 11 decreased
in the presence of CD, and dibromide 12 was the major prod-
uct even with an equimolar amount of bromine. When
Br2/CCl4
r.t.
Cl
Cl
OH
OH
Scheme 3. (a) Possible modes of inclusion of 2 inside b-CD cavity. (b)
Mechanism of bromination of 2 in the presence of b-CD via mode 2a. (c)
Mechanism of bromination of 2 in the presence of b-CD via mode 2b.
In bromination of 2, carried out in water and also in the solid
state, an improved yield of dibromide 12 was observed. This
may be attributed to (a) the poor electron-withdrawing abil-
ity of the chloro group (compared to the nitro group of 1)
with consequent increase in reactivity and (b) the increase in
local concentration of bromine near the substrate in the solid
state bromination. Thus, the results demonstrate that, with
substrate 2, the orientation and reactivity of the hydroxyl
group dominate and the chloro substituent has little effect.
Methanol-mediated bromination of 3 leads to mixtures of
monobromides 13, 14, and 15, dibromides 16–18, and tribro-
mide 19. When carried out with an equimolar amount of
bromine, monobromides 13–15 were formed with a small
amount of a mixture of dibromides 16–18. At higher concen-
tration of bromine, dibromides 16 and 17 and tribromide 19
were formed as major products (Table 4).
Table 5. Complexation energies (DE) in kcal/mol for 1:1 complexes of 1–4
obtained from energy minimization studies
Substrate
Energya
Mode a
Mode b
b-CD/1
b-CD/2
b-CD/3
b-CD/4
À26.53
À23.87
À20.79
À25.27
À22.96
À22.34
À19.10
À20.22
An impressive regioselectivity is also observed in solution as
well as in the solid state bromination of 3 in the presence of
b-CD. In the bromination of 3 in methanol in the presence of
b-CD, monobromide 15 was formed as the exclusive product
a
DEcomplexÀDEhostÀDEguest obtained by CVFF force field. RMS derivative
for each substrate of 0.001 is achieved.

P. Suresh et al. / Tetrahedron 63 (2007) 4959–4967
4963
along with trace amounts of monobromides 13 and 14. Com-
pared to solution bromination, the formation of dibromides
was totally suppressed. Compound 15 is the exclusive prod-
uct, even at higher concentration of bromine (Table 3). In
aqueous medium, the same selectivity was maintained and
monobromide 15 was formed as the major product and poly-
bromides were totally suppressed. The same trend is also ob-
served when the bromination was carried out in the solid
state. However, the percentage conversion was lower in the
solid state. With excess bromine, formation of dibromide
16 increased along with monobromides 13 and 14.
for two possible modes with substrates 1–4 in the presence of
CD are given in Table 5. From the energy minimization
values, modes a (1–4) are more favorable, which also ratio-
nalize the observed regioselectivities in all the cases. The
corresponding energy-minimized modeling structures for
modes a (1–4) are given in Figure 2.
(a)
OH
Cl
Cl
OH
Regioselectivities observed in 3 are also rationalized by spe-
cific modes of complexation of 3 inside the b-CD cavity. As
in other cases, here also two types of inclusion are possible
(modes 3a and 3b, Scheme 4). Molecular modeling studies
(Table 5) support that mode 3a is slightly more favored as
it has the lower complexation energy than mode 3b. In
mode 3a the hydroxyl group is penetrating into the b-CD
cavity and the position ortho to chlorine is more exposed
in the wider secondary hydroxyl side of CD. Bromination
at this position (Scheme 4) leads to the predominant forma-
tion of 15, which is also in accordance with the mesomeric
electron release by chloro and hydroxyl groups.
mode 4a
mode 4b
(b)
OH
Cl
OH
Cl
OH
Br Br
H
Br
Br2/CCl4
r.t.
Cl
20
Scheme 5. (a) Possible modes of inclusion of 4 inside b-CD cavity. (b)
Mechanism of bromination of 4 in the presence of b-CD.
To gain insight into the strength of binding of the brominated
products, complexation energies of their 1:1 b-CD complex
are also calculated and the values are presented in Table 6. A
comparison of the values with that of the starting phenols
1–4 reveals that when the bromo group enters into the ortho-
position to hydroxyl group (which is the predominant
product with substrates 1 and 4 yielding 5 and 20, respec-
tively), the complexation energies are higher in the product.
This may be rationalized by proposing that intramolecular
hydrogen bonding now occurs between bromo and hydroxyl
groups in the products, which weaken the intermolecular
hydrogen bonding between the phenolic hydroxyl group
and cyclodextrin hydroxyl groups.
(a)
Cl
OH
Cl
mode 3b
OH
mode 3a
(b)
Br
Br
H
Br
Cl
Cl
Cl
Br2/CCl4
r.t.
OH
OH
OH
15
When bromine enters into para-position (which is the major
product with 2 and 3 yielding 11 and 15, respectively), com-
plexation energies of products are either comparable (with
11) or lower (with 15). Hence it is likely that in these cases
bothhydroxylandbromogroupsmayenterintointermolecular
hydrogen bonding with both rims of the cyclodextrin. With
dibromo derivatives, lower complexation energies are ob-
tained, reflecting their greater stability inside the cyclodextrin
cavity, which may be due to their increased acidity upon bro-
mination with a concomitant increase in hydrogen bonding.
Scheme 4. (a) Possible modes of inclusion of 3 inside b-CD cavity. (b)
Mechanism of bromination of 3 in the presence of b-CD.
Bromination is also extended to 4, in which the functional
groups are para to each other and their orientating influences
oppose each other, which limit the number of possible
products. Methanol-mediated solution bromination gives
monobromide 20 and dibromide 21.
Dibromide 21 was formed as the only product at higher bro-
mine concentration. A significant selectivity was observed
in the presence of b-CD/methanol-mediated bromination.
Monobromide 20 was formed as the exclusive product.
Even at higher concentration of bromine, 20 was formed
as the major product (Table 4). When the reactions were car-
ried out in water as well as in the solid state, the selectivities
were maintained. Thus, compared to solution bromination,
in the CD-mediated reaction, formation of 20 is increased
and 21 is totally suppressed.
The results observed from molecular modeling studies find
strong support from the 1H–1H NOESY results. Two-dimen-
sional NMR spectroscopy has recently become an important
method for the investigation of the interaction between host
CDs and guest molecules. In these aspects, the mode of
inclusion of substrate 1–4 inside the CD is unequivocally
assigned based on NOESY. The b-CD complex of 3-
nitrophenol 1 shows a cross peak ‘a’, due to the interaction
of H5 proton of b-CD with H5 and H6 protons of 1
(Fig. 3(i)). This confirms the polar nitro group is deeply pen-
etrated inside the hydrophobic cavity shown in Scheme 2.
Figure 3 (ii) shows NOE spectra of b-CD complex of 2-
chlorophenol 2, in which the cross peaks ‘b’ and ‘c’ show
the interaction between H3, H5, and H6 of 2 with CD’s
H3 and H5 protons. A clear cross peak ‘d’ is observed in
This observed selectivity is rationalized by specific modes of
complexation of 4 inside the b-CD cavity. Molecular model-
ing studies show that mode 4a is energetically preferred than
mode 4b (Scheme 5 and Table 5). Energy-minimized values

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P. Suresh et al. / Tetrahedron 63 (2007) 4959–4967
Figure 2. CVFF-optimized b-CD inclusion complexes: (a) 3-nitrophenol (mode 1a), (b) 2-chlorophenol (mode 1b), (c) 3-chlorophenol (mode 1c), and
(d) 4-chlorophenol (mode 1d).
Table 6. Complexation energies (DE) in kcal/mol for 1:1 b-CD complex of
by di-and tribromoderivatives in all thesesubstituted phenols
even in the presence of excess bromine. It is also interesting to
note that electronic effects, which are usually dominant in
phenol bromination, play a less significant role when the sub-
strates 1–4 are included inside the b-CD cavity.
1–4 and their brominated products 5–21a obtained from energy minimiza-
tion studies
Monobromide Energyb Dibromide Energyb Tribromide Energyb
5
À24.28
6
7
8
À28.53
À27.72
À27.09
9
À30.49
4. Experimental
10
11
À22.84 12
À22.03
À24.22
4.1. Materials
13
14
15
À22.85 16
À21.59 17
À23.10 18
À22.19
À22.75
À22.85
b-Cyclodextrin (Aldrich) is used as received. 3-Nitrophenol
(Merck), 2-chlorophenol (Aldrich), 3-chlorophenol (Fluka),
4-chlorophenol (Merck), and bromine (Merck) were used
as received without further purification. Stock solution of
bromine (Merck) was prepared by dissolving 6.25 mL of
bromine in 100 mL of CCl4 and making up to 250 mL in
a standard measuring flask. 1:1 CD complex is prepared
by mixing an equimolar amount of phenols (1–4) and b-
CD, stirred for 12 h, filtered, and washed with small amount
of ether to remove any uncomplexed substrate. This complex
was dried in an air oven at 50 ꢀC for 6 h.
20
À24.62 21
À24.49
a
For structures of 1–21, refer Scheme 1.
DEcomplexÀDEhostÀDEguest obtained by CVFF force field. RMS deriva-
b
tive for each substrate of 0.001 is achieved.
3-chlorophenol 3 with CD, indicates the strong correlation
between CD’s H3 and H5 with H2 of 3 and cross peak ‘e’
H5 of CD’s with H5, H6, and H2 of 3 (Fig. 3 (iii)). These
cross peaks confirm hydroxyl group of 3 is included inside
the cavity and chloro group is focusing in the secondary
side. Similarly cross peaks ‘f’ and ‘g’ are observed due to
the interaction of CD’s H3 and H5 protons with H2 and
H3 protons of 4, respectively (Fig. 3(iv)).
Complex formation of the substrates 1–4 with b-CD was
inferred by calculating the formation constants (Kf) using
Benasi–Hildebrand22 method for 1–4. The formation constant
(Kf molÀ1 dm3) for 1, 2, 3, and 4 are 386, 202, 139, and 106,
respectively.
3. Conclusions
A mild and efficient protocol for the regioselective bromina-
tion of substituted phenols 1–4 has been achieved by employ-
ing CD as a reaction vessel (even with the non-selective
brominating agent Br2/CCl4) both in aqueous and organic
media. The CD cavity provides an effective protection to the
guest controlling the approach of bromine toward the acces-
sible sites in substrates. In addition, b-CD complexation has
also resulted in regioselective monobromination unaffected
Proton magnetic resonance (1H NMR) and NOESY spectra
were recorded on a Bruker 300 MHz instrument in CDCl3/
DMSO-d6 using TMS as an internal standard. Chemical
shifts are given in parts per million (d-scale) and coupling
constants are given in Hertz. The percentage conversion
and relative yield of the final products are carried out by us-
ing gas chromatography (Shimadzu GC-17A model, ZB-5

P. Suresh et al. / Tetrahedron 63 (2007) 4959–4967
4965
Figure 3. 1H–1H NOESY spectra (300 MHz, in DMSO-d6) of b-CD complex of (i) 3-nitrophenol 1, (ii) 2-chlorophenol 2, (iii) 3-chlorophenol 3, and
(iv) 4-chlorophenol 4.
(10%) capillary column with FID detector using high purity
nitrogen as carrier gas). GC–MS were recorded on Finnigan
GC–MS with RTX5-MS capillary column and high purity
helium as carrier gas.
methanol with stirring for the specified time as in Tables
1–4 at room temperature. After completion of the reaction,
the excess of bromine is quenched completely by the addi-
tion of excess NaHSO3, and the product was extracted by
chloroform and analyzed by capillary GC. All brominations
are carried out in bulk and products are separated by column
chromatography (pet. ether/ethyl acetate 9:2) and analyzed
using 1H NMR spectroscopy and other products are identi-
fied by GC–MS.
4.2. Energy minimization studies
Energy minimization calculations21 are carried out for all the
substituted phenols 1–4 and their brominated products 5–21
in the presence of b-CD using Insight II Discover program in
IRIX system. Calculations are done in a vacuum and struc-
tures are minimized using CVFF force field and RMS deriv-
ative 0.001 is achieved in each case.
4.4. General procedure for bromination of b-CD
complexes of 1–4
One hundred milligrams of the solid 1:1 b-CD complex of 1–
4 is dissolved in 5 mL of water/MeOH/CCl4. An equimolar
amount of bromine in CCl4 stock solution was added drop-
wise with continuous stirring at room temperature for
a period of time as in Tables 1–4. After completion of the
reaction, excess of bromine was removed by addition of
4.3. General procedure for bromination of substrates
1–4 in solution
Bromine (0.5 mmol) in CCl4 stock solution was added
slowly by dropwise to the substrate (0.5 mmol) in 5 mL of

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P. Suresh et al. / Tetrahedron 63 (2007) 4959–4967
excess NaHSO3 and complex was dissolved in excess of
water, the products extracted with hot CHCl3, and products
were analyzed by GC. In solid state bromination the proce-
dure is followed in the absence of solvent.
4.4.15. 2,4,6-Tribromo-3-chlorophenol (19). 1H NMR
(300 MHz, CDCl3) d 7.76 (s, 1H); GC–MS m/z 366.0 (M),
368.0 (M+2), 369.6 (M+4).
4.4.16. 2-Bromo-4-chlorophenol (20). 1H NMR (300 MHz,
CDCl3) d 7.45 (s, 1H), 7.18 (d, J 8.7 Hz, 1H), 6.94 (d,
J 8.7 Hz, 1H); GC–MS m/z 207.9 (M), 209.7 (M+2).
4.4.1. 2-Bromo-5-nitrophenol (5). 1H NMR (300 MHz,
CDCl3) d 7.68 (d, J 8.7 Hz, 1H), 7.71 (dd, J 8.7 and
2.4 Hz, 1H), 7.87 (d, J 2.4 Hz, 1H); GC–MS m/z 216.9
(M), 218.9 (M+2).
4.4.17. 2,6-Dibromo-4-chlorophenol (21). 1H NMR
(300 MHz, CDCl3) d 7.46 (s, 1H); GC–MS m/z 285.9 (M),
287.9 (M+2), 290.3 (M+4).
4.4.2. 2,4-Dibromo-3-nitrophenol (6). 1H NMR (300 MHz,
CDCl3) d 7.63 (d, J 8.7 Hz, 1H), 7.37 (d, J 8.7 Hz, 1H); GC–
MS m/z 296.6 (M), 298.6 (M+2).
Acknowledgements
4.4.3. 2,6-Dibromo-3-nitrophenol (7). 1H NMR (300 MHz,
CDCl3) d 7.37 (d, J 8.1 Hz, 1H), 7.68 (d, J 8.1 Hz, 1H); GC–
MS m/z 296.6 (M), 298.6 (M+2), 300.4 (M+4).
Financial assistance from Department of Science and
Technology (DST), New Delhi is gratefully acknowledged.
4.4.4. 2,4-Dibromo-5-nitrophenol (8). 1H NMR (300 MHz,
CDCl3) d 7.14 (s, 1H), 7.68 (s, 1H); GC–MS m/z 296.9 (M),
298.9 (M+2).
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4.4.6. 2-Bromo-6-chlorophenol (10).23 GC–MS m/z 207.5
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1
4.4.7. 4-Bromo-2-chlorophenol (11). H NMR (300 MHz,
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4.4.9. 2-Bromo-5-chlorophenol (13). H NMR (300 MHz,
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4.4.10. 2-Bromo-3-chlorophenol (14).23 GC–MS m/z 207.9
(M), 209.8 (M+2).
4.4.11. 4-Bromo-3-chlorophenol (15). 1H NMR (300 MHz,
CDCl3) d 6.98 (d, J 3 Hz, 1H), 7.41 (d, J 8.7 Hz, 1H), 6.65
(dd, J 8.7 and 2.7 Hz, 1H); GC–MS m/z 207.9 (M), 209.8
(M+2).
4.4.12. 2,4-Dibromo-3-chlorophenol (16). 1H NMR
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8.7 Hz, 1H); GC–MS m/z 285.9 (M), 287.9 (M+2), 290.3
(M+4).
4.4.13. 2,4-Dibromo-5-chlorophenol (17). 1H NMR
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J 8.7 Hz, 1H); GC–MS m/z 286.0 (M), 287.9 (M+2), 290.3
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