A practical highly selective oxybromination of phenols with dioxygen

Article abstract of DOI:10.1016/j.tetlet.2007.06.093

A simple, low cost and highly selective method for the synthesis of mono-bromophenols from phenol and electron-rich phenolic compounds has been developed. Bromide ions are used as halogenating agents, dioxygen as a final oxidant, and Cu(OAc)₂ as a catalyst.

Full text of DOI:10.1016/j.tetlet.2007.06.093

Tetrahedron Letters 48 (2007) 6401–6404
A practical highly selective oxybromination of phenols
with dioxygen
Luciano Menini, Luciana A. Parreira and Elena V. Gusevskaya*
Departamento de Quı´mica, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil
Received 30 May 2007; revised 16 June 2007; accepted 19 June 2007
Available online 23 June 2007
Abstract—A simple, low cost and highly selective method for the synthesis of mono-bromophenols from phenol and electron-rich
phenolic compounds has been developed. Bromide ions are used as halogenating agents, dioxygen as a final oxidant, and Cu(OAc)2
as a catalyst.
Ó 2007 Elsevier Ltd. All rights reserved.
Bromination of aromatic compounds is a fundamental
reaction of organic chemistry widely involved in the
manufacture of many bulk and fine chemicals.1 Bromo-
phenols, in particular, have been recently recognized as
an important group of key flavor compounds, which
cause a typical sea-like taste and flavor.2,3 They are also
commercially used as flame retardants and wood preser-
vatives with fungicide activity.3 Conventional methods
for the synthesis of bromoaromatics involve an electro-
philic aromatic halogenation using various brominating
agents such as bromine,4 N-bromosuccinimide,5 and
hypobromites.6 Lewis or Brønsted acid catalysts are
usually employed in these reactions, often in stoichio-
metric amounts.
result in complex mixtures of mono- and polybromi-
nated products, from which a desired isomer has to be
isolated.7–12 Moreover, the potential oxidation of side-
chains in substituted aromatics can further complicate
the reactions.
Only few examples of aerobic oxybromination have
appeared, all reporting low substrate conversions and/
or low selectivities for individual products in spite of
the use of high oxygen pressures (20–70 atm).7,13,14
Recently, oxybromination of 2-phenylpyridine giving
mono- and dibrominated products under one atmo-
sphere of air has been reported; however, the method in-
volves the use of stoichiometric amounts of Cu(OAc)2
and Br2CHCHBr2 as a bromine source.15
An alternative pathway to bromophenols is the oxida-
tive bromination, which can use bromide ions as a bro-
mine source and a suitable oxidant. Main advantages of
oxybromination compared to the classical direct bro-
mination are atom economy, that is, a full utilization
of bromine atoms with no formation of by-products,
and the use of low value and easy to handle halogenat-
ing agents rather than more expensive and hazardous
ones, like molecular bromine. However, the information
on the oxybromination of aromatics is scarce, especially
little being achieved with the use of the most attractive
oxidant molecular oxygen.7–15 Most of the reported
reactions involve peroxo compounds as oxidants and
In the present work, we report for the first time a simple,
low cost, and highly selective Cu-catalyzed oxidative bro-
mination of phenols under mild aerobic conditions, in
which bromide ions are used as halogenating agents and
molecular oxygen is used as the stoichiometric oxidant.
We have discovered that solutions of eugenol (1a) in
acetic acid containing LiBr and Cu(OAc)2 readily con-
sume dioxygen, with only one product being detected
by gas chromatography (GC).16 Product characteriza-
tion revealed that, under the conditions used, a selective
nuclear bromination of 1a occurred resulting in mono-
brominated product 1c with bromine being exclusively
in ortho-position (Scheme 1).
Keywords: Catalytic oxybromination; Phenols; Dioxygen; Copper
catalyst.
*
This reaction formally consists of a nucleophilic substitu-
tion of aromatic hydrogen by BrÀ and a further oxidation
Corresponding author. Tel.: +55 313 499 5741; fax: +55 313 499
5700; e-mail: elena@ufmg.br
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.093

6402
L. Menini et al. / Tetrahedron Letters 48 (2007) 6401–6404
OH
OH
OH
OH
OH
CH(CH3)2
OCH3
OCH3
H3C
CH3
5a
1a
4a
2a
3a
OH
OH
OH
OH
OH
Br
OCH3
OCH3
CH(CH3)2
CH3
H3C
Br
Br
Br
Br
1c
2b
4b
3b
5b
Scheme 1.
OH
OH
The reaction with phenol itself (2a) occurs slower than
that with eugenol resulting in a 75% conversion for
12 h (run 2). Under non-optimized conditions, para-bro-
mophenol 2b is formed as a main product (80%), along
with 17% of ortho-isomer 2c. On the other hand, pheno-
lic compounds having at least one electron donating
group, such as meta-cresol 3a, guaiacol 4a, and thymol
5a, undergo oxybromination at much higher rates, even
faster than eugenol (runs 3–5). All these reactions show
a dioxygen-coupled catalytic turnover, that is, catalytic
amounts of Cu(OAc)2 are used and dioxygen is con-
sumed as the final oxidant. In the absence of Cu(OAc)2,
no bromination products are formed and no other reac-
tions occur with phenols under the conditions shown in
Table 1.
Cu(OAc)2 (cat)
HOAc, 80 oC
R1
+ H2O
R1
+
1/2 O2 + H+ + Br-
1 atm
R2
R2
Br
1a - 5a
Scheme 2.
of HÀ by CuII (Scheme 2) and seems to be similar to the
CuCl2-catalyzed oxychlorination of phenols reported in
our previous work.17,18 Dioxygen re-oxidizes the reduced
CuI species; thus, catalytic on copper turnover
can be achieved. Under optimized conditions, a 90%
conversion of eugenol occurred for 12 h (Table 1, run
1). Cu(OAc)2 was used in catalytic amounts. The reaction
is remarkably ortho-selective: no even traces of meta-iso-
mer were observed, with chemoselectivity for monobro-
mination being as high as 99%. A GC mass balance
was based on the substrate charged using dodecane as
an internal standard.
All substrates showed good to excellent para-selectivi-
ties. The only exception is eugenol, in which para-posi-
tion is occupied by the allylic group; therefore,
bromination occurs exclusively in ortho-position. Thy-
mol 5a and meta-cresol 3a form para-products in more
than 95% selectivity, whereas phenol 2a and guaiacol
4a show para-selectivity of near 80%, albeit the condi-
tions for two latter substrates have not been opti-
mized yet. In this regard, it should be mentioned that
The reactivity of various aromatic compounds was
examined (Table 1) to evaluate a substrate scope (for
product characterization data see Supplementary data).
Table 1. Copper-catalyzed oxybromination of aromatics with dioxygena
Run
Substrate (0.40 M)
Time (h)
Conversion (%)
Selectivity (%)
b
para-Isomer (2b–5b)
ortho-Isomer (1c–5c)
Smono
1
2
Eugenol (1a)
Phenol (2a)
12
12
24
10
8
6
6
6
6
90
75
95
95
92
92
87
<1
<1
<1
—
80
80
95
82
96
97
—
—
—
99
17
17
4c
17
3
99
97
97
99
99
99
99
—
—
—
3
4
5
6d
7
meta-Cresol (3a)
Guaiacol (4a)
Thymol (5a)
Thymol (5a)
para-Nitrophenol
Nitrobenzene
Toluene
2
—
—
—
8
9
6
a Conditions: solvent–acetic acid, [Cu(OAc)2] = 0.05 M, [LiBr] = 0.80 M, 80 °C, O2 (1 atm). Conversion and selectivity were determined by GC.
Product and substrate structures are given in Scheme 1.
b Selectivity for monobrominated products.
c A mixture of two ortho-isomers.
d [LiBr] = 0.60 M.

L. Menini et al. / Tetrahedron Letters 48 (2007) 6401–6404
6403
CuII
-H+
-CuI
para-bromoaromatics usually have greater commercial
OCuII
.
OH
significance.4
O
2a
A
B
The extremely high chemoselectivity of this reaction for
monobromination products is remarkable. For all sub-
strates studied, a combined selectivity for monobromo-
phenols was 97–99%. Although a substitution of the
ortho-hydrogen in eugenol occurs smoothly, no further
ortho-bromination of para-bromophenols 2b–5b, having
ortho-positions available, has been observed even at
longer reaction times. Thus, the presence of the electron
withdrawing bromine atom, attached to the aromatic
nucleus in the primarily formed products, virtually sup-
presses their further bromination, conferring such a high
monoselectivity on the process. The fact that electron-
poor phenol para-nitrophenol shows no reactivity under
similar conditions (run 7) collaborates with this explana-
tion of the high selectivity to monobrominated products.
CuIIBr2
-CuIBr
.
Br
OH
Br
O
O
2b
Scheme 3.
D
C
Most of the copper-catalyzed oxidations are thought to
proceed via a one-electron oxidation of phenolate by
CuII to the corresponding phenoxy radical.19 Thus, we
suggest the formation of phenoxy radical B, probably,
from CuII (phenolate) complex A or via the direct oxida-
tion of phenol by CuII. Tautomeric cyclohexadienyl
radical C reacts with CuBr2 resulting in CuBr and bro-
minated product D, whose tautomerization gives para-
bromophenol 2b. Re-oxidation of Cu(I) complexes by
dioxygen completes a catalytic cycle. In the absence of
dioxygen under an inert atmosphere, a rapid precipita-
tion of CuBr occurs and the reaction becomes stagnated.
Non-phenolic compounds, both with electron withdraw-
ing and with electron donating groups, that is, nitroben-
zene and toluene, also undergo no transformation at all
under the conditions used for the oxybromination of
substrates 1a–5a (runs 8 and 9). Thus, the method is
highly substrate specific and could be used for the
monobromination of phenols in the mixtures with other
aromatics. Another practical advantage of this catalyst
is its ability to promote with substituted phenols exclu-
sively their nuclear bromination, with neither side-bro-
mination nor oxidation products being observed.
In general, several concurrent transformations can occur
with the tautomeric phenoxy and cyclohexadienyl radi-
cals, such as carbon-carbon and carbon-oxygen cou-
pling to afford diphenoquinones, dihydroxybiphenyls
or polyphenylene ethers.19 Therefore, a high chemose-
lectivity of the reaction described in this work is espe-
cially attractive. It seems that a rate determining step
of the reaction is the formation of radicals B and C,
whereas their bromination occurs faster. Indeed, the
reaction is first-order in copper, but it does not depend
on the concentration of bromide ions. Thus, radicals C
are rapidly trapped by bromine atoms and have no time
for other transformations.
We studied the oxybromination of thymol (5a) in more
details and found that the reaction is approximately first
order in the CuII concentration. On the other hand,
amounts of bromide ions virtually have no effect on
the initial reaction rates and reaction selectivity. Only
when near- or sub-stoichiometric initial bromide con-
centrations are used, the reaction occurs slower at high
substrate conversions. It suggests a pseudo-zero order
of the reaction on bromide ions under these conditions.
Thus, the use of LiBr can be decreased to near stoichi-
ometric amounts (run 6). It should be remembered,
however, that although the dissolved CuI species can
be easily re-oxidized by dioxygen, CuBr is well soluble
in acetic acid only in the presence of an excess of bro-
mine ions. Thus, a precipitation of CuBr at the end of
the reaction for the lack of bromide ions should be
avoided. To keep CuI in the solution and to allow its fast
re-oxidation, a sufficient excess of bromide ions (Br/
Cu P 2/1) has to remain in the reaction solutions after
a complete substrate conversion.
The electron transfer from phenolate to CuII should be
favored by electron donating groups attached to aro-
matic nucleus; therefore, eugenol, meta-cresol, guaiacol,
and thymol are more reactive than phenol itself. On the
other hand, para-nitrophenol as well as primarily
formed monobrominated phenols, all having electron
withdrawing substituents, undergo no bromination at
all under similar conditions. This feature of the process
seems to account for its extremely high monoselectivity.
Within the proposed mechanistic scheme, it also turns
understandable why non-phenolic compounds are not
reactive in oxybromination.
Kinetic data on the oxybromination of thymol obtained
at different temperatures and expressed by means of
the Arrhenius equation yield the activation energy of
ca. 70 kJ molÀ1 in the range of 40–100 °C. This value
is considerably higher than those found for the oxy-
chlorination of thymol (13 kJ molÀ1) and eugenol
(25 kJ molÀ1).18 However, we suppose that the oxybro-
mination of phenols can also be described as a free-rad-
ical process. A proposed mechanism is presented in
Scheme 3 using for simplicity phenol itself as the
substrate.
In summary, we have developed a highly selective Cu-
catalyzed process for the oxidative nuclear monobro-
mination of phenol and electron-rich phenolic com-
pounds under mild aerobic conditions. The use of an
inexpensive copper catalyst, lithium bromide, as a
source of bromine and dioxygen as a final oxidant is a
significant practical advantage. This simple and low
cost method provides a new attractive entry to the syn-
thesis of high-priced low-volume bromoaromatics with
remarkable atom economy and selectivity. Further stud-

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L. Menini et al. / Tetrahedron Letters 48 (2007) 6401–6404
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16. The reactions were carried out in a stirred glass reactor
and followed by measuring the dioxygen uptake and by
gas chromatography using dodecane as an internal stan-
dard (Shimadzu 17 instrument, Carbowax 20 M capillary
column, flame ionization detector). In a typical run, a
solution of the aromatic compound, dodecane, Cu(OAc)2
and LiBr in acetic acid was intensively stirred under
oxygen at 80 °C for a specified time. The products were
isolated by column chromatography and characterized by
1H and 13C NMR (Bruker DRX-400, tetramethylsilane,
CDCl3, COSY, HMQC, DEPT and NOESY experi-
ments). For the product characterization data see Supple-
mentary data.
We acknowledge the financial support from CNPq and
FAPEMIG and scholarship from CNPq (L.M. and
L.A.P.).
Supplementary data
Characterization data for the products are provided.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2007.06.093.
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