On the bromination of aromatics, alkenes and alkynes using alkylammonium bromide: Towards the mimic of bromoperoxidases reactivity

Article abstract of DOI:10.1016/j.tetlet.2016.11.011

This article describes an efficient method of bromination of organic substrates including aromatics, alkenes and alkynes with NH₄VO₃as a catalyst and H₂O₂as an oxidant agent using a non-toxic and easy-to-handle source of bromine, tetrabutylammonium bromide. The process was developed under mild reaction conditions and is an innovation from reported methods in aspects such as: i) short reaction times, ii) the ability to work at room temperature, iii) regioselectivity and good yields.

Full text of DOI:10.1016/j.tetlet.2016.11.011

Accepted Manuscript
On the bromination of aromatics, alkenes and alkynes using alkylammonium
bromide: towards the mimic of bromoperoxidases reactivity
Fabian Mendoza, Rosario Ruíz-Guerrero, Carlos Hernández-Fuentes, Paulina
Molina, Mariano Norzagaray-Campos, Edilso Reguera
PII:
S0040-4039(16)31467-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.011
TETL 48297
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
31 August 2016
27 October 2016
2 November 2016
Please cite this article as: Mendoza, F., Ruíz-Guerrero, R., Hernández-Fuentes, C., Molina, P., Norzagaray-Campos,
M., Reguera, E., On the bromination of aromatics, alkenes and alkynes using alkylammonium bromide: towards
the mimic of bromoperoxidases reactivity, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2
016.11.011
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On the bromination of aromatics, alkenes and alkynes using alkylammonium bromide: towards the
mimic of bromoperoxidases reactivity
a
b
b
a
Fabian Mendoza , Rosario Ruíz-Guerrero* , Carlos Hernández-Fuentes , Paulina Molina , Mariano
c
a
Norzagaray-Campos , Edilso Reguera
a
Centro de Investigación en Ciencia Aplicada y Tecnología Avanzada, Unidad Legaria, Instituto Politécnico
Nacional, Legaria Núm. 694, Col. Irrigación, Miguel Hidalgo, C.P. 11500, Cd. México, México.
b
Centro de Investigación e Innovación Tecnológica, Instituto Politécnico Nacional, Cerrada de Cecati S/N,
Col. Santa Catarina, Azcapotzalco, C.P. 02250, Cd. México, México
c
Centro Interdisciplinario de Investigación para el Desarrollo Integral Regional, Unidad Sinaloa, Bulevar
Juan de Dios Bátiz Paredes Núm. 250, Col. San Joaquín, Guasave, C.P. 81049, Sinaloa, México.
*
E-mail: rosarior@hotmail.com, maruizg@ipn.mx; Tel: (+52) 5557296000 Ext. 68325.
1

Abstract
This article describes an efficient method of bromination of organic substrates including aromatics,
alkenes and alkynes with NH
4
VO
3
as a catalyst and H
2
2
O as an oxidant agent using a non-toxic and easy-
to-handle source of bromine, tetrabutylammonium bromide. The process was developed under mild
reaction conditions and is an innovation from reported methods in aspects such as: i) short reaction times,
ii) the ability to work at room temperature, iii) regioselectivity and good yields.
Keywords:
monoregioselective
bromination,
mild
methods,
ammonium
metavanadate,
tetrabutylammonium bromide, hydrogen peroxide.
1. Introduction
In recent years, considerable emphasis has been oriented to improve the environmental impact of
1
industrial chemical processes. The development of a mild and efficient method of bromination of organic
substrates has received much attention due to the importance of these compounds as agrochemicals, flame
2
retardants and specialty chemicals. Organobromides are also intermediates for the synthesis of
biologically active compounds such as antitumor, antibacterial, antifungal, antiviral and antioxidant
3
agents. Furthermore, organic bromides may result in the formation of macromolecules through the
4
5
6
formation of C-C cross-coupling reactions for aromatic compounds, such as Heck, Stille, Suzuki,
7
8
9
Sonogashira, Negishi and Kharashch.
10
To date, many catalysts have been developed for oxidative bromination with different oxidants. The
11
12
oxidants of choice to be considered within the green chemistry have been H
2
O
2
and O , but also, more
2
sophisticated oxidants, always inspired by those transformations in nature which consists in generating the
1
3
14
15
2
16
brominating reagent in situ from a bromine salt, such as oxone, NaIO
4
, PhI(OAc)
and DMSO, etc.,
have been developed for the oxidative bromination. Metal catalysts based on vanadium, molybdenum and
17
tungsten have been developed for this purpose; nevertheless, the vanadium has shown better
2

performance in halogenation process. The two main catalysts are NH
4
VO
3
and V
2
O . Thus, there is still
5
plenty of room for improvement, and much more efficient procedures could be developed.
Considering the interest on the vanadium reactivity in oxidative halogenation, we are investigating the
experimental conditions which govern an efficient bromination reaction with considerable attention in the
yields of reaction products and easy reaction conditions.
In nature, bromination of organic substrates occurs in the seabed. Vanadate-dependent haloperoxidases are
enzymes that catalyse the two-electron oxidation of a halide to the corresponding hypohalous acids by
18
hydrogen peroxide, as shown in Eq. 1:
-
+
H O
2 2
+ X + H → H O + HOX Equation 1
2
Haloperoxidases that are able to catalyse the oxidation of bromide in the presence of H
2
O are called
2
bromoperoxidases (BPOs). Vanadium bromoperoxidases (VBPOs) are present in a great variety of brown
and red seaweed. The active site in VBPOs contains a vanadate moiety in a trigonal bipyramidal or square
1
9
pyramidal geometry.
According to Equation 1, the HOBr that is formed will rapidly react with organic matter in seawater that
consists mainly of fulvic and humic acids to create brominated compounds that, upon decay, lead to the
formation of bromoform and dibromomethane. Traditional chemical halogenation usually requires harsh
20
reaction conditions and forms by-products, in contrast with biocatalyzed processes. According to this, it
is possible to carry out the bromination of organic substrates using soft methods without toxic and
corrosive Br and HBr, which are commonly used in this type of synthesis.
2
In the present work, we show the advantages of developing a method of brominating of different types of
substrates that is simple, safe, practical and efficient. We highlight the importance of pH in a reaction
medium when using ammonium metavanadate/hydrogen peroxide (NH
4
VO
3
/H
2
O ) as a catalytic system.
2
We show the results of bromination reactions of a series of aromatics, alkenes and alkynes using a non-
toxic salt of tetrabutylammonium bromide (TBAB) as a source of bromine in mild conditions at room
3

temperature. It is worth noting that the adopted process was the result of diverse catalysts systems (mainly
NH VO ) in function of bromide source evaluated with a model arene (see Table 1). Once established the
4
3
experimental conditions, which may be useful with the best performance, we proceeded to evaluate some
substrates with different functional groups. We discuss shortly the reactivity of vanadium complexes that
are formed in function of pH and mechanistic details in the bromination of organic substrates.
2
. Results and Discussions
Bromination of 2-tert-butylphenol with different methods
Initially, for the aromatics, due to the difficulty in obtaining a specific brominated compound in a certain
position and a high yield of reaction, a series of soft reported methods were evaluated in terms of
regioselectivity in the para-bromination of a model molecule. 2-tert-butylphenol (2-TBP) was chosen as a
model to obtain as product 4-bromo-2-tert-butylphenol. Under the conditions described in Table 1, firstly
the para-bromination of 2-TBP proceeded quickly using AlBr
3
as bromine source and (NH
4
3
VO /H
2
O ) as
2
2
1
catalytic system (Table 1, entry 1b). This value was much higher than those of previously reported O
2
-
based system (Table 1, entry 1a). Nevertheless, the AlBr
its high volatility.
3
is not a bromine source of easy handling due to
2
2
More stable bromine sources were also evaluated. A further method using N-Bromosuccinimide (NBS)
as bromine source (Table 1, entry 2) was also evaluated. The yield was rather low, came after 40 min
40%) and remained unchanged even after days of reaction. It has been shown that the reactivity of this
(
23
brominating agent can be modulated with different catalysts, because they have some drawbacks when
using only NBS (long reaction times, low yields and low selectivity). A proposed mechanism for this
2
4
bromination involves formation Br and HBr, responsible for the final bromination of aromatic ring.
2
4

25
When KBr was used as a bromine source with NH
4
VO
3 2
/H O
2
/HClO as catalytic system, 40% yield was
4
obtained, with the formation of p-monobrominated product in a short time (60 min) without by-products.
Substrate conversion to brominated product remains unchanged after 60 min., even adding extra amount
of H O2. However, the yield of reaction is not the most desirable.
2
Tertiary butyl ammonium bromide was evaluated in entries 4a and 4b (Table 1). TBAB salt is crystalline,
easy to handle and maintains the desired stoichiometry with the substrate. In the entry 4a the reaction was
performed using the NH
sources of bromine, this system is able to brominated the 2-TBP regioselectively with average of yield of
0% in 12 hours. If HClO (1 ml of a 1N solution) is added to reaction in Et O/H medium, the reaction
4
3
VO /H
O
2 2
as catalytic system. Although reaction times longer than with other
5
4
2
2
O
2
yield increases significantly up to 96% in just 5 minutes (entry 4b). As is summarized in the Table 1, the
more efficient method is carried out in a biphasic system (entry 4b) in which the catalyst of V(V) and
TBAB salt is present in the aqueous phase and the aromatic substrate is present in the organic phase
(diethyl ether).
-
Table 1. Bromination of 2-tert-butylphenol with different Br sources.
ꢀꢁꢂ
source
Yield
(%)*
Entry
Solvent
Conditions
Time
48 h
Ref.
21
1
1
2
3
a
ꢃꢄ ꢀꢅ
ꢃꢄ ꢀꢅ
NBS
ꢆꢇ ꢉ
ꢊꢋ ꢍꢉ ꢎꢏꢁꢐꢑꢄꢒꢓꢔꢉ
ꢈ
<10
ꢈ
ꢌ
ꢅ
ꢊꢋ ꢍꢉ ꢎꢏꢁꢐꢑꢄꢒꢓ
ꢌ
ꢅ
b
ꢆꢇ ꢉ
10 min 90
40 min 40
60 min 40
--
ꢈ
ꢔꢋ ꢉ ꢎꢕꢖꢖꢁꢐꢑꢄꢒꢓ
ꢈ
ꢈ
MeCN
NH
4
OAc
22
25
ꢊꢋ ꢍꢉ ꢎꢏꢁꢐꢑꢄꢒꢓ
ꢌ
ꢅ
KBr
ꢆꢇ ꢉ
ꢈ
ꢔꢋ ꢉ ꢎꢕꢖꢖꢁꢐꢑꢄꢒꢓꢔꢋꢗꢄꢉ
ꢈ
ꢈ
ꢌ
ꢆꢇ ꢉꢘor
ꢗꢋꢗꢄꢅ
ꢊꢋ ꢍꢉ ꢎꢏꢁꢐꢑꢄꢒꢓ
ꢈ
ꢌ
ꢅ
4
4
a
TBAB
TBAB
12 h
50
96
--
--
ꢔꢋ ꢉ ꢎꢕꢖꢖꢁꢐꢑꢄꢒꢓ
ꢈ
ꢈ
ꢆꢇ ꢉꢘor
ꢊꢋ ꢍꢉ ꢎꢏꢁꢐꢑꢄꢒꢓ
†
ꢈ
ꢌ
ꢅ
b
5 min
ꢗꢋꢗꢄꢅ
ꢔꢋ ꢉ ꢎꢕꢖꢖꢁꢐꢑꢄꢒꢓꢔꢋꢗꢄꢉ
ꢈ ꢈ
ꢌ
Conditions: (1a) NH
AlBr (0.55 mmol), H
NBS (1.05 mmol) at room temperature; (3) NH
temperature; (4a) NH VO (5 mol%), TBAB (1.5 mmol), H
NH VO (5 mol%), TBAB (1.5 mmol), H (200 mol%), Et O or CHCl
temperature.
4
VO
3
(5 mol%), AlBr
(200 mol%), Et O (5 ml) and 2-TBP (0.5 mmol) at reflux; (2) 2-TBP (1 mmol), NH
VO (5 mol%), KBr (1.5 mmol), H (200 mol%), Et O (5 ml) and 2-TBP (0.5 mmol) at room
(200 mol%), Et O (5 ml) and 2-TBP (0.5 mmol) at room temperature; (4b)
(5 ml), HClO (1 ml of a 1N solution) and 2-TBP (0.5 mmol) at room
3
(0.55 mmol), O
2
, Et
2
O (1.5 ml) and 2-TBP (0.5 mmol) at room temperature; (1b) NH
4 3
VO (5 mol%),
3
2
O
2
2
4
OAc (10 mol%), MeCN (5 ml) and
4
3
2
O
2
2
4
3
2
O
2
2
4
3
2
O
2
2
3
4
†
Lower yields are observed with other stoichiometric relations of 2-TBP/TBAB (1/1 and 1/2, with 30% and 40%, respectively).
Yield was determined by GC.
*
5

Next, we examined the bromination of various aromatic compounds with NH
mol%)/HClO and the results are shown in the Table 2.
4
VO
3
(5 mol%)/H
2
2
O (200
4
Reactivity of vanadium in bromide oxidation
It´s important to understand what is happening within the reaction media; to know the experimental
factors that affect both i) the efficiency and ii) time of reaction; we find interesting that a small variation in
the reaction conditions, i.e. pH, produces significant changes in the results. We observed the effect of
strong acid: when the media was not sufficiently acid (1 ml HClO
4
of a0.1N solution), the bromination of
arene are stopped; if an extra amount of HClO is added, the reaction could be prolonged until total
4
consumption of substrate. This effect suggests that there is a relation between the substrate and the
catalytic specie present at that pH.
Coming up, we will discuss the role of the catalyst system in a synthetic bromination of organic
compounds.
It is well known that the formation of a great variety of peroxometal complexes in solutions with high-
valent transition metals is particularly promoted in the presence of hydrogen peroxide. These complex
26
species can differ in function of the pH value in the reaction medium. For the vanadium catalyst, the
presence of hydrogen peroxide promotes the formation of peroxovanadates; in acid conditions, the
+
addition of hydrogen peroxide to a catalyst of V(V) forms oxomonoperoxo VO(O
2
) (red) and
-
27
oxodiperoxo VO(O
2
)
2
(yellow), according to Equations 2 and 3:
+
The formation of VO(O
2
) increases with increasing acidity and decreases with increasing oxidant agents.
-
The presence of the species VO(O
2
)
2
is favoured, increasing the concentration of hydrogen peroxide.
6

2
7
The vanadium specie that promotes the bromination of organic substrates is oxomonoperoxovanadium ,
+
which can be seen as the red-coloured complex VO(O
2
) in the reaction. On the other hand, when the
-
reaction shifts to the formation of a VO(O
2
)
2
complex, it is possible to see the yellow colour that is
characteristic of that complex. This important signal tells us that the bromination reaction has stopped.
However, it was observed that an excess of acidity in the medium contributes to poly-brominations on
aromatic substrates. In this sense, the pH control is important for obtaining mono-brominated products
+
regioselectively (pH 1–2). It is extremely important to have the active species VO(O
2
) in the reaction’s
bromination media as it is capable of oxidizing active “Br”.
The mechanism of action for the brominating agent, “Br”, remains controversial. Several contradictory
opinions have been formulated based on the reactivity of the species. Various mechanisms have been
-
-
proposed to justify the presence of species such as “HOBr”, "Br
because the reaction of these species with H or organic substrates is too fast . In addition, some
authors have reported the presence of more complex species in the presence of vanadium peroxidases,
2
" and "Br " that cannot be detected
3
28
2
O
2
29
such as vanadiumbromo peroxidases V-BrPO, which is capable of producing brominated organic
substrates. Others authors proposed that TBAB bromination is carried out after the formation of the
30
species tri-brominated TBABr
3
(Equation 4), species that has been successfully used in organic
3
1
-
brominations (Eq. 5). However, we could detect and isolate Br
3
like TBABr only in the absence of an
3
organic substrate.
The reaction of TBAB without substrate was conducted with NH
4
VO
3
-H
2
O
2
-HClO
4
at room temperature
) in very high yields.
leading to the isolation of orange–yellow quaternary ammonium tribromide (TBABr
3
The characterization of single-crystal was made by DRX and the details are included in the Supplementary
Data file.
7

We think that bromination with TBAB in acid media and in presence of V(V) is carried out after the
formation of vanadium bromoperoxide species. Some authors propose a mechanism where a hypobromite-
like vanadium intermediate, generated by the reaction between monoperoxido vanadium and bromide ion
25
is capable to react with organic substrates according to Scheme 1.
Scheme 1. Mechanism for V-catalyzed oxybromination of aromatics in two-phase system
Bromination of aromatic compounds with TBAB and NH
4
VO
3
/H
2
O
2
/HClO
4
In the case of p-bromophenol (Table 2, entry 1) was obtained satisfactorily with an almost quantitative
yield. Other methods under similar reaction conditions resulted in high conversions with the same product,
30
but they are inconvenient for producing poly-brominated substrate.
Aniline and anisole produce a para-monobrominated product with a very good yield. Substrates with two
substituents on the aromatic ring (Table 2, entries 4, 5 and 7) showed a preference to yield
monobrominated products. If the para position of the aromatic ring was already occupied, it is possible to
obtain the ortho-brominated product.
When substituent deactivators are present in the aromatic ring (Table 2, entries 8-11) as aldehyde, nitro or
a combination of the two (Table 2, entry 11), bromination was carried out with yields of 90% or less.
However, the presence of one or more substituents activators increases the reaction yield (i.e., selectivity
8

and reactivity depend on the nature of the substituents on the aromatic ring). Aromatic compounds with
electron-donating substituents were brominated readily with high conversion and invariably with high
selectivity for the mono-brominated products. However, with electron-withdrawing substituents,
bromination resulted in lower conversions. Based on our observations, we hypothesized that the presence
of an electron-withdrawing group in combination with an OH group is required to facilitate the
bromination of these substrates by this method.
Table 2. Bromination reaction of aromatic substrates using the
catalytic system NH
4
VO
3 2
/H O
2
and TBAB
Yield
Entry
Substrate
Product
Time
15 min
5 days
15 min
(%)
1
2
3
99
No reaction
-----
95
4
5
6
93
96
94
20 min
5 min
20 min
7
8
9
90
80
90
25 min
25 min
30 min
9

1
1
0
1
85
80
20 min
25 min
Conditions: 1 mmol of substrate, 3 mmol of TBAB, 10 ml of CHCl
TLC and determined by GC.
3
, 5 mol% catalyst, room temperature, 800 r.p.m. Conversion was followed by
Bromination of alkenes and alkynes with TBAB and NH
4
VO
3
/H
2
O
2
/HClO
4
In order to know the scope of bromination method, we have extended the process to a variety of
molecules. Various kinds of alkenes and alkynes structurally diverse were brominated with favourable
results in the major of cases.
The bromination selectivity observed for the alkenes is low. In fact, the two-phase catalyst system resulted
in the formation of the bromohydrins as a major product in almost all reactions. Nevertheless, it should be
noted that the formation of the other products like dibrominated and bromoketones in some cases is
present, such is the case of styrene and cyclohexene, entry 1 and 4, respectively (Table 3). Similar
3
2
situations have been observed in other studies with similar catalytic methods .
Bromination of alkynes by this method leads to formation of dibrominated alkenes mainly (Table 3,
entries 6, 7 and 8). As shown in Table 3, a terminal alkyne produces dibrominated trans-alkene in higher
yield, compared with the evaluated secondary alkynes. In fact, together with the trans-alkene product,
dibrominated cis-alkenes are also formed in moderated yields. This result is unusual, since normally the
3
3
yield of cis-isomers is lower than trans-isomers . Such situation led us to think that there is a superficial
diffusion phenomena linked to reaction kinetics that may favor selectivity towards one of the products.
10

Table 3. Alkenes and alkynes evaluated in bromination reactions.
Entry
1
Substrate
Time
Products (Yield (%))
0.5 h
75
10
1
5
4
min
0
2
100
4
min
5
3
4
66
46
33
20
3
min
0
2
4
3
min
5
5
6
80
60
20
40
3
min
5
2
min
5
7
8
90
10
30
2
min
5
70
Conditions: 1 mmol of substrate, 3 mmol of TBAB, 10 ml of CHCl
Conversion was followed by TLC and determined by GC.
3
, 5 mol% catalyst, room temperature, 800 r.p.m.
Conclusions
After optimizing the reaction conditions, we extended this innovative and more efficient method of
aromatic bromination to alkenes and alkynes. In summary, the catalytic system could act as an efficient
method with various substances, notability for bromination regioselective in aromatic compounds and
dibromination of alkynes. We highlight the importance of pH in the medium reaction which controls the
stability of the complex vanadium specie, able to realize the bromination, using NH
as an oxidant.
4
VO as a catalyst and
3
H O
2 2
11

Acknowledgements
This work was supported by the programs SIP-IPN 20150520. We thank the BEIFI-IPN for their support
844, 1525, 2438.
We are grateful to the Centro de Nanociencias y Micro y Nanotecnologías (CNMN) of the Instituto
Politécnico Nacional for supporting our spectroscopic characterization.
Supplementary data
1
13
Supplementary data associated with this article (Experimental details, MS, H and C RMN spectra) can
be found in the online version.
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14

Graphical Abstract

Highlights
Efficient bromination method of aromatic substrates with NH
conditions
4
VO
3
/H
2
2
O in mild reaction
Bromination of electron-rich aromatics with TBAB as bromine source.
+
VO(O
2
) is the vanadium specie that promotes the bromination of organic substrates.
15