Dibromination of alkenes with LiBr and H2O2 under mild conditions

Article abstract of DOI:10.1039/c7nj04300g

Electron-rich and electron-poor alkenes, and alkenes bearing protecting groups can be efficiently and stereoselectively converted to trans-dibromides using LiBr/H₂O₂ and AcOH as a proton source in 1,4-dioxane. For most substrates addition of 0.1 mol% of PhTeTePh enhances the reaction rate and the yield of the products. Experimental data suggest that the brominating agent prepared in situ is molecular bromine and that LiBr assists the activation of H₂O₂ allowing bromination to occur using AcOH as a mild proton source in uncatalyzed experiments. Scale-up is feasible: 10.0 mmol of 1-octene was quantitatively converted to 1,2-dibromooctene in one hour of reaction at room temperature.

Full text of DOI:10.1039/c7nj04300g

View Article Online
View Journal
NJC
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: N. S. Martins and
E. E. Alberto, New J. Chem., 2017, DOI: 10.1039/C7NJ04300G.
This is an Accepted Manuscript, which has been through the
Volume 40 Number
1 January 2016 Pages 1–846
Royal Society of Chemistry peer review process and has been
accepted for publication.
NJC
Accepted Manuscripts are published online shortly after
New Journal of Chemistry
www.rsc.org/njc
A journal for new directions in chemistry
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
rsc.li/njc

Please do not adjust margins
New Journal of Chemistry
Page 1 of 9
View Article Online
DOI: 10.1039/C7NJ04300G
Journal Name
ARTICLE
Dibromination of Alkenes with LiBr and H2O2 Under Mild
Conditions
Nayara Silva Martins a and Eduardo E. Alberto a*
Received 00th January 20xx,
Accepted 00th January 20xx
Electron-rich, electron-poor and alkenes bearing protecting groups can be efficiently and stereoselectively converted to
trans-dibromides using LiBr/H2O2 and AcOH as proton source in 1,4-dioxane. For most substrates addition of 0.1 mol% of
PhTeTePh enhances the reaction rate and the yield of products. Experimental data suggests that the brominating agent
prepared in situ is molecular bromine and that LiBr assists the activation of H2O2 allowing bromination to occur using AcOH
as a mild proton source in uncatalyzed experiments. Scale-up is feasible: 10.0 mmol of 1-octene was quantitatively
DOI: 10.1039/x0xx00000x
www.rsc.org/
converted
to
1,2-dibromooctene
in
one
hour
of
reaction
at
room
temperature.
salt in aqueous acidic solutions) selectivity is problematic.
Generally only electron-rich aromatic compounds, ketones or
water-soluble functionalized alkenes are appropriate substrates.
Attempts to dibrominate simple alkenes under these conditions,
often produce mixture of products, commonly by the addition of
water to the bromiranium ion, producing bromohydrins as major
products.6,8 Bromination of organic substrates by oxidation of
bromide salts using peroxides activated by a catalyst can also be
performed in non-aqueous solutions.9 Uncatalyzed reactions are
also feasible, but require addition of strong Brønsted–acids (e.g.
HCl, HBr, H2SO4) for activation of peroxide.10 Alternatively,
oxidizing agents such as molecular oxygen,11 oxone,12 NaBrO3,13
Introduction
It’s widely agreed that halogenated organic compounds represent
a paramount class of substances. Among them, brominated
substrates find broad applicability as valuable commodities in
synthetic transformations, as pharmaceuticals, agrochemicals,
etc.1 The simplest approach to produce brominated products is by
the electrophilic addition of elemental bromine to organic
substrates (e.g. alkenes and aromatic compounds).2 One
alternative to avoid the high vapor pressure of Br2 is the use of
ionic liquids tribromide salts.3 Another option is to employ
reagents such as N-bromosuccinimide and derivatives, which
usually require the addition of a catalyst for activation.4 However,
all of these strategies fall back in the use of elemental bromine
(either directly or in an early stage of the process), which is well
known for having severe hazards associated with respect to the
transport, handling, and storage. Additionally, the above-
mentioned transformations are usually carried out in highly
regulated halogenated solvents.
NaIO4 and DMSO15 have been reported for bromination of
14
organic substrates.
Currently, efforts have been directed to achieve approaches to
brominate organic compounds employing efficient and reliable
methods, also bearing in mind environmental aspects.16 However,
despite much progress has been achieved in this field, many of
the reported protocols suffer from one or more of the following
disadvantages (especially in the bromination of alkenes): lack of
substrate generality, use of large excess of reagents, harsh
reactions conditions (e.g. hazardous reagents, halogenated
solvents), undesirable waste formation or low selectivity in the
product formation.3,4,6,8-15
Recently the activation of H2O2 by a catalytic amount of
diphenyl ditelluride (PhTeTePh) and in situ oxidation of
bromide salts to deliver “Br+” species has been disclosed
(Scheme 1).6h Water soluble or highly reactive substrates such
as 4-pentenoic acid and 1,3,5-trimethoxybenzene could be
effectively converted to their respective brominated products
in a 1/1 mixture of phosphate buffer (pH 4.2 – 6.2) and 1,4-
dioxane with excess of NaBr (15.0 equivalents/mmol of
substrate). We attempted to use these conditions for the
Nature has been producing brominated compounds in
a
sophisticated manner: promoting the oxidation of bromide salts
with peroxides through the action of haloperoxidase enzymes
(most commonly found in marine organisms).5 The development
of catalytic systems, which can mimic the action of such enzymes,
is a promising filed of research. Numerous reports in the literature
describe the activation of H2O2 by isolated or cloned
haloperoxidase enzymes, metal and metal-free catalysts, typically
in aqueous solutions.6 In common, all of these protocols require a
source of proton, which is critical to the fate of oxidized bromide
species: under basic conditions the “Br+” species (presumably
HOBr) promotes the irreversible disproportionation of H2O2 to
oxygen and water faster than it can be captured by an organic
substrate.7 Under haloperoxidase-like conditions (H2O2, bromide
dibromination of cyclohexene 1a. However, the desired
product 2a was obtained in only 14% yield (dotted box in
Scheme 1).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 2 of 9
View Article Online
DOI: 10.1039/C7NJ04300G
ARTICLE
Journal Name
reduced (Entry 3). Conversely, reduction of AcOH to 0.25 mL
promoted a slight increase in the selectivity of the process (54/1)
but the reaction yield dropped to 54% (Entry 4). Other solvents,
including polar, either protic or aprotic, and nonpolar solvents
were tested. However, none of them showed better results then
the original combination of AcOH and 1,4-dioxane (Entries 5 –
11).18
Scheme 1. Bromination of 1a in aqueous solution of NaBr and H2O2 catalyzed by
PhTeTePh.
Table 1. Optimization of the reaction for the synthesis of dibromide 2a.a
a Yield calculated by CG analysis using undecane as internal standard.
Therefore, the failure to efficiently promote such
transformation prompted us to further investigate this
important functional group interconversion. Considering the
environment aspects associated to the bromination of alkenes,
we believe that the H2O2/bromide salts combination is very
appealing. Bromide salts are innocuous and abundant, while
H2O2 is a strong oxidizing agent that produces water as
byproduct.17 Our aim was to promote the oxidation of bromide
salts by H2O2 in situ with simultaneous bromination of alkenes.
Moreover, we were interested in deliver a broad range of
brominated products efficiently, both in terms of yield as well
as selectivity, employing mild reaction conditions.
AcOH
(mL)
0.5
0.5
1.0
0.25
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
Cat
(mol%)b
0.1
Entry
Solvent
Br–
2a (%)c
2a/3ac
1d
2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
KBr
65 ± 1
86 ± 2
91 ± 2
54 ± 3
81 ± 1
7 ± 2
43/1
46/1
30/1
54/1
41/1
n.d.f
0.1
3
0.1
4
0.1
5e
6e
7e
8e
9e
10e
11e
12
13
14
15
0.1
0.1
DMF
0.1
60 ± 6
10 ± 1
63 ± 3
16 ± 2
51 ± 1
5 ± 1
60/1
n.d.f
MeCN
0.1
2-Propanol
AcOEt
0.1
32/1
n.d.f
0.1
Toluene
0.1
20/1
n.d.f
Results and discussion
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
0.1
Mass transfer of “Br+” species in aqueous solutions is problematic
for bromination of simple alkenes with H2O2/bromide due to the
hydrophobic nature of the substrate. Consequently, destruction of
H2O2 takes place preferentially unless a strong acid is used.
Nevertheless, solubility of bromide salts in organic solvents
should also be considered. So, in order to provide a proton
source, necessary to drive the reaction to the formation of organic
bromides instead of disproportionation of H2O2 and also to find a
balance between solubility of inorganic salts and organic
substrates, we decided to use acetic acid as a proton source in
combination with an organic solvent.
LiBr
0.1
93 ± 1
19 ± 0
46 ± 1
10 ± 0
> 100/1
n.d.f
NaBr
LiBr
none
none
0.1
> 100/1
n.d.f
16g
LiBr
a
Reaction conditions: cyclohexene 1a (0.5 mmol), bromide salt (1.2 mmol),
acetic acid (0.25 – 1.0 mL), solvent (2.0 mL), undecane (internal standard, 0.25
mmol), H2O2 8.8 M (0.6 mmol) and PhTeTePh (0.0005 mol). One hour of reaction
b
at room temperature. The catalyst was added to the reaction mixture as a freshly
c
prepared 12 mM solution in 1,4-dioxane (40 μL). Determined by GC (average for
d
duplicate runs). NaBr added to the reaction mixture as a 5.0 M solution in distilled
e
f
g
water. 30 minutes of reaction. n.d. = not determined. Aerobic oxidation: H2O2
replaced by a balloon of molecular oxygen.
Initially, we focused in the bromination of cyclohexene 1a, using a
bromide salt (2.4 equivalents), H2O2 8.8 M (1.2 equivalents),
undecane as internal standard and PhTeTePh as catalyst (0.10
mol% related to 1a) in a mixture of acetic acid and 1,4-dioxane at
room temperature (Table 1). After 1 hour of reaction, the mixture
was quenched and the composition of organic products
determined by gas chromatography, comparing with authentic
samples of pure brominated products. In the first attempt to
brominate 1a, NaBr was used as a 5.0 M aqueous solution, along
with 0.5 mL of AcOH and 2.0 mL of 1,4-dioxane, resulting in a
biphasic system. Dibromide 2a was produced in 65% yield along
with bromoacetate 3a in a selectivity of 43/1 favoring the former
(Entry 1). Introduction of pure NaBr enhanced the reaction yield,
but not the selectivity of the reaction (Entry 2). It was observed
that under this condition, NaBr was partially soluble in the mixture
of solvents. We next evaluated the amount of AcOH necessary to
efficiently accomplish the bromination of 1a. Increasing the
amount of AcOH to 1.0 mL resulted in a homogenous solution and
formation of 2a was observed in 91% yield. Nevertheless, as it
could be anticipated, the product selectivity was considerable
Subsequently, we examined the role of the bromide salt in the
outcome of the reaction. Swapping NaBr by KBr resulted in a
dramatic decrease of the reaction yield, most probably due to the
poorest solubility of KBr in organic solvents (Entry 12). On the
other hand, LiBr, which was entirely solubilized within minutes,
increased both the yield and the selectivity for the desired product
2a to a satisfactory level (Entry 13). Lastly, the influence of the
catalyst PhTeTePh on the outcome of the reaction was studied.
We found out that for the bromination of cyclohexene 1a
employing NaBr, addition of 0.10 mol% of PhTeTePh does have a
positive impact in the reaction rate. While the catalyzed reaction
produces dibromide 2a in 86% yield, under the same reaction
conditions, the uncatalyzed experiment delivered the same
product in only 19% (Entries 2 and 14). The impact of catalyst in
the reaction rate is less pronounced when LiBr is the choice of
bromide source. Under this condition, the uncatalyzed reaction
responds to nearly half of the formation of the dibrominated
product 2a within the same range of selectivity (Entries 13 and
15). Increasing the catalyst load doesn’t necessarily means faster
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 3 of 9
View Article Online
DOI: 10.1039/C7NJ04300G
Journal Name
ARTICLE
formation of products. In experiments with higher concentrations
of PhTeTePh, the rate of bromide oxidation is faster and gas
evolution can be observed, most likely molecular oxygen
produced by the disproportionation of H2O2 (results not shown). In
other words, concentrated solutions of “Br+” can either destroy
H2O2 or react with the substrate delivering a bromide product. The
former in an unproductive pathway, consuming two equivalents of
peroxide, while the concentration of bromide salt and substrate
remain unchanged.7 Lastly, in a catalyzed experiment, molecular
oxygen was used as oxidizing agent instead of hydrogen
peroxide. Brominated products were produced in only 10% yield,
revealing that the aerobic contribution for the oxidation of bromide
is negligible compared to the oxidation by H2O2 (Entry 16).
solution turned bright orange. 1a was added after 5 minutes
and the reaction performed as in the previous experiment. At
this time, product analysis indicated that the addition of an
acid stronger then AcOH resulted in the formation of 2a in
quantitative yield (Scheme 2, Set up 3). Although activation of
H2O2 by strong Brønsted acids for bromination reactions with
bromide salts is a well-known strategy,10 the use of a weaker
acid like AcOH would suit better our delineated objectives.
Scheme 2. Exploratory experiments for mechanism elucidation.a
Further experiments were performed to help shed light on the
reaction mechanism. Firstly, we decided to verify if the
oxidation of bromide follows preferentially an ionic or a radical
pathway (Scheme 2, Set up 1). Reactions conducted in the dark
or exposed to the daylight with addition of butylated
hydroxytoluene (BHT) as
a radical scavenger, produced
essentially the same results (yield and selectivity) as those of
the optimized reaction condition (Table 1, Entry 13). These
results strongly suggest that the oxidation of bromide by H2O2
activated by PhTeTePh is the result of ionic rather than radical
species.
Secondly, we were interested in find out the role of the
bromide salt on the reaction outcome. The point to be
considered was if the bromide counterion could somehow
facilitate the activation of H2O2 or the differences observed in
the experiments with LiBr, NaBr and KBr were merely a result
of their solubility in the mixture of solvents. Therefore,
uncatalyzed experiments would be more informative for this
purpose. To circumvent the scarcely solubility of inorganic
bromide salts in organic solvents, we used 1-decyl-3-
buthylimidazolium bromide 4, which was completely miscible
in the mixture of solvents. After one hour of reaction only 17%
of 2a could be detected (Scheme 2, Set up 2, experiment 1).
This result indicate that oxidation of bromide by H2O2 is not
solely a matter of the bromide solubility. We speculate that
LiBr showed better results than other bromide salts for
bromination of 1a not only because it is more soluble, but also
because the ion lithium may assist the activation of H2O2.19
Coordination of Li+ to AcOH may facilitate the protonation of
H2O2, which in combination with Br–, would deliver “Br+”
species (dotted box in Scheme 2).10 This assumption was
reinforced by the prompt formation of “Br+” from the mixture
a Yields and selectivity calculated by CG analysis.
Finally, we were interested in find out which species would be
the best candidate to act as the brominating agent.
Considering the oxidation process of bromide salts by H2O2
(either catalyzed or not) a proton source is required. The first
oxidized species formed is hypobromous acid (HOBr). This
species can either destroy H2O2, or react with another
equivalent of acid and bromide producing bromine (Br2),
of bromide salt
4 and H2O2 when acetic acid was replaced by a
Scheme
3A. However, once that our experiments are
stronger acid, trifluoroacetic acid (TFA). This change in the
reaction condition allowed the production of dibromide 2a in
94% yield and excellent selectivity towards the dibrominated
product (Scheme 2, Set up 2, experiment 2).
performed using excess of AcOH, it is reasonable to consider
that acetate would compete with bromide to react with HOBr
delivering brominating agents such as acetyl hypobromite
(AcOBr).20 Formation of the latter species in higher
concentrations should be facilitated by the nucleophilicity of
the conjugate base A–. Uncatalyzed bromination reactions of
1a with LiBr/H2O2 and three different acids (Et3N•AcOH, AcOH
Furthermore, when a catalyst-free solution of H2O2 and LiBr in
1,4-dioxane was treated with AcOH (0.5 mL), after 5.0 minutes
the mixture became pale yellow. The color of the solution
faded away by the addition of 1a (1.0 equivalent). After 15
minutes the reaction was quenched and product 2a obtained
in 18% yield (Scheme 2, Set up 3). This experiment was
repeated, but at this time in addition to acetic acid, TFA (10.0
equivalents to 1a) was added to the mixture. Rapidly the
and TFA) are depicted on Scheme 3B. If species such as AcOBr
were indeed produced in the reaction mixture, their
concentration would be higher using Et3N•AcOH and AcOH,
once that the trifluoroacetate anion is less nucleophilic to
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 4 of 9
View Article Online
DOI: 10.1039/C7NJ04300G
ARTICLE
react with HOBr. The results suggest that the formation of
Journal Name
Scheme 4. Catalyzed or uncatalyzed oxidation of bromide by H2O2 and product
dibrominated product 2a is directly correlated with the pKa of distribution.
the acid, being the reaction facilitated by stronger acids. The
catalyzed
uncatalyzed
lack of product formation using Et3N•AcOH may be just the
Li
H2O2
LiBr
PhTeTePh
Br
Br
δ
O
Br
O
fact that this acid is not acidic enough to activate H2O2 and
Br
H2O2
Ph Te OOH
HO OH
Br
H
O
AcOH
NaBr / AcOH
deliver HOBr (Scheme 3A). Interestingly, for both acids that
5
promoted formation of brominated products (AcOH and TFA),
no differences in the selectivity between dibromide 2a and
bromoacetate 3a was observed. Formation of a brominating
agent such as AcOBr should be accompanied by an increment
OAc
Br
AcO
Br
R
Br
Br
R
R
R
1a
1a'
2a
3a
in the concentration of bromoacetate 3a
.
To verify the substrate scope and limitations, different alkenes
were used (Table 2). Reactions were performed either catalyzed
by 0.10 mol% of PhTeTePh (condition A) or in catalyst-free
reactions (condition B). For most substrates, the addition of
catalyst resulted in better reaction yields in shorter reaction times.
Aliphatic alkenes were successfully converted to dibromides 2a–d
in a range of 75 to 92% yield in one hour of reaction. Products 2a
and 2b were obtained with excellent stereoselectivity: only trans-
1,2-dibromides could be detected by 1H NMR.
Scheme 3. Acid influence in the oxidation of LiBr by H2O2.a
Table 2. Substrate scope for synthesis of bromides 2a–o.a
a Yields and selectivity calculated by CG analysis.
Perhaps the most important hint to solve this conundrum
comes from the heterogeneous experiment (Table 1, entry 1).
In a biphasic system, the concentration of bromide would be
negligible in the organic phase. Conversely AcOBr, being an
organic compound, should be easily transported to the organic
phase. Therefore, in this scenario it should be expect that
selectivity would favor the formation of bromoacetate 3a
.
However, product distribution in the heterogeneous and
homogeneous reactions were virtually identical (Table 1,
Entries 1 and 2)! So, it is reasonable to assume that most likely
the brominating agent is elemental bromine (Br2).
For reactions catalyzed by PhTeTePh, using for instance NaBr,
formation of the brominating agent is mostly achieved through
the action of pertellurinic acid
5 (as discussed in reference 6h).
Uncatalyzed reactions became competing to the catalyzed
process when LiBr is the source of bromide. In this case,
formation of the brominating agent is facilitated by acid
activation of H2O2, Scheme 4. Formation of bromoacetate 3a
should be the result of competition between bromide and
acetate in the ring opening of bromiranium ion 1a’
.
a
b
Yields reported are for pure isolated products. LiBr = 2.4 equiv; H2O2 = 1.2
equiv. c LiBr = 4.0 equiv; H2O2 = 2.0 equiv.; d d.r. = 17:1 (determined by 1H NMR). e
NMR yield
Representative styrene derivatives were efficiently brominated
producing 2e-g
.
For this compounds, blank experiments
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 5 of 9
View Article Online
DOI: 10.1039/C7NJ04300G
Journal Name
ARTICLE
showed comparable yields to the catalyzed reactions. PhTeTePh is commercial available (CAS Number: 32294-60-3).
Compounds 2h and 2i, prepared from natural products Alternatively, it can be prepared according to literature
estragole and cinnamyl alcohol, respectively, and highly procedures.6h Concentration at reduced pressure was
functionalized 2j were obtained in good yields using both performed on a rotary evaporator. Organic extracts of aqueous
conditions
A and B. Substrates bearing common protecting solutions were dried over MgSO4, filtered and then
groups were employed to verify if they would survive the concentrated. NMR spectra were recorded on a Bruker
1
reaction condition. Pleasantly, 2k-m were isolated in AVANCE DRX400 spectrometer (400 MHz for H and 100 MHz
reasonable yields. No evidence for deprotection was verified in for 13C). Chemical shifts (δ) referenced to the TMS signal are
the due curse of the experiment. For these compounds an given in ppm, coupling constants (J) in hertz and multiplicities
increase in the amount of LiBr and H2O2 was necessary. Lastly, are given as s (singlet), d (doublet), t (triplet), q (quartet), p
electron-deficient alkenes were examined. Besides the change (pentet), m (multiplet) or br (broad). All spectra were recorded
in the amount of LiBr and H2O2, a substantial increase in the at 25 °C unless otherwise noted. Elemental analysis was
reaction time was required to accomplish the task. Additionally recorded on a Perkin Elmer Series II - CHNS/O Analyzer 2400).
to compound 2m, products 2n and 2o were produced in good MS was recorded on a Shimadzu QP2010 Plus GCMS. HRMS
yields. Product 2o was obtained as a crystalline compound, were obtained on a Bruker micrOTOF QII Spectrometer. The
allowing further characterization by single-crystal X-ray progress of the reaction was followed by GC on a Shimadzu GC
diffraction (Figure 1).21
2010-Plus, column RTx® - 5MS (30m x 0,25mm) using
undecane (0.5 equivalent to substrate) as the internal
standard. GC product yields were calculated by the
determination of the product concentration in final reaction
solutions using calibration curves obtained with authentic
product samples and undecane as the internal standard.
Melting points are uncorrected.
Figure 1. ORTEP and selected 1H NMR data for trans-dibromide 2o a
.
(Ha) =4.71 ppm
δ
O
Ha
Br
Ph
doublet
11.4 Hz
Ph
Ph
N
Hb
Br
Procedure for Bromination of Cyclohexene in pH 6 Phosphate
Buffer. A screw capped 3 dram vial was charged with NaBr
(772 mg, 7.5 mmol), pH 6.2 phosphate buffer in distilled water
(0.2 M in PO4, 5.0 mL) and 1,4-dioxane (5.0 mL). After stirring
during five minutes undecane (53 µL, 0.25 mmol) was added
followed by cyclohexene 1a (51 µL, 0.5 mmol), H2O2 8.8 M (85
µL, 0.75 mmol) and PhTeTePh (0.25 mol% related to the
substrate: 100 µL of a freshly prepared 12 mM in 1,4-dioxane).
No precautions were taken to exclude oxygen or water from
the reaction media. After 1 hour the reaction was quenched
with NaHSO3 0.25 M (2.0 mL). The organic phase was
separated, dried over MgSO4, filtered, diluted with AcOEt and
injected in the GC. Reported yields represent an average of
duplicate runs.
(Hb)δ =5.61 ppm
a Hydrogen atoms omitted for clarity; 1H NMR (CDCl3, 400 MHz).
Bromination of 1-octene 1d in a larger scale was also
performed. Addition of 0.01 mmol of PhTeTePh (0.10 mol%) in
a mixture of 10 mmol of substrate, 24 mmol of LiBr and 12
mmol of H2O2 in a solution of AcOH and 1,4-dioxane produced
after one hour 2d in quantitative yield (Scheme 5). It suggests
that the developed protocol might become operational
attractive in a preparative scale, as an alternative to replace
the undesirable use of Br2.
Scheme 5. Scale-up dibromination of 1-octene 1d a
.
Optimization of the Reaction Conditions for Bromination of
Cyclohexene. A screw capped 3 dram vial, was charged with
bromide salt (LiBr, NaBr, KBr or 1-decyl-3-buthylimidazolium
bromide 4; 1.2 mmol), acetic acid (0.25 – 1.0 mL) and solvent
(2.0 mL). After stirring during five minutes undecane (53 µL,
0.25 mmol) was added followed by cyclohexene 1a (51 µL, 0.5
mmol), H2O2 8.8 M (68 µL, 0.6 mmol) and PhTeTePh (0.10
mol% related to the substrate: 40 µL of a freshly prepared 12
mM solution in 1,4-dioxane). When applicable, additives were
also added: trifluoroacetic acid (390 µL, 5.0 mmol) or
Et3N•AcOH (prepared by the addition of Et3N 8.75 mmol, 1.12
mL to a solution of 0.5 mL of AcOH in 1,4-dioxane and stirred
during 5 minutes, followed by the addition of the other
reagents). No precautions were taken to exclude oxygen or
water from the reaction media. After stirring during the time
described in Table 1 the reaction was quenched with NaHSO3
0.25 M (2.0 mL). The organic phase was separated, dried over
MgSO4, filtered, diluted with AcOEt and injected in the GC.
a Yield for pure isolated compound.
Experimental
General Methods and Materials. All solvents and reagents
were used as received unless otherwise noted. 1,4-dioxane
was distilled under NaBH4 to remove organic peroxides, acetic
acid was refluxed with acetic anhydride and 5% (w/w) of
KMnO4 and then fractionally distilled.22 All bromide salts used
in this study were anhydrous compounds. The organocatalyst
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 6 of 9
View Article Online
DOI: 10.1039/C7NJ04300G
ARTICLE
Journal Name
Experiments using bromide
4 or Et3N•AcOH were extracted media. The mixture was then stirred at room temperature for
using a solution of hexanes/AcOEt = 9/1. Reported yields the appropriate amount of time (the progress of the reaction
represent an average of duplicate runs.
was followed by gas chromatography or by TLC – only for the
catalyzed reactions). At the end of the reaction, it was diluted
Procedure for Reaction in the Dark. A screw capped 3 dram with distilled water (20 mL) and the product extracted with a
vial wrapped in aluminium foil, was charged with LiBr (208 mg, 9/1 solution of hexanes/AcOEt (3 x 10 mL) or AcOEt (3 x 10
2.4 mmol), acetic acid (1.0 mL) and 1,4-dioxane (2.0 mL). After mL). The organic phase was washed with Na2CO3 1M (1 x 10
stirring during five minutes, undecane (110 µL, 0.5 mmol) was mL), dried over MgSO4, filtered and the solvents removed
added followed by cyclohexene 1a (102 µL, 1.0 mmol), H2O2 under reduced pressure. Purification was performed by silica
8.8 M (136 µL, 1.2 mmol) and PhTeTePh (0.10 mol% related to gel chromatography.
the substrate: 80 µL of a freshly prepared 12 mM solution in
1,4-dioxane). No precautions were taken to exclude oxygen or Condition B: (uncatalyzed reaction). Same as for the catalyzed
water from the reaction media. After 1 hour, the reaction was reaction except that PhTeTePh was not added to the reaction
quenched with NaHSO3 0.25 M (2.0 mL). The organic phase mixture.
was separated, dried over MgSO4, filtered, diluted with AcOEt
and injected in the GC. Reported yields represent an average Procedure for the Scale-up Bromination of 1-octene. A 100
of duplicate runs.
mL one-neck round-bottom flask was charged with LiBr (2.08
g, 24 mmol), 1,4-dioxane (40.0 mL), glacial acetic acid (10.0
Procedure for Reaction With Radical Inhibitor. A clear screw mL) and 1d (98% purity) (1.6 mL, 10.0 mmol). After stirring
capped 3 dram vial, was charged with LiBr (208 mg, 2.4 mmol), during five minutes, H2O2 8.8 M (1.36 mL, 12.0 mmol) was
acetic acid (1.0 mL) and 1,4-dioxane (4.0 mL). After stirring added followed by PhTeTePh (0.10 mol–% related to the
during five minutes undecane (110 µL, 0.5 mmol) was added substrate: 0.8 L of a freshly prepared 12 mM solution in 1,4-
followed by cyclohexene 1a (102 µL, 1.0 mmol), butylated dioxane). No precautions were taken to exclude oxygen, water
hydroxytoluene – BHT as the radical inhibitor (44 mg, 0.2 or sun light from the reaction media. The mixture was then
mmol), H2O2 8.8 M (136 µL, 1.2 mmol) and PhTeTePh (0.10 stirred at room temperature during one hour. At the end of
mol% related to the substrate: 80 µL of a freshly prepared 12 the reaction, it was diluted with distilled water (50 mL) and the
mM solution in 1,4-dioxane). No precautions were taken to product extracted with a 9/1 solution of hexanes/AcOEt (3 x 25
exclude oxygen or water from the reaction media. After 1 mL). The organic phase was washed with Na2CO3 1M (1 x 50
hour, the reaction was quenched with NaHSO3 0.25 M (2.0 mL), dried over MgSO4, filtered and the solvents removed
mL). The organic phase was separated, dried over MgSO4, under reduced pressure. Purification was performed by silica
filtered, diluted with AcOEt and injected in the GC. Reported gel chromatography (hexanes/AcOEt = 98/2) to afford 2d as a
yields represent an average of duplicate runs.
pale yellow oil (2.71 g, quantitative yield).
Procedure for Aerobic Oxidation of LiBr. A screw capped 3
dram vial was charged with LiBr (208 mg, 2.4 mmol), acetic
acid (1.0 mL) and 1,4-dioxane (4.0 mL). After stirring during
five minutes undecane (110 µL, 0.5 mmol) was added followed
by cyclohexene 1a (102 µL, 1.0 mmol), and PhTeTePh (0.10
mol% related to the substrate: 80 µL of a freshly prepared 12
mM solution in 1,4-dioxane). The reaction was performed
under aerobic conditions (balloon filled with molecular oxygen
attached to the reaction vessel). After 1 hour, the reaction was
quenched with NaHSO3 0.25 M (2.0 mL). The organic phase
was separated, dried over MgSO4, filtered, diluted with AcOEt
and injected in the GC. Reported yields represent an average
of duplicate runs.
Conclusions
Dibromination of alkenes could be efficiently and
stereoselectively achieved by oxidation of bromide salts with
hydrogen peroxide, an inexpensive and potent oxidizing agent,
which produces H2O as by-product. Acetic acid, a mild organic
acid, could be employed satisfactorily as a proton source for
this transformation in 1,4-dioxane as solvent. The issue of
product selectivity in bromination reactions of alkenes
employing bromide salts and H2O2 in acidic media has been
successfully addressed: the ratio of dibromide/side-products
(e.g. bromohydrins, bromoacetate) observed was greater than
100/1, favoring the former. Electron-rich, electron-deficient
and alkenes bearing protecting groups could be successfully
converted to their respective dibromides. For most substrates
used, the addition of a very small amount of commercially
available catalyst PhTeTePh (0.10 mol%) is not necessarily
required. Yet, catalyzed experiments often resulted in better
yields in shorter reaction times. Experimental data suggested
that the brominating agent prepared in situ from the
bromide/H2O2 mixture is molecular bromine, both under
catalyzed or uncatalyzed conditions. Activation of H2O2 in the
uncatalyzed process is well correlated to the acidity of
General Procedure for Bromination of Alkenes
Condition A (catalyzed by PhTeTePh). A 25 mL one-neck
round-bottom flask was charged with LiBr (2.4 – 4.0 mmol),
1,4-dioxane (4.0 mL) and glacial acetic acid (1.0 mL). After
stirring during five minutes, substrate 1a–o (1.0 mmol) was
added followed by H2O2 8.8 M (1.2 – 2.0 mmol) and PhTeTePh
(0.10 mol% related to the substrate: 80 µL of a freshly
prepared 12 mM solution in 1,4-dioxane). No precautions were
taken to exclude oxygen, water or sun light from the reaction
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 7 of 9
View Article Online
DOI: 10.1039/C7NJ04300G
Journal Name
ARTICLE
7
8
(a) R. R. Everett, A. Butler, Inorg. Chem., 1989, 28, 393–395.
(b) R. R. Everett, J. R. Kanofskyen, A. Butler, J. Biol. Chem.,
1990, 265, 4908–4914.
(a) U. Bora, G. Bose, M. K. Chaudhuri, S. S. Dhar, R. Gopinath,
A. T. Khan, B. K. Patel, Org. Lett., 2000, 2, 247–249. (b) B. F.
Brønsted acids tested. For weaker acids such as AcOH,
assistance by coordination with cationic lithium is inferred.
Finally, scale-up of the reaction using 1-octene as substrate
was exanimated. The desired product, 1,2-dibromooctane, was
produced in quantitative yield after only one hour of reaction
at room temperature.
Sels, D. E. Vos, P. A. Jacobs, J. Am. Chem. Soc., 2001, 123
,
8350–8359. (c) R. K. Sharma, C. Sharma, Tetrahedron Lett.,
2010, 51, 4415–4418. (d) F. Mendoza, R. Ruíz-Guerrero, C.
Hernández-Fuentes, P. Molina, M. Norzagaray-Campos, E.
Reguera, Tetrahedron Lett., 2016, 57, 5644–5648. (e) S. P.
Dash, A. K. Panda, S. Dhaka, S. Pasayat, A. Biswas, M. R.
Maurya, P. K. Majhi, A. Crochet, R. Dinda, Dalton Trans.,
2016, 18292–18307.
Conflicts of interest
There are no conflicts to declare.
9
Selected examples: (a) F. Romano, A. Linden, M. Mba, C.
Zonta, G. Licini, Adv. Synth. Catal. 2010, 352, 2937–2942. (b)
K. Yonehara, K. Kamata, K. Yamaguchi, N. Mizuno, Chem.
Commun., 2011, 1692–1694. (c) E. Palmajumder, S. Patra, M.
G. B. Drew, K. K. Mukherjea, New J. Chem., 2016, 8696–8703.
(d) E. Badetti, F. Romano, L. Marchiò, S. Taşkesenlioğlu, A.
Daştan, C. Zonta, G. Licini, Dalton Trans. 2016, 45, 14603–
14608.
Acknowledgements
The authors are grateful to CNPq (grant number 303727/2014-
4), CAPES and FAPEMIG. We are also thankful to prof.
Bernardo L. Rodrigues (UFMG) for the X-Ray analysis of
dibromide 2o, Luana Bettanin and prof. Antonio L. Braga
(UFSC) for HRMS analysis. Prof. Maria H. de Araújo (UFMG) is
10 (a) N. B. Barhate, A. S. Gajare, R. D. Wakharkar, A. V.
Bedekar, Tetrahedron, 1999, 55 11127–11142. (b) A.
Podgorsek, S. Stavber, M. Zupan, J. Iskra, Green Chem., 2007,
, 1212–1218. (c) T. Moriuchi, M. Yamaguchi, K. Kikushima,
,
acknowledging for providing bromide 4.
9
T. Hirao, Tetrahedron Lett., 2007, 48, 2667–2670.
Notes and references
11 (a) G. Zhang, R. Liu, Q. Xu, L. Ma, X. Liang, Adv. Synth. Catal.,
2006, 348, 862–866. (b) A. Molinari, G. Varani, E. Polo, S.
Vaccari, A. Maldotti, J. Mol. Catal. A, 2007, 262, 156–163. (c)
A. Podgorsek, M. Eissen, J. Fleckenstein, S. Stavber, M.
Zupana, J. Iskra, Green Chem., 2009, 11, 120–126. (d) Z.
Huang, F, Li, B. Chen, T. Lu, Y. Yuan, G. Yuan, Chem. Sus.
1
D. Yoffe, R. Frim, S. D. Ukeles, M. J. Dagani, H. J. Barda, T. J.
Benya, D. C. Sanders, D. C. Bromine Compounds. Ullmann's
Encyclopedia of Industrial Chemistry. 2013, 1–31.
I. Saikia, A. J. Borah, P. Phukan, Chem. Rev., 2016, 116, 6837–
7042.
(a) k. Tanaka, R. Shiraishi, F. Toda, J. Chem. Soc. Perkin Trans.
1, 1999, 3069–3070. (b) J. Salazar, R. Dorta, Synlett, 2004,
1318–1320. (c) V. Kavala, S. Naik, B. K. Patel, J. Org. Chem.,
2005, 70 ,4267–4271.
2
3
Chem., 2013, 6, 1337–1340. (e) J. Naapuri, J. D. Rolfes, J. Keil,
C. M. Sapu, J. Deska, Green Chem., 2017, 19, 447–452.
12 (a) K. Moriyama, Y. Izumisawa, H. Togo, J. Org. Chem., 2011,
76, 7249–7255. (b) M. Z. Zhang, W. B. Sheng, Q. Jiang, M.
Tian, Y. Yin, C. C. Guo, J. Org. Chem., 2014, 79, 10829−10836.
(c) J. Xu, R. Tong, Green Chem., 2017, 19, 2952–2956.
13 S. Adimurthy, G. Ramachandraiah, A. V. Bedekar, S. Ghosh, B.
C. Ranu, P. K. Ghosh, Green Chem., 2006, 8, 916–922.
14 G. K. Dewkar, S. V. Narina, A. Sudalai, Org. Lett., 2003, 5,
4501–4509.
15 (a) M. Karki, J. Magolan, J. Org. Chem., 2015, 80, 3701–3107.
(b) S. Song, X. Li, X. Sun, Y. Yuan, N. Jiao, Green Chem., 2015,
17, 3285–3289.
16 For reviews concerning environmental aspects of
bromination reactions see: (a) M, Eissen, D, Lenoir, Chem.
Eur. J., 2008, 14, 9830–9841. (b) A. Podgorsek, M. Zupan, J.
Iskra, Angew. Chem. Int. Ed., 2009, 48, 8424–8450.
17 One can argue that H2O2 may impose more safety concerns
(depending on the conditions it can violently decompose
producing H2O and O2) than Oxone (potassium
monopersulfate). Even though manufactured Oxone is
indeed safer to handle than concentrated solutions of H2O2,
this inorganic salt is generated from Caro’s acid (persulfuric
acid), which can decompose explosively. Additionally, Caro’s
acid is prepared by the addition of H2O2 to hazardous
chlorosulfonic acid.
4
(a) C. Ye, J. M. Shreeve, J. Org. Chem., 2004, 69, 8561–8563.
(b) L. X. Shao, M. Shi, Synlett 2006, 1269–1271. (c) S. D. F.
Tozetti, L. S. de Almeida, P. M. Esteves, M. C. S. de Mattos, J.
Braz. Chem. Soc., 2007, 18, 675–677. (d) G. Hernández-
Torres, B. Tan, C. F. Barbas III, Org. Lett., 2012, 14, 1858–
1861. (e) M. Stodulski, A. Goetzinger, S. V. Kohlhepp, T.
Gulder, Chem. Commun., 2014, 3435–3438. (f) Y. Kitazawa,
R. Takita, K. Yoshida, A. Muranaka, S. Matsubara, M.
Uchiyama, J. Org. Chem., 2017, 82, 1931−1935. (g) L. S.
Pimenta, E. V. Gusevskaya, E. E. Alberto, Adv. Synth. Catal.,
2017, 359, 2297–2303.
5
6
(a) A. Butler, J. V. Walker, Chem. Rev., 1998, 93, 1937–1944
(b) L. C. Blasiak, C. L. Drennan, Acc. Chem. Res., 2009, 42
147–155. (c) A. Butler, M. Sandy, Nature, 2009, 460, 848–
854.
Selected examples: (a) G. J. Colpas, B. J. Hamstra, J. W.
Kampf, V. L. Pecoraro, J. Am. Chem. Soc., 1996, 118, 3469–
3478. (b) J. V. Walker, M. Morey, H. Carlsson, A. Davidson, G.
D. Stucky, A. Butler, J. Am. Chem. Soc., 1997, 119, 6921–
6922. (c) M. D. Drake, F. V. Bright, M. R. Detty, J. Am. Chem.
Soc., 2003, 125, 12558-12566. (d) S. M. Bennett, Y. Tang, D.
.
,
McMaster, F. V. Bright, M. R. Detty, J. Org. Chem., 2008, 73
,
18 We expected that THF would produce a result comparable to
the reaction carried out with 1,4-dioxane. We rationalized
that the better result obtained with the latter may be due to
the fact that this solvent produces a stable complex with Br2,
which seems to be beneficial for the outcome of the
reaction. To date, there is no report describing formation of
such complexes with THF. For 1,4-dioxane•Br2 complex see:
6849–6852. (e) D. Wischang, J. Hartung, T. Hahn, R. Ulber, T.
Stumpf, C. Fecher-Trost, Green Chem., 2011, 13, 102–108. (f)
M. Sandy, J. N. Carter-Franklin, J. D. Martiny, A. Butler,
Chem. Commun., 2011, 12086–12088. (g) E. E. Alberto, A. L.
Braga, M. R. Detty, Tetrahedron, 2012, 68, 10476–10481. (h)
E. E. Alberto, L. M. Muller, M. R. Detty, Organometallics,
2014, 33, 5571–5581. (i) C. M. Gatley, L. M. Muller, M. A.
Lang, E. E. Alberto, M. R. Detty, Molecules, 2015, 20, 9616–
9639.
O. Hassel, J. Hvolsef, Acta Chem. Scand. 1954, 8, 873.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 8 of 9
View Article Online
DOI: 10.1039/C7NJ04300G
ARTICLE
19 Y. Kitazawa, R. Takita, K. Yoshida, A. Muranaka, S.
Journal Name
Matsubara, M. Uchiyama, J. Org. Chem. 2017, 82
1931−1935.
,
20 S. G. Levine, M. E. Wall, J. Am. Chem. Soc. 1959, 81, 2826–
2829.
21 The crystal structure of compound 2o has been deposited at
CCDC, with the assigning number: CCDC 1568276.
22 W. L. F. Armarego, C. L. L. Chai, Purification of Laboratory
Chemicals, Butterworth/Heinemann (Elsevier Science),
Bodmin, UK, 2003.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 9
New Journal of Chemistry
View Article Online
DOI: 10.1039/C7NJ04300G
Activation of H2O2 by LiBr and AcOH is efficiently achieved for dibromination of alkenes
in high yields and selectivity.
R'
R
“ Br+ ”
Br
Br2
LiBr, H2O2, AcOH,
R'
R
PhTeTePh (0.1 mol%)
Br
üꢀ Scale-up to gram scale
üꢀ Electron–rich, poor & protected substrates
üꢀ Stereo & chemoselecEve (dibromide/bromoacetate > 100/1)