Electrochemical bromofunctionalization of alkenes in a flow reactor

Article abstract of DOI:10.1039/d1ob01302e

The bromination of organic molecules has been extensively studied to date, yet there is still a demand for safe and sustainable methodologies. Hazardous reagents, selectivity, low atom economy and waste production are the most persisting problems of brominating reagents. The electrochemical oxidation of bromide to bromine is a viable strategy to reduce waste by avoiding chemical oxidants. Furthermore, thein situgeneration of reactive intermediates minimizes the risk of hazardous reagents. In this work, we investigate the electrochemical generation of bromine from hydrobromic acid in a flow electrochemical reactor. Various alkenes could be converted to their corresponding dibromides, bromohydrines, bromohydrin ethers and cyclized products in good to excellent yields.

Full text of DOI:10.1039/d1ob01302e

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Biomolecular Chemistry
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Electrochemical bromofunctionalization of
alkenes in a flow reactor†
Cite this: Org. Biomol. Chem., 2021,
19, 6892
Jakob Seitz and Thomas Wirth
*
The bromination of organic molecules has been extensively studied to date, yet there is still a demand for
safe and sustainable methodologies. Hazardous reagents, selectivity, low atom economy and waste pro-
duction are the most persisting problems of brominating reagents. The electrochemical oxidation of
bromide to bromine is a viable strategy to reduce waste by avoiding chemical oxidants. Furthermore, the
in situ generation of reactive intermediates minimizes the risk of hazardous reagents. In this work, we
investigate the electrochemical generation of bromine from hydrobromic acid in a flow electrochemical
reactor. Various alkenes could be converted to their corresponding dibromides, bromohydrines, bromo-
hydrin ethers and cyclized products in good to excellent yields.
Received 5th July 2021,
Accepted 26th July 2021
DOI: 10.1039/d1ob01302e
rsc.li/obc
by Nikishin and co-workers (1988).27 Electrochemical dibromi-
nation of alkenes and aromatic bromination has been reported
Introduction
Despite a long history of bromination reactions, the search for by Yuan et al. (2019).28 Kulangiappar et al. (2016) described
safe and sustainable methods is continuously ongoing.1–3
A
the electrochemical dibromination of alkenes under biphasic
large number of different methods for the synthesis of bromo- conditions using NaBr/H2SO4/water and alkene/chloroform
hydrins have been reported as these are very useful building mixtures.29 Aromatic and benzylic electrochemical bromina-
blocks in chemistry.4–8 Bromohydrins have been prepared by tion reactions were performed with similar biphasic systems.30
reacting alkenes in bromine/water9,10 or using N-bromo succi- Hilt et al. (2021) employed paired electrolysis to drive the
nimide (NBS)/dimethyl sulfoxide (DMSO) systems.11–14 dibromination from the anodic oxidation of bromide and
Masuda et al. (1994) generated hypohalous acids from the cathodic reduction of oxygen to hydrogen peroxide and sub-
reduction of HBrO3 and H5IO6 with sodium sulfite to sequent mediation.31 Rueping and co-workers recently pub-
synthesize halohydrins.15 NBS/[bmim]BF4/water was also lished electrochemical alkene oxybrominations for heterocycle
successfully
utilised
for
this
transformation.16 synthesis.32
The potential reduction of waste by electrochemical strat-
Bromodichloroisocyanuric acid in acetone/water mixtures is
another example of a chemical brominating reagent which has egies, in comparison to chemical strategies, is an important
been used in the bromination of alkenes.17 A particularly driving force to their development. By implementing flow
resourceful bromohydroxylation of alkenes with hydrobromic electrochemical methods, the scalability of processes can be
acid in DMSO was reported by Song et al. (2015).18 facilitated while hazardous reagents such as bromine can be
Halofunctionalizations of gem-difluoalkenes were demon- handled in a safe way.3,33–35 Despite the benefits of flow
strated by Zhao and co-workers (2020).19
electrochemical methods, their use for electrochemical
Over the past decade, several electrochemical strategies for bromination reactions is still limited. Tan et al. reported the
the bromination of alkenes using anodically generated electrophilic aromatic bromination of late-stage intermediates
bromine have been reported. Early examples include the bro- and drug molecules in a divided micro-flow electrochemical
mohydroxylation of alkenes which were limited to a small cell with recirculation of the substrate solution from reser-
number of substrates.20–23 Oher examples of electrochemical voirs.36 The electrochemical bromination of fluorescein to
bromohydroxylation utilize the solvolysis of DMSO.24–26 eosin on a decagram scale was demonstrated by Vasudevan
Electrochemical bromoalkoxylation of alkenes was described et al. (2000) by recirculating the substrate through a flow
reactor.37
Herein we describe the electrochemical bromination of
activated and unactivated alkenes in a flow reactor under single-
Cardiff University, School of Chemistry, Park Place, Main Building,
Cardiff CF10 3AT, Cymru/Wales, UK. E-mail: wirth@cf.ac.uk
pass conditions (Fig. 1). These transformations include dibromi-
nations, bromohydroxylations and bromoalkoxylations.
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob01302e
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additional supporting electrolyte could be omitted due to the
significantly smaller interelectrode gap. An increase in the con-
centration of HBr from 200 mM to 400 mM and 600 mM led to
an increase in 2a to 74% and 80% yield, respectively (Table 1,
entries 2 and 3). Pleasingly, a decrease of the bromohydrin
side product could be observed. The concentration of 600 mM
of hydrobromic acid was used for the subsequent experiments.
Changing the graphite anode material to glassy carbon gave
the product 2a in 73% yield while a platinum foil anode
resulted in 79% yield (Table 1, entries 4 and 5). Meanwhile,
increasing the applied charge resulted in 92% (3.5 F mol−1),
86% (4 F mol−1) and 80% (4.5 F mol−1) yield (Table 1, entries
6–8). Increased flow rates at 4 F mol−1, and thereby higher
charge densities, led to a slight decrease in the yield (Table 1,
entries 9 and 10).
By using a platinum coated titanium cathode and a graph-
ite anode, 1,2-dibromo-1-phenylethane (2a) could be obtained
in an 86% isolated yield under the optimized conditions of
100 mM styrene and 600 mM hydrobromic acid in acetonitrile,
a flow rate of 0.4 mL min−1 and a charge of 4 F mol−1 (applied
current: 257 mA) resulting in a productivity of 545 mg h−1
(Table 1, entry 11).
In order to demonstrate the scalability of the protocol, the
optimized conditions were applied for 9.5 hours to afforded
3.93 g of product 2a, which corresponds to a yield of 65% and
a productivity of 413 mg h−1. Alkene and hydrobromic acid
were mixed from two separate reservoirs before entering the
reactor. When premixing the reaction mixture for a 9 hours
experiment, the desired product 2a was obtained with a signifi-
cantly reduced yield of 47%. A control experiment confirmed a
competing side reaction in the syringe, which led to the for-
mation of 1-phenylethanol in the reservoir upon a prolonged
reaction time.
Fig. 1 Difunctionalization of alkenes with electrochemically generated
bromine.
Results and discussion
The reaction conditions for the dibromination of alkenes were
adapted from a batch electrochemical procedure from Lei and
co-workers.28 Flow experiments were carried out using an Ion
Electrochemical Reactor from Vapourtec Ltd equipped with a
platinum foil cathode and graphite anode.38 The electrodes
were separated by a 500 μm FEP spacer to provide a channel
resulting in a reactor volume of 600 μL and an exposed surface
area of 12 mA cm−2 for each electrode. The bromination of
styrene (1a) was targeted in an effort to develop optimal
electrochemical conditions (Table 1). Applying a flow rate of
0.1 mL min−1, an applied current of 48 mA, a styrene concen-
tration of 100 mM and charge of 3.0 F mol−1 gave the dibro-
mide 2a as the main product in 54% yield and the bromohy-
drin 3a in 17% yield (Table 1, entry 1). In contrast to the batch
experiment,28 no additional water was needed and any
Table 1 Optimising reaction conditions for dibromination of styrene 1a
The reaction with allyl benzene gave 64% yield of 1,2-
dibromo-3-phenylpropane (2b) (Fig. 2). 2-(Pent-4-en-1-yl)isoin-
doline-1,3-dione was converted to 2c in 84% yield. The reaction
with 1,4-cyclohexadiene afforded the tetrabrominated product
(2d) in 34% yield while the dibromination product was
observed in trace amounts.
Charge
HBr
[mM]
[F mol−1
]
Flow rate
Yield
Yield
Entry
(current)
[mL min−1
]
2a a [%]
3a a [%]
1
2
200
400
600
600
600
600
600
600
600
600
600
3 (48 mA)
3 (48 mA)
3 (48 mA)
3 (48 mA)
3 (48 mA)
3.5 (56 mA)
4 (64 mA)
4.5 (72 mA)
4 (129 mA)
4 (257 mA)
4 (257 mA)
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.4
0.4
54
74
80
73
79
92
86
80
78
79
86e
17
6
3
17
13
4
3
4
8
9
3
4b
5c
6
7
8
9
10
11d
Reaction conditions: styrene (0.1 M), hydrobromic acid (48% w/w in
water); acetonitrile (MeCN); constant current; undivided cell; graphite
anode (surface area: 12 cm2); Pt foil cathode; amount of water (HBr
[mM]): 2% (200), 5% (400), 7% (600 mM). a Yields are determined by
NMR with 1,3,5-trimethoxybenzene as internal standard. b Glassy
carbon anode. c Pt foil anode. d Pt coated Ti cathode. e Isolated yield,
3a not isolated.
Fig. 2 Electrochemical dibromination of alkenes in flow. Reaction con-
ditions: alkene (0.1 M, 0.7 mmol), hydrobromic acid (48% w/w in water,
0.6 M); MeCN; 0.4 mL min−1, 4 F mol−1 (257 mA); constant current; undi-
vided cell; graphite anode (surface area: 12 cm2); Pt coated Ti cathode.
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Following this, the optimization for the electrochemical Increasing the flow rate to 0.4 mL min−1 or 0.6 mL min−1
bromohydrin formation in flow was targeted. The concen- resulted in decreased yields of 75% and 70%, respectively
tration of water, hydrobromic acid and styrene were considered (Table 2, entries 11 and 13). Interestingly, a simultaneous
as well as the electrode materials, charge density and flow rate. decrease of current to 3 F mol−1 at 0.4 mL min−1 still afforded
The initial conditions consisted of 100 mM styrene and 81% of bromohydrin (Table 2, entry 10).
200 mM hydrobromic acid, a flow rate of 0.2 mL min−1 and 3 F
To demonstrate the versatility of the optimised reaction
mol−1 (97 mA) charge. At a water concentration of 5% in aceto- conditions, several aromatic and aliphatic alkenes were con-
nitrile, the selectivity of the reaction could be switched and the verted to the corresponding bromohydrins (Fig. 3). Since dou-
bromohydrin was observed in 40% yield, while the dibromide bling the flow rate from the optimal conditions (Table 2,
was obtained in 29% yield (Table 2, entry 1). By increasing the entries 8 and 10) did not significantly drop the yield, both con-
water concentration, the formation of the dibromide was ditions were investigated in an effort to maximize the pro-
further suppressed while the yield of bromohydrin 3a peaked ductivity of the system (conditions A and B). The reaction with
at 79% with a water concentration of 20% (Table 2, entry 2).
styrene and styrene derivatives afforded the bromohydrins 3a–f
In the next optimization step, the influence of the hydro- in good to excellent yields. Due to insolubility, 4-vinylbiphenyl
bromic acid concentration was investigated. The lowest con- (80 mM) was reacted in a solvent mixture of H2O/MeCN/THF
centration of 100 mM suppressed the dibromide formation to (3 : 3 : 4). The current and hydrobromic acid concentration
trace amounts, but the yield for bromohydrin was significantly were kept at 129 mA and 180 mM and 3g was obtained in a
decreased to 31% (Table 2, entry 4). The optimal concentration good yield of 65%. The reaction with 2-vinylnaphthalene
of hydrobromic acid was identified at 180 mM which resulted resulted in 54% yield of 3h. The conversion of methyl cinna-
in a yield of 85% of the bromohydrin and 9% of the dibromide
(Table 2, entries 5 and 6).
Next, different electrode materials were tested. Exchanging
a graphite anode to materials such as Panasonic carbon (67%),
glassy carbon (72%) or platinum foil (2%) had a negative effect
on the bromohydrin formation. Also, varying the cathode
material did not impact the yield significantly: platinum
coated on titanium (85%), nickel (75%), graphite (82%) (see
ESI, Table S3†).
Optimization of the applied charge had a positive influence
on the yield. For instance, a yield of 86% for the bromohydrin
was observed with an increased charge of 4 F mol−1 at a flow
rate of 0.2 mL min−1 (Table 2, entry 8). Further increases (5 F
mol−1) or decreases (2 F mol−1) of the charge decreased the
yield to 68% and 63%, respectively (Table 2, entries 7 and 9).
Table 2 Optimising reaction conditions for the bromohydroxylation of
styrene 1a
Yield Yield
H2O
HBr
Charge
Flow rate
2a a
3a a
Entry added[%] [mM] [F mol−1
]
[mL min−1
]
[%]
[%]
1
2
3
4
5
6
7
8
5
20
30
20
20
30
30
30
30
30
30
30
30
200
200
200
100
180
180
180
180
180
180
180
180
180
3 (97 mA)
0.2
0.2
0.2
0.2
0.2
0.2
0.2
29
14
7
1
9
8
9
4
3
7
6
6
6
40
79
81
31
85
85
63
86
68
81
75
72
70
3 (97 mA)
3 (97 mA)
3 (97 mA)
3 (97 mA)
3 (97 mA)
2 (64 mA)
4 (129 mA) 0.2
5 (161 mA) 0.2
3 (193 mA) 0.4
4 (257 mA) 0.4
3 (290 mA) 0.6
4 (386 mA) 0.6
9
10
11
12
13
Fig. 3 Substrate scope for the electrochemical bromohydroylation of
alkenes in flow. Reaction conditions: alkene (100 mM, 0.7 mmol), hydro-
bromic acid (48% w/w in water, 180 mM), additional H2O/MeCN 3 : 7;
method A: 0.2 mL min−1, 4 F mol−1, constant current; Pt plated Nb
cathode, graphite anode (surface area: 12 cm2), A’: alkene (80 mM) in
H2O/MeCN/THF 3 : 3 : 4; method B: 0.4 mL min−1, 3 F mol−1, constant
current 193 mA, Pt foil cathode, graphite anode (surface area: 12 cm2),
B’: THF instead of MeCN. (a) Pt foil cathode; (b) Pt plated Nb cathode.
Reaction conditions: styrene (100 mM), hydrobromic acid (48% w/w in
water); additional H2O/MeCN; constant current; undivided cell; Pt foil
cathode, graphite anode (surface area: 12 cm2). a Yields are determined
by NMR with 1,3,5-trimethoxybenzene as internal standard.
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mate furnished 3l in a moderate yield. Two α,β-unsaturated acetonitrile proceeded with a yield of 57% (0.4 mL min−1
,
ketones were converted in moderate yields to 3m and 3n. The 3 F mol−1) to afford an inseparable mixture of regioisomers.
reaction with allylbenzene gave mixtures of regioisomers 3p The 5-membered ring was obtained as the major isomer 4d
and 3p′ (1.78 : 1) in 43% (method A) or 46% (method B) yield. and the 6-membered ring as the minor one 4d′ in a ratio
The unactivated alkenes 1-hexene and 1-decene resulted in of 9 : 1. The reaction with N-(2-allylphenyl)-4-methyl-
33% yield with a 3.76 : 1 ratio of regioisomers (3q/3q′) and benzenesulfonamide led to cyclization as well as subsequent
59% yield with a 1 : 1.04 ratio of regioisomers (3r/3r′). The bromination of the aromatic ring. The cyclized product 4e was
unsymmetrical internal alkene trans-2-hexene did not afford afforded in 22% yield. Cyclization and bromination of the aro-
the bromohydrin. The bromohydrin 3s was obtained in moder- matic ring gave product 4e′ in 21% yield. The electrochemical
ate yields from cyclohexene with method A and B. The use of brominaton of 2-allyl-6-methylphenol led to the bromination
graphite as a cathode material gave 3a in 78% yield but for 3b of the aromatic ring and the formation of 5- and 6-membered
and 3j yields dropped significantly compared to methods uti- rings with the phenolic oxygen acting as nucleophile. The
lizing platinum cathodes.
resulting complex mixture of products did not allow a con-
Alcohols could be used as nucleophiles to trap the bromo- clusion about the selectivity of the reaction from the crude
nium species, and internal nucleophiles would provide NMR spectrum. A mixture of regioisomers 4f and 4f′ could be
cyclized reaction products (Fig. 4). By changing from water to isolated in a ratio of 2.33 : 1 in 22% yield. Due to the challen-
30% of alcohol in acetonitrile, the bromoalkoxylated products ging purification process, a conclusion on the regioselectivity
were obtained. The reaction of styrene with 150 mM hydro- of the reaction cannot be drawn.
bromic acid gave the corresponding methoxylated and ethoxy-
lated products 4a and 4b in moderate yields at 0.4 mL min−1
and 4 F mol−1. Alkenes containing internal nucleophiles were
Conclusions
used with conditions adapted from method A. The substrates
In this work we provide a flow set-up to conduct various
were electrolyzed in acetonitrile with 180 mM hydrobromic
acid at a flow rate of 0.2 mL min−1 and charge of 4 F mol−1
.
electrochemical brominations of alkenes by using hydro-
bromic acid as bromine source. The outcome of the reaction
was easily controlled by switching the cosolvent.
Bromohydrins, dibromides and vicinal bromo ethers were elec-
trochemically synthesized in flow with moderate to excellent
yields. The use of chemical oxidants, which are commonly
used in bromination reactions, is completely avoided leading
to a substantial reduction of waste. The flow set-up facilitated
a safe handling of the intermediary generated bromine. The
described methods have the potential of facile up-scaling.
Furthermore, internal nucleophiles such as carboxylic acids,
N-tosylaniline and phenol led to cyclized products.
4-Pentenoic acid was converted with a water concentration of
5% in acetonitrile to the corresponding lactone 4c in 74%
yield. The reaction of 2-vinyl benzoic acid with 30% water in
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial support from the School of Chemistry, Cardiff
University, UK, is highly appreciated. We like to thank
B. Winterson for helpful discussions.
References
Fig. 4 Electrochemical bromoalkoxylation and cyclisation of alkenes in
flow. Reactionconditions (alkoxylation): alkene (100 mM, 0.7 mmol),
hydrobromic acid (48% w/w in water, 150 mM), 30% alcohol in aceto-
nitrile; 0.4 mL min−1, 4 F mol−1, constant current 257 mA; Pt foil
cathode, graphite anode (surface area: 12 cm2); reaction conditions
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