Regioselective monobromination of phenols with KBr and ZnAl–BrO3?–layered double hydroxides

Article abstract of DOI:10.3390/molecules25040914

The regioselective mono-bromination of phenols has been successfully developed with KBr and ZnAl–BrO3^?–layered double hydroxides (abbreviated as ZnAl–BrO3^?–LDHs) as brominating reagents. The para site is much favorable and the ortho site takes the priority if para site is occupied. This reaction featured with excellent regioselectivity, cheap brominating reagents, mild reaction condition, high atom economy, broad substrate scope, and provided an efficient method to synthesize bromophenols.

Full text of DOI:10.3390/molecules25040914

molecules
Communication
Regioselective Monobromination of Phenols with
−
KBr and ZnAl–BrO3 –Layered Double Hydroxides
Ligeng Wang *, Chun Feng, Yan Zhang and Jun Hu *
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310004, China;
2111701029@zjut.edu.cn (C.F.); 2111801310@zjut.edu.cn (Y.Z.)
* Correspondence: wanglg@zjut.edu.cn (L.W.); hjzjut@zjut.edu.cn (J.H.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Academic Editor: Narciso M. Garrido
Received: 19 January 2020; Accepted: 16 February 2020; Published: 18 February 2020
Abstract: The regioselective mono-bromination of phenols has been successfully developed with KBr
and ZnAl–BrO3−–layered double hydroxides (abbreviated as ZnAl–BrO3−–LDHs) as brominating
reagents. The para site is much favorable and the ortho site takes the priority if para site is
occupied. This reaction featured with excellent regioselectivity, cheap brominating reagents, mild
reaction condition, high atom economy, broad substrate scope, and provided an efficient method to
synthesize bromophenols.
Keywords: phenol; bromination; regioselecitvity
1. Introduction
Bromophenols are versatile starting materials in a carbon–carbon bond coupling reaction [
They are also important constituents of naturally occurring compounds that possess a range of biological
activities [ ], such as antioxidant, antimicrobial and anticancer effects. Cheap and active molecular
bromine is a traditional brominating reagent despite it being corrosive, having a low atom economy
(up to 50% in substitution reaction) and low selectivity [10 12]. Safer N-bromosuccinimide based
analogues are developed as preferable brominating reagents [13 19]. However, these brominating
reagents employ Br2 in preparation and produce useless organic waste [20 21]. Oxidative bromination
is another approach to brominated substrates [22 26]. This brominating reagent is generated in situ
1–5].
6–9
–
–
,
–
from bromide ion in the presence of oxidants [27]. Various oxidants such as H2O2, DMSO, O2, bromate,
oxone, persulfate, etc., have been applied in oxidative bromination [28–34].
Due to the high activity and multiple substituted sites of phenols, over-bromination frequently
occurs when phenol derivatives undergo bromination [35,36]. It is usually hard to obtain
mono-brominated product, as it is usually a mixture of mono- and multi-brominated substrate
(Figure 1a). Numerous strategies for selective mono-bromination of phenols have been reported
in literature.
Molecules 2020, 25, 914; doi:10.3390/molecules25040914
www.mdpi.com/journal/molecules

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Figure 1. Three bromination of phenols; (a) traditional electrophilic substitution reaction of phenol; (b)
previous mono-bromination of phenol; (c) this work.
Some methods use special brominating reagents or additives (Figure 1b), such as o-xylylene
bis (triethyl ammonium tribromide) [35], bromotrimethylsilane and di-4-chlorophenyl-sulfoxide [37],
(diacetoxyiodo)benzene and AlBr3
polyvinylpolypyrrolidone-Br2 43], 1,3-di-n-butylimidazolium tribromide [44], ethylenebis(N-
methylimidazolium) ditribromide [45], N-benzyl-triethylenediamine tribromide [46], 1-butyl-3-
methylpyridiniumtribromide [47], ZrBr4/diazene [48], -cyclodextrin [49] and tetrabromobenzene-
1,3-disulfonylamide [50]. There are also some methods requiring a catalyst, including thioamide [36],
Cu Mn spinel oxide [51], bromoperoxidase [52], Rhenium-promoted mesoporous zirconia [53],
[38], p-toluenesulfonic acid [39–41], methanol [39,42],
[
β
−
amberlyst-15 [54], mesoporous silica supported sulfated zirconia [55], copper icons [56
,57], UV–vis
light irradiation [58] and ammonium acetate [59].
However, some of these methods are associated with disadvantages such as special and expensive
reagents, demand for catalysts, generation of a large amount of waste, and harsh conditions. Therefore,
the development of simple, efficient approaches to bromophenol is still highly desirable.
Layered double hydroxides (LDHs) is a layered structure material that consists of interlayer
anions and positively charged layers [60]. LDHs have been applied in various fields [61–65]. In our
early work, bromate has been successfully intercalated into LDHs and it is named ZnAl-BrO3−-layered
-
double hydroxides (abbreviated as ZnAl–BrO3−–LDHs). 0.93 g ZnAl-BrO3 -LDHs is equivalent to
1 mmol bromate according to the indirect iodometric method [66]. Please see the specific synthetic
procedure and calculation of iodometric method in the Supplementary Materials. We have utilized
ZnAl–BrO3−–LDHs to achieve bromination of olefins and anilines [67
–69]. Herein, we proposed a
mild and efficient KBr and ZnAl–BrO3−–LDHs system for selective mono-bromination of phenols.
2. Results
4-Methylphenol was chosen as the starting reactant and the optimization result is listed in Table 1.
–
At first, the reaction was carried on at room temperature in presence of ZnAl–BrO3 –LDHs, lithium
bromide and acetic acid. Maintaining the amount of ZnAl–BrO3−–LDHs at 0.2 equivalents, the amount
of lithium bromide was changed from 1.4 to 0.8 equivalents. (Table 1, entry 1–4). The yield of
mono-brominated product 1a altered from low to high then low and got the maximum 76% (entry 3).
Then several different bromide salts (entry 5–7) were tested and potassium bromide gave the best
yield in 83%. The brominated product was not observed in several common organic solvents which
cannot provide acid environment (entry 8–11). This result demonstrates that acid is indispensable
for our oxidative bromination system. Acetic acid plays a dual role as a solvent and acid provider.
After adding a small amount of water, the reaction rate increased significantly and the yield slightly
increased to 86% (entry 12). The possible reason is bromide salt and released bromate have good
solubility in this mixed solvent. By screening reaction temperatures (entry 13–16), we determine 35 ◦C
is sufficient to drive the reaction to completion and higher temperature cannot offer better yield.

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Table 1. Optimization of bromination.1
Entry
Oxidant (equiv.)
Bromide (equiv.)
Solvent 2
Temperature
Yield 3
-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
ZnAl-BrO3--LDHs (0.2)
LiBr (1.4)
LiBr (1.2)
LiBr (1.0)
LiBr (0.8)
NaBr (1.0)
KBr (1.0)
ZnBr2 (0.5)
KBr (1.0)
KBr (1.0)
KBr (1.0)
KBr (1.0)
KBr (1.0)
KBr (1.0)
KBr (1.0)
KBr (1.0)
KBr (1.0)
KBr (2.0)
KBr (2.0)
KBr (1.0)
KBr (1.0)
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
MeOH
EtOH
25 ◦C
25 ◦C
25 ◦C
25 ◦C
25 ◦C
25 ◦C
25 ◦C
25 ◦C
25 ◦C
25 ◦C
25 ◦C
25 ◦C
30 ◦C
35 ◦C
40 ◦C
45 ◦C
35◦C
71
73
76
68
80
83
73
-
-
-
-
86
85
91
81
77
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3--LDHs (0.2)
ZnAl-BrO3 -LDHs (0.4)
KBrO3 (0.4)
DCM
EA
AcOH/H2O
AcOH/H2O
AcOH/H2O
AcOH/H2O
AcOH/H2O
AcOH/H2O
AcOH/H2O
AcOH/H2O
AcOH/H2O
76 (17)
22 (61)
35 (28)
-
35 ◦C
35 ◦C
35 ◦C
KBrO3 (0.2)
-
1 Phenol bromination condition was as following: 4-methylphenol (1mmol), ZnAl-BrO3––LDHs, bromide ion, AcOH
3
(5mL). 2 0.5 mL of water was added in entries 13–20. Isolate yield of 1a. Number in parentheses is the yield of 1b
.
4-Methylphenol has two equal substituted sites, so double dosages of ZnAl–BrO3−–LDHs and
potassium bromide were reasonable (entry 17). Surprisingly, the yield of desired di-brominated
product 1b was only 17%, and 1a was still the main product 76% (entry 17). We conducted a control
experiment that directly used potassium bromate (0.4 equiv.) and potassium bromide (2.0 equiv.) as
brominating reagents. Not like the former result, 1a was not dominant and 1b was produced in large
quantities in 61% (entry 18). Using potassium bromate (0.2 equiv.) and potassium bromide (1.0 equiv.)
also produced 1b in 28% yield (entry 19). Without the addition of ZnAl-BrO3−-LDHs, brominated
product was not obtained (entry 20). Our brominating system could make the bromination stop at
monobromination stage by controlling the dosage of bromine. This is presumably due to the fact that
open bromate produces large amounts of brominating reagents in a short period of time, while the
special structure of LDHs can achieve slow release of BrO3− under acetic acid conditions. This series of
experiments demonstrate that our reagents can achieve mono-bromination in good yield.
3. Discussion
To extend the substrate scope, some similar para-substituted phenols were chosen as substances
(Figure 2). Our reagents show good tolerance for electron-withdrawing and electron-donating
group. Phenol derivatives bearing methoxy and tert-butyl substituent were mono-brominated in
ortho site to offer 2a and 3a in 82% and 71% yield. The bromination of phenol derivatives, which
contain weak electronic withdrawing fluoro, chloro and bromo substituent at the para position,
produced corresponding mono-brominated 4a
4-nitrophenol provided 7a in 51% yield.
–6a in 73%, 81%, and 84% yields, respectively. The inert

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Unless otherwise noted, the mixture of substrate (1 mmol), ZnAl-BrO3––LDHs (0.2 mmol), KBr (1.0
mmol) in AcOH/H2O (5mL/0.5mL) was stirred at 35 ◦C. Isolated yield.2 The reaction temperature was
50 ◦C.
Figure 2. Scope of bromination.
Several ortho-substituted phenol derivatives performed well producing bromophenols. Phenol
derivatives bearing methyl, trifluoromethyl were all mono-brominated to furnish selective
para-brominated products 8a
regioselectively brominated at para site to offer 10a
–
9a in 71%–84% yield. The halogen-containing derivatives could also be
13a (67–89%). These ortho-substituted phenol
–
derivatives all have two different substituted sites, but para-substituted product was dominant, the
and ortho- and multi-brominated products were not observed. This result confirmed our method
could achieve mono-bromination with an excellent yield and high regioselectivity.
Starting from meta-substituted derivatives 3-methyl, 3-trifluoromethyl, 3-fluoro and
3-chlorophenol, 78%, 69%, 70% and 81% yield were obtained for 14a–17a. The para site is still the main
substituted position. Other para-open phenol derivatives 2,6-dimethylphenol, 3,5-dimethylphenol,
2,6-difluorophenol, 3,5-difluorophenol and 2,3-difluorophenol, were mono-brominated at the para site
to offer 18a–22a in high yield (78%–90%). The bromination of 2-naphthol afforded 23a in a 90% yield.
On the basis of the previous reports, the possible mechanism of monobromination of phenols is
proposed in Figure 3. Bromate is stored in LDHs and bromide is open and abundant in solvent, thus
the bromide is the excess in the redox reaction between them. Released bromate reacts with bromide
to produce Br2. Polarization and heterolytic cleavage occurred immediately in solvent. Then, the
electrophilic substitution reaction is executed. Bromide and hydrogen that detached from phenol are
used for next oxidative cycle. ZnAl-BrO3−–LDHs achieve smooth and slow release of brominating
reagent, avoiding a high brominating concentration and violent reaction in the beginning.

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Figure 3. Proposed mechanism of bromination.
4. Materials and Methods
4.1. General Information
All reagents and solvents were purchased from commercial suppliers and were not purified. The
crude products were purified by column chromatography on silica gel (Aladdin Industrial Corporation,
Shanghai, China). Melting points of the compounds were recorded on X-4 melting point detector
1
(Beijing Tech Instrument Co. Ltd., Beijing, China) and are uncorrected. H NMR spectra were recorded
on a Bruker 500 MHz (Beijing, China) and a 400 MHZ spectrometer (Beijing, China) in deuterated
chlororoform using tetramethylsilane as the internal standard. 13C-NMR spectra (Beijing, China) were
recorded at 126 MHz and 101 MHz spectrometer in deuterated chlororoform solutions. Chemical shifts
(δ) and coupling constants (J) were expressed in ppm and Hz, respectively. The high-resolution mass
analyses were recorded on an Agilent high resolution mass spectrometer (Shanghai, China).
4.2. General Procedure for the Bromination
0.11 g (1.0 mmol) of 4-methylphenol, 5 mL of acetic acid, 0.5 mL of water, and 0.12 g (1.0 mmol)
potassium bromide were placed in round-bottomed flask. Then, 0.19 g (0.2 mmol) ZnAl–BrO3––LDHs
was added in the flask under stirring at 35 ◦C. After the addition, stirring was continued to the end of
reaction (monitored by thin layer chromatography). The residual ZnAl–BrO3−–LDHs were removed
by centrifugation. The product was extracted with 3
×
10 mL dichloromethane. The combined extract
was washed with sodium sulfite solution, brine, and dried (Na2SO4). Evaporation of the solvent
left the crude product. The crude product was purified by column chromatography over silica gel
(ethyl acetate-petroleum ether) to obtain pure product.
5. Conclusions
In conclusion, we developed a selective and mild mono-bromination of phenols with
ZnAl-BrO3−–LDHs and potassium bromide as brominating reagents. Our strategy selectively produced
para-brominated phenols, unless the para-position is substituted. As for para-substituted phenols,
ortho-brominated products are obtained. The mild condition, simple experiment operation, high
bromide atom economy, cheap brominating reagents, as well as no catalyst, make the present strategy
prospective for the mono-bromination of phenols.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/25/4/914/s1,
-
general procedure for ZnAl-BrO3 -LDHs, characterization data, 1H NMR and 13C NMR Spectra of products.
Author Contributions: Conceptualization, L.W. and J.H.; data curation, C.F. and Y.Z. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Acknowledgments: Thanks to Qingbao Song for the suggestions for this article.
Conflicts of Interest: The authors declare no conflicts of interest.

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Sample Availability: Samples of the compounds are not available from the authors.
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