Regioselective electrophilic aromatic bromination: Theoretical analysis and experimental verification

Article abstract of DOI:10.3390/molecules19033401

Electrophilic aromatic bromination is the most common synthetic method used to prepare aryl bromides, which are very useful intermediates in organic synthesis. To understand the experimental results in electrophilic aromatic brominations, ab initio calculations are used here for a tentative analysis of the positional selectivity. The calculated results agree well with the corresponding experimental data, and the reliability of the resulting positional selectivity was verified by the corresponding experimental data.

Full text of DOI:10.3390/molecules19033401

Molecules 2014, 19, 3401-3416; doi:10.3390/molecules19033401
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Regioselective Electrophilic Aromatic Bromination: Theoretical
Analysis and Experimental Verification
Hui-Jing Li 1, Yan-Chao Wu 1,*, Jian-Hong Dai 2, Yan Song 2,*, Runjiao Cheng 3
and Yuanyuan Qiao 3
1
School of Marine Science and Technology, Harbin Institute of Technology at Weihai,
Weihai 264209, China
2
School of Materials Science and Engineering, Harbin Institute of Technology at Weihai,
Weihai 264209, China
3
Central Laboratory, College of Chemistry, and Computational Center for Molecular Science,
Nankai University, Tianjin 300071, China
* Authors to whom correspondence should be addressed; E-Mails: ycwu@iccas.ac.cn (Y.-C.W.);
sy@hitwh.edu.cn (Y.S.); Tel.: +86-631-568-7230 (Y.-C.W.); +86-631-568-7772 (Y.S.).
Received: 24 February 2014; in revised form: 10 March 2014 / Accepted: 13 March 2014 /
Published: 20 March 2014
Abstract: Electrophilic aromatic bromination is the most common synthetic method used
to prepare aryl bromides, which are very useful intermediates in organic synthesis. To
understand the experimental results in electrophilic aromatic brominations, ab initio
calculations are used here for a tentative analysis of the positional selectivity. The
calculated results agree well with the corresponding experimental data, and the reliability
of the resulting positional selectivity was verified by the corresponding experimental data.
Keywords: electrophilic aromatic bromination; selectivity; ab initio; natural products
1. Introduction
Aryl bromides have found widespread utility as substrates for Pd-, Ni-, and Cu-catalyzed
cross-coupling reactions to form diverse C–C, CN, CO, and CS bonds [1–9]. Moreover, aryl
bromides have been used as classical precursors to organolithium and Grignard reagents as well as in
benzyne generation and nucleophilic aromatic substitution [10,11]. The most common synthetic
method for preparing aryl bromides is electrophilic aromatic bromination, which continues to be an

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area of focus in synthetic chemistry because aryl bromides are very useful intermediates in the
production of drugs, pharmaceuticals, agrochemicals, pigments, photographic materials, and various
functional natural products [1–37]. This makes the development of regioselective electrophilic
aromatic brominations a high priority. Accordingly, many regioselective electrophilic aromatic
brominations have been developed. Tetraalkylammonium tribromides are highly para-selective for
2−
−
bromination of phenols [12]. LDH-CO3 -Br3 can be used for para-selective monobromination of
some aromatic compounds [13]. Zeolites induce high para-selectivity for electrophilic bromination of
substrates akin to toluene [14–22]. N-bromosuccinimide (NBS)/silica gel is also a good brominating
agent for regioselective electrophilic aromatic brominations [23,24]. Bromine (Br2), produced in situ in
either a Cu(NO3)2/HBr/O2/H2O system [25] or LiBr/ceric ammonium nitrate (CAN) system [26],
displays similar regioselectivity in electrophilic aromatic brominations. N-bromosuccinimide, in either
ionic liquids [27] or THF [28], is highly regioselective for electrophilic aromatic brominations,
whereas bromodimethylsulfonium bromide [29] and 1,3-dibromo-5,5-dimethyihydantoin [30] are less
regioselective for electrophilic aromatic brominations in comparison with NBS. Although direct
comparison is not always valid due to the different reaction conditions, the positional selectivity of
electrophilic aromatic bromination is quite clear. For an analysis of the inherent positional selectivity
of electrophilic aromatic brominations, theoretical calculations may be required as they might provide
insightful quantitative information that would be difficult to obtain by experimental methods.
Usually, an electrophilic aromatic bromination is considered to occur via a stepwise mechanism
(Scheme 1) [31–37]. A π complex [38] or a radical ion pair [39] may or may not be directly involved
in an electrophilic aromatic bromination mechanism and its rapidly reversible formation is usually not
the rate-determining step [31–37]. However, for an electrophilic aromatic bromination to occur, a cationic
reaction intermediate called an arenium ion, known as a σ complex or Wheland intermediate [40], is
usually formed [31]. The formation of bromoarenium ion is difficult due to the loss of the inherent
stability associated with aromaticity and is usually the rate-determining step, in which the transition
state comes later on the reaction coordinate and is closer in energy to the arenium ion [41]. According
to the Hammond postulate [42], the rate-determining transition state resemble the arenium ion, so that
factors stabilizing bromoarenium ion also stabilize the transition state and lower the activation energy,
and thereby usually favor the electrophilic aromatic bromination.
Scheme 1. Electrophilic aromatic bromination.
Br
Br
H
X
H+
+
X
+
X
Br
arenium ion
Substituents can influence the product distribution by favoring the formation of one arenium ion
over another. Based on Hückel molecular orbital theory, the positive charge of the arenium ion is equally
delocalized at the positions that are ortho and para to the site of the substitution (Figure 1) [31–37].
Therefore, a π-donor substituent at one of these positions stabilizes the arenium ion and also stabilizes
the transition state and lowers the activation energy necessary for the electrophilic aromatic
substitution, and thus acts as an ortho/para directing group. In contrast, a π-acceptor substituent at one

Molecules 2014, 19
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of these positions destabilizes the arenium ion and increases the activation energy necessary to attain
the transition state, and thus acts as a meta directing group. The resulting principles, known as the
Holleman rules [43], are easily explained by comparison of the corresponding resonance structures [32].
Figure 1. Charge distribution of the arenium ion based on (a) Hückel molecular orbital
method and (b) the ab initio calculations via GAUSSIAN 09 program package. Values on
C and H atoms in (b) indicate the atomic charge assignments (the positive or negative sign
implies that the atom donates or accepts charges).
Br
0.33
H
0.33
+
0.33
(a)
(b)
With only Holleman rules in hands, some related experimental results in electrophilic aromatic
brominations cannot be explained well. For example, the electrophilic aromatic bromination of
3-hydroxybenzonitrile (1, Scheme 2) afforded 2-bromo-5-hydroxybenzonitrile (2a) and 2-bromo-3-
hydroxybenzonitrile (2b) in 73% and 18% yields, respectively.
Scheme 2. Electrophilic aromatic brominations of 3-hydroxybenzonitrile and 3-methoxy-benzaldehyde.
OH
OH
OH
OH
Br
Br
NBS
+
+
HBF4
CN
CN
CN
CN
1
2a: 73% 2b: 18%
2c: 2%
Br
OCH3
OCH3
OCH3
Br
NBS, CH3CN
0 °C, overnight
+
CHO
CHO
CHO
Br
3
4a: 81%
4b: 0%
In contrast, 4-bromo-3-hydroxybenzonitrile (2c) was isolated in only 2% yield [44]. Similarly,
the electrophilic aromatic bromination of 3-methoxybenzaldehyde (3) afforded exclusively
2-bromo-5-methoxybenzaldehyde (4a) in 81% yield, while the potential isomer of 4-bromo-3-
methoxybenzaldehyde (4b) was not formed at all [45,46]. As witnessed in these two examples, a
π-donor substituent (πDS) usually tends to facilitate its para electrophilic aromatic bromination,
whereas a π-acceptor substituent (πAS) usually tends to prevent the corresponding para electrophilic
aromatic bromination. According to Holleman rules, compounds 2c and 4b should also be the major
products, yet they are not. Why? To understand these experimental results, ab initio calculations are
used here for a tentative analysis of the positional selectivity. Ab initio studies of the bromination of
benzene have already been carried out previously to discuss the reaction pathways [33]. Herein the
results based on ab initio calculations are used to distinguish the ortho/para positional selectivity.

Molecules 2014, 19
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2. Results and Discussion
Calculating the charge distribution in the arenium ion by ab initio calculations via the GAUSSIAN
09 program package [47] did provide some insightful quantitative information. The atomic charge
assignments on the C and H atoms of the arenium ion are shown in Figure 1b, where the positive or
negative sign implies that the atom donates or accepts charges. The calculations indicated that the
overall magnitude of the electron deficiency of the arenium ion over the various positions follows the
order of para > ortho > meta. Without influence of any other factors, a π-donor substituent would direct an
electrophilic aromatic bromination to the position in the preferential order of para > ortho > meta, whereas
a π-acceptor substituent would direct an electrophilic aromatic bromination to the position in the
preferential order of meta > ortho > para.
The analysis is in good agreement with the experimental observations. For example, methoxyl
group is a π-donor substituent due to a resonance effect which helps to delocalize the positive charge
of the arenium ion onto the oxygen atom. Accordingly, the electrophilic aromatic bromination of
anisole (5) under the reported conditions [45,46] afforded exclusively 1-bromo-4-methoxybenzene
(6a) in 96% yield, and the potential product of 1-bromo-2-methoxybenzene (6b) was not detected
(Scheme 3). As in the case of anisole, the electrophilic aromatic bromination of a wide range of arenes
with NBS in acetonitrile proceeded readily and was found to be highly para-selective with respect to
the most activating substituent, in instances where the para position is blocked, bromination occurred
ortho to the most activating substituent [45,46]. Similar positional selectivity was usually found when
the reactions were performed in the other electrophilic aromatic bromination systems [27,28].
Scheme 3. Electrophilic aromatic bromination of anisole.
Br
NBS, CH3CN
+
rt, overnight
Br
OCH3
OCH3
OCH3
5
6a: 96%
6b: 0%
The reliability of the above ab initio calculations could be verified by the energy differences of
transition-states associated with the corresponding isomer products. Take the electrophilic aromatic
bromination of anisole as example, the energy of transition-states associated with the isomer products
have been also performed based on ab initio calculations via GAUSSIAN 09 program package [47].
As shown in Figure 2, the energy of the arenium ion associated with the para isomer is lower than that
associated with the ortho isomer, and the energy of the arenium ion associated with meta isomer is
highest. The study supports the same positional selectivity trends deduced from the viewpoint of the
charge distribution of the arenium ion.
To understand the high positional selectivity in the above electrophilic aromatic bromination of
anisole, the energy differences of the isomer products have also been calculated based on ab initio
calculations via GAUSSIAN 09 program package [47]. As shown in Figure 3, the energy of the para
isomer is lower than that of the ortho isomer, indicating the para isomer is more stable than the ortho
isomer, which also supports the high para/ortho selectivity mentioned above.

Molecules 2014, 19
3405
Figure 2. Total of electronic energies (Hartree) of the transition-states of the isomer
products in the electrophilic aromatic bromination of anisole.
Br
H
Br
H
Br
H
H
H
H
H
H
H
OCH3
H
H
H
H
OCH3
OCH3
H
H
−2918.20748841
−2918.17880944 −2918.21191903
Figure 3. Total of electronic energies (Hartree) of the isomer products in the electrophilic
aromatic bromination of anisole. Energies of isomer product + H+ (large distance between
H and isomer product) are −2918.42094279 (ortho isomer), −2918.42272138 (meta isomer)
and −2918.42204287 (para isomer), respectively.
Br
Br
Br
H
H
H
H
H
H
H
H
H
OCH3
H
OCH3
OCH3
H
H
−2917.90194279
−2917.90372138 −2917.90304287
As the results based on ab initio calculations agree well with the related experimental observations
in electrophilic aromatic brominations, the resulting positional selectivity should be well considered in
the synthesis of various aryl bromides, which are very useful intermediates in organic synthesis. For
example, the positional selectivity has facilitated the synthesis of various bioactive natural products.
As benzyloxyl and tert-butyldimethylsilyloxy are quite comparable activating substituents, the
electrophilic aromatic bromination of compound 7 should give compound 8a as the major isomer
according to the positional selectivity mentioned above (Scheme 4). Indeed, treatment of compound 7
with N-bromosuccinimide and silica gel in carbon tetrachloride at room temperature for 15 min
afforded exclusively the isomer 8a in 97% yield [48,49]. This regiospecific electrophilic aromatic
bromination facilitated the synthesis of (+)-puupehenone (9) and (+)-puupehedione (10, Scheme 4) [48,49].

Molecules 2014, 19
3406
Scheme 4. Electrophilic aromatic bromination of compound 7 and its experimental application.
OBn
OBn
OBn
OBn
NBS, Silica gel
CCl4, rt, 15 min
Br
OTBS
7
OTBS
8a: 97%
O
OH
O
O
O
O
and
H
H
9: (+)-puupehenone
10: (+)-puupehedione
As in the case of compound 7, the electrophilic aromatic bromination of compound 11 with
N-bromosuccinimide and silica gel in carbon tetrachloride at room temperature for 1 h afforded
exclusively compound 12a in 97% yield, which in turn facilitated the synthesis of (+)-puupehenone (9),
(+)-puupehedione (10), (−)-oxopuupehenol (13) and (−)-cyanopuupehedione (14, Scheme 5) [50].
Scheme 5. Electrophilic aromatic bromination of compound 11 and its experimental applications.
OH
O
OBn
OBn
OBn
OBn
NBS, CCl4
O
Silica gel
rt, 1 h
Br
OCONEt2
OCONEt2
H
11
12a: 97%
9: (+)-puupehenone
OH
O
O
OH
O
OH
NC
O
H
and
and
and
O
O
O
H
H
10: (+)-puupehedione
13: (-)-oxopuupehenol
14: (-)-cyanopuupehenone
As shown in Scheme 6, high potential selectivity in the electrophilic aromatic bromination of
catechol (15) was accomplished by carefully controlling the reaction temperature. The reaction of
catechol (15) with N-bromosuccinimide and fluoroboric acid in acetonitrile was performed at −30 °C,
the reaction mixture was allowed to warm up to room temperature, and then stirred at this temperature
overnight to afford 4-bromobenzene-1,2-diol (16a) in 100% yield. This regiospecific electrophilic
aromatic bromination facilitated an elegant synthesis of (+)-puupehenone (9) [51].
We have an ongoing interest in the development of selective reactions [52–60], and have also
studied regioselective electrophilic aromatic brominations along with their applications in the total
synthesis of antitumor antibiotic tetrahydroisoquinoline alkaloids. For example, transformation of
aromatic reactant 17 into 18a, a key intermediate in one total synthesis of quinocarcin, was accomplished
at as low a temperature as possible (Scheme 7) [61]. The electrophilic aromatic bromination at its lowest

Molecules 2014, 19
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effective temperature displayed high para/ortho selectivity and only the para isomer was formed. This
is because the tert-butyldimethylsilyloxyl group is a π-donor substituent that direct the electrophilic
aromatic bromination to the positions in the preferential order of para > ortho > meta. The ortho
isomer was formed when this reaction was performed at a higher temperature. This is because a
higher reaction temperature makes more collisions effective, including the collisions at the position
ortho to the tert-butyldimethylsilyloxyl group, and thereby results in a lower positional selectivity.
The regiospecific electrophilic aromatic bromination effectively obviated the regioselectivity issue
during the following Pictet-Spengler reaction, and thus facilitated an efficient total synthesis of
quinocarcin (20) [61].
Scheme 6. Electrophilic aromatic bromination of compound 15 and its experimental application.
OH
OH
OH
OH
NBS, CH3CN
HBF4-Et2O
Br
15
16a: 100%
OH
O
O
H
9: (+)-puupehenone
Scheme 7. Electrophilic aromatic bromination of compound 17 and its experimental application.
Br
NBS, CH3CN
60 °C, 2 h
Br
Br
OTBS
17
OTBS
18a: 96%
CO2H
Br
H
N
CO2Me
NH
NMe
OMe
OMe
20: (-)-quinocarcin
O
OBn
19
As methoxyl and tert-butyldimethylsilyloxyl are quite comparable strong activating substituents,
the electrophilic aromatic bromination of compound 21 at its lowest effective temperature was found
to be highly para-selective with respect to a strong activating substituent to afford exclusively isomer
22a in 92% yield (Scheme 8) [62], which supports the positional selectivity mentioned previously. It is
noteworthy that this electrophilic aromatic bromination only displays high positional selectivity at its
lowest effective temperature, and another isomer was also formed when the reaction was performed at
a higher temperature such as room temperature. The regiospecific electrophilic aromatic bromination
facilitated the total synthesis of the antitumor antibiotic lemonomycin amide (23) [62].

Molecules 2014, 19
3408
Scheme 8. Electrophilic aromatic bromination of compound 21 and its experimental application.
OMe
OMe
Me
Me
MeO
OH
Br
NBS, CH3CN
0 °C, 30 min
MeO
OTBS
21
OTBS
22a: 92%
OH
O
H
H
Me
MeO
NH
H
N
H
O
OH
O
23: lemonomycin amide
Regioselective electrophilic aromatic brominations have also facilitated the total syntheses of
(−)-renieramycin M (33a, Scheme 9), (−)-renieramycin G (33b), (−)-jorumycin (33c) and (−)-jorunnamycin
A (33d) [63]. As shown in Scheme 9, treatment of compounds 27a–b with N-bromosuccinimide in
acetonitrile at their lowest effective temperature for 8 h efficiently afforded aryl bromides 28a–b that
were used as precursors to key Grignard reagents 29a–b. By exploring the double nucleophilicity of
Grignard reagents 29a–b and triple reactivity of aziridines 31–32, convergent and versatile syntheses
of the above four antitumor antibiotic marine natural products were developed [63].
Scheme 9. Electrophilic aromatic bromination of compounds 27 and their experimental application.
OMe
OMe
OMe
Me
Me
Br
Me
MgBr
NBS, CH3CN
0 °C, 8 h
Mg
MeO
MeO
MeO
OR
OR
28a: 90%
28b: 97%
OR
29a
27a: R1 = Bn
27b: R1 = Boc
29b
OMe
MeO
BnO
Me
BocO
Me
Me
OMe
Me
OMe
O
O
OMe
MeO
O
BrMg
BocN
MgBr
29a
29b
O
R4O
N
O
O
N
NMe
R3
XR4
30
Boc
31
t
CO2 Bu
R2
32
33a (-)-renieramycin M: R2 = CN, R3 = H, R4 = angeloyl
33b (-)-renieramycin G: R2, R3 = O, R4 = angeloyl
33c (-)-jorumycin: R2 = CN, R3 = H, R4 = Ac
33d (-)-jorunnamycin A: R2 = CN, R3 = H, R4 = H
To explain the positional selectivity in an electrophilic aromatic bromination, valence bond theory,
resonance theory and frontier molecular orbital theory have been used, and the related electrostatic
potentials, charge distribution, electrophile affinity and local ionization energy have been
calculated [31–37]. Moreover, various calculation methods and reaction pathways have also been
proposed [31–37]. Although the accurate positional selectivity in an electrophilic aromatic bromination

Molecules 2014, 19
3409
is unclear at this time, more and more related endeavors would complement each other to lead to a
better understanding of the controlling elements behind the corresponding experimental results.
As many factors are usually concurrently involved in an electrophilic aromatic bromination,
it seems difficult to evaluate the individual effects separately. However, the electrophilic aromatic
bromination could be driven toward the desired product if each individual factor is turned the right
way. For example, many π-donor substituents make aromatic reactants nucleophilic and reactive to
electrophiles, and thereby make many collisions effective and result in a lower para/ortho selectivity [29].
One resolution is to perform the electrophilic aromatic bromination at its lowest effective temperature
that would decrease the probabilities of effective collisions and increase the para/ortho selectivity.
3. Experimental
3.1. General Information
Common reagents and materials were purchased from commercial sources and purified by
recrystallization or distillation. Where necessary, organic solvents were routinely dried and/or distilled
prior to use and stored over molecular sieves under argon. Organic extracts were, in general, dried over
anhydrous sodium sulfate (Na2SO4). TLC plates were visualized by exposure to ultraviolet light (UV).
1H and 13C-NMR spectra were measured by Bruker AVANCE III (Bruker; Fallanden, Switzerland)
400 MHz. Chemical shifts for protons are reported in parts per million (δ scale) downfield from
tetramethylsilane and are referenced to residual protium in the NMR solvents (CHCl3: δ 7.26).
Chemical shifts for carbon resonances are reported in parts per million (δ scale) downfield from
tetramethylsilane and are referenced to the carbon resonances of the solvent (CDCl3: δ 77.0). Data are
represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad), coupling constant in Hertz (Hz), and integration. IR spectra were recorded
on a Nicolet 380 FT-IR spectrometer (Thermo Electron Corp., San Jose, CA, USA).
3.2. Calculations
The ab initio calculations of the arenium ion in electrophilic aromatic brominations have been
performed via the GAUSSIAN 09 program package [47]. The calculations were carried out within the
framework of MP2 methodology using 6-311++G (d, p) basis set. The vibration frequency is
calculated for all structures involved to examine the structural stability. Charge densities were
calculated from the electrostatic potential by the method of Merz-Kollman [64] and illustrated in
Figure 2b. The sign of the charges illustrated in these figures indicates whether the atom is a donor
(a cation with positive value) or an acceptor (an anion with negative value).
3.3. Electrophilic Aromatic Bromination of Compound 5
To a solution of compound 5 (99%, 108.9 μL, 1.0 mmol) in acetonitrile (MeCN, 2 mL) at 0 °C was
added N-bromosuccinimide (NBS, 98%, 181.7 mg, 1.0 mmol) in one portion. The resulting mixture
was allowed to come to room temperature, stirred at room temperature overnight, quenched with water
(10 mL), and extracted with dichloromethane (CH2Cl2, 3 × 10 mL). The combined organic layers were
washed with brine, dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated. The

Molecules 2014, 19
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residue was purified by column chromatography on silica gel (100–200 mesh) to afford exclusively
1
1-bromo-4-methoxybenzene (6a, 179.5 mg) in 96% yield. Pale yellow oil; H-NMR (400 MHz,
13
CDCl3) δ 7.38 (d, J = 8.8, 2H), 6.79 (d, J = 8.8, 2H), 3.78 (s, 3H); C-NMR (100 MHz, CDCl3) δ
158.7, 132.2, 115.7, 112.8, 55.4; FTIR (film): 3036, 2937, 1490, 1075, 1012, 800 cm−1. Anal. Calcd.
for C7H7BrO3: C, 44.95; H, 3.77. Found: C, 44.88; H, 3.93.
3.4. Electrophilic Aromatic Bromination of Compound 17
To a solution of compound 17 (301.3 mg, 1.0 mmol) in acetonitrile (MeCN, 2 mL) at room
temperature was added N-bromosuccinimide (NBS, 98%, 181.7 mg, 1.0 mmol) in one portion. The
resulting mixture was stirred at 60 °C for 2 h, quenched with water (10 mL), and extracted with
dichloromethane (CH2Cl2, 3 × 10 mL). The combined organic layers were washed with brine, dried
over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated. The residue was purified by
column chromatography on silica gel (100–200 mesh) to afford exclusively 6-bromo-3-tert-
1
butyldimethylsilyloxybenzyl bromide (18a, 364.9 mg) in 96% yield. Pale yellow oil; H-NMR
(300 MHz, CDCl3) δ 7.40 (d, 1H, J = 8.7 Hz), 6.95 (d, 1H, J = 1.8 Hz), 6.66 (dd, 1H, J = 8.7, 1.8 Hz),
4.53 (s, 2H), 0.99 (s, 9H), 0.21 (s, 6H); 13C-NMR (75 MHz, CDCl3) δ 155.3, 137.8, 133.9, 122.9,
122.0, 115.5, 33.3, 25.6, 18.2, −4.4; FTIR (film) 2928, 2856, 1470, 1290, 1246, 1171, 981, 834, 816,
779, 668 cm−1. Anal. calcd. for C13H20Br2OSi: C, 41.07; H, 5.30. Found: C, 40.99; H, 5.36.
3.5. Electrophilic Aromatic Bromination of Compound 21
To a solution of compound 21 (282.5 mg, 1.0 mmol) in acetonitrile (MeCN, 2 mL) at −10 °C was
added N-bromosuccinimide (NBS, 98%, 181.7 mg, 1.0 mmol) in one portion. The resulting mixture
was stirred at 0 °C for 0.5 h, quenched with water (10 mL), and extracted with dichloromethane
(CH2Cl2, 3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous
sodium sulfate (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography
on silica gel (100–200 mesh) to afford exclusively compound 22a (332.4 mg) in 92% yield. Pale
yellow oil; 1H-NMR (300 MHz, CDCl3) δ 6.89 (s, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 2.23 (s, 3H), 1.00 (s,
13
9H), 0.19 (s, 6H); C-NMR (75 MHz, CDCl3) δ 149.9, 149.5, 145.7, 127.0, 121.8, 110.6, 60.3, 59.8,
25.6, 18.1, 10.1, −4.7; FTIR (film): 2954, 2930, 2895, 2858, 1470, 1417, 1401, 1315, 1252, 1234,
1205, 1171, 1097, 1049, 1001, 860, 837, 800, 781, 683 cm−1. Anal. calcd. for C15H25BrO3Si: C, 49.86;
H, 6.97. Found: C, 49.89; H, 6.87.
3.6. Electrophilic Aromatic Bromination of Compound 27a
To a solution of compound 27a (258.4 mg, 1.0 mmol) in acetonitrile (MeCN, 2 mL) at −10 °C was
added N-bromosuccinimide (NBS, 98%, 181.7 mg, 1.0 mmol) in one portion. The resulting mixture
was stirred at 0 °C for 8 h, quenched with water (10 mL), and extracted with dichloromethane
(CH2Cl2, 3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous
sodium sulfate (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography
on silica gel (100–200 mesh) to afford compound 28a (303.5 mg) in 90% yield. White solids;
mp = 34–36 °C; 1H-NMR (300 MHz, CDCl3) δ 7.47–7.13 (m, 5H), 6.90 (s, 1H), 4.92 (s, 2H), 3.72 (s,

Molecules 2014, 19
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3H), 3.64 (s, 3H), 2.15 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 149.7, 148.8, 147.8, 136.6, 128.5, 128.4,
127.9, 127.3, 115.5, 100.5, 71.2, 60.31, 60.25, 10.1; FTIR (film): 2933, 2866, 1476, 1452, 1421, 1402,
1379, 1313, 1260, 1232, 1175, 1087, 1068, 1028, 1000, 968, 908, 888, 826, 790, 776, 732, 695 cm−1.
HRMS (TOF MS ES+) m/z: Calcd for C16H17O3NaBr [M + Na]+: 359.0259 & 361.0238. Found:
359.0263 and 361.0246.
3.7. Electrophilic Aromatic Bromination of Compound 27b
To a solution of compound 27b (268.4 mg, 1.0 mmol) in acetonitrile (MeCN, 2 mL) at −10 °C was
added N-bromosuccinimide (NBS, 98%, 181.7 mg, 1.0 mmol) in one portion. The resulting mixture
was stirred at 0 °C for 8 h, quenched with water (10 mL), and extracted with dichloromethane
(CH2Cl2, 3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous
sodium sulfate (Na2SO4), filtered, and concentrated. The residue was purified by column
chromatography on silica gel (100–200 mesh) to afford compound 28b (336.7 mg) in 97% yield.
1
Yellow oil; H-NMR (300 MHz, CDCl3) δ 7.21 (s, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 2.26 (s, 3H), 1.55
13
(s, 9H); C-NMR (75 MHz, CDCl3) δ 153.9, 151.4, 150.3, 140.7, 127.6, 124.0, 110.9; FTIR (film):
2980, 2937, 1760, 1471, 1417, 1370, 1272, 1255, 1223, 1147, 1099, 1067, 1004, 969, 882, 753 cm−1.
HRMS (TOF MS ES+) m/z: Calcd. for C14H19BrO5Na [M + Na]+: 369.0314. Found: 369.0318.
4. Conclusions
In summary, the results based on ab initio calculations provide clear indication for the
positional selectivity tendencies in an electrophilic aromatic bromination. Without considering any
other factors, a π-donor substituent would direct an electrophilic aromatic bromination to the position
in the preferential order of para > ortho > meta, whereas a π-acceptor substituent would direct this
substitution to the position in the preferential order of meta > ortho > para. Although direct
comparison is not always valid due to the different reaction conditions, the tendency is nevertheless
quite clear. The regioselective electrophilic aromatic bromination has facilitated the synthesis of
various bioactive natural products, which might allow organic chemists to think more clearly about
their related research. Moreover, the theoretical analysis could also be used for understanding the
regioselectivity of electrophilic aromatic brominations in the related publications.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/19/3/3401/s1.
Acknowledgments
This work was supported by the Science and Technology Development Project of Weihai
(2011DXGJ13, 2012DXGJ02), the Science and Technology Development Project of Shandong
Province (2013GGA10075), HIT.NSRIF (2011097, 2011098), HITWH (201105, 201106) and the
Natural Science Foundation of Shandong Province (ZR2012BM002). We deeply thank Vincent Gandon
(Université Paris-Sud 11, Orsay, France) for helpful calculations and discussions.

Molecules 2014, 19
3412
Author Contributions
H.J.L., Y.-C.W. and Y.S. write the manuscript. J.H.D., R.C. and Y.Q. perform part of the calculations.
Conflicts of Interest
The authors declare no conflict of interest.
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