76
Chapter – 4
Nuclear bromination of aromatic compounds
4.1 Introduction 77 4.2 Experimental 81 4.2.1 Representative experimental procedure 81 4.3 Results and discussion 84 4.4 Spectral data of nuclear brominated compounds 89 4.5 Conclusion 99
4.6 References 100
77
Nuclear bromination of aromatic compounds
4.1 Introduction
Brominated aromatic compounds are valuable intermediates in
organic synthesis and they have been used widely as industrially
important products [1], and biologically active substrates as
antitumor, antifungal, antibacterial, antineoplastic and antiviral
compounds [2]. They can also undergo C-C bond formation via
transmetalation reactions such as Heck, Stille, and Suzuki reactions.
The direct bromination of aromatic compounds using bromine
generates toxic and corrosive HBr and usually forms the mixture of
mono and polybrominated products.
The need for isomerically pure bromoaromatics has led to
investigations into more selective brominating agents and several
methods have been reported in the literature. Reactions making use of
organic ammonium tribromides (OATB) such as tetrabutylammonium
tribromide (TBATB) [3 - 5], N-bromosuccinimide-silica gel [6], 1,8-
diazabicyclo [5,4,0]-undec-7-ene hydrobromide per bromide [7],
pyridine hydrobromide per bromide [8], methods employing anodic
bromination in organic solvents [9], and bromine trifluoride [10] have
been fully investigated. Various methods for oxidative nuclear
bromination of aromatic molecules have been developed including KBr-
H2O2 using metal-oxo catalysts [11], N-bromosuccinimide over ZSM-5
78
[12], N-bromosuccinimide in acetonitrile [13], NBS-HBF4.Et2O in
acetonitrile [14], liquid phase regioselective bromination of aromatic
compounds over Hzsm-5 catalyst [15], KBr-NaBO3·4H2O [16], t-
BuOBr-zeolite [17], LiBr-(NH4)2Ce(NO3)6 and Oxone-NaBr[18].
Firouzabadi and coworkers have reported heteropolyacid cesium salt/
cetyltrimethylammonium bromide as a catalytic heterogeneous system
which allows highly regioselective bromination of aromatic compounds
with bromine [19]. N-bromosaccrain in acetonitrile also used for ring
bromination [20].
Environmentally benign bromination of aromatic amines,
hydrocarbons and naphthol by the action of hydrobromic acid in
presence of hydrogen peroxide was described. This environmentally
clean and safe reaction involves in situ generation of bromine and its
reaction with the substrate was discussed in detail [21]Potassium
bromide/H2O2 catalysed by dioxovanadium(V) complexes encapsulated
in Zeolite also used for bromination [22]. Quite recently,
tetrabutylammonium peroxydisulfate [23], N,N,N1,N1-tetrabromo
benzene-1,3-disulfonylamide,poly(N-bromobenzene-1,3-
disulfonylamide) [24], and N-bromosuccinimide either alone [25] or
along with (i) ionic liquids [26], or (ii) tetrabutylammonium bromide
[27] have been used for the selective monobromination of aromatic
compounds. Tajak et al. showed the bromination of aromatic
79
compounds with potassium bromide in the presence of poly (4-
vinylpyridine)-supported bromated in nonaqueous solution [28]. Das
et al. disclosed an efficient, rapid and regioselective nuclear
bromination of aromatics and heteroaromatics with N-
bromosuccinimide using sulfonicacid–functionalised silica as a
heterogeneous recyclable catalyst [29]. Studies on heteropoly acid
supported Zirconia was used for the oxidative bromination of phenol
using phosphotungstic acid supported on Zirconium [30]. Adibi et al.
carried out a convenient and regioselective oxidative bromination of
electron rich aromatic rings using potassium bromide and
benzyltriphenyl phosphonium peroxymonosulfate under nearly neutral
reaction conditions [31].
Vanadium catalysed bromination reaction was also efficiently
carried out by Moriuchi et al. [32]. Very recently simple catalyst-free
regio- and chemoselective monobromination of aromatics was reported
by Venkatesvarlu et al. using N-bromosuccinimide in polyethylene
glycol as solvent at room temperature [33]. Bromination of aromatic
compounds was triggered by Vilsmeier-Hack reagent (DMF-POCl3)
under solvent free conditions by grinding the reactants in a mortar
with a pestle. The reactions afforded corresponding bromo derivatives
in very good yield with high regioselectivity [34]. Most of the reagents
reported above for bromination are often hazardous, very toxic,
80
expensive, not readily available, need to be freshly prepared, require
drastic conditions or prolonged reaction times and involve tedious
work-ups. Thus a milder, selective, non-hazardous and inexpensive
reagent is still in demand.
In Chapter 3, we reported regioselective α-bromination of alkyl
aromatic compounds by two-phase electrolysis. In that work it was
observed that while most of the alkyl aromatic compounds studied
underwent selective side chain bromination, some were brominated
solely on the aromatic ring. This prompted us to investigate the
bromination potential of a two-phase electrolytic system for nuclear
bromination of aromatic compounds. Herein, we report a mild and
efficient method for the nuclear bromination of activated aromatic
compounds by two-phase electrolysis using anodic oxidation of
bromide ions as the bromine source (Scheme 4.1).
OH OHBr
OMe OMe
Br
Pt/Pt, 0 oC, NaBr
-e-
Pt/Pt, 0 oC, NaBr
-e-
2-naphthol 1-bromo-2-naphthol
2-methoxynaphthalene 2-bromo-6-methoxynaphthalene
Scheme 4.1 Nuclear bromination of activated aromatic compounds
81
4.2 Experimental
The two-phase electrochemical bromination reaction was
conducted in an undivided cell. The electrolyte containing 50%
aqueous NaBr with 5% HBr acting as the upper phase is used as the
bromine source. The substrate, dissolved in chloroform, acted as the
lower phase. The cell is composed of a jacketed glass cell provided
with a coolant inlet and outlet facility. Double distilled water was used
for preparing sodium bromide solutions.
A DC power source (Aplab) was used as the direct current source
for constant current electrolysis. The cell was equipped with a
magnetic stirrer and was used for the electrolysis and two platinum
sheets (10cm2) were used as the anode and the cathode, respectively.
The reaction was conducted galvanostatically and was monitored by
HPLC using a Shimpack ODS-18 column (125 mm x 4.5 mm) as the
stationary phase. The eluent consisted of methanol: water (80:20) at
a flow rate of 1 ml/min. Samples were analysed using a UV detector at
a wavelength of 254 nm.
4.2.1 Representative procedure for electrochemical bromination
A solution of 2-naphthol (1.44 gm,10 mmol) in 25 ml of
chloroform was taken in an undivided jacketed cell. To the above
solution 50-60% aqueous sodium bromide solution (50 ml) of
82
containing 5 ml of HBr (46% solution, 30 mmol) was added. Two
platinum electrodes (10 cm2) were placed in the upper layer of the
aqueous phase. The organic phase alone was stirred with a magnetic
stirrer at a rate of 40 rpm in such a way that the organic layer does
not touch the electrodes. The temperature of the electrochemical cell
contents was maintained at 0 0C throughout the electrolysis. The
electrolysis was conducted galvanostatically at a current density of 30
mA/cm2 until the quantity of charge indicated in Table 4.1 was passed.
During the electrolysis, the reaction was monitored by HPLC.
After completion of electrolysis, the lower organic phase was
separated, washed with water (2x25 ml), dried with anhydrous Na2SO4
and the solvent was removed under reduced pressure to get 2.2gm of
product. The resulting mixture was analysed by HPLC showing the
presence of 94% of 1-bromo -2-naphthol along with 2% of the starting
material and some minor impurities. The crude product was passed
through a column of silica gel (60-120 mesh) and eluted with a
mixture of ethyl acetate: n-hexane (1:9) to afford the pure brominated
product (2.0 g;94%). 1-bromo -2-napthol,(entry 7) mp 78 0C;
83
84
4.3 Results and discussion
The corresponding monobrominated products were formed in
excellent yield. Most of the activated molecules underwent conversion
on passing theoretical charge. Thus a series of aromatic compounds
were subjected to nuclear bromination by two-phase electrolysis at 0 -
5 oC using platinum sheet as electrodes to furnish the corresponding
monobromo arenes and the results are summarised in Table 4.1.
Direct bromination of a wide range of aromatic compounds possessing
electron-donating groups such as methoxy, hydroxy or amino groups
have been carried out by two-phase electrolysis. This electrochemical
method results in high yields (70-98%) of monobromo compounds and
usually with high regioselectivity (>95%) for the para position.
It is believed that an electrochemically generated polarized
bromine molecule combines with water giving one molecule of
hypobromous acid and one molecule of HBr. The hypobromous acid is
unstable due to its pronounced ionic nature and thus in the presence
of hydrobromic acid, one molecule of water is removed from
hypobromous acid giving Br+, which attacks the electron rich aromatic
ring and the product obtained under these conditions is exclusively the
ring-brominated product (p-isomer) and no trace of other regioisomers
or dibromo products were detected .
85
When benzylic positions were present in the starting materials,
no benzylic bromides were detected as products in the crude reaction
mixture. Although the protected aromatic amine and phenol were
para brominated in excellent yields, aniline and phenol-like aromatic
substrates furnished a mixture of o- and p-bromo isomers (o-cresol
gave 30% ortho- and 30% p-bromo isomers along with 40% of
starting material) after passing the theoretical charge, while highly
deactivated compounds such as nitrobenzene and chlorobenzene did
not undergo bromination even on prolonged reaction. In the case of
bromination of 2-naphthol, ortho-brominated material was the sole
product when the –OH group was unprotected. When protected with a
methyl group, the p-brominated product formed exclusively
(equation-3).
Br2 + H2O HOBr + HBr (1)
HOBr Br+ + H2O (2) H+
86
Scheme
OMe OMe
Br
OMe
+ Br+....(3)-H+
B H
+
It is notable that following electrolysis, the brominated aromatic
compound was easily isolated simply by separation of the organic layer
with the remaining bromide salt available for further use in anodic
bromination by replenishing the bromide ion by adding 47% HBr
solution. Thus completely ‘spent reagent’ free electroorganic synthesis
could be demonstrated using two-phase electrolysis (fig.4.7).
87
Table 4.1 Electrochemical nuclear bromination of aromatic compounds by two-phase electrolysis
entry Substrate Producta Charge Passed (F/mol)
Yieldb
(%)
Current efficiency
(%)
1
OMe
OMe
Br
2.3 92 87
2
OMe
OMe
OMe
Br OMe
2.1 95 95
3 OMe
OMe
Br
4.0 98 50
4 N
CH3
CH3
NCH3
Br
CH3
1.9 86 85
5 CH3
CH3
Br
4.0 80 50
6
OH
CHO
OMe
OH
CHO
OMeBr
2.2 95 90
7 OH
OHBr
2.0 94 94
88
8
OHCH3
OHCH3
OHCH3
Br Br
Br
[3:3:3] c
2.0
4.0
60
92d
60
92
9
NH2
BrBr
Br
NH2
6.0 98 98
a Characterised by NMR spectroscopy b Isolated yield c Ratio of unconverted/o-/p-brominated products d 98 % conversion
89
4.4 Spectral data of nuclear brominated compounds
1. 1-Bromo 2-naphthol; Solid, m.p78 0C IR(KBr): ν=
3498,2983,2848,1615,1583,1511,1476,1400,1286,1217,1181,1083,
1026,931,893,866,817,768,665,450 cm-1 1H NMR (400 MHz,CDCl3):
δ=7.91(d,1H,J=8.1Hz),7.74(m,2H),7.56(t,1H,J=8.2Hz),7.41(t,1H,J=8.
2Hz),7.28(d,1H,J=8.1Hz).
2. 1-Bromo 4-methoxy benzene, Liquid, IR(neat):ν=
2936,2638,1605,1597,1518,1472,1400,1293,1226,1171,1097,1028,
926,869,792,601,450 cm-1 1H NMR (400 MHz,CDCl3): δ 3.75(s, 3H),
6.76 (d,2H,J=8.0Hz) 7.36 (d,2H,J=8.0Hz). 13C NMR: 55(CH3), 113(C),
116(CH), 132(CH),159(C).
3. 1-Bromo-3,4-dimethoxy benzene: IR(neat):ν=
2941,2839,1698,1603,1528,1486,1440,1400,1297,1231,1212,1184,1
139,1019,932,841,798,781,695,450 cm-1 1H NMR (400 MHz,CDCl3):
δ 3.8 (s, 3H), 3.9 (S, 3H), 6.75 (d,1H, J= 8.1Hz), 6.9 (d,1H, J=
2.1Hz), 7.1(m, 1H).
4. 4-Bromo-N,N-dimethyl aniline:
1H NMR (400 MHz,CDCl3): δ 2.9 (s, 1H), 6.7 (d, J=9.0Hz,1H).
13 C NMR: 40 (CH3),108(C), δ 114(CH),132 (CH),149 (C).
90
Figure 4.2 HPLC data of 2-methoxy naphthalene (entry 3 ) retention time = 7.5 min.
91
Figure 4.3 HPLC data of reaction mixture (2-methoxy naphthalene bromination) after passing 25% of theoretical charge.
92
Figure 4.4 HPLC data of reaction mixture (2-methoxy naphthalene bromination) after passing 50% of theoretical charge.
93
Figure 4.5 HPLC data of reaction mixture (2-methoxy naphthalene bromination) after passing theoretical charge(2F).Product has
retention time of 9.5min.
94
95
96
Figure 4.8 1HNMR data of 2-bromo 6-methoxy naphthalene.
97
Figure 4.9 13CNMR data of 2-bromo 6-methoxy naphthalene.
98
Figure 4.10 1HNMR data of 1-bromo 2-naphthol(entry ).
99
4.5 Conclusion
It has been demonstrated that a new, mild and efficient method
to brominate aromatic compounds selectively at the p-position by
simple constant current two-phase electrolysis. The amount of bromine
generated can be precisely controlled by simply switching off the
electricity, thereby eliminating the problems of handling, transporting
and storage of liquid bromine. The simple reaction set-up, cheap /
environment friendly reagents, excellent yields of regioselective
monobrominated products and simple work-up make this method
valuable from a preparative point of view.
100
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