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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