Green process development for the preparation of 2,6-dibromo-4-nitroaniline from 4-nitroaniline using bromide-bromate salts in an aqueous acidic medium

Article abstract of DOI:10.1039/c6ra13680j

An organic solvent-free process for the preparation of 2,6-dibromo-4-nitroaniline, (an important intermediate in the synthesis of azo disperse dyes) from 4-nitroaniline using 2:1 bromide-bromate salts under an aqueous acidic medium at ambient conditions has been developed. The 2:1 bromide-bromate couple could be obtained by mixing pure NaBr/NaBrO₃ salts or by adjusting the 5:1 mole ratio of NaBr/NaBrO₃ (obtained in an aqueous solution as an intermediate from the bromine manufacture industry by a cold process) to 2:1 by the addition of a suitable oxidant. After completion of the reaction the product was purified by simple filtration and washing with water. The aqueous acidic filtrate was recycled up to five times without loss of purity and yield of the product. The method was extended to other aromatic substrates.

Full text of DOI:10.1039/c6ra13680j

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Green Process Development for the Preparation of 2, 6-DiDbOrI:o10m.103o9-/C46-RA13680J
nitroaniline from 4-Nitroaniline Using Bromide-Bromate Salts in Aqueous
Acidic Medium
Venkatanarayana Pappula and Subbarayappa Adimurthy*
Academy of Scientific & Innovative Research, CSIR–Central Salt & Marine Chemicals
Research Institute, G.B. Marg, Bhavnagar-364 002. Gujarat (INDIA).
E-mail: adimurthy@csmcri.org
Abstract: Organic solvent-free process for the preparation of 2, 6-dibromo-4-nitroaniline,
(important intermediate in the synthesis of azo disperse dye) from 4-nitroaniline using 2:1
bromide-bromate salts under aqueous acidic medium at ambient conditions has been
developed. The 2:1 bromide-bromate couple could be obtained by mixing pure NaBr/NaBrO3
salts or by adjusting the 5:1 mole ratio of NaBr/NaBrO3 (obtained in aqueous solution as
intermediate from bromine manufacture industry by cold process) to 2:1 by the addition of
suitable oxidant. After completion of the reaction the product was purified by simple filtration
and washing with water. The aqueous acidic filtrate was recycled up to five times without loss
of purity and yield of the product. The method was extended to other aromatic substrates.
------------------------------------------------------------------------------------------------------------------------------------
Bromination of aromatic substrates is a fundamental reaction in organic chemistry1 due
to the importance of the resultant bromo-products which are used as intermediates in the
synthesis of various pharmaceutical industries2 azo-disperse dyes,3 flame retardants,4
pesticides5 and herbicides.6 Particularly, 2,6-dibromo-4-nitroaniline (DBPNA) is a very
important intermediate in azo-disperse dye industry and in the synthesis of star polyfluorenes
which are useful in photovoltaic applications.7 In addition to the above industrial applications,
the antifungal behaviour of this molecule made it pharmaceutically important product.8
DBPNA is a main building block in the synthesis of Nanoputians.9 Due to the important
applications of bromocompounds, a number of brominating reagents have been developed by

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various groups. Among those reagents, liquid bromine is a very classical reagent for industrial
DOI: 10.1039/C6RA13680J
production of desired bromo compounds despite its hazardous nature. To overcome the
hazardness and handling problems associated with liquid bromine at large scale, we have
introduced a new concept of using liquid bromine intermediate, which consists an aqueous
solution of 5:1 bromide-bromate mole ratios during the liquid bromine recovery by cold
-
process.10 This 5:1 mole ratio of Br-/BrO3 could be used for various bromination reactions in
-
combination of mineral acids and suitable oxidants as desirable. Alternately, the 5:1 Br-/BrO3
could be converted to 2:1 mole ratios using oxidants like sodium hypochlorite and can be used
for aromatic substitution reactions under aqueous conditions (Scheme 1).11 During the
bromination process of organic substrates, the addition of any mineral acids to the aqueous
-
solution containing 2:1 Br-/BrO3 salts generates hypobromous acid (BrOH) which is
accountable for electrophilic substitution reactions.
Scheme 1. Bromination of PNA and its applications.
Based on our published reports, one of the textile dye manufacturing industry in India12
approached us to develop a process for the preparation of the dye intermediate 2, 6-dibromo-
4-nitroaniline from para-nitroaniline (PNA) using our concept of environment-friendly
bromination process to dispense the problems associated with liquid bromine. Accordingly, we
undertook the process development of the desired molecule, and performed the reactions using
alkaline intermediate as well as constituted bromide-bromate salts to achieve the desired yield,
purity, product colour and its effluent recyclability which are discussed in this report.
Initially, we performed the reactions with bromide-bromate salts and different mineral acids,
solvents at lab scale (1-2 g of PNA) experiments (see Table S1, in the supporting information
for details). After screening of different conditions, we found that, the good yield of the desired

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product could be obtained by the addition of brominating reagent solution slowly to the
DOI: 10.1039/C6RA13680J
aqueous acidic PNA slurry, rather than addition of acid to the solution containing PNA and
aqueous brominating solution. This mode of addition was also advantageous for the recycling
of the acidic filtrate after collecting the product by filtration under organic solvent-free
conditions. Then, we tested the reaction with brominating reagent prepared from aqueous
alkaline intermediate. The alkaline bromine intermediate solution which contains 5:1 mole
ratio of NaBr/NaBrO3 was selectively oxidized to 2:1 ratio of NaBr/NaBrO3 by the controlled
addition with NaOCl solution (Scheme 1, eq. 1). These 2:1 (NaBr/NaBrO3) aqueous solution
and constituted bromide-bromate salts were used for the bromination of PNA at 10.0 gram
scale and the results are discussed in Table 1.
As the product DBPNA was obtained in 95% yield with 100% purity by GC, by
conducting the reaction only in water, without any column separation but, by simple filtration
and washing with water (Table S1). Then we scaled up the reaction to 10.0 g starting substrate
(PNA) to check the feasibility of the reaction (Table 1). The reaction of PNA with 2:1 ratio of
Table 1. Preparation of DBPNA from PNAa.
aReaction conditions unless otherwise noted: The reactions were carried out at 10 g PNA, aqueous brominating
reagent solution, at room temperature, 4 h. bPurity by HPLC assessed by colourtex industry. cReaction performed
at 100 g scale of PNA.
NaBr/NaBrO3 and three equivalents of hydrochloric acid (w.r.t. PNA), 84% yield of DBPNA
was obtained with 94% purity (Table 1, entry 1). The same reaction with nitric acid gave 85%
yield with reduced purity (Table 1, entry 2). However, with two equivalents of sulfuric acid
H2SO4 the reaction gave 94% yield with 100% purity (Table 1, entry 3). By decreasing the

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amount of acid to 1.5 equivalents also the same yield of the product was obtained with same
DOI: 10.1039/C6RA13680J
purity (Table 1, entry 4). A sample of this product was also tested and evaluated by the
colourtex industry to meet their requirements.13 Further, reducing the H2SO4 to one equivalents,
both the yield and purity was dropped to 86% and 85% respectively (Table 1, entry 5).
Maintaining the H2SO4 at 1.5 equivalents (w.r.t. PNA), the same reaction was performed with
the brominating reagent prepared from the alkaline bromine intermediate, the similar yield of
DBPNA was obtained (Table 1, entry 6). To validate the method, batch scale experiment was
conducted at 100 g of PNA. At large scale, small amount of mono bromo product was observed
with 91% yield of the desired product.14
As stated the product was obtained in a required purity by filtration, and washing, the
filtrate was acidic in nature (as 0.5 equivalent acid was used for the reaction to obtain good
yield of the product) and not suitable to dispose as such. Hence the filtrate containing 0.5
equivalents of acid was collected after filtration of solid product and it was recycled in the
following cycle by the addition of one equivalent of acid along with the required quantities of
NaBr and NaBrO3 with minimum amount of water to dissolve the salts. In this way we
performed up to five such recycles of the filtrate and the results are presented in fig 1. As can
be seen from the fig 1, the similar yield of DBPNA and purity was obtained up to five cycles.
Fig 1. Recyclable study
After filtration of the reaction mixture the filtrate containing excess acid is collected and
reused for the next cycle. H2SO4 required for the synthesis of dibromo-para-nitroaniline is 1.5
equivalents in fresh cycle. Excess of 0.5 equivalents of H2SO4 was recycled along with aqueous
effluent for next recycles. The yield and purity of the product doesn't affect up to 5 continuous
recycles of the aqueous effluent.1 equiv. of H2SO4 only used for up to five recycles. By
recycling the acidic filtrate not only reduces the acid requirement, but also minimize the
effluent discharge which contains hazardous waste into the environment.

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The same bromination procedure was extended to other representative industrially
DOI: 10.1039/C6RA13680J
aromatic substrates (Table 2). Bromination of aniline with three equivalents of aqueous
brominating reagent gave 94% of tribromoaniline by simple filtration and washing with water
(Table 2, entry 1). Similarly, the bromination of other aniline derivatives were performed with
two equivalents of brominating reagent, and obtained the corresponding dibromo derivatives
in good yields (91-95%) (Table 2, entries 2-6). Tribromination of phenol and mono
bromination of anisole were obtained in 90% and 95% yields respectively (Table 2, entries 7
and 8).
Table 2. Bromination of other aromatic substratesa
aReaction conditions unless otherwise stated: All the reactions
were performed at 5.0 mmol scale, at room temperature, 4h
reaction time, for entries 1 and 7, three equivalents of BrOH &
two equivalents of H2SO4, for entries 2-6, two equivalents of
BrOH & 1.5 equivalents of H2SO4 and for entry 8, one
equivalent of each BrOH and H2SO4 were employed, yields of
crude product obtained after filtration and washing with water
b
without column separation. Purity based on area % by GC.
cProduct extracted with DCM.

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General procedure for the preparation of 2,6-dibromo 4-nitro aniline from 4-nDitOrI:o10a.1n03Vi9ile/iwCnA6erRticAl1e3O6n8li0nJe
using NaBr and NaBrO3 salts: To a one liter two necked round bottomed flask fitted with
overhead stirrer and addition funnel was charged with 4-nitro aniline PNA (10 g, 72.5 mmoles)
and aqueous H2SO4 solution [prepared by dissolving 10. 86 g; 110.8 mmol in 60 mL water (i.e.
1:10 v/v)]. The contents were stirred for 5 minutes to get homogeneous slurry of PNA. To the
above mixture, an aqueous solution containing 11.59 g of total bromide (10.0 g; 97.0 mmol
NaBr and 7.21 g; 47.7 mmol NaBrO3 dissolved in 100 mL of water) was added slowly dropwise
through additional funnel during a period of 2 h at room temperature. After complete addition
of the brominating solution, stirring was continued for another 2 h at the same temperature.
The reaction mixture completely turns to yellowish, then the reaction mixture was filtered by
using Buckner funnel connected to vacuum pump. The filtrate (mother liquor) was collected
for recycle in the following batch. The residue containing product was washed with water (3x50
mL). The yellowish solid product obtained was oven dried at 100° C for 1 hour. After drying
product DBPNA 95 % (20.30 g, 68.6 mmol) was obtained it was further characterized by 1H
& 13C NMR, GCMS, LCMS, IR and melting point.
For recycling reactions, to the filtrate collected in the first batch was added another one
equivalent of H2SO4, (7.24 g; 73.9 mmol), fresh 10.g of PNA, stirred for five minutes. Then
the same quantities of aqueous brominating reagent solution as indicated above was added and
the same procedure was followed up to five cycles. The yields and purity of recycled are
indicated in fig 1.
Preparation of 2,6-dibromo 4-nitro aniline from 4-nitro aniline using alkaline
brominating reagent:15 To a ten liter glass reactor connected and equipped with a mechanical
stirrer, cooling condenser and additional funnel facility, was charged with 4-nitro aniline PNA
(100 g, 0.725 moles) and aqueous H2SO4 solution [prepared by dissolving 106.5 g; 1.08 mol in
600 mL water (i.e. 1:10 v/v)]. The contents were stirred for 5 minutes to get homogeneous
slurry of PNA. To the above mixture, an aqueous solution (2.0 L) containing 116.0 g of total
bromide (prepared from the original alkaline bromine solution)15 was added during a period of
2.0 h at room temperature. Stirring was continued for further 2.0 h. The reaction mixture was
treated with 5% Na2S2O3 solution (to reduce the excess bromine). Filtered the product under
vacuum, and the residue was washed with water (3x1000 mL), and the product was dried as
indicated in the above general procedure to get 91% yield (Table 1, entry 7).
Conclusions:

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In conclusion, we have developed a convenient procedure for the quantitative preparation of
DOI: 10.1039/C6RA13680J
2,6-dibromo 4-nitro aniline from 4-nitroaniline using NaBr and NaBrO3 salts in aqueous acidic
medium under ambient conditions without use of organic solvent in the process. The pure
product could be obtained by simple filtration and washing with water, which will meets the
requirement of industrial applications as a dye intermediate. We suggest the mode of addition
of brominating reagent to the aqueous acidic 4-nitroaniline solution to get better yield and it
helps to recycle the acidic filtrate. During the recycle of filtrate, the dilution of water in the
process does not affect either on the yield or the purity of the product. The same procedure was
extended for the preparation of other industrially important aromatic bromoproducts.
Acknowledgement:
CSIR-CSMCRI Communication No. 024/2016. We thank colourtex Industry, Surat, India for
showing initial interest and for the product analysis. V.P. is thankful to UGC, New Delhi, India
for his fellowship. We thank CSIR-Indus Magic (CSC-0123) for financial assistance. We are
also thankful to Dr. P. K. Ghosh for initial discussions.
1
Supporting information available: H and 13C NMR spectra, optimization reactions and
product analysis data by Colourtex Industry.
Notes and References
1 J. E. McMurry and E. E. Simanek, Fundamentals of Organic Chemistry, 6th Edition,
2006.
2
G. W. Gordon, Chem. Soc. Rev., 1999, 28, 335.
3 A. T. Peters, J. Soc. Dyers Colourists, 1988, 104, 344.
4 D. Ioffe and A. Kampf, “Bromine, Organic Compounds” Kirk-Othmer Encyclopedia of
Chemical Technology , John Wiley & Sons, 2002.
5 M. J. Dagani, H. J. Barda, T. J. Benya and D. C.Sanders, Ullmann’s Encyclopedia of
Industrial Chemistry: Bromine Compounds; Wiley-VCH: Weinheim, 2002.
6 M. A. Cutulle, G. R. Armel, J.T. Brosnan, M. D. Best, D. A. Kopsell, B. D. Bruce, H. E.
Bostic and D. S. Layton, J. Agric. Food Chem., 2014, 62, 329.
7 Ch. Chakraborty, A.Layek, P .P. Ray and S. Malik, European Polymer Journal, 2014,
52, 181.
8 H. Gershon, M. W. McNeil, R. Parmegiani and P. K. Godfrey, Appl. Microbiol., 1971,
22, 438.

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DOI: 10.1039/C6RA13680J
9 S. H. Chanteau and J.M. Tour, J. Org. Chem., 2003, 68, 8750.
10 (a) G. Ramachandraiah, P. K. Ghosh, A. S. Mehta, S. Adimurthy, A. D. Jethva and S. S.
Vaghela US Patent 6740253, 2004; (b) G. Ramachandraiah, P. K. Ghosh, S.Adimurthy,
A. V. Bedekar and D. B. Shukla, US Patent 7459139, 2008.
11 (a) S. Adimurthy, G. Ramachandraiah, A. V. Bedekar, S. Ghosh, B. C. Ranu and P. K.
Ghosh, Green Chem., 2006, 8, 916; (b) S. Adimurthy, S. Ghosh, P. U. Patoliya, G.
Ramachandraiah, M. K. Agrawal, M. R. Gandhi, S. C. Upadhyay, P. K. Ghosh and B. C
Ranu, Green Chem., 2008, 10, 232; (c) M. K. Agrawal, S. Adimurthy, B. Ganguly and
P. K. Ghosh, Tetrahedron, 2009, 65, 2791; (d) R. D. Patil, G. Joshi, S. Adimurthy and
B. C. Ranu, Tetrahedron Lett., 2009, 50, 2529; (e) R. D. Patil, G. Joshi and S.
Adimurthy, Ind. Eng. Chem. Res., 2010, 49, 8100; (f) G. Joshi and S.Adimurthy, Ind.
Eng. Chem. Res., 2011, 50, 12271; (g) M. Dinda, M. K. Agrawal, M. R. Gandhi, S. C.
Upadhyay, S. Adimurthy, S. Chakraborty and P. K. Ghosh, RSC- Advances 2012, 2,
6645; (h) S. Adimurthy, G. Ramachandraiah, G. Joshi, R. D. Patil, M. R. Gandhi, M.
Subbareddy and P. Maiti, US Patent 8957239, 2015.
12 Colourtex Industries Ltd. Surat, Gujarat – 395 023, INDIA.
13 For details of analysis please see the Table S2 in the supporting information.
14 When the bromination of PNA was performed with the brominating reagent prepared
from alkaline bromine intermediate under the conditions studied, small amount of
corresponding chloro derivative was observed. This may be due to the presence of NaCl
present in the reagent (Please see ref 10 for details).
15 The alkaline bromine solution obtained from the bromine manufacture industry contains
5:1 mole ratio of NaBr/NaBrO3 (total bromide content of the alkaline solution is 0.20
g/ml) was converted to 2:1 ratio of NaBr/NaBrO3 by the controlled oxidation of bromide
to bromate using 4% NaOCl solution and this aqueous solution was used in the present
procedure. For the recycling experiments the constituted NaBr and NaBrO3 salts were
used unless otherwise indicated. For 100.0 g of PNA, 116 g of total bromine is required.
Hence 579.5 mL of original alkaline bromine solution was treated with 1350 mL of
NaOCl (4% w/v) solution and used for the reaction.

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DOI: 10.1039/C6RA13680J
Green Process Development for the Preparation of 2, 6-Dibromo-4-
nitroaniline from 4-Nitroaniline Using Bromide-Bromate Salts in Aqueous
Acidic Medium
Venkatanarayana Pappula and Subbarayappa Adimurthy*
Academy of Scientific & Innovative Research, CSIR–Central Salt & Marine Chemicals
Research Institute, G.B. Marg, Bhavnagar-364 002. Gujarat (INDIA).
E-mail: adimurthy@csmcri.org
Abstract: Organic solvent-free process for the preparation of 2, 6-dibromo-4-nitroaniline,
from 4-nitroaniline using 2:1 bromide-bromate salts under aqueous acidic medium at ambient
conditions has been developed. The product was purified by simple filtration and washing
with water.