Bromine formation in solid NaBr/KNO3 mixture and assay of this reaction via bromination of activated aromatics

Article abstract of DOI:10.1007/s11696-018-0526-3

Bromine formation in the mixture of solid NaBr and KNO₃ was observed and the process was studied in different acidified organic solvent–water mixtures by monitoring the bromination of acetanilide and other compounds, containing activated aromatic substituents. This assay is based on fast bromination reaction of these aromatic compounds, as differently from the assay of Br₂, the brominated aromatics can be easily determined by conventional gas chromatography–mass spectrometry (GC–MS) methods. It was found that bromine was generated autocatalytically on the surface of salt crystals and the reaction was characterized by a lag period, the duration of which depended on reaction conditions, and importantly on the type of the organic solvent in the reaction mixture. As the bromine formation could be easily controlled by reaction conditions, it was suggested that the studied reaction might have practical applications as an environmentally friendly and economically feasible bromination method. It was also shown that the bromination of aromatics followed the mechanism of classical electrophilic aromatic substitution reaction.

Full text of DOI:10.1007/s11696-018-0526-3

Chemical Papers
https://doi.org/10.1007/s11696-018-0526-3
ORIGINAL PAPER
Bromine formation in solid NaBr/KNO3 mixture and assay of this
reaction via bromination of activated aromatics
Ida Rahu1 · Ott Kekišev1 · Jaak Järv1 · Peeter Burk1
Received: 30 January 2018 / Accepted: 1 June 2018
© Institute of Chemistry, Slovak Academy of Sciences 2018
Abstract
Bromine formation in the mixture of solid NaBr and KNO3 was observed and the process was studied in diferent acidifed
organic solvent–water mixtures by monitoring the bromination of acetanilide and other compounds, containing activated
aromatic substituents. This assay is based on fast bromination reaction of these aromatic compounds, as diferently from the
assay of Br2, the brominated aromatics can be easily determined by conventional gas chromatography–mass spectrometry
(GC–MS) methods. It was found that bromine was generated autocatalytically on the surface of salt crystals and the reaction
was characterized by a lag period, the duration of which depended on reaction conditions, and importantly on the type of
the organic solvent in the reaction mixture. As the bromine formation could be easily controlled by reaction conditions, it
was suggested that the studied reaction might have practical applications as an environmentally friendly and economically
feasible bromination method. It was also shown that the bromination of aromatics followed the mechanism of classical
electrophilic aromatic substitution reaction.
Keywords Feasible in situ method of bromine formation · Reaction with solid salts · Eco-friendly reagents · Bromination
of activated aromatics
Introduction
Szél et al. 2014) have been used as oxidants. Although
the application of molecular bromine is excluded in these
approaches, the harmful and environmentally not friendly
oxidizing reagents are still in use. Therefore, replacing these
oxidizers with less harmful chemicals is a great challenge
to improve the in situ bromination methods (Bansal 1998;
Narender et al. 2002, 2003; Tajik et al. 2005; Salakhov et al.
2008; Yousef et al. 2012; Kumar et al. 2012; Naresh et al.
2013; Hou et al. 2014; Sharma and Agarwal 2014).
Molecular bromine is widely used for the preparation of
various valuable chemical products and organic synthesis
intermediates (Bansal 1998). However, as this chemical
is extremely harmful and a highly reactive substance that
causes safety and environmental issues, attention has been
paid to developing safer reaction systems, where bromine is
generated in situ in the reaction mixture by oxidizing bro-
mide ions (Choudary et al. 2003; Podgoršek et al. 2009). In
these methods, for example, Oxone® (Narender et al. 2002,
2003; Naresh et al. 2013), hydrogen peroxide (Salakhov
et al. 2008), and several highly reactive iodine compounds
(Yousef et al. 2012; Kumar et al. 2012; Hou et al. 2014;
In this report, we describe a simple procedure, where
molecular bromine is generated in situ from solid inorganic
bromide and nitrate, more specifically using NaBr and
KNO3, as was done in this study. Both salts mentioned are
stable and safe compounds, and they are reasonably harm-
less to the environment.
Formation of Br2 was assayed by monitoring the fast
reaction of bromination of acetanilide, added into the reac-
tion mixture, as unlike the rather complicated procedure of
molecular bromine titration, brominated aromatics can be
easily quantifed by conventional GC–MS methods. This
assay procedure was used as a convenient tool for a system-
atic investigation into the bromine formation reaction under
various conditions. Furthermore, it was demonstrated that
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-018-0526-3) contains
supplementary material, which is available to authorized users.
* Ida Rahu
ida@ut.ee
1
Institute of Chemistry, University of Tartu, Ravila 14a,
50411 Tartu, Estonia
Vol.:(0123456789)
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Chemical Papers
bromination of several other aromatic compounds could also
be done under the same conditions, using solid KNO3 and
NaBr mixture. Importantly, the selectivity of the bromina-
tion reaction was in agreement with the conventional electro-
philic aromatic substitution mechanism, and the possibility
of radical mechanism was excluded by the analysis of the
bromination products of toluene.
the temperature program was diferent: 50 °C held for 4 min,
followed by a temperature ramp of 10 °C/min to 240 °C,
followed by 240 °C held for 5 min, giving a total program
length of 28 min.
The oxidative properties of the reaction mixture were ana-
lyzed by iodometry, using sodium thiosulfate for titration
of the formed iodine (Mendham et al. 1989; Skoog et al.
2013a, b, c, d).
Although the bromine formation reaction was obviously
an autocatalytic process, it was possible to control the rate of
the process using diferent acidifed solvent–water mixtures
that may be an important advantage of the proposed method.
Bromination reactions
Acetanilide bromination
Experimental
Acetanilide (5 mmol), NaBr (5.5 mmol), and KNO3
(5.5 mmol) were mixed in 30 mL of organic solvent (die-
thyl ether, sulfolane, or acetonitrile) and hydrochloric acid
(2.5 mL, 37% HCl in water) was added. This reaction mix-
ture was stirred briefy (1 min), but in most experiments
further stirring was not used, as discussed below.
General
The starting materials NaBr, KNO3, acetanilide, benzal-
dehyde, bromobenzene, and phenol were purchased from
Reahim. Hydrochloric acid (Lot no. SZBC1030V) and
4-hydroxy-3-methoxybenzaldehyde (Lot no. STBD2808V)
were purchased from Sigma-Aldrich, and toluene (Batch
no. PP/2013/00040) from Lach:ner. Substrate purities
were verifed by gas chromatography–mass spectrometry
(GC–MS). In addition, the purity of acetanilide was veri-
fed by nuclear magnetic resonance (NMR) and its melting
point was also measured. The solvents diethyl ether (Lot nos.
STBF9065V, SZBC0160V, SZBE2110V) and sulfolane (Lot
no. MKBN9784V) were purchased from Sigma-Aldrich, and
acetonitrile (≥99.9%) was purchased from Merck.
Samples (0.5 mL) were taken from the reaction mixture
at fxed time points. Prior to sampling, the reaction mixture
was stirred briefy for 1 min. The samples were neutralized
with saturated NaHCO3 solution (10 mL) and treated with
Na2S2O3 (5 mL) to remove excess bromine. The aromatic
compounds were then extracted with diethyl ether (3 mL),
and the organic layer was analyzed using GC–MS. The
reactions were characterized by calculating the conversion
values from the peak areas of the substrate (Ssubstrate) and
product (Sproduct) as follows:
NMR spectra were recorded on a Bruker Avance III HD
Sproduct
1
Conversion (%) =
× 100%.
(operating at 700.1 MHz for H spectra and 176.0 MHz
(1)
Sproduct + Ssubstrate
for 13C spectra) at 25 °C in CDCl3 (Lot no. B15097,
Sigma-Aldrich).
Following this equation, a conversion value of 0% means
that no product was detected in the sample and a conversion
value of 100% means that no substrate was detected. The
reaction product 4-bromo-acetanilide was identifed by its
molecular mass, NMR spectrum, and melting point.
In separate experiments, the amounts of HCl, KNO3, and
NaBr were varied, as were the sampling intervals (15 min,
30 min, 1 h, 2 h).
Bromination products were assayed using an Agilent
Technologies 7890A gas chromatograph equipped with a
nonpolar DB-5ms Ultra Inert column (phenyl arylene poly-
mer virtually equivalent to 5% phenyl-methylpolysiloxane)
with length of 30 m, radius of 0.25 mm, and flm thickness
of 0.25 μm (inlet split 20:1, 0.5 μL; carrier gas helium 6.0,
fow rate 2 mL/min, pressure 26.561 psi). The chromato-
graph was equipped with a quadrupole mass spectrometer
(MS) as the detector, using an electron ionization energy of
70 eV, a transfer line temperature of 280 °C, an ion source
temperature of 230 °C, a scanning range of 30–400 amu, a
threshold of 20,000, a reiteration number of 3, and a detector
scan rate of 2 scans/s. The GC–MS system was calibrated
by taking into account the diferent ionization degrees of the
substrate and product, and all relevant data were corrected.
The following temperature program was used to analyze
the acetanilide bromination products: 140 °C held for 4 min,
followed by a temperature ramp of 10 °C/min to 240 °C,
giving a total program length of 14 min. In all other cases,
Bromination of other substrates
The substrate (2 mmol), KNO3 (2.2 mmol), and NaBr
(2.2 mmol) were added to diethyl ether (10 mL) and the
reaction mixture was acidifed with HCl (1 mL, 37% HCl
in water). Samples (ca. 1 mL) were taken from the reac-
tion mixture after 1 and 4 h, and these were treated as in
the acetanilide bromination experiments. After taking the
second sample, the remaining reaction mixture was neutral-
ized with saturated NaHCO3 solution, the excess bromine
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was removed with Na2S2O3 solution, and the mixture was
extracted three times with diethyl ether (15 mL). The organic
layer was analyzed by GC–MS. The reaction products
extracted from the reaction mixture were identifed by their
molecular mass and, in the case of brominated toluene, also
by its NMR spectrum.
As the oxidizing properties of nitrate depend strongly
on pH (Atkins et al. 2010), no bromine formation was
observed in the absence of reasonable amounts of acid
in the reaction mixture. Therefore, the reactions were
performed in the presence of HCl. In separate experi-
ments, the influence of added acid on bromine formation
was studied and the results demonstrated that acid was
essential for the bromination process, although within the
concentration range of 5.5–120 mmol the amount of acid
did not affect the reaction. However, in the presence of a
large excess of acid, side reactions were initiated, such as
the hydrolysis of acetamide and its bromination product,
which reduced the yield of the process (Supplementary
Material).
Results and discussion
Bromine formation
The oxidative properties of nitrate ions are not sufcient for
the generation of bromine from bromide ions in aqueous
solution (Maloy 1985). However, these oxidative properties
can be improved by adding acid (Atkins et al. 2010) and
organic solvents (Reichardt 2003). Here, we observed the
formation of molecular bromine from bromine anions in the
presence of acid and in the used solvents containing up to
10% water. Depending on the reaction conditions, nitrate
ions may be reduced to various nitrogen compounds (Atkins
et al. 2010). In our experiments, the formation of nitrite ions
and NO2 was confrmed by iodometric titration.
Time course of the reaction
The process of bromine formation was followed via monitor-
ing of brominated acetanilide formation, as the latter reac-
tion occurs fast if compared to bromine formation.
The time course of the process was characterized by the
presence of lag time, as shown in Fig. 1 and Supplementary
Material. In acetonitrile and sulfolane, this lag time was over
1 h, whereas in diethyl ether the bromination product was
already observed after 10 min. These preliminary results
are important for further planning of kinetic experiments,
which will be needed for more detailed analysis of the reac-
tion mechanism.
It was found that the bromination of acetanilide
(Scheme 1) was a fast process under the applied reaction
conditions and the bromination step for this substrate was
limited by bromine formation. Therefore, it was convenient
to follow the oxidation of bromide to bromine by monitoring
the bromination product of this reaction.
It was also observed that the rate of bromine formation
depends on the amount of nitrate salt. On the other hand, a
large excess of nitrate led to side reactions, whereas increas-
ing the amount of the bromide salt had no infuence on the
time course of the process. It was also observed that the
excess of acetanilide over the bromide salt decreased the
yield of bromine formation, detected via decreased yield of
bromo-acetanilide (Supplementary Material).
It was found that stirring of the reaction mixture inter-
fered with the bromination process. When the reaction mix-
ture was not stirred, bromine formation was observed on the
surface of the solid salts. This process can be observed visu-
ally by the color change, as well as by monitoring acetani-
lide bromination. Therefore, it can be concluded that direct
contact of the KNO3 and NaBr crystals may be important
for bromine formation. However, as stirring was required for
reliable sampling of the heterogeneous reaction mixtures,
the reactions were stirred shortly 2 min prior to taking each
sample for analysis, and this standardized protocol was used
throughout all experiments.
In summary, it can be concluded that the rate of bromine
formation was controlled by the concentration of nitrate
ions, which in turn, should be responsible for the formation
of bromine from the bromide ions.
Bromination of other aromatic compounds
As the used assay of bromine formation reaction is based on
bromination of acetanilide, which has indeed a strongly acti-
vated phenyl group, it was interesting to study the possibility
of application of other aromatic compounds. The summary
of these experiments is given in Table 1.
It can be seen that the efectiveness of the bromination
reactions (i.e., conversion) was in good agreement with
the understanding of the relative reactivity of aromatic
compounds in electrophilic substitution reactions. Moreo-
ver, no bromination products were detected in the case of
Scheme 1 Bromination of acetanilide
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Fig. 1 Solvent efects and lag period in diethyl ether
Table 1 Bromination of various aromatic compounds with solid NaBr and KNO3 in a diethyl ether–water mixture at 25 °C
Substrate
Products and their conversions (%)
2-Bromophenol (13%)
4-Bromophenol (19%)
2,4-Dibromophenol (8%)
2,4,6-Tribromophenol (trace)
Phenol
2-Bromo-1,4-dimethoxybenzene (27%)
2,5-Dibromo-1,4-dimethoxybenzene (30%)
1,4-Dimethoxybenzene
5-Bromo-4-hydroxy-3-methoxybenzaldehyde
(100%)
4-Hydroxy-3-methoxybenzaldehyde
Reactions were characterized by conversion values after 4 h according to the GC–MS data and Eq. 1
benzaldehyde and bromobenzene after 4 h incubation, even
though the formation of molecular bromine was clearly
observed by the color change of the reaction mixtures.
Second, we tested the possibility of radical bromination
of aromatics, as initiation periods are a characteristic fea-
ture of radical reactions (Clayden et al. 2012). However, no
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bromination of the methyl group of toluene was detected,
whereas bromination of the para- and ortho-positions were
clearly observed, although the yields of these products were
only 2 and 1%, respectively, that agree with relatively weak
activation of the aromatic ring by methyl group in the classi-
cal mechanism of aromatic electrophilic substitution. How-
ever, this does not exclude the possibility that the bromine
formation reaction could occur via a radical autocatalytic
mechanism, as the aforementioned lag time is very charac-
teristic for autocatalytic reactions (Horváth and Nagypál
2015).
to the possibility of the formation of nitrite ions and NO2
in this mixture. Moreover, the iodometric titration revealed
that there was always an excess of oxidizing reagents over
the concentration of bromine, formed in the reaction mix-
ture or externally added in separate experiments. These data
implicitly confrm the suggested autocatalytic mechanism
of spontaneous bromine formation in the reaction mixture
used here.
On the other hand, this autocatalytic reaction mechanism
alone does not explain the sensitivity of the bromine for-
mation reaction toward stirring of the heterogeneous reac-
tion mixture, and this phenomenon points to the possibility
that the proximity or direct contact of the crystal surfaces
of the solid reagents is needed for efcient initiation of the
bromine formation. Similar stirring efect to autocatalytic
clock reactions has been studied before. It was concluded
that any inhomogeneities in these reactions may have essen-
tial impact to reproducibility and involve the so-called crazy-
clock characteristics (Nagypál and Epstein 1986; Horváth
and Nagypál 2015; Valkai et al. 2015). This could be one of
the possible explanations to the discovered phenomenon. To
clarify these issues, a more thorough analysis of the reaction
mechanism would be required, together with kinetic analysis
of the time course of the bromination reaction.
Mechanism of bromine formation
The reaction between nitrate and bromide ions in acidic
media to generate molecular bromine is a relatively slow
and reversible reaction and can be represented as follows
(Lengyel et al. 1989):
NO−3 + 2Br− + 3H+ ⇄ Br2 + HNO2 + H2O.
(2)
It can be seen that the presence of acid is necessary for
bromine formation and water concentration should be kept
to a minimum. Moreover, it was shown that the nitrous acid
formed in this reaction can further autocatalyze bromine
formation through the cascade of reactions depicted in
Scheme 2 (Lengyel et al. 1989).
This autocatalytic mechanism explains the observed lag
period of the process. Importantly, the formation of oxidiz-
ing reagents in the acidifed sulfolane–water mixture with
solid KNO3 was observed by iodometric titration, pointing
Conclusions
The in situ formation of bromine was observed in reaction
mixtures containing solid bromide and nitrate salts in acidi-
fed organic–water mixtures, and this reaction was assayed
via observation of acetanilide bromination that could be eas-
ily monitored by standard GC–MS analysis. The bromine
formation reaction occurs on the surface of the insoluble
salts and was characterized by lag time, the duration of
which depends on solvent composition of the reaction mix-
ture. As this reaction uses environmentally safe reagents, it
may have practical signifcance for bromination of aromatic
compounds.
Acknowledgements This work was supported by the institutional
research funding IUT (IUT20-15) of the Estonian Research Council.
References
Atkins PW, Overton TL, Rourke JP, Weller MT, Armstrong FA (2010)
The group 15 elements. In: Shriver and Atkins’ inorganic chemis-
try, 5th edn. Oxford University Press, Oxford, pp 375–397
Bansal RK (1998) Aromatic electrophilic substitution reactions. In:
Hyde CW (ed) Synthetic approaches in organic chemistry. Jones
& Bartlett Publishers, London
Choudary BM, Someshwar T, Reddy CV, Kantam ML, Ratnam KJ,
Sivaji LV (2003) The frst example of bromination of aromatic
compounds with unprecedented atom economy using molecular
Scheme 2 Autocatalytic bromine formation
1 3

Chemical Papers
bromine. Appl Catal A Gen 251:397–409. https://doi.org/10.1016/
S0926-860X(03)00379-X
Reichardt C (2003) Solvent efects on electron-transfer equilibria. In:
Solvents and solvent efects in organic chemistry, 3rd edn. Wiley-
VCH, Weinheim, pp 137–139
Clayden J, Greeves N, Warren S (2012) Radical reactions. In: Organic
chemistry, 2nd edn. Oxford University Press, New York, pp
1019–1052
Salakhov MS, Bagmanov BT, Umaeva VS, Bagmanova MI (2008)
Oxidative bromination of aniline and its derivatives. Russ J Appl
Chem 81:1479–1481. https://doi.org/10.1134/S10704272080803
14
Horváth AK, Nagypál I (2015) Classification of clock reactions.
ChemPhysChem 16:588–594. https://doi.org/10.1002/cphc.20140
2806
Sharma SK, Agarwal DD (2014) NH4Br-Br2 catalysed oxidative bromi-
nation of aromatic compounds. J Agric Life Sci 1:65–81
Skoog DA, West DM, Holler FJ, Crouch SR (2013a) Applications of
oxidation/reduction titrations. In: Simpson C (ed) Fundamentals
of analytical chemistry, 9th edn. Brooks/Cole, Cengage Learning,
Belmont, pp 509–534
Hou J, Li Z, Jia X-D, Liu Z-Q (2014) Bromination of arenes using
I2O5-KBr in water. Synth Commun 44:181–187. https://doi.
org/10.1080/00397911.2013.796523
Kumar L, Mahajan T, Agarwal DD (2012) Bromination of deactivated
aromatic compounds with sodium bromide/sodium periodate
under mild acidic conditions. Ind Eng Chem Res 51:11593–
11597. https://doi.org/10.1021/ie202851k
Skoog DA, West DM, Holler FJ, Crouch SR (2013b) Applications of
standard electrode potentials. In: Simpson C (ed) Fundamentals
of analytical chemistry, 9th edn. Brooks/Cole, Cengage Learning,
Belmont, pp 473–508
Lengyel I, Nagy I, Bazsa G (1989) Kinetic study of the autocata-
lytic nitric acid-bromide reaction and its reverse, the nitrous
acid-bromine reaction. J Phys Chem 93:2801–2807. https://doi.
org/10.1021/j100344a021
Skoog DA, West DM, Holler FJ, Crouch SR (2013c) Chemicals, appa-
ratus, and unit operations of analytical chemistry. In: Simpson C
(ed) Fundamentals of analytical chemistry, 9th edn. Brooks/Cole,
Cengage Learning, Belmont, pp 15–47
Maloy JT (1985) Nitrogen. In: Bard AJ, Parsons R, Jordan J (eds)
Standard potentials in aqueous solution. Marcel Dekker, New
York, pp 127–139
Skoog DA, West DM, Holler FJ, Crouch SR (2013d) Titrations in ana-
lytical chemistry. In: Simpson C (ed) Fundamentals of analytical
chemistry, 9th edn. Brooks/Cole, Cengage Learning, Belmont,
pp 302–321
Mendham J, Denney RC, Bassett J, Jefery GH (1989) Oxidation and
reduction processes involving iodine: iodometric titrations. In:
Vogel’s textbook of quantitative chemical analysis, 5th edn. Long-
man Group, Essex, pp 384–400
Szél V, Csekő G, Horváth AK (2014) Kinetics and mechanism of the
oxidation of bromide by periodate in aqueous acidic solution. J
Phys Chem A 118:10713–10719. https://doi.org/10.1021/jp509
164e
Nagypál I, Epstein IR (1986) Fluctuations and stirring rate efects in
the chlorite–thiosulfate reaction. J Phys Chem 90:6285–6292.
https://doi.org/10.1021/j100281a044
Narender N, Srinivasu P, Prasad MR, Kulkarni SJ, Raghavan KV
(2002) An efcient and regioselective oxybromination of aro-
matic compounds using potassium bromide and oxone®,*. Synth
Commun 32:2313–2318. https://doi.org/10.1081/SCC-120006001
Narender N, Mohan KVVK, Kulkarni SJ, Raghavan KV (2003) Mild
and regioselective oxidative bromination of aromatic compounds
using ammonium bromide and oxone. J Chem Res 2003:597–598.
https://doi.org/10.3184/030823403322597775
Tajik H, Shirini F, Hassan-zadeh P, Rashtabadi HR (2005) Bromination
of aromatic compounds with potassium bromide in the presence of
poly(4-vinylpyridine)-supported bromate in nonaqueous solution.
Synth Commun. https://doi.org/10.1081/SCC-200064999
Valkai L, Csekő G, Horváth AK (2015) Initial inhomogeneity-induced
crazy-clock behavior in the iodate–arsenous acid reaction in a
bufered medium under stirred batch conditions. Phys Chem Chem
Phys 17:22187–22194. https://doi.org/10.1039/C5CP02572A
Yousef J, Tajeian K, Kolvari E, Koukabi N, Khazaei A, Zolfgol MA
(2012) A green protocol for the bromination and iodination of
the aromatic compounds using H5IO6/NaBr and H5IO6/NaI in
the water. Bull Korean Chem Soc 33:2619–2622. https://doi.
org/10.5012/bkcs.2012.33.8.2619
Naresh M, Kumar MA, Reddy MM, Swamy P, Nanubolu JB, Narender
N (2013) Fast and efcient bromination of aromatic compounds
with ammonium bromide and oxone. Synthesis 45:1497–1504.
https://doi.org/10.1055/s-0033-1338431
Podgoršek A, Stavber S, Zupan M, Iskra J (2009) Environmentally
benign electrophilic and radical bromination ‘on water’: H2O2–
HBr system versus N-bromosuccinimide. Tetrahedron 65:4429–
4439. https://doi.org/10.1016/j.tet.2009.03.034
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