Sustainable Synthesis of Balsalazide and Sulfasalazine Based on Diazotization with Low Concentrations of Nitrogen Dioxide in Air

Article abstract of DOI:10.1002/chem.201605359

Low concentrations of nitrogen dioxide, which arises as a side product from a range of industrial processes, can effectively be recycled through the diazotization of anilines. The studies reported herein now demonstrate that the removal of nitrogen dioxide from gas streams is even more effective when hydrophilic anilines are used as starting materials. The diazonium salts, which are obtained in this way in up to quantitative yields, can directly be employed in azo coupling reactions, thus opening up an attractive route to the industrially important group of azo compounds.

Full text of DOI:10.1002/chem.201605359

A Journal of
Accepted Article
Title: Sustainable synthesis of balsalazide and sulfasalazine based on
diazotization with low concentrated nitrogen dioxide in air
Authors: Markus Rolf Heinrich, Dagmar Hofmann, Eva Gans, and
Jasmin Krüll
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201605359
Link to VoR: http://dx.doi.org/10.1002/chem.201605359
Supported by

10.1002/chem.201605359
Chemistry - A European Journal
COMMUNICATION
Sustainable synthesis of balsalazide and sulfasalazine based on
diazotization with low concentrated nitrogen dioxide in air
Dagmar Hofmann, Eva Gans, Jasmin Krüll and Markus R. Heinrich*[a]
Dedication ((optional))
Abstract: Low concentrated nitrogen dioxide, which arises as side
product from a range of industrial processes, can effectively be
recycled through the diazotization of anilines. The studies reported
herein now demonstrate that the removal of nitrogen dioxide from gas
streams is even more effective when hydrophilic anilines are used as
starting materials. The diazonium salts, which are obtained in this way
in up to quantitative yields, can directly be employed in azo coupling
reactions, thus opening an attractive access to the industrially
important group of azo compounds.
with the diazotization of anilines, and thus with the preparation of
aromatic diazonium salts, is certainly the most versatile.[14]
Starting from nitrogen dioxide[15,16] at concentrations in the range
of 0.25 to 6 vol.-% and a scrubber solution containing 4-chloro-
anilinium hydrochloride, denitrification coupled to diazotization
enabled the synthesis of biphenyls and iodoarenes via radical
Gomberg-Bachmann and Sandmeyer-type reactions (Scheme 1,
(3)).[17]
NO (in air)
R1
R1
CO2R2
N2 BF4
+
L5Fe-NO
CO2R2
ring-subst.
phenylalanines
With a yearly global production in the range of 80 million tons,
nitric acid represents one of the industrially most important bulk
chemicals.[1] Besides its main application, which is the preparation
of the fertilizer ammonium nitrate,[2] considerable amounts of nitric
acid are used for the nitration of aromatics (ca. 8 million
tons/year)[3] and for inorganic reactions such as the production of
diverse metal nitrate salts[4] or the etching of silicon.[5] Despite
(1)
(2)
(3)
N
(DMSO/H2O)
HO
O(H)
NO2 (in air)
(EtOAc)
amino
alcohols
NO2
N
NH2
N
Cl
NO2 (in air)
(HCl/H2O)
biphenyls,
iodoarenes
Cl
many improvements introduced over the last decades,
a
Cl
significant number of those organic and inorganic transformations
based on nitric acid are linked to the formation of gaseous nitric
oxides.[6] Denitrification of the resulting gas streams is nowadays
commonly achieved by selective catalytic reduction (SCR),[7]
selective non-catalytic reduction (SNCR)[8] or by wet scrubber
techniques.[9] In such processes, nitrogen monoxide and nitrogen
dioxide (NOx) are either reduced to simple dinitrogen with the aid
of a reductant (e.g. ammonia, urea), or, in the case of the wet
scrubber, are converted back to nitric acid.
With the aim to devise new sustainable synthetic methods[10] that
are able to make use of such nitrogen oxides, thus following the
concept from “waste to value”,[11] a new access to oximes and
aromatic amino acids could recently be developed using dilute
nitrogen monoxide in air (Scheme 1, (1)).[12] Although the obtained
products are comparably valuable, this first strategy was limited
to gas streams containing nitric monoxide in concentrations of at
least 10 vol.-%. Much lower concentrations of nitric dioxide could
be utilized in the oxidative nitration of styrenes (down to 0.1
vol.-%), at which dilution of the gas stream even led to a favorable
increase in product selectivity (Scheme 1, (2)).[13] Aromatic nitro
alcohols and nitro ketones accessible in this way are direct
precursors for widely applied amino alcohols. Regarding possible
fields of application, the third strategy combining denitrification
Scheme 1. Organic synthesis combined with denitrification: utilization of low-
concentrated nitrogen monoxide and nitrogen dioxide.[12],[13],[17]
In this communication, we now demonstrate that the combination
of denitrification and diazotization is even more effective for
structurally more demanding and more hydrophilic diazonium
salts, which serve as precursors in the syntheses of the
pharmaceuticals balsalazide, olsalazine and sulfasalazine.
The pharmaceuticals balsalazide (1), olsalazine (2) and sulfa-
salazine (3) were chosen as target compounds due to their
particular substitution pattern on the azobenzene substructure,
which enables synthetic access via diazotization (see arylamine
substructures, Figure 1) and azo coupling.[18-20] In this way, the
effectiveness of the denitrification-diazotization step can be
evaluated in combination with a subsequent azo coupling reaction,
at which this two-step sequence is also of fundamental
importance for the multi-ton scale production of a broad range of
azo compounds used as dyes for textiles and many other
purposes.[21],[22]
COOH
O
O
OH
N
OH
H
N
N
N
H
N
O
HO
N
2
1
COOH
O O
S
[a]
M.Sc. D. Hofmann, E. Gans, M.Sc. J. Krüll, Prof. Dr. M. R. Heinrich
Department of Chemistry and Pharmacy, Pharmaceutical Chemistry
Friedrich-Alexander-Universität Erlangen-Nürnberg
Schuhstraße 19, 91052 Erlangen, Germany
COOH
N
H
N
N
E-mail: markus.heinrich@fau.de
HO
COOH
3
Supporting information for this article is given via a link at the end of
the document.
Figure 1. Balsalazide (1), olsalazine (2) and sulfasalazine (3).
This article is protected by copyright. All rights reserved.

10.1002/chem.201605359
Chemistry - A European Journal
COMMUNICATION
From a pharmaceutical point of view, treatments with balsalazide
(1), olsalazine (2) and sulfasalazine (3) require significant
amounts of these compounds reaching maximum doses in the
range of 2-6 grams/day for acute illnesses.[23] Through cleavage
in the intestine, all three compounds can act as pro-drugs for 5-
aminosalicylic acid (5-ASA, mesalazine), which is active against
inflammatory bowel disease including ulcerative colitis and
Crohn’s disease.[24]
The data summarized in Table 1 show that comparable or even
better yields can be obtained in the 10-Liter wet scrubber than in
the small scale diazotization reactions (Scheme 2). No by-
products were formed except for the small amount of phenol 7a
(entry 1), at which the ratio of 7:7a demonstrates the good
predictability of the reaction by the small scale experiment
(Scheme 2). For the diazotization of sulfanilic acid (6), a larger
excess of four equivalents of nitrogen dioxide had to be used to
achieve full conversion to diazonium salt 9, whereas the usual
three equivalents led to only 70% yield and 30% of remaining
starting material 6. The fact that samples from each reaction
The first series of diazotization experiments with arylamines 4-6[25]
were carried out on small scale (0.50 - 1.0 mmol) to get insights
into the feasibility of each diazotization under wet scrubber
conditions, and to evaluate the formation of possible side products. mixture were concentrated under reduced pressure at 50 °C to
In a more general sense, it was of interest in how far results from
small scale reactions would be useful to predict the later process
in a wet scrubber. To simulate the conditions after uptake and
disproportionation of nitrogen dioxide in the acidic scrubber
solution, leading to nitrous and nitric acid, a 1:1 mixture of sodium
nitrite and nitric acid was used. The results obtained after several
optimization experiments are summarized in Scheme 2 (see
Supporting Information for details).
enable analysis by NMR points to a remarkable stability of
diazonium salts 7-9 in acidic aqueous solution. Referring to this,
we can currently not exclude that the formation of phenol 7a from
4 did not occur during diazotization, but may have been caused
by the slightly evelated temperature prior to analysis.
Table 1. Diazotization with nitrogen dioxide in air performed in a 10-Liter wet
scrubber.
R2
R2
NO2
R1
R1
O
O
O
O
(6 vol.-% in air)
NaNO2 (0.75 mmol)
HNO3 (0.75 mmol)
Cl
N2
N
OH
N
OH
(HCl/H2O)
rt
4
5
6
(Cl
)
H
H
H2N
(0.13 M HCl)
rt
H2N
X
7: R1 = CONH(CH2)2CO2H, R2 = H
4-6
(100 mmol)
4 (0.50 mmol)
7: X = N2 (84%)
7a: X = OH (7%)
: R = OH, R2 = CO2H
1
8
9: R1 = SO3H, R2 = H
COOH
OH
COOH
OH
NaNO2 (1.5 mmol)
HNO3 (1.5 mmol)
Entry
Reaction conditions[a]
Diazotization
Yield[b]
By-product
Cl
N2
(1.7 M HCl)
rt
H2N
5 (1.0 mmol)
8
(81%)
1
2
3
NO2 (3 equiv.), 0.13 M HCl
NO2 (3 equiv.), 1.5 M HCl
NO2 (4 equiv.), 0.13 M HCl
7 (77%)
7a (7%)
NaNO2 (1.5 mmol)
HNO3 (1.5 mmol)
8 (100%)
9 (100%)
--
--
SO3H
SO3H
Cl
N2
(0.13 M HCl)
rt
H2N
6
(1.0 mmol)
9 (99%)
[a] Scrubber solution: Arylamine 4-6 (100 mmol) in 4 L HCl/H2O (see Table).
Stream of nitrogen dioxide in air (6 vol%, 5 L/min) generated from Cu powder
and conc. HNO3 was passed through the scrubber solution over 22.4 min (or
30.0 min, entry 3). [b] Yield determined by 1H-NMR analysis using maleic acid
as internal standard.
Scheme 2. Reaction conditions for diazotization optimized on small scale.
Yields determined by 1H-NMR using maleic acid as internal standard.
The NO2 concentrations measured in the outgoing gas streams
are depicted in Figure 2.
The desired diazonium salts 7-9 were obtained in high yields from
all diazotizations, and only the reaction starting from the
balsalazide precursor 4 led to a detectable by-product 7a.[26] As
the intended transfer of the reaction into the wet scrubber requires
full solubility of reactant and product, the diazotization of 5-
aminosalicylic acid (5) had to be conducted under more strongly
acidic conditions. For the synthesis of sulfasalazine, sulfanilic acid
(6) was used as starting material, as diazotization of the larger
pyridinylsulfonamide (see dotted substructure of sulfasalazine (3),
Figure 1) gave low yields and several side-reactions including the
loss of SO2. In the next step, the diazotization reactions were
transferred into a 10-Liter wet scrubber miniplant (see Supporting
Information for pictures of setup). The required stream of nitrogen
dioxide in air was generated through addition of copper powder to
concentrated nitric acid, which leads to nitrogen dioxide in high
purity.[27] This reaction is also of high industrial importance for the
production of copper(II) nitrate, which is used as a precursor for a
broad variety of copper oxide and Claycop catalysts, in materials
science and as a mild nitration reagent.[28],[29]
Figure 2. Concentrations of nitrogen dioxide in outgoing gas stream after
diazotization of arylamines 4-6 and 4-chloroaniline.[13]
This article is protected by copyright. All rights reserved.

10.1002/chem.201605359
Chemistry - A European Journal
COMMUNICATION
Proportional to the ingoing concentration of ca. 60000 ppm (6
vol.-% NO2 in air), all diazotization reactions led to a highly
effective removal of nitrogen dioxide from the gas stream. A
comparison to the previously studied diazotization of 4-chloro-
aniline (max. 172 ppm after wet scrubber)[14] shows that more
polar arylamines such as 4-6 are even better suited for the
combination of denitrification and diazotization. In detail, the best
performance was achieved with 5-aminosalicylic acid (5) (max. 97
ppm) followed by sulfanilic acid (6) (max. 119 ppm) and
balsalazide precursor 4 (max. 139 ppm). Under the chosen
conditions, 5-aminosalicylic acid (5) does meet the requirements
of the European Union for environmental protection (max. NO2
concentration of 100 ppm).[6] Finally, the diazonium salt solutions
obtained from denitrification in the wet scrubber were evaluated
with regard to their suitability for azo coupling reactions. In
contrast to known protocols for azo coupling, the use of the
scrubber solution inevitably results in a much higher dilution.[18-20]
The final outcome of a series of optimization experiments, which
mainly included variations of the pH value and changes of the
reaction temperature, are depicted in Scheme 3 (see Supporting
Information for details).
be significantly more effective than the previously studied 4-
chloroaniline. Besides the significance of this work with a regard
to a future combination of denitrification and azo dye production,
the denitrification-diazotization principle could be used to design
a sustainable process in which nitric oxides arising from an arene
nitration reaction would be employed in a later stage of the same
synthetic sequence to enable diazotization and azo coupling.
Experimental Section
General procedure for denitrification-diazotization in a 10-Liter wet
scrubber. A stream of nitrogen dioxide (generated by slow addition of
copper powder (9.53 g, 150 mmol) to concentrated nitric acid (180 mL,
15.5 M) over 22.4 minutes) in air (6 vol.-% NO2, total flow: ca. 5 L/min) was
passed through a 10-Liter wet scrubber containing the arylamine (100
mmol) in a mixture of water (3.5 L) and 1 N HCl (0.5 L) at room temperature.
After the NO2 generation was finished, the air flow through the scrubber
was maintained for another 38 min. The content of NO2 in the outgoing
gas stream was measured over the time of NO2 generation and for further
23 minutes. A sample of 20 mL (max. 0.50 mmol) of the reaction mixture
was concentrated under reduced pressure and analyzed by 1H NMR
spectroscopy using maleic acid as internal standard. The remaining main
part of the scrubber solution was used in the azo coupling step.
HOOC
O
O
N
OH
HO
H
HOOC
HO
N
10
(1 equiv.)
N
7
NaOH, Na2CO3
(H2O), 0 °C
Acknowledgements
1
balsalazide ( ) (67% on 10 mmol scale)
(50% on 100 mmol scale)
The authors are grateful for the financial support of this project by
the Deutsche Bundesstiftung Umwelt (DBU) (PhD grant No.
80014/189 and Research Grant No. 30388-31). We are further
grateful for support by the Graduate School of Molecular Science
(GSMS), for experimental assistance by Clara Schäfer and for
helpful discussions with Dr. Bernd Schricker (Luft- und Thermo-
technik Bayreuth).
HOOC
HO
SO3H
ROOC
HO
N
10
(1 equiv.)
N
9
NaOH, Na2CO3
(H2O), 0 °C
11
: R = H (57% on 10 mmol scale)
MeOH, H2SO4
ref. 20b
(59% on 100 mmol scale)
12: R = Me (quant.)
sulfasalazine (3)
Keywords: Nitrogen dioxide • Aniline • Diazonium • Balsalazide
Scheme 3. Azo coupling of diazonium salts 7 and 9 – as obtained from wet
scrubber to salicylic acid (10) and synthesis of balsalazide (1) and
sulfasalazine (3).
-
• Sulfasalazine
[1]
[2]
a) G. R. Maxwell, Synthetic Nitrogen Products: A Practical Guide to the
Products and Processes; Kluwer, New York, 2005, 213–250; b) A. A.
Kulkarni, Beilstein J. Org. Chem. 2014, 10, 405–424.
The two azo coupling reactions of diazonium salts 7 and 9 to
salicylic acid (10) were found to proceed best at a pH value of 10.
Despite the unfavorable dilution of the reaction mixture, which
does probably not only affect the coupling itself - but does also
complicate the isolation of the azo compounds through
precipitation, useful yields were obtained for reactions on 10 and
100 mmol scales. Whereas balsalazide (1) was directly formed
from the reaction of diazonium salt 7 and salicylic acid (10), a
formal synthesis of sulfasalazine could be accomplished through
the quantitative esterification of azo compound 11 to give
12.[20b],[30] From a more general point of view, the successful use
diazonium salt 9 is also an important indicator for a future
application in the field of azo dye production, as many currently
used azo dyes comprise a sulfanilic acid substructure.[31]
K.-H. Zapp, K.-H. Wostbrock, M. Schäfer, K. Sato, H. Seiter, W. Zwick,
R. Creutziger, H. Leiter, Ammonium Compounds in Ullmann's
Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2012, DOI:
10.1002/14356007.a02_243.
[3]
a) G. A. Olah, S. C. Narang, J. A. Olah, K. Lammertsma, Proc. Natl. Acad.
Sci. USA 1982, 79, 4487-4494; b) J. Duehr, ACS Symp. Ser. 2013, 1155,
71-82; c) G. Yan, M. Yang, Org. Biomol. Chem. 2013, 11, 2554-2566; d)
B. Galabov, D. Nalbantova, P. v. R. Schleyer, H. F. Schaefer, Acc. Chem.
Res. 2016, 49, 1191-1199. b) D. Firth, Innovations in Pharmaceutical
Technology, 2001, 132-139.
[4]
H. W. Richardson, Copper Compounds in Ullmann's Encyclopedia of
Industrial Chemistry, Wiley-VCH, Weinheim, 2005, DOI:10.1002/
14356007.a07 567.
[5]
[6]
a) B. Schwartz, H. Robbins, J. Electrochem. Soc. 1976, 123, 1903-1909;
b) M. S. Kulkarni, H. F. Erk, J. Electrochem. Soc. 2000, 147, 176-188.
Publication No. 4196 by the German Bundesumweltamt (available online
via www.umweltbundesamt.de/ sites/default/files/medien/461/ publi-
kationen/4196.pdf or http://www.uba.de/uba-info-medien/4196.html,
12.10.2016)
In summary, it has been shown that the coupling of denitri-
fication and diazotization can be successfully applied to the
synthesis of pharmaceutically important azo compounds. In the
denitrification-diazotization step, polar arylamines were found to
This article is protected by copyright. All rights reserved.

10.1002/chem.201605359
Chemistry - A European Journal
COMMUNICATION
[7]
a) K. Hu, K. Griffiths, P. R. Norton, Surf. Sci. 2009, 603, 1740-1750. b)
M. Fu, C. Li, P. Lu, L. Qu, M. Zhang, Y. Zhou, M. Yu, Y. Fang, Catal. Sci.
Technol. 2014, 4, 14-25. c) X. Huang, S. Zhang, H. Chen, Q. Zhong, J.
Mol. Struct. 2015, 1098, 289-297. d) T. V. W. Janssens, H. Falsig, L. F.
Lundegaard, P. N. R. Vennestroem, S. B. Rasmussen, P. G. Moses, F.
Giordanino, E. Borfecchia, K. A. Lomachenko, C. Lamberti, ACS Catal.
2015, 5, 2832-2845.
einfach basisch); b) D. J. Levine, T. Runcevski, M. T. Kapelewski, B. K.
Keitz, J. Oktawiez, D. A. Reed, J. A. Mason, H. Z. H. Jiang, K. A. Colwell,
C. M. Legendre, S. A. FitzGerald, J. R. Long, J. Am. Chem. Soc. 2016,
138, 10143-10150.
[20] a) E. Askelöf, N. Svartz, Verfahren zur Herstellung von am Amidstickstoff
mit einem heterocyclischen Rest substituierten Oxybenzoesäureazo-
benzolsulfonamiden, DE 950555; Chem. Abstr. 53:40046, 1949; b) K. H.
[8]
[9]
M. T. Javed, N. Irfan, B. M. Gibbs, J. Environ. Manage. 2007, 83, 251-
289.
Agback,
4-(4-Hydroxy-
or
acetoxy-3-carbomethoxy-phenylazo)-
benzenesulphonyl chloride, US 4045429; Chem. Abstr. 75:151530,
1977; c) A. Novacek, V. Sedlackova, J. Korner, J. Hromas, V. Dundr, B.
Brunova, J. Kejha, Method of 2-pyroxy-5-/4-/2-pyridinylamino-
sulfonylphenylazo benzoic acid production, CS 273928(B1); Chem.
Abstr. 118:191588, 1991.
a) F. Curtius, Oxidative washing process for cleaning waste gases. EP
0487834 (A1); Chem. Abstr. 115:189023, 1991; b) C. Kennes, M. C.
Veiga, Bioreactors for Waste Gas Treatment, C. Kennes, M. C. Veiga,
Eds.; Springer, Dordrecht, Netherlands, 2001
[10] For recent examples of sustainable syntheses, see: a) S. Morales, J. L.
Acena, J. L. Garcia Ruano, M. B. Cid, J. Org. Chem. 2016, 81, 10016-
10022; b) Y. Zhou, S. Wu, Z. Li, Angew. Chem. 2016, 128, 11819-11822;
Angew. Chem. Int. Ed. 2016, 55, 11647-11650; c) L. Degennaro, D.
Maggiulli, C. Carlucci, F. Fanelli, G. Romanazzi, R. Luisi, Chem.
Commun. 2016, 52, 9554-9557; d) A. Llevot, P.-K. Dannecker, M. von
Czapiewski, L. C. Over, Z. Soeyler, M. A. R. Meier, Chem. Eur. J. 2016,
22, 11510-11521; e) C. J. Chang, ACS Cent. Sci. 2016, 2, 266-267; f) T.
Broja, P. J. W. Fuchs, K. Zeitler, Nat. Chem. 2015, 7, 950-951.
[11] For recent examples of converting “waste to value”, see: a) C.-F. Chow,
W.-L. Wong, K. Y.-F. Ho, C.-S. Chan, C.-B. Gong, Ch em. Eur. J. 2016,
22, 9513-9518; b) D. Pleissner, K. Y. Lau, C. Zhang, C. S. K. Lin,
ChemSusChem 2015, 8, 1686-1691; c) N. Oberleitner, A. K. Ressmann,
K. Bica, P. Gärtner, M. W. Fraaije, U. T. Bornscheuer, F. Rudroff, M. D.
Mihovilovic, Green Chem. 2017, DOI: 10.1039/C6GC01138A; d) S. Foit,
R.-A. Eichel, I. C. Vinke, L. G. J. de Haart, Angew. Chem. Int. Ed. 2016,
DOI: 10.1002/anie.201607552; e) N. T. Huan, P. Simon, A. Benayad, L.
Guetaz, V. Artero, M. Fontecave, Chem. Eur. J. 2016, 22, 14029-14035;
f) K. Beydoun, K. Thenert, E. S. Streng, S. Brosinski, W. Leitner, J.
Klankermayer, ChemCatChem 2016, 8, 135-138; g) K. Beydoun, G.
Ghattas, K. Thenert, J. Klankermayer, W. Leitner, Angew. Chem. 2014,
126, 11190-11194; Angew. Chem. Int. Ed. 2014, 53, 11010-11014.
[12] a) C. de Salas, O. Blank, M. R. Heinrich, Chem. Eur. J. 2011, 17, 9306-
9310; b) C. de Salas, M. R. Heinrich, Green Chem. 2014, 16, 2982-2987.
[13] D. Hofmann, C. de Salas, M. R. Heinrich, ChemSusChem 2015, 8, 3167-
3175.
[21] For azo dyes in textile chemistry, see: a) K. Hunger, P. Mischke, W.
Rieper, Azo Dyes, 1. General in Ullmann's Encyclopedia of Industrial
Chemistry,
Wiley-VCH,
Weinheim,
2011,
DOI:
10.1002/14356007.a03_245.pub2; b) J. Qiu, B. Tang, B. Ju, Y. Xu, S.
Zhang, Dyes Pigm. 2017, 136, 63-69; c) N. Koukabi, S. Otokesh, E.
Kolvari, A. Amoozadeh, Dyes Pigm. 2016, 124, 12-17; d) L. He, H. S.
Freeman, M. Nakpathom, P. D. Boyle, Dyes Pigm. 2015, 120, 245-250.
[22] For azo dyes as molecular switches, see: a) Y. Yang, R. P. Hughes, I.
Aprahamian, J. Am. Chem. Soc. 2012, 134, 15221-15224; b) M. Dong,
A. Babalhavaeji, S. Samanta, A. A. Beharry, G. A. Woolley, Acc. Chem.
Res. 2015, 48, 2662-2670; c) C. Weber, T. Liebig, M. Gensler, A. Zykov,
L. Pithan, J. P. Rabe, S. Hecht, D. Bléger, S. Kowarik, Sci. Rep. 2016, 6,
25605.
[23] For daily dosing, see electronic Medicines Compendium (EMC) at
https://www.medicines.org.uk/emc/.
[24] B. Ye, D. R. van Langenberg, World J. Gastrointest. Pharmacol. Ther.
2015, 6, 137-144.
[25] Arylamine 4 was prepared according to procedures described in ref. 18c.
[26] C. Galli, Chem. Rev. 1988, 88, 765-792.
[27] A. F. Holleman, Holleman-Wiberg’s Inorganic Chemistry, A. F. Holleman,
N. Wiberg, Eds., Academic Press, Berlin, New York, 2001.
[28] For applications of copper nitrate salts, see: a) E. Begari, C. Singh, U.
Nookaraju, P. Kumar, Synlett 2014, 25, 1997-2000; b) Y. Y. Li, X. Y. M.
Dong, X. D. Sun, Y. Wang, J. H. Zhu, ACS Appl. Mater. Inter. 2016, in
press; c) U. Betke, K. S. K. Sharma, A. Rodak, S. Rannabauer, A. Lieb,
F. Scheffler, M. Scheffler, Mater. Lett. 2016, 185, 201-203: d) M. Gao, B.
Xu, Org. Lett. 2016, 18, 4746-4749; e) S. Ghosh, R. Das, M. K. Naskar,
Mater. Lett. 2016, 183, 325-328; f) A. Ramirez, J. L. Hueso, H. Suarez,
R. Mallada, A. Ibarra, S. Irusta, J. Santamaria, Angew. Chem. 2016, 128,
11324-11327; Angew Chem. Int. Ed. 2016, 55, 11158-11161; g) S.
Eibner, F. Broust, J. Blin, A. Julbe, J. Anal. Appl. Pyrolysis 2015, 113,
143-152; h) M. Gao, Y. Li, Y. Gan, B. Xu, Angew. Chem. 2015, 127,
8919-8923; Angew Chem. Int. Ed. 2015, 54, 8795-8799; i) L. H. R. Dos
Santos, A. Lanza, A. M. Barton, J. Brambleby, W. J. A. Blackmore, P. A.
Goddard, F. Xiao, R. C. Williams, T. Lancaster, F. L. Pratt, S. J. Blundell,
J. Singleton, J. L. Manson, P. Macchi, J. Am. Chem. Soc. 2016, 138,
2280-2291.
[14] For recent applications of arenediazonium salts, see: a) F. Mo, G. Dong,
Y. Zhang, J. Wang, Org. Biomol. Chem. 2013, 11, 1582-1593; b) S. Kindt,
M. R. Heinrich, Synthesis 2016, 48, 1597-1606; c) D. P. Hari, B. König,
Angew. Chem. 2013, 125, 4832-4842; Angew. Chem. Int. Ed. 2013, 52,
4734-4743..
[15] For earlier studies, see: a) G. Kaupp, M. A. Metwally, F. A. Amer, E.
Abdel-Iatif, Eur. J. Org. Chem. 2003, 1545-1551. b) G. Kaupp, A.
Herrmann, J. Schmeyers, Chem. Eur. J. 2002, 8, 1395-1406.
[16] For a related review article, see: M. R. Naimi-Jamal, G. Kaupp, Adv.
Chem. Res. 2012, 11, 75-120.
[17] D. Hofmann, J. Hofmann, L. Hofmann, L.-E. Hofmann, M. R. Heinrich,
Org. Process Res. Dev. 2015, 19, 2075-2084.
[29] For recent applications of other metal nitrate salts, see: a) T. Taniguchi,
T. Fujii, H. Ishibashi, J. Org. Chem. 2010, 75, 8126–8132; b) T. H.
Nguyen, S. Fujikawa, T. Harada, J. Chantana, T. Minemoto, S. Nakanishi,
S. Ikeda, ChemSusChem 2016, 9, 2414-2420.
[18] a) E. C. G. Wolf, N. Mohamed, B. R. Guntoori, Safe process for the
preparation of balsalazide, US 7271253; Chem. Abstr. 147:365267,
2007; b) W. B. Wright, D. B. Cosulich, M. J. Fahrenbach, C. W. Waller,
J. M. Smith, M. E. Hultquist, J. Am. Chem. Soc. 1949, 71, 3014-3017; c)
R. P. K. Chan, 2-Hydroxy-5-phenylazobenzoic acid derivatives and
method of treating ulcerative colitis therewith, US 4412992; Chem. Abstr.
97:23470, 1983.
[30] A. Geivandov, S. Palto, Retarder and liquid crystal display comprising
the same, WO 2012052950; Chem. Abstr. 156:601679, 2012.
[31] Important azo dyes possessing a sulfanilic acid substructure are α-
naphthol orange, chryosin S (tropaeolin 0, resorcine yellow), methyl
orange and orange IV (tropaeolin 00, acid orange 5).
[19] a) S. Davaran, M. R. Rashidi, J. Hanaee, A. Khani, M. Mahkam, M.
Hashemi, J. Bioact. Compat. Polym. 2006, 21, 315-326. (Olsalazin,
This article is protected by copyright. All rights reserved.

10.1002/chem.201605359
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
D. Hofmann, E. Gans, J. Krüll, M. R.
Heinrich*
Page No. – Page No.
Sustainable synthesis of balsalazide
and sulfasalazine based on
diazotization with low-concentrated
nitrogen dioxide in air
The removal of nitrogen dioxide from gas streams was found to be highly effective
when combined with the diazotization of polar anilines. In this way, the preparation
of copper(II) nitrate can be coupled to a sustainable synthesis of industrially impor-
tant azo compounds such as the pharmaceuticals balsalazide and sulfasalazine.
This article is protected by copyright. All rights reserved.