A convenient approach to arenediazonium tosylates

Article abstract of DOI:10.1016/j.dyepig.2020.108726

Herein we present a mild, simple and environmentally friendly diazotization protocol of aromatic and heteroaromatic anilines into stable diazonium salts that surpass previously reported procedures. The reaction proceeds with tert-butyl nitrite in the presence of an equimolar amount or small excesses of p-toluenesulfonic acid in ethyl acetate, at room temperature. o-Phenylenediamines yield benzotriazolium tosylates. The resulting diazonium tosylates proved to be bench stable over a long period of time. In selected examples, diazonium salts were let to react with activated aromatic compounds including 2-naphthol and aniline derivatives into the corresponding azo dyes.

Full text of DOI:10.1016/j.dyepig.2020.108726

Journal Pre-proof
A Convenient Approach to Arenediazonium Tosylates
Mateja Mihelač, Ana Siljanovska, Janez Košmrlj
PII:
S0143-7208(20)31423-6
DOI:
https://doi.org/10.1016/j.dyepig.2020.108726
DYPI 108726
Reference:
To appear in: Dyes and Pigments
Received Date: 10 May 2020
Revised Date: 5 June 2020
Accepted Date: 19 July 2020
Please cite this article as: Mihelač M, Siljanovska A, Košmrlj J, A Convenient Approach to
Arenediazonium Tosylates, Dyes and Pigments, https://doi.org/10.1016/j.dyepig.2020.108726.
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© 2020 The Author(s). Published by Elsevier Ltd.

CRediT authorship contribution statement
Mateja Mihelač: Methodology, Investigation, Writing - original draft.
Ana Siljanovska: Methodology, Investigation, Writing - original draft.
Janez Košmrlj: Conceptualization, Supervision, Funding acquisition, Writing - review & editing.

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A Convenient Approach to Arenediazonium Tosylates
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Mateja Mihelač#, Ana Siljanovska#, Janez Košmrlj*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113,
SI-1000, Ljubljana, Slovenia
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# The authors contributed equally
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*Corresponding author: janez.kosmrlj@fkkt.uni-lj.si
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Abstract
Herein we present a mild, simple and environmentally friendly diazotization protocol of aromatic
and heteroaromatic anilines into stable diazonium salts that surpass previously reported
procedures. The reaction proceeds with tert-butyl nitrite in the presence of an equimolar amount
or small excesses of p-toluenesulfonic acid in ethyl acetate, at room temperature. o-
Phenylenediamines yield benzotriazolium tosylates. The resulting diazonium tosylates proved to
be bench stable over a long period of time. In selected examples, diazonium salts were let to
react with activated aromatic compounds including 2-naphthol and aniline derivatives into the
corresponding azo dyes.
Keywords: Diazotization, Diazonium salts, Azo compounds, p-Toluenesulfonic acid
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1. Introduction
Aromatic diazonium salts are highly important building blocks in many fields of
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synthetic organic chemistry. Since their discovery by Griess [1] in 1858 these compounds have
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played a role in named reactions including Sandmeyer, [2] Gomberg-Bachmann [3], Balz-
Schiemann [4], and Meerwein [5], to name just a few. Wide utility in the synthesis of industrially
important chromophores [6], modification of polymer, and nano-materials [7–10] as well as
syntheses of new metallic and non-metallic materials are well documented [11,12]. Aromatic
diazonium salts are excellent electrophiles or proelectrophiles, either directly through nitrogen
coupling, or by releasing a dinitrogen molecule to form in situ aryl carbocation species.
Noteworthy is their application in palladium catalyzed carbon-carbon and carbon-heteroatom
coupling reactions, in which their “superelectrophilicity” is recognized as an advantage over aryl
halides [13,14]. This high reactivity has enabled development of new metal-free carbon-carbon
bond forming reactions [15,16]. Coupling reactions that involve diazonium salts as nitrogen
electrophiles are crucial for the preparation of triazenes, potential antitubercular and antitumor
agents [17,18,19] and synthetic equivalents of amines and diazonium salts [20,21]. Several
radical reactions with diazonium salts are also well known and established as major pathways to
synthetically useful molecules [22,23]. An extremely important industrial application of
diazonium salts is the preparation of azo compounds, well known for their uses as organic dyes
and pigments, pharmaceutical agents and food additives [24].
The propensity of aryl diazonium salts to undergo uncontrolled dediazotization pathways
makes them unstable and potentially explosive. The stability is governed by the nature of
substituents present at the aromatic ring with those having strongly electron-withdrawing
character being less stable. In addition, also the access to those salts is more challenging because
diazotization of weakly basic amines is difficult due to their low reactivity and solubility. In
industrial process, the diazotization of weakly basic amines with sodium nitrite is conducted in
the presence of large excess quantities of concentrated sulfuric acid as a solvent rising economic,
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environmental and safety concerns. It produces high acid content wastewater. The strong dilution
heat effect of concentrated sulfuric acid during the addition of sodium nitrite solution demands
efficient cooling of the reaction mixture to control the temperature of the process. The above
makes aryl diazonium salts with two or three strong electron-withdrawing functional groups,
highly important for the preparation of deep-shade disperse azo dyes with excellent color
fastnesses, challenging. The stability of diazonium salts can be greatly increased by the choice of
counterions such as tetrafluoroborate, hexafluorophosphates, or disulfonimide [25].
Recently, Tang and co-workers reported the synthesis of stable solid diazonium salts of
weakly basic amines through diazotization by tert-butyl nitrite in the presence of excess amounts
of 1,5-naphthalenedisulfonic acid as a proton donor and stabilizer of diazonium salts [24].
Although showing excellent stability profile, the obtained products existed as mixtures of mono-
and di-aryldiazonium 1,5-naphthalenedisulfonates in the ratio that could not be predicted and/or
controlled. Despite the mild reaction conditions used, with ethyl acetate as the reaction solvent,
at room temperature, the relatively high price of 1,5-naphthalenesulfonic acid and undefined
product composition render this method less attractive.
Arenediazonium tosylates reported by Filimonov, Chi and co-authors also exhibit great
high thermal stability. However, although their procedure involves diazotization of anilines in
the presence of cheaper p-toluenesulfonic acid, it utilizes polymer-supported nitrite [26]. The
later was prepared by treating ion exchange of porous tetramethylammonium hydroxide resin
AV-17-86 or Amberlyst A26 with an aqueous solution of NaNO2, rendering the method less
appealing.
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Fig. 1. Representative diazotization methods.
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High demand for a sustainable preparation of isolable and nonhazardous arenediazonium
salts prompted us to combine the above two methods into a truly practical protocol for the
synthesis of arenediazonium tosylates that proceeds in a green reaction solvent and at room
temperature by employing commercially available reagents. We selected tert-butyl nitrite as a
surrogate for nitrous acid (NaNO2/HCl) because it is mild, easy to handle, commercially
available and inexpensive reagent of good solubility in organic solvents [27,28]. It has been
frequently used to generate arenediazonium salts in situ under safe conditions from small to bulk
multikilogram scale [29].
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2. Experimental section
2.1. Materials and instruments
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Starting materials and solvents were used as obtained from the commercial sources
without further purification (Merck, Fluorochem, abcr).
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Melting points were determined on a Leica Galen III micro hot stage and are uncorrected.
IR spectra were obtained with Bruker ALPHA FT-IR equipped with a Platinum ATR as a
solid sample support.
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NMR spectra were recorded with a Bruker Avance III 500 MHz NMR operating at 500
MHz (1H), 471 MHz (19F), and 126 (13C) MHz at 296 K or with a Bruker DPX 300 spectrometer
operating at 300 MHz (1H) at 302 K. Proton spectra were referenced to the residual signals of
CHCl3 (at δ 7.26 ppm) and DMSO-d5 (at δ 2.50 ppm). Carbon chemical shifts are given against
the central line of the solvent signal: CDCl3 (at δ 77.16 ppm), DMSO-d5 (at δ 39.52 ppm). 19F
NMR spectra were referenced to CCl3F and 15% BF3 etherate in CDCl3 as external standard at δ
0. Chemical shifts are given on δ scale (ppm). Coupling constants (J) are given in Hertz.
Multiplicities are indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), or br (broadened).
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An Agilent 6224 time-of-flight (TOF) mass spectrometer equipped with a double
orthogonal electrospray source at atmospheric pressure ionization (ESI) coupled to an Agilent
1260 HLPC was used for recording HRMS spectra. Mobile phase composed of two solvents: A
was 0.1% formic acid in Milli-Q water, and B was 0.1% formic acid in acetonitrile mixed in the
ratio of 1:1. Compounds were prepared by dissolving the samples in acetonitrile. 0.1–10 μL of
each sample and injected into the LC-MS. Flow rate was 0.4 mL/min. Fragmentor voltage was
150 V. Capillary voltage 4000 V. Mass range 100–1700.
For radial chromatography, Chromatotron model 7924T was used. Silica gel 60 PF254
containing gypsum for preparative layer chromatography was used for glass radial
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chromatography plates. Analytical thin-layer chromatography (TLC) was carried out on Fluka
Silica Gel TLC cards, visualized with a UV lamp (254 nm and/or 366 nm).
2.2. General procedure for diazotization of (hetero)arylamines 1a–1n.
In a round bottomed flask equipped with a magnetic stirrer, p-toluenesulfonic acid
monohydrate (1–2.3 mmol) was dissolved in ethyl acetate (10 mL). Aniline (1 mmol) was added
followed by dropwise addition of tert-butyl nitrite (1–6 mmol). The resulting mixture was stirred
for 15 min at room temperature. For the synthesis of 2k and 2l, the reaction mixture was stirred
for 1 h and 24 h, respectively. The product was filtrated, washed with ethyl acetate and air dried
to give pure diazonium tosylate. The exceptions were crude products 2e and 2f, which were
purified by recrystallization from acetone. Compound 2l was oily and was isolated by
evaporation of the solvent under reduced pressure.
Benzenediazonium tosylate (2a): Following the general procedure employing p-
toluenesulfonic acid (190 mg, 1.00 mmol), aniline (1a, 95 mg, 1.00 mmol) and tert-butyl nitrite
(356 µL, 3.00 mmol). The product was obtained as a dark pink solid (276 mg, 0.99 mmol, 99%).
The data were in agreement with those from the literature [30]. Mp: 90.7–91.9 °C. IR: 3092,
2293, 1618, 1568, 1494, 1187 cm–1. 1H NMR (500 MHz, DMSO-d6) δ 8.69–8.65 (m, 2H), 8.28–
8.24 (m, 1H), 8.00–7.96 (m, 2H), 7.48–7.44 (m, 2H), 7.13–7.08 (m, 2H), 2.28 (s, 3H). HRMS
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(ESI+): calcd for C6H5N2 [M]+ m/z 105.0447; found: 105.0450.
The synthesis of product 2a was also conducted on 4 mmol scale following the general
procedure, employing p-toluenesulfonic acid monohydrate (760 mg, 4.00 mmol), ethyl acetate
(15 mL), aniline (365 μL, 4.00 mmol) and tert-butyl nitrite (1425 μL, 12.00 mmol) to give
diazonium tosylate 2a (1.0151 g, 3.67 mmol, 92%).
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3,4-Dichlorobenzenediazonium tosylate (2b): Following the general procedure employing
p-toluenesulfonic acid (190 mg, 1.00 mmol), 3,4-dichloroaniline (1b, 163 mg, 1.00 mmol) and
tert-butyl nitrite (356 µL, 3.00 mmol). The product was obtained as a white solid (314 mg, 0.91
mmol, 91%). Mp: 144.3–145.5 °C. IR: 3105, 2288, 1551, 1445, 1223, 1170, 1029, 817, 678 cm–
1. 1H NMR (500 MHz, DMSO-d6) δ 9.08 (d, J = 2.4 Hz, 1H), 8.68 (dd, J = 2.4, 8.9 Hz, 1H), 8.28
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(d, J = 8.9 Hz, 1H), 7.47–7.44 (m, 2H), 7.13–7.09 (m, 2H), 2.28 (s, 3H). C NMR (126 MHz,
DMSO-d6) δ 145.5, 145.1, 137.8, 133.7, 133.4, 133.2, 132.5, 128.1, 125.5, 115.9, 20.8. HRMS
+
(ESI+): calcd for C6H3Cl2N2 [M]+ m/z 172.9668; found: 172.9671.
The synthesis of product 2b was also conducted on 4 mmol scale following the general
procedure, employing p-toluenesulfonic acid monohydrate (760 mg, 4.00 mmol), ethyl acetate
(30 mL), 3,4-dichloroaniline (1b, 648 mg, 4.00 mmol) and tert-butyl nitrite (1425 μL, 12.00
mmol) to give diazonium tosylate 2b (1.2586 g, 3.65 mmol, 91%).
4-Chloro-3-(trifluoromethyl)benzenediazonium tosylate (2c): Following the general
procedure employing p-toluenesulfonic acid (190 mg, 1.00 mmol), 4-chloro-3-
(trifluoromethyl)aniline (1c, 195 mg, 1.00 mmol) and tert-butyl nitrite (118.8 µL, 1.00 mmol).
The product was obtained as a white solid (337 mg, 0.89 mmol, 89%). Mp: 149.0–151.1 °C. IR:
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3069, 2304, 1591, 1560, 1314, 1181, 1121, 1034, 682 cm–1. H NMR (500 MHz, DMSO-d6) δ
9.32 (d, J = 2.4 Hz, 1H), 8.96 (dd, J = 2.4, 8.9 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 7.48–7.44 (m,
2H), 7.13–7.08 (m, 2H), 2.28 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 145.4, 144.0, 137.8,
137.7, 134.8, 132.8 (q, J = 6.2 Hz), 128.7 (q, J = 33.1 Hz), 128.1, 125.5, 121.0 (q, J = 273.5 Hz),
+
116.7, 20.8. HRMS (ESI+): calcd for C7H3ClF3N3 [M]+ m/z 206.9931; found: 206.9931.
3-Chloro-4-cianobenzenediazonium tosylate (2d): Following the general procedure
employing p-toluenesulfonic acid (190 mg, 1.00 mmol), 4-amino-2-chlorobenzonitrile (1d, 152
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mg, 1.00 mmol) and tert-butyl nitrite (356 µL, 3.00 mmol). The product was obtained as a white
solid (278 mg, 0.83 mmol, 83%). Mp: 130.0–133.3 °C. IR: 3071, 2309, 1453, 1397, 1201, 1032,
818, 677 cm–1. 1H NMR (500 MHz, DMSO-d6) δ 9.13 (d, J = 2.0 Hz, 1H), 8.82 (dd, J = 2.0, 8.7
Hz, 1H), 8.54 (d, J = 8.7 Hz, 1H), 7.47–7.43 (m, 2H), 7.13–7.08 (m, 2H), 2.29 (s, 3H). 13C NMR
(126 MHz, DMSO-d6) δ 145.4, 137.8, 136.9, 136.6, 132.5, 131.5, 128.1, 125.5, 122.8, 121.9,
114.1, 20.8. HRMS (ESI+): calcd for C7H3N3Cl+ [M]+ m/z 164.001; found: 164.0002.
3-Nitrobenzenediazonium tosylate (2e): Following the general procedure employing p-
toluenesulfonic acid (190 mg, 1.00 mmol), 3-nitroaniline (1e, 138 mg, 1.00 mmol) and tert-butyl
nitrite (118.8 µL, 1.00 mmol). Crude product was recrystallized from acetone (beige solid, 175
mg, 0.64 mmol, 64%). The data were in agreement with those from the literature [26]. Mp:
137.4–138.0 °C (lit. [26] 134 °C). IR: 3080, 2306, 1597, 1535, 1349, 1191, 1119, 815, 683 cm–1.
1H NMR (500 MHz, DMSO-d6) δ 9.60 (dd, J = 2.1, 2.3 Hz, 1H), 9.04 (ddd, J = 1.0, 2.1, 8.2 Hz,
1H), 8.96 (ddd, J = 1.0, 2.3, 8.4 Hz, 1H), 8.22 (dd, J = 8.2, 8.4 Hz, 1H), 7.47–7.44 (m, 2H),
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7.13–7.08 (m, 2H), 2.28 (s, 3H). C NMR (126 MHz, DMSO-d6) δ 147.6, 145.4, 138.0, 137.8,
135.0, 133.7, 128.2, 128.1, 125.5, 118.3, 20.9. HRMS (ESI+): calcd for C6H4N3O2 [M]+ m/z
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150.0298; found: 150.0297.
4-Nitrobenzenediazonium tosylate (2f): Following the general procedure employing p-
toluenesulfonic acid (438 mg, 2.30 mmol), 4-nitroaniline (1f, 138 mg, 1.00 mmol) and tert-butyl
nitrite (118.8 µL, 1.00 mmol). Crude product was recrystallized from acetone (beige solid, 144
mg, 0.45 mmol, 45%). The data were in agreement with those from the literature [26]. Mp:
132.4–133.9 °C (lit. [26] 132 °C). IR: 3105, 2306, 1615, 1541, 1347, 1223, 1169, 1119, 822, 682
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cm–1. H NMR (500 MHz, DMSO-d6) δ 8.96–8.92 (m, 2H), 8.71–8.67 (m, 2H), 7.48–7.45 (m,
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2H), 7.12–7.08 (m, 2H), 2.28 (s, 3H). HRMS (ESI+): calcd for C6H4N3O2 [M]+ m/z 150.0298;
found: 150.0302.
2-Bromo-5-nitrobenzenediazonium tosylate (2g): Following the general procedure
employing p-toluenesulfonic acid (190 mg, 1.00 mmol), 2-bromo-5-nitroaniline (1g, 217 mg,
1.00 mmol) and tert-butyl nitrite (118.8 µL, 1.00 mmol). The product was obtained as pale
yellow solid (313 mg, 0.78 mmol, 78%). Mp: 140.8–142.0 °C. IR: 3094, 2302, 1593, 1580,
1530, 1347, 1215, 1192, 1036, 680 cm–1. 1H NMR (500 MHz, DMSO-d6) δ 8.98 (d, J = 3.2 Hz,
1H), 8.05 (dd, J = 3.2, 10.2 Hz, 1H), 7.49–7.45 (m, 2H), 7.13–7.09 (m, 2H), 6.59 (d, J = 10.2 Hz,
1H), 2.29 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 174.9, 145.0, 138.2, 132.6, 132.2, 130.0,
128.3, 125.6, 124.2, 91.0, 20.9. HRMS (ESI+): calcd for C6H3BrN3O2 [M]+ m/z 227.9403;
+
found: 227.94.
4-Nitro-2-(trifluoromethyl)benzenediazonium tosylate (2h): Following the general
procedure employing p-toluenesulfonic acid (190 mg, 1.00 mmol), 4-nitro-2-
(trifluoromethyl)aniline (1h, 206 mg, 1.00 mmol) and tert-butyl nitrite (118.8 µL, 1.00 mmol).
The product was obtained as a yellow solid (289 mg, 0.74 mmol, 74%). Mp: 134.9–136.0 °C. IR:
3099, 3001, 2309, 1618, 1542, 1353, 1162, 796 cm–1. 1H NMR (500 MHz, DMSO-d6) δ 9.35 (d,
J = 9.0 Hz, 1H), 9.13 (d, J = 2.3 Hz, 1H), 9.04 (dd, J = 2.3, 9.0 Hz, 1H), 7.47–7.44 (m, 2H),
7.12–7.08 (m, 2H), 2.28 (s, 3H). 13C NMR spectrum of compound 2h could not be recorded due
to its rapid decomposition in DMSO-d6 solution. HRMS (ESI+): calcd for C7H3F3N3O2 [M]+
+
m/z 218.0172; found: 218.0166.
2-Cyano-4-nitrobenzenediazonium tosylate (2i): Following the general procedure
employing p-toluenesulfonic acid (190 mg, 1.00 mmol), 2-amino-5-nitrobenzonitrile (1i, 163
mg, 1.00 mmol) and tert-butyl nitrite (356 µL, 3.00 mmol). The product was obtained as a
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yellow solid (152 mg, 0.44 mmol, 44%). Mp: 128.6–129.9 °C. IR: 3104, 3060, 2312, 1597,
1348, 1219, 1192, 1119, 1036, 1011, 896, 821, 799, 739, 681 cm–1. 1H NMR (500 MHz, DMSO-
d6) δ 9.19 (d, J = 2.4 Hz, 1H), 8.86 (dd, J = 2.4, 8.9 Hz, 1H), 8.63 (d, J = 8.9 Hz, 1H), 7.49–7.44
(m, 2H), 7.13–7.09 (m, 2H), 2.28 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 151.3, 145.5, 137.9,
137.8, 131.8, 131.2, 128.9, 128.1, 125.5, 113.3, 113.0, 20.8. HRMS spectrum of compound 2i
could not be obtained due to its decomposition under the applied condition.
4-(Trifluoromethoxy)benzenediazonium tosylate (2j): Following the general procedure
employing p-toluenesulfonic acid (190 mg, 1.00 mmol), 4-(trifluoromethoxy)aniline (1j, 135 µL,
1.00 mmol) and tert-butyl nitrite (356 µL, 3.00 mmol). The product was obtained as a white
solid (323 mg, 0.90 mmol, 90%). Mp: 147.3–148.1 °C. IR: 3052, 2297, 1578, 1479, 1314, 1246,
1208, 1172, 1120, 1092, 1034, 1010, 927, 848, 815, 701, 681 cm–1. 1H NMR (500 MHz, DMSO-
d6) δ 8.88–8.84 (m, 2H), 8.00–7.97 (m, 2H), 7.48–7.45 (m, 2H), 7.12–7.09 (m, 2H), 2.28 (s, 3H).
13C NMR (126 MHz, DMSO-d6) δ 155.8 (q, J = 1.9 Hz), 145.6, 137.7, 136.3, 128.1, 125.5,
122.2, 119.5 (q, J = 261.6 Hz), 114.2, 20.8. HRMS (ESI+): calcd for C7H4F3N2O+ [M]+ m/z
189.027; found 189.0275.
2-Chloro-4-nitrobenzenediazonium tosylate (2k): Following the general procedure
employing p-toluenesulfonic acid (190 mg, 1.00 mmol), 2-chloro-4-nitroaniline (1k, 176 mg,
1.00 mmol) and tert-butyl nitrite (356 µL, 3.00 mmol). The reaction mixture was stirred for 1 h.
The product was obtained as a yellow solid (210 mg, 0.59 mmol, 59%). Mp: 143.5–145.2 °C. IR:
3088, 2316, 1542, 1344, 1302, 1193, 1118, 1035, 785, 680 cm–1. 1H NMR (300 MHz, DMSO-d6)
δ 9.13 (d, J = 9.1 Hz, 1H), 9.00 (d, J = 2.3 Hz, 1H), 8.67 (dd, J = 2.3, 9.1 Hz, 1H), 7.49–7.43 (m,
2H), 7.13–7.07 (m, 2H), 2.28 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 153.4, 145.4, 137.8,
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136.8, 136.0, 128.1, 127.0, 125.5, 124.7, 122.60, 20.8. HRMS (ESI+): calcd for C6H3ClN3O2
[M]+ m/z 183.9919; found 183.9918.
2-Benzoyl-4-chlorobenzenediazonium tosylate (2l): Following the general procedure
employing p-toluenesulfonic acid (389 mg, 2.00 mmol), (2-amino-5-
chlorophenyl)(phenyl)methanone (1l, 230 mg, 1.00 mmol) and tert-butyl nitrite (712 µL, 6.00
mmol). The reaction mixture was stirred for 24 h. The solvent was evaporated under reduced
pressure. The product was obtained as brown oil (355 mg, 0.86 mmol, 86%). IR: 3088, 2278,
1665, 1597, 1556, 1283, 1120, 1031, 1005, 948, 813, 735, 708, 679 cm–1. H NMR (500 MHz,
1
DMSO-d6): δ 9.03 (d, J = 8.8 Hz, 1H), 8.39 (dd, J = 1.9, 8.8 Hz, 1H), 8.23–8.20 (m, 1H), 7.93–
7.89 (m, 2H), 7.85–7.80 (m, 1H), 7.69–7.64 (m, 2H), 7.49–7.44 (m, 2H), 7.13–7.09 (m, 2H),
2.29 (s, 3H). 13C NMR (126 MHz, DMSO-d6): δ 188.8, 145.9, 145.5, 138.9, 137.8, 137.2, 134.8,
134.2, 133.7, 133.6, 130.9, 129.0, 128.2, 125.5, 114.1, 20.8. HRMS (ESI+): calcd for
C13H8ClN2O+ [M]+ m/z 243.032; found 243.0318.
6-Methoxypyridine-3-diazonium tosylate (2m): Following the general procedure
employing p-toluenesulfonic acid (190 mg, 1.00 mmol), 3-amino-6-methoxypyridine (1m, 125
mg, 1.00 mmol) and tert-butyl nitrite (356 µL, 3.00 mmol). The product was obtained as a purple
solid (266 mg, 0.86 mmol, 86%). Mp: 147.9–148.9 °C. IR: 3104, 2276, 1580, 1483, 1397, 121,
1197, 1002, 815, 679 cm–1. 1H NMR (500 MHz, DMSO-d6) δ 9.56 (d, J = 2.6 Hz, 1H), 8.77 (dd,
J = 2.6, 9.3 Hz, 1H), 7.48–7.45 (m, 2H), 7.39 (d, J = 9.3 Hz, 1H), 7.13–7.09 (m, 2H), 4.13 (s,
3H), 2.28 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 166.7, 157.1, 145.5, 141.6, 137.7, 128.1,
125.5, 113.4, 105.0, 56.3, 20.8. HRMS (ESI+): calcd for C6H6N3O+ [M]+ m/z 136.0505; found:
136.0509.
11

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The synthesis of product 2m was also conducted on 4 mmol scale following the general
procedure, employing p-toluenesulfonic acid monohydrate (760 mg, 4.00 mmol), ethyl acetate
(30 mL), 6-methoxypyridine-3-amine (1m, 498 mg, 4.00 mmol) and tert-butyl nitrite (1425 μL,
12.00 mmol) to give diazonium tosylate 2m (1.0525 g, 3.42 mmol, 85%).
Benzotriazolium tosylate (2n'): Following the general procedure employing p-
toluenesulfonic acid (380 mg, 2.00 mmol), benzene-1,2-diamine (1n, 108 mg, 1.00 mmol) and
tert-butyl nitrite (356 µL, 3.00 mmol). The product was obtained as a white solid (212 mg, 0.73
1
mmol, 73%). Mp: 143.3–145.0 °C. IR: 1898, 1614, 1223, 1149, 1117, 1007, 822, 753 cm–1. H
NMR (500 MHz, DMSO-d6) δ 7.93–7.89 (m, 2H), 7.49–7.45 (m, 2H), 7.45–7.43 (m, 2H), 7.13–
7.09 (m, 2H), 4.16 (brs, 2H), 2.29 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 144.9, 138.7Btz,
138.3, 128.3, 125.6, 125.5Btz, 115.0Btz, 20.9. Literature data for benzotriazole: 13C NMR (125
+
MHz, CDCl3) δ 138.8, 126.0, 114.9 [31]. HRMS (ESI+): calcd for C6H6N3 [M]+ m/z 120.0556;
found: 120.0561.
2.3. General procedure for the synthesis of azo compounds 3b and 3j.
In a round bottomed flask equipped with a magnetic stirrer, 2-naphthol (1.1 eq) was
dissolved in water (1 mL/1 mmol). pH of the reaction mixture was adjusted to 10–11 by using 10
wt % sodium hydroxide solution and cooled to 0–5 °C. Diazonium salt 2 (1 eq) was added
portionwise within ca. 20 min, maintaining pH at 10–11. The reaction mixture was stirred for 30
min and the resulting pure dye 3 was collected by filtration, washed with water, and air dried.
1-((3,4-Dichlorophenyl)diazenyl)naphthalen-2-ol (3b): Following the general procedure
employing 2-naphthol (48 mg, 0.33 mmol) and 3,4-dichlorobenzenediazonium tosylate (2b, 104
mg, 0.30 mmol). The product was obtained as a red solid (68 mg, 0.21 mmol, 73%). Mp: 139.0–
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139.9 °C. IR: 1622, 1559, 1501, 1452, 1369, 1242, 1205, 1152, 1123, 1022, 986, 822, 753 cm–1.
1H NMR (500 MHz, CDCl3) δ 15.82 (brs, 1H), 8.41 (d, J = 8.1 Hz, 1H), 7.78–7.71 (m, 1H), 7.66
13
(d, J = 9.3 Hz, 1H), 7.59–7.49 (m, 2H), 7.48–7.35 (m, 3H), 6.78 (d, J = 9.3 Hz, 1H). C NMR
(126 MHz, CDCl3) δ 172.2, 144.4, 140.9, 133.9, 133.2, 131.2, 131.0, 130.6, 129.2, 128.8, 128.3,
126.4, 124.6, 121.9, 119.6, 117.9. HRMS (ESI+): calcd for C16H11Cl2N2O+ [M + H]+ m/z
317.0243; found 317.0243.
1-((4-(Trifluoromethoxy)phenyl)diazenyl)naphthalen-2-ol (3j): Following the general
procedure
employing
2-naphthol
(104
mg,
0.70
mmol)
and
4-
(trifluoromethoxy)benzenediazonium tosylate (2j, 231 mg, 0.64 mmol). The product was
obtained as a red solid (185 mg, 0.56 mmol, 87%). Mp: 95.0–96.2 °C. IR: 3067, 1622, 1451,
1
1261, 1208, 1159, 1146, 1098, 986, 833, 753, 651 cm–1. H NMR (500 MHz, CDCl3) δ 15.98
(brs, 1H), 8.50 (d, J = 8.5 Hz, 1H), 7.73–7.68 (m, 3H), 7.58 (d, J = 7.9 Hz, 1H), 7.56–7.52 (m,
1H), 7.42–7.37 (m, 1H), 7.31 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 9.4 Hz, 1H). 13C NMR (126 MHz,
CDCl3) δ 171.1, 148.0, 143. 8, 140.4, 133.5, 130.4, 129.1, 128.8, 128.3, 126.1, 124.5, 122.3,
121.8, 120.1 (q, J = 258.2 Hz), 119.9. 19F NMR (471 MHz, CDCl3) δ –57.92. HRMS (ESI+):
calcd for C16H11Cl2N2O+ [M + H]+ m/z 333.0845, found 333.0847.
2.4. General procedure for the synthesis of azo compounds 4b,i,j,m.
In a round bottomed flask equipped with a magnetic stirrer, N-ethyl-N-(2-
hydroxyethyl)aniline (1 eq) was dissolved in acetic acid (8 mL/1 mmol), to which diazonium
tosylate (1 eq) was added portionwise at room temperature. The reaction mixture was stirred for
15 min and the product was isolated by extraction into dichloromethane (3 × 15 mL). The
combined organic layers were washed with saturated aqueous solution of sodium bicarbonate,
13

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312
dried over anhydrous sodium sulphate, and the solvent was removed by rotary evaporation.
Crude products 4b,i,j,m were purified by radial chromatography on silica gel with petroleum
ether/ethyl acetate (2:1 v/v).
2-((4-((3,4-Dichlorophenyl)diazenyl)phenyl)(ethyl)amino)ethan-1-ol (4b): Following the
general procedure employing N-ethyl-N-(2-hydroxyethyl)aniline (66 mg, 0.40 mmol) and 3,4-
dichlorobenzenediazonium tosylate (2b, 138 mg, 0.40 mmol). The product was obtained as an
orange oil (123 mg, 0.36 mmol, 92%). Mp: 107.3–108 °C. IR: 2980, 2191, 2172, 2005, 1593,
1
1568, 1508, 1487, 1394, 1319, 1246, 1137, 1071, 1020, 815, 612 cm–1. H NMR (500 MHz,
CDCl3) δ 7.93 (d, J = 2.2 Hz, 1H), 7.85–7.80 (m, 2H), 7.69 (dd, J = 2.2, 8.5 Hz, 1H), 7.52 (d, J =
8.5 Hz, 1H), 6.80–6.75 (m, 2H), 3.86 (q, J = 5.8 Hz, 3H), 3.58 (t, J = 5.8 Hz, 2H), 3.52 (q, J =
7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 152.3, 151.2, 143.4, 133.3,
132.8, 130.8, 125.8, 123.2, 122.4, 111.6, 52.5, 46.0, 31.1, 12.2. HRMS (ESI+): calcd for
C16H18Cl2N3O+ [M + H]+ m/z 338.0821; found 338.0819.
2-((4-(Ethyl(2-hydroxyethyl)amino)phenyl)diazenyl)-5-nitrobenzonitrile (4i): Following
the general procedure employing N-ethyl-N-(2-hydroxyethyl)aniline (23 mg, 0.14 mmol) and 4-
(trifluoromethoxy)benzenediazonium tosylate (2i, 49 mg, 0.14 mmol). The product was obtained
as a dark purple solid (41 mg, 0.12 mmol, 87%). Mp: 165.5–166.5 °C. IR: 3538, 2917, 2228,
1595, 1575, 1513, 1322, 1304, 1200, 1113, 1071, 905, 821, 751, 729 cm–1. 1H NMR (500 MHz,
CDCl3) δ 8.57 (d, J = 2.5 Hz, 1H), 8.39 (dd, J = 2.5, 9.1 Hz, 1H), 7.97–7.93 (m, 3H), 6.82–6.78
(m, 2H), 3.92 (q, J = 5.7 Hz, 2H), 3.65 (t, J = 5.7 Hz, 2H), 3.61 (q, J = 7.1 Hz, 2H), 1.77–1.72
(m, OH), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 157.8, 153.2, 146.3, 144.3,
129.2, 128.3, 127.9, 117.9, 115.8, 112.1, 111.9, 60.4, 52.6, 46.4, 12.3. HRMS (ESI+): calcd for
+
C17H18N5O3 [M + H]+ m/z 340.1404, found 340.1405.
14

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330
331
332
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335
2-(Ethyl(4-((4-(trifluoromethoxy)phenyl)diazenyl)phenyl)amino)ethan-1-ol
(4j):
Following the general procedure employing N-ethyl-N-(2-hydroxyethyl)aniline (55 mg, 0.33
mmol) and 4-(trifluoromethoxy)benzenediazonium tosylate (2j, 117 mg, 0.33 mmol). The
product was obtained as a red solid (94 mg, 0.27 mmol, 81%). Mp: 83.3–84.5 °C. IR: 3252,
1
2988, 1600, 1513, 1396, 1213, 1152, 1129, 1057, 849, 818, 666 cm–1. H NMR (500 MHz,
CDCl3) δ 7.88–7.83 (m, 4H), 7.33–7.29 (m, 2H), 6.82–6.78 (m, 2H), 3.87 (q, J = 5.8 Hz, 2H),
3.59 (t, J = 5.8 Hz, 2H), 3.53 (q, J = 7.1 Hz, 2H), 1.73–1.69 (m, OH), 1.23 (t, J = 7.1 Hz, 3H).
13C NMR (126 MHz, CDCl3) δ 151.6, 150.9, 149.8 (q, J = 1.9 Hz), 143.6, 125.5, 123.6, 121.5,
120.0 (q, J = 258.5 Hz), 111.7, 52.5, 46.0, 31.1, 12.2. 19F NMR (471 MHz, CDCl3) δ –57.76.
HRMS (ESI+): calcd for C17H18F3N3O2 [M + H]+ m/z 354.1424; found 354.1424.
+
2-(Ethyl(4-((6-methoxypyridin-3-yl)diazenyl)phenyl)amino)ethan-1-ol (4m): Following
the general procedure employing N-ethyl-N-(2-hydroxyethyl)aniline (38 mg, 0.23 mmol) and 6-
methoxypyridine-3-diazonium tosylate (2m, 71 mg, 0.23 mmol). The product was obtained as an
orange solid (58 mg, 0.19 mmol, 84%). Mp: 107.3–108 °C. IR: 3362, 2968, 2871, 1709, 1593,
1558, 1511, 1442, 1395, 1346, 1310, 1231, 1182, 1141, 1112, 1042, 881, 818, 668 cm–1. H
1
NMR (500 MHz, CDCl3) δ 8.69 (d, J = 2.6 Hz, 1H), 8.07 (dd, J = 2.6, 8.9 Hz, 1H), 7.83–7.78
(m, 2H), 6.80 (d, J = 8.9 Hz, 1H), 6.79–6.75 (m, 2H), 4.01 (s, 3H), 3.85 (q, J = 5.8 Hz, 2H), 3.57
(t, J = 5.8 Hz, 2H), 3.51 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz,
CDCl3) δ 164.8, 150.5, 146.2, 144.5, 143.7, 128.7, 125.1, 111.7, 111.6, 54.1, 52.5, 45.9, 31.1,
+
12.2. HRMS (ESI+): calcd for C16H21N4O2 [M + H]+ m/z 301.1659; found 301.1666.
3. Results and discussion
3.1. Synthesis of diazonium salts
15

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349
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351
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353
354
Herein, we report an effective method for the synthesis of stable diazonium salts in the
presence of tert-butyl nitrite and p-toluensulfonic acid as a source of mild acidic conditions at
room temperature in ethyl acetate. Solid diazonium salts were isolated from the reaction mixture
by simple filtration in pure form.
The reaction between aniline, p-toluenesulfonic acid and tert-butyl nitrite in ethyl acetate
as the reaction solvent at room temperature was selected as a model reaction. Optimization of
diazotization conditions was conducted with different molar ratios of aniline (1a), p-
toluenesulfonic acid and tert-butyl nitrite. The optimal ratio was found to be 1:1:3, respectively,
affording phenyldiazonium tosylate (2a) in 99% isolated yield (Table 1, Entry 4). Although the
result is similar to that for the aniline:1,5-naphthalenesulfonic acid:tert-butyl nitrite (1:1:1.5)
system reported by Tang [24], it is much better as in the case of aniline:polymer-supported
nitrite:TsOH of Filimonov, Chi et al. [26], for which the optimal molar ratio was reported to
range from 1:3:3 to 1:6:6. Varying the amount of ethyl acetate or prolonging the reaction time
had no effect on the yield of 2a. As judged by TLC monitoring, optimal reaction time was 15
min, although precipitate started to form immediately after the addition of tert-butyl nitrite into
the reaction mixture. No nitrogen oxides could be observed during the process.
Table 1
The effect of TsOH and tert-butyl nitrite loading on diazotization of aniline (1a).
355
Entry 1a (mmol) TsOH (eq.) tert-butyl nitrite (eq.) EtOAc (mL) 2a, yield (%)a
16

1
2
3
4
1
1
1
1
1
1
1
1
1
1
2
3
10
20
10
10
71
72
94
99
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
a Refers to isolated yield of pure product (average value of two independent runs).
With the optimized reaction conditions in hand, the substrate scope was investigated, and
the results are collected in Fig. 2. In general, aromatic amines with electron-accepting
substituents proved to be better substrates for diazotization under these reaction conditions [24].
In some cases, that of 2c,e–h, adding only one equivalent of tert-butyl nitrite was enough to
obtain the insoluble diazonium salt. The reactions were completed within 15 min. Longer
reaction times were only required for strongly electron deficient and sparingly soluble 2-chloro-
4-nitroaniline (1k) as well as sterically demanding (2-amino-5-chlorophenyl)(phenyl)methanone
(1l). In case of 4-nitroaniline (1f) and (2-amino-5-chlorophenyl)(phenyl)methanone (1l) an
excess (2.0–2.3 equiv.) of p-toluenesulfonic acid was used to achieve reasonable conversions.
All products, except for 2e and 2f, were obtained in pure form by filtration from the reaction
mixture, without further purification needed. Analytically pure products 2e and 2f were obtained
by recrystallization. The obtained tosylates were soluble in both protic and aprotic polar solvents,
which is an advantage over other types of stable diazonium salts. Interestingly, diazonium salt 2l
appeared as an oily product and was isolated from the reaction mixture by evaporation of the
solvent under reduced pressure. Scalability of the protocol was tested in diazotization of aniline
(1a), 3,4-dichloroaniline (1b) and 3-amino-6-methoxypyridine (1m) on 4 mmol scale, affording
products 2a, 2b and 2m, respectively, in comparable yields as on 1 mmol scale.
17

375
376
377
a
b
Fig. 2. Substrate scope, 3 equiv. of tert-butyl nitrite were employed 1 equiv. of tert-butyl
nitrite were employed c 2.3 eq of TsOH and 1 equiv. of tert-butyl nitrite were employed d 2 equiv.
of TsOH and 6 equiv. of tert-butyl nitrite were employed
378
379
380
381
382
383
384
385
All products were bench stable at room temperature for a long period of time. The
1
stability of the products was monitored by re-acquiring H NMR spectra of the isolated solid
compounds that were stored at room temperature. Diazonium salts 2c and 2m, for example,
showed no structural changes even after a year of storage. The only exceptions were products 2a
and 2k, which decomposed within a week.
18

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389
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391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
To further explore the scope, benzene-1,2-diamine (1n) as a representative example of o-
phenylenediamines was let to react with tert-butyl nitrite in the presence of p-toluenesulfonic
acid (Fig. 2). As expected, the transformation proceeds through intermediately formed 2-
aminobenzenediazonium tosylate (2n) and smoothly returned benzotriazolium tosylate (2n'). In
an unoptimized reaction, the product was obtained in pure form in 73% isolated yield (Fig. 2).
13
The 1H NMR and C NMR spectra of the product benzotriazolium salt 2n' recorded in DMSO-
d6 are in agreement with those for the parent benzotriazole [31]. Benzotriazoles are important
entities in organic synthetic and medicinal chemistry and have been recently prepared by tert-
butyl nitrite mediated nitrogen transfer to o-phenylenediamines [31]. Crystal structure of
benzotriazolium tosylate has been reported [32].
3.2. Synthesis of azo compounds
3.2.1. Synthesis of azo compounds 3
Diazonium tosylates 2b and 2j were tested in the synthesis of azo dyes with 2-naphthol
(Fig. 3). The reactions were conducted in alkaline aqueous solutions with pH being maintained at
10–11 to enhance the reactivity of the naphthol coupling partner. As judged by TLC analysis the
reactions were complete once the coupling partners were combined. To allow for complete
precipitation of the products, the reaction mixtures were stirred for additional 30 min after which
crude products 3b and 3j were isolated by filtration in 73% and 83% yields, respectively. The
crude products were NMR pure and required no additional purification. The coupling protocol
and the results are comparable to those reported by Tang and co-workers [33], and superior to
the traditional approach that involves diazotization under strongly acidic conditions, especially
for weakly basic anilines, followed by azo coupling reaction at high pH [34].
19

409
410
411
Fig. 3. Synthesis of azo dyes 3 from selected diazonium salts 2
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
3.2.1. Synthesis of azo compounds 4
In addition to 2-naphthol, coupling of diazonium tosylates was also tested with N-ethyl-
N-(2-hydroxyethyl)aniline to give azo compounds 4. The interest in using this coupling partner
steams form the fact that the resulting rod-like products of structure 4 having a delocalized π-
system have the potential to label protein aggregates of different compositions formed in the
brain of patients suffering from neurodegenerative diseases like Alzheimer disease [35,36]. The
frameworks based on azo dyes like Chrysamine G, Thiazine Red, Sirius Red F3B, and Benzo
Scarlet 4BNS (amyloid red) are notable [37]. Furthermore, the N-(2-hydroxyethyl) fragment
enables a facile entry to radiolabeled fluorine-18 N-(2-[18F]fluoroethyl) derivatives that can be
used as radiotracers to image neurodegenerative diseases [38]. Other applications in
optoelectronic devices and other functional materials can be envisioned [39].
Diazotization of N-ethyl-N-(2-hydroxyethyl)aniline was conducted with 2(b,i,j,m) at
room temperature. Acetic acid was used as a reaction solvent to assure the solubility of the
aniline coupling partner. Products 4, formed almost instantly after the reactants were combined,
20

427
428
429
430
were isolated by extraction into dichloromethane and purified by radial chromatography. This
protocol is notably different to the classical diazotization where the use of strongly acidic
reaction conditions largely deactivates anilines by protonation. [40].
431
432
Fig. 4. Synthesis of azo dyes 4 from selected diazonium salts 2
433
434
435
436
437
438
439
440
4. Conclusion
We have demonstrated an efficient, environmentally friendly, and simple protocol for the
synthesis of stable diazonium tosylates from the appropriate aromatic amines, p-toluenesulfonic
acid and tert-butyl nitrite in ethyl acetate at room temperature. The substrate scope shows that
aromatic amines with electron-withdrawing substituents are more suitable substrates for
diazotization under the employed reaction conditions. In most cases the products were obtained
in pure form by simple evaporation of the reaction solvent and exhibited great stability over a
21

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447
448
449
450
451
452
453
454
455
longer period of time. The method is applicable for the transformation of o-phenylenediamines
benzotriazolium tosylates. Application in the synthesis of azo dyes has been demonstrated.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The Slovenian Research Agency (Research Core Funding Grant P1-0230, Project J1-8147,
Project J1-9166) and the Ministry of Education, Science and Sport, Republic of Slovenia (PhD
Scholarship to M.M.) are gratefully acknowledged for financial support. The authors thank to Dr.
Damijana Urankar from the Research Infrastructure Centre at the Faculty of Chemistry and
Chemical Technology University of Ljubljana for HRMS analyses.
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