An unusual substitution reaction of an aromatic sulfonic group based on 3-carbonyl-4-phenolsulfonic acid

Article abstract of DOI:10.1016/j.cclet.2013.04.016

An unusual substitution reaction of an aromatic sulfonic group based on 3-carbonyl-4-phenolsulfonic acid was discovered in a diazo-coupling process. The reaction occurred under mild reaction conditions (pH 8.0-9.0, 0-5 C, solvent: water) within a short reaction time (1 h). A plausible substitution reaction mechanism by phenol-ketone resonance was proposed.

Full text of DOI:10.1016/j.cclet.2013.04.016

Chinese Chemical Letters 24 (2013) 613–616
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
An unusual substitution reaction of an aromatic sulfonic group based
on 3-carbonyl-4-phenolsulfonic acid
a
a
a,b
Yun-Ming Wang a, Bing-Tao Tang a, , Wei Ma , Shu-Fen Zhang , De-Feng Zhao
*
a State Key Laboratory of Fine Chemicals, Dalian University of Technology (West Campus), Dalian 116024, China
b Jihua Group Co., Ltd., Dalian 116024, China
A R T I C L E I N F O
A B S T R A C T
Article history:
An unusual substitution reaction of an aromatic sulfonic group based on 3-carbonyl-4-phenolsulfonic
acid was discovered in a diazo-coupling process. The reaction occurred under mild reaction conditions
(pH 8.0–9.0, 0–5 8C, solvent: water) within a short reaction time (1 h). A plausible substitution reaction
mechanism by phenol–ketone resonance was proposed.
Received 22 January 2012
Received in revised form 21 March 2013
Accepted 28 March 2013
Available online 20 May 2013
ß 2013 Bing-Tao Tang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
Aromatic sulfonic groups
Substitution reaction
Diazo-coupling
Diazonium salt
1. Introduction
possibilities for substituting aromatic sulfonic acid under mild
reaction conditions (pH 8.0–9.0, 0–5 8C, solvent: water) during the
In organic synthesis, sulfonic groups are important protecting
groups and widely used for pharmaceutical and total synthesis [1].
Generally, the desulfonation and regioselective substitutions of
aromatic sulfonic acids are difficult processes [2]. Stoichiometric
reduction reagents (e.g., RANEY1 Nickel) [3] and catalysts [4] are
usually required to give good conversions. Harsh conditions are
also needed [5], like heating with concentrated hydrochloric acid
at 180 8C for many hours [6], heating with a strong base at about
200–300 8C until melting [7], or heating with strong nitric acid [8].
Under mild conditions, sulfonic groups are almost impossible to be
substituted from aromatic compounds. Therefore, the desulfona-
tion and regioselective substitutions of aromatic sulfonic acids
would be very useful for the synthesis of active medicines and dyes
under mild conditions.
In the present paper, we discovered a new and unexpected
substitution reaction of a sulfonic group by a diazonium salt in a
diazo-coupling process (Scheme 1). The substitution reaction of
the aromatic sulfonic groups occurred under significantly milder
conditions (pH 8.0–9.0, 0–5 8C, solvent: water) than those
previously mentioned [2–8]. The novel and interesting specific
substitution reaction of this aromatic sulfonic groups spurred us to
determine optimal conditions and investigate the scope of the
reaction. More importantly, these research results open new
synthesis of medicines and dyes.
2. Experimental
2.1. General procedures for the formation of compounds 1–3 and 8–9
A mixture of nitroaniline (1.38 g, 10.0 mmol), 3.6 mL concen-
trated hydrochloric acid and 25 mL H2O was stirred vigorously for
0.5 h at 70 8C. The resultant solution was cooled below 5 8C with
the aid of an ice bath and stirred as NaNO2 (0.73 g, 10.5 mmol) in
5 mL H2O was added rapidly. The reaction mixture was stirred at
5 8C until a clear solution was formed. This solution was added to
87 mL ethanol and 10 mL H2O containing compound 2-hydroxy-4-
methoxybenzophenone-5-sulfonic acid (UV-284) (3.08 g, 10 mmol)
and Na2CO3 (2.40 g, 45.4 mmol) while keeping the temperature
below À20 8C. The volume ratio of ethanol and water was 2:1 in the
final solution, which was stirred for 2.5 h at À20 8C. Then, the pH of
the reaction solution was adjusted to 3.0 by adding 1 mol/L
hydrochloric acid solution. The ethanol was distilled out from
the above reaction solution, and the remaining solution was
cooled to 0–5 8C. The solid was filtered and dried to yield a yellow
solid. The compounds 1–3 were obtained by silica gel column
chromatography using ethyl acetate/petroleum ether (60/90)
mixtures as the eluent.
The compounds 8 and 9 were synthesized and purified
according to the procedures described before.
* Corresponding author.
E-mail address: tangbt@dlut.edu.cn (B.-T. Tang).
1001-8417/$ – see front matter ß 2013 Bing-Tao Tang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.04.016

[
Y.-M. Wang et al. / Chinese Chemical Letters 24 (2013) 613–616
H
Table 1
N2+
OCH3
Unusual reactions of sulfonic acid substitution with p-nitrobenzenediazonium ion
under different conditions.
O
O
R1
O
O
N N
R
R1
0-5 ºC, pH 8-9
Entry
Temperature (8C)
Ethanol/H2O (v/v)
Yield (%)
H
19.2a
OCH3
1
2
3
4
5
0–5
0/1
1/1
2/1
2/1
2/1
0–5
33.5a
R
SO3H
0–5
37.5a
À10 to À15
À20 to À25
40.8a
Scheme 1. The unusual substitution reaction of an aromatic sulfonic group based on
43.9a, 38.3b
3-carbonyl-4-phenolsulfonic acid.
a
Determined by HPLC analysis.
b
The obtained products were purified on silica gel column using ethyl acetate/
2.2. The procedures for the formation of compound 4
petroleum ether (60/90) mixture as eluent.
Sodium nitrite (0.69 g, 10 mmol) was dissolved in 8 mL
concentrated H2SO4 at 70 8C, and then the reaction mixture was
cooled to 0 8C. 2,4-Dinitroaniline (1.83 g, 10 mmol) was added to
the above solution over 30 min. After being stirred for 6 h, the
diazonium salt was added dropwise in 87 mL ethanol and 10 mL
H2O containing compound 2-hydroxy-4-methoxybenzophenone-
5-sulfonic acid (UV-284) (3.08 g, 10.0 mmol) and Na2CO3 (2.40 g,
45.4 mmol) while keeping the temperature below À20 8C. The
resulting solution was stirred for 2.5 h at À20 8C. Then, the pH of
the reaction solution was adjusted to 3.0 by adding 1 mol/L
hydrochloric acid solution. The ethanol was distilled out from the
above reaction solution, and the remaining solution was cooled to
0–5 8C. The solid was filtered and dried to yield a yellow solid. The
compound 4 was isolated by silica gel column chromatography
using ethyl acetate/petroleum ether (60/90) mixtures as the
eluent.
reaction. A high yield (43.9%) was also surprisingly obtained when
the reaction temperature was decreased to À20 8C to À25 8C
(entry 5). The yield of compound 1 was improved under reducing
reaction temperature. This was caused by the stability of
Table 2
Diazonium salt diversity in the novel reaction of sulfonic acid substitution.
Entry
1
Diazonium salt
Product
Yield (%)a
43.9
OCH3
N
[DT$LINE]
O2N
N2+
O
H
N
NO2
[DT$LINE]
O
1
OCH3
N
O
O
N
2.3. The procedures for the formation of compounds 5–7
H
2
3
[
10.7
5.1
N2+
NO2
[DT$LINE]
A mixture of aromatic amines (10.0 mmol), 2.5 mL concentrat-
ed hydrochloric acid and 20 mL H2O was stirred vigorously. The
resulting solution was cooled below 5 8C with the aid of an ice bath
and stirred as NaNO2 (0.73 g, 10.5 mmol) in 5 mL H2O was added
rapidly. The reaction mixture was stirred at 5 8C until a clear
solution was formed. The solution was added to 87 mL ethanol and
10 mL H2O containing compound 2-hydroxy-4-methoxybenzo-
phenone-5-sulfonic acid (UV-284) (3.08 g, 10 mmol) and Na2CO3
(2.40 g, 45.4 mmol) while keeping the temperature below À20 8C.
The volume ratio of ethanol and water was 2:1 in the final solution,
which was stirred for 2.5 h at À20 8C. Then, the pH of the reaction
solution was adjusted to 3.0 by adding 1 mol/L hydrochloric acid
solution. The ethanol was vacuum removed from the above
reaction solution, and the remaining solution was cooled to 0–5 8C.
The solid was filtered and dried to give a yellow solid. The
compounds 5–7 were obtained by silica gel column chromatogra-
phy using ethyl acetate/petroleum ether (60/90) mixtures as the
eluent.
O2N
2
OCH3
N2+
NO2
[DT$LINE]
O
O
N
N
H
[DT$LINE]
O2N
3
4
OCH3
9.9
O2N
N2+
NO2
[DT$LINE]
O
O
N
N
NO2
H
[DT$LINE]
O2N
4
5
[
OCH3
Negligible
N2+
O
O
N
N
H
[DT$LINE]
3. Results and discussion
5
Initial solvent and temperature screenings were carried out by
changing the ratio of ethanol-H2O (v/v) or the reaction tempera-
ture. The reaction between p-nitrobenzenediazonium ion and 2-
hydroxy-4-methoxybenzophenone-5-sulfonic acid (UV-284) was
used as the model. The results were listed in Table 1.
6
OCH3
Negligible
[DT$LINE]
H3CO
N2+
O
O
N
N
OCH3
H
[DT$LINE]
6
OCH3
N
3.1. Substitution conditions and substrate scope
7
13.2
[DT$LINE]
F3C
N2+
The reaction system used in the usual diazo-coupling condi-
tions (0–5 8C, in water) gave an encouraging yield of 19.2% for
compound 1 (entry 1). This reaction between p-nitrobenzenedia-
zonium ion and aromatic sulfonic groups cannot occur in
traditional diazo-coupling reactions [9]. A remarkably improved
yield was obtained when ethanol was added (entries 2 and 3) to the
O
O
N
CF3
H
[DT$LINE]
7
a
Determined by HPLC analysis.

Y.-M. Wang et al. / Chinese Chemica
[
l Letters 24 (2013) 613–616
615
H
Table 3
O
O
Aromatic sulfonic group diversity in the substitution reaction.a
O
O
OH
H
Entry Coupling component Product
1
Yield (%)b
13.0
OCH3
OCH
3
O
SO3H
N
N
NO2
SO3
A
B
H
SO3H
O
O
[TD$LINE]
[DT$LINE]
O
H
OH
H
8
9
OH
O
O
2
Negligible
O
5
O
7
[TD$LINE]
HO
SO3H
HO
N
N
NO2
2
[DT$LINE]
6
1
3
4
8
pH
8-9
OCH3
10
9
a
12
OCH3
H2O
11
Reaction conditions: the coupling reaction temperature 0–5 8C.
Determined by HPLC analysis.
N
b
C
D
N
SO3
Ar
p-nitrobenzenediazonium ion was improved in low temperature.
Additionally, with keeping diazonium salt at the low temperature
for 1 h, the HPLC yield of compound 1 was 50.7%. Indeed, the
substitution reaction of the sulfonic group in UV-284 proved to be
efficient even at À10 8C to À25 8C (entries 4 and 5).
Ar
N2
Scheme 2. Plausible mechanism of a substitution reaction using phenol–ketone
isomers.
The type of diazonium salt was found to be an essential factor
affecting the regioselectivity substitution of the present substitu-
tion reaction. Therefore, the effects of the type of diazonium salt
was investigated using the optimal reaction conditions (pH 8.0–
9.0, À20 8C in ethanol/H2O (2/1 (v/v)). The results were summa-
rized in Table 2.
4. Conclusion
In summary, an unusual substitution reaction of an aromatic
sulfonic group based on 3-carbonyl-4-phenolsulfonic acid was
discovered under 0–5 8C in the water solution of pH 8.0–9.0. This
discovery established possibilities of replacing sulfonic acids in
aromatic compounds under mild conditions.
As presented in Table 2, the sulfonic group in UV-284 was
substituted by a diazonium salt containing a nitro group, then
converted into the corresponding compounds 1–4 in over 5% yields
(entries 1, 2, 3, and 4). With the decrease of the activity of
diazonium salt, the yield of the regioselectivity substitution
gradually decreased. However, the yields of compounds 4 and 7
were still low, which could be ascribed to the increased steric
constraints. With aniline or 4-methoxyaniline diazonium salt, the
desired products were not obtained at all (entries 5 and 6) due to
the low reactive activity of this type of diazonium salt [10].
To further expand coupling components based on the diazo-
coupling process, we investigated the scope of the reaction with p-
hydroxybenzenesulfonic acid and 5-sulfosalicylic acid dihydrate
under the optimized reaction conditions (Table 1). It was found
that the sulfonic groups of UV-284 and 5-sulfosalicylic acid
dihydrate (Table 3) had high substituents efficiency by p-
nitrobenzenediazonium ion under the optimal reaction conditions
(pH 8.0–9.0, À20 8C in ethanol/H2O (2/1 (v/v)). But, the 4-
hydroxybenzenesulfonic acid did not react in the coupling process.
So, the aromatic sulfonic groups were easily replaced by diazonium
salt in diazo-coupling process, based on the o-hydroxy position of
p-hydroxybenzenesulfonic acid with electron-withdrawing
groups.
Acknowledgments
This work was supported by the National Natural Science
Foundation for Young Scholar of China (No. 21276042), the
National Science and Technology Pillar Program (No.
2013BAF08B06), Jiaogai Foundation of DUT (No. JGXM201224).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2013.04.016.
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