A comprehensive electrochemical study of 2-mercaptobenzoheterocyclic derivatives. Air-assisted electrochemical synthesis of new sulfonamide derivatives

Article abstract of DOI:10.1016/j.electacta.2020.136451

In this work, we have introduced a green air-assisted electrochemical method for the synthesis of new sulfonamide derivatives via oxidative coupling of heterocyclic thiols and amines. The synthetic method was designed based on the data collected from electrochemical oxidation of heterocyclic thiols, 2-mercaptobenzoxazole (MBO), 2-mercaptobenzothiazole (MBT) and 2-mercaptobenzimidazole (MBI) in the absence and presence of amines. The electrochemical results indicate that the oxidation of MBO and MBT lead to the formation of the corresponding dimers, which as an intermediate is essential for sulfonamide synthesis. The results also show that, in the time scale of our voltammetric experiments, oxidation of MBI does not lead to dimer formation. Our voltammetric studies suggest that the formed dimer is adsorbed on the electrode surface. The amount and intensity of adsorption depends on the type heterocyclic thiol, solvent, switching potential and solution pH. The mechanism of synthesis of sulfonamide compounds has been established based on the disappearing of the dimer reduction peak in the cyclic voltammogram of MBO in the presence of amines along with increasing the number of electrons transferred in this condition, as well as spectroscopic data of the products. These compounds have been successfully synthesized in water/ethanol mixture solutions in an undivided cell, at carbon rod electrodes, by constant current electrolysis at room temperature. The proposed method does not need to use toxic solvent, metal, catalyst and challenging workups. This method is easy to scale-up and the products have antibacterial activity.

Full text of DOI:10.1016/j.electacta.2020.136451

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A Comprehensive Electrochemical Study of 2-Mercaptobenzoheterocyclic
Derivatives. Air-Assisted Electrochemical Synthesis of New Sulfonamide Derivatives
Nesa Youseflouei, Saber Alizadeh, Mahmood Masoudi-Khoram, Davood Nematollahi,
Hojjat Alizadeh
PII:
S0013-4686(20)30844-6
DOI:
https://doi.org/10.1016/j.electacta.2020.136451
EA 136451
Reference:
To appear in: Electrochimica Acta
Received Date: 5 March 2020
Revised Date: 11 May 2020
Accepted Date: 12 May 2020
Please cite this article as: N. Youseflouei, S. Alizadeh, M. Masoudi-Khoram, D. Nematollahi, H.
Alizadeh, A Comprehensive Electrochemical Study of 2-Mercaptobenzoheterocyclic Derivatives. Air-
Assisted Electrochemical Synthesis of New Sulfonamide Derivatives, Electrochimica Acta, https://
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A Comprehensive Electrochemical Study of 2-Mercaptobenzoheterocyclic
Derivatives. Air-Assisted Electrochemical Synthesis of New Sulfonamide
Derivatives
Nesa Youseflouei,a Saber Alizadeh,a Mahmood Masoudi-Khoram,a Davood Nematollahi*a and
Hojjat Alizadehb
Graphical Abstract
In this work, we have introduced a green air-assisted electrochemical method for the synthesis of new sulfonamide
derivatives via oxidative coupling of heterocyclic thiols and amines.

Highlights
‹
‹
Electrochemical synthesis of new sulfonamide derivatives.
Comprehensive electrochemical study of 2-mercaptobenzoheterocyclic
derivatives.
‹
Antimicrobial activity of synthesized sulfonamide and sulfonamide
derivatives.
‹
‹
Scaling up experiments.
Mechanistic studies.

A Comprehensive Electrochemical Study of 2-Mercaptobenzoheterocyclic
Derivatives
.
Air-Assisted Electrochemical Synthesis of New
Sulfonamide Derivatives
a
a
a
Nesa Youseflouei, Saber Alizadeh, Mahmood Masoudi-Khoram, Davood
*a
b
Nematollahi and Hojjat Alizadeh
E-Mail: nemat@basu.ac.ir
a
Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran. Zip Code 65178-38683
b
Rooyana veterinary laboratory, Saqqez, Kurdistan, Iran
*
Corresponding author. Tel.: + 0098 813 8271541; fax: +0098 813 8272404.
E-mail addresses: nemat@basu.ac.ir, dnematollahi@yahoo.com (D. Nematollahi).
Fax: +0098 813 8257407, Tel: +0098 813 8282807.
1

ABSTRACT
In this work, we have introduced a green air-assisted electrochemical method for the
synthesis of new sulfonamide derivatives via oxidative coupling of heterocyclic thiols and
amines. The synthetic method was designed based on the data collected from
electrochemical oxidation of heterocyclic thiols in the absence and presence of amines.
These compounds have been successfully synthesized in water/ethanol mixture solutions in
an undivided cell, at carbon rod electrodes, by constant current electrolysis at room
temperature. The proposed method does not need to use toxic solvent, metal, catalyst and
challenging workups. This method is easy to scale-up and the products have antibacterial
activity.
Keywords: 2-Mercaptobenzoheterocyclic compounds, Sulfonamide derivatives, Green
chemistry, Electrochemical synthesis, Cyclic voltammetry, Sulfenamide derivatives.
1
. Introduction
Sulfonamides are the first group of antibiotics to be used systemically in the treatment
of bacterial infections [1]. In addition, they are used as anticancer, anti-inflammatory and
antiviral agents [2-6]. Some of them, also used for the treatment of type II diabetes [7],
coronary artery disease and asthma [8], Alzheimer’s disease [9] and respiratory diseases
[
10]. Despite the importance of these compounds, the methods used to synthesize
sulfonamides have serious problems [11]. A literature survey reveals that the conventional
methods for the synthesis of sulfonamides are the reaction of amines with sulfonyl chlorides
[
12-14], palladium-catalyzed sulfination of aryl and heteroaryl halides [15,16], gold(I)-
catalyzed sulfination of aryl boronic acids [17], palladium-catalyzed reaction of haloarenes
bearing amino groups with sulfur dioxide [18], three-component reaction of sodium
2

metabisulfite, sodium azide and aryldiazonium [19], Cu(II)-catalyzed reaction of (hetero)aryl
boronic acids and amines, along with sulfur dioxide [20], copper-catalyzed regioselective
cleavage of C−X and C−H bonds [21], copper-catalyzed reaction of tri-arylbismuth, Na S O
2
2 5
and nitro compounds in a deep eutectic solvent [22], cobalt-phthalocyanine-catalyzed
aerobic oxidative coupling of thiols and amines [23], I O -mediated oxidative coupling of aryl
2
5
thiols and amines [24] and electrochemical methods [25,26]. Although some of these
methods are efficient but they include compounds such as sulfonyl chlorides, DABSO (SO2
surrogate) and choline chloride that are expensive, unstable and unsafe. In addition, these
methods have the disadvantages such as heavy metal pollution, strongly acidic/basic media,
unsafe solvent, tedious work-up, high temperature and long reaction time. A very
interesting paper recently published on the electrochemical synthesis of sulfonamide
compounds via oxidative coupling of thiols with amines [27]. Although many problems have
been addressed in this paper, there still exist problems associated with this paper including
the use of toxic acetonitrile solvent, strong acidic media and the inability to synthesis of
sulfonamide based on 2-mercaptobenzoheterocyclic compounds.
Another series of compounds synthesized in this study are sulfenamides. These
compounds containing divalent sulfur bonded to trivalent nitrogen, which have been widely
used in the vulcanization of rubbers as accelerator [28]. For example, N-tert-butyl-2-
benzothiazole sulfenamide (TBBS) is the most widely used sulfonamide in the rubber
industry as vulcanization accelerator [29,30]. In addition to rubber industry, sulfenamides
are widely used in agriculture as plant growth regulators, pesticides and fungicides
[
28,31,32]. They have also shown many important biological activities such as antitumor,
antiplatelet, antiasthmatic, antimicrobial and lipoxygenase activities [28,31-36].
3

The importance of sulfonamide and sulfenamide compounds has prompted many
researchers to search for new compounds with higher activity and/or develop efficient
methods of synthesis. Our literature survey shows that methods for the synthesis of
sulfenamide consist of metal-assisted synthesis [37,38], hypervalent iodine(III) activated
method [39], microwave-assisted synthesis [40], reaction of amines with thiophthalimides
[
41], transamination of N-unsubstituted sulfonamides [42], copper-catalyzed [43,44]. These
methods [37-44], have the disadvantages such as heavy metal pollution, tedious work-up,
low atom economy, safety problems, high temperatures, toxic and expensive reagents.
However, the development of a simple and environmentally friendly methodology is still
required for the synthesis of sulfonamide and sulfenamide compounds. The present work
describes an air-assisted electrochemical method for the synthesis of titled compounds via
electrochemical oxidation of 2-mercaptobenzoxazole in the presence of some amines under
simple and green conditions, without toxic solvents and reagents, using carbon electrode in
water/ethanol mixture. Another feature of the proposed method is its amenability to scaling
up which is discussed in the text.
In addition, a comprehensive study on the electrochemical behavior of 2-
mercaptobenzoxazole
(MBO),
2-mercaptobenzothiazole
(MBT)
and
2-
mercaptobenzimidazole (MBI) in water/ethanol mixture were carried out by cyclic
voltammetry. This work proposed the mechanisms for the electrochemical oxidation of
MBO, MBT and MBI in the absence and presence of amines.
2
. Experimental
2
.1. Reagents and apparatus
4

2
-Mercaptobenzoxazole (MBO) (95%), 2-mercapto benzothiazole (MBT) (97%), 2-
mercaptobenzimidazole (MBI) (98%), diethylamine (AM1) (≥99.5%), cyclohexylamine (AM2)
≥99%), piperidine (AM3) (≥99%), sodium hydrogen phosphate (99%) and sodium dihydrogen
(
phosphate (99%) were obtained from Sigma-Aldrich. Ethanol, sodium bicarbonate (98%),
sodium carbonate (98%), hydrochloric acid (37%), sodium hydroxide (99%) were obtained from
Merck (Darmstadt, Germany). These chemicals were used without further purification. The
buffered solutions were prepared based on Kolthoff tables.
The glassy carbon electrode was polished using alumina slurry (3.0 – 0.1 μm). Melting points
were measured with a Barnstead Electrothermal 9100 apparatus. IR spectra (KBr) were
1
13
recorded on Perkin–Elmer GX FT-IR spectrometer. H and C NMR spectra were recorded on a
Bruker Avance DRX-400 spectrometer at 400 MHz and INOVA 500 MHz. The mass spectra were
recorded on MS Model: 5975C VL MSD with Tripe-Axis Detector. Cyclic voltammetry was
performed using a Sama-500 potentiostat/galvanostat. Typical voltammetry experiments were
carried out on a classical three electrode undivided cell configuration with a platinum auxiliary
2
electrode and a glassy carbon (GC) working electrode (surface area = 1.8 mm ). The working
electrode potentials were measured versus Ag/AgCl (3M KCl) (all electrodes from AZAR
electrode). The Macro-scale electrolysis was carried out with a two electrode system under
constant current condition by a dc power supply Dazheng ps-303D. The working electrode
(anode) used in macro-scale electrolysis was an assembly of five ordinary soft carbon rods (38
2
2
cm ), placed circularly around a stainless steel cylinder cathode (25 cm area).
Autolab model PGSTAT302N potentiostat/galvanostat was used for preparative electrolysis,
2
controlled-potential coulometry and cyclic voltammetry. A glassy carbon disc (1.8 mm areas)
and a platinum wire were used as working and counter electrodes, respectively. An assembly of
2
four graphite rods (30 cm ) and a large stainless steel gauze were used as working and counter
5

electrodes in controlled-potential coulometry and macro scale electrolysis, respectively. The
potential of the working electrode was measured against Ag/AgCl (AZAR electrode). All
chemicals were purchased from commercial sources and used without further purification.
2
.2. Characteristic of the products
N,N-diethylbenzo[d]oxazole-2-sulfonamide (SO1) (C H N O S). Light yellow oil, yield:
1
1
14
2
3
1
5
2
9%, H NMR (400 MHz, DMSO-d ) δ/ppm: 7.48 (d, J = 8 Hz, 2H, aromatic), 7.25 (d, J = 8 Hz,
6
1
3
H, aromatic), 2.94 (q, 4H, methylene), 1.17 (t, 6H, methyl). C NMR (100 MHz, DMSO-d )
6
-
1
δ/ppm: 11.0, 41.3, 109.7, 110.8, 123.4, 124.9, 132.2, 148.3, 180.2. IR (KBr) v/cm : 2971,
823, 2776, 1764, 1618, 1507, 1449, 1279, 1247, 1132, 1096, 1008, 931, 744, 647, 607. MS
EI, 70 eV) m/z (%): 256 (M, 3), 192 (3), 151 (100), 91 (26), 58 (62).
2
(
1
N-Cyclohexyl-2-benzoxazole sulfonamide (SO2) (C H N O S). Light yellow oil, yield: 79%. H
13
16
2
3
NMR (500 MHz, DMSO-d ) δ/ppm: 7.62 (d, J = 7.8, 1H, NH), 7.21 (d, J = 7.7 Hz, 1H, aromatic), 7.16 (d,
6
J = 7.5 Hz, 1H, aromatic), 7.04 (t, J = 7.5 Hz, 1H, aromatic), 6.96 (t, J = 7.3 Hz, 1H, aromatic), 3.01 (s,
1
1
1
1
4
1
H, CH), 1.92 (d, J = 10.1 Hz, 2H, CH), 1.70 (d, J = 12.1 Hz, 2H, CH), 1.55 (d, J = 12.8 Hz, 1H, CH), 1.37 -
1
3
.14 (m, 5H, CH). C NMR (100 MHz, DMSO-d ) δ/ppm: 182.1, 150.8, 142.1, 123.2, 121.0, 113.5,
6
-
1
08.2, 49.9, 30.8, 25.0, 24.2. IR (KBr) v/cm : 3476, 2935, 2854, 2588, 2523, 2048, 1890, 1759, 1698,
643, 1538, 1507, 1464, 1431, 1381, 1346, 1252, 1132, 1114, 1070, 1003, 890, 741, 625, 605, 552,
50, 417. MS (EI, 70 eV) m/z (%): 279 (M, 3), 41 (75), 57 (86), 76 (16), 104 (25), 132 (7), 149 (100),
67 (15).
N-Piperidin-2-benzoxazole sulfonamide (SO3) (C H N O S). Light yellow oil, yield:
1
2
14
2
3
1
6
2%. H NMR (500 MHz, DMSO-d ) δ/ppm: 7.31 (d, J = 7.9 Hz, 1H, aromatic), 7.21 (d, J = 7.7
6
Hz, 1H, aromatic), 7.12 (t, J = 7.1 Hz, 1H, aromatic), 7.06 (t, J = 7.1 Hz, 1H, aromatic), 3.09 -
1
3
2
1
.73 (m, 4H, CH), 1.68 - 1.51 (m, 6H, CH). C NMR (126 MHz, DMSO-d ) δ/ppm: 181.6,
6
-1
50.0, 138.3, 124.0, 122.2, 112.6, 109.0, 44.1, 22.7, 22.1. IR (KBr) v/cm : 3445, 3049, 2941,
6

2
855, 1774, 1640, 1578, 1501, 1451, 1424, 1248, 1131, 1069, 1004, 921, 743, 627, 552, 418.
MS (EI, 70 eV) m/z (%): 266 (M, 0.2), 41 (32), 64 (74), 91 (65), 84 (62), 134 (48), 151 (100),
1
6
73 (10), 202 (35), 256 (10).
N,N-diethylbenzo[d]thiazole-2-sulfenamide (SE4) (C H N S ). Light yellow oil, yield:
1
1 14 2 2
1
5%. H NMR (500 MHz, DMSO-d ) δ/ppm: 7.95 (d, J = 7.9 Hz, 1H, aromatic), 7.76 (d, J = 8.1
6
Hz, 1H, aromatic), 7.39 (t, J = 7.7 Hz, 1H, aromatic), 7.28 (t, J = 7.6 Hz, 1H, aromatic), 3.08 (q,
1
3
J = 7.0 Hz, 4H, methylene), 1.14 (t, J = 7.1 Hz, 6H, methyl). C NMR (126 MHz, DMSO-d )
6
-
1
δ/ppm: 178.3, 155.1, 134.9, 126.4, 124.1, 122.0, 121.6, 52.3, 13.7. IR (KBr) v/cm : 2972,
2
4
931, 2855, 1563, 1468, 1429, 1376, 1310, 1273, 1159, 1081, 1023, 1009, 756, 727, 669,
32. MS (EI, 70 eV) m/z (%): 239 (M, 33), 167 (20), 108 (4), 72 (100), 42 (15).
N-Cyclohexyl-2-benzothiazole sulfenamide (SE5) (C H N S ). White solid, yield: 88%,
1
3 16 2 2
1
isolated yield: 53%. mp: 95-97 ℃. H NMR (500 MHz, DMSO-d ) δ/ppm: 7.98 (d, J = 8.5 Hz,
6
1
5
1
1
2
H, aromatic), 7.73 (d, J = 8.1 Hz, 1H, aromatic), 7.41 (t, 1H, aromatic), 7.29 (t, 1H, aromatic),
.49 (d, J = 5.8 Hz, 1H, NH), 2.77 (m, J = 9.2, 4.4 Hz, 1H, CH), 1.97 (s, 2H, CH), 1.70 (s, 2H, CH),
1
3
.54 (d, J = 11.6 Hz, 1H, CH), 1.22 (t, 5H, CH). C NMR (126 MHz, DMSO-d ) δ/ppm: 181.4,
6
-
1
55.3, 134.8, 126.4, 123.9, 122.1, 121.4, 59.9, 33.5, 25.8, 24.8. IR (KBr) v/cm : 3443, 3222,
930, 2850, 1560, 1463, 1427, 1316, 1241, 1187, 1068, 1012, 753, 726. MS (EI, 70 eV) m/z
(%): 265 (M, 86), 41 (70), 55 (64), 83 (14), 98 (100), 122 (11), 149 (15), 167 (86), 182 (17),
2
21 (11).
1
N-Piperidin-2-benzothiazole sulfenamide (SE6) (C H N S ). Light yellow oil, yield: 74%. H NMR
12
14
2 2
(
500 MHz, DMSO-d ) δ/ppm: 8.00 (d, J = 7.9 Hz, 1H, aromatic), 7.77 (d, J = 8.1 Hz, 1H, aromatic), 7.41
6
(
t, J = 7.6 Hz, 1H, aromatic), 7.30 (t, J = 7.6 Hz, 1H, aromatic), 3.17 - 2.86 (m, 4H, CH), 1.67 - 1.40 (m,
1
3
6
H, CH). C NMR (126 MHz, DMSO-d ) δ/ppm: 176.9, 155.2, 135.0, 126.5, 124.2, 122.2, 121.7, 57.9,
6
7

-
1
2
1
7.4, 22.9. IR (KBr) v/cm : 3064, 2939, 2847, 1559, 1453, 1467, 1427, 1362, 1310, 1271, 1157, 1126,
081, 1008, 919, 856, 761, 729, 667, 429. MS (EI, 70 eV) m/z (%): 251 (M, 39.5), 42 (36), 69 (6.5), 55
(
33), 84 (100), 108 (5.9), 167 (18.3).
3
. Results and Discussion
3
.1. Electrochemical study of 2-mercaptobenzoheterocyclic compounds
In this work, electrochemical oxidation of MBO, MBT and MBI have been studied in
two stages. The first stage involves studying the electrochemical behavior of these
compounds in order to better understand the oxidation mechanism, electrochemical
properties of the compounds and produced intermediates. The second part involves the
electrochemical study of these compounds in the presence of diethylamine,
cyclohexanamine and piperidine in order to obtain the necessary information for synthesis
of sulfonamide and sulfenamide compounds.
Fig. 1, part I, shows the cyclic voltammograms of MBO (1.0 mM) in aqueous
phosphate buffer (c = 0.2 M, pH = 7.0) by changing the potential scan rate between 10 and
1
000 mV/s. The Figure shows that at the scan rate of 10 mV/s, the voltammogram has two
anodic peaks (A and A ) and one sharp and symmetric cathodic peak (C ). The effect of
1
2
1
increasing scan rate on the voltammetric response is quite complex. At first with increasing
scan rate from 10 to 50 mV/s, the anodic peak A removed and both I and IpC1 increase
2
pA1
linearly with v. With further increase in scan rate, IpA1 continues to increase linearly (IpA1
=
2
0
.03 v + 1.80, R = 0.9925) (Fig. 1 part II). In order to obtain further data on the
adsorption/diffusion behavior of MBO, the log I changes were plotted against the log v
pA1
(Fig. 1 part III).
[
Figure 1]
8

The slope of the line is a measure of the adsorption/diffusion of MBO on the surface of
electrode. It is found that when the slope of the line is equal to 0.5, the process is pure
diffusion-controlled, however, when the slope is 1, the process is pure adsorption-
controlled [45]. The slope of the line is 0.75, which are higher than 0.5 and less than one
that confirms the adsorption-diffusion process for electrochemical oxidation of MBO. With
increasing potential scan rate from 50 mV/s, the voltammetric behavior of peak C is quite
1
complex (Fig. 1 parts I and IV).
At low scan rates (10, 25 and 50 mV/s), the peak is sharp and symmetrical and increases
linearly with v (characteristic of an adsorption peak [45]). However, with increasing
potential scan rate, IpC1 changes abnormally (Fig. 1 part I). At high scan rates (500, 750 and
1
000 mV/s), the cathodic peak C becomes almost a normal diffusion peak and its current
1
1
/2
increases linearly with v at high scan rates (characteristic of a diffusion peak [45]) (Fig. 1
part IV, inset).
Figure 2 part I compares the electrochemical behavior of MBO in water (phosphate buffer,
pH = 7.0 and c = 0.2 M), at two different switching potentials. The Figure clearly shows that
when the switching potential increases from 0.30 V to 0.65 V, the amount of adsorbed
material and adsorption intensity have increased dramatically. Based on these results, it can
be concluded that the over-oxidation of MBO appears to lead to the formation of materials
with a higher adsorption property.
Figure 2 part II compares peak C in different water (phosphate buffer, pH = 8.0, c = 0.2
1
M)/ethanol mixtures. As can be seen, when the percentage of ethanol in the mixture is zero
(
curve a), the cathodic peak C shows the characteristic of a complete adsorption peak.
1
However, with increasing ethanol percentage in the solvent mixture, peak C tends to
1
become a normal diffusion peak (curve c).
9

[
Figure 2]
Fig. 3 shows the linear sweep voltammograms of MBO at scan rate of 10 mV/s, in
ethanol/H O (with different pH values) (20/80, v/v) mixture. As can be seen at all studied
2
pHs, the voltammograms show an anodic peak (A ) in the positive going scan. The shift of
1
peaks towards negative potentials with increasing pH values is a sign of the participation of
proton in the redox process. According to these data, and taking into account the previously
reported data [27,46,47], we proposed the following mechanism for electrochemical
oxidation of MBO at different pH solutions.
[
Figure 3]
At pH values less than 3.5, the oxidation mechanism of MBO is shown in Eq. 1. According
to this equation, two protonated MBOs become dimer after losing two electrons and four
protons. At this condition, the slope for the E-pH line is 113 mV/pH, which is close to the
theoretical value of 118 mV/pH for a two-electron/four-proton process.
At pH values more than 3.5 and less than 6.9, the oxidation mechanism of MBO is shown
in Eq. 2. In this condition, the slope for the E-pH line is 53 mV/pH, which is close to the
theoretical value of 59 mV/pH for a two-electron/two-proton process.
1
0

At pH values more than 6.9, the oxidation mechanism of MBO is shown in Eq. 3. In this
region (pH > 6.9), MBO is in its anionic form and in its redox process the proton is not
exchanged. In addition, from data shown in Fig. 3 part II, we can conclude that the pKa
+
-
values for acid/base equilibria of MBOH /MBO and MBO/MBO are 3.5 and 6.9, respectively
(Eqs. 4 and 5). These data are in agreement with previously published data [46,48].
+
According to our data, the anodic peak A pertains to the oxidation of MBO (MBOH
1
-
●
and/or MBO ) to the MBO radical (MBO ). At the next step, the reaction of two MBO
radicals leads to the formation of 1,2-bis(benzo[d]oxazol-2-yl)disulfane dimer (DMBO). So,
at slow or moderate potential scan rates, peak C pertains to the reduction of adsorbed
1
DMBO to MBO (Eqs. 1-3). At high scan rates, however, there is no sufficient time for
●
dimerization reaction, so, diffusion peak C is related to the reduction of MBO to MBO. The
1
change of IpC1 at different pH is shown in Fig. 3, part III. As can be seen, with increasing pH
from 1.4 to 5.0, the adsorption activity of DMBO increases. We think that the relative
protonation of DMBO and formation of a more suitable medium for hydrogen bonding is
important factor for less adsorption activity of DMBO in more acidic solutions. The
1
1

adsorption activity of DMBO decreased with increasing pH from 5.0, so that at pH 9.0, peak
C1 shows the characteristic of a complete diffusion peak.
Figure 4 shows the cyclic voltammograms of MBT (curve a) and MBI (curve c) in
comparison with MBO (curve b). As can be seen, these voltammograms are basically similar.
However, they have some differences in detail. For example, the oxidation of MBO is higher
than those of MBT and MBI due to the more electron donating ability of S and N atoms in
the structure of MBT and MBI in comparison with O atom.
[
Figure 4]
Other important differences in the voltammograms of MBT, MBO and MBI are different
in adsorption ability of synthesized dimers and peak to peak separation (∆E = E – E ).
p
pA1
pC1
As can be seen, MBT shows largest peak-to-peak separation (∆E = 0.68 V) and its dimer
p
have highest adsorption activity. The result can be related to more adsorption activity of S
atom in comparison with N and O atoms present in the structures of MBO and MBI. Figure 4
also shows that the lowest adsorption activity and peak-to-peak separation ( E = 0.13 V)
p
belongs to MBI.
The effect of increasing potential scan rate on the cyclic voltammograms of MBT is
shown in Fig. 5 part I. As can be seen, MBT shows a similar trend with that of MBO (Fig. 1).
These experiments confirm previous results that at high scan rates, there is no sufficient
●
time for dimerization reaction, so, peak C is attributed to the reduction of MBT to MBT. At
1
these scan rates, peak C becomes like a normal diffusion peak and its current increases
1
1
/2
linearly with v .
[
Figure 5]
The effect of increasing potential scan rate on the cyclic voltammograms of MBI is
shown in Fig. 5 part II. Different with MBO and MBT, the cathodic peak C shows a normal
1
1
2

behavior with increasing scan rate. The presence of two N atoms in the structure of MBI,
●
●
●
makes MBI more stable than MBT and MBO . Consequently, we think that in the time
●
scale of our experiments, MBI dimer is not formed and peak C belongs to reduction of MBI
1
to MBI.
Fig. 6 shows the linear sweep voltammograms of MBT at scan rate of 10 mV/s, in
ethanol/H O (with different pH values) (20/80, v/v) mixture. The shift of peak A towards
2
1
negative potentials with increasing pH values confirmed the participation of proton in the
redox process. According to the data presented in Fig. 6, the following equations for
electrochemical oxidation of MBT at different pH values are proposed. At pHs less than 4.0,
the oxidation mechanism of MBT is shown in Eq. 6. In this range of pH, the slope for the E-
pH line is 53 mV/pH, which is close to the theoretical value of 59 mV/pH for a two-
electron/two-proton process. At pH values more than 4.0 and less than 7.2, the oxidation
mechanism of MBT is shown in Eq. 7. In this region of pH, the slope for the E-pH line is 85
mV/pH, which confirms the occurrence of a two-electron/three-proton process as shown in
Eq. 7.
[
Figure 6]
1
3

It is necessary to mention that the theoretical value for a two-electron/three-proton
process is about 88 mV/pH. At pHs more than 7.2 and less than 8.0, the oxidation
mechanism of MBT is shown in Eq. 8. In this narrow region of pH, the slope for the E-pH line
is 50 mV/pH, which confirms the occurrence of a two-electron/two-proton process. In the
-
basic region (pH > 8.0), MBT is in its anionic form (MBT ) and so its redox process is not
dependent on the pH (Eq. 9). In addition, from these data, we can determine the pK of the
a
2
+
+
+
-
acid/base couples, DMBTH /DMBTH , MBTH /MBT and MBT/MBT . The calculated pk
a
values are 4.0, 7.2 and 8.1, respectively (Eqs. 10-12). These data are in agreement with
previously published data [48].
1
4

Similar research was conducted on MBI. Fig. 7 shows the linear sweep voltammograms
of MBI in ethanol/H O (with different pH values) (20/80, v/v) mixture at scan rate of 10
2
mV/s. According to the data presented in Fig. 7, the following equations for electrochemical
oxidation of MBI at different pH values are proposed. At pHs less than 7.9, the oxidation
mechanism of MBI is shown in Eq. 13. In this range of pH, MBI is in its protonated form and
the slope for the E-pH line is 35 mV/pH, which is close to the theoretical value of 29.5
mV/pH for a one-electron/two-proton process.
[
Figure 7]
In the pH ranging from 7.9 to 9.9, the slope for the E-pH line is 67 mV/pH, which is close
to the theoretical value of 59 mV/pH for a one-electron/one-proton process (Eq. 14). In the
-
basic region (pH > 9.9), MBI is in its anionic form (MBI ) and so the proton does not get
involved in the redox process (Eq. 15). In addition, from these graphs we can calculate the
+
-
pK values for of the acid/base couples, MBIH /MBI and MBI/MBI . The calculated pk
a
a
values are 7.9 and 9.9, respectively (Eqs. 16 and 17). These data are in agreement with
previously published data [48].
1
5

3
.2. Electrochemical study of 2-mercaptobenzoheterocyclic compounds in the presence of
diethylamine
In this part, to obtain the information needed for the synthesis of new compounds
based on MBO oxidation, electrochemical study of MBO was carried out in the presence of
diethylamine (AM1) to find the most suitable conditions for the synthesis as well as
evaluation of the reaction mechanism. Cyclic voltammograms of MBO in the presence of
AM1 are shown in Fig. 8 (part I curve b) and have been compared with that of in the
absence of AM1 (curve a). Comparison of these voltammograms shows that the most
important change is the removal of the cathode peak C . Since peak C is related to the
1
1
reduction of dimer (DMBO), its disappearance is a sign of the lack of dimer at the electrode
surface. In other words, the occurrence of a fast chemical reaction between AM1 and
DMBO, removed the dimer from the electrode surface. Our data also show that IpC1 depends
on the AM1 concentration so that it decreases with increasing AM1 concentration.
Increasing the AM1 concentration increases the reaction rate of amine with the dimer
1
6

results in the disappearance of the peak C at high amine concentration. We also have found
1
that there is a significant influence of potential sweep rate on the shape of the
voltammogram (Fig. 8 part II). It is seen that the current of peak C (I ) increase with
1
pC1
increasing potential scan rate due to the decrease in the time available for the reaction of
amine with dimer at higher scan rates.
[
Figure 8]
Constant current electrolysis was performed in water (pH=8.0)/ethanol mixture
-
2
containing MBO and AM1 at the current density of 0.26 mA.cm (10 mA). The electrolysis
progress was monitored using cyclic voltammetry (Fig. 9) and thin layer chromatography. It
was found that, proportional to the electrolysis progress, the anodic peak current (IpA1)
decreased. The electrolysis was ended when the peak A decay more than 95% (after
1
consumption of 190 C electricity). In this condition, the spot of MBO disappeared on TLC.
By putting together voltammetric and amount of charge passed along with the results
obtained from spectroscopic analysis of the product (mass spectroscopy and NMR), the
mechanism shown in Scheme 1, is proposed for the electrochemical oxidation of MBO in the
presence of AM1. According to Scheme 1, sulfonamide SO1 is synthesized in four steps from
MBO. First: electrolytic formation of MBO , second: formation of dimer DMBO, third:
ox
nucleophilic addition of AM1 to DMBO, S-S bond cleavage and formation of corresponding
sulfenamide (SE1) and fourth: the air oxidation of sulfonamide [49-51] and converting it into
the final product (SO1). The air oxidation of sulfonamide has caused the main product of
MBO in the presence of AM1 to be SO1 and only a little amount of sulfenamide (SE1) was
observed chromatographically.
[
Figure 9]
1
7

Scheme 1. Electrochemical oxidation pathway of MBO in the presence of the amines.
In the case of MBT, the same reaction mechanism was observed, however, the air
oxidation process is not carried much. Therefore, when MBT is used as the starting material,
the main product is sulfenamide (SE) and only small amounts of sulfonamide (SO) were
observed (Scheme 2).
Scheme 2. Electrochemical oxidation pathway of MBT in the presence of the amines.
Different with MBO and MBT, when MBI is used as the starting material, as discussed in
the preceding sections, the MBI dimer is not formed and we could not synthesize any
sulfonamide or sulfenamide compounds from oxidation of MBI in the presence of amines.
1
8

3
.3. Constant current electrolysis
Current density is one of the most important factors controlling yield and purity. The
synthesis of SO2 and SE5, were studied at different current densities ranging from 0.06 to
2
0
.72 mA/cm , while other parameters (charge: 190 C, temperature: 298 K, MBO and MBT
amount: 0.5 mmol and cyclohexylamine (AM2) amount: 1.5 mmol) remain constant (Fig.
1
0). Our results show that the highest yield for SO2 (88%) and SE5 (79%) were obtained at a
2
current density of 0.26 and 0.52 mA/cm , respectively. In the synthesis of SO2, at the
2
current densities lower than 0.26 mA/cm , the amount of MBO radicals produced per unit
time decreases. As a result, they are less likely to react together to form DMBO. In such
conditions, the MBO radicals participate either in the side reactions or in the back reaction
in the cathode surface, therefore, despite equal charge consumption, the production yield is
2
low. On the other hand, at the current densities higher than 0.26 mA/cm , the over
oxidation of DMBO and/or SE2 reduces the production yield.
[
Figure 10]
3
.4. Electrochemical synthesis of sulfonamides (SO1-SO3) and sulfenamides (SE4-SE6)
For the synthesis of sulfonamides SO1-SO3, an 80 ml solution containing phosphate
buffer (pH = 8.0, c = 0.2 M)/ethanol (20/80 v/v) was pre-electrolyzed in an undivided cell.
Then 0.5 mmol of MBO, 1.5 mmol of amine (AM1, AM2 or AM3) was subjected to
-
2
electrolysis at constant current of 10 mA (0.26 mA cm ), in an undivided cell. The progress
of the electrolysis was followed by TLC using n-hexane/ethyl acetate (2:1) and also cyclic
voltammetry. At the end of electrolysis, the reaction mixture was filtered and then the
ethanol was removed under vacuum. The residual was extracted with 3 x 10 ml of ethyl
acetate. The extracted organic phase was dried over anhydrous sodium sulphate, filtered
1
9

and evaporated under reduced pressure. The resulting residue was purified by flash
chromatography on silica gel (eluent 2:1 n-hexane–ethyl acetate) to afford the
corresponding sulfonamide (Table 1).
[
Table 1]
For the synthesis of sulfenamides SE4-SE6, in a solution containing carbonate buffer (pH
12.0, c = 0.2 M)/ethanol (20/80 v/v), MBT and amine (AM1, AM2 or AM3) was subjected
=
-
2
to electrolysis at constant current of 20 mA (0.52 mA cm ), in an undivided cell. Other
conditions for the synthesis of sulfenamides SE4-SE6, are similar to the synthesis of
sulfonamides (Table 2).
[
Table 2]
3
.5. Scaling up experiments
In this part, we describe the large scale synthesis of SO2 and SE5. Fig. 11 shows the
electrochemical cell designed and manufactured for this purpose [52]. The working
electrode (anode) used in large-scale electrolysis was an assembly of fifteen ordinary carbon
plate (11 cm × 1.5 cm × 0.3 cm), placed beside of fifteen stainless steel plate cathode (11
cm× 1.5 cm × 0.1 cm). Under these conditions, the electrode surface increases up to 247
2
cm . In a typical procedure, for the large scale synthesis of SO2, 300 ml solution containing
phosphate buffer (pH = 8.0, c = 0.2 M)/ethanol (20/80 v/v) was pre-electrolyzed in the cell;
then 10 mmol of MBO, 30 mmol of AM2 was subjected to electrolysis at the constant
-
2
current of 0.22 mA cm (yield 72%).
The large scale synthesis of SE5 was carried out in a 300 ml solution containing
carbonate buffer (pH = 12.0, c = 0.2 M)/ethanol (20/80 v/v), then 10 mmol of MBT and 30
2
0

-
2
mmol of AM2 was subjected to electrolysis at the constant current of 0.51 mA cm (yield
8
1%). Other conditions are similar to those of the previous section.
The large scale synthesis of SE5 was carried out in a 300 ml solution containing
carbonate buffer (pH = 12.0, c = 0.2 M)/ethanol (20/80 v/v), then 10 mmol of MBT and 30
-
2
mmol of AM2 was subjected to electrolysis at the constant current of 0.51 mA cm (yield
8
1%). Other conditions are similar to those of the previous section.
Figure 11]
[
3
.6. Antibacterial susceptibility
This part of the investigation was initiated to evaluate the antibacterial susceptibility of
the synthesized sulfonamide (SO1-SO3) and sulfenamide (SE4-SE6) derivatives. Antobiogram
studies revealed that all gram positive (Bacillus cereus and Staphylococcus aureus) and gram
negative bacteria (Escherichia coli and Salmonella enteritidis) were sensitive to SO2 and
SO3. Gram positive bacteria were sensitive to SE4 and SE6 while, gram negative bacteria
showed resistance to SE4 and SE6. Gram negative bacteria were sensitive to SE5 (see
Supplementary Information). All bacteria was resistance to SO1. The results of antibacterial
activity of SO1-SO3 and SE4-SE6 compounds are summarized in Table 3.
[
Table 3]
4
. Conclusion
In this work, an efficient and green strategy based on the electrochemical oxidation of 2-
mercaptobenzoheterocyclic compounds in the presence of some amines was developed for
the synthesis of some new sulfonamide (SO) and sulfenamide (SE) derivatives. All reactions
were carried out in a simple cell, consisting of carbon and stainless steel electrodes in
water/ethanol mixture under constant current condition, without using any catalyst. It is
2
1

also shown that the products can be easily synthesized in preparative scales with impressive
yields. The product type is dependent upon the 2-mercaptobenzoheterocyclic type. When
MBO is used as the starting material, sulfonamide compounds (SO) are the main products.
Unlike MBO, when MBT is the starting material, then sulfenamide (SE) derivatives are the
main products. It should be noted that Unlike MBO and MBT, upon the oxidation of MBI in
the presence of amines, we could not isolate these two types of products. The product
yields are dependent upon the current density. In this paper, also, the electrochemical
behavior of MBO, MBT and MBI has been comprehensively investigated and unique
information has been published.
Acknowledgements
The authors wish to acknowledge Iran National Science Foundation (INSF) for financial
support of this work. We also acknowledge the Bu-Ali Sina University Research Council and
Center of Excellence in Development of Environmentally Friendly Methods for Chemical
Synthesis (CEDEFMCS) for their support of this work.
Appendix A. Supplementary data
1
13
Supplementary data including FT-IR, H NMR C NMR and MS spectra of SO1-SO3 and
SE4-SE6 and antibacterial activity of products associated with this article can be found, in
the online version, at http://dx.doi.org
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