Acid-catalyzed hydrolysis of 5-substituted-1H,3H-2,1,3-benzothiadiazole 2,2-dioxides (5-substituted benzosulfamides): Kinetic behavior and mechanistic interpretations

Article abstract of DOI:10.1002/poc.3419

The acid-catalyzed hydrolysis of a series of 5-substituted-1H,3H-2,1,3-benzothiadiazole 2,2-dioxides has been investigated in aqueous solutions of sulfuric, perchloric, and hydrochloric acid at 85.0 ± 0.05 °C. Analysis of the kinetic data by the excess acidity method, Arrhenius parameters, the order of the catalytic effects of strong acids, the kinetic deuterium isotope effect, and the substituent effect have indicated that the hydrolysis of 5-substituted benzosulfamides 1a, 1b, 1c, 1d occur with a mechanistic switchover from A2 to A1 in the studied range: an A2 mechanism in low acidity regions and an A1 mechanism in high acid concentrations.

Full text of DOI:10.1002/poc.3419

Research Article
Received: 31 October 2014,
Revised: 16 December 2014,
Accepted: 23 December 2014,
Published online in Wiley Online Library: 23 February 2015
(wileyonlinelibrary.com) DOI: 10.1002/poc.3419
Acid-catalyzed hydrolysis of 5-substituted-
H,3H-2,1,3-benzothiadiazole 2,2-dioxides
5-substituted benzosulfamides): kinetic
behavior and mechanistic interpretations
1
(
a
b
Aliye Gediz Erturk * and Yunus Bekdemir
The acid-catalyzed hydrolysis of a series of 5-substituted-1H,3H-2,1,3-benzothiadiazole 2,2-dioxides has been investigated in
aqueous solutions of sulfuric, perchloric, and hydrochloric acid at 85.0 ± 0.05 °C. Analysis of the kinetic data by the excess
acidity method, Arrhenius parameters, the order of the catalytic effects of strong acids, the kinetic deuterium isotope effect,
and the substituent effect have indicated that the hydrolysis of 5-substituted benzosulfamides 1a–d occur with a mechanistic
switchover from A2 to A1 in the studied range: an A2 mechanism in low acidity regions and an A1 mechanism in high acid
concentrations. Copyright © 2015 John Wiley & Sons, Ltd.
Keywords: acid-catalyzed hydrolysis; benzosulfamides; excess acidity; kinetics; mechanism
INTRODUCTION
EXPERIMENTAL
Materials and instruments
The sulfamide functional group (-HNSO NH-), which is an im-
2
portant class of organosulfur compounds, is interesting be-
cause of the practical uses of the compounds as reagents in
All chemical reagents were purchased from Sigma-Aldrich, Acros and
Merck and were used without further purification. Product synthesis
was carried out under microwave irradiation by using a domestic
microwave oven (Bosch model HMT 812C 2450 MHz (Germany)) that
was modified by fitting a reflux system and internal camera. Analytical
thin layer chromatography (TLC) was performed on precoated plates
(Merck silica gel 60, F254 (USA)), and visualization was achieved by ultra-
violet light. All products were characterized by comparison of their phys-
[1,2]
[3,4]
synthesis
or as possible medicinal agents.
This molecular
framework is used as inhibitors of ATP-sensitive potassium
[5]
[6]
channels
and carbonic anhydrase,
diuretics and anti-
glaucoma agents, and it has recently emerged that they also
[
7]
[8]
have potential as anti-convulsant, anti-tuberculous, anti-
[
9]
obesity, anti-cancer, anti-pain and anti-infective drugs, and
as therapeutic actions against diabetes.
1
ical data with samples prepared by conventional methods. The H and
[
10]
Cyclic sulfamides,
13
C NMR spectra were recorded on a Bruker AC 200 MHz Spectrometer
in particular, are widely used as components of insecticide
(
6
Germany) at 200 and 50 MHz, respectively, with DMSO-d as solvent.
[
11]
mixtures and as myorelax-anti-inflammatory agents.
Aryl-
Chemical shifts were reported in parts per million (p.p.m) relative to
TMS as the internal reference. Infrared (IR) spectra were recorded with
a MATTSON 1000 FTIR Spectrophotometer (USA). Melting points were
determined on an Electrothermal 9100 Melting Point Apparatus (China).
All kinetic measurements of the sulfamides were performed on a GBC Cin-
tra 20 model ultraviolet-visible (UV–VIS) spectrophotometer (Australia) with
a fitted thermostated cell compartment.
substituted seven-membered and eight-membered cyclic
sulfamides inhibit HIV-1 protease, serine protease and
[
9,12]
metalloprotease.
so far only Spillane and his coworkers
acid-catalyzed hydrolysis of N,N-diarylsulfamides in the pH
range and measured the pK values of some cyclic
none of which were performed in a highly
However, despite its obvious importance,
[
13]
have studied the
a
[14]
sulfamides,
acidic medium. Likewise, in a previous work,
[
15]
we examined
thoroughly the hydrolysis mechanisms of open chain N,N’-
diarylsulfamides in aqueous mineral acid solutions and the
principal reaction pathways were hydrolyzed by an A2 mecha-
nism at low acidity. At higher acidities, a changeover to an A1
mechanism was supported.
*
Correspondence to: Aliye Gediz Erturk, Department of Chemistry, Faculty of
Science and Arts, Ordu University – Cumhuriyet Campus, 52200, Ordu, Turkey.
E-mail: aliyeerturk@gmail.com
The aim of the present work is to gain further information on the
hydrolysis of a series of 5-substituted-1H,3H-2,1,3-benzothiadiazole
a A. Gediz Erturk
Department of Chemistry, Faculty of Science and Arts, Ordu University –
Cumhuriyet Campus, 52200, Ordu, Turkey
2,2-dioxides 1a–d (Scheme 1-referred to herein as 5-substituted
benzosulfamides-) from cyclic sulfamides in aqueous solutions of
mineral acids at elevated temperatures by using a range of physical
organic mechanistic techniques.
b Y. Bekdemir
Department of Molecular Biology and Genetics, Faculty of Science and Arts,
Canik Basari University – Gurgenyatak Campus, 55080, Canik/Samsun, Turkey
J. Phys. Org. Chem. 2015, 28 358–364
Copyright © 2015 John Wiley & Sons, Ltd.

ACID-CATALYZED HYDROLYSIS OF 5-SUBSTITUTED BENZOSULFAMIDES
Kinetic procedure
The hydrolysis rates of the cyclic substrates 1a–d were measured at
wavelengths in the range of 235–320 nm, using a UV–VIS spectropho-
tometer with a thermostated cell holder at 85.0 ± 0.05 °C. For all com-
Scheme 1. The 5-substituted-1H,3H-2,1,3-benzothiadiazole 2,2-dioxides
ꢀ4
pounds, kinetic runs were initiated by injecting 50 μL of 3.0×10
M
1a–d
stock solution of the substrate in acetonitrile into 3.0 mL of the acid solu-
tion contained in a quartz cuvette and equilibrated at 85.0 ± 0.05 °C. The
course of reactions was monitored over (at least) up to three-half lives
and the absorbance values at infinity were obtained after ten-half lives
in all cases. Good first-order behavior was observed with clean isosbestic
Preparation of 5-substituted-1H,3H-2,1,3-benzothiadiazole
[
14,16]
2,2-dioxides (1a–d)
We prepared a series of 5-substituted-benzosulfamides 1a–d from the re-
action of the corresponding substituted o-phenylenediamines with
sulfamide in the presence of diglyme by using a modified domestic
microwave oven at 900 W and irradiated for 5–8 min under reflux
1
points. The values of Pseudo first-order rate constants (k ) were calcu-
lated from the plots of ln(A–A∞) against time using the least squares pro-
cedure, where A is the absorbance at time t and A∞ is the absorbance at
infinity. All acid reaction solutions were prepared from analytical grade
concentrated acids, using deionized water and HPLC grade acetonitrile,
making appropriate allowance for the water content of the acid. All
kinetic runs were duplicated and the average deviation from the mean
was less than 5%.
[17]
followed by using the general method.
The o-Phenylenediamine (280 mg, 2.6 mmol) and sulfamide (250 mg,
.6 mmol) were dissolved in diglyme. Diglyme was used as a neat
2
solvent. The resulting solution was placed inside a modified domestic
microwave oven at 900 W and irradiated for 8 min under reflux. The
reaction was completed as determined by TLC monitoring, using
ether/petroleum ether (3 : 1) as the eluent. The reaction mixture was
removed from the oven, then cooled in ice, and filtered. The residue
was dissolved in ether (20 mL) and washed successively with 2 N HCl
Product analysis
Analysis of the hydrolysis products was also determined by comparing
the UV spectrum obtained after completion of the kinetic experiment
with the spectrum of the expected product with the same concentration
and under the same conditions. The UV–VIS spectra of the product of the
acid-catalyzed hydrolysis of the compounds 1a–d were found to be
identical to the UV–VIS spectra of the corresponding substituted
o-phenylenediamines recorded under the same conditions. (See Supple-
mentary data). Also the product of the hydrolysis of a typical cyclic
sulfamide (1a), which was isolated and recrystallized from benzene,
was found to be o-phenylenediamine, m.p. 100-102 °C. The structure of
(5 mL) three times and with saturated brine (3 mL). The ether solution
was dried and benzylamine (1 mL) was added. The sulfamide salt was
precipitated: it was filtered off, washed with ether and shaken with 2 N
HCl (10 mL). The acidic solution was extracted with ether (5 mL) four
times and the combined organic layers were dried over Na SO and
2 4
evaporated in vacuo. The crude product was purified by crystallization
from hot ethanol to yield pure 1a–d.
1
this compound was confirmed by H and IR spectra.
1H,3H-2,1,3-benzothiadiazole 2,2-dioxide (1a)
White solid (355 mg, 80%); m.p. 176–177 °C; Rf (75% ether/benzene): 0.51;
ꢀ
1
RESULTS AND DISCUSSIONS
IR (KBr) (νmax, c1m ): 3280 (N-H), 3058, (Ar. C-H), 1600 (C = C), 1300 and
160 (N-SO ); H-NMR (200 MHz, DMSO-d ) (δ , p.p.m): 6.76–6.96 (4H,
m, arom.), 10.90 (2H, s, 2NH); C-NMR (50 MHz, DMSO-d ,) (δ , p.p.m):
1
2
6
H
13
Specific acid-catalyzed reactions, where the only protonation
6
C
+
source is H
3
O , can occur in two different ways. The catalysis also
129.5, 121.3, 110.2.
proceeds by fast, pre-equilibrium protonation before a rate-
limited step for both mechanisms. If the protonated substrate
+
4-Methyl-1H,3H-2,1,3-benzothiadiazole 2,2-dioxide (1b)
(SH ) evolves in the rate-determining step and subsequently
turns speedily to products, a monomolecular mechanism ꢀA1
White solid (360 mg, 75%); mp 169–170 °C; Rf (75% ether/benzene):
ꢀ
1
is described (Eqn 1 in Scheme 2). If the protonated substrate
0
1
.55; IR (KBr) (νmax, cm ): 3300 (N-H), 3080 (Ar. C-H), 2940 (C-H),
+
1
(
SH ) is attacked by the nucleophile (Nu) in the rate-limited step,
2 6
610 (C = C), 1310 and 1165 (N-SO ); H-NMR (200 MHz, DMSO-d ,)
[
18]
(
2
δ
H
, p.p.m): 2.23 (3H, s, Me), 6.68–6.62 (3H, m, arom.), 10.80 (2H, s,
a bimolecular mechanism ꢀA2 is formed (Eqn 2 in Scheme 2).
1
3
NH); C-NMR (50 MHz, DMSO-d
6
) (δ
C
, p.p.m): 130.7, 129.8, 127.2,
In order to reliably designate reaction mechanisms at medium
and high acidity levels, an array of criteria dealing with the
121.6, 110.8, 110.3, 20.8.
[
19]
kinetic data such as the catalytic order of strong acids, shapes
of profiles,
modynamic data,
substituent effects are available.
[
20]
[21]
excess acidity method,
measurements of ther-
4-Chloro-1H,3H-2,1,3-benzothiadiazole 2,2-dioxide (1c)
[22]
[23]
kinetic deuterium isotope effect,
and
[
19]
[24]
White solid (395 mg, 74%); mp 192–193 (Lit.
199–200) °C; Rf (75%
ꢀ
1
ether/benzene): 0.48; IR (KBr) (νmax, cm ): 3270 (N-H), 3060 (Ar. C-H),
The pseudo-first-order rate coefficients, k for the hydrolysis of
1
1
1605 (C = C), 1300 and 1155 (N-SO
2
), 750 (C-Cl); H-NMR (200 MHz,
1a–d in aqueous solutions of mineral acids are given in Table 1.
DMSO-d ) (δ , p.p.m): 6.76–6.95 (3H, m, arom.), 11.30 (2H, s, 2NH);
6
H
In Fig. 1, the hydrolysis of 1a in sulfuric, perchloric, and hydro-
chloric acid shows that the catalytic effectiveness of the added
acids was HCl > H SO > HClO . Also for the hydrolysis of 1b–c,
2 4 4
1
3
6 C
C-NMR (50 MHz, DMSO-d ) (δ , p.p.m): 130.5, 128.2, 125.0, 120.8,
111.2, 109.8.
4-Nitro-1H,3H-2,1,3-benzothiadiazole 2,2-dioxide (1d)
[
20]
Yellow solid (308 mg, 55%); mp 190–191 (Lİt.
190) °C; Rf (75%
ꢀ
1
ether/benzene): 0.38; IR (KBr) (νmax, cm ): 3250 (N-H), 3040 (Ar. C-H),
1
1
600 (C = C), 1550 (C-NO
DMSO-d ) (δ , p.p.m) 6.65 (1H, d, J = 8.7 Hz, arom.), 7.56 (1H, d,
J = 2.4 Hz, arom.), 7.84–7.90 (1H, dd, J = 6.4, 2.4 Hz), 11.77 (2H, s, 2NH);
2 2
), 1310 and 1140 (N-SO ); H-NMR (200 MHz,
6
H
1
3
C-NMR (50 MHz, DMSO-d
6
); (δ
C
, p.p.m): 140.7, 135.7, 129.0, 118.4,
Scheme 2. Specific acid-catalyzed reactions. (1) Monomolecular reac-
tion – A1, (2) Bimolecular reaction – A2
108.7, 104.3.
J. Phys. Org. Chem. 2015, 28 358–364
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

A. GEDIZ ERTURK AND Y. BEKDEMIR
5
ꢀ1
Table 1. Values of rate constants 10 k
1
(s ) for the hydrolysis of 1a–d in different aqueous acids at 85.0 ± 0.05 °C
+
[
H ]/(M)
1a
1b
1c
1d
H
2
SO
4
HClO
4
HCl
H
2
SO
4
HClO
4
HCl
H
2
SO
4
HClO
4
HCl
H
2
SO
4
HClO
4
HCl
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
1
.00
.00
.00
.00
.00
.00
.00
.00
0.19
0.50
1.24
2.10
3.55
6.26
10.33
17.19
18.58
9.86
6.80
4.66
3.14
1.65
2.03
4.44
10.10
20.92
36.82
57.71
0.16
0.33
0.68
1.25
2.29
3.79
5.76
4.63
2.66
1.77
1.42
—
—
—
—
—
—
—
—
—
0.81
1.28
3.08
8.02
13.81
21.09
38.50
92.99
82.79
28.69
20.28
16.58
12.70
—
—
—
—
—
—
—
0.19
0.37
0.56
1.03
2.11
4.47
8.09
12.32
14.74
8.72
0.20
0.37
0.60
1.29
2.89
6.41
11.50
9.05
4.71
2.43
1.88
—
—
—
—
—
—
—
—
—
1.71
3.47
5.98
9.36
13.34
20.69
29.11
39.17
26.23
17.38
14.30
11.41
9.70
—
—
—
—
—
—
—
0.22
0.87
1.79
3.36
6.51
12.15
20.48
28.11
22.72
10.76
5.08
4.16
3.33
2.78
1.80
1.21
2.72
6.78
16.53
32.51
0.17
0.49
0.87
1.74
3.68
7.77
11.42
9.20
4.43
1.98
0.88
—
—
—
—
—
—
—
—
—
2.12
3.29
5.16
9.16
17.14
31.40
42.54
28.59
7.55
1.61
0.93
0.85
0.78
—
—
—
—
—
—
—
1.98
2.93
3.21
5.14
8.95
1.32
1.98
2.35
3.83
7.04
10.48
9.08
5.77
3.32
2.41
2.15
—
—
—
—
—
—
—
—
—
5.37
7.15
9.47
15.32
24.81
34.43
45.24
59.82
32.07
19.55
15.11
10.84
9.23
—
—
—
—
—
—
—
19.04
31.55
39.02
30.78
15.11
7.44
4.44
3.12
1.57
1.06
0.90
1.87
4.16
6.82
9.21
.00
0.00
0.53
1.00
1.44
2.00
3.00
4.00
5.00
6.00
7.00
7.85
4.32
3.06
2.77
3.63
7.01
14.65
30.42
54.53
76.06
90.17
Figure 2. Rate profiles for hydrolysis of 1a–d in sulfuric acid at 85.0
± 0.05 °C. Δ: p-NO ; ○: p-Cl; ◊: p-H; *: p-CH
Figure 1. Plots of rate constants (k
in aqueous acidic solutions at 85.0 ± 0.05 °C. Δ: HCl; ○: H
1
) for acid-catalyzed hydrolysis of 1a
SO ; ◊: HClO
2
3
2
4
4
10.00–14.00 M) and finally increase again for 1a,b after 12.00 M
this order varied in a similar way, as expected. Bunton and his
(for 1c,d after 14.00 M). Similar rate maxima have been observed
[19,25]
coworkers
have suggested that such an order is characteris-
for acid-catalyzed hydrolysis of other compounds such as
[
26]
[27]
[21,28]
tic of a bimolecular (A2) mechanism, because the transition state
of the positive character is being preferentially stabilized by
sultams,
N-arylsulfinylphthalimides,
hydroxamic acids,
[
29]
[30]
primary acetate esters, N-acetylsulfonimidic esters and N,N’-
diarylsulfamides. The initial downward curvatures, which were
ꢀ
[15]
small anions of high charge density such as Cl . On the contrary,
the transition states of the unimolecular A1 mechanism are
preferred for stabilization by anions of low charge density such
exhibited are typical of an A2 reaction in which extensive proton-
ation of the 5-substituted benzosulfamides occurs in the regions
of acidity in which the activity of the water is falling. The rates of
hydrolysis of the 5-substituted benzosulfamides at higher concen-
trations of the sulfuric acid solutions pass through a minimum and
then increase sharply. An upward linear region is typical of an A1
process. In addition, the final increases are associated with a
changeover of mechanism from A2 to A1 with increasing concen-
tration of the acid. Similar behavior has also been observed for
ꢀ
as ClO , so the order of the A1 reaction is HClO > H SO > HCl.
4
4
2
4
Profiles of the acid-catalyzed hydrolysis of the benzosulfamides
a–d in aqueous solutions of sulfuric acid at 85.0± 0.05 °C are
1
shown in Fig. 2. For 1a,b in the 1.00–9.00 M (for 1c,d in the
.00–8.00 M) region, the rate of hydrolysis increased with increas-
1
ing acid concentration. While 1a,b show a clearly defined rate max-
imum at 9.00 M (for 1c,d at 8.00 M), after that the rates decrease,
pass a minimum for 1a,b around 10.00–12.00 M (for 1c,d around
[
20]
acid-catalyzed hydrolysis of seconder alkyl and benzyl esters.
wileyonlinelibrary.com/journal/poc
Copyright © 2015 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2015, 28 358–364

ACID-CATALYZED HYDROLYSIS OF 5-SUBSTITUTED BENZOSULFAMIDES
The excess acidity method has been put forward as a powerful
device for the mechanistic explanation of a wide variety of reac-
tions in highly acidic aqueous media, particularly in sulfuric acid.
The kinetic data for sulfuric acid solution in Table 1 were ana-
The increasing values of log activity of the species reacting
+
with SH are subtracted from the left-hand side of the equation
[
31]
until linearity of the result against X is achieved.
In the
5-substituted benzosulfamides hydrolysis process, subtraction
one of the water activity from the left-hand side of Eqn 3 is
required to obtain good straight line correlations, which implies
involvement of one water molecule in the transition state for
[
31–34]
lyzed by the excess acidity treatment of Cox and Yates.
The kinetic equation for mainly unprotonated substrates – Eqn
was used;
3
5
-substituted benzosulfamides (Fig. 4 and Eqn 3 where r = 1). In
þ
þ
the light of this evidence, we can say that the first parts of the
profiles (3.00–8.00 M or 3.00–9.00 M) proceed with an A2 mecha-
nism involving one water molecule in the transition state, where
r is 1. The slope and intercept values of the lines obtained in Fig. 4
for 1a–d are given in Table 2. According to Ghosh and Cox,
m*m > 1 is for A1 processes, and m*m < 1 is for A2 pro-
cesses.
are lower than 1, which implies an A2 mechanism on the left-
hand side of the rate maxima in sulfuric acid profiles. Similar
log k1 ꢀ log CH ꢀ log CS=ðCS þ CSH Þ
≠
þ
¼
m*m X þ r log αNu þ log ðko=KSH Þ
(3)
eq 3)
(
The pseudo-first-order rate constants, k
the Eqn 3 in the case of the A2 mechanism. In this equation, C
and CSH are the concentrations of the unprotonated and proton-
1
, in sulfuric acid obey
≠
≠
S
+
[21,38]
≠
For 1a–d, values of m*m have been found, which
+
ated substrate in the aqueous acid with concentration C
H
[= c
)]. Because of the extremely low basicity of the
-substituted benzosulfamides studied, the protonation correc-
(
5
H
2
SO
4
≠
plots and slope values (m m*) were obtained for the hydrolysis
of benzohydroxamic acids, classified as an A2 mechanism.
+
[21,38]
tion term [log C
S
/(C
S
+ CSH)] can be neglected in the low acidity
region (up to 8.00 or 9.00 M). X is the excess acidity and aNu is
The thermodynamic parameters were calculated from an
Arrhenius equation with a least squares procedure by using the
values of specific rate constant at different temperatures. Table 3
tabulates the calculated activation enthalpy and entropy values.
+
[32,35]
[36]
the water activity (C , X,
and aNu were corrected accord-
H
ing to temperature, and the recent molarity-based log a values
Nu
[33]
by Cox were used because of their correct standard state) and
r is the number of water molecules in the transition state.
m*m are the combined slope parameters, where m* gives infor-
[
33,35]
The entropies in 1.00 and 7.00 M sulfuric acid are negative
≠
ꢀ1 ꢀ1
(ꢀ97.92 and ꢀ87.28 J mol
K ) and would support a bimolecu-
≠
mation about the protonation site (for the nitrogen compounds
lar mechanism exclusively for 1a. In 14.00 M ΔS is reasonably
[
20]
≠
ꢀ1 ꢀ1
m* is in the range of 0.7–1.0), while m accounts for the char-
positive (+214.16 J mol
K ) and would indicate a monomolecu-
≠
[31]
acteristics of the transition state (for A1 reactions m > 1).
ko
lar mechanism for 1a. The values for the hydrolysis of 1b–c
stands for the medium-independent rate constant of the rate-
limiting step and KSH for the thermodynamic dissociation con-
change in a similar way, as expected. The acid-catalyzed hydrolysis
+
stant of the protonated form of the substrate.
For the hydrolysis of 1a–d in sulfuric acid solutions, a plot of the
+
left-hand side of this equation (log k ꢀ log C ) versus X yields a
1
H
curve (Fig. 3). If we focus on the 3.00–9.00 M acidity region in Fig. 3,
where the acidity is low, then the protonation can be almost
neglected because of the low basicity of the sulfamides. The
slightly downward curvature of this region allows easy distinction
of A2 reactions involving water in the rate-determining step.
Similar behavior has been observed for the hydrolysis of
[
37]
[21]
[26]
iminosulfonate esters,
benzohydroxamic acids,
sulfinylphthalimides, and N,N’-diarylsulfamides.
sultams,
[27]
[15]
+
Figure 4. (log k
1
ꢀ log C
H
ꢀ log aH2O) versus X plot of the acid-cata-
SO region for 1a,b and in 3.0–9.0 M
region for 1c,d at 85.0 ± 0.05 °C, showing the involvement of one
water molecule – A2 mechanism. Δ: p-NO ; ○: p-Cl; ◊: p-H; *: p-CH
lyzed hydrolysis in 3.0–8.0 M H
SO
2
4
H
2
4
2
3
Table 2. Excess acidity of treatment into the acid-catalyzed
hydrolysis of the cyclic sulfamides 1a–b (for 3.00–8.00 M
H SO region) and 1c,d (for 3.00–9.00 M H SO region)
2
4
2
4
≠
+
2
Compound
Slope (m*m ) Intercept [log (k
o
/KSH)]
R
1
1
1
1
a
b
c
0.863
0.989
0.946
0.903
ꢀ7.56
ꢀ7.96
ꢀ7.43
ꢀ7.18
0.996
0.994
0.998
0.992
+
Figure 3. (log k
1
ꢀ log C
H
) versus X (temperature corrected) plot of the
SO region for 1a, b and in
region for 1c,d at 85.0 ± 0.05 °C. Δ: p-NO ; ○: p-Cl; ◊: p-H;
acid-catalyzed hydrolysis in 3.0–8.0 M H
.0–9.0 M H SO
: p-CH
2
4
3
2
4
2
d
*
3
J. Phys. Org. Chem. 2015, 28 358–364
Copyright © 2015 John Wiley & Sons, Ltd.
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A. GEDIZ ERTURK AND Y. BEKDEMIR
5
ꢀ1
Table 3. Values of rate constants 10 k
1
(s ) and thermodynamic parameters for the hydrolysis of the 5-substituted-1H, 3H-2,1,3-
benzothiadiazole 2,2-dioxides 1a–d at different temperatures
≠
≠
ΔH
ΔS
ꢀ
1
ꢀ1 ꢀ1
2
Compound
H
2
SO
4
80.0 °C
85.0 °C
90.0 °C
95.0 °C
(kJ mol
)
(J mol
K
)
R
1
1
1
1
a
b
c
7.00
0.00
6.00
7.00
0.00
6.00
7.00
0.00
6.00
7.00
0.00
6.00
7.02
6.32
8.12
5.05
3.02
20.20
11.94
5.12
2.80
18.50
8.12
1.71
10.33
9.86
20.92
8.09
14.82
15.02
51.82
12.82
7.18
151.20
33.72
19.92
15.72
54.82
27.82
9.68
21.42
22.42
114.20
20.00
10.72
414.20
53.42
37.82
36.42
95.20
51.42
21.42
80.24 ± 0.04
109.50 ± 0.06
189.95 ± 0.35
96.96 ± 0.13
101.12 ± 0.14
218.53 ± 0.22
107.49 ± 0.6
142.72 ± 0.27
184.70 ± 0.05
104.49 ± 0.16
133.18 ± 0.09
181.76 ± 0.15
ꢀ97.92 ± 0.12
ꢀ68.17 ± 0.18
214.16 ± 0.98
ꢀ53.11 ± 0.35
ꢀ41.16 ± 0.40
302.25 ± 0.61
ꢀ16.23 ± 0.44
76.57 ± 0.75
0.9999
0.9999
0.9993
0.9997
0.9996
0.9998
0.9995
0.9993
0.9999
0.9995
0.9999
0.9999
1
1
1
1
4.72
54.53
20.48
10.76
6.78
31.55
15.11
4.16
1
1
190.22 ± 0.15
ꢀ21.10 ± 0.46
53.12 ± 0.24
d
1
1
177.91 ± 0.42
[
22]
of the esters and amides
proceed with an A1 mechanism,
≠
-1 -1
Table 4. Kinetic data and kinetic isotope effects at 85.0
± 0.05 °C for the hydrolysis of 1a in sulfuric acid solutions
ΔS ~ 0–41.8J mol K , while those proceeding with an A2 mech-
≠
ꢀ1 ꢀ1
anism have ΔS ~ ꢀ62.8 to ꢀ125.5J mol
K . It is suggested
≠
that the negative values of ΔS for an A2 mechanism are a reflec-
tion of the loss of rotational and translational freedom of the wa-
ter molecules in the transition state, where the water molecule
5
ꢀ1
(Acid)/M
10 k
1
(s
)
k
D2O/kH2O
6.00 M D O/D SO
6.00 M H O/H SO
2 2
6.70
6.26
1.07
2
2
4
4
≠
acts as a nucleophile. The positive values of ΔS in 14.00 M acid,
for the hydrolysis of 1a–d, indicate that no water molecule is
involved in the rate-determining step, and so a monomolecular
mechanism is proposed. Thus, the bimolecular mechanism
proposed for hydrolysis at low acid concentrations and the mono-
molecular mechanism for the high acid concentrations are further
11.00 M D O/D SO
2.58
4.66
38.77
20.92
0.55
1.85
2
2
4
11.00 M H O/H SO
2
2
4
16.00 M D O/D SO
2
2
4
16.00 M H O/H SO
2
2
4
≠
[39]
supported by this change in ΔS .
The solvent effect could be taken into account for the transi-
tion state. There might be some differences in solvation struc-
ture, but from the initial state to transition state in both
mechanisms has quite similar solvation requirements, because
both have protonated substrate in the rate-determining step≠.
As Long and Schalenger reported, large negative values of ΔS
imply an A2 mechanism due to attaching water molecules where
it loses some freedom. Still these values need to be supported
with other criteria such as Hammett plots and catalytic activity
rate constants. Generally, for the A2 mechanism in the rate-
determining step, when the nucleophilic attacks of water take
place on the protonated substrate, the values of kD2O/kH2O lie
closer to unity than those observed for the A1 mechanism.
Values of 1.02 and 1.19 were obtained for the acid-catalyzed
[
27]
hydrolyses of N-(4-substituted-arylsulfinyl)phthalimides
arylsulfonyl phthalimides, respectively. The mechanistic
changeover is also supported by the values of the KDIEs.
and
[
43]
[
44]
[
22,40]
of the acids and so on for the proposed mechanism.
The kinetic deuterium isotope effect (KDIE) for the
acid-catalyzed hydrolysis of 1a was measured in D O/D SO
and H O/H SO solutions and was found to be kD2O/kH2O = 1.07
in 6.00 M) and 1.85 (in 16.00 M) (Table 4). The former value sup-
Additionally, in 11.00 M acid, kD2O/kH2O was measured as 0.55.
This concentration lies on the right side of the maxima of the
rate profile. Because of high protonation and decreasing activa-
2
2
4
2
2
4
tion of the water in this region, an increase in the rate of H
solution involved, is observed. Also this increase has arisen from
the larger nucleophilicity of H O with respect to D O. Similar
results were obtained from the hydrolysis of amidosulfides and
cyclic sulfonamides. In comparison, for the amidosulfides, kD2O
2
O
(
ports a bimolecular A2 pathway whereas the latter value shows a
monomolecular A1 mechanism. In the A1 mechanism, the rate-
determining step is not affected significantly by the change of
solvent because it does not involve the solvent or transfer of pro-
2
2
/
k
H2O was measured as 0.58 for 4.61 M HClO
4
which was taken
[
20]
ton. Thus, the main effect of changing the solvent from H
O lies in its influence on the first step involving the proton-
ation equilibrium. In the A1 mechanism, k ~ k and the ratio
kD2O/kH2O are influenced by the KSD /K ratio. In D O, the con-
2
O to
on the right side of the maxima,
amides this ratio was evaluated as 0.51 at 14.50 M acid.
and for the cyclic sulfon-
[
45]
D
2
D
H
Structure-reactivity effects were investigated by studying the
effect of changing the substituents (X) in compound 1 in 2.00,
10.00, and 17.85 M H SO at 85.0 ± 0.05 °C, on the rates of reac-
+
+
SH
2
+
centration of the conjugate acid of the substrate [SD ] is higher
2
4
+
than [SH ] in H O because most acids are stronger in H O than in
tion. Hammett plots illustrate these effects (See Supplemental
materials). The substituent effects are well correlated by a satis-
2
2
[
23,41,42]
D2O. Therefore, the ratio is expected to be around 2–4.
For example, the k /k ratios for the acid-catalyzed hydroly-
sis of ethylene oxide
[
24]
factory Hammett plot.
The slope of the Hammett plot (log k/
D2O H2O
42]
[
[23]
and t-butyl acetate
are 2.2 and 2.0,
ko = ρσ) gives the ρ value. As a general convention, if the ρ value
is positive it implies that electron-withdrawing groups accelerate
the rate of reaction and electron releasing groups retard the
respectively. The ratio kD2O/kH2O is controlled not only by the
+
+
SH
KSD /K ratio but also by the difference between the k and kH
D
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Copyright © 2015 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2015, 28 358–364

ACID-CATALYZED HYDROLYSIS OF 5-SUBSTITUTED BENZOSULFAMIDES
[
48–50]
spectral curves from passing through an isosbestic point.
The values of pKBH+ and m* could not be estimated. So the
direct evidence concerning the site of protonation of
-substituted benzosulfamides could not be obtained. However,
the protonation behaviors of the sultams and sulfamate esters
5
were studied. The values of pKBH
+
of the substituted
[
26]
sultams = 5.96–8.3.
water-organic media. Sulfamides have two electron donor ni-
trogen atoms. So protonation of the sulfamides might take place
Sulfamate esters have pK values of ≈ 8 in
a
[
51]
[
52]
[53]
on nitrogen as observed for the sultams and sulfinamides.
When both the mechanisms are examined, the possible hydroly-
sis products are arylsulfamic acids and their corresponding
amines. However, we could not observe any o-aminoarylsulfamic
acids. Phenylsulfamic acid has already been studied by Spillane
[
13]
and his coworkers,
and they found the rate of hydrolysis of
phenylsulfamic acid was around 100× faster than the rate of
hydrolysis of diphenylsulfamide. Accordingly, the final products
of the hydrolysis of 1a–d are found to correspond to the
o-phenylenediamines.
Scheme 3. Suggested A2 mechanism of acid-catalyzed hydrolysis of
5-substituted benzosulfamides 1a–d
CONCLUSIONS
The accumulated evidence from the above range of physical
organic mechanistic techniques have indicated that the acid-
catalyzed hydrolysis mechanism of the cyclic sulfamides
1
1
a–d proceeds with an A2 mechanism at low acidities (for
c,d 1.00–8.00 M and for 1a,b 1.00–9.00 M), as shown in
Scheme 3. In this first step, rapid pre-equilibrium protonation
of the 5-substituted benzosulfamides is involved. It is
assumed that the protonation occurs on the nitrogen atom,
and subsequently, a water molecule attacks the sulfur atom
as the nucleophile in the rate-determining step. At acidity
Scheme 4. Suggested A1 mechanism of acid-catalyzed hydrolysis of
+
+
levels higher than 12.00 M (H ) for 1a,b [14.00 M (H ) for 1c,
d], rapid protonation on the nitrogen atom is followed by
S–N bond cleavage in the transition step, and the
acid-catalyzed hydrolysis mechanism of the 5-substituted
benzosulfamides 1a–d could be described as an A1 reaction
mechanism as shown in Scheme 4.
5-substituted benzosulfamides 1a–d
reaction (A2 mechanism). A negative ρ value simply implies the
[
46,47]
opposite contribution of the substituent (A1 mechanism).
2
The values of Hammett ρ are 0.957 (R : 0.9992) at 2.00 M
H SO and 0.247 (R : 0.9939) at 10.00 M H SO . The electron-
2 4 2 4
2
withdrawing substituents produce the highest rate of hydroly-
sis (i.e., 1d > 1b in Fig. 1). Clearly at these acidities [up to 12.00
+
REFERENCES
(or 14.00) M (H )], the electron-withdrawing substituents
increase the positive charge on the sulfur atom, so the nucle-
ophilicity of the water molecule becomes more effective
because of the positively charged sulfur atom in the rate-
[
1] B. Gong, C. Zheng, E. Skrzypczak-Jankun, Y. F. Yan, J. H. Zhang, J. Am.
Chem. Soc. 1998, 120, 11194–11195.
2] S. V. Pansare, M. G. Malusare, Tetrahedron Lett. 1996, 37, 2859–2862.
3] A. Scozzafa, M. D. Banciu, A. Popescu, C. T. Supuran, J. Enzyme Inhib.
[
[
determining transition state for the A2 mechanism. The ρ
2
000, 15, 443–453.
2
value is ꢀ1.0371 [R : 0.9991] at 17.85 M H2SO
4
. At acidity levels
[
4] V. J. Aran, P. Goya, C. Ochoa, Adv. Heterocycl. Chem. 1988, 44,
+
higher than 12.00 (or 14.00) M [H ], the electron-donating
substituents produce the highest rate of hydrolysis (i.e.,
81–197.
[5] C. Guo, L. Dong, S. Kephart, X. Hou, Tetrahedron Lett. 2010, 51,
909–2913.
[
2
1b > 1d in Fig. 1). With these acidities, the electron-donating
6] D. Vullo, W. Leewattanapasuk, F. A. Mühlschlegel, A. Mastrolorenzo,
substituents increase the basicity and assist protonation of
the 5-substituted benzosulfamides. Electron-donating substitu-
ents also facilitate heterolysis of the sulfur-nitrogen bond,
and thus, a strong negative substituent effect can be expected
for an A1 mechanism. Also, the position of the rate maximum
on the rate profiles parallels the electronic properties of the
C. Capasso, C. T. Supuran, Bioorg. Med. Chem. Lett. 2013, 23,
2
647–2652.
[7] D. F. McComsey, V. L. Smith-Swintosky, M. H. Parker, D. E.
Brenneman, E. Malatynska, H. S. White, B. D. Klein, K. S. Wilcox, M.
E. Milewski, M. Herb, M. F. A. Finley, Y. Liu, M. L. Lubin, N. Qin, A. B.
Reitz, B. E. Maryanoff, J. Med. Chem. 2013, 56, 9019–9030.
[
8] S. M. Ameen, M. Drancourt, Antimicrob. Agents Chemother. 2013, 57,
substituents (Fig. 2).
We studied the ionization ratio (CBH/C ) of 5-substutited
6370–6371.
+
[9] A. Di Fiore, G. De Simone, Bioorg. Med. Chem. Lett. 2010, 20,
601–3605.
10] K. Aksu, M. Nar, M. Tanc, D. Vullo, I. Gülçin, S. Göksu, F. Tümer, C. T.
Supuran, Bioorg. Med. Chem. 2013, 21, 2925–2931.
11] E. W. Parnell, J. Chem. Soc. 1960, 4366–4368.
[12] J. Searles, S. Nukina, Chem. Rev. 1959, 59, 1077–1103.
B
3
benzosulfamides and observed shifts of absorption peak posi-
tion with increasing acidity due to the medium effects. We could
not see any good isosbestic point at ambient temperature. It is
presumed that the medium effects prevented the family of
[
[
J. Phys. Org. Chem. 2015, 28 358–364
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

A. GEDIZ ERTURK AND Y. BEKDEMIR
[
[
[
[
13] W. J. Spillane, J. A. Barry, F. L. Scott, J. Chem. Soc. Perkin Trans. 2
[36] S. A. Attiga, C. H. Rochester, J. Chem. Soc. Perkin Trans. 2 1978, 5,
466–471.
[37] H. Kutuk, J. G. Tillett, Phosphorus, Sulfur Silicon Relat. Elem. 1993, 85,
1
973, 481–483.
14] P. O. Burke, S. D. McDermott, T. J. Hannigan, W. J. Spillane, J. Chem.
Soc. Perkin Trans. 2 1984, 1851–1854.
15] Y. Bekdemir, A. G. Erturk, H. Kutuk, J. Phys. Org. Chem. 2014, 27,
217–224.
[38] R. A. Cox, M. F. Goldman, K. Yates, Can. J. Chem. 1979, 57,
2960–2966.
[39] R. W. Taft, J. Am. Chem. Soc. 1952, 74, 5372–5376.
[40] C. Reichardt, Solvents and Solvent Effects in Organic Chemistry, Third,
Updated and Enlarged Edition, Wiley-VCH, Weinheim, 2003.
[41] R. P. Bell, Adv. Catal. 1952, 4, 151–210.
9
4–98.
16] D. L. Forster, T. L. Gilchrist, C. W. Rees, J. Chem. Soc. (C) 1971,
93–999.
9
[
[
17] A. G. Erturk, Y. Bekdemir, Phosphorus Sulfur 2014, 189, 285–292.
18] B. Garcia, F. J. Hoyuelos, S. Ibeas, J. M. Leal, J. Org. Chem. 2006, 71,
3
718–3726.
19] C. A. Bunton, J. H. Crabtree, L. Robinson, J. Am. Chem. Soc. 1968, 90,
258–1265.
[42] J. G. Pritchard, F. A. Long, J. Am. Chem. Soc. 1956, 78, 6008–6013.
[43] H. Kutuk, S. Ozturk, Phosphorus Sulfur 2009, 184, 332–340.
[44] J. G. Pritchard, F. A. Long, J. Am. Chem. Soc. 1958, 80, 4162–4165.
[45] S. Cox, O. M. H. El Dusouqui, W. McCormack, J. G. Tillett, J.Org. Chem.
1975, 40, 949–950.
[46] L. P. Hammett, Chem. Rev. 1935, 17, 125–136.
[47] L. P. Hammett, J. Am. Chem. Soc. 1937, 59, 96–103.
[48] J. T. Edward, S. C. Wong, J. Am. Chem. Soc. 1977, 99, 4229–4232.
[49] K. K. Ghosh, P. Tamrakar, S. K. Rajput, J. Org. Chem. 1999, 64,
3053–3059.
[
1
[
[
[
[
[
20] K. Yates, R. A. McClelland, J. Am. Chem. Soc. 1967, 89, 2686–2692.
21] K. K. Ghosh, S. Ghosh, J. Org. Chem. 1994, 59, 1369–1374.
22] L. L. Schalenger, F. A. Long, Adv. Phys. Org. Chem. 1963, 1, 1–33.
23] C. A. Bunton, J. Shiner, J. Am. Chem. Soc. 1961, 83, 3207–3214.
24] R. A. Y. Jones, Physical and Mechanistic Organic Chemistry,
Cambridge University Press: Cambridge, 1984.
[
25] C. A. Bunton, J. H. Fendler, J. Org. Chem. 1966, 31, 3764–3771.
[26] Y. Bekdemir, J. G. Tillet, R. I. Zalewski, J. Chem. Soc. Perkin Trans. 2
[50] B. Garcia, S. Ibeas, F. J. Hoyuelos, J. M. Leal, J. Org. Chem. 2001, 66,
1
993, 1643–1646.
27] H. Kutuk, Y. Bekdemir, Y. Soydas, J. Phys. Org. Chem. 2001, 14,
24–228.
7986–7993.
[
[51] C. J. A. McCaw, W. J. Spillane, J. Phys. Org. Chem. 2006, 19,
512–517.
2
[
[
[
28] A. J. Buglass, K. Hudson, J. G. Tillet, J. Chem. Soc. (B) 1971, 123–126.
29] K. Yates, Acc. Chem. Res. 1971, 4, 136–144.
30] K. T. Douglas, J. P. Hallett, F. M. Said, J. G. Tillet, Phosphorus Sulfur
[52] F. M. Menger, L. Mandell, J. Am. Chem. Soc. 1967, 89, 4424–4426.
[53] B. Bujnicki, J. Drabowicz, M. Mikolajczyk, A. Kolbe, L. Stefaniak, J. Org.
Chem. 1996, 61, 7593–7596.
1
988, 37, 21–26.
[
[
[
[
31] R. A. Cox, K. Yates, Can. J. Chem. 1979, 57, 2944–2951.
32] R. A. Cox, K. Yates, J. Am. Chem. Soc. 1978, 100, 3861–3867.
33] R. A. Cox, Adv. Phys. Org. Chem. 2000, 35, 1–66.
34] E. E. Moran, Q. K. Timerghazin, E. Kwong, A. M. English, J. Phys. Chem.
B 2011, 115, 3112–3126.
SUPPORTING INFORMATION
Additional supporting information may be found in the online
[35] R. A. Cox, Acc. Chem. Res. 1987, 20, 27–31.
version of this article at the publisher’s web site.
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