Protonation and anion-binding properties of aromatic sulfonylurea derivatives

Article abstract of DOI:10.1039/d1ra04738h

In this work the anion-binding properties of three aromatic sulfonylurea derivatives in acetonitrile and dimethyl sulfoxide were explored by means of NMR titrations. It was found that the studied receptors effectively bind anions of low basicity (Cl^?, Br^?, I^?, NO₃^?and HSO₄^?). The stoichiometry of the complexes with receptors containing one binding site was 1?:?1 exclusively, whereas in the case of the receptor containing two sulfonylurea groups 1?:?2 (receptor?:?anion) complexes were also detected in some cases. The presence of strongly basic anions (acetate and dihydrogen phosphate) led to the deprotonation of the sulfonylurea moiety. This completely hindered its anion-binding properties in DMSO and only proton transfer occurred upon the addition of basic anions to the studied receptors. In MeCN, a complex system of equilibria including both ligand deprotonation and anion binding was established. Since ionisation of receptors was proven to be a decisive factor defining the behaviour of the sulfonylurea receptors, their pK_avalues were determined using several deprotonation agents in both solvents. The results were interpreted in the context of receptor structures and solvent properties and applied for the identification of the interactions with basic anions.

Full text of DOI:10.1039/d1ra04738h

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Protonation and anion-binding properties of
aromatic sulfonylurea derivatives†
Cite this: RSC Adv., 2021, 11, 23992
ab
a
ac
a
a
*
D. Barisic,
ˇ ´
N. Cindro,
N. Vidovic,
N. Bregovic
and V. Tomisic
ˇ ´
´
´
In this work the anion-binding properties of three aromatic sulfonylurea derivatives in acetonitrile and
dimethyl sulfoxide were explored by means of NMR titrations. It was found that the studied receptors
effectively bind anions of low basicity (Clꢀ, Brꢀ, Iꢀ, NO3 and HSO4ꢀ). The stoichiometry of the
ꢀ
complexes with receptors containing one binding site was 1 : 1 exclusively, whereas in the case of the
receptor containing two sulfonylurea groups 1 : 2 (receptor : anion) complexes were also detected in
some cases. The presence of strongly basic anions (acetate and dihydrogen phosphate) led to the
deprotonation of the sulfonylurea moiety. This completely hindered its anion-binding properties in
DMSO and only proton transfer occurred upon the addition of basic anions to the studied receptors. In
MeCN, a complex system of equilibria including both ligand deprotonation and anion binding was
established. Since ionisation of receptors was proven to be a decisive factor defining the behaviour of
the sulfonylurea receptors, their pKa values were determined using several deprotonation agents in both
solvents. The results were interpreted in the context of receptor structures and solvent properties and
applied for the identification of the interactions with basic anions.
Received 18th June 2021
Accepted 24th June 2021
DOI: 10.1039/d1ra04738h
rsc.li/rsc-advances
the b-cells of the pancreas thereby lowering the level of glucose
in the blood.2 Some of the SU agents were also shown to
Introduction
improve insulin sensitivity. Metabolism of SU derivatives occurs
both in the liver and the kidneys, which makes them suitable
for patients with hepatic or renal dysfunction. The lower costs
of SU derivatives with respect to other drugs make them more
accessible to patients worldwide.3 In addition, SU derivatives
have been used as diuretic agents,4 anticancer drugs,5,6 anti-
malarial drugs,7 and agents active against tuberculosis.8 It
should be pointed out that the application of sulfonylureas is
not limited to the pharmaceutical industry and these derivatives
have been applied as catalysts in organic synthesis.9 Further,
SUs are also common structural motifs in agrochemicals, most
frequently used as herbicides.10
To understand the properties of SU derivatives, it is impor-
tant to perform a detailed study of their acidity and potential to
establish non-covalent interactions resulting in supramolecular
complexes. A large number of neutral receptors possessing NH
groups that interact through hydrogen bonds with the anionic
guests, such as amides,11,12 peptides,13,14 pyrroles,15,16 indoles,17
sulfonamides,18 and (thio)urea derivatives,19–28 have been
successfully implemented in anion recognition.29 Considering
the extensive knowledge regarding the anion coordination
chemistry in solution, it is obvious that sulfonylurea moiety
features several key attributes for efficient anion coordination.
This includes high affinity as a hydrogen-bond donor (acidity),
its simple incorporation into different molecular scaffolds, and
the fact that it possesses two directed hydrogen bond-donating
NH groups which could enhance the stability of the complexes
The class of sulfonylurea receptors received relatively low
attention, despite advantageous features of these compounds
regarding anion coordination making them prospective candi-
dates as selective and efficient supramolecular hosts. The
pharmaceutical relevance of this class of compounds provides
added value to corresponding fundamental research as it
provides deeper insight into their properties and unlocks new
potential in their application. In the process of rational design
of new active pharmaceutical ingredients, it is of great impor-
tance to understand and predict their interactions with diverse
species encountered in living organisms. Thus, the study of
supramolecular complexes of derivatives belonging to an
important class of pharmaceuticals facilitates the development
of new, more potent drugs.
Sulfonylurea (SU) derivatives have played a crucial role in the
treatment of type II diabetes for several decades as the rst oral
hypoglycemic agents. Hyperglycemia in type II diabetes is the
consequence of defects in insulin secretion from pancreatic b-
cells and insulin sensitivity in peripheral tissues such as liver,
muscle, and fat.1 SU-based drugs stimulate insulin release from
aDepartment of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102/A
10000, Zagreb, Croatia. E-mail: nbregovic@chem.pmf.hr
b
ˇ
´
ˇ
Division of Physical Chemistry, Rudꢀer Boskovic Institute, Bijenicka cesta 54, 10000
Zagreb, Croatia
c
ˇ
Institute of Agriculture and Tourism, K. Huguesa 8, 52440 Porec, Croatia
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra04738h
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Scheme 1 Sulfonylurea receptors studied in this work.
and introduce a basis for selective recognition. Interactions of solvents this feature can also lead to proton transfer (receptor to
some SU-based pharmaceuticals with methacrylate anion have anion) in the presence of basic anions like dihydrogen phos-
been studied, employing the concept of molecular imprinting phate or carboxylates. Such behaviour of NH-based anion
for their extraction.30–32 Still, the potential of sulfonylureas as receptors has been reported in numerous cases in recent liter-
anion receptors remained almost completely unexplored.
ature.18,23,33,34 Manesiotis et al. clearly demonstrated that proton
As mentioned above, due to their enhanced acidity, SU transfer from SU to carboxylate occurs in solutions.32 By
derivatives are expected to form stronger hydrogen bonds with employing interactions between methacrylate and sulfonylurea
anions, compared to their urea analogues. However, in aprotic drugs as the basis for molecular imprinting, the authors
Fig. 1 (a) 1H NMR titration of 2H (c ¼ 1.15 ꢁ 10ꢀ3 mol dmꢀ3) with TEACl (c ¼ 2.10 ꢁ 10ꢀ2 mol dmꢀ3) in MeCN-d3 at (25.0 ꢂ 0.1) ꢃC, V0 ¼ 0.53 mL.
(b) Dependence of NHb proton chemical shift on n(TEACl)/n(2H) molar ratio. - Experimental, – calculated. (c) Distribution of species during the
titration of 2H with TEACl.
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encountered deactivation of binding sites due to the exchange stabilisation of the complexes. The NHa proton signal could not
of protons between the SU drug and methacrylate, showcasing be detected in the NMR spectrum which can be attributed to its
the importance of understanding the interplay between anion high acidity leading to the coalescence of the corresponding
binding and deprotonation.
signal.
The stability constants obtained by multivariate non-linear
In this work we studied three aromatic sulfonylurea deriva-
tives (Scheme 1) and provided valuable insight into their anion- regression analysis of the titration data are listed in Table 1.
binding and protonation properties in non-aqueous solutions. Among the tested anions, the studied receptors form the most
A detailed investigation of the correlation between the receptor stabile complexes with chloride (approximately one order of
structures and the relevant properties, which will enable ne- magnitude higher stability constant compared to that with Brꢀ).
tuning of their characteristics was carried out. We strongly This nding is in line with the highest basicity of Clꢀ in terms of
believe that the results presented will endorse the development hydrogen-bond formation. Consequently, the prepared sulfo-
of the anion receptor chemistry of sulfonylureas, possibly nylureas can be regarded as moderately selective receptors of
enhancing the understanding of their pharmacokinetic chloride. Compounds 1H and 2H exhibit similar binding
behaviour.
properties with the aromatic derivative being slightly better
anion receptor, most likely stemming from weak resonance
effects of the benzyl group. The anion binding affinity of
compound 3H2 was found to be signicantly higher than that of
1H and 2H (comparing stabilities of 1 : 1 complexes). This is
partly the result of an additional binding site that statistically
favours complexation, but cooperative interactions of both
binding sites with the anion are also possible. A signicant
difference in the stability constants obtained for 1 : 1 and 1 : 2
complexes (the latter being much less stabile) supports the
assumption of cooperative interaction of both sulfonylurea
groups in the 1 : 1 complex. Great differences in the binding
constants determined in the two solvents are in line with the
competitive nature of the DMSO molecules which act as strong
H-bond acceptors in contrast to MeCN which does not signi-
cantly compete for hydrogen bonds. Consequently, the anion
complexes with nitrate, hydrogen sulphate, and iodide were not
detected in DMSO at the experimental conditions used, most
likely due to their very low stability.
The comparison of the herein studied hosts with previously
reported ones belonging to urea or thiourea families is not
straightforward since many effects (sterical, inductive, etc.)
govern the performance of the anion hosts.29,36 Within the
available literature, most data has been collected for dihy-
drogen phosphate and carboxylate complexes.27 These data
cannot be compared to the presented results since deprotona-
tion of SU group is favoured over anion coordination occurred
(see next chapter). However, the effect of SU moiety in terms of
Results and discussion
Synthesis
The studied receptors (1H, 2H and 3H2) were prepared from
tosyl isocyanate by reaction with amines in dichloromethane
(DCM).35 Upon reaction, the target products precipitated from
the reaction mixture and ltration yielded pure compounds. By
using DCM as the solvent pure products were obtained and the
system did not show any tendency to form a gel, unlike when
several other solvents were employed (benzene, toluene, THF).
ꢀ
Anion binding – weakly basic anions (Clꢀ, Brꢀ, Iꢀ, NO3
,
ꢀ
HSO4
)
The binding of a series of anions including halides, nitrate, and
hydrogen sulphate (added as tetraalkylammonium salts) was
investigated by means of 1H NMR titrations in deuterated
DMSO and acetonitrile (Fig. 1 and S7–S35 in the ESI†). Titration
curves of receptors 1H and 2H could be processed by assuming
1 : 1 complex stoichiometry (Fig. 1), whereas compound 3H2
formed 1 : 1 and 1 : 2 (receptor : anion) complexes since this
receptor possesses two binding sites. As expected, the most
pronounced changes in the chemical shi were detected for
NHb protons which exhibited a signicant downeld shi
(Fig. 1b). This nding affirmed sulfonylurea groups as the
binding sites and hydrogen bond formation between the SU
moieties and the anion as the main interaction providing
Table 1 Stability constants (log K) of anion complexes with receptors 1H, 2H, and 3H2 in MeCN and DMSO determined by 1H NMR spectroscopy
at 25 ꢃCa
MeCN
1H
DMSO
1H
2H
2H
3H2
3H2
1 : 1
1 : 1
1 : 1
1 : 2
1 : 1
1 : 1
1.16(1)
1 : 1
1 : 2
Clꢀ
Brꢀ
Iꢀ
HSO4
NO3
3.22(1)
2.28(1)
1.21(1)
2.06(1)
1.72(1)
3.27(1)
2.41(1)
1.30(1)
2.04(1)
1.89(1)
3.96(1)
2.97(1)
1.76(2)
2.45(1)
2.24(9)
1.76(4)
1.28(2)
0.74(8)
<1b
1.09(1)
1.72(2)
0.54(4)
0.71(4)
—
ꢀ
ꢀ
1.07(5)
a
Uncertainties are given in parentheses as standard deviation. b Estimated.
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Table 2 pKa values of 1H, 2H and 3H2 in DMSO determined by 1H NMR
spectroscopy at 25 ꢃC using different deprotonating agentsa
complex stability can be assessed if chloride binding properties
of non-macrocyclic urea or thiourea derivatives in MeCN or
DMSO are considered. For instance, uorescent thiourea re-
ported by Gunnlaugsson did not exhibit any change in uo-
rescence spectrum upon the addition of chloride.37 An
elaborate, preorganised thiourea receptor reported by Johnson
et al. was able to bind chloride and bromide with comparable
affinity but still lower than SU derivatives 1H or 2H.38 In our
previous study, it was shown that non-aromatic urea derivatives
of dehydroacetic acid also do not bind chloride in neither
DMSO nor MeCN.11 The same result was obtained for aromatic
mono- and bis-urea derivatives in DMSO.23 The aromatic urea
1H
2H
3H2
Base
pKa,1
pKa,1
pKa,1
pKa,2
DIPEA
OAcꢀ
H2PO4
9.69(1)
9.74(4)
9.72(1)
9.41(1)
9.6(1)
9.58(3)
9.2(1)
—
9.5(1)
10.65(6)
10.4(1)
10.39(2)
ꢀ
a
Uncertainties are given in parentheses as standard deviation.
ˇ
derivatives bearing adamantane moiety reported by Blazek et al.
than those described above. In DMSO the obtained titration
curves were monotonous but featured a decrease in chemical
shi of the NHb proton. Such spectral change is the opposite of
the behaviour expected for anion coordination, i.e., downeld
shi as was observed by the addition of non-basic anions.
Increased shielding of NHb can be accounted for by dissociation
of the sulfonylurea moiety (NHa proton) caused by the addition
of basic anions. The acquired data was processed assuming the
proton transfer, treating the anions as bases, and omitting the
formation of anion complexes from the model. All additional
processes affecting the protonation equilibria (dimerization
and homoassociation of anions and their conjugated acids)
were taken into account in the course of data analysis using the
values determined previously (more details are given in the
also featured a rather low affinity for chloride in DMSO or
MeCN.26 It can thus be unambiguously argued that sulfonylurea
moiety provides stronger stabilisation of the chloride complex
stemming from enhanced acidity. Moreover, the fact that the
sulfonylurea group can be deprotonated by the addition of base,
provides a possibility of controlled anion release. Namely, the
deprotonated form of anion would not be active as an anion
host and complex dissociation would occur upon the addition
of a base.
Protonation properties and interactions with basic anions
Upon addition of more basic anions, (acetate and dihydrogen
phosphate), rather different spectral changes were detected
Fig. 2 (a) 1H NMR titration of 3H2 (c ¼ 1.20 ꢁ 10ꢀ3 mol dmꢀ3) with TBAH2PO4 (c ¼ 8.56 ꢁ 10ꢀ3 mol dmꢀ3) in DMSO-d6 at (25.0 ꢂ 0.1) ꢃC, V0
¼
0.53 mL. (b) Dependence of Hb proton chemical shift on n(TBAH2PO4)/n(3H2) molar ratio. - Experimental, – calculated. (c) Distribution of
protonation species of 3H2 during the titration of 3H2 solution with TBAH2PO4.
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experimental part).39 Excellent agreement of the experimental initial part of titration, a downeld shi was detected, sug-
and calculated data was obtained in this way. This procedure gesting that in MeCN anion binding is favoured at a low
ꢀ
yielded very similar pKa values using both H2PO4 (Fig. 2 and anion : ligand ratio (up to 1 equivalent). Upon further addition
S36 and S37 in the ESI†), and OAcꢀ (Fig. S38–S40 in the ESI†) as of anions, shielding of the NHb proton was enhanced, which
bases (Table 2). Due to the high basicity of acetate, the corre- could again be ascribed to ligand deprotonation coupled with
sponding titration curve featured a sharp break at 1 : 1 molar anion protonation (and other secondary processes). Rather
ratio for 1H and 2H. In the case of 3H2 the NMR spectrum similar results and qualitatively almost identical titration curves
continued to change up to 2 : 1 molar ratio since both sulfo- were previously reported by Gale et al. studying other
nylurea moieties could undergo deprotonation. In the case of compounds bearing acidic NH group.18 In an effort to study the
dihydrogen phosphate, the curves were smoother, reecting the underlying equilibria in a quantitative manner, we again per-
lower basicity of dihydrogen phosphate. Still, the chemical formed the titrations of sulfonylureas with amine bases in
shis measured aer adding an excess of the base were the MeCN (Fig. 3, S52 and S53 in the ESI†). DIPEA was again used to
same regardless of the anion added. Moreover, analogous deprotonate 1H2 and 2H2, whereas diethylamine (DEA) was
results were obtained by using N,N-diisopropylethylamine applied in the case of 3H2 due to lower pKa values of 3H2 and
(DIPEA) as the base (Fig. S42–S44 and S37 in the ESI†).‡ This intermediate exchange kinetics (signal coalescence) encoun-
tertiary amine with bulky substituents is able to deprotonate the tered by the addition of DIPEA. In this way, we were able to
sulfonylurea group but it is not expected to interact with the study the proton dissociation independently of anion binding
studied receptors in any other way. Titrations of studied and obtain reliable pKa values in MeCN (Table 3).
compounds with DIPEA yielded rather similar pKa values (Table
As expected, the sulfonylurea moiety is much less acidic in
2) and characteristic spectra of deprotonated forms as in the MeCN compared to DMSO with the corresponding difference
cases when OAcꢀ and H2PO4ꢀ were used as bases (Tables S7–S9 pKa(MeCN) ꢀ pKa(DMSO) z 9. In both studied solvents 2H is
in the ESI†). This conrmed that in DMSO no anion complex- somewhat more prone to dissociation compared to 1H. Diprotic
ation occurred and that reliable pKa values were measured.
Dissociation of 1H, bearing aliphatic sidearm was the least pKa value lower compared to the other two sulfonylureas.
favourable, while the introduction of benzyl moiety resulted in With the dissociation constants at hand, we were able to
ligand 3H2 is again the most acidic SU derivative with the rst
stabilisation of the anionic form, due to delocalisation of the include these data in the tting procedure for titration curves
negative charge. Receptor 3H2 was more prone to release the obtained for OAcꢀ and H2PO4ꢀ. Unfortunately, we could still
rst proton compared to monoprotic derivatives. This could, in not achieve satisfactory agreement of the experimental and
great part, be ascribed to the statistical factor. The second calculated data by including only anion binding and proton
deprotonation of 3H2 was signicantly less favourable, as the transfer in the model. In spite of our best effort, we could not
negative charge generated by rst proton dissociation hindered identify and quantitatively describe any other processes
the following deprotonation reaction.
possibly taking place in the solution. As already mentioned,
The primary reason for the dominance of proton transfer Gale et al. reported almost identical shape of the titration curves
over potential anion coordination is a large difference in pKa with several systems.18,40 In the case of diamidopyrrole deriva-
values of acetic and phosphoric acid compared to those of SU tives this was rationalised by a “narcissistic dimer” formation.
derivatives (SU being much stronger acids). The apparent On the other hand, sulfonamide receptors were found to form
basicity of the studied anions is further increased by homo- anion complexes, but receptor deprotonation caused its disso-
association processes (AH2 formation). The lack of anion ciation as the anion concentration was increased. With the aim
binding affinity of the deprotonated receptors is not surprising of resolving the underlying reactions in the present system we
as these species become poor H-bond donors and their negative performed a DOSY NMR titration, measuring the diffusion
charge introduces unfavourable electrostatic interactions with coefficient of 1H in the presence of an increasing amount of
anions. Further on, DMSO molecules compete strongly for the DEA, OAcꢀ, or H2PO4ꢀ at different molar ratios (Fig. S56 in the
H-bonds which are the origin of the stability of most anion ESI†). Upon addition of DEA approximately 10% decrease in
complexes. In general, it can be concluded that in DMSO highly diffusion coefficient at 1 : 1 molar ratio was observed for all
basic anions will only cause deprotonation of sulfonylurea NHa three bases which would correspond to z50% increase in
groups, whereas only the anions of low basicity are coordinated molecular volume.41,42 Although this change is not negligible, it
by this class of receptor molecules.
does not provide rm proof that dimeric species of receptors are
In MeCN the titration curves obtained by the addition of formed in solution. Deprotonation itself might also cause the
acetate or dihydrogen phosphate salts to SU derivatives featured increase in effective molecular volume via changes in solvation
a much more complex shape (Fig. S45–S50 in the ESI†). Again, or conformation of the molecule upon ionisation. As described
the NHb proton underwent the most signicant change in above, in the case of DEA addition, the diffusion coefficient
chemical shi providing the most valuable information about dropped continuously throughout the titration. In contrast,
the reactions taking place in the investigated solutions. In the during titration with acetate or phosphate, Deff decreased at
a low molar ratio, but a change in the trend was detected as an
excess of acetate or phosphate was added, i.e., Deff started to
‡ The protonation equilibrium constant for DIPEA in both solvents was measured
increase. This feature revealed that at least two processes
occurred during the titration.
by means of UV-Vis titration using bromochresol green or bromothymole blue as
the indicator in MeCN and DMSO, respectively (Fig. S41 and S51 in the ESI†).
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Fig. 3 (a) 1H NMR titration of 1H (c ¼ 1.16 ꢁ 10ꢀ3 mol dmꢀ3) with DIPEA (c ¼ 1.97 ꢁ 10ꢀ2 mol dmꢀ3) in MeCN-d3 at (25.0 ꢂ 0.1) ꢃC, V0 ¼ 0.53 mL.
(b) Dependence of Hb proton chemical shift on n(DIPEA)/n(1H) molar ratio. - Experimental, – calculated. (c) Distribution of protonation species
of 1H during the titration of 1H solution with DIPEA.
Considering all results gathered in this study and previously anion complexation since DMSO is polar and acts as a strong H-
reported research, we conclude that anion binding does occur bond acceptor. MeCN, on the other hand, is not an H-bonds
in parallel to receptor deprotonation. It should be stressed out acceptor, which allows the anion complexes to be formed.
that the receptors are roughly 1000 times more acidic than Hence, the systems studied in this work represent an inter-
acetic acid. In spite of this, anion complexation is detected, esting example of solvent-control over receptor behaviour.
which suggests that sulfonylureas form very strong hydrogen
bonds with OAcꢀ and H2PO4ꢀ in MeCN, and the stability of the
corresponding anion complex hinders their ionisation to some
Conclusion
extent. However, due to the high acidity of the NHa proton, its
In this study three aromatic sulfonylurea derivatives were
dissociation cannot be avoided, and a complex system of
prepared and characterized. Their anion binding and proton
equilibria is established, which prevented us from describing
dissociation reactions were studied in detail in acetonitrile and
DMSO. The gathered results affirmed SU derivatives as good
anion binders and provided insight into their structure–reac-
tivity relationship. The performed NMR titrations indicated that
this system quantitatively. Interestingly, in DMSO such behav-
iour was not detected and only proton dissociation occurred,
showcasing a distinct solvent effect on the reaction equilibria.
Namely, in DMSO the dissociation is strongly favoured over
strongly basic anions deprotonate SU derivatives, inhibiting
their anion-binding potential. These ndings revealed
a striking difference in solvent effect on the underlying chem-
Table 3 pKa values of 1H, 2H and 3H2 in MeCN determined by 1H NMR
ical equilibria. The presented work could serve as a strong
spectroscopy at 25 ꢃC using DIPEA (1H, 2H) or DEA (3H2) as depro-
foundation for the further development of sulfonylurea anion-
tonation agentsa
receptor chemistry.
1H
2H
3H2
pKa,1
pKa,2
19.28(1)
18.70(3)
18.01(9)b Experimental part
18.67(9)b
Synthesis
b
a
Uncertainties are given in parentheses as standard deviation. DEA
was used as base.
General procedure. p-Toluenesulfonyl isocyanate (1 mmol)
and dry DCM (10 mL) were added to a round bottom ask. The
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mixture was cooled to 0 ꢃC and kept under argon. Corre- 129.82, 127.60, 36.94, 30.15, 21.48. HRMS (ESI+) m/z:
sponding amine (1 mmol) was added dropwise, and the reac-
tion mixture was stirred for 24 h at RT. The product was ltered
off, washed with DCM, and was used without further
purication.
Synthesis of N-(methylcarbamoyl)-4-methylbenzenesulfonamide
(1H)43
C
19H24N4O6S2 [M + H]+ calcd: 469.1216, found: 469.1199.
Solution studies
Materials. The solvents used (acetonitrile (MeCN, J. T. Baker,
HPLC Grade), deuterated acetonitrile (MeCN-d3, Eurisotop,
>99.8%), dimethyl sulfoxide (DMSO, Sigma-Aldrich, spectro-
photometric grade) and deuterated dimethyl sulfoxide (DMSO-
d6, Eurisotop, >99.8%)) were used as received. The salts used
were tetrabutylammonium dihydrogen phosphate (TBAH2PO4,
Sigma-Aldrich, >97%), tetrabutylammonium acetate (TBAOAc,
Sigma-Aldrich, >97%), tetraethylammonium chloride (TEACl,
Sigma-Aldrich, >98%), tetrabutylammonium bromide (TBABr,
Sigma-Aldrich, >98%), tetrabutylammonium iodide (TBAI,
Sigma-Aldrich, >99%), tetrabutylammonium hydrogensulfate
(TBAHSO4, Sigma-Aldrich, >97%) and tetrabutylammonium
nitrate (TBANO3, Sigma-Aldrich, >99%). Bromocresol green
(BCGH2, Kemika, >95%), bromothymol blue (BTBH2, Kemika,
>95%), diethylamine (DEA, Sigma-Aldrich > 98%) and N,N-dii-
sopropylethylamine (DIPEA, Sigma-Aldrich > 99.0%) solutions
were standardised prior to use by means of potentiometric
titrations. A known amount of titrant was dissolved in water and
titrated with the standardised solution of hydrochloric acid (in
the case of DIPEA and DEA) or sodium hydroxide (in the case of
BCGH2 and BTBH2). The concentration was calculated using the
inection point of the obtained titration curves.
Following the general procedure, 1H was prepared from TsNCO
(774 mL, 5.07 mmol) and methylamine (2.6 mL, 5.2 mmol, 2 M
in THF). Pure product 1H (0.4 g, 1.75 mmol, 35%) was isolated
as a white powder. 1H NMR (400 MHz, DMSO-d6) d/ppm: 10.63
(s, 1H), 7.78 (d, J ¼ 8.3 Hz, 2H), 7.40 (d, J ¼ 8.2 Hz, 2H), 6.37 (q, J
¼ 4.7 Hz, 1H), 2.50 (s, 3H), 2.39 (s, 3H). 13C NMR (400 MHz,
DMSO-d6) d/ppm: 152.34, 143.99, 137.98, 129.87, 127.68, 26.66,
21.49. HRMS (ESI+) m/z: C9H12N2O3S [M + H]+ calcd: 229.0647,
found: 229.0638.
Synthesis of N-(benzylcarbamoyl)-4-methylbenzenesulfonamide
(2H)35
NMR titrations. NMR spectra were recorded using a Bruker
Avance III HD 400 MHz/54 mm Ascend spectrometer. The
temperature was kept constant at 25 ꢃC. Chemical shis are
reported in ppm and referenced to the residual solvent signal.
Calibrated syringes (Hamilton) were used for the addition of
titrant and titrant solutions. All NMR titration data were pro-
cessed by nonlinear regression analysis using the HypNMR
program.44
In all cases the tting procedure was performed in a multi-
variate fashion, and all proton signals which exhibited signi-
cant changes and could be monitored throughout the titration
were included in the data processing. Concentration depen-
dences of 1H NMR spectra of all investigated receptors in MeCN-
d3 and DMSO-d6 at 25 ꢃC were acquired to dismiss the
Following the general procedure, 2H was prepared from TsNCO
(774 mL, 5.07 mmol) and benzylamine (553 mL, 5.07 mmol). Pure
product 2H (0.98 g, 3.22 mmol, 63%) was isolated as a white
powder. 1H NMR (400 MHz, DMSO-d6) d/ppm: 10.68 (s, 1H), 7.80
(d, J ¼ 8.4 Hz, 2H), 7.41 (d, J ¼ 8.2 Hz, 2H), 7.31–7.19 (m, 3H),
7.16–7.11 (m, 2H), 6.99 (t, J ¼ 6.0 Hz, 1H), 4.16 (d, J ¼ 6.0 Hz,
2H), 2.40 (s, 3H). 13C NMR (400 MHz, DMSO-d6) d/ppm: 151.98,
144.11, 139.62, 137.83, 129.91, 128.72, 127.72, 127.46, 127.33,
43.17, 21.51.
Synthesis of 1,10-trimethylenebis[3-(p-tolylsulfonyl)-urea] (3H2)
Following the general procedure, 3H2 was prepared from possibility of ligand aggregation. The concentration was varied
TsNCO (774 mL, 5.07 mmol) and 1,3-diaminopropane (211 mL, by stepwise addition of receptors stock solutions to MeCN-d3
2.53 mmol). Pure product 3H2 (0.98 g, 2.09 mmol, 41%) was and DMSO-d6 covering the range 8.0 ꢁ 10ꢀ5 < c (receptors)/mol
isolated as a white powder and additionally triturated with dmꢀ3 < 2.0 ꢁ 10ꢀ2
.
MeOH. 1H NMR (400 MHz, DMSO-d6) d/ppm: 10.30 (s, 2H), 7.77
Protonation properties of receptors. Protonation constants
(d, J ¼ 8.4 Hz, 4H), 7.37 (d, J ¼ 8.1 Hz, 4H), 6.51 (t, J ¼ 6.0 Hz, of investigated receptors in MeCN and DMSO were determined
1
2H), 2.86 (q, J ¼ 6.4 Hz, 4H), 2.37 (s, 6H), 1.36 (p, J ¼ 6.7 Hz, 2H). by means of H NMR titrations with DIPEA or with DEA in the
13C NMR (400 MHz, DMSO-d6) d/ppm: 152.30, 143.84, 138.17, case of 3H2 in MeCN. Considering titrations in MeCN, solution
23998 | RSC Adv., 2021, 11, 23992–24000
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of DIPEA (c z 2.0 ꢁ 10ꢀ2 mol dmꢀ3) was added to solutions of analysis, protonation constants of bromocresol green and bro-
1H or 2H (c z 1.2 ꢁ 10ꢀ3 mol dmꢀ3, V0 ¼ 0.53 mL) in MeCN-d3 mothymol blue were kept xed at the literature value
or in the case of 3H2 solution of DEA (c ¼ 7.7 ꢁ 10ꢀ3 mol dmꢀ3
)
(log KH1 (BCGH2) ¼ 18.5, log K2H (BCGH2) ¼ 11.0, log KH (BTBH2)
was added to solution of 3H2 (c ¼ 1.1 ꢁ 10ꢀ3 mol dmꢀ3, V0 ¼ ¼ 11.3).48,49
0.50 mL) in MeCN-d3 at 25 ꢃC. Considering titrations in DMSO,
Spectrophotometric titrations were carried out at (25.0 ꢂ
solution of DIPEA (c z 1.5 ꢁ 10ꢀ2 mol dmꢀ3 in the case of 1H 0.1) C by means of a Varian Cary 5 spectrophotometer equip-
ꢃ
and 2H and c ¼ 6.6 ꢁ 10ꢀ2 mol dmꢀ3 in the case of 3H2) was ped with a thermostatting device. The titrant solution was
added to solutions of receptors (c z 1.2 ꢁ 10ꢀ3 mol dmꢀ3, V0 ¼ added in stepwise fashion directly into the measuring quartz
ꢃ
0.53 mL or V0 ¼ 0.50 mL) in DMSO-d6 at 25 C.
cell (Hellma, Suprasil QX, l ¼ 1 cm) using calibrated syringes
Protonation constants of receptors in DMSO were also (Hamilton). The spectral changes were recorded aer each
studied by means of 1H NMR titrations with TBAOAc and addition. Absorbances were sampled at 1 nm intervals with 0.2 s
TBAH2PO4. Solution of TBAOAc (c z 1.2 ꢁ 10ꢀ2 mol dmꢀ3 in integration time. All titrations were done in triplicate.
the case of 1H and 2H or c ¼ 8.2 ꢁ 10ꢀ3 mol dmꢀ3 in the case of
3H2) or TBAH2PO4 (c z 1.0 ꢁ 10ꢀ2 mol dmꢀ3 in the case of 1H
Conflicts of interest
and 2H or c ¼ 8.6 ꢁ 10ꢀ3 mol dmꢀ3 in the case of 3H2) was
added to solutions of receptors (c z 1.1 ꢁ 10ꢀ3 mol dmꢀ3, V0 ¼ There are no conicts of interest to declare.
ꢃ
0.53 mL or V0 ¼ 0.50 mL) in DMSO-d6 at 25 C.
In the data tting procedure, the protonation constant of
Acknowledgements
DIPEA in MeCN and DMSO was kept xed at the value deter-
mined spectrophotometrically and the protonation constant of This work has been fully supported by the Croatian Science
DEA in MeCN was kept xed at the literature value (log KH (DEA) Foundation under the project IP-2019-04-9560 (MacroSol).
¼ 18.8).45,46 Processes dening acid–base properties of acetic and
phosphoric acid in DMSO (protonation, homoassociation and
dimerisation) were accounted for and their equilibrium
References
constants were kept xed at the values recently reported by us:
(log KH(AcOH) ¼ 12.82, log K(AcOH$OAcꢀ) ¼ 2.45, log Kd((-
AcOH)2) ¼ 1.45, log KH(H3PO4) ¼ 10.80, log Kd((H2PO4ꢀ)2) ¼ 2.26,
1 S. Fukuen, M. Iwaki, A. Yasui, M. Makishima, M. Matsuda
and I. Shimomura, J. Biol. Chem., 2005, 280, 23653–23659.
2 D. K. Tanwar, A. Ratan and M. S. Gill, Org. Biomol. Chem.,
2017, 15, 4992–4999.
3 U. M. Kabadi, J. Diabetes Mellitus, 2015, 05, 211–226.
4 H. Knauf and E. Mutschler, Clin. Pharmacokinet., 1998, 34, 1–
24.
ꢀ
log K(H3PO4$H2PO4ꢀ) ¼ 4.23, log K(H3PO4$(H2PO4 )2) ¼ 2.92).39
1
In the case of titration of 3H2 with DEA in MeCN-d3, H NMR
chemical shis of protons characteristic for a protonated form of
3H2 were kept xed at the values acquired prior to the addition of
DEA. In the tting procedure regarding titrations of 3H2 with
TBAOAc in DMSO, log KH2 (3H2) was kept xed at the value
´
´
5 K. Szafranski and J. Sławinski, Molecules, 2015, 20, 12029–
12044.
1
˙
´
determined by H NMR titration with TBAH2PO4. The protons
6 B. Zołnowska, J. Sławinski, A. Pogorzelska, J. Chojnacki,
chemical shis of the protonated form of 3H2 were kept xed at
the values acquired prior to the addition of titrant solutions.
Anion complexation. Anion complexation properties of
D. Vullo and C. T. Supuran, Eur. J. Med. Chem., 2014, 71,
135–147.
´
´
7 C. Leon, J. Rodrigues, N. Gamboa de Domınguez, J. Charris,
1
´
studied compounds were investigated by performing H NMR
J. Gut, P. J. Rosenthal and J. N. Domınguez, Eur. J. Med.
titrations of receptors with solutions of TBAOAc, TBAH2PO4,
Chem., 2007, 42, 735–742.
TEACl, TBABr, TBAI, TBAHSO4 and TBANO3 in MeCN-d3 and
DMSO-d6 at 25 C. Solutions of salts were added in a stepwise
8 M. Dong, D. Wang, Y. Jiang, L. Zhao, C. Yang and C. Wu,
Saudi Med. J., 2011, 32, 1122–1126.
ꢃ
manner to the solutions of investigated receptors (c z 1.2 ꢁ
9 F. Xu, L. Zou, Y. Liu, Z. Zhang and C. N. Ong, Mass Spectrom.
Rev., 2011, 30, 1143–1172.
10ꢀ3 mol dmꢀ3, V0 ¼ 0.53 mL, or V0 ¼ 0.50 mL). The concen-
tration of the titrant solutions differed signicantly (7.7 ꢁ 10 J. H. Ryoo, H. Kuramochi and H. Omokawa, Biosci.
10ꢀ3 mol dmꢀ3 to 6.0 ꢁ 10ꢀ1 mol dmꢀ3), depending on the
system, i.e. the equilibrium constant of the binding process.
Spectrophotometry
Biotechnol. Biochem., 1998, 62, 2189–2193.
´
ˇ
ˇ ´
11 N. Bregovic, N. Cindro, B. Bertosa, D. Barisic, L. Frkanec,
´
ˇ ´
K. Uˇzarevic and V. Tomisic, Chem.–Eur. J., 2017, 23, 10396–
Protonation constants of DIPEA. Protonation constants of
10406.
DIPEA in MeCN and DMSO were determined at 25 ꢃC by means 12 W. Liu, A. G. Oliver and B. D. Smith, J. Am. Chem. Soc., 2018,
of spectrophotometric titrations which were carried out by
140, 6810–6813.
adding a solution of DIPEA (c z 9.2 ꢁ 10ꢀ4 mol dmꢀ3) to the 13 N. Vidovic, G. Horvat, D. Riva, T. Rinkovec, N. Cindro,
ˇ ´
´
solution of bromocresol green (c z 4.0 ꢁ 10ꢀ5 mol dmꢀ3, V0 ¼
V. Tomisic and G. Speranza, Org. Lett., 2020, 22, 2129–2134.
2.08 mL) in the case of MeCN or by adding a solution of DIPEA (c 14 N. A. Tzioumis, K. K. Y. Yuen and K. A. Jolliffe, Supramol.
z 3.4 ꢁ 10ꢀ2 mol dmꢀ3) to the solution of bromothymol blue (c
Chem., 2018, 30, 667–673.
z 8.4 ꢁ 10ꢀ5 mol dmꢀ3, V0 ¼ 2.36 mL) in the case of DMSO. 15 J. L. Sessler, D. E. Gross, W.-S. Cho, V. M. Lynch,
Spectrophotometric data were processed by nonlinear regres-
sion analysis using the HypSpec program.47 In the course of data
F. P. Schmidtchen, G. W. Bates, M. E. Light and P. A. Gale,
J. Am. Chem. Soc., 2006, 128, 12281–12288.
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 23992–24000 | 23999

View Article Online
RSC Advances
Paper
¨
16 Q. He, M. Kelliher, S. Bahring, V. M. Lynch and J. L. Sessler, J. 34 V. Amendola, M. Boiocchi, L. Fabbrizzi and A. Palchetti,
Am. Chem. Soc., 2017, 139, 7140–7143. Chem.–Eur. J., 2005, 11, 120–127.
17 P. A. Gale, S. E. Garcıa-Garrido and J. Garric, Chem. Soc. Rev., 35 J. D. Walker and J. S. Madalengoitia, Tetrahedron Lett., 2015,
2008, 37, 151–190. 56, 3786–3789.
18 C. Caltagirone, G. W. Bates, P. A. Gale and M. E. Light, Chem. 36 N. H. Evans and P. D. Beer, Angew. Chem. Int. Ed., 2014, 53,
Commun., 2008, 61–63. 11716–11754.
19 V. Blazek Bregovic, N. Basaric and K. Mlinaric-Majerski, 37 T. Gunnlaugsson, A. P. Davis and M. Glynn, Chem. Commun.,
Coord. Chem. Rev., 2015, 295, 80–124. 2001, 1, 2556–2557.
20 V. Amendola, L. Fabbrizzi, L. Mosca and F. P. Schmidtchen, 38 C. N. Carroll, O. B. Berryman, C. A. Johnson, L. N. Zakharov,
´
´
´
´
ˇ
Chem.–Eur. J., 2011, 17, 5972–5981.
21 A.-F. Li, J.-H. Wang, F. Wang and Y.-B. Jiang, Chem. Soc. Rev.,
2010, 39, 3729.
M. M. Haley and D. W. Johnson, Chem. Commun., 2009,
2520–2522.
ˇ ´
ˇ ´
´
39 D. Barisic, V. Tomisic and N. Bregovic, Anal. Chim. Acta,
´
´
ˇ
22 N. Bregovic, N. Cindro, L. Frkanec, K. Uzarevic and
2019, 1046, 77–92.
ˇ ´
V. Tomisic, Chem.–Eur. J., 2014, 20, 15863–15871.
40 S. Camiolo, P. A. Gale, M. B. Hursthouse, M. E. Light and
A. J. Shi, Chem. Commun., 2002, 2, 758–759.
ˇ ´
´
´
ˇ
23 D. Barisic, N. Cindro, M. J. Kulcsar, M. Tireli, K. Uzarevic,
´
ˇ ´
N. Bregovic and V. Tomisic, Chem.–Eur. J., 2019, 25, 4695– 41 T. S. C. MacDonald, B. L. Feringa, W. S. Price,
4706.
S. J. Wezenberg and J. E. Beves, J. Am. Chem. Soc., 2020,
142, 20014–20020.
42 W. S. Price, F. Tsuchiya and Y. Arata, J. Am. Chem. Soc., 1999,
121, 11503–11512.
24 B. R. Linton, M. Scott Goodman, E. Fan, S. A. Van Arman and
A. D. Hamilton, J. Org. Chem., 2001, 66, 7313–7319.
25 V. Blaˇzek, N. Bregovic, K. Mlinaric-Majerski and N. Basaric,
´
´
´
ˇ
Tetrahedron, 2011, 67, 3846–3857.
43 I. Butula, V. Vela and M. V. Prostenik, Croat. Chem. Acta,
ˇ
´
´
´
ˇ
26 V. Blazek, K. Molcanov, K. Mlinaric-Majerski, B. Kojic-Prodic
1979, 52, 47–49.
´
and N. Basaric, Tetrahedron, 2013, 69, 517–526.
44 A. Vacca, S. Ghelli, C. Frassineti, L. Alderighi, P. Gans and
A. Sabatini, Anal. Bioanal. Chem., 2003, 376, 1041–1052.
45 K. Izutsu, Electrochemistry in Nonaqueous Solutions, Wiley-
VCH Verlag GmbH & Co. KGaA, Weinheim, FRG, 2002.
46 K. Izutsu, Acid–Base Dissociation Constants in Dipolar
Aprotic Solvents, IUPAC Chemical Data Series No. 35,
Blackwell Scientic, Oxford, 1990.
27 V. Amendola, L. Fabbrizzi and L. Mosca, Chem. Soc. Rev.,
2010, 39, 3889.
28 D. M. Gillen, C. S. Hawes and T. Gunnlaugsson, J. Org.
Chem., 2018, 10398–10408.
29 L. Chen, S. N. Berry, X. Wu, E. N. W. Howe and P. A. Gale,
Chem, 2020, 6, 61–141.
30 F. Pessagno, A. N. Hasanah and P. Manesiotis, RSC Adv., 47 P. Gans, A. Sabatini and A. Vacca, Talanta, 1996, 43, 1739–
2018, 8, 14212–14220. 1753.
31 A. J. Hall, P. Manesiotis, M. Emgenbroich, M. Quaglia, E. De 48 I. M. Kolthoff, S. Bhowmik and M. K. Chantooni, Proc. Natl.
Lorenzi and B. Sellergren, J. Org. Chem., 2005, 70, 1732–1736. Acad. Sci. U.S.A., 1966, 56, 1370–1376.
32 A. N. Hasanah, F. Pessagno, R. E. Kartasasmita, S. Ibrahim 49 I. M. Kolthoff, M. K. Chantooni and S. Bhowmik, J. Am.
and P. Manesiotis, J. Mater. Chem. B, 2015, 3, 8577–8583.
Chem. Soc., 1968, 90, 23–28.
´
33 V. Amendola, D. Esteban-Gomez, L. Fabbrizzi and
M. Licchelli, Acc. Chem. Res., 2006, 39, 343–353.
24000 | RSC Adv., 2021, 11, 23992–24000
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