Recognition and Extraction of Sodium Chloride by a Squaramide-Based Ion Pair Receptor

Article abstract of DOI:10.1021/acs.inorgchem.8b02163

We synthesized an ion pair receptor 1 consisting of a crown ether cation binding site and a squaramide anion binding domain and compared its binding properties to those of its analogous urea counterpart 2. We studied their salt binding properties using spectrophotometric and spectroscopic measurements in an acetonitrile solution and in acetonitrile/water mixtures. Apart from carboxylate anions, all of the anions tested were found to associate with receptor 1 and 2 more strongly in the presence of sodium cations. A homotopic anion receptor 3, lacking a crown ether unit, was unable to bind sodium salt more strongly than tetrabutylammonium salts. Solution and solid-state X-ray measurements revealed strong sodium chloride coordination to receptor 1, which is able to bind this salt even in the presence of 10% water. In contrast to the urea-based ion pair receptor 2 or anion receptor 3, ditopic receptor 1 is capable of extracting sodium chloride from aqueous media to the organic phase, as was evidenced unambiguously by ¹H nuclear magnetic resonance, mass spectrometry, and atomic absorption spectroscopy analyses.

Full text of DOI:10.1021/acs.inorgchem.8b02163

Article
pubs.acs.org/IC
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
Recognition and Extraction of Sodium Chloride by a Squaramide-
Based Ion Pair Receptor
́
Damian Jagleniec, Sylwia Siennicka, Łukasz Dobrzycki, Marcin Karbarz, and Jan Romanski*
Faculty of Chemistry, University of Warsaw, Pasteura 1, PL 02-093 Warsaw, Poland
S
* Supporting Information
ABSTRACT: We synthesized an ion pair receptor 1 consisting
of a crown ether cation binding site and a squaramide anion
binding domain and compared its binding properties to those of
its analogous urea counterpart 2. We studied their salt binding
properties using spectrophotometric and spectroscopic meas-
urements in an acetonitrile solution and in acetonitrile/water
mixtures. Apart from carboxylate anions, all of the anions tested
were found to associate with receptor 1 and 2 more strongly in
the presence of sodium cations. A homotopic anion receptor 3,
lacking a crown ether unit, was unable to bind sodium salt more
strongly than tetrabutylammonium salts. Solution and solid-
state X-ray measurements revealed strong sodium chloride
coordination to receptor 1, which is able to bind this salt even
in the presence of 10% water. In contrast to the urea-based ion pair receptor 2 or anion receptor 3, ditopic receptor 1 is capable
1
of extracting sodium chloride from aqueous media to the organic phase, as was evidenced unambiguously by H nuclear
magnetic resonance, mass spectrometry, and atomic absorption spectroscopy analyses.
explored in terms of ion pair binding, or are able to bind only
anions with transition metal cations.
INTRODUCTION
■
The design and synthesis of squaramide-based molecular
receptors is an emerging field of modern supramolecular
chemistry.1 Several monotopic receptors that can bind anions
have recently been proposed and found to be more efficient
than their urea or thiourea analogues.2 The squaramide moiety
has an excellent hydrogen bonding capacity, and this feature
has been used in the synthesis of various synthetic receptors.
Some of them are so effective that they can be used to
recognize anions in highly competitive aqueous media.3 The
reaction of diesters of squaric acid with excess amines
generates symmetrical squaramide-based receptors.4 In this
context, by using terminal diamines and alkoxysquarate, an
elegant approach to the synthesis of fluorescent poly-
(squaramide) that can detect anions was proposed.5 However,
the most convenient method is the successive amidation of
squaric acid esters and generation of asymmetric squaramides.6
Such an approach creates the unique opportunity to synthesize
receptors in a modular fashion by combining two functional
parts whose properties can be directed toward specific
purposes. Within this, the combination of suitable reporters
and cation binding domains possessing amino function with
dialkoxysquarate derivatives is especially promising and can
lead to ion pair receptors. Nevertheless, this area of
supramolecular chemistry is highly unexplored, and to date,
only a few papers concerning ditopic ion pair receptors
consisting of squaramide units have been published.7 Some of
these receptors require multistep synthesis, are not fully
Recently, more attention has been paid to small molecules
that can facilitate the transport of anions across lipid bilayers.
Because of this ability, such compounds can be treated as
potential drugs in the treatment of channelopathies.8 In this
context, squaramides have been shown to be potent trans-
membrane transporters with anion transport activities that are
better than those of the corresponding ureas and thioureas.
Very recently, it has been suggested that squaramide-based
anion receptors can be used as prospective anticancer agents. It
was shown experimentally for the first time that such
monotopic receptors can perturb cellular chloride concen-
trations, promote sodium chloride influx into cytosol, disrupt
autophagy, and induce apoptosis.9 Thus, we envisioned that
using squaramide-based, small drug-like molecules that can
bind cations and anions simultaneously can lead to molecular
receptors that are more efficient than monotopic ones and can
be applied to affect sodium cation and chloride anion
concentrations simultaneously under interfacial conditions.
Therefore, the aim of this study was to examine the binding
properties of squaramide-based ion pair receptor 1 and
compare them with the salt recognition ability of urea-based
ion pair receptor 2 and monotopic anion receptor 3, which
does not have a crown ether moiety.
Received: July 31, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.8b02163
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Table 1. Crystal Data and Structural Refinement Parameters for the Obtained Complexes of 1 with Various Salts
a
[1×NaCl]
[1×NaCl/NaNO3]
[1×NaBr]
chemical formula
4×1 + 4×NaCl + 7×DMSO
1 + 0.56×NaCl + 0.44×NaNO3
1 + NaBr
C
118H138Cl4F24N8Na4O35S7
C26H24Cl0.56F6N2.44NaO8.32
C26H24BrF6N2NaO7
693.37
100(2)
Mx (g/mol)
T (K)
λ (Å)
3142.54
100(2)
0.71073
660.68
110(2)
0.71073
0.71073
crystal size
crystal system
space group
unit cell dimensions
0.113 mm × 0.246 mm × 0.371 mm 0.115 mm × 0.123 mm × 0.390 mm 0.098 mm × 0.284 mm × 0.464 mm
triclinic triclinic triclinic
P1 P1 P1
̅
̅
̅
a = 15.8755(11) Å
b = 21.5070(15) Å
c = 23.3742(16) Å
α = 65.485(2)°
β = 71.362(2)°
γ = 83.716(2)°
6878.0(8), 2
1.517
a = 7.6253(18) Å
b = 12.254(3) Å
c = 15.887(4) Å
α = 96.465(8)°
β = 101.607(8)°
γ = 102.405(8)°
1401.2(6), 2
1.566
a = 7.6840(5) Å
b = 12.5243(8) Å
c = 15.4520(9) Å
α = 77.0664(13)°
β = 75.7210(13)°
γ = 78.0090(13)°
1386.11(15), 2
1.661
V (Å3), Z
Dx (g/cm3)
μ (mm−1
F(000)
)
0.316
0.205
1.588
3244
676
700
θmin, θmax
index ranges
2.19°, 25.05°
−17 ≤ h ≤ 18
−22 ≤ k ≤ 25
2.34°, 25.04°
−9 ≤ h ≤ 9
−14 ≤ k ≤ 14
−18 ≤ l ≤ 18
23992/4911
Rint = 0.1016
99.1
2.91°, 25.04°
−9 ≤ h ≤ 9
−14 ≤ k ≤ 14
−18 ≤ l ≤ 18
33708/4894
Rint = 0.0242
99.9
0 ≤ l ≤ 27
b
no. of reflections collected/independent 211398 / 24338
b
Rint = 0.0829
completeness (%)
99.9
absorption correction
multiscan
multiscan
multiscan
T
max, Tmin
0.965, 0.892
full-matrix least squares on F2
24338/231/1991
1.114
19740 data; I > 2σ(I)
R1 = 0.0805
wR2 = 0.2110
all data
0.977, 0.924
full-matrix least squares on F2
4911/41/452
1.060
2931 data; I > 2σ(I)
R1 = 0.0961
wR2 = 0.2321
all data
0.860, 0.526
full-matrix least squares on F2
4894/6/410
1.066
4763 data; I > 2σ(I)
R1 = 0.0193
wR2 = 0.0485
all data
refinement method
data/restraints/parameters
goodness of fit on F2
final R indices
R1 = 0.1039
wR2 = 0.2270
0.0005(1)
R1 = 0.1537
wR2 = 0.2663
−
R1 = 0.0202
wR2 = 0.0491
0.0048(4)
extinction coefficient
ρmax, ρmin (e Å−3
)
0.748, −0.801
0.598, −0.356
0.347, −0.230
a
b
Crystal twinned with partial overlap of reflections; data integration based on two domains. Number of all collected reflections and Rint value given
for data up to θ = 25.41°.
tetrahydrofuran (THF)/MeOH mixture (1:4) was added 25 mg of
10% Pd/C. The reaction mixture was kept under a H2 atmosphere
(balloon pressure) at room temperature overnight. The catalyst was
removed by filtration through a pad of Celite and washed with
MeOH. The filtrate was concentrated under reduced pressure to give
the crude product in quantitative yield (856 mg). The amine was used
in the next step without further purification.
EXPERIMENTAL SECTION
■
All reagents and chemicals were of reagent grade quality and
purchased commercially. 1H and 13C nuclear magnetic resonance
(NMR) spectra were recorded on a Bruker 300 MHz spectrometer.
1H NMR chemical shifts (δ) are reported in parts per million
referenced to a residual solvent signal [dimethyl sulfoxide-d6 (DMSO-
d6) or CD3CN].
To the solution of amine (456 mg, 1.61 mmol) in MeOH (5 mL)
was added a compound S3 (543 mg, 1.60 mmol) at room
temperature. The mixture was stirred at room temperature for 2
days. The reaction mixture was filtered, and the collected solid
material was washed with MeOH. The obtained white solid was dried
in vacuo to give the desired receptor containing one molecule of
methanol per molecule of receptor 1 in a 90% yield (900 mg, 1.45
mmol). The residual solvent can be removed by dissolution of the
receptor in chloroform and evaporation of the solvent under reduced
pressure: HRMS (ESI) calcd for C26H24F6N2O7Na [M + Na]+
Preparation of Compound S3. To a solution of 3,4-dimethoxy-
3-cyclobutane-1,2-dione (2.00 g, 14.1 mmol) in MeOH (20 mL) was
added 3,5-bis(trifluoromethyl)aniline (2.40 mL, 15.5 mmol, 1.1
equiv) at room temperature. After being stirred for 3 days, the
reaction mixture was filtered, and the collected solid material was
washed with MeOH. The obtained light yellow solid was dried in
vacuo to give desired product S3 (4.54 g, 13.4 mmol, 95%): HRMS
(ESI) calcd for C13H7F6NO3Na [M + Na]+ 362.0228, found
1
362.0225; H NMR (300 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.05
(s, 2H), 7.78 (s, 1H), 4.41 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ
187.4, 184.5, 179.9, 169.1, 140.2, 131.9, 131.4, 131.0, 130.5, 128.5,
124.9, 121.3, 119.2, 117.6, 116.1, 61.0.
1
613.1385, found 613.1379; H NMR (300 MHz, CD3CN) δ 8.42−
8.23 (bs, 2H), 7.98 (s, 2H), 7.67 (s, 1H), 7.15−7.05 (m, 1H), 6.96−
6.89 (m, 1H), 6.85−6.75 (m, 1H), 4.15−4.05 (m, 4H), 3.86−3.75
(m, 4H), 3.25−3.10 (m, 8H); 13C NMR (75 MHz, DMSO-d6) δ
Preparation of Receptor 1. To a degassed solution of 4-
nitrobenzo-15-crown-5-ether (940 mg, 3 mmol) in 50 mL of a
B
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Figure 1. Structures of receptors 1−3.
a
Scheme 1. Synthesis of Receptors 1 and 2
a
Reagents and conditions: (i) H2, Pd/C, MeOH/THF, 12 h, room temperature, quantitative; (ii) methanol, 72 h, room temperature, 95%; (iii)
methanol, 48 h, room temperature, 90%; (iv) aniline, methanol, 48 h, room temperature, 71%; (v) 3,5-trifluoromethylisocyanate, methylene
dichloride, 12 h, room temperature, 75%.
182.8, 181.3, 166.4, 163.8, 149.1, 145.3, 140.6, 131.8, 131.3, 130.9,
130.4, 124.6, 121.0, 118.2, 115.2, 114.7, 111.1, 106.2, 70.0, 69.7, 69.5,
69.2, 68.7, 68.4. Anal. Calcd for C26H24F6N2O8·H2O: C, 51.32; H,
4.31; N, 4.60. Found: C, 51.35; H, 4.28; N, 4.76.
added to a cuvette. Then small aliquots of TBAX, containing a
constant concentration of the receptor, were added, and a spectrum
was acquired after each addition. Where applicable, the solution also
contained 1 molar equivalent of cation (1 equiv of NaClO4, LiClO4,
or KPF6 with respect to the receptor). The resulting titration data
were analyzed using the BindFit (version 0.5) package, available
online at http://supramolecular.org.
Preparation of Receptor 2. To a solution of 4-aminobenzo-15-
crown-5-ether (500 mg, 1.77 mmol) in methylene dichloride (10 mL)
was added 3,5-trifluoromethylisocyanate (300 μL, 1.76 mmol) at
room temperature. After being stirred for 12 h, the reaction mixture
was filtered, and the collected solid material was washed with diethyl
ether. The obtained white solid was dried in vacuo to give the desired
product in a 75% yield (710 mg, 1.32 mmol): HRMS (ESI) calcd for
1H NMR Titration Experiments. The 1H NMR titration was
performed on a Bruker 300 spectrometer at 298 K in CD3CN. In each
case, 500 μL of a freshly prepared 3.13 mM solution of receptor 1 was
added to a 5 mm NMR tube. In the case of ion pair titration, the
solution also contained 1 molar equivalent of sodium perchlorate.
Then small aliquots of a solution of TBAX, containing 1 at a constant
concentration, were added, and a spectrum was acquired after each
addition. The resulting titration data were analyzed using the BindFit
(version 0.5) package, available online at http://supramolecular.org.
Crystallization and Single-Crystal X-ray Diffraction. Crystals
containing 1 and NaCl that were suitable for X-ray diffraction were
obtained by a slow evaporation of a saturated salt solution of 1 in
DMSO. Crystals containing a mixture of NaCl and NaNO3 accidently
grew from an acetonitrile/methanol solution during diffuse crystal-
lization by diethyl ether. The complex of 1 with NaBr was precipitated
form a saturated acetonitrile/methanol solution using diethyl ether.
The obtained crystals are denoted as [1×NaCl], [1×NaCl/NaNO3],
and [1×NaBr] complexes.
1
C23H24F6N2O6Na [M + Na]+ 561.1436, found 561.1440; H NMR
(300 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.81 (s, 1H), 8.13 (s, 2H),
7.63 (s, 1H), 7.20 (s, 1H), 6.90 (s, 2H), 4.11−3.95 (m, 4H), 3.87−
3.75 (m, 4H), 3.70−3.57 (m, 8H); 13C NMR (75 MHz, DMSO-d6) δ
152.9, 149.2, 144.7, 142.5, 133.3, 131.8, 131.4, 131.0, 130.5, 125.6,
122.0, 118.4, 115.2, 112.0, 106.6, 70.8, 70.4, 70.2, 69.5, 68.9. Anal.
Calcd for C23H24F6N2O6: C, 51.31; H, 4.49; N, 5.20. Found: C,
51.38; H, 4.56; N, 5.15.
Preparation of Receptor 3. To a solution of compound S3 (204
mg, 0.60 mmol) in MeOH (5 mL) was added aniline (56 mg, 0.60
mmol) at room temperature. The mixture was stirred for 2 days. Then
the reaction mixture was filtered, and the collected solid material was
washed with MeOH. The obtained white solid was dried in vacuo to
give the desired receptor (170 mg, 0.425 mmol, 71%): HRMS (ESI)
calcd for C18H10F6N2O2Na [M + Na]+ 423.0544, found 423.0535; 1H
NMR (300 MHz, CD3CN) δ 8.40−8.21 (bs, 2H), 7.96 (s, 2H), 7.66
(s, 1H), 7.44−7.32 (m, 4H), 7.21−7.10 (m, 1H); 13C NMR (75
MHz, DMSO-d6) δ 182.5, 181.9, 166.5, 164.4, 140.5, 137.8, 131.3,
130.9, 128.9, 123.4, 120.9, 118.6, 118.4, 115.0. Anal. Calcd for
C26H24F6N2O8: C, 54.01; H, 2.52; N, 7.00. Found: C, 53.83; H, 2.66;
N, 6.90.
The X-ray measurements of the investigated crystals were
performed on a Bruker D8 Venture diffractometer equipped with a
TRIUMPH monochromator using Mo Kα (λ = 0.71073 Å) radiation.
The samples were measured at low temperatures yielding either
100(2) K for [1×NaCl] and [1×NaBr] complexes or 110(2) K for
the [1×NaCl/NaNO3] compound. Diffraction data were collected
with either Bruker APEX210 or APEX311 programs. The frames were
integrated with the Bruker SAINT software package.12 In the case of
the twinned crystal of [1×NaCl] with partial overlap of reflections,
two twin domains were included in the processing followed by
absorption correction using the multiscan method and scaling
Ultraviolet−Visible (UV−vis) Titration Experiments. The
UV−vis titration was performed using a Thermo Spectronic Unicam
UV500 spectrophotometer at 298 K in acetonitrile. In each case, 2500
μL of a freshly prepared 2.93 × 10−5 M solution of the receptor was
C
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Figure 2. Representative UV−vis titration spectra of receptor 1 (upon gradual addition of tetrabutylammonium nitrate). [1] = 2.93 × 10−5 M;
optical path length of 10 mm.
performed in TWINABS.13 In the case of the single crystals of
investigation, dilution studies were first performed. The
dilution experiments showed a linear dependence of the UV
absorption on the concentration, which suggests that receptor
[1×NaCl/NaNO3] and [1×NaBr], data were scaled and corrected for
absorption effects using the multiscan method implemented in
SADABS.14 All the structures were determined and refined with the
1 does not aggregate in the concentration range studied (1 ×
SHELX software suite15,16 with the atomic scattering factors taken
10−5 to 8 × 10−5 M). Likewise, test experiments with
from the International Tables.17 The crystal data and final structure
tetrabutylammonium perchlorate excluded the interaction of
refinement parameters are listed in Table 1. The details of single-
receptor 1 with these ions. Adding incremental amounts of
various anions (as TBA salts) to a solutions of 1 resulted in
bathochromic shifts in the absorption maximum of the
receptor, allowing us to calculate stability constants (Figure
2). The association constants calculated by the nonlinear
regression analysis of the binding isotherms are summarized in
Table 2.
crystal diffraction experiments, including data collection, integration,
and structural refinement, are available in the appropriate part of the
Supporting Information. The molecular graphic plots and the
geometry analysis of the obtained structures were performed in
Mercury CSD 3.10 software.18
The crystallographic data have been deposited with the Cambridge
Crystallographic Data Center under the following numbers: CCDC
1812264, CCDC 1855570, and CCDC 1855571 for the [1×NaCl],
[1×NaCl/NaNO3], and [1×NaBr] complexes, respectively.
Table 2. Association Constants for Interactions of
Receptors 1 and 2 with Selected Anions and Apparent
Association Constants for Interactions of 1 and 2 with
RESULTS AND DISCUSSION
■
a
Receptor Design and Synthesis. Receptor 1 was
designed to simultaneously bind cations and anions with a
particular affinity for sodium chloride. Namely, the diaryl-
squaramide unit, a binding domain that can effectively
associate with halide ions,2,4e was combined with sodium
selective crown ether. The heteroditopic ion pair receptor 2,
comprising a urea-based anion binding domain, and homo-
topic anion receptor 3, lacking a crown ether unit, were
selected as reference compounds (Figure 1). In the structure of
ion pair receptors 1 and 2, the benzo-15-crown-5-ether is an
integral part of the anion binding site; thus, we expected that
binding of a sodium cation by this domain would reduce the
electron density on the adjacent phenyl ring, increasing the
acidity of the squaramide protons and as a consequence
reinforcing anion binding. Receptors 1 and 3 were synthesized
starting with successive amidation of dimethyl squarate with
3,5-trifluoromethylaniline, followed by 4-aminobenzo-15-
crown-5 for 1, or with aniline for 3, respectively. Receptor 2
was obtained in two steps, reduction of the nitro group of 4-
nitrobenzo-15-crown-5 to the corresponding amine and
subsequent reaction with 3,5-trifluoromethylisocyanate
(Scheme 1). It should be emphasized that the synthesis of
all receptors is straightforward and does not require chromato-
graphic purification. All intermediates and receptors can be
simply purified by crystallization and thus are easy to obtain on
a large scale.
Anions in the Presence of 1 equiv of Sodium Perchlorate
2 + 1
1 + 1 equiv of
equiv of
NaClO4
1
NaClO4
2
−
−
NO3
Br−
NO2
Cl−
2200
47500
79200
3600
82800
147000
K11 = 1400000
K21 = 166000
b
b
550
760
2220
8900
1200
5800
9920
K11 = 789000
K21 = 109000
18600
PhCOO−
CH3COO−
b
b
490200
1181200
353000
907500
a
UV−vis, solvent CH3CN, 293 K, [1] = 2.93 × 10−5 M, [2] = 3.36 ×
10−5 M, anions added as TBA salts, where [TBAX] ∼ 3 × 10−3 M;
b
M−1, errors of <10%. Deprotonation.
We found that receptor 1 binds these anions with moderate
to very high strength, in the following order: NO3 < Br− <
−
NO2 < Cl−. In the case of the interaction of 1 with
−
carboxylate anions such as benzoate or acetate, deprotonation
of the receptor was observed. This was supported by 1H NMR
measurements that displayed a disappearance of signals
assigned to the squaramide protons upon addition of these
anions.
Strikingly, when receptor 1 was titrated in the presence of 1
equiv of sodium cations (added as NaClO4), all bound anions
were found to interact in an enhanced manner, with a 1.6-fold
higher association constant. The strong influence of sodium
cation association on anion binding was also supported by an
analysis of the TBANO2 titration experiment performed in the
Binding Studies. A quantitative evaluation of the anion
and salt binding ability of 1 was performed by UV−vis
titrations in acetonitrile. To rule out the self-association event
that might be occurring in the range of concentrations under
D
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1
Figure 3. Partial H NMR spectra of (a) receptor 1, (b) receptor 1 with 2 equiv of TBAClO4, and (c) receptor 1 with 2 equiv of NaClO4 in
CD3CN.
absence and presence of 1 and 5 equiv of sodium cations.
These experiments showed that as the amount of sodium
cations increases (1 and 5 equiv), receptor 1 can bind nitrite
anions with 1.86- and 3.60-fold higher association constants,
respectively, than in the absence of Na+. Therefore, the data
obtained from titrations conducted in the presence of metal
cations should be analyzed in terms of the binding
cooperativity of ion pairs and should be treated as apparent
stability constants, because they are highly dependent on the
concentration of metal cations.
with chloride salts, fitting the data to the 1:1 stoichiometry. We
found that under such conditions chloride anions are
recognized less strongly than in pure acetonitrile, with an
association constant of 114300 M−1. In the presence of 1 equiv
of sodium cations, the enhancement of chloride binding was
still observed and the apparent stability constant thus obtained
was calculated to be 196700 M−1.
A similar enhancement of anion binding, as was detected for
sodium cations, was observed when receptor 1 was titrated
with TBABr in the presence of 1 equiv of lithium perchlorate
in acetonitrile. Specifically, in the presence of 1 equiv of
lithium cations (added as LiClO4), receptor 1 binds bromide
anions even as much as 2 times more strongly than in the
absence of Li+, with an apparent association constant (KLiBr) of
98600 M−1. On the other hand, when the receptor was titrated
with TBABr in the presence of 1 equiv of potassium or
ammonium cations (added as KPF6 or NH4PF6, respectively),
no enhancement of bromide binding was observed and
receptor 1 binds bromide anions less strongly than in the
absence of these cations, with the following apparent
Interestingly, in the case of the chloride anion, a very strong
interaction with 1 was observed and a mixed 2:1 + 1:1
(receptor:chloride) binding mode was better suited than a 1:1
binding stoichiometry, while 1:1 fitting produced a high error
rate and sinusoidal residuals (Supporting Information).19 This
suggests that upon titration of receptor 1 with chloride anions
apart from 1:1 complexes, 2:1 complexes (receptor:chloride)
are also formed. This was especially pronounced when titration
was performed in the presence of sodium cations. The
evidence for a binding equilibrium more complex than 1:1
1
came from titration experiments performed under H NMR
association constants: KKBr = 44500 M−1 and KNH4Br
=
control. We found that upon incremental addition of chloride
anions to an acetonitrile solution of receptor 1 containing 1
equiv of sodium cations, the signals corresponding to the
aromatic protons were shifted inconsistently. These signals
were initially shifted downfield, and after >1.3 equiv of chloride
anions had been added, the signals were moved upfield
(Supporting Information). This may suggest that in the
acetonitrile solution, initially 2:1 and 1:1 complexes are in
equilibrium and upon addition of an excess of chloride anions
the 1:1 complex becomes the predominant species. To obtain
more reliable data and calculate the stability constants for
chlorides, we performed UV−vis titration experiments in more
competitive media. When titration experiments were con-
ducted in the presence of 0.5% water (pH 3) in acetonitrile, we
could determine the association constants for complexes of 1
43300 M−1.
The enhancement of anion binding in the presence of
sodium or lithium cations can be explained in terms of the
formation of strong 1:1 complexes with receptor 1 and metal
cations, cation complexation-induced electrostatic interactions,
and the cation complexation-induced increased acidity of
squaramide protons that reinforce interactions with anions.
Indeed, when sodium cations were added as sodium
perchlorate, both of the signals corresponding to squaramide
protons were shifted downfield, indicating their higher acidity,
and as a consequence increased their ability to recognize
anions (Figure 3).20
Furthermore, to test cooperativity in ion pair binding, we
also investigated the influence of anion binding on sodium
association. When sodium cations (added as NaClO4) were
E
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Figure 4. Partial 1H NMR spectra of a 2.6 mM solution of 1 in CD3CN with (a) 10% water, (b) 10% aqueous HClO4 (pH 3), (c) 10% aqueous
HClO4 (pH 3) and 1 equiv of NaCl, and (d) 10% aqueous HClO4 (pH 3) and 3 equiv of NaCl.
associated with receptor 1 moderately with an association
The titration of receptor 1 in acetonitrile with nitrate salts was
selected, taking into account the range of the estimated
suitable stability constant calculated using the 1H NMR
technique. We found that, upon incremental addition of
tetrabutylammonium nitrate, both of the signals corresponding
to squaramide protons were gradually shifted downfield and
perturbations in signals corresponding to aromatic protons
were also observed. Analyzing the nitrate anion complexation-
induced shifts of all protons engaged in anion binding allowed
constant KNa of 10000 M−1, in the presence of 1 equiv of
+
−
−
NO3 , Br−, NO2 , and Cl− anions, they were bound in an
enhanced manner, namely 1.40, 4.46, 6.50, and 7.56 times
more strongly, respectively. This corresponds to the increasing
binding strength of receptor 1 with the anions investigated.
To establish the role of the crown ether units in salt binding,
monotopic receptor 3 lacking a crown ether binding domain
was tested for anions and ion pairs. We found that anion
receptor 3 can bind bromide anions like ditopic receptor 1
does with a stability constant KTBABr of 48200 M−1. However,
the absence of a cation binding domain in receptor 3 has
serious implications in terms of ion pair binding. Specifically, in
the presence of sodium cations, monotopic receptor 3 binds a
bromide anion less strongly than in the absence of sodium
cations, with an apparent stability constant KNaBr of 43800
M−1.
us to calculate the stability constant as KTBANO = 2390 M−1.
3
This corresponds well with the data obtained from UV−vis
titration. Titration of 1 in the presence of 1 equiv of sodium
cations with tetrabutylammonium nitrate induced analogous
shifts for all mentioned protons of receptor 1, although the
changes were more drastic. We found that in the presence of
sodium cations the association of nitrate anions was greatly
enhanced, and the stability constant thus obtained was even
To confirm the high affinity of the squaramide group of
receptor 1 for anions and ion pairs, we decided to vary the
anion binding site. For this purpose, analogous, heteroditopic
ion pair receptor 2 supported with a urea-based anion binding
site was tested. As Table 2 shows, receptor 2 associates with
TBA salts of nitrate, bromide, nitrite, and chloride anions with
weak to moderate strength. The association constant values for
these anions are at least 1 magnitude of order weaker than for
squaramide-based receptor 1. Interestingly, it was found that
receptor 2 forms stable complexes with acetate and benzoate
anions, which readily caused deprotonation of receptor 1.
When ion pair binding experiments were performed in the
presence of sodium cations, we found that, with the exception
of carboxylates, all the anions were associated with the
receptors more strongly than in the presence of tetrabuty-
lammonium countercations. Nevertheless, even in the presence
of sodium cations, urea-based receptor 2 cannot interact with
anions as strongly as squaramide 1 or 3. For example, in the
presence of a sodium cation, receptor 2 binds bromide anions
moderately with an apparent stability constant of 2200 M−1.
On the other hand, monotopic receptor 3 and ditopic receptor
1 form complexes that are 1 magnitude of order stronger with
bromides, with apparent stability constants of 43800 and
82800 M−1, respectively.
higher than that obtained from UV−vis titration (KNaNO
=
3
5880 M−1 from 1H NMR vs KNaNO = 3600 M−1 from UV−vis
3
titrations). This further supports the strong influence of
sodium cations on anion binding. In particular, in the case of
1H NMR titration, the concentration of receptor 1 is 2 orders
of magnitude higher than in the case of UV−vis measurements,
which is responsible for the higher fraction of receptor 1
molecules occupied by a sodium cation in the MeCN-d3
solution, namely, 84% at 3.13 × 10−3 M versus 19% at 2.93
× 10−5 M. To be as close as possible to unified measurement
conditions and reach a comparable fraction of receptor 1
occupied by a sodium cation, a comparative binding study was
performed. Specifically, we performed UV−vis titration
experiments at 3.36 × 10−4 M using a 1 mm cuvette and H
1
NMR titrations at 6.05 × 10−4 M receptor 1. The apparent
stability constants thus obtained are in good agreement with
each other and were calculated to be 4500 and 4800 M−1 for
1
UV−vis and H NMR conditions, respectively.
Taking into account the strong ability of receptor 1 to
associate with chloride anions and sodium chloride, titration in
the presence of water was conducted under UV−vis control.
The addition of 5% water to the solution of receptor 1 in
acetonitrile caused a considerable bathochromic shift in the
absorption maximum, suggesting the formation of strong
hydrogen bonds with water molecules. However, similar
To gain more insight into the anion and ion pair binding
1
mechanism, H NMR titration experiments were conducted.
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Figure 5. Displacement ellipsoid plot at the 50% probability level for structures of (a) [1×NaCl], (b) [1×NaCl/NaNO3], and (c) [1×NaBr].
Figure 6. Dimers of SQP ligands in the crystals of [1×NaCl].
changes in the UV−vis spectrum were observed upon addition
of 1 equiv of tetrabutylammonium hydroxide to the receptor 1
solution, rather suggestive of a deprotonation event. Indeed,
1H NMR experiments revealed that deprotonation takes place
under such conditions, and the disappearance of both signals
corresponding to squaramide protons is detected (Figure 4a).
To protect water-induced deprotonation of receptor 1,
aqueous perchloric acid (pH 3) was used instead of pure
water in UV−vis titration experiments.
An aqueous environment opens up the unique opportunity
to use sodium chloride instead of salt generated in situ and
conduct experiments with 5 and 10% water (pH 3) in
acetonitrile. We found that in the presence of 5% water,
receptor 1 binds chloride anions (added as TBACl) weakly
with a binding constant KTBACl of 890 M−1. Interestingly, in
G
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Article
such a competitive mixture of solvents, NaCl is associated
more strongly than TBACl, namely with a stability constant
KNaCl of 1350 M−1. In the presence of 10% water (pH 3), a
further decrease in binding strength was observed and only
sodium chloride was noticeably recognized using the UV−vis
technique. However, the value of the calculated stability
constant was too low to be precisely determined using the
UV−vis technique (KNaCl = 250 M−1 was assumed). Thus, the
ability for sodium chloride to be recognized by receptor 1 in
the presence of 10% water (pH 3) in acetonitrile was
supported by 1H NMR measurements. Specifically, upon
addition of 1 and 3 equiv of sodium chloride to the solution of
receptor 1 in CD3CN, the squaramide protons that initially
resonated at δ = 9.50 and 9.78 ppm were shifted downfield to δ
= 9.82 and 10.20 ppm with the addition of 1 equiv of NaCl and
to δ = 10.32 and 10.76 ppm in the presence of 3 equiv of this
salt, respectively (Figure 4). This clearly indicates that receptor
1 is able to interact with sodium chloride in 10% water (pH 3)
in acetonitrile. However, upon addition of a larger amount of
sodium chloride, precipitation occurs, not enabling the stability
cation is coordinated by only one DMSO molecule, whereas in
the corresponding SQP-B moiety, two DMSO species are
bonded to the Na+ ion. In the structure, the two remaining
DMSO molecules act as space fillers and form no hydrogen
bonds with the other entities. In the crystal, the molecules are
packed to form layers parallel to the (011) lattice plane with
̅
the CF3 groups and some DMSO molecules located between
them, as presented in Figure 7a.
1
constant to be determined by H NMR spectroscopy.
X-ray Measurements. The high affinity of receptor 1 for a
variety of Na salts is confirmed by single-crystal X-ray
diffraction experiments. During the studies, three solid-state
structures of 1 with NaCl, a NaCl/NaNO3 mixture, and NaBr
were obtained. The structures are denoted as [1×NaCl],
[1×NaCl/NaNO3], and [1×NaBr], respectively. The crystal of
[1×NaCl] contains in the asymmetric part of the unit cell four
ligands named SQPA−SQPD, four Na+/Cl− ion pairs, and
seven DMSO molecules (Figures 5 and 6).
Figure 7. Packing diagrams of single-crystal structures of (a)
[1×NaCl], (b) [1×NaCl/NaNO3], and (c) [1×NaBr].
The next two structures with 1 and sodium salts, in spite of
their different compositions, are very similar. The first one is a
In the structure, the crown ether fragment with the Na+ ion
in the SQPA moiety is disordered over two sites. All but one of
the Cl− anions are also disordered over two positions. The
same applies for the two DMSO molecules. In all the ligands,
sodium cations and chloride anions interact directly with the
corresponding binding domains. Sodium occupies the crown
ether cavity and is bonded by five etheric oxygen atoms. The
distances between O and Na atoms for all the molecules are in
the range from 2.35 to 2.48 Å. The anions are coordinated by
N−H groups of the squaramide fragments forming unequal H-
bonds with most of the N···Cl distances varying from 2.99 to
3.16 Å. The two protruding distances, concerning a disordered
anion in the SQPD ligand, are equal to 3.27 and 3.66 Å;
however, the latter corresponds to the N−H···Cl contact that
is slightly longer than the sum of the van der Waals radii of the
H and Cl− moieties.18,21 There are also some weak H-bonds
between Cl− anions and aliphatic or aromatic H atoms of
neighboring molecules. These contacts, however, seem to be a
secondary effect of the packing of the molecules. In the crystal
lattice of [1×NaCl], ligands are forming SQPA···SQPC and
SQPB···SQPD dimers with one of the Na ions coordinated by
the carbonyl groups of another molecule of 1, as shown in
Figure 6.
In the dimers, the ligands are translated relative to one
another, which results in an inequivalent environment of the
Na ions. The formation of these dimers is supported by the
parallel π−π stacking interaction between the phenyl moiety of
the benzo-15-crown-5-ether unit and the unsaturated squar-
amide ring. The shortest distances between the LSQ plane
fitted to the phenyl ring and a C atom of the squaramide are
equal to 3.24 and 3.14 Å for the SQPA···SQPC and SQPB···
SQPD dimers, respectively. These two molecular aggregates
are not chemically identical. In the SQPA unit, the sodium
crystal containing mixed Cl−/NO3 sites with an occupancy
−
ratio of the anions equal to 0.56(1):0.44(1). The second
example is a crystal incorporating Na+/Br− ionic pairs. The
crystals contain, in the asymmetric part of the unit cell, a SQP
unit and the corresponding ions. There are no additional
solvent molecules present in the crystal lattices. Although the
unit cell angles of the mentioned crystals are different (all
obtuse vs all acute), these phases can be considered as
isostructural, as can be seen by comparing panels b and c of
Figure 7 presenting the packing of the molecules. The
substitutional disorder in the crystals of [1×NaCl/NaNO3]
results in a visible increase in the displacement parameters of
the atoms (compare panels b and c of Figure 5). In both
structures, as in the case of [1×NaCl], the Na+ ions are
coordinated by the crown ether moieties, whereas anions are
bound by the nitrogen atoms of the squaramide unit. Contacts
between Na+ cations and O atoms of the crown ether are in the
range of 2.34−2.38 Å for [1×NaCl/NaNO3] and 2.33−2.37 Å
for [1×NaBr] complexes and thus are comparable to those
observed in the structure of [1×NaCl]. Distances between N
and halogen anions are equal to 3.20 and 3.33 Å in [1×NaCl/
NaNO3] and [1×NaBr] structures, respectively. The relatively
long N···Cl− distance probably results from the substitutional
disorder and averaging of the whole structure. In the mixed
crystal, the NO3− anion interacts with both N−H groups with
N···O distances equal to 2.78 and 2.98 Å. In both crystals, SQP
moieties form centrosymmetric dimers (Figure 8).
In such aggregates, Na+ cations located in the crown ether
cavities are in addition coordinated by the anions. In the
dimers, the distances between the LSQ planes of the phenyl
rings in the benzo-15-crown-5-ether fragments are 3.52 and
3.56 Å in the [1×NaCl/NaNO3] and [1×NaBr] crystals,
H
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Figure 9. Histogram of distances between the Na+ cation and LSQ
mean plane fitted to the [15-crown-5] ether ring for the single-crystal
structures retrieved from the Cambridge Structural Database.23
structures with distances from Na+ to the mean plane of >1.5
Å, the cation is coordinated by two crown ether units on both
sides, forming a sandwichlike complex. In the crystals of
[1×NaCl], the distances are equal to 1.21 Å/1.00 Å, 1.35 Å,
1.16 Å, and 1.08 Å for Na(1A)/Na(1E) in the disordered
SQP-A moiety, SQP-B, SQP-C, and SQP-D ligands,
respectively. In the isostructural crystals of [1×NaCl/
NaNO3] and [1×NaBr], the corresponding distances are
0.58 and 0.54 Å, respectively.
Extraction Studies. Ion pair receptors offer substantial
advantages in terms of affinity as compared to corresponding
single-ion receptors and can be utilized under interfacial
conditions as efficient extractants.24 Therefore, we tested
receptors 1−3 in an extraction of sodium chloride from the
aqueous to the organic phase. To be as close as possible to the
conditions that correlate well with the transport abilities of
squaramide-based anion receptors toward lipid bilayers,8b we
performed liquid−liquid extractions using a 0.5 M aqueous
solution of sodium chloride and 1 mM solutions of receptors in
deuterated nitrobenzene. A comparison of the 1H NMR
spectrum of free receptor 1 in wet nitrobenzene revealed
significant changes in the resonance signals of both squaramide
protons after being in contact with a 0.5 M aqueous solution of
NaCl. The protons that initially resonated at δ = 9.32 and 9.72
ppm were shifted downfield Δδ = 0.72 and 0.79 ppm,
respectively (Figure 6). This clearly indicates the ability of 1 to
extract sodium chloride from the aqueous phase and form
complexes in the organic layer. This is supported by
electrospray ionization mass spectrometric measurements of
the extracted organic solution, which clearly shows character-
istic peaks appearing at m/z 625.5 [1 + Cl−] and m/z 647.5 [1
− H+ + NaCl] (Supporting Information). Furthermore, the
Figure 8. SQP ligands forming dimers in the crystals of (a) [1×NaCl/
NaNO3] and (b) [1×NaBr].
respectively. The phenyl rings, however, are visibly displaced;
thus, this type of interaction is secondary and probably
originates from strong cooperative attraction between the
anions and N−H groups. Nevertheless, strong parallel π−π
stacking can be observed between the dimers where the
distances from LSQ planes of the phenyl moiety in the benzo-
15-crown-5-ether fragments are equal to 3.30 and 3.31 Å in the
−
Cl−/NO3 and Br− ion-containing structures, respectively.
These types of interactions result in the formation of columns
of the moieties parallel to the [100] direction (Figure 7b,c).
Interestingly, both structures are similar to the known
structure of the NaNO3 complex of a ligand analogous to 2
containing no CF3 groups.22 In this structure, the molecules
also form centrosymmetric dimers, though with ether frag-
−
ments positioned closer, yet longer amide to NO3 distances.
Although the Na+ fits perfectly into the cavity of the 15-
crown-5 moiety in all the structures of 1 described here, the
cation is bound externally, with the coordination sphere
formed by the ether on one side and additional ligands on the
other. Such a behavior is typical for Na+ complexes with an
ether of such size, as is confirmed by the analysis of the single-
crystal structures retrieved from Cambridge Structural Data-
base.23 The histogram presenting the number of structures
depending on the distance from the mean LSQ plane fitted to
all the atoms of the ether ring to the Na+ ion is presented in
Figure 9. In only a couple of the structures the cation is located
approximately in the equatorial plane of the ether, complexed
on both sides by small molecules like H2O. In the case of
distances between 0.5 and 1.5 Å, the cation is coordinated by
the ether on one side only and complexed by additional ligands
on the other side. The size and/or number of these ligands
increases from the left to the right side of the picture. In the
1
organic phase was then back-extracted into H2O. The H
NMR spectrum of the nitrobenzene phase after being in
contact with water is essentially identical to the spectrum of
the free receptor (Figure 10). In contrast, almost no
1
discernible chemical shift changes were observed in the H
NMR spectrum of the nitrobenzene phase containing receptor
2 or monotopic anion receptor 3 after intensive washing with a
0.5 M aqueous NaCl solution (Figure 11).
To quantify the sodium content in the organic phase and
calculate the extraction efficiency in the experiments described
above, we used atomic absorption spectroscopy (AAS).25 The
content of sodium in 0.5 mM solutions of receptors in
nitrobenzene obtained after extraction with the 0.5 M NaCl
solution was determined to be 24 mg/L for 1, which
corresponds to a 22% extraction efficiency and negligible for
I
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water. We demonstrated that the crown ether unit in the
receptor 1 structure is responsible for reinforcing anion
binding in the presence of sodium cations. In contrast to
urea-based ion pair receptor 2 and monotopic receptor 3
lacking a crown ether unit, squaramide-based ditopic receptor
1 can extract sodium chloride from the aqueous to the organic
phase, as shown independently by 1H NMR and MS
measurements and supported quantitatively by AAS. These
measurements clearly show that receptor 1 is a promising
candidate for transporting sodium cations and chloride anions
simultaneously across membranes. To the best of our
knowledge, compound 1 is the first example of such a simple
and effective, non-multimacrocyclic ion pair receptor capable
of recognizing sodium chloride in the presence of water and
extracting it from the aqueous to the organic phase.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.8b02163.
1
Figure 10. Partial H NMR spectra of receptor 1 (a) at 1.0 mM in
wet PhNO2-d5, (b) after NaCl extraction from the aqueous phase, and
1H and 13C NMR spectra, UV−vis and 1H NMR
titration spectra, UV−vis and NMR binding isotherms,
extraction procedures, and crystal data of [1×NaCl],
[1×NaCl/NaNO3], and [1×NaBr] complexes (PDF)
(c) after back-extraction to distilled water.
Accession Codes
CCDC 1812264 and 1855570−1855571 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jarom@chem.uw.edu.pl.
■
1
Figure 11. Partial H NMR spectra of receptor 3 (a) at 1.0 mM in
wet PhNO2-d5 and (b) after NaCl extraction from the aqueous phase.
ORCID
́
Jan Romanski: 0000-0002-7675-885X
Notes
2, 3, or 4-nitrobenzo-15-crown-5-ether.26 When a dual-
receptor strategy was employed, i.e., extraction of NaCl from
the aqueous phase with a binary mixture of anion receptor 3
and 4-nitrobenzo-15-crown-5-ether in nitrobenzene, the
extraction efficiency was significantly reduced and determined
to be 4%. This clearly shows that the assembly of a strong
anion binding domain with a directly linked crown ether in the
structure of heteroditopic receptor 1 is needed for the
preparation of an effective salt extractant. The ability not
only to take up but also to release sodium chloride by receptor
1 was confirmed by the back-extraction experiment, which
showed a decrease in the sodium cation concentration in the
organic phase after washing with water. Taking these results
together, we concluded that squaramide-based ion pair
receptor 1 is capable of extracting sodium chloride from
aqueous media, in contrast to urea-based ion pair receptor 2 or
squaramide-based anion receptor 3.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grant DEC-2013/09/B/ST5/
00988 from the Polish National Science Center. The X-ray
structure was determined in the Advanced Crystal Engineering
Laboratory (aceLAB) of the Faculty of Chemistry of the
University of Warsaw.
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(25) The extraction efficiency is defined as the fraction of receptor
molecules occupied by the complex in the organic phase.
(26) The extraction efficiency was determined to be 72% for
extraction of solid NaCl with a nitrobenzene solution of receptor 1. In
the case of extraction of a more lipophilic salt such as sodium nitrate,
the extraction efficiency was higher and was determined to be 37 and
87% under liquid−liquid and solid−liquid conditions, respectively.
This demonstrates that under interfacial conditions the selectivity of
receptor 1 is consistent with the Hofmeister bias. Similarly, in the case
of extraction of an aqueous solution of chloride salts consisting of
fewer (LiCl) and more (KCl) lipophilic cations (with respect to Na+)
with a nitrobenzene solution of 1, the extraction efficiency was
determined to be 3 and 53%, respectively (selectivity order LiCl <
NaCl < KCl). Interestingly, under solid−liquid conditions, the
selectivity order is strongly reversed and the extraction efficiency is
determined to be 54 and 84% for KCl and LiCl, respectively
(selectivity order KCl < NaCl < LiCl).
L
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