Anion binding and fluoride ion induced conformational changes in bisurea receptors

Article abstract of DOI:10.1039/c9nj05785d

Two types of bisurea receptors, containing either 2,6-substituted phenyl or 2,6-substituted pyridine, are prepared, and their anion binding properties are investigated. Compared with the phenyl bisurea receptors, the pyridine bisurea receptors can be more easily converted to a cis-cis conformation from a trans-trans conformation, providing a cavity that more closely matches the volume of a fluoride ion and increasing the number of NH sites bound to the fluoride ion. As a result, the pyridine bisurea in cis-cis conformation shows stronger affinity and higher selectivity to fluoride ions, which is supported by crystal structure analysis and NMR titration experiments. Through DFT calculations, a mechanism of fluoride ion induced conformational changes of pyridine bisurea receptors is proposed, and the energy barriers of conformational changes for both types of receptors are determined.

Full text of DOI:10.1039/c9nj05785d

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Anion binding and fluoride ion induced conformational changes
in bisurea receptors
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Xi Shu, Yu Fan, Shoujian Li, Yongdong Jin, Chuanqin Xia and Chao Huang*
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College of Chemistry, Sichuan University, No.29 Wangjiang Road, Chengdu 610064,
Sichuan, PR China.
*E-mail: chuang@scu.edu.cn
Abstract
Two types of bisurea receptors, containing either 2,6-substituted phenyl or 2,6-
substituted pyridine, are prepared, and their anion binding properties are investigated.
Compared with the phenyl bisurea receptors, the pyridine bisurea receptors can be more
easily converted to a cis-cis conformation from a trans-trans conformation, providing
a cavity that more closely matches the volume of a fluoride ion and increasing the
number of NH sites bound to the fluoride ion. As a result, the pyridine bisurea in cis-
cis conformation shows stronger affinity and higher selectivity to fluoride ions, which
is supported by crystal structure analysis and NMR titration experiments. Through DFT
calculations, a mechanism of fluoride ion induced conformational changes of pyridine
bisurea receptors is proposed, and the energy barriers of conformational changes for
both types of receptors are determined.
Keywords: bisurea receptors; anion recognition; crystal structure; NMR titration;

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Introduction
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Anions play indispensable roles in catalysis, environmental science, and biological
systems, including in medicine.1-7 Typically, F− ions are widely present in soil,
groundwater, and the ocean at concentrations of 101 ‒ 102 μM.8 Long-term intake of
excess fluoride (>1.5ꢀmgꢀL−1)9 is a serious hazard to human health, resulting in dental
and bone fluorosis or neurological damage.10 Anion receptors can identify, detect, and
remove anions (such as fluoride ions) in the environment to prevent excessive amounts
of anions from harming people. In recent years, many urea-based receptors for anion
recognition have been developed.11-13 Specifically, a series of highly efficient urea
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receptors were designed by attaching urea groups to calixarenes14-18, ferrocene19,20
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triethylamine21,22, macrocyclic compounds23-26, crown ethers27,28, oxazoles29 and
oximes30,31. In most of these, the urea groups are present in a cis conformation.32 From
crystal structure analysis of urea compounds, in general, the urea groups exist in two
stable conformations, cis and trans, as shown in Scheme 1.33-37 It is well known that
conversions in conformation are very important.38 For example, the properties of nano-
dimensional assemblies38, surfaces39, and biological molecules40 can be affected by
conformational transitions. Therefore, it is necessary to determine the factors and
mechanisms that influence conformational changes for anion receptors.41 The main
factors causing conformational changes are hydrogen bonding42-45, van der Waals
forces46, dipole-dipole interactions47.
Scheme 1. The cis and trans conformations of a urea group.
Recently, interesting crystal structures of novel urea-based receptors were
measured48,49 in which the urea groups all exhibited the cis conformation, the same as
most of the reported urea receptor structures listed above.14-31 However, the urea group
of pyridine bisurea receptors showed a trans conformation. This is due to hydrogen
bonding between the carbonyl group of the pyridine and one of the N‒H groups of the
urea, which leads to the formation of a six-membered ring, favoring the trans-trans
conformation across the molecule (Scheme 2). However, when a F− ion is added, it

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disrupts the intramolecular hydrogen bonds, causing the OC‒NH single bond to rotate
and inducing a transition of the receptor from trans-trans to cis-cis. To the best of our
knowledge, fluoride ion induced transition of a urea conformation from trans to cis has
not been reported previously. It should be noted that there are only a few examples of
conformational transition in general of urea-based receptors in the cis conformation.
For example, Gale et al. found that CH3COO− can cause an N‒C single bond rotation
between a urea and phenyl group in 1, 3-diindolylureas.50 Makuc et al. found that
CH3COO− can also induce conformational changes of indole functionalized urea
receptors.51 Yamato et al. have proposed that F− ions cause a conformation change in
thiacalix[4]arene receptors, specifically, that the intramolecular hydrogen bonds
between the two adjacent urea groups in one receptor were destroyed.52 However, these
studies did not provide crystal structures to illustrate the absolute conformational
changes of urea receptors.
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Scheme 2. Fluoride ion induced conformational conversion of the bisurea L3 from a trans-trans
conformation to a cis-cis conformation.
In this paper, the synthesis and characterization of a series of pyridine bisurea
receptors is described (L1-L3 in Scheme 3). The conformational stability of these urea
receptors and their interactions with anions are systematically investigated through
crystal structure analysis, NMR titration, and theoretical calculations. In order to further
understand the influence of the pyridine ring on conformational stability and transition
of urea group, phenyl bisurea receptors were also synthesized (L4-L5 in Scheme 3).
The structures and anion binding properties of L4 and L5 are compared with the
pyridine bisurea receptors.
Scheme 3. Synthetic route for the receptors L1-L5

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Experimental
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Materials and general methods
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Unless otherwise stated, chemical reagents were obtained from commercial
suppliers and used without further purification. All solvents used were purified and
dried by standard methods prior to use. 1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were recorded on a Bruker AV III 400 MHz spectrometer with either DMSO-d6
or CDCl3 as the solvent, and tetramethylsilane (TMS) as an internal reference. High
resolution mass spectrometry (HRMS) was carried out on a Shimadzu LCMS-IT-TOF
(ESI) spectrometer.
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Synthesis
L1-L2 were prepared following a procedure identical to one previously reported
in the literature.53 L3-L5 were prepared following a similar procedure as L1-L2,
described as follows:
A mixture of pyridine-2, 6-dicarboxylic acid or isophthalic acid (10 mmol), SOCl2
(10 mL) and DMF (0.2 mL) was refluxed for 5 h under a nitrogen atmosphere. Excess
SOCl2 was removed by reduced pressure distillation, and the mixture was further cooled
in an ice bath. 50 mL of a solution of ethylurea, n-butylurea, or phenylurea (22 mmol)
in CH2Cl2 was then added dropwise. The mixture was stirred overnight at room
temperature. Solvents were removed from the reaction mixture, and the resulting
material was washed alternately with diethyl ether and water by vigorous stirring to
obtain a white solid.
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L1: 1.51 g, yield 49%. Melting point: 193-196 ℃. H NMR (400 MHz, CDCl3) δ =
10.76 (s, 2H, Ha), 8.49 (t, 2H, J = 5.3 Hz, Hb), 8.44 (d, 2H, J = 7.9 Hz, Hc), 8.16 (t, 1H,
J = 7.4 Hz, Hd), 3.41 (dq, 4H, J = 7.2 Hz, He), 1.24 (t, 6H, J = 7.3 Hz, Hf).
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L2: 2.44 g, yield 67%. Melting point: 187-190 ℃. H NMR (400 MHz, CDCl3) δ =
10.77 (s, 2H, Ha), 8.58 (t, 2H, J = 5.7 Hz, Hb), 8.44 (d, 2H, J = 7.8 Hz, Hc), 8.14 (t, 1H,
J = 7.8 Hz, Hd), 3.34 (dt, 4H, J = 6.9 Hz, J = 5.7 Hz, He), 1.42, 1.57 (two multiplets,
8H, Hg,f), 0.92 (t, 6H, J = 7.2 Hz, Hh).

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L3: 2.72 g, yield 68%. Melting point: 231-234 ℃. H NMR (400 MHz, CDCl3) δ =
10.98 (s, 2H, Ha), 10.56 (s, 2H, Hb), 8.55 (d, 2H, J = 7.8 Hz, Hc), 8.24 (t, 1H, J = 7.8
Hz, Hd), 7.46 (d, 4H, J = 7.9 Hz, He), 7.27 (t, 4H, J = 7.3 Hz, Hf), 7.10 (t, 2H, J = 7.4
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Hz, Hg). C NMR (101 MHz, CDCl3) δ = 164.25, 151.04, 147.59, 139.85, 137.00,
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128.89, 127.20, 124.50, 120.72. HRMS (ESI+): calcd for C22H20N2O8Na+ [M+Na]+
426.1173; found 426.1168.
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L4: 1.43 g, yield 47%. Melting point: 213-217 ℃. H NMR: H NMR (400 MHz,
CDCl3) δ = 9.47 (s, 2H, Ha), 8.59 (t, 2H, J = 5.7 Hz, Hb), 8.47 (s, 1H, Hc), 8.15 (d, 2H,
J = 7.8 Hz, Hd), 7.65 (t, 1H, J = 7.8 Hz, He), 3.38 (dq, 4H, J = 7.2 Hz, Hf), 1.21 (t, 6H,
J = 7.3 Hz, Hg). 13C NMR (101 MHz, DMSO-d6) δ = 167.71, 153.56, 133.17, 132.62,
129.57, 127.98, 34.50, 15.42. HRMS (ESI+): calcd for C14H18N4O4Na+ [M+Na]+
329.1220; found 329.1182.
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L5: 1.98 g, yield 54%. Melting point: 204-208 ℃. H NMR (400 MHz, CDCl3) δ =
10.19 (s, 2H, Ha), 8.71 (t, 2H, J = 5.7 Hz, Hb), 8.56 (s, 1H, Hc), 8.23 (d, 2H, J = 7.8 Hz,
Hd), 7.63 (t, 1H, J = 7.8 Hz, He), 3.32 (td, 4H, J = 7.0 Hz, J = 5.6 Hz, Hf), 1.53 (p, 4H,
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J = 7.1 Hz, Hg), 1.36 (m, 4H, Hh), 0.91 (t, 6H, J = 7.3 Hz, Hi). C NMR (101 MHz,
CDCl3) δ = 167.50, 154.43, 132.95, 132.62, 129.30, 127.35, 39.62, 31.48, 20.08, 13.71.
HRMS (ESI+): calcd for C18H26N4O4Na+ [M+Na]+ 385.1846; found 385.1805.
NMR titration
1H NMR titration measurements were conducted in either CDCl3 or DMSO-d6, in
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both cases at room temperature. F NMR titration measurements were conducted in
DMSO-d6 at room temperature.
In the case of CDCl3, the initial concentration of receptors L3 and L4 was 5 × 10−3
−
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M. 0.05 M stock solutions of the anions (F−, Cl−, Br−, I−, NO3 , PF6 , CH3COO−, ClO4 ,
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HSO4 , H2PO4 or ReO4 , as tetrabutylammonium, TBA, salts) were prepared by
dissolving the salt in CDCl3 solution. NMR samples were then prepared by adding the
anion solution (50 μL) to 500 μL of the receptor solution.
For DMSO-d6 solutions, the initial concentration of receptors L3 and L4 was
2.0×10-3 M. Stock solutions of the anion, Cl, Br, H2PO4 and CH3COO as TBA salts,
were 0.4 M in DMSO-d6 solution. NMR samples were prepared by adding varying
amounts of the anion solutions (0–25 μL) to 500 μL of the receptor solution.

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X-ray crystallography
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Crystals suitable for X-ray diffraction (XRD) were obtained for L1, L3 and L5.
Single crystal XRD data for these materials were collected on an Agilent Gemini, Dual,
Cu at zero, EosS2 diffractometer equipped with a graphite-monochromated Cu Kα (λ
= 0.154184 nm) source. The intensity data was collected by the u scan technique. Using
Olex2, the structure was solved with the ShelXT structure solution program using
Direct Methods and refined with the ShelXL refinement package by least-squares
minimization.54-56 X-ray crystallographic information data (CIFs) is available in the
Cambridge Crystallographic Data Centre under numbers 1536295 (L1), 1944338
(L1·H2O), 1944331 (L3), 1944326 (L3·TBAF), and 1944332 (L5).
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Crystal Data for C26H34N10O8 (L1) (M = 614.63 g/mol): triclinic, space group P-1 (no.
2), a = 9.0672(4) Å, b = 13.1124(7) Å, c = 14.5279(7) Å, α = 92.323(4)°, β =
106.840(4)°, γ = 110.178(5)°, V = 1532.64(14) Å3, Z = 2, T = 293.52(10) K, μ(CuKα)
= 0.851 mm-1, Dcalc = 1.332 g/cm3, 13339 reflections measured (10.678° ≤ 2Θ ≤
144.85°), 5849 unique (Rint = 0.0446, Rsigma = 0.0446) which were used in all
calculations. The final R1 was 0.0835 (I > 2σ(I)) and wR2 was 0.2226 (all data).
Crystal Data for C13H19N5O5 (L1·H2O) (M =325.33 g/mol): monoclinic, space group
P21/c (no. 14), a = 7.9330(3) Å, b = 21.6567(7) Å, c = 9.2173(3) Å, β = 105.934(4)°,
V = 1522.70(9) Å3, Z = 4, T = 294.33(10) K, μ(CuKα) = 0.937 mm-1, Dcalc = 1.419
g/cm3, 8364 reflections measured (10.786° ≤ 2Θ ≤ 144.906°), 2967 unique (Rint
=
0.0307, Rsigma = 0.0289) which were used in all calculations. The final R1 was 0.0529
(I > 2σ(I)) and wR2 was 0.1405 (all data).
Crystal Data for C42H34N10O8 (L3) (M =806.79 g/mol): triclinic, space group P-1 (no.
2), a = 10.0589(9) Å, b = 12.8100(9) Å, c = 15.9508(13) Å, α = 77.077(7)°, β =
87.942(7)°, γ = 78.291(7)°, V = 1961.5(3) Å3, Z = 2, T = 295.0(3) K, μ(CuKα) = 0.812
mm-1, Dcalc = 1.366 g/cm3, 21475 reflections measured (8.978° ≤ 2Θ ≤ 147.772°),
7653 unique (Rint = 0.0728, Rsigma = 0.0743) which were used in all calculations. The
final R1 was 0.0797 (I > 2σ(I)) and wR2 was 0.2301 (all data).
Crystal Data for C37H53FN6O4 (L3·TBAF) (M =664.85 g/mol): monoclinic, space
group P21/n (no. 14), a = 12.2710(3) Å, b = 17.4802(4) Å, c = 19.5368(4) Å, β =

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-1
107.634(3)°, V = 3993.72(16) Å , Z = 4, T = 296.31(10) K, μ(CuKα) = 0.612 mm ,
Dcalc = 1.106 g/cm3, 22804 reflections measured (9.098° ≤ 2Θ ≤ 145.65°), 7792 unique
(Rint = 0.0342, Rsigma = 0.0278) which were used in all calculations. The final R1 was
0.0641 (I > 2σ(I)) and wR2 was 0.2042 (all data).
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Crystal Data for C18H26N4O4 (L5) (M =362.43 g/mol): monoclinic, space group C2/c
(no. 15), a = 16.8164(6) Å, b = 12.1616(4) Å, c = 9.6474(3) Å, β = 98.674(3)°, V =
1950.46(12) Å3, Z = 4, T = 295.39(10) K, μ(CuKα) = 0.727 mm-1, Dcalc = 1.234 g/cm3,
5510 reflections measured (10.644° ≤ 2Θ ≤ 145.206°), 1895 unique (Rint = 0.0226,
Rsigma = 0.0190) which were used in all calculations. The final R1 was 0.0766 (I > 2σ(I))
and wR2 was 0.1810 (all data).
Theoretical studies
All calculations were performed using Gaussian 09.57 Geometries were optimized
using the M06-2X functional58 with the basis set 6-311G (d, p) for all atoms. Frequency
computations were performed at the same theoretical levels to ensure that the
determined structures correspond to a local minimum on the potential energy surface.
The single point energy was calculated according to the M06-2X/ def2-TZVP59 level
for the optimized geometry. 3D molecular structures of all species shown here were
drawn with the CYL view program.60

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Results and discussion
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As shown in Scheme 3, receptors L1 through L5 were synthesized using similar
methods. Briefly, pyridine-2,6-dicarboxylic acid or isophthalic acid is reacted with
thionyl chloride under nitrogen to give an acid chloride, which is reacted with urea
derivatives to obtain the corresponding crude product. The crude product was washed
with diethyl ether and water, respectively, to generate a white powdery solid (L1-L5,
yield: 40‒70%), which was characterized by 1H-NMR, 13C-NMR, HR-MS.
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Crystal Structures
Figure 1. (a, b) Two views of the crystal structure of L1; (c) chemical structure of L1. (C: gray, H:
white, O: red, N: blue)
As shown in Figure 1a, L1 adopts a dimer form. The C=Ob of one receptor
molecule forms two intermolecular hydrogen bonds with N‒Ha groups of another
receptor (N‒Ha …Ob: 2.200, 2.237 Å). Meanwhile, C=Ob of the second receptor
molecule and two N‒Ha groups of the first also form intermolecular hydrogen bonds
with length 2.232 and 2.342 Å. In addition, the two urea groups of each receptor
molecule have a trans-trans conformation, like the trans-trans conformation in Scheme
2. The two distal N‒Hb of the urea groups form intramolecular hydrogen bonds with
the C=Oa (C=Oa…Hb‒N:L1, 2.002, 2.013 Å; L1’, 2.043, 2.053 Å), constituting two
stable six-membered ring structures. The pyridine NPy atom forms two intramolecular
hydrogen bonds with the N‒Ha of the two urea groups (L1: 2.273, 2.271 Å; L1’: 2.283,
2.304 Å).

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As shown in Figure 1b, the two six-membered ring planes are almost coplanar
with the plane of the pyridine ring. The dihedral angles between the six-membered ring
and the pyridine ring are 9.98°(L1), -0.93°(L1) and 4.98°(L1’), 0.92° (L1’),
respectively. Moreover, the two receptor molecules are stacked in a cross-structure
manner (Figure 1b).
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Figure 2. (a, b) Two views of the crystal structure of L3 (c) chemical structure of L3. (C: gray, H:
white, O: red, N: blue)
The crystal structure of L2 has been reported elsewhere53, and we have also
obtained the crystal structure of L3 (Figure 2). There are no significant differences in
the molecular conformations of L1, L2, and L3, except for slight differences in the
length of the hydrogen bonds and the dihedral angles.
Figure 3. (a, b) Two views of the crystal structure of L1·H2O (c) chemical structure of L1·H2O.
(C: gray, H: white, O: red, N: blue)

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The crystal structure of the L1·H2O complex is shown in Figure 3a. The two urea
groups in the receptor molecule are still adopt a trans-trans conformation, and the two
distal N‒Hb of the urea groups form intramolecular hydrogen bonds with the carbonyl
oxygen (C=Oa…Hb‒N: 1.994, 2.072 Å), generating stable six-membered ring structures.
The oxygen atom in water and two N‒Ha on urea groups form N‒Ha…O intermolecular
hydrogen bonds (2.213 Å and 2.216 Å). Due to the insertion of the water molecule, as
shown in Figure 3b, the receptors were stacked in parallel and no longer cross-coupled
as seen in Figure 1b. In addition, due to the interaction with water, the six-membered
ring planes formed by the intramolecular hydrogen bonds in the urea groups on both
sides of L1 are closer to the same plane of the pyridine ring, the dihedral angle of which
is 0.98° and 0.40°, respectively (the structure of L1 is same as L1’).
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Figure 4. (a, b) Two views of the crystal structure of L3·TBAF (c) chemical structure of
L3·TBAF. (TBA cation omitted for clarity；C: gray, H: white, O: red, N: blue, F: green)
The crystal structure of the L3·TBAF complex (TBAF: tetrabutylammonium
fluoride) is shown in Figure 4a. The addition of an F− ion destroys the two
intramolecular hydrogen bonds (C=Oa…Hb‒N ), and the two single bonds (HaN‒COb)
in the receptor are rotated, meaning that the conformations of the urea groups in L3 are
converted from a trans to a cis conformation. As a result, all of the four N‒H groups
can cooperatively surround the single F− ion, forming four hydrogen bonds (1.792,
1.806, 1.966, and 1.973 Å). The receptor molecule is almost in the same plane as the
F− ion (Figure 4b). DFT calculations below will explore the differences between the
trans and cis conformational stability of the receptor, and the change in the energy
barriers for conformational transitions caused by F− ions.

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Figure 5. (a, b) Two views of the crystal structure of L5 (c) chemical structure of L5. (C: gray, H:
white, O: red, N: blue)
The crystal structure of L5 is shown in Figure 5a. Similar to L1-L3, the carbonyl
oxygen atoms (C=Oa) form intramolecular hydrogen bonds with the Hb‒N on the
adjacent urea group (C=Oa…Hb‒N: 2.056, 2.056 Å). As shown in Figure 5b, the phenyl
bisurea receptor L5 differs from the pyridine bisurea receptors L1-L3 in two ways. The
first is that in L5, the C=Ob and N‒Ha groups on one side form single intermolecular
hydrogen bonds (2.048, 2.048 Å) with the N‒Ha and C=Ob groups on one side of
another molecule, and so the molecules take on a stacked configuration, rather than
cross-linked as in L1. The second is that because of the small distances between N‒Ha
on both sides of the molecule and the Hc on the central benzene ring (2.085, 2.085 Å),
these atoms mutually repel. This results in the six-membered ring planes formed by
hydrogen bonding involving the carbonyl urea on both sides no longer being coplanar
with the benzene ring, the dihedral angles being 27.2° and -27.2° (the structure of L5
is same as L5’). One effect of this is that the volume of the cavity between the urea
groups on both sides of L5 (Ha to Ha' distance: 3.996 Å) is larger than that of L1 (Ha to
Ha' distance: 2.970 Å), L2 (Ha to Ha' distance: 2.842 Å) and L3 (Ha to Ha' distance: 2.992
Å). This may explain why the phenyl bisurea receptors have stronger affinity with larger
−
volume anions such as HSO4 (28.7 Å3) and Cl− (24.8 Å3)61, while the binding ability
of pyridine bisurea receptors with large anions is much weaker.

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NMR titration
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Figure 6. 1H NMR spectra of L3 (5 mM) with 1 equivalent of TBAx (where x is the anion shown
in the figure) in CDCl3 at 298 K.
In order to study the binding properties of the two types of receptors with anions,
L3 and L4 were selected as being representative of the two types, and an NMR titration
study was carried out. As shown in Figure 6, the addition of F− ions leads to the
disappearance of two peaks of the L3 urea groups (Ha, Hb), indicating that F− ion
interacts strongly with four total N‒H groups, suggesting that L3 is likely to bind with
F− ions in a cis-cis conformation in solution. At the same time, the signals of the
pyridine hydrogen atoms (Hc, Hd) move to higher field (∆δ 0.19, 0.17 ppm). The
hydrogen signals of the benzene ring (He-g) appear to be slightly perturbed. Specifically,
the signals from He and Hf move to higher field (∆δ 0.12, 0.04 ppm) while the signal
from Hg moves to lower field (∆δ 0.16 ppm).
−
H2PO4 and CH3COO− only broaden one hydrogen signal of the urea group (Ha),
and the shift in the signals from pyridine (Hc and Hd) shift by a smaller amount
compared to the F− case. The signals associated with the benzene ring (He-g) show no
−
significant shift, indicating that L3 interacts with H2PO4 and CH3COO− in a trans-
trans conformation. The other anions induce almost no change in the chemical shifts of
the L3 hydrogen atoms, implying that these anions interact weakly with L3. In summary,
the strength of the interaction between L3 and this group of anions is consistent with
the Hofmeister series.62

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Figure 7. Stacked 1H NMR spectra for titration of L3 (0.002 M) with TBAF (0-10 equivalents) in
DMSO-d6 at 298 K.
The addition of one equivalent of F− ions causes the disappearance of four NH
groups hydrogen signals (Figure 6), which might be due to the strong interaction of
intermolecular hydrogen bonds between F− ions and NH groups, or the deprotonation
of NH protons by F− ions. To elucidate this, NMR titrations for L3 with OH− and F−
ions were carried out (Figure S7 and S8). Obviously, the addition of 0.5 equivalent of
F− ions leads to the disappearance of two peaks of the L3 urea groups (Ha, Hb). In
contrast, even the addition of OH− ions up to 1.0 equivalent only leads to subtle shifts
−
of the two peaks Ha and Hb. Moreover, at the same time, there are no HF2 signals
appeared in the NMR spectrums (Figure 7), implying the abstraction of protons does
not occur. These results reveal that the strong interaction between F− ions and receptor
L3 causes the disappearance of NH proton signals. However, when two equivalent F−
ions are added, the deprotonation of NHa group occurs. Specifically, the proton signal
−
19
of the HF2 appears at around 16 ppm (Figure 7) and F signal appears at −142 ppm
(Figure S9). It is worth noting that the Hb signal reappears when 4 equivalent of F− ions
is added. We speculate that this may be due to the complete deprotonation of both N-
Ha groups, resulting in the formation of the new anionic species L32−.

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−
As shown in Figure 8, the addition of F ions causes one hydrogen signal from the
urea group of L4, Ha, to disappear, while the other hydrogen signal of the urea group,
Hb, broadens and shifts slightly to lower field (∆δ 0.08 ppm). Meanwhile, one hydrogen
signal from the benzene ring, Hc, shifts to lower field (∆δ 0.41 ppm), and two other
hydrogen signals from the benzene ring, He and Hd, shift to high field (∆δ 0.03, 0.07
ppm).
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The addition of H2PO4 or CH3COO− significantly shifts one hydrogen signal of
the urea group of L4, Ha. F− and H2PO4 have a strong interaction with the Hc on the
−
−
benzene ring of L4, causing a change in the relative positions of the Hc and Hb signals.
However, CH3COO− has little interaction with Hc. The addition of HSO4 or Cl− can
−
significantly shift one hydrogen signal of the urea group of L4 (Ha). However, the other
anions cause little change in the signal from this hydrogen.
Figure 8. 1H NMR spectra of L4 (5 mM) with 1 equivalent of TBAx (where x is the anion shown
in the figure) in CDCl3 at 298 K.
These results indicate that although L4 has a strong interaction with F− ions, its
binding mode is likely to be dominated by a trans-trans conformation, because the Hb
signal of L4 changes little, while both the Ha and Hb signals of L3 completely disappear.
Similarly, the binding mode of L4 to H2PO4 , CH3COO−, HSO4 , or Cl− anions is likely
to be in a trans-trans conformation. This finding is consistent with the result of the DFT
calculations below. Note that the interaction between the two types of receptors and
−
−
anions is slightly different. For example, HSO4 and Cl− have a strong affinity with L4,
−

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and a weak affinity with L3. This phenomenon might be due to matching of the receptor
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cavity size and the anion volume based on the analysis of crystal structure data.
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Figure 9. Stacked 1H NMR spectra for titration of L3 (0.002 M) with TBACH3COO (0-10
equivalents) in DMSO-d6 at 298 K (left), and chemical shifts of Ha protons of the L3 plotted
against the CH3COO− concentration (right).
Table 1. Association constants of anions with receptors L3 and L4.a
Anion
L3
254
201
L4
106
294
CH3COO−
−
H2PO4
a: NMR titration, solvent: DMSO-d6, 298 K, [L] = 2 × 10−3 M, anions added as TBA salts, where
[TBAX] ∼2 × 10−2 M; Models: 1:1; M-1, errors <10%.
To verify this hypothesis, and to further understand the interactions between
anions and the two types of receptors, we performed NMR titration experiments using
−
L3 and L4 with varying concentrations of H2PO4 and CH3COO−. As an example, the
left panel of Figure 9 shows the results of the titration of L3 with CH3COO−. As the
CH3COO− concentration increases gradually, the signals from Ha and Hb move toward
lower field, while signals from Hc and Hd move to higher field. The chemical shifts of
the Ha proton are fit to a curve (Figure 9, right), from which binding constants can be
extracted, with a summary of results shown in Table 1.63-65 The binding constant of L3
−
with CH3COO− is slightly larger than that for H2PO4 , which is consistent with the
−
Hofmeister series. However, the binding constant of L4 to H2PO4 is almost three times
that of CH3COO−. This phenomenon is consistent with a larger cavity between the urea
groups of the receptor, providing better spatial matching with large volume anions, so
−
−
that the binding with H2PO4 is stronger (H2PO4 volume: 33.5 Å3, CH3COO− volume:
17.8 Å3).61

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Theoretical studies
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Table 2. Calculated binding energies for the receptor L1 with three anions (kJ/mol).
Binding Energy
cis-cis
F−
Cl−
Br−
−396.0
−269.2
−254.5
−113.4
−218.8
−87.4
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trans-trans
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To further explore the binding mechanism between urea receptors and anions, DFT
calculations were performed on the receptor and receptor/anion complexes. First, the
change in energy (ΔE) of the receptor L1 in combination with several anions (F−, Cl−,
Br−) in the cis-cis and trans-trans conformations was compared, as shown in Table 2.
The binding strength trend is F− >Cl− >Br−, whether the receptor is in the trans-trans or
cis-cis conformation. The DFT optimized structures of L1 in cis-cis conformations with
halide ions is shown in Figure 10. We found that when the cis-cis conformation of L1
is combined with one F− ion, it can be accommodated in the cavity of the four urea
group NH, and the F− ion and the pyridine ring are in the same plane. However, the
combination of L1 with other halide ions is different. For example, when a Cl− ion is
bound to four NH groups, it is out of the plane of the pyridine ring. The reason may be
that due to the large volume of the Cl− ion (F− volume: 9.9 Å3; Cl− volume: 24.8 Å3)61,
there is a poor match with the volume of the cavity formed by the four NH groups in
L1. Further, the Br− ion is farther away from the plane of the urea group and the pyridine
ring, perhaps because of the even larger radius of the Br− ion (Br− volume: 31.5 Å3)61.
This result is consistent with the binding constants of L3 with Cl− ions (binding constant:
0.06) and Br− ions (binding constant: 0.04) (Table S7), indicating much weaker
interactions in comparison with pyridine receptor and F− ion. Therefore, we suspect that
pyridine bisurea receptors binds mainly to the F− ion in a cis-cis conformation and a
trans-trans conformation to larger volume anions such as Cl− and Br−. These findings
are consistent with crystal structure analysis and the results of NMR titration.

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Figure 10. Optimized structures of L1 with F−(a), Cl−(b), Br−(c) anions in a cis-cis conformation
at the M06-2X/6-311G(d,p) level.
Figure 11. Energy profile for (HaN)−(COb) single bond rotation in L1 at the M06-2X/def2TZVP
level.

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Figure 12. Energy profile for (HaN)−(COb) single bond rotation in L1 bound to an F− ion at M06-
2X/def2TZVP level.
The discussion above has established that the receptor L1 binds to the F− ion in a
cis-cis conformation, but it is not clear how the receptor undergoes conformational
transitions in the presence of F− ion. Therefore, conformational changes of the pyridine
bisurea receptor and the receptor/F− complex were studied using DFT calculations. It
was found that, in the absence of F− ions, L1 can be transformed from a trans-trans to
a cis-cis conformation by two N−C(Ob) single bond rotations, as shown in Figure 11.
However, this transformation is very difficult. Specifically, the energy barrier for a urea
group to go from trans to cis is 48.7 kJ/mol, and the total energy barrier for both urea
groups to go from trans to cis is 96.2 kJ/mol. Furthermore, due to the presence of two
intramolecular hydrogen bonds, the trans-trans conformation of L1 is more stable than
the cis-cis conformation, with the trans-trans conformational energy being 89 kJ/mol
lower. In contrast, when an F− ion is present, the energy barriers for the two steps
required for L1 to go from trans-trans to cis-cis conformation are significantly reduced,
as shown in Figure 12, to 33.6 kJ/mol and 29 kJ/mol. The relative energy of the
receptor/F− complex in a cis-cis conformation is 37.8 kJ/mol lower than that in a trans-
trans conformation. This indicates that the F− ion can promote an inversion in the
conformation of the urea groups of L1, stabilize an intermediate trans-cis conformation,
and further stabilize a cis-cis product conformation. These results are consistent with
the crystal structure analysis discussed above.

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Figure 13. Energy profile for (HaN)−(COb) single bond rotation in L4 at the M06-2X/def2TZVP
level.
Figure 14. Energy profile for (HaN)−(COb) single bond rotation in L4 bound to an F− ion at the
M06-2X/def2TZVP level.
As a comparison with the pyridine ligands, we also calculated the energy profile
for trans-trans to cis-cis conformational changes in the phenyl receptor L4. As shown
in Figure 13, in the absence of F− ion, it is also very difficult for L4 to reconfigure to a
cis-cis conformation from the trans-trans conformation, which requires two rotations
of the (HaN)−(COb)single bond. Specifically, the energy barrier for one of the urea
groups to go from trans to cis is 53.3 kJ/mol, and the total energy barrier for the
transition of both urea groups is 103.3 kJ/mol. In addition, similar to L1, L4 is more
stable in the trans-trans conformation compared to the cis-cis conformation due to the
presence of two intramolecular hydrogen bonds, with the energy of the trans-trans

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−
conformation 90.7 kJ/mol lower. As shown in Figure 14, when an F ion is present, the
energy barriers for the urea group of L4 to go from trans-trans to cis-cis are reduced to
42.8 and 35.3 kJ/mol. Also similar to L1, the receptor/F− complex is more stable in the
cis-cis conformation than the trans-trans, with the cis-cis energy 17.6 kJ/mol lower. By
comparing the urea group transition processes of L1 and L4 (Figure 15), we find that
the urea group conformational conversion energy barriers for L4 are higher than that of
L1, regardless of the presence of an F− ion. In general, receptor L1 is more likely to
bind with an F− ion in the cis-cis conformation.
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Figure 15. Energy profiles for (HaN)−(COb) single bond rotation at the M06-2X/def2TZVP level.
Conclusions
Two types of similar receptors, L1-L5, were synthesized and characterized.
Crystal structure analysis indicated that the carbonyl group in these receptors
participates in an intramolecular hydrogen bond with the N‒H at the distal end of the
urea group, forming a six-membered ring. This makes the trans-trans conformation
more stable than the cis-cis conformation. The Npy atom of the pyridine receptors (L1-
L3) forms two intramolecular hydrogen bonds with the proximal N‒H of the urea
groups, which promotes co-planarity of the two urea groups in the molecule. This
reduces the volume of the cavity between the two urea groups, improving spatial
matching to the small volume of the F− ion. In contrast, the center C‒H on the phenyl
ring of the phenyl receptors (Hc in L4 and L5) and the hydrogen atoms on the urea

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groups of the two sides of the molecule have a mutual repulsion, enlarging the cavity
of the two urea groups. The phenyl receptors favor binding larger volume anions. NMR
titration studies further showed that although both types of receptors have strong
affinities with the F− ion, pyridine receptors have stronger affinity and higher selectivity
for this ion. It was found by DFT that the pyridine receptor L1 provides better spatial
matching for the F− ion. Both pyridine and phenyl based receptors are more stable in
the trans-trans compared to cis-cis conformation. Binding to an F− ion lowers the
energy barrier for conformational change, and the receptor/F− complex in cis-cis
conformation is more stable compared to trans-trans. These results may provide a
theoretical framework for selective detection of F− ions, as well as the study of
conformational stability and transformations in urea-based receptors.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the National Natural Science Foundation of China
(grant number: 21501123) and the International Collaboration Project of Department of
Science and Technology of Sichuan Province, China (grant number: 2018HH0063). We
would like to acknowledge the “Comprehensive Training Platform of Specialized
Laboratory, College of Chemistry, Sichuan University” for HRMS, NMR and XRD
analyses. We appreciate the help from Dr. Yue Qi and Dr. Meng Yang for X-ray
diffraction measurements of single-crystal.

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