Macrocyclic bis-urea receptor: Synthesis, crystal structure and phosphate binding properties

Article abstract of DOI:10.1016/j.tetlet.2019.02.004

A macrocyclic bis-urea receptor (L1) and two acyclic bis-urea analogues (L2 and L3) have been synthesized. The crystal structure of L1 was obtained. The experimental results show that the receptor L1 has high selectivity to H₂PO₄ ^?. Meanwhile, compared with the acyclic receptors L2 and L3, L1 has higher binding ability to H₂PO₄ ^?. The results of density functional theory (DFT) calculations deepened our understanding on L1 conformations stability and its anion-binding property.

Full text of DOI:10.1016/j.tetlet.2019.02.004

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Macrocyclic bis-urea receptor: Synthesis, crystal structure and
phosphate binding properties
⇑
Xi Shu, Ruyu Wang, Yu Fan, Shoujian Li, Chao Huang
College of Chemistry, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, Sichuan, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A macrocyclic bis-urea receptor (L1) and two acyclic bis-urea analogues (L2 and L3) have been synthe-
sized. The crystal structure of L1 was obtained. The experimental results show that the receptor L1
has high selectivity to H2POÀ4 . Meanwhile, compared with the acyclic receptors L2 and L3, L1 has higher
binding ability to H2PO4À. The results of density functional theory (DFT) calculations deepened our under-
standing on L1 conformations stability and its anion-binding property.
Received 14 December 2018
Revised 30 January 2019
Accepted 1 February 2019
Available online xxxx
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Macrocyclic bis-urea
Anion-binding
Crystal structure
NMR titration
Introduction
Results and discussion
Anions play important roles in the areas of biological systems,
environmental science, catalysis and medicine [1–7]. Typically,
phosphate plays a significant role in life system, and is a vital part
for the pharmaceutical industry and fertilizers [8]. On the other
hand, phosphorylated compounds is one of the culprits in the
eutrophication of natural water sources [9,10]. Over the past
20 years, many sensors or probes based on receptors have been
reported for the detection of phosphates and other anions in aque-
ous media or organic solvents. So far, novel receptors are still being
developed. These efforts are driven by two factors: 1) raising the
selectivity and detection sensitivity; 2) better understanding of
the details of binding modes to improve the recognition ability
for phosphate anions. However, since anions have relatively low
charge/radius ratio, it is very challenging to design efficient and
highly selective anion recognition receptors [11,12]. Among vari-
ous anion-binding receptors, thiourea and urea functional groups
are excellent candidates because they can form hydrogen bonds
with anions in two directions, which is beneficial to improve the
ability of receptors to select anions [13–15]. Meanwhile, cyclic
urea with flexible cavity sizes and pre-organized binding sites
has drawn much attention for anion recognition [16]. Thus, we
designed and synthesized a new macrocyclic urea receptor, which
demonstrates better binding affinity towards dihydrogen phos-
phate anion.
Based on our previous study on acyclic multi-urea receptors for
anion-binding with relatively low affinity and selectivity [17,18],
herein, we would like to report a novel 42-membered macrocyclic
bis-urea receptor, incorporating two urea subunits (as cooperative
binding sites for anions) and a polyether moiety (L1, Scheme 1). In
addition, two analogies of acyclic bis-urea L2 and L3 similar to
receptor L1 with two urea subunits were further synthesized for
comparison. The anion-binding properties of the macrocyclic bis-
urea (L1) were fully investigated by NMR, solid state structures
and theoretical studies.
The macrocyclic bis-urea receptor L1 was prepared by the reac-
tion of 1 equiv of diamine 4a with 2 equiv of oligomeric ethylene
glycol di(4-nitrophenyl-N-(4-phenyl)-carbamate) 5a (Scheme S1).
The expected carbamate 5a, without further purification, was
reacted with an additional portion of diluted solution of diamine
4a, yielding the macrocyclic product L1. The crude product was
readily purified by washing with DMSO and Et2O several times.
As expected, as in most cases, the cyclization reaction resulting
in macrocycles proceeds inefficiently at an isolated yield of 24%
on account of the closure of the ring competes with the formation
of linear oligomers. To overcome this issue, high-dilution and tem-
plate techniques were usually utilized [19,20]. First, according to
the chloride-templated synthesis of macrocyclic amides and
urea-containing functional receptors by Böhmer’s [21], Kondo
[22] and Jarosz’s [23,24], on the addition of 1 equiv of chloride ions,
while, in our case the yield of this macrocyclic product did not
increased. Moreover, the addition of sodium ions as template
⇑
Corresponding author.
E-mail address: chuang@scu.edu.cn (C. Huang).
https://doi.org/10.1016/j.tetlet.2019.02.004
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: X. Shu, R. Wang, Y. Fan et al., Macrocyclic bis-urea receptor: Synthesis, crystal structure and phosphate binding properties, Tetra-
hedron Letters, https://doi.org/10.1016/j.tetlet.2019.02.004

2
X. Shu et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. The synthesis of L1–L3.
slightly increased the yield of macrocycle L1 (Supporting Informa-
tion). This led us to the assumption that sodium cations might be
participating in the cation-templated stabilization of a folded con-
formation of the corresponding linear intermediates of L1, which is
quite reasonable that the flexible polyether chain of the precursor
4a might prefer to bind a sodium ion similar to crown ether [25]
before the macrocyclization initiated, inducing the conformation
of 4a pre-organized from a linear orientation to a U-turn bent ori-
entation, which is much more favourable for the cyclization reac-
tion in comparison with the linear polymerization [16,19,20].
To gain insight into the anion-binding properties for macrocycle
receptor, 1H NMR titration experiments were carried out (Fig. 1). In
each case, 2 equiv of various anion (TBAX salts, X = FÀ, ClÀ, BrÀ, IÀ,
NOÀ3 , PFÀ6 , CH3COOÀ, ClO4À, HSO4À, H2PO4À or ReOÀ4 ) were added to a
2.5 mM of receptor L1 dissolved in DMSO d6 solution. We found
that, upon addition of anions, the signals of urea protons were evi-
dently shifted downfield. It interests to mention that on the addi-
tion of CH3COOÀ or H2POÀ4 , the perturbations in signals of aromatic
protons were also observed.
Specifically, receptor L1 showed higher affinity for FÀ, CH3-
COOÀ, H2PO4À, HSOÀ4 , ClÀ than other anions. It has to be noted that,
on the addition of 2 equiv of fluoride anions, the proton signals of
the urea subunits in L1 were broadened; whereas these signals
were disappeared in L2 and L3 (Figs. S11 and S12). This is possibly
because that the acidity of the urea subunits in L2 and L3 is much
stronger than that in L1 and their deprotonation might favour due
to an electron-withdrawing nitro substituents on the covalently
connected phenyl ring [26].
In order to obtain the binding stoichiometry of the receptor L1–
L3 to the anions, the Job plot is used to determine the binding
model of the host and the guest. The Job plot supported a 1:1 bind-
ing stoichiometry as evidenced by the plot maximum near 0.5 for
L1 and L3 while a 1:2 model for L2 with H2POÀ4 anion (Figs. S18–
S23). The reason may be that L2 is more flexible than L1 and L3,
and its molecular structure may exhibit a linear conformation,
resulting in two urea groups being far apart and unable to syner-
gistically bind one H2POÀ4 , but the two urea groups are respectively
combined with one H2POÀ4 in the 1:2 mode.
To further understand the nature of receptor L1 towards H2PO4À
(Fig. 2), CH3COOÀ (Fig. S13), ClÀ (Fig. S14), HSO4À (Fig. S15) anions,
NMR titration experiments were performed. Building from the
binding stoichiometry, binding constants of receptor L1 towards
these anions were calculated [27–29] (www.supramolecular.org)
and collected in Table 1. Particularly, the receptor L1 binds to dihy-
drogen phosphate most strongly and has high selectivity (Fig. 3).
This behaviour is characteristic for urea-containing receptors and
is closely related to the high basicity and geometrical matching
of the anion. In the case of more basic anions, Y-shaped carboxy-
lates are associated with moderate strength. This trend is opposite
to the Hofmeister series [30] and our calculated binding energies
Fig. 1. 1H NMR spectra of receptor L1 (2.5 mM) with 2 equiv of TBAX in DMSO d6 at
298 K.
Please cite this article as: X. Shu, R. Wang, Y. Fan et al., Macrocyclic bis-urea receptor: Synthesis, crystal structure and phosphate binding properties, Tetra-
hedron Letters, https://doi.org/10.1016/j.tetlet.2019.02.004

X. Shu et al. / Tetrahedron Letters xxx (xxxx) xxx
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Table 2
Association constants of receptors L1-L3 with H2PO4À a
.
Receptors
Model
H2POÀ4
L1
L2
L3
1:1
1:2
1:1
K11 = 820.4
K11 = 40.1; K12 = 100.5
K11 = 307.4
NMR titration, solvent DMSO d6, 298 K, [L] = 2 Â 10À3 M, H2PO4À added as TBA
a
salts, where [TBAH2PO4] ꢀ 2 Â 10À2 M; errors <10%.
binding to hydrogen sulfate anions with appreciable strength
while very weakly coordinating with chloride. The receptor L1 is
also capable of binding to hydrogen sulfate and chloride anions
with weakly coordinating.
In order to compare the difference between acyclic receptors
and macrocyclic receptors, the binding constants of L2/L3 towards
H2POÀ4 were obtained by NMR titration experiments (Fig. S16 and
S17), as shown in the Table 2. We found that the binding ability
of acyclic receptor L2 (K11 = 40.1; K12 = 100.5) or L3 (307.4) to
H2POÀ4 were weaker than that of L1 (820.4) even though nitro sub-
stituents on the covalently connected phenyl ring enhanced the
acidity of the urea subunits [26], which was mainly due to the
specific conformation of macrocyclic bis-urea receptor and was
more geometrically advantageous to its binding with H2POÀ4 .
Suitable crystals for X-ray diffraction were obtained for L1 from
a DMSO solution. The crystal structure of L1 (Fig. 4) showed that
the 42-membered macrocyclic receptors, with all of the polyether
oxygen atoms without any internal or inter hydrogen bonds, pos-
sess two internal hydrogen bonds between the two urea subunits
in one L1 molecule. Namely, two urea subunits adopt parallel con-
formation. Taking into account the formation of intramolecular
hydrogen bonding (NAHÁ Á ÁO@C distances 2.019 and 2.193 Å), the
crown-shaped ring of L1 adopts a shrink-ring conformation with
two relatively small cavities around the polyether moieties. In
addition, the molecules assemble into one-dimensional chains,
which are stabilized by the formation of two intermolecular hydro-
gen bonds (NAHÁ Á ÁO@C distances 2.028 and 2.181 Å) between the
urea groups and adjacent L1. On the other hand, in contrast to the
parallel conformation in the structure of L1 of the opposing urea
functionalities in the crystal structure of complex L1Á2HCO3À
(Fig. S25) are oriented oppositely as antiparallel conformation, pre-
sumably owing to the anion-binding induced conformation
change. Indeed, DFT calculations (M06-2X/ma-TZVP//TZVP) sug-
gested that the parallel conformation is energetic favourable in
comparison with the antiparallel conformation with 35 kJ/mol
(Fig. 5). In addition, although the quality of single crystals of
L1Á2HCOÀ3 for X-ray diffraction was not suitable for completely
diffraction data collecting, luckily, the structure skeleton is quite
clear that two HCOÀ3 ions forming a dimer are adjacent to two L1
molecules through four H-bonding with two urea subunits
(Fig. S25). More importantly, urea subunits are not intramolecu-
larly hydrogen-bonded and thus are free to ‘cleft’ bind HCOÀ3 ions
separately. Interestingly, these HCOÀ3 ions were generated in situ
by fixing CO2 from air, which is similar to the case reported by Fab-
brizzi, fortunately, the structure of complex ligand-HCOÀ3 was suc-
cessfully collected in their case. [26]
Fig. 2. Changes of the chemical shifts of Ha-c signals upon titration of receptor L1
with TBAH2PO4 (Top); Stacked 1H NMR spectra for titration of L1 (0.002 M) with
TBAH2PO4 (0–10 equiv) in DMSO d6 at 298 K (Bottom).
Table 1
Association constants of receptor L1 with various anions.a
Anions
H2POÀ4
820.4
CH3COOÀ
147.1
ClÀ
HSOÀ4
22.2
L1
27.1
a
NMR titration, solvent DMSO d6, 298 K, [L] = 2 Â 10À3 M, anions added as TBA
salts, where [TBAX] ꢀ 2 Â 10À2 M; Models: 1:1; MÀ1, errors <10%.
Conclusion
Fig. 3. Selectivity of receptor L1 to anions (H2POÀ4 , CH3COOÀ, ClÀ and HSO4À).
In summary, we reported a new macrocyclic bis-urea L1. Crystal
structure analysis showed that receptor L1 had different conforma-
tions (parallel and antiparallel orientations), in which urea subunits
were parallel or antiparallel to the ring. DFT calculation indicated
that the parallel conformation is more energetic favorable than
the antiparallel conformation. Furthermore, this macrocyclic
(Table S9) that more basic acetate should has stronger affinities in
comparison with less basic dihydrogen phosphate anions, indicat-
ing a cooperatively of the two urea units during the recognition of
different shape of anions and L1 may provide a better cavity for
dihydrogen phosphate anion. The receptor L1 is also capable of
Please cite this article as: X. Shu, R. Wang, Y. Fan et al., Macrocyclic bis-urea receptor: Synthesis, crystal structure and phosphate binding properties, Tetra-
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X. Shu et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 4. X-ray OLEX2 structure of L1. (a) Unit cell with indicated intra-molecular hydrogen bonds; (b) packing structure with indicated inter-molecular hydrogen bonds.
Fig. 5. The energy difference of ‘parallel’ and ‘antiparallel’ conformations of L1 calculated in DMSO by M06-2X/ma-TZVP//TZVP with SMD model.
Please cite this article as: X. Shu, R. Wang, Y. Fan et al., Macrocyclic bis-urea receptor: Synthesis, crystal structure and phosphate binding properties, Tetra-
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X. Shu et al. / Tetrahedron Letters xxx (xxxx) xxx
5
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Please cite this article as: X. Shu, R. Wang, Y. Fan et al., Macrocyclic bis-urea receptor: Synthesis, crystal structure and phosphate binding properties, Tetra-
hedron Letters, https://doi.org/10.1016/j.tetlet.2019.02.004