Construction of unsymmetrical bis-urea macrocyclic host for neutral molecule and chloride-ion binding

Article abstract of DOI:10.1002/jhet.4329

Construction of synthetic macrocyclic host that can bind with neutral molecules and anions has potential applications in supramolecular chemistry. Herein, we have designed and synthesized blue light emitting an unsymmetrical neutral bis-urea macrocyclic host. This macrocycle can bind with neutral DMF molecule (1:1) as well as Cl^? ion (1:1) through noncovalent interactions. X-Ray crystal structure, ¹H NMR titrations with Job's Plot, HRMS with isotropic distribution pattern, FT-IR, and density functional theory analysis revealed the binding of bis-urea macrocyclic host with the guest molecule.

Full text of DOI:10.1002/jhet.4329

Received: 20 April 2021
DOI: 10.1002/jhet.4329
Revised: 3 June 2021
Accepted: 7 June 2021
A R T I C L E
Construction of unsymmetrical bis-urea macrocyclic host
for neutral molecule and chloride-ion binding
Biprajit Paul | Ayan Mukherjee | Deepak Bhuyan | Samit Guha
Department of Chemistry, Organic
Abstract
Chemistry Section, Jadavpur University,
Kolkata, India
Construction of synthetic macrocyclic host that can bind with neutral mole-
cules and anions has potential applications in supramolecular chemistry.
Herein, we have designed and synthesized blue light emitting an unsymmetri-
cal neutral bis-urea macrocyclic host. This macrocycle can bind with neutral
Correspondence
Samit Guha, Department of Chemistry,
Organic Chemistry Section, Jadavpur
University, Kolkata 700032, India.
Email: samitfsu@gmail.com; samit.guha@
jadavpuruniversity.in
À
DMF molecule (1:1) as well as Cl ion (1:1) through noncovalent interactions.
1
X-Ray crystal structure, H NMR titrations with Job's Plot, HRMS with isotro-
pic distribution pattern, FT-IR, and density functional theory analysis revealed
the binding of bis-urea macrocyclic host with the guest molecule.
Funding information
Science and Engineering Research Board,
Grant/Award Number: ECR/2017/001405
1
| INTRODUCTION
hydrogen bonds to construct host–guest compound also
depends on the geometry of the receptor. Shimizu's group
Neutral molecules and ions are indispensible for life and
have a wide range of chemical, biological, environmental,
and industrial applications [1]. Design and construction
of synthetic receptors for neutral molecules and anions
have attracted great attention in supramolecular chemis-
has seminal contributions for the development of symmet-
rical bis-urea macrocycles that self-assemble to form
columnar structures [12]. Jiang and co-workers have also
reported the synthesis and host–guest chemistry of urea
macrocycles [13]. Herein, we have designed and con-
structed blue light emitting unsymmetrical neutral macro-
cyclic receptor with urea functionality. The unsymmetrical
bis-urea macrocyclic receptor is capable of binding with
À
try [2]. Misregulation of Cl transport is associated with
nephrolithiasis (kidney stones), myotonia, Bartter's syn-
À
drome, and cystic fibrosis [3]. Synthetic Cl receptors
À
and transporters could be an encouraging strategy in
neutral dimethylformamide (DMF) molecule and Cl ion.
‘
channel replacement therapy’ for the treatment of cystic
fibrosis [4]. The majority of the receptors depend on
noncovalent interactions such as hydrogen bonding, 2 | RESULTS AND DISCUSSION
hydrophobic effect, π–π interactions, anion–π interac-
tions, van der Waals forces, and electrostatic interactions 2.1 | Synthesis
for binding of ions or neutral molecules. The preorganized
macrocyclic receptors such as crown ethers [5], calix[n]
arenes [6], calix[n]pyrroles [7], cucurbit[n]urils [8], and
cyclodextrins [9] are well known in the literature. Cyclic
peptide-based receptors are also used for ion recognition
and transportation [10]. Incorporation of appropriate
hydrogen bond donors, such as amide or specifically urea
groups, helps to form a stringently defined supramolecular
architecture [11]. The urea NH groups are respectable
hydrogen bond donors, and the urea O is an excellent
hydrogen bond acceptor. The directionality of the
The bis-urea macrocycle (6) is synthesized by multistep reac-
tions using commercially available low-cost starting mate-
rials, for example, anthracene (1) and m-xylylenediamine (4)
outlined in Scheme 1 with reasonable yield (48%). At first,
9,10-bis(aminomethyl)anthracene (3, yield 65%) is synthe-
sized by an efficient way from anthracene via 9,10-bis
(bromomethyl)anthracene (2, yield 85%). The m-xylylene
diisocyanate (5, yield 88%) is prepared from easily available
m-xylylenediamine (4) and solid triphosgene (safer equiva-
lent of phosgene gas). The macrocycle 6 is constructed by
J Heterocyclic Chem. 2021;1–6.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1

2
PAUL ET AL.
SCHEME 1 Synthesis of unsymmetrical
bis-urea macrocycle
8
5%
65%
8
8%
4
8%
simple drop wise mixing of the two compounds 3 (diamine)
and 5 (diisocyanate) in ice cold condition over a period of 6 h
using high-dilution technique in DCM followed by the con-
tinuation of the reaction (monitored by TLC) for two days at
room temperature to favor macrocyclization over polymeri-
zation (see Data S1). The macrocycle 6 is purified and char-
acterized by H NMR, C NMR, high resolution mass
spectrometry (HRMS), FT-IR, X-ray powder diffraction, and
X-Ray crystallography (Figures S5–S11).
one DMF molecule in the asymmetric unit. The
cocrystallized guest–solvent DMF in the solid state is
associated with the macrocycle (1:1) through strong
hydrogen bonding between the NH group of the urea
macrocycle and >C═O group of the DMF with the
ꢀ
H-bond length 2.07 Å and N─H─C bond angle 160
1
13
along with two weak hydrogen bonding in between CH of
the macrocycle and >C═O group of the DMF and CH of
the DMF and urea >C═O group of the macrocycle
(
Figure 1(A), Figure S10 and Table S2). Although trans-
trans urea bond is more favorable, however, in our case,
urea groups adopt trans–cis conformations that are
thought to be less favorable energetically. In compound 6,
the urea groups are oriented approximately perpendicular
to the plane of the macrocycle and the urea carbonyl
groups pointing in opposite directions to each other pre-
sumably to minimize dipole interactions. Bis-urea mac-
rocycles are further self-assembled through intermolecular
hydrogen bonding and offset π–π stacking of anthracene
residues (Figure 1(B) and Figure S10). The crystals of the
macrocycle 6 are grounded to a powder and studied by
X-ray powder diffraction (XRPD). XRPD of the microcrystal-
line powders indicate that they are single phase and retain
structural similarity to the single crystals (Figure S11).
2
.2 | Photophysical characterization
The photophysical property of the bis-urea macrocycle is
examined in DMSO (Figure S8). The absorption spectra
of the macrocycle displayed characteristic peaks at
3
43 nm, 360 nm, 380 nm, and 401 nm in DMSO and it is
due to anthracene chromophore (Figure S8a). The mac-
rocycle exhibited large molar extinction coefficient of
4
À1
À1
1
.5 Â 10 M cm . The bis-urea macrocycle contains a
blue light emitting anthracene chromophore (Figure S8b).
The fluorescence emission of the bis-urea macrocycle is
observed at 408 nm, 430 nm, 454 nm, and 486 nm in
DMSO (λex = 365 nm) (Figure S8b).
2.3 | Single-crystal X-Ray
2.4 | Anion-binding experiments
diffraction study
We have focused on the anion-binding capability of the
neutral bis-urea macrocyclic receptor. We have
established the anion-binding capability of the host by
HRMS, FT-IR, NMR titration, and theoretical calculation.
From anion-binding assay, it is clear that the neutral
Light yellow monoclinic crystals with space group P 2 /c
1
of the bis-urea macrocycle suitable for X-ray diffraction
studies are obtained from DMF solvent by slow vapor dif-
fusion of hexane (Table S1). Tables of hydrogen bonds,
data collection, and refinement details can be found in
the Data S1. The bis-urea macrocycle crystallizes with
À
macrocycle can bind selectively with the spherical Cl
À
À
among the other halide anions Br and I .

PAUL ET AL.
3
FIGURE 1 (A) X-ray crystal structure of bis-urea macrocycle cocrystallized with DMF solvent. Trans-cis urea bonds are oriented almost
perpendicular to the plane of the macrocycle and the urea carbonyl functionalities pointing in opposite directions to each other. (B) Packing
diagram of bis-urea macrocycle. It is self-assembled through intermolecular H-bonding and offset π–π stacking of anthracene residues
FIGURE 2 HRMS (ESI, Àve mode) of bis-
À
urea macrocycle:Cl (1:1) with isotropic
distribution pattern
2
.5 | High-resolution ESI-MS (Àve mode)
selectively, and the overall negatively charged 1:1 host–
guest complex gives a peak at m/z = 458.1484 (Figure 2).
À
The direct experimental evidence for Cl binding of the
macrocycle in the gas phase is obtained from the HRMS
(
ESI-MS, Àve mode) study. HRMS study with isotropic
2.6 | FT-IR study
distribution pattern confirms the 1:1 binding of the macro-
À
cyclic host with Cl in negative (Àve) mode (Figure 2).
The characteristic stretching frequency of the N─H
bond of the bis-urea macrocycle 6 is observed at
À
The neutral bis-urea macrocyclic host captures the Cl ion

4
PAUL ET AL.
got separated on addition of TBACl. The two NH group
9
8
7
6
0
0
0
0
has shifted to downfield from 5.99 ppm to almost
À
6
.20 ppm in the presence of Cl . DMSO-d does not sol-
6
À
vate Cl well, however, strongly interacts with the mac-
rocyclic urea N─Hs through hydrogen bond. Cl
À
binding to these urea N─Hs, therefore, requires dis-
placement (at least partial) of DMSO-d molecules. The
6
Job's Plot indicates 1:1 binding stoichiometry between
T
À
1
00
the macrocycle and Cl (Figure 4(B), Table S3,
Figure S14) which is also in good agreement with the
1
7
5
2
5
0
HRMS data. Moreover, no significant H NMR chemical
shift changes of bis-urea macrocycle are perceived in
presence of excess of Br and I ions which indicates
selectivity of Cl among the other halide anions. It
could be attributed that the hydrogen-bonding interac-
tions of neutral macrocycle to Cl is stronger than those
to Br and I . Moreover, size of spherical Cl is smaller
À
À
À
5
4
À
000
3000
2000
1000
À
À
À
-1
Wavenumber / cm
À
À
than those to Br and I .
FIGURE 3 FT-IR spectra of the host bis-urea macrocycle
(
blue) and bis-urea macrocycleÁClÀ (red) host–guest complex
2.8 | Theoretical calculation
À1
3
408 cm . This macrocycle shows a broad IR absorp-
Theoretical calculation is used to determine the binding
energy. Gaussian-09 program is applied to optimize the
structure of the macrocycle using B3LYP functional and
6-31+G** basis set. The density functional theory (DFT)
optimized structure of the macrocyclic host (Figure S15)
À
tion for N─H stretching in the presence of Cl
Figure 3). This indicates host–guest complexation
through hydrogen bonding interaction between the urea
(
À
NH and Cl .
adopted C1 symmetry with the energy value E1
=
À1374.4206 a.u. Electrostatic potential (ESP) map of this
optimized structure indicates the electron-deficient
regions of the macrocycle where the anion can be bound
(Figure S15). We have also optimized the structure of
the host–guest complex using the same program and
same basis set. B3LYP/6-31+G** energy minimization
shows that all the urea N-Hs of the macrocycle point
2
.7 | NMR titration
1
H NMR titration is performed to find the interaction
between the bis-urea macrocyclic host and the anionic
À
guest Cl . Commercially available solid tetrabutyl ammo-
nium chloride (TBACl) is used as the source of Cl . For
the experiment, initially a stock solution of the mac-
rocycle and a stock solution of the guest (TBACl) are pre-
pared in polar aprotic DMSO-d solvent. Then ten NMR
samples are prepared separately by varying the amount
of TBACl from very lower to extremely higher; however,
the concentration of the macrocycle and total solvent vol-
ume remains constant. The experiment was performed at
room temperature. In case of bis-urea macrocycle, the
chemical shift values of urea NH appeared at δ 5.99 ppm
signifying the absence of intramolecular NHÁÁÁO═C
hydrogen bonding. The ─NH protons shifted gradually
toward downfield region with the increasing concentra-
tion of the guest (Figure 4(A), Figures S12 and S13). This
downfield shift indicates the hydrogen bonding interac-
À
À
toward the Cl and serve as an extremely preorganized
À
À
receptor able to bind Cl through four N─HÁÁÁCl
À
hydrogen bonds with N─HÁÁÁCl distances of 2.40 Å and
6
À
2.54 Å (Table 1, Figure 5). In the macrocycleÁCl (1:1)
host–guest complex, urea groups adopt trans–trans con-
formations as expected thermodynamically unlike the
À
macrocycle. Moreover, in macrocycleÁCl (1:1) complex
the urea groups are oriented almost perpendicular to
the plane of the macrocycle and urea carbonyl groups
pointing in the same directions to each other. The
energy value E = À1835.1522 a.u is obtained from the
2
DFT energy optimized structure of the host–guest com-
plex. The ESP map of the host–guest complex is
depicted in Figure S16. From this theoretical calcula-
tion, the binding energy is calculated to ΔE =
À460.7316 a.u. (ΔE = E À E ). Here the highly nega-
À
tion between the ─NH groups of host and Cl guest. Ini-
tially, the two types of ─NH protons, which are merged
together and appeared as a broad coagulated signal at
2
1
À
tive value of ΔE confirms the association of the Cl
5
.99 ppm in the NMR spectrum of the macrocyclic host,
with the macrocycle.

PAUL ET AL.
5
1
FIGURE 4 (A) Partial H NMR
stacking spectra (300 MHz, DMSO-d
6
,
2
98 K) of macrocycle titrated with
6
TBACl in DMSO-d solution. (B) Job's
plot supports the 1: 1 binding
stoichiometry between the host bis-urea
À
macrocycle and guest Cl
TABLE 1 Hydrogen bond
D-HÁÁÁA
N(4)-H (5)ÁÁÁCl (56)
N(6)-H(57)ÁÁÁCl (56)
N(3)-H(55)ÁÁÁCl (56)
HÁÁÁA (Å)
DÁÁÁA (Å)
3.5
D-HÁÁÁA (deg)
À
parameters of bis-urea macrocycleÁCl
À
2.5
2.4
2.5
2.4
157
157
157
157
(
1:1) host–guest complex
À
3.4
À
3.5
À
N(7)-H (8)ÁÁÁCl (56)
3.4
FIGURE 5 B3LYP/6-31
G** energy minimized
+
structure of the bis-urea
macrocycleÁClÀ (1:1). (A) Ball
and stick model. (B) Capped
stick model
3
| CONCLUSIONS
DATA AVAILABILITY STATEMENT
The data that supports the findings of this study are avail-
able in the supplementary material of this article.
In summary, we report the design, synthesis, and self-
assembly of an unsymmetrical bis-urea macrocycle recep-
tor and its structure is determined by single-crystal X-ray
ORCID
À
diffraction. This macrocycle can bind Cl anion and neu-
Samit Guha https://orcid.org/0000-0001-6643-9882
tral DMF molecule through noncovalent interactions.
Developments of synthetic neutral macrocyclic receptor
that imitate the job of natural protein carriers have thera-
peutic potential. Chloride binding and transportation
have potential future application in the treatment of both
cystic fibrosis and cancer.
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ACKNOWLEDGMENTS
This work is supported by grants from the DST-SERB,
Govt. of India (file no. ECR/2017/001405).

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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
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How to cite this article: B. Paul, A. Mukherjee,
D. Bhuyan, S. Guha, J Heterocyclic Chem 2021, 1.
https://doi.org/10.1002/jhet.4329