A novel C3v-symmetric molecular clip with tris(diamide) recognition sites on trindane platform for H2PO4? recognition

Article abstract of DOI:10.1016/j.tetlet.2018.03.055

To avoid the deprotonation events occurred in the receptor upon recognition of basic anions, a novel C_3v-symmetric anion receptor 2 with two amide groups appended in each arm was designed and synthesized by using the trindane tricarboxylic acid as tripodal molecular framework. The anion recognition ability by 2 was examined by ¹H NMR titration study in DMSO-d₆, which revealed that the addition of H₂PO₄^? guests caused substantial downfield shifts of the amide-NH protons peaks due to the formation of a host-guest complex in 1:1 binding stoichiometry with the estimated binding constant (K_a) of 244 M^?1. No noticeable binding of 2 was observed with other tested anions such as F^?, Cl^?, Br^?, I^?, NO₃^? and HSO₄^? under similar conditions.

Full text of DOI:10.1016/j.tetlet.2018.03.055

Accepted Manuscript
A novel C 3v-symmetric molecular clip with tris(diamide) recognition sites
−
on trindaneplatform for H2PO4 recognition
Gi-Dong Kim, Shilpa Bothra, Suban K Sahoo, Heung-Jin Choi
PII:
S0040-4039(18)30369-1
https://doi.org/10.1016/j.tetlet.2018.03.055
TETL 49824
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
14 February 2018
19 March 2018
Please cite this article as: Kim, G-D., Bothra, S., Sahoo, S.K., Choi, H-J., A novel C 3v-symmetric molecular clip
with tris(diamide) recognition siteson trindaneplatform for H2PO4 − recognition, Tetrahedron Letters (2018),
doi: https://doi.org/10.1016/j.tetlet.2018.03.055
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A novel C3v-symmetric molecular clip with tris(diamide) recognition sites on trindane
−
platform for H2PO4 recognition
Gi-Dong Kima, Shilpa Bothrab, Suban K Sahoob and Heung-Jin Choia,*
a Department of Applied Chemistry, Kyungpook National University, Daegu, 41566, Korea.
b
Department of Applied Chemistry, SV National Institute of Technology, Surat-395007,
Gujarat, India.
Abstract
To avoid the deprotonation events occurred in the receptor upon recognition of basic
anions, a novel C3v-symmetric anion receptor 2 with two amide groups appended in each arm
was designed and synthesized by using the trindane tricarboxylic acid as tripodal molecular
1
framework. The anion recognition ability by 2 was examined by H NMR titration study in
−
DMSO-d6, which revealed that the addition of H2PO4 guests caused substantial downfield
shifts of the amide-NH protons peaks due to the formation of a host-guest complex in 1:1
binding stoichiometry with the estimated binding constant (Ka) of 244 M-1. No noticeable
−
−
binding of 2 was observed with other tested anions such as F−, Cl−, Br−, I−, NO3 and HSO4
under similar conditions.
−
Keywords: C3v symmetric anion receptor; Trindane; H2PO4 recognition; 1H NMR.
*Corresponding author: Tel.: +82 (53) 950 5582; fax: +82 (53) 950 6594; e-mail address:
choihj@knu.ac.kr (H.-J. Choi).
1

Anions are ubiquitous and well known to play important roles in a wide array of
chemical, biological and environmental processes [1,2]. Among the various bioactive anions,
the phosphates are the most important anions due to their key roles in various information
processing, energy storage, and signal transduction [3]. It is a component of adenosine
triphosphate (ATP), a fundamental energy source in living things and is deeply involved in
DNA duplication and transcription [4]. Phosphate ions are widely employed in the fertilizers
which is considered as the main nutrients of plants and animals [5,6]. Excessive level of
phosphate ions causes detrimental effect to the environment and can lead to eutrophication
causing disruption of aquatic life cycles [7,8]. Hence, the detection and recognition of
phosphate ions concentration in the soil and aqueous samples are of great significance for the
controlling and guarding against the eutrophication and human disease occurrence [9]. Also,
determining phosphate ions concentrations in body fluids can help to diagnose various health
problems such as hyperparathyroidism, vitamin D deficiency and Fanconi syndrome [5].
The advancement of the host-guest chemistry in the recent few decades led to the
development of numerous molecular receptors for the selective recognition and sensing of
target anionic guest. Most of the reported neutral receptors possess groups like amide, urea,
thiourea, imidazole, indole, amine, pyrrole and sulphonamide moieties with hydrogen bond
donor functionalities whereas the cationic receptors are derived from ammonium, guanidium,
quinolinium, phosphonium protonated quinoxaline salts, with electrostatic interaction
between the anionic guest and cationic receptors [10,11]. However, the factors like high
hydration energy and versatile geometry of anions have created several challenges to develop
suitable receptor for the selective recognition of target anion. For example, the recognition of
hydrogen phosphate may be interfered with the most basic anions like fluoride which can
deprotonate the hydrogen bond donor functionalities of the receptor. Therefore, there is a
search of new receptor which can selectively recognize the bioactive hydrogen phosphate
2

anion without any interference from the other anions. In designing new receptor for hydrogen
phosphate, efforts are made to develop multi-dimensional molecular scaffolds possessing
adequate flexibility and preorganized structure with a suitable cavity to accommodate the
tetrahedral shaped anion through multiple hydrogen binding sites. Various multifunctional
anion receptors with linear, dipodal and tripodal structures are reported for the selective
recognition of hydrogen phosphate. Among the various multi-dimensional molecular
scaffolds, much emphasis have been given to develop preorganized C3v symmetric tripodal
receptors with multiple binding sites, increase binding dimension because the tripodal
conformation has the ability to form spheroidal cavity to encapsulate anions of perfect fitting
[12,13].
−
Our group have demonstrated various C3v-symmetric anionic receptor for H2PO4
containing urea/thiourea group at each lower feet of trindane framework that shows a
moderate binding affinity toward an anionic guest and also deprotonated upon excess
addition of fluoride anion [14-17]. Continuing our research in the development of the
structurally modified anion receptor based on C3v-symmetric trindane framework with a
preorganized anion binding cavity, herein, a new tripodal anion receptor 2 possessing
tris(diamide) recognition sites on trindane platform was synthesized (Scheme 1) and its anion
recognition ability was examined by 1H NMR in DMSO-d6.
Scheme 1. Synthesis of the C3v-symmetric anion receptor 2.
3

The C3v trindane-tricarboxylic acid 1, cis,cis,cis-2,5,8-tribenzyltrindane-2,5,8-tricarboxylic
acid was prepared by following our reported method, hydrolyzing trindane tricarboxylate
ester. [14, 17, 19] The known diamide podal moiety, 2-amino-N-phenylacetamide is prepared
from readily available compounds. Boc-Gly-OH and aniline was coupled via activation of
carboxylic acid with N,N'-carbonyldiimidazole (CDI) in DMA to yield Boc-2-amino-N-
phenylacetate, which was treated with trifluoroacetic acid to deprotect Boc group to give 2-
amino-N-phenylacetamide in high yield. [SI]
The tripodal receptor 2 possessing three diamide-podants on trindane platform was
synthesized first by treating with CDI to form the active intermediate acylimidazole, which
then react with the amine nucleophile, 2-amino-N-phenylacetamide at 70 ºC for 48 hours. To
complete the reaction on the threefold multi-reaction sites, the reaction condition was
optimized for reaction period, temperature and dryness of solvent and reagents. The carbonyl
activating reagent CDI was chosen because of sterically small imidazole moiety and easy
removal of imidazole byproduct from the amide bond formation. In optimizing process other
polar and bulky active ester intermediates from carbodiimide type reagents hindered to block
the second and third attacks of the amine nucleophiles by intramolecular hydrogen bonding
interaction. It was apparent that the reaction condition require unusually high temperature to
overcome the interaction between carbonyl activating intermediate and the amine nucleophile
with bulky and polar functional groups. The moderate yield of the receptor 2 was still due to
laborious separation from the mono- and di-substituted incomplete products which have
similar structure and chemical properties. The 1H NMR spectrum 2 revealed the
disappearance of –COOH protons peak of 1 at  12.47 and the appearance of two amide
protons peaks at δ 9.95 and δ 8.23 ppm. Also, the C3v-symmetry conformation of the trindane
derivative 2 was confirmed from the two sets of doublets at δ 3.08 and 2.78 ppm with the
4

coupling constant of 2J = 15.5 Hz assigned for the two diastereotopic benzylic protons and a
singlet for the methylene groups of benzyl groups at 2.96 ppm. In 13C NMR, the peaks for the
two carbonyl groups present in 2 were observed at δ 175.8 and 167.9 ppm. These results
along with the mass data confirmed the formation of tris(diamide) based anion receptor 2.
The possible 3D structure of the receptor 2 was proposed through the DFT calculations in the
gas phase by using the B3LYP/6-31* method. As shown in Figure 1, the three appended arms
of 2 are interconnected by multiple intrastand hydrogen bonding which provides a C3v-
symmetry structure and also not appreciable conformation adjustment is required in 2 to
accommodate the perfect fit anions. The molecular electrostatic map (MEP) of 2 reveals that
the most positive region located in blue color was observed over the amide protons, which are
expected to encapsulate the perfect fit anion by forming the hydrogen bonds.
Figure 1. DFT computed structure of the receptor 2: (a) tube model showing the intrastand
hydrogen bonding (Å), (b) space filling model showing the compactness of the three
appended arms, and (c) molecular electrostatic map (MEP).
The anion recognition ability of the tris(diamide) receptor 2 (4 mM) was investigated
1
by the H NMR method by adding ten equivalents of various n-tetrabutylammonium (TBA)
−
−
anions (TBAX, where X = F−, Cl−, Br−, I−, NO3− , HSO4 and H2PO4 ) in DMSO-d6. As
shown in Figure 2, there is no noticeable shift in the 1H NMR spectrum of 2 was observed in
−
−
the presence of anions such as F−, Cl−, Br−, I−, NO3 and HSO4 due to the very weak interaction
5

with the receptor 2. However, the amide protons peaks of 2 at δ 9.95 and δ 8.23 ppm were
broadened and shifted to downfield region respectively to δ 10.91 and δ 9.13 ppm in the
−
presence of H2PO4 anion. Also, a slight downfield shift of the peak at δ 7.59 ppm of the
aromatic protons closer to the amide groups was observed. The selective affinity of 2 towards
−
H2PO4 anion may be attributed to the tetrahedral geometry that fitted well within the tripodal
cavity created by the tris(diamide) arms. Also, the downfield shift of the amide protons peaks
−
of 2 indicate the formation of a host-guest complex with the H2PO4 anion among the other
tested anions through multiple hydrogen bonding interactions.
1
Figure 2. Partial H NMR spectral changes of a DMSO-d6 solution of 2 (4 mM) upon
addition of ten equivalents of different anions.
1
The H NMR titration of 2 (4 mM) was performed by successive addition of
incremental addition of n-tetrabutylammonium dihydrogen phosphate (TBA∙H2PO4) in
DMSO-d6 (Figure 3a). Similar titrations were also performed with some non-selective anions
to check the changes in the tris(diamide) protons peaks with the successive increasing
6

-
-
concentrations of the anions like F-, HSO4 , Br- and NO3 (Fig. 3b). The results shown in
−
Figure 3 indicate that upon addition of H2PO4 to 2 solution resulted in a significant
downfield shift for both amide-NH peaks without any appreciable shift in the other protons
peaks. It may be expected that the receptor 2 retained the C3v symmetry and the interactions
−
of amide-NH groups of the receptor with H2PO4 in solution formed the host-guest complex.
The complexation-induced shift of the amide-NH NMR signals were fitted by using a
nonlinear least squares regression program WinEQNMR [18], which gave the best fit for a
1:1 binding model with the estimated binding constant (Ka) of 244 M-1.
1
Figure 3a. Partial H NMR spectral changes of a DMSO-d6 solution of 2 (4 mM) upon
addition of TBA∙H2PO4.
7

Figure 3b. NMR titration curves of tris(diamide) receptor 2 with TBA salts of anionic guests
o
in DMSO-d6 at 25 C ([H]o = 4.0 mM, [G]o = 40.0 mM; axis: CIS of the amide proton). (,
-
-
-
H2PO4 ; , F-; , HSO4 ; , Br-; , NO3 ).
−
Based on the experimental evidences, the interactions of 2 with H2PO4 was further
evaluated by density functional theory (DFT) calculations. The different 3D views of the
−
optimized structure of the 2∙H2PO4 complex are shown in Figure 4. The estimated binding
−
energy for H2PO4 was 21.29 kcal/mol to form the host-guest complex, where the host
−
arrange its three appended arm to a perfect C3v symmetry in order to encapsulate the H2PO4
−
anion. As shown in Figure 4a, the H2PO4 anion is wrapped within the tripodal cavity of 2 via
six NH⋯O hydrogen bonds (1.799–2.154 Å). Three of the four oxygen atoms present in
−
H2PO4 anion are held by the six amide-NH groups present in the receptor 2. The MEP
−
−
calculation of 2∙H2PO4 complex revealed an internal change transfer between the H2PO4
anion and the receptor 2, which resulted in the decrease in receptor 2 band gap (ΔE = ELUMO
-
8

−
EHOMO) from 6.71 eV to 4.79 eV upon formation of 2∙H2PO4 complex.
−
Figure 4. DFT computed structure of 2∙H2PO4 complex: (a) tube model showing the
−
hydrogen bonding (Å) between 2 and H2PO4 , (b) space filling model showing the
−
compactness during the encapsulation of H2PO4 by the three appended arms, and (c) the
molecular electrostatic map (MEP).
In conclusion, a new C3v symmetrical anion receptor 2 was synthesized from the
trindane tripodal platform possessing six amide-NH groups to recognize the anionic guests.
This tris(diamide) receptor 2 is structurally analogous to the numerous anion receptors
reported with the urea/thiourea recognition unit, but the inherent selectivity towards the
−
bioactive H2PO4 anion and silent towards the other oxo-anions and basic halides makes the
receptor 2 unique. The flexibility of the tris(diamide) arms in 2 provides a perfect tripodal
−
cavity to encapsulate the H2PO4 anion via six NH⋯O hydrogen bonds. The present research
outcomes will accelerate many more research on developing new multi-dimensional anion
receptors by using the tris(diamide) arms in different tripodal platform with varying
−
flexibility. Also, the selective recognition of 2 towards H2PO4 anion will gives new direction
−
for the designing of optically active receptors to detect H2PO4 anion, and to study its
extraction and transport properties.
9

Acknowledgements
This research was supported by Basic Science Research Program through the
National Research Foundation of Korea (NRF) funded by the Ministry of Education
(NRF-2017R1D1A1B03032108).
Supplementary data
Supplementary data associated with this article can be found, in the online version,
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11

Graphical Abstract
12

Highlights
 A novel tripodal C3v-symmetric anion receptor 2 with two amide groups appended in
each arm of trindane tricarboxylic acid was synthesized.
 The anion recognition ability by 2 was examined by 1H NMR in DMSO-d6.
−
 Addition of H2PO4 guests caused substantial downfield shifts of the amide-NH
protons peaks of 2.
−
 Receptor 2 formed a host-guest complex with H2PO4 in 1:1 binding stoichiometry
with the estimated binding constant (Ka) of 244 M-1 in DMSO-d6.
13