Design and synthesis of two armed molecular receptor for recognition of Gd3+ metal ion and its computational study

Article abstract of DOI:10.1002/aoc.4502

New receptor Phenylene-Bis-Methylfuran-yl-2-Methyele Acetohydrazide (PBMMA) has been synthesized by condensation of hydrazide and 5-methyl furfural. Synthesized receptor has been fully characterized by IR, ¹H NMR, ¹³C NMR, mass spect

Full text of DOI:10.1002/aoc.4502

Received: 13 March 2018
DOI: 10.1002/aoc.4502
Revised: 17 May 2018
Accepted: 12 June 2018
F U L L P A P E R
Design and synthesis of two armed molecular receptor for
3
+
recognition of Gd metal ion and its computational study
1
2
3
1
1
Brij Mohan
| Krunal Modi
| Chirag Patel | Pankaj Bhatia | Ashwani Kumar |
1
Harish Kumar Sharma
1
Department of Chemistry, Kurukshetra
New receptor Phenylene‐Bis‐Methylfuran‐yl‐2‐Methyele Acetohydrazide
(PBMMA) has been synthesized by condensation of hydrazide and 5‐methyl
University, Kurukshetra 136119, India
2
J. Heyrovsky Institute of physical
Chemistry, Academy of Sciences of the
1
furfural. Synthesized receptor has been fully characterized by IR, H NMR,
Czech Republic, Dolejškova 2155/3, 182
1
3
C NMR, mass spectroscopic and thermo gravimetric analysis. The receptor
23 Prague 8, Czech Republic
3+
3
PBMMA shows selective recognition potential towards Gd ion when tested
Department of Botany, Bioinformatics
+
+
2+
2+
2+
2+
3+
3+
and Climate Change Impacts
Management, University School of
Sciences, Gujarat University, Ahmedabad,
Gujarat 380009, India
with several metal ions such as Na , K , Mg , Cu , Cd , Hg , Y , La ,
3+
3+
3+
6+
4+
Eu , Sm , Gd , Re and Th ion as their sulfates by UV–visible and fluo-
3+
rescence spectroscopic studies. Binding nature of PBMMA with Gd ion was
further studied by mass spectroscopic and cyclic voltammetric studies. The
Correspondence
Brij Mohan, Department of Chemistry,
Kurukshetra University Kurukshetra‐
3+
stoichiometry of PBMMA‐Gd ion has been established, 1:1 by Benesi‐
Hildebrand plot method and method of continuous variation (Job's plot) with
136119, India.
4
−1
association affinity K = 6.491 × 10 M . In addition to these, molecular
docking, molecular dynamic stimulation and binding energy of complex;
through Density Function theory −595.66 kcal/mol has also indication of
strong binding. The electron transfer energy of Higher occupied molecular
orbital (HOMO) to Lower unoccupied molecular orbital (LUMO) is about
Email: brizharry17@gmail.com
Funding information
University Grants Commission, New
Delhi, India, Grant/Award Number: Sch./
S‐I/14/1179; Grant Agency of the Czech
Republic, GAČR, Grant/Award Number:
3+
4.186 eV and 295 nm for PBMMA‐Gd Complex.
17‐18108S
KEYWORDS
DFT, fluorescence, mass spectroscopy, receptor, UV–visible
1
| INTRODUCTION
structures have been synthesised for metal ions by using
supramolecular interactions.
[
14,15]
In recent years, development of multifunctional recep-
Metals specially lanthanides are found to have impor-
tant role in the field of medical and biochemical
[1]
tors or sensors is growing area of research due to their
potential applications in sensing, separation, catalysis,
[
16]
science.
Gadolinium is found to be used as contrast
[
2–4]
[17]
function of enzyme and ion channels etc.
Receptors
agent in Magnetic Resonance Imaging (MRI).
Gado-
[5]
with two arms or multi arms are expected to play role
linium in form of intravenous injection is utilized to
enable sensitive identification of a number of pathologies
such as vascular abnormalities, cardiac infarcts and
[6,7]
as novel sensing platforms
due to their better chelat-
ing opportunities through apparent convergence of func-
tionalities that can wrap the target toxicant, metal ions
[
18,19]
tumors.
The use of metal ligand complexes espe-
[8–13]
and molecules.
Now a days, receptors with different
cially chelates in medicine is a developing field in novel
Appl Organometal Chem. 2018;e4502.
wileyonlinelibrary.com/journal/aoc
© 2018 John Wiley & Sons, Ltd.
1 of 11
https://doi.org/10.1002/aoc.4502

2
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MOHAN ET AL.
therapeutic and in treatment of many diseases, also two
armed molecular receptors with electron rich sites are
found to coordinate with metal ions.
in the electrospray ionization (ESI) modes. The reference
values for the residual solvent were taken as δ = 2.601
[20–22]
1
(DMSO‐d ) for H‐NMR and δ = 77.1 (CDCl ), δ = 40
6
3
13
Vital role of gadolinium complexes in medical chem-
istry has motivated researchers for the development of
(DMSO‐d ) for C‐NMR. The abbreviations: s = singlet,
6
d = doublet, m = multiplets were used for multiplicities
of coupled signals given in hertz. Electronic spectra of
receptor and metal ions with receptor were recorded on
T 90 (PG Instruments Ltd) UV/Vis spectrometer in the
region 700–200 nm CH OH:H O in 1:1 as solvent system
[23–27]
new gadolinium specific receptors.
Furfural based
organic compounds are found to interact with gadolin-
[28]
ium metal ion.
The utilization of such type of organic
framework as hosts is key to design highly sensitive and
selective receptor for gadolinium ion.
3
2
and emission spectra were recorded on Shimadzu‐5301pc
Herein, we synthesized a two armed receptor with
good thermal stability and also that selectively binds with
gadolinium ions among various metal ions in solvent sys-
tem. The synthesized receptor PBMMA shows good
absorption and emission spectra in methanol–water
solvent system and spectra changes upon addition of
gadolinium metal ions only among a series of metal ions
used as sulfate salts. The receptor is found to be a good
photo sensor for gadolinium. The cyclic voltammetric
studies introduce the reversible binding of PBMMA‐
spectrofluorophotometer in CH OH:H O in 1:1 as solvent
3
2
system. Cyclic voltammetry measurements were recorded
on Ivium Stat Electrochemical Analyzer by using KCl as
supporting electrolyte.
2.3 | Synthesis of receptor
Compound 1 i.e. (diethyl 2,2′‐(1,3‐phenylenebis (oxy))
diacetate) was synthesized with slightly modification in
[
15]
the reported process
by refluxing the mixture of resor-
3+
Gd . Computational studies of PBMMA and PBMMA‐
cinol (0.0182 mol), ethyl bromoacetate (0.0363 mol) and
K CO (0.1097 mol) as catalyst in anhydrous acetonitrile
3+
Gd ion gives a valuable information about the results
of main singlet vertical electron transition energies (ΔE),
wavelengths (λ), oscillator Strengths (f), and % contribu-
tion calculated at the TDDFT/CAMB3LYP level. Molecu-
2
3
for 24 hrs. Compound 2 i.e. (2,2′‐(1,3‐phenylenebis
(oxy))di (acetohydrazide)) was synthesized with a
[
15]
slightly change in reported process ; to a solution of
compound 1 0.658 g (2.63 mmol) in methanol, hydrated
hydrazine 0.920 g (18.4 mmol, 99%) was added and the
reaction mixture was stirred at room temperature for
10 hrs.
3+
lar docked structure defined the binding mode of Gd
with PBMMA. More interestingly the results obtained
out from computational studies are similar to the observed
experimental results of UV/Vis studies.
2
2
| EXPERIMENTAL
2.3.1 | Synthesis of receptor 2,2′‐(1,3‐
phenylenebis (oxy))bis (N′‐((E)‐(5‐
methylfuran‐2‐yl)methylene)
.1 | Chemicals and reagents
acetohydrazide) (Phenylene‐Bis‐
Methylfuran‐yl‐2‐Methyele Acetohydrazide
All HPLC grade reagents and solvents were used without
further purification during synthesis and evaluation of
receptor. Thin‐layer chromatography was performed
using silica‐aluminium plates and the plates were visual-
ized using ultraviolet light both long range and short
range.
(PBMMA)
0.278 g (1.04 mmol) of hydrazide 2 and 0.229 g (2.1 mmol)
of 5‐methyl furfural and 2–3 drops of glacial acetic acid as
catalyst was refluxed in ethanol for 30 hrs (Scheme 1).
The reaction progress was noticed with the help of thin
layer chromatography in petroleum‐ether:ethyl‐acetate
solvent system. The contents were cooled at room tem-
perature to obtain precipitates, which was filtered and
washed with cold ethanol to yield PBMMA a light yellow
solid; Yield: 60%. The melting point was observed by
open capillary instrument and found to be uncorrected.
2
.2 | Instruments
All glassware was dried in an oven for 12 hrs before use.
Open capillaries were used to determine melting point
and are thus found uncorrected. Thermal Gravity Analy-
sis was observed at Perkin Elmer TGA 4000 by heating at
the rate of 5 °C per minute. IR spectra were recorded on
ABB MB 3000 IR Spectrophotometer. NMR data were
recorded on a Bruker AV (III)‐400 MHz. All samples were
analyzed in CDCl /DMSO‐d . Mass spectra were recorded
−
1
Melting point: 220–225 °C. IR (υ = cm ): 3256 (NH
stretching), 2885 (CH stretching), 2824 (CH strectching),
1759 (C=O stretching), 1643 (C=N stretching), 1605; H
1
NMR (Figure S1) (400 MHz, DMSO‐d ): δ (ppm) 11.356
3
6
6
on a Xevo G2‐S Q‐Tof spectrometer (Waters, USA), capa-
ble of recording high‐resolution mass spectrum (HRMS)
(s, 0.6H, NH), 11.017 (s, 0.40H, NH), 8.418 (s, 0.64H,
CH=N), 8.208 (s, 0.39H, CH=N), 7.760 (d, 0.49H, furan),

MOHAN ET AL.
3 of 11
SCHEME 1 (i) K
refluxed 24 hours (ii) NH
2
CO
3
/acetonitrile/
NH .H O/
2
2
2
methanol/stirred 10 hrs (iii) 5‐methyl
furfural/acetic acid glacial/ethanol/
refluxed 30 hrs
7
6
0
1
2
.645 (d, 0.82H, furan), 7.211–7.168 (m, 0.97H, Ar‐H),
.824 (t, 0.80H, Ar‐H), 6.672 (t, 0.58H, Ar‐H), 6.561 (m,
.72H), 6.520 (m, 0.54H), 6.203 (s, 0.84H), 6.106 (s,
.03H), 4.588 (s, 1.21H, COCH ), 4.562 (s, 0.92H, COCH ),
were same and the emission spectra were recorded on
Shimadzu‐5301pc spectrofluorophotometer.
2
2
13
.424 (s, 2.89H, ‐CH ), 2.380 (s, 3.42H, ‐CH ); C NMR
3
3
2.5 | Computational methodology
(Figure S2) (75 MHz, CDCl3): δ (ppm) 149.87, 147.50,
1
1
34.57, 129.75, 118.77, 115.44, 114.67, 108.91, 108.12,
01.85, 67.21, 64.80, 13.71. Mass spectroscopy is found to
2.5.1 | Molecular docking
The binding potency of chosen guest with appropriate
host can be decipher by molecular docking approach.
Geometry optimized three dimensional structure of both
be in good agreement with the proposed structures of
receptor PBMMA; MS‐ESI‐TOF (m/z) (Figure S3)
+
[
M + Na ] (m/z) 461.1422.
3+
host (PBMMA) and guest (Gd ) pertained to figure
out the best binding pose and binding energy in Hex
[
29]
8.0.0 software.
The Accelrys Discovery Studio visual-
2
.4 | General procedure for the detection
izer version 16 was employed to measure various interac-
tions found between host‐guest docking which reveals the
potency of binding formation.
of cations by spectrophotometry
Stock solutions of 5‐methyl furfural derivative tweezer
PBMMA (17 μM) and the sulfate salts (17 μM) of various
metal ions (Na , K , Mg , Cu , Cd , Hg , Y , La ,
Eu , Sm , Gd , Re and Th ) were prepared in
CH OH:H O (1:1 v/v) solvent system. In a 5 ml volumet-
+
+
2+
2+
2+
2+
3+
3+
3+
3+
3+
6+
4+
2.5.2 | Molecular dynamics simulation
3
2
ric flask, 2.5 ml of the solution PBMMA and 2.5 ml of
metal salt stock solutions were combined so that the
effective concentrations of both PBMMA and metal ions
were same. Absorption studies were performed using
the as prepared solutions. A Benesi‐Hildebrand plot
Molecular dynamics simulation was performed based on
identical simulation protocol of Desmond v3.6 package
to model the different states of host‐guest (PBMMA‐
3+
Gd ) complex for 10 ns time trajectory with 1 ns integra-
[
30]
tion step.
Optimized Potentials for Liquid Simulations
(
Figure 6) and Job's plot (Figure 7) were obtained based
(OPLS) all‐atom force field 2005 was applied for the cubic
periodic box containing Simple Point Charge (SPC)
(10 Å × 10 Å × 10 Å). This box also contains the van
der Waals interactions computation cut off based on cou-
lomb electrostatics distance which was 7.86, while other
parameters were extensively computed by temperature
at 298 K, pressure at 1 bar, pH 7.0, 0.9% NaCl, solvent
on the absorption studies to establish the stoichiometry
and association affinity of receptor‐metal. Mass analysis
(Figure S4) was also characterized to know binding of
3+
Gd with PBMMA.
For fluorescence study of PBMMA (3 × 10 M) with
metal ions (3 × 10 M), a stock solution of the receptor
−
4
−
4
[
31]
PBMMA and metal sulfates were prepared in CH OH:
density 0.997, pH 7.0, periodic boundaries.
Methanol
3
H O (1:1 v/v) solvent system. In a 5 ml volumetric flask,
was chosen as solvent to equilibrate the host‐guest com-
plex with NPT ensemble system. In this event, various
interactions were optimized to gauge the structural stabi-
2
2
.5 ml of the solution PBMMA and 2.5 ml of metal salts
stock solutions were combined so that the effective
3+
[31]
concentrations of both PBMMA and Gd metal ion
lization and conformational change feasibility.

4
of 11
MOHAN ET AL.
2.5.3 | DFT calculations
3.1 | Thermal studies
[
33]
The Theoretical calculations were performed at density
functional level of theory (DFT) using Becke's three‐
parameter hybrid exchange (B3LYP) in Gaussian 09
Thermal study
of PBMMA was analyzed in nitrogen
environment (Figure 1). Thermo gravimetric analysis
(TGA) data (Figure S5 and Figure S6) for all the samples
were obtained in the standard form of % weight loss as
[32]
(G09) software package.
In the calculation, the 6‐
−
1
3
1G(d,p) basis set was assigned to all elements with
function of temperature at heating rate 5 °C min is
shown in Figures 1. There was no weight loss was
observed up to 120 °C. The major weight loss observed
was found in two stages. In stage first, major weight loss
of 57.76% (calc. 56.20%) occurred in the temperature
range 120–311 °C. This weight loss was due to the decom-
position of methyl furfural hydrazine moiety. In second
stage weight loss of 38.36% (calc. 43.80%) was occurred
in between the temperature range 311–790 °C at a con-
stant rate due to loss of benzene, carbonyl and other part
of the compound. At the temperature 790 °C the remain-
ing yield of the PBMMA was found 3.88%.
the exception of gadolinium, for which MWB53 basis
set was employed. The geometric structures of the com-
plex in the ground state (singlet) were fully optimized at
the B3LYP in both gas and solvent phase methanol
using the conductor‐like polarizable continuum model
(CPCM). Vibration frequency calculations were per-
formed to ensure that the optimized geometries repre-
sent local minima associated with positive eigen values
only. The ligands and metal complexes were demon-
strated using Avogadro version 1.2.0 software. The
single point energy calculations were carried out to
calculate the strength of the complex in the term of
binding energy. The binding energy of the PBMMA
3+
3.2 | UV–visible spectroscopic studies
_
Gd complex was calculated by energies as mentioned
as in equation (1).
UV–visible spectroscopic studies provide a vital evidence
for absorption behaviour of the receptor and receptor‐
cation complexes. Sensitivity and selectivity of the synthe-
sized receptor can be evaluated by observing changes in
their UV–visible spectra of receptor by evaluating with
different metal ions in CH OH:H O (1:1) solvent system.
BE ¼ EðM−ComplexÞ−ðEL þ EMÞ
(1)
3
2
Where, (
is the energy of the metal complex
M‐complex)
3+
(
PBMMA‐Gd ) and E and E are the energies of
L
M
+
3
the PBMMA and Metal ion Gd , respectively.
Time dependent‐Density functional Theory (TD‐DFT)
level of calculation was also performed for absorption
spectra calculation. The effect of solvent (Methanol) was
also monitored for all step using conductor‐like Polariz-
able Continuum Model (CPCM).
3.2.1 | Interaction of cations with receptor
PBMMA by UV–visible studies
1
7 μM solution of receptor PBMMA in CH OH:H O
3 2
gives a very good absorption spectra due to electronic
transactions and absorption maxima was observed at
312 nm with a hump near 358 nm due to n‐π* and
π − π* transition (Figure 2). The cation binding
3
| RESULTS AND DISCUSSIONS
The current section is organized as follows. Thermo
gravimetrical analysis TGA of PBMMA was analyzed.
The metal cation binding nature of PBMMA was deter-
mined by treating various metal ions as their sulfates
with the help of UV–visible and fluorescence spectro-
3+
scopic techniques. PBMMA‐Gd
ion binding was
further studied with the help of mass spectroscopy and
cyclic voltammetric studies. The geometric and energetic
3+
features associated with the binding of PBMMA‐Gd
were discussed by computational studies. Finally, we
found that the results of absorption spectra at TDDFT
level of calculation and experimental UV–visible spectra
changes are almost same for interaction between the
3+
−1
PBMMA and Gd ion.
FIGURE 1 TGA curves of PBMMA at heating rates of 5 °C min

MOHAN ET AL.
5 of 11
+
FIGURE 3 Observed interference study of the metal cations (Na ,
+
2+
2+
2+
2+ 3+
3+
3+
3+
6+
4+
K , Mg , Cu , Cd , Hg , Y , La , Eu , Sm , Re and Th
)
FIGURE 2 UV–visible spectra of receptor PBMMA (17 μM)
3
+
3
+
+
+
2+
2+
2+
2+
3+
3+
3 2
with ions PBMMA + Gd (17 μM; CH OH:H O in 1:1 v/v) as
with metal Gd , Na , K , Mg , Cu , Cd , Hg , Y , La
,
3
+
3+
6+
4+
solvent system at same concentration
3 2
Eu , Sm , Re and Th in CH OH:H O (1:1 v/v) as solvent
system. UV–visible (electronic spectra) of receptor and metal ions
with receptor was recorded on T 90 (PG Instruments Ltd) UV/VIS
spectrometer in the region 700–200 nm
receptors using fluorescence spectroscopy was found to
be important biologically in vitro‐vivo and sensors as
[
37–40]
light‐emitting diodes.
PBMMA has been used for
3+
properties of receptor PBMMA was investigated by eval-
detection of Gd due to metal chelating sites that lead
photo physical properties.
+
+
2+
2+
2+
2+
[41,42]
uating sulfate salts of Na , K , Mg , Cu , Cd , Hg ,
3+
3+
3+
3+
3+
6+
4+
Y , La , Eu , Sm , Gd , Re and Th metal ions
and their UV–visible spectra were recorded. Receptor
3
.3.1 | Interaction of cations with receptor
+
+
2+
PBMMA showed negligible response to Na , K , Mg ,
PBMMA by fluorescence spectral studies
2
+
2+
2+
3+
3+
3+
3+
6+
Cu , Cd , Hg , Y , La , Eu , Sm , Re and
4+
Th metal ions (Figure 2), changes were observed only
Fluorescence spectroscopic studies of PBMMA
(3 × 10 M) with metal ions (3 × 10 M) were carried
out in CH OH:H O (1:1) solvent system (Figure 4). This
emission of PBMMA shows a weak emission spectra
band near 405 nm at excited wavelength 312 nm due to
photoinduced electron transfer (PET) mechanism from
electron denser part (N and O atoms) of receptor to the
acceptor part. Further binding studies of receptor
3
+
3+
−4
−4
with Gd metal ion. On addition of Gd ions, there
was a decrease in the intensity of absorbance at 312 nm
and 358 nm with generation of a new band at 295 nm as
well as hypsochromic shift of 17 nm respectively along
with appearance of an isosbestic point at 301 nm
3
2
(Figure 2). The shifting of λmax toward lower wavelength
could be due to interaction between receptor N, O atoms
electrons with metal ions to form metal ion complexes. It
is evident that 1:1 (receptor:metal) formation of complex
by Benesi‐Hildebrand plot (Figure 6) and method of con-
tinuous variation i.e. Job's plot (Figure 7) with association
[
34,35]
4
−1
3+
affinity
K = 6.491 × 10 M for Gd .
[36]
The effect of different metal
ions with respect to
gadolinium metal ion was also checked at the same con-
centration (Figure 3). The results showed that the pres-
+
+
2+
2+
2+
ence of other metal ions (Na , K , Mg , Cu , Cd ,
2+
3+
3+
3+
3+
6+
4+
3+
Hg , Y , La , Eu , Sm , Re and Th ) with Gd
metal ions had a minimal effect on the absorption spectra
3+
of ions PBMMA + Gd ion.
3
.3 | Fluorescence spectroscopic study
FIGURE 4 Fluorescence emission spectra of receptor PBMMA
−
4
3+
+
+
2+
2+
2+
PBMMA acts as sensors for gadolinium ion, as sensors
are part of modern research areas within the field of
supramolecular chemistry. Detection of ions by molecular
(
3 × 10 M) and with metal Gd , Na , K , Mg , Cu , Cd ,
2
+
3+
3+
3+
3+
6+
4+
−4
Hg , Y , La , Eu , Sm , Re and Th ions (3 × 10 M) in
1:1(v/v) CH OH:H O (1:1 v/v) as solvent system
3
2

6
of 11
MOHAN ET AL.
+
PBMMA were conducted with various metal ions (Na ,
+
2+
2+
2+
2+
3+
3+
3+
3+
K , Mg , Cu , Cd , Hg , Y , La , Eu , Sm ,
3+
6+
4+
Gd , Re and Th ); none of these showed significant
change in fluorescence emission spectra, expect Gd
metal ion. Upon addition of Gd
3+
3
+
ions to receptor
PBMMA, fluorescence enhancement was observed with
two new emission bands near 355 nm and 485 nm were
observed at excited wavelength 312 nm (Figure 4). The
mechanism of fluorescence was attributed to chelation‐
[
43]
enhanced fluorescence mechanism (CHEF).
Due to
3+
chelation of Gd metal ion with receptor PBMMA, pho-
toinduced electron transfer (PET) prevented and chela-
[43,44]
tion‐enhanced fluorescence.
3
+
FIGURE 5 UV–visible spectra of receptor PBMMA (17 μM)
The receptor PBMMA is specific for Gd metal ion
among various metal cations when studied under UV–
visible (Figure 2) and fluorescence spectroscopic studies
3
+
with increasing concentration of Gd ions (0–5 equivalent) in
CH OH:H O (1:1 v/v) as solvent system. UV–visible (electronic
3
2
spectra) of receptor PBMMA and with increasing concentration of
(
Figure 4) in CH OH:H O (1:1) solvent system. The com-
plexation of PBMMA with Gd metal ion suggests that
the complexation is result of the structural rearrange-
ments and chelation binding of Gd and this is also
supported by computational studies (Figure 9). The
3+
3
2
Gd to PBMMA (0–5 equivalent) were recorded on T 90 (PG
3+
Instruments Ltd) UV/VIS spectrometer in the region 700–200 nm
3+
3+
binding feasibility of PBMMA with Gd ion is due size
and charge complementary that leads interaction and
+
+
found less likely with other metal cations (Na , K ,
2
+
2+
2+
2+
3+
3+
3+
3+
3+
Mg , Cu , Cd , Hg , Y , La , Eu , Sm , Gd ,
6+
4+
Re and Th ).
3.4 | Binding stoichiometry
3+
To gain further information of the Gd cation binding
interaction with the receptor, UV–visible spectrophoto-
metric titration studies has been performed. On succes-
3+
sive addition of Gd
(0–5 equivalent) to receptor
PBMMA (17 μM) the band at 312 nm changes with
hypsochromic shift in its intensity with the appearance
of a new band at 295 nm with isobestic point at 301 nm
as shown in Figure 5. The inferred isobestic point in an
evident for the formation of new species in the solution
3
+
FIGURE 6 Benesi‐Hildebrand plot of PBMMA with Gd metal
ion at 312 nm in CH OH:H O (1:1 v/v) as solvent system. Using
Benesi‐Hildebrand method employing 1/(A ‐ A ) = 1/(A ‐ A ) + 1/K
) [Gd ] equation and observed linearity in the plot which
indicated the formation of a 1:1 complex with association affinity
3
2
o
f
3+
(
A ‐ A
f
3+
i.e. there is interaction between PBMMA and Gd ion.
Receptor PBMMA (17 μM) when gradually titrated by
4
−1
K = 6.491 × 10 M
3+
Gd metal ions (Figure 5) gave the spectra that have
3+
been used to draw a plot between 1/(A –A) vs. 1/[Gd ]
o
complex. The mass study of complexation is evident for
using Benesi–Hildebrand equation. Linearity was
3
+
[
45]
1:1 complexation of the PBMMA‐Gd complex.
observed by the Benesi‐Hildebrand plot
also results observed from job's plot
(Figure 6);
(Figure 7) indi-
cated the formation of a 1:1 complex with association
[46]
3
.4.1 | Job's plot
4
−1
3+
affinity K = 6.491 × 10 M for Gd ion. Also complex-
ation of PBMMA‐Gd ion was determined by MS‐ESI
spectroscopy and MS‐ESI‐TOF (M + Gd ); (m/z) for
3+
To perform method of continuous variation (Job's plot),
stock solutions (100 ml) of receptor PBMMA and Gd
metal salts of same concentrations were prepared. Then
10 solutions with varying mole fractions of each receptor
and metal ions were prepared in CH OH:H O (1:1 v/v) as
−
3+
3+
3+
PBMMA + Gd
37.2372 for PBMMA (Figure S4). Mass spectroscopic
studies have been found to be in good agreement with
complex found 595.7167 and m/z
4
3
2
3+
the proposed structures of receptor PBMMA‐Gd
solvent system, keeping over all concentration constant

MOHAN ET AL.
7 of 11
3
+
FIGURE
(
7
Job's
plot
for
PBMMA
and
Gd ;
3
+
−5
[PBMMA] + [Gd ]) = 13.694 × 10 M in 1:1(v/v) methanol–
FIGURE
8
Cyclic voltammetric study for PBMMA and
water solvent
3+
−3
3 2
PBMMA + Gd ion in 3 × 10 M in CH OH:H O (1:1 v/v) as
solvent system
−
5
as 13.694 × 10 M. UV–visible spectra were recorded to
[46]
3+
perform Job's plot. The stoichiometry
Gd was determined by the method of continuous varia-
of PBMMA‐
binding reveals the affinity of Gd towards the PBMMA
compound which depict the interactions with nitrogen
and oxygen atom with 2.09 Å and 2.05 Å distance
(Figure 9). There are two metal‐acceptor bonds that
describe the polarity of ligand toward metal ion.
3+
tion (Job's plot). The total concentration of the receptor
3
+
−5
PBMMA‐Gd was kept constant (13.694 × 10 M),
3+
with a continuous variable molar fraction of guest Gd .
Figure 7 shows the Job's plot of compound for
3+
3+
PBMMA‐Gd at 312 nm. The PBMMA‐Gd Complex
3
.6.2 | Molecular dynamics stimulation
concentration approaches a maximum when the molar
3+
fraction of PBMMA‐Gd
PBMMA‐Gd complex formed a 1:1 (Host:Guest) com-
is 0.5. It means that
The structural integrity and stability of docked complex
(PBMMA‐Gd ) was evaluated through the molecular
dynamics simulation during 10 ns time trajectory. The
3+
3+
4
−1
plex with association affinity K = 6.491 × 10 M .
MD simulation executed by event and quality analysis
(
Table 1 and Figure S10). The Root Mean Square Fluctu-
3
.5 | Cyclic voltammetric study
ation (RMSF) of ligand PBMMA described the frame by
frame fluctuation confined by every atom which ranged
between 1 to 3 Å (Figure S11) which reverse the fluctua-
tions of ligand.
[47,48]
Electrochemical studies
PBMMA‐Gd ion (Figure S9) in solution, recorded in
3
of PBMMA (Figure S8) and
3+
−
3
× 10 M in CH OH:H O (1:1 v/v) as solvent system
3 2
The conformational changes were identified by rotat-
able bonds (RB) present in host (PBMMA) and evaluated
by torsions plot throughout the simulation trajectory (0
through 10 ns). The color‐coded rotatable bonds were
retained in 2D schematic diagram and accompanied by
a dial plot and bar plots of the same color. The center of
using KCl as supporting electrolyte at room temperature
with scan rate of 0.1 V/s in the potential range − 1.0 to
+
3.0 V (Figure 8). It shows that it is quasi‐reversible elec-
tron transfer redox process which exhibit two waves. The
main anodic and cathodic peaks observed for PBMMA
Epa = 0.0713 V and Epc = −0.1567 V; peaks observed
3+
for PBMMA‐Gd
ion are Epa = 0.4069 V and
Epc = 0.7936 V. The observed peaks for PBMMA and
3+
PBMMA‐Gd ion are different, this happens due to
3+
the binding of PBMMA with Gd ion and change in
electrochemical properties of receptor.
3
3
.6 | Computational studies
.6.1 | Molecular docking
The host and guest were docked with the binding energy
36.09 KJ/mol and two metal‐acceptor bonding. This
3
+
−
FIGURE 9 Docked structure of PBMMA + Gd ion

8
of 11
MOHAN ET AL.
TABLE 1 Simulation quality analysis
−1
Sr. No.
Properties
Average
Std. Dev.
Slope (ps )
1
2
3
4
5
Total energy (kcal/mol)
Potential energy (kcal/mol)
Temperature (K)
1935.818
−1818.760
295.778
15.840
53.710
2.794
0.003
−0.001
0.000
Pressure (bar)
−70.126
140.403
576.865
0.001
3
Volume (cm )
61451.992
−0.011
TABLE 2 Optimization details
Optimization Energy
Optimization step
Sr. No
Name
Gas Phase (Hatree)
Optimization step
Methanol (Hatree)
1
2
PBMMA
69
40
−1521.376566
−1556.720961
28
29
−1521.403284
−1556.839791
3
+
PBMMA _Gd
radial plot is the key point which related to the initiation
of simulation event. However, dial plots (or radial plots)
showed the conformation and density of torsion angle
gas phase (Figure S14) as well as solvent phase (Figure
S15) and optimization energy details given in Table 2.
3
+
The binding Energy of Complex (PBMMA _Gd ) in
Gas phase and solvent phase are −595.6679383 kcal/mol
and − 498.0607959 kcal/mol, respectively. It shows
that Strong binding between PBMMA and Gadolinium
and also gives an outline about the stable complex forma-
tion during the geometry optimization in both gas and
solvent phase.
(Figure S12A and Figure S12B).
RMSD (Å), radius of Gyration (Å), intramolecular
hydrogen bonds, Molecular surface area (Å), Solvent
accessible surface area (Å), Polar surface area (Å) were
different parameters observed during the quality analysis
which revealed the ligand PBMMA compatibility to deci-
pher the structural level integrity (Figure S13).
Absorption spectra at TDDFT level of calculation
TD‐DFT level of studies highlighted the nature of the
absorption spectra analysis. The experimental and theo-
retical transition from the topologies of the Kohn–sham
orbital; Figure 10 shows frontier molecular orbitals
3
.6.3 | DFT studies
Density functional theory calculations
The geometry optimization of PBMMA and
PBMMA_Gd complex has been performed on both
3+
(
FMO's) of PBMMA and the maximum wavelength
FIGURE 10 Frontier molecular orbitals
HOMO and LUMO) of the PBMMA at
(
CPCM‐TD‐cam‐b3lyp/gen level of
approximation

MOHAN ET AL.
9 of 11
TABLE 3 Main Singlet Vertical Electron Transition Energies (ΔE), Wavelengths (λ), Oscillator Strengths (f), and % contribution Calculated
at the TDDFT/CAMB3LYP Level
Sr.
No Name
Excitation
(eV)
Hypsochromic Oscillator
λexcitation Shift strength Key transitions
%
hypsochromic
Contribution λexp Shift
1
PBMMA
3.9872
310.96
14.77
1.8067
HOMO‐1‐‐ > LUMO
HOMO‐‐ > LUMO+1 56.73
41.64
312 17
295
2
PBMMA‐
4.186
296.19
0.9255
HOMO‐2‐‐ > LUMO+1 8.91
3
+
Gd
HOMO‐2‐‐ > LUMO
12
HOMO‐‐ > LUMO+3 28.45
3.37
+
HOMO‐‐ > LUMO+6
HOMO‐‐ > LUMO+7
2.22
4.92
HOMO‐‐ > LUMO+11 10.03
HOMO‐‐ > LUMO+12 78.55
HOMO‐‐ > LUMO+13 2.68
HOMO‐‐ > LUMO+15 4.60
HOMO‐‐ > LUMO+17 3.03
absorption (λmax) is presented in Table 3. The UV–visible
spectra were emerged due to the transition from higher
energy orbital (HOMO‐1, and HOMO) to lower energy
orbital (LUMO). The transition was obtained due to
amalgam of FMO's which was presented in Table 3. On
spectra developed due to the electronic transition of
higher‐energy orbitals (HOMO‐1, and HOMO) to lower
energy orbitals (LUMO, LUMO+1, LUMO+3, LUMO
+6, LUMO+7, LUMO+11, LUMO+12, LUMO+13,
LUMO+15, and LUMO+17). Among that, all transitions
HOMO ➔LUMO+12 and HOMO ➔LUMO+3 contribute
more than 28% so it plays a key role for the hypsochromic
shift transition. It was clearly observed that the PBMMA
3+
the other hand, The FMOs of PBMMA‐Gd can be
found in Figure 11 and wavelength absorption (λmax) is
presented in Table 3. Note that the HOMO and LUMO
3+
3+
were distributed on PBMMA moiety and Gd metal
ion, respectively. It was observed that the UV–visible
gives a hypsochromic shift of 17 nm with Gd metal ions
due to complexation.
3
+
FIGURE 11 Frontier molecular orbitals (HOMO and LUMO) of the Gd complexes of PBMMA at CPCM‐TD‐cam‐b3lyp/gen level of
approximation

10 of 11
MOHAN ET AL.
4
| CONCLUSIONS
Botany, Bioinformatics and Climate Change Impacts
Management, Gujarat University for providing an oppor-
tunity to access the bioinformatics research facilities.
In conclusion, we have reported synthesis and recogni-
tion potential of molecular receptor PBMMA, which
was characterized by various spectroscopic methods.
TGA was also carried out to explain the thermal behavior
of PBMMA. The receptor PBMMA has been found very
efficient for the selective recognition of Gd metal ions
among various cations, such as Gd , Na , K , Mg ,
Cu , Cd , Hg , Y , La , Eu , Sm , Re and
Th metal ions used as sulfates. The stoichiometry of
the complex formed by receptor and Gd metal ions
was established to be 1:1 by Benesi‐Hildebrand plot
method and method of continuous variation (Job's plot)
with association affinity K = 6.491 × 10 M with a shift
of 17 nm from 312 nm to 295 nm. In fluorescence study it
was concluded that PBMMA acts as good sensor for
Gd . Cyclic voltammetric study also gives crucial infor-
mation with change in redox potential upon addition of
Gd ions to PBMMA. The binding modes and mecha-
nism of PBMMA with Gd was further explained by
molecular docking. TDDFT study also prove that the
hypsochromic shift of 17 nm appear due to the energy
transfer from HOMO‐LUMO's in a complex between
PBMMA and Gd . In conclusion receptor has been
found selective and good sensor for Gd ions. However,
DISCLOSURE STATEMENT
No potential conflict of interest was reported by the
authors.
3
+
3
+
+
+
2+
2+
2+
2+
3+
3+
3+
3+
6+
4+
ORCID
3+
Brij Mohan http://orcid.org/0000-0003-2414-9152
Krunal Modi http://orcid.org/0000-0002-1151-1207
4
−1
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