Cobalt Metallogel Interface for Selectively Sensing l -Tryptophan among Essential Amino Acids

Article abstract of DOI:10.1021/acs.inorgchem.9b00455

The development of metallogels widens the span of sensing activity as it opens new opportunities to develop chemosensors through metal-ligand interactions. Herein, a new nitrile-substituted 1,3,5-tricarboxamide-based gelator G4 has been fabricated and shows aggregate-induced enhanced emission (AIEE) after gelation in the presence of water. A dimethylformamide (DMF) solution of the gelator shows rapid crystallization, but addition of water to a DMF solution of gelator G4 leads to gelation at room temperature. In addition, gelator G4 was used for the formation of metallogels, and among them, the cobalt metallogel has been found to be effective for sensing l-tryptophan in the gel state through the quenching of AIEE. Interestingly, the gel is also effective in sensing bovine serum albumin protein at the nanomolar level, which contains an l-tryptophan residue. The limit of detection of Co(II)G4 for selective sensing of tryptophan has been found to be 2.4 × 10^-8 M. To the best of our knowledge, there have been no reports to date of a metallogel being utilized to discriminate and selectively sense an amino acid and a protein. The gelation properties of the organic gelator molecule and metallogels have been explored through various spectroscopic tools and physicochemical experiments.

Full text of DOI:10.1021/acs.inorgchem.9b00455

Article
pubs.acs.org/IC
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
Cobalt Metallogel Interface for Selectively Sensing L‑Tryptophan
among Essential Amino Acids
Novina Malviya,† Chanchal Sonkar,† Rakesh Ganguly,‡ and Suman Mukhopadhyay*,†,§
†Department of Chemistry, School of Basic Sciences, Indian Institute of Technology Indore, Khandwa Road, Simrol, Indore 453552,
India
‡Division of Chemistry and Biological Chemistry, Nanyang Technological University, Singapore 639798
§Discipline of Biosciences and Biomedical Engineering, School of Engineering, Indian Institute of Technology Indore, Khandwa
Road, Simrol, Indore 453552, India
S
* Supporting Information
ABSTRACT: The development of metallogels widens the span of sensing activity as it
opens new opportunities to develop chemosensors through metal−ligand interactions.
Herein, a new nitrile-substituted 1,3,5-tricarboxamide-based gelator G4 has been
fabricated and shows aggregate-induced enhanced emission (AIEE) after gelation in the
presence of water. A dimethylformamide (DMF) solution of the gelator shows rapid
crystallization, but addition of water to a DMF solution of gelator G4 leads to gelation
at room temperature. In addition, gelator G4 was used for the formation of metallogels,
and among them, the cobalt metallogel has been found to be effective for sensing L-
tryptophan in the gel state through the quenching of AIEE. Interestingly, the gel is also
effective in sensing bovine serum albumin protein at the nanomolar level, which
contains an L-tryptophan residue. The limit of detection of Co(II)G4 for selective
sensing of tryptophan has been found to be 2.4 × 10−8 M. To the best of our
knowledge, there have been no reports to date of a metallogel being utilized to discriminate and selectively sense an amino acid
and a protein. The gelation properties of the organic gelator molecule and metallogels have been explored through various
spectroscopic tools and physicochemical experiments.
dipole−dipole interactions, van der Waals interactions, and
hydrogen bonding), which play a significant role during self-
assembly.11−13
INTRODUCTION
■
The world of gel materials has attracted more attention in the
past few years as they have been explored for use in various
facets of life.1−3 In recent years, π-conjugated fluorescent
molecules have been widely synthesized, and their self-
assembly behavior was used in fields from optoelectronics to
sensing applications. However, synthesis of such a class of π-
conjugated molecules is challenging, tedious, and perilous to
the environment. To overcome these challenges, supra-
molecular chemistry has attracted an extensive amount of
attention as an alternative approach for designing highly
fluorescent materials.4 The self-assembly tendency of these
compounds leads to the aggregation-induced enhanced
emission (AIEE) effect, which is used for the development
of various devices like light-emitting diodes, sensors, and light-
emitting liquid crystals.5 The self-assembled materials could be
classified on the basis of the presence and absence of metal
centers. The self-assembled materials that include a metal
complex or ion are called metallogels, whereas the self-
assembled materials of organic compounds are called organo-
gels or hydrogels depending upon their major (solvent)
components. The design and fabrication of selected metal ions
with various organic compounds and ligands are particularly
appealing because of their broader range of applications.6−10
The self-assembled materials show several kinds of non-
covalent interactions (π−π stacking, C−H−π interactions,
In search of novel self-assembled materials, a large number
of C3 symmetric derivatives of 1,3,5-tricarboxamide (BTA)-
based gelator molecules have been synthesized. Such molecules
form a columnar packing owing to the intramolecular
hydrogen bonding within the consecutive amide groups that
results in the formation of supramolecular assemblies of
gelators. The advantage of derivatives of BTA in supra-
molecular chemistry is that it could be fabricated with various
metals and the chemical structure could be easily varied due to
the greater number of functional groups available in it. It is
worth mentioning that nitrile derivatives of BTA make up an
important class of gelators because of the electron-withdrawing
tendency of nitrile groups that establish strong noncovalent
interactions between aromatic rings.5,14 The introduction of
the metal ion into a nitrile-substituted gelator molecule
reorganizes the structure significantly through coordination
interaction between the donor (ligand) and acceptor (metal).
In general, metallogels have been proven to be quite effective
in sensing certain anions when assembled with different
gelators.15−19 There have also been certain reports in which a
Received: February 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.9b00455
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metallogel acted as a sensor material for ammonia, hydrogen
sulfide, triethylamine, pyridine, and picric acid through
different spectroscopic methodologies.20−23 Visual chiral
detection of (R)- and (S)-binap has also been achieved
through the collapse of a platinum-based metallogel.24
However, in no study have metallogels been utilized to
discriminate between biomolecules of the same family.
Developing sensors that can discriminate between various
biomolecules from the same kind of family is extremely
important as it can help to screen the deficiencies of any
particular biomolecule in a physiological state. In recent years,
soft materials have been closely studied as a promising class of
chemical sensors that sense various molecules even under
biological conditions. The sensing and recognition of
important biological substrates, for example, an amino acid,
are very promising for the amino acid pool that is responsible
for achieving a balanced metabolism.25 Amino acids act as
potential biomarkers and precursors for various key biological
substances.26 The inadequacy of any amino acid may lead to a
weakening of protein metabolism. Among the various amino
acids, L-tryptophan is an important one because it is essential
for neuronal balancing mechanisms.27 Tryptophan contains an
indole moiety that is a potentially useful pharmacologically
active compound with various applications in areas from
chemistry to biology.28 Tryptophan is an essential amino acid
that is vital for nitrogen balance in adults, normal growth of the
animal body, and in vivo biosynthesis of proteins. Tryptophan
plays integral roles in various biological processes; for example,
L-tryptophan works as a precursor to influence the biosynthesis
of serotonin or 5-hydroxytryptamine (5-HT) in the brain.
Second, in animals tryptophan is used to synthesize niacin and
melatonin. 5-HT is a monoamine neurotransmitter produced
in the central nervous system (CNS) that influences a variety
of neural functions and CNS disorders, including those related
to mood, stress, anxiety, sleep, pain, depression, aggressive
behavior, and memory functions.28,29 As described previously,
250 mg/day tryptophan is required for nitrogen balance in
various biochemical processes.29,30 5-HT is obtained by
metabolism of 1% ingested tryptophan, and a majority
(90%) of ingested tryptophan is converted nicotinic acid by
a hepatic enzyme.29,30 Therefore, the development of a sensor
for the selective identification of L-tryptophan in the complex
structure of a protein and peptide would be a very promising
area of research.
Scheme 1. Colorimetric Sensing of L-Tryptophan by
Co(II)G4 Revealing the Role of Water in the Transition
a
between the Sol−Gel and Crystal of Gelator G4
a
(a) Chemical structure of G4. (b) Pictorial representation of G4. (c)
Image of AIEE of gelator G4 after self-assembly under ultraviolet
light. (d) Self-assembly of Co(II)G4. (e) Optical photograph of
Co(II)G4. (f) Optical photograph of Co(II)G4+BSA protein that led
to a colorimetric change. (g) Cooling of the G4 solution that leads to
crystallization. (h) Addition of water to the G4 solution that leads to
gel formation at room temperature.
being successfully applied for detection of a particular amino
acid even in a protein environment. This work also reports the
role of water as a solvent in sol−gel transformation and the
solid-state structure of gelator G4. These experimental findings
could lead to a facile, robust, and cost-effective approach for
tryptophan sensing in areas from material chemistry to biology.
EXPERIMENTAL SECTION
■
Materials and Methods. Trimesic acid, 4-aminobenzyl cyanide,
and metal perchlorate salts were commercially obtained from Sigma-
Aldrich and used as supplied. The amino acids and BSA (fraction V
powder) protein used in experiments were purchased from SRL
chemicals. All of the analytical grades solvents (triethylamine and
thionyl chloride) from Merck were used as purchased. We used Milli-
Q water during the experiment. An AV III 400 Ascend Bruker BioSpin
machine was used to record nuclear magnetic resonance (NMR)
spectra where dimethyl sulfoxide-d6 (DMSO-d6) was used as a solvent
at ambient temperature. The values for chemical shift (parts per
million) with respect to downfield of tetramethylsilane and the peak
multiplicities are shown: singlet (s) and doublet (d). By using KBr
pellets on a Bruker Tensor 27 FTIR spectrophotometer, Fourier
transform infrared (FTIR) spectroscopy was performed. Mass
spectrometric analysis was conducted with a microTOF-Q II
Bruker-Daltonics mass spectrometer.
Though the interactions of metal ions with different amino
acids have been explored extensively,31−33 sensing of
tryptophan in solution has been achieved by various method-
ologies, including liquid chromatography, capillary electro-
phoresis, and spectroscopic detection.34,35 The metallogel
being utilized as a sensor is a new approach for discriminating
an amino acid.
In this work, we design a cobalt-based metallogel
synthesized utilizing the gelator N1,N3,N5-tris(4-cyanometh-
yl-phenyl)benzene-1,3,5-tricarboxamide G4. We have success-
fully crystallized gelator G4, and its columnar stacking due to
its various noncovalent interactions has been explored. We
report the application of a cobalt metallogel interface that
senses L-tryptophan selectively in a gel state by drastic
quenching of AIEE (Scheme 1). Interestingly, our cobalt-
based metallogel also senses the tryptophan amino acid residue
present in a complex structure like bovine serum albumin
(BSA) protein even by the naked eye. To the best of our
knowledge, this is the first report of a metallogel interface
Synthesis of Gelator G4 [N1,N3,N5-tris(4-cyanomethyl-
phenyl)benzene-1,3,5-tricarboxamide]. One gram (4.75 mmol)
of trimesoyl chloride was ice-cooled in the presence of dry
dimethylformamide (DMF) (8 mL). Then, 2.18 g (16.5 mmol, 3.5
molar equivalents) of 4-aminobenzyl cyanide was slowly added to the
trimesoyl chloride solution that contained triethylamine (2.35 mL,
16.8 mmol) for the synthesis of gelator G4 followed by stirring of the
reaction mixture overnight under ambient conditions. The resultant
solution was worked up by the addition of 100 mL of ethyl acetate
and dilute HCl (1 N, 100 mL). The combined organic layer was
further washed with the saturated Na2CO3 (100 mL) aqueous
solution and brine (100 mL). The resultant organic layer was dried
over anhydrous sodium sulfate, and white powder was obtained by
B
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Scheme 2. Systematic Scheme for the Synthesis of Gelator G4
evaporation of all of the solvent under reduced pressure. The obtained
500−4000 cm−1 over 64 scans at a resolution of 4 cm−1 and an
interval of 1 cm−1.
gelator G4 was dried at 28 °C under moderate vacuum: yield 80%
1
Powder X-ray Diffraction (PXRD). Powder X-ray diffraction
(PXRD) spectra were recorded with the help of a Rigaku Smart
Lab automated multipurpose X-ray diffractometer with a Cu Kα
source (the wavelength of X-rays was 0.154 nm). The tube voltage
and current were 40 kV and 30 mA, respectively. The XRD patterns
were recorded between 20° and 80° (2θ) with a step size and a scan
speed of 0.02° and 2°/min, respectively.
Circular Dichroism (CD) Spectroscopy. The CD experiment was
performed with a JASCO J-815 spectropolarimeter at 25 °C using a
quartz cell (path length of 1 mm). The concentration-dependent
UV−vis CD spectra were recorded for BSA protein (2 μM) and 2 μM
BSA by varying the concentration (from 0 to 24 μM) of the
Co(II)G4 metallogel. The solution was scanned at a 1 nm bandwidth
and a 20 nm min−1 scanning speed with a 1 s response time. All of the
spectra were recorded within the range of 190−260 nm with a data
pitch of 0.1 nm. Experimental data were recorded as an accumulation
of three scans, and the average values are reported.
Morphological Study. Field emission scanning electron micros-
copy (FE-SEM) (Carl Zeiss Microscope, model-Supra 55) was used
to observe the various morphologies and sizes of the gels. For this
experiment, the sample was prepared by diluting 100 μL of the gel in
400 μL of water. After this, a small amount (50 μL) of gel was placed
on a glass coverslip. After the sample was dried, the gold coating was
used for analysis.
Rheological Properties. The mechanical properties of the G4
organogel and their metallogels were quantified via oscillating
rheology. The rheology experiments were performed at 25 °C on
an Anton Paar Physica MCR 301 rheometer. A 25 mm stainless steel
parallel plate with a TruGap of 0.5 mm was used for the rheology test.
The mechanical strength of the gels was measured at 0.5% strain by
measuring the storage (G′) and loss (G″) moduli. Gels (1 mL) were
transferred very carefully onto the rheometer plate using a small
spatula, and the solvent trap was used to keep the gel hydrated.
Single-Crystal X-ray Diffraction (SXRD). For X-ray crystallographic
analysis, we used the yellow needlelike crystal of G4 with approximate
dimensions of 0.020 mm × 0.060 mm × 0.080 mm. Quartz fibers
were used to mount the crystals, and the X-ray diffraction intensity
data were measured with a Bruker APEX II diffractometer equipped
with a CCD detector at 153 K, employing Mo Kα radiation (λ =
0.71073 Å), with the SMART suite of programs.37 The data were
processed and corrected for Lorentz and polarization effects with
SAINT and for absorption effects with SADABS.38 The SHELXTL
suite of programs was used for structure solution and refinement.39
The multiscan method (SADABS) was used to correct the data for
absorption effects. The structures were determined by Patterson maps
to locate the heavy atoms, followed by the difference in maps for the
light, non-hydrogen atoms. All non-hydrogen atoms were refined with
anisotropic thermal parameters. All of the data (crystal data and
refinement and collection parameters) for G4 are listed in Tables S1
and S2. SQUEEZE was applied to remove the disorder in a solvent of
crystallization.
(for G4); H NMR (400 MHz, 298 K, DMSO-d6) δ 10.86 (3H,
amide, s), 8.81 (3H, aromatic, s), 7.94 (6H, aromatic, d), 7.44 (6H,
aromatic, s), 4.10 (6H, aliphatic CH2, s); 13C NMR (100 MHz, 293
K, DMSO-d6) δ 164 (amide), 138 (aromatic), 135 (aromatic), 130
(aromatic), 128 (aromatic), 127 (aromatic), 121 (aromatic), 119
(nitrile), 22 (aliphatic CH2); FTIR of G4 (KBr) ν = 3223, 3139,
2272, 1696, 1631, 1564, 1482 cm−1; MS (ESI) of G4 m/z 551.20 (in
negative mode).
Preparation of Gels. Gelator G4 (15 mM) was placed in 1.5 mL
of DMSO or DMF, and then, 0.5 mL of Milli-Q water was added to
the glass vial. Spontaneous formation of the organogel was observed
when the solution was left undisturbed for a few minutes. However,
metallogels were obtained via mixing 15 mM gelator G4 in 1 mL of
DMSO with 1 mL of an aqueous metal perchlorate salt (7.5 mM, 2:1
molar ratio) solution.
Gel to Crystal Transition. The solution (obtained from heating
of the G4 gel) was left undisturbed at room temperature. We
observed the formation of crystals when this solution was gradually
cooled. However, the solution when left undisturbed after the
addition of 0.5 mL of Milli-Q water formed a stable gel.
Gel Melting Temperature. The gel melting temperature (Tgel) of
G4 was measured by the test tube inversion method. The steel ball
(approximately 100 mg) was kept on top of the G4 gel. The gel was
heated at a rate of 2 °C/5 min, and the height of the steel ball was
recorded with temperature. The steel ball started to move in the
downward direction of the vial after the gel gradually melted into the
sol form. However, the gel melting temperature is the temperature at
which the gel starts melting.
Characterization. Ultraviolet−Visible (UV−vis) Spectroscopy.
Absorption spectra were analyzed by a Varian Carry 100 Bio UV−vis
spectrophotometer using a quartz cuvette (10 mm × 10 mm).
Fluorescence Spectroscopy. A Fluoromax-4 spectrofluorometer
(HORIBA Jobin Yvon, model FM-100) was used to record emission
spectra of the gels in a quartz cuvette (10 mm × 10 mm). The
excitation and emission slit width and data pitch were 2 and 1 nm.
The excitation wavelength (λex) of 356 nm was set to record the
emission spectra of the G4 organogel.
The absolute fluorescence quantum yield of the G4 organogel was
calculated at λex = 356 nm under ambient conditions by using a
standard, viz., quinine sulfate (ϕ = 0.53).36 The expression for the
quantum yield is
i
j
j
j
j
j
y
z
z
z
z
z
i
j
j
yi
zj
zj
y
z
z
z
z
z
η
x2
ηr2
K
Kx
D
x
r
Q = Q j zj
j
j
zj
zj
x
r
D
r
k
{k
{
k
{
where Q is the quantum yield, K denotes the average detector output
per photon over the emission spectrum (Kr/Kx = 1 for estimates of
yields for compounds emitting below 600 nm), D represents the
detector response, η is the refractive index of the solvent (η = 1.483
for DMSO, and η = 1.33 for H2O), and x and r subscripts denote the
unknown and standard reference, respectively.19
L-Tryptophan Sensing by the Co(II)G4 Metallogel. Fluo-
rescence spectroscopy was used to study the interaction of metallogels
with different amino acids. An appropriate amount of a stock of
metallogels [Fe(II)G4, Fe(III)G4, Co(II)G4, Ni(II)G4, Cu(II)G4,
FTIR Spectroscopy. A Bruker (Tensor 27) FTIR spectropho-
tometer was used to record the FTIR spectrum with the help of a KBr
pellet. The wavenumber range for the FTIR measurement was around
C
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Zn(II)G4, Ag(I)G4, abd Cd(II)G4] of gelator G4 was prepared by
the addition of 0.03 mmol of gelator G4 with 0.015 mmol of metal
perchlorate salts (2:1 G4:Mn+ molar ratio) in 2 mL of solvent (1 mL
of DMSO and 1 mL of Milli-Q water). All of the metallogels were
treated with the different amino acids (Try, Leu, Lys, Phe, Trp, Ala,
Glu, Asp, Ser, His, Arg, Pro, and Cys) at a molar ratio of 1:0.5. The
fluorescence spectra of the amino acid-treated gels were recorded
using a standard (10 mm × 10 mm) quartz cuvette. The gels were
excited at 356 nm, and the emission spectra were monitored in the
range of 365−650 nm. Both excitation and emission slit widths with a
1 nm data pitch were set to 2 nm.
shown in Table S3. The influence of a certain quantity of water
on gel formation was studied utilizing different DMSO:water
ratios (Table S4). The critical gel concentration (CGC) of
gelator G4 was found to be 15 mM in DMSO/water (Table
S4).
The standard heating−cooling technique and temperature-
dependent fluorescence spectroscopic experiments were used
to investigate the propensity of the gelator to exhibit AIEE.
Gelator G4 was non-emissive when in a solution state, whereas
the gel state showed intense emission because of AIEE, which
might be due to curbing of free rotations of molecules, which
results in blockage of nonradiative emission pathways of the
excited state and consequently unlocks the radiative decay in
the aggregate state.46,47 During gradual heating of the gel from
25 to 95 °C, emission maxima moved because of the
disturbance of self-assembly upon heating. At 85 °C, the gel
converts into a sol state, which is known as the phase transition
temperature (Tgel). However, it shows significant shifting in its
emission maximum from 412 to 464 nm during gelation. In the
gel phase, gelator G4 has shown red-shifts probably due to J
aggregation, which specifies π−π stacking among aromatic
moieties (Figure 2).48 Astonishingly, a heated DMF solution of
RESULTS AND DISCUSSION
■
In a strategic approach for designing a self-assembling gelator,
we chose a nitrile derivative of the BTA molecule because the
self-assembling ability is enhanced by the nitrile group through
the participation of various noncovalent interactions. It is
widely accepted that the higher charge density and
nucleophilicity of the nitrile group offer suitable metal−ligand
interactions.19,40 Gelator molecule G4 was successfully
synthesized by the treatment of trimesoyl chloride with an
excess of 4-aminobenzyl cyanide (3.5 equiv) in the presence of
triethylamine (Scheme 2). The gelator from the resultant
reaction mixture was extracted with ethyl acetate. In addition,
the obtained gelator was well characterized by various
spectroscopic techniques [electrospray ionization mass spec-
trometry (ESI-MS), IR, 1H NMR, and 13C NMR spectroscopy
and SXRD]. Analysis of the IR spectrum of gelator G4 revealed
that the characteristic bands for carboxamide N−H at 3139
cm−1, for CO at 1695 cm−1, and for −CN at 2272 cm−1
(Figure S1).19,41 The molecular ion peak at m/z 551.20
(negative mode) in the ESI-MS spectrum confirms the
1
formation of gelator G4 (Figure S2). The H NMR spectrum
of G4 indicates the aromatic ring protons in the region from
8.81 to 7.44 ppm, the aliphatic proton of benzyl nitrile at 4.10
ppm, and carboxamide protons at 10.86 ppm (Figure S3).42
The 13C NMR spectrum displays the peaks at 164.92 and
119.74 ppm for the carboxamide and nitrile carbons,
respectively (Figure S4), apart from the signature peaks of
the aromatic and benzyl carbon.43 The gelation nature of
gelator G4 was further determined by the “test tube inversion”
method (Figure 1). The solubility of gelator G4 is good in
Figure 2. Temperature-dependent fluorescence spectra of G4 (in
DMSO) during the gelation process (λex = 356 nm).
G4 upon gradual cooling in the absence of water deposits
yellow-colored crystals (Figure 1). In the absence of water,
gelator molecules slowly self-assemble in a multidirectional
way, which may lead to crystallization of the gelator.44
A detailed crystallographic study of gelator G4 signifies that
the gelator is crystallized with one molecule of DMF as a
solvent of crystallization (Figure 3a). Interpretation of the
single-crystal structure of gelator reveals the required
information about noncovalent interactions that might be
responsible for the establishment of supramolecular gel
assembly. The molecular packing of G4 determines the varied
molecular recognition pattern. The amide group present in the
middle of the columnar arrangements utilizes its hydrogen
bond as a donor and acceptor in molecular recognition with its
neighboring molecules. The hydrogen bonding sites between
the solvent of crystallization and gelator have been revealed by
the crystallographic data of gelator G4. The DMF solvent, C
O group, and NH group of gelator G4 have played a critical
role during intermolecular hydrogen bonding. Hirshfeld
surface analysis was used to determine the hydrogen bonding
Figure 1. Role of water in phase transitions from sol to gel and sol to
crystal state.
DMF/DMSO solvent but not in any other solvents even while
being heated. However, gelation is initiated by the addition of
water in a DMF/DMSO solution. During this process, water
molecules assist unidirectional noncovalent interactions
(hydrogen bonding, π−π stacking, and van der Waals
interactions). These needlelike aggregates become entangled
in the three-dimensional (3D) network and encapsulate the
solvent molecules by capillary action.44,45 The results are
D
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Figure 3. (a) Single-crystal X-ray diffraction structure of G4. (b) Columnar aggregation of gelator G4 showing the molecular recognition between
molecules through N−H···O hydrogen bonds.
Table 1. Donor−H···Acceptor Hydrogen Bonds and Bond Angles of Gelator G4
bond distance (Å)
donor−H···acceptor
D−H
H···A
D···A
bond angle D−H···A (deg)
symmetry code
1
2
3
4
5
6
7
8
N (1)−H (1)···O (4)
N (2)−H (2A)···O (1)
N (3)−H (3)···O (3)
C (9)−H (9)···O (1)
C (22)−H (22)···O (2)
C (27)−H (27)···O (3)
C (32)−H (32A)···N (6)
C (32)−H (32B)···O (2)
0.87
0.87
0.87
0.94
0.94
0.94
0.98
0.98
2.00
2.41
1.93
2.41
2.33
2.45
2.57
2.59
2.831(5)
3.013(4)
2.738(4)
2.912(5)
2.860(5)
2.908(5)
3.548(7)
3.204(5)
160
126
154
113
115
110
174
120
x, y, z
1 + x, y, z
1 + x, y, z
x, y, z
x, y, z
x, y, z
1 + x, y, z
2 − x, 1 − y, −z
interactions and close contacts in the crystal structure.49 The
dark red spots of hydrogen bond acceptors of the N−H···O,
C−H···O, and C−H···N types were visualized through the
Hirshfeld surface of G4 (Figure 3b). Hydrogen bonds are
shown along the a-axis through N3−H3···O3, while the solvent
molecule, DMF, forms discrete hydrogen bonds through N1−
H1···O4 (Figure S5 and Table 1). The supramolecular
assembly of the crystal structure of gelator G4 indicates π−π
stacking and intercolumnar stacking between the benzene ring
during the gelation. Each column of gelator molecules contains
two N−H···O intracolumnar hydrogen bonds, and a distance
of 4.885 Å was found between the central phenyl rings of
successive molecules (Figure S6). Gelator G4 yielded a one-
dimensional molecular assembly via π−π stacking and
hydrogen bonding. Furthermore, bond distances and bond
angles between atoms of gelator G4 are comparable with those
of similar molecules from previous reports.50
The absolute fluorescence quantum yield experiment was
performed to gain deeper insight into the emissive nature of
the gel. Gelator G4 did not show fluorescence emission in the
DMSO solution state. However, the fluorescence intensity
increased after the addition of 0.5 mL of water to the solution
of G4 described above. The fluorescence quantum yield
reaches around 0.015 after gelation.
that the self-assembled gel structure was established not only
by the extensive hydrogen bonding between carboxamide and
nitrile but also by the presence of intercolumnar stacking, π−π
stacking, and van der Waals interactions.52,53 A closer
1
concentration-dependent study of self-assembly through H
NMR spectroscopy indicates that with an increase in the
concentration from 10 to 150 mM, aromatic and carboxamide
protons have shifted downfield, revealing the role of hydrogen
bonding (Figure S7) in a concentrated solution.54,55 In the IR
spectra of the powder and xerogel, almost all of the important
vibrations shift toward lower wavenumbers after gelation,
showing hydrogen bond network formation (Figure 4 and
Figures S1 and S8).56
The powder X-ray diffraction of the G4 xerogel had an
intense peak around 2θ = 20.8° with a 4.20 Å d spacing that
represented intercolumnar stacking.57 The peaks at 2θ =
24.49° and 25.71° equivalent to 3.63 and 3.43 Å d spacing,
respectively, confirmed the π−π stacking between aromatic
rings.58,59 The peak at 2θ = 34.16° equivalent to 2.62 Å d
spacing indicates the hydrogen bonding between the nitrile
group and amide NH proton (Figure 5).60
Induction of the aggregate morphology of the G4 organogel
was further examined with the help of FE-SEM.61,62 The
morphology of the gel was also influenced by the different
amount of water during formation of the G4 organogel. The
SEM image of the G4 organogel (1500 μL of DMSO and 500
μL of H2O) shows the 1 μm approximate length of the dense
The presence of noncovalent interactions (π−π stacking,
weak supramolecular interactions, and hydrogen bonding)
indicates a specific role during gelation.51,52 It was expected
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different DMSO:H2O ratios. The rheology data reveal that a
certain quantity (1500 μL of DMSO and 500 μL of H2O) of
water is essential for gel formation.
The organogel upon addition of different transition metal
salts maintained its gel structure. As a result, the metallogel
formed and its fluorescence responses were explored and found
to be comparable to those of our previous works.18,19 The
complete quenching of fluorescence occurred in the case of
Fe2+/Fe3+ among various metal perchlorate salts (Fe2+, Fe3+,
Ni2+, Co2+, Cu2+, Zn2+, Cd2+, and Ag+) (Figure S9) when taken
as 2:1 DMSO/H2O mixture. We have tried but failed to
crystallize the metal complexes formed from solution. It could
be due to a lack of potent donor sites surrounding the metal
ions. Also, the addition of different unidentate heterocyclic
moieties to fulfill the coordination geometry surrounding the
metal center led to an interesting observation. Upon treatment
with an indole ligand, the cobalt metallogel showed drastic
quenching of fluorescence (Figure S10). This observation
provided a unique opportunity to extend the sensing ability of
the cobalt metallogel for discrimination of L-tryptophan with
an indole side chain among other essential amino acids. We
treated all metallogels [Ag(I)G4, Cd(II)G4, Zn(II)G4,
Cu(II)G4, Ni(II)G4, and Fe(II)G4] with the different amino
acids in a molar ratio of 1:0.5 (Tyr, Leu, Lys, Phe, Trp, Ala,
Glu, Asp, Ser, His, Arg, Pro, and Cys) (Figure S11).
Remarkably, the Co(II)G4 metallogel selectively sensed L-
tryptophan by significantly quenching the fluorescent emissive
band (Figure 8 and Figure S12). Interestingly, the change in
color of the metallogel can be noticed even by the naked eye.
Co(II)G4 showed a green-colored solution in DMSO, and
upon addition of a small quantity of water, a pinkish color was
seen. It is worth mentioning that upon addition of L-
tryptophan (aqueous solution), the visible color of the gel
turned yellow, which could be easily observed (Figure 9). The
tryptophan binding with Co(II)G4 changes the coordination
environment around the metal center, which might be the
factor for such a drastic color change that can be observed by
the naked eye. Furthermore, the efficacy of metallogels toward
sensing of an amino acid was determined by analyzing the
effect on the change in fluorescence peak intensity with an
increase in L-tryptophan concentration (Figure S13).
Figure 4. FTIR spectra of the powder and gel state of G4.
Figure 5. Powder XRD patterns of the G4 xerogel.
needlelike morphology that indicates the aggregation of the
material (Figure 6).
The sensing experiment was performed under a multi-
analytical condition to determine the efficiency of the
metallogel system for a specific amino acid that reveals
selective sensing of L-tryptophan (Figure S14). Additionally,
we carried a selectivity experiment, and the results indicated
the Co(II)G4 metallogel was more selective than other
metallogels in sensing L-tryptophan when the fluorescence
was turned off (Figure S15).
The mechanistic aspect of sensing behavior was investigated
by fluorescence, IR spectroscopy, and mass spectrometry.
These experiments show electron transfer from tryptophan
(donor) to cobalt (acceptor) would be the driving force
behind selective tryptophan sensing by quenching of
fluorescence.63,64 We have carried out a concentration-
dependent fluorescence study for the cobalt metallogel with
each amino acid (Tyr, Leu, Lys, Phe, Ala, Glu, Asp, Ser, His,
Arg, Pro, and Cys). The concentration-dependent fluorescence
study demonstrates a gradual decrease with a red-shift in the
fluorescence intensity of the cobalt metallogel only after
addition of tryptophan (from 0.1 to 1000 μM) (Figure S14),
although such an effect is not observed in the case of other
aromatic amino acids like tyrosine and histidine. The detection
Figure 6. FE-SEM images of the G4 organogel (1500 μL of DMSO
and 500 μL of H2O).
The rheological experiment conclusively proved the elastic
nature of gel, as the average storage modulus (G′) was ∼8 ×
103 Pa, which is greater than the loss modulus (G″). There was
no crossover point found for G4. The shear stress was found to
be ∼8.3 × 103 Pa during the frequency sweep (Figure 7). To
understand the effect of the different amount of water on the
gel strength, the rheological experiments were performed at
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Figure 7. (a) Linear viscoelastic (LVE) and (b) dynamic frequency sweep for the G4 organogel (1500 μL of DMSO and 500 μL of H2O).
10−9 M (Figures S17 and S18). In addition, the identification
of BSA protein can be observed through a significant color
change as in the case of L-tryptophan with the naked eye
(Figure S19). To further explore the effect of the cobalt
metallogel on the protein structure, we have recorded the
fluorescence (λex = 295 nm) by altering the BSA:Co(II)G4
metallogel ratio. Addition of the Co(II)G4 metallogel (from 0
to 24 μM) to BSA protein (2 μM) results in a shift of λmax from
352 to 344 nm with a quenching of fluorescence intensity
(Figure S20). The quenching of fluorescence intensity occurs
due to the interactions between tryptophan (Trp-134) and the
cobalt metallogel. An increase in the concentration of the
cobalt metallogel results in the complete quenching of the
fluorescence intensity. These data suggest binding of the cobalt
metallogel with Trp-231 buried in the hydrophobic environ-
ment. The entire result indicates that our cobalt metallogel
behaves like the SDS anionic surfactant that was used
Figure 8. Fluorescence spectra of the Co(II)G4 metallogel (15 mM
G4 and 7.5 mM cobalt perchlorate) in the presence of various amino
previously for the denaturation of protein.67 In addition, the
protein structure was validated by CD spectroscopy. The CD
spectrum of BSA protein shows one positive signal at 196 nm
and two negative signals around 208 and 223 nm. The different
concentrations of the Co(II)G4 metallogel with BSA protein
lead to protein denaturation. The CD signal can no longer be
seen at a 1:10 BSA:Co(II)G4 metallogel molar ratio (Figure
S21).
acids at 100 μM (in DMSO) (λex = 356 nm).
A Stern−Volmer plot has been used to understand
quenching in AIEE caused by the tryptophan amino acid.
The data from the Stern−Volmer plot suggest linear sensing of
tryptophan by Co(II)G4 (Figure S22; details are given in the
Supporting Information).68 To investigate the type of
interaction during self-assembly, we have carried out various
experiments. A Job plot was used to determine the possible
ligand:metal ratio in cobalt metallogel formation, and this has
been found to be a 1:1 stoichiometric ratio (Figure S23).
Additionally, the mass spectrometry and IR spectroscopy data
also reveal the binding of tryptophan with the cobalt complex.
The IR spectra of metallogel Fe(II)G4, metallogel Co(II)G4,
Trp, and metallogel Co(II)G4+Trp have been recorded
(Figures S24−S27), and significant shifts of the stretching
frequencies of CO, amide 1, amide 2, and the nitrile group
have been observed. In the case of Fe(II)G4, the nitrile
stretching frequency shifts were much more pronounced and
observed at 2125 cm−1, indicating that the nitrile becomes
attached to Fe2+ centers through π-coordination, which might
cause the disordered aggregated structure and consequent
quenching in AIEE.18,69 However, the Co(II)G4 metallogel
Figure 9. Colorimetric changes during formation of the Co(II)G4
metallogel with 15 mM gelator and 7.5 mM metal salt (2:1 molar
ratio) and sensing of 100 μM tryptophan.
limit of a particular amino acid using the equation detection
limit = 3S/k (S represents the standard deviation of the blank
solution, and k the slope between the emission intensity with
respect to the amino acid) was calculated to determine the
metallogel sensing capability.65,66 The detection limit for an L-
tryptophan amino acid in [Co(II)G4] has been found to be
2.4 × 10−8 M (Figure S16; details are given in the Supporting
Information). To further confirm whether it can sense L-
tryptophan residues in proteins, we have tested the sensing
property of the cobalt metallogel for BSA, which also
responded similarly with a detection limit of protein of 8.7 ×
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shows the stretching frequency of the CO group shifts
toward a lower wavenumber of 1668 cm−1 indicating the
coordination of CO of the amide group to a metal center
(Figure S25). It has been observed that a shift in the nitrile
group stretching frequency is insignificant in the case of the
cobalt metallogel, but upon treatment with L-tryptophan, the
nitrile stretching frequency splits into two closely spaced bands
(2243 and 2200 cm−1) indicating “a nitrile−metal σ bond” and
“a nitrile−metal π-interaction” (Figure S27).18,19 The carbox-
ylic stretching frequency of the amino acid is shifted from 1670
to 1710 cm−1, confirming the possible interaction between the
carboxylate and a metal ion, suggesting electron transfer from
tryptophan to metal in the gel state (Figures S26 and S27).
These interactions between tryptophan and the cobalt
metallogel may be responsible for selective sensing of
tryptophan among other amino acids. However, such strong
shifting is not observed in the case of other amino acids. We
have also investigated the probable composition of the cobalt
metallogel in the presence of L-tryptophan by ESI-MS. A peak
around 892.50 indicates a possible composition of [CoG4(2-
amino-3-(1H-indol-3-yl)propanoate)(DMSO)]+, where the
cobalt center most probably has coordinated through the
carboxylate/indole (Figure S28).
The PXRD spectrum of Fe(II)G4 showed the disappearance
of the peak around 2θ = 25.71° indicating disruption of π−π
stacking. The Co(II)G4 spectrum features a pattern similar to
that of the original organogel. After incorporation of
tryptophan with the Co(II)G4 metallogel, significant shifts
with a decrease in peak intensity centered at 2θ = 24.56° and
25.54° with 3.62 and 3.48 Å d spacing, respectively, were
observed, which indicates a disruption of π−π stacking.58,59
The shifting of the peak centered at 2θ = 35.43° and 44.06°
corresponding to 2.54 and 2.05 Å d spacing, respectively,
reveals the probable disruption of hydrogen bonding that
might lead to fluorescence quenching (Figures S29−S31).70,71
Additionally, the FE-SEM technique plays a central role in
the identification of morphological features in the G4
metallogel. SEM of both Fe(II)G4 and Co(II)G4 metallogels
reveals a cylindrical rodlike morphology with a length of almost
1 μm. These results indicate that metallogels show significant
changes in morphology due to interaction between the gelator
molecule and a metal ion. Interestingly, Co(II)G4 selectively
binds with tryptophan, which is manifested by the alteration in
the morphological features. Co(II)G4+Trp showed a 3D
flower leaf-like microstructure with dimensions of around 1−2
μm (Figures S32−S34). The FE-SEM images of other
metallogels were also recorded to investigate the structural
morphology in the aggregate state. The changes in self-
assembly behavior would be the reason for the different
morphology of materials.72
respectively. The shear stress was calculated with the help of a
frequency sweep, which was found to be 2 × 104 Pa for
Fe(II)G4, 500 Pa for Co(II)G4, and 176 Pa for Co(II)-
G4+Trp. The entire positive sweep range for all samples and a
higher value of G′ show the viscoelastic nature of the gels.
CONCLUSIONS
■
A nitrile derivative of the BTA molecule was synthesized and
well characterized using spectroscopic tools and X-ray
crystallography. The compound tends to show gelation
behavior in a DMSO/water mixture with the subsequent
enhancement of emission because of self-assembly and AIEE.
A closer look into the possible interaction between the
molecules reveals the formation of extensive hydrogen
bonding, π−π stacking, and intercolumnar stacking as the
reason behind the molecular aggregation, which enhances the
emission by blocking the nonradiative emission pathways of
the excited state. Though the incorporation of various metal
ions in the gel affects the morphology of the gel to some
extent, the integrity of the gels remains intact, and they
recognize the ferrous ion through turning off the AIEE as the
nitrile group tends to form π-bonds with the metal center.
Surprisingly, the cobalt metallogel can selectively sense L-
tryptophan among the various amino acids by quenching of the
AIEE and visual color change. Proteins like BSA with an L-
tryptophan residue also respond similarly, and the load of
detection is found to be in the range of 10−8−10−9 M, making
the system very much efficient. The interaction between the
indole center and the metallogel was found to be the key
behind the molecular recognition pattern. A thorough search
of the relevant literature revealed the novelty of the work as the
metallogel has not been utilized to discriminate and selectively
sense L-tryptophan and protein containing an L-tryptophan
residue. Moreover, the notable point is that the presence of
water in the gel has played a crucial role in gelation whereas
the gelator molecule can crystallize from the sol state only in
absence of a water molecule. We believe that our designed
material would be a feasible and new tool for selective
detection of L-tryptophan-containing proteins and peptides
such as BSA, HSA, and lysozyme. Additionally, the crystal and
gel data should encourage researchers to design and under-
stand the supramolecular arrangement of the gelator in
different environments.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.9b00455.
The strength and stiffness of the metallogel were determined
by rheology (Figures S35−S37).73 The G4 incorporated with
the Fe2+ metal ion showed a dramatic increase in the value of
the average storage modulus, indicating an increase in the
stiffness that might be due to the formation of the efficient
metal−organic framework (MOF) disrupting the self-
assembled organogel aggregate. In addition, in the case of
Co(II)G4, the average storage modulus was found to be 2 ×
103 Pa, indicating the formation of a metallogel with a decrease
in stiffness, whereas upon addition of tryptophan in Co(II)G4,
the average storage modulus decreased and was found to be
219 Pa. The crossover points for Fe(II)G4, Co(II)G4, and
Co(II)G4+Trp were observed around 1200, 30, and 4 Pa,
Spectroscopic characterizations and additional figures
(PDF)
Accession Codes
CCDC 1551439 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
H
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: suman@iiti.ac.in. Phone: +91731 2438 735. Fax: +91
731 2361 482.
ORCID
(14) Cantekin, S.; de Greef, T. F.; Palmans, A. R. Benzene-1, 3, 5-
Tricarboxamide: A Versatile Ordering Moiety for Supramolecular
Chemistry. Chem. Soc. Rev. 2012, 41, 6125−6137.
Suman Mukhopadhyay: 0000-0002-5314-891X
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work is supported by CSIR, India [File 01(2829)/15/
EMR-II]. N.M. sincerely thanks the Ministry of Human
Resource Development (MHRD), India, for a doctoral
fellowship. The authors acknowledge the Sophisticated
Instrumentation Centre (SIC), IIT Indore, for providing all
other instrumental facilities.
ABBREVIATIONS
■
G4, N1,N3,N5-tris(4-cyanomethyl-phenyl)benzene-1,3,5-tri-
carboxamide; AIEE, aggregate-induced enhanced emission;
DMSO, dimethyl sulfoxide; Tgel, phase transition temperature;
CGC, critical gel concentration; Tyr, tyrosine; Leu, leucine;
Lys, lysine; Phe, phenylalanine; L-Trp, L-tryptophan; Ala,
alanine; Glu, glutamic acid; Asp, aspartic acid; Ser, serine; L-
His, L-histidine; MOF, metal−organic framework.
(21) Lee, J. H.; Baek, Y. E.; Kim, K. Y.; Choi, H.; Jung, J. H.
Metallogel of Bis (Tetrazole)-Appended Pyridine Derivative with
CoBr2 As a Chemoprobe for Volatile Gases Containing Chloride
Atom. Supramol. Chem. 2016, 28, 870−873.
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