A pillar[5]arene-based fluorescent sensor for sensitive detection of L-Met through a dual-site collaborative mechanism

Article abstract of DOI:10.1016/j.saa.2020.118569

L-Methionine (L-Met) is one of the essential amino acids in human health, efficiently detect L-Met is a significant issue. Herein, a concept “dual-site collaborative recognition” had been successfully introduced into the design and achieved high selective

Full text of DOI:10.1016/j.saa.2020.118569

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A pillar[5]arene-based fluorescent sensor for sensitive detection
of L-met through a dual-site collaborative mechanism
Qing-Yu Yang, You-Ming Zhang, Xiao-Qiang Ma, Hong-Qiang
Dong, Yun-Fei Zhang, Wen-Li Guan, Hong Yao, Tai-Bao Wei, Qi
Lin
PII:
S1386-1425(20)30548-5
https://doi.org/10.1016/j.saa.2020.118569
SAA 118569
DOI:
Reference:
Spectrochimica Acta Part A: Molecular and Biomolecular
Spectroscopy
To appear in:
Received date: 11 April 2020
Revised date:
28 May 2020
9 May 2020
Accepted
date:
2
Please cite this article as: Q.-Y. Yang, Y.-M. Zhang, X.-Q. Ma, et al., A pillar[5]arene-
based fluorescent sensor for sensitive detection of L-met through a dual-site collaborative
mechanism, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy
(2020), https://doi.org/10.1016/j.saa.2020.118569
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2020 Published by Elsevier.

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A pillar[5]arene-based fluorescent sensor for sensitive detection
of L-Met through a dual-site collaborative mechanism
a
a, b
a
a
Qing-Yu Yang , You-Ming Zhang* , Xiao-Qiang Ma , Hong-Qiang Dong , Yun-Fei
a
a
a
a
a
Zhang , Wen-Li Guan , Hong Yao , Tai-Bao Wei and Qi Lin*
a
Key Laboratory of Eco-functional Polymer Materials of the Ministry of Education; Key
Laboratory of Eco-environmental Polymer Materials of Gansu Province, College of Chemistry
and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu, 730070, China.
b
Gansu Natural Energy Research Institute, Lanzhou, Gansu 730046, China.
Abstract
L-Methionine (L-Met) is one of the essential amino acids in human health,
efficiently detect L-Met is a significant issue. Herein, a concept “dual-site
collaborative recognition” had been successfully introduced into the design and
achieved high selective and sensitive recognition of L-Met. In order to realize the
“dual-site collaborative recognition”, we rationally designed and synthesized an ester
functionalized pillar[5]arene-based fluorescent sensor (SP5). And it shows blue
Aggregation-induced emission (AIE) fluorescence. In the SP5, the pillar[5]arene
group act as C-H···π interactions site, and ester group serve as multi hydrogen
bonding acceptor. Interestingly, the SP5 exhibited high selectivity and sensitivity
-8
(
2.84 × 10 M) towards L-Met based on the collaboration of eletron-rich cavernous
pillar[5]arene group and ester group through C-H···π and H-bond interactions,
respectively. This “dual-site collaborative recognition” mechanism has been
1
investigated by H NMR, ESI-MS and theoretical calculation including frontier
orbital (HOMO and LUMO), electrostatic potential (ESP) and the noncovalent

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interaction (NCI). These theoretical calculations not only support the proposed
host-guest recognition mechanism, but also provided visualized information on the
“dual-site collaborative recognition” mode. Furthermore, the concept “dual-site
collaborative recognition” is an effective strategy for easily detecting biological
molecules.
Keywords: Fluorescent sensor; Dual-site collaborative recognition; AIEgen;
Pillar[n]arenes; DFT calculation.
1
. Introduction
As we all know, amino acids play significant roles in different biological areas and
participate in various life activities, such as sustaining normal physiological processes,
affecting Organs and tissues function and so on [1-4]. L-Methionine (L-Met) is one of
the essential amino acids of human body. It can lower blood pressure, protect
myocardium, resist cirrhosis and fatty liver, anti-depression and remove poison.
Simultaneously, methionine is the most important methyl donor in DNA methylation
[
5, 6]. Based on the above, there are abundant research efforts devoted to create
sensors for amino acids and their derivatives detection [7, 8]. Various methods for
amino acid determination have been reported, such as high-performance liquid
chromatography [9], electrochemistry, spectrophotometry [10-12] and mass
spectrometry [13, 14]. However, these methods always suffer from high cost, low
specificity, as well as complicated sample pretreatment. Therefore, it's still an
important subject to develop novel method and sensor for conveniently and efficiently
detecting L-Met.
Aggregation-induced emission (AIE), a very important concept presented by Tang
and co-workers [15]. AIEgens are dim or no emission in dilute solution but much
enhanced emission in aggregates or solid state [16]. The AIE phenomenon could be
put down to the restriction of intramolecular motion (RIM), including rotation and
vibration [17]. AIE probes (aggregation means local viscosity increase) are
viscosity-sensitive probes, thus, if the analyte or environmental factor is not viscosity,

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the application of AIE may have some limitations [18]. By far, a variety of AIEgen
compounds had been designed and synthesized and widely applied in various
important fields, such as organic light-emitting diode (OLED) [19], chemo and
biosensor [20, 21], as well as fluorescent imaging techniques in the last twenty years
[
22-24]. Therefore, using the concept of AIE to design amino acids fluorescent sensor
become a promising way.
Pillar[n]arene[25-27], a rising star of macrocyclic host, shows the merits including
rigid electron-rich macrocyclic structure and various host-guest interactions [28]. The
pillar[n]arenes have been applied in many fields, such as ions and molecules sensing
[
29-31], smart materials[32, 33], molecular machines [34, 35], drug controllable
releasing systems [36, 37], adsorbents[38, 39], chemocatalysis and so on [40, 41].
Interestingly, recent research found that pillar[5]arene also possess AIE activity [42].
Therefore, although numerous applications in ions and molecules recognize have been
developed [43, 44], the pillar[n]arene still supplied a new way for developing novel
AIE-based fluorescent sensors.
In view of these and as a part of our research interests in supramolecular host-guest
chemistry [45], herein, we design and synthesized an ester functionalized
pillar[5]arene-based fluorescent sensor (SP5) through rationally introducing the
concept “dual-site collaborative recognition” [46, 47]. Our strategies are as follows:
firstly, the pillar[5]arene group can offer eletron-rich cavity and C-H···π interactions
site to accommodate guest molecules. Secondly, the pillar[5]arene also could act as
AIE signal group [42]. Moreover, the ester group could serve as multi hydrogen-bond
acceptor. Benefited from these rational designs, the SP5 shows effectively fluorescent
detection for L-Met through the dual-site collaboration of pillar[5]arene group and
ester group via C-H···π, H-bond interactions.
2
. Experiment
2
.1. Materials

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All initial reagents and solvents were commercially available at analytical grade
and were used without further purification. All amino acids were used as the L style
and purchased from commercial suppliers without further purification. Fresh double
distilled water was used throughout the experiment.
2
.2. Instruments
Melting points were measured on an X-4 digital melting-point apparatus
1
(
uncorrected). H NMR spectra were recorded on Varian Mercury-400 BB
1
spectrometer (400 MHz) and Varian Inova 600 instruments (600 MHz). H chemical
shifts are reported in ppm downfield from tetramethylsilane. Mass spectra were
performed
on
a
Bruker
Esquire
3000
plus
mass
spectrometer
(Bruker-FranzenAnalytik GmbH Bremen, Germany) equipped with ESI interface and
ion trap analyzer. The IR spectra were performed on a Digilab FTS-3000 Fourier
transform-infrared spectrophotometer. Fluorescence spectra were recorded on a
Shimadzu RF-5301PC spectrofluorophotometer. Ultraviolet-visible (UV-vis) spectra
were recorded on a Shimadzu UV-2550 spectrometer. Study of scanning electron
microscopy (SEM) was performed on a JSM-6701F FE-SEM microscope.
2
.3. Synthesis of SP5
Synthesis of SP5: Pillar[5]arene 2 (0.90 g,1.0 mmol), K CO (0.14 g, 1.0 mmol)
2
3
and ethyl mercaptoacetate (0.60 mL,5.5 mmol) were added to acetonitrile (150 mL).
The above solution was kept for another 24 h at 60℃. Then the precipitate was filtered
off and the filtrate was concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (petroleum ether: CH Cl = 20:1) to produce
2
2
1
SP5 as a white solid (0.70 g, 75%). Mp: 168-170 °C. H NMR (Fig. S3)(600 MHz,
CDCl ) δ (ppm): 6.79-6.75 (m, 10H), 4.17-4.14 (q, J = 6.0 Hz, 2H), 3.84-3.82 (t, J =
3
1
1
2 Hz, 2H), 3.78-3.75 (m, 10H), 3.67-3.64 (m, 27H), 3.20 (s, 2H), 2.60-2.59 (t, 2H),
1
3
.79-1.76 (m, 2H), 1.58 (m, 2H), 1.49-1.43 (m, 4H), 1.26-1.23 (t, 3H). C NMR (Fig.
S4) (150 MHz, CDCl ) δ (ppm): 170.51, 150.70, 150.65, 150.60, 149.96, 128.29,
3
1
28.22, 128.14, 114.79, 113.95, 113.90, 68.27, 61.25, 55.73, 53.66, 55.59, 33.75,

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+
3
2.58, 29.69, 29.56, 29.34, 28.87, 25.85, 14.11. ESI-MS m/z: (M+H) Calcd for
C H O S 939.43; Found 939.43 (Fig. S6).
54
67 12
3
. Results and discussion
The synthetic route of fluorescent sensor SP5 is shown in Scheme 1. The
1
13
intermediates and product were characterized by H NMR spectra, C NMR spectra,
FT-IR spectrum and ESI-MS (Fig. S1-S6). Then, a series of DMF/H O binary
2
solutions with different water contents of SP5 were used to conduct optical
-4
measurements at a fixed concentration (1.0 × 10 M). Because the DMF is a good
solvent for SP5, while water is a poor solvent for it, upon the gradually increasing of
water, the SP5 solution exhibits fluorescence enhancing (Fig. 1). When water content
increased to f =30%, the solution showed the strongest emission intensity at in 325
w
nm (λ = 295 nm). This result indicated that the fluorescence enhancing of the SP5
ex
solution is AIE. Because with the increasing of water content, the SP5 carried out an
aggregation process and led to the restriction or absence of intramolecular motions in
ring structures, which induce the AIE. So, the SP5 could serve as a novel AIEgen.
The fluorescence quantum yields of SP5 in pure DMF and DMF/ H O binary solution
2
(fw=30%) were determined as 19.33% and 36.25%, respectively, according to the
corresponding formula, using quinine sulfate as standard [48]. In addition, the AIE
feature of SP5 could be directly observed by the fluorescence color changes taken
under 300 nm UV lamp (Fig. 1, inset). However, when the water volume fraction was
higher than 30%, because water is a poor solvent for SP5, the SP5 precipitated out
from the solution, which induced the decreasing of the fluorescent emission.

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Scheme 1. Synthesis of the pillar[5]arene SP5
.
Fig. 1. Fluorescence spectra of SP5 in DMF/H O binary solution with different water fraction,
2
-4
solution concentration: 1.0 × 10 M (λ =295 nm). Inset: photographs of SP5 in DMF/H O binary
ex
2
solution taken under 300 nm UV lamp.
Tyndall phenomenon and SEM had been carried out, interestingly, with increasing
of the water content, especially when the water content reached 30%, a significant
Tyndall phenomenon (Fig. 2a) was observed in DMF/H O binary solution, indicating
2
that the aggregation of SP5 induced enhancement of AIE fluorescence. Meanwhile,
after aggregation of SP5 in DMF/H O binary solution, the surface morphology
2
showed microspheres (Fig. 2b), this could be attributed to the hydrophobic effect.
-4
Fig. 2. (a) The Tyndall effect of SP5 (1.0 × 10 M) with different volumetric fractions of water,
(b) the SEM image of SP5, (c) the SEM image of SP5+L-Met.

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In order to investigate the amino acids recognition property of the fluorescent
sensor SP5, we carried out a series of host–guest recognition experiments. The
responses of fluorescent sensor SP5 to some natural amino acids (L-Phe, L-Gln, L-Ile,
L-Thr, L-Glu, L-Ala, L-Ser, L-Met, L-Val, L-Tyr, L-Arg, L-Asp, L-Pro, L-His, L-Leu,
L-Gly, L-Trp, L-Lys, L-Asn, and L-Cys) were primarily investigated by using
fluorescence spectroscopy. In the fluorescence spectrum, the maximum emission of
SP5 appeared at 325 nm, with the addition of 2.0 equivalents of various amino acids,
only L-Met induced the fluorescence intensity of SP5 quenched obviously, but the
addition of other amino acids exhibited almost no changes (Fig. 3). Therefore, the
SP5 showed specific fluorescence selectivity for L-Met. In addition, the selectivity of
the SP5 for L-Met over other competitive amino acids was investigated by
competitive experiments (Fig. 4). The results also showed that the SP5 could
recognize L-Met with high selectivity.
Fig. 3. Fluorescence spectra responses for SP5 and each of the various amino acids (0.1 M, 2.0
equiv.) in the DMF/H O (7:3, v/v) binary solution (λ = 295 nm).
2
ex

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-4
Fig. 4. Fluorescence response of SP5 (1.0 × 10 M) in the presence of L-Met (2.0 equiv.) and the
addition of other amino acids (0.1 M, 2.0 equiv.) in DMF/H O (7:3, v/v) binary solution (λ = 295
2
ex
nm): L-Phe, L-Gln, L-Ile, L-Thr, L-Glu, L-Ala, L-Ser, L-Val, L-Tyr, L-Arg, L-Asp, L-Pro, L-His,
L-Leu, L-Gly, L-Trp, L-Lys, L-Asn and L-Cys.
To further investigate the efficiency of the fluorescent sensor SP5 toward L-Met
detection, we carried out fluorescence emission titration experiments. In the
fluorescence spectrum, when adding L-Met (0-4.48 equiv.) to the solution of SP5, the
fluorescence emission was quenched gradually (Fig. 5). The detection limit from the
-8
fluorescence spectrum changes calculated on the basis of 3δ/S is 2.84 × 10 M (Fig.
6
-1
S8), and the association constant Ka was also determined to be 1.24 × 10 M (Fig.
S9), indicating the high sensitivity of the fluorescent sensor towards L-Met [49].

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-4
Fig. 5. Fluorescence spectra of SP5 (1×10 M) in the presence of different concentration of L-Met
in DMF/H O (7:3, v/v) solution (λ = 295 nm).
2
ex
Furthermore, in order to investigate the recognition mechanism of SP5 and L-Met,
1
the H NMR titration, 2D NOESY, ESI-MS, the Job's plot and SEM experiments were
1
carried out. In the partial H NMR spectra (Fig. 6), after the addition of L-Met, the
signal peaks H of SP5 showed downfield shift, and the signal peaks of Ha at L-Met
1
showed upfield shift, suggesting that these protons were located in the shielding
region of the cyclic pillar structure, like C-H···π interactions, and the signal peaks Hb
of L-Met showed downfield shift, which indicated that the N-H···O hydrogen bond
interaction between amino-group of L-Met and ester group of SP5. Besides, the signal
peaks H of SP5 also showed downfield shift, which indicated that the C-H···O
2
hydrogen bond interaction between ethyl group of SP5 and carboxyl group of L-Met.
Based on the above researches, we proposed this dual-site collaborative mechanism
(Scheme 2). In addition, the 2D NOESY spectrum (Fig. S10) of an equimolar solution
of SP5 and L-Met shows cross peaks representing the correlations. These signs
indicated that the assembly of SP5 with L-Met took place in solution. Additionally,
ESI-MS of an equimolar solution of SP5 and L-Met exhibited a peak at m/z =
-
1
086.48 (Fig. S11), corresponding to [SP5+L-Met-H] which revealed a 1:1
stoichiometry for the complexation between SP5 and L-Met. In the Job's plot, the
slope turning point appears at the mole fraction of 0.5 ([L-Met]/[SP5] + [L-Met])
indicates that SP5 and L-Met formed a 1:1 complex (Fig. S12). Meanwhile, the SEM
image also shows surface morphology changed from microspheres to block structures
after adding L-Met into the SP5 solution (Fig. 2c).

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1
Fig. 6. Partial H NMR spectra of SP5 (400 MHz, DMSO-d ) (a) SP5, (b) L-Met, and various
6
equivalents of L-Met:(c) 0.2 equiv., (d) 0.5 equiv., (e)1.0 equiv.
Moreover, in order to better understand the interactions and mechanism between
SP5 and L-Met, the SP5, L-Met and SP5+L-Met optimized structure were obtained
at B3LYP/6-311G* level of theory using the Gaussian 09 package suite [50],
Multiwfn software (Fig. S13) [51]. The electron cloud on the benzene ring can
interact with a C-H bond to form a C-H···π bond, which provides a favourable
condition for holding L-Met in the cavity. Based on Fig. S13, it is reasonable to exist
the C-H···π interactions, C-H···O and N-H···O hydrogen bond interactions [52, 53].
So as to elucidate the electronic structure properties of the host-guest interaction
system, the frontier orbital (HOMO and LUMO) and electrostatic potential (ESP) are
also performed. The highest occupied molecular orbitals (HOMO), lowest unoccupied
molecular orbitals (LUMO), and electrostatic potential (ESP) maps of SP5, L-Met
and host-guest complexes SP5+L-Met are shown in Fig. 7. About the SP5, the
HOMO extends over oxygen atoms as well the adjacent C=C bonds of aromatic rings,
whereas the LUMO extends over the ester group. The L-Met fragment only has a
minor contribution to the frontier orbitals. This finding indicates that the structural
stability of guest in host-guest complex is increased. And for the SP5+L-Met
complex, HOMO and LUMO are asymmetric and complicated, which means the
obvious multiple supramolecular interactions between SP5 and L-Met [54].

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Scheme 2. The proposed detecting mechanism of SP5 for L-Met.
In the ESP map of SP5, the cavity of pillar[5]arene shows negative charge
distribution, the sulfur methyl group of L-Met shows positive unit charge distribution
therefore SP5 possesses the ability of attracting the linear molecule L-Met to form
C-H···π interactions. Meanwhile, the oxygen atom is negatively charged of the ester
group from SP5, the nitrogen atom is positively charged of the amino group from
L-Met, and the carbon atom is positively charged of ethyl group from SP5, the
oxygen atom is negatively charged of the carboxyl group from L-Met, so the N-H···O
and C-H···O multiple hydrogen bonds are easily formed due to the electrostatic
attractions[55, 56].

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Fig. 7. The frontier orbitals (HOMO and LUMO) and electronic potential maps (ESP) of L-Met,
SP5 and SP5+L-Met.
For the purpose of reveal the supramolecular interactions intuitively, the
noncovalent interaction (NCI) graph were obtained through the IGM (the so-called
Independent Gradient Model) approach (Fig. 8). It further visualizes the interactions
between SP5 and L-Met, green represents the van der Waals force, which are C-H···π
interactions, blue represents the attractions, so, the presence of N-H···O and C-H···O
hydrogen bonding interactions are thus evident [51, 54].
Fig. 8. the NCI graph of SP5+L-Met.
Based on the above researches, theoretical calculations vividly show the
interactions between SP5 and L-Met, and the accuracy of results that dual-site
collaborative effects have also been proved. In other words, the synergy of
eletron-rich cavity and ester group strengthen the SP5 recognition of L-Met through
multiple supramolecular interactions.
4
. Conclusion
In summary, based on the “dual-site collaborative recognition” strategy, an ester
functionalized pillar[5]arene fluorescent sensor (SP5) was designed and synthesized.
It shows AIE fluorescence in DMF/H O (7:3, v/v) binary solution, it can detect L-Met
2
-8
with specific selectivity and high sensitivity (2.84 × 10 M). It is worth noting that
other natural amino acids did not afford any obvious interfering response.

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Simultaneously, the results showed the SP5 could dual-site collaboratively recognize
L-Met by multiple supramolecular interactions, and the theoretical calculations
support the proposed host-guest recognition mechanism clearly, also showed the
C-H···π, H-bond interactions between SP5 and L-Met visibly. Therefore, this work
provides a new idea and method for conveniently detecting amino acid. It may also
offer a theoretical basis for enriching the host-guest chemistry and understanding the
supramolecular interactions.
Acknowledgements
This work was supported by the National Natural Science Foundation of China
(NSFC) (No. Nos. 21661028; 21662031; 21574104) and the Program for Changjiang
Scholars and Innovative Research Team in University of Ministry of Education of
China (IRT 15R56).
Conflicts of interest
The authors declare no conflicts of interest.
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Author statement
Qing-Yu Yang: Software, Formal analysis, Data Curation, Writing - Original Draft.
You-Ming Zhang: Conceptualization, Funding acquisition, Validation.
Xiao-Qiang Ma: Data Curation.
Hong-Qiang Dong: Data Curation.
Yun-Fei Zhang: Data Curation.
Wen-Li Guan: Data Curation.
Hong Yao: Supervision, Project administration.
Tai-Bao Wei: Funding acquisition, Methodology, Visualization.
Qi Lin: Funding acquisition, Investigation, Writing - Review &Editing.

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Declaration of interests
The authors declare that they have no known competing financial interests or
☒
personal relationships that could have appeared to influence the work reported in this
paper.
☐The authors declare the following financial interests/personal relationships which
may be considered as potential competing interests:

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Graphical Abstract
The ester functionalized pillar[5]arene-based fluorescent sensor SP5 shows
selective fluorescent sensing for L-Met through dual-site collaborative multiple
supramolecular interactions.

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Highlights
1
. Pillar[5]arene-based fluorescent sensor (SP5) was designed and synthesized.
2
3
4
5
. The SP5 shows blue Aggregation-induced emission (AIE) fluorescence.
. The SP5 shows fluorescent sensing for L-Met by a dual-site collaboration way.
-8
. The LODs of SP5 for detecting L-Met is reach up to 2.84 ×10 M.
. Theoretical calculations support the proposed dual-site collaboration mechanism.