Highly sensitive and selective “naked eye” sensing of Cu(II) by a novel acridine-based sensor both in aqueous solution and on the test kit

Article abstract of DOI:10.1016/j.tet.2018.09.027

A highly selective and sensitive acridine-based colorimetric sensor 2-((7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino)phenol (NAP) was developed for detection of Cu²⁺ ions both in aqueous solution and on test papers. Sensor NAP responses to Cu²⁺ ions by changing its color from yellow to pink, which could be easily observed by the naked eyes. Furthermore, the mechanism of the binding model of NAP-Cu²⁺ complex was investigated by ¹H NMR, HRMS analysis, and DFT calculations.

Full text of DOI:10.1016/j.tet.2018.09.027

Accepted Manuscript
Highly sensitive and selective “naked eye” sensing of Cu(II) by a novel acridine-based
sensor both in aqueous solution and on the test kit
Qiuzi Dai, Chunmei Gao, Yijia Liu, Haiyang Liu, Boren Xiao, Chengken Chen, Jiwei
Chen, Zigao Yuan, Yuyang Jiang
PII:
S0040-4020(18)31106-2
10.1016/j.tet.2018.09.027
TET 29799
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 July 2018
Revised Date: 6 September 2018
Accepted Date: 14 September 2018
Please cite this article as: Dai Q, Gao C, Liu Y, Liu H, Xiao B, Chen C, Chen J, Yuan Z, Jiang Y, Highly
sensitive and selective “naked eye” sensing of Cu(II) by a novel acridine-based sensor both in aqueous
solution and on the test kit, Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.09.027.
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ACCEPTED MANUSCRIPT
2
+
The first acridine derivative used as a colorimetric sensor for Cu detection was
reported with a color change from yellow to pink observed by naked-eyes.

ACCEPTED MANUSCRIPT
Highly sensitive and selective “naked eye” sensing of Cu(II) by a novel
acridine-based sensor both in aqueous solution and on the test kit
a,b
b,c
c
a,b
a,b
Qiuzi Dai , Chunmei Gao , Yijia Liu , Haiyang Liu , Boren Xiao , Chengken
a,b
a,b
d
b,d,e
Chen , Jiwei Chen , Zigao Yuan * , Yuyang Jiang *
a
Department of Chemistry, Tsinghua University, Beijing, 100084, PR China
b
State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical
Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen,
Guangdong 518055, PR China
c
College of Chemistry and Chemical Engineering, Shenzhen University, Shenzhen,
5
18060, PR China
d
Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen, 518055, PR China
e
Department of Pharmacology and Pharmaceutical Sciences, School of Medicine,
Tsinghua University, Beijing, 100084, P. R. China
Abstract
A highly selective and sensitive acridine-based colorimetric sensor
2
-((7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino)phenol (NAP) was
2
+
developed for detection of Cu ions both in aqueous solution and on test papers.
2
+
Sensor NAP responses to Cu ions by changing its color from yellow to pink, which
could be easily observed by the naked eyes. Furthermore, the mechanism of the
1

ACCEPTED MANUSCRIPT
2
+
1
binding model of NAP-Cu complex was investigated by H-NMR, HRMS analysis,
and DFT calculations.
2
+
Keywords: Cu ion; acridine; Colormetric sensor; sensitive; selective; paper test.
1
. Introduction
Copper (II) ion (Cu ), the third essential trace element found in the human body,
2
+
plays a crucial role in many physiological processes, such as hemoglobin biosynthesis,
dopamine production, nerve function regulation, gene expression, bone development,
and the functional as well as structural enhancement of proteins [1-4]. However,
excessive amounts of copper in cells was discovered in many neurodegenerative
diseases including Menkes, Wilson’s, Parkinson’s, Alzheimer’s, and prion diseases
[
5-7], and the kidney and liver damage [8-9]. Recent studies also indicate that it can
regulate tumor cell growth [10-11]. Many methods have been developed for copper
detection, including atomic absorption spectrometry (AAS), inductively coupled
plasma mass spectrometry (ICP-MS), inductively coupled plasma atomic emission
spectrometry (ICP-AES), total reflection X-Ray fluorimetry (TXRF), and anodic
stripping voltammetry (ASV), which often require expensive and sophisticated
instrument or complex sample preparation procedures [12-18]. Alternatively, color
changing based chemical probes that can be observed by the naked eyes are widely
explored in recent years owing to its convenient and efficient dection. Such as
Thiadiazole [19-20], rhodamines [21-23] and quinolones [24-30] derivatives are
2

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widely used for the detection of metal ions in aqueous solution and living system.
Colormetric sensors are widely applied for the environmental inspection due to its
highly selectivity, rapid and convenient dection. Our group has been focusing on
developing new acridine and quinolone derivatives [31-34] to study their application
2+
in pharmaceutical chemistry and metal ions detection fields. In order to develop Cu
sensors whose performance could be detected by the naked eyes, based on our
previous studies [35-36], herein we designed and synthesized
-((7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino) pheno (NAP) sensor.
a
2
2
+
We believe that the hydroxyl and nitrogen of NAP can bind with Cu to form a
extend conjugation plane, which might cause a great change in color. The sensitivity
2+
and selectivity of NAP for Cu detection were systematically investigated. The
2
+
results showed that only Cu could induce significant changes of the absorption
spectra of NAP accompanied with a color change from yellow to pink. The binding
2
+
1
model of NAP-Cu complex was investigated by H-NMR, HRMS analysis, and
2
+
DFT calculations. We proposed that NAP could recognize Cu by forming a large
2
+
conjugation plane with Cu , resulting in a red shift of electronic transition and
correspondingly color-transform of NAP. Meaningfully, a simple colorimetric
2
+
paper-made test kit based on NAP was developed for detection of Cu . Together, a
2
+
convenience, low cost, effective and easily-prepared Cu colorimetric acridine sensor
was prepared, which is the first report of an acridine derivative as a colorimetric
2
+
sensor for Cu .
3

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2
+
Fig. 1. Colorimetric sensor NAP and NAP-Cu diagram.
2
. Experimental section
2
.1 Methods and measurements
Chemicals and reagents 2, 4-dichlorobenzoic acid (98%, Energy),
5
-amino-2-methoxypyridine (98%, Energy), POCl (99.5%, Energy), 2-aminophenol
3
(
99%, Energy) were obtained commercially and used without further purification.
Solutions of the metal ions were prepared from MgCl ·6H O, MnCl ·4H O (Fuchen
2
2
2
2
Chemical), NiCl ·6H O, CoCl ·6H O (Sigma alorich), KCl, NaCl (Sangan Biotech),
2
2
2
2
PbCl , CrCl ·6H O, ZnCl ·6H O, CaCl ·4H O, CuCl ·3H O, BaCl , AlCl ·9H O,
2
3
2
2
2
2
2
2
2
2
3
2
-
2-
4
2-
2-
-
-
FeCl ·9H O and SnCl (Aladin). Sodium salts (NO , HPO , S O , ClO , Cl , OH ,
3
2
2
2
2
5
-
2-
-
2-
I , SO , H PO , S ) to prepare anions solutions (0.001 M) were purchased from
4
2
4
Energy. All the organic solvents were purchased from Adamas. All solutions were
prepared using ultrapurified water (18.4 Mꢀ cm) deionized by a Milli-QSP reagent
water system (Millipore). Nuclear magnetic resonance (NMR) spectra were recorded
on a Bruker Ultrashield TM 400 PLUS spectrometer. UV-Vis spectroscopy
measurements were acquired on a SCINCOS-4100 UV/Vis spectrophotometer. Mass
spectrum (MS) was obtained with a Waters Q-TOF premier Mass Spectrometer.
Melting points were determined on a Thomas-Hoover capillary melting point
4

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apparatus. Microplate Reader was gained from TECAN Infinite M1000PRO.
3
. Results and discussion
3
.1 Molecular structure of NAP
NAP was synthesized via a simple procedure that had been reported by our
previous work [36] as shown in Scheme 1. The character identification data,
1
13
H/ C-NMR and HRMS of NAP were shown in Figure S1-S3.
Scheme 1. The synthetic route for NAP
2
+
3
.2 NAP color transformation towards Cu
To tentatively evaluate the potential of using NAP as a colorimetric sensor for
copper (II), we test its UV-Vis absorption spectrum. As shown in Fig.2, upon addition
2
+
of 5.0 equiv of Cu to the pure NAP (20 µM) dissolved in CH CN/H O (1:9, V/V), a
3
2
2
+
newly-presented red shift of the absorption spectrum of NAP-Cu solution was
observed compared with the pure NAP. Consequently, the color of the NAP solution
5

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2
+
(
20 µM) was changed from light yellow to pink after the addition of Cu (100 µM)
2
+
（
Fig. 2）. The obvious color change upon addition of Cu makes NAP a potential
2
+
colorimetric sensor for Cu inspected by the naked-eyes.
Fig. 2. UV-Vis absorption spectrum of pure NAP (20 µM) in CH CN/H O (V/V, 1: 9)
3
2
2
+
and upon addition of 5.0 equiv of Cu . Inset: pure NAP solution (left) and NAP + 5.0
2
+
equiv of Cu (right)
2
+
3
3
.3 Sensing performance of NAP towards Cu
.3.1 Selectivity and interference from other metal ions
2
+
To examine the selectivity of NAP to Cu , the UV-vis absorption spectra of NAP
in the presence of different transition metal ions were tested. As shown in Fig. 3, after
3
+
+
3
＋
+
2+
2+
2+
the addition of different mental ions including Al , Na , Fe , K , Zn , Sn , Pb ,
2
+
2+
2+
2+
3+
2+
2+
2+
Ba , Co , Ni , Ca , Cr , Mg , Mn , and Fe to the NAP solution dissolved in
CH CN-H O (V/V, 1: 9), no significant spectra change was observed in the absorption
3
2
2
+
band of NAP. While for the Cu , a new absorption band was observed around the
6

ACCEPTED MANUSCRIPT
2
+
5
00 nm to 600 nm. At the same time, the color of the NAP solution mixed with Cu
gave rise to a yellow to pink color change.
3
+
+
Fig. 3. UV-vis spectra responses of NAP (20 µM) with different metal ions: Al , Na ,
3
＋
+
2+
2+
2+
2+
2+
2+
2+
2+
3+
2+
2+
2+
Fe , K , Cu , Zn , Sn , Pb , Ba , Co , Ni , Ca , Cr , Mg , Mn , Fe . (5
equiv., 100 µM respectively) in CH CN/H O (V/V, 1: 9). Inset: photograph of NAP
3
2
upon addition of different metal ions.
2
+
To examine the sensitivity of NAP towards Cu , a titration experiment of NAP
2
+
(
20 µM) with Cu (0-10 µM) in the solvent CH CN/H O (V/V, 1: 9) was carried out.
3 2
As shown in Fig. 4a, the UV-vis spectra were recorded after addition with different
2
+
concentrations of Cu from 2 µM to 20 µM. Increased absorption intensity at
2
+
5
40-600 nm was observed upon the addition of enhanced concentration of Cu . As
2
shown in Fig. 4b, a good linear relationship (R = 0.9655) between the absorption
2
+
2+
intensity and Cu concentration (0-10 µM) demonstrated that Cu concentration can
7

ACCEPTED MANUSCRIPT
−7
be quantitatively derived with a limitation detection of 1.6 × 10 M on the basic of
3
σ/k [37-38] by the NAP sensor, which is below the stipulated limitation of copper
concentration in drinking water (31.5 ꢁM) with the World Health Organization (WHO)
guideline [39-41], indicating its potential use in the environmental protection aspect.
2
+
These results suggest that compound NAP has a high selectivity to Cu , and could be
2
+
exploited as a colorimetric sensor for Cu .
2
+
Fig. 4. (a) UV-vis spectra of NAP in the presence of different concentrations of Cu
in CH CN/H O (V/V, 1: 9). (b) Calibration curve obtained for UV-vis spectra intensity
3
2
2
+
(
at 553 nm) of NAP versus the concentration changes of Cu ions (0 - 10 µM) in
CH CN/H O (V/V, 1: 9)
3
2
To estimate the specificity of NAP, competitive experiments were carried out
(Fig. 5a). From the instrumental read-outs, the spectral responses of NAP to different
+
+
2+
2+
cations can be classified into two types. For type 1 cations such as K , Na , Zn , Cd ,
2
+
2+
2+
2+
2+
2+
2+
2+
Pb , Co , Ni , Ca , and Mg , Mn , Ba ,Sn , the spectral changes of the
solutions of NAP were negligible before and after these cations added. Trivalent ions
8

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3
+
3+
3+
(
Fe , Cr , Al ) are the type 2 cations that induced the slightly absorbance of
2
+
NAP-Cu solution, which is possible to distinguish between trivalent cations and
monovalent/bivalent cations [42].
To evaluate the effect of anions on the detection efficiency of NAP, we
2
+
investigated the binding behavior of the metal-based sensor (NAP-Cu complex)
-
2-
-
-
-
2-
2-
towards various anions including NO , HPO , ClO , Cl , I , SO and S (Fig. 5b).
2
4
2
4
2
-
The results show that these anions except S have modest interference in the
2
+
2+
detection of Cu , and block the color and absorption-change of the NAP-Cu system,
2
-
except for S which can coordinate with copper ions to form a more stable species
copper sulfide precipitation, ensuing on release of the free NAP (Fig. S6), In addition,
2
+
addition of EDTA to the NAP-Cu complex solution, the absorbance intensity of this
solution was recovered (Fig.S7). This was attributed to the higher chelating ability of
2
+
2+
2+
EDTA for Cu (lgK
ꢂ=ꢂ18.8). Cu was removed from the surface of NAP-Cu
Cu–EDTA
with the addition of EDTA to the system resulting in the restoration of absorption,
which is consistent with the previously reported studies [43].
2
+
Fig. 5. UV-Vis absorption spectrum of NAP (20 µM) and Cu (100 µM) upon the
addition of various (a) cations (100 µM) and (b) anions (100 µM) in CH CN/H O
3
2
(V/V, 1: 9).
9

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3
.3.2 Effect of pH
To explore the appropriate pH condition for successful operation of the sensor,
the absorption of NAP was tested in buffer solution with different pH values. As
shown in Fig. 6, NAP absorption performed well from pH 5 to 8. For the buffer with
pH greater than 8, the absorption of the NAP solution decreased, likely due to the
precipitation of Cu(OH) in the alkaline conditions [44-45], which can weaken the
2
2
+
absorption intensity of NAP-Cu complex at 540-600 nm. For the buffer with pH
2
+
below 5, NAP was failed to response to the Cu , which might be caused by the
protonation of the nitrogen atom in the acridine. Compared the absorption spectra of
2
+
NAP alone and the mixture of NAP and Cu , pH 6-7, with a maximum absorption
2
+
difference, is the appropriate condition for NAP to identify Cu .Thus, pH 6-7 was
chosen as an optimum experimental condition for the following experiments of
potential applications.
Fig 6. UV-Vis absorption spectrum of NAP (20 ꢁM) at various pH values in the
2+
absence or presence of 5 equiv. Cu in Tris-HCl buffer solution.
1
0

ACCEPTED MANUSCRIPT
2
+
3
.3.3 Possible sensing mechanism of NAP with Cu
To determine the binding stoichiometry of NAP and Cu , Job’s method for
UV-Vis absorption was carried out (Fig. 7). The maximum absorption band was
2
+
2
+
reached at a molar fraction of 0.5, indicating a 1:1 ratio for NAP-Cu complex,
which could be further confirmed by ESI mass spectra. As shown in Fig. 8, the cluster
+
peaks at 352.0852 and 412.9986 corresponded to [NAP + H] (calcd = 352.0847) and
2
+
+ +
[
NAP + Cu - H ] (calcd = 412.9976), respectively were observed. This results
2
+
further suggested that the formation of a 1:1 NAP/Cu complex. The proposed
2
+
NAP-Cu binding modes were discussed and shown in Fig. S5.
2
+
Fig. 7. Job’s plot obtained for NAP and Cu ion in CH CN/H O (V/V, 1: 9). The total
3
2
2
+
concentration of NAP and Cu was fixed at 20 ꢁM. The UV-vis absorption was
measured at 553 nm.
1
1

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Fig. 8. ESI mass spectra of NAP in the presence of CuCl (2 equiv.), indicating the
2
2
+
formation of a 1:1 NAP/Cu complex.
1
2+
Fig. 9. H NMR titration analysis of (1) NAP, (2) NAP + 0.5 equiv. Cu , (3) NAP +
2+
2+
1
.0 equiv. Cu , and (4) NAP + 2.0 equiv. Cu in DMSO-d .
6
2
+
1
Further insights into the nature of NAP-Cu interactions were provided by H
NMR experiments in DMSO-d solvent (Fig. 9). The cation-induced chemical shift
6
2
+
changes were measured with the variation of the mole ratio (Cu /NAP, 0-2 equiv.).
1
2

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2
+
Cu is a paramagnetic cation and can affect the proton signals, which leads to the
2+
tardily disappeared split of the peaks. With the addition of Cu , all the chemical shift
of the aromatic hydrogens (ArH) have few shift. Obviously, the H signals of the
phenolic hydroxyl (–OH–) and secondary amine (–NH–) became broader and weaker,
which indicate that the phenolic hydroxyl and nitrogen of the secondary amide might
2
+
have participate in the binding with Cu , which were in accordance with previous
reports [46-47].
DFT calculation on NAP suggests that the highest occupied molecular orbital
(HOMO) of NAP is mainly distributed on the phenyl group while the lowest
unoccupied molecular orbital (LUMO) localizes on the phenol chain of an empty d
orbital of NAP, as shown in Fig. 10. The band gap between HOMO (-5.65 eV) and
LUMO (-2.15 eV) of NAP was calculated as 3.50 eV. On the other hand, the band
2
+
gap between HOMO (-4.93 eV) and LUMO (-2.50 eV) of the NAP-Cu complex had
2
+
increased to 2.43 eV. From this calculation, we noticed that the color changes by Cu
could be rationalized in terms of the occupancy of the frontier orbitals, the conversion
2
+
of NAP to NAP-Cu decreases the energy gap, leading to a large-scale spectrum red
shift, guaranteeing the requirement for colorimetric detection from yellow to pink,
which is similar to that reported by Fang and Kim [48-49].
1
3

ACCEPTED MANUSCRIPT
2
+
Fig. 10. Frontier molecular orbital profiles of NAP-Cu
based on DFT
(B3LYP/6-31G*) calculations.
4
. Potential applicability of NAP
To explore the potential applications of sensor NAP, test strips were prepared by
immersing filter papers into a MeOH solution of NAP (20 ꢁM) and then drying in air.
The test strips containing NAP were utilized to sense different cations by being
immersed into different cation solutions for 10 s. After several drops of ethanol (to
dissolve NAP) were added, the obvious color change was only observed by the
2+
immersion of Cu solution. Also, these test strips were tested for sensing different
2
+
concentrations of Cu , colorimetric changes can be observed and distinguished by
naked-eyes. The pink color of the test strips intensified from increased concentration
2
+
of Cu at 0, 1.0 ꢁM, 5.0 ꢁM to 10 ꢁM demonstrate that the test strips can responsive
1
4

ACCEPTED MANUSCRIPT
2
+
and indicate different concentrations of Cu even at a low concentration of 1.0 ꢁM.
2
+
Different concentration of Cu in tap water could also be detected by the NAP sensor
(Figure S4).
2
+
Fig. 11. Photographs of the test kits with NAP for detecting Cu ion in aqueous
solution with different concentrations. Left to right: 10 ꢁM, 5.0 ꢁM, 1.0 ꢁM, 0 M.
5
. Conclusions
In summary, an acridine-based colorimetric sensor NAP was designed and
synthesized, which is the first report of an acridine derivative used as a colorimetric
2
+
sensor for Cu with high selectivity and sensitivity in CH CN/H O (V/V, 1: 9)
3
2
2
+
solution. Mechanism study show that Cu binds with NAP at 1:1 mole ratio to form a
more stable and regular structure. Furthermore, NAP responds to paper strip tests for
2
+
Cu detection by a color change from yellow to pink. This type of highly selective
naked-eye colorimetric sensor would be useful for development of new sensors for
sensing ions in aqueous media.
Acknowledgement
We gratefully acknowledge the Shenzhen Municipal government SZSITIC (No.
1
5

ACCEPTED MANUSCRIPT
JCYJ20160301153959476, JCYJ20160301153753269, JCYJ20160324163734374).
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