A rhodamine based chemosensor for solvent dependent chromogenic sensing of cobalt (II) and copper (II) ions with good selectivity and sensitivity: Synthesis, filter paper test strip, DFT calculations and cytotoxicity

Article abstract of DOI:10.1016/j.saa.2021.120099

A new chemosensor 1 was synthesized by reacting rhodamine B hydrazide and 2,3,4-trihydroxybenzaldehyde, which was then characterized by spectroscopic techniques and single crystal X-ray crystallography. Sensor 1 has the ability to sense Co²⁺/Cu²⁺ ions by “naked-eye” with an apparent colour change from colourless to pink in different solvent system, MeCN and DMF respectively. Furthermore, it can selectively detect Co²⁺/Cu²⁺ among wide range of different metal ions, and it exhibits low detection limit of 4.425 × 10^?8 M and 1.398 × 10^?7 M respectively. Binding mode of the two complexes were determined to be 1:1 stoichiometry for Co²⁺ complex and 1:2 stoichiometry for Cu²⁺ complex through Job's plot, IR spectroscopy, mass spectrometry and ¹H NMR spectroscopy. Moreover, reversibility of the sensor 1 as copper (II) ion detector was determined by using EDTA and the results showed that sensor 1 can be reused for at least 6 cycles. Other than that, a low cost chemosensor test strips were fabricated for the convenient “naked-eye” detection of Co²⁺ and Cu²⁺ in pure aqueous media. The MTT assay was conducted in order to determine the cytotoxicity of sensor 1 towards human cell lines.

Full text of DOI:10.1016/j.saa.2021.120099

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 262 (2021) 120099
Contents lists available at ScienceDirect
Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy
journal homepage: www.elsevier.com/locate/saa
A rhodamine based chemosensor for solvent dependent chromogenic
sensing of cobalt (II) and copper (II) ions with good selectivity and
sensitivity: Synthesis, filter paper test strip, DFT calculations and
cytotoxicity
a
b
b
a
c
Wei Chuen Chan , Hazwani Mat Saad , Kae Shin Sim , Vannajan Sanghiran Lee , Chee Wei Ang ,
c
a,
⇑
Keng Yoon Yeong , Kong Wai Tan
a
Department of Chemistry, Faculty of Science, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
Institute of Biological Sciences, Faculty of Science, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
School of Science, Monash University Malaysia Campus, Jalan Lagoon Selatan, Bandar Sunway, Selangor 47500, Malaysia
b
c
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
ꢀ
ꢀ
A new rhodamine based chemosensor
was synthesized and characterized.
Selectively detect Co /Cu in
different solvent systems (MeCN and
DMF).
1
2
+
2+
ꢀ
ꢀ
Sensor 1 as copper (II) ion detector
can be reused with proper treatment.
Filter paper test strip for detection of
Co and Cu in pure aqueous
solution.
2
+
2+
ꢀ
Sensor 1 showed no significant
cytotoxicity towards CCD-18Co and
HT-29 cell lines.
a r t i c l e i n f o
a b s t r a c t
Article history:
A
new chemosensor
1
was synthesized by reacting rhodamine
B
hydrazide and 2,3,4-
Received 20 March 2021
Received in revised form 9 June 2021
Accepted 19 June 2021
trihydroxybenzaldehyde, which was then characterized by spectroscopic techniques and single crystal
X-ray crystallography. Sensor 1 has the ability to sense Co /Cu ions by ‘‘naked-eye” with an apparent
colour change from colourless to pink in different solvent system, MeCN and DMF respectively.
Furthermore, it can selectively detect Co /Cu among wide range of different metal ions, and it exhibits
2+
2+
Available online 23 June 2021
2
+
2+
ꢂ8
ꢂ7
low detection limit of 4.425 ꢁ 10 M and 1.398 ꢁ 10 M respectively. Binding mode of the two com-
Keywords:
Chemosensor
Rhodamine
2+
2+
plexes were determined to be 1:1 stoichiometry for Co complex and 1:2 stoichiometry for Cu complex
1
through Job’s plot, IR spectroscopy, mass spectrometry and H NMR spectroscopy. Moreover, reversibility
of the sensor 1 as copper (II) ion detector was determined by using EDTA and the results showed that
sensor 1 can be reused for at least 6 cycles. Other than that, a low cost chemosensor test strips were fab-
ricated for the convenient ‘‘naked-eye” detection of Co and Cu in pure aqueous media. The MTT assay
was conducted in order to determine the cytotoxicity of sensor 1 towards human cell lines.
Ó 2021 Elsevier B.V. All rights reserved.
‘
‘Naked-eye” detection
Solvent dependent sensing
2
+
2+
2+
Co
Cu
2
+
1
. Introduction
⇑
Corresponding author.
E-mail address: kongwai@um.edu.my (K.W. Tan).
Essential trace elements such as metal ions play an important
role in biological system and are fundamental to the health of living
https://doi.org/10.1016/j.saa.2021.120099
386-1425/Ó 2021 Elsevier B.V. All rights reserved.
1

W.C. Chan, H.M. Saad, K.S. Sim et al.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 262 (2021) 120099
2. Experimental
organisms. Trace elements such as cobalt, copper, iron, zinc and
others are needed to mediate vital biochemical reactions and human
body requires about 100 mg per day to stay healthy [1]. However,
overload of these elements in the human body might cause several
diseases, such as Alzheimer’s and Parkinson’s disease [2].
2.1. Materials and instruments
Chemical reactants and solvents used for this research were
bought from SIGMA and MERCK. Chloride salts and nitrate salts
Cobalt is an essential trace element that is found in cobalamin
+
3+
2+
[
3]. Cobalamin is important in the formation of myelin, which is
were used to prepare the 12 metal ions solution (Ag , Al , Ca ,
2
+
2+
2+
3+
2+
+
2+
2+
2+
an insulating layer around the nerves [4]. Other than that, as an
important component of vitamin B12, cobalt plays major part in
various biological system [5]. Studies showed that cobalt is not
only important for human but also for plants, where the Co con-
taining porphyrin enzyme can catalyses decarbonylation of alde-
hydes [6]. However, excess level of cobalt in human body could
be dangerous and leads to various complications such as asthma,
cardiac disease, lung disease and dermatitis [7]. Similar to cobalt,
copper is also an essential trace element and is the third most
abundant metal in human body [8]. Deficiency of copper in human
body can cause several brain related diseases such as Alzheimer,
Parkinson and Menkes disorder [9–12]. However, excess of copper
is harmful to human body since copper is able to produce reactive
oxygen species (ROS) that will obstruct cellular metabolism [13].
Hence, it is important to trace these metal ions in the surround-
ing in order to maintain good human health. Traditional quantita-
tive approaches was able to detect these analytes at high accuracy
using instruments such as atomic absorption spectrometry (AAS)
and inductively coupled plasma atomic emission spectrometry
Cd , Co , Cu , La , Mn , Na , Ni , Pb , Zn ). JEOL ECX spec-
trometer was used to obtain NMR spectra, with tetramethylsilane
as internal reference and deuterated DMSO as solvent. FT-IR spec-
tra were obtained on a Perkin-Elmer Spectrum RX-1 spectrometer.
Shimadzu UV-2600 series spectrophotometer was utilized for
absorption spectra. Mass spectra were recorded with a Waters
Xevo TQ-S micro triple quadrupole mass spectrometer system
using positive ESI.
2.2. Synthesis of rhodamine B hydrazide
Rhodamine B (0.479 g, 1 mmol) was dissolved in ethanol
(
20 mL) and hydrazine hydrate (0.5 mL) was added in excess.
The solution was refluxed for 4 h until the colour of solution
changes from dark purple to light orange. Then, the solution was
cooled down and evaporated at room temperature. 1 M hydrochlo-
ric acid solution was added until a clear red solution was obtained,
followed by addition of 1 M sodium hydroxide solution with slow
stirring until pH 9–10 was achieved and a pink precipitate was
formed. The precipitate formed was filtered and washed with dis-
tilled water. Lastly, recrystallization process was carried out using
(
ICP-AES) [14,15]. However these methods have some disadvan-
tages such as the need for sophisticated instrumentations, tedious
sample preparation and trained operators. Hence, a chemosensor
that allowed ‘‘naked eye” detection was preferred over these meth-
ethanol and purple crystals were obtained. Yield: (0.424 g, 92.9%).
ꢂ1
FT-IR (ATR, cm ):
m = 3332, 3246, 2962, 2925, 2866, 1716, 1687,
ods [16].
1
Synthesis of probe as Co2+ and Cu2+ detector have gained con-
1633,
400 MHz, DMSO d
.29 (q, J = 7.2 Hz, 8H, NCH
1613, 1373, 1215, 1116, 1017, 815, 753.
), d (ppm): 1.06 (t, J = 7.2 Hz, 12H, NCH
CH ); 4.25 (s, 2H, NH ); 6.32 (s, 4H,
H
NMR
(
3
6
2
CH );
3
siderable interest from researchers, and much effort had been
undertaken for developing fluorometric method [17–19]. However,
fluorometric method is harder for real time detection due to the
2
3
2
Xanthene-H); 6.35 (d, J = 5.2 Hz, 2H, Xanthene-H); 6.95 (m, 1H,
paramagnetic properties of Co2 and Cu that culminate to fluo-
+
2+
Aromatic-H); 7.46 (m, 2H, Aromatic-H); 7.77 (m, 1H, Aromatic-
1
3
H). C NMR (100 MHz, DMSO d
4
1
6
), d (ppm): 12.93 (NCH
); 65.40 (C-N); 97.91, 105.76, 108.33, 122.76,
23.95, 128.17, 128.71, 128.94, 133.03, 148.68, 152.40, 153.54
2 3
CH );
rescence quenching problem [20,21]. Compared to fluorometric
probe, colorimetric detectors have obtained some interest for
enabling ‘‘naked-eye” detection in a cheap and straightforward
manner [22,23].
2 3
4.21 (NCH CH
(
Aromatic-C); 166.01 (C=O).
As a new design concept, chemosensors that can detect more
than one metal ion are more favourable because it offer advantages
such as cost reduction when comparing to a probe that can detect
only one metal ion [24]. Multiple ions detection can be achieved by
different methods such as combining multiple responsive units
into one single probe, detection of metal ions using different mech-
anism, covalent approaches and others [24,25]. However, some of
these methods require intense synthesis work. Furthermore, some
of the reported sensor showed that the detectable change from dif-
ferent analytes that emerge at same time with same trend may
cause some qualification error [26]. To overcome this issue, some
had suggested ‘‘solvent dependent sensing” method [27,28]. Detec-
tion of multiple metal ions can be attained by using different reac-
tion media which was done by Wang’s group [27]. In that study,
the acylhydrazide isoquinoline Schiff base sensor was able to
0
0
2.3. Synthesis of sensor 1, 3 ,6 -bis(diethylamino)-2-((2,3,4-
0
trihydroxybenzylidene)amino) spiro[isoindoline-1,9 -xanthen]-3-one
Rhodamine B hydrazide (0.0913 g, 0.2 mmol) and 2,3,4-
trihydroxybenzaldehyde (0.0308 g, 0.2 mmol) was dissolved in
ethanol and refluxed for 6 h as illustrated in Scheme 1. The reaction
solution was concentrated and left to cool at room temperature.
Upon slow evaporation of solvent, purple crystal was obtained
and the resulting precipitate was filtered and washed with cold
ethanol. Yield: (0.1023 g, 88.7%). FT-IR (ATR, cm ):
ꢂ1
m = 3211,
1
2973, 2931, 1676, 1607, 1372, 1219, 1119, 1021, 813, 783.
NMR (400 MHz, DMSO d ), d (ppm): 1.05 (t, J = 7.2 Hz, 12H, NCH
CH ); 3.29 (q, J = 6.8 Hz, NCH CH ); 6.32 (m, 2H, Xanthene-H); 6.36
(d, J = 2.4 Hz, 1H, Aromatic-H); 6.42 (m, 4H, Xanthene-H); 6.56 (d,
J = 8.8 Hz, 1H, Aromatic-H); 7.06 (d, J = 7.2 Hz, 1H, Aromatic-H);
H
6
2
-
3
2
3
2
+
2+
detect Mg in acetonitrile and Zn in DMF-water.
Herein we presented a new rhodamine B Schiff base derivative
based on a 2,3,4-trihydroxybenzaldehyde moiety, known as sensor
7.57 (m, 2H, Aromatic-H); 7.88 (dd, J
matic H); 8.39 (s, 1H, Imine-H); 8.93 (s, 1H, Hydroxyl-H); 9.63 (s,
1 2
= 2 Hz, J = 1.2 Hz, 1H, Aro-
1
3
1. The three hydroxyl group of the moiety might provide extra
1H, Hydroxyl-H); 10.59 (s, 1H, Hydroxyl-H). C NMR (100 MHz,
DMSO d ), d (ppm): 12.89 (NCH CH ); 44.17 (NCH CH ); 65.91
binding sites for metal ions, and it could help to improve the water
6
2
3
2
3
solubility as well. Sensor 1 was able to sense Co2 and Cu in dif-
+
2+
(C-N); 97.76, 105.09, 108.33, 108.69, 111.28, 122.44, 123.47,
124.21, 128.22, 129.15, 129.31, 129.39, 133.10, 134.31, 147.89,
149.05, 149.78, 151.63, 153.16 (aromatic C); 154.38 (C=N);
ferent solvent system with good sensitivity and selectivity. Other
than that, detection of Co2 and Cu in pure aqueous media can
be achieved by using the filter paper test strip fabricated. Further-
more, MTT assay was conducted to test the potential of sensor 1 for
the detection of metal ions in living cells.
+
2+
36 4 5
163.84 (C=O). ESI-MS m/z calc. for C35H N O
[1+H]+ 593.27,
found 593.22. The structure of sensor 1 was further established
by X-ray crystallography (Fig. 1). CCDC: 2080271. Crystal data
2

W.C. Chan, H.M. Saad, K.S. Sim et al.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 262 (2021) 120099
Scheme 1. Synthesis routes of sensor 1.
shows that sensor 1 has a monoclinic crystal system with the space
group of P2 /c. As shown in Fig. 1, the xanthene and spirolactam
moiety are forming a vertical plane that perpendicular to each
other. These will break the conjugation of whole structure, explain-
ing why free sensor 1 appears to be non-fluorescence in closed ring
state.
chased from American Type Culture Collection (ATCC, USA). The
MTT assay was carried out using the method previously described
by Heng et al. [34] with cisplatin as positive control. The data was
shown as mean ± standard deviation of triplicate experiments.
1
3
. Results and discussion
2.4. Procedures of the metal ion sensing
3.1. UV–Vis spectral response of sensor 1
Stock solution of sensor 1 (5 mM) was prepared in DMSO. On
To investigate the Co2+/Cu2+ detection properties of sensor 1,
UV–Vis absorption response experiment was performed. The free
sensor 1 was colourless with almost no absorption value above
the other hand, nitrate salts and chloride salts of the 12 metal ions
+
3+
2+
2+
2+
2+
3+
2+
+
2+
2+
2+
(
(
Ag , Al , Ca , Cd , Co , Cu , La , Mn , Na , Ni , Pb , Zn
)
5 mM) were prepared separately in distilled water. Sensor stock
5
60 nm, showing that rhodamine B spirolactam form was predom-
solution (3 mL) was placed in scintillation vial, diluted to 3 mL
and added with an appropriate aliquot of each ion stock to obtain
a test solution.
2+
2+
inant. As shown in Fig. 2, upon addition of 1 equiv. of Co /Cu to
the colourless solution of free sensor 1 (5 mM), the solution turned
pink and showed a new absorption band at 558 nm in two different
solvent systems, which are MeCN/HEPES buffer (7:3, v/v, pH 7.0)
and DMF/HEPES buffer (7:3, v/v, pH 7.0) respectively. This sug-
gested the formation of an open ring amide form upon complexa-
2
.5. X-ray data
Oxford Rigaku SuperNova Dual diffractometer equipped with a
2+
2+
tion of sensor 1 with Co /Cu . Absorption spectra of sensor 1 in
Mo-Κa
X-ray source (k = 0.71073 Å) with Atlas detector was used
+
3+
2+
2+
the presence of other metal ions such as Ag , Al , Ca , Cd
,
to analyse the intensity data of the crystals and the unit cell
parameters. Cell refinement, data acquisition and reduction were
carried out with CrysAlis Pro software [29]. SADABS was used to
carry out absorption corrections. The structure solution and refine-
ments were done by using SHELXL97 [30]. Olex2 and Ortep3 was
used to draw molecular graphics [31–33].
2+
2+
3+
2+
+
2+
2+
2+
Co /Cu , La , Mn , Na , Ni , Pb and Zn were recorded to
confirm the response of sensor towards various metal ions. The
results showed that the other metal ions did not cause any new
band formation and the sensor solution remain colourless. These
observations demonstrate the potential of sensor 1 as a ‘naked-
2+
2+
eye’ detector for Co /Cu ions.
2.6. MTT cytotoxicity assay
3.2. Optimization of reaction condition
The CCD18-Co (normal colon fibroblast) and HT-29 (human col-
orectal adenocarcinoma) cell lines used in this study were pur-
As shown in Fig. S1, sensor 1 in aq. DMSO did not show any
+
3+
2+
2+
3+
2+
+
noticeable response when Ag , Al , Ca , Cd , La , Mn , Na ,
2
+
2+
2+
Ni , Pb and Zn were added. However, the colour of solution
2
+
2+
changes from colourless to purple when Co and Cu were added.
The colour change suggested that sensor 1 can be served as a
2
+
2+
potential candidate as a ‘‘naked-eye” detector of Co and Cu
.
2
+
2+
Since both Co and Cu were showing similar colour changes,
responsive signal that appear at the same time may cause qualifi-
cation error. ‘‘Solvent-dependent sensing” method was used to
overcome this problem. To optimize the reaction condition, choice
of organic solvent, overall solvent-buffer composition, pH and
reaction time were investigated.
3.2.1. Choice of organic solvent
Since sensor 1 was insoluble in pure aqueous solution, five
organic solvent (ethanol, methanol, acetonitrile, DMSO and DMF)
were chosen as co-solvent in the reaction media. However, free
sensor 1 appeared as pink colour in aq. ethanol and aq. methanol
solution as shown in Fig. S2. Such characteristic makes ethanol
and methanol not suitable for the ‘‘naked-eye” ‘‘off-on” detection
of metal ions. In aq. DMSO, sensor 1 was colourless and it turns
Fig. 1. ORTEP plot of sensor 1. Hydrogen atoms were omitted for clarity.
2
+
2+
(
Probability level = 50%).
purple in the presence of Co and Cu , the responsive signal that
3

W.C. Chan, H.M. Saad, K.S. Sim et al.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 262 (2021) 120099
Fig. 2. a) Colour change and b) UV–Vis spectrum of sensor 1 (5 mM) with different metal ions (5 mM) in MeCN/HEPES buffer (7:3, v/v, pH7), 10 min incubation time. c) Colour
change and d) UV–Vis spectrum of sensor 1 (5 mM) with different metal ions (5 mM) in DMF/HEPES buffer (7:3, v/v, pH7), 2 min incubation time.
appear at the same time may cause some qualification error. In aq.
the response towards Co2+ started to show when there was 40%
acetonitrile and aq. DMF, sensor 1 was able to selectively detect
Co and Cu respectively by fine tuning the composition of
organic and aqueous content.
aqueous content in the reaction media (60% DMF). Hence 70%
DMF was chosen as reaction media for the detection of Cu .
2
+
2+
2+
3.2.3. Effect of pH
3
.2.2. Effect of aqueous content
To study the effect of pH and determine an appropriate pH
As shown in Fig. S3, sensor 1 showed response towards Co2+
range in which sensor 1 can detect Co /Cu effectively, acid base
titration experiment was performed. As shown in Fig. S4, free sen-
sor 1 did not show obvious characteristic colour change between
pH 4.0–12.0, suggesting that the spirolactam ring remain closed
and sensor 1 was insensitive towards pH change in this range.
2+
2+
when 10% MeCN to 90% MeCN was used and the response towards
Cu began to show when there was 40% aqueous content in the
reaction media (60% MeCN). Hence 70% MeCN was chosen as reac-
2
+
2+
tion media for the detection of Co . On the other hand, sensor 1
showed response towards Cu2 from 10% DMF to 90% DMF and
+
Addition of Co causing the absorbance enhancement at pH range
2+
4

W.C. Chan, H.M. Saad, K.S. Sim et al.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 262 (2021) 120099
of 6.0–10.0, which is due to the opening of the spirolactam ring
into ring open amide form. Besides, addition of Cu2 led to the
absorbance enhancement at pH range of 4.0–8.0. Result shows that
Thus, optimized reaction conditions for Co2+ and Cu2+ were
10 min incubation time in MeCN/HEPES buffer (7:3, v/v, pH 7),
and 2 min incubation time in DMF/HEPES buffer (7:3, v/v, pH 7).
+
sensor 1 may be used for the detection of Co2 /Cu in approximate
physiological conditions. Therefore, further colorimetric assays
were carried out in pH 7.0 HEPES buffered solution.
+
2+
3.3. Various concentration of metal ions
To gain insight on the quantitative properties of sensor 1
2
+
2+
towards Co /Cu , titration experiment was carried out with grad-
2
+
2+
3
.2.4. Effect of reaction time
The kinetic characteristics of the reaction system were studied
ual addition of Co /Cu to the free sensor 1 solution. In different
reaction system, the UV–Vis spectra of free sensor 1 were similar.
As shown in Fig. 3b, free sensor 1 itself showing two absorption
and shown in Fig. S5. The absorbance value of free sensor 1
5 mM) was almost zero and no obvious change was detected
(
band at ~277 nm and ~324 nm, which may be due to
n– * electronic transition [27]. Conjugation between the lone pair
of imine group nitrogen atom and the bond of the benzene ring
may led to n– * transition [35]. Upon gradual addition of Co /Cu
to the free sensor 1, new absorption band at 558 nm was observed
and the absorbance value increased with the increasing concentra-
tion of metal ions. The presence of two isosbestic points at
~300 nm and ~353 nm indicate that the interaction between sensor
p–p* and
throughout the whole study, indicating that the spirolactam ring
structure of sensor 1 is quite stable. Addition of Co2 causes
enhancement in the absorbance value and the value increased with
reaction time. The absorbance value reached its maximum value at
around 10th minutes. Hence, 10 min incubation time was chosen
for the detection of Co to ensure that the reaction between sensor
1
1
p
+
p
2+
2+
p
2
+
2
+
and Co is complete. On the other hand, the interaction of sensor
2
+
2+
2+
with Cu was completed within 2 min. So, 2 min incubation time
1 and Co /Cu were clean and no side reactions occurred [27].
Plots of absorbance value vs. concentration of metal ion were
plotted in Fig. 3 inset. A good linear relationship between absor-
2+
was chosen for the detection of Cu . Rapid response of sensor 1
allows this system to be used as real time monitoring of Co /Cu
2
+
2+
.
Fig. 3. Absorption spectra of sensor 1 (5 mM) with the increasing concentration of a) Co2+ in MeCN/HEPES buffer (7:3, v/v, pH 7) and b) Cu2+ in DMF/HEPES buffer (7:3, v/v, pH
7
). Inset: Plot of absorbance value at kmax 558 nm vs. concentration. [Sensor 1] = 5 mM.
5

W.C. Chan, H.M. Saad, K.S. Sim et al.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 262 (2021) 120099
2+ 2+
Cu2+, La3+, Mn2+, Na , Ni , Pb and Zn2+. Similar procedure was
+
repeated by replacing Co with Cu2+. As shown in Fig. 4, when sen-
2+
sor 1 acted as a cobalt (II) ion colorimetric probe, most of the metal
2
+
ions barely perturbed the absorbance change of sensor 1 with Co
.
The most inhibition of absorbance change was done by Al3+, which
was only 18% inhibition of the original absorbance of sensor 1 with
2
+
Co . When sensor 1 acted as a copper (II) ion colorimetric probe,
2
+
2+
Ni and Zn showed the most inhibition (20%) in the absorbance
2
+
change of sensor 1 with Cu . The interference of other metal ions
was tabulated in Table S1. This observation confirms that sensor 1
is very selective towards Co or Cu even in the presence of other
metal ions. Such characteristic is very important as the environ-
ment water sample usually contains mixture of ions.
2
+
2+
Fig. 4. UV–Vis absorbance response of sensor 1 (5
lM) at kmax 558 nm to various
Fig. 5. UV–Vis absorbance response of sensor 1 (5
l
M) at kmax 558 nm after the
cation in a) MeCN/HEPES buffer (7:3, v/v, pH 7) and b) DMF/HEPES buffer (7:3, v/v,
pH 7). The black bars represent the absorbance of sensor 1 in the presence of cations
of interest. The red bars represented changes that occur upon subsequent addition
2+
sequential addition of Cu (5
pH 7).
l
M) and EDTA (5 lM) in DMF/HEPES buffer (7:3, v/v,
of a) Co2 and b) Cu . Data is expressed as mean ± SD (n = 3).
+
2+
bance value and concentration of Co2+/Cu2+ was observed in the
2
2
range of 0–10 mM (R = 0.98) and 0–16 mM (R = 0.98) respectively.
This showing the potential of sensor 1 to be use for the quantitative
determination of cobalt (II) and copper (II) ion. Detection limit
2
+
2+
(
LOD) of sensor 1 for Co /Cu were calculated using the equation
LOD = 3 S /m, where S is the standard deviation of blank solution
and m is the slope of calibration curve [36]. LOD for Co /Cu were
b
b
2+
2+
ꢂ8
ꢂ7
calculated to be 4.42 ꢁ 10 M and 1.40 ꢁ 10 M, respectively.
2+
2+
The association constant, Ka of 1-Co and 1-Cu complexes
were determined by the Benesi-Hildebrand equation [37]:
1
1
1
¼ A
max ꢂ A
þ
0
þ
A ꢂ A
0
Amax ꢂ A K ½M ꢃ
0
a
where, A is the absorbance at the given concentration of metal ion,
max is the absorbance at the maximum concentration of metal ion,
and A is the absorbance of the free sensor without metal ion. Asso-
ciation constant was studied graphically by plotting 1/A-A vs. 1/
M ]. Data were linearly fitted as shown in Fig. S7, and the Ka values
were obtained using the slope and intercept of the graph. The Ka
A
0
0
+
[
2
+
2+
3
ꢂ1
3
ꢂ1
values of 1-Co /1-Cu are 6.46 ꢁ 10
M
and 1.88 ꢁ 10
M ,
respectively. High association constant, Ka indicates the high affin-
ity of free sensor 1 towards Co2 /Cu ions [38].
+
2+
2
+
2+
3
.4. Tolerance of sensor 1 to Co /Cu over other metal ions
The effects of other metal ions were evaluated through compet-
itive experiment. The absorbance changes of sensor 1 were
obtained after treatment of 1 equiv. of Co2 in the presence of 1
+
2+
Fig. 6. Job’s plot of complexes a) 1-Co in MeCN/HEPES buffer (7:3, v/v, pH 7) and
+
3+
2+
2+
2+
equiv. other interfering metal ions, including Ag , Al , Ca , Cd
,
b) 1-Cu in DMF/HEPES buffer (7:3, v/v, pH 7).
6

W.C. Chan, H.M. Saad, K.S. Sim et al.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 262 (2021) 120099
2+ 2+
2
+
2+
3.5. Reversibility of the interaction between sensor 1 and Co /Cu
3.6. Binding mode of sensor 1 with Co /Cu
Practical application of a sensor is much dependent on the
Job’s plot analysis was carried out to identify the binding stoi-
reusability. The coordination between sensor 1 and Cu2 was rever-
+
chiometry between sensor 1 and Co /Cu , as shown in Fig. 6.
2+
2+
2
+
sible, which was proven by adding EDTA into the solution contain-
For 1-Co , the maximum absorbance was observed when the mole
2
+
ing sensor 1 and Cu . As shown in Fig. 5, introduction of EDTA
fraction of sensor is around 0.5. This shows that the binding mode
2
+
(
5
l
(5
M) could immediately restores the absorbance of free sensor
of the 1-Co is most likely a 1:1 binding stoichiometry. Whereas
2
+
2+
1
lM). When Cu (5
lM) was added to the reaction solution
for 1-Cu , the maximum absorbance was observed when the mole
again, the absorbance of sensor 1 was enhanced. This process could
be repeated for 6 cycles before the absorbance value drops drasti-
cally. This shows that sensor 1 could be reused with proper treat-
ment for the detection of Cu2 . Besides, this also further supports
that the colour change of colourless to pink is due to the complex-
fraction of sensor is around 0.33. Such observation shows that the
formation of complex was the highest when the mole fraction of
sensor is 0.33 and mole fraction of metal ions is 0.67, which is ratio
+
2+
of 1:2 with excess metal ions. Hence, the binding mode of 1-Cu is
most likely a 1:2 (sensor: metal) binding stoichiometry.
2
+
2+
2+
ation of 1-Cu
.
IR spectra of sensor 1, 1-Co and 1-Cu were obtained to study
the binding mechanism (Fig. S9). For free sensor 1, five bands at
While for Co2+, interaction between sensor 1 and Co2+ will not
ꢂ1
ꢂ1
ꢂ1
ꢂ1
ꢂ1
be affected by EDTA. Addition of EDTA into the solution containing
3211 cm , 1677 cm , 1607 cm , 1373 cm and 1119 cm
,
2
+
sensor 1 and Co did not affect the absorbance spectrum as shown
in Fig. S8. The absorbance value only decreased 9.4% even after
addition of 1000 equiv EDTA.
were ascribed to the OH hydroxyl, C=N imine, N-C=O amide car-
2
+
2+
bonyl and C-N group respectively. Upon addition of Co /Cu
imine and amide carbonyl peak at 1677 cm
,
ꢂ1
ꢂ1
and 1607 cm
Fig. 7. 1H NMR spectrum of sensor 1 in the presence and absence of a) Co2+ and b) Cu2+ in DMSO d
.
6
7

W.C. Chan, H.M. Saad, K.S. Sim et al.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 262 (2021) 120099
Fig. 7 (continued)
Scheme 2. Proposed mechanism for interaction between sensor 1 and Co2+/Cu2+
.
shifted to 1643 cm and 1583 cm for 1-Co2+. While for 1-Cu2+,
ꢂ1
ꢂ1
ꢂ1
of 1-Co2+ was found to be 1:1 from previous Job’s analysis. This
was further supported by the IR spectrum of 1-Co since there
ꢂ1
2+
the two peaks shifted to 1647 cm and 1586 cm . These suggest
that the imine N and amide carbonyl O of sensor 1 are involved in
was free OH peak in the spectrum, indicating that not all OH group
are involved in coordination with Co . While for 1-Cu which
the coordination with Co2 /Cu . Opening of the spirolactam ring
+
2+
2+
2+
upon coordination with Co /Cu2+ is proven by the disappearance
2+
binds in 1:2 stoichiometry, disappearance of OH peak indicates
ꢂ1
ꢂ1
2+
of C-N peak at 1373 cm and 1119 cm . Binding stoichiometry
that all the OH group were involved in coordination with Cu .
8

W.C. Chan, H.M. Saad, K.S. Sim et al.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 262 (2021) 120099
Fig. 8. Optimized structure of sensor 1, 1-Co2+, 1-Cu2+ calculated at B3LYP level using LANL2DZ basis set. Energy diagram of HOMO and LUMO of sensor 1, 1-Co2+, 1-Cu2+
calculated at B3LYP level using LANL2DZ basis set.
Fig. 9. Filter paper test strips of sensor 1 (5 mM) for the detection of different metal ions (100 mM) in 100% aqueous solution (water).
Interaction between sensor 1 and Co2+/Cu2+ were further stud-
shift upon addition of Co2+). Other than that, singlet peak at
8.39 ppm was assigned to proton signal of imine (H ) and the pro-
1
ied through H NMR experiment in DMSO d
6
. As shown in Fig. 7,
I
2
+
2+
peaks at 6.42 ppm were assigned to the proton signal of xanthene
ton signal disappeared after addition of Co /Cu . This showed
that the nitrogen atom of imine group was involved in the binding
2
+
(
H
D
) and a downfield shift was observed upon addition of Cu
2
+
2+
1
which indicates the formation of delocalized xanthene (upfield
with Co /Cu . Furthermore, H NMR spectra obtained were able
9

W.C. Chan, H.M. Saad, K.S. Sim et al.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 262 (2021) 120099
Fig. 10. Color change of sensor 1 (5 mM) filter paper test strips with the increasing concentration of Co2+/Cu2+ in 100% aqueous solution (water). (top = Co2+, bottom = Cu2+).
According to the results obtained above, a proposed binding
2
+
2+
mechanism of 1 with Co /Cu was shown in Scheme 2. For 1-
2
+
Co , oxygen on the amide carbonyl group, nitrogen on the imine
moiety and oxygen on one of the hydroxyl group can participate
2
+
in the coordination with Co , forming a 1:1 metal complex. For
2
+
2+
2+
1
-Cu , one of the Cu binds to 1 in similar method as 1-Co while
2
+
the other Cu binds to the two remaining OH group, forming a 1:2
metal complex. Complexation of 1 with Co /Cu induced the
2
+
2+
opening of spirolactam ring, which causes the colour change from
2
+
colourless to pink. For 1-Cu , this process is reversible as proven
by the test using EDTA.
3.7. Density functional theory (DFT) calculations
To further study the interaction of sensor 1 with Co2+/Cu2+
,
Gaussian 09 program was used to carry out density functional the-
ory (DFT) calculation [39]. Calculation was done to obtained the
2
+
2+
optimized structure of sensor 1, 1-Co and 1-Cu at B3LYP [40–
2] level using LANL2DZ basis set. Molecular orbital diagrams
4
and HOMO-LUMO energy were also calculated at the same level
of theory. As shown in Fig. 8, HOMO is distributed over the whole
molecule, while LUMO is located on substituted spirolactam ring
2
+
for free sensor 1. In 1-Co complex, the
p electrons of HOMO are
mainly located on spirolocatam moiety while electrons of LUMO
are mainly located on xanthene moiety. Whereas in 1-Cu2+ com-
plex, the
p electrons of HOMO are mainly located on spirolactam
moiety and electrons of LUMO are located in substituted ring struc-
ture. The results support the breakdown of C-N bond and opening
of spirolactam ring in the complexation process to aid the reaction
2
+
2+
between the carbonyl oxygen atom and Co /Cu . Other than that,
2+
Fig. 11. Cytotoxic activity of sensor 1 against a) CCD-18Co and b) HT-29 cell lines.
Cisplatin was used as positive control. Data is expressed as mean ± SD (n = 3).
energy gap between HOMO and LUMO for free sensor 1, 1-Co , 1-
2+
Cu were calculated to be 2.32739 eV, 0.60518 eV and 2.08167 eV,
to explain the binding stoichiometry of sensor 1 with Co2+/Cu2+
Three singlet peaks at 8.93 ppm, 9.63 ppm and 10.60 ppm were
respectively. The reduction in the energy gap implies that metal
complexes formed are more stable than free sensor 1. Thus, the
proposed coordination complexation was favourable. Furthermore,
.
assigned to the proton of three hydroxyl group in sensor 1. When
2
+
2+
2
+
the binding stoichiometry (1:1 for 1-Co and 1:2 for 1-Cu ) from
Co was added to sensor 1 only one of the –OH peak (9.63 ppm)
DFT calculations support and complementary the results obtained
showed broadening effect, indicating that only one –OH group
1
was involved in the complexation with Co2 . However when Cu
+
2+
from previous Job’s plot, IR, H NMR and MS studies.
was added to sensor 1, all three –OH peaks were broadened and
started to disappear. This shows that all the –OH groups were
3.8. Filter paper test strip application
involved in the complexation with Cu2
+
.
ESI-MS analysis was employed to further confirm the different
Sensor test strips were fabricated by immersing Whatman filter
paper into acetonitrile solution of sensor 1 (5 mM) for 5 min and
the test strips were air-dried before use. As shown in Fig. 9, when
2+
2+
binding stoichiometry of sensor 1 with Co /Cu . As shown in
Fig. S10, ESI-MS spectra of 1-Co2 and 1-Cu display peaks at m/
+
2+
+
2+
2+
z 621.21 and 443.10, which correspond to [1 – H + Co – C
and 1/2[1 – 3H + 2Cu + 2Cl + 2MeCN + H
proves the 1:1 complexation of 1-Co complex and 1:2 complex-
H
2 5
]
the test strip was dipped into pure aqueous solution of Co /Cu ,
+
2
O] respectively. This
the colour of the test strip changed from colourless to pink, while
other potential competitive metal ions did not produce any colour
changes on the test strip. As seen from Fig. 10, increasing concen-
2+
2
+
ation of 1-Cu complex.
10

W.C. Chan, H.M. Saad, K.S. Sim et al.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 262 (2021) 120099
Table 1
Important aspects of sensor 1 and reported Co2+/Cu2+ sensors.
ꢂ1
Structure
Reaction condition
Target
analyte
LOD
(mM)
K
a
(M
)
Anti-interference
Good
Rev. Test
strip
Ref.
CN/HEPES (4:1, v/v, pH 7.4) Co2+
0.260
1.20 ꢁ 10
4
ꢁ
[47]
CH
3
Co2+
0.098
1.50 ꢁ 10
5
Good
U
ꢁ
[48]
3
CH CN
CN/HEPES (1:1, v/v, pH 7.4) Co2+
0.310
6.91 M (log
K )
a
ꢂ2
Good
–
ꢁ
[49]
CH
3
ꢂ2
General (Ag+)
CH
3
3
CN/HEPES (4:6, v/v, pH 7.2) Co2+
1.000
–
7.95 M (log
K )
a
–
U
[50]
[51]
Cu2+
6.91 ꢁ 10
4
General (Fe2+
)
U
ꢁ
CH
CN/Tris-HCl (5:5, v/v, pH
7
.0)
2
+
6
4
4
MeOH/H
2
O (5:5, v/v)
Cu
Al
Fe
0.009
0.011
0.019
1.10 ꢁ 10
5.90 ꢁ 10
5.00 ꢁ 10
Good
Good
–
U
U
U
U
[46]
[52]
3+
3+
Poor (Al3+, Cu2+
,
–
3+
Cr
)
4
EtOH/HEPES (9:1, v/v, pH 7.0)
Cu2+
2.000
6.01 ꢁ 10
Good
U
ꢁ
(
continued on next page)
11

W.C. Chan, H.M. Saad, K.S. Sim et al.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 262 (2021) 120099
Table 1 (continued)
ꢂ1
Structure
Reaction condition
Target
analyte
LOD
(mM)
K
a
(M
)
Anti-interference
General (Hg2+
Rev. Test
strip
Ref.
Cu2+
6.470
5.72 ꢁ 10
4
)
U
ꢁ
[53]
DMF/Acetate buffer (3:2, v/v,
pH 3.6)
EtOH/Tris-HCl (9:1, v/v, pH 7.4) Cu2
+
–
–
General (Mn2+,
U
U
ꢁ
[54]
3
+
2+
Fe
Fe )
Poor (Co2+, Cu2+
,
2+
Zn
)
Cu2+
0.380
–
Good
ꢁ
ꢁ
[55]
3
CH CN/H
2
O (1:1, v/v)
MeCN/HEPES (7:3, v/v, pH 7.0) Co2
+
0.044
0.140
6.46 ꢁ 10
1.88 ꢁ 10
3
3
Good
Good
ꢁ
U
U
This
work
2+
DMF/HEPES (7:3, v/v, pH 7.0)
Cu
U
a
LOD = Limit of Detection, K = Association constant, Ref. = Reference.
tration of metal ions produced more intense pink colour and the
such as easy-to-synthesis structure, rapid response that allows
real-time monitoring, wide-working pH range, low limit of detec-
tion, excellent selectivity towards targeted metal ions, reusability
of sensor and ability to detect metal ions in 100% aqueous medium
using fabricated test strip. Among reported Co /Cu sensors, most
of them were single metal ion detector. For those that were multi-
ple ion detectors, their selectivity towards target analyte will be
affected by interference of other target analytes as shown in
Table 1.
To the best of our knowledge, there are three rhodamine B
based chemosensor with poly-hydroxybenzaldehyde moiety had
been published [43–46], where all three sensors contain dihydrox-
ybenzaldehyde moiety (2,3-, 2,4- and 2,5-). Limited hydroxyl group
rendered them only the ability to target one analyte which is Cu2+
test strip was able to detect Co2 /Cu as low as 5 mM. Ability of
the test strip to detect low concentration metal ions in pure aque-
ous solution makes it useful for practical application.
+
2+
2
+
2+
3.9. Cytotoxicity of sensor 1 towards CCD-18Co and HT-29 cell lines
Selective quantification and qualification of certain species is an
interesting area of current research, and bio-imaging methodology
has been commonly used in analysis for metal ions. For practical
bio-applicability, it is important to evaluate the cytotoxicity of
the sensor in human cells. On the other hand, targeted cancer cell
imaging is highly recognized owing to the support of cancer diag-
nose and proper treatment options. MTT assay was conducted here
to study the viability of CCD-18Co and HT-29 cells after treating
with sensor 1, using cisplatin as positive control. As shown in
Fig. 11, cell viability of CCD-18Co was higher than 97% after treated
to a dose of 30 mg/mL (~50 mM) sensor 1 for 72 h. While for HT-29,
cell viability was higher than 80% after exposure to a concentration
of 3 mg/mL (~5 mM) sensor 1 for 72 h. Such results suggested that
sensor 1 showed no significant cytotoxicity under the optimized
for
2,4-dihydroxybenzaldehyde
[43]
and
2,5-
3
+
dihydroxybenzaldehyde [44]; Al for 2,3-dihydroxybenzaldehyde
[45]. Gupta’s group was able to prepare a rhodamine B sensor with
2,5-dihydroxybenzaldehyde that can detect more than one metal
ions (Cu , Al , Fe ) in aqueous MeOH solution. However, selec-
tivity of sensor towards Fe was affected in the presence of Cu
2
+
3+
3+
3
+
2+
3
+
and Al [46]. In this work, ‘‘solvent dependent sensing” method
condition for detection of Co2 /Cu (sensor 1 concentration:
mM; incubation time: <10 min), which summarize the safe use
for future bio-imaging application.
+
2+
2+
was utilized thus enabling sensor 1 to selectively detects Co
/
2
+
5
Cu without interfering each other in different solvent system
(MeCN and DMF). Compared to reported dihydroxybenzaldehyde
sensors, sensor
1 with trihydroxybenzaldehyde moiety was
3
.10. Sensor 1 vs. referenced sensors
expected to have better water solubility due to the extra hydroxyl
group that can form more hydrogen bond. Furthermore, extra
hydroxyl group in the sensor allowed more possibilities of binding
stoichiometry between sensor and metal ions (1:1 or 1:2), thus
enabling multiple ions detection.
Several important aspects of sensor 1 and other reported sen-
sors in literature studies were listed and compared in Table 1.
Compared to these sensors, sensor 1 shows several good properties
12

W.C. Chan, H.M. Saad, K.S. Sim et al.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 262 (2021) 120099
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Wei Chuen Chan: Writing - original draft, Validation, Investiga-
tion, Visualization, Data curation, Methodology, Conceptualization.
Hazwani Mat Saad: Validation, Investigation. Kae Shin Sim: Writ-
ing - review & editing, Supervision. Vannajan Sanghiran Lee:
Writing - review & editing, Supervision. Chee Wei Ang: Validation,
Investigation. Keng Yoon Yeong: Validation, Investigation. Kong
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The authors declare that they have no known competing finan-
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