A rhodamine based fluorescent chemodosimeter for the selective and sensitive detection of copper (II) ions in aqueous media and living cells

Article abstract of DOI:10.1016/j.molstruc.2020.129037

A rhodamine-based fluorescent probe, integrated with phosphonate group, demonstrated highly selective and sensitive recognition towards copper (II) ions over other metal species. Operating via ring opening reaction, the probe molecule (RhP) offered extensive properties such as “turn-on” fluorescence response, naked-eye detection, low detection limit (15 nM) and fast response time (<15 s). Detection of copper (II) ions in living cells as a biological application is also successfully reported.

Full text of DOI:10.1016/j.molstruc.2020.129037

Journal of Molecular Structure 1224 (2020) 129037
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
A rhodamine based fluorescent chemodosimeter for the selective and
sensitive detection of copper (II) ions in aqueous media and living
cells
Erman Karakus¸
Organic Chemistry Laboratory, Chemistry Group, The Scientific and Technological Research Council of Turkey, National Metrology Institute, (TUBITAK UME),
41470, Gebze, Kocaeli, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A rhodamine-based fluorescent probe, integrated with phosphonate group, demonstrated highly selective
and sensitive recognition towards copper (II) ions over other metal species. Operating via ring opening
reaction, the probe molecule (RhP) offered extensive properties such as “turn-on” fluorescence response,
naked-eye detection, low detection limit (15 nM) and fast response time (<15 s). Detection of copper (II)
ions in living cells as a biological application is also successfully reported.
Received 22 March 2020
Revised 27 July 2020
Accepted 6 August 2020
Available online 6 August 2020
Keywords:
©
2020 Elsevier B.V. All rights reserved.
Rhodamine
Phosphonate
Copper (II) ions detection
“
Turn-on” chemodosimeter
1
. Introduction
Recently, developing selective and sensitive signaling systems
for determining and monitoring heavy and transition metal ions
has been an alluring research topic in the chemosensing and
molecular imaging fields [15–28]. In contrast to the traditional
instrumental techniques such as atomic absorption spectroscopy
(AAS), atomic emission spectroscopy (AES) and inductively coupled
plasma mass spectroscopy (ICP-MS), fluorescent based detection
methods are preferred due to their simplicity, low cost, instant
detection, and high sensitivity. The trick of constructing a metal-
Copper, the third most abundant trace element on earth crust
besides iron and zinc, is a necessary micronutrient for animals,
plants, and people. Copper (II) ions play an important role in
various physiological processes such as red blood cell formation,
proper growth and maintenance of brain tissues, kidney, heart and
other organs of the body [1–5]. Also, copper (II) ions serve as a
catalytic co-factor for a different type of metalloenzymes including
superoxide dismutase, cytochrome oxidase and tyrosinase [6–8].
However, in sharp contrast to its beneficial effects, copper (II) ions
are so toxic for some organisms containing several bacteria and
viruses. Because of its bacterial toxicity, high concentrations of
copper obstruct the self-purification ability of ocean or rivers and
kill biological water reprocessing systems [9]. The normal level of
total copper in the blood sample is the range from 15.7 to 23.6 μM
and the U.S. Environmental Protection Agency (EPA) has set a
limit for copper ion in drinking water as 20 μM [10]. Abnormal
accumulation of copper (II) ions results in several diseases such
as Menke’s syndrome [11], Wilson’s diseases [12], and neurode-
generative diseases including Alzheimer’s and Parkinson’s diseases
specific fluorescent sensor relies on modifying
a fluorophore
with a reactive unit that has the binding ability to the related
metal ion. Then, the binding event gives reversible or irreversible
fluorescence signal upon the interaction of the fluorophore with
metal species. In this regard, there are several copper ion-selective
molecular probes utilizing various fluorophore units such as rho-
damine [29–34], BODIPY [35,36], fluorescein [37,38], naphthalimide
[39,40] and anthracene [41–43].
Among the known fluorescent molecules, the rhodamine
molecule is a distinguished example for generating off-on type
fluorescent probes due to its unique spectroscopic features such
as large molar extinction coefficients, high fluorescence quantum
yields, both long absorption, and emission wavelengths. Depending
on the pH of solution media, the spirocyclic rhodamine dye can
be found in two structural forms. In the closed form, the rho-
damine derivative is colourless and non-fluorescent at neutral pH;
however, in the open form, the dye is seen as brilliant pink color
and exhibits strong orange fluorescence (pH < 5.0). This excellent
[
13,14]. Due to the adverse effect, reliable and straightforward
recognition methods are highly demanded to detect copper ions
with high selectivity.
E-mail address: erman.karakus@tubitak.gov.tr
https://doi.org/10.1016/j.molstruc.2020.129037
0
022-2860/© 2020 Elsevier B.V. All rights reserved.

2
E. Karaku s¸ / Journal of Molecular Structure 1224 (2020) 129037
property of rhodamine dye has been utilized as a signal reporter
for developing and designing chemical sensors [18,44–46].
pound 2 (158.5 mg, 0.6 mmol) were mixed in 10 mL of CH CN
3
in the presence of trimethylamine (NEt ) (1.4 mL, 10 mmol). The
3
Herein, a novel copper (II) ion-selective rhodamine based fluo-
rescent probe is presented with privileged features including fast
response, low detection limit (concerning previous works), work-
ing in aqueous media, operability in cell imaging experiments, and
solution mixture was refluxed for 4 h under nitrogen atmosphere.
At the end of the reaction, resulted mixture was extracted with
dichloromethane (3 × 10 mL), then the obtained organic parts
were dried over anhydrous MgSO , evaporated under vacuum, and
4
the ability to discriminate Cu2 from Cu .
+
+
purified by column chromatography (hexane/EtOAc = 4/1) to give
2
20 mg of RhP (65%) as a light pink solid. 1H NMR (600 MHz,
2
. Experimental details
CDCl ): δ ppm 7.96 (d, J = 7.2 Hz, 1H), 7.53 – 7.48 (m, 2H), 7.20
3
(
t, J = 7.2 Hz, 4H), 7.12 – 7.02 (m, 7H), 6.52 (s, 2H), 6.27 (s, 4H),
.99 (d, J = 32.4 Hz, 1H, NH), 3.27 (s, 8H), 1.10 (t, J = 7.2 Hz,
2H). 13C NMR (150 MHz, CDCl ): δ ppm 170.3, 156.4, 153.3, 136.2,
2
.1. General methods
4
1
3
All chemicals were obtained by commercial suppliers such as
132.0, 131.9, 131.4, 131.1, 127.4, 127.0, 126.0, 123.0, 122.6, 118.1,
Sigma-Aldrich and/or Merck and used without applying further pu-
rification. Varian VNMRJ 600 Nuclear Magnetic Resonance Spec-
trometer was used for 1H NMR and 13C NMR measurements. Mass
analysis was conducted with Thermo Q Exactive Orbitrap device.
Ultraviolet (UV) absorption spectra were obtained with a spec-
trophotometer (UV-2550, Shimadzu). Fluorescence emission mea-
surements were obtained using Varian Cary Eclipse Fluorescence
spectrophotometer. Zeiss Axio fluorescence microscope was used
to capture cell images.
10.7, 100.5, 69.3, 47.2, 15.1. 31P-NMR (242 MHz, CDCl ): δ ppm
1
3
+
−
9.3. HRMS: m/z: Calcd. for (C40H41N O P) [M + H ]: 689.28928;
4
5
found, 689.28870.
. Results and discussion
Rhodamine B acyl chloride and compound 2 were mixed in
3
CH CN at reflux temperature to obtain the title compound, RhP,
3
with a yield of 65% (Scheme 1). The structure of RhP stayed highly
stable during the purification period and its chemical structure was
confirmed by 1H NMR, 13C NMR, 31P NMR and HRMS techniques,
as depicted in the Supporting Information (SI).
2
.2. Preparation of UV–vis and emission measurement solutions
The stock solution of probe molecule RhP (1 mM) was prepared
We commenced our investigation by screening solution me-
in CH CN and stock solutions of metal ion salts (20 mM) were pre-
3
dia. After trying different solvent combinations such as EtOH–H O,
2
pared in triple distilled deionized water. During the measurements,
the metal ion solution was added into the probe solution (2 mL)
using a micropipette. Samples were placed in 1.0 cm path length
quartz cuvettes for fluorescence measurements. The emission spec-
tra were taken over the range 525 nm to 750 nm upon excitation
at 510 nm (Both excitation and emission slit width 5 nm / 5 nm).
All measurements were repeated at least three times.
DMSO–H O, and CH CN–H O, a mixture of CH CN–H O (1:4 v:v)
2
3
2
3
2
was found to be a highly effective system for the sensing event.
A major restriction of rhodamine-based fluorescent probes is that
rhodamine molecules are highly sensitive to acidity changes. Usu-
ally, the rhodamine spirolactam derivatives exist in their open iso-
meric form (colourful and fluorescence) at acidic pH which can af-
fect negatively with the detection of analyte species. To eliminate
the inconsistency of acidity changes, we investigated the effect of
pH changes on the fluorescence intensity of the sensing medium.
As can be seen in Fig. 1, the free RhP did not display obvious fluo-
2
.3. Cell imaging experiments
Human colon carcinoma cell (HCT-116) lines were grown in
rescence emission changes in the absence of Cu2 at pH 6.0 – 10.0.
However, we set the pH of sensing media as 7.0 by using HEPES
buffer for physiological applications.
+
DMEM supplemented with 10% FBS (fetal bovine serum) in an at-
mosphere of 5% CO2 at 37 °C. The cells were cultured on 12 mm
cover glasses in a 6-well plate and set up to grow for 24 h. Before
the experiments, the cells were rinsed with PBS buffer solution,
and then the cells were incubated RhP (10 μM) for 30 min at 37 °C
As we expected, the free RhP was colourless in 4:1
HEPES/CH CN (v/v) at pH=7.0 solution, exhibited no visible ab-
3
2
+
sorption peak and it was non-emissive due to its stable ring-closed
isomeric form. Upon addition of Cu2+ions into the RhP solution, a
new absorption peak appeared at 554 nm belonging to the open
form of the rhodamine dye along with a strong increase in the flu-
orescence intensity at 584 nm (Fig. 2).
then washed with PBS three times. After then, incubation of Cu
ions (20 μM) was applied for 30 min at 37 °C. HCT-116 cells were
washed with PBS three times, and DAPI (2 μM) for 15 min at 37
°C then rinsed with PBS three times. Then Zeiss Axio fluorescence
microscope was used to take the fluorescence images.
With the systematic increment of Cu2+concentration to RhP so-
lution, the emission band at 584 nm increased linearly and we
evaluated the detection limit to be 15 nM (0.95 ppb) based on
S/N = 3 (Figure S1). The saturation point was obtained when 5
equiv. of Cu2 ions were added (Fig. 3). Although the naked eye re-
2
.4. Synthesis of RhP
Compound 1 and 2 were synthesized according to the literature
+
procedures [47,48]. Compound 1 (231.0 mg, 0.5 mmol) and com-
Scheme 1. Synthesis pathway of RhP.

E. Karaku s¸ / Journal of Molecular Structure 1224 (2020) 129037
3
Fig. 1. Effect of pH on the fluorescence intensity of RhP (10 μM) in 4:1
HEPES/CH3CN in the absence (black line) and presence (red line) of Cu2 (1.0
+
equiv.).
Fig. 4. (a) Fluorescence intensities of RhP (10 μM) in 4:1 HEPES/CH3CN at pH=7.0
2
+
in the presence of Cu (5.0 equiv.) and other metal ions (50.0 equiv.). (b) Fluores-
cence intensities of RhP (10 μM) in 4:1 HEPES/CH3CN at pH=7.0 in the presence of
2
+
+
+
+
2+
Cu (5.0 equiv.) and 50.0 equiv. other metal ions 1, Na ; 2, K ; 3, Li ; 4, Ca ; 5,
Mg2 ; 6, Ba ; 7, Cu ; 8, Ag ; 9, Cd ; 10, Co ; 11, Ni ; 12, Pb ; 13, Hg ; 14,
+
2+
2+
2+
+
+
2+
2+
2+
2+
2+
Fig. 2. (a) Absorbance spectra of RhP (10 μM) in the absence (black line) and pres-
3+
3+
3+
2+
Mn ; 15, Zn ; 16, Fe ; 17, Cr , 18, Al , 19, Cu .
ence (green line) of 5 equiv. of Cu2 and fluorescence spectra of RhP (10 μM) in the
+
absence (red line) and presence (blue line) of 5 equiv. of Cu2 in 4:1 HEPES/CH3CN
+
at pH=7.0.
Fig. 3. Fluorescence spectra of RhP (10 μM) in 4:1 HEPES/CH3CN at pH=7.0 in the presence of Cu + (mole equivalents = 0 – 10).
2

4
E. Karaku s¸ / Journal of Molecular Structure 1224 (2020) 129037
Fig. 5. Images of HCT-116 cells: (a) Cells were incubated with RhP (10 μM) in the absence of Cu2 (b) cells are detected with DAPI nuclear counter-stain (control) (c) cells
+
were incubated with RhP (10 μM) and Cu2 (20 μM) d) merged images of the frame (b) and (c) DAPI blue, RhP red.
+
Scheme 2. Proposed mechanism for the detection of Cu2 ions.
+
sponse of RhP was so fast (<15 s), the complete saturation of the
the new rhodamine structure (Figure S3). With the help of NMR
spectroscopy method, the structure of the obtained new product
was proved to be rhodamine B[49]. The proposed sensing mecha-
fluorescent intensity was seen after 20 min. (Figure S2). As seen
in Table S1, RhP has many outstanding advantages over other pub-
lished works previously in terms of sensing media, detection limit,
and live cell imaging application [49].
nism could be described as simultaneous coordination of Cu2 ions
with heteroatoms (N, O, and P) on the ligand and dye, which trig-
gered ring-opening reaction, followed by fast hydrolysis of C = N
bond via the addition of water to imine moiety, causing the forma-
tion of rhodamine B product (Scheme 2).
+
It was essential to exclude the possible effect of other metal
ions in the sensing process. Hence, the selectivity study of RhP
+
+
+
2+
2+
2+
+
to other metal ions such as Na , K , Li , Ca , Mg , Ba
Cu ,
Ag , Cd , Co , Ni , Pb , Hg , Mn , Zn , Fe , Cr , Al3+was
examined under the same sensing situation. Fortunately, all other
metal ions except for Cu2+did not cause the ring-opening reaction
to give a spectral response (Fig. 4a). Moreover, interference of other
metal ions was further assessed through competitive experiments
+
2+
2+
2+
2+
2+
2+
2+
3+
3+
Based on the distinct properties of RhP, it was questioned
whether RhP could be used for monitoring the copper ions in the
living milieu. Human colon carcinoma cells (HCT-116) were incu-
bated with RhP (10 μM) for 30 min to which was added Cu2
+
(20 μM) to be incubated for an additional 30 min. Also, the cells
were stained with DAPI (2 μM) for another 15 min. By using fluo-
rescence microscopy, the fluorescence images were obtained which
in which RhP was treated with Cu2 ions (5 equiv.) in the pres-
+
ence of excess other metal ions (50 equiv.). The results exhibited
that RhP can smoothly recognize Cu2 ions even in the presence
of a high concentration of other competing metal ions (Fig. 4b).
To figure out the nature of the overall sensing mechanism to
+
indicated turn-on response towards Cu ions in the cells (Fig. 5).
2+
4. Conclusion
−
2−
be irreversible or not, an excess amount of CN and S
(10.0
equiv.) were added to RhP solution including Cu2 ions. Interest-
ingly, the solution maintained its pink color and orange emission
which verified the irreversibility of the sensing mechanism. The re-
sulted product of the sensing event could be simply visualized by
thin-layer chromatography (TLC). The coming out an orange fluo-
rescent spot on the TLC plate was strong proof of the formation of
+
In sum, it was developed rhodamine based “off-on” type flu-
orescent sensor showing notable fluorescence intensity enhance-
2+
ment towards Cu
ions with significant selectivity over other
metal species. The sensor molecule (RhP) also exhibited a low
detection limit (15 nM), the rapid naked eye response (<15 s),
and operability in aqueous media. The sensing mechanism of RhP

E. Karaku s¸ / Journal of Molecular Structure 1224 (2020) 129037
5
based on the selective coordination of Cu2+ions following C = N
bond hydrolysis reaction. Also, it was successfully achieved the de-
tection of Cu2+ions in living cells as a biological application.
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