Water switched aggregation/disaggregation strategies of a coumarin-naphthalene conjugated sensor and its selectivity towards Cu2+ and Ag+ ions along with cell imaging studies on human osteosarcoma cells (U-2 OS)

Article abstract of DOI:10.1039/c8nj01631c

A simple coumarin-naphthalene conjugated chemosensor (R1) exhibited an excellent AIE effect in methanol/water (50/50, v/v) with a perfect rectangular shape of aggregation, which was confirmed by SEM analysis. R1 could recognise Cu²⁺ ions functioning as a selective chemosensor and identify Ag⁺ in a chemodosimeter approach. The biocompatibility of R1 and bio-sensing of Cu²⁺/Ag⁺ ions were also evaluated in human osteosarcoma cells (U-2 OS). A single crystal X-ray analysis confirmed the structure as well as the hydrogen bonding interaction for the dimerization of the compound.

Full text of DOI:10.1039/c8nj01631c

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Water switched aggregation/disaggregation
strategies of a coumarin–naphthalene conjugated
sensor and its selectivity towards Cu and Ag
Cite this:DOI: 10.1039/c8nj01631c
2+
+
ions along with cell imaging studies on human
osteosarcoma cells (U-2 OS)†
a
a
a
b
Ashish Kumar, Surajit Mondal, Kumari Somlata Kayshap, Sumit Kumar Hira,
c
d
a
Partha Pratim Manna, Wim Dehaen and Swapan Dey
*
A simple coumarin–naphthalene conjugated chemosensor (R1) exhibited an excellent AIE effect in
Received 4th April 2018,
Accepted 18th May 2018
methanol/water (50/50, v/v) with a perfect rectangular shape of aggregation, which was confirmed by
2+
+
SEM analysis. R1 could recognise Cu ions functioning as a selective chemosensor and identify Ag in a
2+
+
chemodosimeter approach. The biocompatibility of R1 and bio-sensing of Cu /Ag ions were also
evaluated in human osteosarcoma cells (U-2 OS). A single crystal X-ray analysis confirmed the structure
as well as the hydrogen bonding interaction for the dimerization of the compound.
DOI: 10.1039/c8nj01631c
rsc.li/njc
highly in demand for selective sensing of heavy and noxious
Introduction
15
metal ions. Coumarin and naphthalene have both been used as
16–18
Aggregation induced emission (AIE) is now widely studied, fluorophores in different sensors reported earlier.
Fluorescent
because of its promising applications in organic light-emitting sensors have several advantages over other methods due to
1
2
3
diodes, chemosensors, fluorescent bioprobes, mechanochromic their specificity, sensitivity, and very fast response towards
4
19,20
materials etc. In 2001, Tang’s group discovered the novel complexation.
Small molecules based on fluorescence sensing
phenomenon of aggregation-induced emission (AIE) which probes are generally more attractive for metal ion detection in
2
1
2+
attracted attention because it offers a good opportunity to solve relation to AIE and bioimaging. Previously, a metal ion like Cu
4
–6
many key problems.
Molecules having hexaphenylsilole was used as a fluorescence quencher through an energy and
7
8,9
18,22
+
(HPS), or tetraphenylethylene (TPE) moieties were reported as electron transfer process.
A high concentration of Ag ions
23a,b
very good AIE chemosensors. In addition to this, some conjugated also creates adverse health effects and brain damage.
These
groups like polyarylated ethenes, butadienes, pyrans, and adverse effects of Cu and Ag ions create a need to develop a
1
0
11
12
2+
+
1
3
fulvenes were also found to have substantial AIE effects in highly selective and sensitive chemosensor to serve both environ-
2
3c–g
different solvents. AIE based chemosensors have also been mental and human health purposes.
extensively used in supramolecular chemistry, medicinal chemistry Thus, a new compound (R1) was developed in our laboratory
and biological chemistry. Beside these, AIE chemosensors are also which showed AIE in a certain proportion of water present in
14
2
+
methanol. The compound is also effective to recognize Cu
and Ag using a higher wavelength output. Possible utilization
of R1 as an intracellular sensor of Cu and Ag ions was also
evaluated by fluorescence microscopy.
The coumarin–naphthalene conjugated chemosensor (R1) was
synthesized through a simple reaction of 1-isothiocyanato-
naphthalene and 3-amino-7-diethylaminocoumarin, resulting
in a thiourea linkage between the two moieties (Scheme 1).
The compound 3-amino-7-diethylaminocoumarin (4) was prepared
+
a
2+
+
Department of Applied Chemistry, Indian Institute of Technology (ISM), Dhanbad
26 004, Jharkhand, India. E-mail: swapan@iitism.ac.in; Fax: +91 326 2296563;
8
Tel: +91 326 2235607
b
c
Department of Zoology, The University of Burdwan, Burdwan,
West Bengal 713104, India
Department of Zoology, Institute of Science, Banaras Hindu University,
Varanasi 221005, India
d
Department of Chemistry, KU Leuven, Celestijnenlaan 200F, box: 3001, Belgium
†
Electronic supplementary information (ESI) available: Experimental section,
24
following previous reports. All compounds were characterized
1
13
H-NMR, C-NMR, ESI-MS, FT-IR analysis, binding constant calculation, limit of
detection, quantum yield calculation, biological applications, and single crystal
X-ray structure of R1. CCDC 1552023. For the ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c8nj01631c
1
13
by FTIR, H-NMR, C-NMR, MS analysis and single crystal
X-ray analysis and aggregation of R1 was confirmed by SEM
(Fig. 4).
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solution of NaOH (4 N) was added to the reaction mixture until
complete neutralization. The crude product was isolated by using
20 mL of ethylacetate. This process was repeated three times
to ensure complete extraction. Anhydrous MgSO4 was added
to the organic phase to completely remove water and it was
concentrated under reduced pressure. Finally, coumarin amine
(4) was obtained with a high yield (76%) and it was used for
further reaction without purification.
Scheme 1 Synthetic route of R1.
Synthesis of R1
3
-Amino-7-diethylamino coumarin (4) (100 mg, 0.43 mmol) was
Experimental
dissolved in 20 mL of dry acetonitrile and 1-isothiocyanato-
naphthalene (5) (80 mg, 0.43 mmol) was added into the
coumarin solution. The reaction mixture was heated under
reflux conditions for 24 h. The formation of the product was
monitored through thin layer chromatography. After completion,
distilled water (20 mL) was added and it was extracted three times
with ethyl acetate (100 mL). Anhydrous MgSO was added to
4
remove water and the desired compound (R1) was purified by
column chromatography (silica gel) from the residue of evapora-
tion under reduced pressure (product yield 45.0%, 80.0 mg). m.p.
All the chemicals were purchased from Sigma-Aldrich and
Alfa-Aesar, and were used without additional purification. In
the period of use, the solvents were distilled following usual
procedure. Perchlorate salts were prepared in the laboratory,
whereas, nitrate salts were purchased from Sigma-Aldrich.
All reactions were done in dried glassware and the reaction
mixtures were purified by silica gel column chromatography.
1
13
For analysis, H-NMR and C-NMR spectra were recorded at
00 MHz and 100 MHz, respectively. For NMR analysis, CDCl3
4
1
À162 1C, H-NMR (400 MHz, CDCl
3
) of R1: d (ppm) 9.23 (s, 1H),
solvent was used with TMS as a reference, and chemical shifts
are assigned in d (ppm) units. Mass spectra (MS and HRSM)
data were recorded in positive ion mode with an ESI source.
UV-visible and fluorescence titrations were completed through
a PerkinElmer Lambda 365 and LS 55, respectively, where the
path length of the cuvette is 10 mm.
8.31 (s, 1H), 7.98 (d, J = 6.8, Hz, 1H), 7.89–7.85 (m, 3H), 7.53–7.49
(m, 4H), 7.25 (d, J = 8.8 Hz, 1H) 7.18 (s, 1H), 6.53 (d, J = 8.8 Hz,
1
H), 6.36 (s, 1H) 3.31 (q, J = 7.2 Hz, 4H), 1.11 (t, J = 7.2 Hz, 6H).
1
3
3
C NMR (125 MHz, CDCl ) of R1: d (ppm) 178.57, 160.09, 152.81,
149.69, 134.79, 131.45, 129.81, 129.39, 129.08, 128.67, 127.58,
127.37, 127.14, 125.87, 125.18, 122.17, 119.29, 109.60, 107.75,
97.32, 44.75, 12.46. ESI-MS (+): calculated C H N O S: 417.1511,
2
4 23 3 2
General methods of photo-physical studies
+
found: 418.1583 [M + H , 50], 440.141 [M + Na, 100], 857.3092
2M + Na, 98].
Photo-physical (UV-vis and fluorescence) studies were carried
[
À6
out with a stock solution of R1 (c = 5.4 Â 10 M, at pH = 7.2 Æ
0.05), which was prepared in MeOH : H
2
O (9 : 1, v/v, at pH 7.2, Reagents & cells
À4
2+
HEPES buffer). Stock solutions of guest metal ions (10 M),
The culture medium used throughout the study was RPMI-1640
supplemented with penicillin (100 U mL ) and streptomycin
3
+
+
3+
2+
3+
2+
2+
2+
2+
such as Al , K , Cr , Mn , Fe , Fe , Co , Ni , Cu , Zn ,
À1
+
2+
2+
2+
2+
3+
Ag , Cd , Ba , Hg , Pb and Bi perchlorate and nitrate salts were
prepared in 10 mL volumetric flasks. The UV-vis and fluorescence
titration studies were performed taking a 2 mL solution of R1 in a
cuvette and gradually increasing the concentration of metal ions.
À1
(100 mg mL ) (Cell clone, Genetix, India) and 10% fetal bovine
serum (Cell clone, Genetix, India). Henceforth, this combination
was considered as complete medium. Other general and fine
chemicals were procured from SIGMA, USA, unless otherwise
stated. Human bone osteosarcoma cells U-2 OS (ATCC HTB-96t)
were cultured in complete medium. Human peripheral blood
mononuclear cells (PBMCs) were separated from whole blood
using the Ficoll Hypaque technique as described earlier.
Monocytes and lymphocytes were isolated from PBMC as
described by us before. The cells were washed in phosphate
buffer saline (PBS) twice, and suspended in complete medium
before use.
Synthesis of compound 3
4-(Diethylamino)salicylaldehyde (500 mg, 2.58 mmol) was dissolved
2
5
in 1-butanol (15 mL), and ethyl nitroacetate (300 mL, 2.83 mmol) was
added to the solution. Piperidine (50 mL) and acetic acid (100 mL)
were added to the reaction mixture in a catalytic amount. Then the
reaction mixture was refluxed for 24 h with continuous stirring.
After completion, it was removed from the oil bath and cooled at
room temperature. A solid compound (3) was precipitated and
2
6
2
4
isolated in pure form (yield 70%).
Cellular imaging study
In order to investigate the possible application of the coumarin
based chemosensor (R1), we have explored the suitability of the
Synthesis of compound 4
Compound 3 (200 mg, 0.763 mmol) was taken in 5 mL compound as a chemosensor in bio-imaging. U-2 OS cells were
concentrated hydrochloric acid, and 1.0 g (5.0 mmol) of tin chloride incubated in the presence or absence of varying concentrations
À6
À5
À4
2+
+
was added slowly to the reaction mixture over 15 minutes. The (0, 1 Â 10 , 1 Â 10 & 1 Â 10 M) of Cu and Ag ions for
reaction mixture was stirred for 6 h at room temperature. The 4 hours (h) at 37 1C and 5% CO in culture medium. After
solution of the reaction mixture became transparent. An aqueous washing with PBS (Â3), the remaining metal ions were removed
2
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À5
and the cells were incubated with R1 (1 Â 10 M) for 1 hour at
room temperature. The cells were washed with PBS (Â2) and
s
fluorescence images of the cells were obtained using an EVOS
FL Cell Imaging System, Life Technologies, USA.
Biocompatibility studies
The biocompatibility of the coumarin based chemosensor (R1)
2
+
+
or the R1:Cu and R1:Ag complex was assessed by an MTT
2
7
assay for the proliferation of U-2 OS cells as described earlier.
Fig. 1 UV-vis titration of R1 in MeOH : H O (9 : 1, v/v, at pH-7.2, HEPES
2
2+
The lytic activity of the above compounds against U-2 OS cells buffer) (a) with continuous addition of Cu ions and (b) with continuous
+
addition of Ag ions.
was measured by a non-radioactive cytotoxicity assay using the
CytoTox 96 Non-Radioactive Cytotoxicity assay kit (Promega,
3
USA). U-2 OS cells (5 Â 10 ) were added to a 96-well tissue
The UV-vis absorption spectrum of R1 contains a peak at
lmax 400 nm and titration was carried out with Cu and Ag
culture dish and exposed to serial concentrations (10, 25, 50,
2+
+
and 100 mM) of free R1 or R1-loaded ions and incubated for
ions, separately. The observed peak intensity was continuously
1
8 h at 37 1C, 5% CO
2
. Percent-specific lysis was determined
2+
decreased in the presence of Cu and two isosbestic points
2
7
using the formula described earlier.
were generated at lmax 360 nm and lmax 437 nm (Fig. 1a), but in
+
the presence of Ag ions, no changes were observed in the
Hemocompatibility studies
absorption spectrum of R1 (Fig. 1b).
The effect of the coumarin based chemosensor (R1) on the
R1 itself shows weak fluorescence properties, and the fluores-
viability of human monocytes and lymphocytes was evaluated cence intensity was enhanced continuously upon the addition of
2+
by a colorimetric XTT (sodium 3-[1-(phenylaminocarbonyl)-3,4- Cu ions. When it was excited at lex 400 nm, the emission spectra
tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate) at lem 480 nm were recorded, accordingly. Moreover, the fluores-
3
assay (Roche Molecular Biochemicals, Indianapolis, IN). Human cence intensity of R1 has been quenched and a new compound R2
3
+
monocytes or lymphocytes (5 Â 10 cells per well) were plated in a was formed (Scheme 2), upon addition of Ag ions (Fig. 2). In the
+
9
6-well culture dish and exposed to serial concentrations (10, 25, presence of Ag ions, the fluorescence intensity was quenched
0, and 100 mM) of the compounds and incubated at 37 1C, 5% without the formation of a new emission band, which resulted in
5
CO
2
, for 18 h. OD was measured at 450 nm using a Synergy HT quenching of the fluorescence intensity through an energy-transfer
28b,c
Multi-Mode Microplate Reader, BioTek, USA. The data were (ET) process.
According to Hard and Soft Acid and Base (HSAB)
presented as the percentage of viable cells calculated from the theory, the S-atom behaves as a soft base, and it has a more
29
28
formula reported earlier.
polarized lone pair of electrons, which can easily form a complex
A hemolysis assay was performed as previously described by with soft acids (Ag ions).30a–d Therefore, Ag ions formed a stable
+
+
3
us. In brief, normal human RBCs were treated with increasing complex with the S-atom of thiourea in order to convert R2.
concentrations of R1 for 4 h at 37 1C. The percentage of Consequently, when the S-atom was replaced by the O-atom, the
haemolysis was determined by using the formula as described fluorescence emission intensity was low because the O-atom
2
7
30e,f
by us before.
worked as a fluorescence quencher.
Most of the metal ions (up to 10.0 equivalents) did not cause
Statistical analysis
significant changes to the peak shifting of R1. Besides these,
À6
photo-physical studies of R1 (c = 5.0 Â 10 M) have also been
The mean Æ SD was calculated for each experimental group.
carried out in a mixture of solvents by changing the percentage
‘‘n’’ represents the number of times the experiment was performed.
Differences between the groups were analyzed by unpaired
Student’s t-test and one- or two-way analysis of variance (ANOVA)
depending on the requirement.
Results and discussion
À6
The photo-physical experiments of R1 (c = 5.4 Â 10
M)
were carried out using UV-vis and fluorescence techniques in
MeOH : H O (9 : 1, v/v, at pH-7.2, HEPES buffer) with various
2
3
+
+
3+
nitrate/perchlorate salts of metal ions, such as Al , K , Cr ,
2
+
3+
2+
2+
2+
2+
2+
+
2+
2+
2+
Mn , Fe , Fe , Co , Ni , Cu , Zn , Ag , Cd , Ba , Hg ,
2
+
3+
2+
Pb , and Bi . Amongst the metal ions tested, only Cu and
Ag ions cause a change in the fluorescence intensity, which
+
2+
+
Scheme 2 Probable mode of complexation of R1 with Cu and Ag and
the formation of R2 in the presence of AgNO
was also explained using a bar diagram (ESI,† Fig. S8).
3
.
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À6
Fig. 4 (a) Effect of fluorescence intensity and (b) SEM images of different
Fig. 2 Fluorescence titration spectra of R1 (c = 5.4 Â 10
M) in
2+
2 3
proportions of H O in CH OH.
2
MeOH :H O (9 : 1, v/v, pH-7.2, HEPES buffer) (a) with Cu ions up to 3.0
equiv. and (b) with Ag ions up to 3.0 equiv. (Inset: Fluorescence change).
+
Fortunately, a single crystal of R1 was grown by slow
evaporation of 20% methanol in chloroform. Each unit cell consists
of two molecules (Z = 2) with a P1 space group and triclinic system.
The solid-state structure of compound R1 is quite interesting having
of water in the methanol–water mixture. The fluorescence
intensity of R1 was changed with different fractions of water
in methanol (Fig. 4a). R1 showed a weak fluorescence in pure
methanol, but the addition of water in methanol continuously short contacts and hydrogen-bonding interactions. The molecule
increased the fluorescence intensity until the MeOH/H
2
O ratio took part in the complementary dimerization of SÁÁÁH–N and
became 1 : 1. After that the fluorescence intensity was quenched N–HÁÁÁS with two hydrogen bonding interactions (Fig. 5). Short
sharply with an increase in the percentage of water (up to 90%) contact interactions are important for propagating the chain in a
in methanol (Fig. 4a). The enhancement in fluorescence supramolecular array. The stacking interaction between the two
intensity has been explained as a result of the morphological
changes like the aggregation induced emission (AIE) of the
chemosensor R1 varying the percentage of water in methanol.
coumarin rings was also found at a distance of 3.47 Å, which helped
in aggregation of the molecules in water.
1
According to the H-NMR spectra of R1, two NH protons of
Above, the course of disaggregation quenched the fluorescence R1 were observed at d 9.24 (1H, s) and d 6.36 (1H, s) ppm and
intensity through a disaggregation-caused quenching (DCQ) the coumarin proton at C4 appeared at d 8.31 ppm (1H, s). After
mechanism with the help of SEM analysis.
the addition of Cu(ClO ) , the three mentioned protons of R1
4 2
The quantum yield (f) and corresponding lmax of R1 itself in were shifted to d 9.97 ppm, 6.58 ppm (down field) and d 8.28 ppm
2
+
+
different solvents and its complex with Cu and Ag were (up field), respectively. AgNO was highly reactive towards R1 which
3
2
0
calculated in methanol and are shown in Fig. 3. The binding
caused the replacement of the S-atom of thiourea into a urea
linkage (R2, Scheme 2). This observation was clearly supported by
mass spectroscopy as peaks appeared at 402.1897 (R2 + H ) and
424.1626 (R2 + Na ). As a result, when AgNO was reacted with
2
+
+
constants (K ) of R1:Cu and R1:Ag were found to be 1.9 Â
a
5
À1
5
À1
31
+
1
0 M and 1.5 Â 10 M respectively. The detection limits
of R1 were recorded as 8.1 Â 10 M and 44.0 Â 10À9 M for Cu
À9 2+
+
3
+
32
and Ag ions, respectively.
chemosensor R1, a black precipitate of Ag S was isolated and the
2
The SEM images as shown in Fig. 4b(i–iv) depicted that, in fluorescence intensity was quenched (Fig. 2b).
pure methanol (10-0), the size of R1 was not predictable. But, in
the case of the 50% water in methanol mixture, R1 was observed Gaussian 09 program with the Gauss-View 5.0 visualization
to have an aggregated morphology with rectangular shape and
this is shown in a magnified view in Fig. 4b(iv). Furthermore, the
aggregation was destroyed in a 90% water–methanol mixture and
no prominent image was obtained [Fig. 4b(ii)]. The aggregated
surface morphology in 50% water–methanol caused an enhance-
ment in the fluorescence intensity, which was gradually quenched
on further addition of water.
Quantum chemical calculations were carried out using the
Fig. 3 R1 in different organic solvents; (a) fluorescence spectra and (b)
wavelength (lmax) and quantum yield (f).
Fig. 5 Single crystal X-ray structure of R1: (a) short contact and
H-bonding interactions and (b) ORTEP diagram of R1.
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was observed in the cells [Fig. 7F–H and J–L] with different
concentrations of Cu(ClO
were observed when their respective filters were used. The cell
U-2 OS) proliferation and direct cytotoxicity of R1 as well as its
4 2
) . The blue and green fluorescence
(
complexes were investigated (ESI,† Fig. S14) along with hemo-
lysis and viability (ESI,† Fig. S15), which concluded that R1 was
safe and non-toxic to live cells.
Conclusions
In conclusion, a simple chemosensor (R1) was reported which
was built up with coumarin–thiourea–naphthalene moieties.
The sensor exhibited an important role in sensing, bio-imaging,
Fig. 6 (a) Optimized structure of R1 using the DFT/B3LYP/6-311G
+
method. (b) MEP diagram of R1. (c) Optimized structure of R1:Ag using and solvent induced aggregation/disaggregation. Aggregation
2+
the Lan2LMB method. (d) Optimized structure of R1:Cu using the B3LYP/
induced emission (AIE) with the increase of water content up
to 50% in methanol and disaggregation-caused quenching
6
-311G method.
(DCQ) on raising the percentage of water in methanol above
3
3
50% were observed. AIE and DCQ both were confirmed by
fluorescence spectroscopy and SEM imaging. Besides these,
program. The density functional theory (DFT) method was
+
applied for the optimization of the structures of R1, R1:Ag and
R1:Cu using a different basis set. The basis set B3LYP/6-311G
2
+
+
2
+
R1 is also a very good sensor for Cu and Ag selectively in
methanol at pH = 7.2 Æ 0.05, in HEPES buffer solution. In
2
+
+
was applied for R1 and R1:Cu and Lan2LMB for R1:Ag . The
Molecular Electrostatic Potential (MEP) diagram (Fig. 6b) of R1
is shown in red and blue colour, where red colour indicates an
electron rich region and blue colour is for any electron deficient
region. The red colour is located above the electronegative
S atom and two O atoms of coumarin. The total energy of R1
addition to that AgNO reacted with R1 replacing the S-atom of
3
the thiourea linkage to convert it to a urea linkage (R2). All of
1
this evidence was confirmed by H-NMR and mass analysis. The
limit of detection and binding constant between host and guest
were calculated using the usual methods. It was shown that R1
and its metallated derivatives were safe and non-toxic to a wide
range of cells including WBCs and RBCs, and did not hinder
cellular growth, indicating its suitability as a biosensor.
2
+
(
E = À1641 a.u.) was higher compared to R1:Cu (À3218 a.u.)
+
and lower compared to R1:Ag (À1383 a.u.), so it clearly
2
+
indicated that R1 was less stable than R1:Cu and more stable
+
than R1:Ag (Fig. 6).
We further investigated intracellular fluorescence for visualization
of R1 with Cu and Ag ions in live cells. Human osteosarcoma
Conflicts of interest
2
+
+
cells U-2 OS were first incubated with various concentrations (0,
There are no conflicts to declare.
À6
À5
À4
1
4
 10 M, 1  10 M and 1  10 M) of Cu(ClO
4 2
) (Fig. 7) for
À5
.0 h followed by treatment with 1 Â 10 M R1 for 30 minutes
before imaging.
Acknowledgements
Very negligible fluorescence was observed in the cells (Fig. 7E
and I) that were exposed to only R1, while strong fluorescence
SD acknowledges SERB-DST, Govt. of India for the financial
assistance (project no. EMR/2016/002183) and AREAS+ (under
Erasmus Mundus) for providing a postdoctoral fellowship. AK,
SM and KSK are thankful to IIT (ISM), Dhanbad for providing a
research fellowship.
Notes and references
1
2
3
4
5
Z. Zhao, J. W. Y. Lam and B. Z. Tang, J. Mater. Chem., 2012,
2, 23726–23740.
M. Wang, G. Zhang, D. Zhang, D. Zhu and B. Z. Tang,
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W. Qin, D. Ding, J. Liu, W. Z. Yuan, Y. Hu, B. Liu and
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Chem. Soc., 2012, 134, 9956–9966.
Y. Hong, J. W. Y. Lam and B. Z. Tang, Chem. Soc. Rev., 2011,
40, 5361–5388.
2
Fig. 7 Representative fluorescence images of U-2 OS cells exposed to
À5
various concentrations of Cu(ClO
4
)
2
in R1 (1 Â 10 M). (A, E and I) R1 only,
2+
À5
2+
(
B, F and J) R1 with 1 Â 10À6 M Cu , (C, G and K) R1 with 1 Â 10 M Cu
,
À4
2+
and (D, H and L) R1 with 1 Â 10 M Cu for 4 h followed by R1.
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