Construction and properties of a phototriggered Cd2+ release system

Article abstract of DOI:10.1002/ejoc.201001500

A phototriggered Cd²⁺ release complex has been prepared by using benzothiazoline as a ligand. With visible-light (λ ≥ 400 nm) irradiation, bound Cd²⁺ can be released from the complex, and the ligand is converted into a benzothiazole

Full text of DOI:10.1002/ejoc.201001500

FULL PAPER
DOI: 10.1002/ejoc.201001500
Construction and Properties of a Phototriggered Cd2+ Release System
Xu Zhang[a] and Yi Chen*[a]
Keywords: Photochemistry / Cadmium / Sensors / Fluorescence / Synthetic methods
A phototriggered Cd2+ release complex has been prepared
by using benzothiazoline as a ligand. With visible-light (λ Ն
400 nm) irradiation, bound Cd2+ can be released from the
complex, and the ligand is converted into a benzothiazole
derivative. Accompanying the process of photoconversion,
turn-on fluorescence is observed. The fluorescence intensity
increases with photoconversion until Cd2+ is completely re-
leased, which provides a convenient method to monitor the
phototriggered Cd2+ release process.
ligand. In comparison to other known photorelease sys-
tems,[4a,9] the system presented herein has some significant
features: (1) It is a visible-light trigger. (2) The release pro-
cess can be monitored by fluorescence intensity. (3) Photo-
cyclization is observed instead of photocleavage during
photochemical reaction of the ligand, in most cases. It was
found that in such a system, Cd2+ can be efficiently released
with a phototrigger.
Introduction
The phototriggered release of molecules is not only a
powerful mechanistic tool for the characterization of reac-
tive intermediates in chemical synthesis[1] and the activation
and transport of small molecules,[2] but it also has practical
applications in catalysis and chemotherapy.[3] Currently, the
light-activated release of metal ions has attracted consider-
able interest because some biologically active metals make
them an essential cofactor in numerous enzymes that are
critical for life.[4] Metal photodelivery may be a valuable
tool for the delivery of heavy metal ions to study the mecha-
nisms of metal-ion trafficking and applications, such as che-
motherapy, where toxic metal ions could be released to in-
duce cell death by catalyzing DNA and RNA cleavage or by
binding active sites of proteins competitively with essential
metals.[5]
Cadmium is a toxic metal that inhibits biological func-
tion.[6] Cadmium treatment affects transcription of many
genes, including those related to oxidative stress response;
unfolded protein response; protein synthesis, transport, and
degradation; apoptosis; cell cycle; and immune function. It
is known that cadmium forms a strong bond with sulfur
and can therefore displace essential metal ions such as Zn2+
and Ca2+ from the binding sites of certain enzymes.[7] Zn,
for instance, represents an essential structural and func-
tional component of many proteins, including those in-
volved in DNA and RNA processing;[8] therefore, the com-
petition of Cd with Zn changes enzymatic activities, re-
sulting in cell death, which may provide a new strategy for
chemotherapy.
Scheme 1. Outline of the phototriggered Cd2+ release system.
Results and Discussion
Synthesis of Complex 1
Complex 1 was designed and prepared in terms of the
report that metal ions induce rearrangements of bisbenzo-
thiazolines to Schiff base chelates.[10] Complex 1 was ob-
tained starting from salicylaldehyde, which reacted with 1,2-
dibromoethane in acetonitrile to afford dialdehyde 4 in 80%
yield. Condensation of dialdehyde 4 with 2-aminobenzo-
thiol in absolute ethanol produced benzothiazoline 3 in
86% yield. Addition of cadmium acetate in methanol to a
solution of 3 in methanol afforded orange crystalline 1 in
96% yield (Scheme 2).
In this paper, we design and prepare a phototriggered
Cd release system (Scheme 1) by using benzothiazoline as a
[a] Key Laboratory of Photochemical Conversion and
Optoelectronic Materials, Technical Institute of Physics and
Chemistry, The Chinese Academy of Sciences,
Beijing 100190, China
Phototriggered Cd2+ Release from Complex 1
Phototriggered Cd2+ release was performed with visible-
light irradiation. Upon irradiation (λ Ն 400 nm, irradiation
Fax: +86-10 62564049.
E-mail: yichencas@yahoo.com.cn
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Construction and Properties of a Phototriggered Cd2+ Release System
pletely released during the conversion of 1 into 2. This
suggestion was also confirmed by TLC: it was found that
the spot corresponding to 1 on the TLC plate (Rf = 0.15,
petroleum/ethyl acetate = 2:1) disappeared and new spot
attributable to 2 appeared (Rf = 0.56, petroleum/ethyl acet-
ate = 2:1) after irradiation for 240 min. Further study found
that the conversion of 1 into 2 is efficient and that a high
quantum yield (Φf = 0.86) was obtained. Moreover, a con-
trol experiment also found that 2 was stable in solution and
that it could not be converted back into 1 in the presence
of Cd2+, which indicates that the photorelease system is not
reversible after visible-light irradiation.
Fluorescence of 2
Turn-on fluorescence was detected during the process of
Cd2+ photorelease. It was found that weak fluorescence of
1 (λem = 371 nm, Φf = 0.03) was detected in DMSO when
using an excitation wavelength of 324 nm; the fluorescence
did, however, increase significantly during the conversion of
1 into 2 by the phototrigger. As presented in Figure 2, the
fluorescence intensity increased as the irradiation time was
increases, and the largest fluorescence intensity was ob-
tained with an irradiation time of 240 min. At that time,
the conversion of 1 into 2 was complete.
Scheme 2. Synthesis of complex 1.
power: 0.23 W), the absorption of 1 (λmax = 430 nm, ε =
6.95ϫ103 Lmol–1 cm–1 in DMSO) decreased and disap-
peared with an increase in irradiation time, and ac-
companying this process, a new band at 322 nm appeared
(Figure 1). To elucidate the species that corresponded to the
absorption of 322 nm, the product resulting from 1 with
visible-light irradiation was isolated and analyzed. Both 1H
NMR spectroscopy and HRMS (see the Experimental Sec-
tion) confirmed that the species corresponding to absorp-
tion at 322 nm is 1,2-bis[2-(benzothiazol-2-yl)phenoxy]eth-
ane (2; Scheme 1). The result indicated that 1 was converted
into 2 upon light irradiation and Cd2+ was released during
the photoconversion process. As presented in Figure 1, the
absorption at 430 nm disappeared completely when the
solution of 1 was irradiated for about 240 min (irradiation
time for complete Cd2+ release could be changed by chang-
ing the concentration of the solution or by changing the
irradiating power). This suggested that Cd2+ was com-
Figure 2. Fluorescence changes of 1 (20 μm, in DMSO) upon vis-
ible-light irradiation (λ Ն 400 nm, irradiation power: 0.23 W.
Periods: 0, 40, 80, 120, 160, 200, 240, and 280 min, λex = 324 nm).
To elucidate the fluorescence properties of 2, pure 2 was
prepared and investigated. The absorption and fluorescence
spectra of 2 are presented in Figure 3. It was found that the
absorption and emission profiles of 2 were similar to those
of pure compound 2, and the absorption (λmax = 322 nm)
and emission (λmax = 371 nm) maxima were at the same
position (Figures 1 and 2 vs. Figure 3). Strong fluorescence
of 2 (λem = 371 nm) was observed in DMSO with an exci-
tation wavelength of 324 nm, and a large fluorescence quan-
tum yield (Φf = 0.87) was obtained. In addition, control
experiments showed that benzothiazole 2 is photostable,
and no distinct changes in absorption or fluorescence was
detected after the solution of 2 was irradiated for 240 min
Figure 1. Absorption changes of 1 (20 μm in DMSO) upon visible-
light irradiation (λ Ն 400 nm, irradiation power = 0.23 W. Periods:
0, 40, 80, 120, 160, 200, 240, and 280 min).
1
with visible light. Moreover, the absorption spectra and H
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X. Zhang, Y. Chen
FULL PAPER
NMR spectroscopy confirmed that no significant binding new band at 430 nm appeared, which corresponded to the
between 2 and Cd2+ was detected.
absorption of complex 1. UV/Vis titration experiments for
the system Cd2+–3 showed the formation of a 1:1 ligand–
metal species (Figure 5, inset). Monitoring the changes at
430 nm upon Cd2+ addition, a large binding constant (logK
= 7.24) was obtained by nonlinear least-squares treatment
of the titration profile.[11] The large binding constant indi-
cates that the concentration of free Cd2+ in the background
is very low, which is one of key requirements in practical
use.
Figure 3. Absorption and fluorescence of pure compound 2 (20 μm
in DMSO, λex = 324 nm).
Fluorescence Monitoring of Phototriggered Cd2+ Release
The kinetics of Cd2+ photorelease at different irradiation
times were also investigated by monitoring the fluorescence
changes of 2. As presented in Figure 4, the fluorescence in-
tensity of 2 increased as the irradiation time was increased
until the photorelease of Cd2+ was complete. The corre-
lation between the fluorescence intensity and the irradiation
time is excellent before release is complete, which indicates
that the amount of Cd2+ released could be manipulated by
controlling the irradiation time, which is beneficial for drug
release in terms of quantity, location, and time.
Figure 5. Titration of 20 μm of ligand 3 with Cd(OCOCH3)2 in
DMSO. The inset is the plot of the optical density of 1 (at 430 nm)
against the amount of Cd2+
.
Possible Mechanism for the Photoreaction
A possible mechanism for the photoreaction consists of
a two-step sequence involving the formation of benzothiaz-
oline followed by oxidation and dehydration (Scheme 3).[12]
Preliminary investigation found that benzothiazoline for-
mation is a prerequisite to convert a Schiff base into benzo-
thiazole by photon induction. Control experiments showed
Figure 4. The kinetics of Cd2+ photorelease with different irradia-
tion times (monitoring fluorescence intensity of 2 at 371 nm).
Binding Ratio and Binding Constant of the Complex
The binding ratio and the binding constant of complex
1 were determined by titration of ligand 3 with Cd2+. Ab-
sorption changes of ligand 3 (20 μm in DMSO) with the
addition of Cd2+ [Cd(OCOCH3)2, 0.01 m in H2O] are pre-
sented in Figure 5. Upon addition of Cd2+ to a solution of
Scheme 3. A possible pathway for the conversion of 1 into 2 by
3 (λmax = 318 nm, ε = 1.1ϫ104 Lmol–1 cm–1) in DMSO, a phototriggering.
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Construction and Properties of a Phototriggered Cd2+ Release System
(6.1 g, 50 mmol) and 1,2-dibromoethane (4.7 g, 25 mmol) in aceto-
nitrile (150 mL) was added potassium carbonate (6.9 g, 50 mmol)
and potassium iodide (0.4 g, 2.5 mmol). The mixture was heated at
reflux. When no starting material (salicylaldehyde) was detectable
by TLC, the solution was concentrated and the crude product was
added to water (100 mL). The solution mixture was extracted with
dichloromethane (3ϫ50 mL). The combined organic solution was
dried with Na2SO4, the resulting solution was concentrated, and
the crude product was purified by flash column chromatography
(petroleum ether/ethyl acetate, 2:1) to afford dialdehyde 4 (5.4 g) in
80% yield. (b) A solution of 4 (0.54 g, 2 mmol) in absolute ethanol
(20 mL) was heated until 4 was dissolved completely, and the solu-
tion was then cooled to ambient temperature. To the solution was
added a solution of 2-aminobenzothiol (0.5 g, 4 mmol) in absolute
ethanol (10 mL), and the solution mixture was stirred at ambient
temperature until 4 was no longer detectable by TLC. A small
amount of deionized water (0.5 mL) was added slowly to the solu-
tion, and the solid was separated out. The crude product was
washed with ethanol (3ϫ10 mL) and water (10 mL) to afford tar-
get compound 3 (0.83 g) without further purification. Yield: 86%.
M.p. 121–122 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 7.45 (d, J
that oxygen in the air played a minor role in the conversion
reaction. A similar conversion yield of 2 (ca. 60%) was ob-
tained when the irradiation of 1 was carried out in an air-
saturated solution or in degassed solution, although the
mechanism for the photoreaction in the absence of oxygen
is not known. It is worth noting that complex 1 is stable at
ambient temperature and no significant change (detection
by absorption spectral) was detected when a solution of 1
was kept in the dark, which indicates that the conversion of
1 into 2 did not occur in the absence of light.
This study represents a platform for the development of
controlled photorelease systems with fluorescence monitor-
ing. Although the system presented herein has some short-
comings at present, including the inability to be performed
in aqueous solution and the fact that both irradiation and
excitation occur in the short wavelength region, the system
has advantages that include controlled photorelease and
turn-on fluorescence monitoring. A controlled photorelease
system is a great benefit to drug delivery in terms of quan-
tity, location, and time, which is a key goal for drug delivery = 7.6 Hz, 2 H, ArH), 7.29 (t, J = 7.4 Hz, 2 H, ArH), 7.11 (d, J =
8.1 Hz, 2 H, ArH), 6.95 (t, J = 7.5 Hz, 2 H, ArH), 6.93–6.82 (m,
4 H, ArH), 6.80 (s, 2 H, ArH), 6.70–6.62 (m, 2 H, NH), 6.61–6.50
(m, 4 H, ArH), 4.41 (d, J = 3.1 Hz, 4 H, CH2) ppm. HRMS (TOF,
EI): calcd for C28H24N2O2S2 [M]+ 484.1279; found 484.1254. (c) To
a boiling solution of 3 (484 mg, 1.0 mmol) in methanol (150 mL)
was added dropwise a solution of cadmium acetate dihydrate
(267 mg, 1.0 mmol) in methanol (10 mL). The mixture was heated
at reflux for 15 min and then cooled down to ambient temperature.
The orange crystalline solid was filtered off, washed with methanol
(3ϫ10 mL), and pure 1 (0.57 g) was obtained after drying under
vacuum without further purification. Yield: 96%. M.p. Ͼ300 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 8.76 (s, 2 H, CH=N), 7.92–
7.74 (m, 2 H, ArH), 7.52 (t, J = 7.8 Hz, 2 H, ArH), 7.28 (t, J =
7.8 Hz, 4 H, ArH), 7.22 (dd, J = 7.5, 1.7 Hz, 2 H, ArH), 7.10 (t, J
= 7.5 Hz, 2 H, ArH), 6.87 (ddt, J = 9.0, 7.3, 3.8 Hz, 4 H, ArH),
science, as improved control maximizes therapeutic effect
while minimizing side effects.[13] In addition, preliminary
studies show that the system is not only suitable for Cd2+
release, but also for the release of other metal ions such as
Zn2+ and Hg2+. From a practical viewpoint, it is desirable
for the system to be used in buffer solution with visible-
light (λ Ն 650 nm) irradiation and excitation. Modifying
molecular structure to meet the requirements, and exploring
the applications in biological processing will be the subject
of future studies.
Conclusions
In summary, a simple and efficient system for phototrig-
gered Cd2+ release has been developed. It was demonstrated
that Cd2+ can be released completely from metal–ligand
complex 1 with a phototrigger. The system presented herein
4.62 (s,
4 H, CH2) ppm. HRMS (TOF, EI): calcd. for
C28H22CdN2O2S2 [M – 1]+ 595.0156; found 595.0393.
Preparation of Benzothiazole Derivative 2: A solution of 1 (100 mg)
dissolved in DMSO (100 mL) was irradiated with a xenon lamp
has some advantages including facile preparation, stable (500 W) until no starting material was detected by TLC. The mix-
ture was concentrated, and the crude product was purified by flash
column chromatography (petroleum ether/ethyl acetate, 2:1) to af-
ford 2. M.p. 213–215 °C. 1H NMR (400 MHz, CDCl3): δ = 8.55
(d, J = 8.1 Hz, 2 H, ArH), 8.03 (d, J = 8.1 Hz, 2 H, ArH), 7.73 (d,
J = 7.7 Hz, 2 H, ArH), 7.48 (dt, J = 7.3, 1.8 Hz, 2 H, ArH), 7.41
(dt, J = 7.1, 1.1 Hz, 2 H, ArH), 7.31 (dt, J = 7.1, 0.9 Hz, 2 H,
ArH), 7.21–7.17 (m, 4 H, ArH), 4.80 (s, 4 H, CH2) ppm. HRMS
(TOF, EI): calcd. for C28H20N2O2S2 [M]+ 480.0966; found
480.0991.
complex, turn-on fluorescence monitoring, and controlled
photorelease.
Experimental Section
1
General Information: H NMR spectra were recorded at 400 MHz
with TMS as an internal reference and [D6]DMSO as the solvent.
HRMS spectra were recorded with a GC-TOF MS spectrometer.
UV absorption spectra and fluorescence spectra were measured
with an absorption spectrophotometer (Hitachi U-3010) and a
fluorescence spectrophotometer (F-2500), respectively. All chemi-
cals for synthesis were purchased from commercial suppliers, and
solvents were purified according to standard procedures. Reactions
were monitored by TLC silica gel plate (60F-254). Column
chromatography was performed on silica gel (Merck, 70–
230 mesh). A xenon lamp (500 W) with wavelength filter was used
as light sources for photorelease (irradiation power: 0.23 W).
Acknowledgments
This work was supported by the National Nature Science Founda-
tion of China (No. 21073214).
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Received: November 9, 2010
Published Online: January 20, 2011
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