A ratiometric and exclusively selective CuII fluorescent probe based on internal charge transfer (ICT)

Article abstract of DOI:10.1016/j.tet.2011.05.001

A new ratiometric and exclusively selective fluorescent probe N-butyl-4,5-di[N-(phenyl)-2-(amino)-acetamino]-1,8-naphthalimide (1) was designed and synthesized on the basis of the mechanism of internal charge transfer (ICT). The probe 1 showed exclusively selectivity for Cu^II in the presence of a variety of other metal ions in aqueous ethanol solutions and the binding mode of probe 1 with Cu^II was 1:1 metal-ligand complex. Fluorescent emission spectra of probe 1 in the presence of Cu ^II showed a 50 nm blue shift, which is from 521 nm to 471 nm. Furthermore, probe 1 shows the same fluorescent change with the Cu^II in living cells.

Full text of DOI:10.1016/j.tet.2011.05.001

Tetrahedron 67 (2011) 4869e4873
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A ratiometric and exclusively selective CuII fluorescent probe based on internal
charge transfer (ICT)
*
*
Xiufu Chen, Jingyun Wang, Jingnan Cui , Zhaochao Xu, Xiaojun Peng
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new ratiometric and exclusively selective fluorescent probe N-butyl-4,5-di[N-(phenyl)-2-(amino)-
acetamino]-1,8-naphthalimide (1) was designed and synthesized on the basis of the mechanism of internal
charge transfer (ICT). The probe 1 showed exclusively selectivity for CuII in the presence of a variety of other
metal ions in aqueous ethanol solutions and the binding mode of probe 1 with CuII was 1:1 metaleligand
complex. Fluorescent emission spectra of probe 1 in the presence of CuII showed a 50 nm blue shift, which is
from 521 nm to 471 nm. Furthermore, probe 1 shows the same fluorescent change with the CuII in living
cells.
Received 11 February 2011
Received in revised form 21 April 2011
Accepted 3 May 2011
Available online 7 May 2011
Keywords:
Ratiometric fluorescent probe
Exclusively selective CuII
Imaging agent
Ó 2011 Elsevier Ltd. All rights reserved.
Blue shift
1. Introduction
fluorescence responses based on ICT mechanism were obtained.
Soon afterward, it was observed that the amines conjugated to 1,8-
The development of highly selective and ratiometric fluorescent
probes capable of reporting transitionemetal ions has attracted
considerable attention.1 In particular, the design of ratiometric
fluorescent sensors for copper ions in the presence of a variety of
other metal ions is actively investigated.2e5 As is well-known, cop-
per is a vital trace element, the third most abundant in humans, and
is present at low levels in a variety of cells and tissues with the
highest concentrations in the liver.6 CuII plays an important role in
living systems, such as those occurring in the human nervous sys-
tem, gene expression, and the functional and structural enhance-
ment of proteins.7 Therefore fast detection of CuII in aqueous
solution or biosystems is significant for life sciences and environ-
mental sciences. However, design and synthesis of excellent fluo-
rescent probes for selective detection of transition metal ions in
biosystems remain a great challenge, because they often coexist and
most of them have a similar reactivity with common fluorescent
probes. To achieve CuII-only ratiometric sensing in aqueous solution
or biosystems, fluorescent probes require deliberate design.
naphthalimide can be deprotonated in the presence of CuII, which
resulted in the color change from primrose yellow to pink (probe
B).4b But some disadvantages exist in these two probes, probe A is
not a highly selective fluorescent sensor, it is interfered by other
metal ions, such as Co2þ, Fe2þ, Ni2þ, Agþ; probe B has a lower sen-
sitivity for CuII and poor fluorescent quantum yield because of the
PET from aniline to fluorophore. Recently, Xu et al. have shown that
the addition of a carbonyl group between 1,8-naphthalimide and di-
2-picolylamine (probe C)8 demonstrated the ability to notonly block
heavy and transition metal (HTM) ions from interacting with the
naphthalimide but also increase the oxidation potential of naph-
thalimide and to act as a sacrificial donor in order to maintain
fluorescence.9 For probe 1 in this work, two 2-amino-N-phenyl-
acetamide ligands were introduced to 4 and 5 positions of 1,8-
naphthalimide bases on probe B for the high selectivity with the
similar tetradentate receptor, the addition of a carbonyl group at the
side of aniline not only provides more Lewis basic binding site but
also reduces the steric hindrance by avoiding the interaction of two
aniline groups. Besides, it repressed PET from aniline to fluorophore,
thus increasing the fluorescent quantum yield.
1,8-Naphthalimide with an electron donor and an acceptor (EDA)
group is characteristic of an internal charge transfer (ICT) chromo-
phore.4 In our previous study, two 2-(aminomethyl)pyridine ligands
had been introduced to 4 and 5 positions of 1,8-naphthalimide
(Fig. 1, A),4a forming a tetradentate receptor, which displayed a spe-
cial cavity and had a strong binding with CuII. As a result ratiometric
2. Results and discussion
2.1. Synthesis
Probe 1 synthesized by conjugating compound 2 and 3 was
shown in Scheme 1. The intermediate compound 2 was synthesized
* Corresponding authors. E-mail addresses: jncui@dlut.edu.cn (J. Cui), pengxj@
dlut.edu.cn (X. Peng).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.001

4870
X. Chen et al. / Tetrahedron 67 (2011) 4869e4873
O
N
O
O
O
N
N
O
N
O
O
N
O
O
HN
NH HN
NH HN
NH HN
N
NH HN
HN
O
O
NH
N
N
N
1
B
C
A
Fig. 1. Structures of probe A, B, C, and 1.
from acenaphthene following a literature procedure.10 2-Azido-N-
phenylacetamide was prepared in 90% yield by the condensation of
2-bromine-N-phenylacetamide with sodium azide and was sub-
sequently reduced into compound 3 in 100% yield, probe 1 was
easily synthesized by conjugating compound 2 and compound 3 in
83.5% yield.
quenching was most likely caused by the photoinduced electron
transfer (PET) from the fluorophore to protonated aniline in strong
acids condition,11 which was similar to the findings of de Silva in
the design of an ‘off-on-off’ fluorescent PET sensor.12 And PET from
deprotonated aniline to the fluorophore in strong alkali condition.
Therefore, further fluorescence studies were carried out at pH 7.4
maintained with HEPES buffer (30 mM).
2.3. Optical behavior of 1 with CuII
H
O
N
O
N
NH2
3
, DIPEA
The emission spectra of 1 and its fluorescence titration with CuII
were recorded in an ethanolewater solution (90:10, v/v) (Fig. 3),
and the emission spectrum of free 1 displays a broad band with
a maximum at 521 nm. When CuII was added to the solution of 1,
the fluorescence emission intensity at 521 nm decreased signifi-
cantly and a blue-shifted emission band centered at 471 nm
showed up, which was attributed to the formation of a 1/CuII
complex. The inset in Fig. 3 exhibits the dependence of the intensity
ratios of emission at 471 nm to that at 521 nm (I471/I521) on the
concentrations of CuII, which indicates the formation of a 1/CuII
adduct of 1:1 stoichiometry. The FF values of free 1 and 1/CuII ad-
duct (1:1) are 0.5378 and 0.1138, respectively.13 In the UVevis ab-
sorption spectra of 1, no significant changes was found with the
addition of Cu2þ. This would indicate that the blue shift of fluo-
rescence spectra was caused by a change of the charge-transfer
character of the emissive species.
O
1
CH2OHCH2OCH3, N2,reflux
NO2 Br
2
Scheme 1. Synthesis of probe 1.
2.2. The effect of pH
Fluoroionophores are usually disturbed by a proton in the de-
tection of metal ions. Thus, the influence of pH on the fluorescence
of 1 was first determined by fluorescence titration (Fig. 2). The
fluorescence of 1 at 521 nm remains unaffected between pH
12.56e1.99 and rapidly decreases from pH 1.99 to 0.96 and pH
12.56 to 13.04, leading to a vaulted curve. The fluorescence
2
500
500
450
400
350
300
250
I
(471)
I(521)
1
0
400
300
200
100
0
0
10
20
II
c(Cu )/µM
0
II
[Cu ]
50µM
450
500
550
600
650
700
Wavelength (nm)
10
12
14
0
2
4
6
8
Fig. 3. Fluorescent emission spectra of 1 in the presence of different concentrations of
CuII(0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 50
M) in ethanolewater solution (90:10,
v/v, 30 mM HEPES buffer, pH 7.4). Excitation wavelength was 447 nm, and emission
pH
m
Fig. 2. Influence of pH on the fluorescence of 1 in the ethanolewater solution (90:10,
v/v). Excitation wavelength is 447 nm, [1]¼10 M. The pH was modified by adding 75%
HClO4 or 25% Nþ(CH3)4OHꢀ
m
was at 471 and 521 nm. The concentration of 1 was 10 mM. Inset: ratiometric cali-
.
bration curve I471/I521 as a function of CuII concentration.

X. Chen et al. / Tetrahedron 67 (2011) 4869e4873
4871
The fluorescence titration of 1 with various metal ions in etha-
nolewater solution was conducted to examine the selectivity. As
shown in Fig. 4b, the addition of Cu2þ induced a selective increase
in emission band at 471 nm. The addition of other metal ions, such
O
N
O
O
N
O
O
N
O
as Liþ, Naþ, Kþ, Mg2þ, Ca2þ, Mn2þ, Al3þ, Co2þ, Ni2þ, Zn2þ, Cd2þ, Fe2þ
,
Fe3þ, Cr3þ, Agþ, Hg2þ, Pb2þ, Ce2þ, and Ba2þ, produced a negligible
change in the fluorescence spectra of 1. Fig. 4a shows the de-
pendence of the intensity ratios (I475/I525) on the metal ions. The
competition experiments were conducted in the presence of Cu2þ
NH NH
N
N
Cu2+
Cu2+
NH NH
NH NH
Cu2+
HN
O
O
NH
at 10
mM mixed with other metal ions at 30 mM, as well as in
N
N
a mixture of the metal ions, respectively, no significant variation in
the intensity ratios (I471/I521) was found by comparison with that
without the other metal ions besides Cu2þ (Fig. 4c). Therefore, in
aqueous solutions, probe 1 is an outstandingly high selectivity
fluorescent sensor for CuII.
A + Cu2+
1 + Cu2+
B + Cu2+
Fig. 5. Proposed mechanism of binding mode of A, B, and 1 with Cu2þ
.
Proposed mechanism of binding mode of probe 1 with Cu2þ is
shown in Fig. 5, which is similar to probe A’s binding way.4a Probe
1 bases on probe B for the high selectivity with the similar tet-
radentate receptor, but the addition of a carbonyl group at the side
of aniline lead to forming a tetradentate receptor site with the
carbonyl oxygen donors, which provides the more Lewis basic
binding site to bind Cu2þ more strongly within the cavity, making
it unavailable for fluorescence quenching, and as a result fluo-
rescence is maintained. In other words, the M (CuII)eR (receptor)
interaction has been increased to reduce indirectly the commu-
nication between M and F (fluorescence).14 Also, the amide link-
age can increase the inflexibility of the receptor to reduce the
steric hindrance by avoiding the interaction of two aniline groups.
The capture of Cu2þ by the tetradentate receptor resulted in the
reduction of the electron-donating ability of the two amino
groups conjugated to the naphthalene ring, thus, the receptor
showed a 50 nm blue shift of fluorescence emission base on the
internal charge transfer (ICT).
2.4. Cell imaging of 1 with CuII
The utility of probe 1 for fluorescence imaging of Cu2þ in living
cells was investigated. To determine the cell permeability of 1,
MCF7 cells were incubated with 10 m
M 1 for 30 min at 37 ꢁC and
washed with PBS to remove the remaining 1. A clear yellow
fluorescent image could be observed obviously from fluorescence
microscopy as shown in Fig. 6c. In Fig. 6d, the cells were pre-
treated with Cu2þ in the growth medium for 30 min. The cells
were then washed with PBS to remove the remaining Cu2þ and
further incubated with probe 1 for 30 min. The resulting bright
green fluorescence image demonstrates that probe 1 is cell
membrane permeable and able to display a fluorescence blue-
shift response to Cu2þ in the living cells. It should be poten-
tially useful for the study of the toxicity or bioactivity of Cu2þ in
living cells.
+
+
+
2+ 2+ 3+
2+
(a)
(b)
Li , Na , K , Mg , Ca , Mn , Al ,
500
400
300
200
100
0
2+ 2+ 2+ 2+ 3+ 3+
Co , Zn , Cd , Fe , Fe , Cr
,
+
2+
2+
2+
2+
Ag , Hg , Pb , Ce , Ba
2.0
1.5
2+
Ni
I
(471)
I
(521)
1.0
0.5
2+
Cu
0.0
450
500
550
600
650
700
noCuLiNaKMgCaMnAlCoNiZnCdFeFeCrAgHgPbCeBa
Wavelength (nm)
(c)
2.0
I
1.5
1.0
0.5
0.0
(471)
I
(521)
noLiNaKMgCaMnAlCoNiZnCdFeFeCrAgHgPbCeBaAll
Fig. 4. (a) Fluorescence response of 1 to various metal ions (30
of different HTM ions (30 M). (c) The fluorescent response of 1 containing 10
521 nm. The concentration of 1 was 10 M.
m
M) in ethanolewater solution (90:10, v/v, 30 mM HEPES buffer, pH 7.4). (b) Fluorescence spectra of 1 in the presence
m
m
M Cu2þ to the selected metal ions (30
mM). Excitation was at 447 nm, and emission was at 471 and
m

4872
X. Chen et al. / Tetrahedron 67 (2011) 4869e4873
Fig. 6. Bright field and fluorescence images of MCF7 cells. (a) bright field images of MCF7 cells were incubated with probe 1 (10
m
M) for 30 min at 37 ꢁC; (b) bright field images of
m
M) for 30 min at 37 ꢁC; (c) fluorescence images of MCF7 cells shown in
MCF7 cells pre-treated with CuII (4 equiv) for 30 min at 37 ꢁC and then further incubated with probe 1 (10
(a); (d) fluorescence images of MCF7 cells shown in (b).
3. Conclusions
4.3. Synthesis of 2-amino-N-phenylacetamide 3
Probe 1 was designed with the extra carbonyl group based on
strategies that not only provides more Lewis basic binding site but
also reduces the steric hindrance by avoiding the interaction of two
aniline groups, and we have demonstrated that probe 1 displayed
colorimetric response with fluorescence spectra from yellow to
green, which was useful for easy detection of CuII with a ratio-
metrically and exclusively selectivity in the presence of a variety of
other metal ions in aqueous solutions. And especially, probe 1 can
be used to successfully detect CuII in cultured cells with the same
fluorescent change. Blue shift emission (50 nm) was attributed to
the reduction of the electron-donating ability of the two amino
groups conjugated to the naphthalene ring. The design strategy of
the sensor with the addition of a carbonyl group will help to im-
prove the development of fluorescent sensors for detect other
metal ions.
2-Bromine-N-phenylacetamide (1.07 g, 1.0 equiv) was added to
a reaction vessel containing a solution of NaN3 in DMSO (1.1 equiv,
0.5 M). The reaction was monitored by NMR analysis. Upon
completion of the reaction, water (50 mL) was added and the
product was extracted with ether (3ꢂ50 mL). The combined or-
ganic layers were washed with water (2ꢂ50 mL) and brine (50 mL)
and dried with natrium sulfate. The organic solvent was removed
to provide 2-azido-N-phenylacetamide as a colorless liquid in 90%
yield. 1H NMR (400 MHz, CDCl3):
d 8.00 (bd s, 1H), 7.54 (d,
J¼8.6 Hz, 2H), 7.35 (dd, J1¼8.4 Hz, J2¼7.5 Hz, 2H), 7.16 (d, J¼8.6 Hz,
1H), 4.15 (s, 2H).15
A solution of 2-azido-N-phenylacetamide (5 mmol) in 40 mL of
methanol was hydrogenated over 3.5% Pd/C (300 mg) in autoclave
(1 Mp) for overnight, and starting material disappeared, then cat-
alyst was removed by filtration through Celite and washed with
5 mL of methanol. The filtered solution was concentrated by rotary
evaporation to give 2-amino-N-phenylacetamide 3 as colorless
liquid (100% yield). 1H NMR (CDCl3, 400 MHz)
(s, 2H), 7.03 (t, J¼7.2 Hz, 1H), 7.27 (t, J¼7.6 Hz, 2H), 7.55 (d, J¼8.0 Hz,
d 1.69 (s, NeH), 3.32
4. Experimental
2H), 9.45 (s, NeH); 13C NMR (CDCl3, 100 MHz)
d 45.12, 119.58,
4.1. Materials and methods
124.05, 128.90, 137.80, 171.46; IR (KBr, cmꢀ1): 3320, 3275, 3058,
2915, 1655, 1600, 1498, 1447, 1313, 1076, 755, 692; HRMS (ES) calcd
for C8H11N2O [MHþ] 151.0871, found 151.0873.
Unless otherwise noted, materials were obtained from com-
mercial suppliers and were used without further purification. 1H
NMR were measured on a Bruker AV-400 spectrometer with
chemical shifts reported as parts per million (in CDCl3/DMSO-d6,
TMS as internal standard). Mass spectra were measured on an HP
1100 LCeMS spectrometer. Melting points were determined by an
X-6 micro-melting point apparatus and are uncorrected. IR spectra
were recorded on a Nicolet Nexus 770 spectrometer. All pH mea-
surements were made with a Sartorius basic pH-Meter PB-20.
Fluorescence spectra were determined on a Hitachi F-4500. Ab-
sorption spectra were determined on a PGENERAL TU-1901 UVevis
Spectrophotometer.
4.4. Synthesis of probe 1
2-Amino-N-phenylacetamide 3 (7.72 mmol) was added dropwise
to a solution of 145 mg (0.38 mmol) N-butyl-4-bromo-5-nitro-1,8-
naphthalimide 2 and 128 ml (2.0 equiv) N,N-diisopropylethylamine
(DIPEA) in 3 mL 2-methoxyethanol, and then the mixture was
heated to reflux for 3 h and monitored by TLC. After the reaction was
completed, the solution was cooled at room temperature to give
yellow needle crystals. The product was filtered off, washed with
2-methoxyethanol, and then dried in the air in 83.5% yield (177 mg).
Mp: 276.2e278.4 ꢁC; 1H NMR (DMSO-d6, 400 MHz)
d 0.90
4.2. Preparation of fluorometric metal ion titration solutions
(t, J¼7.2 Hz, 3H), 1.28e1.34 (m, J¼7.2 Hz, 2H), 1.54e1.57 (m, J¼7.6 Hz,
2H), 3.98 (t, J¼7.2 Hz, 2H), 4.21 (s, 4H), 6.75 (d, J¼8.8 Hz, 2H), 7.07
(t, J¼7.2 Hz, 2H), 7.32 (t, J¼8.0 Hz, 4H), 7.59 (d, J¼7.6 Hz, 4H), 7.71
(s, NeH), 8.25 (d, J¼8.4 Hz 2H), 10.22 (s NeH); 13C NMR (DMSO-d6,
All the solvents were of analytic grade and used as received.
The solutions of metal ions were prepared from LiClO4$3H2O,
NaClO4, KClO4, BaCl2$2H2O, CaCl2, FeCl2$4H2O, MnCl2$4H2O,
CoCl2$6H2O, NiCl2$6H2O, ZnCl2, CdCl2$1/2H2O, HgCl2, AlCl3,
FeCl3$6H2O, AgNO3, Pb(NO3)2, Mg(NO3)2$2H2O, Cu(NO3)2$3H2O,
Ce(NO3)3$6H2O, Cr(NO3)3$9H2O, respectively, and were dissolved
in distilled water. Stock solutions of host (0.01 mM) in DMSO
were also prepared. Test solutions were prepared by placing
4e40 mL of the probe stock solution into a test tube, adding an
appropriate aliquot of each metal stock, and diluting the solution
to 4 mL with 0.3 M HEPES (pH 7.4). For all measurements, exci-
tation was at 447 nm. Both excitation and emission slit widths
were 3 nm or 5 nm.
100 MHz)
d 14.23, 20.29, 30.35, 40.03, 48.20, 107.20, 110.73, 110.86,
119.99, 124.06, 129.26, 132.19, 133.66, 139.03, 152.67, 163.75, 168.15;
IR (KBr, cmꢀ1): 3342, 2956, 2872, 1666, 1626, 1600, 1557, 1499, 1446,
1314, 1107, 748, 691; HRMS (EI) calcd for C32H31N5O4 [Mþ] 549.2376,
found 549.2368.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (90713030; 20876025).

X. Chen et al. / Tetrahedron 67 (2011) 4869e4873
4873
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a
standard
(FF¼0.81) Guo, X.;