Synthesis and characterization of novel indole-containing half-crowns as new emissive metal probes

Article abstract of DOI:10.1016/j.tetlet.2009.06.073

Two new indole derivatives have been synthesized by a one-pot procedure and their potential as fluorescence probes for metal ions was investigated. The sensor capability of 1 and 2 toward cations such as Ag⁺, Cu²⁺, Zn²⁺, C

Full text of DOI:10.1016/j.tetlet.2009.06.073

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Tetrahedron Letters 50 (2009) 4930–4933
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and characterization of novel indole-containing half-crowns
as new emissive metal probes
a,b,
Angelo Rocha a, M. Manuel B. Marques a, , Carlos Lodeiro
*
*
a REQUIMTE-CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia, Univeridade Nova de Lisboa, Quinta da Torre, 2829-516 Monte de Caparica, Portugal
b BIOSCOPE Research Group, Faculty of Science, Physical-Chemistry Department, Campus of Ourense, University of Vigo, E-32004 Ourense, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new indole derivatives have been synthesized by a one-pot procedure and their potential as fluores-
cence probes for metal ions was investigated. The sensor capability of 1 and 2 toward cations such as Ag+,
Cu2+, Zn2+, Cd2+, Pb2+, and Hg2ꢀ was studied in dichloromethane solution by absorption, fluorescence
emission, and 1H NMR titrations. Both probes showed selectivity for Ag+ and Hg2+ ions. The results sug-
gest that these compounds may serve as promising models for future design of novel and more potent
sensors.
Received 15 May 2009
Revised 9 June 2009
Accepted 12 June 2009
Available online 17 June 2009
Keywords:
Indole
Ó 2009 Elsevier Ltd. All rights reserved.
Chemosensors
Silver(I)
Half-crown
The indole scaffold is an important and privileged structural
motif found in a wide array of biologically active natural products,
as well as in various indole-derived drugs possessing relevant bio-
logical activity. Indeed, synthesis of indole-containing compounds
has attracted considerable attention from chemists searching for
novel properties.1 Despite the limited information on the metal–
indole complexes, versatile metal–indole bonds in chemical
systems have been reported.2,3 Moreover, the indole ring–metal
binding in biological systems has been recently identified.4
Fluorescence spectroscopy is an extremely powerful and useful
technique to visualize molecular recognition interactions, and
when combined with the fluorescent property of the indole nu-
cleus allows the exploration of novel indole derivatives as potential
fluorescent chemosensors.
Our continued interest in the development of metal-ion fluores-
cence chemosensors,5 led us to explore the potential utility of no-
vel indole-containing half-crowns as emissive probes. Herein we
report the synthesis, characterization, and photophysical studies
of two novel indole derivatives 1 and 2 (Fig. 1) and the known li-
gand L6 as potential fluorescence probes for metal ions.
through a chemical spacer.9 Taking this into account, although a
variety of crown-ether integrating chromophores are known as
chemosensors,10 the corresponding acyclic ones are comparatively
rare.11
Thus, the indolic sulfur–oxygen donor half-crown ethers 1 and
2 were prepared by a one-pot procedure as depicted in Scheme
1. The first step consisted of the treatment of 3 with thiourea
and iodine in the ratio 1:2:1 under inert atmosphere, according
to the reported procedure,12 to afford the S-(3-indolyl)isothiuroni-
um iodide 4. Due to the easy oxidation of indolethiol 5 to the cor-
responding di(3-indolyl)disulfide L, the following steps were
carried in situ, without isolation of iodide 4. After alkaline hydroly-
sis of 4, under reflux conditions, the dibromide 6 was subsequently
added to afford compound 1 in 28% yield.13 Similarly, addition of
the dimesylate 714 to the alkaline solution of 4 afforded compound
2 in 34% yield.15 Despite all efforts, the formation of the di(3-indo-
lyl)disulfide L could not be avoided, and after reaction the crude
n = 1, 2
S S
Our research interest is focused on heavy and contaminant met-
als such as palladium(II), lead(II), mercury(II), zinc(II), cadmium(II),
and silver(I).7,8 The usual configuration of a chemosensor involves
an organic emissive chromophore incorporating a binding site
O
S
S
N
H
N
H
N
N
H
H
L
1 n = 1
2
n = 2
* Corresponding authors. Tel.: +351 21 2948300x10983; fax: +351 21 2948550
(M.M.B.M.); tel.: +34 988 387072; fax: +34 988 387001 (C.L.).
E-mail addresses: mmbmarques@dq.fct.unl.pt (M.M.B. Marques), clodeiro@
uvigo.es (C. Lodeiro).
Figure 1. Structure of the prepared indole-containing half-crowns 1 and 2 and the
disulfide L.6
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.073

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A. Rocha et al. / Tetrahedron Letters 50 (2009) 4930–4933
4931
I
O
6
NH2
Br
Br
S
NH2
S
i
ii
iii
1
N
N
N
H
H
H
3
4
5
iv
O
7
O
MsO
OMs
2
Scheme 1. Synthesis of the half-crowns 1 and 2: Reagents and conditions: (i) thiourea, I2, KI, MeOH/H2O, rt; (ii) NaOH/H2O, reflux, 10 min; (iii) 6, rt, overnight; (iv) 7, rt,
overnight.
Table 1
UV–vis and fluorescence data of compounds L, 1, and 2
Compound
UV–vis
Fluorescence
kexc (nm)
e
ꢁ 104 (molꢀ1 cmꢀ1
)
kem (nm)
/
Stokes’ shift (nm)
F
L
1
2
279
279
279
1.93
1.94
2.03
371
388
389
0.02
0.19
0.39
92
109
110
product was purified by column chromatography to afford pure
compounds 1 and 2. Compound L was prepared according to the
known procedure.16
The photophysical characterization for compounds L, 1, and 2 is
summarized in Table 1. The fluorescence quantum yield increases
with the half-crown chain length, thus representing a higher sepa-
ration between the sulfur atoms. This effect is stronger for com-
pound 2.
fluorescence quantum yield was determined using as reference
solution naphthalene with Uf = 0.23 in cyclohexane.18
In order to explore the effect of metal cations on the absorption
and fluorescence emission spectra, several titrations with Ag+,
Cu2+, Zn2+, Cd2+, Pb2+, and Hg2+ were performed using absorption
and fluorescence spectroscopies.19 To conduct the analyses, the li-
gands were dissolved in dichloromethane and titrated with the
analytes.
The absorption spectra of L, 1, and 2 in dichloromethane show a
Selectivity toward Ag+ and Hg2+ over the other metals studied
was observed for L, where addition of 10 equiv of metal induced
a 10-fold increase in the fluorescence emission band, but these
spectra show an intense evolution with time. The emission spec-
band centered at 279 nm assigned to the p–p
* transitions in the li-
gand (see Fig. 2). This band presents the characteristic shape of the
indole group and is attributed to the two close low-lying pp* ex-
cited states 1La and 1Lb.17
The absorption spectra of L show a shoulder centered at
340 nm, and could indicate some interactions between the indole
rings in the ground state. This shoulder disappears when the dis-
tance between both indole rings increases in compounds 1 and 2.
The ligands exhibit a broad emission band centered at 371(L),
388(1), and 389(2) nm with a relative fluorescence quantum yield
trum remains stable only upon 48 h. However, addition of Cu2+
,
Zn2+, Cd2+, and Pb2+ in the same conditions did not produce any ef-
fect on the fluorescence band of L.
In order to understand the effect produced by the oxygen
atoms, in the flexible chain between the indole units, introducing
an extra stability in the complexes, the same metal titrations were
performed with 1 and 2. In general the absorption spectrum shows
very small changes upon the metal interaction. A very small red-
of
U
= 0.02 (L), 0.19 (1), and 0.39 (2), when excited at 280 nm. The
0.3
1
1
1
A
2
Zn2+;Cd2+; Hg2+
Cu2+; Pb2+
0.2
1
L
Ag+
0.1
1
2
L
300
350
400
450
500
550
0
250 300 350 400 450 500
Wavelength / nm
Wavelength (nm)
Figure 3. Fluorescence emission spectra of 1 in dichloromethane after the addition
of 1 equiv of AgBF4, Zn(CF3SO2)2, Cd(BF4)2, Hg(CF3SO2)2, Cu(CF3SO2)2, and Pb(ClO4)2.
(kexc = 280 nm; [1] = 1.0 ꢁ 10ꢀ5 M).
Figure 2. Absorption and emission spectra of L, 1, and 2 in dichloromethane.
(kexc = 280 nm; [L] = [1] = [2] = 1.0 ꢁ 10ꢀ5 M).

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4932
A. Rocha et al. / Tetrahedron Letters 50 (2009) 4930–4933
In respect to compound 2, a comparative study with 1 can be
performed. In this compound the distance between both indole
chromophores is longer, thus increasing the flexibility to chelate
metal ions. This structural effect is observed upon metal
complexation.
For the same quantity of metal added now the quenching ob-
served is higher in all cases. After the addition of one equivalent
of silver(I) the quenching reaches 90% becoming complete after
the addition of the second metal ion.
In the case of the divalent metals, addition of 20 equiv to 1 in
dichloromethane produces a 90% of quenching in the presence of
mercury(II), 60% for lead(II), 50% for copper(II), and 40% for cad-
mium(II) and zinc(II), suggesting stronger interactions than ligand
1. In Figure 4 is represented the fluorescence titration of 2 upon sil-
ver(I) interaction. In the inset is observed that with the addition of
1 equiv of Ag+, the band at 390 nm reaches a plateau confirming
the formation of a 1:1 complex.
0.15
A
1
1
Ag
0.1
0.05
0
0
1
2
3
4
5
6
[Ag ] / [2]
240 320 400 480 560 640 720 800
Wavelength / nm
Figure 4. Fluorescence emission titration of 2 and absorption spectra in dichloro-
methane after the addition of increased amount of AgBF4, (kexc = 280 nm;
[2] = 1.0 ꢁ 10ꢀ5 M). In the inset is shown the maxima of emission at 390 nm.
Since ligand 2 showed to be the most selective for Ag+ the com-
plexation and interaction in solution with this metal were investi-
gated by 1H NMR. Thus, increasing amounts of AgBF4 in CD2Cl2
were added to a 0.05 M solution of 2 in the same solvent. The 1H
NMR spectra of the resulting solutions were recorded at room tem-
perature, 30 min after addition of Ag+ (Fig. 5). The total amount of
Ag+ added was determined by ICP (24.71 ppm).
shift in 3–5 nm was observed. More interesting was to study the
fluorescence spectra of 1 and 2 in the presence of increasing
amounts of the metals.
A quenching effect upon metal complexation was observed for 1
in the presence of all the metal ions studied, even for the d10 metals
Ag+, Zn2+, Cd2+, and Hg2+, but the intensity of this CHEQ (Chelating
Enhancement of the Quenching) effect was different in all of them.
The most effective quenching was upon Ag+ complexation,
after the addition of one equivalent the intensity of the emission
was reduced in 65%, while a complete quenching of the emission
was observed upon addition of the fifth equivalent. These results
suggest a stronger complexation with Ag+ when compared to the
other metals, while after the addition of 20 equiv the intensity
was reduced in 90% for Hg2+, 30% for Pb2+, and only 15% for
An increase in the silver ion concentration gradually downfield-
shifted the proton resonance of H20 (indolic proton), H3 as well as
H1 from the half-crown, the latter being the most affected. This
behavior suggests that Ag+ is binding via the sulfur atoms as well
as oxygen atoms.
The spectra resolution increases with the metal ion amount,
suggesting that a more rigid conformation is forming in solution,
in the presence of Ag+. Moreover, these observations indicate that
in solution, the complexed cation interacts not only with the half-
crown moiety but also with the aromatic nuclei (H20).
In conclusion, two new fluorescence indole-containing ligands 1
and 2, with an S2O and S2O2 donor set have been synthesized and
their photophysical properties have been evaluated. Their capacity
Zn2+, Cd2+, and Cu2+
.
In Figure 3 are shown the fluorescence spectra of 1 in dichloro-
methane in the presence of 1 equiv of each metal ion.
to act as a potential sensor for the soft metal ions Ag+, Cu2+, Zn2+
,
Figure 5. 1H NMR spectra of ligand 2 in CD2Cl2 without Ag+ and with increasing amounts of a solution of AgBF4 in CD2Cl2 (400 MHz).

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A. Rocha et al. / Tetrahedron Letters 50 (2009) 4930–4933
4933
Cd2+, Pb2+, and Hg2+ was evaluated in dichloromethane solution.
Among the cations studied, probes 1 and 2 have demonstrated a
remarkable selectivity for Ag+ and a high affinity for Hg2+ at higher
concentrations, and a stronger interaction with silver(I), depending
on the mobility of the indole ring according to the crown chain
length. The observed selectivity of the new probes is of interest
due to their use as building blocks in the design of more complex
chemosensors for this metal ion.
9. (a) Czarnik, A. W. Acc. Chem. Res. 1994, 27, 302–308; (b) Prasanna de Silva, A.;
Gunaratne, H. W. N.; Gunnlaugsson, T.; Huxley, A. J. M.; McCoy, C. P.;
Rademacher, J. T.; Rice, T. E. Chem. Rev. 1997, 97, 1515–1566.
10. See for example: Gokel, G. W.; Leevy, W. M.; Weber, M. E. Chem. Rev. 2004, 104,
2723–2750.
11. Morozumi, T.; Anada, T.; Nakamura, H. J. Phys. Chem. B 2001, 105, 2923–2931;
Mello, J. V.; Finney, N. S. Angew. Chem., Int. Ed. 2001, 40, 1536–1538.
12. Levkoskaya, G. G.; Rudyakova, E. V.; Mirskova, A. N. Russ. J. Org. Chem. 2002, 38,
1641–1646.
13. General procedure: To a stirring solution of indole (503 mg, 4.3 mmol) and
thiourea (650 mg, 8.6 mmol) in degassed methanol (9 mL), was slowly added a
solution of iodine (1.1 g, 4.3 mmol)and KI (713 mg, 4.3 mmol) in degassed
Acknowledgments
water (3 mL), at room temperature. After consumption of the indole,
degassed 20% aqueous solution of NaOH was added, and the resulting
mixture was refluxed for 10 min. The dibromide (0.9 mmol) was then
a
6
The authors are grateful to REQUIMTE Research Fund for finan-
cial support. C.L. thanks Xunta de Galicia, Spain, for the Isidro Parga
Pondal Research Program and INOU-UVIGO K914/2009 Research
Project.
added and the resulting mixture was stirred overnight at room temperature.
The mixture was diluted with 10 mL of water and extracted with
dichloromethane (2ꢁ, 10 mL). The organic layer was dried over sodium
sulfate, filtered, and the solvent removed under reduced pressure. The crude
was purified by column chromatography (silica, ethyl ether/hexane, 9:1) to
afford pure
1 (439 mg, 28%): IR (film)
m
max/cmꢀ1 3400; 1H NMR (CDCl3,
400 MHz): dH 8.08 (2H, s, NH), 7.67 (2H, d, J = 7.7 Hz, ArH), 7.31 (2H, d,
J = 7.9 Hz, ArH), 7.12 (6H, m, ArH), 3.42 (4H, t, J = 6.8 Hz, CH2OCH2), 2.75 (4H, t,
J = 6.8 Hz, SCH2); 13C NMR (CDCl3, 100.63 MHz): dC 136.2, 129.7, 129.4, 122.7,
120.5, 119.4, 111.4, 105.3, 69.9, 35.3. acc. mass: 368.101476, C20H20N2OS2
requires 368.101707.
References and notes
1. Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875–2911.
2. Li, Y.; Yang, C. M. J. Am. Chem. Soc. 2005, 127, 3527–3530; Motoyama, T.;
Shimazaki, Y.; Yajima, T.; Nakabayashi, Y.; Naruta, Y.; Yamauchi, O. J. Am. Chem.
Soc. 2004, 126, 7378–7385; Kaminskaia, N. V.; Ullmann, G. M.; Fulton, D. B.;
Kostié, N. M. Inorg. Chem. 2000, 39, 5004–5013; Kaminskaia, N. V.; Johnson, T.
W.; Kostié, N. M. J. Am. Chem. Soc. 1999, 121, 8663–8664.
3. For a review see: Shimazakia, Y.; Yajimab, T.; Takanic, M.; Yamauchib, O. Coord.
Chem. Rev. 2009, 253, 479–492.
4. Xue, Y.; Davis, A. V.; Balakrishnan, G.; Stasser, J. P.; Staehlin, B. M.; Focia, P.;
Spiro, T. G.; Penner-Hahn, J. E.; O’Halloran, T. V. Nat. Chem. Biol. 2008, 4, 107–
109.
14. Rabouin, D.; Perron, V.; N’Zemba, B.; Gaudreault, R.-C.; Berube, G. Bioorg. Med.
Chem. Lett. 2003, 13, 557–560.
15. Compound 2: mp: 82–84 °C; IR (film)
m
max/cmꢀ1 3400; 1H NMR (CDCl3,
400 MHz): dH 8.20 (2H, s, NH), 7.76 (2H, d, J = 7.5 Hz, ArH), 7.38–7.18 (8H, m,
ArH), 3.55 (4H, t, J = 6.9 Hz, SCH2CH2O), 3.50 (4H, s, OCH2CH2O), 2.84 (4H, t,
J = 6.9 Hz, SCH2). 13C NMR (CDCl3, 100.63 MHz): dC 136.2, 129.8, 129.3, 122.6,
120.4, 119.2, 111.5, 111.0, 104.9, 103.4, 70.3, 70.1, 35.3. acc. mass: 414.080804,
C22H24N2O2S2 requires 414.080697.
16. Shirani, H.; Janosik, T. Synthesis 2007, 17, 2690–2698.
17. (a) Serrano-Andrés, L.; Roos, B. O. J. Am. Chem. Soc. 1996, 118, 185; (b) Borin, A.
C.; Serrano-Andrés, L. Chem. Phys. 2000, 262, 253.
18. Montalti, M.; Credi, A.; Prodi, L.; Gandolfi, M. T. Handbook of Photochemistry,
3rd ed.; CRC Press, Taylor & Francis Group: Boca Raton, New York, 2006.
5. See for example: Lodeiro, C.; Pina, F. Coord. Chem. Rev. 2009, 253, 1353–1383.
6. Woodbridge, D. J. Am. Chem. Soc. 1950, 72, 4320–4322.
7. For example (a) Bazzicalupi, C.; Bencini, A.; Berni, E.; Bianchi, A.; Borsari, L.;
Giorgi, C.; Valtancoli, B.; Lodeiro, C.; Lima, J. C.; Parola, A. J.; Pina, F. Dalton
Trans. 2004, 591–597; (b) Bazzicalupi, C.; Bencini, A.; Bianchi, A.; Danesi, A.;
Giorgi, C.; Lodeiro, C.; Pina, F.; Santarelli, S.; Valtancoli, B. Chem. Commun 2005,
2630–2632; (c) Tamayo, A.; Escriche, L.; Casabó, J.; Covelo, B.; Lodeiro, C. Eur. J.
Inorg. Chem. 2006, 2997–3004; (d) Tamayo, A.; Pedras, B.; Lodeiro, C.; Escriche,
L.; Casabó, J.; Capelo, J. L.; Covelo, B.; Kivekas, R.; Sillampa, R. Inorg. Chem. 2007,
46, 7818–7826; (e) Batista, R. M. F.; Oliveira, E.; Costa, S. P.; Lodeiro, C.; Raposo,
M. M. M. Tetrahedron Lett. 2008, 49, 6575–6578; (f) Pedras, B.; Fernandes, L.;
Oliveira, E.; Rodríguez, L.; Raposo, M. M. M.; Capelo, J. L.; Lodeiro, C. Inorg.
Chem. Commun. 2009, 12, 79–85.
8. (a) Park, C. S.; Lee, J. Y.; Kang, E.-J.; Lee, J.-E.; Lee, S. S. Tetrahedron Lett. 2009, 50,
671–675; (b) Schwarze, T.; Müller, H.; Dosche, C.; Klamroth, T.; Mickler, W.;
Kelling, A.; Löhmannsröben, H.-G.; Saalfrank, P.; Holdt, H.-J. Angew. Chem., Int.
Ed. 2007, 46, 1671–1674; (c) Iyoshi, S.; Taki, M.; Yamamoto, Y. Inorg. Chem.
2008, 47, 3946–3948.
19. Absorption spectra were recorded on
a
Perkin Elmer lambda 35
spectrophotometer, and fluorescence emission on a Perkin Elmer LS45. The
linearity of the fluorescence emission versus concentration was checked in the
concentration range used (10ꢀ4–10ꢀ6 M). Corrections for the absorbed light
and dilutions were performed when necessary. All spectrofluorimetric
titrations were performed as follows:
a stock solution of the ligand (ca.
1.00 ꢁ 10ꢀ3 M) was prepared by dissolving an appropriate amount of the
ligand in
a 50 mL volumetric flask and diluting to the mark with
dichloromethane UVA-sol. The titration solutions ([L = 1 = 2] = 1.00 ꢁ 10ꢀ6
and 1.00 ꢁ 10ꢀ5 M) were prepared by appropriate dilution of the stock
solution. Titrations were carried out by addition of microliter amounts of
standard solutions of the ions dissolved in absolute ethanol or
dichloromethane.