Synthesis of Biindole-Diazo conjugates as a colorimetric anion receptor

Article abstract of DOI:10.1021/ol100830b

A colorimetric anion receptor based on an indole scaffold has been synthesized by incorporating an azobenzene chromophore to the 5-position of indole. The receptor binds anions by hydrogen bonds which are effectively transmitted through resonance to the chromophore to give rise to color changes. The cyanide ion induced a pronounced color change from light yellow to reddish orange, but less intense or negligible changes were observed with the other anions examined here.

Full text of DOI:10.1021/ol100830b

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2634-2637
Synthesis of Biindole-Diazo Conjugates
as a Colorimetric Anion Receptor
Gang Woo Lee, Nam-Kyun Kim, and Kyu-Sung Jeong*
Center of BioactiVe Molecular Hybrids and Department of Chemistry, Yonsei
UniVersity, Seoul 120-749, Korea
ksjeong@yonsei.ac.kr
Received April 12, 2010
ABSTRACT
A colorimetric anion receptor based on an indole scaffold has been synthesized by incorporating an azobenzene chromophore to the 5-position
of indole. The receptor binds anions by hydrogen bonds which are effectively transmitted through resonance to the chromophore to give rise
to color changes. The cyanide ion induced a pronounced color change from light yellow to reddish orange, but less intense or negligible
changes were observed with the other anions examined here.
Anions play crucial roles in many chemical and biological
processes, which inspire supramolecular chemists to design
and synthesize a variety of anion receptors.1,2 The binding
event has been analyzed by many spectroscopic techniques
that display characteristic absorption, emission, or electro-
chemical signals before and after the formation of the
corresponding receptor-anion complexes. Visual detection
is simple and convenient, not requiring expensive instru-
ments, and is highly desirable for applications in rapid
screening processes and in environmental field work.3
In recent years, we and others have prepared a variety of
indole-based anion receptors including oligoindole foldamers,
macrocycles, and molecular clefts.4-9 These receptors strongly
bind anions by hydrogen bonds, but only a few of them
display color changes upon anion binding.10 For example,
Sessler et al. prepared 3-diindol-3-yl quinoxalines which
showed a distinct color change from yellow to brown or
orange upon binding fluoride or dihydrogen phosphate.10d
Shiraishi et al. synthesized a bisindolyl molecule that
exhibited noticeable changes in color and fluorescence in
the presence of excess fluoride.10e
Herein, we report for the first time the synthesis of a
biindole-diazo conjugate 10 that has been further utilized
to prepare a colorimetric anion receptor 11. In the presence
of relatively basic anions such as fluoride, acetate, dihydrogen
(3) For some selected examples, see: (a) Beer, P. D.; Gale, P. A. Angew.
Chem., Int. Ed. 2001, 40, 486. (b) Mart´ınez-Mán˜ez, R.; Sanceno´n, F. Chem.
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M. A. Coord. Chem. ReV. 2006, 250, 2929. (d) Quinlan, E.; Matthews,
S. E.; Gunnlaugsson, T. J. Org. Chem. 2007, 72, 7497. (e) Cho, D.-G.;
Kim, J. H.; Sessler, J. L. J. Am. Chem. Soc. 2008, 130, 12163. (f) Zapata,
F.; Caballero, A.; Espinosa, A.; Ta´rraga, A.; Molina, P. J. Org. Chem. 2008,
73, 4034. (g) Lu, Q.-S.; Dong, L.; Zhang, J.; Li, J.; Jiang, L.; Huang, Y.;
Qin, S.; Hu, C.-W.; Yu, X.-Q. Org. Lett. 2009, 11, 669. (h) Bhosale, S. V.;
Bhosale, S. V.; Kalyankar, M. B.; Langford, S. J. Org. Lett. 2009, 11, 5418.
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74, 4849.
(1) Sessler, J. L.; Gale, P. A.; Cho, W.-S. Anion Receptor Chemistry
(Monographs in Supramolecular Chemistry), Stoddart, J. F., Ed.; RSC:
Cambridge, UK, 2006
.
(2) For selected recent reviews, see: (a) Kang, S. O.; Begum, R. A.;
Bowman-James, K. Angew. Chem., Int. Ed 2006, 45, 7882. (b) Lankshear,
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Garrido, S. E.; Garric, J. Chem. Soc. ReV. 2008, 37, 151. (d) Lee, C.-H.;
Miyaji, H.; Yoon, D.-W.; Sessler, J. L. Chem. Commum. 2008, 24. (e) Steed,
J. W. Chem. Soc. ReV. 2009, 38, 506. (f) Caltagirone, C.; Gale, P. A. Chem.
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10.1021/ol100830b  2010 American Chemical Society
Published on Web 05/06/2010

Scheme 1. Synthesis of 11
phosphate, and cyanide, compounds 10 and 11 display
noticeable color changes from pale yellow to orange or
reddish orange due to the formation of hydrogen bonds or
deprotonation in 10% (v/v) DMSO/CH3CN.
In general, colorimetric receptors consist of binding and
signaling subunits that are electronically conjugated to each
other to effectively induce color changes. In this context,
the chromogenic diazo unit is introduced at the 5-position
of indole to achieve direct resonance between them.11 As
shown in Figure 1, the electron-withdrawing ester group at
the end increases not only the degree of π-conjugation but
also the hydrogen bond donor ability of the indole NH.
The synthesis of biindole-diazo conjugates 10 and 11
began with 4-nitroaniline (1) (Scheme 1). Compound 1 was
reacted with I2/Ag2SO412 to give 2,6-diiodo-4-nitroaniline (2,
65% yield), which was reduced with SnCl2·2H2O to give 2,6-
diiodobenzene-1,4-diamine (3, 82% yield). On the other
hand, nitroso compound 6 was prepared from ethyl 4-ami-
nobenzoate (4) via two steps: transesterification (52% yield)
and oxidation with oxone. 6 was then directly used for the
next reaction without further purification. Condensation of
3 and 6 gave a diazobenzene derivative 7 in 69% yield.13
The Sonogashira coupling reaction14 of 7 with 1-trimethyl-
silylethyne (1 equiv), followed by a protic desilylation with
Bu4NF (1.1 equiv) and CH3COOH (1.1 equiv), afforded 8
in 45% yield (two steps). 8 was sequentially subjected to
Glaser-type oxidative homocoupling15 (93% yield) and
cyclization in the presence of copper iodide16 (50% yield)
(5) (a) Chang, K.-J.; Kang, B.-N.; Lee, M. H.; Jeong, K.-S. J. Am. Chem.
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Org. Lett., Vol. 12, No. 11, 2010
2635

Figure 1. Resonance structures of indole-diazo scaffold.
to give a biindole-diazo conjugate 10. Finally, 11 was
obtained in 76% yield by the Sonogashira reaction of 10
and 2-methylbut-3-yn-2-ol.
We first examined anion-induced color changes of 10 and
11 in 10% (v/v) DMSO/CH3CN. Compound 10 displays
noticeable color changes from pale yellow to orange or
reddish orange upon addition (5 equiv) of fluoride, acetate,
dihydrogen phosphate, and cyanide (Figure 2). Other anions
such as chloride, bromide, iodide, azide, nitrate, and hydro-
gen sulfate caused no change in color. These observations
are consistent with changes in UV-visible absorption
spectra. Addition of relatively basic anions such as F-, AcO-,
Figure 2
.
UV/vis spectra (a) and color changes (b) of 10 (2.0 ×
10-5 M) and 11 (2.0 × 10-5 M) in the presence of various anions
(5 equiv) in 1:9 (v/v) DMSO/CH3CN.
-
H2PO4 , and CN- to 10 increases the absorption (λmax 480
Table 1. Association Constants (Ka, M-1) of 10 and 11 with
Anions in DMSO/CH3CN (v/v, 1:9) at 25 ( 1 °Ca
nm) between 440 and 560 nm,17 but negligible changes were
observed with other anions.
association constant (Ka, M-1
)
Anions are hydrogen bonded tighter to the NHs in 10,
optimizing the interactions because it possesses only two
hydrogen bond donors of indole NHs. On the other hand,
11 contains two additional OH donors and therefore anions
may be situated in the middle of four donors in a way to
maximize total hydrogen bonding interactions. As a result,
perturbation of the indole N-H bonds by anion binding in
11 is presumably weaker than that in 10, which may be
responsible for smaller changes in color and absorption
spectra of 10. It should be mentioned that addition of
tetrabutylammonium hydroxide to 10 and11 yielded a new
strong band between 440 and 560 nm (Supporting Informa-
tion), similar to those observed with cyanide. This suggests
that the inherent basicity of cyanide ion is responsible for
the most pronounced changes by causing deprotonation of
the indole NHs under the given conditions.18
anion
10
11
ratio of 11/10
b
F-
-
200 000
8 900
1 300
<5
Cl-
Br-
I-
57
<5
<5
156
>260
-
N3
120
330
3
b
-
CH3CO2
-
77 000
40 000
59
b
-
H2PO4
NO3
HSO4
-
-
<5
<5
>12
>11
-
56
a Titrations were duplicated by 1H NMR (Cl-, Br-, I-, N3-, NO3
,
-
HSO4-) or UV/vis spectroscopy (F-, AcO-, H2PO4-), using tetrabutylam-
monium salts of anions, and errors in Ka values were within 20%.
b Association constants for these anions could not be estimated because
the binding process competes with deprotonation under the titration
conditions.17
The association constants (Ka, M-1) of 10 and 11 with
nium salts in 9:1 (v/v) CD3CN/DMSO-d6, the 1H NMR signal
of NHs was considerably downfield (∆δ up to 1.2 ppm),
while the aromatic CH signals were slightly upfield shifted
(∆δ ≈ 0.1 ppm) (Figure 3). These observations are consistent
with the formation of hydrogen bonds between the indole
NHs and anions. In addition, UV-visible titrations showed
clear isosbestic points, indicative of two species being in
1
anions were determined by either H NMR or UV-visible
titraions. Upon addition of anions as their tetrabutylammo-
(16) Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.; Pe´rez, M.;
Garc´ıa-Mart´ın, M. A.; Gonza´lez, J. M. J. Org. Chem. 1996, 61, 5804.
1
(17) Upon addition of basic anions F-, AcO-, and H2PO4-, H NMR
signals for the NHs of 10 disappeared in 10% (v/v) d6-DMSO/CD3CN at
room temperature. When a solution containing 10 and each anion (1.5 equiv)
was cooled to -40 °C, the signal for HF2- appeared at 16.3 ppm as a triplet,
indicative of deprotonation. In cases of AcO- and H2PO4-, the NH signals
of the corresponding complexes could be seen at 12.9 and 11.9 ppm,
respectively (Supporting Information). In addition, the UV-visible spectra
(Figure 2a and Supporting Information) show a new absorption band (λmax
480 nm) corresponding to deprotonation but the absorption intensities are
considerably weaker compared to those obtained with OH- and CN-. These
results suggest that both processes of binding and deprotonation occur and
compete with each other under the given conditions.
(18) For deprotonation of neutral amide and urea NHs by basic anions,
see: (a) Esteban-Go´mez, D.; Fabbrizzi, L.; Licchelli, M. J. Org. Chem. 2005,
70, 5717. (b) Esteban-Go´mez, D.; Fabbrizzi, L.; Licchelli, M.; Monzani,
E. Org. Biomol. Chem. 2005, 3, 1495. (c) Evans, L. S.; Gale, P. A.; Light,
M. E.; Quesada, R. Chem. Commun. 2006, 965. (d) Lin, C.-I.; Selvi, S.;
Fang, J.-M.; Chou, P.-T.; Lai, C.-H.; Cheng, Y.-M. J. Org. Chem. 2007,
72, 3537. (e) Quinlan, E.; Matthews, S. E.; Gunnlaugsson, T. J. Org. Chem.
2007, 72, 7497.
2636
Org. Lett., Vol. 12, No. 11, 2010

constants summarized in Table 1, two trends are apparent.
First, basic anions bind more strongly to 10 and 11, as
commonly seen in anion receptors based on hydrogen
bonding interactions. Second, 11 shows much higher affini-
ties than 10 by up to 2 orders of magnitude, suggesting that
the two additional hydroxyl groups are simultaneously
involved in hydrogen bonding with the anion.
In summary, we synthesized a biindole-diazo conjugate
10 that can be used as a useful building block for the
construction of colorimetric anion receptors. By using this
scaffold, anion receptor 11 has been prepared which strongly
binds anions by four hydrogen bonds and produces a color
change. Incorporation of the colorimetric unit 10 to foldamers
and macrocycles may afford molecular probes and materials
that can produce characteristic visual signals upon applying
anionic stimulation.
Acknowledgment. This work was financially supported
by the Center for Bioactive Molecular Hybrids (CBMH).
K.S.J. thanks Dr. H. Juwarker (Yonsei University) for helpful
discussion and proofreading of the manuscript. G.W.L. and
N.K.K. acknowledge the fellowship of BK 21 Programs from
the Ministry of Education, Science and Technology of Korea.
Figure 3. Proposed molecular structures of complexes (top) and
partial 1H NMR spectra (bottom) (400 MHz, 10% DMSO-d6/
CD3CN, 25 °C) of (a) 10 (1.0 mM), (b) 10 + TBACl (5 equiv), (c)
11 (1.0 mM), and (d) 11 + TBACl (5 equiv)
equilibrium. The titration curves were all analyzed by the
nonlinear curve fitting method19 and fitted to a 1:1 binding
isotherm. Job’s plots19b also support 1:1 stoichiometries of
complexes (Supporting Information). From the association
Supporting Information Available: Synthesis and char-
acterization of new compounds and binding studies. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) (a) Long, J. R.; Drago, R. S. J. Chem. Educ. 1982, 59, 1037. (b)
Connors, K. A. Binding Constants; Wiley: New York, 1987.
OL100830B
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