Folding and anion-binding properties of fluorescent oligoindole foldamers

Article abstract of DOI:10.1002/chem.200801713

A series of oligoindole foldamers 1a-d that are highly fluorescent were prepared by using a biindole derivative as the repeating unit, and their folding and anion-binding properties were revealed by ¹H NMR and fluorescence spectroscopy. The oli

Full text of DOI:10.1002/chem.200801713

DOI: 10.1002/chem.200801713
Folding and Anion-Binding Properties of Fluorescent Oligoindole Foldamers
Uk-Il Kim, Jae-min Suk, Veluru Ramesh Naidu, and Kyu-Sung Jeong*[a]
Abstract: A series of oligoindole fol-
damers 1a–d that are highly fluores-
cent were prepared by using a biindole
derivative as the repeating unit, and
their folding and anion-binding proper-
ties were revealed by 1H NMR and
fluorescence spectroscopy. The oligoin-
doles exist in an extended conforma-
tion, but adopt a compact helical struc-
ture in the presence of an anion. The
anion is entrapped inside the tubular
cavity of the helical strand, comprising
four aryl units per turn, by multiple hy-
drogen bonds with the indole NHs.
These structural features were con-
firmed by 1H NMR and fluorescence
spectroscopy. When folded by anion
binding, 1b–d show characteristic
downfield shifts of the NH signals and
upfield shifts of the aromatic CH sig-
nals by Dd=0.1–1.0 ppm. The average
chemical shift for all the aromatic sig-
nals of 1a–d is more upfield shifted as
the chain lengthens, as anticipated
from the degree of overlapped aromat-
ic surfaces in the helical strand. More-
over, 1a–d are strongly fluorescent in
the absence of an anion. Upon binding
an anion such as a chloride, the shorter
oligoindoles 1a and b lead to negligible
change in the emission spectra, where-
as the longer ones 1c and d result in
dramatic changes, that is, large hypo-
chromic and bathochromic shifts (Dl=
65 and 70 nm) of the emission band,
confirming the helical folding. The as-
sociation constants (Ka) between oli-
goindoles and tetrabutylammonium
chloride strongly depend on the chain
length; <1mÀ1 for 1a, 630mÀ1 for 1b,
1.1ꢀ105 mÀ1 for 1c, and 2.9ꢀ105 mÀ1 for
1d in 20% (v/v) MeOH/CH2Cl2 at 24Æ
18C. In addition, the association con-
stants of 1c and 1d with other anions
such as fluoride, bromide, iodide, azide,
cyanide, acetate, and nitrate are deter-
mined to be in the order of 103–106 mÀ1
under the same conditions.
Keywords: anions · foldamers · hel-
ical structures · hydrogen bonding ·
receptors
Introduction
blocks,[3–11] and others.[12] In recent years, more efforts have
been made in the development of functional foldamers able
to serve as synthetic receptors[13–15] or enzyme mimics.[16]
Indole, a key component of tryptophan, possesses a good
hydrogen-bond donor of NH. It is, therefore, not surprising
to find proteins and enzymes that utilize indole NHs for hy-
drogen bonding with anions, such as in sulfate-binding pro-
tein[17] and haloalkane dehalogenase.[18] We[19] and
others[20–22] have demonstrated that indole can serve as a
useful molecular building block for the construction of syn-
thetic anion receptors. Among these, oligoindole foldamers
have proven to adopt a helical structure upon binding a
chloride, which leads to the conformational change of large
amplitude.[15a] If this conformational variation results in ab-
sorption and or emission change, the foldamer would be
highly attractive for possible applications as molecular sen-
sors and smart materials responsive to external stimulation.
With this in mind, we herein prepared a series of strongly
fluorescent oligoindoles 1a–d containing between two and
eight indole rings, and their folding and anion-binding prop-
erties were characterized by 1H NMR and fluorescence
spectroscopy.
Despite high diversity and complexity, proteins and enzymes
possess common structural motifs such as helices, sheets,
and turns, which are stabilized by hydrogen bonds, dipole–
dipole interactions, and other non-covalent forces. Over the
last decade, chemists have prepared a variety of synthetic
molecules capable of folding into an ordered array, so-called
foldamers,[1] to gain insight into the fundamental principles
for folding as well as to develop functional materials respon-
sive to external stimulus. Examples include peptidomimetic
foldamers derived from natural or unnatural amino acids,[2]
aryl strand foldamers from rigid aromatic building
[a] U.-I. Kim, J.-m. Suk, V. R. Naidu, Prof. Dr. K.-S. Jeong
Center for Bioactive Molecular Hybrids and
Department of Chemistry
Yonsei University, Seoul 120-149 (Korea)
Fax : (+82)2-364-7050
E-mail: ksjeong@yonsei.ac.kr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem200801713.
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FULL PAPER
afford a helical structure comprising four indole units per
turn. The actual molecule we used as the repeating scaffold
is a 2,2’-biindole derivative 6. Here, the side chain of me-
thoxyethoxyethyl esters at 5,5’-positions greatly increases
the solubility of the oligomers in organic solvents, and the
iodo groups at 7,7’-positions serve for the connection
through Sonogashira coupling[23] under mild conditions. Fi-
nally, the fluorescent properties of oligoindoles have been
found to be highly sensitive to the nature of terminal
groups. Among those prepared in this laboratory, the ben-
zoate group confers the strongest emission and, moreover,
shows the largest change in intensity and wavelength of the
band upon anion binding.
The longer sequences 1b–d are able to fold into helical
The synthesis began with 4-aminobenzoate 2, which was
reacted with I2/Ag2SO4 to give 4-amino-3,5-diiodobenzoate
(3, 91% yield).[24] The coupling reaction[23] of 3 and trime-
thylsilylethyne (1 equiv), followed by removal of the TMS
group, gave compound 4 (51% yield for two steps), which
was sequentially subjected to oxidative coupling[25] (95%
yield) and indolization[26] (93% yield) in the presence of
copper salts to give a biindole 6. Then, 3-ethynylbenzoate 7
(1 equiv) was coupled to 6 to give 8 (49% yield) and dimer
1a (22% yield). By similar procedures, tetramer 1b, hexa-
mer 1c, and octamer 1d were prepared from 6 and 8 as de-
scribed in the Experimental Section (Scheme 1).
structures in the presence of an anion, as demonstrated by
1
characteristic upfield shifts of the H NMR aromatic signals
and bathochromic (Dl=65–70 nm) and hypochromic shifts
of the emission bands. In particular, the dramatic changes in
the fluorescence spectra allow us to conveniently determine
and compare the binding affinities between 1c, d and anions
in a competitive medium 20% (v/v) MeOH/CH2Cl2.
Results and Discussion
Design principles and synthesis: For the construction of a
foldamer, a key task is to select or design a proper monomer
bearing all the information necessary for elongation and
folding, such as proper functional groups, bending angle,
and orientation. We chose an indole derivative functional-
ized at the 2- and 7-positions as a molecular building block
because 1) it possesses a good hydrogen-bonding donor NH,
and 2) the relative orientation between the 2- and 7-posi-
tions of indole is nearly perpendicular and, therefore, the
elongation of the strand through these positions would
Computer modeling: The repeating biindole scaffold exists
in the s-trans conformation between two indole rings; two
NHs are in the opposite direction to minimize dipole–dipole
repulsion according to computer modeling (MacroMo-
del 9.1, MMFF force field).[28,29] Upon anion binding, the
conformation switches to the s-cis, so that two indole NHs
are able to simultaneously participate in hydrogen bonding
with an anion.
Scheme 1. Synthesis of 1a–d. a) I2, Ag2SO4, EtOH, RT, 91%; b) [Pd
RT, 51% (2 steps); c) Cu(OAc)2·H2O, pyridine, RT, 95%; d) CuI, DMF, 124–1368C, 93%; e) [Pd
(22%); f) [Pd(PPh3)2Cl2], CuI, trimethylsilylethyne, Et3N/THF, 56–598C, then TBAF, AcOH, THF, RT, 9 (74%), 11 (67%); g) [Pd
Et3N/THF, 56–628C, 10 (55%), 1c (18%); h) the same as g): 1b (48%), 1d (50%).
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
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K.-S. Jeong et al.
1b–d are able to fold into a helical conformation of one-
and-a-half, two, and two-and-a-half turns, respectively
(Figure 1 for 1d and also see Supporting Information).
1
Folding studies by H NMR spectroscopy: Oligoindoles 1a–c
1
give well-resolved H NMR spectra in [D6]acetone at room
1
temperature (Figure 2). In contrast, the H NMR spectrum
of the longest octamer 1d is completely broadened out in
the absence of an anion, but becomes sharp and nicely re-
solved upon addition of an anion, for example, a chloride
(Figure 2g). In all cases, the NH signals for all the oligoin-
doles are shifted downfield in the presence of tetrabutylam-
monium chloride as a result of hydrogen bonding in
[D6]acetone. For example, the NH signal of 1a is shifted
from 11.50 to 14.27 ppm, and those of 1b are shifted from
11.49 and 12.13 ppm to 11.56 and 13.57 ppm. Interestingly,
among three NH signals in 1c two are downfield shifted but
one is slightly upfield shifted upon binding the chloride ion.
This is possibly ascribed to the combination of hydrogen
bonding, stacking, and desolvation associated with the con-
formational switching from an open extended arrangement
to a compact helical one.
Figure 1. Side (left) and top (right) views of an energy-minimized struc-
ture[27] for complex 1d-ClÀ (MacroModel 9.1,[28] MMFF[29] force field, gas
phase). The ester side chains of 1d have been replaced with hydrogen
atoms.
The aromatic CH signals provide clear evidence for the
helical folding of oligoindoles in the presence of the chloride
ion. The H NMR data for the aromatic signals are summar-
ized and compared in Table 1. The shortest strand 1a, a ref-
erence without any stacking between aromatic surfaces,
shows negligible changes in the chemical shifts of aromatic
signals, except those for Ha and Hd involved in the CH···ClÀ
hydrogen bonds. On the other hand, the longer sequences
1b and 1c are able to fold into a helical conformation, thus
Oligoindoles 1a–d exist in an extended conformation in
the absence of an anion, but fold into a compact helical
structure upon anion binding. The anion, for example, the
chloride ion becomes entrapped inside the tubular cavity by
multiple hydrogen bonds with the indole NHs (Figure 1).
The relative orientation between i and i+2 residues of the
sequence is nearly perpendicular, thus leading to one turn
consisting of four aromatic components. As a consequence,
1
Figure 2. Partial 1H NMR spectra (400 MHz, [D6]acetone, 258C) of a) 1a (0.5 mm), b) 1a (0.5 mm)+nBu4N+ClÀ (1 equiv), c) 1b (0.5 mm), d) 1b
(0.5 mm)+nBu4N+ClÀ (1 equiv), e) 1c (0.3 mm), f) 1c (0.3 mm)+nBu4N+ClÀ (1 equiv), and g) 1d (0.1 mm)+nBu4N+ClÀ (1 equiv).
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Fluorescent Oligoindole Foldamers
FULL PAPER
allowing for intramolecular aromatic stacking. In the pres-
ence of the chloride ion (<1 equiv), 1b and 1c show two
separate sets of 1H NMR signals, one for the free and anoth-
er for its complex, due to slow exchange on the NMR
(400 MHz) timescale in [D6]acetone at room temperature
(see Supporting Information). When more than one equiva-
lent of the chloride ion is added, the signals for the complex
can be only seen in the expense of the free. The trend and
magnitude of the chemical-shift changes in Table 1 are con-
sistent with the energy-minimized structures of 1b and 1c
that afford helical structures of one-and-a-half turns and
two turns, respectively. In the presence of excess TBA+ClÀ
(5 equiv), the 1H NMR spectrum of 1b and 1c became
broadened without changing the chemical shifts of the sig-
Figure 4. Average chemical shifts of aromatic proton signals of 1a–d
when complexed with tetrabutylammonium chloride in [D6]acetone at
258C.
Table 1. Changes in the chemical shift of 1H NMR aromatic signals of
oligoindoles 1a–c upon addition of tetrabutylammonium chloride
(1 equiv) in [D6]acetone at 258C.
1
nals, but the longer oligoindole 1d afforded broad H NMR
signals with different chemical shifts, possibly attributed to
the formation of a 2:1 ClÀ/1d complex under these condi-
tions. Additional evidence for the helical conformation was
Induced chemical-shift change
Aromatic
[ppm, Dd=dcomplexÀdfree
]
proton
1
1a
1b
1c
obtained from 2D H ROESY experiments with a 1:1 mix-
Ha
Hb
Hc
Hd
He
Hf
Hg
Hh
Hi
+0.95
À0.03
À0.05
+0.24
À0.05
À0.06
À0.02
À0.11
À1.00
À0.82
À0.04
À0.28
À0.24
À0.21
À0.02
À0.04
+0.07
À0.16
À0.61
À0.50
À0.11
À0.41
À0.44
À0.34
À0.53
À0.59
À0.33
0.00
ture of 1c and tetrabutylammonium chloride (Figure 3). Nu-
clear Overhauser effect (NOE) correlations are clearly ob-
served between Hh and Hf, Hj and He, and Hm and Hc, which
are not detectable without the anion, confirming the anion-
induced helical conformation. Finally, the average chemical
shift for the aromatic signals of 1a–d in the presence of the
chloride ion is plotted against the chain length (Figure 4).
More upfield shift is observed as the chain grows, which is
consistent with the degree of stacked aromatic surfaces in
the helically folded strand. All of the observations described
above consistently support that oligoindoles 1b–d fold into
a compact, helical conformation in the presence of the chlo-
ride ion.
Hj
Hk
Hl
À0.19
Hm
À0.24
these conditions, oligoindoles 1a–d showed strong emission
bands with the highest intensities at wavelengths 418, 427,
428, and 433 nm, respectively. The quantum yields[30] were
measured to be 0.82 (1a), 0.70 (1b), 0.49 (1c), and 0.39 (1d)
by using quinine sulfate as a reference.[31] Upon addition of
tetrabutylammonium chloride up to 1000 equivalents, the
emission spectrum of 1a remained unchanged, whereas that
of 1b showed slight red shift (ꢀ10 nm) without any noticea-
ble hypochromic shift. In contrast, the longer strands 1c and d
Folding studies by fluorescence spectroscopy: Fluorescence
spectroscopy has been widely used to characterize the fold-
ing of aromatic strand foldamers.[4,8,11] The helical folding
often leads to the bathochromic and/or hypochromic shifts
of the emission spectra because of the intramolecular exci-
mer formation in the stacked aromatic array. The fluores-
cence spectra of 1a–d were taken with excitation at 310 nm
in 20% (v/v) MeOH/CH2Cl2 at room temperature. Under
1
Figure 3. 2D H NMR ROESY spectrum of 1c in the presence of tetrabutylammonium chloride (1 equiv) in [D6]acetone at 258C. The NOE cross-peaks,
diagnostic signals for helical folding, are observed between Hh and Hf, Hj and He, and Hm and Hc.
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K.-S. Jeong et al.
capable of folding into helical structures showed dramatic
changes. That is, the emission band at 428 (1c) or 433 nm
(1d) were significantly quenched and a new broad band ap-
peared at 493 nm (1c) or 503 nm (1d) (Figure 5). This result
must be attributed to excimer formation between over-
lapped indole surfaces, which strongly supports the helical
folding of 1c and d. As demonstrated in Figure 5, a solution
of 1c (or 1d) turns from bright blue to dim bluish-green
upon addition of tetrabutylammonium chloride (>1 equiv)
in acetone.
15mÀ1, indicative of two NHs participating in the same bind-
ing event. The association constants of the longer strands 1c
and d with the chloride ion could not be determined by the
1H NMR titration because of high affinities and severe ag-
gregation at the concentration for the H NMR spectrosco-
py.
Fluorescence spectroscopy was used to quantify the asso-
ciation constants between 1c and d and anions. Prior to the
titration, we demonstrated that the fluorescence intensity of
1c and d is linearly proportional to the concentration rang-
ing from 0.2ꢀ10À6 m to 4ꢀ10À6 m in 20% (v/v) [D3]CH3OH/
[D2]CH2Cl2. The titration experiments were conducted at
the constant concentration (1.0ꢀ10À6 m) of 1c (or 1d) by
gradually increasing the concentration of an anion, which re-
sulted in significant quenching of the emission band at
428 nm (1c) or 433 nm (1d) and arising of a new broad
band at 493 nm (1c) or 503 nm (1d). The association con-
stants, analyzed by nonlinear least-squares fitting,[32] are
summarized in Table 2. First, the association constants of 1c
1
Table 2. Association constants (Ka Æ20%, mÀ1) of oligoindoles 1c and d
with anions in 20% (v/v) MeOH/CH2Cl2 at 24Æ18C.
Ka [mÀ1
]
Anion
1c
1d
FÀ
5.1ꢀ105
1.1ꢀ105
1.6ꢀ104
4.0ꢀ103
8.5ꢀ104
6.0ꢀ104
4.8ꢀ103
2.9ꢀ104
1.2ꢀ106
2.9ꢀ105
5.0ꢀ104
2.1ꢀ104
1.1ꢀ105
1.2ꢀ105
8.0ꢀ104
9.4ꢀ104
ClÀ
BrÀ
IÀ
CNÀ
N3
À
À
NO3
AcOÀ
Figure 5. Fluorescence spectral changes of 1c (left) and 1d (right) upon
addition of tetrabutylammonium chloride in 20% (v/v) MeOH/CH2Cl2 at
24Æ18C. The fluorescence color of each solution (2ꢀ10À6 m) changes
from blue to bluish-green upon addition of tetrabutylammonium chloride
(5 equiv) in acetone.
and 1d with the chloride ion are estimated to be 1.1ꢀ105 mÀ1
and 2.9ꢀ105 mÀ1, respectively, which are much higher than
that of tetramer 1b (625mÀ1). The difference in the associa-
tion constants of 1b and 1c is approximately 180-fold, but
only threefold between 1c and 1d, although the indole NHs
increase by the same number upon going from 1b to 1c to
1d. Jobꢂs plots[32b,33] show that 1b, 1c, and 1d form 1:1 com-
plexes with anions.[34] These results imply that the chloride
ion is effectively wrapped up by 1c with six indole units
and, therefore, two additional indole NHs in 1d contribute
little to the stability of the complex. Finally, the binding af-
finities of 1c and 1d with other anions are compared with
each other. In a series of halides, the binding affinity paral-
lels with the hydrogen-bonding ability of a halide. Consider-
ing the basicities, halides bind more strongly relative to
polyatomic anions. According to computer modeling, spheri-
cal halides are better entrapped in a sandwiched manner in
between two turns of the helical conformation.
Binding studies: To quantitatively reveal and compare the
binding affinities, titrations were performed in a hydrogen-
bond-competitive medium 20% (v/v) MeOH/CH2Cl2 at 24Æ
1
18C using H NMR spectroscopy for 1a and b and fluores-
cence spectroscopy for 1c and d. As mentioned above, the
NH signal of 1a was largely downfield shifted (Dl=
2.8 ppm) in [D6]acetone upon addition of tetrabutylammoni-
um chloride (1 equiv). However, in a more competitive
medium 20% (v/v) [D3]CH3OH/[D2]CH2Cl2, the induced
shift is negligible (Dd<0.05 ppm), even in the presence of
excess (ꢀ10 equiv) tetrabutylammonium chloride due to a
weak binding constant (Ka <1mÀ1). On the other hand, two
NH signals of 1b were significantly downfield shifted from
11.30 and 11.47 ppm to 11.72 and 12.92 ppm during the titra-
tion in 20% (v/v) [D3]CH3OH/[D2]CH2Cl2 at 24Æ18C. The
time-averaged 1H NMR signals of the free and complex
were observed in this medium, unlike in acetone. The non-
linear least-squares fitting[32] of two NH titration curves
yielded an identical association constant (Ka) of 625Æ
Conclusions
We have described a series of oligoindoles 1a–d that adopt
a compact helical structure induced by an anion entrapped
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Fluorescent Oligoindole Foldamers
FULL PAPER
termediate was dissolved in THF (40mL) and the solution was cooled to
08C (iced-water bath), to which acetic acid (1.1 equiv) and tetrabutylam-
monium fluoride (TBAF) (1m in THF, 1.1 equiv) were sequentially
added and the solution was stirred for 30 min at RT. After concentration,
the reaction mixture was dissolved in EtOAc, washed with saturated
NaHCO3 solution, brine and water. The crude product was purified by
flash column chromatography (EtOAc/hexane 1:2) to give 4 (7.3g, 51%)
as a white solid. M.p. 73–748C; 1H NMR (500 MHz, [D6]DMSO, 258C,
DMSO): d=8.19 (s, 1H), 7.82 (s, 1H), 6.08 (s, 2H; NH2), 4.64 (s, 1H),
4.34 (m, 2H), 3.75 (m, 2H), 3.61 (m, 2H), 3.49 (m, 2H), 3.29 ppm (s,
3H); 13C NMR (126 MHz, [D6]DMSO, 258C, DMSO): d=163.8, 153.0,
140.7, 133.7, 118.6, 104.7, 87.0, 81.4, 79.2, 71.3, 69.6, 68.3, 63.8, 58.1 ppm;
ꢁ
in the tubular cavity through multiple hydrogen bonds with
the indole NHs. Helical folding was unambiguously proven
by results of H NMR spectroscopy, which shows character-
1
istic upfield shifts of the aromatic CH signals, together with
downfield shifts of the NH signals as a result of the hydro-
gen bonding. Oligoindoles 1a and d bind anions, and the
binding strengths depend on the number of hydrogen bonds
and the nature of anions. Upon binding an anion, the longer
oligoindoles 1c and d display large hypochromic and batho-
chromic shifts of the emission bands, along with the fluores-
cence color change from blue to bluish-green. This color
change informs us of the folded or unfolded state of oligoin-
doles, as well as the anion-binding event. Consequently, the
foldamer described here not only functions as a synthetic re-
ceptor or sensor for anions but also has potential to be uti-
lized for external stimuli-responsive materials with fluores-
cence signaling.
IR (KBr): n˜ =3429 (NH2), 2101
411.8 [M+Na]+.
(C C), 1706 (C=O) cmÀ1; ESI-MS: m/z:
ACHTUNGTRENNUNG
Compound 5: Compound 4 (6.0 g, 15 mmol) was dissolved in pyridine
(60 mL) and Cu
(OAc)2·H2O (3.4 g, 17 mmol) was added.[25] After stirring
AHCTUNGTRENNUNG
at RT for 16 h, the mixture was filtered through Celite and the filtrate
was concentrated. The residue was dissolved in CH2Cl2, and the organic
solution was washed with saturated aqueous NaHCO3 solution, brine and
water, and dried over anhydrous MgSO4. After concentration, the residue
was purified by column chromatography (EtOAc/hexane 2:1) to give 5 as
a
yellow solid (5.7 g, 95%). M.p. 112–1138C; 1H NMR (500 MHz,
[D6]DMSO, 258C, DMSO): d=8.18 (s, 1H), 7.88 (s, 1H), 6.42 (s, 2H;
NH2), 4.40 (m, 2H), 3.78 (m, 2H), 3.65 (m, 2H), 3.54 (m, 2H), 3.37 ppm
(s, 3H); 13C NMR (126 MHz, [D6]DMSO, 258C, DMSO): d=163.6,
153.8, 141.5, 134.4, 118.6, 103.1, 82.0, 79.2, 71.2, 70.0, 68.3, 64.0, 58.1 ppm;
Experimental Section
General: Air- or moisture-sensitive reactions were carried out under ni-
trogen or argon. All chemicals were used as purchased unless noted. Trie-
thylamine was distilled over CaH2, and THF was distilled from sodium/
benzophenone. Column chromatography was performed on silica gel 60
(230–240 mesh). 1H NMR spectra were recorded by using Bruker
DRX 400 and DRX 500 instruments, and chemical shifts were reported
in ppm relative to the residual protonated peaks (CHCl3: d=7.26 ppm
IR (KBr): n˜ =3470 (NH2), 2128 (C C), 1704 (C=O) cmÀ1; ESI-MS: m/z:
ꢁ
799.1 [M+Na]+.
Biindole 6: A solution containing 5 (4.0 g, 5.2 mmol) and CuI (2.0 g,
10 mmol, 2.1 equiv) in DMF (50 mL) was heated at 124–1368C for
8.5 h.[26] The reaction mixture was cooled to ambient temperature, fil-
tered through Celite, and concentrated. The residue was dissolved in
CH2Cl2 and the organic solution was washed with saturated aqueous
NaHCO3 solution, brine and water, dried over anhydrous MgSO4, and
concentrated. The residue was washed with a small amount of EtOAc
(slightly soluble) to give 6 as a white solid (3.7 g, 93%). M.p. 161–1628C;
1H NMR (500 MHz, [D6]DMSO, 258C, DMSO): d=11.66 (s, 2H; NH),
8.24 (s, 2H), 8.10 (s, 2H), 7.48 (s, 2H), 4.39 (m, 4H), 3.77 (m, 4H), 3.61
(m, 4H), 3.47 (m, 4H), 3.26 ppm (s, 6H); 13C NMR (126 MHz,
[D6]DMSO, 258C, DMSO): d=165.2, 141.3, 132.3, 132.0, 128.0, 123.2,
122.4, 104.0, 76.2, 71.2, 70.0, 68.4, 64.0, 58.1 ppm; IR (KBr): n˜ =3437
(NH), 1711 (C=O) cmÀ1; ESI-MS: m/z: 799.1 [M+Na]+.
for H, d=77.16 ppm for 13C; DMSO: d=2.50 ppm for H, d=39.52 ppm
for 13C; acetone: d=2.05 ppm for 1H). Melting points were measured by
using a Barnstead Electrothermal (IA9100) apparatus and are uncorrect-
ed. The UV/Vis spectra were recorded by using an Agilent 8453 UV-visi-
ble spectrophotometer, fluorescence spectra by using a F-4500 fluores-
cence spectrophotometer, and FTIR spectra by using a Nicolet Impact-
400 FTIR spectrometer. Elemental analyses were obtained from the Na-
tional Center for Inter-University Research Facilities at the Seoul Na-
tional University.
1
1
2-(2-Methoxyethoxy)ethyl 4-amino-3,5-diiodobenzoate (3): I2 (60g, 0.24
mol, 2.2 equiv) and Ag2SO4 (74g, 0.24 mol, 2.2 equiv) were added to a so-
lution of 2 (27.0g, 113mmol) in EtOH (1.4 L).[24] The mixture was me-
chanically stirred for 1h at RT, then filtered through Celite and the fil-
trate was concentrated. The residue was dissolved in CH2Cl2 (500mL).
The solution was washed with 1n NaOH aqueous solution, saturated
aqueous NaHCO3 solution, brine and water, dried over anhydrous
MgSO4 and concentrated. The residue was purified by column chroma-
tography (CH2Cl2/EtOAc 1:3) to give 3 as a white floppy solid (50.6g,
2-(2-Methoxyethoxy)ethyl-3-ethynylbenzoate
(7):
3-Bromobenzoate
(3.16 g, 10 mmol), [Pd(dba)2] (dba=(E,E)-dibenzylideneacetone) (60 mg,
AHCTUNGTRENNUNG
0.1 mmol, 0.01 equiv), PPh3 (140 mg, 0.5 mmol, 0.05 equiv), and CuI
(20 mg, 0.1 mmol, 0.01 equiv) were placed in a Schlenk flask. The flask
was degassed under high vacuum and back-filled with nitrogen. This pro-
cess was repeated three times. Dried THF (20 mL), Et3N (30 mL), and
trimethylsilylethyne (2.3 mL, 15 mmol, 1.5 equiv) were added. The solu-
tion was stirred under nitrogen at 82–878C for 19 h, and cooled to ambi-
ent temperature. The mixture was filtered through Celite and the filtrate
was concentrated. The residue was dissolved in EtOAc, and washed with
saturated NaHCO3 solution, brine and water. The organic layer was
dried over anhydrous MgSO4. Without further purification, the crude
product was dissolved in THF (30 mL) to which acetic acid (1m in THF,
10 mL) and TBAF (1m in THF, 10 mL) were sequentially added at 08C,
and the solution was stirred for 30 min at RT. After concentration, the re-
action mixture was dissolved in EtOAc, washed with saturated NaHCO3
solution, brine and water. The organic layer was dried through anhydrous
MgSO4. The crude product was purified by flash column chromatography
(CH2Cl2) to give 7 as an oily liquid (2.38 g, 92%). 1H NMR (400 MHz,
[D6]DMSO, 258C, DMSO): d=7.96–7.94 (2H, two peaks overlapped),
7.74 (d, J=7.6 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 4.37 (t, J=4.4 Hz, 2H),
4.31 (s, 1H), 3.72 (t, J=4.4 Hz, 2H), 3.56 (t, J=4.8 Hz, 2H), 3.42 (t, J=
4.4 Hz, 2H), 3.21 ppm (s, 3H); 13C NMR (100 MHz, [D6]DMSO, 258C,
DMSO): d=164.9, 136.3, 132.1, 130.3, 129.6, 129.5, 122.3, 82.3, 82.02,
1
91%). M.p. 80–818C; H NMR (500 MHz, CDCl3, 258C, CHCl3): d=8.28
(s, 2H), 5.06 (s, 2H; NH2), 4.40 (m, 2H), 3.78 (m, 2H), 3.65 (m, 2H),
3.54 (m, 2H), 3.37 ppm (s, 3H); 13C NMR (126 MHz, CDCl3, 258C,
CHCl3): d=163.8, 149.8, 141.1, 122.4, 79.4, 72.8, 70.6, 69.3, 64.1,
59.2 ppm; IR (KBr): n˜ =3428 (NH2), 1705 (C=O) cmÀ1; ESI-MS: m/z:
513.8 [M+Na]+.
2-(2-Methoxyethoxy)ethyl 4-amino-3-ethynyl-5-diiodobenzoate (4): Com-
pound 3 (18.0g, 36.7mmol), [PdACHTNUGTRNENUG(PPh3)2Cl2] (0.52g, 0.02 equiv), and CuI
(0.18g, 0.025 equiv) were placed in a Schlenk flask. The flask was de-
gassed under high vacuum and back-filled with nitrogen. This process
was repeated three times. Dried THF (50mL), Et3N (300mL), and trime-
thylsilylethyne (5.2mL, 1.0 equiv) were added, and the solution was
stirred at 58–608C for 18h. The mixture was filtered through Celite, the
organic solution was concentrated, and the residue was dissolved in
CH2Cl2. The organic solution was washed with saturated aqueous
NaHCO3 solution, brine and water, dried over anhydrous MgSO4 and
concentrated. The residue was purified by column chromatography
(EtOAc/hexane 1:3) to give a TMS-protected precursor (ꢀ8.0 g). This in-
ꢁ
81.99, 71.3, 69.7, 68.3, 64.4, 58.1 ppm; IR (thin film): n˜ =2251 (C C),
1720 (C=O) cmÀ1; ESI-MS: m/z: 271.1 [M+Na]+.
Chem. Eur. J. 2008, 14, 11406 – 11414
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11411

K.-S. Jeong et al.
Compound 8: Compound 6 (2.41 g, 3.10 mmol, 1.1 equiv), CuI (10 mg,
0.06 mmol, 0.02 equiv), and [Pd(PPh3)2Cl2] (20 mg, 0.03 mmol, 0.01 equiv)
1709 (C=O), 1601 (C=C) cmÀ1
C72H75IN4O20: C 59.92, H 5.24, N 3.88; found: C 59.24, H 5.21, N 3.84.
;
elemental analysis calcd (%) for
C
were placed in a Schlenk flask. The flask was degassed under high
vacuum and back-filled with nitrogen. This process was repeated three
times. Dried THF (20 mL) and Et3N (70 mL) were added. Then, a de-
gassed THF solution (10 mL) of 7 (0.7 g, 2.82 mmol, 1.0 equiv) was
added under a cannula. The resulting solution was stirred under nitrogen
at 56–628C for 15 h, and cooled to ambient temperature. The mixture
was filtered through Celite and the filtrate was concentrated. The residue
was dissolved in EtOAc, and washed with saturated NaHCO3 solution,
brine and water. The organic layer was dried over anhydrous MgSO4.
After concentration, the residue was purified by column chromatography
(EtOAc/hexane 4:1) to give 8 as a slightly yellowish solid (1.23 g, 49%),
Compound 11: This compound was obtained from 10 as a white solid
(67% yield) according to the same procedure for the preparation of 9
from 8. M.p. 198–2008C; 1H NMR (400 MHz, [D6]DMSO, 258C, DMSO):
d = 12.29 (s, 2H; NH), 12.18 (s, 2H; NH), 8.42 (s, 1H), 8.38 (s, 1H),
8.35 (s, 1H), 8.26 (m, 4H), 7.99 (m, 2H), 7.93 (d, J=8.0 Hz, 1H), 7.86 (s,
1H), 7.55 (m, 5H), 4.58 (s, 1H), 4.43 (m, 10H), 3.79 (m, 10H), 3.63 (m,
10H), 3.47 (m, 10H), 3.24 ppm (m, 15H); 13C NMR (100 MHz,
[D6]DMSO, 258C, DMSO): d
= 166.0, 165.81, 165.75, 165.1, 139.8,
139.42, 139.37, 139.3, 136.1, 133.0, 132.87, 132.86, 132.79, 132.0, 130.1,
129.41, 129.38, 129.2, 128.42, 128.41, 128.2, 127.2, 127.1, 127.0, 126.89,
126.9, 123.61, 123.55, 123.48, 123.43, 123.0, 121.8, 121.7, 121.6, 105.5,
105.1, 103.27, 103.25, 103.1, 102.92, 102.90, 85.5, 79.5, 78.7, 69.68, 69.65,
69.62, 68.5, 68.4, 68.2, 64.3, 64.0, 63.95, 63.91, 63.88, 58.05, 58.04 ppm; IR
1
together with 1a (0.57 g, 22%). Compound 8: M.p. 111–1128C; H NMR
(400 MHz, [D6]DMSO, 258C, DMSO): d=12.20 (s, 1H; NH), 11.71 (s,
1H; NH), 8.35 (m, 2H), 8.30 (d, J=1.2 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H),
8.06 (d, J=1.6 Hz, 1H), 8.04 (d, J=1.2 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H),
7.69 (t, J=8.0 Hz, 1H), 7.53 (s, 2H), 4.43 (m, 6H), 3.79 (m, 6H), 3.63 (m,
6H), 3.48 (m, 6H), 3.27 (s, 3H), 3.26 (s, 3H), 3.23 ppm (s, 3H); 13C NMR
(100 MHz, [D6]DMSO, 258C, DMSO): d=165.8, 165.3, 165.1, 141.5,
139.2, 136.3, 132.72, 132.68, 132.2, 131.9, 130.3, 129.6, 129.5, 128.4, 128.0,
126.9, 123.6, 123.2, 123.1, 122.5, 121.8, 105.3, 103.7, 103.3, 92.34, 86.4,
76.2, 71.3, 69.69, 69.67, 68.5, 68.4, 68.3, 64.4, 64.0, 58.1, 58.08 ppm; IR
À1
ꢁ
(thin film): n˜ =3429 (NH), 2115 (C C), 1718 (C=O), 1648 (C=C) cm
;
elemental analysis calcd (%) for C74H76N4O20: C 66.26, H 5.71, N 4.18;
found: C 65.68, H 5.97, N 3.93.
Dimer 1a: See procedure for
8 described above. M.p. 116–1178C;
1H NMR (400 MHz, [D6]DMSO, 258C, DMSO): d = 12.30 (s, 2H; NH),
8.37 (d, J=8.8 Hz, 3H), 8.05 (t, J=7.2 Hz, 4H), 7.99 (s, 2H), 7.67 (t, J=
8.0 Hz, 3H), 7.45 (s, 2H), 4.43 (m, 8H), 3.79 (m, 8H), 3.62 (m, 8H), 3.47
(m, 8H), 3.266 (s, 3H), 3.264 (s, 3H), 3.233 (s, 3H), 3.231 ppm (s, 3H);
13C NMR (100 MHz, [D6]DMSO, 258C, DMSO): d = 165.8, 165.1, 139.4,
136.3, 132.9, 132.2, 130.3, 129.5, 129.4, 128.4, 126.8, 123.6, 123.1, 121.8,
105.4, 103.2, 92.4, 86.3, 71.3, 69.7, 68.4, 68.3, 64.4, 63.9, 58.08, 58.05 ppm;
IR (thin film): n˜ =3330 (NH), 1709 (C=O) cmÀ1; elemental analysis calcd
(%) for C56H60N2O16: C 66.13, H 5.95, N 2.75; found: C 66.18, H 6.00, N
2.71.
À1
ꢁ
(thin film): n˜ =3312 (NH), 2202 (C C), 1713 (C=O), 1597 (C=C) cm
;
elemental analysis calcd (%) for C42H45IN2O12: C 56.26, H 5.06, N 3.12;
found: C 56.22, H 5.02, N 3.11.
Compound 9: Compound 8 (1.19 g, 1.33 mmol), CuI (10 mg, 0.025 equiv)
and [PdACHTUNGTRENNUNG(PPh3)2Cl2] (20 mg, 0.02 equiv) were placed in a Schlenk flask.
The flask was degassed under high vacuum and back-filled with nitrogen.
This process was repeated three times. Dried THF (5 mL), Et3N (10 mL),
and trimethylsilylethyne (0.30 mL, 1.0 mmol, 1.5 equiv) were added. The
solution was stirred under nitrogen at 56–598C for 19 h, and then cooled
to ambient temperature. The mixture was filtered through Celite and the
filtrate was concentrated. The residue was dissolved in EtOAc, and
washed with saturated NaHCO3, brine and water. The organic layer was
dried over anhydrous MgSO4. After concentration, the residue was puri-
fied by column chromatography (EtOAc/hexane 3:1) to give a TMS-pro-
tected precursor (0.89 g). The TMS group (0.89 g, 1.03 mmol) was care-
fully removed with acetic acid (1.1 equiv) and TBAF (2.0 equiv) in THF
(10 mL) to give 9 as a slightly yellowish solid (0.78 g, 74%). M.p. 109–
Tetramer 1b: Using 8 (0.21 g, 0.23 mmol) and 9 (0.18 mg, 0.23 mmol,
1 equiv), 1b was prepared as a slightly greenish solid (0.12 g, 48% yield)
by the same procedure described for the preparation of 1a. The product
was first purified by column chromatography (MeOH/CH2Cl2 1:49), then
washed with water to remove any inorganic salt possibly contaminated
during the column chromatography. M.p. 171–1738C; 1H NMR
(400 MHz, [D6]DMSO, 258C, DMSO): d = 12.25 (s, 4H; NH), 8.41 (s,
2H), 8.31 (s, 2H), 8.24 (s, 4H), 7.99 (s, 4H), 7.97 (d, J=7.6 Hz, 1H), 7.91
(d, J=7.6 Hz, 1H), 7.57 (t, J=8.0 Hz, 2H), 7.50 (s, 4H), 4.42 (m, 12H),
3.78 (m, 12H), 3.62 (m, 12H), 3.47 (m, 12H), 3.26 (s, 6H), 3.24 (s, 6H),
3.22 ppm (s, 6H); 13C NMR (100 MHz, [D6]DMSO, 258C, DMSO): d =
166.0, 165.8, 165.0, 139.4, 136.1, 132.92, 132.85, 132.0, 130.1, 129.4, 129.2,
128.4, 127.1, 126.9, 123.7, 123.6, 123.5, 123.0, 121.80, 121.76, 106.0, 105.4,
103.2, 103.1, 103.0, 92.4, 89.6, 86.3, 71.3, 71.2, 69.70, 69.66, 69.54, 68.50,
68.4, 68.2, 64.3, 64.0, 63.9, 58.1 ppm; IR (thin film): n˜ =3360 (NH), 1722
(C=O) cmÀ1; elemental analysis calcd (%) for C86H90N4O24: C 66.06, H
5.80, N 3.58; found: C 65.74, H 5.82, N 3.58.
1
1108C; H NMR (400 MHz, [D6]DMSO, 258C, DMSO): d=12.16 (s, 2H;
NH), 8.35 (s, 2H), 8.33 (s, 1H), 8.06 (d, J=1.6 Hz, 1H), 8.04 (d, J=
1.6 Hz, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.52
(s.1H), 7.45 (s, 1H), 4.68 (s, 1H), 4.43 (m, 6H), 3.79 (m, 6H), 3.63 (m,
6H), 3.48 (m, 6H), 3.27 (s, 3H), 3.26 (s, 3H), 3.23 ppm (s, 3H); 13C NMR
(100 MHz, [D6]DMSO, 258C, DMSO): d=165.84, 165.79, 165.1, 139.8,
139.3, 136.3, 132.9, 132.2, 131.54, 131.45, 130.3, 129.6, 129.5, 128.5, 128.3,
127.05, 126.8, 123.6, 123.5, 123.1, 121.8, 121.6, 105.3, 105.1, 103.1, 103.0,
92.3, 86.3, 85.6, 79.6, 71.3, 69.68, 69.66, 68.4, 68.3, 64.4, 63.9, 58.11,
Hexamer 1c: See the procedure for 10 described above. After column
chromatography (MeOH/CH2Cl2 1:39), the product was washed with
ethyl acetate to remove unknown organic impurities, then with water to
remove any inorganic salt contaminated during the column chromatogra-
phy. M.p. 236–2388C; 1H NMR (400 MHz, [D6]DMSO, 258C, DMSO):
d=12.33 (s, 2H; NH), 12.15 (s, 4H; NH), 8.37 (s, 2H), 8.28 (m, 7H), 8.08
(s, 2H), 7.96 (m, 7H), 7.56 (m, 4H), 7.43 (s, 4H), 4.43 (m, 16H), 3.76 (m,
16H), 3.61 (m, 16H), 3.47 (m, 16H), 3.23 ppm (m, 18H); 13C NMR
(100 MHz, [D6]DMSO, 258C, DMSO): d=166.0, 165.9, 165.8, 165.1,
139.31, 139.29, 139.24, 136.1, 132.8, 132.7, 132.1, 130.1, 129.3, 129.2, 128.4,
128.28, 128.25, 127.2, 126.9, 123.54, 123.48, 123.45, 123.29, 123.27, 123.1,
121.9, 121.6, 106.1, 105.8, 105.3, 103.2, 102.9, 92.3, 89.8, 89.6, 86.5, 71.28,
71.26, 71.25, 71.23, 69.69, 69.67, 69.63, 68.5, 68.3, 64.3, 63.94, 63.86, 58.07.
ꢁ
58.07 ppm; IR (thin film): n˜ =3282 (NH), 2206 (C C), 1713 (C=O), 1597
(C=C) cmÀ1; elemental analysis calcd (%) for C44H46N2O12: C 66.49, H
5.83, N 3.52; found: C 66.51, H 5.83, N 3.50.
Compound 10: Using 6 (1.89 g, 2.43 mmol, 1.1 equiv) and 9 (1.76 g,
2.21 mmol, 1.0 equiv), 10 was prepared following the same procedure de-
scribed for the preparation of 8. The product was purified by column
chromatography (MeOH/CH2Cl2 1:49) to give 10 as a white solid (1.76 g,
55%), together with 1c as a white solid (0.84 g, 18%). Compound 10:
M.p. 218–2208C; 1H NMR (400 MHz, [D6]DMSO, 258C, DMSO): d=
12.30 (s, 2H; NH), 12.23 (s, 1H; NH), 11.74 (s, 1H; NH), 8.42 (s, 1H),
8.39 (s, 1H), 8.34 (s, 1H), 8.24 (m, 4H), 8.10 (s, 1H), 7.99 (m, 2H), 7.92
(d, J=8.0 Hz, 1H), 7.56 (m, 5H), 4.43 (m, 10H), 3.79 (m, 10H), 3.62 (m,
10H), 3.47 (m, 10H), 3.26 (s, 3H), 3.25 (s, 3H), 3.24 (s, 3H), 3.23 ppm (s,
3H); 13C NMR (100 MHz, [D6]DMSO, 258C, DMSO): d=166.0, 165.8,
165.3, 165.1, 141.5, 139.5, 139.4, 139.3, 136.1, 133.0, 132.9, 132.8, 132.6,
132.1, 131.9, 130.1, 129.4, 129.2, 128.4, 128.0, 127.1, 126.9, 123.63, 123.55,
123.2, 123.0, 122.5, 121.8, 106.02, 105.96, 105.5, 103.8, 103.3, 103.2, 103.18,
103.13, 92.4, 89.7, 89.6, 86.4, 76.1, 71.33, 71.27, 69.7, 69.8, 68.5, 68.4, 68.3,
ꢁ
58.05, 58.03 ppm; IR (thin film): n˜ =3338 (NH), 2279 (C C), 1709 (C=
O), 1661 (C=C) cmÀ1; elemental analysis calcd (%) for C116H120N6O32: C
66.02, H 5.73, N 3.98; found: C 65.39, H 5.70, N 3.51.
Octamer 1d: This compound was prepared as a white solid (0.32 g, 50%
yield) from 10 (0.24 g, 0.17 mmol) and 11 (0.23 g, 0.17 mmol) by the same
procedure described for the preparation of 1b. After column chromatog-
raphy (MeOH/CH2Cl2 1:24), the product was washed with ethyl acetate
to remove unknown organic impurities, then with water to remove any
inorganic salt contaminated during the column chromatography. M.p.
ꢁ
64.4, 64.0, 63.9, 58.1 ppm; IR (thin film): n˜ =3308 (NH), 2210 (C C),
11412
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11406 – 11414

Fluorescent Oligoindole Foldamers
FULL PAPER
280–2828C; 1H NMR (400 MHz, [D6]DMSO, 258C, DMSO): d=12.22
(m, 8H; NH), 8.26 (m, 12H), 8.12 (m, 4H), 7.95 (m, 6H), 7.50 (m, 10H),
4.41 (m, 20H), 3.76 (m, 20H), 3.61 (m, 20H), 3.46 (m, 20H), 3.23 ppm
(m, 30H); 13C NMR (100 MHz, [D6]DMSO, 258C, DMSO): d=166.54,
166.50, 166.46, 166.4, 165.6, 139.9, 139.80, 139.78, 136.7, 133.4, 133.32,
133.28, 132.6, 130.7, 129.9, 129.7, 128.8, 127.87, 127.85, 127.83, 127.79,
127.72, 127.70, 127.41, 127.40, 127.38, 127.35, 123.7, 122.24, 122.17, 106.54,
106.52, 105.8, 103.58, 103.52, 103.49, 103.46, 103.45, 103.42, 92.8, 90.3,
87.0, 71.86, 71.83, 71.82, 70.28, 70.24, 70.20, 69.1, 68.8, 64.9, 64.47, 64.43,
64.38, 58.63, 58.60 ppm; IR (thin film): n˜ =3468 (NH), 1718 (C=O), 1631
(C=C) cmÀ1; elemental analysis calcd (%) for C146H150N8O40: C 66.00, H
5.69, N 4.22; found: C 65.45, H 5.70, N 4.12.
1H NMR titration: Stock solutions of 1b (1.00ꢀ10À3 m) and tetrabutylam-
monium chloride (1.0ꢀ10À2 m) in 4:1 (v/v) [D2]CH2Cl2/[D3]CH3OH were
separately prepared. An amount, 450 mL, of 1b was transferred to an
NMR tube, and an initial spectrum was taken at 258C. Small portions of
the tetrabutylammonium chloride solution were added, the spectrum was
recorded after each addition, and 17 data points were obtained. The asso-
ciation constant (Ka, mÀ1) was determined by nonlinear least-squares fit-
ting of the titration curves.
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Fluorescence titration: Dichloromethane and methanol of a spectroscopic
grade were degassed prior to use. A stock solution (1.0ꢀ10À6 m, 10 mL)
of 1c (or 1d) was prepared in 4:1 (v/v) CH2Cl2/methanol. Using this solu-
tion, each stock solution (2.0–3.0 mL) of tetrabutylammonium anions was
prepared and the concentrations were between 3.0ꢀ10À5 and 2.0ꢀ10À3 m,
depending on the magnitude of the association constant. A solution of 1c
(or 1d) (1.0 mL) was transferred to a fluorescence cell, and an initial
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nonlinear least-squares fitting of the titration curves.
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Acknowledgements
This work was supported by the Center for Bioactive Molecular Hybrids
(CBMH). U.I.K, J.m.S, and V.R.N. acknowledge the fellowship of the
BK21 program from the Ministry of Education and Human Resources
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Chem. Eur. J. 2008, 14, 11406 – 11414