Indolocarbazole-based foldamers capable of binding halides in water

Article abstract of DOI:10.1021/ja804845m

A series of indolocarbazole-based foldamers have been prepared which can fold into a helical array with an internal cavity encircled by multiple indole NHs, thus allowing for binding anions by hydrogen bonds. The helical folding has been confirmed by comp

Full text of DOI:10.1021/ja804845m

Published on Web 08/14/2008
Indolocarbazole-Based Foldamers Capable of Binding Halides in Water
Jae-min Suk and Kyu-Sung Jeong*
Center for BioactiVe Molecular Hybrids, Department of Chemistry, Yonsei UniVersity, Seoul, 120-749, S. Korea
Received June 25, 2008; E-mail: ksjeong@yonsei.ac.kr
Scheme 1. Synthesis of Foldamers 3, 4, and 5
The structure and function of proteins and enzymes stem from
folding of the primary sequences through various noncovalent
interactions in water. The binding pocket, generated by the folding
process, is surrounded by organic fragments and segregated from
the bulk water. As a consequence, the hydrogen bond still plays a
key role in binding and transporting an anion in aqueous media as
seen in sulfate- and phosphate-binding proteins and a CIC chloride
channel.1 In contrast, most of the synthetic receptors based on the
hydrogen bond are not able to bind an anion in water because the
binding sites are completely exposed to the outside and strongly
solvated by water molecules, which reduce the binding affinity
between the receptor and the anion.2
Foldamers are synthetic molecules capable of folding into ordered
arrays such as helical structures.3-5 Some helical foldamers possess
an internal cavity able to accommodate a complementary guest.4-6
In particular, a water-soluble foldamer composed of the aromatic
scaffold may fold to create a binding cavity shielded from the bulk
water,7 which would possibly allow anion binding to be studied in
water. With this in mind, we here prepared a series of indolo-
carbazoles 3, 4, and 5 which can fold into a helical array to render
an internal cavity with multiple indole NHs.8 A water-soluble
foldamer of the longest strand 5b binds small halides such as
fluoride, chloride, and bromide in water but does not bind larger
anions such as iodide and perchlorate. Interestingly, the chloride
ion binds in water slightly better than the fluoride ion, which is
reverse to the binding trend (F- > Cl-) of 5a in an organic medium,
4:1 (v/v) DMSO/MeOH.
For the preparation of foldamers, indolocarbazole 1 with two
indole NHs and an extended aromatic surface9 was prepared as
the repeating unit (Scheme 1). Using the Pd/CuI catalyzed reaction,
1 and 2 were coupled through ethynyl linkers to yield 3a, 4a, and
5a with ester side chains which were subsequently hydrolyzed with
KOH/DMSO-H2O to give the corresponding water-soluble deriva-
tives, 3b, 4b, and 5b. Details are described in the Supporting
Information.
be observed only in the helically folded conformation (see Sup-
porting Information). These observations suggest consistently that
5a adopts a compact helical conformation upon binding a chlo-
ride. Finally, the association constant of 5a with tetrabutyl-
ammonium chloride is determined to be 36 800 M-1 in a highly
polar medium 4:1 (v/v) DMSO/MeOH at 24 ( 1 °C, while those
of 3a and 4a are only 11 and 560 M-1, respectively.11 The
magnitude of the association constants reflects the number of
possible hydrogen bonds in complexes. It should be noted that the
helical folding of 5a is the only way for all the existing NHs able
to participate in hydrogen bonding with a chloride, thus forming a
1:1 complex.12
Next, the folding and binding properties in water were revealed
with water-soluble derivatives, 3b, 4b, and 5b. Regardless of the
chain length, the foldamers display concentration-independent (<1.0
1
× 10-3 M) and well resolved H NMR signals in D2O at room
The folding properties of 3a, 4a, and 5a were first investigated
in organic media. The 1H NMR spectra of the short strands 3a and
4a are sharp and well-resolved in acetone-d6. On the other hand,
the 1H NMR spectrum of the longer one 5a is completely broadened
out on the baseline but becomes sharpened upon addition of
tetrabutylammonium chloride (see Supporting Information). Three
NH signals of 5a are clearly resolved, and all appear at far downfield
regions (12.82, 11.64, and 11.01 ppm) as a result of hydrogen
bonding with the chloride ion. The aromatic CH signals are upfield
shifted relative to the corresponding signals of 3a. The average
chemical shifts for the aromatic signals of 3a, 4a, and 5a in the
presence of chloride are more upfield shifted as the chain length
grows. The computer modeling10 shows that 4a and 5a are capable
of folding into a helical structure of approximately one and one-
half turns and two turns, respectively. In addition, the 2D 1H NMR
ROESY experiment with a 1:1 mixture of 5a and tetrabutylam-
monium chloride shows characteristic NOE cross-peaks which can
temperature. In addition, signals for the terminal benzoate of 5b
are noticeably upfield shift (∆δ ) 0.4-1 ppm) relative to those of
3b. These observations imply that 5b exists in a nonaggregated,
compact form, unlike the ester derivative 5a in organic solvents.
The binding properties of 3b, 4b, and 5b with sodium salts were
qualitatively compared in water. The 1H NMR spectra of the shorter
chains 3b and 4b remained unchanged when a large excess (∼400
equiv) of any kind of sodium halides was added. On the other hand,
the spectral behavior of 5b depends on the kind of sodium salts;
the spectral changes are apparent with small anions (NaF, NaCl,
and NaBr) but negligible with large anions (NaI and NaClO4) as
shown in Figure 1b. The 2D 1H NMR ROESY spectrum of complex
5b·Cl- confirms the helical folding in water, showing the NOE
cross-peaks between Hc and Hl, He and Hj, Hf and Hh (Figure 1a
and Supporting Information).13 The 1H NMR titration experiments
were carried out at a constant concentration of 5b (2.0 × 10-4 M)
by increasing the amount of a salt in D2O at 24 ( 1 °C, showing
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11868 J. AM. CHEM. SOC. 2008, 130, 11868–11869
10.1021/ja804845m CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
determined in an organic medium, 4:1 (v/v) DMSO/MeOH. As
anticipated based on the hydrogen-bonding capability, the
association constants decrease in the order F- (183 000 M-1
)
> Cl- (36 800 M-1) > Br- (1350 M-1) > I- (86 M-1).
In conclusion, we have prepared indolocarbazole-based foldamers
which can adopt a helical conformation affording a tubular cavity
functionalized by multiple indole NHs. In particular, a water-soluble
derivative of the longest strand 5b binds smaller halides by multiple
hydrogen bonds in the order Cl- > F- > Br- in water, different
from the binding trend in organic media due to the competing
solvation energy. We are currently pursuing development of a water-
soluble foldamer which not only imparts the enhanced affinity and
selectivity toward an anion but also functions as a synthetic anion
carrier or channel through lipid membranes.
Acknowledgment. This work was supported by the Center for
Bioactive Molecular Hybrids (CBMH). We thank Dr. H. Park for
the NMR spectroscopic assistance, and J.-m.S. acknowledges the
fellowship of the BK21 program from the Ministry of Education
and Human Resources Development.
Supporting Information Available: Synthetic procedures, charac-
terization of compounds, computer modeling, and all of the binding
studies. This material is available free of charge via the Internet at
http://pubs.acs.org.
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Figure 1. (a) NOE cross-peaks are marked by double-headed arrows,
1
1
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