Biindolyl-based molecular clefts that bind anions by hydrogen-bonding interactions

Article abstract of DOI:10.1016/j.tetlet.2006.06.157

Molecular clefts were synthesized from 2,2′-biindolyl scaffold that contains good hydrogen bond donors of two indole NHs. The molecular clefts were systematically modified in two different manners to increase binding affinities toward chloride. The associ

Full text of DOI:10.1016/j.tetlet.2006.06.157

Tetrahedron Letters 47 (2006) 6385–6388
Biindolyl-based molecular clefts that bind anions by
hydrogen-bonding interactions
Kyoung-Jin Chang, Min Kyung Chae, Changsoon Lee, Ji-Yeon Lee and Kyu-Sung Jeong*
Center for Bioactive Molecular Hybrids and Department of Chemistry, Yonsei University, Seoul 120-749, Republic of Korea
Received 19 June 2006; accepted 29 June 2006
Available online 20 July 2006
Abstract—Molecular clefts were synthesized from 2,20-biindolyl scaffold that contains good hydrogen bond donors of two indole
NHs. The molecular clefts were systematically modified in two different manners to increase binding affinities toward chloride.
The association constant dramatically increased when additional hydrogen-bonding sites of two benzamide units were incorporated
to the biindolyl scaffold. For example, the association constants of 1a and 1b are 5.1 · 103 and 1.4 · 104 Mꢀ1 in CH3CN at
22 1 ꢀC, while reference molecule 10 having only two indole NHs showed the association constant of 340 Mꢀ1 under the same
conditions. When the biindolyl backbone was structurally preorganized, the binding affinities toward anions were further increased
with additional stabilization energy (ꢀDDG) of 2.0 0.2 kcal/mol).
ꢁ 2006 Elsevier Ltd. All rights reserved.
The development of synthetic molecules that can bind
and sense an anion is a current topic of much interest
in the field of supramolecular chemistry. Hydrogen
bonds and electrostatic forces are two key interactions
to bind and transport anions in the biological systems
such as sulfate- and phosphate-binding proteins1 and a
CIC chloride channel.2 For example, sulfate binds to
the cavity of the sulfate-binding protein by seven hydro-
gen bonds with peptide backbone NHs and side chains
(Ser–OH, Trp–NH) of amino acids.1a,c In a CIC chlo-
ride channel, chloride was found to be stabilized by mul-
tiple hydrogen bonds and electrostatic interactions. Like
in the natural system, the polar interactions have been
extensively employed in the construction of synthetic
receptors that bind anions strongly and selectively.3
For this purpose, the amido and (thio)ureido groups
were most frequently utilized. In addition, the pyrrole
and imidazole rings were also used as building blocks
for the preparation of anion receptors.
hydrogen bond donors of two amide NHs were intro-
duced to the 2,20-biindolyl scaffold to enhance binding
affinities toward anions. In addition, the pre-organiza-
tion effects on the binding event were clearly noticed
when the association constants of the biindolyl-based
clefts were compared with those of the corresponding
indolocarbazole-based ones. Two indole NHs in the
latter are conformationally organized to form simulta-
neous hydrogen bonds with anions, thus leading to
much stronger binding affinities.
The syntheses of 1 and 2 are outlined in Scheme 1,
and begin with the iodination6 and Sonogashira cou-
pling reaction7 of p-(tert-butyl)aniline (3) with tri-
methylsilylethyne (1 equiv). Then, compound 5 was
subjected to oxidative homocoupling8 followed by
double indolization,9 which afforded 5,50-di(tert-butyl)-
7,70-diiodo-2,20-biindolyl (7). Compound 7 was coupled
with N-methyl (or N-phenyl) 3-ethynylbenzamide (9a
and 9b) in the presence of Pd(dba)2/CuI catalyst to give
molecular clefts 1a and 1b.10 On the other hand, the
reaction of 7 with (dimethylamino)acetaldehyde diethyl
acetal11 in acetic acid afforded a rigid scaffold 8, which
was in turn converted into molecular clefts 2a and 2b.10
Recently, our group4 and Beer’s group5 demonstrated
that the NHs of 2,20-biindolyl and indolocarbazole
could serve as good hydrogen bond donors. These
scaffolds possess two indole NHs capable of simulta-
neously forming hydrogen bonds with an anion. We
here prepared molecular clefts 1 and 2 where additional
The binding properties were first examined with 1a and
chloride in the 1H NMR spectroscopy. When tetrabutyl-
ammonium chloride (10 equiv) was added to a CD3CN
(0.3 mM) solution of 1a, the signals of indole NHs
and amide NHs were downfield shifted from 10.0 and
*
Corresponding author. Tel.: +82 2 2123 2643; fax: +82 2 364 7050;
e-mail: ksjeong@yonsei.ac.kr
0040-4039/$ - see front matter ꢁ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.157

6386
K.-J. Chang et al. / Tetrahedron Letters 47 (2006) 6385–6388
C(CH3)3
C(CH3)3
C(CH3)3
(H3C)3C
C(CH3)3
a
c
b
I
I
I
I
NH2
H2N
I
NH2
NH2
NH2
3
4
6
5
(H3C)3C
C(CH3)3
C(CH3)3
(H3C)3C
e
d
N
H
N
H
N
N
H
I
H
I
I
I
7
8
9a R = CH3
9b R = Ph
H
N
f
f
R
2a R = CH3
2b R = Ph
1a R = CH3
1b R = Ph
O
Scheme 1. Syntheses of molecular clefts
1 and 2. Reagents and conditions: (a) I2/Ag2SO4, EtOH, room temperature, 1 h, 73%; (b)
trimethylsilylethyne (1 equiv), Pd(PPh3)2Cl2, CuI, THF/Et3N (v/v 1:1), 50–55 ꢀC, then K2CO3/MeOH, room temperature, 30 min, 52% for two
steps; (c) Cu(OAc)2ÆH2O, pyridine, room temperature, 12 h, 90%; (d) CuI, DMF, 110–115 ꢀC, 4 h, 80%; (e) (dimethylamino)acetaldehyde diethyl
acetal, CH3CO2H, reflux, 2 h, 68%, and (f) 9a or 9b, Pd(dba)2, CuI, PPh3, THF/Et3N, overnight, 55–60 ꢀC, 62–73%.
N
N
H
H
H
H
N
R
N
R
O
N
O
1
N
H
H
H
N
H
N
R
R
O
O
2
7.1 ppm to 12.4 and 7.7 ppm, respectively (Fig. 1b).
More interestingly, the aryl CHb signal was also largely
shifted from 8.2 to 9.2 ppm. These observations indicate
that chloride binds to 1a by two CHꢁ ꢁ ꢁClꢀ hydrogen
bonds as well as four NHꢁ ꢁ ꢁClꢀ hydrogen bonds. The
computer modeling shows that all of six hydrogens
(two indole NHs, two amide NHs, and two CHs) closely
contact with chloride to form hydrogen bonds in the
structure of complex 1aÆClꢀ (Fig. 2).
Figure 1. Partial 1H NMR spectra (500 MHz, CD3CN) of: (a) 1a
(0.3 mM); (b) 1a (0.3 mM) + Bu4N+Clꢀ (3 mM), and (c) a UV–vis
titration curve and a Job plot (inset) between 1a (20 lM) and
Bu4N+Clꢀ in CH3CN at 22 1 ꢀC.
The titration experiment of 1a with chloride was per-
formed in CH3CN at 22 1 ꢀC using the UV–vis spec-
troscopy. The absorption spectrum was gradually
changed as a solution of chloride was added while keep-
ing the concentration (2.0 · 10ꢀ5 M) of 1a constant. The
association constant was estimated to be 5.1 · 103 Mꢀ1
by nonlinear least-squares fitting analysis of the titration
data (Fig. 1c).12 The association constant between 1b
and chloride was determined to be 1.4 · 104 Mꢀ1, which
is slightly higher than that of 1a. This is possibly attrib-
uted to the better hydrogen bond donor of the arylamide

K.-J. Chang et al. / Tetrahedron Letters 47 (2006) 6385–6388
6387
N
N
H
H
10
Figure 2. Energy-minimiꢀzed structures (MacroModel 7.1, MM2* force
field)14 of complex 1aÆCl . Hydrogen bond distanꢀces are 2.25 A for the
˚
ꢀ
˚
˚
indole NHꢁ ꢁ ꢁCl , 2.38 A for the amide NHꢁ ꢁ ꢁCl , and 2.57 A for the
aryl CHꢁ ꢁ ꢁClꢀ.
H
N
NHs compared to the alkylamide NHs. As a reference,
compound 10 was prepared which bears only two indole
NHs, not amide NHs. The association constant between
10 and chloride was found to be 340 Mꢀ1 under the
same conditions. This result clearly supports that the ap-
pended amide NHs of 1a and 1b participated in the com-
plexation to greatly enhance the association constants.
The 1:1 stoichiometry of the complex was in all cases
confirmed by the continuous variation (Job) method,13
and a representative example is shown in Figure 1c
(inset).
N
H
s-trans
A-
N
H
N
H
A-
s-cis
hydrogen
bond
According to computer modeling,14 the biindolyl scaf-
fold exists in a s-trans conformation, two indole NHs
being in an opposite direction, to minimize dipole–di-
pole repulsion. When complexed, however, it adopts a
s-cis conformation to simultaneously form hydrogen
bonds with chloride (Fig. 3). This structural reorganiza-
tion on the binding process decreases the binding energy
in terms of both enthalpy and entropy. With this in
mind, we synthesized a rigid scaffold 8 where two indoles
are bridged with ethyno group at 3,30 position to be di-
rected to the same side. Molecular clefts 2a and 2b were
prepared by incorporating two benzamide units to this
scaffold, just like in 1a and 1b. The association constants
of 2a and 2b with chloride were found to be 1.1 · 105
and 3.7 · 105 Mꢀ1, respectively, in CH3CN at 22 1 ꢀC.
Figure 3. Conformational switch of biindolyl scaffold when complexed
with an anion, chloride.
Table 1. Association constants (Ka 20%, Mꢀ1) of clefts 1a and 2a
and anions in CH3CN at 22 1 ꢀCa
Anion
Ka (Mꢀ1
)
Ratio Ka (1a)/Ka (2a)
1a
2a
Clꢀ
Brꢀ
Iꢀ
HSO4
CH3CO2
5.1 · 103
2.1 · 102
6b
77
1.4 · 105
1.1 · 105
8.7 · 103
1.8 · 102
2.1 · 103
>2 · 106
22
41
30
27
—
ꢀ
c
ꢀ
a Titration experiments were all duplicated in UV–vis spectroscopy, in
which the concentration of 1a (or 2a) remains constant
(2.0 · 10ꢀ5 M) throughout each titration and anions were used as
tetrabutylammonium salts.
Next, the binding properties of two representative clefts
1a and 2a were revealed with other common anions and
the association constants were compared with each
other. As summarized in Table 1, the association con-
stants of bothꢀ1a and 2a increase in the order of
1
b The association constant between 1a and Iꢀ was evaluated in the H
NMR spectroscopy.
c The association constants of 1a and 2a with acetate were determined
in 10% (v/v) DMSO/CH3CN.
CH3CO2 > Cl > Brꢀ > HSO4 > Iꢀ, as anticipated
from mainly electrostatic nature of hydrogen-bonding
interaction. Furthermore, the conformationally preor-
ganized cleft 2a, compared to 1a, shows consistently
higher binding affinities toward all anions examined
here. The relative ratios of the association constants
are in the range of 20–40, reflecting that the pre-organi-
zation in 2a results in gaining additional stabilization
energy (ꢀDDG) of 2.0 0.2 kcal/mol.
ꢀ
ꢀ
tion of the biindolyl backbone. By the variation of the
appended amide units, we are currently focusing on
the development of functional molecular clefts such as
a colorimetric chemosensor and a transporter of an
anion through biological membrane.
In conclusion, molecular clefts were synthesized as a
new class of anion receptors based on hydrogen bonds.
The binding affinities greatly increased up to 40-folds
when additional hydrogen-bonding sites were intro-
duced in a convergent manner. The binding affinities
further increased by the conformational pre-organiza-
Acknowledgements
This work was financially supported by the Ministry of
Commerce, Industry, and Energy, Korea (Project No.
10022947) and the Center for Bioactive Molecular
Hybrids (CBMH).

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K.-J. Chang et al. / Tetrahedron Letters 47 (2006) 6385–6388
8.33 (s, 2H), 7.97 (t, J = 7.6 Hz, 4H), 7.81 (d, J = 7.6 Hz,
References and notes
4H), 7.66 (d, J = 1.2 Hz, 2H), 7.63 (t, J = 7.8 Hz, 2H),
7.44 (d, J = 2.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 4H), 7.20 (d,
J = 2.0 Hz, 2H), 7.12 (t, J = 7.4 Hz, 2H), 1.38 (s, 18H);
13C NMR (400 MHz, DMSO-d6): d (ppm) 164.8, 142.4,
139.0, 135.4, 135.3, 134.4, 131.9, 130.6, 128.9, 128.6, 123.8,
123.1, 120.4, 104.5, 101.0, 93.2, 91.9, 75.7, 51.9, 34.3, 33.3,
31.6, 30.s7; Anal. Calcd for C54H46N4O2: C, 82.84; H,
5.92; N, 7.16. Found: C, 82.86; H, 5.93; N, 7.17; HRMS-
FAB (m/z) [M]+ calcd for C54H46N4O2 782.3621; found
782.3624.
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R.; Campbell, E. B.; MacKinnon, R. Science 2003, 300,
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108–112; (c) Faraldo-Gomez, J. D.; Roux, B. J. Mol. Biol.
Compound 2a: mp 245–246 ꢀC; 1H NMR (400 MHz,
DMSO-d6): d (ppm) 11.13 (s, 2H; NH), 8.60 (m, 2H;
NH), 8.31 (d, J = 1.6 Hz, 2H), 8.20 (s, 2H), 8.05 (s, 2H),
7.92–7.88 (m, 4H), 7.66 (d, J = 1.6 Hz, 2H), 7.63 (t,
J = 7.6 Hz, 2H), 2.80 (d, J = 8.0 Hz, 6H), 1.45 (s, 18H);
13C NMR (400 MHz, DMSO-d6) d (ppm) 166.3, 142.7,
138.2, 135.6, 134.5, 130.7, 129.6, 128.0, 126.4, 126.1,
124.4, 123.2, 121.3, 118.4, 113.0, 104.7, 92.9, 87.6, 35.1,
32.3, 31.3; Anal. Calcd for C46H42N4O2: C, 80.91; H,
6.20; N, 8.20. Found: C, 80.91; H, 6.21; N, 8.21;
HRMS-FAB (m/z) [M]+ calcd for C46H42N4O2 682.3308;
found 682.3311.
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202; (h) Martınez-Manez, R.; Sancenon, F. Chem. Rev.
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Chem. Commun. 2005, 3761–3772; (l) Yoon, J.; Kim, S.
K.; Singh, N. J.; Kim, K. S. Chem. Soc. Rev. 2006, 35,
355–360.
Compound 2b: mp 227–228 ꢀC; 1H NMR (400 MHz,
DMSO-d6): d (ppm) 11.54 (s, 2H; NH), 10.52 (s, 2H;
NH), 8.34 (s, 2H), 8.32 (d, J = 1.6 Hz, 2H), 8.05 (s, 2H),
7.94–7.98 (m, 4H), 7.79 (d, J = 1.6 Hz, 2H), 7.77 (s, 2H),
7.68 (d, J = 1.6 Hz, 2H), 7.62 (t, J = 7.8 Hz, 2H), 7.33 (t,
J = 8.0 Hz, H), 7.10 (t, J = 7.4 Hz, 2H), 1.45 (s, 18H);
13C NMR (400 MHz, DMSO-d6): d (ppm) 165.2, 142.7,
139.6, 138.3, 136.1, 134.9, 131.2, 130.1, 129.7, 129.2,
128.7, 126.4, 126.1, 124.7, 123.9, 121.3, 121.6, 118.5,
113.0, 104.7, 92.9, 87.9, 35.1, 33.3; Anal. Calcd for
C56H46N4O2: C, 83.35; H, 5.75; N, 6.94. Found: 83.34;
H, 5.77; N, 6.94; HRMS-FAB (m/z) [M]+ calcd for
C56H46N4O2 806.3621; found 806.3630.
4. (a) Chang, K.-J.; Kang, B.-N.; Lee, M.-H.; Jeong, K.-S. J.
Am. Chem. Soc. 2005, 127, 12214–12215; (b) Chang, K.-J.;
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5. Curiel, D.; Cowley, A.; Beer, P. D. Chem. Commun. 2005,
236–238.
6. Lindsay, D. M.; Dohle, W.; Jensen, A. E.; Kopp, F.;
Knochel, P. Org. Lett. 2002, 4, 1819–1822.
Compound 10: mp 219–220 ꢀC; 1H NMR (400 MHz,
DMSO-d6): d (ppm) 11.46 (s, 2H; NH), 7.77 (d, J = 2.0
Hz, 2H), 7.75 (d, J = 1.6 Hz, 2H), 7.62 (d, J = 1.6 Hz,
2H), 7.46–7.51 (m, 6H), 7.39 (d, J = 2.0 Hz, 2H), 7.16
(d, J = 2.0 Hz, 2H), 1.37 (s, 18H); 13C NMR (400 MHz,
DMSO-d6): d (ppm) 143.0, 135.8, 132.4, 132.4, 132.4,
132.2, 129.2, 124.1, 123.5, 123.5, 117.9, 105.4, 101.4,
93.2, 97.6, 34.9, 32.2; Anal. Calcd for C40H36N2: C,
88.20; H, 6.66; N, 5.14. Found: C, 88.20; H, 6.64; N,
5.13; HRMS-FAB (m/z) [M]+ calcd for C40H36N2
544.2878; found 544.2880.
7. Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reac-
tions; Diederch, F., Stang, P. J., Eds.; Wiley-VCH:
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3721–3723.
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1039.
10. Physical properties and spectral data of molecular clefts.
Compound 1a: mp 240–241 ꢀC; 1H NMR (400 MHz,
DMSO-d6): d (ppm) 11.52 (s, 2H; NH), 8.59 (s, broad, 2H;
NH), 8.20 (s, 2H), 7.88 (d, J = 7.6 Hz, 4H), 7.65 (s, 2H),
7.57 (t, J = 7.6 Hz, 2H), 7.41 (s, 2H), 7.18 (s, 2H), 2.81 (d,
J = 4.4 Hz, 6H), 1.38 (s, 18H); 13C NMR (400 MHz,
DMSO-d6): d (ppm) 166.5, 143.0, 135.9, 135.5, 134.5,
132.5, 130.7, 129.3, 129.3, 127.7, 124.3, 123.6, 118.2, 105.1,
101.5, 92.6, 88.2, 34.9, 32.2, 26.9; Anal. Calcd for
C44H42N4O2: C, 80.21; H, 6.43; N, 8.50. Found: C,
80.22; H, 6.42; N, 8.49; HRMS-FAB (m/z) [M]+ calcd for
C44H42N4O2 658.3308; found 658.3295.
13. (a) Connors, K. A. Binding Constants; John Wiley & Sons:
New York, 1987; (b) Schneider, H.-J.; Yatsimirsky, A. K.
Principles and Methods in Supramolecular Chemistry; John
Wiley & Sons: New York, 2000.
14. The modeling study was carried out using MM2* force
field implemented in MacroModel 7.1 program on a
Silicon Graphics Indigo IMPACT workstation. To find an
energy-minimized structure, 1000 separate search steps
were conducted with a Monte Carlo conformational
search.
Compound 1b: mp 222–223 ꢀC; 1H NMR (400 MHz,
DMSO-d6): d (ppm) 11.52 (s, 2H; NH), 10.38 (s, 2H; NH),