Anion receptors based on 7,7′-diamido-2,2′-diindolylmethane

Article abstract of DOI:10.1039/b907164d

7-Aminoindole has been successfully used as a building block for the construction of new anion receptors that have strong a affinity towards anions, especially dihydrogen phosphate, even in very competitive solvents. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b907164d

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Anion receptors based on 7,70-diamido-2,20-diindolylmethanew
a
ab
Pawe$ Dydio,ab Tomasz Zielinski and Janusz Jurczak*
´
Received (in Cambridge, UK) 8th April 2009, Accepted 28th May 2009
First published as an Advance Article on the web 22nd June 2009
DOI: 10.1039/b907164d
7-Aminoindole has been successfully used as a building block for
the construction of new anion receptors that have strong a
affinity towards anions, especially dihydrogen phosphate, even
in very competitive solvents.
overall yield.17 We also developed a more general method, that
started with the Bartoli type synthesis of 7-amino-3-methyl-
indole 4, followed by the reaction with an aldehyde in hydro-
chloric acid. The nitro derivative 5 was then hydrogenated to
bisamine 6, and subsequently reacted with three different acid
chlorides leading to the desired ligands 1a–c in good yields
(Scheme 2).
An understanding of the host–guest chemistry of anions is
important in the fields of catalysis, analytical applications,
medicine and industrial processes,1 and the design and
synthesis of receptors for anions is currently an area of
extensive exploration.2 Much effort has been devoted to
ligands that exploit hydrogen bonding, since such interactions
can potentially lead to highly selective receptors. Due to its
unique ability to act only as a hydrogen bond donor, the
pyrrole moiety is one of the most attractive building blocks for
the construction of binding sites.3
The stability constants of receptors 1a–c with model anions
were determined by 1H NMR titrations (Table 1). The
preliminary results showed a remarkable affinity of the new
diindolylmethanes 1a–c towards oxo-anions. They interacted
too strongly to be measured in the commonly used solvent:
DMSO + 0.5% H2O. Thus, we had to use an even a more
competitive medium and increase the water content up to 5%,
which also allowed us to make a direct comparison with the
parent compounds 2.15
Pyrrole-based anion receptors have been introduced and
developed by the Sessler group,4 while receptors with a
combination of pyrrole and amide groups have been contributed
by Gale and co-workers.5 A further, logical extension of the
pyrrole-based designs should include benzopyrroles, which
also contain only hydrogen bond donors, but are more acidic,
usually more stable and offer broader structural diversity than
pyrroles. However, only recently have indoles,6,7 biindoles,8
carbazoles9,10 and indolocarbazoles11 attracted the attention
of researchers for applications in anion recognition.12
Ligands 1a–c had a common preference for more basic
oxoanions over halides (Fig. 1), and formed complexes with
a 1 : 1 stoichiometry, which was also confirmed by the Job
plots. The association constants determined independently
using amide and indole NH signals are in good agreement,
Amides derived from 7-aminoindole have been indepen-
dently investigated by both the Gale group13 and us.14 This
structural subunit has two hydrogen bond donors which are
situated similarly to 2-amidopyrrole. Inspired by this observa-
tion, we decided to prepare amides 1, the indole-based
analogues of 2,20-bisamidodipyrrolylmethanes 2, which are
efficient anion receptors.15 (Scheme 1).
Scheme 1
Contrary to the reactivity of pyrroles, direct condensation
of indoles and carbonyl compounds leads to 3,30-diindolyl-
methanes, which were exploited in the preparation of a
colorimetric sensor.16 To facilitate the synthesis, we had to
block the 3-position of indole with a methyl substituent. In our
first approach, 7,70-bisnitro-2,20-diindolylmethane 5 was obtained
in a one-pot synthesis that combined the Fisher indole
synthesis and subsequent condensation with propional, in 40%
a Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224, Warsaw, Poland.
E-mail: jurczak@icho.edu.pl; Fax: +48 22 632 66 81;
Tel: +48 22 632 05 78
b Department of Chemistry, Warsaw University, Pasteura 1, 02-093,
Warsaw, Poland
w Electronic supplementary information (ESI) available: Synthesis of
receptors 1a–c, description of titration experiments, Job plots, crystallo-
graphic data. CCDC 707058, 725837 and 707057. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b907164d
Scheme 2 Synthesis of receptors 1a–c. (a) CH3CHQCHMgBr;
(b) C2H5CHO, HCl; (c) H2, Pd/C; (d) RCOCl.
ꢀc
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Table 1 Binding constants [Mꢁ1] for the formation of 1 : 1 complexes
of ligands 1a–c with various anions in DMSO–H2O mixturesa
improve the affinity towards anions. Smaller values of Ka and
Ddmax for the pyrrole NH in 1c (see ESIw) suggest that this
group is too far from the ‘‘binding center’’ of the receptor.
Moreover, the structural analysis of 1c shows an unfavourable
pre-organisation.
Stability constant (Ka/Mꢁ1
)
Anion
Clꢁ
% waterb
0.5
Signalc
1a
1b
1c
d
In order to judge how successful our design was, we
compared receptors 1 with parent ligands 2. The diindolyl-
methane-based receptor 1a interacts with anions more
strongly than any of the previously reported dipyrrolyl-
methane-based ligands. Receptor 1b has an anion affinity that
is similar to 2b, however, 1b is superior to the meso-substituted
analogues of 2. It is worth mentioning that all the compounds
1a–c, unlike 2, are stable in the solution even in the presence of
anions.
amide
indole
amide
indole
amide
indole
amide
indole
amide
indole
amide
indole
amide
indole
amide
indole
amide
indole
amide
indole
amide
indole
—
470
20
20
410 000
410 000
410 000
410 000
30
30
130
80
o2
o2
1020
1660
—
—
20
20
o2
o2
260
300
130
400
—
—
—
—
Brꢁ
0.5
0.5
0.5
5
o2
o2
2010
2140
3850
4460
7
ꢁ
PhCO2
ꢁ
e
H2PO4
Clꢁ
e
d
—
150
10
7
Brꢁ
5
o2
o2
360
340
980
990
10
We obtained diffraction-grade crystals of the solvated
ligand 1b and of two complexes: 1aꢂTBAPhCO2 and
1cꢂTBACl, which allowed us to characterise the geometric
properties of these new diindolylmethane-based receptors.z
The structural analysis of 1b monohydrate reveals that the
ligand adopts a ‘‘bent sheet’’ conformation (the angle between
the indolyl planes is 651) in which all NH groups point
convergently to the centre of the binding cleft (Fig. 2a). Both
indole NHs form hydrogen bonds with a water molecule
(N–O distances of 2.92 and 2.96 A). The guest water molecule
is positioned in such a manner, that its hydrogen atoms are
almost perpendicular to the ligand and interact with the
carbonyl groups of neighbouring ligands, bridging every third
molecule of the receptor (the O–O distances are 2.74 and
2.80 A). It is also noteworthy that the phenyl rings contribute
to the binding of water through CH–O interactions (the CH–O
distances are 2.65 and 2.74 A). Each two ligand molecules
form a centrosymmetric dimer stabilized by a pair of hydrogen
bonds formed by the amide groups (the N–O distances are
3.06 A). In this structure, ligand 1b is better pre-organised
than the reported dipyrrolylmethanes, in which the pyrrole
rings are almost perpendicular to each other.
ꢁ
PhCO2
5
1880
2060
410 000
410 000
540
ꢁ
H2PO4
PhCO2
5
ꢁ
f
f
10
10
25
—
—
f
f
590
ꢁ
ꢁ
f
f
H2PO4
H2PO4
5980
5640
210
—
—
f
f
f
o2
—
—
f
210
o2
a
Values determined by 1H NMR titration experiments at T = 298 K,
errors o 10%, tetrabutylammonium (TBA) salts were the source of
b
anions. DMSO-d6 + H2O mixture used as the solvent, water content
c
as specified in the column. NH signal used for the calculations.
d
e
Fitting failed due to too small signal shift. Fitting failed due to
f
signal broadening. Not measured.
The X-ray analysis of 1aꢂTBAPhCO2 shows that the
independent part of the structure contains two complexes that
are very similar in their geometry. In both subunits, the ligands
have a bent sheet shape (plane angles are about 631) and bind
benzoate with all four NHs (Fig. 2b). The anion is positioned
almost centrally above the receptor with its phenyl ring
pointing outwards. Each oxygen forms two hydrogen bonds
with indole and amide NHs, however one pair of bonds is
shorter than the other one, so the anion is slightly tilted. Such
a binding motif is different from the one observed for the
diindolylurea-based receptors,7 in which hydrogen bonds are
almost coplanar while the carboxylate group is perpendicular
to the ligand plane. Judging by the bonds lengths, indole NHs
interact with the anion more strongly than the amide groups
(N–O distances are 2.72–2.82 A for indoles and 2.86–2.91 A
for amides), this observation is in agreement with the results of
the titration experiments.
Fig. 1 1H NMR titration of ligand 1a with different anions in
DMSO-d6 + 5% H2O. Changes of chemical shift of indole NH
(solid symbols) and amide NH (void ones).
with slightly higher values for the indole measurements.
Aliphatic amide 1a binds anions the strongest, and has an
exceptional affinity towards H2PO4ꢁ: the exact value of its
association constant could only be determined in DMSO
containing 10–25%ꢁ water. The relative selectivity for
ꢁ
H2PO4 over PhCO2 is not affected by the water content in
the medium, and is approximately 10 for 1a and around 2 for 1b.
Unexpectedly, the phenyl derivative 1b is a much weaker
receptor than 1a, despite the higher acidity of its amide NH
groups. A similar observation was reported for the carbazole-
based bisamides,9 and at this moment, it can only be
rationalised in terms of steric hindrance.
Finally, the crystal structure of the complex 1cꢂTBACl
consists of two independent fragments, that differ slightly in
ligand conformation. The chloride anion is bound by four NH
groups of the receptor and lies above the bent sheet shaped
ligand molecule (the angles between indole planes are about
661) (Fig. 2c). The two hydrogen bonds formed by indole NHs
A comparison of the Ka for receptors 1b and 1c reveals that
the introduction of the additional pyrrole moiety does not
ꢀc
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Fig. 2 Different views of the crystal structures of (a) 1bꢂH2O; (b) 1aꢂTBAPhCO2; (c) 1cꢂTBACl; some parts are omitted for clarity
are evidently stronger than the ones engaging the amide
groups (the N–Cl distances are in the range 3.11–3.27 A for
indole and between 3.40–3.70 A for amide). The amidopyrrole
subunit adopts the anti conformation preferred by this
building block, which prevents it from interacting with the
anion and explains the results of titration experiments.
Nevertheless, the pyrrole rings are involved in hydrogen
bonds, but with carbonyl groups of adjoining molecules
(the N–O distances are about 2.8 A), which leads to the
formation of a supramolecular chain with chloride–ligand
complexes linked together.
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4 P. A. Gale, J. L. Sessler, V. Kral and V. Lynch, J. Am. Chem. Soc.,
1996, 118, 5140–5141; A. Andrievsky, F. Ahuis, J. L. Sessler,
F. Vogtle, D. Gudat and M. Moini, J. Am. Chem. Soc., 1998,
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7849–7853; P. A. Gale, S. Camiolo, C. P. Chapman, M. E. Light
and M. B. Hursthouse, Tetrahedron Lett., 2001, 42, 5095–5097.
6 F. M. Pfeffer, K. F. Lim and K. J. Sedgwick, Org. Biomol. Chem.,
2007, 5, 1795–1799; J. O. Yu, C. S. Browning and D. H. Farrar,
Chem. Commun., 2008, 1020–1022; G. W. Bates, Triyanti,
M. E. Light, M. Albrecht and P. A. Gale, J. Org. Chem., 2007,
72, 8921–8927.
7 C. Caltagirone, P. A. Gale, J. R. Hiscock, S. J. Brooks,
M. B. Hursthouse and M. E. Light, Chem. Commun., 2008,
3007–3009; C. Caltagirone, J. R. Hiscock, M. B. Hursthouse,
M. E. Light and P. A. Gale, Chem.–Eur. J., 2008, 14, 10236–10243.
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and K. S. Jeong, Chem.–Eur. J., 2008, 14, 11406–11414;
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Remarkably, all three crystal structures of receptors 1a–c
show similar conformations despite the different ligand side
chains and different guests present (Fig. 2). This suggests that
this geometry is preferred by this building block, and its
binding site is readily available for the interactions involving
all four hydrogen bond donors.
To summarise, we prepared stable and efficient diindolyl-
methane-based receptors that show high affinity and selectivity
towards dihydrogen phosphate even in a very polar medium.
This work confirmed how effective and versatile 7-aminoindole is
as a building block for the construction of anion receptors.
Moreover, we demonstrated how further progress in anion
recognition can be achieved by the modification of known
structures by replacing pyrrole-containing subunits with benzo-
pyrroles, maintaining an equivalent array of hydrogen bonds.
We would like to thank the Ministry of Science and Higher
Education (Project N N204 092735) for support of this work.
12 P. A. Gale, Chem. Commun., 2008, 4525–4540.
13 G. W. Bates, P. A. Gale and M. E. Light, Chem. Commun., 2007,
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14 T. Zielinski, P. Dydio and J. Jurczak, Tetrahedron, 2008, 64,
568–574.
Notes and references
z Crystal data for compounds 1b, 1aꢂTBAPhCO2 and 1cꢂTBACl can
be found in the ESIw or accessed using the following CCDC numbers:
707058, 725837, 707057.
15 I. E. Vega, P. A. Gale, M. B. Hursthouse and M. E. Light, Org.
Biomol. Chem., 2004, 2, 2935–2941; I. E. Vega, S. Camiolo,
P. A. Gale, M. B. Hursthouse and M. E. Light, Chem. Commun.,
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16 X. M. He, S. Z. Hu, K. Liu, Y. Guo, J. Xu and S. J. Shao, Org.
Lett., 2006, 8, 333–336.
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ꢀc
This journal is The Royal Society of Chemistry 2009
4562 | Chem. Commun., 2009, 4560–4562