Anion induced conformational switch of a macrocyclic amide receptor

Article abstract of DOI:10.1016/j.tetlet.2004.09.135

Isophthalic acid-based macrocyclic tetraamide 4 shows considerable conformational change during anion binding. In the solid state and in solution the free receptor exists in nonbonding, closed conformation stabilized by two intramolecular hydrogen bonds.

Full text of DOI:10.1016/j.tetlet.2004.09.135

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8699–8703
Anion induced conformational switch of a macrocyclic amide
receptor
a
Michał J. Chmielewski, Agnieszka Szumna and Janusz Jurczak
a
a,b,
*
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, PL01-224 Warsaw, Poland
b
Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
Received 6 August 2004; revised 13 September 2004; accepted 21 September 2004
Available online 8 October 2004
Abstract—Isophthalic acid-based macrocyclic tetraamide 4 shows considerable conformational change during anion binding. In the
solid state and in solution the free receptor exists in nonbonding, closed conformation stabilized by two intramolecular hydrogen
bonds. Upon anion complexation, the receptor switches to a conformation with convergent arrangement of hydrogen bond donors.
À
The conformational switch is evidenced by 2D NMR and X-ray analyses of the free ligand and its Cl complex.
ꢀ
2004 Elsevier Ltd. All rights reserved.
In Nature, conformational changes upon substrate bind-
ing, amplified and space propagated, are one of the most
commonly used pathways of signal generation. Artificial
systems based on that principle utilize mostly cation
O
O
O
O
O
O
N
H
N
H
N
H
N
H
n
n
N
N
1,2
H
N
H
N
H
N
H
N
coordination to trigger molecular shape changes. An
analogous and complementary approach, based on
O
O
3
anion binding by hydrogen bond donating groups, only
1
2
n = 0
n = 1
3 n = 3
4
recently reached the stage of development that allows
for its use as a tool in supramolecular chemistry. There-
fore there is still a limited number of well-defined anion-
4
–6
triggered shape switching systems.
have already been applied for the construction of fluo-
Of these some
5
bonds involving pyridine nitrogen atoms, form well-
defined cavities with convergent arrangement of all amide
hydrogens and are well preorganized for anion binding.
Nevertheless, the electron lone pairs of the pyridine
rescent and chromogenic sensors or for controlled
6
translocation of a macrocyclic ring in a rotaxane. In
9
this communication we describe an isophthalic acid-
based macrocyclic tetraamide 4 that switches from a
highly folded, ÔclosedÕ conformation to an open form
upon anion binding.
1
0
nitrogen atoms interact unfavorably with anions.
Therefore we resolved to check whether isophthalic
acid-based analogs of 1–3 would be better anion recep-
tors. Because 20-membered macrocycle 2 formed more
Tetraamide 4 was synthesized during our ongoing pro-
ject concerning optimization of the structure of macro-
À
À
stable complexes with simple anions (Cl , AcO ,
À
H PO ) than either 1 or 3, we decided first to study
2 4
8
7
,8
cyclic amides for anion binding purposes.
Previously, we have studied anion binding by the series
a macrocycle of the same size. To enhance the solubility
of isophthalamides in organic solvents we introduced
tert-butyl groups into the structure, taking advantage
of the commercial availability of 5-tert-butylisophthalic
acid. Receptor 4 thus designed was synthesized accord-
ing to Scheme 1 in 32% yield.
of macrocyclic tetraamides 1–3 derived from 2,6-pyri-
7
,8
dinedicarboxylic acid. Macrocyclic amides of this
type, owing to the presence of intramolecular hydrogen
Keywords: Anion binding; Conformational change; Macrocyclic
receptor.
Qualitative observations suggested strong anion binding
by 4: addition of tetrabutylammonium chloride or
acetate to the suspension of the receptor in CH Cl
*
Corresponding author. Tel.: +48 22 632 05 78; fax: +48 22 632 66
1; e-mail: jurczak@icho.edu.pl
8
2
2
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.135

8700
M. J. Chmielewski et al. / Tetrahedron Letters 45 (2004) 8699–8703
O
O
NH
NH
HN
HN
CH Cl , Et N rt
2
2
3
H N
NH2
O
O
+
2
Cl
Cl
O
O
4
Scheme 1.
caused immediate solubilization of an otherwise insolu-
ble solid. However, the binding constants of receptor 4
1
with various anions, determined by H NMR titra-
1
1
tions in DMSO-d , turned out to be considerably low-
6
er than the values obtained earlier for 2 under analogous
conditions (Table 1).
Figure 1. Crystal structure of 4. (a) Top view. (b) Side view. Distances
are given in A˚ .
The X-ray crystal structure of tetraamide 4 and its chlo-
ride complex shed some light on the reasons for this
unexpected behavior. The free ligand adopts a highly
twisted conformation in the solid state, stabilized by
The symmetry observed in the 1D NMR spectra must be
therefore due to rapid interconversion between two
equivalent, unsymmetrical conformations. This dynamic
two intramolecular NHÁ Á ÁO
hydrogen bonds (Fig.
). Amide groups of both, symmetrically equivalent
amide
1
isophthalic moieties are in a syn–anti relationship, that
is, two N–H bonds of the same isophthalic moiety point
in opposite directions. The macrocyclic cavity in such a
conformation is closed, and the molecule can form only
weak, external complexes with anions, via single hydro-
gen bonds.
1
13
In DMSO-d solution, H and C NMR spectra suggest
6
that 4 exists in a more symmetrical conformation, since
only 1/4 of the maximum number of signals are visible.
However, 2D NOESY spectra reveal NOEs between
amide NH protons and both internal and external CH
protons of the benzene ring (Fig. 3a). This means that
there is a considerable proportion of both syn- and
anti-positioned amide hydrogen atoms in an averaged
conformation and suggests that the conformation
observed in the solid state predominates also in solution.
À1
Table 1. Binding constants (M ) for the formation of 1:1 complexes
a
6
of 2 and 4 with various anions in DMSO-d at 298K
Anion
2
4
À
À
b
Cl
Br
1930
15020
378
À
b
AcO
H
3240
3130
c
4À
b
2
PO
7410
4À
b
HSO
75
<5
a
Errors are estimated to be <10%. Tetrabutylammonium salts were
used as anion sources.
Values from Ref. 8.
4
Figure 2. Crystal structure of 4 · Ph PCl. (a) Top view. Distances are
b
c
˚
À
given in A. (b) Side view. Cl sphere reflects its van der Waals radius.
Part of the disorder was removed for clarity.
The data does not fit satisfactorily to a simple 1:1 binding model.

M. J. Chmielewski et al. / Tetrahedron Letters 45 (2004) 8699–8703
8701
process is fast on the NMR time scale even at À70ꢁC (in
sion between the amide proton and aromatic hydrogen
1
2
DMF-d ).
7
atoms in the ortho-position. Side views reveal another
significant difference between the two structures:
whereas the free receptor is roughly planar (Fig. 1b), it
adopts a V-shape in the complex, with an angle between
the arms of 79ꢁ (Fig. 2b).
As evidenced by X-ray and NMR studies the molecule is
not well suited for convergent anion binding. The ques-
tion therefore arises whether anion complexation inside
the cavity can be strong enough to compete with the two
intramolecular hydrogen bonds and compensate for the
To probe the structure of anion complexes in solution,
NMR studies were conducted. Titration of a DMSO-
d6 solutions of 4 with tetrabutylammonium fluoride,
chloride, acetate, or hydrogenphosphate caused consid-
erable downfield shifts of the amide NH and internal
aromatic CH signals, whereas external aromatic protons
were virtually untouched. This proves that the complex-
ation/decomplexation process is fast on the NMR time
scale and furthermore suggests that all these anions
are encapsulated inside the macrocyclic cavity and that
the complex structure is analogous to that observed in
the solid state. The magnitudes of the downfield shifts
cost of a necessary conformational change. The X-ray
À
structure of the chloride complex 4 · Cl (4 · PPh Cl)
4
undoubtedly proves that the anion can indeed open
the macrocyclic cavity breaking two intramolecular
hydrogen bonds and switch the macrocycle to a com-
À
pletely different conformation (Fig. 2). The Cl anion
in the complex forms four hydrogen bonds with amide
hydrogen atoms and also lies in close proximity to both
internal aromatic protons suggesting additional favor-
able interactions. We note also that the amide groups
are almost co-planar with the benzene rings. This is in
contrast with the structure of the free ligand 4 and also
most known structures of benzamides and isophthala-
mides, in which these groups are usually tilted with
respect to the adjacent benzene ring due to steric repul-
À
of the internal aromatic CH signals (0.55ppm for Cl ,
0.43 for AcO , 0.69 for H PO ) are particularly
À
À
2
4
impressive; such large values point to quite strong non-
1
3
classical CHÁ Á Áanion hydrogen bonding interactions.
Figure 3. NOESY spectra of 4 and its anion complexes in DMSO solutions: (a) free ligand 4, (b) 4 + 1.1equiv of TBACI, (c) 4 + 1.7equiv of TBAF,
d) 4 + 1.1equiv of TBAAcO.
(

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M. J. Chmielewski et al. / Tetrahedron Letters 45 (2004) 8699–8703
À
Also there is an unusually small effect of Cl binding on
amide signal shifts. This is most probably due to the fact
that the amide protons had already been engaged in
intramolecular hydrogen bonding before complexation.
Further evidence concerning the conformation of ligand
applications of anions as effectors in supramolecular
switching devices.
We thank the State Committee for Scientific Research
for Financial Support (Project T09A 087 21).
4
in anion complexes comes from the 2D NOESY spec-
tra (Fig. 3). In the case of the chloride complex of 4
4 + 1.1equiv of TBACl in DMSO-d ) incidental signal
(
6
Supplementary data
overlapping of amide protons and internal aromatic
CH protons precluded observation of the NOE between
them. However, in accordance with the proposed struc-
ture, no effect could be detected between the amide and
The synthetic procedure and characterization data for
compound 4; details concerning determination of bind-
ing constants and X-ray crystal data for 4 and
· Ph PCl are available. Crystallographic data (exclud-
1
the external aromatic protons. In the H NMR spectra
4
4
of fluoride and acetate complexes of 4 all aromatic
and amide signals were clearly distinguishable and
NOE were observed between amide NH protons and
internal aromatic CH protons. At the same time, no ef-
fect was detected between the amide protons and the
external aromatic protons. These spectra indicate that
in the presence of anions the syn–syn conformation of
the isophthalic moieties largely predominates. Taken to-
gether, it is evident that anion induced conformational
change took place and consequently all amide NHs
point toward the cavity (Scheme 2).
ing structure factors) for the structures in this paper
have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication num-
bers CCDC 246610and 246611. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-
1
223-336033 or e-mail: deposit@ccdc.cam.ac.uk]. Sup-
plementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2
004.09.135.
Summing up, simple isophthalamides may exist as a
mixture of three possible conformers: syn–syn, syn–anti,
and anti–anti. In the case of tetraamide 4 however,
macrocyclic topology and intramolecular hydrogen
bonds impose additional constraints to the system and
lock both isophthalic units in a syn–anti conformation.
We have shown here that anion binding is able to break
these two intramolecular hydrogen bonds and switch
both isophthalic moieties into a syn–syn conformation
leading to a completely different shape for the entire
molecule. Analogous behavior was previously observed
for amides derived from 2,6-pyridinedicarboxylic acid.
They may be switched from the preferred syn–syn con-
formation to an anti–anti conformation through either
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1