Cylindrical sheet formation of oligo-meta-aniline foldamers

Article abstract of DOI:10.1039/b909446f

Ortho-nitro- and ortho-alkoxy-oligo-meta-aniline units fold in solution through hydrogen bonds and aromatic stacking into compact structures that were characterized in the solid state as cylindrical β-sheet like structures.

Full text of DOI:10.1039/b909446f

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Cylindrical sheet formation of oligo-meta-aniline foldamersw
a
b
b
a
´ ´ ´ ´ ´
Victor Maurizot,* Stephane Massip, Jean-Michel Leger and Gerard Deleris
Received (in Austin, TX, USA) 12th May 2009, Accepted 14th August 2009
First published as an Advance Article on the web 4th September 2009
DOI: 10.1039/b909446f
Ortho-nitro- and ortho-alkoxy-oligo-meta-aniline units fold in
solution through hydrogen bonds and aromatic stacking into
compact structures that were characterized in the solid state as
cylindrical b-sheet like structures.
between H4 and H5 protons on the two adjacent rings are in
agreement with a similar structure of 1 in solution.
A shift from planarity of terminal aromatic units is observed
in the crystal, probably caused by the repulsion of the close
aromatic protons inside the curved molecule (dH–H = 2.09 A).
This tilting provokes an elongation of the structuring
hydrogen bonds NHꢀ ꢀ ꢀOAr (dH–O = 2.23 A).9
During the last decade, efforts have been made to develop new
organic oligomers backbones that adopt specific predefined
architectures. These oligomers known as foldamers are
designed to mimic natural biomolecule secondary structures
such as b-sheets and helices.1 Two different approaches have
been used for the design of such compounds: (i) the ‘‘top-down
approach’’, which involves structural variation of parent chain
molecules to create peptidomimetic2 or nucleotidomimetic3
foldamers, and (ii) the ‘‘bottom-up approach’’ which involves
abiotic backbones. This class of foldamers often takes advantage
of the rigidity and solvophobicity of aromatic units. Aromatic
units can be directly connected to each other through C–C
bonds4 and C–N bonds5 or using amide,6 urea7 or hydrazide8
functions. These functional groups are used to facilitate the
synthesis of long oligomers and to induce the folding of the
molecule through hydrogen bonds.
Helical structures are expected for longer oligomers since a
fourth aromatic unit cannot lie in the same plane as the three
first units. To allow the n and n + 3 units to overlap and to
keep the hydrogen bonds network, an overall elongation of
each hydrogen bond should occur.
The NMR spectrum of the oligomer
2 (Fig. 3(b)),
constituted of five aromatic units, shows downfield amine
proton signals (d = 9.68 ppm in CDCl3), which reflect the
involvement of these protons in hydrogen bonds. An upfield
shifting of aromatic protons signals of 2 compared to 1 (for
example H5 shifts from d = 6.61 ppm in 1 to d = 6.41 ppm
in 2) is observed, and can be explained by an increase of the
aromatic stacking, consistent with a compact structure of 2.
To overcome problems due to superimposition of NMR
signals on 2D-ROESY spectrum, selective 1D-ROESY
experiments were performed on 2 (see ESIw). Selective pulse
on H5 proton signal shows correlations with H4 and H7
proton signals, indicating the spatial proximity of H5 with
H4 and H7. This result confirms the presence of a stable folded
structure in solution that may have an helical architecture.
However, in the solid state, the expected helical organization
of the oligomer 2 is not observed. The pseudo-planar
organization of the three first units observed in 1 is conserved
but the fourth unit lies perpendicular to this initial plane
(Fig. 2(b)). In this structure, no hydrogen bond is formed
In this paper, we present a new class of aromatic oligoamine
foldamers that adopt compact folded structures in solution
through hydrogen bonds and aromatic stacking. These foldamers
show cofacial architectures, in the solid state, that can be
compared to cylindrical b-sheets.
Our design is based on the use of alternating 1,5-diamino-
2,4-dinitrobenzene units and 1,5-diamino-2,4-dialkoxybenzene
units (Fig. 1). The ortho position of the amine and the nitro
groups allows the formation of a six-membered hydrogen
bond ring between the amine proton and the oxygen of the
nitro group. The ortho position of the amine and the alkoxy
group leads to the formation of a five-membered hydrogen
bond ring between the same amine proton and the oxygen of
the alkoxy group.
This hydrogen bond pattern when applied to a three-
aromatic unit oligomer 1 gives rise, in the solid state, to a
pseudo-planar crescent shape molecule (Fig. 2(a)). Downfield
chemical shift of the amine proton NMR signal (d = 9.73 ppm
in CDCl3, Fig. 3(a)), that reflect its implication in strong
hydrogen bonds, and observation of a NOE correlation
a
´
CNAB – UMR5084, Universite Victor Segalen Bordeaux 2,
Universite Bordeaux 1, CNRS, 146 rue Leo Saignat, 33076,
´
Bordeaux, France. E-mail: victor.maurizot@u-bordeaux2.fr;
Fax: +33 5 57 57 17 02; Tel: +33 5 57 57 10 05
b
´
Laboratoire de Pharmacochimie-Universite Victor Segalen Bordeaux 2,
146 rue Leo Saignat, 33076, Bordeaux, France
´
w Electronic supplementary information (ESI) available: Experimental
details for the synthesis of 1–3 and analysis. CCDC 731795–731797
and 740015. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b909446f
Fig. 1 Structures and folding of the oligomers through intramolecular
hydrogen bonds.
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expected helix (this steric hindrance was already observed in 1);
(ii) the hydrogen bond of the six-membered ring between the
amine proton and the nitro group is too strong to allow
its elongation, indeed the pseudo-sp2 hybridization of the
nitrogen and oxygens allows the optimal orientation of the
hydrogen bond; (iii) the hydrogen bond of the five-membered
ring is long and too weak to overcome its required elongation
for the formation of the helix (the lone pair of electrons of the
sp3 oxygen is not well oriented for hydrogen bonding). In
addition to crystal packing constraints, these effects trigger the
loss of the structuring hydrogen bond in the solid state.
In the crystal, the oligomer 3 composed of seven aromatic units
adopts a compact structure, again different from the expected
helical conformation (Fig. 2(c)). Like in 1 and 2, extremities are
pseudo-planar. These extremity planes are involved in strong
intramolecular p–p stacking interactions (dplane–plane E 3.5 A),
and are organized in an anti-parallel way. The fourth unit, that
is the central one, stands perpendicular to these planes and
induces a b-turn like structure. This turn results from a similar
hydrogen bond disruption observed in 2, between the oxygen of
the alkoxy group of the third unit and the amine proton of the
fourth unit. Unlike 2, no intermolecular interactions are observed
in the solid state for 3 but crystal packing and optimization of the
orientation of the intramolecular p–p stacking interaction could
be the driving force for this organization.
Fig.
2
Top and side view of crystal structuresz and schematic
representation of their spatial organisation of: (a) 1 (crystal grown from
nitrobenzene–methanol), (b) 2 (crystal grown from chloroform–methanol)
and (c) 3 (crystal grown from chloroform–methanol). Arrows show NOE
effects observed by NMR. Included solvent molecules, alkyl chains and
hydrogens have been omitted for clarity.
The solution 1H NMR spectrum of 3 (Fig. 3(c)) shows a strong
upfield shifting of the H9 signal compared to the H5 signal. This
shielding is in agreement with its position between the two
aromatic rings in the crystal structure but could also be explained
by its position in the hollow of the expected helix.
2D-ROESY NMR experiment shows strong cross-peaks
between protons of adjacent aromatic units, inside the curved
structure: H4 2 H5 2 H7 2 H9 (Fig. 5), which are in
agreement with a compact folded organization in solution. Other
weak NOE correlations are observed between these aromatic
protons and their respective neighbouring amine hydrogens:
NH1 2 H5 2 NH2 2 H7 2 NH3 2 H9. These correlations
result from the fact that during the mixing time of the NMR
experiment these protons are close enough in space to allow
polarisation transfer. This indicates a temporary loss of
structuring hydrogen bonds and the presence of a dynamic
equilibrium of the compact structure with an unfolded
conformation. However, the intensity of these cross-peaks
are, on average, 10 times weaker than the NOE correlations
described earlier, indicating that the oligomer adopts
preferentially a folded structure in solution. Additional structural
analysis is required to determine which organization prevails
in solution: the sheet conformation or the helical structure.
In summary, a surprising non-conventional sheet structure
was observed in the solid state for these ortho-hydrogen bond
acceptor-meta-aniline oligomers. Propagation of this motif
that may arise from crystal packing can be expected for longer
oligomers. In solution, we have shown that these oligomers
adopt stable compact folded structures, and therefore represent a
new class of foldamers. These oligomers enrich the scope of
abiotic backbones that could be used for the design of more
complex and functional molecular architectures, such as
previously suggested: synthetic receptors, enzyme mimics,
molecular devices or tunable materials.1
1
Fig. 3 Part of the H NMR spectra of (a) 1, (b) 2 and (c) 3 at room
temperature in CDCl3. The symbol K indicates an impurity in
compound 3.
between the amine proton and the oxygen of the alkoxy group
of the third unit, which results in a non-symmetrical architecture.
The disruption of the hydrogen bond network may emerge
from crystal packing effects since the fourth aromatic unit is
involved in p–p stacking interactions with its neighbour
molecule and in an intermolecular hydrogen bond through
its nitro group (Fig. 4).
Moreover, loss of the NHꢀ ꢀ ꢀOR hydrogen bond in the solid
state can be explained by three different factors: (i) the strong
repulsion of the aromatic protons inside the hollow of the
Fig. 4 View of intermolecular interactions of 2 in the crystal.
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Fig. 5 2D-ROESY spectrum of the aromatic and amine proton
region of 3 in CDCl3. Values indicated on the spectrum are integration
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9 1,3-Di(aminophenyl)-4,6-dinitrobenzene (CCDC 740015) was
prepared and crystallized to enlighten the influence of the methoxy
group. The dihedral angle of the terminal aromatic units and the
dinitro unit are around 501, compared to 281 in 1 (see ESIw).
z Crystal data: 1: C20H18N4O6, M = 410.38, orthorhombic, space
group Pnma, a = 19.9110(18), b = 23.1854(3) A, c = 4.0727(14) A,
V = 1880.1(7) A3, T = 293(2) K, Z = 4, l = 0.154180 nm, reflections
measured = 23 008, 1849 unique (R(int) = 0.0369), final R indices
were R1 (I 4 2s(I)) = 0.0452, wR2 (all data) = 0.1197. 2:
C41H43.8Cl3N8O13.40, M = 969.39, monoclinic, space group P21/a,
a = 15.4253(9), b = 16.0157(8), c = 18.8913(8) A, b = 89.956(4)1,
V = 4667.0(4) A3, T = 193(2) K, Z = 4, l = 0.154180 nm, reflections
measured = 26 487, 4076 unique (R(int) = 0.1282), final R indices
were R1 (I 4 2s(I)) = 0.0996, wR2 (all data) = 0.2987. The poor
quality of this structure is due to disordered solvent molecules
and crystal decomposition during measurement. 3: C60H66N12O18,
M = 1243.25, monoclinic, space group C2/c, a = 18.0066(9),
b
=
33.8684(11),
c
=
20.2630(10) A,
b
=
92.719(2)1,
V = 12343.6(10) A3, T = 193(2) K, Z = 8, l = 0.154180 nm,
reflections measured = 85 375, 11 511 unique (R(int) = 0.0751), final
R indices were R1 (I 4 2s(I)) = 0.0778, wR2 (all data) = 0.2655.
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This journal is The Royal Society of Chemistry 2009
5700 | Chem. Commun., 2009, 5698–5700