Two novel quadruple hydrogen-bonding motifs: the formation of supramolecular polymers, vesicles, and organogels

Article abstract of DOI:10.1016/j.tetlet.2009.10.115

Two new hydrazide-based quadruple hydrogen-bonding motifs are described. Dipodals based on these two motifs are revealed to form supramolecular polymers, which can further aggregate to form vesicles and/or organogels in hydrocarbons. The quadruple hydroge

Full text of DOI:10.1016/j.tetlet.2009.10.115

Tetrahedron Letters 51 (2010) 188–191
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Two novel quadruple hydrogen-bonding motifs: the formation
of supramolecular polymers, vesicles, and organogels
*
*
Ping Du, Gui-Tao Wang, Xin Zhao , Guang-Yu Li, Xi-Kui Jiang, Zhan-Ting Li
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new hydrazide-based quadruple hydrogen-bonding motifs are described. Dipodals based on these
two motifs are revealed to form supramolecular polymers, which can further aggregate to form vesicles
and/or organogels in hydrocarbons. The quadruple hydrogen-bonding motifs are characterized by the X-
ray diffraction and (2D) 1H NMR experiments, while the vesicles and organogels are evidenced by SEM,
AFM, TEM, and fluorescent microscopy.
Received 8 September 2009
Revised 21 October 2009
Accepted 27 October 2009
Available online 30 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
OCH2CH(CH3)2
Hydrogen bonding is the most reversible noncovalent forces for
forming well-defined supramolecular entities. In the past decades,
the quadruple hydrogen-bonding motifs have received consider-
able attention due to their generally increased stability compared
to the double or triple hydrogen-bonding motifs.1 Moreover, this
series of binding patterns has been widely utilized to construct dy-
namic supramolecular polymers.2 We previously reported the self-
assembly of a series of stable quadruple hydrogen-bonding pattern
from complementary aromatic hydrazide-derived monomers.1h
More recently,3 we also constructed a variety of foldamers from
aromatic hydrazide oligomers by using intramolecular hydrogen
bonding as the driving force. We herein report two novel quadru-
ple hydrogen-bonding motifs, whose monomers dimerize by
adopting a twisted or perpendicular conformation. Notably, hydro-
gen-bonded supramolecular polymers constructed based on these
motifs can self-assemble into both vesicles and organogels.4
Different from their aryl amide analogues, which usually form
single C@OÁ Á ÁH–N hydrogen-bonding chains, 1,2-dibenzoylhydra-
zines generate stronger double C@OÁ Á ÁH–N hydrogen-bonding
chains.5,6 We therefore synthesized compounds 1a, 1b, 2a, 2b,
and 3a–c. We envisioned that 1a and 1b would form a homodimer
that is stabilized by four C@OÁ Á ÁH–N hydrogen bonds, while the
dipodals might form supramolecular polymers that are linked by
this motif. The two outside NH units are locked by intramolecular
six-membered OÁ Á ÁH–N hydrogen bonds,7 which should suppress
the formation of the intermolecular hydrogen bonding and thus
improve their assembling selectivity.
O
O
N
H
N
O
HN
O
H
RO 2N
H1
OR
1a: R = CH2CH(CH3)2
1b
H8
H7
H5
: R = n-C8H17
OR
H
RO
H2
H6
N
O
O
N
O
O
HN
H3
N
O
H1
O
O
H4
HN
N
H
NH
N
H
O
O
O
2a
: R =CH2CH(CH3)2
OR
RO
2b: R = n-C8H17
OR1
O
N
O
R2O
N
O
H1
N
O
O
O
N
O
N
H
HN
H
H
NH
HN
H
O
OR2
The crystal structure of 1a exhibited a dimeric motif that is sta-
bilized by two pairs of C@OÁ Á ÁH–N hydrogen bonds (d = 2.03 and
2.11 Å) (Fig. 1a). Notably, only one of the two iso-butoxy O atoms
was engaged in the intramolecular hydrogen bonding, even though
O
O
OR1
: R1 = R2 = CH2CH(CH3)2
3a
3c: R1 = R2 = n-C8H17
3b
: R1 = CH2CH(CH3)2, R2 = n-C8H17
* Corresponding authors. Tel.: +86 21 54925023; fax: +86 21 64166128 (X.Z.).
E-mail addresses: xzhao@mail.sioc.ac.cn (X. Zhao), ztli@mail.sioc.ac.cn (Z.-T. Li).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.115

P. Du et al. / Tetrahedron Letters 51 (2010) 188–191
189
it is very stable and occurs even in aqueous media.7,8 The two cen-
R
O
R
O
tral benzene rings of the dimer stacked in a face-to-face manner,
which should also stabilize the hydrogen-bonding motif (Fig. 2a).
The neighboring dimers were further connected with two strong
C@OÁ Á ÁH–N hydrogen bonds (d = 2.05 Å), while the peripheral ben-
zene rings also stacked (not shown).
H
N
H
N
O
O
O
O
N
H
N
H
O
O
O
O
H
N
H
N
O
O
The crystal structure of 1b revealed another quadruple hydro-
gen-bonding motif (Fig. 1b). The two monomers were arranged
perpendicularly (Fig. 2b). The N–HÁ Á ÁO distances were different
slightly due to the unsymmetry of the arrangement. The octoxy
O atoms were all engaged in intramolecular hydrogen bonding,
while the octyl chains stacked with their counterparts of neighbor-
ing molecules (not shown). Different from that of 1a, no aromatic
stacking or other intermolecular hydrogen bonding was observed
for 1b. It seems that the larger peripheral aliphatic groups played
a key role in promoting the formation of this motif. Compounds
1a and 1b are similar in shape to the V-styled N1,N3-bis(6-acylami-
nopyridin-2-yl)isophthalamides that can bind barbiturates via six
hydrogen bonds.9,10 However, they form homodimers due to their
self-complementary feature.
N
H
N
H
O
O
R
R
RO
H
R
O
N
N
O
H
N
N
O
O
O
H
O
H
H
O
O
H
N
O
N
O
N
H
O
N
H
RO
O
R
The crystal structure of 2a (Fig. 3a) revealed the formation of a
stair-styled supramolecular polymer that was mediated by a qua-
druple hydrogen-bonding motif very similar to that of 1a. The cen-
tral benzene rings stacked with each other, while the peripheral
benzene rings stacked alternately with those of the neighboring
polymeric chains. The crystal structure of 2b exhibited another
kind of supramolecular polymer (Fig. 1d) formed through a hydro-
gen-binding motif similar to that of 1b (Fig. 2b). No stacking or
other intermolecular hydrogen bonds were observed in the pack-
ing structure. All the octyl chains were arranged along the poly-
meric framework and stabilized the packing structure through
intermolecular van der Waals force.
Figure 2. The two quadruple hydrogen-bonding motifs: (a) the central benzene
rings stack with each other (for 1a and 2a); (b) the monomers are located
perpendicularly (for 1b and 2b).
1H NMR experiments in CDCl3 supported that the quadruple
hydrogen-bonding motif also exists in solution. Diluting the solu-
tion of 1a and 1b in CDCl3 from 64 or 100 mM to 0.25 mM caused
the H-1 signal (see the structures) to shift upfield by 0.83 or
Figure 3. The quadruply hydrogen-bonded supramolecular polymers of (a) 2a and
(b) 2b in the crystal structures (only the amide hydrogen atoms are shown for
clarity). The single crystal of 2a was grown by slow evaporation of its methanol
solution and that of 2b was grown by diffusing acetonitrile to its DMF solution.
1.05 ppm, indicating that it was strongly involved in intermolecu-
lar hydrogen bonding. In contrast, the H-2 signal was shifted
downfield by only 0.24 or 0.26 ppm. The results were consistent
with the above-mentioned X-ray results. By fitting the plots of
D
d versus the concentration to a nonlinear equation of the 1:1
binding model, association constants (Kassoc) of 1a–1a and 1b–1b
were derived to be 600 and 480 M
À1 11 The values are modest, pos-
.
sibly due to the twisting of the framework.
2D NOESY experiment for 2b in CDCl3 revealed NOEs between
the central ethylene hydrogen (H-3) and the H-4, H-5, and H-6
atoms (see the structure), but not the H-2, H-7, or H-8 atom,
indicating that the peripheral aromatic units were confined and
did not rotate around the inner-located (Ar)C–C(@O) bond. Be-
cause the distances between H-3, H-4, H-5, and H-6 in the crystal
Figure 1. The crystal structures of (a) 1a and (b) 1b (only the amide hydrogen
atoms are shown for clarity).

190
P. Du et al. / Tetrahedron Letters 51 (2010) 188–191
structure of 2a are generally shorter than the corresponding ones
in the crystal structure of 2b, these results evidenced that in solu-
tion 2b the first dimeric motif should also form. Diffusion-ordered
2D NMR (DOSY) experiments were further preformed for 1b, 2b,
and 3c at two different concentrations,12 giving the corresponding
diffusion coefficients of 2.6 Â 10À9 (1b, 10 mM), 2.5 Â 10À9 (1b,
100 mM), 5.0 Â 10À9 (2b, 10 mM), 6.0 Â 10À10 (2b, 100 mM),
5.1 Â 10À9 (3c, 10 mM), and 1.2 Â 10À9 (3c, 30 mM) m2/s. The val-
ues of 1b are close, implying that it formed a simple dimer at both
concentrations. In contrast, the values of 2b and 3c at higher con-
centration were remarkably smaller than those at lower concentra-
tion, clearly supporting that the dipodal compounds could form
supramolecular polymers. At higher concentrations, they had a
higher degree of polymerization, a larger size, and thus a smaller
diffusion coefficient. The values of isomers 2b and 3c at 10 mM
are comparable, indicating that their degree of polymerization
was comparable as a result of formatting the identical hydrogen
bonding motif.
formation of vesicles. These results indicated that the formation
of the supramolecular polymers and their aggregation were the
keys for the generation of the vesicles: The addition of 1b weak-
ened the supramolecular polymers, while the addition of chloro-
form and tetralin, which might competitively stack with the
aromatic units of the dipodals, reduced the aggregation of the
supramolecular polymers.13
AFM also supported that 2a, 2b, and 3a self-assembled into ves-
icles in decalin (see the Supplementary data). The diameter/height
ratio of the vesicles was 5–15, evidencing their hollowness. Upon
being transferred onto the surface, the vesicles were dried due to
the evaporation of the entrapped solvent, leaving them like flat
balls. The fluorescence micrographs also supported the hollowness.
As shown for 2b (Fig. 4c), the light spots all exhibit obvious lumi-
nance differences between the outer rings and inner areas,3b sug-
gesting that they were hollow and filled with the solvent in
solution. When they were transferred onto the surface, the en-
trapped solvent was evaporated, leading to the difference in thick-
ness and luminance.
Since the new dimeric segments have a relatively large aromatic
framework, we further investigated the potential of the supramo-
lecular polymers to generate ordered structures in nonpolar hydro-
carbons, including n-hexane, n-octane, n-dodecane, decalin,
tetralin, benzene, and toluene, in which the hydrogen bonding
and aromatic stacking should be enhanced. At room temperature,
all the dipodals displayed low solubility in these solvents. Upon
heating, the solubility of 2a, 2b, and 3a in decalin was increased
considerably (>1.0 mM). SEM images showed that all these com-
pounds formed spherical vesicles with average diameters of ca.
0.6, 1.0, and 1.4 m (Fig. 4a and b), respectively. SEM images also
indicated that 2b formed vesicles in n-dodecane (1 mM), but the
vesicles were generally separate. In all the hydrocarbons, 1a and
1b did not form vesicles. Adding 1b to the decalin solution of 2b
reduced the capacity of 2b of forming vesicles, and 4 equiv of 1b
destroyed the vesicles completely. Adding chloroform to the deca-
line solution also suppressed the formation of the vesicles and
when its content was 40%, no spherical structures were observed
from the SEM images. Adding tetralin to the above-mentioned
solutions in decalin also weakened, and at 25%, it prevented the
TEM also evidenced the hollowness of the vesicles. Figure 4d
shows the image of a vesicle of 2b, which had an average wall
thickness of ca. 2.6 nm. The crystal structures of 2a and 2b revealed
that the width of their aromatic segments was ca. 2.0 nm. Due to
their dynamic feature, the supramolecular polymers should exhibit
a larger apparent thickness. Therefore, this result supports that the
vesicles might have a monolayer structure that was generated by
the aggregation of the polymeric frameworks’ (Fig. 5). The mole-
cules should also be movable in the membranes. Thus we propose
that the two hydrogen-bonding motifs shown in Figure 2 should
co-exist in the vesicles.
Compounds 1a, 1b, 2a, and 3a did not gelate any of the above-
mentioned solvents. In contrast, 2b gelated the mixtures of decalin
and tetralin when the content of tetralin was 20–40%, while 3b and
3c gelated both of them and their mixtures (see the Supplementary
data for details). The long octyl chains should contribute essen-
tially by increasing the solubility and promoting the formation of
the entangled networks.14 Adding 1b to the above-mentioned
organogels could cause the latter to turn to solution, again support-
Figure 4. SEM images of the samples of (a) 2a (1.0 mM) and (b) 2b (1.0 mM), (c) the fluorescence micrograph of the sample of 2b (20 mM), and d) TEM image of the sample of
2b (0.4 mM) in decalin.

P. Du et al. / Tetrahedron Letters 51 (2010) 188–191
191
Figure 5. Tentative models for the formation of vesicles and organogels from the quadruply hydrogen-bonded supramolecular polymers in apolar media.
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In conclusion, two novel quadruple hydrogen-bonding motifs
have been developed from aromatic hydrazide-based monomers,
which can be utilized to construct supramolecular polymers.
Although the stability of the novel motifs is modest, the supramo-
lecular polymers exhibit unique self-assembling property, that is,
forming both vesicles and organogels in hydrocarbons. Because
the binding segments consist of three benzene units, they may
stack to stabilize the intermolecular hydrogen bonding in polar
media,15 which will be exploited in the future.
Acknowledgments
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We thank NSFC (Nos. 20942004, 20621062, 20672137,
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Crystallographic data (excluding structure factors) for struc-
tures 1a, 1b, 2a, and 2b in this Letter have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication Nos. CCDC 746809, 725875, 746808, and 725874,
respectively. Copies of the data can be obtained free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: t44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk). Syn-
thesis and characterizations, selected (2D) 1H and 13C NMR spectra,
additional AFM and SEM images, gelation results, typical procedure
for the evaluation of association constants. Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.10.115.
References and notes
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Sijbesma, R. P.; Meijer, E. W. Angew. Chem., Int. Ed. 1998, 37, 75–78; (b) Beijer, F.