Noncovalent synthesis of shape-persistent cyclic hexamers from ditopic hydrazide-based supramolecular synthons and asymmetric induction of supramolecular chirality

Article abstract of DOI:10.1021/ja9029335

With properly encoded recognition sites and a well-defined algorithm for intermolecular and intramolecular interactions, the 120° spacer linked ditopic hydrazide-based supramolecular synthons were found to self-assemble into shape-persistent cyclic hexame

Full text of DOI:10.1021/ja9029335

Published on Web 08/17/2009
Noncovalent Synthesis of Shape-Persistent Cyclic Hexamers
from Ditopic Hydrazide-Based Supramolecular Synthons and
Asymmetric Induction of Supramolecular Chirality
Yong Yang, Min Xue, Jun-Feng Xiang, and Chuan-Feng Chen*
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition
and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
Received April 13, 2009; E-mail: cchen@iccas.ac.cn
Abstract: With properly encoded recognition sites and a well-defined algorithm for intermolecular and
intramolecular interactions, the 120° spacer linked ditopic hydrazide-based supramolecular synthons were
found to self-assemble into shape-persistent cyclic hexamers in apolar solvents. The two hydrazide motifs
displayed separate sets of signals in the NMR spectra because of the interlocked conformation. While in
hydrogen bonding competitive solvent such as DMSO-d6 the spectra were in agreement with the structures
with C2 axes. Moreover, the terminative groups were found to affect the stability of the assemblies
substantially. Consequently, the monomer with ureido-hydrazide terminative groups could form the most
stable cyclic hexamer in solution for the attractive spectator secondary electrostatic interactions. Owing to
the dynamically and kinetically stable nature of these kinds of assemblies, the assembly from the monomer
with chiral auxiliary terminative groups also displayed supramolecular chirality in solution, which was
confirmed by concentration-dependent CD spectra.
systems.5 Successful examples include G-quartets6 and Janus
GC hybrids independently developed by Lehn et al.,7 Mascal
Introduction
Self-assembly,1 the process by which a target species forms
spontaneously from its components without human intervention,
has proven to be a powerful and efficient tool for the bottom-
up construction of nanostructures in supramolecular chemistry.2
Though self-assembly is a widespread phenomenon in biological
systems,3 the principles governing the process have not been
completely mastered or understood by human beings. Thanks
to lessons from biological systems, this pivotal and powerful
tool has been widely used by chemists. Intensive attention has
been paid to the construction of designed and well-defined
structures with nanoscale dimensions from single fragments by
self-assembly. Particularly, great interest goes into the H-
bonding mediated cyclic rosettelike structures.4 Nucleotide
mimics have dominated in this field, thanks to the inspiration
from the complementarity of nucleotides found in biological
et al.,8 Zimmerman et al.,9 Fenniri et al.,10 and Perrin et al.11
Other examples include pyridone-based cyclic trimers,12 carb-
oxylic acid-based hexamers,13 ureidodeazapterin (DeAP)-based
hexamers,14 and ureidopyrimidinone (UPy)-based pentamers,
(5) (a) Jeffrey, G. A. An Introduction to Hydrogen Bonding; Oxford
University Press: Oxford, 1997. (b) Jeffrey, G. A.; Saenger, W.
Hydrogen Bonding in Biological Structures; Springer: Berlin, 1991.
(6) For excellent recent reviews on G-quartets, see: (a) Davis, J. F. Angew.
Chem., Int. Ed. 2004, 43, 668–698. (b) Davis, J. T.; Spada, G. P. Chem.
Soc. ReV. 2007, 36, 296–313.
(7) Marsh, A.; Silvestri, M.; Lehn, J.-M. Chem. Commun. 1996, 1527–
1528.
(8) (a) Mascal, M.; Hext, N. M.; Warmuth, R.; Moore, M. H.; Turkenburg,
J. P. Angew. Chem., Int. Ed. Engl. 1996, 35, 2204–2206. (b) Mascal,
M.; Hext, N. M.; Warmuth, R.; Arnall-Culliford, J. R.; Moore, M. H.;
Turkenburg, J. P. J. Org. Chem. 1999, 64, 8479–8484. (c) Mascal,
M.; Farmer, S. C.; Arnall-Culliford, J. R. J. Org. Chem. 2006, 71,
8146–8150.
(9) (a) Kolotuchin, S. V.; Zimmerman, S. C. J. Am. Chem. Soc. 1998,
120, 9092–9093. (b) Ma, Y.; Kolotuchin, S. V.; Zimmerman, S. C.
J. Am. Chem. Soc. 2002, 124, 13757–13769.
(1) (a) Lindoy, L. F.; Atkinson, I. M. Self-Assembly in Supramolecular
Systems; Royal Society of Chemistry: Cambridge, 2000. (b) Pelesko,
J. A. Self Assembly: The Science of Things That Put ThemselVes
Together; Chapman & Hall/CRC: Boca Raton, FL, 2007. (c) Lehn,
J.-M. Science 2002, 295, 2400–2403. (d) Whitesides, G. M.; Grzy-
bowski, B. Science 2002, 295, 2418–2421. (e) Philp, D.; Stoddart,
J. F. Angew. Chem., Int. Ed. Engl. 1996, 35, 1154–1196.
(10) (a) Fenniri, H.; Mathivanan, P.; Vidale, K. L.; Sherman, D. M.;
Hallenga, K.; Wood, K. V.; Stowell, J. G. J. Am. Chem. Soc. 2001,
123, 3854–3855. (b) Fenniri, H.; Deng, B. L.; Ribbe, A. E. J. Am.
Chem. Soc. 2002, 124, 11064–11072. (c) Fenniri, H.; Deng, B. L.;
Ribbe, A. E.; Hallenga, K.; Jacob, J.; Thiyagarajan, P. Proc. Natl.
Acad. Sci. U.S.A. 2002, 99, 6487–6492. (d) Moralez, J. G.; Raez, J.;
Yamazaki, T.; Motkuri, R. K.; Kovalenko, A.; Fenniri, H. J. Am. Chem.
Soc. 2005, 127, 8307–8309. (e) Johnson, R. S.; Yamazaki, T.;
Kovalenko, A.; Fenniri, H. J. Am. Chem. Soc. 2007, 129, 5735–5743.
(11) Asadi, A.; Patrick, B. O.; Perrin, D. M. J. Am. Chem. Soc. 2008, 130,
12860–12861.
(2) (a) Lehn, J.-M. Supramolecular Chemistry: Concepts and PerspectiVes;
VCH: Weinheim, Germany, 1995. (b) Steed, J. W.; Atwood, J. L.
Supramolecular Chemistry, 2nd ed.; Wiley & Sons: New York, 2009.
(3) Metzler, D. E. Biochemistry: The Chemical Reactions of LiVing Cells;
Academic Press: New York, 2003.
(4) For an excellent and comprehensive review on hydrogen bonding
mediated cyclic aggregates, see: Ballester, P.; de Mendoza, J. In
Modern Supramolecular Chemistry: Strategies for Macrocycle Syn-
thesis; Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.; Wiley-VCH:
Weinheim, Germany, 2008; pp 69-111.
(12) (a) Zimmerman, S. C.; Duerr, B. F. J. Org. Chem. 1992, 57, 2215–
2217. (b) Boucher, E.; Simard, M.; Wuest, J. D. J. Org. Chem. 1996,
60, 1408–1412.
(13) Zimmerman, S. C.; Zeng, F.; Reichert, D. E. C.; Kolotuchin, S. V.
Science 1996, 271, 1095–1098.
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A R T I C L E S
Yang et al.
Figure 1. Spectator secondary electrostatic interaction analysis of the hydrazide-based supramolecular synthons with different terminative groups. Double-
headed arrow: repulsive interaction; mono-headed arrow: attractive interaction.
hexamers,15 and tetramers.16 Whitesides and Reinhoudt’s cyan-
uric acid-melamine rosettes are excellent examples of two
component assemblies.17,18 As we can see, all these examples
are based on heterocyclic building blocks. As a consequence,
long synthetic and purification procedures, difficulties of deriva-
tion, and isomerization often accompany self-assembly, which
deeply limits their applications. Moreover, the formation of
cyclic rosettes of most of the aforementioned examples relies
on additional factors such as metal ion binding, periphery
crowding, or covalent preorganization.
and this supramolecular chirality in solution was confirmed by
the concentration-dependent CD spectra.
Results and Discussion
Spectator Secondary Electrostatic Interaction Analysis. Ac-
cording to the results we previously reported,22a,b the acetyl-
terminated hydrazide-based supramolecular synthon 1b (Figure
1) is a dimer in both solution and solid states, with a dimerization
constant of 16 M-1. Weak association was observed for 1a22d
because of repulsive secondary electrostatic interaction22h,24
inherent with the Boc group. For the purpose of this study, we
need a stronger associating module. We envisioned that
substitution of the Boc group with a urea group (i.e., the
repulsive interaction was replaced by an attractive interaction)
Shape-persistent macrocycles are structures with rigid, non-
collapsible backbones and lumens of various sizes. Intensive
focus of chemical research has been paid to this unique kind of
structure because of its wide applications in material science.19
However, the synthesis of shape-persistent macrocycles presents
a great challenge even with the present-day synthetic technology.
Rare examples of a one-step method have thus been reported,
whereas multistep chemical reactions and purification procedures
were also typically required in most cases. Alternatively,
noncovalent synthesis could provide a convenient and economic
way to construct such structures.17c
(14) (a) Corbin, P. S.; Lawless, L. J.; Li, Z.; Ma, Y.; Witmer, M. J.;
Zimmerman, S. C. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 5099–5104.
(b) Todd, E. M.; Zimmerman, S. C. J. Am. Chem. Soc. 2007, 129,
14534–14535. (c) Todd, E. M.; Zimmerman, S. C. Tetrahedron 2008,
64, 8558–8570.
(15) Keizer, H. M.; Gonzalez, J. J.; Segura, M.; Prados, P.; Sijbesma, R. P.;
Meijer, E. W.; de Mendoza, J. Chem.sEur. J. 2005, 11, 4602–4608.
(16) Ohkawa, H.; Takayama, A.; Nakajima, S.; Nishide, H. Org. Lett. 2006,
8, 2225–2228.
(17) For reviews on cyanuric acid-melamine rosettes, see: (a) Whitesides,
G. M.; Simanek, E. E.; Mathias, J. P.; Seto, C. T.; Chin, D. N.;
Mammen, M.; Gordon, D. M. Acc. Chem. Res. 1995, 28, 37–44. (b)
Lawrence, D. S.; Jiang, T.; Levett, M. Chem. ReV. 1995, 95, 2229–
2260. (c) Prins, L. J.; Reinhoudt, D. N.; Timmerman, P. Angew. Chem.,
Int. Ed. 2001, 40, 2382–2426.
It is well-known that when the atoms of a molecule are
arranged in one unique manner in space, it displays chirality.20
Similarly, when the components (molecules) of a self-assembled
noncovalent architecture are arranged asymmetrically, the
assembly also displays chirality. This phenomenon is called
supramolecular chirality.18 Nature is the expert in the control
of supramolecular chirality. It is this precise control that ensures
complex biological processes such as protein folding, and the
expression and transfer of genetic information to be fulfilled
accurately. While it has dramatic consequences in chemical
systems and is very important for applications in molecular
recognition and mimicking of catalytic activity of enzymes, the
control of supramolecular chirality in synthetic self-assembled
systems is still in its infancy and presents a great challenge for
chemists.
(18) (a) Mateos-Timoneda, M. A.; Crego-Calama, M.; Reinhoudt, D. N.
Chem. Soc. ReV. 2004, 33, 363–372. (b) Vazquez-Campos, S.; Crego-
Calama, M.; Reinhoudt, D. N. Supramol. Chem. 2007, 19, 95–106.
(19) (a) Zhang, W.; Moore, J. S. Angew. Chem., Int. Ed. 2006, 45, 4416–
4439. (b) Ho¨ger, S. Chem.sEur. J. 2004, 10, 1320–1329.
(20) Eliel, E. L.; Wilen, S. H.; Doyle, M. P. Basic Organic Stereochemistry;
Wiley & Sons: New York, 2001.
(21) (a) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311–
2327. (b) Desiraju, G. R. Chem. Commun. 1997, 1475–1482.
(22) (a) Yang, Y.; Zhang, Y.-Z.; Tang, Y.-L.; Chen, C.-F. New J. Chem.
2006, 30, 140-142. (b) Yang, Y.; Hu, H.-Y.; Chen, C.-F. Tetrahedron
Lett. 2007, 48, 3505–3509. (c) Yang, Y.; Yan, H.-J.; Chen, C.-F.; Wan,
L.-J. Org. Lett. 2007, 9, 4991–4994. (d) Yang, Y.; Yang, Z.-Y.; Yi,
Y.-P.; Xiang, J.-F.; Chen, C.-F.; Wan, L.-J.; Shuai, Z.-G. J. Org. Chem.
2007, 72, 4936–4946. (e) Yang, Y.; Xiang, J.-F.; Chen, C.-F. Org.
Lett. 2007, 9, 4355–4357. (f) Yang, Y.; Chen, T.; Xiang, J.-F.; Yan,
H.-J.; Chen, C.-F.; Wan, L.-J. Chem.sEur. J. 2008, 14, 5742–5746.
(g) Yang, Y.; Xiang, J.-F.; Xue, M.; Hu, H.-Y.; Chen, C.-F. J. Org.
Chem. 2008, 73, 6369–6377. (h) Yang, Y.; Xiang, J.-F.; Xue, M.;
Hu, H.-Y.; Chen, C.-F. Org. Biomol. Chem. 2008, 6, 4198–4203.
(23) Lehn et al. reported a hydrazide-based trimeric supramolecular disk
from a heterocyclic compound. See: Sua´rez, M.; Lehn, J.-M.;
Zimmerman, S. C.; Skoulios, A.; Heinrich, B. J. Am. Chem. Soc. 1998,
120, 9526–9532.
In this article, we report the noncovalent synthesis and
characterization of the first examples of shape-persistent,
rosettelike cyclic hexamers from the self-assembly of a 120°
spacer linked nonheterocyclic ditopic hydrazide-based supramo-
lecular synthons.21-23 Moreover, by using a monomer with
chiral auxiliary terminative groups, an asymmetric arrangement
of the components for the assembly could also be achieved,
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A R T I C L E S
Figure 2. Conformation and aggregation analysis of 120° spacer linked hydrazide-based ditopic monomers: nonsymmetric conformation vs symmetric
conformation; cyclic hexamer vs linear polymer, with hydrogen labeling scheme indicated.
1
would give rise to a stronger association module. Indeed,
nonlinear regression analysis25,26 of the dilution 1H NMR data
yielded a dimerization constant of 42 M-1 for ureido-hydrazide-
based 1c·1c.
Self-Assembly in Solution. The H NMR spectrum of 2b in
CDCl3 (10 mM) (Figure 3d) displayed a complicated picture:
numerous minor peaks were present and each hydrazide motif
displayed separate sets of signals. In DMSO-d6, the spectrum
is in agreement with its structure with the C2 axis (Figure S5d
Design and Synthesis. If the hydrazide-based supramolecular
synthons were linked through a 120° spacer, with properly
encoded recognition sites, the simple fragments could assemble
spontaneously into well-defined rosettelike hexameric structures
as shown in Figure 2. However, conformational flexibility could
allow for many other isomers to be present in solution. For
example, if the monomers adopt a conformation with a C2 axis
(Figure 2), there is the possibility of many linear polymers in
solution. With this idea in mind, monomers 2a-2c were
designed and synthesized. The synthesis of the monomers was
straightforward and based on standard amide/peptide coupling
chemistry.26
1
in the Supporting Information). The H NMR spectrum of 2a
in CDCl3 (10 mM) (Figure 3b) displayed low resolvability, even
though we can discern that the signals corresponding to He and
He′ clearly displayed two double peaks. However, the 1H NMR
spectrum of 2c contained well-defined peaks at the same
concentration in CDCl3, in which each hydrazide motif also
displayed separate sets of signals (Figure 3f), whereas both
compounds 2a and 2c displayed 1H NMR spectra in DMSO-d6
(Figures S5b,f in the Supporting Information) consistent with
their structures with C2 axes as indicated in Figure 2. These
findings might indicate the different aggregation modes for
compounds 2a-c in CDCl3 and DMSO-d6.
The 13C NMR experiments also provided results similar to
those of the H NMR experiments. Consequently, compound
(24) For the interactions deriving from hydrogen bonding sites not
participating in primary hydrogen bonding interactions, see: (a)
Jorgensen, W. L.; Pranata, J. J. Am. Chem. Soc. 1990, 112, 2008–
2010. (b) Pranata, J.; Wierschke, S. G.; Jorgensen, W. L. J. Am. Chem.
Soc. 1991, 113, 2810–2819. (c) Murray, T. J.; Zimmerman, S. C. J. Am.
Chem. Soc. 1992, 114, 4010–4011. (d) Zimmerman, S. C.; Murray,
T. J. Tetrahedron Lett. 1994, 35, 4077–4080. (e) Beijer, F. H.;
Sijbesma, R. P.; Vekemans, J. A. J. M.; Meijer, E. W.; Kooijman, H.;
Spek, A. L. J. Org. Chem. 1996, 61, 6371–6380.
1
2c displayed a 13C NMR spectrum in DMSO-d6 (Figure 4b)
corresponding to its structure with C2 axis, whereas in CDCl3
(Figure 4a) the spectrum displayed a complicated picture: the
symmetric nature disappeared and each part displayed separate
sets of signals. Especially in the range of 70-60 ppm where
OCH2 signals appeared, there were three signals (67.8, 66.8,
66.6 ppm) in the spectrum in CDCl3 and two signals (69.7, 68.7
(25) Wilcox, C. S. In Frontiers in Supramolecular Organic Chemistry and
Photochemistry; Schneider, H.-J., Durr, H., Eds.; VCH: New York,
1991; p 123.
1
(26) See Supporting Information for more details.
ppm) in DMSO-d6. The H-15N correlation HMQC spectrum
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1
Figure 3. Stacked partial H NMR spectra of (a) 1a, (b) 2a, (c) 1b, (d) 2b, (e) 1c, and (f) 2c in CDCl3, 10 mM, 298 K, 600 MHz.
Figure 4. Stacked partial 13C NMR spectra of 2c in (a) in CDCl3, 75 MHz, and (b) DMSO-d6, 150 MHz, 298 K.
of 2c in CDCl3 (Figure 5) also displayed eight different kinds
of NH groups, which might result from the nonsymmetrical
nature of the two hydrazide motifs.
Vapor pressure osmometry (VPO) was used to determine the
aggregation mode of the ditopic hydrazide monomers in apolar
solvents. Consequently, VPO studies on 2c were conducted at
37 °C in alcohol-free CHCl3 over the concentration range of
10-64 g/kg (sample/solvent) using sucrose octaacetate as
molecular weight standard, which consistently gave an apparent
molecular weight of 6.3 × 103, corresponding to the hexamer
(calculated for (2c)6: 6428).26 Because of the poor solubility of
2b, VPO experiments failed to give satisfactory results. No
satisfactory VPO result for 2a was also obtained, maybe because
of the low stability from the repulsive secondary electrostatic
interactions inherent with the Boc groups in 2a.
Formation of the hexamer of 2c was further confirmed by its
MALDI-TOF mass spectrum. As a result, a peak at m/z 6428
for (2c)6 was clearly observed (Figure S38 in the Supporting
Information). These observations suggested that the cyclic
hexameric structures (Figure 2) could be formed for 2a-2c in
Figure 5. Partial 1H-15N correlation HMQC spectrum of 2c in CDCl3,
298 K, 600 MHz, showing eight kinds of NH groups in 2c.
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A R T I C L E S
CHCl3, in which successive hydrogen bonding interactions
locked their conformation. Because of the difference in associa-
tion strength derived from different spectator secondary elec-
trostatic interactions associated with the terminative groups, for
2a and 2b, in addition to the main aggregation species, there
were also other aggregates, whereas for 2c with additional
attractive interactions, cyclic hexamer architecture was exclu-
sively formed in CHCl3. Different chemical surroundings (Figure
2) for the inner and outer hydrazide motifs led to their different
NMR (1H NMR, 13C NMR, 1H-15N correlation HMQC) signals,
whereas in DMSO-d6, which is a highly competitive solvent
for hydrogen bonding, 2a-2c existed as monomers, and they
only displayed the NMR spectra corresponding to the structures
with C2 axes.
Combined with the results of COSY, TOCSY, and NOESY
experiments, precise assignment of the 1H NMR signals for 10
mM (2b)6 and (2c)6 in CDCl3 was fulfilled (Figure 3).26 The
assignment process started with the assumption that the rota-
tional freedom of the inner NCH2 (Hg1 and Hg2) and OCH2 (Hn1
and Hn2) groups was restricted because of stereo hindrance in a
confined space, which displayed two separate peaks (Figure
3d,f).27 Additionally, OCH2 (Hk1 and Hk2) groups from the
central linkers also displayed two separate signals. This
phenomenon was evidenced remarkably from 2e26 with a
benzyl-substituted central spacer: two double peaks at 5.18 and
5.31 ppm were observed for the central OCH2 group, with a
relatively large coupling constant (J ) 11.3 Hz) (Figure S39 in
the Supporting Information). These observations suggested that
there were two cycloenantiomers in solution. This hypothesis
was further confirmed by 2d with chiral auxiliary terminative
groups (vide infra). Consequently, cross contacts between Hg1
(Hg2) and Hc′, Hg′ and Hc, Hj and Hd′ were observed in the
NOESY spectrum (Figures S27 and S28 in the Supporting
Information), which provided diagnostic evidence for the
hexameric structure.
To determine the stability of (2c)6, dilution 1H NMR
experiments were performed. Within the concentration range
of 100-1 mM (monomer concentration), no prominent changes
were observed (Figure S30 in the Supporting Information),
which might suggest high stability of the assembly. When 10
mM 2c in CDCl3 was titrated with DMSO-d6, in addition to
the signals corresponding to the hexamer, new signals corre-
sponding to the monomer also appeared when DMSO-d6/CDCl3
ratio reached 3%.26 No other signals were found during the
whole titration process. This phenomenon suggested that the
self-assembly/deassembly of hexamer (2c)6 was a highly
cooperative process and the process was slow on the NMR time
scale. By precise integration of signal for He′ of (2c)6 and signal
for He of 2c, the association constant at different solvent ratios
could be determined. The results were provided in Table 1.
Results based on titration experiments with a 20 mM solution
were also provided. The similar results evidenced the legality
of this method. Considering the dimerization constant (42 M-1
,
vide supra) of ureido-hydrazide-based supramolecular synthon,
the high association constants also indicated that the assembly/
deassembly process was highly cooperative (i.e., the dimeriza-
(27) Reinhoudt et al. also observed this phenomenon in their calyx[4]arene
double rosettes: (a) Vreekamp, R. H.; van Duynhoven, J. P. M.; Hubert,
M.; Verboom, W.; Reinhoudt, D. N. Angew. Chem., Int. Ed. Engl.
1996, 35, 1215–1218. Wang et al. also observed a similar phenomenon
in their molecular baskets: (b) Wang, B.-Y.; Rieth, S.; Badjic, J. D.
J. Am. Chem. Soc. 2009, 131, 7250–7252.
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Yang et al.
Figure 6. Representation of two forms of the cyclic hexamers: clockwise
fashion vs counterclockwise fashion.
tion preference of ureido-hydrazide supramolecular synthon was
largely amplified in this 120° spacer linked ditopic derivative).
Asymmetric Induction of Supramolecular Chirality. Because
of their wide applications, preparation of enantiopure chiral
molecules has been a widely explored and mature area in organic
synthesis.28 While in the field of noncovalent synthesis,17c the
control of supramolecular chirality is still in its infancy for
chemists. It was found that the above-discussed cyclic hexamers
should exist as two forms: one with all monomers arranged in
a clockwise fashion and the other with all monomers arranged
in a counterclockwise fashion (Figure 6). We hypothesized that
the dynamically and kinetically (at least on the NMR time scale)
stable nature of the above cyclic hexamers would be an ideal
model to explore supramolecular chirality of the cyclic rosette
structures.29,30 To bias the equilibrium between these two
cycloenantiomers,31,32 monomer 2d (Figure 7a) with chiral
auxiliary terminative groups was synthesized. For a comparison,
monotopic monomer 1d was also synthesized.26
Circular dichroism (CD) is an ideal tool for monitoring
supramolecular chirality of self-assembled systems in solution
because of its outstanding sensitivity to chiral perturbation of
the systems under investigation.33 As shown in Figure 7b, 2d
displayed concentration-dependent CD spectra in CHCl3. Below
a concentration of 2 × 10-4 M, no significant CD activities
could be detected. By increasing the concentration, the CD
spectra displayed stronger activities at about 350 nm, while the
minimum showed red shift. At 9 × 10-4 M of 2d, the strongest
Figure 7. (a) Chemical structures of 2d and 1d with chiral auxiliary
terminative groups. (b) CD spectra of 2d at different concentrations in
CHCl3, concentration: (1-9) × 10-4 M (at 10-4 M intervals), (1-10) ×
10-3 M (at 10-3 M intervals).
CD activity (-26.5 mdeg at 347.5 nm) was observed. Above
this concentration, the CD activity became weaker, and the
minimum still shifted toward red band. For the monotopic 1d,
the CD spectra did not show any significant CD activity within
the range of concentrations investigated (1 × 10-6 to 1 × 10-2
M). The observed CD activity is thus clearly a direct result of
assembly formation and not an intrinsic property of the
individual components. The concentration-dependent behavior
could be explained in three ways. First, the introduction of a
chiral auxiliary group biases the equilibrium between the two
cycloenantiomers, and one of the enantiomers predominates in
solution. Second, when the concentration is too low, there are
not enough cyclic hexamers in solution for a detectable CD
spectrum. Third, the cyclic hexamer may further stack to form
tubular structures, which might account for the red shift of the
minimum of CD signals and weaker CD activity above 9 ×
10-4 M. This unique phenomenon might be worthwhile for
further investigation.
(28) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638–4660.
(29) Reinhoudt et al. extensively studied supramolecular chirality in
cyanuric acid-melamine hydrogen-bonded double-rosette assemblies: (a)
Prins, L. J.; Huskens, J.; de Jong, F.; Timmerman, P.; Reinhoudt, D. N.
Nature 1999, 398, 498–502. (b) Prins, L. J.; de Jong, F.; Timmerman,
P.; Reinhoudt, D. N. Nature 2000, 408, 181–184. (c) Prins, L. J.;
Verhage, J. J.; de Jong, F.; Timmerman, P.; Reinhoudt, D. N.
Chem.sEur. J. 2002, 8, 2302–2313.
Conclusions
(30) Supramolecular chirality was also studied by Fenniri et al. in their
GC hybrid-based rosette structures; see refs 10b and 10e.
(31) Cycloenantiomerism was first discussed in the case of cyclopeptides
where it depends on the ring direction and the distribution pattern of
the stereogenic centers in the amino acid units: (a) Prelog, V.; Gerlach,
H. HelV. Chim. Acta 1964, 47, 2288–2294. (b) Goodman, M.; Chorev,
M. Acc. Chem. Res. 1979, 12, 1–7.
In conclusion, we have described the noncovalent synthesis
and characterization of the shape-persistent cyclic hexamers
from the self-assembly of 120° spacer linked ditopic hydrazide-
based supramolecular synthons. We found that the self-assembly
process was spontaneous and highly cooperative. The dimer-
ization preference of the hydrazide-based supramolecular syn-
thons was largely amplified. The self-assembly was just based
on the instructions stored in the building blocks and the
predefined algorithms of inter- and intramolecular interactions.
Secondary electrostatic interactions led to varying stabilities for
the assemblies. Because the flexible conformation of the
monomers was interlocked, the different signals for the two
(32) For some examples of cycloenantiomers in supramolecular chemistry,
see: (a) Yamamoto, C.; Okamoto, Y.; Schmidt, T.; Ja¨ger, R.; Vo¨gtle,
F. J. Am. Chem. Soc. 1997, 119, 10547–10548. (b) Saito, S.; Nuckolls,
C.; Rebek, J., Jr. J. Am. Chem. Soc. 2000, 122, 9628–9630. (c) Szumna,
A. Org. Biomol. Chem. 2007, 5, 1358–1368. (d) Paletta, M.; Klaes,
M.; Neumann, B.; Stammler, H.; Grimme, S.; Mattay, J. Eur. J. Org.
Chem. 2008, 555–562.
(33) Gottarelli, G.; Lena, S.; Masiero, S.; Pieraccini, S.; Spada, G. P.
Chirality 2008, 20, 471–475.
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12662 J. AM. CHEM. SOC. VOL. 131, NO. 35, 2009

Hydrazide-Based Cyclic Hexamers
A R T I C L E S
7.18 (d, J ) 9.1 Hz, 2H, He), 6.27 (t, J ) 5.6 Hz, 2H, Hj), 4.12-4.09
(m, 6H, Hm, Hk), 3.02 (q, 4H, Hg), 1.81-1.74 (m, 6H, CH2),
1.48-1.21 (m, 46H, CH2), 0.86-0.82 (m, 15H, CH3). 13C NMR
(150 MHz, DMSO-d6, TMS, 298 K, ppm): δ 165.0, 164.4, 159.3,
158.1, 153.3, 136.9, 132.8, 125.4, 123.5, 121.9, 119.9, 118.6, 117.0,
114.0, 69.7, 68.7, 31.8, 31.6, 30.4, 29.2, 26.5, 26.1, 22.6, 14.5. 1H
NMR (600 MHz, CDCl3, 10 mM, TMS, 298 K, ppm): δ 10.16 (s,
1H, Hc), 9.89 (s, 1H, Hc′), 9.35 (s, 1H, Hb′), 9.11 (s, 1H, Hb), 8.18
(d, J ) 8.4 Hz, 1H, Hf), 8.07 (s, 1H, Hd), 7.92 (s, 1H, Hd′), 7.82 (s,
1H, Hh), 7.75 (s, 1H, Ha), 7.68 (s, 2H, Ha′, Hi), 7.26 (merged in the
signal of CHCl3, Hf′), 7.17 (s, 1H, Hi′), 6.59 (d, J ) 8.3 Hz, 1H,
He′), 6.50-6.40 (br, 1H, Hj), 6.13 (d, J ) 9.2 Hz, 1H, He′),
5.35-5.27 (br, 1H, Hj), 4.20-3.95 (m, 4H, Hm, Hk), 3.35-3.18
(m, 4H, Hn1, Hn2, Hg′), 2.64-2.60 (m, 1H, Hg1), 2.30-2.22 (m,
1H, Hg2), 1.95-1.80 (m, 4H, CH2), 1.52-1.00 (m, 48H, CH2),
0.97-0.91 (m, 9H, CH3), 0.89 (t, J ) 7.2 Hz, 3H, CH3), 0.82 (t, J
) 7.3 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3, TMS, 298 K,
ppm): δ 166.0, 163.4, 162.6, 162.0, 157.2, 156.9, 156.0, 151.0,
150.3, 136.4, 133.3, 131.6, 130.3, 124.7, 123.1, 121.8, 120.9, 116.6,
116.4, 115.9, 114.5, 114.1, 113.5, 110.0, 108.8, 67.8, 66.8, 66.6,
38.3, 38.2, 30.00, 29.98, 29.94, 29.7, 29.6, 28.4, 27.7, 27.61, 27.56,
27.44, 27.39, 27.35, 27.26, 26.8, 24.8, 24.4, 24.3, 24.1, 20.8, 12.22,
12.16, 12.14.
hydrazide motifs in NMR spectra (1H, 13C, 1H-15N correlation
HMQC) were observed. Moreover, precise determination of
association constant in solution was also obtained because of
the slow assembly/deassembly process at the NMR time scale.
This is the first example of rosettelike structures from nonhet-
erocycle-based building blocks, which are devoid of many
problems intrinsic with heterocycle-based building blocks.
Furthermore, the kinetically and dynamically stable nature of
these kinds of assemblies led to an asymmetric induction of
supramolecular chirality from a monomer with chiral auxiliary
terminative groups, which subsequently exhibited concentration-
dependent CD activities in apolar solvent because of excess of
one of the cycloenantiomers. We believe that the synthetic
accessibility, easy derivation, and fining tuned stability of the
hydrazide-based supramolecular synthons can make them a good
scaffold for the preorganization of functional groups with
appealing properties. Further functionalization of the hexameric
structures will be the aim of our future studies.
Experimental Section
Typical Procedure for the Preparation of 2c. Hydrogen was
bubbled continually into a solution of N-hexyl-2-(5-nitro-2-(oct-
yloxy)benzoyl)hydrazinecarboxamide (0.87 g, 2 mmol) in CH2Cl2/
methanol (20 mL/20 mL) using Pd/C 10% (100 mg) as catalyst.
The reduction was completed in about 2 h, and the catalyst was then
removed via filtration. After evaporation of the solvent, the amine was
used in the next step without further purification. The coupling of
5-(octyloxy)isophthalic acid (0.29 g, 1 mmol) and the above amine
was realized using EDC ·HCl (0.48 g, 2.2 mmol) as reagent in
CH2Cl2. The purification was achieved via crystallization from hot
acetonitrile. Compound 2c (0.98 g) was obtained as a white solid
in 92% yield via two steps. Mp: 140-141 °C. MALDI-TOF MS:
m/z 1093.4 [M + Na]+, 1109.4 [M + K]+. Anal. Calcd for
C60H94N8O9 ·2H2O: C, 65.07; H, 8.92; N, 10.12. Found: C, 65.21;
H, 8.96; N, 10.29. 1H NMR (600 MHz, DMSO-d6, 10 mM, TMS,
298 K, ppm): δ 10.38 (s, 2H, Hc), 9.72 (s, 2H, Hb), 8.15 (s, 5H,
Hd, Ha, Hh), 7.97 (dd, J ) 2.2, 8.8 Hz, 2H, Hf), 7.68 (s, 2H, Hi),
See Supporting Information for detailed procedures and char-
acterization data for other compounds.
Acknowledgment. We thank the National Natural Science
Foundation of China (20625206, 20802080), National Basic
Research Program (2007CB808004, 2008CB617501) of China, and
the Chinese Academy of Sciences for financial support.
Supporting Information Available: Experimental procedures
and characterization data for new compounds, determination of
dimerization constant for 1c·1c, NOESY, COSY, and TOCSY
spectra for 2b and 2c, data analysis of VPO experiments, and
determination of association constants for (2c)6. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA9029335
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