Helical organization in foldable aromatic oligoamides by a continuous hydrogen-bonding network

Article abstract of DOI:10.1021/ol802679p

Introduction of a continuous internal hydrogen-bonding network suppressed the conformational flexibility of a series of oligoaromatic foldamers with a lengthened backbone. The helical ordering over up to six aromatic repeating units was established in solution by a 2D NOESY study and in the solid state by an X-ray diffraction method. Computational molecular modeling further corroborates the experimentally observed helical propagation in this class of foldable molecular strands.

Full text of DOI:10.1021/ol802679p

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1201-1204
Helical Organization in Foldable
Aromatic Oligoamides by a Continuous
Hydrogen-Bonding Network
Yan Yan,† Bo Qin,† Yingying Shu,† Xiuying Chen,‡ Yeow Kwan Yip,†
Dawei Zhang,§ Haibin Su,‡ and Huaqiang Zeng*,†
Department of Chemistry and NUS MedChem Program of the Office of Life Sciences,
National UniVersity of Singapore, 3 Science DriVe 3, Singapore 117543, DiVision of
Materials Science, Nanyang Technological UniVersity, 50 Nanyang AVenue, Singapore
639798, and DiVision of Chemistry and Biological Chemistry, Nanyang Technological
UniVersity, 21 Nanyang Link, Singapore 637371
chmzh@nus.edu.sg
Received November 20, 2008
ABSTRACT
Introduction of a continuous internal hydrogen-bonding network suppressed the conformational flexibility of a series of oligoaromatic foldamers
with a lengthened backbone. The helical ordering over up to six aromatic repeating units was established in solution by a 2D NOESY study
and in the solid state by an X-ray diffraction method. Computational molecular modeling further corroborates the experimentally observed
helical propagation in this class of foldable molecular strands.
Largely driven by a strong desire to build biopolymer-like
functions into much simpler yet completely abiotic systems,
much progress has been made in elegantly designed unnatural
folding helices that mimic helices in Nature.1 In particular,
the helical organization emanating from multiple centered
hydrogen bonds (H-bonds) has attracted special interest in
recent years.1a-k Despite the progress,2 the exact helical
dimensions and other structural features for a large portion
of reported helices have remained unknown due to lack of
three-dimensional structures.1j,3 Obtaining quantitative de-
scriptions of structural properties at the molecular level is
critically important as it very often leads to insightful, testable
hypotheses2i,m-o and novel applications such as in functional
foldamer design.1j,m,4 It can also reveal gaps in our current
understanding that need to be filled in order to move the
field forward.
† National University of Singapore.
‡ Division of Materials Science, Nanyang Technological University.
§ Division of Chemistry and Biological Chemistry, Nanyang Techno-
logical University.
(1) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (b) Gong, B.
Chem. Eur. J. 2001, 7, 4336. (c) Hill, D. J.; Mio, M. J.; Prince, R. B.;
Hughes, T. S.; Moore, J. S. Chem. ReV. 2001, 101, 3893. (d) Sanford, A. R.;
Gong, B. Curr. Org. Chem. 2003, 7, 1649. (e) Schmuck, C. Angew. Chem.,
Int. Ed. 2003, 42, 2448. (f) Huc, I. Eur. J. Org. Chem. 2004, 17. (g) Sanford,
A. R.; Yamato, K.; Yang, X. W.; Yuan, L. H.; Han, Y. H.; Gong, B. Eur.
J. Biochem. 2004, 271, 1416. (h) Cheng, R. P. Curr. Opin. Struct. Biol.
2004, 14, 512. (i) Licini, G.; Prins, L. J.; Scrimin, P. Eur. J. Org. Chem.
2005, 969. (j) Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F.
Nat. Chem. Biol. 2007, 3, 252. (k) Bautista, A. D.; Craig, C. J.; Harker,
E. A.; Schepartz, A. Curr. Opin. Chem. Biol. 2007, 11, 685. (l) Albrecht,
M. Chem. ReV. 2001, 101, 3457. (m) Cheng, R. P.; Gellman, S. H.; DeGrado,
W. F. Chem. ReV. 2001, 101, 3219. (n) Li, X.; Yang, D. Chem. Commun.
2006, 3367. (o) Garner, J.; Harding, M. M. Org. Biomol. Chem. 2007, 5,
3577–3585.
Early investigations3c,5 have established a crescent folding
backbone in the solid state for internally H-bonded dimers
and trimers with repeating units represented by oligomers
1-3. However, the corresponding helical conformation for
longer oligomers in either solution or solid state has not been
established. Moreover, a molecular modeling5a on a hexamer
3 using the MM3 force field suggested that it should adopt
a crescent, two-dimensional conformation that encloses an
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Published on Web 02/17/2009
2009 American Chemical Society

acyclic, open-ended cavity of ∼4.3 Å in a radius defined by
six interior methoxy oxygen atoms (or 2.9 Å after deducting
a covalent radius of 1.4 Å for oxygen atom); on this basis,
a hexameric, head-to-tail binding mode was proposed to
account for the helicity induction in a porphyrin-modified
hexamer by six chiral C60-incorporating histidines.3c The
existence of a cavity as large as 2.9 Å may seem quite
uncertain as amide linkages are known to exhibit a significant
degree of plasticity in bond angles, allowing the backbone
to curve due to H-bonding interactions.1f,2c To test this
hypothesis, we carried out computational molecular modeling
at the level of B3LYP/6-31G* on 1a, and indeed, the results6
(Figure 1b) showed that oligomers higher than tetramers
should take up a helical backbone rather than the planar
conformation as proposed previously.3c,5a Consequently, a
helical cavity of ∼1.4 Å in a radius that is much smaller
than 2.9 Å should result. This helical conformation was
further supported by replica exchange molecular dynamics.6
To confirm this computational result, we provide here the
solid-state evidence of helical organizations in 1a and 2a
by a continuous H-bonding network as well as the convincing
2D NOESY studies that support the crescent and helically
folded conformations adopted by 1b and 2b in solution.
These distinct helically folded conformations may better
explain the helicity induction observed previously.3c
(2) (a) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc.
1997, 119, 10587. (b) Berl, V.; Huc, I.; Khoury, R. G.; Krische, M. J.;
Lehn, J. M. Nature 2000, 407, 720. (c) Gong, B.; Zeng, H. Q.; Zhu, J.;
Yuan, L. H.; Han, Y. H.; Cheng, S. Z. Proc. Natl. Acad. Sci. U.S.A. 2002,
99, 11583. (d) Jiang, H.; Le´ger, J.-M.; Huc, I. J. Am. Chem. Soc. 2003,
125, 3448. (e) Garric, J.; Huc, J.-M. L. I. Angew. Chem., Int. Ed. 2005, 44,
1954. (f) Tie, C.; Gallucci, J. C.; Parquette, J. R. J. Am. Chem. Soc. 2006,
128, 1162. (g) Wu, C. W.; Kirshenbaum, K.; Sanborn, T. J.; Patch, J. A.;
Huang, K.; Dill, K. A.; Zuckermann, R. N.; Barron, A. E. J. Am. Chem.
Soc. 2003, 125, 13525. (h) Yang, D.; Zhang, Y.-H.; Li, B.; Zhang, D.-W.;
Chan, J. C.-Y.; Zhu, N.-Y.; Luo, S.-W.; Wu, Y.-D. J. Am. Chem. Soc. 2004,
126, 6956. (i) Choi, S. H.; Guzei, I. A.; Gellman, S. H. J. Am. Chem. Soc.
2007, 129, 13780. (j) Schmitt, M. A.; Choi, S. H.; Guzei, I. A.; Gellman,
S. H. J. Am. Chem. Soc. 2006, 128, 4538. (k) Horne, W. S.; Price, J. L.;
Keck, J. L.; Gellman, S. H. J. Am. Chem. Soc. 2007, 129, 4178. (l) Gan,
Q.; Bao, C. Y.; Kauffmann, B.; Grelard, A.; Xiang, J. F.; Liu, S. H.; Huc,
I.; Jiang, H. Angew. Chem., Int. Ed. 2008, 47, 1715. (m) Sadowsky, J. D.;
Schmitt, M. A.; Lee, H.-S.; Umezawa, N.; Wang, S.; Tomita, Y.; Gellman,
S. H. J. Am. Chem. Soc. 2005, 127, 11966. (n) Zhang, F.; Bai, S.; Glenn,
P. A. Y.; Tarwade, V.; Fox, J. M. J. Am. Chem. Soc. 2005, 127, 10590. (o)
Dong, Z. Z.; Karpowicz, R. J.; Bai, S.; Glenn, P. A. Y.; Fox, J. M. J. Am.
Chem. Soc. 2006, 128, 14242.
Oligomers 1 and 2 were synthesized from commercially
available salicylic acid and 2,5-dihydroxybenzoic acid in
12-18 steps.6 Crystals of 1a and 2a suitable for X-ray
structure determination were obtained by slow evaporation
of 1a and 2a in mixed solvents containing hexane and
chloroform (1:1 v/v) for 1a and hexane and dichloromethane
(1:1 v/v) for 2a at room temperature.6 Their crystal structures
viewed along or perpendicular to the helical axis are
presented in Figure 1a and c. The common structural features
shared between 1a and 2a are the following: (1) Both unit
cells contain two enantiomeric helices of opposite helical
senses (e.g., right-/left-handed) that tightly stack on each
(3) (a) Li, C.; Ren, S.-F.; Hou, J.-L.; Yi, H.-P.; Zhu, S.-Z.; Jiang, X.-
K.; Li, Z.-T. Angew. Chem., Int. Ed. 2005, 44, 5725. (b) Sinkeldam, R. W.;
Hoeben, F. J. M.; Pouderoijen, M. J.; DeCat, I.; Zhang, J.; Furukawa, S.;
DeFeyter, S.; Vekemans, J. A. J. M.; Meijer, E. W. J. Am. Chem. Soc.
2006, 128, 16113. (c) Hou, J.-L.; Yi, H.-P.; Shao, X.-B.; Li, C.; Wu, Z.-
Q.; Jiang, X.-K.; Wu, L.-Z.; Tung, C.-H.; Li, Z.-T. Angew. Chem., Int. Ed.
2006, 45, 796. (d) Nelson, J. C.; Saven, J. G.; Moore, J. S.; Wolynes, P. G.
Science 1997, 277, 1793. (e) Cuccia, L. A.; Lehn, J.-M.; Homo, J.-C.;
Schmutz, M. Angew. Chem., Int. Ed. 2000, 39, 233. (f) Dolain, C.; Maurizot,
V.; Huc, I. Angew. Chem., Int. Ed. 2003, 42, 2738. (g) Yang, X. W.; Brown,
A. L.; Furukawa, M.; Li, S.; Gardinier, W. E.; Bukowski, E. J.; Bright,
F. V.; Zheng, C.; Zeng, X. C.; Gong, B. Chem. Commun. 2003, 56. (h)
Gorp, J. J. v.; Vekemans, J. A. J. M.; Meijer, E. W. Chem. Commun. 2004,
60. (i) Hou, J. L.; Shao, X. B.; Chen, G. J.; Zhou, Y. X.; Jiang, X. K.; Li,
Z. T. J. Am. Chem. Soc. 2004, 126, 12386. (j) Abe, H.; Masuda, N.; Waki,
M.; Inouye, M. J. Am. Chem. Soc. 2005, 127, 16189. (k) Khan, A.; Kaiser,
C.; Hecht, S. Angew. Chem., Int. Ed. 2006, 45, 1878. (l) Zhao, Y.; Zhong,
Z. Q.; Ryu, E. H. J. Am. Chem. Soc. 2007, 129, 218. (m) Li, X.; Zhan, C.;
Wang, Y.; Yao, J. Chem. Commun. 2008, (21), 2444. (n) Yang, D.; Zhang,
Y.-H.; Zhu, N.-Y. J. Am. Chem. Soc. 2002, 124, 9966.
(4) (a) Tang, H.; Doerksen, R. J.; Jones, T. V.; Klein, M. L.; Tew, G. N.
Chem. Biol. 2006, 13, 427. (b) Gillies, E. R.; Deiss, F.; Staedel, C.;
Schmitter, J. M.; Huc, I. Angew. Chem., Int. Ed. 2007, 46, 4081. (c) Horne,
W. S.; Boersma, M. D.; Windsor, M. A.; Gellman, S. H. Angew. Chem.,
Int. Ed. 2008, 47, 2853. (d) Hara, T.; Durell, S. R.; Myers, M. C.; Appella,
D. H. J. Am. Chem. Soc. 2006, 128, 1995. (e) Sadowsky, J. D.; Fairlie,
W. D.; Hadley, E. B.; Lee, H. S.; Umezawa, N.; Nikolovska-Coleska, Z.;
Wang, S. M.; Huang, D. C. S.; Tomita, Y.; Gellman, S. H. J. Am. Chem.
Soc. 2007, 129, 139. (f) Wang, D.; Lu, M.; Arora, P. S., Angew. Chem.,
Int. Ed. 47, 1879. (g) Rodriguez, J. M.; Hamilton, A. D. Angew. Chem.,
Int. Ed. 2007, 46, 8614.
Figure 1. Side and top views of (a) crystal structure of pentamer
1a, (b) ab initio calculated structure of 1a, and (c) crystal structure
of hexamer 2a. Interior methoxy methyl groups are omitted for
clarity.
(5) (a) Yi, H. P.; Li, C.; Hou, J. L.; Jiang, X. K.; Li, Z. T. Tetrahedron
2005, 61, 7974. (b) Kanamori, D.; Okamura, T. A.; Yamamoto, H.; Ueyama,
N. Angew. Chem., Int. Ed. 2005, 44, 969.
(6) See Supporting Information.
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Org. Lett., Vol. 11, No. 6, 2009

other with no inclusion of solvent molecules. (2) Both
structures possess a helical periodicity of ∼5 repeating units
per turn. (3) The interior methoxy groups, pointing up and
down alternatively, fill the helix hollow cavity of ∼1.4 Å in
radius7 and completely prevent them from encapsulating
guest molecules. (4) As expected, all the inward-pointing
amide protons and methoxy oxygen atoms participate in the
formation of a continuous internally located H-bonding
network that comprises up to 10 intramolecular H-bonds
(NH···OMe ) 1.933-2.306 Å). One difference between 1a
and 2a involves the helical pitch. While hexamer 2a has a
pitch of ∼3.4 Å typically observed in aromatic foldamers,2a-f
an appreciably larger helical pitch of ∼5 Å is observed in
1a. Such a large pitch may stem, in part, from the steric
crowdedness involving the two end methoxy groups in the
absence of favorable π-π stacking interactions, which was
also found in an aliphatic peptoid foldamer in the solid
state.2g The solid-state structures of 1a and 2a (1) provide
the most conclusive evidence for the adoption of a helical
conformation by the foldable molecular strands 1a and 2a,
(2) validate our conceptual reasoning and others’
observations,1f,2c detailing a significant effect the H-bonding
forces may have on the backbone curvature of aromatic
foldamers, and (3) corroborate the power of ab initio
molecular modeling at the B3LYP/6-31G* level in the
satisfactory prediction of 3D topologies of aromatic
foldamers.2f,8
protons (Figure 2b). The amide protons resonating at low
fields (9.87-10.36 ppm) are in line with the existence of
strong intramolecular H-bonds in 1b.2c,d Since the interatomic
distances between amide and methoxy protons measured
from the crystal structure of 1a range from 2.279 to 3.690
Å, two NOE contacts between every amide proton and its
adjacent methoxy methyl groups should be seen in the 2D
NOESY spectrum if a folded conformation does prevail for
1b in solution. The well-resolved amide protons and internal
methoxy groups of 1b indeed permit us to observe the
expected eight NOE cross peaks, two for each amide protons
(Figure 3a). Except for the NOE contact between protons 5
The highly repetitive nature of 1a (Figure 2a) and 2a6 led
to extensive 1H NMR signal overlaps among aromatic
Figure 3. (a) NOE contacts (NOESY, 800 MHz, 25 mM, 298 K,
500 ms, CDCl3) seen between amide protons and their adjacent
interior methoxy protons of 1b. (b) End-to-end NOE (top, 500 MHz,
20 mM, 283 K, 500 ms, CDCl3) and ROE (bottom, ROESY, 500
MHz, 15 mM, 298 K, 200 ms, CDCl3/25%DMSO-d6) contacts seen
between the end units of 2b.
Figure 2.
1H NMR spectra of (a) pentamer 1a (500 MHz, 5 mM,
298 K, CDCl3) and (b) pentamer 1b (800 MHz, 25 mM, 298 K,
CDCl3).
protons, hampering the elucidation of their folded structures
in solution. To overcome this difficulty, linear and branched
alkoxyl side chains as well as a methyl group para to the
interior methoxy groups are deliberately introduced into 1b.
At 25 mM,9 the 1H NMR spectrum of 1b recorded in CDCl3
displays highly dispersed proton resonances for most of its
and 6, the NOE intensities of all the other seven NOE cross-
peaks between interior methoxy protons and amide protons
in Figure 3a were much stronger than those weak NOE
contacts between amide protons and the neighboring aromatic
protons ortho to the amide bonds (protons 4, 7, 9, etc; Figure
S2a, Supporting Information),6 suggesting that the methoxy
protons stay much closer to the amide protons than to the
aromatic protons, a consequence resulting from the enforced
folding of the backbone by those internal hydrogen bonds.
The NOEs between the end residues that are indicative of
the helical conformation of 1b were not detected, presumably
due to its unusually large helical pitch (∼5 Å)
(7) This helically wrapped interior cavity of radius as small as 1.4 Å is
remarkably identical to the circular cavity radius found in a pentagon-shaped
circular aromatic pentamer recently reported by us: Qin, B.; Chen, X. Y.;
Fang, X.; Shu, Y. Y.; Yip, Y. K.; Yan, Y.; Pan, S. Y.; Ong, W. Q.; Ren,
C. L.; Su, H. B.; Zeng, H. Q. Org. Lett. 2008, 10, 5127.
(8) Buffeteau, T.; Ducasse, L.; Poniman, L.; Delsucb, N.; Huc, I. Chem.
Commun. 2006, 2714
.
Org. Lett., Vol. 11, No. 6, 2009
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Similarly, the incorporation of two different side chains
into 2b at only one end differentiates the aromatic proton
signals of the modified end units from all other remaining
units in the same molecule in CDCl3.6 Addition of 25%
DMSO-d6 into CDCl3 further separates ester methyl protons
1 from the interior methoxy methyl protons 5. As such, the
ROE cross peak between the end units (methoxy protons 1
and aromatic proton 24, Figure 3b) is clearly identifiable.
This end-to-end ROE, along with the observation of numer-
ous ROE contacts among amide protons and their adjacent
interior methoxy protons,6 strongly supports the presence of
the H-bond enforced helical ordering in 2b in solution that
leads to the stacking of one end over the other. Observation
of these end-to-end NOE or ROE contacts in 2b (Figure 3b)
accords with the shortest interatomic distance (2.748 Å)
found between protons 1 and 24 in the crystal structure of
2a.
To summarize, the helical propagation over several
internally rigidified, lengthened oligoaromatic backbones as
in 1 and 2 in solution and the solid state has been established
experimentally and substantiated theoretically by the com-
putational molecular modeling at the B3LYP/6-31G* level.
The detailed elucidation of such structural information
contained within the helically folded framework should guide
the design of supramolecular (bio)nanoarchitectures of
increasing complexity via peripheral functionalizations,
which may find important applications in a number of fields
including materials,3c medicinal1m,4 and biological sciences,
and engineering.1m,4a-e
Acknowledgment. Financial support of this work by
Faculty of Science and Office of Life Sciences at National
University of Singapore is gratefully acknowledged.
Supporting Information Available: Synthetic procedures
for oligomers 1 and 2 along with a full set of characterization
(9) Given the approximate dimentionality of 8 Å × 25 Å × 20 Å
(estimated based on the crystal structure of pentaer 1a) for side-chain-
modified pentamer 1b, a simple calculation shows that the seperation
distance between any two molecules of 1b is more than 20 Å at 25 mM.
Estimation based on 2a suggests a similar dimentionality of 8 Å × 25 Å ×
20 Å for pentamer 2b and subsequent calculation leads to a separation
distance of >30 Å at 15 mM between any two molecues of 2b. These large
separation distances suggest that the NOE/ROEs observed in Figure 3 are
due to the intramolecular rather than intermolecular proton-proton interac-
tions that occur through the space.
1
data including CIF files (1a and 2a), H NMR, 13C NMR,
HRMS, NOESY, and TOCSY, as well as molecular model-
ing results. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL802679P
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