Hydrogen-bonding-mediated anthranilamide homoduplexes. Increasing stability through preorganization and iterative arrangement of a simple amide binding site

Article abstract of DOI:10.1021/ja064218i

This paper describes the assembly of two new series of self-complementary duplexes by making use of amide units, the simplest assembling units of hydrogen bonding, as binding sites. All the new monomers possess a rigidified anthranilamide skeleton, which is stabilized by intramolecular hydrogen bonding. Amide units are iteratively introduced to one side of the preorganized skeletons to facilitate the formation of intermolecular hydrogen bonding. Compounds 2 and 3 bear two and three CONH₂ units, respectively, while 4, 6, and 7 are incorporated with two, three, and four AcNH units, respectively. For comparison, compound 5, which is similar to 4 but contains one AcNH and one CF₃CONH unit, is also prepared. X-ray diffraction analysis of 2, 4, and 5 revealed homodimeric motifs in the solid state which are stabilized by two or more intermolecular hydrogen bonds. ¹H NMR investigations in CDCl₃ indicated that all the compounds form hydrogen-bonded homoduplexes. Duplexes 3-3, 6-6, and 7-7 are highly stable in CDCl₃, with a lower K_assoc limit of 2.3 × 10 ⁵ M^-1. The K_assoc values of the three duplexes in more polar CDCl₃/CD₃CN (9:1, v/v) were determined with the ¹H NMR dilution method. The result opens the way for the development of new polymeric duplexes of well-ordered structures.

Full text of DOI:10.1021/ja064218i

Published on Web 08/29/2006
Hydrogen-Bonding-Mediated Anthranilamide Homoduplexes.
Increasing Stability through Preorganization and Iterative
Arrangement of a Simple Amide Binding Site
Jiang Zhu,†,‡ Jian-Bin Lin,† Yun-Xiang Xu,† Xue-Bin Shao,† Xi-Kui Jiang,† and
Zhan-Ting Li*,†
Contribution from the State Key Laboratory of Bio-Organic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China, and DiVision of Chemistry, North Sichuan Medical College,
234 Fujiang Lu, Nanchong 637007, China
Received June 15, 2006; E-mail: ztli@mail.sioc.ac.cn
Abstract: This paper describes the assembly of two new series of self-complementary duplexes by making
use of amide units, the simplest assembling units of hydrogen bonding, as binding sites. All the new
monomers possess a rigidified anthranilamide skeleton, which is stabilized by intramolecular hydrogen
bonding. Amide units are iteratively introduced to one side of the preorganized skeletons to facilitate the
formation of intermolecular hydrogen bonding. Compounds 2 and 3 bear two and three CONH2 units,
respectively, while 4, 6, and 7 are incorporated with two, three, and four AcNH units, respectively. For
comparison, compound 5, which is similar to 4 but contains one AcNH and one CF3CONH unit, is also
prepared. X-ray diffraction analysis of 2, 4, and 5 revealed homodimeric motifs in the solid state which are
1
stabilized by two or more intermolecular hydrogen bonds. H NMR investigations in CDCl3 indicated that
all the compounds form hydrogen-bonded homoduplexes. Duplexes 3‚3, 6‚6, and 7‚7 are highly stable in
CDCl3, with a lower Kassoc limit of 2.3 × 105 M-1. The Kassoc values of the three duplexes in more polar
1
CDCl3/CD3CN (9:1, v/v) were determined with the H NMR dilution method. The result opens the way for
the development of new polymeric duplexes of well-ordered structures.
Introduction
cyclic derivatives, in which hydrogen-bonding donors or
acceptors are compactly arranged in a designed direction, as
Self-assembly of linear oligomers into double- and multiple-
stranded complexes is ubiquitous in biology and prerequisite
for biomacromolecules to generate discrete higher structures and
functions.1 In addition to their utility for structural mimicking
of biomacromolecules and development of abiotic self-replicat-
ing systems,2 unnatural duplexes are of fundamental importance
for the construction of multicomponent and polymeric archi-
tectures of functional properties.3 Because of its great direc-
tionality and strength, hydrogen bonding is an ideal noncovalent
force for this purpose.4 Two general strategies have been
developed for the design of hydrogen-bonding-mediated mo-
lecular building blocks. The first strategy is based on hetero-
demonstrated by the recent self-assembly of various quadruply
hydrogen-bonded binding modes.5 The second strategy involves
iteratively incorporating simple binding residues into linear
backbones. Examples of this family of dimeric aggregates
include sheetlike aromatic and aliphatic amide duplexes,6,7 3,6-
diaminopyridazine-based homoduplexes,8 and hydrazide-derived
(4) (a) Lawrence, D. S.; Jiang, T.; Levitt, M. Chem. ReV. 1995, 95, 2229. (b)
Conn, M. M.; Rebek, J., Jr. Chem. ReV. 1997, 97, 1647. (c) Zimmerman,
S. C.; Corbin, P. S. Struct., Bonding 2000, 96, 63. (d) Archer, E. A.; Gong,
H.; Krische, M. J. Tetrahedron 2001, 57, 1139. (e) Brunsveld, L.; Folmer,
B. J. B.; Meijer, E. W.; Sijbesma, R. P. Chem. ReV. 2001, 101, 4071. (f)
Prins, L. J.; Reinhoudt, D. N.; Timmerman, P. Angew. Chem., Int. Ed. 2001,
40, 2383. (g) Schmuck, C.; Wienand, W. Angew. Chem., Int. Ed. 2001,
40, 4363. (h) Sijbesma, R. P.; Meijer, E. W. Chem. Commun. 2003, 5. (i)
Shenhar, S.; Rotello, V. M. Acc. Chem. Res. 2003, 36, 549. (j) Lukin, O.;
Vo¨gtle, F. Angew. Chem., Int. Ed. 2005, 44, 1456.
(5) (a) Lu¨ning, U.; Ku¨hl, C. Tetrahedron Lett. 1998, 39, 5735. (b) Beijer, F.
H.; Kooijman, H.; Spek, A. L.; Sijbesma, R. P.; Meijer, E. W. Angew.
Chem., Int. Ed. 1998, 37, 75. (c) Sessler, J. L.; Wang, R. Angew. Chem.,
Int. Ed. 1998, 37, 1726. (d) Beijer, F. H.; Sijbesma, R. P.; Kooijman, H.;
Spek, A. L.; Meijer, E. W. J. Am. Chem. Soc. 1998, 120, 6761. (e) Corbin,
P. S.; Zimmerman, S. C. J. Am. Chem. Soc. 1998, 120, 9710. (f) Gong, B.;
Yan, Y.; Zeng, H.; Skrzypczak-Jankunn, E.; Kim, Y. W.; Zhu, J.; Ickes,
H. J. Am. Chem. Soc. 1999, 121, 5607. (g) Park, T.; Zimmerman, S. C.;
Nakashima, S. J. Am. Chem. Soc. 2005, 127, 6520. (h) Park, T.; Todd, E.
M.; Nakashima, S.; Zimmerman, S. C. J. Am. Chem. Soc. 2005, 127, 18133.
(i) Ong, H. C.; Zimmerman, S. C. Org. Lett. 2006, 8, 1589.
† Chinese Academy of Sciences.
‡ North Sichuan Medical College.
(1) Horton, R. H.; Moran, L. A.; Ochs, R. S.; Rawn, D. J.; Scrimgeour, G. K.
Principles of Biochemistry; Prentice Hall International, Inc.: London, 1992;
826 pp.
(2) (a) O’Neil, K. T.; Hoess, R. H.; Degrado, W. F. Science 1990, 249, 774.
(b) von Kiedrowski, G.; Sievers, D. Nature 1994, 369, 221. (c) Wintner,
E. A.; Conn, M. M.; Rebek, J., Jr. Acc. Chem. Res. 1994, 27, 198.
(3) (a) Vo¨gtle, F. Supramolecular Chemistry: Introduction; Teubner: Stuttgart,
1989; 447 pp. (b) Lehn, J.-M. Supramolecular Chemistry: Concepts and
PerspectiVes; VCH: Weinheim, 1995; 262 pp. (c) Steed, J. W., Atwood,
J. L., Eds. Supramolecular Chemistry: A Concise Introduction; John Wiley
& Sons: Chichester, 2000; 400 pp. (d) Schneider, H.-J., Yatsimirsky, A.
K., Eds. Principles and Methods in Supramolecular Chemistry; Wiley:
Chichester, 2000; 349 pp. (e) Lehn, J.-M., Atwood, J. L., Davies, J. E. D.,
MacNicol, D. D., Vo¨gtle, F., Eds. ComprehensiVe Supramolecular Chem-
istry; Pergamon: Oxford, 1996; Vols. 1-11.
(6) (a) Zeng, H.; Yang, X.; Flowers, R. A.; Gong, B. J. Am. Chem. Soc. 2002,
124, 2903. (b) Yang, X. W.; Gong, B. Angew. Chem., Int. Ed. 2005, 44,
1352.
(7) (a) Nowick, J. S.; Chung, D. M. Angew. Chem., Int. Ed. 2003, 42, 1765.
(b) Chung, D. M.; Nowick, J. S. J. Am. Chem. Soc. 2004, 126, 3062.
9
10.1021/ja064218i CCC: $33.50 © 2006 American Chemical Society
J. AM. CHEM. SOC. 2006, 128, 12307-12313
12307

A R T I C L E S
Zhu et al.
Figure 1. Intermolecular hydrogen-bonding-driven self-assembly of homoduplexes, directed by the backbone preorganization.
heteroduplexes.9 To achieve high binding stability and selectiv-
ity, both strategies require preorganization and rigidity of the
backbones and binding sites of monomers, which is usually
realized by making use of intramolecular hydrogen bonding.10
Foldamers are linear molecules that are induced by nonco-
valent forces to adopt well-established secondary structures.11
Also due to its directionality and strength, hydrogen bonding
has proven itself to be highly efficient for constructing this
family of structurally unique artificial secondary structures.11
Particularly, a number of hydrogen-bonding-mediated aromatic
amide foldamers of well-defined conformations have been
assembled,12-22 some of which represent a new generation of
non-ring receptors for saccharides,21b,c alkylammoniums,21d or
encapsulation of water.22b As part of a program in hydrogen-
bonding-mediated self-assembly, we reported the construction
of a new series of planar zigzag artificial secondary structures.23
Recently we succeeded in utilizing them as rigidified backbones
to develop assembled zinc porphyrin molecular tweezers that
are able to efficiently complex fullerene and several fullerene
derivatives.24 One critical feature of the new assembled tweezers
is the predictable preorganization of their aromatic oligoamide
backbones, driven by consecutive intramolecular hydrogen
bonds. In this paper, we report that this strategy has been
successfully used to assemble two new classes of highly stable
homoduplexes by making use of the cooperative interaction of
amides, the simplest self-binding motif of hydrogen binding,
as the driving force.
(8) (a) Archer, E. A.; Sochia, A. E.; Krische, M. J. Chem. Eur. J. 2001, 7,
2059. (b) Archer, E. A.; Cauble, D. F., Jr.; Lynch, V.; Krische, M. J.
Tetrahedron 2002, 58, 721. (c) Archer, E. A.; Krische, M. J. J. Am. Chem.
Soc. 2002, 124, 5074. (d) Gong, H.; Krische, M. J. J. Am. Chem. Soc.
2005, 127, 1719.
(9) Zhao, X.; Wang, X.-Z.; Jiang, X.-K.; Chen, Y.-Q.; Li, Z.-T.; Chen, G.-J.
J. Am. Chem. Soc. 2003, 125, 15128.
Results and Discussion
Previous investigations have demonstrated that the back-
bones of oligomers 1 adopt a rigidified zigzag conformation.23
It was envisioned that iterative introduction of recogni-
tion residues at the 5-positions of the phthalic diamide
moieties of the oligomers would produce rigidified, highly
preorganized monomers which could self-assemble to generate
new zipper-styled molecular duplexes as a result of cooperative
intermolecular interactions (Figure 1). Compounds 2-7, which
possess two to four amide units, were therefore designed and
(10) Hydrogen-bonded duplexes from un-preorganized monomers have been
reported: (a) Bisson, A. P.; Carver, F. J.; Eggleston, D. S.; Haltiwanger,
R. C.; Hunter, C. A.; Livingstone, D. L.; McCabe, J. F.; Rotger, C.; Rowan,
A. E. J. Am. Chem. Soc. 2000, 122, 8856. (b) Mayer, M. F.; Nakashima,
S.; Zimmerman, S. C. Org. Lett. 2005, 7, 3005.
(11) For reviews, see: (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (b)
Stigers, K. D.; Soth, M. J.; Nowick, J. S. Curr. Opin. Chem. Biol. 1999, 3,
714. (c) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. ReV. 2001, 101, 3893. (d) Cubberley, M. S.; Iverson, B. L. Curr.
Opin. Chem. Biol. 2001, 5, 650. (e) Schmuck, C. Angew. Chem., Int. Ed.
2003, 42, 2448. (f) Huc, I. Eur. J. Org. Chem. 2004, 17. (g) Cheng, R. P.
Curr. Opin. Struct. Biol. 2004, 14, 512. (h) Sanford, A.; Yamato, K.; Yang,
X. W.; Yuan, L. H.; Han, Y. H.; Gong, B. Eur. J. Biochem. 2004, 271,
1416. (i) Licini, G.; Prins, L. J.; Scrimin, P. Eur. J. Org. Chem. 2005, 969.
(j) Stone, M. T.; Heemstra, J. M.; Moore, J. S. Acc. Chem. Res. 2006, 39,
11.
(18) (a) Hunter, C. A.; Spitaleri, A.; Tomas, S. Chem. Commun. 2005, 3691.
(b) Hu, Z.-Q.; Hu, H.-Y.; Chen, C.-F. J. Org. Chem. 2006, 71, 1131.
(19) Kanamori, D.; Okamura, T.; Yamamoto, H.; Ueyama, N. Angew. Chem.,
Int. Ed. 2005, 44, 969.
(20) Masu, H.; Sakai, M.; Kishikawa, K.; Yamamoto, M.; Yamaguchi, K.;
Kohmoto, S. J. Org. Chem. 2005, 70, 1423.
(21) (a) Wu, Z.-Q.; Jiang, X.-K.; Zhu, S.-Z.; Li, Z.-T. Org. Lett. 2004, 6, 229.
(b) 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. (c) Yi, H.-P.; Shao, X.-B.;
Hou, J.-L.; Li, C.; Jiang, X.-K.; Li, Z.-T. New J. Chem. 2005, 29, 1213.
(d) 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. (e) 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.
(22) (a) Jiang, H.; Le´ger, J.-M.; Huc, I. J. Am. Chem. Soc. 2003, 125, 3448. (b)
Garric, J.; Le´ger, J.-M.; Huc, I. Angew. Chem., Int. Ed. 2005, 44, 1954. (c)
Dolain, C.; Zhan, C.; Le´ger, J.-M.; Daniels, L.; Huc, I. J. Am. Chem. Soc.
2005, 127, 2400.
(23) Zhu, J.; Wang, X.-Z.; Chen, Y.-Q.; Jiang, X.-K.; Chen, X.-Z.; Li, Z.-T. J.
Org. Chem. 2004, 69, 6221.
(24) Wu, Z.-Q.; Shao, X.-B.; Li, C.; Hou, J.-L.; Wang, K.; Jiang, X.-K.; Li,
Z.-T. J. Am. Chem. Soc. 2005, 127, 17460.
(12) (a) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1996, 118,
7529. (b) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc.
1997, 119, 10587.
(13) (a) Corbin, P. S.; Zimmerman, S. C.; Thiessen, P. A.; Hawryluk, N. A.;
Murray, T. J. J. Am. Chem. Soc. 2001, 123, 10475. (b) Mayer, M. F.;
Nakashima, S.; Zimmerman, S. C. Org. Lett. 2005, 7, 3005. (c) Violette,
A.; A.-P., Marie C.; Semetey, V.; Hemmerlin, C.; Casimir, R.; Graff, R.;
Marraud, M.; Rognan, D.; Guichard, G. J. Am. Chem. Soc. 2005, 127, 2156.
(d) Sinkeldam, R. W.; van Houtem, M. H. C. J.; Koeckelberghs, G.;
Vekemans, J. A. J. M.; Meijer, E. W. Org. Lett. 2006, 8, 383.
(14) (a) Yang, X. W.; Martinovic, S.; Smith, R. D.; Gong, B. J. Am. Chem.
Soc. 2003, 125, 9932. (b) Yang, X. W.; Yuan, L. H.; Yamato, K.; Brown,
A. L.; Feng, W.; Furukawa, M.; Zeng, X. C.; Gong, B. J. Am. Chem. Soc.
2004, 126, 3148.
(15) Kolomiets, E.; Berl, V.; Odriozola, I.; Stadler, A.-M.; Kyritsakas, N.; Lehn,
J.-M. Chem. Commun. 2003, 2868.
(16) (a) Recker, J.; Tomcik, D.; Parquette, J. R. J. Am. Chem. Soc. 2000, 122,
10298. (b) Huang, B.; Prantil, M. A.; Gustafson, T. L.; Parquette, J. R. J.
Am. Chem. Soc. 2003, 125, 14518.
(17) Yang, D.; Li, W.; Qu, J.; Luo, S.-W.; Wu, Y.-D. J. Am. Chem. Soc. 2003,
125, 13018.
9
12308 J. AM. CHEM. SOC. VOL. 128, NO. 37, 2006

H-Bonding-Mediated Anthranilamide Homoduplexes
A R T I C L E S
Chart 1
Figure 2. Solid-state structure of compound 2, showing the dimeric binding
motif which is stabilized by eight intramolecular and six intermolecular
hydrogen bonds.
Chart 2
synthesized (Chart 1). The synthetic routes are provided in the
Supporting Information.
A crystal of compound 2 suitable for X-ray crystallographic
analysis was obtained from chloroform by slow evaporation.
As expected, in the solid state compound 2 adopted a U-shaped
planar conformation due to the formation of four intramolecular
hydrogen bonds.23,25 This preorganized conformation directed
two molecules to form a self-complementary dimeric structure.
The dimer was stabilized mainly by two intermolecular hydro-
gen bonds between the peripheral amides (NH‚‚‚O distance )
2.039 Å, NH‚‚‚O angle ) 160.6°) (Figure 2). Interestingly, the
exo amino proton (cis to the CdO oxygen) of one of its
peripheral amides also forms two weak hydrogen bonds with
the oxygen atoms of the central two amides of another molecule
(NH‚‚‚O distances ) 2.454 and 2.691 Å, NH‚‚‚O angles )
178.1 and 173.1°, respectively), which further rigidify the
planarity of the dimeric structure. The dimeric units are further
organized into an extended array through R22(8) dimerization
of the unpaired amide sites.26 Previously, it has been reported
that benzamide exists in the R22(8) dimerizing pattern in the
solid state.27 For comparison, compound 8 (Chart 2) was also
prepared (see the Supporting Information), and its solid-state
structure is provided in Figure 3. As expected, 8 dimerizes in
the R22(8) pattern, similar to that observed for benzamide. The
different self-binding pattern exhibited by compound 2 in the
solid state can be rationalized by considering two factors. First,
the R22(8) mode would produce a large cavity in the center of
the dimeric structure, which is unfavorable in the solid state in
the absence of solvent molecules. Second, the observed dimer-
izing motif possesses six hydrogen bonds, while the R22(8)
motif has only four.
1
The H NMR spectra of compounds 2 and 8 in CDCl3 are
provided in Figure 4. The NH signals of 2 have been assigned
by the NOE and gradient experiments. The amide protons of 8
display two broad signals (5.70 and 6.01 ppm, respectively) as
a result of the rotation of the amino group around the C-N
bond. In contrast, the NH2 protons of 2 exhibit two sharp signals
in the downfield area (6.38 and 8.06 ppm, respectively). These
results clearly indicate that the amide protons of 2 are involved
in much stronger intermolecular hydrogen bonding, which
decreases the rotation of the NH2 groups around its N-CO bond.
(25) Gong, B. Chem. Eur. J. 2001, 7, 4337.
Figure 3. Solid-state structure of compound 8, showing the R22(8)
dimerizing mode. The crystal was grown by slow evaporation of a
chloroform solution.
(26) Etter, M. C. Acc. Chem. Res. 1990, 23, 120.
(27) Edgar, R.; Schultz, T. M. Rasmussen, F. B.; Feidenhans, R.; Leiserowitz,
L. J. Am. Chem. Soc. 1999, 121, 632.
9
J. AM. CHEM. SOC. VOL. 128, NO. 37, 2006 12309

A R T I C L E S
Zhu et al.
Chart 3
Figure 4. Partial 1H NMR spectra (400 MHz) of (a) 8 (10 mM), (b) 2 (10
mM), and (c) 3 (3.8 mM) in CDCl3 at 25 °C.
Chart 4
Figure 5. Plot of the chemical shifts of H-a (9) and H-b (b) of 2 and H-a
(2) and H-d (1) of 3 in CDCl3 at 25 °C.
1H NMR dilution studies in CDCl3 (from 12 to 0.2 mM)
revealed important upfield shifting for the H-a signal (Figure
5). A fit of the chemical shift data to a 1:1 binding mode
afforded an association constant Kassoc of (3.0 ( 0.2) × 103
pared to the signals of the NH2 protons of 8, the H-a (8.47 ppm)
and H-b (8.30 ppm) signals of compound 3 appeared in even
more downfield (∆δ ) 2.46 and 2.29 ppm, respectively), even
at the reduced concentration. This result implies that these
protons are involved in stronger intermolecular hydrogen
bonding than the corresponding amide protons of compound 2.
Dilution of the CDCl3 solution of 3 from 5.0 to 0.2 mM did
not lead to significant shifting of the H-a and H-d signals (<0.07
ppm, Figure 5). A conservative estimate of 90% self-association
resulted in a lower Kassoc limit of 2.3 × 105 M-1 for homoduplex
3‚3.5d,32 It is reasonable to propose that this homoduplex may
also adopt a binding pattern similar to that of dimer 2‚2 (Chart
4).
M-1 28
. The value is substantially larger than the reported value
of 40 M-1 for benzamide, even in benzene of lower polarity,29,30
and shows that important cooperativity exists for the peripheral
amide units of 2 to induce the formation of the dimeric structure.
Pronounced upfield shifting was also observed for the H-b signal
upon dilution of the CDCl3 solution (Figure 5), which corre-
sponds to a Kassoc of (3.0 ( 0.3) × 102 M-1 obtained by fitting
to the data to a 1:1 binding mode. The value is remarkably
smaller than that derived from the H-a data. This discrepancy
implies that, in addition to the compact chain-dimerizing motif
2‚2 observed in the solid state (Figure 2, Chart 3), 2 may also
self-associate through an R22(8) binding pattern, as revealed for
benzamide.27 In principle, at high concentrations, homodimer
2‚2 may further self-assemble to more complicated supramo-
lecular architectures through two R22(8)-type hydrogen bonds.31
Increasing the polarity of the solvent should decrease the
1
binding stability of the duplexes. Therefore, H NMR dilution
experiments were performed for both 2 and 3 in a more polar
CDCl3/CD3CN (9:1, v/v) mixture. Fitting the data of the
chemical shift change against the concentration to a 1:1 binding
mode gave rise to Kassoc values of (8.0 ( 1.0) × 102 and (2.1
( 0.3) × 104 M-1 for duplexes 2‚2 and 3‚3, respectively. The
fact that 3‚3 is remarkably more stable than 2‚2 in both solvent
systems strongly suggests an important cooperativity of the
appended amide units in driving the formation of this series of
duplex structures and demonstrates the high efficiency of the
intramolecular hydrogen-bonding-driven preorganization of the
oligomeric backbone.
1
The H NMR spectrum of compound 3 in CDCl3 is also
provided in Figure 4. The signals of the protons of the appended
amides have been assigned by a combination of NOESY
experiments and comparison of the integrated strength. Com-
(28) (a) Conners, K. A. Binding Constants: The Measurement of Molecular
Complex Stability; Wiley: New York, 1987. (b) Wilcox, C. S. In Frontiers
in Supramolecular Organic Chemistry and Photochemistry; Schneider, H.-
J., Du¨rr, H., Eds.; VCH: New York, 1991; p 123.
Crystals of compound 4 suitable for X-ray analysis were
grown from methanol, chloroform, and benzene, respectively,
(29) Hobbs, M. E.; Bates, J. Am. Chem. Soc. 1952, 74, 746.
(30) The Kassoc of 8 could not be evaluated by 1H NMR dilution experiments
due to the low resolution of the NH2 signals.
(31) Martin, R. B. Chem. ReV. 1996, 96, 3043.
(32) Jun, H.; Steeb, J.; Kaifer, A. E. J. Am. Chem. Soc. 2006, 128, 2820.
9
12310 J. AM. CHEM. SOC. VOL. 128, NO. 37, 2006

H-Bonding-Mediated Anthranilamide Homoduplexes
A R T I C L E S
Figure 7. Solid-state structure of compound 5.
Figure 6. Solid-state structure of the crystal of 4 grown by slow evaporation
of a chloroform solution. The crystal obtained from benzene exhibits the
identical structural pattern.
by slow evaporation. The solid-state structure of the crystal of
4 obtained from polar methanol (see the Supporting Information)
revealed a linear staggered stacking pattern. The backbone of
the molecule remains planar due to the intramolecular hydrogen
bonding. Neighboring molecules are connected by one hydrogen
bond between the end amide units. The solid-state structure of
the crystal produced from chloroform of lower polarity is shown
in Figure 6, which reveals a centrosymmetric dimeric motif.
Surprisingly, the appended acetamide units adopt opposite
orientations in the solid state.33 The fact that all the acetamide
units are arranged in a straight line with identical separation
distance suggests that the structure of the monomer is perfect
for the formation of dimeric structure through consecutive
intermolecular hydrogen bonding. Single crystals of 4 were also
grown from dichloromethane of decreased size. X-ray analysis
did reveal a dimeric structure, stabilized by two intermolecular
hydrogen bonds (see the Supporting Information). What is
different for this solid structure is that the cavity of the U-shaped
monomer is filled with a dichloromethane molecule.34
The solid-state structure of compound 4 shown in Figure 6
is intriguing. To explore whether the dimeric motif is general
for this series of diamide monomers, a crystal of compound 5,
which is incorporated with one trifluoroacetamide unit, was also
grown from chloroform, and its X-ray solid-state structure is
provided in Figure 7. It can be seen that this asymmetric
molecule also self-assembled to a dimeric structure, which is
stabilized by two intermolecular hydrogen bonds. Obviously due
to the increased steric hindrance, in the dimeric structure the
two CF3 groups are located on the outside. Also notably, both
protons of the trifluoroacetamide units served as hydrogen-
Figure 8. Partial 1H NMR spectra (400 MHz) of (a) 9 (5 mM), (b) 4 (5.0
mM), (c) 5 (5.0 mM), (d) 6 (3.5 mM), (e) 7 (3.5 mM) in CDCl3, and (f) 7
(3.5 mM) in CD3CN/CDCl3 (1:9, v/v) at 25 °C.
bonding donors, which may be ascribed to their stronger acidity
relative to that of their fluorine-free counterparts.
The self-assembling behaviors of compounds 4-7 in solution
1
were then investigated. Their H NMR spectra in CDCl3 are
provided in Figure 8. The signals of all the compounds in the
downfield area have been assigned on the basis of NOESY
experiments, together with their integrated strength (for 6). Due
to the feature of structural symmetry, all the compounds
displayed relatively simple spectra. Compared to the signal of
the amide proton of 9 (7.11 ppm), the signals of all the protons
of the appended amides of 4-7 shifted substantially downfield
(∆δ ≈ 1.09-2.93 ppm), indicating that all these protons were
involved in much stronger intermolecular hydrogen bonding.
Important intermolecular NOE connections were also observed
for 4, 6, and 7 (Charts 5, 6, and 7, vide infra). Under identical
experimental conditions, no similar connections were observed
for compound 9. All these results support that stable homodu-
plexes were formed in solution for these oligomers. Charts 5
and 6 provide the proposed structures for these duplexes. With
the elongation of the oligomers, the resolution of their 1H NMR
spectrum became lower and the protons of the appended amides
of 7 displayed only two broadened signals. This result may be
(33) This result was originally ascribed to the low quality of the crystal. However,
crystals of different sizes grown from chloroform or toluene gave the
identical structural pattern. Therefore, we attribute this unexpected structural
pattern to the possibility that the opposite orientation of the ending amide
units is very similar in energy and occurs with identical probability.
(34) The two methylene units connected to the central benzenes are not resolved
in the solid structure.
9
J. AM. CHEM. SOC. VOL. 128, NO. 37, 2006 12311

A R T I C L E S
Chart 5
Zhu et al.
Figure 9. Plots of the chemical shifts of AcNH of 9 (b), AcNH of 4 (9),
NH-b (1) of 6, and NH-a of 6 (2) versus their concentration in CDCl3 at
25 °C.
probe because this proton had been revealed by X-ray analysis
(Figure 7) to be a hydrogen-bonding donor for the formation
of dimer 5‚5. The Kassoc value for dimer 4‚4 is substantially
larger than that of 9‚9, supporting that cooperativity exists for
the two acetamide units of 4 in inducing the formation of dimer
4‚4. The Kassoc of dimer 5‚5 is notably lower than that of dimer
4‚4, which may be attributed to the increased spatial hindrance
of the trifluoromethyl group relative to its fluorine-free coun-
terpart. Dilution of the CDCl3 solution of compound 6 from
8.0 to 0.2 mM did not lead to significant shifting of the NH-a
(<0.03 ppm) and NH-d (<0.07 ppm) signals. Also, by assuming
a conservative estimate of 90% association, we could obtain a
lower limit of 2.3 × 105 M-1 for the Kassoc of homoduplex 6‚6
(Chart 7).5d,32 The signals of the NH protons of the appended
acetamides of 7 in the 1H NMR spectrum in CDCl3 are of low
resolution (Figure 9e). Therefore, no useful information could
be obtained for duplex 7‚7 (Chart 7) from the 1H NMR dilution
experiments. To explore the dependence of the stability of this
series of self-assembled architectures on the length of the
Chart 6
1
monomers, H NMR dilution experiments were performed for
9, 4, 6, and 7 in the more polar CDCl3/CD3CN (9:1, v/v) mixture
(see the Supporting Information), which gave rise to Kassoc values
of <5, 80 ( 9, (1.2 ( 0.2) × 103, and (1.4 ( 0.2) × 104 M-1
for duplexes 9‚9, 4‚4, 6‚6, and 7‚7, respectively.
The association constants of the new series of amide-mediated
homoduplexes and the related free energies are summarized in
Table 1. Figure 10 provides the plot of the stability of the
homoduplexes (-∆G) against the number of binding amides.
The graph clearly shows the increase in the binding stability of
the duplexes with the elongation of the oligomeric monomers.
One general trend is that the series of CONH2-mediated duplexes
is more stable than that of the AcNH-mediated counterparts with
an identical number of binding units. This may be attributed to
the increased number of intermolecular hydrogen bonds in the
former series. It is also noteworthy that the stability of duplex
6‚6 is substantially greater than that of duplex 4‚4 and is
comparable to that of the compact and rigid DDD-AAA
binding motif, which has been reported to be most stable for
the recognition mode of three hydrogen bonds.36 We propose
attributed to the increased confinement of the rotation of these
amide units around the N-C(Ph) bond as a result of increased
binding stability of the duplexes. However, in a CDCl3/CD3-
CN (9:1, v/v) mixture of higher polarity, their 1H NMR spectra
were of high resolution, obviously due to reduced self-binding
1
affinity; the H NMR spectrum of 7 is provided in Figure 8f.
Dilution of the solution of compound 4 in CDCl3 from 25 to
0.2 mM caused significant upfield shifting of the signal of the
protons of the appended amides (Figure 9). Fitting the data of
the change of the chemical shift against the concentration to a
1:1 self-binding mode afforded a Kassoc of (2.6 ( 0.3) × 102
M-1 for dimer 4‚4. With an identical method, the Kassoc values
of dimers 9‚935 and 5‚5 in CDCl3 were determined to be ca. 10
and (1.2 ( 0.2) × 102 M-1, respectively. For the case of 5, the
signal of the NH proton of its trifluoroacetamide was used as a
(35) The analysis for 9 is based on the assumption that monomer-dimer
equilibrium is the predominant self-binding process; see ref 7 and also:
Tobe, Y.; Utsumi, N.; Kawabata, K.; Nagano, A.; Adachi, K.; Araki, S.;
Sonoda, M.; Hirose, K.; Narmura, K. J. Am. Chem. Soc. 2002, 124, 5350.
(36) Zimmerman, S. C.; Corbin, P. S. Struct. & Bonding 2000, 96, 63.
9
12312 J. AM. CHEM. SOC. VOL. 128, NO. 37, 2006

H-Bonding-Mediated Anthranilamide Homoduplexes
A R T I C L E S
Chart 7
Figure 10. Free energies of binding (-∆G) of the homoduplexes in CDCl3
(in black) and CDCl3/CD3CN (9:1, v/v) (in blue) plotted against the number
of the appended amides.
recognition residues can be preorganized at the ideal positions
for the formation of efficient intermolecular hydrogen bonding,
which leads to remarkable coorperativity. Therefore, although
the self-binding of a single amide unit is rather weak, iterative
introduction of this simple self-binding motif can give rise to a
robust force to generate duplex structures of high stability.
In the past decade, artificial secondary structures based on
aromatic amide oligomers and many other linear species have
received increasing attention. The present work well demon-
strates that incorporation of additional functional units at
rationally designed positions could produce new interesting
assembling functions. It is expected that polymeric structures
consisting of the same repeated segments will form supramo-
lecular DNA-like duplex architectures, while replacement of the
self-binding amide units with other binding residues such as
urea units should lead to the generation of artificial duplexes
of increased stability. Endeavors in these directions may
ultimately lead to the creation of nanoscale functional oligomeric
or polymeric supramolecular materials.
Table 1. Association Constants of the Homoduplexes in CDCl3 at
25 °C, Determined by the 1H NMR Dilution Method
1
duplex
Kassoc (M-
)
−∆G (kJ/mol)
2‚2
(3.0 ( 0.2) × 103
(8.0 ( 1.0) × 102
>2.3 × 105
19.8
16.6
30.6
24.6
13.8
10.9
11.9
30.6
17.6
23.6
5.7
2‚2a
3‚3b
3‚3a
4‚4
(2.1 ( 0.3) × 104
(2.6 ( 0.3) × 102
80 ( 9
4‚4a
5‚5
(1.2 ( 0.2) × 102
6‚6b
6‚6a
7‚7a
9‚9
>2.3 × 105
(1.2 ( 0.2) × 103
(1.4 ( 0.2) × 104
10
9‚9a
<5
4.0
Acknowledgment. We thank the National Natural Science
Foundation of China (Nos. 20321202, 20332040, 20372080,
20425208, and 20572126) and the Chinese Academy of Sciences
for financial support.
a In CDCl3/CD3CN (9:1, v.v). b Lower limit of value.
the consecutive hydrogen-bonding pattern to explain the in-
creased binding affinity of the longer oligomers, in which an
increase of one amide unit will increase to two the number of
intermolecular hydrogen bonds.
Supporting Information Available: Experimental Section;
method for measurement of the association constants; X-ray
crystal structure of 4 (grown from dichloromethane); 1H NMR
Conclusion
1
dilution data of 9, 4, 6, and 7 in CDCl3/CD3CN (9:1, v/v); H
Two new series of dimeric, trimeric, and/or tetrameric
homoduplexes have been developed, based on the self-recogni-
tion of the amide units, the simplest motif of the hydrogen-
bonding-driven self-assembly. The most important feature for
the self-assembly of the new series of homoduplexes is the
accurate control of the anthranilamide backbones by consecutive
stable intramolecular hydrogen bonding. As a result, all the
NMR dilution spectra of 6 in CDCl3; 2D NOESY spectra of 2,
3, 4, 6, and 7 in CDCl3; and crystallographic information (CIF
files) on 2, 4, 5, and 8 and three related compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA064218I
9
J. AM. CHEM. SOC. VOL. 128, NO. 37, 2006 12313