Helical aromatic oligoamides: Reliable, readily predictable folding from the combination of rigidified structural motifs

Article abstract of DOI:10.1021/ja046858w

Factors responsible for the folding of aromatic oligoamides with backbones rigidified by local three-center H-bonds were investigated. The stability of the three-center H-bonds was quantified by the half-lives of amide proton-deuterium exchange reactions,

Full text of DOI:10.1021/ja046858w

Published on Web 11/23/2004
Helical Aromatic Oligoamides: Reliable, Readily Predictable
Folding from the Combination of Rigidified Structural Motifs
Lihua Yuan, Huaqiang Zeng, Kazuhiro Yamato, Adam R. Sanford, Wen Feng,
Hanudatta S. Atreya, Dinesh K. Sukumaran, Thomas Szyperski, and Bing Gong*
Contribution from the Department of Chemistry, Natural Sciences Complex, UniVersity at
Buffalo, The State UniVersity of New York, Buffalo, New York 14260
Received May 27, 2004; E-mail: bgong@chem.buffalo.edu
Abstract: Factors responsible for the folding of aromatic oligoamides with backbones rigidified by local
three-center H-bonds were investigated. The stability of the three-center H-bonds was quantified by the
half-lives of amide proton-deuterium exchange reactions, which show that the three-center H-bonds were
largely intact at room temperature in the oligomer examined. This result is consistent with our current and
previous 2D NMR studies. The overall helical conformation of nonamer 1 was found by variable-temperature
NOESY studies to be dynamic. As temperature rose, the end-to-end NOEs rapidly disappeared, while the
amide side chain NOEs were still readily detectable, corresponding to the “breath” and stretching of the
helix by slightly twisting the local H-bonded rings. Based on the simple repetition of the same structural
motif and local conformational preference, undecamer 2 was found to fold into well-defined helical
conformation. The predictability of the folding of these backbone-rigidified aromatic oligoamides was
demonstrated by a simple modeling method using structural parameters from oligomers with known crystal
structures. The reliability and generality of the modeling methods were shown by the excellent agreement
between the modeled structures corresponding to 1 and 2 and data from NOESY studies.
Introduction
operative action of noncovalent forces, have also resulted in
well-defined conformations.20
Many unnatural oligomers that fold into well-defined second-
ary structures have been reported since the pioneering work of
Gellman and Seebach on â-peptides.1,2 Among reported ex-
amples, foldamers adopting various helical conformations have
attracted the most attention.3-6 Helical foldamers include
â-peptides,7,8 γ-peptides9,10 δ-peptides,11,12 and peptoid oligo-
mers,13 pyridine-pyrimidine oligomers and helical polyhet-
erocyclic strands,14 helicates,15 oxapeptides,16 N,N′-linked oli-
goureas,17 and solvent-dependent helical oligo(phenylene
ethynylenes).18 Other foldamers involving unnatural backbones
were also described.19 In addition to folded oligomers, related
systems based on the combination of inter- and intramolecular
noncovalent interactions, particularly those involving the co-
We21 and others22 recently described backbone-rigidified
aromatic oligomers that fold into helical conformations. One
class of the helical foldamers developed by us involve aromatic
oligoamides whose backbones are rigidified by a novel set of
three-center intramolecular H-bonds consisting of the S(5) and
S(6) type23 hydrogen-bonded rings. The localized three-center
H-bonds, combined with rigid aromatic rings, lead to preferred,
i.e., “locked” local conformations. The combination of these
preferred local conformations results in an overall rigidified,
crescent backbone for the corresponding oligomers. The rigidi-
(13) (a) Patch, J. A.; Barron, A. E. J. Am. Chem. Soc. 2003, 125, 12092. (b)
Sanborn, T. J.; Wu, C. W.; Zuckerman, R. N.; Barron, A. E. Biopolymers
2002, 63, 12. (c) Wu, C. W.; Sanborn, T. J.; Huang, K.; Zuckermann, R.
N.; Barron, A. E. J. Am. Chem. Soc. 2001, 123, 6778. (d) Armand, P.;
Kirshenbaum, K.; Goldsmith, R. A.; Farr-Jones, S.; Barron, A. E.; Truong,
K. T.; Dill, K. A.; Mierke, D. F.; Cohen, F. E.; Zuckermann, R. N.; Bradley,
E. K. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 4309. (e) Kirshenbaum, K.;
Barron, A. E.; Goldsmith, R. A.; Armand, P.; Bradley, E. K.; Truong, K.
T.; Dill, K. A.; Cohen, F. E.; Zuckermann, R. N. Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 4303.
(14) (a) Cuccia, L. A.; Ruiz, E.; Lehn, J.-M.; Homo, J.-C.; Schmutz, M. Chem.-
Eur. J. 2002, 8, 3448. (b) Cuccia, L. A.; Lehn, J.-M.; Homo, J.-C.; Schmutz,
M. Angew. Chem., Int. Ed. 2000, 39, 233. (c) Ohkita, M.; Lehn, J.-M.;
Baum, G.; Fenske, D. Chem. Eur. J. 1999, 5, 3471. (d) Hanan, G. S.; Lehn,
J.-M.; Kyritsakas, N.; Fischer, J. J. Chem. Soc., Chem. Commun. 1995,
765.
(15) (a) Garrett, T. M.; Koert, U. Lehn, J.-M.; Rigault, A.; Meyer, D.; Fischer,
J. J. Chem. Soc., Chem. Commun. 1990, 557. (b) Lehn, J. M. Supramo-
lecular Chemistry; VCH: Weinheim, Germany, 1995, and references
therein. (c) Lehn, J.-M.; Rigault, A. Angew. Chem., Int. Ed. 1988, 27, 1095.
(16) (a) Yang, D.; Qu, J.; Li, B.; Ng, F.-F. Wang, X.-C.; Cheung, K.-K.; Wang,
D.-P.; Wu, Y.-D. J. Am. Chem. Soc. 1999, 121, 589. (b) Wu, Y. D.; Wang,
D. P.; Chan, K. W. K.; Yang, D. J. Am. Chem. Soc. 1999, 121, 11189.
(17) Semetey, V.; Rognan, D.; Hemmerlin, C.; Graff, R.; Briand, J. P.; Marraud,
M.; Guichard, G. Angew. Chem., Int. Ed. 2002, 41, 1893.
(1) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman,
S. H. J. Am. Chem. Soc. 1996, 118, 13071.
(2) Seebach, D.; Overhand, M.; Ku¨hnle, F. N. M.; Martinoni, B.; Oberer, L.;
Hommel, U.; Widmer, H. HelV. Chim. Acta 1996, 79, 913.
(3) Sanford, A. R.; Gong B. Curr. Org. Chem. 2003, 7, 1649.
(4) Gong, B. Chem. Eur. J. 2001, 7, 4336.
(5) Huc, I. Eur. J. Org. Chem. 2004, 17.
(6) Rowan, A. E.; Nolte, R. J. M. Angew. Chem., Int. Ed. 1998, 37, 63.
(7) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
(8) Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015.
(9) (a) Hanessian, S.; Luo, X. H.; Schaum, R.; Michnick, S. J. Am. Chem.
Soc. 1998, 120, 8569. (b) Hanessian, S.; Luo, X. H.; Schaum, R.
Tetrahedron Lett. 1999, 40, 4925.
(10) Seebach, D.; Brenner, M.; Rueping, M.; Jaun, B. Chem. Eur. J. 2002, 8,
573.
(11) Szabo, L.; Smith, B. L.; McReynolds, K. D.; Parrill, A. L.; Morris, E. R.;
Gervay, J. J. Org. Chem. 1998, 63, 1074.
(12) (a) Hungerford, N. L.; Claridge, T. D. W.; Watterson, M. P.; Aplin, R. T.;
Moreno, A.; Fleet, G. W. J. J. Chem. Soc., Perkin Trans. 1 2000, 3666.
(b) Brittain, D. E. A.; Watterson, M. P.; Claridge, T. D. W.; Smith, M. D.;
Fleet, G. W. J. J. Chem. Soc., Perkin Trans. 1 2000, 3655.
9
16528
J. AM. CHEM. SOC. 2004, 126, 16528-16537
10.1021/ja046858w CCC: $27.50 © 2004 American Chemical Society

Helical Aromatic Oligoamides
A R T I C L E S
fied backbone forces an oligomer of a sufficient length to adopt
a helical conformation containing a large, hydrophilic interior
cavity. Our previous results revealed that the helical conforma-
tion was present both in solution and in solid state. The folded
structures were independent of the nature of the side chains
carried by the corresponding oligomers. Despite their rigidity,
the folded conformations of these oligoamides are effected by
reversible intramolecular H-bonding interactions. These oligo-
mers are therefore true foldamers that should undergo dynamic
exchange between folded and partially folded (or even unfolded)
states as environmental factors such as temperature and solvent
change. To use these backbone-rigidified folding oligomers as
reliable, shape-persistent molecular building blocks for con-
structing large nanostructures, it is necessary to understand the
stability of their folded conformations. For example, although
we previously found that the three-center H-bonds were
stabilized by positive cooperativity, it is still not clear how these
three-center H-bonds, which play the critical role of defining
the local conformational preference, would differ in their
stabilities when placed in different locations along the backbone
of a folded oligomer. What is the effect of temperature change
on the overall folded conformation of an oligomer? Another
concern about these oligomers is related to their H-bond-
rigidified backbones. Is it possible that in long oligomers, the
steric hindrance becomes so severe that some of the backbone-
rigidifying intramolecular H-bonded rings will be broken,
leading to interruption of the H-bonded crescent and helical
conformations? Finally, since long oligomers are constructed
by simple repetition of the same structural motif and local
conformational preference, is it possible to accurately predict
the folded conformations of long oligomers based on structural
data from their shorter homologues?
In this paper, we first describe a method for quantifying the
stability of the local three-center H-bonds based on the deter-
mination of the half-lives of amide proton-deuterium exchange.
We then investigate the effect of temperature changes on the
folded helical conformation of nonamer (9-mer) 1. To probe
the effect of chain length on folded conformations, we synthe-
sized and characterized undecamer (11-mer) 2. Results from
extensive NMR studies suggest that this longer oligomer still
adopts H-bond enforced, helical conformations. Finally, we have
developed a modeling method for predicting the folded struc-
tures of oligomers 1b and 2b based on data from the crystal
structures of short oligoamides. The reliability of the modeled
structures was shown by their excellent agreement with results
from two-dimensional (2D) nuclear Overhauser enhancement
spectroscopy (NOESY) studies.
(18) (a) Goto, H.; Heemstra, J. M.; Hill, D. J.; Moore, J. S. Org. Lett. 2004, 6,
889. (b) Heemstra, J. M.; Moore, J. S. Org. Lett. 2004, 6, 659. (c) Heemstra,
J. M.; Moore, J. S. J. Am. Chem. Soc. 2004, 126, 1648. (d) Stone, M. T.;
Moore, J. S. Org. Lett. 2004, 6, 469. (e) Oh, K.; Jeong, K. S.; Moore, J. S.
J. Org. Chem. 2003, 68, 8397. (f) Cary, J. M.; Moore, J. S. Org. Lett.
2002, 4, 4663. (g) Matsuda, K.; Stone, M. T.; Moore, J. S. J. Am. Chem.
Soc. 2002, 124, 11836. (h) Zhao, D. H.; Moore, J. S. J. Am. Chem. Soc.
2002, 124, 9996. (i) Hill, D. J.; Moore, J. S. Proc. Natl. Acad. Sci. U.S.A.
2002, 99, 5053. (j) Tanatani, A.; Hughes, T. S.; Moore, J. S. Angew. Chem.,
Int. Ed. 2001, 41, 325. (k) Oh, K.; Jeong, K. S.; Moore, J. S. Nature 2001,
414, 889. (l) Prince, R. B.; Moore, J. S.; Brunsveld, L.; Meijer, E. W.
Chem.-Eur. J. 2001, 7, 4150. (m) Brunsveld, L.; Meijer, E. W.; Prince, R.
B.; Moore, J. S. J. Am. Chem. Soc. 2001, 123, 7978. (n) Tanatani, A.;
Mio, M. J.; Moore, J. S. J. Am. Chem. Soc. 2001, 123, 1792. (o) Lahiri, S.;
Thompson, J. L.; Moore, J. S. J. Am. Chem. Soc. 2000, 122, 11315. (p)
Mio, M. J.; Prince, R. B.; Moore, J. S.; Kuebel, C.; Martin, D. C. J. Am.
Chem. Soc. 2000, 122, 6134. (q) Yang, W. Y.; Prince, R. B.; Sabelko, J.;
Moore, J. S.; Gruebele, M. J. Am. Chem. Soc. 2000, 122, 3248. (r) Prince,
R. B.; Barnes, S. A.; Moore, J. S. J. Am. Chem. Soc. 2000, 122, 2758. (s)
Prest, P. J.; Prince, R. B.; Moore, J. S. J. Am. Chem. Soc. 1999, 121, 5933.
(t) Prince, R. B.; Saven, J. G.; Wolynes, P. G.; Moore, J. S. J. Am. Chem.
Soc. 1999, 121, 3114. (u) Gin, M. S.; Yokozawa, T.; Prince, R. B.; Moore,
J. S. J. Am. Chem. Soc. 1999, 121, 2643. (v) Prince, R. B.; Okada, T.;
Moore, J. S. Angew. Chem., Int. Ed. 1999, 38, 233. (w) Nelson, J. C.;
Saven, J. G.; Moore, J. S.; Wolynes, P. G. Science 1997, 277, 1793.
(19) (a) Gabriel. G. J.; Iverson, B. L. J. Am. Chem. Soc. 2002, 124, 15174. (b)
Zych, A. J.; Iverson, B. L. J. Am. Chem. Soc. 2000, 122, 8898. (c) Nguyen,
J. Q.; Iverson, B. L. J. Am. Chem. Soc. 1999, 121, 2639. (d) Lokey, R. S.;
Iverson, B. L. Nature 1995, 375, 303. (e) Nowick, J. S.; Cary, J, M.; Tsai,
J. H. J. Am. Chem. Soc. 2001, 123, 5176. (f) Nowick, J. S.; Mahrus, S.;
Smith, E. M.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 1066. (g) Hagihara,
M.; Anthony, N. J.; Stout, T. J.; Clardy, J.; Schreiber, S. L. J. Am. Chem.
Soc. 1992, 114, 6568. (h) Gennari, C.; Salom, B.; Potenza, D.; Williams,
A. Angew. Chem., Int. Ed. Engl. 1994, 33, 2067. (i) Cho, C. Y.; Moran, E.
J.; Cherry, S. R.; Stephans, J. C.; Fodor, S. P.; Adams, C. L.; Sundaram,
A.; Jacobs, J. W.; Schultz, P. G. Science 1993, 261, 1303. (j) Smith, A. B.,
III; Keenan, T. P.; Holcomb, R. C.; Sprengeler, P. A.; Guzman, M. C.;
Wood, J. L.; Carroll, P. J.; Hirschmann, R. J. Am. Chem. Soc. 1992, 114,
10672. (k) Winkler, J. D.; Piatnitski, E. L.; Mehlmann, J.; Kasparec, J.;
Axelsen, P. H. Angew. Chem., Int. Ed. 2001, 40, 743. (l) Jones, T. V.;
Blatchly, R. A.; Tew, G. N. Org. Lett. 2003, 5, 3297.
(20) (a) Zeng, H. Q.; Yang, X. W.; Brown, A. L.; Martinovic, S.; Smith, R. D.;
Gong, B. Chem. Commun. 2003, 1556. (b) Zeng, H. Q.; Ickes, H.; Flowers,
R. A.; Gong, B. J. Org. Chem. 2001, 66, 3574. (c) Zeng, H. Q.; Yang, X.
W.; Flowers, R. A.; Gong, B. J. Am. Chem. Soc. 2002, 124, 2903. (d)
Hirschberg, J. H. K. K.; Brunsveld, L.; Ramzi, A.; Vekemans, J. A. J. M.;
Sijbesma, R. P.; Meijer, E. W. Nature 2000, 407, 167. (e) Prins, L. J.; De
Jong, F.; Timmerman, P.; Reinhoudt, D. N. Nature 2000, 408, 181.
(21) (a) 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.
(b) Yang, X. W.; Martinovic, S.; Smith, R. D.; Gong, B. J. Am. Chem.
Soc. 2003, 125, 9932. (c) 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. (d) Gong, B.; Zeng, H. Q.; Zhu,
J. Yuan L. H.; Han, Y. H.; Cheng, S. Z.; Furukawa, M.; Parra, R. D.;
Kovalevsky, A. Y.; Mills, J. L.; Skrzypczak-Jankun, E.; Martinovic, S.;
Smith, R. D.; Zheng, C.; Szyperski, T.; Zeng, X. C. Proc. Natl. Acad. Sci.
U.S.A. 2002, 99, 11583. (e) Parra, R. D.; Zeng, H. Q.; Zhu, J.; Zheng, C.;
Zeng, X. C.; Gong, B. Chem.-Eur. J. 2001, 7, 4352. (f) Parra, R. D.;
Furukawa, M.; Gong, B.; Zeng. X. C. J. Chem. Phys. 2001, 115, 6030. (g)
Parra, R. D.; Gong, B.; Zeng. X. C. J. Chem. Phys. 2001, 115, 6036. (h)
Zhu, J.; Parra, R. D.; Zeng, H.; Skrzypczak-Jankun, E.; Zeng, X. C.; Gong,
B. J. Am. Chem. Soc. 2000, 122, 4219.
(22) (a) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1997, 119,
10587. (b) Berl, V.; Khoury, R. G.; Huc, I.; Krische, M. J.; Lehn, J.-M.
Nature 2000, 407, 720. (c) Huc, I.; Maurizot, V.; Gornitzka, H.; Leger, J.
M. Chem. Commun. 2002, 578. (d) Jiang, H.; Leger, J. M.; Huc, I. J. Am.
Chem. Soc. 2003, 125, 3448. (e) Jiang, H.; Le´ger, J.-M.; Dolain, C.;
Guionneau, P.; Huc, I. Tetrahedron 2003, 59, 8365. (f) Jiang, H.; Dolain,
C.; Leger, J. M.; Gornitzka, H.; Huc, I. J. Am. Chem. Soc. 2004, 126, 1034.
(23) Berstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1555.
Results and Discussion
Synthesis. The synthesis of nonamer 1a was reported by us
before.21d Nonamer 1 was synthesized on the basis of the same
procedures for synthesizing 1a and other similar 9-mers. The
symmetrical 11-mer 2, consisting of a central isophthalic acid
residue and two identical oligoamide “arms”, was synthesized
on the basis of a convergent route by coupling the corresponding
4,6-disubstituted isophthaloyl chlorides with the amino-
terminated pentamer (Scheme 1a). Hexamer 2a was similarly
prepared by acylating the amino-terminated pentamer with
9
J. AM. CHEM. SOC. VOL. 126, NO. 50, 2004 16529

A R T I C L E S
Scheme 1
Yuan et al.
2-methoxybenzoyl chloride. The amino oligoamides were
synthesized by stepwise (C-to-N) coupling of the corresponding
monomer building blocks on the basis of acid chloride chemistry
(Scheme 1b). The yield of each amide formation step ranged
from 72 to 87%. Except for the first aniline residue, the other
monomers were incorporated via nitrobenzoic acid chlorides.
The resulting nitro-terminated oligoamide intermediates were
hydrogenated (Pd/C) into the corresponding amino-terminated
analogues, which were then subjected to the next coupling step.
Hydrogenation of the nitro-terminated oligoamides was usually
carried out at 40-55 °C under pressure (4 Pa) in chloroform/
ethanol (2:1) for 4 h.
Amide Proton-Deuterium Exchange. Previous NOESY
studies on our folding aromatic oligoamides clearly demon-
strated the presence and persistence of the three-center H-bonds
that played the critical role in enforcing the local conformational
preference on the repeating structural motifs.21d,e,h To quanti-
tatively measure the stability of these three-center H-bonds,
H-D exchange experiments were performed on the previously
characterized nonamer (9-mer) 1a21d and dimers 3, 3a, and 3b.21e
The half-lives of H-D exchange for the amide protons are
indicated in Figure 1. Consistent with the greatly enhanced
stability of its corresponding three-center H-bond, dimer 3
showed a much longer half-life of amide H-D exchange than
dimers 3a and 3b, each containing only two-center H-bonds.
Dimer 3a, with a six-membered H-bonded ring, was found to
be slightly more resistant toward H-D exchange than 3b with
a five-membered H-bonded ring. The amide protons of 1a
showed half-lives of H-D exchange that were comparable or
much longer than that of 3, indicating that all of the amide
protons in 1a were involved in strong three-center H-bonding.
The existence of three-center H-bonds suggests that each of the
amide linkages in 9-mer 1a was rigidified, enforcing a confor-
mational preference that results in a tapelike, helical backbone.
The half-lives of H-D exchange also provided a convenient
comparison on the relative stabilities of the individual three-
center H-bonds. For example, amide proton d of 1a was found
to exchange more easily than the other amide protons, indicating
that the corresponding amide group was the weak point along
the backbone of this 9-mer. This is consistent with both the
crystal structure of a similar 9-mer previously determined by
us and the results from theoretical calculations on an oligomer
Figure 1. Half-lives of amide proton-deuterium exchange based on 1D NMR experiments (500 MHz, CDCl3/DMSO-d7/D2O ) 2:19:19).
9
16530 J. AM. CHEM. SOC. VOL. 126, NO. 50, 2004

Helical Aromatic Oligoamides
A R T I C L E S
Figure 2. (a) Two identical end-to-end NOEs (red arrows) of 1 followed by variable-temperature NOESY experiments (2 mM in CDCl3; 500 MHz; mixing
time, 140-500 ms). (b) The results show a rapid decrease in the intensity of the end-to-end NOEs as temperature rises.
involving a central isophthalic acid residue.21d The ability to
follow the strength of an individual three-center H-bond should
also facilitate studies on the inermolecular stacking interaction
of these folding aromatic oligoamides.
is that IMe‚‚‚b1 will be affected by temperature-dependent
conformational changes that cause the Me‚‚‚b1 distance to
change. As temperature rises, it is expected that the helical
conformation of 1 will become increasingly dynamic, due to
the temperature-dependent changes associated with the torsional
angles of each of the numerous amide-aryl single bonds.
Correspondingly, the average distance between the protons Me
and b1 will also fluctuate more rapidly at higher temperatures.
As a result, IMe‚‚‚b1 will decrease rapidly and the ratio IMe‚‚‚b1/I0
will reflect the corresponding conformational dynamics. Indeed,
results from NOESY experiments (500 MHz, in CDCl3)
indicated that the NOEs between protons Me and b1 diminished
rapidly as temperature rose from 0 to 21 °C. This end-to-end
(Me‚‚‚b1) contact disappeared completely when temperature
rose above 30 °C. As shown in Figure 2b, the ratio IMe‚‚‚b1/I0 at
21 °C is less than 10% of that at 0 °C. Considering that the
measured intensity of I0 at 21 °C is still 78% of that measured
at 0 °C, the decrease of the intensity of IMe‚‚‚b1 at elevated
temperatures was very dramatic and indicated the dynamic
nature of the helical conformation of 1, which is equivalent to
an increase in the average distance between the protons and
reflects the “breath” and elongation of the helix.
Variable-Temperature 2D NMR (NOESY) Experiments.
The effect of temperature on the folded conformation of 1 was
investigated by variable-temperature NOESY experiments. The
end methyl group (Me) serves as a convenient spectroscopic
label for assigning the 2D NMR spectra. Results from our
previous studies on similar symmetrical nonamers indicated that
the two identical NOE contacts between the protons of the end
methyl group and aromatic proton b1 could serve as a direct
indicator for the corresponding helical conformation.21d Indeed,
an obvious NOE between protons of Me and proton b1 was
observed in the NOESY spectrum of 1 (Figure 2a). To examine
the dynamic nature of the folded conformation of 1, the
temperature-dependent changes of the intensity of Me‚‚‚b1
contact were followed.
Due to the influence of factors such as temperature and
mixing time on the NOE intensities (integrated volumes) of a
specific contact, NOEs measured at different temperatures
cannot be directly compared. To correlate the changes of NOE
intensities with conformational mobility or flexibility, the
average intensity (I0) of the NOEs between protons Me and their
neighboring aromatic protons a1 and a2 was chosen as the
internal standard:
The temperature-dependent conformational flexibility of 1 is
further confirmed by examining the NOEs between amide
protons a and c with their adjacent ether side chains. Two sets
of NOEs associated with proton a or c were monitored: one
set (IS(6)) are those between the amide proton and the methyl or
R-methylene protons of the side chains involved in the six-
IMe‚‚‚a1 + IMe‚‚‚a2
I0 )
membered H-bonded rings (Figure 3a), and the other set (IS(5)
)
2
are those between the amide hydrogen and the methyl or
R-methylene protons of the chains involved in the five-
membered H-bonded rings (Figure 3b). The temperature-
dependent trend revealed by the amide group-side chain
contacts is consistent with that of the end-to-end contact: the
relative NOE intensities (I/I0) dropped as temperature rose,
suggesting that the helical conformation became increasingly
dynamic as temperature rose. However, compared to the end-
to-end NOE (IMe‚‚‚b1), the localized amide-side chain NOEs
(IS(6) and IS(6)) decreased much more slowly. For example, at
30 °C, IS(5) and IS(6) could still be clearly detected, while IMe‚‚‚b1
completely disappeared. It is also noticeable that IS(6) decreased
more slowly than IS(5), suggesting the S(5) ring is the weaker
of the two two-center components in a three-center H-bond.
Since the average distances between the Me protons and protons
a1 and a2 are fixed in the covalent structure, any observed
changes of I0 from NMR experiments carried out in the same
solvent should be due to experimental conditions, such as
temperature and mixing times. Thus, any NOE (I) measured
simultaneously with I0 should be subjected to the same influence
of experimental conditions. Comparing the ratio I/I0 measured
at various temperatures and mixing times should provide a more
accurate indicator for any conformation-dependent changes in
I.
If the distance between protons Me and b1 were unaffected
by temperature, the ratio IMe‚‚‚b1/I0 would remain largely
unchanged as temperature varies. A much more likely scenario
9
J. AM. CHEM. SOC. VOL. 126, NO. 50, 2004 16531

A R T I C L E S
Yuan et al.
Figure 3. Temperature-dependent changes of the relative intensities of the NOEs between amide proton a or c and the protons on its neighboring side
chains.
Thus, the temperature-dependent changes of the measured
I/I0 values were fully consistent with the H-bond-enforced,
helical conformation of nonamer 1: the end-to-end (Me‚‚‚b1)
contact was affected by the accumulative effect of conforma-
tional changes that resulted from all of the local H-bonded rings
and was thus the most sensitive. At elevated temperatures, the
less stable S(5) type intramolecularly hydrogen bonded rings
were twisted more easily than the more stable S(6) type rings.
As temperature kept rising, the N-Ph bond, as part of the S(5)
ring, was the first to rotate freely, which should eventually lead
to a completely random coil conformation of nonamer 1. Given
the fact that, as temperature rises, the end-to-end NOE disap-
pears much more rapidly than the amide proton-side chain
contacts, the helical structure of 1 probably breathes and extends
such as a spring as the H-bonded rings distort.
and the strong intermolecular aromatic stacking interactions of
2 due to its large aromatic surfaces.
1
(2) Two-Dimensional H NMR Spectroscopy (NOESY).
The conformation of 11-mer 2 was characterized by NOESY
studies. The presence of the three-center H-bonds along the
backbone of 2 should be revealed by three NOE contacts
between each of the amide protons and the protons on its
adjacent side chains. The three NOEs include one with the
methoxy and two with the (R and â) methylene groups (Figure
1
5). Although the methoxy and O-methylene H NMR signals
cannot be clearly assigned due to the overlap of signals, three
of the five amide proton NMR signals of 2 are well-resolved,
which should lead to well-separated NOE cross-peaks in the
2D spectrum. Figure 5 shows the partial NOESY spectrum
corresponding to the amide-alkoxy side chain NOEs of 2. For
the well-resolved amide protons a, b, and e, the expected NOEs
were clearly detected. Each of protons b and e exhibited three
well-separated cross-peaks with the OCH3 and OCH2 regions.
Proton a showed two cross-peaks, one of which corresponded
to a single NOE and the other should corresponded to two NOEs
on the basis of its intensity. The signals of protons b and d,
which are placed in very similar environments, partially
overlapped. Correspondingly, three intense NOE cross-peaks
for b and d were detected. The intensity of these NOE peaks,
by comparing to those of the well-resolved protons b and e,
suggested that each of these three cross-peaks corresponded to
two overlapped NOEs, consistent with the overlap of the b and
d signals. Thus, the observed NOEs between each of the amide
protons of 2 and its neighboring protons on the two adjacent
side chains are fully consistent with the presence of the three-
centered H-bonds that rigidified the amide groups, which in turn
should lead to an overall curved and helical conformation of 2.
Characterization of 11-mer 2. To probe whether an oligomer
longer than nonamers can still fold into a helical structure, we
designed and synthesized 11-mer 2.
1
(1) One-Dimensional H NMR Spectroscopy. The assign-
ments of the 1D 1H NMR spectrum of 2 and hexamer 2a were
aided by the COSY and NOESY spectra of these two oligomers.
Figure 4 shows that the partial 1D NMR spectra of 2 and 2a
correspond to the range containing the amide and aromatic
signals. The presence of sharp signals in both spectra is
consistent with the well-defined and stable conformations
adopted by these two oligomers. Although 2 and 2a have the
same residues that are connected in the same order, compared
to those of 2a, which can be regarded as half of 2, the 1H NMR
signals of 2 are more widely dispersed. For example, the signals
of the five interior aromatic protons of 2, Ha1 to Hf1, are
completely resolved. This confirms that 2 adopts a folded
conformation that places its amide and aromatic protons in
microenvironments different from those in 2a. Most of the amide
and aromatic signals of 2 shifted to upfield positions as
compared to those of 2a, which may be due to both the
intramolecularly overlapped (or stacked) residues (see below)
While the presence of strong NOEs between the amide
protons and those of their neighboring side chains provided
direct evidence for a H-bond rigidified backbone of 2, the most
conclusive evidence for the adoption of a helical conformation
9
16532 J. AM. CHEM. SOC. VOL. 126, NO. 50, 2004

Helical Aromatic Oligoamides
A R T I C L E S
1
Figure 4. One-dimensional H NMR spectra (600 MHz spectrometer equipped with a cryogenic probe, 0.30 mM in 15:85 CDCl3/DMF-d7, 278 K) of (a)
nonamer 2 and (b) hexamer 2a.
by 2 would be the presence of NOEs between protons on remote
residues. The above variable-temperature NOESY experiments
on nonamer 1 indicated that, to detect any end-to-end (remote)
NOEs, the NOESY experiments need to be carried out at low
temperatures. Therefore, the same experimental conditions,
which involved room temperature, used to detect the amide-
side chain NOEs (Figure 5) were not suitable for studying NOEs
between remote protons of 2. The NOESY experiments were
then carried out on a 600 MHz NMR spectrometer at 5 °C. In
the resultant NOESY spectrum, the amide and end methyl (Me)
protons of 2 were followed to reveal NOEs between nonadjacent
protons. These protons were chosen because their signals
appeared at positions that were well-separated from those of
other protons in the 1D NMR spectrum of 2. As shown in Figure
6, three sets of NOEs were clearly detected for 2: one set
between amide protons a and b, another between a and aromatic
proton c2, and the third between the protons of the end methyl
(Me) group and amide proton d. In contrast, similar NOESY
study on the reference compound 2a, which can be regarded as
half of 2, failed to reveal any of the NOEs between the
corresponding protons. Therefore, these NOEs revealed in the
NOESY spectra of 2 were the result of the approach of the two
termini of 2, which clearly indicated a folded helical conforma-
tion that brought the otherwise remote ends into close proximity.
Computer Modeling. We previously determined the crystal
structures of a number of crescent oligoamides from dimer 5
up to 9-mer 9 (Figure 7a).20d,h The crystal structures of these
oligomers provided several sets of parameters, such as bond
lengths, bond angles, dihedral angles, and internuclear distances
that can serve as structural constraints. On the basis of these
parameters, we decided to develop a simple modeling method
that may be generally applicable to the prediction of the folded
structures of other homologous oligoamides. Such a modeling
method would be particularly helpful in predicting the folded
structures of long oligomers that are otherwise difficult to
characterize by high-resolution methods such as 2D NMR or
X-ray crystallography due to signal overlap or the difficulty of
growing single crystals. Among the numerous parameters that
can be chosen, the distances between the exterior (dexterior) and
interior (dinterior) aromatic carbons of two neighboring meta-
linked benzene rings were tested as distance constraints (Figure
7b). Restraining these two distances in a modeled structure is a
direct reflection of the rigidifying effect of the localized three-
center H-bonds, which lead to crescent, tapelike backbones.
9
J. AM. CHEM. SOC. VOL. 126, NO. 50, 2004 16533

A R T I C L E S
Yuan et al.
Figure 5. Amide proton-side chain NOEs revealed by the NOESY spectrum of 2 (500 MHz; 0.3 mM in 15:85 CDCl3/DMF-d7; 298 K; mixing time,
0.4 s).
Specifically, by measuring the two distances based on the
crystal structures of oligomers 5-9, average values of 7.812
and 5.384 Å were found for dexterior and dinterior, respectively.
Similar to the calculation of protein structures based on NOE
data, “randomly” folded, H-bond-rigidified starting helical
structures were first generated for 9-mer 1b and 11-mer 2b,
respectively, on the basis of the default structural parameters
provided by the modeling program ChemBats3D. These two
structures, with all of their side groups being methyl, correspond
to the backbones of oligomers 1 and 2 described above. The
three helical structures were constrained by setting all of the
dexterior and dinterior with the corresponding average values. The
constrained structures were then optimized (MM3 force filed)
using the software Cache 3.2, which led to energy-minimized
structures as shown in Figure 8. All three computed structures
exhibit a helical pitch between 3.5 and 3.6 Å, an interior cavity
of ∼10 Å across, and about seven residues for a helical turn.
These results were consistent with the crystal structure of 9-mer
9 and thus supported the validity of this modeling method.
The reliability of the modeling method was verified by
comparing the modeled helical structure of 1b and 2b with the
experimentally determined remote NOEs for 1 and 2.
For 9-mer 1 and other 9-mers with the same backbones, an
NOE contact between the end methyl (Me) and the second
interior aromatic proton b1 have been consistently observed in
their NOESY spectra. This Me‚‚‚b1 contact provides direct
evidence for a helical conformation adopted by 1 in solution
and, at the same time, suggests that the protons of the end methyl
groups and the two protons b1 are brought into close proximity
by the folded structure. Indeed, in the modeled structure of 1b,
the protons Me and b1 were found to be the closest among
others, with a shortest distance of 3.8 Å and an average of 4.6
Å. Thus, protons Me and b1 were in close proximity for an
NOE to be readily detected. In addition, the modeled structure
Table 1. Comparison of Internuclear Distances and the Intensities
of the Corresponding Remote NOEs
internuclear contact
Me‚‚‚Hd
Ha‚‚‚Hb
Ha‚‚‚Hc2
H‚‚‚H distancea (Å)
5.513 (av)
4.437 (shortest)
311.3
4.843
4.398
NOE intensityb (integrated vol)
relative NOE intensity
760.3
2.4
1122.0
3.6
1.0
a Based on the modeled structure of 2b. b From the NOESY spectrum
of 2.
also indicates that one of the three Me protons was 4.16 Å away
from amide proton b and the other two Me protons were 5.5
and 5.8 Å away from proton b. This suggest that an NOE may
be detected between protons Me and b1. This NOE, in addition
to the Me‚‚‚b1 contact, was indeed found in the NOESY
spectrum of a previously characterized nonamer that differs from
1 only in its side groups.20d All other nonadjacent groups of
protons in the modeled structure of 1b were found to be too far
away for any NOEs to be detected, which was also consistent
with results from NOESY studies on 1 and other nonamers.
The intensities of the three remote NOEs observed for 11-
mer 2 showed excellent correlation with the corresponding
internuclear distances revealed by the modeled structure of 2b.
As shown in Table 1, among the three NOEs, the strongest is
that between protons a and c2, consistent with which is the
internuclear distance between the two protons that was found
to be the shortest on the basis of the modeled structure of 2b;
the weakest NOE and the longest (average) H‚‚‚H distance are
found for proton Me and d; and the NOE and H‚‚‚H distance
for protons a and b lies in the middle. The Me‚‚‚d average
distance of 5.513 Å suggests that there should be no detectable
NOE between these protons. However, the modeled structure
of 2b shows that one of the three methyl protons can be as
9
16534 J. AM. CHEM. SOC. VOL. 126, NO. 50, 2004

Helical Aromatic Oligoamides
A R T I C L E S
Figure 6. Long-range NOEs revealed by the NOESY spectra of 2 (600 MHz; 0.30 mM in 15:85 CDCl3/DMF-d7; 278 K; mixing time, 400 ms). The
corresponding NOEs were not detected in the NOESY spectrum of 2a recorded under the same conditions.
close as 4.437 Å away from proton d. Due to the free rotation
of the methyl-aryl bond, each of the three methyl protons can
lie transiently within distances (<5 Å) from proton d that allow
the detection of the NOE, which led to the detection of the weak
NOE detected. Thus, the modeled, folded structure of 2b
reflected and explained the observed remote NOEs for 2 rather
accurately.
The above comparison between the remote NOEs and
modeled internuclear distances clearly showed the reliability
of this simple modeling method. We believe it was the well-
defined, repetitive backbone structures of our crescent oligo-
amides that allowed the success modeling of their conformations.
The constrained structure of an oligomer based on the average
internuclear distances obtained from the crystal structures of
short oligomers should represent the average of a series of
dynamic conformations of the corresponding oligomer. Such
an averaged conformation is in fact the one measured by NMR
in solution. Thus, the modeled structure should be particularly
useful for the explanation or prediction of structural data
obtained from 2D NMR experiments, as already being demon-
strated above. By extracting structural parameters from the
crystal structures of short oligomers, the concept as illustrated
by this simple modeling method should be applicable not only
to our backbone-rigidified oligoamides but also to other systems
of backbone-rigidified foldamers.
Conclusions
In this paper, the persistence of the three-center H-bonds that
play the critical role in maintaining the overall folded conforma-
tion of the aromatic oligoamides developed by us has been
demonstrated by amide H-D exchange. This method not only
serves to quantify the strength of the three-center H-bonds but
also provides a convenient measurement of the relative stability
of individual three-center H-bonds located at different positions
along the backbone of an oligomer. The reliability of the three-
center H-bonds leads to well-defined, stably folded, and yet
dynamic oligoamide backbones as revealed by 2D NMR. The
fact that NOEs between an amide proton and those of its
adjacent side chains can be detected even at elevated temperature
support the persistence of the three-center H-bonds. Compared
to amide-side chain NOEs, the much more rapid disappearance
of end-to-end NOEs at elevated temperatures suggests that the
distortion of the H-bonded rings associated with each amide
group allows the helical structure of the nonamer to extend and
breathe like a spring. The numerous remote NOEs detected in
the NOESY spectrum of the undecamer demonstrates that longer
9
J. AM. CHEM. SOC. VOL. 126, NO. 50, 2004 16535

A R T I C L E S
Yuan et al.
Figure 7. On the basis of (a) the previously determined crystal structures of oligomers 5-9, determination of the average values (b) of distances dexterior
and dinterior
.
Figure 8. Energy-minimized structures of (a) 9-mer 1b and (b) 11-mer 2b. The protons that are involved in remote NOE contacts revealed by the NOESY
spectra of 1 and 2 are indicated in green. Except for the indicated and amide protons, all other protons are removed for clarity. The structures were optimized
by restraining the distances dexterior and dinterior using their corresponding average values obtained from oligomers with known crystal structures (see
Figure 8).
MHz). Tetramethylsilane (TMS) or deuterated solvent DMSO-d6 was
used as the internal standard for 1H NMR. Chemical shifts are reported
in parts per million values downfield from tetramethylsilane, and J
values are reported in hertz. MALDI-TOF MS spectra were recorded
on a Bruker Biflex IV MS spectrometer with dithranol as a matrix.
Electrospray ionization (ESI) mass spectra were obtained by Themo
Finnigan LCQ Advantage mass spectrometer.
Nonamer 1. This oligomer was obtained in 51% on the basis of the
same procedures reported by us before for preparing nonamer 1a.20d
1H NMR (500 MHz, 285 K, DMF-d7): δ 10.38 (s, 2H), 10.36 (s, 2H),
10.17 (s, 2H), 9.93 (s, 2H), 9.39 (s, 2H), 9.33 (s, 2H), 9.23 (s, 2H),
9.00 (s, 2H), 8.40 (s, 2H), 7.00 (s, 2H), 6.95 (s, 1H), 6.93 (s, 2H), 6.89
(s, 2H), 6.80 (d, J ) 8.5 Hz, 2H), 6.59 (d, J ) 8.0 Hz, 2H), 4.44 (t,
4H), 4.39 (m, 8H), 4.13 (s, 6H), 4.12 (t, 4H), 4.08 (s, 6H), 4.04 (s,
6H), 4.02 (s, 6H), 3.90 (m, 8H), 3.78 (t, 4H), 3.25-3.60 (m, side
chains), 3.14, 3.13, 3.10 (s, s, s, 18H), 2.50 (t, J ) 7.5 Hz, 4H), 2.17
(q, 4H), 2.06 (s, 6H). MALDI-TOF MS m/z. Calcd for C126H170N8O46-
Na (M + Na+): 2554.11. Found: 2554.5.
oligomers also fold predictably into helical conformation in
solution. Finally, predictability of the folded conformations of
these aromatic oligoamides is demonstrated by the excellent
agreement between the modeled structures and results from
NOESY studies. The modeling method should be particularly
useful for future design of long oligomers that are difficult to
characterize by methods such as NMR and X-ray crytstallog-
raphy. The modeling method described here should be generally
applicable to the prediction of folded structures of other
backbone-rigidified oligomers when the crystal structures of
short oligmers are known.
Experimental Section
General Methods. All reactions were performed under argon. All
chemicals were obtained from commercial suppliers and were used as
received unless otherwise noted. CH2Cl2 was dried over CaH2. Unless
otherwise specified, all solvents were removed with a rotary vacuum
evaporator. Analytical thin-layer chromatography (TLC) was conducted
on Analtech Uniplate silica gel plates with detection by UV light. NMR
analyses were carried out on a Varian INOVA 500 spectrometer (500
Undecamer 2. This oligomer was synthesized by coupling 4,6-
dimethoxyisophthaloyl choride24 with the corresponding amino-pen-
tamer that was prepared by stepwise (C-to-N) coupling of the
9
16536 J. AM. CHEM. SOC. VOL. 126, NO. 50, 2004

Helical Aromatic Oligoamides
A R T I C L E S
corresponding monomer building blocks based on acid chloride
chemistry. Specifically, 4,6-dimethoxyisophthaloyl choride, obtained
from 4,6-dimethoxyisophthalic acid (24.0 mg, 0.106 mmol) and oxalyl
chloride (0.134 g, 1.06 mmol) in dry CH2Cl2 (5 mL), was added
dropwise at room temperature to the CH2Cl2 (20 mL) solution of the
amino-pentamer (320 mg, 0.22 mmol). The mixture was stirred
overnight. The reaction mixture was worked up by using column
chromatography (silica gel, CHCl3/EtAc/MeOH ) 5:2:3), which
afforded 0.15 g of faint-yellow solid (42.4%). Preparative TLC
separation (CHCl3/EtAc/MeOH ) 10:2:4) gave a pure yellow crystal
analyzed with the program VNMR 6.1C. The 600 MHz machine is
equipped with a cryogenic probe. Temperatures in the probe of
spectrometers were calibrated with use of the 1H resonances of
methanol. [1H,1H]-NOESY spectra25 of 1 were recorded at a 500 MHz
1H spectrometer frequency with a mixing time, τmix, of 150-500 ms
and at T (sample) of -10, -5, 0, 15, and 21 °C in CDCl3, and from
200 to 54 ms and at T (sample) of -20, -10, -5, 0, 10, and 21 °C in
DMF-d7 for 14-20 h. The NOESY spectrum of 2 was recorded at a
1
600 MHz H spectrometer frequency with a mixing time of 400 ms
for 8 h. τmix at different temperature was scaled with 1/τc, where τc
represents the correlation time for the overall rotational tumbling
estimated as described.26 It needs to be pointed out that these 2D NMR
measurements on 2 would not be possible without the sensitivity
provided by the cryogenic probe which allows the spectra to be recorded
before the molecules precipitated out.
1
suitable for analysis. H NMR (500 MHz, 273 K, 20/80 DMSO-d6-
CDCl3): δ 10.37 (s, 2H), 10.10 (s, 2H), 10.08 (s, 2H), 9.92 (s, 2H),
9.98 (s, 2H), 9.29 (s, 2H), 9.25 (s, 2H), 9.14 (s, 2H), 9.03 (s, 1H), 8.98
(s, 2H), 8.48 (s, 2H), 6.60-6.73 (m, 8H), 6.66 (s, 1H), 6.59 (s, 2H),
6.53 (s, 2H), 3.24-4.38 (m, side chains), 2.26 (s, 6H). MALDI TOF
MS m/z. Calcd for C158H220N10O60Na (M + Na+): 3240.43. Found:
3240.3.
Hexamer 2a. This compound was obtained in 78% yield on the
basis of the similar procedures for preparing 11-mer 2 by acylating
the corresponding amino-pentamer with anisoyl chloride. 1H NMR (500
MHz, 273 K, 20:80 DMSO-d6/CDCl3): δ 10.49 (s, 1H), 10.42 (s, 1H),
10.31 (s, 1H), 10.08 (s, 1H), 10.06 (s, 1H), 9.35 (s, 1H), 9.34 (s, 1H),
9.19 (s, 1H), 9.16 (s, 1H), 8.54 (s, 1H), 8.30 (d, 1H), 7.54 (t, J ) 8.5
Hz, 1H), 7.14 (t, J ) 8.0 Hz, 1H), 7.11 (d, J ) 8.0 Hz, 1H), 6.84 (m,
2H), 6.75 (s, 1H), 6.71 (s, 1H), 6.66 (s, 1H), 4.41-4.36 (m, 8H), 4.26
(t, 2H), 4.14 (s, s, 6), 4.12 (s, 3H), 4.07 (s, 3H), 4.04 (s, 3H), 3.98-
4.00 (m, 8H), 3.94 (t, 2H), 3.44-3.77 (m, side chains), 2.35 (s, 3H).
ESI MS m/z. Calcd for C82H114N5O30 (M + H)+: 1648.75. Found:
1649.0.
Amide H-D Exchange. Solutions of 1a, 3, 3a, and 3b (2 mM)
were prepared by dissolving the compounds into 50% DMSO-d6 in
CDCl3 (total volume: 0.95 mL) and the spectra were recorded at room
temperature as the reference spectra at t ) 0. The H-D exchange
experiments were initiated by adding 0.05 mL of D2O into each of the
samples, which resulted in a solution in a mixed solvent of 5:47.5:
47.5 D2O/DMSO-d6/CDCl3. The resultant spectra were then recorded
(500 MHz) at appropriate time intervals, based on which the time-
dependent peak areas of the amide protons were obtained and fitted
into the pseudo-first-order reaction rate equation of (It - I∞)/(Io - I∞)
) e-kt, where It, I∞, and I0, correspond to the integrated area of the
corresponding proton at t ) t, t ) ∞, and t ) 0; k is the decay rate
constant. The half-life T1/2 is related to k by T1/2 ) ln 2/k. Thus, the
half-life T1/2 was obtained by fitting the time-dependent peak areas into
the above equation [(It - I∞)/(Io - I∞) ) e-kt] with the program
Kaleidagraph on a Macintosh computer.
Two-Dimensional NMR Spectroscopy. NMR experiments were
recorded on Varian Inova 500 and 600 spectrometers, processed, and
(24) (a) Zeng, H.; Miller, R.; Flowers, R. A.; Gong, B. J. Am. Chem. Soc. 2000,
122, 2635. (b) Gong, B.; Yan, Y.; Zeng, H. Q.; Skrzypczak-Jankunn, E.;
Kim, Y. W.; Zhu, J.; Ickes, H. J. Am. Chem. Soc. 1999, 121, 5607.
(25) Ernst, R. R.; Bodenhausen, G.; Wokaun, A. Principles of Nuclear Magnetic
Resonance in One and Two Dimensions; Clarendon Press: Oxford, U.K.,
1987.
Acknowledgment. This work was supported by grants from
NIH (R01GM63223), ONR (N000140210519), and NSF
(CHE-0314577).
(26) Skalicky, J. J.; Mills, J. L.; Sharma, S.; Szyperski, T. J. Am. Chem. Soc.
2001, 123, 388.
JA046858W
9
J. AM. CHEM. SOC. VOL. 126, NO. 50, 2004 16537