Backbone-Rigidified Oligo(m-phenylene ethynylenes)

Article abstract of DOI:10.1021/ja039416d

Oligo(m-phenylene ethynylenes) (oligo(m-PE)) with backbones rigidified by intramolecular hydrogen bonds were found to fold into well-defined conformations. The localized intramolecular hydrogen bond involves a donor and an acceptor from two adjacent benze

Full text of DOI:10.1021/ja039416d

Published on Web 02/19/2004
Backbone-Rigidified Oligo(m-phenylene ethynylenes)
Xiaowu Yang,† Lihua Yuan,† Kazuhiro Yamato,† Amy L. Brown,† Wen Feng,†
Mako Furukawa,‡ Xiao Cheng Zeng,‡ and Bing Gong*,†
Contribution from the Department of Chemistry, UniVersity at Buffalo, The State UniVersity of
New York, Buffalo, New York 14260, and Department of Chemistry, UniVersity of Nebraska -
Lincoln, Lincoln, Nebraska 68588
Received November 4, 2003; E-mail: bgong@chem.buffalo.edu
Abstract: Oligo(m-phenylene ethynylenes) (oligo(m-PE)) with backbones rigidified by intramolecular
hydrogen bonds were found to fold into well-defined conformations. The localized intramolecular hydrogen
bond involves a donor and an acceptor from two adjacent benzene rings, respectively, which enforces
globally folded conformations on these oligomers. Oligomers with two to seven residues have been
synthesized and characterized. The persistence of the intramolecular hydrogen bonds and the corresponding
1
curved conformations were established by ab initio and molecular mechanics calculations, 1D and 2D H
NMR spectroscopy, and UV spectroscopy. Pentamer 5, hexamer 6, and heptamer 7 adopt well-defined
helical conformations. Such a backbone-based conformational programming should lead to molecules whose
conformations are resilient toward structural variation of the side groups. These m-PE oligomers have
provided a new approach for achieving folded unnatural oligomers under conditions that are otherwise
unfavorable for previously described, solvent-driven folding of m-PE foldamers. Stably folded structures
based on the design principle described here can be developed and may find important applications.
Schultz,29 oligopyrrolidones by Smith,30 anthracene-adduct based
Introduction
oligomers by Winkler,31 and alkoxy-substituted ortho-phenylene
Unnatural oligomers that fold into well-defined secondary
structures (foldamers) have attracted intense interest in recent
years.1-9 Most of the recently described foldamers involve
helical conformations that are inspired by the helical and
multiple helical structures found in nature.10 Examples of helical
foldamers include â-peptides reported by Gellman11 and See-
bach,12 γ-peptides by Hanessian13 and Seebach,14 δ-peptides
by Gervay15 and Fleet,16 peptoid oligomers described by
Zuckermann and Barron,17 pyridine-pyrimidine oligomers and
helical polyheterocyclic strands by Lehn,18 oligo(pyridine di-
carboxamides) by Lehn and Huc,19 oligoanthrilamides by
Hamilton,20 helicates by Lehn,21 aromatic δ-peptides by Huc,22
oxa-peptides by Yang and Wu,23 and N,N′-linked oligoureas
by Guichard.24 Many other folding oligomers involving un-
natural backbones, such as aedamers developed by Iverson,25
N,N-linked oligoureas by Nowick,26 vinylogous peptides by
Schreiber,27 sulfonopeptides by Gennari,28 oligocarbamates by
ethynylene oligomers by Tew,32 have also been reported.
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† SUNY, University at Buffalo.
‡ University of Nebraska - Lincoln.
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10.1021/ja039416d CCC: $27.50 © 2004 American Chemical Society

Backbone-Rigidified Oligo(m-phenylene ethynylenes)
A R T I C L E S
Moore et al. established an elegant helical foldamer system
based on solvent-driven folding of helical oligo(m-phenylene
ethynylenes) (oligo(m-PE)).33 By attaching polar side chains to
oligo(m-PE) backbones, the resultant oligomers were found to
adopt well-defined conformations in polar solvents. For these
m-PE oligomers, folding was effected by the solvaphobic nature
of the PE backbone and the solvaphilicity of the polar side
chains. In nonpolar solvents such as chloroform, these PE
oligomers were found to be random coils. The meta-substituted
benzene rings introduce a curvature into the m-PE backbones,
which results in helical conformations for oligomers consisting
of greater than six phenylene ethynylene residues. Different from
many other foldamer systems, these helical PE oligomers contain
a hydrophobic cavity of ∼8 Å across. Studies showed that the
hydrophobic cavities can serve as hosts for a variety of organic
molecules in polar solvents.
We have developed helical foldamers based on a strategy of
backbone-rigidification.5,34 By incorporating intramolecular H-
bonds along the backbone of aromatic oligoamides, we obtained
oligomers whose backbones were forced to adopt crescent or
helical conformations. By tuning the curvature of the backbone-
rigidified oligoamides, nanosized cavities of 10 and 30 Å across
have been created. Large cavities or channels, which are usually
found at the tertiary and quaternary structural level of biopoly-
mers, have been realized in few unnatural foldamer systems.
Our folding oligoamides, along with the helical foldamers
described by Lehn18 and Moore,33 represent one of the few
helical foldamer systems with large cavities. Besides, our
crescent oligoamide system also allows the tuning of cavity
sizes.
It is known that a very small barrier (∼0.6 kcal/mol) exists
for the internal rotation of diphenylacetylene.35 As a result, the
conformations of simple o- and m-PE oligomers and polymers
are expected to be very flexible and random. By incorporating
an intramolecular H-bond into diphenylacetylene, the resulting
2a′ should adopt a well-defined conformation that is enforced
by this additional noncovalent interaction. Indeed, Kemp
reported that diphenylacetylene such as 2b′, with its intramo-
lecular H-bond, adopted a H-bonded conformation and could
serve as â-turn mimetics.36 Introducing such intramolecular
H-bonding interactions into longer m-PE oligomers should thus
limit the internal rotation of the backbone, leading to well-
defined (folded) conformations.
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We reported our preliminary studies on folding m-PE
oligomers based on backbone-rigidification.34b By introducing
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A R T I C L E S
Yang et al.
of 8 Å in diameter were obtained. Moore et al. also described
that introducing one intramolecular H-bond into long m-PE
oligomers led to enhanced stability.33a As compared to the
solvent-driven PE foldamers established by the Moore group,
the folding of our backbone-rigidified m-PE oligomers is based
on a different mechanism that involves intramolecular H-bonds
incorporated into the backbone. The effects of solvents on the
folding of our PE oligomers are thus opposite to those of the
Moore system: In nonpolar solvents such as chloroform, our
PE oligomers are stably folded due to the presence of intramo-
lecular H-bonds, while the PE foldamers described by Moore
are folded in polar solvents and denatured in chloroform.
In this Article, we describe the detailed design, preparation,
and characterization of a series of our backbone-rigidified m-PE
oligomers. Specifically, oligomers 2, 3, 4, 5, 6, and 7 containing
two, three, four, five, six, and seven benzene rings, respectively,
were designed on the basis of these considerations: (1) To
facilitate the comparison of chain-length-dependent changes by
1D and 2D NMR, the two different termini of each of the
oligomers were designed to be consistent across this series of
oligomers, which allows the “terminal” aromatic protons t1-
t4 and a1-a2 to be directly comparable among the oligomers.
(2) The carbonyl oxygen atoms of benzoate ester groups should
act as the acceptors for intramolecular H-bonds. Ester groups
were chosen to avoid any potential steric hindrance that may
exist between the benzamide proton (or large N-substituent) and
the neighboring aromatic protons. (3) Finally, benzoate ester
groups were chosen on the basis of the long-term consideration
of preparing a variety of oligomers with different side chains
via simple transesterification reactions.
Oligomers 2-6 were examined by computational studies, 1H
NMR, and UV spectroscopy. The results obtained are fully
consistent with the expected H-bonded conformations. The
1
newly synthesized heptamer 7 has been characterized by H
NMR, mass spectometry, and UV spectroscopy. The successful
development of this new foldamer system based on the PE
backbone, along with the system we developed before, dem-
onstrates that backbone-rigidification by noncovalent interactions
should be applicable to a variety of different oligomers, leading
to foldamers with different properties and applications.
octanol. Coupling 1i with (trimethylsilyl)acetylene gave 1k,
which was converted into 1m and 1n by hydrolysis and
treatment with methyl iodide. Based on monomers 1l, 1m, and
1n, oligomers 2-6 were synthesized by Sonogashira coupling
reactions.
As shown in Scheme 2, coupling 1m and 1n led to dimer 2e
that was deprotected to give 2f. Treating 2f with ester 1p, which
was obtained from the commercially available acid 1o, resulted
in trimer 3. Dimer 2 was obtained by coupling 1p with 1l.
Treating 3 with methyl iodide led to the iodide 3a. Trimer 3a
was then converted to tetramer 4 and pentamer 5 by coupling
with 1m and 2f, respectively.
Results and Discussion
Synthesis. The synthesis of monomer building blocks is
shown in Scheme 1. Methyl 3-nitrobenzoate was hydrogenated
in the presence of acetic anhydride to give 1a, which was
nitrated to give 1b. Compound 1b was then deprotected with
H2SO4 in methanol, and the product 1c was converted into 1d
by iodination. Treating 1d with acetic anhydride in the presence
of H2SO4 in CH2Cl2 led to 1e that was reduced to 1f. Conversion
of 1f into 1g was realized by treating 1f with HNO2 followed
by Et2NH. Pd-catalyzed Sonogashira coupling37 of 1g with
(trimethylsilyl)acetylene gave 1j which was converted to iodide
1l using methyl iodide.38 Compound 1g was then converted to
the octyl ester 1i by hydrolysis followed by esterification with
Scheme 3 shows the preparation of hexamer 6. To increase
1
the H NMR signal dispersion of 6 and to test a strategy of
segment condensation involving longer intermediates, hexamer
6 was synthesized by first preparing another trimeric intermedi-
ate 3c. Coupling 1l and 1m gave dimer 2g, which was
hydrolyzed to 2h. Trimer 3c was obtained by hydrolyzing 3b,
which in turn was from coupling 2h with 1n. The Pd-catalyzed
coupling of trimers 3c and 3a went smoothly, leading to hexamer
6 in 73% yield.
Heptamer 7 was prepared in 22% yield by coupling dimer 2i
and pentamer 5a, which in turn were prepared on the basis of
similar procedures used for preparing 2f and 5 (Scheme 4). The
reaction conditions for preparing 7 are being optimized to
achieve a better yield.
(37) (a) Sonogashira, K. In ComprehensiVe Organic Synthesis; Trost, B. M.,
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Backbone-Rigidified Oligo(m-phenylene ethynylenes)
A R T I C L E S
Scheme 1
Scheme 2
Computational Studies. We previously demonstrated results
from ab initio molecular orbital calculations39 that 2a′ adopted
a completely planar conformation due to the presence of the
intramolecular H-bond in its structure.34b This result was
9
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A R T I C L E S
Yang et al.
Scheme 3
Scheme 4
supported by the X-ray structure of a dimer. A more detailed
calculation indicated that interrupting the intramolecular H-bond
of 2a′ by rotating around one of the C-Ph bonds led to the
conformation 2c′ which was significantly less stable. Deviation
from the planar conformation by distorting and eventually
interrupting the intramolecular H-bond led to a rapid increase
in energy. An energy difference of 5.78 kcal/mol was found
between optimized conformer 2a′ and optimized conformer 2c′.
A rotational barrier of 7.19 kcal/mol exists between optimized
2a′ and unoptimized 2c′ (Figure 1), suggesting that the H-bonded
2a′ should be overwhelmingly favored over other conformations
that involve the interruption of the intramolecular H-bonds.
To probe the conformations of longer oligomers, molecular
mechanics calculations (MM3 force field) were carried out on
analogues of 4, 5, 6, and 7. Figure 2 shows the energy-
minimized conformations of these four oligomers. The tetramer
adopts a planar, crescent conformation that is rigidified by
intramolecular H-bonds (Figure 2a). The pentamer, on the other
hand, adopts a helical conformation already (Figure 2b).
Although the PE backbone of the pentamer is not long enough
for it to adopt a helical conformation, the presence of the
Figure 1. The energy of the various conformers between 2a′ and 2c′ as a
function of the degree of rotation about the Ph-C bond.
diethyltriazenyl group adds additional length, leading to a helical
conformation in which the two methyls of the diethyltriazenyl
group and the other end of the molecule are brought into close
proximity. The hexamer, in combination with its diethyltriazenyl
tail, is long enough to adopt a helical conformation (Figure 2c).
In this conformation, the diethyltriazenyl group overlaps more
significantly with the other end of the molecule. The backbone
of the heptamer is long enough, which allows a stacking
interaction between the terminal aromatic rings (Figure 2d). A
helical pitch of ∼3.4 Å is observed for this heptamer.
(39) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Rega, N.; Salvador,
P.; Dannenberg, J. J.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B.
B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin,
R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara,
A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M.
W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople,
J. A. Gaussian 98, revision A.11; Gaussian, Inc.: Pittsburgh, PA, 2002.
One-Dimensional (1D) 1H NMR Spectroscopy. In chloro-
1
form, the H NMR spectrum of heptamer 7 shows extensive
signal-overlap and line-broadening, which prevents proper
assignment of the spectrum. Therefore, only the 1H NMR spectra
of oligomers 2-6 are compared. In Table 1, the chemical shift
1
values of the amide H signals of 1k and oligomers 2-6 are
9
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Backbone-Rigidified Oligo(m-phenylene ethynylenes)
A R T I C L E S
Figure 2. The energy-minimized (MM3 force field) conformations of (a) a tetramer, (b) a pentamer, (c) a hexamer, and (d) a heptamer with their backbones
corresponding to 4, 5, 6, and 7 with methyls on the ester side chains.
1
Figure 3. Concentration-dependent changes of H chemical shifts of (a) amide protons 4 and (b) amide protons a, d, and e, and aromatic protons t1-t4
of 6.
Table 1. Chemical Shifts of Amide Protonsa
those of 4, the amide protons Ha, Hd, and He of hexamer 6
also demonstrate downfield shifts from 8 to 0.125 mM (Figure
oligomer
Ha
Hb
Hc
Hd
He
3b). However, unlike the small shifts of the NH signals of
tetramer 4, the three resolved NH signals of 6 show much larger
concentration-dependent shifts of 0.344 (Ha), 0.338 (Hd), and
0.287 (He) ppm. The downfield shifts of the NH groups upon
diluting the solution of 4 or 6 suggest that they are not involved
in intermolecular H-bonding, because interrupting intermolecular
H-bonds should lead to upfield, rather than downfield, shifts of
the NH signals. Instead, these downfield shifts of NH signals
are consistent with the interruption of intermolecular π-π
stacking interactions at low concentrations. That the observed
changes in the shifts of amide protons are not related to
H-bonding is further confirmed by examining aromatic protons
t1-t4 of 6. From 8 to 0.125 mM, protons t1-t4 showed the
same nonlinear, downfield shifts as those of amide protons a,
d, and e, indicating that the observed shifts of the amide protons
were not due to H-bonding.
6
5
4
3
2
1k
9.11
9.48
9.49
9.45
9.27
7.92
9.45
9.46
9.46
9.27
9.44
9.43
9.29
9.11
9.28
8.98
a Measured at room temperature, 1 mM in CDCl3 (500 MHz).
listed. As compared to the chemical shift of the amide proton
of 1k, which cannot form any intramolecular H-bond, the amide
protons of oligomers 2-6 showed significant (>1 ppm)
downfield shifts, consistent with the expectation that these NH
groups are involved in intramolecular H-bonding interactions.
Upon diluting a sample of tetramer 4 from 8 to 0.125 mM
(CDCl3, 295 K, 500 MHz), the three NH signals of 4 show
very small downfield shifts of 0.016 (Ha), 0.016 (Hb), and 0.01
(Hc) ppm, respectively (Figure 3a), typical of amide protons
involved in intramolecular H-bonding interactions. Similar to
Variable-temperature 1H NMR measurements (2 mM, CDCl3,
500 MHz) of the amide proton signals of tetramer 4 and hexamer
9
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A R T I C L E S
Yang et al.
1
Figure 4. Temperature-dependent changes of H chemical shifts of the amide and terminal aromatic protons of (a) tetramer 4 and (b) hexamer 6.
Figure 5. 1H chemical shifts (1 mM, CDCl3, 500 MHz, 295 K) of (a) protons t1-t4 and a1-a2 versus chain length of oligomers 2-6, and (b) the methyl
(Me1 and Me2) and methylene (Met1 and Met2) protons of the diethyltriazenyl group.
6 provided additional evidence for the prevalence of intramo-
lecular H-bonds (Figure 4). From -20 to 60 °C, the three amide
NH signals of 4 show small upfield shifts of -2.25 × 10-3
(Ha), -2.23 × 10-3 (Hb), and -2.29 × 10-3 (Hc) ppm/K
(Figure 4a). These values are typical of intramolecular
H-bonding.34d,40 In comparison, aromatic protons t1-t4 have
almost no temperature-dependent change. Instead of moving
upfield, the amide NH protons a, d, and e of hexamer 6 showed
downfield shifts of 4.06 × 10-3 (Ha), 4.25 × 10-3 (Hd), and
2.07 × 10-3 (He) ppm/K, as the temperature was raised (from
-20 to 60 °C in CDCl3) (Figure 4b). A similar trend of
temperature-dependent downfield shifts is associated with the
aromatic protons t1-t3 of 6, suggesting that the observed shifts
of amide protons are not due to the interruption of intramolecular
H-bonding. These observations are most likely the results of
two opposite trends: (1) the small upfield shifts of the intra-
molecularly H-bonded amide protons of 6 as the temperature
was raised, and (2) the downfield shifts of almost all of the
protons of 6 due to the disruption of intermolecular aromatic
stacking interactions at elevated temperatures. Obviously, be-
tween the two trends, interruption of the intermolecular interac-
tion at elevated temperatures played the dominant role in
A more detailed examination revealed (Figure 4b) that the
NMR signals of protons t2 and t3 showed obvious downfield
shifts with rising temperature, proton t1 was less sensitive, and
proton t4 showed the least change in its position. In contrast,
the corresponding protons t1-t4 of tetramer 4 all showed almost
no temperature-dependent shifts. This suggests that the end
protons t1-t4 of 6 are located in a local environment that is
different from those of other shorter oligomers such as 4. Most
likely, this local environment that is unique to 6 is due to its
length and folded conformation: the backbone of 6 is long
enough to bring its two ends into close proximity. Consistent
with this picture, protons t2 and t3, which are at the very tip of
the molecule, shifted more significantly than protons t1 and t4.
If the observed downfield shifts of the aromatic end proton
signals of 6 were due to a folded conformation, the chemical
shifts of these proton signals should be sensitive to a change in
temperature. The folded conformation will be partially inter-
rupted (or “denatured”) at raised temperatures, which should
change (increase) the distance between the two ends and should
1
thus cause the H NMR signals of the end protons to move
downfield. This is, as shown in Figure 4, indeed the case.
Comparing the chemical shifts of aromatic protons t1-t4 and
a1-a2 on the termini of oligomers 2-6 reveals the effect of
chain length on the resonances of these protons (Figure 5a).
An interesting trend is observed: from dimer 2 to tetramer 4,
1
affecting the H chemical shifts of hexamer 6.
(40) Gong, B.; Yan, Y.; Zeng, H.; Skrzypczak-Jankunn, E.; Kim, Y. W.; Zhu,
J.; Ickes, H. A. J. Am. Chem. Soc. 1999, 121, 5607.
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A R T I C L E S
Figure 6. Partial NOESY spectra 4 (8 mM in CDCl3, 500 MHz, 263 K, mixing time: 0.3 s) revealing the side-chain NOE contacts of (a) tetramer 4,
(b) pentamer 5, and (c) hexamer 6. The contacts between ester protons (R) and the amide methyl protons are shown in the structures. These contacts are
indicated by arrows in the spectrum.
the chemical shifts of protons a1-a2 and t1-t4 show very little
changes. In contrast, the end protons of pentamer 5 move slightly
upfield as compared to those of 2-4. As compared to 5, the
corresponding protons of hexamer 6 have shifted significantly
to upfield positions. The shifts are particularly substantial (up
to 0.5 ppm) for protons t2 and t3. The same trend of upfield
shifts is observed for the methyl (Me1 and Me2) and methylene
(Met1 and Met2) protons of the diethyltriazenyl groups (Figure
9
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A R T I C L E S
Yang et al.
Figure 7. Partial NOESY spectra 4 (8 mM in CDCl3, 500 MHz, 263 K, mixing time: 0.3 s) revealing the presence of end-to-end NOE contacts in
(a) hexamer 6 (8 mM in CDCl3, 500 MHz, 263 K, mixing time: 0.3 s), (b) pentamer 5, and (c) the absence of such NOEs in the spectrum of tetramer 4.
These NOEs are indicated by arrows in the spectrum.
5b): while those of 2-4 remain constant, those of 5 and 6 show
upfield shifts. Shifts up to 0.7 ppm are observed for the methyl
protons. These results can only be explained by the correspond-
ing oligomer’s adopting a curved backbone: while oligomers
2-4 are not long enough, pentamer 5 is long enough for its
two termini to approach (or “feel”) each other; hexamer 6
reaches a length which, in combination with its rigidified
(curved) backbone, allows its two otherwise remote termini to
be brought into close proximity. This folded conformation
caused the pronounced upfield shifts41 of the corresponding
aromatic protons on the two termini of 6.
Two-Dimensional (2D) NMR Spectroscopy. Tetramer 4 was
first examined by 2D (NOESY) H NMR studies (Figure 6a).
1
The three acetamido methyl signals, aMe, bMe, cMe, appear at
2.449, 2.483, and 2.487 ppm as three peaks, two of which
partially overlapped each other. The NOEs (indicated by arrows)
are well separated in the NOESY spectrum. These NOEs include
the side-chain contacts between protons aMe, bMe, and cMe of
the acetamido methyl groups and the R-CH2 groups (R1, R2,
and R3) of the ester side chains.
(41) Perkins, S. J. Biol. Magn. Reson. 1982, 4, 193.
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Backbone-Rigidified Oligo(m-phenylene ethynylenes)
A R T I C L E S
Figure 8. UV spectra of (a) 2-6 at 10 µM in chloroform; (b) 2-7 at 2 µM in chloroform; (c) 2-6 at 2 µM in chloroform at 60 °C; (d) 2-7 at 2 µM in
chloroform/methanol (v/v 1/1).
For pentamer 5, NOEs between the acetamido methyl protons
(aMe, bMe, cMe, and dMe) and the R-methylene protons of the
ester groups are observed (Figure 6b). Unfortunately, the H
between the amide NH protons and the protons of the ester side
chains could not be clearly identified due to overlap of the
signals.
1
signals of the R-methylene groups R2, R3, and R4 overlap. As
a result, only two, instead of the expected three, NOE cross-
peaks are detected. Another cross-peak that is well separated
represents the contact between the protons of methyl dMe and
methylene R4. Although signal overlap prevents the NOEs from
being clearly assigned to individual side-chain contacts, the
number and intensities of the detected NOEs are consistent with
the expected four amide-ester side-chain contacts. Among the
three NOEs, the intensity of the largest cross-peak is about twice
those of the other two, indicating that this largest cross-peak is
the result of two sets of amide-ester contacts.
Among the five ester R-methylene groups of 6, the 1H signals
of three (R2-R4) overlap in the corresponding 1D NMR
spectrum. Nevertheless, the five amide-ester side-chain NOE
contacts of hexamer 6 are clearly discerned by NOESY. These
correspond to the side-chain-side-chain contacts between the
Comparing the NOESY spectrum of 4 to that of 5 or 6
revealed a significant difference (Figure 7): NOEs between
protons of the two diethyltriazenyl methyl groups (Me1 and Me2)
and proton t1 of 6 (Figure 7a), or between protons of Me1 and
Me2 and t2 (or t3 or both) of 5 (Figure 7b), are observed. These
NOEs are absent in the NOESY spectrum of 4 (Figure 7c).
Although the upfield shifts of protons a1 and t1 of 6 lead to
1
the overlap of their H NMR signals, the observed NOEs can
only be those between proton t1 and the protons of Me1 and
Me2. The reason is that in the NOESY spectrum of either 4 or
5, no NOEs are observed between proton a1 and those of Me1
and Me2. The end-to-end NOEs observed for 5 and 6 provide
additional convincing evidence for the proposed, rigidified
backbones of these oligomers. The backbone of 4 is too short
for its two ends to be in close proximity. As results from the
above molecular mechanics calculation show, pentamer 5
already adopts a helical conformation due to the presence of
the diethyltriazenyl group. This is confirmed by the detection
of NOEs between the methyl protons and proton t2 or t3.
Consistent with its longer backbone, hexamer 6 brings its two
ends into close proximity in such a way that the end-to-end
contacts are now between proton t1, instead of proton t2 or t3
(as for pentamer 5), and those of Me1 and Me2. To place Me1
and Me2 closer to t1 rather than to t2 and t3, hexamer 6 must
adopt a helical conformation, which is fully consistent with the
above results from computational and 1D NMR studies.
protons of the five acetamido methyl groups (aMe, bMe, cMe, dMe
,
and eMe) and the five ester R-methylene groups (R1-R5) of
the ester groups (Figure 6c). No attempts were made to assign
all of the NOEs to their corresponding contacts.
These side-chain NOE contacts are consistent with the
existence of the intramolecular H-bonds, which are consistent
with curved conformations adopted by oligomers 4, 5, and 6.
In the NOESY spectrum of 4, NOEs between the three amide
protons a, b, and c and the ester R-CH2 groups are also observed
(data not shown). In the NOESY spectra of 5 and 6, NOEs
9
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A R T I C L E S
Yang et al.
UV Spectroscopy. The UV spectra of oligomers 2-7 in
chloroform are shown in Figure 8. Each of the six compounds
shows a very strong absorption band at ∼330 nm. The shapes
of the spectra of dimer 2, trimer 3, and tetramer 4 are very
similar. However, a new band appears for pentamer 5 at ∼370
nm and more so for hexamer 6. The 370-nm shoulder for 5 or
6 should not be due to intermolecular interaction because the
concentrations used for measuring the UV spectra are already
very low (Figure 8a, 10 µM) and diluting the samples to 2 µM
led to a set of spectra of nearly identical shapes (Figure 8b).
Recording the UV spectra at an elevated temperature (60 °C)
only slightly weakened the 370-nm bands of 5 and 6 (Figure
8c). In spectra recorded in the mixed solvent of chloroform/
methanol (1:1), the shapes of the spectra of 2-4 remain
unchanged in this mixed solvent (Figure 8d). The presence of
methanol in chloroform should weaken the intramolecular
H-bonds and may thus disturb the folded conformations. Indeed,
the 370-nm bands of 5 and 6 are greatly diminished. Considering
the structural similarity between oligomers 2-6, these UV
results suggest that the 370-nm shoulders of 5 and 6 in
chloroform seem to be associated with their two termini that
are brought into close proximity by the corresponding folded
conformation.
generated. A variety of applications, for example, the design
of novel hosts, sensors, and porous materials, can be envisaged.
Experimental Section
General. All chemicals were purchased from Aldrich or Acros and
were used as received unless otherwise noted. Triethylamine was dried
from sodium and degassed before use. The coupling reactions were
carried out under dry argon. All reactions were followed by thin-layer
chromatography (precoated 0.25 mm silica gel plates from Aldrich),
and silica gel column chromatography was carried out with silica gel
60 (mesh 230-400). All 1H NMR and 13C NMR spectra were recorded
on a Varian Unity INOVA-500 spectrometer (500 MHz). NMR
chemical shifts are reported in ppm relative to internal standard TMS,
and the coupling constant, J, is reported in hertz (Hz). The following
splitting patterns are designated as s, singlet; d, doublet; t, triplet; q,
quartet; b, broad; m, multiplet. UV spectra were recorded on a Varian
Cary 50 UV-vis spectrometer.
Methyl 5-Acetylaminobenzoate (1a). Compound 1a was synthe-
sized starting from commercially available 3-nitrobenzoic acid which
was initially esterified (98.9%) followed by reduction of the nitro group
and protection of the corresponding amino group using acetic anhydride
(94.3%) to afford a white solid. TLC, Rf ) 0.40 (petroleum ether/
1
EtOAc, 1/2). H NMR (500 MHz, CDCl3): δ 2.20 (s, 3H, Ac), 3.90
(s, 3H, MeO), 7.39 (t, 1H, Ar-H), 7.65 (s, 1H, NH), 7.78 (d, 1H, Ar-
H, J ) 7.5 Hz), 7.92 (d, 1H, Ar-H, J ) 7.5 Hz), 8.02 (s, 1H, Ar-H).
The 370-nm bands are thus very likely the results of exciton
coupling between the two termini, which act as two component
chromophores, each of 5 and 6. Thus, the closer the two termini
are in an oligomer, the more obvious (or stronger) this band
may become. If this is the case, the 370-nm band should be
enhanced in the UV spectra of PE oligomers longer than 5 and
6. This expectation is confirmed by the UV spectrum of the
newly synthesized heptamer 7. In chloroform, the 370-nm band
is further enhanced in the spectrum of 7 and, similar to 5 and
6, is significantly weakened in the presence of 50% methanol
in chloroform. This band at 370 nm could serve as a convenient
spectroscopic means for the rapid assay of the folding of higher
homologues . For oligomers carrying chiral side-chain groups
that induced the twist sense bias in the backbones, exciton
coupling can be detected even more clearly using CD spectros-
copy.
Methyl 5-Acetamido-2-nitrobenzoate (1b). Compound 1a (35 g,
181 mmol) was added to concentrated H2SO4 (120 mL) cooled in an
ice-water bath. To this solution, a cooled mixture of 70% HNO3 (12.3
mL) and concentrated H2SO4 (58 mL) was added dropwise over a period
of 0.5 h at 0 °C. After being stirred for 20 min, the reaction mixture
was poured into cracked ice (1 kg), and the mixture was extracted with
dichloromethane (150 mL × 3). The combined extracts were then
washed with aqueous NaHCO3 and water, respectively, dried over
anhydrous Na2SO4, filtered, and concentrated to provide a brown
residue. The resulting solid was recrystallized from dichloromethane
to afford 24 g (55.7%) of 1b as a pale yellow needle. TLC, Rf ) 0.36
1
(petroleum ether/EtOAc, 1/3). H NMR (500 MHz, CDCl3): δ 2.24
(s, 3H, Ac), 3.93 (s, 3H, MeO), 7.61 (d, 1H, Ar-H), 7.86 (dd, 1H,
Ar-H), 7.94 (b, 1H, NH), 7.98 (d, 1H, Ar-H, J ) 7.5 Hz). 13C NMR
(125 MHz, CDCl3): δ 25.11, 54.03, 119.49, 121.18, 126.35, 130.37,
142.46, 143.55, 167.28, 167.78.
Methyl 5-Amino-2-nitrobenzoate (1c). To a solution of 1b (2.17
g, 9.12 mmol) in MeOH (50 mL) was added concentrated H2SO4 (0.9
mL) with stirring. The solution was refluxed for 0.5 h, and the solvent
was removed in vacuo to provide a pale yellow oil. The oil was
dissolved in dichloromethane (30 mL) and washed with NaHCO3, water,
and brine. After being washed, the organic layer was dried over Na2-
SO4 and filtered. The filtrate was then concentrated in vacuo to yield
a light yellow solid, which was recrystallized from EtOAc to afford
1.65 g (92.3%) of 1c as a colorless solid. TLC, Rf ) 0.24 (petroleum
ether/EtOAc, 3/2). 1H NMR (500 MHz, CDCl3): δ 3.92 (s, 3H, MeO),
4.56 (s, 2H, NH2), 6.61 (m, 2H, Ar-H), 7.94 (d, 1H, Ar-H, J )
9.5 Hz). 13C NMR (125 MHz, CDCl3): δ 53.19, 112.99, 114.31, 127.23,
132.11, 151.77, 167.54.
Conclusions
Strong intramolecular H-bonds act to rigidify the otherwise
flexible conformations of oligo(m-phenylene ethynylenes), lead-
ing to folded conformations from the dimer up. This study has
demonstrated the feasibility of designing backbone-rigidified
PE oligomers with stably folded, crescent or helical conforma-
tions. Extending the design principle to longer oligomers and
polymers is the obvious next step. Furthermore, by incorporating
building blocks with the two ethynyl linkages being placed in
a para-geometry on the same benzene ring, the curvature of
the backbones can be adjusted. This, combined with the
localized nature of backbone-rigidification, allows the develop-
ment of PE helices with larger interior cavities. This new class
of PE foldamers, with their unsaturated (fluorescent) backbones,
is reminiscent of helicenes.42 By incorporating chiral side chains,
it should be possible to control the twist sense bias of oligomers
with lengths over one helical turn. Helical materials with
interesting chiroptical properties may result. A more exciting
prospect involves the well-defined, large hydrophobic cavities
Methyl 5-Amino-4-iodo-2-nitrobenzoate (1d). To a vigorously
stirred solution of 1c (4.42 g, 22.6 mmol) in glacial acetic acid (20
mL) was added dropwise a solution of ICl (3.67 g, 22.6 mmol) in glacial
acetic acid (5 mL). After 10 min, a yellow precipitate appeared, and
the solution was allowed to stir for another 12 h. Upon completion,
the yellow solution was poured into water (50 mL) and filtered to yield
a yellow solid, which was recrystallized from MeOH to afford 5.7 g
(78.3%) of the yellow solid 1d. TLC, Rf ) 0.42 (petroleum ether/EtOAc,
3/2). 1H NMR (500 MHz, CDCl3): δ 3.91 (s, 3H, MeO), 4.88 (b, 2H,
NH2), 6.73 (s, 1H, Ar-H), 8.42 (s, 1H, Ar-H). 13C NMR (125 MHz,
CDCl3): δ 53.57, 81.67, 94.81, 111.87, 114.38, 131.46, 136.17, 151.61.
(42) Katz, T. J. Angew. Chem., Int. Ed. 2000, 39, 1921.
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A R T I C L E S
Methyl 5-N-Acetylamino-4-iodo-2-nitrobenzoate (1e). To a solu-
tion of 1d (1.6 g, 4.97 mmol) in dichloromethane (15 mL) was added
concentrated H2SO4 (0.85 mL) at 0 °C. After 5 min, a solution of acetic
anhydride (1.17 mL, 12.38 mmol) in dichloromethane (5 mL) was added
dropwise at 0 °C. Upon addition, the mixture was warmed to room
temperature and stirred for 1 h until completion was detected by TLC.
The resulting solution was washed with water, aqueous NaHCO3, and
brine, dried over anhydrous Na2SO4, and filtered. The resulting filtrate
was evaporated in vacuo to yield a pale yellow solid, which was
recrystallized from MeOH to afford 1.6 g (93.8%) of 1e as a white
(40 mL) was stirred for 1 h at room temperature, to which were added
n-octanol (1.11 g, 8.54 mmol) and more DCC (1.6 g, 7.77 mmol),
respectively. The reaction mixture was stirred for 48 h at room
temperature, filtered, and concentrated to give a red oil, which was
purified by silica gel flash column chromatography (petroleum ether/
EtOAc, 4/1) to provide 3.27 g (85.3%) of 1i as a pale yellow oil. TLC,
Rf ) 0.33 (petroleum ether/EtOAc, 2/1). 1H NMR (500 MHz, CDCl3):
δ 0.88 (t, 3H), 1.22-1.39 (m, 16H), 1.72 (m, 2H), 2.20 (s, 3H, Ac),
3.75 (b, 4H, CH2), 4.23 (t, 2H, CH2O), 7.42 (s, 1H, Ar-H), 7.87 (s,
1H, NH), 8.37 (s, 1H, Ar-H). 13C NMR (125 MHz, CDCl3): δ 11.46,
14.33, 14.78, 22.88, 24.93, 26.12, 28.89, 29.39, 29.50, 32.03, 41.91,
49.40, 65.59, 94.02, 122.07, 127.97, 128.93, 134.83, 146.79, 167.85,
168.23.
1
solid. TLC, Rf ) 0.48 (petroleum ether/EtOAc, 1/2). H NMR (500
MHz, CDCl3): δ 2.31 (s, 3H, Ac), 3.93 (s, 3H, MeO), 7.71 (b, 1H,
NH), 8.44 (s, 1H, Ar-H), 8.67 (s, 1H, Ar-H). 13C NMR (125 MHz,
CDCl3): δ 25.56, 53.97, 89.43, 119.96, 130.55, 135.17, 142.45, 143.53,
166.02, 168.91.
Octyl 5-N-Acetylamino-2-[3,3-diethyl-1-triazenyl]-4-[2-(1,1-tri-
methylsilyl)-1-ethynyl] Benzoate (1k). A 50 mL flask under argon
was charged with 1i (0.77 g, 1.49 mmol), dichlorobis(triphenylphos-
phine) palladium(II) (21 mg, 0.030 mmol), copper(I) iodide (5.7 mg,
0.03 mmol), and triethylamine (23 mL). The solution was then stirred
and warmed to 40 °C, to which was added dropwise degassed
trimethylsilylacetylene (220 µL, 1.54 mmol) by syringe. The reaction
mixture was allowed to stir for 12 h at the same temperature, filtered,
and then concentrated to yield a dark oil. The oil was purified by flash
silica gel column chromatography (petroleum/EtOAc, 8/1) to afford
0.68 g (93.8%) of 1k as a colorless solid. TLC, Rf ) 0.39 (petroleum
ether/EtOAc, 5/1). 1H NMR (500 MHz, CDCl3): δ 0.30 (s, 9H, SiMe3),
0.88 (t, 3H), 1.29 (b, 16H), 1.72 (m, 2H), 2.20 (s, 3H, Ac), 3.73 (b,
4H, CH2), 4.26 (t, 2H, CH2O), 7.49 (s, 1H, Ar-H), 7.92 (s, 1H, NH),
8.61 (s, 1H, Ar-H). 13C NMR (125 MHz, CDCl3): δ 0.099, 11.89,
14.27, 14.33, 22.84, 24.94, 26.16, 28.89, 29.36, 29.47, 32.00, 41.97,
49.23, 65.54, 100.18, 103.35, 114.36, 119.21, 121.61, 128.69, 136.17,
145.05, 167.85, 168.09. Anal. Calcd for C26H42N4O3Si: C, 64.16; H,
8.70; N, 11.51. Found: C, 64.14; H, 8.60; N, 11.61.
Methyl 5-N-Acetylamino-4-iodo-2-aminobenzoate (1f). To a mix-
ture of 1e (5.6 g, 15.4 mmol) in absolute ethanol (88 mL) and glacial
acetic acid (88 mL) was added iron powder (2.58 g, 46.7 mmol). The
mixture was then heated to reflux for 2 h. The red reaction solution
was allowed to cool to room temperature, diluted with water (300 mL),
and extracted with dichloromethane (100 mL × 3). The combined
organic extracts were then washed with water and dried over anhydrous
Na2SO4. The solvent was removed in vacuo to provide a pale yellow
solid, which was recrystallized from MeOH to afford 4.36 g (84.8%)
of 1f as a white needle. TLC, Rf ) 0.36 (petroleum ether/EtOAc, 1/2).
1H NMR (500 MHz, CDCl3): δ 2.22 (s, 3H, Ac), 3.87 (s, 3H, MeO),
5.69 (b, 2H, NH2), 7.06 (b, 1H, NH), 7.18 (b, 1H, Ar-H), 8.29 (s, 1H,
Ar-H). 13C NMR (125 MHz, CDCl3): δ 24.19, 51.81, 101.0, 111.24,
126.11, 126.26, 127.31, 148.29, 167.87, 168.43.
Methyl 5-N-Acetylamino-4-iodo-2-[3,3-diethyl-1-triazenyl] Ben-
zoate (1g). A solution of sodium nitrite (0.49 g, 7.1 mmol) in water
(4.5 mL) was cooled to 0 °C and then added dropwise over a 10 min
period to a 0 °C solution of 1f (2.13 g, 6.38 mmol) and concentrated
hydrochloric acid (1.8 mL) in water (12 mL) and acetonitrile (20 mL).
The mixture was stirred for 0.5 h at 0 °C and then added dropwise to
a solution of diethylamine (2.33 mL, 22 mmol) and potassium carbonate
(2.9 g, 21 mmol) which was precooled to 0 °C. During the addition,
more diethylamine (2.3 mL) was added to the reaction solution. After
addition, the mixture was warmed to room temperature for 0.5 h. During
that period, a yellow solid precipitated. Upon completion, the solution
was extracted with dichloromethane (80 mL × 2). The combined
organic extracts were then washed with brine and water, dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo to yield a yellow
solid, which was recrystallized from MeOH to afford 2.39 g (86.2%)
of 1g as a colorless needle. TLC, Rf ) 0.23 (petroleum ether/EtOAc,
Methyl 5-N-Acetylamino-2-[3,3-diethyl-1-triazenyl]-4-[2-(1,1-tri-
methylsilyl)-1-ethynyl] Benzoate (1j). Compound 1j was prepared
from 1g (6.12 g, 14.64 mmol) as described for 1k to afford a brown
oil. The oil was purified by silica gel column chromatography
(petroleum ether/EtOAc, 2/1) to afford 5.58 g (98.2%) of 1j as a pale
1
yellow solid. TLC, Rf ) 0.38 (petroleum ether/EtOAc, 2/1). H NMR
(500 MHz, CDCl3): δ 0.30 (s, 9H, SiMe3), 1.26 (b, 6H, CH3), 2.20 (s,
3H, Ac), 3.73 (b, 4H, CH2), 3.86 (s, 3H, MeO), 7.49 (s, 1H, Ar-H),
7.92 (b, 1H, NH), 8.63 (s, 1H, Ar-H). 13C NMR (125 MHz, CDCl3):
δ 0.39, 11.09, 14.57, 25.26, 42.08, 49.83, 52.57, 100.4, 103.85, 114.92,
119.70, 121.96, 128.29, 136.41, 145.55, 168.19, 168.65. Anal. Calcd
for C19H28N4O3Si: C, 58.73; H, 7.26; N, 14.42. Found: C, 58.77; H,
7.26; N, 14.48.
1
3/2). H NMR (500 MHz, CDCl3): δ 1.31 (b, 6H, Me), 2.24 (s, 3H,
Methyl 5-N-Acetylamino-2-iodo-4-[2-(1,1-trimethylsilyl)-1-ethyn-
yl] Benzoate (1l). To a sealed tube were added 1j (2.39 g, 6.16 mmol)
and iodomethane (10 mL) under argon. The mixture was stirred for 12
h at 120 °C. After filtration, the filtrate was concentrated to yield a
brown oil, which was purified by silica gel column chromatography
(petroleum ether/EtOAc, 3/1) to afford 2.09 g (81.9%) of 1m as a white
Ac), 3.74 (b, 4H, CH2), 3.85 (s, 3H, MeO), 7.35 (b, 1H, NH), 7.86 (s,
1H, Ar-H), 8.41 (s, 1H, Ar-H). 13C NMR (125 MHz, CDCl3): δ
11.09, 14.52, 24.71, 41.80, 49.20, 52.08, 93.94, 121.97, 127.15, 128.79,
134.63, 146.74, 167.83, 167.98.
5-N-Acetylamino-4-iodo-2-[3,3-diethyl-1-triazenyl] Benzoic Acid
(1h). A solution of 1g (1.4 g, 3.35 mmol) in MeOH (9 mL) was heated
to reflux, to which was added dropwise aqueous NaOH (3.7 mL, 1 N).
The resulting solution was refluxed for 0.5 h and then cooled to room
temperature. Upon cooling, water (20 mL) was introduced. The solution
was then extracted with Et2O, and the water phase was neutralized to
pH 3 with 1 N HCl. After filtration, the solid was dried in vacuo to
1
solid. TLC, Rf ) 0.53 (petroleum ether/EtOAc, 2/1). H NMR (500
MHz, CDCl3): δ 0.31 (s, 9H, SiMe3), 2.22 (s, 3H, Ac), 3.92 (s, 3H,
MeO), 7.90 (s, 1H, Ar-H), 7.99 (s, 1H, Ar-H), 8.86 (s, 1H, Ar-H).
13C NMR (125 MHz, CDCl3): δ -0.041, 25.02, 52.90, 85.46, 97.90,
106.29, 116.10, 120.95, 136.03, 139.42, 143.37, 166.54, 168.25.
Octyl 5-N-Acetylamino-2-[3,3-diethyl-1-triazenyl]-4-ethynyl Ben-
zoate (1m). To a solution of the compound 1k (0.95 g, 1.95 mmol) in
MeOH (15 mL) was added potassium carbonate (15 mg, 0.11 mmol)
as described for 1l to yield a brown oil. The oil was then purified by
silica gel column chromatography (petroleum ether/EtOAc, 2/1) to
afford 0.73 g (90.2%) of 1m as a light yellow oil. TLC, Rf ) 0.48
1
afford 1.27 g (93.8%) of 1h as a white solid. H NMR (500 MHz,
CDCl3): δ 1.31 (t, 3H), 1.44 (t, 3H), 2.24 (s, 3H, Ac), 3.78 (q, 2H),
3.95 (q, 2H), 7.43 (s, 1H, NH), 8.12 (s, 1H, Ar-H), 8.71 (s, 1H, Ar-
H), 13.96 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3): δ 10.27,
14.36, 24.44, 43.47, 51.03, 98.62, 122.24, 125.98, 126.26, 135.98,
145.30, 166.34.
1
(petroleum ether/EtOAc, 1/1). H NMR (500 MHz, CDCl3): δ 0.87
Octyl 5-N-Acetylamino-4-iodo-2-[3,3-diethyl-1-triazenyl] Ben-
zoate (1i). A solution of the white acid 1h (3.0 g, 7.43 mmol), DCC
(1.6 g, 7.77 mmol), and DMAP (0.27 g, 2.21 mmol) in dichloromethane
(t, 3H), 1.26-1.38 (m, 16H), 1.72 (m, 2H), 2.20 (s, 3H, Ac), 3.55
(s, 1H), 3.72 (b, 4H), 7.54 (s, 1H, Ar-H), 7.91 (s, 1H, NH), 8.58
(s, 1H, Ar-H). 13C NMR (125 MHz, CDCl3): δ 11.41, 14.28, 14.67,
9
J. AM. CHEM. SOC. VOL. 126, NO. 10, 2004 3159

A R T I C L E S
Yang et al.
22.83, 24.94, 25.98, 26.14, 28.85, 29.48, 31.98, 32.97, 41.80, 49.26,
63.06, 65.57, 79.08, 85.35, 113.56, 119.75, 122.40, 128.843, 136.17,
145.08, 168.18, 168.33.
room temperature, and then water (8 mL) was added. Upon addition,
the solution was extracted with dichloromethane (10 mL × 3), and the
resulting organic extracts were then washed with water (10 mL), dried
over Na2SO4, filtered, and concentrated to afford 0.51 g (96.5%) of
dimer 2f as a pure pale yellow oil. TLC, Rf ) 0.39 (petroleum ether/
Octyl 5-N-Acetylamino-2-iodo-4-[2-(1,1-trimethylsilyl)-1-ethynyl]
Benzoate (1n). The compound was synthesized from 1k (0.97 g, 1.99
mmol) by a procedure similar to that used for 1m to yield a light yellow
oil. The oil was then purified by silica gel column chromatography
(petroleum ether/EtOAc, 15/1, 10/1) to afford a colorless oil, which
was left standing overnight to afford 0.81 g (79.4%) of 1n as a white
1
EtOAc, 1/3). H NMR (500 MHz, CDCl3): δ 0.88 (m, 6H), 1.28-
1.45 (m, 26H), 1.78 (m, 4H), 2.26 (s, 3H, Ac), 2.40 (s, 3H, Ac), 3.66
(s, 1H, CCH), 3.74 (b, 4H), 4.27 (m, 4H, CH2O), 7.52 (s, 1H, Ar-H),
7.74 (s, 1H, Ar-H), 7.96 (s, 1H, NH), 8.84 (s, 1H, Ar-H), 9.12
(s, 1H, NH), 9.18 (s, 1H, Ar-H). 13C NMR (125 MHz, CDCl3): δ
14.27, 22.84, 24.69, 25.04, 26.11, 28.73. 28.91, 29.35, 29.37, 29.41,
29.49, 31.97, 32.01, 65.51, 66.22, 77.72, 87.54, 90.42, 94.60, 114.10,
114.90, 118.68, 119.60, 121.36, 121.74, 128.81, 131.61, 137.44, 137.79,
139.32, 144.59, 165.42, 168.37, 168.60, 169.82.
1
wax. TLC, Rf ) 0.58 (petroleum ether/EtOAc, 5/1). H NMR (500
MHz, CDCl3): δ 0.31 (s, 9H, SiMe3), 0.88 (t, 3H), 1.29 (m, 10H),
1.78 (m, 2H), 2.22 (s, 3H, Ac), 4.32 (t, 2H, CH2O), 7.91 (s, 1H, NH),
7.97 (s, 1H, Ar-H), 8.83 (s, 1H, Ar-H). 13C NMR (125 MHz,
CDCl3): δ -0.032, 14.29, 22.83, 25.00, 26.11, 28.72, 28.85, 29.38,
31.97, 66.30, 85.25, 97.94, 106.08, 115.91, 120.83, 136.66, 139.43,
143.20, 166.32, 168.20.
Dimer 2. A mixture of the acetylene 1q (78 mg, 0.25 mmol), 1p
(112 mg, 0.28 mmol), bis(dibenzylideneacetone) palladium (4.6 mg,
0.0053 mmol), copper(I) iodide (1 mg, 0.0052 mmol), and triphen-
ylphosphine (6.9 mg, 0.025 mmol) in triethylamine (15 mL) was heated
at 70 °C under argon for 12 h. The solution was concentrated to yield
a brown oil, which was purified by PTLC (CH2Cl2/acetone, 10/1) to
afford 130 mg (89.1%) of 2 as a yellow solid. TLC, Rf ) 0.34 (CHCl3/
acetone, 8/1). 1H NMR (500 MHz, CDCl3): δ 1.28 (m, 6H), 2.40
(s, 3H, Ac), 3.36 (s, MeO, 3H), 3.52 (t, CH2O, 2H), 3.63-3.76 (m,
10H), 3.87 (m, 5H), 4.48 (t, CH2O, 2H), 7.43 (t, 1H), 7.58 (m, 2H),
7.71 (d, 1H, J ) 7.5 Hz), 8.15 (d, 1H, J ) 8.0 Hz), 8.87 (s, 1H), 9.27
(s, 1H). 13C NMR (125 MHz, CDCl3): δ 24.76, 52.22, 59.22, 64.85,
69.18, 70.82, 70.86, 70.99, 72.13, 90.79, 95.60, 114.50, 119.89, 122.02,
124.17, 128.14, 128.55, 130.21, 131.13, 132.73, 134.21, 137.77, 144.90,
165.85, 168.54, 169.77.
2-[2-(2-Methoxyethoxy) ethoxy]ethyl 2-Iodobenzoate (1p). To a
solution of 2-iodobenzoic acid (1o) (1.26 g, 5.08 mmol) and triethyl-
amine (2.5 mL) in dichloromethane (20 mL) was added dropwise
trimethylacetyl chloride (1.8 mL) at 0 °C. The reaction solution was
allowed to warm to room temperature and stirred for 1 h. The solution
was then cooled in an ice-water bath, to which a solution of
triethyleneglycol monomethyl ether (1.05 g, 6.40 mmol) in dichloro-
methane (10 mL) was added dropwise. The reaction mixture was
allowed to stir for 12 h at room temperature, washed with water, dried
over Na2SO4, filtered, and concentrated to afford a red oil. The oil was
purified by silica gel column chromatography (petroleum ether/EtOAc,
3/1) to afford 1.92 g (96.0%) of 1p as a pale yellow oil. TLC, Rf )
0.48 (CHCl3/acetone, 10/1). 1H NMR (500 MHz, CDCl3): δ 3.35
(s, 3H, MeO), 3.52 (m, 2H), 3.63-3.85 (m, 6H), 3.85 (t, 2H), 4.89
(t, 2H), 7.15 (m, 1H), 7.40 (m, 1H), 7.83 (d, 1H), 7.96 (d, 1H). 13C
NMR (125 MHz, CDCl3): δ 27.34, 59.16, 63.67, 64.80, 69.10, 70.78,
72.08, 94.29, 128.06, 131.26, 132.84, 15.19, 141.40, 166.51.
Methyl 5-N-Acetylamino-2-[3,3-diethyl-1-triazenyl]-4-ethynyl Ben-
zoate (1q). To a solution of 1j (0.50 g, 1.29 mmol) in methanol (8
mL) was added potassium carbonate (12 mg, 0.087 mmol). The solution
was stirred for 5 min at room temperature, diluted with water (10 mL),
and then extracted with dichloromethane (10 mL × 20). The pale yellow
extracts were washed with water, dried over Na2SO4, and concentrated
to yield an oil. The oil was purified by silica gel column chromatog-
raphy (petroleum ether/EtOAc, 1/1) to afford 0.39 g (96.2%) of 1q as
a pale yellow solid. TLC, Rf ) 0.57 (petroleum ether /EtOAc, 1/3). 1H
NMR (500 MHz, CDCl3): δ 1.26 (m, 6H, CH3), 2.22 (s, 3H, Ac),
3.53 (s, 1H, CCH), 3.72 (m, 4H, CH2), 3.86 (s, H, MeO), 7.53 (s, 1H,
Ar-H), 7.82 (s, 1H, NH), 8.62 (s, 1H, Ar-H). 13C NMR (125 MHz,
CDCl3): δ 25.02, 52.27, 79.18, 85.21, 113.54, 119.84, 122.50, 128.36,
136.20, 145.29, 168.11, 168.32.
Dimer 2e. The acetylene 1m (0.74 g, 1.79 mmol), 1n (0.76 g, 1.48
mmol), bis(dibenzylideneacetone) palladium (22 mg, 0.024 mmol),
copper(I) iodide (4.7 mg, 0.024 mmol), and triphenylphosphine (33
mg, 0.12 mmol) in dry triethylamine (20 mL) were stirred at 70 °C for
24 h under argon. The reaction solution was then concentrated to yield
a dark oil, which was purified by silica gel column chromatography
(petroleum ether/EtOAc, 5/1) to afford 1.05 g (88.9%) of dimer 2e as
a yellow solid. TLC, Rf ) 0.63 (petroleum ether/EtOAc, 2/1). 1H NMR
(500 MHz, CDCl3): δ 0.33 (s, 9H, SiMe3), 0.88 (m, 6H), 1.27-1.44
(m, 26H), 1.74 (m, 2H), 1.80 (m, 2H), 2.26 (s, 3H, Ac), 2.41 (s, 3H,
Ac), 3.76 (m, 4H, CH2), 4.27 (t, 2H), 4.33 (t, 2H), 7.55 (s, 1H), 7.75
(s, 1H), 8.03 (s, 1H), 8.84 (s, 1H), 9.16 (s, 1H), 9.22 (s, 1H). 13C NMR
(125 MHz, CDCl3): δ -0.009, 14.33, 22.87, 24.74, 25.08, 26.13, 26.19,
28.74, 28.91, 29.38, 29.40, 29.43, 29.52, 31.99, 32.04, 65.53, 66.23,
90.41, 94.73, 98.43, 106.47, 114.17, 118.66, 119.62, 120.79, 121.69,
128.77, 131.33, 136.83, 137.80, 139.06, 144.63, 165.52, 168.32, 169.88.
Dimer 2f. To a solution of dimer 2e (0.58 g, 0.72 mmol) in MeOH
(8 mL) and dichloromethane (1 mL) was added potassium carbonate
(5 mg, 0.026 mmol). The mixture was allowed to stir for 10 min at
Trimer 3. Following the coupling procedure as described for 2e,
the mixture of the acetylene 2f (139 mg, 0.19 mmol), 1p (102 mg,
0.26 mmol), bis(dibenzylideneacetone) palladium (3.5 mg, 0.0038
mmol), copper(I) iodide (1 mg, 0.0052 mmol), and triphenylphosphine
(5.2 mg, 0.019 mmol) in triethylamine (10 mL) was heated at 70 °C
under argon for 5 h. The solution was then filtered and concentrated
to yield a dark oil, which was purified by silica gel column chroma-
tography (dichloromethane/MeOH, 30/1, 20/1) to afford 131 mg
(69.4%) of 3 as a yellow solid. TLC, Rf ) 0.45 (CHCl3/acetone, 10/1).
1H NMR (500 MHz, CDCl3): δ 0.88 (s, 6H), 1.39 (m, 26H), 1.74 (m,
2H), 1.82 (m, 2H), 2.42 (s, 3H, Ac), 2.45 (s, 3H, Ac), 3.36 (s, 3H,
MeO), 3.53 (m, 2H), 3.67-3.76 (m, 10H), 3.87 (t, 2H), 4.27(t, 2H),
4.32 (t, 2H), 4.49 (t, 2H), 7.49 (t, 1H), 7.58 (s, 1H), 7.85 (s, 1H, Ar-
H), 7.62 (t, 1H), 7.72 (d, 1H, J ) 7.5 Hz), 8.17 (d, 1H, J ) 8.0 Hz),
8.86 (s, 1H), 9.27 (s, 1H), 9.38 (s, 1H), 9.45 (s, 1H). 13C NMR (125
MHz, CDCl3): δ 14.09, 22.65, 24.49, 24.54, 24.63, 24.68, 25.92, 25.97,
28.56, 28.70, 29.17, 29.22, 29.30, 31.79, 31.82, 59.06, 64.79, 65.28,
65.94, 68.94, 70.65, 70.68, 70.82, 71.94, 89.01, 89.85, 94.79, 97.40,
114.15, 115.57, 117.90, 121.25, 121.46, 121.52, 123.39, 128.44, 130.20,
131.09, 131.20, 132.73, 134.12, 136.84, 136.88, 137.62, 140.57, 144.45,
165.56, 165.69, 168.08, 169.68, 170.11. Anal. Calcd for C56H75N5O11:
C, 67.65; H, 7.60; N, 7.04. Found: C, 67.80; H, 7.63; N, 7.09.
Trimer 3a. To a sealed tube were added trimer 3 (0.23 g, 0.23 mmol)
and iodomethane (1.5 mL). The mixture was stirred for 24 h at 120 °C
to yield a brown residue. The residue was then purified by silica gel
column chromatography (dichloromethane/MeOH, 15/1, 10/1) to afford
173 mg (73.7%) of 3a as a yellow solid. TLC, Rf ) 0.52 (CHCl3/
1
acetone, 10/1). H NMR (500 MHz, CDCl3): 0.88 (m, 6H), 1.29-
1.46 (m, 20H), 1.81 (m, 4H), 2.41 (s, 3H, Ac), 2.44 (s, 3H, Ac), 3.36
(s, 3H, MeO), 3.52 (t, 2H), 3.64-3.73 (m, 6H), 3.88 (t, 2H), 4.31 (m,
4H), 4.46 (m, 2H), 7.47 (t, 1H, Ar-H), 7.59 (t, 1H, Ar-H), 7.67 (d,
1H, J ) 7.5 Hz), 7.75 (s, 1H, Ar-H), 8.01 (s, 1H, Ar-H), 8.15 (d,
1H, J ) 8 Hz), 9.08 (s, 1H, Ar-H), 9.27 (s, 1H, NH), 9.38 (s, 1H,
Ar-H), 9.40 (s, 1H, NH). 13C NMR (125 MHz, CDCl3): δ 14.33,
22.87, 24.78, 24.81, 24.89, 26.13, 26.12, 28.72, 29.39, 29.43, 32.00,
32.02, 59.24, 59.27, 65.01, 66.18, 66.22, 69.11, 70.85, 71.00, 72.12,
84.79, 87.83, 88.95, 97.20, 97.94, 115.87, 116.17, 117.31, 121.40,
9
3160 J. AM. CHEM. SOC. VOL. 126, NO. 10, 2004

Backbone-Rigidified Oligo(m-phenylene ethynylenes)
A R T I C L E S
123.43, 129.17, 130.13, 131.11, 131.31, 132.98, 134.39, 135.87, 137.20,
140.96, 141.19, 143.27, 165.57, 165.73, 166.39, 170.30, 170.36.
168.29, 168.35, 169.81. Anal. Calcd for C38H51N5O6Si: C, 65.02; H,
7.32; N, 9.98. Found: C, 64.87; H, 7.22; N, 10.13.
Tetramer 4. Following the coupling procedure as described for
trimer 3, compound 1m (31 mg, 0.075 mmol), trimer 3a (51 mg, 0.050
mmol), bis(dibenzylideneacetone) palladium (1 mg, 0.0011 mmol),
copper(I) iodide (0.5 mg, 0.0026 mmol), and triphenylphosphine (1.5
mg, 0.0056 mmol) in triethylamine (15 mL) were heated at 70 °C under
argon for 28 h. The solution was filtered and concentrated to give a
dark oil, which was purified by silica gel column chromatography
(dichloromethane/acetone, 10/1) to give 48.5 mg (74.3%) of 4 as a
yellow solid. TLC, Rf ) 0.53 (CHCl3/acetone, 5/1). 1H NMR (500 MHz,
CDCl3): δ 0.88 (m, 9H), 1.29-1.46 (m, 36H), 1.76 (m, 2H), 1.83 (m,
4H), 2.42 (s, 3H, Ac), 2.47 (s, 6H, Ac), 3.37 (s, 3H, MeO), 3.53 (m,
2H), 3.65-3.89 (m, 12H), 4.27 (m, 2H, CH2O), 4.33 (m, 4H, CH2O),
4.51 (t, 2H), 7.51 (t, 1H, Ar-H, J ) 8 Hz), 7.57 (s, 1H), 7.63 (t, 1H),
7.75 (d, 1H, J ) 7 Hz), 7.82 (s, 1H), 7.86 (s, 1H), 8.20 (d, 1H, J )
7 Hz), 8.86 (s, 1H), 9.29 (s, 1H), 9.39 (s, 1H), 9.42 (s, 1H), 9.46
(s, 1H), 9.49 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 14.12, 22.66,
24.54, 24.62, 24.71, 25.92, 25.98, 28.54, 28.55, 28.70, 29.18, 29.24,
29.31, 31.80, 31.83, 59.07, 64.84, 65.29, 65.92, 66.09, 68.93, 70.65,
70.67, 70.82, 71.92, 88.17, 88.78, 89.69, 94.92, 97.14, 97.71, 114.22,
115.74, 115.77, 117.12, 117.82, 119.47, 121.22, 121.35, 121.53, 123.25,
128.33, 129.01, 130.14, 130.90, 131.14, 131.25, 132.74, 134.15, 136.60,
136.89, 137.00, 137.65, 140.54, 141.11, 144.41, 165.56, 165.66, 168.11,
169.76, 170.25, 170.27. Anal. Calcd for C75H98N6O14: C, 68.89; H,
7.55; N, 6.43. Found: C, 68.66; H, 7.56; N, 6.40.
Dimer 2h. To a solution of the dimer 2g (0.57 g, 0.81 mmol) in
MeOH (10 mL) was added potassium carbonate (6 mg, 0.043 mmol),
and the reaction was carried out as described for 2f to afford 0.46 g
(90.2%) of the desired 2h as a yellow oil. TLC, Rf ) 0.55 (petroleum
1
ether/EtOAc, 1/3). H NMR (500 MHz, CDCl3): δ 0.88 (t, 3H), 1.29
(m, 16 H), 1.74 (m, 2H), 2.26 (s, 3H, Ac), 2.42 (s, 3H, Ac), 3.65
(s, 1H, CCH), 3.74 (b, 4H, CH2), 3.93 (s, 3H, MeO), 4.27 (b, 2H,
CH2O), 7.52 (s, 1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.95 (s, 1H, NH),
8.83 (s, 1H, Ar-H), 9.09 (s, 1H, Ar-H), 9.16 (s, 1H, NH). 13C NMR
(125 MHz, CDCl3): δ 14.27, 22.84, 24.71, 25.04, 26.18, 28.91, 29.37,
29.49, 32.01, 52.90, 65.54, 77.67, 87.61, 90.48, 94.54, 114.05, 115.11,
119.78, 119.58, 121.45, 121.75, 128.85, 131.06, 137.47, 139.26, 144.56,
165.83, 168.42, 168.64, 169.85.
Trimer 3b. A mixture of 2h (263 mg, 0.42 mmol), 1n (300 mg,
0.58 mmol), bis(dibenzylideneacetone) palladium (7.6 mg, 0.0083
mmol), copper(I) iodide (2 mg, 0.01 mmol), and triphenylphosphine
(15 mg, 0.056 mmol) in dry triethylamine (28 mL) was stirred at
70 °C under argon for 24 h. The solution was then filtered and
concentrated to yield a brown oil, which was purified by silica gel
column (petroleum ether/dichloromethane/MeOH, 3/1/0.5) to afford
280 mg (66.0%) of 3b as a yellow oil. TLC, Rf ) 0.51 (petroleum
ether/CHCl3/acetone, 1/1/0.5). 1H NMR (500 MHz, CDCl3): 0.88 (m,
6H), 1.29-1.46 (m, 26H), 1.75 (t, 2H), 1.81 (t, 2H), 2.26 (s, 3H, Ac),
2.42 (s, 6H, Ac), 3.75 (b, 4H), 3.92 (s, 3H, MeO), 4.29 (m, 4H, CH2O),
7.54 (s, 1H, Ar-H), 7.73 (b, 2H, Ar-H), 8.01 (s, 1H, NH), 8.87
(s, 1H, Ar-H), 9.17 (s, 1H), 9.22 (s, 1H, NH), 9.32 (s, 1H, NH), 9.34
(s, 1H, Ar-H). 13C NMR (125 MHz, CDCl3): δ -0.05, 14.28, 22.85,
24.74, 24.79, 25.00, 26.12, 26.18, 28.71, 28.92, 29.35, 29.38, 29.42,
29.50, 31.97, 32.02, 52.82, 65.47, 66.35, 88.58, 89.97, 94.96, 97.15,
98.18, 106.76, 114.27, 115.95, 116.03, 117.84, 118.11, 119.59, 120.96,
121.39, 121.74, 128.66, 130.57, 136.91, 137.82, 139.64, 140.66, 144.58,
165.41, 166.11, 168.30, 168.39, 169.89, 170.38.
Pentamer 5. A mixture of dimer 2f (47 mg, 0.065 mmol), trimer
3a (50.9 mg, 0.05 mmol), bis(dibenzylideneacetone) palladium (2 mg,
0.0022 mmol), copper(I) iodide (0.5 mg, 0.0026 mmol), and triphen-
ylphosphine (3.1 mg, 0.012 mmol) in triethylamine (10 mL) was stirred
at 70 °C under argon for 28 h. After removal of solvent, the resulting
residue was purified by silica gel PTLC (dichloromethane/acetone,
10/1) to afford 64 mg (60.8%) of yellow solid 5. TLC, Rf ) 0.47
1
(CHCl3/acetone, 5/1). H NMR (500 MHz, CDCl3): δ 0.88 (s, 12H),
1.32 (m, 46H), 1.73 (m, 2H), 1.83 (m, 6H), 2.42 (s, 3H, Ac), 2.48
(s, 9H), 3.37 (s, 3H), 3.55 (t, 2H), 3.73 (m, 10 H), 3.89 (m, 2H), 4.32
(m, 8H), 4.49 (t, 2H), 7.41 (t, 1H), 7.46 (t, 1H), 7.51 (s, 1H), 7.63 (d,
1H, J ) 8.0 Hz), 7.75 (s, 1H), 7.78, 7.80 (d, 2H), 8.15 (d, 1H, J )
7.5 Hz), 8.82 (s, 1H), 9.20 (s, 1H), 9.33, 9.36, 9.38, 9.39 (q, 4H), 9.42
(s, 1H), 9.43 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 14.12, 22.68,
24.68, 24.75, 25.96, 28.58, 28.74, 29.21, 29.29, 29.33, 31.83, 59.05,
64.88, 65.25, 65.92, 66.08, 66.14, 68.96, 70.67, 70.70, 70.84, 71.96,
87.95, 88.03, 88.71, 89.59, 94.82, 95.01, 97.29, 97.48, 97.75, 114.25,
115.74, 115.80, 115.92, 117.02, 117.08, 117.78, 119.40, 121.08, 121.19,
121.28, 121.37, 121.44, 123.19, 128.32, 130.01, 130.69, 130.81, 131.08,
131.15, 132.60, 136.60, 136.89, 137.10, 140.59, 141.07, 141.22, 144.28,
165.45, 165.58, 168.03, 169.75, 170.25, 170.27, 170.35. Anal. Calcd
for C94H121N7O17: C, 69.65; H, 7.52; N, 6.05. Found: C, 69.43; H,
7.55; N, 5.90.
Hexamer 6. To a solution of 3b (30 mg, 0.029 mmol) in MeOH
(3 mL) was added potassium carbonate (0.5 mg, 0.0036 mmol). The
reaction solution was stirred for 10 min at room temperature, and then
water (5 mL) was introduced. Upon addition, the mixture was extracted
with chloroform (5 mL × 3), and the combined organic extracts were
washed with water, dried over Na2SO4, and concentrated to yield 26
mg of a yellow oil. The oil was a single spot on a TLC plate and was
used for the next step without purification. To the above oil (26 mg,
0.028 mmol) were added trimer 3a (21.5 mg, 0.021 mmol), bis-
(dibenzylideneacetone) palladium (0.8 mg, 0.87 µmol), copper(I) iodide
(0.5 mg, 2.6 µmol), triphenylphosphine (2.1 mg, 0.008 mmol), and
triethylamine (20 mL). The reaction mixture was then stirred at 70 °C
under argon for 24 h. After removal of solvent, the resulting residue
was purified by PTLC (chloromethane/acetone, 10/1) to afford 28 mg
(72.7%) of hexamer 6 as a yellow solid. TLC, Rf ) 0.45 (CHCl3/
1
Dimer 2g. A mixture of 1l (0.52 mg, 1.25 mmol), 1m (0.58 g, 1.40
mmol), bis(dibenzylideneacetone) palladium (21 mg, 0.023 mmol),
copper(I) iodide (4.4 mg, 0.023 mmol), and triphenylphosphine (31
mg, 0.12 mmol) in triethylamine (30 mL) was stirred at 70 °C under
argon for 12 h. The solution was then filtered and concentrated to yield
a brown residue, which was purified by silica gel column (petroleum/
EtOAc, 3/2) to afford 0.81 g (92.4%) of the dimer 2g as a yellow solid.
acetone, 3/1). H NMR (500 MHz, CDCl3): δ 0.88-0.96 (m, 18H),
1.13 (b, 3H), 1.26-1.40 (m, 40H), 1.49 (m, 3H), 1.65 (m, 2H), 1.86
(m, 6H), 2.44-47 (m, 15H, Ac), 3.22 (b, 2H), 3.37 (s, 3H, MeO),
3.53 (m, 4H), 3.65 (m, 2H), 3.69 (m, 2H), 3.73 (m, 2H), 3.88 (t, 2H),
3.93 (s, 3H, MeO), 3.94 (s, 3H), 4.14 (t, 2H, J ) 5 Hz), 4.31 (m, 6H),
4.45 (t, 2H, J ) 4 Hz), 6.87 (b, 1H, Ar-H), 7.08 (b, 1H, Ar-H), 7.38
(b, 2H), 7.69 (s, 1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.80 (s, 1H, Ar-H),
7.82 (s, 1H, Ar-H), 7.98 (d, 1H, Ar-H, J ) 7.5 Hz), 8.75 (s, 1H,
Ar-H), 8.95 (b, 1H), 9.05 (m, 3H), 9.23 (b, 1H), 9.37 (s, 1H), 9.42
(ts, 3H). 13C NMR (125 MHz, CDCl3): δ 14.11, 14.14, 22.66, 22.71,
24.65, 24.72, 25.75, 26.01, 28.54, 28.56, 28.68, 29.22, 29.32, 29.38,
29.39, 31.83, 31.86, 52.64, 59.01, 64.86, 64.98, 66.08, 66.13, 66.22,
68.96, 70.64, 70.66, 70.76, 71.93, 78.03, 87.69, 87.74, 87.79, 88.09,
89.51, 94.43, 97.34, 97.68, 97.73, 97.98, 113.58, 115.77, 115.79, 115.85,
115.89, 117.02, 117.12, 117.85, 118.65, 120.62, 120.79, 122.69, 128.52,
129.09, 129.45, 130.05, 130.11, 130.24, 130.65, 132.20, 134.29, 136.80,
1
TLC, Rf ) 0.43 (petroleum ether/EtOAc, 1/1). H NMR (500 MHz,
CDCl3): δ 0.33 (s, 9H, SiMe3), 0.88 (t, 3H), 1.29 (m, 16 H), 1.74
(t, 2H, CH2), 2.25 (s, 3H, Ac), 2.42 (s, 3H, Ac), 3.75 (b, 4H, CH2),
3.94 (s, 3H, MeO), 4.27 (t, 2H, CH2O), 7.54 (s, 1H, Ar-H), 7.75
(s, 1H, Ar-H), 8.03 (s, 1H, NH), 8.88 (s, 1H, Ar-H), 9.12 (s, 1H,
Ar-H), 9.21 (s, 1H, NH). 13C NMR (125 MHz, CDCl3): δ -0.032,
14.29, 22.85, 24.72, 25.03, 26.18, 28.91, 29.38, 29.50, 32.02, 52.89,
65.50, 90.50, 94.61, 98.40, 106.57, 114.10, 118.76, 119.64, 120.90,
120.90, 121.71, 128.86, 130.84, 136.84, 137.79, 139.03, 144.62, 165.94,
9
J. AM. CHEM. SOC. VOL. 126, NO. 10, 2004 3161

A R T I C L E S
Yang et al.
137.19, 137.47, 140.39, 140.97, 141.11, 143.48, 164.76, 164.81, 164.89,
164.99, 165.50, 167.94, 169.87, 170.27, 170.32, 170.40, 170.45. Anal.
Calcd for C106H130N8O20: C, 69.33; H, 7.14; N, 6.10. Found: C, 69.26;
H, 7.21; N, 5.87.
Ac), 2.27 (s, 3H, Ac), 1.28 (br, 6H, CH3). MS m/z calcd for
C
128H158N10O42 (M+) 2507.05; found (M + 2H)2+ 1255; (M + H +
Na)2+ 1266; (M + 2Na)2+ 1277.
Ab Initio and Molecular Mechanics Calculations. The ab initio
computations were carried out using the Gaussian 98 revision A.9
program. The geometry of each conformation was optimized at the
B3LYP/6-31G(d,p) level. The two optimized structures were used to
compute the single-point energy at the MP2/6-31G(d) level. One of
the C-Ph bonds of the optimized conformer 2a′ was rotated 180° to
obtain the structure of conformer 2c′. The same was done for conformer
2c′ to obtain a structure of 2a′.
Heptamer 7. To a sealed tube fitted with a magnetic stirring bar
were added 5a (24 mg, 1.30 × 10-2 mmol), 2i (31 mg, 3.90 × 10-2
mmol), Pd(dba)3 (3.1 mg, 3.90 × 10-3 mmol), CuI (ca. 0.8 mg,
4.20 × 10-3 mmol), Ph3P (1.5 mg, 5.72 × 10-3 mmol), and a mixed
dry solvent of acetonitrile/triethylamine (2:1) (3 mL). The mixture was
degassed three times, back-filled with nitrogen, and gradually heated.
At ∼60 °C, the tube was sealed and allowed to react for 2 days at
75 °C. After being cooled to room temperature, the mixture was diluted
with methanol, filtered, and concentrated. The brown residue was
dissolved in a mixed solvent of CHCl3/EtAc/MeOH (10:1:0.5) and
subjected to flash chromatography with gradient elution (10:1:0.5,
10:1:0.8, 10:1:1, and 10:1:1.2). After several impurity bands, the last
yellow band was collected (Rf: 0.15; developing agent, CHCl3/EtAc/
MeOH 10:1:1.2), and a faint-brown solid was provided after removing
the solvent (7.1 mg, 21.7%). The 1H NMR spectrum in CDCl3 showed
a broad signal in the amide and aromatic region. 1H NMR (500 MHz,
DMSO-d6/CD3OD(60/40)): δ 7.25-6.68 (br, 15H, Ar), 4.40 (br, over-
lapped, CH2), 3.50-3.70 (br, CH2), 3.26 (m, 21H, CH3), 2.60 (m, 18H,
Molecular mechanics calculations were carried out using the CaChe
program (version 3.22). Energy-minimized conformations of the
corresponding tetramer, pentamer, and hexamer were obtained using
the MM3 force field.
Acknowledgment. This work was supported by grants from
the NSF (CHE-0314577), NIH (R01GM63223), and ONR
(N000140210519), and by the Research Computing Facility at
UNL.
JA039416D
9
3162 J. AM. CHEM. SOC. VOL. 126, NO. 10, 2004