Probing the dynamic environment-associated conformational conversion from secondary to supersecondary structures in oligo(phenanthroline dicarboxamide)s

Article abstract of DOI:10.1021/jo900647d

(Figure Presented) The special structural features of the oligo(phenanthroline dicarboxamide)s and their dynamic environmentassociated conformational conversion from secondary helical structure to supersecondary helix-turn structure, owing to the conversi

Full text of DOI:10.1021/jo900647d

Probing the Dynamic Environment-Associated Conformational
Conversion from Secondary to Supersecondary Structures in
Oligo(phenanthroline dicarboxamide)s
Hai-Yu Hu,†,‡ Wei Xue,†,‡ Zhi-Qiang Hu,† Jun-Feng Xiang,† Chuan-Feng Chen,*,† and
Sheng-Gui He*,†
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and
Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China, and Graduate
School, Chinese Academy of Sciences, Beijing 100049, China
cchen@iccas.ac.cn
ReceiVed March 27, 2009
The special structural features of the oligo(phenanthroline dicarboxamide)s and their dynamic environment-
associated conformational conversion from secondary helical structure to supersecondary helix-turn
structure, owing to the conversion of the CONH bond from s-cis form to s-trans form, have been
experimentally and theoretically characterized by X-ray crystallographic, variable-temperature 1H NMR,
variable-temperature circular dichroism techniques, and computational studies. It has been demonstrated
that the solvent effects together with intramolecular hydrogen bonds and π-π stacking play a key role
in stabilizing both the secondary and supersecondary structures. Furthermore, by introducing the
intramolecular F · · ·H-N hydrogen bond to restrict the rotation about the CONH-aryl bonds, the oligomers
6 and 7 have been synthesized, which showed well-defined and predictable secondary helical conformations
in solution and in the solid state.
Introduction
and stability became a subject that has generated intense research
interest with the recognition that disease states arise from
aberrant folding or stability.3
The long-held tenet of protein folding that “one sequence
determines one structure” was breaking down to some extent,
and some sequences encode two or more folded states,1 which
was referred to as structural duality.2 Meanwhile, protein folding
The remarkable features of proteins have prompted chemists
to investigate oligomers capable of adopting well-defined,
compact conformations for mimicking the structures and func-
tions of biological macromolecules. In the past decade, synthetic
helical foldamers4,5 have attracted great attention in mimicking
the conformational behavior of biopolymers and showing
potential applications in molecular recognition, sensing, trans-
† Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory
of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy
of Sciences.
‡ Graduate School, Chinese Academy of Sciences.
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10.1021/jo900647d CCC: $40.75  2009 American Chemical Society
Published on Web 05/29/2009
J. Org. Chem. 2009, 74, 4949–4957 4949

Hu et al.
port, and catalysis.6 Recently, helical aromatic oligoamides7 have
attracted increasing interest for they feature a remarkable
combination of structural predictability, stability, tunability, and
ease of synthesis. Consequently, helical foldamers based on
oligoanthranilamides,8 oligopyridine dicarboxamides,9 quinoline-
derived oligoamides,10 and meta-connected diaryl amides11 have
been developed. Moreover, previous theoretical and experimen-
tal studies demonstrated that variations in macromolecular
architecture have an impact on the physical and chemical
properties of foldamers in solution,12 and structural changes of
aromaticoligoamidesinducedbyionbinding13 andprotonation14,17b
have been described. However, there are only a few studies
directly evaluating the effect of localized shifts in the confor-
FIGURE 1. Local variation of steric interaction related to the amide
s-cis/s-trans isomerization process in oligo(phenanthroline dicarboxa-
mide)s.
mational equilibria of a structural subunit on the consequent
global properties in solid and solution15 induced by solvent16
and temperature effects, and the examples are especially rare
in aromatic oligoamides.
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We recently reported a new class of aromatic oligoamides
based on phenanthroline dicarboxamides, which exhibited well-
defined helical secondary structures in solution and in the solid
state.17 Furthermore, we presented the first artificial aromatic
oligoamide based helix-turn-helix (HTH) supersecondary
structure,17b and very recently, we demonstrated the helical
molecular strands derived from the oligo(phenanthroline dicar-
boxamide)s displayed an acid- and base-controlled structural
switching process,17c and also found such helical foldamers
could be applied in folding-induced selective reduction of the
9,10-anthraquinone analogues.17d As part of our continuing
work, we herein experimentally and theoretically characterize
the structural features of the oligo(phenanthroline dicarboxa-
mide)s and their dynamic environment-associated conforma-
tional conversion from secondary to supersecondary structure,
owing to the conversion of the CONH-aryl bond from s-cis
form to s-trans form.
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Results and Discussion
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Design Principles. It is difficult to predict the conformation
of a macromolecule or supramolecule; however, a major
structural change of macromolecules or supramolecules some-
times depends on the conformational switching of a small
structural unit.18 Therefore, there has been considerable interest
in understanding, predicting, and controlling the conformation
of small structural units in the past few years.19
The o-phenylenediamide is an important structural unit in the
backbone of oligo(phenanthroline dicarboxamide)s. Since there
is no specific attractive or repulsive interaction between the two
amides of the o-phenylenediamide moieties, it can form s-cis
and s-trans conformations with rotation about the CONH-aryl
bond (Figure 1), which can be a rate-limiting step in the folding
mechanism. The factors that favor specific isomer geometry
around o-phenylenediamide can thus contribute significantly
toward controlling the structures of the oligo(phenanthroline
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5057. (b) Zhao, Y.; Zhong, Z. J. Am. Chem. Soc. 2005, 127, 17894–17901.
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4950 J. Org. Chem. Vol. 74, No. 14, 2009

Oligo(phenanthroline dicarboxamide)s
dicarboxamide)s. However, in our preceding research, the
o-phenylenediamide bonds all favored s-cis conformation, which
made the oligomers form secondary helical structures in solid
and solution.17 Subsequently, we wonder whether the helical
structure is the only conformation of these oligo(phenanthroline
dicarboxamide)s, and whether the conformation of o-phenylene-
diamide bonds could change to the s-trans conformation in
response to environmental factors such as solvent acceptor
ability. To confirm this thought, we decided to choose the
oligomers with three phenanthroline units as the model for
investigating the conformational conversion phenomena. When
the conformational transition occurs in one of the o-phenylene-
diamide subunits in the oligomer triggered by an s-cis to s-trans
180° rotation, the simplest environment-associated supersec-
ondary helix-turn structure will be formed.
Solid-State Structure of Oligomer 3a. Understanding the
fundamental principles of protein folding requires the integration
of experimental and theoretical approaches. X-ray crystal-
lography is the preeminent technique in the determination of
protein structure. In the oligo(phenanthroline dicarboxamide)s,
the special conversion phenomenon was first observed in the
X-ray single-crystal structure of oligomer 3a, which also
provided direct evidence for the formation of the helix-turn
supersecondary structure. The single crystals of oligomer 3a
suitable for X-ray diffraction were obtained from its mixture
solution of CH2Cl2/MeOH through slow evaporation at room
temperature. As shown in Figure 2b, the oligomer 3a consisted
of a regular helix and a turn, which formed a helix-turn
supersecondary motif. It was found that the helical pitch in 3a
is about 3.5 Å, which indicates intramolecular π-π stacking
between the two phenanthroline. In addition, the turn side was
also stabilized by an additional intramolecular seven-membered
hydrogen bond between the amides with a CdO· · ·HN distance
of 2.49 Å. Interestingly, we further found that one MeOH
molecule was presented at the outside of one of the helical
terminals (Figure 2c). There exist multiple intermolecular
hydrogen bonds between the methanol molecule and the helix,
which enhanced the helical stability. It is also noteworthy that
after the inversion, there is an intermolecular face-to-face π-π
stacking between the two phenanthroline rings of the adjacent
foldamers with a distance of 3.50 Å, which can bring about
significant additional stabilization of the supersecondary structure.
FIGURE 2. (a) Chemical structures of oligomers1a-4a. (b) Crystal
structures of 3a obtained in CH2Cl2/CH3OH. (c) Crystal packing of 3a
with methanol molecules presented at the helical ends. (d) Crystal
packing of 3a with H2O molecules presented at the helical ends obtained
in CH2Cl2/CH3CN. Isobutyl chains and hydrogen atoms not involved
in the hydrogen bonds are omitted for clarity.
We attempted to grow the single crystals of 3a from other
solutions and hoped to obtain the regular helical structure. As
a result, the oligomer 3a similarly crystallized from CH2Cl2/
j
CH3CN, affording a clear, triclinic crystal with a P1 space group;
however, the X-ray experiment result showed that 3a still forms
the helix-turn structure, and there was a H2O molecule instead
of MeOH at each end of the helix-turn (Figure 2d). The turn
side was also stabilized by an additional intramolecular seven-
membered hydrogen bond between the amides with a CdO· · ·HN
distance of 2.45 Å. The intermolecular distance between the
two planes containing the phenanthroline groups is 3.50 Å,
corresponding to the van der Waals contact. We considered that
because of the addition of intermolecular face-to-face π-π
stacking at the turn side, the helix-turn structure is more stable
than the helix structure in the crystal state. Since crystallization
is a kinetically controlled process, this X-ray structure does not
necessarily represent the energy minimum of the system.
concentration of 10 mM, no new signals were observed for
oligomers 1a and 2a, which indicated oligomers 1a and 2a
preferred stable planar and helical conformations, respectively
1
(see the Supporting Information). In contrast, the H NMR
spectra of oligomers 3a and 4a exhibited more sensitivity to
temperature. As shown in Figure 3, 3a shows the spectrum of
a compound of C2 symmetry at room temperature (298 K),
which suggests that the inversion between different conforma-
tions is fast in the NMR time scale. With lowering of the
temperature, signals corresponding to NHs broadened. At 238
K, new signals in the NH zone appeared, while new broad
signals also came into sight in the area between 6 and 9 ppm.
These observations implied that more than one conformation
of the oligomer in solution could exist at low temperature and
the interconverting equilibrium of the two conformations (s-cis
and s-trans) might depend on temperature. For the longer
1
Solution-State Structure. Variable-temperature H NMR
studies on oligomer 1a-4a were further carried out to examine
their conformations in CDCl3 solution. At 213 K and a
J. Org. Chem. Vol. 74, No. 14, 2009 4951

Hu et al.
1
FIGURE 3. Temperature-dependent H NMR spectra (600 MHz, 10 mM, CDCl3) of 3a.
oligomer 4a at the same condition, two sets of signals for C2
symmetrical molecules were observed at 213 K. The NHs
signals, which appeared broad in the downfield area between
9.9 and 11.3 ppm at 298 K, exhibited 8 sharp signals in this
field (see the Supporting Information). This indicated that the
NH bonds of the middle o-phenylenediamides might invert from
s-cis form to s-trans form, and the oligomer 4a could adopt
both secondary and supersecondary conformations at low
temperature.
Chirality Induction. Circular dichroism (CD) spectroscopy
is of considerable importance to the study of proteins as a
quantitative tool in the estimation of secondary structure,20 and
it is also a useful tool to investigate the secondary structure of
synthetic oligomers.21 Therefore, to investigate the conforma-
tional properties of the oligomers in solution, a chiral, nonra-
cemic 1-phenylethanamine group was employed as the terminal
to cause the M and P helical conformations at the periphery to
be related as diastereomeric conformations, and the effect of
solvent on the special conformational preference of the oligo-
mers could be investigated by CD spectroscopy.22 First, we used
oligomers 1-4 to carry out their CD experiments in methanol
at room temperature. As shown in Figure 4, the helical foldamers
2-4 show a positive and then a negative CD band between
300 and 420 nm due to the π-π* electronic transition of the
phenanthroline moiety, which indicates that the oligoamides may
have a predominant one-handed (R-M) helical structure.23
FIGURE 4. (a) Chemical structures of oligomers 1-4 and (b) CD
spectra of oligomers 1-4 in MeOH (c ) 5 × 10-5 M).
(20) Whitford, D. Protions Structure and Function; John Wiley & Sons, Ltd.:
Chichester, England, 2006.
However, in contrast with the amplification of the optical activity
CD spectra of helical oligomers 1-4 in acetonitrile,17c the
intensity of the molar CD (∆ε) of 2 and 3 is almost the same
in methanol. There is a loss of helicity in longer oligomer 3, in
(21) (a) Circular Dichroism and the Conformational Analysis of Biopolymers;
Fasman, G. D., Ed.; Plenum Publishing: New York, 1996. (b) Maeda, K;
Yashima, E. Top. Curr. Chem. 2006, 265, 47–88.
(22) (a) Parquette, J. R. C. R. Chimie 2003, 6, 779–789. (b) Hofacker, A. L.;
Parquette, J. R. Angew. Chem., Int. Ed. 2005, 44, 1053–1057.
4952 J. Org. Chem. Vol. 74, No. 14, 2009

Oligo(phenanthroline dicarboxamide)s
(see the Supporting Information). Similar bandshapes were
obtained in each of the solvents, and the ∆ε values increased
as the numbers of the phenanthroline group increased in both
of the solvents, which indicated that the helical structures are
more stable. These studies support the supposition that the
solution is a source of or contributing factor to the s-cis and
s-trans conformation inversion. In nonprotic solutions, a highly
biased helical secondary structure is present in 3, and it is guided
to secondary and helix-turn supersecondary conformation
equilibria in protic solutions.
FIGURE 5. Crystal structure of 3 with ethanol molecules presented
at the helical ends. Isobutyl chains and hydrogen atoms not involved
in the hydrogen bonds are omitted for clarity.
A clear, colorless plate-like crystal of oligomer 3 was obtained
by slow evaporation of an EtOH solution. The crystal structure
indicated that the oligomer adopts a helical-turn conformation
in the solid state (Figure 5). Similar to oligomer 3a, there is
also an intermolecular π-π stacking at the turn side. It is
noteworthy that, because of the inversion, both the right-handed
and the left-handed diastereomers have cocrystallized in the
crystal structures, which could give any CD singles in the
phenanthroline UV-absorbing region at 363 nm. That may be
one reason that the intensities of the molar CD (∆ε) of 2 and 3
are almost the same in methanol.
agreement with our assumption that besides the helical structure,
strand 3 may have the other conformations in methanol. Next,
the temperature dependence of the oligo(phenanthroline dicar-
boxamide)s on their conformational conversion behavior was
also investigated by CD spectroscopy in acetonitrile and in
methanol. In contrast to oligomer 2, which displayed preferences
for the helical conformation in both the acetonitrile and methanol
solvents, oligomers 3 and 4 were significantly affected by
external conditions, such as the solvent and temperature. The
molar CD values at 363 nm of oligomers 3 and 4 in acetonitrile
slightly increased, which demonstrated that their helical con-
formations were more stable in acetonitrile with decreasing
temperature. However, decreasing the temperature of a solution
of oligomers 3 and 4 in methanol from 25 to -10 °C led to
destabilization of the helical conformation as evidenced by the
decreasing CD intensity at 363 nm (see the Supporting Informa-
tion). To obtain more insights into the effect of solvent on the
special conformation, we further carried out the CD experiments
of oligomers 1-4 in CH2Cl2 and high-polarity solvent DMSO
The fluxional nature of the molecule was evident in the
temperature-dependent1H NMR spectra of 3 in CDCl3 (Figure
6). At room temperature (298 K), only one set of signals of
oligomer 3 were observed, which indicated an extremely biased
conformational equilibrium or the inversion between different
conformations was fast in the NMR time scale. With lowering
of the temperature, signals corresponding to NHs and the
aromatic protons broadened. At a temperature where the rate
of conformation interconversion was slow on the NMR time
scale, new signals in the NH zone appeared; new broad signals
also come into sight in the area between 6 and 9 ppm, which
1
FIGURE 6. Temperature-dependent H NMR spectra (600 MHz, 10 mM, CDCl3) of 3.
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Hu et al.
FIGURE 7. Optimization of oligo(phenanthroline dicarboxamide) 3a at the B3LYP/3-21g** level.
indicated another conformation of oligomer 3 appeared. We also
take the variable-temperature H NMR studies on the longer
bond but addition of π-π stacking. These rotations result in
an over 5.2 kJ/mol additional conformational energy. The energy
barrier for rotation is only 25 kJ/mol. To simplify the research
model, we added two solvent molecules instead of the solvent.
It is noteworthy that the preference for s-trans over s-cis
conformations decreases significantly from 5.2 kJ/mol in the
gas phase to -9.9 kJ/mol in 3a-2CH3CN, which means that
the helical structure is much more stable than the helix-turn
structure in CH3CN. It is also worthy of note that the preference
for s-cis conformation becomes very small (about 0.1 kJ/mol)
when two MeOH molecules are added to oligomer 3a. In this
case, the helical structure and the helix-turn structure will both
exist in MeOH. Accordingly, we can conclude that together with
hydrogen bonds and intramolecular π-π stacking, solvent
effects also play an important role in the stability of oli-
go(phenanthroline dicarboxamide)s. Theoretical conformational
searching of 3a with the B3LYP/3-21g** predicts a helical
structure in nonprotic solvent whereas it predicts a conforma-
tional equilibria of helical and helix-turn structures in protic
solvent, in accord with the CD studies. It also demonstrated
that the low energy barrier to the s-cis/s-trans interconvertion
produced a highly dynamic conformational equilibrium at
ambient temperature. This work suggests the potential of
foldamers to exhibit conformational responses to localized
structural perturbations.
1
strand 4. Similar to 4a, multiple sets of sharp signals were
observed at 213 K; however, it is hard for us to confirm the
position of the NH bonds of the o-phenylenediamides which
inverted from s-cis form to s-trans form (see the Supporting
Information).
Conformational Energy and Molecular Dynamics
Simulations of Oligomer 3a. Computational studies suggest
the possibility of conformational conversion from secondary to
supersecondary structure. We calculated the difference in free
energy (∆G) between the helically ordered state and the
supersecondary helix-turn conformations of oligomer 3a. Op-
timization of oligo(phenanthroline dicarboxamide) 3a at the
B3LYP/3-21g** level of theory revealed two unique conforma-
tions. These conformations corresponded to carboxamide groups
of the o-phenylenediamide toward the same direction or opposite
directions, one s-cis conformer and s-trans conformer. In the
gas phase (Figure 7), the helix-turn conformer is the most stable.
The second lowest energy conformer was the helical structure.
They differ from the former by an ca. 180° rotation about one
of the aryl--H linkages on one of the o-phenylenediamide rings,
which can occur with disruption of one intramolecular hydrogen
(23) Tanatani, A.; Yokoyama, A.; Azumaya, I.; Takakura, Y.; Mitsui, C.;
Shiro, M.; Uchiyama, M.; Muranaka, A.; Kobayashi, N.; Yokozawa, T. J. Am.
Chem. Soc. 2005, 127, 8553–8561.
4954 J. Org. Chem. Vol. 74, No. 14, 2009

Oligo(phenanthroline dicarboxamide)s
SCHEME 1. Synthetic Route of Compounds 5-7
Restricted Rotation Around the CONH-Aryl Bonds.
Rotation around the CONH-aryl bonds could be restricted by
a hydrogen bond between the amide proton and a hydrogen bond
acceptor at the ortho position on the aryl group.7a In ref 24, the
intramolecular F · · ·H-N hydrogen bond has been utilized to
stabilize the binding conformation of the oligomers; therefore,
the fluorine-containing compounds 5-7 were synthesized, which
were prepared from the appropriate acid with 2-fluorobenzene-
1,3-diamine25 in dichloromethane in the presence of dicyclo-
hexylcarbodiimide and 1-hydroxybenzotriazole (Scheme 1).
consistent with helical structures of 6 and 7, which have been
assigned stacked, possibly helical conformations in solution.
The X-ray crystal structures of 6 and 7 have been determined,
and they showed that both molecules take up a helical
conformation in the solid state. The structure of 6 shows (Figure
9a,b) a clear helical arrangement of the five rings stabilized by
a network of intramolecular hydrogen bonds (NHe · · ·N, 2.05
Å; NHe · · ·F, 2.30 Å; NHd · · ·N, 2.19 Å). Figure 9b shows the
left-handed helix with a complete turn; however, the crystal is
racemic with both right- and left-handed forms present in the
unit cell. The structure of the longer strand 7 also shows (Figure
9c,d) a clear helical arrangement of the five rings stabilized by
a network of intramolecular hydrogen bonds (NHf · · ·N, 2.11
Å; NHe · · ·F, 2.28 Å; NHe · · ·N, 2.06 Å; NHe · · ·F, 2.21 Å;
NHd · · ·N, 2.23 Å). This network of hydrogen bonds serves to
restrict the rotation about the CONH-aryl bonds to a cisoid
conformation, and the oligomer assumes an overall helix shape.
Similar to oligomer 6, Figure 9d shows the right-handed helix
with two turns; however, the crystal is also racemic with both
right- and left-handed forms present in the unit cell. Accordingly,
we can conclude that the addition of the F· · ·H-N hydrogen
bond could be utilized to stabilize the binding conformation of
the oligomers. The F · · ·H-N distance is between 2.30 and 2.21
Å, which is about 15% shorter than the sun of the van der Waals
radii (2.67 Å). Compared with the crystal structures of the
o-phenylenediamide connecting oligomers reported by us before,
the increase in the hole of the helix made the partial overlap of
the two adjacent phenanthroline units disappeared, which
reduced the π-π stacking of the oligomers, hence, the F · · ·H-N
1
Compounds 5-7 have been characterized by H NMR, 13C
NMR, elemental analyses, and MALDI-TOF mass spectrometry.
1
Figure 8 shows the H NMR spectra of solutions of 5-7 in
CDCl3. Increasing strand length results in a strong shielding of
aromatic protons Ha, Hb, and Hc, which can be attributed to
tight contacts between aromatic rings. The 1H NMR spectra are
(24) Li, C.; Ren, S.-F.; Hou, J.-L.; Yi, H.-P.; Zhu, S.-Z.; Jiang, X.-K.; Li,
Z.-T. Angew. Chem., Int. Ed. 2005, 44, 5725–5729.
(25) Hudilicky, M.; Bell, H. M. J. Fluorine Chem. 1974, 4, 19–23.
FIGURE 8. Partial 1H NMR spectra (10 mM, 600 MHz, CDCl3, 283K)
of (a) 5, (b) 6, and (c) 7.
J. Org. Chem. Vol. 74, No. 14, 2009 4955

Hu et al.
NMR, variable-temperature circular dichroism techniques, and
computational studies. We have further demonstrated that the
solvent effects together with intramolecular hydrogen bonds and
π-π stacking play a key role in stabilizing both the secondary
and supersecondary structures. Moreover, we have also proved
that by introducing the intramolecular F · · ·H-N hydrogen bond
to restrict the rotation about the CONH-aryl bonds, the
oligomers 6 and 7 subsequently showed well-defined and
predictable secondary helical conformations in solution and in
the solid state. The results presented here suggested that similar
to biomolecules, the differences in local conformational equi-
libria of the oligo(phenanthroline dicarboxamide)s could also
be dominated by hydrophobic effects at the global structural
level, and this environment-responsive type of conformational
control could have considerable potential for controlling the
shape of macromolecules or supramolecules. Our further work
will focus on the investigation of the possible conformations
of the longer and more complicated systems, and develop
materials with novel functional capabilities exhibiting an
amplified global environment response to a local event.
Experimental Section
Quantum Chemical Calculations. All quantum chemical cal-
culations were performed at the B3LYP/3-21g** level of ab initio
MO theory employing the Gaussian03 software package. The
geometries of the molecules were completely optimized.
X-ray Crystallography. X-ray diffraction data for compounds
3a obtained in CH2Cl2/CH3OH, 3a obtained in CH2Cl2/CH3CN, 3,
6, and 7 were collected on a Rigaku Saturn X-ray diffractometer
with graphite-monochromator Mo KR radiation (λ ) 0.71073 Å).
Intensities were collected for absorption effects by using the
multiscan technique SADABS. The structures were solved by
direction methods and refined by a full matrix least-squares
technique based on F2, using SHELXL 97 program. All non-
hydrogen atoms were refined anisotropically and H atoms were
located from difference electron density maps. Especially for 7,
the disordered solvent molecules were deleted with the SQUEEZE
program. The crystals 6 and 7 were easy to effloresce, so they were
all measured in sealed tubes. The poor qualities of the structures
may be due to weak diffraction intensity and strong disorganization
of isobutyl side chains and included solvent molecules. However,
all C and N atoms belonging to the backbone of the helix except
those for the end benzene rings were accurately located. The X-ray
crystallographic data are summarized in Table 1.
Compound 5. To the solution of 2-fluorobenzene-1,3-diamine
9 (630 mg, 5 mmol) in CH2Cl2 (50 mL) were added the acid 8
(2.43 g, 5 mmol), 1-hydroxylbenzotriazole (HOBt) (1.24 mg, 6
mmol), and DCC (918 mg, 6 mmol). The reaction mixture was
stirred at room temperature, and then refluxed for 10 h. The
precipitates were removed by filtration through the Celite. The
solution was concentrated, and the residue was washed with MeOH.
The solid was purified by silica gel column chromatography (ethyl
acetate/dichloromethane/petroleum ether 1:2:3) to give the product
FIGURE 9. Crystal structures of the (a) top view and (b) side view of
6 and the (c) top view and (d) side view of 7. Isobutyl chains and
hydrogen atoms not involved in the hydrogen bonds are omitted for
clarity.
1
(yield 91%) as a white solid. Mp >300 °C; H NMR (CDCl3, 600
MHz) δ 11.12 (d, 1H, J ) 2.1 Hz, NH), 10.44 (s, 1H, NH), 8.28
(d, 2H), 8.03 (t, 2H, J ) 7.5 Hz), 7.94 (s, 1H), 7.93 (d, J ) 8.0
Hz, 2H), 7.47 (t, J ) 7.7 Hz, 2H), 7.23 (t, J ) 7.4 Hz, 1H), 7.02
(t, J ) 7.9 Hz, 1H), 6.58 (t, J ) 7.9 Hz, 1H), 4.14 (d, 2H, J ) 6.5
hydrogen bond plays a key role in the enhanced helical stability.
This simple expansion of the helical structure offers potential
in the future for subtle modification of the folded structures.
Hz, -OCH2CH(CH3)2), 4.12 (d, 2H,
J
)
6.5 Hz,
Conclusion
-OCH2CH(CH3)2), 3.62 (br s, 2H, -NH2), 2.35-2.30 (m, 2H,
-OCH2CH(CH3)2), 1.19-1.17 (m, -OCH2CH(CH3)2, 12H); 13C
NMR (CDCl3, 150 MHz) δ 163.5, 163.4, 162.5, 161.9, 150.9, 150.5,
144.6, 144.58, 144.49, 143.0, 141.4, 137.8, 134.2, 134.1, 128.8,
126.85, 126.80, 124.75, 124.70, 124.67, 122.7, 121.4, 121.4, 120.6,
120.5, 112.1, 110.0, 101.9, 101.3, 75.6, 75.5, 28.23, 28.21, 19.2;
MALDI-TOF MS m/z 596.3 [M + H]+. Anal. Calcd for
In conclusion, we have characterized the structural features
of the oligo(phenanthroline dicarboxamide)s, and presented their
dynamic environment-associated conformational conversion
from secondary helical structures to supersecondary helix-turn
1
structures by X-ray crystallographic, variable-temperature H
4956 J. Org. Chem. Vol. 74, No. 14, 2009

Oligo(phenanthroline dicarboxamide)s
TABLE 1. X-ray Crystallographic Data
3a·CH3OH
3a·H2O
3
6
7
empirical formula
Mr
C90H90N12O12 ·CH3OH C90H90N12O12 ·H2O
C92H94N12O12 ·2CH3CH2OH C62H61FN8O8 ·5CH2Cl2 C102H103F2N12O12
1562.77
1548.69
1651.93
1489.82
1726.96
crystal size [mm3]
0.42 × 0.39 × 0.12
0.42 × 0.39 × 0.12 0.20 × 0.18 × 0.14
0.26 × 0.18 × 0.16
monoclinic
20.318(4)
18.965(4)
18.194(4)
90(9)
90.13(3)
90(9)
7011(2)
0.26 × 0.18 × 0.16
monoclinic
14.1007(16)
35.769(4)
22.459(2)
90
118.483(3)
90
9956.5(19)
1.152
crystal system space group triclinic
a [Å]
b [Å]
c [Å]
triclinic
triclinic
13.471(3)
17.872(4)
18.764(4)
103.82(3)
91.95(3)
110.35(3)
4079.2(14)
1.272
13.257(3)
18.769(4)
19.131(4)
117.56(3)
91.60(3)
103.68(3)
4047.9(15)
1.163
13.387(2)
17.522(2)
23.044(3)
111.151(9)
96.563(11)
103.945(9)
4770.2(11)
1.150
R [deg]
ꢀ [deg]
γ [deg]
V [Å3]
d [g cm-3
Z
]
1.411
2
2
2
4
4
T [K]
293(2)
293(2)
113(2)
113(2)
113(2)
R1, wR2 [I > 2σ(I)]
R1, wR2 (all data)
quality of fit
0.1551, 0.1551
0.4040, 0.2312
1.008
0.1666, 0.2907
0.3297, 0.3913
1.192
0.1343, 0.4111
0.1603, 0.4329
1.585
0.0632, 0.1733
0.0742, 0.1832
1.126
0.0699, 0.1973
0.0846, 0.2117
1.053
C34H34FN5O4: C, 68.56; H, 5.75; N, 11.76. Found: C, 68.30; H,
5.79; N, 11.67.
2H, NH), 10.77 (s, 2H, NH), 10.07 (s, 2H, NH), 8.40 (br s, 4H),
8.36 (br s, 2H), 8.14 (br s, 2H), 8.01 (s, 2H), 7.82 (s, 2H), 7.42-7.41
(m, 2H), 7.26 (br, J ) 7.4 Hz, 4H), 7.03 (d, J ) 7.8 Hz, 2H), 6.12
(t, J ) 7.6 Hz, 4H), 5.66 (t, J ) 8.1 Hz, 2H), 5.54 (t, J ) 6.8 Hz,
2H), 4.30-4.27 (m, 12H, -OCH2CH(CH3)2), 2.50-2.40 (m, 6H,
-OCH2CH(CH3)2), 1.30-1.17 (m, -OCH2CH(CH3)2, 36H); 13C
NMR (CDCl3, 75 MHz) δ 163.4, 163.3, 162.9, 162.2, 161.9, 161.2,
151.0, 149.9, 149.6, 144.8, 144.6, 137.5, 127.5, 126.1, 123.3, 122.8,
122.7, 122.5, 122.3, 120.5, 120.4, 120.2, 119.0, 114.3, 112.8, 102.1,
101.2, 101.0, 75.7, 75.5, 28.3, 19.39, 19.36, 19.34; MALDI-TOF
MS m/z 1567.9 [M + H]+. Anal. Calcd for C90H88F2N12O12 ·2H2O:
C, 67.40; H, 5.78; N, 10.48. Found: C, 67.39; H, 5.76; N, 10.32.
Compound 6. To the solution of 2-fluorobenzene-1,3-diamine
9 (315 mg, 2.5 mmol) in CH2Cl2 (50 mL) were added the acid 8
(2.43 g, 5 mmol), HOBt (1.24 mg, 6 mmol), and DCC (918 mg, 6
mmol). The reaction mixture was stirred at room temperature, and
then refluxed for 10 h. The precipitates were removed by filtration
through the Celite. The solution was concentrated, and the residue
was washed with MeOH. The solid was purified by silica gel
column chromatography (ethyl acetate/dichloromethane/petroleum
ether 1:2:3) to give the product (yield 82%) as a white solid. Mp
1
280-281 °C; H NMR (CDCl3, 600 MHz) δ 11.22 (s, 2H, NH),
10.22 (br s, 2H, NH), 8.28 (d, 2H), 8.49 (t, 2H, J ) 7.8 Hz),
8.37-8.33 (m, 4H), 8.07 (br s, 2H), 7.99 (s, 2H), 7.41 (t, J ) 8.2
Hz, 1H), 7.34 (d, 4H), 6.27-6.24 (m, 4H), 5.61 (t, J ) 6.8 Hz,
2H), 4.24-4.21 (m, 8H, -OCH2CH(CH3)2), 2.42-2.37 (m, 4H,
-OCH2CH(CH3)2), 1.24-1.21 (m, -OCH2CH(CH3)2, 24H); 13C
NMR (CDCl3, 150 MHz) δ 163.4, 163.0, 162.3, 161.9, 150.8, 149.8,
144.7, 144.0, 142.4, 137.6, 127.6, 126.7, 126.6, 125.5, 122.6, 122.6,
122.4, 120.8, 120.1, 118.9, 115.2, 101.8, 100.9, 75.6, 28.3, 19.3;
MALDI-TOF MS m/z 1065.6 [M + H]+. Anal. Calcd for
C62H61FN8O8 ·0.5H2O: C, 69.32; H, 5.82; N, 10.43. Found: C, 69.25;
H, 5.84; N, 10.44.
Acknowledgment. We thank the National Natural Science
Foundation of China (20625206), CMS-CX200826, and Na-
tional Basic Research Program of China (2007CB808004,
2008CB617501) for financial support. We also thank Prof. Eiji
Yashima and co-workers at Nagoya University for doing CD
experiments at various temperatures, and Dr. Hai-Bin Song at
Nankai University for determining the crystal structures.
1
Supporting Information Available: Copies of H and 13C
Compound 7. To the solution of 5 (1.19 mg, 2 mmol) in CH2Cl2
(50 mL) were added the acid 10 (412 mg, 1 mmol), HOBt (618
mg, 3 mmol), and DCC (459 mg, 3 mmol). The reaction mixture
was stirred at room temperature, and then refluxed for 10 h. The
precipitates were removed by filtration through the Celite. The
solution was concentrated, and the residue was washed with MeOH.
The solid was purified by silica gel column chromatography (ethyl
acetate/dichloromethane/petroleum ether 1:2:3), and crystallized
from dichloromethane/methanol to give 7 (yield 85%) as white
NMR spectra, TOCSY and NOESY spectra of 5-7; CD spectra
of oligoamides 1a-4a in various solvents; variable-temperature
1H NMR spectra of oligoamides 1-4 and 1a-4a, variable-
temperature CD spectra of oligoamides 1, 3, and 4 in CH3CN
and 2-4 in MeOH; and X-ray crystallographic files (CIF) for
oligomers 3, 3a·CH3OH, 3a·H2O, 6, and 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
crystals. Mp >300 °C; H NMR (CDCl3, 600 MHz) δ 11.10 (s,
JO900647D
J. Org. Chem. Vol. 74, No. 14, 2009 4957