Chiral induction in phenanthroline-derived oligoamide foldamers: An acid- and base-controllable switch in helical molecular strands

Article abstract of DOI:10.1021/ol8001688

A series of phenanthroline-derived oligoamides bearing a chiral (R)-phenethylamino end group were synthesized that displayed chiral helical induction and subsequently formed one-hand helical foldamers in solution. Moreover, an acid- and base-controllable switch in the helical molecular strands was observed, which has been demonstrated by NMR, UV-vis, and circular dichroism spectroscopy.

Full text of DOI:10.1021/ol8001688

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1275-1278
Chiral Induction in
Phenanthroline-Derived Oligoamide
Foldamers: An Acid- and
Base-Controllable Switch in Helical
Molecular Strands
Hai-Yu Hu,†,‡ Jun-Feng Xiang,† Yong Yang,† and Chuan-Feng Chen*,†
Beijing National Laboratory for Molecular Sciences, Center for Chemical Biology,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China, and
Graduate School, Chinese Academy of Sciences, Beijing 100049, China
cchen@iccas.ac.cn
Received January 24, 2008
ABSTRACT
A series of phenanthroline-derived oligoamides bearing a chiral (R)-phenethylamino end group were synthesized that displayed chiral helical
induction and subsequently formed one-hand helical foldamers in solution. Moreover, an acid- and base-controllable switch in the helical
molecular strands was observed, which has been demonstrated by NMR, UV−vis, and circular dichroism spectroscopy.
The macromolecular and supramolecular helicities are one
of the most important and unique chiralities as exemplified
by biological macromolecules, such as proteins, nucleic acids,
and their helical assemblies.1 In recent years, artificial helical
foldamers with a predominantly one-hand helix sense have
attracted great interest not only for their mimicking biological
macromolecules such as DNA and proteins, but also for their
possible applications in material sciences including enanti-
oselective adsorbents and catalysts.2 However, the successful
examples of one-hand artificial helical foldamers still remain
rare,3 especially in aromatic oligoamide-based systems.4,5
It is known that the folding/unfolding molecular motion
between a helical state and a random form is an important
natural phenomenon in biology,6 but related artificial systems
(3) For chiral induction in synthetic helical strands, see: (a) Gin, M. S.;
Yokozawa, T.; Prince, R. B.; Moore, J. S. J. Am. Chem. Soc. 1999, 121,
2643-2644. (b) Prince, R. B.; Brunsveld, L.; Meijer, E. W.; Moore, J. S.
Angew. Chem., Int. Ed. 2000, 39, 228-230. (c) Sanji, T.; Kato, N.; Kato,
M.; Tanaka, M. Angew. Chem., Int. Ed. 2005, 44, 7301-7304. (d) Waki,
M.; Abe, H.; Inouye, M. Chem. Eur. J. 2006, 12, 7839-7847. (e) Sanji,
T.; Kato, N.; Tanaka, M. Org. Lett. 2006, 8, 235-238. (f) Stone, M. T.;
Fox, J. M.; Moore, J. S. Org. Lett. 2004, 6, 3317-3320.
(4) (a) Jiang, H.; Dolain, C.; Lehn, J.-M.; Gornitzka, H.; Huc, I. J. Am.
Chem. Soc. 2004, 126, 1034-1035. (b) Dolain, C.; Jiang, H.; Lehn, J.-M.;
Guionneau, P.; Huc, I. J. Am. Chem. Soc. 2005, 127, 12943-12951.
(5) (a) Dong, Z. Z.; Yap, G. P. A.; Fox, J. M. J. Am. Chem. Soc. 2007,
129, 11850-11853. (b) Li, C.; Wang, G.-T.; Yi, H.-P.; Jiang, X.-K.; Li,
Z.-T.; Wang, R.-X. Org. Lett. 2007, 9, 1797-1780. (c) Maurizot, V.; Dolain,
C.; Huc, I. Eur. J. Org. Chem. 2005, 1293-1301.
† Institute of Chemistry, Chinese Academy of Sciences.
‡ Graduate School, Chinese Academy of Sciences.
(1) (a) Hecht, S. M.; Huc, I. Foldamers: Structure, Properties and
Applications; Wiley-VCH: Weinheim, Germany, 2007. (b) Gellman, S. H.
Acc. Chem. Res. 1998, 31, 173-180. (c) Hill, D. J.; Prince, R. B.; Hughes,
T. S.; Moore, J. S. Chem. ReV. 2001, 101, 3893-4011.
(2) Maeda, K; Yashima, E. Top. Curr. Chem. 2006, 265, 47-88 and
references therein.
10.1021/ol8001688 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/27/2008

are limited.7 One particular interest example is the oligopy-
ridine-dicarboxamide system reported by Huc and Lehn’s
groups, which showed protonation-induced molecular mo-
tions from one helical structure to another.8 Recently, we
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.9
As part of our continuing work, we herein report a series of
new phenanthroline-derived oligoamides bearing a chiral (R)-
phenethylamino end group, which shows the chiral helical
induction and subsequently forms one-hand helical foldamers
in solution. Moreover, such helical molecular strands also
display an acid and base controlled structural switching
process, which is demonstrated by NMR, UV-vis, and CD
spectroscopy.
hypochromic effect with an increased number of phenan-
throline rings was observed, indicating that helical ordering
and π-π* stacking of the phenanthroline units in 2-4 might
exist.10,11
1
It is noteworthy that the H NMR spectra of the oligoa-
mides 2-4 showed only one set of signals in CDCl3 at
ambient temperature, which implied that they could exist in
one-hand helical conformation in solution. These results are
different from those of the chiral induction in quinoline-
derived oligoamide foldamers, in which an equilibrium
between R-P and R-M distereomers existed.4
The chirality induction in the oligoamide foldamers was
further studied by circular dichroism (CD) spectroscopy.12
Consequently, the CD spectra of 1-4 were recorded in CH3-
CN and shown in Figure 1. In contrast with the silent CD
Synthesis of oligoamides 1-4 is depicted in Scheme 1.
Scheme 1. Synthesis of Oligoamides 1-4
By the reaction of the appropriate monoacid 59 with (R)-1-
phenylethanamine (6a) in dichloromethane in the presence
of dicyclohexylcarbodiimide (DDC) and 1-hydroxybenzot-
riazole (HOBt), oligoamides 1-3 were synthesized in
excellent yields. Following the similar method, oligoamide
4 was synthesized by the condensation reaction of monoacid
5c and monoamine 6b. The structures of new compounds
were confirmed by the 1H NMR, 13C NMR, MS spectra, and
elemental analysis.10
Figure 1. CD spectra of the molecular strands 1 (black), 2 (red),
3 (green), and 4 (blue) in CH3CN (c ) 2 × 10-5 M).
spectra of helical oligomers bearing no chiral groups and
the CD spectrum of 1 with no chirality induction, 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.13 Furthermore, the increase in the molar
CD (∆ꢀ) from 2 to 4 (factor of 3.8) is much larger than the
increase in UV/vis absorption coefficient ꢀ (factor of 1.8),
which displays a marked amplification of the optical activity
in 3 and 4.
Similar to the oligo(phenanthroline dicarboxamide)s
1
we previously reported,9 the H NMR and 2D NOESY
studies clearly supported formation of helical secondary
structures of oligoamides 2-4 in solution.10 The UV/vis
absorption spectra further confirmed the intramo-
lecular interactions of the helical foldamers. As expected, a
Oligoamides 2-4 fold into stable helical structures arising
from the strongly preferred conformation of phenanthroline
dicarboxamide units, which is stabilized by intramolecular
hydrogen bonds as shown in the X-ray crystal structure of
phenanthroline dicarboxamide (Figure 2a). We speculated
(6) Kreis, T.; Vale, R. Cytoskeletal and Motor Proteins; Oxford
University Press: Oxford, 1999.
(7) (a) Hill, D. J.; Moore, J. S. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
5053-5057. (b) Barboiu, M.; Lehn, J.-M. Proc. Natl. Acad. Sci. U.S.A.
2002, 99, 5201-5206. (c) Stadler, A. M.; Kyritsakas, N.; Lehn, J.-M. Chem.
Commun. 2004, 2024-2025.
(8) (a) Dolain, C.; Maurizot, V.; Huc, I. Angew. Chem., Int. Ed. 2003,
42, 2738-2740. (b) Kolomiets, E.; Berl, V.; Odriozola, I.; Stadler, A. M.;
Kyritsakas, N.; Lehn, J.-M. Chem. Commun. 2003, 2868-2869. (c)
Kolomiets, E.; Berl, V.; Lehn, J.-M. Chem. Eur. J. 2007, 13, 5466-5479.
(9) (a) Hu, Z.-Q.; Hu, H.-Y.; Chen, C.-F. J. Org. Chem. 2006, 71, 1131-
1138. (b) Hu, H.-Y.; Xiang, J.-F.; Yang, Y.; Chen, C.-F. Org. Lett. 2008,
10, 69-72.
(11) Nelson, J. C.; Saven, J. G.; Moore, J. S.; Wolynes, P. G. Science
1997, 277, 1793-1796.
(12) Circular Dichroism and the Conformational Analysis of Biopoly-
mers; Fasman, G. D., Ed.; Plenum Publishing: New York, 1996.
(13) 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.
(10) See the Supporting Information.
1276
Org. Lett., Vol. 10, No. 6, 2008

proton was observed, while each of the amide protons
showed two sets of broadening signals (Figure 3b). The
results suggested that the partial protonation occurred on one
of the two phenanthroline groups in 2. Furthermore, it was
found that the amide protons in 2 only showed a set of signals
while the signal for NH+ protons became stronger upon the
addition 2 equiv of triflic acid (Figure 3c), which implied
the formation of the protonated species 2-(H+)2 as a random
structure. The addition of another equivalent triflic acid into
the above solution did not cause any new amide proton
signals,10 indicating no further protonation occurred on the
species 2-(H+)2. When the above mixture was treated with
3 equiv of Et3N, it was interestingly found that the proton
signals14 went back to the original positions of 2 (Figure
3d), indicating the helical structure of 2 restored.
Figure 2. Crystal structures of (a) phenanthroline dicarboxamide
and (b) 1-TfOH, green lines denote the intra- and intermolecular
hydrogen bonds. Isobutyl chains and hydrogen atoms not involved
in the hydrogen bonds are omitted for clarity.
The reversibility of the protonation process was also
corroborated by absorption spectra experiments. The UV-
vis spectrum of oligomer 2 in CH3CN displays absorption
maxima at 321 nm due to the π-π* electronic transition of
the phenanthroline moiety. Treating oligomer 2 with 1 equiv
of triflic acid, the UV spectrum showed a new band at the
longer wavelength, which indicated the formation of the
protonated species 2-H+. Addition of another 1 equiv of triflic
acid resulted in an increase of the new band, which suggested
the formation of the protonated species 2-(H+)2. Addition
of more triflic acid did not cause further obvious spectral
changes.10 However, neutralization of the above solution with
Et3N could result in the restored absorption spectra (Figure
4). Correspondingly, the color of the solution was changed
that protonation of the phenanthroline might be expected to
cause a conformational inversion, so as to allow formation
of new hydrogen bonds between the carbonyl groups and
the phenanthrolinium protons. As a result, when a suspension
of oligoamides 1-4 in acetonitrile was treated with triflic
acid separately, the corresponding protonated species of 1-4
formed immediately. The subsequent compounds became
soluble, and the color of the solutions changed from colorless
to light yellow.
We further obtained single crystals of protonated species
of 1 from the mixture solution of 1 in CH3CN in the presence
of excess triflic acid by a slow evaporation at room
temperature, and the X-ray crystal structure provided a direct
evidence for the formation of the phenanthrolinium salt. As
shown in Figure 2b, it was interestingly found that the
protonation occurred only on one of the nitrogen atoms of
the phenanthroline group, which resulted in a 180° rotation
about the adjacent arylamide linkage due to the intramo-
lecular NH+‚‚‚OC hydrogen bond.
The acid and base controllable switch in oligoamide 2 with
a helix extending to one complete turn was first studied by
1
the H NMR method. As shown in Figure 3, when 1 equiv
Figure 4. UV-vis spectra of 2 (2 × 10-5 M) in CH3CN (black),
protonated species 2-(H+) (red), 2-(H+)2 (blue) upon the addition
of triflic acid and deprotonated species 2-(H+) (green) and 2 (pink)
upon the addition of Et3N.
1
Figure 3. Partial H NMR spectra (10 mM, 600 MHz, CDCl3,
283 K) of (a) free 2, (b) protonated species 2-(H+), and (c) 2-(H+)2
upon the addition of triflic acid and (d) deprotonated species 2 upon
the addition of Et3N.
from light yellow back to its original colorless. The results
provided another evidence for the acid and base controlled
structural switch in the helical molecular strand.
(14) The sharper signals of the NH protons may be ascribed to the
formation of more stable helical structure of 2 in the polar and/or protonic
solvent. Similar phenomena see reference 9.
of triflic acid was added into the solution of 2 in CDCl3, a
very unshielded signal at 14.2 ppm for the phenanthrolinium
Org. Lett., Vol. 10, No. 6, 2008
1277

The structural switch in the helical molecular strand was
further demonstrated by the CD spectroscopy. As shown in
Figure 5, the solution of 2 in CH3CN showed a strong
restoration of the CD signal of oligoamide 2, which is in
agreement with the acid and base controllable switch. Similar
to 2, the longer helical molecular strands 3 and 4 also
displayed the acid and base controllable structural switching,
which was demonstrated by the UV-vis and CD spectros-
copy.10
In conclusion, we have synthesized a series of new
phenanthroline-derived oligoamides bearing a chiral (R)-
phenethylamino end group, and found that they could show
chiral helical induction and subsequently form one-hand
helical foldamers in solution. Moreover, we have also found
that the protonation of phenanthroline group could occur on
one of the two nitrogen atoms, and a subsequent acid and
base controllable switch in the phenanthroline dicarboxam-
ide-based helical molecular strands could be obtained, which
has been demonstrated by NMR, UV-vis and circular
dichroism spectroscopy. The results presented here will be
helpful to develop new one-hand synthetic helical foldamers,
and also find potential applications in the artificial molecular
machines.
Figure 5. CD spectra of 2 (2 × 10-5 M) in CH3CN (black),
protonated species 2-(H+) (red) and 2-(H+)2 (blue) upon the addition
of triflic acid and deprotonated species 2-(H+) (green) and 2 (pink)
upon the addition of Et3N.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (20625206), National Basic
Research Program (2007CB808004), and the Chinese Acad-
emy of Sciences for financial support. We also thank X. Hao
and T. L. Liang at the Institute of Chemistry, Chinese
Academy of Sciences, for determining the crystal structure.
negative Cotton effect at 353 nm, which was almost
disappeared upon the addition of 1 equiv of triflic acid. The
results implied a transition from the helical conformation of
2 to the unfolded, undulating ribbon of protonated species
2-(H+). However, when another equivalent triflic acid was
added into the above solution, a weak positive CD signal
was observed, which might be attributed to the protonation-
induced molecular motion resulting in an unregular right-
hand helical structure of species 2-(H+)2. Furthermore,
neutralization of the above solution with Et3N showed the
Supporting Information Available: Synthesis and char-
1
acterization data of the new compounds. Copies of H and
13C NMR spectra. TOCSY and NOESY spectra of 2 and
UV-vis and CD spectra of oligoamides 1-4 in the presence
of acid and base. X-ray crystallographic files (CIF) for
phenanthroline dicarboxamide and 1-TfOH. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL8001688
1278
Org. Lett., Vol. 10, No. 6, 2008