A hetero-stranded double helix composed of m-diethynylbenzene-based complementary molecular strands stabilized by amidinium-carboxylate salt bridges

Article abstract of DOI:10.1039/c0cc03952g

A hetero-stranded double helix with a controlled helix sense was designed and synthesized from an optically active dimeric amidine and its complementary achiral dicarboxylic acid strand with conjugated m-diethynylbenzene backbones, being stabilized by the

Full text of DOI:10.1039/c0cc03952g

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A hetero-stranded double helix composed of m-diethynylbenzene-based
complementary molecular strands stabilized by amidinium-carboxylate
salt bridgesw
Zong-Quan Wu, Yoshio Furusho,* Hidekazu Yamada and Eiji Yashima*
Received 18th September 2010, Accepted 8th October 2010
DOI: 10.1039/c0cc03952g
A hetero-stranded double helix with a controlled helix sense
was designed and synthesized from an optically active dimeric
amidine and its complementary achiral dicarboxylic acid strand
with conjugated m-diethynylbenzene backbones, being stabilized
by the salt bridges.
m-diethynylbenzene skeletons have been widely employed for
constructing various supramolecular complexes including single
and double helices, because of their well-defined geometry as
well as shape-persistent nature.13 In addition, m-diethynylbenzene
skeletons can be constructed through the Sonogashira coupling
that requires relatively mild conditions, which extends the
possibility for the further design of artificial double helices. We
now report the design and synthesis of a new, more compact
double helix stabilized by salt bridges by replacing the m-terphenyl
groups with simpler m-phenylene ones (Fig. 1).
Helical structures are the central structural motifs for
biomacromolecules, such as DNA, proteins, and polysaccharides,
and also direct the sophisticated functions of these macromolecules
in living systems. Since the inspirational discovery of the DNA
double helix by Watson and Crick,1 chemists have been
prompted to design and synthesize artificial polymers and
oligomers that fold into a helical conformation.2 In contrast
to a wide variety of synthetic single helical polymers and
oligomers, the structural motifs available for constructing
double helices are limited in number.2h,m,3 Of particular
importance is the driving force for intertwining two molecular
strands, which includes metal–ligand coordination,4 aromatic
interactions,5 hydrophobic effects,6 and hydrogen-bonding
interactions.7,8 The hydrogen-bonding interaction is a useful
tool for assembling various supramolecular complexes.9
However, most supramolecular duplexes stabilized by
hydrogen-bonding interactions fail to form double helical
conformations, resulting in the formation of ladder- or
zipper-like duplexes.10 We have recently reported hetero-
stranded double helices with a controlled helix sense that
consist of optically active dimeric amidine strands and their
complementary, achiral carboxylic acid strands, of which the
formation relies on the salt bridge formation.7 The amidinium-
carboxylate salt bridge has been widely used as supramolecular
junctions, because of its high association constants and well-
defined geometry due to its doubly bridged hydrogen bonding
nature.11 The helical sense of the double helices can be
controlled by the optically active substituents on the amidine
groups. Another key feature of this design is the use of
m-terphenyl skeletons that facilitate the formation of
intertwined duplexes. However, the preparation of m-terphenyl
skeletons bearing functional groups at the 20-position requires
the cumbersome Hart coupling involving the formation
of organolithium intermediates that restrict further molecular
design.12 In the field of supramolecular chemistry, simpler
The optically active amidine and achiral carboxylic acid
strands that are complementary to each other ((R)-1 and 2)
were synthesized according to Scheme 1. An amidine group
was introduced by treating the iodide 314 with n-BuLi,
followed by N,N0-bis[(R)-1-phenylethyl]carbodiimide.7,15
During the reaction, the TMS groups were partially
lost because of the highly basic conditions, and the mono-
silylated amidine, (R)-4, was isolated by SiO2–NH2 column
Fig. 1 Schematic illustration of the strategy for the design of short
double helices.
Department of Molecular Design and Engineering, Graduate School of
Engineering, Nagoya University, Chikusa-ku, Nagoya 464-8603,
Japan. E-mail: furusho@apchem.nagoya-u.ac.jp,
yashima@apchem.nagoya-u.ac.jp; Fax: +81 52-789-3185
w Electronic supplementary information (ESI) available: Details of the
experimental procedures and the DFT calculation of (R)-1ꢀ2. See DOI:
10.1039/c0cc03952g
Scheme 1 Synthesis of diamidine (R)-1 and dicarboxylic acid 2.
Reagents and conditions: (a) (i) n-BuLi, TMEDA; (ii) N,N0-bis[(R)-1-
phenylethyl]carbodiimide; (iii) H2O, (b) 1,4-diiodobenzene,
PdCl2(PPh3)2, CuI, Et3N, rt, 6 h, (c) (i) n-BuLi, TMEDA; (ii) CO2,
rt, 12 h; (iii) H3O+, (d) TBAF, THF, 0 1C, 1 h, (e) MOMCl, Et3N,
THF, 0 1C, 10 min, (f) HCl, THF, 45 1C, 4 h.
c
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chromatography. The dimeric amidine strand, (R)-1, was
obtained by the Sonogashira coupling of (R)-4 and 1,4-
diiodobenzene. The dicarboxylic acid 2 was similarly prepared
from the iodide 3. The iodide 3 was lithiated and then treated
with CO2 to yield the carboxylic acid 5, of which one TMS
group was removed by treatment with tetrabutylammonium
fluoride (TBAF) to give the monosilyl 6. During the deprotec-
tion, a base-catalyzed intramolecular cyclization proceeded
under the basic conditions to produce a lactone as a
by-product (Fig. S9, ESIw).16 The direct coupling of 6 and
1,4-diiodobenzene under the Sonogashira conditions failed to
afford the corresponding dimeric acid strand because of the
base-catalyzed intramolecular cyclization that took place,
giving the lactone as the major product. To prevent the
undesirable side reaction, the carboxyl group was protected
as a methoxymethyl (MOM) ester. After protection of the
carboxyl group of 6, the monosilyl 7 was dimerized by
the Sonogashira coupling with 1,4-diiodobenzene to afford
the dimeric strand, 8, of which the methoxymethyl (MOM)
groups were removed by hydrolysis with hydrochloric acid to
yield the dicarboxylic acid 2.
Fig. 3 Capped-stick drawings of the energy-minimized structure for
the right-handed conformation of (R)-1ꢀ2 obtained by the DFT
calculation. The hydrogen atoms are omitted for clarity.
Repeated attempts failed to produce crystals of (R)-1ꢀ2
suitable for an X-ray crystallographic study. The density
functional theory (DFT) calculations were then conducted
to obtain more information about the three-dimensional
structure of the duplex (R)-1ꢀ2 (Fig. 3 and Fig. S8, ESIw).
The calculation results suggested that (R)-1ꢀ2 more likely
adopted a right-handed double helical conformation than a
left-handed one, as in the case of the double helices bearing
m-terphenyl groups with (R)-1-phenylethyl substituents.7a In
the calculated structure, the two p-phenylene linkers stack
together with a centroid distance of 3.6 A, which indicates
the presence of p–p stacking interactions between the linkers.
The absorption spectrum of the duplex showed a remarkable
hypochromicity with a blue shift, which also supports the
aromatic interactions between the two linkers in solution
(Fig. 4a). The 2D NMR studies including the COSY
and ROESY measurements of (R)-1ꢀ2 also supported the
right-handed double helical structure (Fig. S2–S4, ESIw).
The circular dichroism (CD) spectrum of the duplex (R)-1ꢀ2
showed intense CD signals above 250 nm in CHCl3, whereas
(R)-1 exhibited rather weak Cotton effects in this region
(Fig. 4a). The significant enhancement of the Cotton effects
of the (R)-1ꢀ2 complex, especially in the absorption region of
the p-diethynylbenzene conjugated linkers (ca. 280–370 nm),
indicates that (R)-1ꢀ2 likely adopts a preferred-handed double
helical structure induced by the chiral (R)-1-phenylethyl
substituents on the amidine groups. The CD spectrum of
(R)-1ꢀ2 in CHCl3 showed a slight temperature dependence
between ꢁ10 and 50 1C: the Cotton effect intensities slightly
increased with decreasing temperature, reflecting the dynamic
nature of the double helix (Fig. S5, ESIw). The 1H NMR
signals of (R)-1ꢀ2 in CDCl3 did not show chemical shift
changes nor splits due to the diastereomeric pairs over the
Complexation of the diamidine (R)-1 with the dicarboxylic
acid 2 was first investigated by 1H NMR spectroscopy (Fig. 2).
The 1H NMR spectrum of (R)-1 in CDCl3 was highly
broadened at 25 1C owing to the presence of several conformers
originating from the E–Z isomerism of the CQN double bonds
and the restricted rotation about the C–C bond between the
1
amidine and the ethynylene linkers. In contrast, the H NMR
spectrum of (R)-1ꢀ2 showed very simple signals, thus indicating
the presence of only one isomer. This result is consistent with
the formation of salt bridges between (R)-1 and 2, and the
geometry around the amidines residues is likely fixed in the
E configuration. The resonances of the NH protons were
observed as two sharp signals at the low magnetic fields of
13.83 and 13.77 ppm, which are indicative of the formation of
salt bridges. Furthermore, the formation of the duplex (R)-1ꢀ2
was also confirmed by ESI-MS measurements; the ESI-MS
spectrum of a CHCl3 solution of (R)-1ꢀ2 showed signals at m/z
1440.6 corresponding to [(R)-1ꢀ2–H]ꢁ (Fig. S1, ESIw).
Fig. 4 (a) CD and absorption spectra of (R)-1, 2, and (R)-1ꢀ2 in
CHCl3 (0.2 mM, cell length = 0.1 cm) at 25 1C. (b) Absorption
(dashed lines) and fluorescence (solid lines) spectra of (R)-1, 2, and
(R)-1ꢀ2 measured in CDCl3 (3.8 mM, 1 cm cell) at 25 1C excited at
330 nm. The signal intensities have been normalized.
Fig. 2 Partial 1H NMR (500 MHz, CDCl3, 25 1C) spectra of (a) (R)-1
(5.0 mM), (b) (R)-1ꢀ2 (2.0 mM), and (c) 2 (2.0 mM).
c
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temperature range of 55 to ꢁ60 1C, and thereby it is not possible
to quantify the twist-sense bias of the double helix. The associa-
tion constant (Ka) of the monomeric amidine and carboxylic
acid was estimated to be 4.73 ꢂ 105 Mꢁ1 in CHCl3 at 25 1C by
CD titration experiments, while that of (R)-1ꢀ2 was evaluated to
be much higher than 108 Mꢁ1 (Fig. S6 and S7, ESIw).
The fluorescence spectra of (R)-1, 2, and (R)-1ꢀ2 measured
in CDCl3 at 25 1C are shown in Fig. 4b. When excited at
330 nm, both (R)-1 and 2 exhibited a strong fluorescent
emission over the range of 350 to 550 nm, arising from their
conjugated backbones. The duplex, (R)-1ꢀ2, showed a red
shifted fluorescence, which suggested the formation of an
inter-strand excimer.
4 For reviews on helicates, see: (a) E. C. Constable, Tetrahedron,
1992, 48, 10013–10059; (b) J. M. Lehn, Supramolecular Chemistry
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5 For examples of aromatic oligoamide-based double helices, see:
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6 For examples of oligo- and poly(m-phenylene)-based double
helices, see: (a) H. Goto, H. Katagiri, Y. Furusho and
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Org. Lett., 2006, 8, 2583–2586; (d) T. Hasegawa, Y. Furusho,
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5885–5888; (e) Y. Furusho, Y. Tanaka, T. Maeda, M. Ikeda and
E. Yashima, Chem. Commun., 2007, 3174–3176; (f) T. Maeda,
Y. Furusho, S.-I. Sakurai, J. Kumaki, K. Okoshi and E. Yashima,
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In summary, we have designed and synthesized a novel
hetero-stranded double helix with a controlled helix sense that
consists of an optically active dimeric amidine strand and its
complementary achiral dicarboxylic acid strand based on
simple m-diethynylbenzene backbones. Although the present
system has a slightly less stability than the prototype bearing
m-terphenyl backbones, it has a greater advantage than the
m-terphenyl-based one from the viewpoint of the synthetic
accessibility. The present results described in this report will
expand the design possibility of synthetic double helices, due
no longer to the need of cumbersome m-terphenyl skeletons.
This work was supported in part by Grant-in-Aids for
Scientific Research from the Japan Society for the Promotion
of Science (JSPS) and for Scientific Research on Innovative
Areas, ‘‘Emergence in Chemistry’’ (21111508) from the MEXT.
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8964 Chem. Commun., 2010, 46, 8962–8964
This journal is The Royal Society of Chemistry 2010