Oligoresorcinols fold into double helices in water

Article abstract of DOI:10.1021/ja062171v

We report the first double helices with a controlled helicity in water based on oligoresorcinols as a new, simplest water-soluble structural motif. The molecular strands of the oligoresorcinols self-assemble into double helices with the aid of aromatic interactions in water as characterized by ¹H NMR and absorption spectroscopies together with the X-ray crystallographic study of the pentamer. The double helix formation is sensitive to the chain length, solvent composition, and temperature. Moreover, a bias in the screw sense of the double helices was achieved by covalently attaching chiral substituents to both ends of the molecular strands. Copyright

Full text of DOI:10.1021/ja062171v

Published on Web 05/10/2006
Oligoresorcinols Fold into Double Helices in Water
Hidetoshi Goto,† Hiroshi Katagiri,† Yoshio Furusho,*,† and Eiji Yashima*,†,‡
Yashima Super-structured Helix Project, ERATO, Japan Science and Technology Agency (JST),
101 Creation Core Nagoya, 2266-22 Shimoshidami, Moriyama-ku, Nagoya 463-0003, Japan, and
Institute for AdVanced Research, Nagoya UniVersity, Nagoya 464-8603, Japan
Received March 30, 2006; E-mail: furusho@yp-jst.jp; yashima@apchem.nagoya-u.ac.jp
Double helical structures are frequently found in Nature and are
deeply connected to the exquisite biological functions of biomac-
romolecules, such as nucleic acids.1 Since the discovery of the
double helix of DNA,2 the double helical structures have attracted
ever-increasing attention as synthetic targets. Nevertheless, double
helices formed from synthetic strands are relatively rare when
compared to synthetic single helices.3 The metal-directed self-
assembly is the most widely used strategy to construct doubly
stranded helical complexes, or so-called helicates.4 Some aromatic
oligoamides as well as peptide analogues of nucleic acids give rise
to double helical structures by utilizing hydrogen-bonding and
aromatic-aromatic interactions.5,6 Although plenty of supramo-
lecular duplexes assembled with hydrogen bonding have been
reported, most of their three-dimensional structures are not inter-
twined, but are characterized as ladder- or zipper-like linear
conformations.7 Thus, the recognition motifs utilized so far for
constructing doubly stranded assemblies rely on the ligand-metal
coordination, hydrogen bonding, or aromatic stacking. It should
be emphasized that there have been no examples of wholly artificial
double helices that are formed by the self-assembly process in water,
in which biomacromolecules form single or double helices. Here
we describe oligoresorcinols, a kind of oligophenol, as a new,
simplest structural motif, which self-assemble into well-defined
double helices resulting from interstrand aromatic stacking in
water.8 In addition, a bias in the helical twist sense was
achieved by incorporating chiral substituents at both ends of the
strands.
We synthesized three oligoresorcinols with different chain
lengths, which are soluble in common organic solvents and in
water.9,10 The aggregation of the oligoresorcinol strands in water
was first suggested by the 1H NMR spectra of the nonamer (9merH,
Figure 1A). In methanol, the NMR signals were sharp, and each
signal was assigned to a single strand with a random coil
conformation. These signals significantly shifted upfield, ac-
companied by considerable broadening with an increase in the
content of water, suggesting the aggregate formation of 9merH.
The upfield shifts of the aromatic protons suggest parallel stacking
of the aromatic rings, which is favored in water.11 The absorption
spectra of 9merH also showed a noticeable hypochromic effect
with the increasing amount of water, indicating a π-stacking
interaction (Figure 1B). The chemical shifts (δ) and the maximum
absorptivity (ꢀmax) at ca. 290 nm of 9merH in water-methanol
mixtures were plotted versus the water content (Figure 1C). These
plots clearly showed a transition point at ca. 72 vol % of water.
These results indicate that the molecular strands of 9merH self-
assemble above 72 vol % of water. Moreover, the aggregate
dissociated with increasing temperature in the 72 vol % of water
(Figure S3).9
Figure 1. Double helix formation of 9merH. (A) 1H NMR and (B)
absorption spectra of 9merH in D2O/CD3OD (D2O: 0-100 vol %) at 25
°C; [9merH] ) 1 mM; pD ) 6.2-6.4. 1,4-Dioxane in D2O was used as
the external standard for the chemical shifts. (C) Plots of chemical shifts
of the marked signals and ꢀmax at ca. 290 nm of 9merH in D2O/CD3OD at
25 °C. The chemical shifts of 9merH were assigned on the basis of 2D
COSY and NOESY spectra. (D) MM-calculated structures of the single
(left) and double (right) helices of 9merH. The parameter, “relative electric”,
was set to 4 as recommended for calculations in water.
Molecular mechanics (MM) calculations for 9merH suggest a
51-helical conformation as an energy-minimized structure for the
single-stranded 9merH (Figure 1D); this structure is similar to that
reported in the crystal structures of the m-phenylene oligomers and
polymers.9,12 However, the single helical conformation of 9merH
is not stable and changed to a rather random conformation after 1
† ERATO.
‡ Nagoya University.
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C O M M U N I C A T I O N S
Figure 3. Capped sticks (top) and space-filling (bottom) drawings of the
crystal structures of the single helix (A) and the double helix (B) of 5merH.
Carbon, gray (or brownish gray); hydrogen, white; oxygen, red. The
structures were determined by X-ray diffraction study of two independent
crystals grown from CHCl3/CH3CN (single helix) and H2O (double helix).
Solvent molecules are omitted for clarity. (A) Single helical structure of
5merH with a pseudo-51-helical conformation. The crystal consists of an
equimolar mixture of the right-handed and left-handed helices, and only
the left-handed helix is shown. (B) Double helical structure of 5merH. Each
strand has almost identical structure. The crystal consists of an equimolar
mixture of the right-handed and left-handed double helices, and only the
right-handed double helix is shown.
1
Figure 2. Chain-length-dependent spectral changes. H NMR of oligore-
sorcinols (3merH, 6merH, and 9merH) in D2O (A) and CD3OD (B) at 25
°C. (C) Plots of ꢀmax at ca. 290 nm per repeating unit of oligoresorcinols in
D2O (blue) and CD3OD (red) versus the repeating unit number ([oligomers
(per repeating units)] ) 9 mM) and plots of the degree of aggregation of
the oligomers estimated by VPO measurements in H2O at 40 °C (green,
degree of aggregation ) Mn(found)/Mn(calcd)); at that temperature, the
double helical structure was retained, as confirmed by 1H NMR (Figure
S2).9
concentrations as low as 0.1 mM, suggesting a dimerization constant
of >104 M-1 at 25 °C in water (Figure S1).9
It should be stressed that 5merH was found to crystallize in a
single or a double helix depending on the solvent (Figure 3).9 The
single helix crystallized from CHCl3/CH3CN, whereas the single
crystals of the double helix were grown from water. This is
consistent with the fact that the double helix formation of the
oligoresorcinols is mainly driven by the aromatic interactions in
water. In the solid state, the double helical structure of 5merH is
stabilized by several π-π and CH-π interactions (Table S2).9 This
single-crystal structure is in good agreement with the hypochro-
ns molecular dynamics (MD) simulations at 300 K. On the other
hand, the duplex of 9merH adopting a double helical structure was
energetically more stable than the single helix of 9merH and
retained the double helix even after 1 ns MD simulations at 300 K
(Figure S8).
Next, the chain-length dependence of the oligoresorcinols on their
aggregation behavior was investigated by 1H NMR and absorption
1
spectroscopies in water and in methanol. In water, the H NMR
signals of 6merH and 9merH exhibited considerable upfield shifts
of ca. 0.4-0.5 ppm compared to those of 3merH (Figure 2A). In
methanol, however, the 1H NMR signals of the oligomers appeared
at similar chemical shifts (Figure 2B). The absorption spectra of
these oligomers showed a similar tendency (Figures S7).9 The ꢀmax
values per repeating unit at ca. 290 nm of the oligomers in methanol
slightly increased, but significantly decreased in water as the chain
length increased (for plots of the ꢀmax value versus the repeating
unit, see Figure 2C). In addition, 6merH was found to have a
melting temperature of Tm ) ca. 30 °C, while Tm ) ca. 40 °C was
observed for 9merH (Figure S5).9 These results suggest that 6merH
and 9merH self-assemble in water and 3merH exists as a single
strand, whereas all the oligomers do not form aggregates in
methanol.
To estimate the degree of aggregation of the oligomers in water,
vapor pressure osmometer (VPO) measurements were conducted
in water at 40 °C (Figure 2C).9 The degree of aggregation (Mn-
(found)/Mn(calcd)) of 3merH was nearly equal to unity, that is,
3merH exists as a single strand in water, while those of 9merH
and 6merH were 1.9 and 1.5, respectively (Figure S6), suggesting
that 9merH almost quantitatively self-assembles to form the double
helices and 6merH exists as a ca. 1:1 mixture of the single strand
and the double helix under equilibrium in water.5a,13 These VPO
data are consistent with the above 1H NMR and absorption spectral
behaviors. The 9merH maintained the double helical structure at
1
micity of the absorption spectra and the upfield shifts of the H
NMR signals of the double helices of the oligoresorcinols in water.
The double helices of the oligoresorcinols formed in aqueous
solution exist as equimolar mixtures of the right- and left-handed
forms, that is, racemates. The introduction of an optically active
group to a part of the oligoresorcinol derivatives may cause a bias
in the screw sense of the double helices, resulting in an excess
helical sense, because the helical oligomers bearing the chiral units
become diastereomeric pairs (Figure 4). We then synthesized an
undecamer bearing two (S)-2-methylbutyl groups at both ends of
the strand (11merHR2).9 We confirmed that 11merHR2 also
formed the double helix in water as evidenced by the upfield shifts
1
and significant broadening of its H NMR signals together with a
large hypochromicity of its absorption spectra, as in the cases of
the achiral oligomers (Figure 4A,B). In methanol, 11merHR2
showed no CD in the backbone chromophore (200-350 nm) as
expected from the fact that it takes a random-coil conformation in
methanol. In sharp contrast, large Cotton effects were observed at
25 °C in water, in the region of the chromophore assigned to
11merHR2, which is a strong evidence that 11merHR2 forms the
double helix with an excess one-handed screw sense (Figure 4B).
The fact that the specific rotation of 11merHR2 dramatically
increased from +4.6° in methanol to +107° in water also supports
the predominant one-handed double helix formation. The induced
CD (ICD) reversibly changed in response to temperature (Figure
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C O M M U N I C A T I O N S
Supporting Information Available: The experimental procedures
for the synthesis and characterization of 3merH, 5merH, 6merH,
9merH, and 11merHR2, the crystallographic data for the single and
double helices of 5merH, and the MM and MD calculation studies for
9merH and 11merHR2. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Figure 4. Double helix formation of 11merHR2 with an excess one-handed
screw sense. (A) 1H NMR spectra of 11merHR2 in CD3OD (top) and D2O
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interactions in water. The double helix formation is sensitive to
the chain length, solvent composition, and temperature. Further-
more, a bias in the twist sense of the double helices can be achieved
by incorporating chiral substituents at both ends of the strands. We
believe that this simple structural motif will be used to design and
develop water-soluble, more complex supramolecular assemblies
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Acknowledgment. We thank Bruker AXS K.K. for providing
generous access to the Bruker Smart Apex II CCD-based X-ray
diffractometer. We also thank Nippoh Chemicals Co. Ltd. for the
kind supply of 1,3-diiodo-5,5-dimethylhydantoin (DIH).
JA062171V
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