Azacrown-attached meta-ethynylpyridine polymer: Saccharide recognition regulated by supramolecular device

Article abstract of DOI:10.1039/b902269d

Polymeric synthetic host 2, azacrown-attached 2,6-pyridylene ethynylene polymer, was investigated for its saccharide recognition and the additive effect of triethylene tetramine-trifluoroacetic acid; heteroallosteric effects were observed on the basis of CD and UV/Vis analyses, which indicated saccharide-dependent stabilization and destabilization of helical complexes by the formation of pseudopolyrotaxanes.

Full text of DOI:10.1039/b902269d

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Azacrown-attached meta-ethynylpyridine polymer: saccharide recognition
regulated by supramolecular devicewz
Hajime Abe,* Shunsuke Takashima, Tsuyoshi Yamamoto and Masahiko Inouye*
Received (in Cambridge, UK) 3rd February 2009, Accepted 4th March 2009
First published as an Advance Article on the web 17th March 2009
DOI: 10.1039/b902269d
Polymeric synthetic host 2, azacrown-attached 2,6-pyridylene
ethynylene polymer, was investigated for its saccharide recogni-
tion and the additive effect of triethylene tetramine–trifluoroacetic
acid; heteroallosteric effects were observed on the basis of CD
and UV/Vis analyses, which indicated saccharide-dependent
stabilization and destabilization of helical complexes by the
formation of pseudopolyrotaxanes.
Fig. 2 Mechanical design of 2. Stabilization of a helix by pseudo-
Helical biomolecules carry out important functions in nature,1
and such molecules are regulated in a sophisticated way in
their structures and performance by circumstance and
chemical species, sometimes showing allosterism.
polyrotaxane formation.
the formation of pseudopolyrotaxanes with an axial guest
molecule such as polyammonium cations.
The outline of the mechanical design of 2 is depicted in
Fig. 2. A 24-crown-8 ring is known to make a rotaxane with a
secondary ammonium axis.7 Plural 1-aza-24-crown-8 sites
(blue ring) in 2 and oligoammonium axes (purple sticks) can
form pseudopolyrotaxanes to stabilize helical structures of the
polymer (green) by bridging between the pitches of the helix.
By distributing a crown ether at every three pyridines in 2, it is
expected that two bridges are built at opposite sides of the
helix. The resulting inside hole can be suitable (or unsuitable)
to accommodate a targeted guest saccharide, which biases the
chiral sense of the complex to induce circular dichroism (CD).
The biases might be regulated by the formation of the pseudo-
polyrotaxanes, i.e., heterotropic allosteric behavior.
Recently, we have developed artificial foldamers, 2,6-pyridylene
ethynylenes or ‘‘meta-ethynylpyridines’’, which consist of
4-substituted pyridine rings linked at their 2,6-positions with
acetylene bonds (Fig. 1, 1). These artificial foldamers carry out
saccharide recognition2,3 by hydrogen bonding in organic and
aqueous media, and the key feature is the formation of helices
to accommodate the saccharide.3–5 The substituent R on the
pyridine rings of 1 adds optional nature to the foldamer.5
Herein, a new type of meta-ethynylpyridine co-polymer
2 has been developed, which possesses a crown ether at the
4-position of every third pyridine ring (Fig. 1). Octyloxy
groups were introduced at the remaining pyridine rings to
improve solubility. We expected the crown ether to play a role
as a scaffold6–8 to effect structural behavior and saccharide
recognition ability of the meta-ethynylpyridine moiety by
The azacrown-attached co-polymer 2 was prepared as
shown in Scheme 1. Citrazinic acid was converted into
2,6-dibromo-4-(hydroxymethyl)pyridine (3), then it was bromi-
nated to 4. Next, 4 was condensed with 1-aza-24-crown-8 to
give 5. After diethynylation of 5 to 7, co-trimer 9 was made
from
7
and 2,6-diiodo-4-octyloxypyridine5e (8). Further
diethynylation of 9 yielded 11, the counterpart of 9. The final
co-polymerization between the diiodide 9 and the diacetylene
11 was carried out by Sonogashira reaction to obtain 2. The
molecular weight of 2 was estimated as Mn ¼ 8800 g molꢀ1
after brief purification using Sephadex, and the fraction of
larger molecular weight (Mn ¼ 11 500 g molꢀ1) was taken out
by preparative GPC to use in the following experiments.
The saccharide recognition manner of 2 was surveyed
qualitatively by CD measurements. First, when octyl
Fig. 1 Polymeric meta-ethynylpyridines 1 and 2.
b-D-glucopyranoside (b-D-Glc) was added to
a CH2Cl2
solution of 2, an induced negative CD band appeared around
340 nm (Fig. 3A, brown solid line). The shape of this CD band
strongly resembles that in the cases of other types of meta-
ethynylpyridines associated with b-D-Glc.5,9 Therefore, the CD
band observed here indicates that 2 also formed a similar
helical complex with b-D-Glc. Next, triethylene tetramine
(TETA) was added to the mixture, then the induced CD
band slightly increased (Fig. 3A, blue solid line). Finally,
Graduate School of Pharmaceutical Sciences, University of Toyama,
Sugitani 2630, Toyama, Toyama 930-0194, Japan.
E-mail: inouye@pha.u-toyama.ac.jp; Fax: þ81 76-434-5049
w Dedicated to Professor Seiji Shinkai on the occasion of his 65th
birthday.
z Electronic supplementary information (ESI) available: Detailed
experimental procedures, additional CD and UV/Vis spectra and
titration curves. See DOI: 10.1039/b902269d
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Scheme 1 Preparation of azacrown-attached co-polymer 2. TMSA ¼ (trimethylsilyl)acetylene, TBSA ¼ (tert-butyldimethylsilyl)acetylene,
TBAF ¼ tetrabutylammonium fluoride.
causes a significant red shift in the UV/Vis spectra.5b On the
other hand, when TETA and TFA were added to 2 or a
mixture of 2 and b-D-Glc, such red shifts were sluggish
(Fig. S2z and 3B). This finding means that the contribution
of pyridinium species would be negligible here and most of the
TFA would give its proton to TETA to form oligoammonium
cation TETAꢂnH1. Instead of a red shift, the addition of the
TETA–TFA combination brought a substantial hypochromic
effect on the wavelength region where the induced CD band
appeared (see also Fig. S3 and S4z). Therefore, the contribu-
tion of p-interaction seems to accompany the stabilization of
Fig. 3 The changes of (A) CD and (B) UV/Vis spectra of the mixture
the helical structure.10 TFA alone did not enhance the glucoside
of 2 and b-D-Glc in the presence and absence of triethylene tetramine
recognition enough without TETA. When only TFA was
added to the mixture of 2 and b-D-Glc, the change of CD
was very little (Fig. 3A, black dashed line). In this case, a small
red shift was observed in the UV/Vis spectrum, being due to
the protonation of pyridine rings (Fig. 3B, black dashed line).
Quantitative evaluation of the heteroallosteric behavior of 2
with the TETA–TFA combination was carried out by CD
titration experiments using b-D-Glc as a titrant (Fig. S5z). In
CH2Cl2, the formal binding constant11 between 2 and b-D-Glc
(TETA) and trifluoroacetic acid (TFA). Black solid: only 2; brown
solid: 2 þ b-D-Glc; blue solid: 2 þ b-D-Glc þ TETA; red solid: 2 þ b-D-
Glc þ TETA þ TFA; brown broken: 2 þ b-L-Glc; blue broken: 2 þ
b-L-Glc þ TETA; red broken: 2 þ b-L-Glc þ TETA þ TFA; black
dashed: 2 þ b-D-Glc þ TFA. Conditions: 2 (1.0 ꢄ 10ꢀ3 M, unit conc.),
b-D-Glc or b-L-Glc (2.0 ꢄ 10ꢀ3 M), TETA (1.7 ꢄ 10ꢀ4 M), TFA
(6.7 ꢄ 10ꢀ4 M), CH2Cl2, 25 1C, path length ¼ 1 mm.
trifluoroacetic acid (TFA) was added to the mixture, then
significant enhancement of the CD band was observed
(Fig. 3A, red solid line). The enantiomeric glycoside, octyl
b-L-glucopyranoside (b-L-Glc), induced mirror-image CDs
corresponding to those in the cases of b-D-Glc (Fig. 3A, broken
lines), reflecting the chirality transfer from the added saccha-
rides to the polymer. On the other hand, when diethylamine
was used as the representative monoamine instead of TETA,
no meaningful additive effect could be observed even after the
addition of TFA (Fig. S1z).
was obtained as K00 ¼ (1.0 ꢃ 0.3) ꢄ 102
M
ꢀ1. After the
addition of TETA, the binding constant increased to K01
¼
(8.0 ꢃ 0.7) ꢄ 102 Mꢀ1, and further addition of TFA gave most
improved binding strength as expected, K02 ¼ (1.5 ꢃ 0.3) ꢄ
103
M
ꢀ1. These results indicate that the oligoammonium
TETAꢂnH1 stabilizes the chiral helical structure of the
complex 2ꢂb-D-Glc by the formation of a pseudorotaxane
consisting of azacrown rings and oligoammonium axes.
Other kinds of glycosides, octyl b-D-fructopyranoside
(b-D-Fru) and octyl b-D-mannopyranoside (b-D-Man), induced
The changes of UV/Vis spectra were also studied. In a
previous study on a strongly basic ethynylpyridine polymer,
it was found that the protonation of pyridine into pyridinium
positive CDs in
2 around 340 nm as the previous
(meta-ethynylpyridine)s did.5a–c However, the addition of
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TETA–TFA to a mixture of 2 and b-D-Fru caused inversion of
the sign of the CD band (Fig. S3z). The formation of a
pseudopolyrotaxane with the TETA–TFA combination
might change the helical pitch, resulting in the geometrical
rearrangement of the hydrogen-bonding pyridine nitrogens.
The hydrogen-bonding array in the reversed helix is likely to
interact with b-D-Fru more preferentially than that of the
original helix. On the other hand, in the case of b-D-Man,
the TETA–TFA combination slightly weakened the positive
CD band at 344 nm and increased a negative CD band at
334 nm (Fig. S4z). These observations illustrate that some
negative heteroallosteric behavior or partial helix inversion of
2 might occur against b-D-Man. Thus, the additive effects of
the TETA–TFA combination on saccharide recognition with 2
were demonstrated. The chirality transfer from glycosides to
the helical complexes and recognition affinity of 2 were altered
with the TETA–TFA combination.
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11 Binding constants were determined on the assumption that the
molecular weight of the polymer was uniform and that the polymer
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of the molecular length.
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Chem. Commun., 2009, 2121–2123 | 2123