Helicity inversion in responsive foldamers induced by achiral halide ion guests

Article abstract of DOI:10.1002/anie.200800796

(Graph Presented) A surprising about-face: Click chemistry was used for the efficient synthesis of a newclass of foldamers, referred to as clickamers, that display unusual folding and recognition properties. In the presence of halide ions - achiral species - they undergo an unprecedented helix inversion.

Full text of DOI:10.1002/anie.200800796

Communications
DOI: 10.1002/anie.200800796
Molecular Recognition
Helicity Inversion in Responsive Foldamers Induced by Achiral Halide
ion Guests**
Robert M. Meudtner and Stefan Hecht*
Interest in foldamers[1] and helically folding polymers[2] has
increased considerably over the past decade, reflecting the
vast potential of this emerging field.[3] One particularly
attractive aspect is associated with the well-defined yet
dynamic conformation of the backbone along with its
responsiveness towards external stimuli that can be used to
implement various functions for applications in targeting
actuation,[4,5] delivery,[5] and sensing.[6] In the latter case, the
inherent chirality of the helical backbone makes it possible to
conveniently monitor conformational changes by circular
dichroism (CD) spectroscopy. Ideally the binding of various
guests leads to the formation of an excess of one helical form,
which is associated with an externally induced CD effect.[7,8]
The transfer of chirality to the usually achiral backbone is
caused by interaction with a chiral guest,[7,9] and as a result,
the inversion of the (excess) helical twist sense[10] is typically
caused by the binding of the same guest but the other
enantiomeric form.[11] Further insights into the fundamentals
of chirality transfer and amplification as one potential
mechanism responsible for the homochirality in biomacro-
molecules[12] will enable the design of new materials for chiral
recognition, sensing, and separation as well as catalysis.[13] For
this purpose, the facile access to a responsive foldamer
platform, which allows for convenient tuning of properties
(even under abiotic conditions), is desirable. Here, we present
our workon a novel family of responsive foldamers, so-called
“clickamers”, and describe their efficient synthesis and
investigations of their folding behavior under a variety of
conditions. Importantly, we report on an unprecedented
phenomenon of helix inversion[11] observed in response to
achiral guest molecules (halide ions).
strong preference of bipyridine and various aza-arenes for
adopting an anti conformation to generate helical struc-
tures.[14] We utilize the highly efficient Cu-catalyzed 1,3-
dipolar cycloaddition reaction of aryl azides and aryl acety-
[15]
lenes, commonly referred to as the clickreaction,
to
generate a backbone consisting of embedded helicogenic
motifs based on alternating triazole and pyridine moieties.
The resulting 2,6-bis(1,2,3-triazol-4-yl)pyridine structure has
a strong preference for the anti,anti conformation,[16a] and the
preorganized kinked building blocks are connected by meta-
phenylene hinges. Rotation about a minimal number of
connecting bonds (at the meta-phenylene hinges) leads to
folding into a helical conformation that is enthalpically
stabilized by the resulting p–p stacking interactions
(Figure 1). In an amphiphilic system, further stabilization
can be induced by the solvophobic effect as well.[17] Models of
an oligomer bearing 17 (hetero)aromatic moieties illustrate
another interesting structural feature of our clickamers as
Our foldamer design is inspired by the “helicity codon”
approach developed by Lehn and co-workers that exploits the
[*] R. M. Meudtner, Prof. Dr. S. Hecht
Department of Chemistry
Humboldt-Universität zu Berlin
Brook-Taylor-Strasse 2, 12489 Berlin (Germany)
Fax: (+49)30-2093-6940
E-mail: sh@chemie.hu-berlin.de
Homepage: http://www.hechtlab.de
[**] We thank Jutta Schwarz and IrØn Fischer for carrying out some
monomer syntheses, as well as Dr. Ralf Bienert and Prof. Dr.
Andreas Thünemann (BAM) for help with the dynamic light-
scattering measurements. Generous support by the German
Research Foundation within the ERA Chemistry Net (Project
“SurConFold”) and the Fonds der Chemischen Industrie is grate-
fully acknowledged. We thank Wacker AG, BASF AG, Bayer Industry
Services, and Sasol Germany for generous donations of chemicals.
Figure 1. Concept of clickamers as foldamers prepared by click chemis-
try. Top: Helical folding is based on connecting preorganized 2,6-bis(1-
aryl-1,2,3-triazol-4-yl)pyridine units (red) by meta-phenylene units
(black) as well as p–p stacking interactions induced by solvophobic
forces in polar solvents as a result of the amphiphilic structure (R and
R* shown in blue represent polar side chains). Bottom: Top and side
views of a space-filling model of the heptadecamer displaying two
complete turns (van der Waals radii are shown and side chains are
omitted for clarity).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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they exhibit a rather unusual fourfold symmetry relative to
the number of side chains per turn.[14c,d,18]
were achieved by carefully optimizing the conditions for the
clickreaction, for example, by use of tris(benzyltriazolylme-
thyl)amine (TBTA) as a CuI-stabilizing ligand[16a,21] and the
choice of the triisopropylsilyl (TIPS) moiety as an orthogonal
protecting group.[16a] Polar oligo(ethyleneglycol) side chains
were attached to the nonpolar (hetero)aromatic backbone to
provide a further driving force for folding based on the
solvophobic effect operating in the resulting amphiphilic
structure.[17] Furthermore, the side chains ensure good
solubility in various solvents and incorporation of chiral
centers at every meta-phenylene unit enables the use of CD
spectroscopy to investigate the conformational behavior in
solution.
The oligomer strands were prepared by a repetitive
bidirectional synthesis in which the clickreaction served as
the coupling step and protiodesilylation was the activation
step (Scheme 1).[16a,19] Initially, the starting building blocks
pyridine bisacetylene 1 (AA’ monomer) and phenyl bisazide 2
(B2) were coupled to afford the protected central core
building block 3 (A2’) as well as the extended monoprotected
monomer (A’B) 4. The unprotected core 5 (or a higher
homologue such as 7) was coupled with monomer 4 and the
product then deprotected to afford the next higher oligomer.
This sequence was repeated to extend the oligomers to overall
eight (hetero)aromatic repeat units per sequence and was
finally terminated by reaction with monofunctional azide 8 to
afford nonamer 9 and heptadecamer 10.[20] High overall yields
After successful synthesis and standard characterization,
the conformational behavior of clickamer 10, which displays
two complete turns and hence a significant number of
Scheme 1. Synthesis of clickamers 9 and 10 by means of a bidirectional growthapproachbased on repetitive sequences of 1) coupling with
elongated A’B monomer 4 and 2) deprotection followed by capping of the backbone termini. Na asc.=sodium ascorbate, TBAF=tetra-n-
butylammonium fluoride, TBTA=tris(benzyltriazolylmethyl)amine, TIPS=triisopropylsilyl.
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stabilizing p–p stacking contacts, was investigated in dilute
urements. In addition, the CD spectra do not change
significantly within the accessible temperature range (5–
758C), suggesting that chirality induction is indeed based on
intramolecular chirality transfer and not formation of aggre-
gates.[23] While these experiments provide strong evidence
that clickamer 10 adopts a helical conformation in water/
acetonitrile mixtures, the corresponding spectroscopic meas-
urements with the shorter oligomer 9 indicate only a slight
population of the helical conformation.
solution by various optical spectroscopy techniques. As the
optical spectra of 10 in acetonitrile did not deviate substan-
tially from those in chloroform solution,[18b] the addition of
significant amounts of water was necessary to enhance the
solvophobic driving force of folding.[17] The UV/Vis absorp-
tion spectra of 10 (Figure 2, top) show a hypochromic and
Isolated
2,6-bis(1-aryl-1,2,3-triazol-4-yl)pyridines
undergo a dramatic structural change from the kinked
anti,anti conformation to an extended syn,syn conformation
upon either metal ion complexation or simply protonation.[16a]
Therefore, we studied the response of clickamer 10, which
incorporates four such switchable subunits, towards protona-
tion (Figure 3). Surprisingly, the addition of HCl did not result
Figure 3. Optical response of clickamer 10 (8”10À6 m, 75 vol% water
in acetonitrile, 258C) to various halide ions: KF, KCl, and KBr (all at
neutral pH) as well as HCl.
Figure 2. Optical spectra of clickamer 10 (5”10À6 m) in acetonitrile
withincreasing water content at 25 8C. Top: UV/Vis absorption spectra.
Bottom: CD spectra.
bathochromic shifts of the bands at 230 nm and 306 nm,
respectively, indicating stacked chromophores with increasing
water content. At higher water content, the more intense
short-wavelength absorption maximum of the clickamer
backbone is associated with an intense bisignate signal
exhibiting positive exciton chirality[22] and zero-crossing at
246 nm as well as another bathochromically shifted, positive
signal at 260 nm (Figure 2, bottom). This indicates the
population of a helical conformation with excess helicity as
a result of chirality transfer from the chiral side chains to the
backbone (chiral anisotropy factor g = 0.0006 in 80 vol%
water).[19] The folding transition at higher water content is
also reflected in the fluorescence spectra, which show a
transition from a sharp monomerlike emission at 373 nm to a
broad, excimerlike emission centered around 409 nm, which
is characteristic of stacked chromophores (in a helical
conformation).[19] The folding transition is particularly effec-
tive above a threshold amount of 60 vol% water in acetoni-
trile, as indicated by the nonlinear relationship of each optical
signature as a function of the water content (insets in
Figure 2). Aggregation as another potentially contributing
factor can be excluded since dilution experiments showed a
linear response over the relevant concentration range, and no
aggregates were detected in dynamic light-scattering meas-
in denaturation of the helical conformation but rather an
exact inversion of the CD signal. To examine the involvement
of the counterion in the recognition process, the effect of
various halide anions on the CD spectra was investigated at
neutral pH. Whereas addition of fluoride ions led to a slight
increase in CD intensity relative to the neat oligomer 10, the
presence of chloride ions caused an inverted signature of
small intensity, and finally addition of bromide ions gave an
inverted CD spectrum of higher intensity. It is important to
note that all CD spectra display an isodichroic point at 248 nm
and that the positions and relative intensities remain constant,
reflecting an inversion of the same helical conformation; in
other words, only the helical twist sense is altered without
other structural changes.
To the best of our knowledge, this represents the first
example of a helix inversion[10] in response to an achiral
stimulus.[11] Furthermore, this finding is remarkable in light of
the observed selectivity for various halide anions since anions
are notoriously difficult to recognize, in particular in aqueous
systems.[24] Although we can only speculate about the
mechanism of anion recognition, clearly the size of the
halide anion plays an important role for the interaction with
the helix. Although decreasing the pH seems to enhance the
effect, the accompanying countercation is most likely not
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molecules: f) R. Nonokawa, E. Yashima, J. Am. Chem. Soc.
2003, 125, 1278 – 1283. For reviews, see; Refs. [6a–c].
involved in the recognition process as complexation of the
potassium ions with [18]crown-6 did not alter the CD
signal.[19] In view of the clean inversion to the helix mirror
image, even at neutral pH, it seems likely that the halide ions
interact with the oligo(ethyleneglycol) side chains, thereby
altering intramolecular[25] chirality transfer to the (hetero)-
aromatic backbone. It is remarkable that a rather subtle
interaction with the halide ion(s) is translated into such
significant observed changes in the CD spectra, reflecting the
bias of the equilibrium between the left- and right-handed
helices.
In summary, we have introduced clickamers as a new
promising family of foldamers with unique folding and
recognition behavior in aqueous systems. In addition to
their straightforward and efficient synthesis, these clickamers
display an unprecedented helix inversion in response to
achiral halide ions. Ongoing workin our laboratories is
concerned with elucidating the structural basis for halide
recognition and extension to the recognition of transition-
metal cations.[16] Furthermore, the influence of the nature of
the monomer building blocks, which determine the preorga-
nization and strength of p–p stacking, on the folding behavior
are currently under investigation.[26]
[8] In some artificial foldamers, the population of
a helical
conformation can be forced by interior binding of small
inorganic cations: a) R. B. Prince, T. Okada, J. S. Moore,
Angew. Chem. 1999, 111, 245 – 249; Angew. Chem. Int. Ed.
1999, 38, 233 – 236; b) F. Zhang, S. Bai, G. P. A. Yap, V. Tarwade,
J. M. Fox, J. Am. Chem. Soc. 2005, 127, 10590 – 10599; or small
inorganic anions: c) K.-J. Chang, B.-N. Kang, M.-H. Lee, K.-S.
Jeong, J. Am. Chem. Soc. 2005, 127, 12214 – 12215; d) V. Berl,
M. J. Krische, I. Huc, J.-M. Lehn, M. Schmutz, Chem. Eur. J.
2000, 6, 1938 – 1946. However, owing to the absence of a chiral
bias in all these examples, only racemic mixtures of helices
displaying no CD signal were obtained.
[9] In some special cases, helicity “memory” has been reported
when the chiral guest was removed: a) E. Yashima, M. Katshiro,
Y. Okamoto, Nature 1999, 399, 449 – 451; b) M. Ishikawa, K.
Maeda, Y. Mitsutsuji, E. Yashima, J. Am. Chem. Soc. 2004, 126,
732 – 733; c) K. Maeda, M. Ishikawa, E. Yashima, J. Am. Chem.
Soc. 2004, 126, 15161 – 15166.
[10] The term “helicity inversion” is referred to as a “clean”
structural inversion where the inverted helical conformation
maintains the relative orientation of backbone repeat units and
only the twist sense has been altered.
[11] For an example of helicity inversion by binding of opposite
enantiomers in foldamers, see: Ref. [7a]. For an example of
helicity inversion by binding of opposite enantiomers in helical
polymers, see: Ref. [7f]. For a recent comprehensive review, see:
G. A. Hembury, V. V. Borovkov, Y. Inoue, Chem. Rev. 2008, 108,
1 – 73.
Received: February 18, 2008
Published online: May 21, 2008
Keywords: chirality · click chemistry · foldamers ·
helical polymers · helix inversion
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[18] Usually, the use of meta-linked phenylene repeat units in
foldamers is associated with a hexagonal, that is, sixfold,
symmetry, as described in: a) K. Matsuda, M. T. Stone, J. S.
Moore, J. Am. Chem. Soc. 2002, 124, 11836 – 11837. For an
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[1] a) S. H. Gellman, Acc. Chem. Res. 1998, 31, 173 – 180; b) D. J.
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[7] In foldamers, CD activity has been induced by interior binding of
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[19] See the Supporting Information for details.
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[20] The designation of compound 9 as a nonamer and compound 10
[24] Foldamer-based molecular recognition is reviewed in: a) J.
Becerril, J. M. Rodriguez, I. Saraogi, A. D. Hamilton in
Ref. [3], pp. 195–228. For a recent review about anion receptors
based on organic frameworks, see: b) P. A. Gale, S. E. Garcꢀa-
Garrido, J. Garric, Chem. Soc. Rev. 2008, 37, 151 – 190.
as a heptadecamer 10 is based on the total number of hetero-
(aryl) and triazole repeat units.
[21] T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett.
2004, 6, 2853 – 2855.
[25] Under the employed conditions, that is, concentration and
solvent composition, aggregation as an alternative mechanism of
intermolecularly mediated helicity inversion can be ruled out
since dilution studies showed a linear response, temperature-
independent CD spectra, and the absence of aggregates as
probed by dynamic light-scattering.
[22] a) N. Berova, K. Nakanishi in Circular Dichroism Principles and
Applications (Eds.: N. Berova, K. Nakanishi, R. B. Woody),
Wiley-VCH, Weinheim, 2000, pp. 337 – 376; b) D. A. Lightner,
J. E. Gurst, Organic Conformational Analysis and Stereochem-
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heim, 2000, pp. 423 – 454.
[26] Note added in proof: After submission of this manuscript, meta-
phenylene-triazole-based macrocyclic octamers and linear non-
amers, which both bind chloride ions in organic solvents, were
reported, see Y. Li, A. H. Flood, Angew. Chem. 2008, 120, 2689 –
2692; Angew. Chem. Int. Ed. 2008, 47, 2649 – 2652; H. Juwarker,
J. M. Lenhardt, D. M. Pham, S. L. Craig, Angew. Chem. 2008,
120, 3800 – 3803; Angew. Chem. Int. Ed. 2008, 47, 3740 – 3743.
[23] Related amphiphilic oligo(m-phenylene ethynylene)s self-
assemble into stacked helical columns at higher water content.
This is indicated by the strong temperature dependence of the
CD signal which is associated with inter- and intramolecular
chirality transfer processes: L. Brunsveld, E. W. Meijer, R. B.
Prince, J. S. Moore, J. Am. Chem. Soc. 2001, 123, 7978 – 7984.
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