Template-induced screw motions within an aromatic amide foldamer double helix

Article abstract of DOI:10.1002/anie.201101697

Screwed in place: An anti-parallel double-helical aromatic oligoamide foldamer was shown to bind to a series of rodlike guests of various lengths upon the winding of the duplex around the guests (see scheme). Solid-state crystal structures of the host-guest complexes show that the two strands of the duplex undergo a relative screw motion to adjust the distance between hydrogen-bond donors located at the end of one of their extremities so that they bind to hydrogen-bond acceptors of the guest. Copyright

Full text of DOI:10.1002/anie.201101697

Communications
DOI: 10.1002/anie.201101697
Molecular Machines
Template-Induced Screw Motions within an Aromatic Amide Foldamer
Double Helix**
Yann Ferrand, Quan Gan, Brice Kauffmann, Hua Jiang,* and Ivan Huc*
Important steps have been made to control motion at the
molecular scale in synthetic systems. Examples of elementary
molecular motions such as rotations[1] and translations[2] have
been reported, as well as combined motions such as coupled
rotations,[3] coupled translations,[4] and springlike exten-
sions.[5] In addition, the direction of molecular movements
can sometimes be controlled in translations (shuttling)[6] and
in rotations.[7] Herein, we focus on a less-investigated motion,
the screw motion, which consists of the linear combination of
a rotation and a translation. We found that the sliding of two
molecular tapes along one another within a double-helical
duplex can be controlled by rodlike guests, so that the length
of the duplex matches with the length of the guest (Fig-
ure 1a).
We recently described the ability of some multiturn single-
helical aromatic amide foldamers to wind around rodlike
guests and form stable complexes in which the guest resides in
the helix cavity.[8] By analogy with rotaxanes, these complexes
can be termed foldaxanes.[9] When the rods have bulky
residues at the termini, foldaxanes do not form by the
threading of the rod into the helix cavity but by the unfolding/
refolding of the helix around the rod. This creates a high
kinetic barrier, owing to the high energy cost to unfold a
helical aromatic oligoamide foldamer, as shown, for example,
in quinolinecarboxamide oligomers.[10] The unusual kinetic
stability of the foldaxanes has allowed us to induce and
Figure 1. a) A schematic representation of the screw motion of the two
strands of a molecular duplex, and of the trapping of screwed (left)
and unscrewed (right) double helices upon binding to short and long
rodlike guests, respectively. Hydrogen-bond acceptors (the sticks
observe shuttling of the helix between distinct stations along a
dumbbell rod at timescales that are much shorter than the
timescale of foldaxane dissociation. Foldaxane formation is
protruding from the rods) on the guests match with hydrogen-bond
[*] Dr. Y. Ferrand, Q. Gan, Dr. I. Huc
Universitꢀ de Bordeaux—CNRS UMR5248
Institut Europꢀen de Chimie et Biologie
2 rue Robert Escarpit, 33607 Pessac (France)
E-mail: i.huc@iecb.u-bordeaux.fr
donors (small rings) at the ends of a double helix; b) the structure of
helical aromatic oligoamide foldamer 1; c) the structure of guests of
various lengths, which possess carbonyl groups as hydrogen-bond
acceptors; d) the structure of a guest having two distinct stations, a
long one and a short one, to which a double helix can bind.
Dr. B. Kauffmann
Universitꢀ de Bordeaux—CNRS UMS3033
Institut Europꢀen de Chimie et Biologie
2 rue Robert Escarpit, 33607 Pessac (France)
thermodynamically favored owing to intermolecular hydro-
gen bonds between binding sites, which are located at each
extremity of the helix (namely 2,6-pyridinedicarboxamide
hydrogen-bond donors), and anchor points on the rods
(carbonyl hydrogen-bond acceptors).[8] It follows that a
strict match between helix and rod lengths is required to
ensure foldaxane stability; the tolerance is typically one CH2
unit of the rod.
Following this, we proposed that foldaxanes might form
not only with aromatic oligoamide sequences that are folded
as single helices, but also when they hybridize into double
helices.[5d,e,11] For example, sequences related to 1 (Figure 1b)
have been shown to hybridize into stable double-helical
antiparallel duplexes.[11,12] Because the double helix (1)2
Q. Gan, Prof. H. Jiang
Beijing National Laboratory for Molecular Sciences
CAS Key Laboratory of Photochemistry
Institute of Chemistry, Chinese Academy of Sciences
Beijing 100190 (China)
E-mail: hjiang@iccas.ac.cn
[**] This work was supported by the CNRS, the Conseil Rꢀgional
d’Aquitaine, an ANR grant (ANR-09-BLAN-0082-01), the Chinese
Academy of Sciences, and the National Natural Science Foundation
of China (20972164). We thank Axelle Grꢀlard for her assistance
with NMR measurements.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101697.
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possesses two 2,6-pyridinedicarboxamide hydrogen-bond
donors, that is one on each strand, we predicted that it
might also bind to rodlike guests having carbonyl hydrogen-
bond donors. Titrations between (1)2 and 2a–2 f (Figure 1c) in
CDCl3 were monitored by 1H NMR spectroscopy and, in
some cases, revealed the formation of a new species that was
in slow exchange with (1)2 on the NMR timescale (Figure 2a–
c). Specifically, the longest (2 f) and shortest (2a) rods do not
form inclusion complexes, whereas rods of intermediate sizes
2b–2e do, with binding constants of 55, 20, 140, and
35 LmolÀ1, respectively. These complexes all formed at rates
1
too fast to monitor by H NMR spectroscopy, as equilibrium
is reached before the first 1H NMR spectrum could be
measured, which takes approximately 2 min. This process is
faster than that previously observed for single-helical foldax-
anes that are derived from longer aromatic amide sequences.
Thus, to bind a rod of given length, two short strands appear
to unwind and rewind faster than a long one.[8]
The X-ray crystal structures of (1)2ꢀ2b, (1)2ꢀ2d, and
(1)2ꢀ2e were obtained (Figure 3),[13] and confirmed the
stoichiometry, symmetry, and the structure of the double-
helical foldaxanes, in agreement with the NMR titration data.
In particular the crystal structures revealed: 1) the expected
hydrogen bonds between the 2,6-pyridinedicarboxamide units
and carbonyl groups on the rod, as observed for single-helical
foldaxanes;[8] 2) the antiparallel nature of the double helices;
Figure 3. Solid-state structures of a) (1)2ꢀ2b, b) (1)2ꢀ2d, and
c) (1)2ꢀ2e. The antiparallel strands of (1)2 are shown in red and blue
(tube representation). Rodlike guests are shown in CPK (C gray,
H white, O red, N light blue). Illustrations of the screw motion are
shown in d) (1)2ꢀ2b; and e) (1)2ꢀ2d. Rods are in yellow CPK
representations. The carbonyl oxygen atoms of the carbamate groups
are shown in green. L and ‘ represent the distance between the two
pyridine clefts in each complex (1)2ꢀ2b and (1)2ꢀ2d, and are equal to
6.8 ꢁ and 9.0 ꢁ, respectively. The red and blue arrows illustrate the
screw-motion mechanism between complex (1)2ꢀ2b and (1)2ꢀ2d.
Isobutyl side chains and included solvent molecules have been
omitted for clarity.
3) the C2-symmetrical structure of the complexes; 4) that the
double-helix cavity accommodates the alkyl and carbamate
moieties of the guest, but that the terminal benzyl groups are
too large to be threaded through the helix, thus suggesting a
helix unfolding/refolding mechanism of formation for the
double-helical foldaxanes, as demonstrated for single-helical
foldaxanes.[8]
Unlike single-helical foldaxanes, double-helical foldax-
anes feature a high tolerance with respect to guest length; 2e
is three CH2 units longer than 2b, yet they have comparable
affinities for (1)2. In addition, the binding constants as a
function of guest length do not follow a trend. A close-up look
at the X-ray crystal structures shows that to accommodate 2b
or 2d, the two strands of (1)2 undergo a relative screw motion
of over a third of a turn to adjust the distance along the helix
axis between the two 2,6-dicarboxamide units, and their
angular orientation is perpendicular to the helix axis. The
structure of (1)2ꢀ2e is almost superimposable on that of
(1)2ꢀ2d, except that the alkyl segment of the guest is
compacted in the case of 2e so as to accommodate its extra
CH2 unit, an effect which has been observed in other
systems.[14] In agreement with the solid-state structures,
1H NMR analysis of the solutions showed that signals
belonging to terminal functionalities of the strands, for
example, the pivaloyl protons and some pyridine protons
(see Figure S5 in the Supporting Information), consistently
shift upfield when the guest is shortened, thus suggesting an
increase of ring-current effects as would be expected when the
two strands screw into one another. Screwing is also the
mechanism by which these double helices are presumed to
form from single-stranded precursors in the absence of a
Figure 2. Part of the 1H NMR spectra (700 MHz) showing the amide
and some pyridine proton resonances of (1)2 (8 mm) in CDCl3: a) at
258C in the absence of guest; b) at 08C in the presence of 2b
(10 equiv); c) at 08C in the presence of 2e (10 equiv); d) at 08C in the
presence of 2b and 2e (10 equiv each); e) at 08C in the presence of 3
(10 equiv). The signals of the starting double helix (1)2 are marked
*
*
with , the signals of (1)2ꢀ2b with , and the signals of (1)2ꢀ2e with
&
. Sharper NMR spectra could be recorded at 08C as shown in this
figure.
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Communications
rodlike guest.[15] Here, it is the length of the guest that
templates the extent of the relative screwing of the two
strands within each duplex. The binding constants as a
function of guest length do not follow a trend; this result is
probably due to the fact that an adjustment in the distance
between the 2,6-pyridinedicarboxamide units of the duplex is
accompanied by a concomitant change in their angular
orientation, therefore not allowing a perfect match for all
guests.
A titration of (1)2 with an equimolar mixture of 2b and 2e
was then carried out, and produced a mixture of (1)2ꢀ2b and
(1)2ꢀ2e in a 2:1 ratio (Figure 2d). Rotating-frame nuclear
Overhauser effect 2D spectroscopy (ROESY) measurements
(Figure S6) were recorded on this mixture and showed intense
exchange peaks between the corresponding protons of the
two complexes. Correlations were also observed between
each foldaxane and the uncomplexed (free) double helix (1)2.
This experiment demonstrates that the double helix may
dissociate from one rod and then reassociate with another rod
having a different length. The net outcome of this exchange
process is a screw or unscrew motion within the duplex, yet it
does not proceed through correlated translations and rota-
tions of the strands, but through an unwinding/rewinding
mechanism.
This process was taken a step further by placing two helix
binding stations of different lengths on a single rod. For this
purpose, guest 3 was equipped with two binding stations
equivalent to those of 2b and 2e. Upon titrating (1)2 with a
large excess of 3 the complex (1)2ꢀ3 forms, in which a single
duplex binds to 3. No measurable amount of the higher
aggregate, in which two double helices are bound to 3, was
observed. As expected, the 1H NMR spectrum of (1)2ꢀ3
revealed two sets of signals that corresponded to two isomers
in which (1)2 was positioned either on the long station or on
the short station of 3 (Figure 2e). Neither of these two
isomers has a symmetrical structure; the two strands of the
duplex are inequivalent in each isomer (Figure 4a). Conse-
quently, the 1H NMR spectrum of (1)2ꢀ3 features four times
as many signals as that of, for example, (1)2ꢀ2b (Figure 2e
and b). ROESY experiments on (1)2ꢀ3 in CDCl3 solutions
revealed that intense exchange takes place between the
isomer in which (1)2 is positioned on the long station of 3 and
the one in which (1)2 is positioned on the short station, while
cross-peaks with traces of the free (1)2 were very weak. As
above, the net outcome of this exchange is a screw or an
unscrew motion within (1)2. Remarkably, ROESY data
demonstrate that exchange and consequently the screw/
unscrew motion, proceed through the shuttling of the
duplex along the guest and not by a dissociation/association
mechanism. If the latter would occur, each of the four signals
of any given proton of the duplex would correlate with the
three others (Figure 4c) because the positions on the strands
would be randomized in the dissociation process. However,
correlations show that any given proton of one isomer of
(1)2ꢀ3 exchanges with a single proton of the other isomer
(Figure 4b and d), consistent with the shuttling of the duplex
along the rod, and the concomitant screw motion. Shuttling
requires the disruption of hydrogen bonds between the rod
and the duplex and the screw motion of the two strands into
Figure 4. a) A schematic representation of the controlled screw/
unscrew of a molecular duplex by its shuttling between two inequiva-
lent stations of a rodlike guest. b) A schematic representation of the
number of cross-peaks upon exchange of the duplex between the two
inequivalent stations when exchange takes place by shuttling or c) by a
dissociation/association mechanism. d) Expansion of the 1H–1H
ROESY spectrum at 48C (700 MHz) of (1)2ꢀ3 (8 mm) recorded with
300 ms mixing time, thus showing that any given proton of one
isomer of (1)2ꢀ3 exchanges with a single proton of the other isomer.
NOE cross-peaks are observed in red whereas exchange peaks are
seen in blue. P1, P2, P3 denote protons that belong to independent
pyridine spin systems but have not been assigned to each pyridine
ring in the sequence. C3 or C6 denotes the number (3 or 6) of CH2
units in the alkyl chain of the station of the guest on which the double-
helix resides.
one another, but these processes occur faster than foldaxane
dissociation.
This work thus gave access to control over an unusual
screw motion.[16] Steps are now being made to increase its
amplitude, to trigger it by an external stimulus, and to control
the absolute sense of rotation in the right- or left-handed
helices.
Received: March 9, 2011
Published online: June 29, 2011
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Angew. Chem. Int. Ed. 2011, 50, 7572 –7575

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