Orchestrating Directional Molecular Motions: Kinetically Controlled Supramolecular Pathways of a Helical Host on Rodlike Guests

Article abstract of DOI:10.1021/jacs.7b04884

An aromatic oligoamide sequence was designed to fold and self-assemble into a double helical host having a cylindrical cavity complementary to linear oligocarbamate guests. Formation of helical pseudorotaxane complexes, foldaxanes, between the host and guests having binding stations of different affinities was evidenced by NMR and X-ray crystallography. Rodlike guests possessing two or three binding stations, long alkyl or oligoethylene glycol spacers or bulky barriers in-between the binding stations, and a single bulky stopper at one end were synthesized. Kinetic investigations of the threading and translation of the double helix along multistation rods were monitored by ¹H NMR. Results show that multiple events may occur upon sliding of the host from the nonbulky end of the rod to reach the thermodynamically most stable state before unfolding-mediated dissociation has time to take place, including binding on intermediate stations and rapid sliding along nonbinding spacers. Conversely, installing a kinetic barrier that blocks sliding allows for the deliberate integration of a helix dissociation reassociation step in the supramolecular trajectory. Typical sliding processes can be monitored over the course of hours whereas steps involving unwinding-rewinding of the helix proceeded over the course of days. These results further demonstrate the interest in foldaxanes to design complex sequences of supramolecular events within networks of equilibria through the adjustment of the kinetics of the individual steps involved.

Full text of DOI:10.1021/jacs.7b04884

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Article
Orchestrating Directional Molecular Motions: Kinetically Con-trolled
Supramolecular Pathways of a Helical Host on Rod-like Guests
Xiang Wang, Barbara Wicher, Yann Ferrand, and Ivan Huc
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 13 Jun 2017
Downloaded from http://pubs.acs.org on June 13, 2017
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Journal of the American Chemical Society
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Orchestrating Directional Molecular Motions: Kinetically Controlled
Supramolecular Pathways of a Helical Host on Rod-like Guests
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Xiang Wang, Barbara Wicher,† Yann Ferrand,* and Ivan Huc*
CBMN laboratory, Univ. Bordeaux, CNRS, IPB, Institut Européen de Chimie Biologie, 2 rue Escarpit 33607 Pessac, France.
KEYWORDS: foldaxane, pseudo-rotaxane, foldamer, double helix, dynamic self-assembly, molecular recognition, direction-
al motion, molecular shuttle, supramolecular pathways.
ABSTRACT: An aromatic oligoamide sequence was designed to fold and selfꢀassemble into a double helical host having a cylinꢀ
drical cavity complementary to linear oligo–carbamates guests. Formation of helical pseudo–rotaxane complexes – foldaxanes –
between the host and guests having binding stations of different affinities was evidenced by NMR and xꢀray crystallography. Rodꢀ
like guests possessing two or three binding stations, long alkyl or oligoethylene glycol spacers or bulky barriers inꢀbetween the
binding stations, and a single bulky stopper at one end, were synthesized. Kinetic investigations of the threading and translation of
the double helix along multistation rods were monitored by 1H NMR. Results show that multiple events may occur upon sliding of
the host from the nonꢀbulky end of the rod to reach the thermodynamically most stable state before unfoldingꢀmediated dissociation
has time to take place, including binding on intermediate stations and rapid sliding along nonꢀbinding spacers. Conversely, inꢀ
stalling a kinetic barrier that blocks sliding allows for the deliberate integration of a helix dissociation reꢀassociation step in the
supramolecular trajectory. Typical sliding processes can be monitored over the course of hours whereas steps involving unwindꢀ
ing/rewinding of the helix proceeded over the course of days. These results further demonstrate the interest of foldaxanes to design
complex sequences of supramolecular events within networks of equilibria through the adjustment of the kinetics of the individual
steps
involved.
stations on the rods having different affinities for helix hosts to
create thermodynamic gradients.
INTRODUCTION
A majority of the selfꢀassembled artificial supramolecular
architectures described to date form under thermodynamic
control. Yet, a growing number of examples have been
reported where kinetic control is essential to produce
particular structures.1 Controlling the kinetics of selfꢀassembly
processes is important to create artificial molecular machines2
capable of directional motions. It is indeed the rates at which
concommittent events take place that eventually determine in
which order these events occur. Orchestrating the time scales
of various molecular associations, dissociations and motions
may thus allow for the design of sequences of events in a
certain order between an initial state and a thermodynamically
more stable state through a defined supramolecular trajectory.
In the following, we report the design and characterization of
such kinetically controlled supramolecular trajectories in the
context of the association of aromatic amide helical foldamers
with oligoꢀalkycarbamate rodꢀlike guests to form helixꢀrod
hostꢀguest complexes termed foldaxanes. Foldaxane
subcomponents may undergo several simultaneous dynamic
processes. The generation of wellꢀdefined supramolecular
pathways therefore required the integration of multiple
parameters including foldamer helix folding; foldamer selfꢀ
association into double helical dimers; equilibrium between
parallel and antiꢀparallel forms of the duplexes; stabilization of
the antiꢀparallel duplexes upon binding to rodꢀlike guests to
form foldaxane structures; availability of two foldaxane
formation mechanisms (threading or direct winding around the
rod) to create kinetic gradients; and availability of binding
Foldaxane translation along molecular rods reproduce in
model systems an important aspect of biomolecular
machinery: the segregation on different timescales of several
potentially reversible events. For instance biomolecular
machines’ subcomponents – proteins or nucleic acids – adopt
folded conformation that are long lived, i.e. that do not
undergo frequent spontaneously unfolding. Furthermore, these
components selfꢀassemble into larger supraꢀstructures, e.g. the
ribosome and multimeric protein complexes such as ATP
synthase, that also are long lived and do not undergo
spontaneous disassembly in the time frame required for their
work regime. Thus, multiple motions can be implemented
such as the disassembly of nucleic acid double helices by
helicase, the transport of cargos within the cell by kinesin, or
even the motility of entire cells through the motion of a
flagellum as in spermatozoids on timescales much shorter than
the assembly and dissociation time scales of the subꢀ
components.
Translational molecular motions
–
typically the
directional progression of a molecular shuttle along a
molecular track – have been the object of particular attention.
For example, the elucidation of the kinesin I motion
mechanism3 inspired the development of artificial molecular
walkers,4,5 designed to undergo a directional motion on a
single molecular track through repetitive operations powered
by an external source of fuel. Translation is also involved in
the catalytic activity of DNA polymerase, a protein assembly
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that forms a pseudorotaxaneꢀlike complex with a DNA strand
foldaxanes9 akin to other helixꢀrod hostꢀguest complexes.10
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and moves along it while synthetizing a complementary
sequence. Somewhat related to DNA polymerase are some
artificial architectures in which a directional motion follows
the threading of a macrocyclic molecule at one extremity of a
rod possessing a stopper at the other extremity. Thus, pseudoꢀ
rotaxanes based on cyclodextrins6 or other macrocyclic7
architectures have been extensively used for the threading on
oligomers or polymers. Some of these designs have even been
shown to perform processive catalysis along the polymer
track.8
These helical molecular tapes slowly wrap around
oligocarbamate dumbbell rods then slide rapidly along them
between two adjacent binding stations. The segregation of
winding and sliding motion kinetics allowed for the
construction of selfꢀassembled molecular pistons9a,b without
having to rest on permanently interlocked architectures.11
Herein, we report on our efforts at extending the scope of
shuttling motions of helical aromatic oligoamide foldaxanes.
We find that several sliding steps and processes – e.g. transient
stops on intermediate binding stations and fast transit over rod
segments deprived of binding stations – have time to proceed
before dissociation through unwinding becomes significant.
We also show that dissociationꢀreassociation can be purposely
integrated in complex supramolecular trajectories to overcome
a high kinetic barrier installed before a thermodynamic well
that cannot be reached through sliding. These results further
demonstrate the interest of foldaxanes to design complex
sequences of supramolecular events within networks of
equilibria through the adjustment of the kinetics of the
individual steps involved.
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RESULTS AND DISCUSSION
Design and synthesis. We have previously shown that single
and double helical aromatic oligoamide foldamers may bind to
rodꢀlike guests bearing carbamate groups separated by nꢀalkyl
segments.9aꢀc Specifically, sequence 19c (Figure 2A) folds and
selfꢀassembles as an antiꢀparallel double helix presenting two
pyridine trimers, one at each extremity, that both act as hydroꢀ
gen bond donors to complex the carbonyl functions of a guest
(Figure 1A). The combined sixteen 8ꢀfluoroquinoline monoꢀ
mers of the two strands define a one nanometerꢀlong cylindriꢀ
cal cavity that accommodates nꢀalkanes. A match between the
host and the guest lengths is required for optimal binding.
Since (1)2 is a dynamic structure capable of screwingꢀ
unscrewing motions, it may, to a limited extent, adjust its own
length to that of the guest.9b,c Yet, upon varying guest length
sufficiently, foldaxane thermodynamic stability varies to a
large extent: binding constants ranging from 97 L mol–1 to 2.9
104 L mol–1 have been measured upon increasing guest length
from 6 to 12 methylene units.9c
We reasoned that several binding stations having an inꢀ
creasing affinity for (1)2 may be placed sequentially along a
multiꢀstation rod so as to create a thermodynamic binding
gradient. To induce the directional movement of a helix along
that gradient, we planned to introduce several design features:
(i) a bulky stopper may be placed at one extremity of the guest
while the other extremity would consist of a short linear alꢀ
kane that can quickly thread itself into the helix cavity. In this
way, loading the helix on the rod by threading can be proꢀ
grammed to occur exclusively at a defined extremity regardꢀ
less of the location of the best binding station; (ii) the affinity
of (1)2 for the first binding station (αꢀstation) on the rod
should be high enough to favor a mostly associated state under
measurement conditions (typically NMR tube concentration)
yet low enough not to hamper its sliding to a subsequent bindꢀ
ing station along the rod; (iii) binding affinities should increꢀ
mentally increase along the rod to bias the direction of the
helix motion and to facilitate monitoring the helix progression
through the successive appearance of sufficiently populated
bound states; (iv) spacers of different nature, length and bulkiꢀ
ness may be placed inꢀbetween binding stations to control the
Figure 1. (A) Cartoon representation of the hostꢀguest compoꢀ
nents and assembly. The host exists as an antiꢀparallel double
helix. Rodꢀlike guests possess carbonyl hydrogen bond acceptors
(yellow or green sticks) defining two distinct binding stations
having either a weak (α−station) or a strong affinity (ω−station)
for the host. Each rod has a nonꢀbulky terminus on which the host
can be threaded, a bulky stopper at the other extremity, and a
spacer (blue spheroid) of varying size connecting the two stations.
I, II and III stand for three distinct supramolecular states of the
host. (B) Formula of the different spacers used in this study. (C)
Cycle showing the sliding pathway followed by the host with a
nonꢀbulky spacer. (D) Cycle showing the winding pathway folꢀ
lowed by the host with a bulky spacer.
Our group has shown that multiꢀturn helical aromatic
oligoamide foldamers may wind around dumbbell shape
molecules and form stable pseudoꢀrotaxane complexes termed
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sliding rates of the helix. Bulky spacers may eventually block tions were also synthesized. Benzene (10) and anthracene (11)
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the helix and impose other supramolecular pathways towards
the most stable foldaxane; (v) when the helix reaches the last
binding station (ωꢀstation), the bulky stopper then prevents
unslippage and makes the thermodynamically most stable state
be kinetically stable as well.
were selected as bulky obstacles of varying size able to block
the helix and to impose another supramolecular pathway,
namely unwindingꢀwinding, for the helix to reach the best
binding station.
Self-assembly of 1 into double helical (1)2. The antiꢀ
parallel nature of (1)2 was assessed both in solution and in the
A series of rodꢀlike guests having up to three binding
stations separated by spacers of varied length, polarity and
bulkiness were designed and synthesized (Figure 2B,C,D).
Synthetic routes and experimental details are provided in the
supporting information. Typically, carbamate functions were
produced by reaction of a primary alcohol or amine with 4ꢀ
nitrophenyl chloroformate. The resulting activated 4ꢀ
nitrophenyl carbamates reacted with primary alcohols to proꢀ
duce carbamates in boiling chloroform. Conversely, the resultꢀ
ing activated 4ꢀnitrophenyl carbonates reacted with primary
amines to produce carbamates at room temperature. Binding
stations having, 7, 8 or 11 methylenes were used depending on
the desired binding affinity. These affinities have been deterꢀ
mined previously using single station rods9c (see below). Lineꢀ
ar non hindered spacers between two binding stations were
introduced to investigate whether they create a kinetic barrier
to helix sliding along the rod. For instance, linear alkyl spacers
of various length up to 18 methylenes (2, 3, 4 and 5) and oliꢀ
goethylene glycol spacers of various length up to 17 atoms (2,
6 and 7) were all placed between the same two stations. Note
that the shortest spacer of compound 2 is the same for both
series. In addition, two rods having three binding stations were
prepared (8, 9), which differ by the nature of the middle staꢀ
tion, to generate more complex sliding pathways. In parallel
rods bearing bulky spacers that hinder or forbid sliding moꢀ
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solid state. As shown by H NMR, duplex (1)2 exists as a
mixture of parallel and antiparallel assemblies after purificaꢀ
tion on silica gel chromatography (Figure S1). Fortunately, the
precipitation of the double helix from methanol provides (1)2
exclusively in its antiparallel configuration. Xꢀray quality
crystals of (1)2 were obtained from the slow diffusion of nꢀ
hexane in a chloroform solution. The solidꢀstate structure was
solved and confirmed the antiparallel arrangement of (1)2 as
well as the existence of a one nanometerꢀlong cylindrical
cavity lined with fluorine atoms (Figure 3AꢀC). 1H NMR
monitoring of freshly dissolved antiparallel (1)2 (4 mM in
CDCl3 at 17°C) showed that the parallel/antiparallel equilibriꢀ
um was slowly reached after 10 hours (Figures S1 and S2,
final ratio antiparallel/parallel = 63/37). Only the antiparallel
form of (1)2 binds to rodꢀlike guests. Thus, in the presence of
the guests, the antiparallel form is further stabilized and the
parallel form does not appear anymore, being disfavored both
kinetically and thermodynamically. The main advantage of
isolating the pure antiparallel duplex by the precipitation
method mentioned above is thus to avoid a slow antiparallel to
parallel duplex conversion to interfere with, and become the
rate limiting factor of, the various transformations to be studꢀ
ied here.
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Figure 2. Formula of aromatic oligoamide host 1 and of the various rodꢀlike guests used in this study.
Structural and thermodynamic study of foldaxane for-
mation. Single station rods 12 and 13 possess one bulky stopꢀ
per and one terminal nꢀbutyl carbamate. Their binding to (1)2
was assessed to be compared to the recently measured binding
of dumbbellꢀshaped guests having two benzylꢀcarbamates.9c
The two rods possess 8 and 11 methylenes, respectively, beꢀ
tween their carbamate functions. Upon adding guests 12 and
13 to a CDCl3 solution containing antiparallel (1)2, single sets
of wellꢀresolved NMR signals were immediately observed as a
result of the formation of (1)2⊃12 and (1)2⊃13 (Figures S3 and
S4). Despite the absence of stoppers on the rod, exchange
between free (1)2 and bound (1)2 was found to be slow on the
NMR time scale. Association constants for (1)2⊃12 and
(1)2⊃13 were measured accurately through the integral ratios
of the free and bound host amide resonances to be Ka = 6.4 103
and 4.8 104 L mol−1, respectively, at 17°C in CDCl3. These
values are both about 40% higher than measured with bisꢀ
benzyl carbamate guests at 25°C.9c The ratio between these
association constants was confirmed in a competition experiꢀ
ment (Figure S5): the addition of rod 13 (1 equiv.) to foldaxꢀ
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plex. A closeꢀup look at the two crystal structures confirmed
ane (1)2⊃12 caused the dissociation of (1)2 and its quick
threading on 13 to form (1)2⊃13 (final ratio
[(1)2⊃13]/[(1)2⊃12] = 79/21). The 7.5 fold difference between
the two affinities was considered to be sufficient to create a
gradient of affinity on multistation rod molecules. As shown in
the subsequent steps of this study, the design of single station
rods 12 and 13 as models of individual stations on multiꢀ
station rods 2ꢀ11 proved to be valid except in the case of rod 2.
The two stations of 2 are close to each other and both possess
an enhanced affinity for 1 (vide infra). In this case, 14 is a
better model than 12 of the first binding station of 2.
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different extents of the relative screwing of the two strands in
each double helix.9b,c This allows (1)2 to accommodate guests
of different lengths by adjusting the positions of the pyridine
trimer pinchers so that they match with the positions of the
carbonyl groups of the rod (Figures 3D,E). In solution, an
indicator of the variable positioning of the two strands of 1 is
the different chemical shift values of the protons in position 4
of the 2,6ꢀpyridinedicarboxamide units which are found near
8.8 ppm in (1)2⊃13 and below 8.4 ppm in (1)2⊃12 (Figures S3
vs. S4, see also Figure 4A vs. 4C and Figure 2 in reference
9b). One may note that the terminal diamino pyridine unit of
each strand is flipped out in the structure of (1)2⊃12. This has
been observed previously in other duplexes involving terminal
pyridine units even in the absence of guest.9a,12
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Structural insights were also gathered in the solid state.
Crystals of (1)2⊃12 and (1)2⊃13 were obtained from the slow
diffusion of nꢀhexane in a chloroform solution of each comꢀ
Figure 3. Structures in the solid state analyzed by single crystal xꢀray crystallography of the antiparallel double helix of (1)2 and of its
complexes with various oligocarbamate rods. (AꢀC) structure of (1)2: side views in tube (A) and CPK (B) representations and top view (C)
in CPK representation. In (C), terminal pyridine trimers have been deleted to highlight the cavity of the helix; fluorine atoms are shown in
light blue color. (D) Structure of the [3]foldaxane (1)2⊃12 in tube (double helix) and CPK (rod) representations. (E) Structure of the
[3]foldaxane (1)2⊃13 in tube (double helix) and CPK (rod) representations. (FꢀI) Structure of (1)4⊃2. (F) Structure of the rodꢀlike guest 2
as it exists in [5]foldaxane (1)4⊃2. (G) Side view of (1)4⊃2. The guest and the helices appear in CPK and tube representations, respectiveꢀ
ly. In (H) and (I) one double helix of (1)4⊃2 has been omitted on the strong binder or the weak binder stations, respectively to illustrate
possible structures of (1)2⊃2α and (1)2⊃2ω, respectively. Only P helical enantiomers are shown. The structures belong to nonꢀSohncke
(enantiogenic) space groups and thus also contain M enantiomers. Isobutoxy side chains and included solvent molecules have been omitted
for clarity.
Directional sliding motion in double station rods. Foldaxꢀ
ane formation was then investigated with double station rods
2ꢀ7 (Figure 1A and 2B). These rods all bear both a weak bindꢀ
ing station (αꢀstation, 8 methylenes as in 12) and a strong
binding station (ωꢀstation, 11 methylenes as in 13). In the
parent compound of the series, guest 2, the two stations are
separated by a single ethylene glycol unit (Figure 3F). Upon
adding an excess13 of rod 2 (10 equiv. with respect to (1)2) to a
CDCl3 solution of antiparallel (1)2 NMR showed that a single
new species was immediately and quantitatively formed that
corresponds to the fast and quantitative threading of (1)2 on 2
(Figure 4B). Intense nOe correlations between the bound rod
and the double helix clearly indicate that (1)2 is then located
on the α−station (Figure S26). This [3]foldaxane was named
(1)2⊃2α in reference to the weak binding α−station and repreꢀ
sents a kinetically favored intermediate: the helix does not
immediately reach the more favorable ω−station. Upon standꢀ
ing at 17°C, (1)2⊃2α disappeared over the course of days and
was replaced by another foldaxane species (Figure 4CꢀE)
reflecting that (1)2⊃2α is not the most stable complex. The
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excess of guest 2 to favor the crystallization of the
new species was assigned to be (1)2⊃2ω in which the double
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2
helix (1)2 is positioned on the strong binding station near the
[3]foldaxane (1)2⊃2ω, the resolution of the solidꢀstate strucꢀ
ture revealed a five component assembly made of two double
helices threaded on rod 2 (Figure 3GꢀI). This structure conꢀ
firms that (1)2 can complex both stations of 2 and provides an
illustration of what both (1)2⊃2ω (Figure 3I) and (1)2⊃2α
(Figure 3H) may look like. The crystallization of [5]foldaxane
(1)4⊃2 may have two nonꢀexclusive explanations: (i) the undeꢀ
tected selective crystallization or precipitation of excess 2, if it
occurs first, will enrich the mixture in (1)4⊃2; (ii) (1)4⊃2 may
be much less soluble and much more prone to crystallization
than (1)2⊃2ω, and may form crystals first even when it repreꢀ
sents a minor component of the crystallization mixture.
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bulky stopper. Most amide H NMR resonances are slightly
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downfield shifted in (1)2⊃2ω with respect to (1)2⊃2α which is
consistent with chemical shift differences between the resoꢀ
nances of (1)2⊃12 and (1)2⊃13 (Figure S5). The equilibrium
was reached after almost 3 days and the final ratio ω/α was
found to be 75/25 (Table 1) as expected from the ratio of assoꢀ
ciation constants with 12 and 13.
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Xꢀrayꢀquality single crystals were obtained by slow difꢀ
fusion of nꢀhexane into a CDCl3 solution of (1)2 and 2 at therꢀ
modynamic equilibrium. Unexpectedly, despite the use of an
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Figure 4. Kinetic and thermodynamic characterization of foldaxane formation between (1)2 and double station rods 2ꢀ7. (AꢀE) Time deꢀ
pendent H NMR spectra (400 MHz in CDCl3 at 290K, aromatic amide resonances region) showing the threading of 2 into (1)2 to form
(1)2⊃2α and then (1)2⊃2ω. (A) initial antiparallel (1)2 (2 mM); (B) 15 min. after the addition of 2 (20 mM), then after (C) 20 hours, (D) 40
1
hours, (E) 56 hours at equilibrium. Resonances of the free double helix (1)2 are denoted with empty circles. Black circles and black squares
indicate signals of (1)2⊃2α and (1)2⊃2ω, respectively. Stars denote aromatic resonances (protons in position 4 of 2,6ꢀpyridine dicarboxꢀ
amide rings). (F) Time traces of threading and sliding motion of (1)2 on rods 2 (
+
), 3 (
▲), 4 (
ꢀ
), 5 ( ), 6 (●) and 7 (ꢁ). The concentration
ꢀ
of host on each station was obtained through the integration of 1H NMR amide resonances. (G) Schematic representation of the unidirecꢀ
tional sliding of the double helix along a double station rod.
Table 1. Kinetic data for the sliding of the investigated complexes determined by 1H NMR.
[3]foldaxane
k (10ꢀ5 sꢀ1)a
τb (hours)
(1)2⊃2 (1)2⊃3 (1)2⊃4 (1)2⊃5 (1)2⊃6 (1)2⊃7 (1)2⊃8 (1)2⊃9 (1)2⊃10 (1)2⊃11 (1)2⊃15
1.2
18.0
75
37.3
0.44
81
11.3
1.82
82
9.7
2.12
81
36.3
0.50
83
23.0
0.96
85
n. d.
37.0
80
n. d.
102
64
n. d.
122.4
76
n. d.
117.8
76
n. d.
97.9c
69d
% of (1)2 on the ωꢀ
station at equilibrium
number of atoms in the
spacer
2
6
12
18
11
17
18
19
n. a.
n. a.
n. a.
a pseudoꢀfirst order kinetic constants k were calculated based on the integration of the 1H NMR amide resonances corresponding to each complex (1)2⊃2α
and (1)2⊃2ω. The slope extracted from the plot of –ln([(1)2⊃2α]/[(1)2]total) as function of time corresponds to the kinetic constant of the sliding process.
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Calculation was performed during the initial phase of the helix motion for which the back sliding can be considered negligible; b time required to reach 50%
c
of (1)2 on the ω−station corresponding to [(1)2⊃ω−station] = 1 m
M
;
competition experiment between (1)2⊃12 and (1)2⊃15. Double helix (1)2 is already
1
2
d
threaded on 12 prior to the addition of a stoichiometric amount of 15; proportion of (1)2 on rod 15. n. d.: not determined; n. a.: not applicable.
37.3 105 sꢀ1). Further elongation somewhat decelerated the
motion but sliding remained 8 times faster on the longest rod 5
than on 2. This non monotonous trend was also observed upon
elongating the central ethylene glycol into oligoꢀethylene
glycols: when compared to the short ethylene glycol spacer of
2, sliding rates along tetraethylene glycol (6) and hexaethylene
glycol (7) were found to be higher by 30 and 20 fold, respecꢀ
tively. If one excludes 2 and its very short spacer, elongating
spacers eventually slows down sliding but the attenuation of
the rate constant is not pronounced. Furthermore, sliding along
oligoethyleneglycols is faster than along alkanes, despite the
preference of the former to adopt multiple gauche conforꢀ
mations that are a priori not compatible with the narrow cavity
of (1)2. For instance, sliding along rods 6 (resp. 7) was found
to be 2ꢀ3 times faster than along 4 (resp. 5) despite their simiꢀ
lar lengths (Table 1).
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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50
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60
The distinctly slower sliding along 2 must in some manꢀ
ner relate to the proximity between the central carbamate
functions of this rod. To explore what may slow down sliding
from the αꢀ to the ωꢀstation of 2, we prepared rod 14 which
possesses an αꢀstation plus a single carbamate group connectꢀ
ed by an ethylene glycol (Figure 5A). The relative affinity of
14 for (1)2 was assessed in a competition experiment: 12 and
Figure 5. (A) Formula of rod 14 (top) and zoom on the binding
14 were mixed in excess (2 equiv. each) with (1)2. The ratio
pattern between rod 14 and the two strands of (1)2 in an energy
[(1)2⊃14]/[(1)2⊃12] was calculated by integrating NMR sigꢀ
minimized model of (1)2⊃14 obtained by molecular mechanics
nals and showed that the additional carbamate group of 14 is
(minimization with MMFFs force field) using Maestro v.6.5
responsible for an enhancement of binding to (1)2 by a factor
(bottom); (B) Formula of rod 12 (top) and zoom on the binding
of 1.7 with respect to 12 (Figure 5CꢀD). A comparison beꢀ
pattern between rod 12 and the two strands of (1)2 as observed in
tween the xꢀray structure of (1)2⊃12 and an energy minimized
the crystal structure (1)2⊃12 (bottom). The two strands of (1)2 are
molecular model of (1)2⊃14 revealed the presence of an addiꢀ
tional hydrogen bond between the NH of the terminal 8ꢀ
shown in tube representation and are colored in either salmon or
light blue. The rod is shown in tube representation and color
fluoroquinoline of (1)2 and the extra carbamate carbonyl group
at the extremity of 14 (Figure 5A,B). This interaction is possiꢀ
bly responsible for the higher binding to 14 and is unlikely to
occur with spacers longer than an ethylene glycol between
carbamate functions. Thus, the singular slow kinetics of slidꢀ
ing of (1)2 along two station rod 2 might arise from a higher
affinity (1)2 with both the αꢀ and ωꢀstations as compared to
rods in which the αꢀ and ωꢀstations are more distant.
coding is as follow: carbon (grey), nitrogen (blue), oxygen (red)
and hydrogen (white). Hydrogen bonds are shown in magenta.
1
Excerpt of the H NMR spectra (400 MHz, CDCl3, 298K) of the
amide region of 1 (2 mM) in the presence of: (C) 2 equiv. of rod
12; (D) 2 equiv. of rod 14 and (E) 2 equiv. of both 12 and 14.
Based on the experiments described above, the mechaꢀ
nism (sliding or winding/unwinding) of the transformation of
(1)2⊃2α into (1)2⊃2ω cannot be ascertained. However, sliding
above an ethylene glycol spacer has been established previousꢀ
ly9a,b and there is no reason to dismiss it in this case (see the
subsequent section for experimental proof that sliding prevails
here as well). NMR monitoring then provides an estimate of
the sliding rate. Assuming that pseudoꢀfirst order kinetics
apply when sliding starts, i.e. when the reverse sliding back to
(1)2⊃2α is negligible because there is little (1)2⊃2ω formed, a
pseudoꢀfirst order kinetic constant was calculated to be k = 1.2
10–5 s–1 (Table 1, Figure 1 and Figure S6ꢀS7).
Directional sliding motion in triple station rods. Rod design
was taken one step further by placing an additional, βꢀbinding
station, inꢀbetween the αꢀ and ωꢀstations. Triple station rods 8
and 9 both possess the same αꢀ and ωꢀstations as double staꢀ
tion rods. In rod 8, the central βꢀstation has a weak affinity for
antiparallel (1)2 (Ka = 1100 L molꢀ1). In rod 9, the central βꢀ
station is identical to the αꢀstation. All stations are separated
by an ethylene glycol spacer. Threading experiments with rods
8 and 9 were analyzed by 1H and 19F NMR. The determination
of a pseudoꢀfirst order rate constant was not as straightforward
as for the other rods due to binding to, and reverse sliding
from, the βꢀstation. Instead, to compare with the others rods
we monitored for each foldaxane the time required to reach
50% occupancy of (1)2 on the ω−station (τ in Table 1). When
compared to rods 3ꢀ7, sliding kinetic of (1)2 to reach equilibriꢀ
um (Table 1) was found to be at least 17 times slower. Both
rods 8 and 9 showed a much longer sliding time (τ = 37 and
102 hours, respectively) to join the terminal ωꢀstation. As
We then examined the effect of elongating the central
ethylene glycol spacer into longer alkanediols on the sliding
rate of (1)2. Sliding along 3, 4 and 5 proceeded as it did along
2, with the quick formation of a complex on the α station
followed by the slow migration of (1)2 to the ω station (Figure
4G). Pseudoꢀfirst order rate constants were calculated (Table
1). In each of this three rods the spacer length was elongated
to reach 6, 12 and 18 methylenes, respectively. Yet, the sliding
was found to be 30 times faster on rod 3 than on rod 2 (k =
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Journal of the American Chemical Society
expected, the final percentage of double helix on the terminal (Figure 6A,B). The emergence of a new set of resonances
1
2
3
4
5
6
7
8
ωꢀstation of 9 was found to be lowered by the competition
binding between the ωꢀ and both αꢀ and βꢀstations. In the case
of rod 8, at thermodynamic equilibrium, the final ratio was
found to be only slightly altered due to weak competition of
the intermediate binding site with the ωꢀstation.
corresponding to (1)2⊃10ω was considerably slower than with
nonꢀbulky spacers. Again, to compare the motion kinetics of
(1)2 on rod equipped with bulky spacers the τ value defined in
Table 1 was used. The time to reach 50% of (1)2 on the
ω−station was found to be over 5 days (Figure 6C), a value
which is almost 7 times larger than the one of the slowest
linear foldaxane analog (1)2⊃2.
In summary of the two sections above, when (1)2 is mixed
with rods having two or three binding stations separated by
linear nonꢀhindered alkyl or ethylene glycol spacers, the quick
formation of a kinetically favored intermediate is observed,
followed by a slower migration to the best binding station. The
kinetics of the overall process much depends on what is beꢀ
tween the αꢀ and ωꢀstations (length and chemical nature of the
spacer, additional station), which is consistent with the hyꢀ
pothesis that the helix actually slides along the molecular track
from the unhindered end to the bulkier side of the rod.
Foldaxane formation with (1)2⊃11 proceeded at the same
rate as with (1)2⊃10 hinting at comparable mechanisms. Thus,
a bulkier spacer does not further slow down binding to the ωꢀ
station, suggesting that the benzene or anthracene moieties are
not close to the helix during foldaxane formation. Sliding over
the spacer at the cost of major distortions appears to be unlikeꢀ
ly as it may be slower with the bulkier spacer. Furthermore, an
additional experiment was performed in which single station
foldaxane (1)2⊃12 was mixed with single station dumbbell rod
15. The latter matches exactly with the spacer and ωꢀstation of
11, but it is not connected to any αꢀstation. As in previous
studies,9a the formation of (1)2⊃15 should occur via an unꢀ
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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34
35
36
37
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42
43
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45
46
47
48
49
50
51
52
53
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55
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57
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60
Threading−sliding vs. winding-unwinding mechanisms. To
ascertain the sliding mechanism hypothesized above and to
promote an alternate supramolecular pathway, we introduced
double station rods 10 and 11 in which the spacers separating
the two stations contain a bulky component (Figure 2C), either
benzene or anthracene, that are a priori too large to pass
through the cavity of (1)2 without a major distortion. In these
designs, the helix may quickly thread onto the αꢀstation, but
reaching the thermodynamically favored (1)2⊃10ω and
(1)2⊃11ω complexes requires a winding of the helix around
the ωꢀstation, presumably after its dissociation from the αꢀ
station. Selfꢀassembly processes were monitored as for other
rods. As expected, upon mixing 10 with (1)2, a kinetically
favored species assigned to (1)2⊃10α is quickly observed
1
windingꢀrewinding mechanism. H NMR monitoring of the
mixture of (1)2⊃12 and 15 (Figure S23) showed that the rate
of formation of (1)2⊃15 is very close to that of (1)2⊃10ω and
(1)2⊃11ω, suggesting that for these two as well, the helix
unwinds and rewinds to move from the α−station to the
ω−station. These results altogether also confirm that the faster
processes observed for rods 2ꢀ8 are dominated by sliding
motions. In the case of triple station rod 9, reaching the ω
station is as slow as with 10 and 11, experimental results are
thus not conclusive in this case as sliding and unwindingꢀ
rewinding cannot be distinguished and may both contribute.
Figure 6. Kinetic and thermodynamic characterization of foldaxane formation between (1)2 and triple and double station rods 8ꢀ11. (AꢀE)
1
Time dependent H NMR spectra (400 MHz in CDCl3 at 290K, aromatic amide resonances region) showing the fast threading of 10 into
1
(1)2 to form (1)2⊃10α and the slow conversion into (1)2⊃10ω. (A) H NMR spectra of free (1)2 (2 m
M
); (B) 10 min. after the addition of
10 (20 mM), then after (C) 2 days, (D) 5 days and (E) 15 days at equilibrium. Black colored signals are those of the free (1)2 whereas red
and blue resonances belong to (1)2⊃10α and (1)2⊃10ω, respectively. Green resonances were not assigned due to signal overlap. Stars
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Page 8 of 9
denote aromatic resonances. (F) Time traces of the conversion of α into ω complexes of (1)2 on rods 2 (
+
), 8 (
ꢀ
), 9 (
ꢂ
), 10 (
+
) and 11 ( );
ꢃ
unfoldingꢀrefolding of (1)2 from rod 12 to 15 (ꢀ
). Concentration of host on each station was assessed by 1H NMR through the integration
1
of the amide resonances of the double helix. (G) Schematic representation of the overcoming of a bulky obstacle by a double helix through
an unwindingꢀrewinding mechanism.
2
3
4
5
The authors declare no competing financial interest.
CONCLUSION
6
7
8
Our results demonstrate how a clear sequence of events can be
designed in a complex supramolecular system by exploiting
ACKNOWLEDGMENT
This work was supported by the China Scholarship Council (preꢀ
doctoral fellowship to X.W.) and by the European Research
Council under the European Union’s Seventh Framework Proꢀ
gramme (grant agreement no. ERCꢀ2012ꢀAdGꢀ320892, postꢀ
doctoral fellowship to B.W.). The authors thank Brice Kauffmann
(IECBꢀUMS 3033) for his help during data collection and resoluꢀ
tion of the crystal structures.
the different time scales on which each of these events takes
place. The antiꢀparallel form of dimer (1)2 was isolated by
precipitation and then trapped in solution in foldaxane strucꢀ
tures upon binding to rodꢀlike guests before the parallel form
of (1)2 had time to appear. Rodꢀlike guest binding can be made
to occur selectively through the kinetically favored less hinꢀ
dered end of the rod to produce a foldaxane on the first bindꢀ
ing station, even though thermodynamically preferred binding
stations may be available in the system. Once threading of the
rod into (1)2 is achieved, sliding of (1)2 along the rod takes
place at rates substantially faster than helix dissociation and
reꢀassociation through an unwindingꢀrewinding mechanism.
The sliding direction along the rod can be biased by installing
a gradient of binding stations of increasing thermodynamic
stability. Along the sliding path, small barriers can be installed
such as long segments deprived of binding stations that do not
significantly hamper motion. However, if a sufficiently large
barrier is placed on the rod, sliding is blocked at the binding
station that precedes the barrier and a slower dissociation and
reꢀassociation through an unwindingꢀrewinding mechanism is
imposed for (1)2 to reach a thermodynamically more favorable
station placed further on the rod.
9
10
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Experimental details for synthetic procedures, spectroscopic data
(PDF).
Crystallographic information files for (1)2, (1)2⊃12, (1)2⊃13, and
(1)4⊃2 (CIF).
AUTHOR INFORMATION
Corresponding Authors
*y.ferrand@iecb.uꢀbordeaux.fr
*i.huc@iecb.uꢀbordeaux.fr
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† Department of Chemical Technology of Drugs, Poznan Univerꢀ
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Notes
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(13) With excess rod, no measurable amount of the higher aggregate,
[5]foldaxane, in which two double helices are bound to the rod, was
observed.
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