A molecular cage-based [2]rotaxane that behaves as a molecular muscle

Article abstract of DOI:10.1021/ol802648h

(Figure Presented) We report a molecular cage-based [2]rotaxane that functions as an artificial molecular muscle through the control of the addition and removal of fluoride anions. The percentage change in molecular length of the [2]rotaxane is about 36%

Full text of DOI:10.1021/ol802648h

ORGANIC
LETTERS
2009
Vol. 11, No. 2
385-388
A Molecular Cage-Based [2]Rotaxane
That Behaves as a Molecular Muscle
Chun-Ju Chuang,† Wan-Sheung Li,‡ Chien-Chen Lai,§ Yi-Hung Liu,†
Shie-Ming Peng,† Ito Chao,*,‡ and Sheng-Hsien Chiu*,†
Department of Chemistry, National Taiwan UniVersity, No. 1, Sec. 4, RooseVelt Road,
Taipei, Taiwan 10617, R.O.C., Institute of Chemistry, Academia Sinica, Nankang,
Taiwan, R.O.C., and Institute of Molecular Biology, National Chung Hsing UniVersity
and Department of Medical Genetics, China Medical UniVersity Hospital,
Taichung, Taiwan, R.O.C.
shchiu@ntu.edu.tw; ichao@chem.sinica.edu.tw
Received November 17, 2008
ABSTRACT
We report a molecular cage-based [2]rotaxane that functions as an artificial molecular muscle through the control of the addition and removal
of fluoride anions. The percentage change in molecular length of the [2]rotaxane is about 36% between the stretched and contracted states,
which is larger than the percentage change (∼27%) in human muscle.
Skeletal muscles are responsible for the motion of many
biological systems. On the molecular scale, these muscles
are delicately controlled linear machines1exhibiting revers-
ible, programmed contraction and stretching movements. To
mimic the unique function of biological muscles, several
groups are developing artificial linear molecular assemblies
that undergo controllable stretching and contraction.2 The
design of these interlocked molecular muscles is elegant: two
interlocked components of hermaphroditic rotaxane-like
systems move with respect to one another upon the sequential
application and removal of a stimulus, thereby changing the
distance between the two termini in a controllable manner
(Figure 1).3 Staying with the concept of rotaxane-based
systems, we envisioned an alternative type of molecular
muscle: one in which the thread-like component can exist
in both extended and folded conformations within its
encircling container-like macrocycle; muscle-like molecular
motion would ensue if different recognition sites on the
† National Taiwan University.
‡ Academia Sinica.
§ Institute of Molecular Biology.
(1) For reviews, see: (a) Balzani, V.; Credi, A.; Raymo, F. M.; Stoddart,
J. F. Angew. Chem., Int. Ed. 2000, 39, 3348–3391. (b) Kay, E. R.; Leigh,
D. A.; Zerbetto, F. Angew. Chem., Int. Ed. 2007, 46, 72–191. (c) Champin,
B.; Mobian, P.; Sauvage, J.-P. Chem. Soc. ReV. 2007, 36, 358–366.
(2) (a) Jime´nez-Molero, M. C.; Dietrich-Buchecker, C.; Sauvage, J.-P.
Angew. Chem., Int. Ed. 2000, 39, 3284–3287. (b) Collin, J.-P.; Dietrich-
Buchecker, C.; Gavina˜, P.; Jime´nez-Molero, M. C.; Sauvage, J.-P. Acc.
Chem. Res. 2001, 34, 477–487. (c) Marsella, M. J.; Piao, G.; Tham, F. S.
Synthesis 2002, 1133–1135. (d) Jime´nez-Molero, M. C.; Dietrich-Buchecker,
C.; Sauvage, J.-P. Chem. Commun. 2003, 1613–1616. (e) Tseng, H.-R.;
Vignon, S. A.; Stoddart, J. F. Polym. Prepr. (Am. Chem. Soc. DiV. Polym.
Chem.) 2003, 44, 377–378. (f) Liu, Y.; Flood, A. H.; Bonvallet, P. A.;
Vignon, S. A.; Northrop, B. H.; Tseng, H.-R.; Jeppesen, J. O.; Huang, T. J.;
Brough, B.; Baller, M.; Magonov, S.; Solares, S. D.; Goddard, W. A.; Ho,
C.-H.; Stoddart, J. F. J. Am. Chem. Soc. 2005, 127, 9745–9759. (g) Coutrot,
F.; Romuald, C.; Busseron, E. Org. Lett. 2008, 10, 3741–3744. (h) Wu, J.;
Leung, K. C.-F.; Ben´ıtez, D.; Han, J.-Y.; Cantrill, S. J.; Fang, L.; Stoddart,
J. F. Angew. Chem., Int. Ed. 2008, 47, 7470–7474. (i) Dawson, R. E.;
Lincoln, S. F.; Easton, C. J. Chem. Commun. 2008, 3980–3982.
(3) For doubly threaded hermaphroditic systems known as [c2]daisy
chains, see: (a) Hoshino, T.; Miyauchi, M.; Kawaguchi, Y.; Yamaguchi,
H.; Harada, A. J. Am. Chem. Soc. 2000, 122, 9876–9877. (b) Fujimoto, T.;
Sakata, Y.; Kaneda, T. Chem. Commun. 2000, 2143–2144. (c) Cantrill, S. J.;
Youn, G. J.; Stoddart, J. F.; Williams, D. J. J. Org. Chem. 2001, 66, 6857–
6872. (d) Onagi, H.; Easton, C. J.; Lincoln, S. F. Org. Lett. 2001, 3, 1041–
1044. (e) Chiu, S.-H.; Rowan, S. J.; Cantrill, S. J.; Stoddart, J. F.; White,
A. J. P.; Williams, D. J. Chem. Commun. 2002, 2848–2849. (f) Guidry,
E. N.; Li, J.; Stoddart, J. F.; Grubbs, R. H. J. Am. Chem. Soc. 2007, 129,
8944–8945. (g) Ueng, S.-H.; Hsueh, S.-Y.; Lai, C.-C.; Liu, Y.-H.; Peng,
S.-M.; Chiu, S.-H. Chem. Commun. 2008, 817–819.
10.1021/ol802648h CCC: $40.75
Published on Web 12/19/2008
2009 American Chemical Society

Figure 1. Cartoon representation of the operation of the molecular
muscles based on doubly threaded and molecular cage-based systems.
1
Figure 2. Partial H NMR spectra (400 MHz, CD3CN, 298 K) of
(a) an equimolar mixture of 1 and 3-H2·3PF6 (2 mM); (b) the
mixture in (a) heated at 323 K for 1 h; (c) the mixture in (a) heated
at 323 K for 4 h; (d) 4-H2·4PF6; and (e) the [2]rotaxane 2-H2·4PF6.
thread-like component interacted with the macrocyclic
component under orthogonal conditions. Previously, we
reported that the molecular cage 1 forms two types of
[2]pseudorotaxane-like complexes, i.e., where complemen-
tary guest species are threaded through its two types of
macrocyclic cavities.4 Herein, we report a [2]rotaxane, which
incorporates this molecular cage, that functions as an artificial
molecular muscle that can be controlled through the addition
and removal of fluoride ions.
set of signals for the complex in the 1H NMR spectrum (Figure
2c); the shifts in the positions of the signals of the pyridinium
protons and their neighboring are minor compared with the
dramatic shifts in the signals of the n-octyl unit’s protons,
relative to those in the spectrum of the dumbbell 4-H2·4PF6
(Figure 2d), suggesting that the structure of this complex in
solution was most likely the semirotaxane (1⊃3-H2)·3PF6. After
adding 4-(3,5-di-tert-butylphenyl)pyridine 56 (200 mM) to a
solution of the semirotaxane (1⊃3-H2)·3PF6, prepared by heating
a CH3CN solution of the molecular cage 1 (50 mM) and the
thread-like tricationic salt 3-H2·3PF6 (60 mM) for 4 h at 323
K, the solution mixture was stirred for 6 days, and the desired
[2]rotaxane 2-H2·4PF6 was obtained in 30% yield after ion
exchange and column chromatography (Scheme 1).
To mimic the function of biological muscle, [2]rotaxane
+
2-H2·4PF6, which contains two NH2 and pyridinium units
in the thread component linked by flexible n-alkyl chains,
was designed. We anticipated that by controlling which of
+
the recognition sites (NH2 or pyridinium stations) of the
dumbbell-shaped component interacted with the DB24C8-
like openings of the molecular cage component, we would
obtain both stretched and contracted conformations of the
[2]rotaxane, such that the distance between the termini of
the thread-like component would vary substantially, thereby
mimicking muscle-like behavior.
We synthesized the thread-like trication 3-H2·3PF6 from
ditosylated 1,8-octanediamine5 in three steps (see Supporting
Information). An equimolar (2 mM) mixture of the molecular
cage 1 and 3-H2·3PF6 in CD3CN at room temperature
provided a complicated 1H NMR spectrum that implied the
presence of more than one type of complex, with corre-
sponding rates of association and/or dissociation slower than
the NMR spectroscopic time scale under these conditions
(Figure 2a). Heating this solution at 323 K for 4 h gave a single
2D COSY and NOSY experiments helped us to identify
most of the signals in the 1H NMR spectrum of the
[2]rotaxane 2-H2·4PF6 in CD3CN at 298 K (see Supporting
Information). The significant upfield shifts of the signals for
the methylene units of the central n-octyl chain relative to
those of the n-hexyl protons linking the ammonium and
pyridinium stationssin addition to the negligible shifts in
the signals of the protons of the pyridinium units compared
with those of the dumbbell 4-H2·2PF6ssuggested that, under
these conditions, the molecular cage interacted noncovalently
+
with the two NH2 stations. Thus, the “stretched” form of
the [2]rotaxane 2-H2·4PF6 predominated in solution under
these conditions.
(4) Lin, C.-F.; Liu, Y.-H.; Lai, C.-C.; Peng, S.-M.; Chiu, S.-H. Angew.
Chem., Int. Ed. 2006, 45, 3176–3181.
We grew single crystals suitable for X-ray crystallography
through liquid diffusion of isopropyl ether into a solution
mixture of CH3CN and MeOH (1:1) of 2-H2·4PF6. The solid-
state structure7,8 (Figure 3) reveals the expected [2]rotaxane
(5) (a) Iwata, M.; Kuzuhara, H. Bull. Chem. Soc. Jpn. 1982, 55, 2153–
2157. (b) Iwata, M.; Kuzuhara, H. J. Org. Chem. 1983, 48, 1282–1286.
(6) Chen, N.-C.; Lai, C.-C.; Liu, Y.-H.; Peng, S.-M.; Chiu, S.-H. Chem.
Eur. J. 2008, 14, 2904–2908.
(7) Crystallographic data (excluding structure factors) for rotaxane
2-H2·4PF6 has been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC-702214. Copies of the data
can be obtained free of charge upon application to CCDC, 12 Union Road,
Cambridge CB21EZ, UK [fax: (+44) 1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk].
(8) Crystal data for 2-H2·4PF6: [C118H170O16N4·4CH3CN·2CH3OH][4PF6],
Mr ) 2708.76, monoclinic, space group p21/c, a ) 20.6795 (12), b )
21.8470 (8), c ) 15.2230 (7) Å, V ) 6745.0 (6) Å3, Fcalcd ) 1.334 g cm-3
,
µ(Mo KR) ) 1.363 mm-1, T ) 150(2) K, yellow cubes; 18,446 independent
measured reflections, F2 refinement, R1 ) 0.0623, wR2 ) 0.1607
.
386
Org. Lett., Vol. 11, No. 2, 2009

We suspect that responsibility for this behavior lies in (i)
+
the two less-acidic complexed NH2 centers in the [2]ro-
taxane9 and (ii) an insufficient gain in stability, through new
ion-dipole and [C-H· · ·O] hydrogen bonding interactions
between the pyridinium and DB24C8-like units, to compen-
sate for the loss of [N+-H· · ·O] hydrogen bonds.
Scheme 1
.
Synthesis of a [2]Rotaxane That Functions As a
Molecular Muscle Cage-Based System
Because the interactions between secondary dialkylam-
monium ions and crown ethers are affected by the nature of
the counteranions,10 we turned our attention to controlling
the muscle-like behavior of the [2]rotaxane 2-H2·4PF6
through anion exchange (Figure 4). After adding 2 equiv of
Figure 4. Mimicking the operation of a muscle using the molecular
cage-based [2]rotaxane.
tetrabutylammonium fluoride (TBAF) to a CD3CN solution
1
of 2-H2·4PF6, the H NMR spectrum revealed an equal
amount of a new translational isomer in addition to the
original one, i.e., translational isomerization of the [2]rotax-
4+
ane 2-H2 (i) was slow under these conditions and (ii)
required the exchange of all four of its counteranions. The
addition of an additional 2 equiv of TBAF to this solution
completely removed the signals of the original “stretched”
isomer from the spectrum, resulting in the new translational
isomer becoming the only species in solution (Figure 5). The
significant downfield shift of the pyridinium protons suggests
their possible [C-H· · ·O] hydrogen bonding with the oxygen
atoms of the DB24C8-like units; the slight broadening of
the aromatic signal (HAr) and the complicated signals for
the protons of the ethylene glycol units of the molecular cage
component are consistent with extrusion of the n-octyl chain
through one of the 34-membered-ring openings. Through 2D
COSY and NOSY experiments, we identified most of the
Figure 3. Ball-and-stick representation of the solid state structure of the
[2]rotaxane 2-H24+. Atom labels: C, gray; H, pink; O, orange; N, blue.
molecular geometry: the dumbbell-shaped component is
threaded through the two 24-membered-ring openings of the
+
molecular cage unit, and the two NH2 centers are located
1
signals of this new translational isomer in the H NMR
within the crown ether-like cavities.
spectrum in CD3CN at 298 K. In this translational isomer,
the methylene protons of the n-hexyl chain of the dumbbell-
shaped component are strongly shielded (see, for example,
the signals of H3 and H4) by the aromatic units of molecular
Initially, we attempted to contract the [2]rotaxane
2-H2·4PF6 through the addition of bases. We found, however,
no conclusive 1H NMR spectroscopic evidence for contrac-
tion when we added 10 equiv of triethylamine (Et3N), 1,8-
diaminonaphthalene (proton sponge), or potassium tert-
butoxide to a CD3CN solution of the [2]rotaxane 2-H2·4PF6
(see Supporting Information).
(9) Kihara, N.; Tachibana, Y.; Kawasaki, H.; Takata, T. Chem. Lett.
2000, 506–507.
(10) Jones, W. J.; Gibson, H. W. J. Am. Chem. Soc. 2003, 125, 7001–
7004.
Org. Lett., Vol. 11, No. 2, 2009
387

water and in the gas phase (see Supporting Information).
When starting the MD simulation from the solid state
structure of the [2]rotaxane 2-H24+, in which both pyridinium
units are stacked with the aromatic component of the
4+
molecular cage, the molecular conformation of 2-H2
changed into the stretched form during the equilibration step
under all solvent models. This result suggests that the
stacking structure was not the predominant coconformation
4+
of the [2]rotaxane 2-H2 in solution. Using the aromatic
carbon atoms located between the two tert-butyl groups as
reference points, our MD simulations revealed that the
average lengths of the thread in the stretched and contracted
states were 39.7 and 25.3 Å, respectively. Thus, the percent-
age change in molecular length is about 36% between the
two states, which is larger than the percentage change
(∼27%) in human muscle.2a Figure 6 provides the lowest-
Figure 5.
1H NMR spectra (400 MHz, CD3CN, 298 K) of (a) the
[2]rotaxane 2-H2·4PF6; (b) the mixture obtained after adding TBAF
(2 equiv) to the solution in (a); (c) the mixture obtained after adding
TBAF (2 equiv) to the solution in (b); (d) the mixture obtained after
adding Ca(BF4)2 (1 equiv) to the solution in (c); and (e) the mixture
obtained after adding Ca(BF4)2 (1 equiv) to the solution in (d).
cage 1, whereas those of the n-octyl group (see, for example,
H3′ and H4′) are dramatically less shielded (Figure 5c). In
addition, the presence of a cross peak between the signals
of the methylene protons adjacent to the pyridinium group
and the aromatic protons of the molecular cage component
in the 2D NOSY spectrum supports the “contracted” nature
of this translational isomer.
4+
Figure 6. Lowest-energy structures of 2-H2 obtained from MD
simulations of the (a) stretched and (b) contracted forms. Atom
labels: C, gray; O, red; N, blue.
We believe that the main driving force leading to this
unique “contracted” form is the fluoride anions’ disruption
of [N+sH· · ·O] hydrogen bonding between the NH2+ centers
and the DB24C8-like units of molecular cage 1 being
relatively stronger than that of the [C-H· · ·O] hydrogen
bonding of the pyridinium ions. Subsequent addition of 2
equiv of CaBF4, to remove the fluoride anions from solution
through precipitation of CaF2, provided a spectrum (Figure
5e) similar to that of the original [2]rotaxane 2-H2·4PF6 in
the same solvent (Figure 5a), i.e., the stretched form of
2-H24+ was regenerated. Thus, the contracted and elongated
forms of the [2]rotaxane 2-H24+ can be generated reversibly
4+
energy structures of 2-H2 in the two different states
obtained from simulations in the continuum water model.
We have prepared a molecular cage-based [2]rotaxane that
functions as an artificial molecular muscle that is controlled
through the addition and removal of fluoride anions. The
unique container-like structure of molecular cage 1 compared
to common macrocycles provides an alternative possibility
in the design of molecular muscles. We are at present
investigating the further use of container-like host molecules
within other functional molecules.
-
in CD3CN through counteranion exchange (F- vs PF6 /
-
BF4 ), providing a simple system for mimicking the function
of skeletal muscles. The addition of Cl-, Br-, or I- ions (as
tetrabutylammonium salts) to a CD3CN solution of the
[2]rotaxane 2-H2·4PF6 failed to contract the molecular
muscle; thus, the operation of the molecular muscle is
selectively controlled by the formation of the tight binding
Acknowledgment. We thank the National Science Council
(Taiwan) for financial support (NSC-95-2113-M-002-016-
MY3) and the National Center for High-performance Com-
puting for computational resources.
Supporting Information Available: Synthetic procedures
and characterization data for the [2]rotaxane 2-H2·4PF6. This
material is available free of charge via the Internet at
http://pubs.acs.org.
+
NH2 /F- ion pair.
To estimate the percentage change in the length of the
thread-like component between the contracted and stretched
states of the [2]rotaxane 2-H24+, we performed molecular
dynamics (MD) simulations in continuums of CHCl3 and
OL802648H
388
Org. Lett., Vol. 11, No. 2, 2009