Synthesis and Dynamics of Nanosized Phenylene-Ethynylene-Butadiynylene Rotaxanes and the Role of Shape Persistence

Article abstract of DOI:10.1002/anie.201509702

Phenylacetylene-based [2]rotaxanes were synthesized by a covalent-template approach by aminolysis of the corresponding prerotaxanes. The wheel and the bulky stoppers are made of phenylene-ethynylene-butadiynylene macrocycles of the same size. The stoppers

Full text of DOI:10.1002/anie.201509702

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International Edition: DOI: 10.1002/anie.201509702
German Edition: DOI: 10.1002/ange.201509702
Interlocked Systems
Synthesis and Dynamics of Nanosized Phenylene–Ethynylene–
Butadiynylene Rotaxanes and the Role of Shape Persistence
Christopher Schweez+, Philip Shushkov+, Stefan Grimme,* and Sigurd Hçger*
Abstract: Phenylacetylene-based [2]rotaxanes were synthe-
sized by a covalent-template approach by aminolysis of the
corresponding prerotaxanes. The wheel and the bulky stoppers
are made of phenylene–ethynylene–butadiynylene macrocycles
of the same size. The stoppers are large enough to enable the
synthesis and purification of the rotaxane. However, the wheel
unthreads from the axle at elevated temperatures. The deslip-
ping kinetics and the activation parameters were determined.
We described theoretically the unthreading by state-of-the-art
DFT-based molecular-mechanics models and a string method
for the simulation of rare events. This approach enabled us to
characterize in detail the unthreading mechanism, which
involves the folding of the stopper during its passage through
the wheel opening, a process that defies intuitive geometrical
considerations. The conformational and energetic features of
the transition allowed us to infer the molecular residues
controlling the disassembly timescale.
Many synthetic methods for the preparation of rotaxanes
have been reported. Often templates have been used to
increase the efficiency of the synthesis by organizing the
reactants.[4] These templates generally utilize various weak
interactions and supramolecular concepts.[5–8] The covalent-
template approach, which was often employed in the early
days of rotaxane synthesis,[9] has received considerable
attention recently because of the emergence of novel
synthetic methods for the development of extended struc-
tures.[10–13] In particular, also terephthalic acid derivatives
have been described as templates for the construction of
rotaxanes based on shape-persistent phenylacetylene macro-
cycles, but this attempt was not successful.[14]
Besides the intricate synthetic pathways, rotaxanes exhibit
distinctive molecular dynamics, which can be characterized by
several timescales.[15] These dynamics include the relative
motion of the rotaxane constituents and the spontaneous
disassembly of the complex, which gives rise to novel methods
for building molecular assemblies but at the same time
hampers the rotaxane function by disengaging the molecular
parts.
M
olecular nanotechnology, which aims to build artificial
molecular assemblies that mimic the function of sophisticated
biological complexes,[1] has relied upon the development of
mechanically interlocked molecules, such as rotaxanes, cate-
nanes, and pretzel-shaped molecules, for nearly half a cen-
tury.[2] Such mechanically interlocked molecules have been
used to design various miniature devices, including switches,
shuttles, elevators, and even protein-synthesizing machines
similar to the ribosome.[3] Understanding of the persistence of
shape has been mandatory for the design of nanoarchitectures
and the function of molecular machines.
[*] C. Schweez,[+] Prof. Dr. S. Hçger
KekulØ Institut für Organische Chemie und Biochemie
Rheinische Friedrich-Wilhelms-Universität Bonn
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
E-mail: hoeger@uni-bonn.de
Dr. P. Shushkov,[+] Prof. Dr. S. Grimme
Mulliken Center for Theoretical Chemistry
Institut für Physikalische und Theoretische Chemie
Rheinische Friedrich-Wilhelms-Universität Bonn
Beringstrasse 4, 53115 Bonn (Germany)
E-mail: grimme@thch.uni-bonn.de
[+] These authors contributed equally.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509702.
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original
work is properly cited, the use is non-commercial and no modifica-
tions or adaptations are made.
Figure 1. Top: Two novel [2]rotaxanes, 1@2a and 1@2b, based on
shape-persistent macrocycles. Bottom: Illustration of the short-term
dynamic behavior of the [2]rotaxane: the shuttling of the wheel along
the axis.
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Shape-persistent phenylacetylene macrocycles have
groups at the ring exterior are expected to guarantee that the
attracted considerable interest during the last two decades
because their rigidity allows the formation of structures with
predictable shape and defined positioning of functional
groups.[16] The building blocks of the ring are rather rigid,
and they are connected in such a way that the target structure
is thought to be unfoldable under normal conditions.
wheel could not leave the axis. However, the rotaxane,
surprisingly, disassembles spontaneously. Accordingly, we
report a detailed theoretical investigation of the unthreading
of the wheel from the rotaxane axis. This analysis helped us
deduce the molecular residues that control the stability and
the mechanics of this molecular assembly.
We report herein a covalent-template approach for the
modular and tailored synthesis of the nanosized phenylene–
ethynylene–butadiynylene rotaxanes 1@2a and 1@2b
(Figure 1) with different axis lengths. This approach builds
upon our earlier work on template-directed synthesis[17,18] and
should in principle enable the preparation of even more
complex mechanically interlocked molecules, of which we
show herein the first examples. The rotaxane features the
wheel 1 and the stopper–axis building blocks 2a and 2b. Both
the rotaxane wheel and the stoppers are shape-persistent
macrocycles of the same size, which together with the
occupied wheel interior and the tert-butylphenyl and alkoxy
The synthetic route towards the [2]rotaxanes is shown in
Scheme 1. The macrocycles 3 and 7 are obtained by template-
directed syntheses of the half-rings[17] and the template
molecules (see the Supporting Information). To avoid the
steric repulsion between the central wheel macrocycle and the
terminal stopper macrocycles, the monoprotected bisacety-
lene spacers 4a and 4b were attached to 3 by a twofold
coupling reaction under standard conditions to give 5a in
quantitative yield and 5b in good yield. Subsequent depro-
tection with tetra-n-butylammonium fluoride (TBAF) in the
presence of water (4 vol%) avoided the undesired cleavage of
the ester bonds.[18] The resulting compound 6 was then
Scheme 1. a) [PdCl2(PPh3)2], CuI, PPh3, THF, NEt3, 608C, 18 h, 5a: quant., 5b: 51%; b) TBAF, H2O (4 vol%), THF, room temperature, 50 h, 6a:
61%, 6b: 96%; c) [PdCl2(PPh3)2], CuI, toluene, NEt3, 1008C, 18 h, 8a: 38%, 8b: 22%; d) n-propylamine, NH4Cl, THF, 508C, 16 h, 1@2a: 21%,
1@2b: 13%. CPDIPS=(3-cyanopropyl)diisopropylsilyl.
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coupled with the macrocycle 7 in a double Sonogashira–
Hagihara reaction with [PdCl2(PPh3)2] and CuI in toluene and
NEt3 at 1008C to yield the [2]prerotaxane 8a in 38% yield or
8b in 22% yield, both of which were purified by column
chromatography and preparative recycling GPC (recGPC).
In the [2]prerotaxanes, the macrocyclic stoppers 7 are
covalently attached through benzylic ether bonds to the axis,
whereas the wheel macrocycle is connected through phenolic
ester bonds to the axis, which allows selective bond cleavage
at the carboxy group by nucleophilic substitution. The
[2]rotaxane 1@2 was therefore prepared by aminolysis with
n-propylamine. Purification by preparative recycling GPC
gave the [2]rotaxanes 1@2 as yellow solids in surprisingly low
yields (1@2a: 21%; 1@2b: 13%). Both rotaxanes dissolve
well in dichloromethane, chloroform, and THF, and the
successful syntheses were confirmed by 1H NMR spectrosco-
py, MALDI-TOF MS, and GPC analysis (see the Supporting
Information).
for a prolonged time at room temperature. MS analysis of
these samples confirmed the presence of the free wheel 1 and
axes 2a and 2b besides the [2]rotaxanes, and the absence of
any other decomposition products (see the Supporting
Information). This observation suggests that the wheel
unthreads from the axis by a slow deslipping process.[19,20]
However, despite the plausibility of the unthreading process,
it poses a mechanical puzzle: the stoppers are shape-
persistent macrocycles that are identical to the wheel by
design, which should make it highly improbable for the wheel
to slip off the axis.
The deslipping process of the [2]rotaxane 1@2a was
analyzed at elevated temperatures in THF by recGPC, which
allowed the separation of the [2]rotaxane, the axis, and the
free wheel. From the rate constants at different temperatures
(half-lives t1/2: 33 h/323 K; 8.7 h/333 K; 6.6 h/338 K), the
activation barrier is estimated to be around (24 Æ 4) kcal
molÀ1 (see the Supporting Information).
The observed low yields can be explained by the presence
of the free rotaxane wheel 1 and axes 2a and 2b, which were
isolated from the reaction mixture in addition to the
[2]rotaxanes, as determined by GPC and MS. The presence
of the disassembled rotaxane components might be attributed
to the formation of two precursor isomers as already
proposed by Morin and co-workers (Figure 2).[14] Only
isomer A leads to rotaxane formation, whereas isomer B
generates after aminolysis the free wheel and the stopper–axis
unit. However, neither NMR spectroscopy nor chromato-
graphic methods indicated the presence of two isomers.
Attempts to separate the isomers of 8 by recGPC were
unsuccessful, and their existence remains uncertain. Thus, the
separation into the components could be the result of an
unthreading during the aminolysis reaction.
To gain further insight into the mechanism of unthreading,
we described theoretically the rotaxane deslipping reaction.
A simplified rotaxane complex was investigated with the long
alkyl side chains of the macrocycles, which influence primarily
the solubility of the complex, replaced by methyl groups. All
atoms of the rotaxane were accounted for explicitly, whereas
the solvent, tetrahydrofuran, was treated implicitly by a cus-
tomized generalized Born model including an energetic
contribution proportional to the molecular surface.[21] Ab
initio calculation of the rotaxane potential-energy surface in
molecular dynamics (MD) is prohibitive owing to the large
number of atoms (720 in total) in the system. Therefore,
a customized molecular-mechanics force field (QMDFF) was
parameterized on the basis of ab initio density functional
theory calculations[22] (see the Supporting Information for
details). Since direct simulation of the deslipping event is
unfeasible, because the unthreading occurs over a very long
timescale, as suggested by the high activation barrier, we
applied the finite-temperature string method,[23] which repre-
sents the sequence of conformational events by a succession
of equidistant images. The optimized string takes into account
enthalpic effects, which give preference to the low-energy
regions of the potential-energy surface, and entropic effects,
which bias the path to flatter regions of the surface. A
representative optimized path is shown in Figure 3, and
further details of the computational method are deferred to
the Supporting Information. For movies of the unthreading
simulations, see Ref. [24].
Further experimental observations of the pure rotaxane
showed the appearance of additional signals in the GPC and
mass spectrum after solutions of 1@2a and 1@2b were kept
The Gibbs free energy profile of the unthreading exhibits
a few metastable minima separated by barriers corresponding
to the major conformational bottlenecks (Figure 3A). In the
initial and final states of the process, the system assumes an
extended conformation, in which both angles (depicted by the
green vectors in Figure 3B) between the stopper tert-butyl-
phenyl groups are nearly straight. As the system moves along
the transition path, a remarkable conformational rearrange-
ment takes place: one of these angles gradually decreases,
which correlates with the folding of the stopper, and as
a result, the bulky moieties that otherwise stick out from the
periphery of the stopper ring can fit within the opening of the
wheel. This rearrangement is facilitated by the flexibility of
Figure 2. Precursor isomers. Only isomer A features prerotaxane
geometry. The aminolysis of isomer A leads to the desired [2]rotaxane,
whereas isomer B generates the free wheel and axis.
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Figure 3. Theoretical description of the unthreading. a) Gibbs free energy (black line), entropy times temperature (red line), solvation free energy
(green line), and bonding part of the enthalpy (blue line) of the optimized finite-temperature string. A: associated state, T1–T3: transition regions,
D: dissociated state. b) Conformational changes during the unthreading. The axle is depicted in blue and the wheel in red. The left and right
columns show a top and a side view of the rotaxane, and the rows correspond to the regions in (a) according to the same naming convention. In
the left column, the green vectors describe the angle formed by the phenyl rings of the stopper tert-butylphenyl residues and the phenyl group at
the attachment point. This angle gradually decreases, which correlates with the stopper folding. During folding, strain builds up mainly in the
bisacetylene and phenoxy groups, as shown in (c). In the right column, the orange vectors describe the angle between the axis and the bisector of
the angle formed by the green vectors. This angle steadily increases and portrays the rotation of the stopper about the attachment point to the
axis during the passage through the wheel opening. c) Van der Waals representation of the transition state T2, in which only the actively
participating wheel (metallic color) and stopper (full color) are depicted. The entire opening of the wheel is occupied by the bulky substituents of
the stopper. The atom color depicts the change in the energy per atom with respect to the associated state (see the Supporting Information for
a precise definition). The color ranges from blue to red as the magnitude of energy deviations increases. The red regions therefore correspond to
hot spots of energy accumulation.
the phenoxy hinges connecting the stopper to the axis, and
places a substantial strain on the unsaturated bisacetylene
groups that build the sides of the stopper ring (Figure 3C).
These conformational changes prepare the stage for the
largest-scale motion: as the wheel steadily slips off the axis,
and concomitantly with the stopper folding, the entire stopper
macrocycle rotates about its attachment point to the axis
(depicted by the orange vectors in Figure 3B) and passes
through the wheel. Along this trajectory, the system goes
through a couple of smaller barriers T1 and T3, which mark
the initial entry and final escape of the stopper from the wheel
interior, and the transition state T2, in which the stopper
occupies the entire opening of the wheel. The unthreading
reaction thus involves large-scale collective conformational
changes, which encompass virtually all atoms of the stopper
and wheel macrocycles.
The deslipping process is predicted to be close to
thermoneutral (Figure 3A). The highest of the transition
states, T2, is roughly (30 Æ 3.5) kcalmolÀ1 above the initial
associated state and corresponds to the most spatially
crowded conformation of the system. The computed free
energy of activation is in a good agreement with the
experimentally measured value of (24 Æ 4) kcalmolÀ1. The
free energy was decomposed further into a sum of four
contributions: the bonding and nonbonding enthalpy of the
rotaxane, the solvation free energy, and the entropy multi-
plied by temperature. The bonding enthalpy is local because it
accounts for the interactions between rotaxane atoms that are
separated by no more than two neighbors, whereas the
nonbonding enthalpy contains the interactions of distant
atomic pairs. The sum of these two terms equals the total
rotaxane enthalpy change, and three out of the four contri-
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butions (all but the nonbonding enthalpy) are shown in
Figure 3A.
As the system approaches the transition state T2 from the
side of the associated state, the entropy decreases because of
the reduced conformational freedom of the crowded bottle-
neck region. Past the transition, the entropy increases and
partly compensates the energetic losses incurred in the
breaking of noncovalent interactions. The solvent free
energy follows a similar trend: initially, the rotaxane des-
olvates because of the crowding, and then it solvates again as
the stopper leaves the wheel. Remarkably, the entropy and
solvation free energy nearly compensate the nonbonding
enthalpy (not shown in Figure 3A), and thus the remaining
part, the bonding enthalpy, determines the free-energy profile
of the unthreading (Figure 3A). This energy compensation
has important consequences for the influence of structural
changes on the unthreading. Local modifications, which affect
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control of the disassembly. On the other hand, structural
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exhibit the “all-or-nothing” effect.[19] Such variations either
completely abort disassembly or barely influence it. Finally,
solvation alone provides a way of varying the activation
barrier: if the absolute solvation energy of the rotaxane
increases, the desolvation of the transition state becomes
more costly.
In summary, we synthesized two novel phenylacetylene-
based [2]rotaxanes, in which both the wheel and the bulky
stoppers are phenylene–ethynylene–butadiynylene macrocy-
cles of the same size. The stoppers are large enough to enable
the synthesis, purification, and characterization of the rotax-
anes. However, the wheel unthreads from the axis at 608C
with a half-life of about 10 h. We described theoretically the
unthreading by state-of-the-art DFT-based molecular-
mechanics models and a string-based method for the simu-
lation of rare events. This approach enabled us to characterize
in detail the mechanism of the deslipping process and to
determine the residues controlling the disassembly timescale.
We demonstrated for the first time the use of molecular
simulation to gain insight into the intricate dynamics of
molecular nanoarchitectures that defy intuitive geometrical
considerations.
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Acknowledgements
Financial support by the Fonds der Chemischen Industrie
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Keywords: density functional calculations ·
interlocked systems · molecular modeling · rotaxanes ·
template synthesis
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Received: October 23, 2015
Revised: December 8, 2015
Published online: February 2, 2016
Angew. Chem. Int. Ed. 2016, 55, 3328 –3333
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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