Precision Molecular Threading/Dethreading

Article abstract of DOI:10.1002/anie.202003064

The general principles guiding the design of molecular machines based on interlocked structures are well known. Nonetheless, the identification of suitable molecular components for a precise tuning of the energetic parameters that determine the mechanical

Full text of DOI:10.1002/anie.202003064

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Accepted Article
Title: Precision molecular threading/dethreading
Authors: Jessica Groppi, Lorenzo Casimiro, Martina Canton, Stefano
Corra, Mina Jafari-Nasab, Gloria Tabacchi, Luigi Cavallo,
Massimo Baroncini, Serena Silvi, Ettore Fois, and Alberto
Credi
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10.1002/anie.202003064
Angewandte Chemie International Edition
RESEARCH ARTICLE
Precision molecular threading/dethreading
Jessica Groppi,[a] Lorenzo Casimiro,[a,b] Martina Canton,[a,c] Stefano Corra,[a,d] Mina Jafari-Nasab,[b]
Gloria Tabacchi,[e] Luigi Cavallo,[f] Massimo Baroncini,[a,d] Serena Silvi,[a,b] Ettore Fois,*[e] and Alberto
Credi*[a,c]
[a]
Dr. J. Groppi,[+] L. Casimiro,[+] M. Canton, Dr. S. Corra, Dr. M. Baroncini, Prof. S. Silvi, Prof. A. Credi
CLAN–Center for Light Activated Nanostructures, Istituto ISOF-CNR
via Gobetti 101, 40129 Bologna, Italy.
[+] Equal contribution.
[b]
L. Casimiro, M. Jafari-Nasab, Prof. S. Silvi
Dipartimento di Chimica “G. Ciamician”, Università di Bologna
via Selmi 2, 40126 Bologna, Italy.
[c]
M. Canton, Prof. A. Credi
Dipartimento di Chimica Industriale “Toso Montanari”, Università di Bologna
viale del Risorgimento 4, 40136 Bologna, Italy
E-mail: alberto.credi@unibo.it
[d]
[e]
Dr. S. Corra, Dr. M. Baroncini
Dipartimento di Scienze e Tecnologie Agro-alimentari, Università di Bologna
viale Fanin 44, 40127 Bologna, Italy
Prof. G. Tabacchi, Prof. E. Fois
Dipartimento di Scienza ed Alta Tecnologia and INSTM, Università dell’Insubria
via Valleggio 11, 22100 Como, Italy.
E-mail: ettore.fois@uninsubria.it
[f]
Prof. L. Cavallo
KAUST Catalysis Center, King Abdullah University of Science and Technology,
Thuwal 23955-6900, Saudi Arabia.
Supporting information for this article is given via a link at the end of the document.
Abstract: The general principles guiding the design of molecular
machines based on interlocked structures are well known.
Nonetheless, the identification of suitable molecular components for
a precise tuning of the energetic parameters that determine the
mechanical link is still challenging. Indeed, what are the reasons of
the “all-or-nothing” effect, which turns a molecular “speed-bump” into
because of their tiny mass and movement at ambient
temperature is dominated by thermal agitation.[2c, 3 ] Another
significant difference between a macroscopic and a nanoscale
structure is that, for the latter, the surrounding medium consists
of objects (i.e., molecules) of approximately the same size of the
structure itself. The interlocking of molecular components[4] is the
concept at the basis of the mechanical bond, which in the past
three decades has enabled the development of mechanically
interlocked molecules, an entirely new class of compounds
a
stopper in pseudorotaxane-based architectures? Here we
investigate the threading and dethreading processes for
a
representative class of molecular components, based on symmetric
dibenzylammonium axles and dibenzo[24]crown-8 ether, with a joint
experimental-computational strategy. From the analysis of
quantitative data and an atomistic insight, we derive simple rules
correlating the kinetic behaviour with the substitution pattern, and
provide rational guidelines for the design of modules to be integrated
in molecular switches and motors with sophisticated dynamic
features.
endowed with highly appealing structural and dynamic
5 ]
properties.[
Of particular interest in this regard are the
rotaxanes, i.e., species composed minimally of a macrocycle
surrounding dumbbell-shaped molecule. Rotaxanes are
a
usually obtained by self-assembly of complementary ring and
axle molecular components to obtain a threaded supramolecular
complex (pseudorotaxane), and successively attaching bulky
groups (stoppers) at the extremities of the axle to prevent the
escape of the ring. The efficacy of the mechanical interlocking is
determined by the energy barrier for dethreading which, in turn,
depends on the bulkiness of the stoppers, the flexibility of the
ring, and the possible presence of electronic interactions that
could change the energetic barrier to (de)threading. Indeed, the
possibility of adjusting the threading and dethreading barriers by
molecular design, and modulating the corresponding rates by
temperature changes, highlights the ill-defined nature of
pseudorotaxanes,[6] and has been successfully exploited to self-
assemble rotaxanes by the so-called slippage route (Figure
Introduction
In the macroscopic world, engineering a proper fitting between
the component parts is key for the design of any static or
dynamic mechanical structure. In general, this is also true at the
nanoscale, wherein molecules can be tailored to behave as
building blocks for the construction of supramolecular
architectures with valuable structural or functional properties.[1,2]
The parts commonly used to build macroscopic structures are
made of hard materials with well-defined mechanical properties.
Conversely, molecules are floppy (because of the softness of
the potential energy profiles that determine bond lengths and
angles) and sticky (because of the presence of attractive
intermolecular forces, including the ubiquitous van der Waals
interactions) objects, in which steric and electronic effects are
intimately connected. Inertial effects are negligible for molecules
1).[
Besides size complementarity, other approaches
7
, 8 ]
examined for affecting (de)threading rates rely on electrostatic
effects[9] and on the conformational freedom of long threads.[10]
(Pseudo)rotaxanes endowed with end groups that can change
their size and shape upon external (e.g., light) stimulation have
also been reported.[11]
1
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10.1002/anie.202003064
Angewandte Chemie International Edition
RESEARCH ARTICLE
strategy by dissecting the threading and dethreading processes
of a series of symmetric dibenzylammonium ions, bearing
different substituents, with dibenzo[24]crown-8 ether (DB24C8)
in CH2Cl2. The choice of this particular self-assembling
architecture[23] is dictated primarily by its widespread popularity
in supramolecular chemistry[1,2,5,24,25] and related applications,[26]
that include self-assembled materials,[ 27 ] catalysis,[ 28 ] and
molecular switches and motors.[17,18,
By combining
29
]
experimental and computational techniques, we unravel the
molecular-level factors that govern with atomistic precision the
corresponding energy barriers. Finally, we derive general
guidelines for the rational identification of (pseudo)stopper
components that can be useful for designing novel molecular-
based devices, machines and materials based on mechanically
interlocked molecules and supramolecular counterparts.
Figure 1. Schematic potential energy profile describing the threading and
dethreading of molecular ring- and dumbbell-shaped components to yield
(pseudo)rotaxanes.
Results and Discussion
Design and synthesis of the components
The energy barriers associated with the relative movement of
threaded ring and axle components are also of paramount
importance for the construction of molecular motors based on
The investigated compounds are summarized in Scheme 1. The
ring is DB24C8, and the dumbbell-shaped guests are symmetric
dibenzylammonium-type cations (hexafluorophosphate salts)
bearing methoxy and/or methyl substituents on either phenyl
ring. The driving force for the formation of the threaded
complexes in low polarity solvents arises essentially from [N+–
H···O] and [C–H···O] hydrogen bonds, with a contribution from p-
p stacking interactions involving the phenyl rings.[6a,21,22a,23]
Indeed, the minimum energy structures calculated for two
representative compounds in the gas phase (Figure 2 and SI)
suggest that the threaded complexes are thermodynamically
stable. To maximize p-p stacking, the ring adopts a chair
conformation (Figure 2b,e) while its elliptical cavity perfectly fits
rotaxanes and related systems.[1a,2c,
The directionally
12
]
controlled movements that take place in a molecular motor can
only be obtained with the application of ratchet mechanisms that
bias (that is, rectify) random thermal motion via the stimuli-
controlled modulation of the energy wells and barriers that
describe the intercomponent movements.[2c,13] In other words, a
time-dependent potential landscape with repeating asymmetric
features is required to break the spatial and time-reversal
symmetries along the direction of motion and establish
directional control. This approach was ingeniously implemented
on catenanes to make rotary motors,[14] and its potentialities are
well exemplified by the recent development of supramolecular
pumps – systems in which macrocyclic rings can be moved
+
to the central part of the axle, constituted by the –CH2NH2 CH2–
moiety. This arrangement allows both the ammonium hydrogen
atoms to form hydrogen bonds with the oxygen atoms of
DB24C8, while the –CH2– groups are engaged in weaker [C–
H···O] interactions (see the SI, Figure S1).
directionally along an oriented axle under chemical,[
15
]
electrical[ 16 ] or light[ 17 ] energy supply. Although the current
systems operate in solution, wherein exploiting the transport to
perform a function is very challenging, the natural development
of this research is towards systems that can operate in
compartmentalized environments – for example, membrane-
separated solutions – in which the molecular pumping can lead
to, e.g., the buildup of a concentration gradient that can
subsequently be harnessed.[18]
kin
K =
kout
O
O
PF6_
O O
O
PF6_
kin
O
O
O
O
+
O
O
O
O
+
N
H2
N
+
R
R
H2
R
R
A precise engineering of the energy barriers associated with
relative ring-axle movements in (pseudo)rotaxanes is indeed
crucial for the design of such novel functional supramolecular
kout
O O
O
pumps,[11b,15,17,
as well as dynamic polymeric materials
19
]
[1-10 DB24C8]+
1-10+
DB24C8
containing mechanical bonds.[20] Despite the huge amount of
work performed on self-assembled ring-and-axle complexes in
terms of stability,[5,21] systematic analyses on the threading and
dethreading rates of pseudorotaxanes are relatively rare in the
literature.[6,7,11c,22] These studies highlighted the complexity of
these phenomena and showed that, even in the absence of
electrostatic effects, size complementarity of ring and stopper
should be used with caution as a criterion for interpreting
(de)slipping processes.[22b,g] It is therefore not surprising that the
problem of designing supramolecular complexes and related
interlocked species that exhibit intercomponent mobility with
predetermined kinetics is usually tackled with an empirical
approach. This work lays down a knowledge-based design
R
O
1+
2+
3+
4+
5+
Cmpd.
R
O
O
6+
7+
8+
9+
10+
Cmpd.
Scheme 1. Structure formulas of the investigated molecular components and
their self-assembly into (pseudo)rotaxane species.
2
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10.1002/anie.202003064
Angewandte Chemie International Edition
RESEARCH ARTICLE
Because of the structural similarity, we envisioned that guests
1–10+ could exhibit (i) a comparable thermodynamic affinity for
DB24C8 and (ii) similar solubility properties, thus constituting a
homogeneous series of compounds to investigate the role of the
terminal groups in the association and dissociation kinetics. The
objective of this study is to investigate the borderline between
rapidly equilibrating supramolecular complexes and kinetically
inert rotaxanes. The choice of the substitution patterns shown in
Scheme 1 was performed accordingly, and was guided by size
complementarity considerations based on the inspection of
physical molecular models.
UV-visible spectroscopic measurements on dilute solutions to
gain quantitative information on the thermodynamic and kinetic
aspects
of
the
self-assembly.
Non-coordinating
hexafluorophosphate was adopted as the counterion of the
ammonium guests because it is known that, thanks to its low
tendency to ion pairing, it does not affect the self-assembly in
the examined concentration range.[30]
Binding constants
1H NMR Spectroscopy was employed to gain qualitative
evidence for the formation of the complexes and to verify their
threaded nature. As an illustrative example, the comparison
between the separate 1H NMR spectra in CD2Cl2 at room
temperature of DB24C8 and thread 4+ (blue line for 4+ and green
line for DB24C8 in Figure 3a) and of an equimolar mixture of the
two (red line in Figure 3a) evidences the formation of a
[2]pseudorotaxane complex characterized by a high association
constant and whose (de)threading processes are slow in the
NMR timescale. The new multiplet at 4.75 ppm, which appears
in the spectrum of the mixture, is indicative of the involvement of
the benzylic protons of 4+ in hydrogen bonding with the oxygen
atoms inside the cavity of the crown ether macrocycle. Moreover,
the marked shielding of the aromatic protons and methyl groups
of 4+ confirms the presence of a significant p-p stacking
interaction between the catechol moieties of DB24C8 and the
phenyl groups of the thread. These observations are in full
agreement with previous studies dealing with the formation of
[2]pseudorotaxanes between dibenzylammonium-type threads
and DB24C8.[6a,23]
The formation of a complex was also accompanied by
changes in the UV-visible absorption spectrum. Both DB24C8
and the dialkylammonium guests exhibit absorption bands in the
250-300 nm region (see the SI), which are perturbed when the
components are assembled (see, e.g., Figure 3b). The
absorption spectral changes were employed to determine the
binding constants, K, by means of titrations. In the case of slow
threading, particular care was taken to ensure that equilibrium
had been reached for each data point during the titration
experiments.
Figure 2. Space-filling representations of the minimum energy structure
computed for supramolecular complexes of DB24C8 with guest 6+ (a: front
view; b: side view; c: back view) and with guest 8+ (d: front view; e: side view;
f: back view). In all structures, the –CH2NH2+CH2– moiety of the axle is not
visible, as it is completely encapsulated by the elliptical cavity of the ring. Atom
color codes: C (ring) = cyan; C (axle) = grey; O = red; H = white.
With a similar purpose, Stoddart and coworkers studied the
assembly of DB24C8 with symmetric dialkylammonium guests
bearing cycloalkane end groups.[23b] The interest of these
compounds in a general context, however, is limited with respect
to dibenzylammonium-type ions because of the much poorer
binding with crown ethers and the nontrivial synthetic issues
associated with the inclusion of cycloalkane units in the axle
components of molecular machines. Conversely, the
incorporation of substituted phenyl units in extended axle-type
molecules appears to be a feasible way to implement kinetic
barriers or “speed bumps” for ring (de)threading or
shuttling.[15,19,22a,d,e,24]
DB24C8 is commercially available, while the ammonium
guests 1–10·PF6 were prepared by using conventional
procedures; details are provided in the SI. All the experiments
were performed in air equilibrated dichloromethane at room
temperature (298±2 K). The choice of the solvent was dictated
by the large binding constants expected in the non-competitive
and apolar CH2Cl2.[23b] The strong association between the
components enables the use of steady-state and time-resolved
3
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10.1002/anie.202003064
Angewandte Chemie International Edition
RESEARCH ARTICLE
Figure 4. Absorption spectra of a 3.0´10–4 M solution of DB24C8 in CH2Cl2
upon addition of 4+. The inset shows the absorption changes at 240 nm
together with the fitted curve corresponding to a 1:1 binding model.
Table 1. Thermodynamic and kinetic data (CH2Cl2, 298 K).
K (105
kin
[d]
Guest[a]
kout (s–1
)
t1/2 (min)[e]
[b]
[c]
L mol–1
)
(L mol–1 s–1
)
1+
2+
3+
4+
5+
6+
7+
8+
9+
10+
22±4
> 2´107 [f]
< 7´10–5 [h,i]
< 7´10–5 [h,i]
37.9±0.4
< 7´10–5 [h,i]
12±1
> 9 [g]
< 0.003
[h]
[h]
8±3
(4.7±0.5)´10–5
246
Figure 3. (a) 1H NMR spectra (500 MHz, 298 K, CD2Cl2) of: 4+ (3.0´10–3 M)
(blue line), DB24C8 (3.0´10–3 M) (green line), and a 1:1 mixture of 4+ and
DB24C8 (both components 3.0´10–3 M) (red line). (b) Sum of the absorption
spectra of separated CH2Cl2 solutions of DB24C8 and 4+ (black line) and
absorption spectrum of the same solutions after mixing (red line).
Concentrations in the mixture: [DB24C8] = 1.6´10–4 M, [4+] = 1.5´10–4 M.
[h]
1.7±0.7
(7.0±0.7)´10–5
(4.9 ± 0.2)´10–5
165
236
7±2
34±1
[h]
< 7´10–5 [h,i]
[j]
[j]
Titrations were performed in CH2Cl2 by adding small aliquots of
a concentrated solution of the guest to a sub-mM solution of
DB24C8. The corresponding titration curves, obtained by
plotting the absorbance value at selected wavelengths (Figure 4
and SI), can be satisfactorily fitted with a least-squares nonlinear
procedure according to a 1:1 binding model, in agreement with
the formation of [2]pseudorotaxanes. The binding constants
(Table 1), on the order of 105–106 L mol–1, are in line with those
previously determined in similar conditions for this kind of
complexes.[30]
[h]
< 7´10–5 [h,i]
[a] Shaded entries highlight the axles that undergo fast threading. [b] Binding
constant. [c] Threading rate constant. [d] Dethreading rate constant. [e] Half-
life of the complex, calculated as t1/2 = ln2/kout. [f] The process is faster than
the time resolution of our stopped-flow spectrometer; lower limiting value of kin
determined as described in the SI. [g] Estimated as kout = kin/K. [h] No complex
is detected by 1H NMR after 72 h. [i] Upper limiting value determined as
described in the SI. [j] Data could not be obtained because of the poor
solubility of axle 9+ in CH2Cl2. Measurements performed in acetonitrile indicate
that this axle belongs to the “threading” category.
In general, the binding constant decreases slightly, in
comparison with dibenzylammonium, when the phenyl rings of
the secondary ammonium guest bear methyl or methoxy
substituents (1+ versus 4+, 6+ and 7+, Table 1). In line with
previous observations,[21] it can be hypothesized that the
presence of electron-donor substituents lowers the hydrogen
Threading and dethreading rate constants
The UV-visible spectral changes observed upon self-assembly
(Figure 3b) were also employed to measure the threading rate
constants, kin, by monitoring the absorbance as a function of
time after rapid mixing of the components in equimolar amounts.
Depending on the threading time scale, the kinetic experiments
+
bond donor ability of the NH2 moiety and of the adjacent
benzylic groups, thus diminishing the interaction with the crown
ether. The association of DB24C8 with guest 9+ could not be
studied quantitatively because, quite unexpectedly, the latter
were either performed by manual mixing in
a normal
–
(PF6 salt) is insoluble in CH2Cl2. The formation of a threaded
spectrophotometer, or with a stopped-flow instrument. The
threading and dethreading rate constants were determined from
the fitting of the time-dependent absorbance traces (Figure 5)
with an equilibrium model (second-order association and first-
1
complex, though, was observed in acetonitrile by means of H
NMR spectroscopy. This result suggests that the 2,3-
dimethylphenyl end group of 9+ can thread through the ring at
room temperature and thus behaves as a pseudostopper.
4
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10.1002/anie.202003064
Angewandte Chemie International Edition
RESEARCH ARTICLE
order dissociation) in which the binding constant was fixed to the
value obtained from the titrations. The results are gathered in
Table 1, and the corresponding energy barriers are listed in
Table 2.
down the assembly/disassembly process by at least five orders
of magnitude (Table 1). Even more striking is the fact that
(de)threading is allowed or prevented simply by changing the
relative position of two methyl substituents on the phenyl ring
(compare, for example, the behaviour of 2+ and 3+ with that of 4+
and 6+). Such an “all-or-nothing” effect, which was also observed
in a previous investigation on related (pseudo)rotaxanes,[22a]
suggests that the (de)threading kinetics are determined by
rigorous size complementarity requirements in which also the
conformational freedom of the components presumably plays a
role.
It is also interesting to note that the replacement of a methyl
group for a methoxy group in the 4-position has very different
consequences, depending on the position of the other methyl
substituent. In fact, while in the case of the 2,4-derivatives a
methoxy group in the place of a methyl in the 4-position seems
to even accelerate the threading (6+ versus 7+), for 3,4-
derivatives the presence of the 4-methoxy substituent prevents
the formation of the complex (9+ versus 10+). The introduction of
a further methoxy substituent in the 4-position of the 2,5-
dimethyl species (4+ versus 5+) also blocks the threading.
The self-assembly of DB24C8 with the ammonium-type
guests was also investigated in CD3CN by 1H NMR
spectroscopy (Figure S16-S25). Spectrophotometric methods
could not be used in this solvent because of the very low
association under dilute conditions. Nonetheless, the NMR
results confirm qualitatively the behaviour observed in
dichloromethane, namely, the terminal units of 2+, 3+, 5+, 8+ and
10+ behave as real stoppers at room temperature. This
observation suggests that the nature of the solvent, while likely
contributing to the fine-tuning of the transition state(s), does not
change significantly the (de)threading mechanism.
Figure 5. Time-dependent absorption changes at 279 nm recorded upon
mixing DB24C8 and 4+ in CH2Cl2 at 298 K. The red line represents the data
fitting. Concentrations after mixing: [DB24C8] = 1.6´10–4 M, [4+] = 1.5´10-4 M.
Table 2. Energetic parameters at 298 K, in kcal mol–1
.
Guest[a]
Experimental
DG° [b]
Computed
DG‡
DG‡
DG‡
[c]
[c]
[d]
in
out
out
1+
2+
3+
4+
5+
6+
7+
8+
9+
10+
–8.6
< 7.4
> 23
> 23
15.3
> 23
16.0
15.3
< 16
Computational studies
The experimental data clearly indicate that, with regard to
threading, the ten structurally similar axles can be classified into
–8.1
23.4
two categories: “threading” (relatively fast formation of
a
pseudorotaxane; shaded entries in Tables 1 and 2) and “non-
threading” (complex formation is not observed on the
experimental timescale). To understand the molecular origin of
this “all-or-nothing” behaviour, we modeled two representative
examples of the “threading” and “non-threading” categories – the
complexes of DB24C8 respectively with 6+ and 8+ – which differ
only for the relative position of one methyl substituent. As
illustrated in Figure 2, the gas-phase structures of the
complexes are very similar because they are stabilized by
hydrogen bonds and p-p stacking interactions of similar strength.
The similarity between the two adducts is maintained in the
equilibrium structures of the solvated complexes at 300 K
(Figure 6a for 6+ and 6d for 8+).
–7.1
–8.0
23.1
23.3
19.8
> 23
>100
[e]
[e]
> 23
[a] Shaded entries highlight the axles that undergo fast threading. [b]
Association free energies, calculated from the measured K values (Table 1)
using the expression ΔG° = −RTlnK. [c] Activation free energies for the
threading (ΔG‡in) and dethreading (ΔG‡out) processes, calculated from the
measured rate constants (Table 1) using the relationships ΔG‡
=
in
−RTln(kinh/kBT) and ΔG‡
= −RTln(kouth/kBT), respectively; R, h and kB
out
Starting from these structures, we induced the dethreading
of the two axles with ab initio metadynamics (see the SI and
Movie S1).[31] For each complex, we took the displacement of
the axle with respect to the ring as a “reaction coordinate”, and
computed the free energy during the transit of the axle through
the macrocycle. We chose to model the dethreading process for
the following reasons: (i) the ability of the terminal unit of the
axle to act as a molecular “speed bump” in rotaxane-like
architectures is essentially related to dethreading; (ii) in
comparison with guest entrance, the exit process is less affected
correspond respectively to the gas, Planck and Boltzmann constants. [d]
Activation free energies for dethreading, determined from metadynamics
simulations. [e] Data could not be obtained because of the poor solubility of
axle 9+ in CH2Cl2. Measurements performed in acetonitrile indicate that this
axle belongs to the “threading” category.
The first significant observation is that, while the threading of
dibenzylammonium 1+ into DB24C8 is immediate on the
investigated time scale (the time resolution of our stopped-flow
apparatus, dictated by the reactants mixing time, is 2 ms), the
presence of two methyl substituents in the phenyl rings slows
5
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10.1002/anie.202003064
Angewandte Chemie International Edition
RESEARCH ARTICLE
by the solvent reorganization.[11c] Hence, the markedly different
dethreading behaviour of 6+ and 8+ may be directly correlated to
their different interactions with the ring along the transit process,
sketched in Figure 6b,c and 6e,f, respectively.
Clearly, the metadynamics simulations provide a yes/no
outcome for the dethreading processes of 6+ and 8+, respectively
(Figure 7). Whereas the exit of 6+ occurs at a relatively modest
free energy cost (about 20 kcal mol–1), over 100 kcal mol–1 are
not sufficient to expel 8+ from the ring cavity (Table 2). Indeed,
the maximum displacement of 8+ along the simulated free
energy path (Figure 6e,f) corresponds to situations where both
phenyl rings are still inside the cavity. Conversely, in the
dethreading profile of 6+, one of the phenyl moieties of the axle
is entirely outside the ring already at the free energy maximum
(Figure 6b), and the exit is essentially complete at the end of the
simulation.
Figure 7. Free energy profile for the dethreading of the complexes of DB24C8
with guest 6+ (black line) and 8+ (red line) as a function of the displacement of
the axle, defined by the collective variable. The latter is selected as the
displacement of the 9 carbon atoms of one phenyl unit of the axle (including
the C atoms of its two methyl substituents and of the methylene group) with
respect to the 8 oxygen atoms of the macrocycle. The free energy cost
associated to dethreading of 6+ is 19.8 kcal mol–1, while no dethreading can
occur for 8+ (free energy barrier above 100 kcal mol–1).
Interestingly, the trajectories of the 6+ and 8+ complexes
reveal that both axles tend to remain strongly hydrogen bonded
to the macrocycle: in particular, 6+ forms hydrogen bonds with
different O atoms of the ring especially in the transition state of
the exit process. Hence, the [N+–H···O] hydrogen bonding
interactions may be instrumental in assisting 6+ to overcome the
dethreading barrier. This mechanism, however, does not seem
to work for 8+, which, despite forming hydrogen bonds with
different DB24C8 oxygens along the simulation, is unable to
leave the cavity.
In the case of 8+, we found that the ring enlarges significantly
along its shorter axis to initiate the insertion of the end group of
the guest. Yet such a distortion is not sufficient to enable the
transit, which would require a substantial elongation of the ring
along its main axis. In contrast, the deformation of DB24C8
during the exit process of 6+ is far less pronounced, i.e.,
dethreading of 6+ occurs without significant elongations of the
macrocycle along its long axis. Indeed, vibrational motions of the
ring are smooth and synchronized with the movement of the axle
– a common feature of transit movements in supramolecular
systems and at molecule-material interfaces.[32]
Figure 6. (a-c) Snapshots from the calculated dethreading path of the complex
of DB24C8 with guest 6+: (a) initial state (threaded); (b) transition state
(partially dethreaded); (c) final state (dethreaded). (d-f) Snapshots from the
metadynamics simulation of the complex of DB24C8 with guest 8+, which
predicted no dethreading. The atoms belonging to the complex are shown in a
space-filling representation; color codes: C (ring) = cyan spheres; C (guest) =
grey spheres; O = red; N: blue; H = white. Atoms of the solvent (CH2Cl2) and
counterion (PF6–) are shown in a stick and ball-and-stick representation;
respectively; color codes: C = cyan, Cl = yellow, H = white, P = dark grey, F =
green.
It remains to be understood why the elongation of DB24C8
along its main axis – never observed in our simulations – is
apparently forbidden. By inspecting the vibrations of the ring, we
found two normal modes – at 614 and 809 cm–1 respectively –
which achieve the maximum elongation of the ring (Figure 8 and
Movies S2-S3). This deformation, which would be essential for
the dethreading of 8+, is however not accessible at room
temperature. Indeed, the vibrational modes responsible for ring
elongation are too energetic with respect to kBT, and would
require the displacement and reorganization of a large number
of solvent molecules. On the other hand, the dethreading of the
[6
Ì
DB24C8]+ complex is facilitated by lower energy vibrations
(below 200 cm–1) associated to more circular distortions of the
ring, which enable the transit while preserving as much as
possible the stabilizing host-guest interactions in the course of
the exit process.
6
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10.1002/anie.202003064
Angewandte Chemie International Edition
RESEARCH ARTICLE
Figure 8. Vibrational modes of DB24C8 at 614 cm–1 (a) and at 809 cm–1 (b)
which allow for the maximum elongation of the ring. Color codes: C = grey; O
= red; H = white. The green arrows indicate the direction of the atomic
displacements.
In order to provide further insight on the transition state (TS)
governing the dethreading process of the [6
Ì
DB24C8]+ complex,
we performed a TS search using a different approach,[ 33 a]
namely, via geometry optimization by adopting two different
Density Functional Theory approximations: the PBE-D2[31gh] one
– which is the same adopted in the metadynamics study – and a
hybrid functional (ωB97xd).[33b] A continuum polarizable solvent
model[33c] was adopted for this approach (see the SI for details).
Within the geometry optimization methodology, we obtained an
activation free energy of 34.5 kcal mol–1 and 33.0 kcal mol–1 for
the PBE-D2/D95(d,p) and ωB97xd/D95(d,p) level of theory,
respectively. These values are higher than both the
experimental data (23.1 kcal mol–1) and the metadynamics
results (19.8 kcal mol–1; see Table S2). This point deserves
some comments because it might shed light on the
(de)threading mechanism. The main difference between the
geometry optimization and the metadynamics approaches stems
from the presence/absence of the CH2Cl2 solvent molecules in
thermal equilibrium. Actually, in the real experiment, the
supramolecular complex is caged by the solvent molecules, that
may exchange kinetic energy with the complex via thermally
induced collisions (Brownian motion). Such collisions, accounted
for in the metadynamics simulations, provide a kinetic energy
reservoir that the complex exploits to accomplish the
energetically costly deformations needed for the axle-ring
separation, thus effectively diminishing the dethreading barrier.
Interestingly, such structural changes preferentially involve
thermally accessible deformations, namely the ones which
cause an elliptical to circular modification of the ethereal ring.
Such a thermally accessible deformation allows for the exit of
the axle 6+ from the ring. This kind of circular deformation of the
macrocycle is also predicted for the TS obtained via geometry
optimization (see Figure 9 and SI Table S3, Scheme S1, and
Movie S4), whose geometry is very similar to the structures in
the activated complex region sampled by the metadynamics.
However, at difference with the finite-temperature metadynamics
simulation, in the optimized TS models no kinetic energy
reservoir is present to facilitate the barrier crossing. Hence,
while the presence/absence of solvent molecules does not seem
to affect significantly the structure of the transition state, it plays
indeed a key role on the kinetics of the process.
Figure 9. Optimized geometry of the transition state of the dethreading of the
axle 6+ from DB24C8, obtained with static quantum chemical calculation at the
ωB97xd/D95(d,p) level of theory. a) Top view, highlighting the circular
deformation of the ring; b) side view, highlighting the location of the transiting
methyl group inside the DB24C8 cavity. Color codes: C (ring) = cyan; C
(guest) = grey; O = red; N: blue; H = white. Blue dashed lines = hydrogen
bonds.
Finally, we investigated the effect of the methoxy substituent in
compounds 7+ and 10+. Interestingly, replacing a methyl for a
methoxy group on going from 6+ to 7+ does not change the
threading behaviour of the axle, while the same change on going
from 9+ to 10+ makes the latter compound unable to thread
through the ring (Table 1). To rationalize such an observation,
we simulated the dethreading of 10+ from DB24C8 in the gas
phase. We found that 10+ could exit the ring only if the methoxy
substituent performed an energetically costly rotation around its
C–O axis, bringing the CH3 group in close contact with the
adjacent methyl substituent (SI, Figure S2). As the passage of
10+ through the ring would require energetically unfavourable
conformational changes, we conclude that this process should
be very unlikely, in agreement with the experimental results.
Discussion
We can now try to generalize the findings reported above and
explain the belonging of the guests to the “threading” and “non-
threading” categories. First, all investigated guests except 5+
have two more substituents on each phenyl ring with respect to
dibenzylammonium (1+). In these compounds, the “threading” or
“non-threading” behaviour is determined not only by the relative
position of the two substituents on the phenyl ring that is being
traversed, but also by their position with respect to the axis
individuated by the C–C bond of the methylene substituent
attached to the ammonium centre (blue dashed line in Figure
10). As the methylene group must necessarily pass through the
cavity during threading or dethreading, this axis is somehow
related to the transit direction.
7
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10.1002/anie.202003064
Angewandte Chemie International Edition
RESEARCH ARTICLE
ring. Remarkably, changing the position of just one methyl
substituent on the terminal phenyl rings is sufficient to switch the
category of the axle.
Computational modelling of the dethreading process
revealed that hydrogen bonding between the host and the guest
is still present in the transition state, and that vibrational modes
that cause an extension of the macrocyclic cavity play a key role.
The kinetic energy reservoir provided by the solvent molecules
in thermal equilibrium facilitates the activation of the (pseudo)-
rotaxane for dethreading, allowing for ring deformations.
However, only elongations of the ring along its shorter axis are
accessible at room temperature; in other words, the crown cavity
cannot become more elliptical. This is probably the reason for
the all-or-nothing kinetic selectivity observed for structurally
similar axles – namely, the fine mechanics of the self-assembly
process is actually ruled by quantum mechanics. From these
insights, simple rules correlating the kinetic behaviour with the
substitution pattern have been derived.
Figure 10. Correlation between the substitution pattern and the kinetic
behaviour of DB24C8 threading for symmetric dibenzylammonium-type guest
bearing two methyl substituents in each phenyl ring. (a-c) “Non-threading”
category, methyl substituents shown in red. (d-f) “Threading” category, methyl
substituents shown in green. The blue dashed line shows the axis related to
the transit direction.
The present work has provided
understanding of the (de)threading reactions and has enriched
on fundamental basis the generally accepted
a detailed molecular
a
When the two substituents on each phenyl ring are methyl
groups, a rather simple correlation exists between the kinetic
behaviour of the guests and the substitution pattern (Figure 10).
Specifically, when the two methyl substituents are positioned
symmetrically with respect to the principal axis mentioned in the
previous paragraph (Figure 10a,b, compounds 2+ and 3+), or
adjacent and off-axis (Figure 10c, compound 8+), the guest
belongs to the “non-threading” category. When one of the two
methyl groups is located on-axis, the position of the other
substituent is irrelevant and the guest is of the “threading” type
(Figure 10d,e, compounds 6+ and 9+). Threading can also be
obtained when the two methyl groups are off-axis but neither
adjacent nor symmetrically arranged (Figure 10f, compound 4+),
probably because in this pattern the steric encumbrances of the
two groups along the (de)threading coordinate cannot add up
effectively.
When the on-axis methyl group is replaced by a methoxy,
which has a larger size and conformational freedom, our results
seem to indicate that the distance between the two substituents
becomes crucial. Probably, the combined presence of the
methyl substituent and of particular conformations of the
methoxy group can cause a significant steric hindrance only if
the two groups are nearby, as in 10+, in line with the
computational results. This effect vanishes in 7+, wherein the two
substituents are more spaced.
phenomenological picture. By studying a representative class of
molecular components, rational guidelines for the design of
pseudostoppers or “speed bumps”, necessary for the realization
of molecular mechanical switches and motors with
predetermined dynamic features have been formulated. Jointly
with these practical rules, the fundamental knowledge acquired
on the kinetic behaviour may be extended to other self-
assembling architectures in which the mechanical fit of the
components can give rise to technologically relevant
functionalities.
Acknowledgements
Financial support from the EU (ERC AdG “Leaps” n. 692981),
MIUR (Fare “Ampli” R16S9XXKX3, Prin “Nemo” 20173L7W8K),
and University of Insubria (FAR2018) is gratefully acknowledged.
L.C. and E.F acknowledge the King Abdullah University of
Science and Technology (KAUST) Supercomputing Laboratory
(KSL) for providing computational resources on Shaheen II Cray
XC40 Supercomputer within project k1345.
Keywords: kinetics • metadynamics • molecular machine •
supramolecular chemistry • rotaxane
Conclusion
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We have employed a combined experimental and computational
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10.1002/anie.202003064
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
Fine mechanics: with a systematic experimental and computational investigation, we explain why tiny structural changes in the
extremities of a molecular axle can allow or prevent its insertion in the cavity of a macrocycle. These results provide guidelines to
design interlocked molecules with predetermined dynamic features, that can be used to make nanostructured machines, motors and
materials.
Institute and/or researcher Twitter usernames: @erc_leaps, @UniboMagazine; @fe_ga_to; @BL76276
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