Disabling Molecular Recognition through Reversible Mechanical Stoppering

Article abstract of DOI:10.1021/acs.orglett.9b00310

Mechanical stoppering of a guest molecule prevents its self-assembly with a macrocycle unit, so that both species coexist in a medium but do not recognize each other. The application of a chemical or physical stimulus reverses mechanical stoppering and su

Full text of DOI:10.1021/acs.orglett.9b00310

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Disabling Molecular Recognition through Reversible Mechanical
Stoppering
Miguel A. Soto† and Mark J. MacLachlan*,†,‡
†
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
‡
WPI Nano Life Science Institute, Kanazawa University, Kanazawa, 920-1192, Japan
*
S Supporting Information
ABSTRACT: Mechanical stoppering of a guest molecule prevents its self-assembly with a macrocycle unit, so that both species
coexist in a medium but do not recognize each other. The application of a chemical or physical stimulus reverses mechanical
stoppering and subsequently enables molecular recognition. This process, which occurs without cross-reactivity and is
perceptible at the macroscopic scale, could facilitate programming on/off states in supramolecular materials and molecular
devices.
otaxanes, catenanes, and molecular knots are part of the
1
R
vast array of mechanically interlocked molecules
MIMs) that have been important in supramolecular chemistry
(
2
−4
5,6
7,8
for developing sensors,
actuators, molecular machines,
9
−11
and other intriguing structures.
These systems are equally
relevant for emerging concepts such as supramolecular
1
2−14
15,16
catalysis
and molecular protection,
where the
mechanical bond plays a critical role to prevent chemical
degradation and efficiency loss.
The mechanical bond has recently been involved in creating
ever more sophisticated MIMs, including hetero[n]-
1
7
rotaxanes, i.e., species composed of a dumbbell-shaped
molecule and at least two different macrocycles. Figure 1a
illustrates a hetero[4]rotaxane containing two identical outer
macrocycles and a larger one in the center, all of them threaded
onto a dumbbell-shaped axle. The interlocked nature of this
assembly is preserved through an artful design; the dumbbell
end-caps are bulky enough to prevent the outer macrocycles
from escaping, and these rings are bigger than the cavity of the
central macrocycle, so it cannot escape if the outer macrocycles
are present. This stoppering effect emerges in a cascade-like
manner, as previously introduced by Schalley in a self-sorting
Figure 1. Schematics of (a) a hetero[4]rotaxane and (b) a disabled/
enabled recognition process by mechanical stoppering.
mechanical stoppering might be a powerful tool to program
on/off stages for distinct processes, including chemical
transformations, reconfiguration of mechanically bonded
molecules, and the hierarchical assembly of supramolecular
materials.
Here, we present as a proof-of-concept the use of mechanical
stoppering to disable a molecular recognition process between
1
8
system. The outer rings and dumbbell end-caps synergisti-
cally operate as a physical barrier: a mechanical stopper.
This class of stoppering has been used to prevent the
19,20
disassembly of a few hetero[n]rotaxane structures,
but not
attempted to prevent other phenomena to occur such as
chemical reactivity or self-assembly. We envisaged that
blocking/unblocking a functional species via reversible
Received: January 25, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00310
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
Figure 2. (a) Chemical structure and proton assignment for thread, macrocycle, and [2]pseudorotaxane species. (b) H NMR spectra (CD CN,
3
2
+
−3
4
00 MHz, 25 °C) of (i) thread [1·H ] , (ii) a 1:1 mixture of [1·H ][PF ] and [CBPQT][PF ] (5 × 10 M), (iii) thread 1, and (iv) an
equimolar solution of [1·H ][PF ] and [CBPQT][PF ] (5 × 10 M). (c) Partial EXSY NMR (CD CN, 400 MHz) collected from (ii).
2
2
6
2
6 4
−
3
2
6
2
6
4
3
a thread-like molecule and a macrocycle, a process that would
otherwise occur extremely rapidly. Figure 1b illustrates our
concept: structure A, which does not contain a central
macrocycle, comprises two mechanical stoppers along with a
central station suitable for macrocycle B. When A and B are
mixed, mechanical stoppering prevents the molecular recog-
nition between the thread and B. If the mechanical stoppers in
A are removed by a stimulus-controlled dissociation, macro-
cycle B can bind the thread to give C, a pseudorotaxane
complex; this may be accompanied by a change in color or
other properties.
easily accessible, (ii) both components assemble in solution
quickly and with moderate affinity in noncompetitive solvents,
(iii) their self-assembly leads to a detectable color change, and
(iv) the similar size of both selected macrocycles, [CBPQT]
vs 22C6 (Figure S1), ensures effective stoppering.
4
+
With these choices in mind, we designed and synthesized
2
+
the dicationic structure [1·H2] incorporating two independ-
ent dibenzylammonium moieties, an electron-rich phenylene
core, and two tetraethylene glycol bridging chains (Figure 2a).
The end-groups of this molecule were designed as scaffolds for
the synthesis of two mechanical stoppers, whereas the central
To demonstrate our approach, we first focused on molecular
design and screened for species functioning as reversible
stoppers. Metastable rotaxanes, also referred to in the literature
component was intended as a recognition site for macrocycle
4+
[
CBPQT] . In addition, we expected the bridging chains to
4+
reinforce the interaction of the central core with [CBPQT] ,
as previously reported by Stoddart. Compound [1·H ][PF ]
2
1−23
as size-complementary rotaxanes, seem ideal.
These
25
2
6 2
systems remain assembled under specific environments but
disassemble under others to deposit the dumbbell and
macrocycle components in solution. We identified a minimalist
system reported by Dasgupta and Wu, composed of a
was synthesized in four steps in 36% overall yield and
characterized by NMR spectroscopy and mass spectrometry
(
see Supporting Information (SI)).
+
Following synthesis, we first analyzed the molecular
dibenzylammonium cation (DBA ) and a [22]-membered
4
+
+
24
recognition process of [CBPQT] with the thread molecule
crown ether (22C6), i.e. a [2]rotaxane, [DBA⊂22C6] . This
molecule undergoes full disassembly in just a few minutes
when exposed to two combined stimuli, polarity and
temperature (DMSO, 100 °C), and cannot regenerate.
Because of its structural simplicity and stimuli-responsiveness,
we chose this species as a potential stopper. On the other hand,
we selected a hydroquinone-based guest and the cyclobis-
2
+
in its protonated [1·H2] and neutral 1 form. When CD CN
3
solutions of [CBPQT][PF ] and [1·H ][PF ] were com-
6 4
2
6 2
bined in a 1:1 ratio, the solution immediately changed from
colorless to orange. An absorption band at 450 nm in the UV−
visible spectrum (see Figure S25) confirms the formation of a
charge-transfer complex between the electron-rich phenylene
4
+
2+
(
paraquat-p-phenylene) macrocycle (Figure 2a), [CBPQT] ,
core on [1·H
2
]
and the electron-poor macrocycle
4
+
as the target pair for molecular recognition. This selection was
made based on the following judgments: (i) these species are
[CBPQT] , in good agreement with other similar pseudor-
26
otaxane complexes.
B
DOI: 10.1021/acs.orglett.9b00310
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Organic Letters
Letter
1
On the other hand, the recorded H NMR spectrum exhibits
distinct sets of signals corresponding to the complexed and
uncomplexed (free) components (Figure 2b, i−ii). Resonances
for the tetraethylene glycol portions and the phenylene core
(
[
H ) are the most dramatically affected by the presence of
Hq
4
+
CBPQT] . The resonance for H moves upfield by 3.1
Hq
ppm, which is ascribed to a π−π stacking between the host and
guest components. The position of this pair of signals was
unequivocally assigned using 2D exchange NMR spectroscopy
(
EXSY), where cross peaks for the complexed and
uncomplexed species are evident (Figure 2c). Both EXSY
and H NMR spectra also revealed a slight effect on the
1
dibenzylammonium resonances, e.g. the inner benzyl proton
4
+
HBz‑1 (Δδ
= −0.2 ppm), implying that host [CBPQT]
HBz‑1
2+
sits on the central recognition site of [1·H ] to yield
2
6+
pseudorotaxane [1·H ⊂CBPQT] . Moreover, signals corre-
2
sponding to the macrocycle show moderate shifts, for instance,
Hm‑Py moves from 8.2 to 7.8 ppm.
Similarly, we confirmed the assembly of the pseudorotaxane
1⊂CBPQT] through three spectroscopic observations:
4
+
[
Figure 3. (a) Chemical structure and proton assignment for the
1
upfield shift for the H (ΔδHHq = −3.2 ppm), H
obtained stoppered system. H NMR spectra (CD CN, 400 MHz) of
Hq
Bz‑1/2
= −0.4 ppm)
3
(
Δδ
≈ −0.3 ppm), and H
(Δδ
(i) [1·H ][PF ] and (ii) [1·H ⊂(22C6) ][PF ] ; DOSY NMR is
HBz‑1/2
m‑Py
Hm‑Py
2
6
2
2
2
6 2
1
resonances in the H NMR spectrum (Figure 2b, iii−iv);
through-space coupling between H and H protons,
shown in the bottom section.
Hq
o/m‑Py
observed by NOESY NMR spectroscopy (which implies that
both the phenylene and bipyridinium planes are in close
proximity); and an absorbance band centered at 465 nm in the
UV−vis experiment. These results together corroborate the
expected π−π stacked structure for pseudorotaxane
molecule per two 22C6 units, which was supported by HRMS
where the parent ion [1 + 2 × (22C6) + 2H] was detected at
2
+
m/z = 747.4554.
By comparing the collected H spectrum with a pure sample
1
4
+
of [1·H ][PF ] , we verified that the most affected regions are
2
6 2
[
1⊂CBPQT] (Figures S28−S29).
2
+
those corresponding to the dibenzylammonium units, con-
Interestingly, the charge difference between [1·H ] and 1
2
sistent with the 22C6 rings wrapping exclusively around the
has two main consequences in the association process with
+
NH
4
+
ammonium stations. Indeed, protons H
and HCH2 register a
[
CBPQT] . First, the exchange in solution between the
2
complexed and uncomplexed species operates on different time
downfield shift of 0.6 and 0.3 ppm, respectively, which is
6
+
+
scales: slow for [1·H ⊂CBPQT] (as confirmed by EXSY
ascribed to the intercomponent [ N−H···O] hydrogen
2
4+
NMR, Figure 2c) and fast for [1⊂CBPQT] . Second, the
stability of the complexes (ΔG , measured in CD CN at 25
bonding. This was further supported by NOESY NMR (see
Figure S21), where cross peaks between the dibenzylammo-
nium signals and the 22C6 glycolic protons were noticed. We
asso
3
°
[
C) drops by 5.7 ± 0.2 kJ/mol for the hexacationic complex
6+ 2
−1
additionally proved, by diffusion-ordered NMR spectroscopy
1·H ⊂CBPQT] [Kasso = (8.1 ± 0.1) × 10 M ] with
2
1
4+
(
DOSY), that the identified H resonances correspond to a
respect to the tetracationic species [1⊂CBPQT] [Kasso
=
3
−1
single species, which diffuses in solution (CD CN, 25 °C) at
(
7.9 ± 0.2) × 10 M ]. This behavior may be explained by the
3
−
6
2 −1
4+
ca. 8.0 × 10 cm ·s .
cation−cation repulsion between host [CBPQT] and guest
2
+
The obtained molecule is soluble in a range of solvents such
[
1·H ] , which would not occur for the 1-based system.
2
as MeCN, Me CO, CH Cl , and THF and remains assembled
Similar effects have been identified for other cation-gated
2
2
2
pseudorotaxane complexes containing [CBPQT]4 as a host.
+
27
when stored in solution. In principle, it could disassemble as its
+
parent [2]rotaxane [DBA⊂22C6] , reported by Dasgupta and
Despite these differences, the linear species in both states,
2
+
4+
Wu, in DMSO-d at 100 °C. Nonetheless, DMSO may
[
1·H2] and 1, quickly assemble with [CBPQT] , enabling
6
interfere in the recognition process between the thread
the recognition process as revealed by a color change.
4
+
Therefore, we employed [1·H2]2 to synthesize the stoppered
molecule, a [3]rotaxane (Figure 3a), aiming to disable
molecular recognition.
+
molecule and [CBPQT] , so we targeted and evaluated two
stimuli (base and heat), using MeCN as solvent. Treating a
CD CN solution of [1·H ⊂(22C6) ][PF ] with 2 equiv of
3
2
2
6 2
base (NaOH ) leads to fast deprotonation of the thread
Ring-closing metathesis of pentaethylene glycol dibut-4-enyl
ether in the presence of [1·H ][PF ] , followed by hydro-
(aq)
component followed by dissociation; 1 and two 22C6 units
were detected in solution as free components (Figure S33).
This process was too fast to quantitatively analyze by NMR
spectroscopy.
2
6 2
genation, generated [1·H ⊂(22C6) ][PF ] in 40% overall
2
2
6 2
1
yield (see SI). Figure 3b shows the partial H NMR spectrum
of the isolated product, where three principal regions are
distinguished: (i) glycol resonances from 2.9 to 4.1 ppm (from
both the crown ether units and the thread); (ii) dibenzy-
On the other hand, the use of temperature as a trigger also
causes disassembly, although the process is clearly slowed
down compared to the effect of proton transfer. Heating a
lammonium moieties observed at 4.5 (HCH2), 7.0−7.6 (HBz),
2+
sample containing [1·H ⊂(22C6) ] (70 °C, CD CN)
2
2
3
+
NH
and 7.9 ppm (H ); and (iii) the central core (H ) at 6.8
2
Hq
triggers gradual disassembly in a stepwise fashion, generating
2
+
ppm. The relative integrals on the spectrum confirm the
stoichiometry of the structure, corresponding to one linear
first the one-ring-containing molecule [1·H ⊂22C6] , which
2
2
+
ultimately disassembles to release [1·H ] . The presence of
2
C
DOI: 10.1021/acs.orglett.9b00310
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2
+
2+
these species along the dissociation process was verified by
NMR spectroscopy and HRMS (Figures S34−S35). From the
H ⊂(22C6) ] and [1·H ⊂22C6] , the release of 22C6
2
2
2
units, and the self-assembly of pseudorotaxane [1·
6
+
obtained kinetic data, the half-life (t1 ) to reach full
H ⊂CBPQT] , although we do not discard the presence of
/2
2
−
6
−1
6+
dissociation is 63 ± 3 h [koff = (3.1 ± 0.2) × 10 s ], ca.
complex [CBPQT⊃1·H ⊂22C6] along the process. The
2
+
twice the value we measured for rotaxane [DBA⊂22C6] (t
relative concentration of these species varies over time,
reaching completion in about 6 days. Interestingly, the
unstoppering/recognition sequence was also detected at the
macroscopic scale. The initial pale-yellow mixture gradually
transforms into an orange solution (Figure 4b). This
1
/2
=
33 ± 3 h), which has only one ring (see Table S2).
+
With both the dissociation of [1·H ⊂(22C6) ] and the
2
2
2+
[
2]pseudorotaxane formation between [1·H ] (or 1) and
2
4+
[
CBPQT] confirmed, we interrogated our system toward
molecular recognition. Initially, a CD CN solution of [1·
phenomenon is attributed to the presence of pseudorotaxane
3
1
6+
H ⊂(22C6) ][PF ] was probed by H NMR spectroscopy
[1·H ⊂CBPQT] , evidenced by an absorbance band at 450
2
2
6 2
2
before and after the addition of 2 equiv of [CBPQT][PF ] .
nm in the UV−vis spectrum. Indeed, this band gradually
increases in intensity in parallel to the heating time and reaches
a maximum in 6 days (Figure 4c), after the unstoppering
process has been completed.
6
4
1
The H NMR spectrum is unaffected by the presence of
CBPQT] (see HHq resonance in Figure 4a), and no changes
4
+
[
In summary, we have installed mechanical stoppers on a
guest molecule to disable its molecular recognition with a
macrocycle. By applying a specific stimulus (heat or base), we
directed the controlled disassembly of the mechanical stoppers
to subsequently enable molecular recognition and yield a
pseudorotaxane complex with a readout: a macroscopic change
of color. We anticipate that this method may serve for the
development of new supramolecular materials, those con-
structed by the controlled disassembly of mechanically
stoppered species. This concept is now under investigation
in our group.
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00310.
1
Figure 4. (a) H NMR spectrum (400 MHz, CD CN) for the process
3
driven by proton transfer using 1 M NaOH(aq) as base. (b,c)
Photographs and absorption spectra of the unstoppering/recognition
sequence triggered by heat.
Full experimental description, spectroscopic character-
ization (NMR, UV−vis and HRMS), and kinetic
analyses for the unstoppering processes (PDF)
were noticed after several days at 25 °C, suggesting an effective
stoppering process that prevents the threading of [CBPQT]
onto the linear component. A faint yellow color for the
solution may be attributed to a weak intercomponent
interaction, possibly due to the external stacking of
4
+
AUTHOR INFORMATION
■
Corresponding Author
*
E-mail: mmaclach@chem.ubc.ca.
4
+
2+
[
CBPQT] with the electron-rich core of [1·H ⊂(22C6) ] .
2
2
2+
ORCID
The mixture of both components, [1·H ⊂(22C6) ] and
2
2
4+
free macrocycle [CBPQT] , was then treated with an alkaline
Miguel A. Soto: 0000-0002-7464-009X
Mark J. MacLachlan: 0000-0002-3546-7132
Notes
solution to control the unstoppering process. Upon addition of
.5 equiv of base [NaOH(aq)], the solution immediately
changed color, from pale to deep yellow, which we ascribe to
the formation of a charge-transfer complex between the
released thread 1 and [CBPQT] . By H NMR spectroscopy,
we saw a drop in the relative intensity of the rotaxane signals,
including HHq (6.8 ppm). Moreover, two new sets of
resonances were identified, one for free 22C6 (H , 3.4
ppm), and another set for pseudorotaxane [1⊂CBPQT]
e.g., H at 6.5 ppm); see Figure 4a. After addition of an
excess of base, all resonances for the stoppered species were no
longer observed, while HBz‑1 and HAlk attained maximum
intensity. This corroborates that base addition triggers
unstoppering to rapidly enable molecular recognition, allowing
for the assembly of a pseudorotaxane.
Heating the system at 70 °C generates comparable results,
although the process is significantly slowed down, as confirmed
0
The authors declare no competing financial interest.
4+
1
ACKNOWLEDGMENTS
■
M.A.S. acknowledges Conacyt for a postdoctoral scholarship,
and M.J.M. thanks NSERC for funding (Discovery Grant).
Alk
4
+
(
Bz‑1
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Org. Lett. XXXX, XXX, XXX−XXX