Chemical On/Off Switching of Mechanically Planar Chirality and Chiral Anion Recognition in a [2]Rotaxane Molecular Shuttle

Article abstract of DOI:10.1021/jacs.9b00941

We exploit a reversible acid-base triggered molecular shuttling process to switch an appropriately designed rotaxane between prochiral and mechanically planar chiral forms. The mechanically planar enantiomers and their interconversion, arising from ring shuttling, have been characterized by NMR spectroscopy. We also show that the supramolecular interaction of the positively charged rotaxane with optically active anions causes an imbalance in the population of the two enantiomeric coconformations. This result represents an unprecedented example of chiral molecular recognition and can disclose innovative approaches to enantioselective sensing and catalysis.

Full text of DOI:10.1021/jacs.9b00941

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Communication
Chemical On/Off Switching of Mechanically Planar Chirality and
Chiral Anion Recognition in a [2]Rotaxane Molecular Shuttle
Stefano Corra, Christiaan de Vet, Jessica Groppi, Marcello
La Rosa, Serena Silvi, Massimo Baroncini, and Alberto Credi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00941 • Publication Date (Web): 25 May 2019
Downloaded from http://pubs.acs.org on May 25, 2019
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Chemical On/Off Switching of Mechanically Planar Chirality and
Chiral Anion Recognition in a [2]Rotaxane Molecular Shuttle
Stefano Corra,†,# Christiaan de Vet,†,# Jessica Groppi,† Marcello La Rosa,† Serena Silvi,‡ Massimo
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Baroncini,*,†,§ and Alberto Credi*,†,§
† Center for Light Activated Nanostructures (CLAN), Dipartimento di Scienze e Tecnologie Agroalimentari, Università di
Bologna, Via Gobetti 101, 40129 Bologna, Italy
‡ Dipartimento di Chimica “G. Ciamician”, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy
§ Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, Via Gobetti 101, 40129 Bologna,
Italy
Supporting Information Placeholder
(Figure 1a).8 When the ring and axle are interlocked,
ABSTRACT: We exploit a reversible acid-base triggered
the improper symmetry operations of the separated
components are not symmetry operations of the
rotaxane, which therefore becomes chiral (Figure 1b).6
The synthesis of mechanically planar (MP) chiral
rotaxanes was pioneered by Vögtle and coworkers,9
and further investigated in more recent times,10,11,12,13
when efficient and stereoselective methodologies have
enabled the synthesis of highly enantiopure
samples.14,15 The exploitation of MP stereogenic
elements of MIMs for the development of novel
chiroptical materials, enantioselective sensors and
asymmetric catalysis, is a fascinating research topic
with development opportunities.6,16
molecular shuttling process to switch an appropriately
designed rotaxane between prochiral and mechanically
planar chiral forms. The mechanically planar
enantiomers and their interconversion, arising from
ring shuttling, have been characterized by NMR
spectroscopy. We also show that the supramolecular
interaction of the positively charged rotaxane with
optically active anions causes an imbalance in the
population of the two enantiomeric co-conformations.
This result represents an unprecedented example of
chiral molecular recognition and can disclose
innovative approaches to enantioselective sensing and
catalysis.
Mechanically interlocked molecules (MIMs)1,2 such as
catenanes and rotaxanes may exhibit large amplitude
motion of their interlocked components that renders
them ideal candidates for the construction of molecular
machines.2,3,4 While the absence of covalent bonds
between the components enables facile relative
movements, the mechanical constriction limits the
possibilities for their mutual arrangement, with
interesting outcomes from a stereochemical viewpoint.
In fact chiral MIMs can be obtained by interlocking
molecular components which are themselves achiral.5,6
This happens, for example, when an axle with C∞v
symmetry – i.e., having a principal axis and mirror
planes aligned along the axle length – is surrounded by
a macrocycle with a Cs symmetry7 – i.e. having only one
mirror plane coinciding with the plane of the ring
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that has identical extremities, provided that the ring is
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located on either side of the mirror plane at the center
of the axle (Figure 1c).6,17 In other words, it is the
position of the oriented macrocycle that
desymmetrizes the axle component, yielding a MP
chiral [2]rotaxane. In systems of this kind, ring shuttling
along the axle leads to interconversion of the two
enantiomers by passing through an achiral co-
conformation in which the ring is located in the center
of the axle (Figure 1c). Only one co-conformationally
mechanically planar chiral rotaxane has been reported
to date, whose enantiomers were separated and their
racemization rate was determined.17 However, in this
case the position of the ring along the axle could not be
controlled because of the absence of any recognition
site.
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The relation between co-conformational dynamics
and chirality13 in systems such as those shown in Figure
1c prompted us to investigate the possibility to exploit
the stimuli-controlled switching of a molecular shuttle
to enable MP chirality. Here we describe a [2]rotaxane
that can be reversibly switched between prochiral and
chiral states upon chemical stimulation. The presence
of two enantiomers in the chiral state was probed
experimentally, and the inversion of the MP
stereogenic element via thermally activated ring
shuttling was investigated. Finally, we report on the
effect of optically active counteranions on the co-
Figure 1. Schematic representation of: a C∞v symmetric axle
and a Cs symmetric ring (a); the two enantiomers of a
mechanically planar (MP) chiral rotaxane (b); the two
enantiomers of a co-conformationally MP chiral rotaxane and
their interconversion by ring shuttling through an achiral co-
conformation that features a mirror plane (c).
conformational
behavior
and
stereochemical
properties of the positively charged rotaxane.
MP Chiral rotaxanes can also be obtained by
interlocking a Cs symmetric macrocycle with an axle
HPby
O
HPay
R
1H3+ R =
2H3+ R = H
t-Bu
t-Bu
O
O
3I_
O
O
O
+
+
N
t-Bu
+
N
t-Bu
N
N
N
N
N
H
2 O
O
O
+ Base
+ Base
O O
HTr
+ Acid
+ Acid
R
R
t-Bu
O
t-Bu
t-Bu
t-Bu

O
2I_
2I_
O
O
+
N
+
N
t-Bu
t-Bu
t-Bu
t-Bu
+
+
N
N
N
N
N
N
N
N
N
O
O
O
O
O
O
N
N
H
N
H
O
O
O
O
O
O
HTcr
O
HTur
O
O
O
R = CH2OCH2C16H9
R = H
(Smp)-12+
ENANTIOMERS
(Rmp)-12+
22+
SAME MOLECULE
22+
Scheme 1. Rotaxanes 1H3+ and 2H3+ (top), and their base-triggered switching to 12+ and 22+ (bottom). The latter species can
exist in two interconverting co-conformations, that constitute an enantiomeric pair for 12+ (see ref. 6 for the assignment of
the absolute configurations) while they are the same molecule in the case of 22+. The starting rotaxanes are regenerated
upon addition of an acid.
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We based our design on a crown ether macrocycle,
the deprotonated rotaxane they should resonate at
different frequencies and form a coupled spin system.23
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and on dibenzylammonium and triazolium recognition
sites located along the axle (Scheme 1) to exploit acid-
base stimulation of the molecular shuttle.18,19,20
A
dibenzo[24]crown-8 (DB24C8)-type ring encircles
preferentially the ammonium center because of strong
hydrogen bonding, and can be moved on the triazolium
station upon deprotonation of the ammonium.
Rotaxanes 1H3+ and 2H3+, equipped respectively with
an oriented (Cs) and a non-oriented (D2h) macrocycle
(Scheme 1, top), were synthesized by stoppering of the
corresponding pseudorotaxanes via CuAAC. In
rotaxane 1H3+ the DB24C8 skeleton is desymmetrized
by placing a substituent in the 4-position of one of its
1,2-dioxybenzene moieties. A pyrenyl tether was
chosen as the ring orienting substituent, with the aim
of (i) enhancing the transfer of chiral information with a
large aromatic moiety, and (ii) having a fluorescent
reporter for the switching process. In the symmetric
rotaxane 2H3+ the ring is plain DB24C8.
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In both 1H3+ and 2H3+ the ring encircles the
ammonium center, in line with literature data.18–20 We
treated 2H3+ with a polymer-bound phosphazene base
in CD2Cl2 to afford rotaxane 22+ (Scheme 1, bottom).
1
The H NMR signal of HTr in 2H3+ (9.14 ppm) splits at
u
HcTr
HTr
low temperature into two,
and
, associated
respectively with the complexed and uncomplexed
triazolium station in slow exchange on the NMR
c
u
1
timescale. Total line-shape analysis of
and
at
HTr
HTr
Figure 2. (a) Variable temperature (VT) H NMR spectra (500
MHz, CD2Cl2) of 22+ in the region of the triazolium protons (
various temperatures (Figure 2a) allowed us to
estimate the shuttling activation parameters (see the
SI). These results confirm that the crown ether
encircles one of the two equivalent triazolium sites, and
moves between them. Similar results were obtained
upon deprotonation of 1H3+ to yield 12+ (Figure 2b),
showing that the pyrenyl tether of the macrocycle does
not affect the kinetics of the co-conformational
equilibrium.
u
c
HTr, HTr). (b) VT H NMR spectra (500 MHz, CD2Cl2) of 12+ in
1
the regions of the triazolium protons (HuTr, HTc r; left) and of the
methylene protons in the pyrenyl tether of the macrocycle,
adjacent to the dioxybenzene unit (HaPy, HPby; right). See
Scheme 1 and SI for proton labeling.
The H NMR spectra of 12+ recorded at 223 K and
203 K showed that the signal at 4.60 ppm, associated
with HPy, consistently splits into a couple of two almost
overlapped doublets (Figure 2b).24 Additionally,
1
In contrast with 22+, however, ring shuttling in 12+
generates a 50:50 population of two mirror image co-
conformations, that is, a racemic mixture of two
enantiomers (Rmp)-12+ and (Smp)-12+.21 In this regard, 12+
is an example of a degenerate molecular shuttle22
whose co-conformations are energetically equivalent
but not superimposable (Scheme 1, bottom). The
presence of the MP enantiomers of 12+ in the racemate
was confirmed by analyzing the NMR signals of the two
methylene protons in the pyrenyl thether of the
macrocycle, adjacent to the dioxybenzene unit (HPy,
Scheme 1). These protons are enantiotopic – and thus
a/b
u/c
analysis of the signals corresponding to
and
in
HTr
HPy
CD2Cl2 revealed that the rate constants for shuttling
(ksh) and racemization (krac) are approximately the same
(see the SI). This observation confirms that in 12+ ring
shuttling and inversion of the MP chiral configuration
are two aspects of the same phenomenon (Scheme 1)
which, interestingly, can be monitored separately. In
u
c
fact, while the exchange of
and
(Figure 2b, left)
HTr
HTr
yields information on the ring shuttling rate – an
observation that can also be made for 22+ (Figure 2a) –
a
b
isochronous
–
in 1H3+, while they become
the exchange of
and
(Figure 2b, right) is related
HPy
to the racemization rate. This set of results is
HPy
diastereotopic in 12+. We therefore envisioned that in
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consistent with the emergence of two enantiomers of
the two different diastereomeric ion pairs (analysis of
other resonances also supports this interpretation; see
the SI). Deconvolution of these peaks affords a
diastereomeric ratio of 85:15, which corresponds to a
difference in stability of the two diastereoisomers of
3.2 kJ mol–1. Titration data show that the
diastereomeric ratio does not depend on the CS/12+
stoichiometry. Moreover, the spectra recorded upon
addition of the opposite enantiomer [(–)-CS] display
identical resonances and integral ratio, in full
agreement with the formation of a diastereomeric pair
that is enantiomerically related to that observed upon
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12+ upon deprotonation.
The switching of 1H3+/12+ can also be followed by
absorption and luminescence spectroscopy (Figure 3).
The spectrum of 1H3+ shows an absorption tail in the
280-430 nm region assigned to a charge-transfer
interaction between the pyrenyl electron donor and a
triazolium electron acceptor. Such a tail disappears in
12+, presumably because the pyrenyl unit cannot
undergo efficient electronic interactions with either
triazolium unit (the complexed one is surrounded by
the crown ether, and the free one is relatively distant).
Consistently, in 1H3+ the pyrenyl fluorescence is
strongly quenched with respect to the free
macrocycle,19d,g and it is 5-fold enhanced upon addition
of base. Such a luminescence turn-on behavior
provides a useful signal to monitor the occurrence of
the chiral state, even by the naked eye (see the SI).
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addition of (+)-CS (see the SI). In all cases the signal of
u
shifts downfield from 9.14 ppm to 9.58 ppm (major
HTr
diastereoisomer), confirming that the sulfonate anion
is coordinated by the free triazolium unit of the
c
rotaxane.25 Conversely, the fact that the signal of
is
HTr
almost unaffected by the presence of the anion
indicates that the macrocycle wrapped around the
triazolium prevents a tight ion pairing.
Taken together, these observations (see also the SI)
suggest that the ring-axle arrangement in 12+ creates a
nonsymmetric environment around the unencircled
triazolium such that enantioselective anion recognition
can take place. The encircled triazolium site does not
effectively compete for anion binding and it does not
contribute to the stereodifferentiation. The fact that
the recognition occurs relatively far away from the site
of the mechanical entanglement – where the
stereogenic unit is formally located – is quite
remarkable.26 A possible explanation is that the
molecule folds to create a ‘chiral pocket’ similar to that
of an enzyme, suggesting that such MIMs can have
significant potential in chiral sensing.
Figure 3. Absorption and fluorescence (inset, exc = 328 nm)
spectra of the free macrocycle (black), 1H3+ (blue) and 12+
(red). Air equilibrated CH2Cl2, 20°C.
The addition of tetrabutylammonium -TRISPHAT27
to 12+ in toluene-d8 at 243 K28 also causes a splitting of
u
Having confirmed that 12+ exists as a dynamic
racemic mixture of (Smp) and (Rmp) forms, we
investigated the possibility to induce an enantiomeric
excess. Since the triazolium stations are positively
charged, an interesting option is ion pairing with an
optically active anion.25 In such a case, two
diastereomeric salts would be formed, which can have
different energies and thus exhibit unbalanced
populations of the macrocycles on the stations (Figure
4a).
the NMR singlet corresponding to the
proton into
HTr
two overlapping singlets (∆ = 0.02 ppm; Figure 4b,
right). Integration of these signals, however, revealed
that the two diastereoisomers have the same
concentration within errors. Thus, -TRISPHAT plays
the role of a chiral shift reagent27 by ion-pairing with 12+
in an apolar solvent, but enantioselective molecular
recognition does not occur. Presumably, the large and
soft TRISPHAT anion, being loosely bound to the
triazolium site, is unable to ‘read’ the mechanical
chirality of 12+ and determine an imbalance of its two
co-conformations.
Upon addition of the enantiopure anion (1S)-(+)-10-
camphorsulfonate [(+)-CS] (tetrabutylammonium salt)
u
to 12+ in CD Cl at 223 K, the NMR signal of the
HTr
2
2
proton – that appears as a singlet at 9.14 ppm in the
iodide salt – splits into two singlets with different
intensities (∆ = 0.02 ppm; Figure 4b, left), assigned to
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Furthermore, we have induced a difference in the
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population of the stations by interaction with an
optically active anion, which is of interest for, e.g.,
enantioselective sensing and catalysis,16ab,29 or
activating molecular machines with a chiral trigger.
Considering the central role of chirality in chemistry,
and the fact that mechanical chirality of MIMs is often
overlooked,30 studies of this kind not only have exciting
implications for basic science, but can also open new
avenues for the development of molecular devices and
materials for practical applications.
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on
the ACS Publications website. General methods and
experimental procedures, synthesis, NMR and CD spectra
(PDF).
AUTHOR INFORMATION
Corresponding Author
*massimo.baroncini@unibo.it, alberto.credi@unibo.it
Author Contributions
#S. C. and C. d. V. contributed equally.
ACKNOWLEDGMENT
We thank Prof. Steve Goldup for fruitful discussions and
Dr. Massimo Capobianco for assistance in the MS
experiments. This work was supported by the European
Research Council (H2020 AdG n. 692981) and the
Ministero dell'Istruzione, Università e Ricerca (FARE grant
n. R16S9XXKX3).
Figure 4. (a) Interconversion between two diastereomeric ion
pairs composed of a co-conformationally MP chiral rotaxane
dication, such as 12+, and a chiral monoanion. In the proposed
structures, one anion is coordinated to the unencircled
triazolium, while another is weakly paired with the encircled
site. Simplified potential energy curves for the location of the
ring along the axle are also shown. As the two ion pairs can
have different stabilities [ G°  0], the ring distribution
between the two identical stations can become unbalanced.
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(b) Partial H NMR spectra (500 MHz) of the HTr resonance in
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(CD2Cl2, 223 K; left) or -TRISPHAT (toluene-d8, 243 K; right).
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(a) Kameta, N.; Nagawa, Y.; Karikomi, M.; Hiratani, K.
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TRISPHAT
=
[Tris(tetrachlorobenzenediolato)
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The solvent was changed from CD2Cl2 to toluene-d8 in
order to favor ion pairing and thus enhance chiral shift effects on the
signals. The 1H NMR spectra of 12+·2I– in toluene-d8 are consistent
with those in CD2Cl2.
A Switchable [2]Rotaxane Asymmetric
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See, e.g.: (a) Cakmak, Y.; Erbas-Cakmak, S.; Leigh, D. A.
Asymmetric Catalysis with a Mechanically Point-Chiral Rotaxane. J.
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Garcia, J.; Leigh, D. A.; Marcos, V.; Pisano, S.; Singleton, T. A.
Switching between Anion-Binding Catalysis and Aminocatalysis with
a Rotaxane Dual-Function Catalyst. J. Am. Chem. Soc. 2017, 139,
9376-9381. (c) Lim, J. Y. C.; Marques, I.; Felix, V.; Beer, P. D.
Enantioselective Anion Recognition by Chiral Halogen-Bonding
[2]Rotaxanes. J. Am. Chem. Soc. 2017, 139, 12228-12239.
(30) See, e.g., ref. 19i and: (a) Li, J.; Li, Y.; Guo, Y.; Xu, J.; Lv, J.;
Li, Y.; Liu, H.; Wang, S.; Zhu, D. A Novel Supramolecular System:
Combination of Two Switchable Processes in a [2]Rotaxane. Chem.
Asian J. 2008, 3, 2091-2096. (b) Iwamoto, H.; Yawata, Y.; Fukazawa,
Y.; Haino, T. Highly Efficient Synthesis of [3]Rotaxane Assisted by
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Energy Trabfer and Concentration-Dependent Conformational
Modulation: A Porpyrin-Containing [3]Rotaxane. Chem. Asian J.
a
a Bistable Acid–Base Switchable
Triazolium Sites of Interaction in
a Three-Station [2]Rotaxane
Molecular Shuttle. Chem. Eur. J. 2017, 23, 11529-11539. (g) Ghosh,
A.; Paul, I.; Adlung, M.; Wickleder, C.; Schmittel, M. Oscillating
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20, 1046-1049. (h) Zhu, K.; Baggi, G.; Loeb, S. J. Ring-Through-Ring
Molecular Shuttling in a Saturated [3]Rotaxane. Nat. Chem. 2018,
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