Single-Step Enantioselective Synthesis of Mechanically Planar Chiral [2]Rotaxanes Using a Chiral Leaving Group Strategy

Article abstract of DOI:10.1021/jacs.0c03447

We report a one-step enantioselective synthesis of mechanically planar chiral [2]rotaxanes. Previous studies of such molecules have generally involved the separation of enantiomers from racemic mixtures or the preparation and separation of diastereomeric intermediates followed by post-assembly modification to remove other sources of chirality. Here, we demonstrate a simple asymmetric metal-free active template rotaxane synthesis using a primary amine, an activated ester with a chiral leaving group, and an achiral crown ether lacking rotational symmetry. Mechanically planar chiral rotaxanes are obtained directly in up to 50% enantiomeric excess. The rotaxanes were characterized by NMR spectroscopy, high-resolution mass spectrometry, chiral HPLC, single crystal X-ray diffraction, and circular dichroism. Either rotaxane enantiomer could be prepared selectively by incorporating pseudoenantiomeric cinchona alkaloids into the chiral leaving group.

Full text of DOI:10.1021/jacs.0c03447

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Article
Single-Step Enantioselective Synthesis of Mechanically Planar
Chiral [2]Rotaxanes Using a Chiral Leaving Group Strategy
Chong Tian, Stephen Fielden, Borja Pérez-Saavedra, Inigo J. Vitorica-Yrezabal, and David A. Leigh
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 01 May 2020
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Single-Step Enantioselective Synthesis of Mechanically Planar Chiral
[2]Rotaxanes Using a Chiral Leaving Group Strategy
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Chong Tian,†§ Stephen D. P. Fielden,†§ Borja Pérez-Saavedra,† Iñigo J. Vitorica-Yrezabal,† David A.
Leigh*†‡
†Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
‡School of Chemistry and Molecular Engineering, East China Normal University, 200062 Shanghai, China
Supporting Information Placeholder
ABSTRACT: We report a one-step enantioselective synthesis of
mechanically planar chiral [2]rotaxanes. Previous studies of such
molecules have generally involved the separation of enantiomers
from racemic mixtures or the preparation and separation of
diastereomeric intermediates followed by post-assembly
modification to remove other sources of chirality. Here we
demonstrate a simple asymmetric metal-free active template
rotaxane synthesis using a primary amine, an activated ester with a
chiral leaving group and an achiral crown ether lacking rotational
symmetry. Mechanically planar chiral rotaxanes are obtained
directly in up to 50% enantiomeric excess. The rotaxanes were
characterized by NMR spectroscopy, high-resolution mass
spectrometry, chiral HPLC, single crystal X-ray diffraction and
circular dichroism. Either rotaxane enantiomer could be prepared
selectively by incorporating pseudo-enantiomeric cinchona
alkaloids into the chiral leaving group.
INTRODUCTION
Mechanical planar chirality arises in rotaxanes with achiral
components when an unsymmetrical axle is threaded through a
macrocycle lacking rotational symmetry (Figure 1).1-4 Although
lacking classical elements of chirality, studies on mechanically
planar chiral rotaxanes suggest their asymmetry can be well
Figure 1. Enantioselective synthesis of mechanically planar chiral
rotaxanes through metal-free active template N-acylation using a
macrocycle lacking rotational symmetry and an electrophile with a
point-chiral leaving group.
expressed for applications.5-7 However, despite mechanically
planar chiral rotaxanes being known for nearly 50 years, their
enantioselective synthesis remains challenging.1d,8 Most studies on
these systems rely on the separation of enantiomers from racemic
mixtures by chiral stationary phase HPLC, limiting the scale of
Metal-free active template reactions have recently been developed
in which rotaxanes13 are spontaneously assembled under kinetic
control in a single step by combining a primary amine, electrophile
and crown ether14 in apolar solvents. Crown ethers stabilize the
transition states of various nucleophilic substitution reactions
through the cavity by C-H hydrogen bonding, thereby favoring the
formation of rotaxanes over the unthreaded axle. Different
reactions, amines and leaving groups result in different degrees of
accelerated reaction through the ring, affording different
rotaxane:thread selectivities. We chose crown ether-stabilized N-
acylation for the present study (Scheme 1), as this active template
enantioenriched material that can readily be obtained.9
Goldup et al. have addressed this synthetic problem through a
chiral auxiliary approach that forms intermediate diastereomeric
rotaxanes having both point-chirality and mechanically planar
chirality.10,11 Separation of these diastereomeric intermediates by
flash chromatography, followed by removal of the point-chirality
by either substitution10 or symmetrization,11 afforded
enantioenriched mechanically planar chiral rotaxanes. The only
single-step synthesis of enantioenriched mechanically planar chiral
rotaxanes to date used
a chiral catalyst to resolve the
reaction often results in
a
particularly high ratio of
interconverting enantiomers of a crown ether-ammonium pseudo-
rotaxane by capping.12 Despite attempts to optimize this method it
produced rotaxanes in just 4% enantiomeric excess (e.e.). Here we
rotaxane:thread.14 This suggested the reaction might be tolerant of
the additional functionality necessary in the macrocycle (to break
rotational symmetry) and axle building blocks (to provide a chiral
leaving group).
report
a simple, single-step, enantioselective synthesis of
mechanically planar chiral rotaxanes that produces either
enantiomer in up to 50% e.e..
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Scheme 1: (a) Achiral rotaxane synthesis by active template N-acylation using rotationally symmetrical crown ethers. (b)
Racemic and unoptimized enantioselective synthesis of a mechanically planar chiral rotaxane.
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An example of an active template N-acylation is the reaction of
24-crown-8 1, primary amine 2 and electrophile 3 in toluene at
room temperature, producing amide [2]rotaxane 4 in 84% yield
(Scheme 1a).14b The rate determining step of crown ether catalyzed
N-acylation reactions is the collapse of the tetrahedral intermediate
formed on addition of an amine to the activated ester.15 The nitro-
phenol ester used in the reaction of 1, 2 and 3 thus provides an
opportunity for a chiral directing group to be incorporated into the
leaving group that could interact with a rotationally unsymmetrical
macrocycle in the transition state (Figure 1).16
flash chromatography) obtained from electrophile 9 revealed that
the (+) enantiomer (determined by polarimetry) had been formed
in 12% e.e., confirming that a point-chiral leaving group was able
to induce enantioselectivity in a mechanically planar rotaxane.
Increasing the electronic difference between the two aromatic
substituents within the macrocycle improved the enantioselectivity
of the active template reaction. Macrocycle 10, with a nitro group
on the catechol unit (see Supporting Information for its synthesis),
afforded rotaxane (+)-11 in 23% e.e. at room temperature, which
increased to 40% e.e. (55% yield) when the rotaxane-forming
reaction was performed at −40 °C (Figure 2a). Lowering the
reaction temperature beyond −40 °C did not result in further
improvements in enantioselectivity.17
RESULTS AND DISCUSSION
Development of an enantioselective synthesis
To establish that functionalized crown ethers could take part in
the active template reaction, amine 2 and activated ester 3 were
treated with commercially available dibenzo-24-crown-8 5 in
toluene, yielding the corresponding [2]rotaxane 6 in 73% yield
(Scheme 1a). However, although the rotaxane axle is
unsymmetrical, dibenzo-24-crown-8 (5) is D2h symmetric and so
rotaxane 6 is achiral.1 Macrocycle 7, containing two different
aromatic rings, lacks rotational symmetry (it has C1h symmetry,
alternatively referred to as Cs). Reaction of 7 with 2 and 3 furnished
racemic mechanically planar chiral rotaxane 8 in 78% yield
(Scheme 1b). The enantiomers of 8 could be separated by chiral
stationary phase HPLC (see Supporting Information).
The opposite enantiomer of the rotaxane, (−)-11, could be
selectively accessed using electrophile 12, derived from (+)-
cinchonine, a pseudo-enantiomer of cinchonidine (see Supporting
Information for synthesis).18 Combining 2, 10 and 12 at −40 °C
gave rotaxane (−)-11 in 50% e.e. and 51% yield. (Figure 2a). The
difference in enantioenrichment is a consequence of electrophiles
9 and 12 being diastereomers rather than true enantiomers.
Characterization of rotaxanes
Comparison of the 1H NMR spectra of macrocycle 10, rotaxane
11, and the unthreaded axle (see Supporting information for
synthesis) in CDCl3 at 298 K (Figure 2b) confirmed the interlocked
structure of 11. The geminal protons of the crown ether display
twice the number of environments in rotaxane 11 as in unthreaded
10 due to desymmetrization of the two macrocycle faces upon
rotaxane formation, while H3 and H5 of the axle (hydrogen labeling
shown in Figure 2a), which are situated either side of the amide
group, display strong diastereotopic splitting (  0.39 and 0.22
ppm respectively) within the chiral environment of rotaxane 11, but
not in the corresponding achiral non-interlocked axle. Upfield
shifts of H6 and H7 (  −0.32 and −0.34 ppm) in the threaded axle
and HA, HB and HC (  −0.49, −0.21 and −0.37 ppm) of the
nitrocatechol unit of the threaded macrocycle result from π-π
interactions involving these moieties. These intercomponent
interactions may play a role in rigidifying the transition state of the
Next, we investigated the structure and location for an effective
chiral leaving group in the electrophile. Preliminary screening
studies identified nitrophenol ester 9, in which the chiral
information stems from an O-alkylated cinchonidine unit adjacent
to the nitro-group (Scheme 1b). This electrophile was reactive
under the rotaxane-forming conditions despite the introduction of
the deactivating electron-donating ether linkage. Combining 2, 7
and 9 in a 1:1:1 stoichiometry in toluene at room temperature
afforded rotaxane 8 in 43% yield (Scheme 1b). Under similar
conditions, electrophiles based on alkyl (thio)esters or with the
cinchonidine unit positioned at the ortho position of the nitrophenol
ring were either unreactive or generated less rotaxane (see
Supporting Information). HPLC analysis of rotaxane 8 (isolated by
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collapsing tetrahedral intermediate. The large downfield shift of the
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amide N-H proton H4 ( = +1.74 ppm) in 11 is indicative of
intercomponent hydrogen bonding between the amide and the
glycol chain of the macrocycle. An upshield shift of HD ( = −1.29
ppm) results from hydrogen bonding with the amide oxygen
atom.14b
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Figure 2. (a) Enantioselective synthesis of mechanically planar chiral rotaxane 11. Reaction conditions: 2 equiv. of amine 2, 1 equiv. each
of electrophile and crown ether 10; toluene, [0.14M], −40 °C, 24 h. (b) Partial 1H NMR spectra (600 MHz, CDCl3, 295 K) of macrocycle 10
(top), rotaxane 11 (middle) and the corresponding unthreaded axle (bottom).
shows similar intercomponent interactions to those observed by 1H
NMR for 11 in solution (Figure 2b). Hydrogen bonds are present
between an oxygen of the macrocycle glycol chain and the amide
Enantioenriched samples of rotaxane 11 (40% e.e. for the (+)
enantiomer and 50% e.e. for the (−) enantiomer) were compared by
circular dichroism (Figure 3a). The CD spectra of the mechanically
planar chiral rotaxane enantiomers are symmetrical in terms of
curve shape and have exciton couplings of opposite sign with
maxima at 243 nm. The difference in intensity (normalized for
absorption) of the spectra in Figure 3a corresponds to the difference
in enantioenrichment of the samples.
hydrogen atom of the axle and between the amide oxygen and a
macrocycle C-H hydrogen atom (analogous to HD in 11).14 The
di(alkoxyl)naphthalene
ring
of
the
macrocycle
and
bis(trifluoromethyl)benzene unit of the axle -stack (Figure 3d,
closest centroid-centroid distance = 3.67 Å),19 with the nitro-
catechol moiety positioned so as to cover one face of the amide
group. A similar arrangement in the transition state of the active
template reaction would orient the macrocycle with respect to the
axle building blocks such that one mechanically planar chiral
enantiomer would be favored over the other.
Although we were unable to obtain high quality single crystals
of 11, single crystals of a racemic sample of 13 suitable for analysis
by X-ray diffraction were grown by slow evaporation of an
isopropanol/hexane solution of 13 (Figure 3b). Rotaxane 13
contains the same macrocycle as 11 and an axle derived from amine
2 and a different acyl stopper. The X-ray crystal structure of 13
(Figure 3c), containing both rotaxane enantiomers in the unit cell,
Origin of enantioselectivity
A preliminary indication of the origin of chiral transduction in
these systems comes from the relative energies of the tetrahedral
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intermediates preceding (+)- and (−)-11, calculated at PM6 level20
lengths: N47—HO16, 2.20 Å; O49—HC6, 2.63 Å. Hydrogen bond
angles: N47—H—O16, 158.4°; O49—H—C6, 161.8°. (d) X-Ray
crystal structure of 13 viewed along the axle showing -stacking
between the macrocycle 1,2-dihydroxynaphthalene and axle
bis(trifluoromethyl)phenyl rings. Centroid-centroid distance, 3.67
Å. Angle described by C40 and centroids, 97.6°. Solvate molecules
and other hydrogen atoms omitted for clarity.
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using the Gaussian 09 software package21 (Supporting Information
and Figure 4). The collapse of similar tetrahedral intermediates has
previously been shown15a to be the rate determining step for the
glyme catalysis of ester aminolysis. Following the Hammond
postulate, the differences between the diastereomeric tetrahedral
intermediates to (+)- and (−)-11 from 9 and 12 may resemble those
between the transition states. The lowest energy intermediate
calculated for both pseudo-enantiomeric leaving groups featured an
(S) stereocenter adjacent to the ammonium unit, but with the
macrocycle orientation inverted for the two pseudo-enantiomers
(Figure 4), meaning changing between the leaving groups of 9 and
12 favors the formation of a different enantiomer of 11, as observed
experimentally. The somewhat surprising indication that the two
chiral leaving groups both favor an (S)-tetrahedral intermediate
may reflect why the pseudo-enantiomers do not generate equal and
opposite e.e’s in the active template reaction. The non-covalent
interactions in the intermediate (e.g. the stacking of the electron-
rich naphthalene unit with the electron-poor aryl group of the
nucleophile, and the hydrogen bonding to the glycol oxygens to the
H-N atoms) are reminiscent of those present in the X-ray crystal
structure of rotaxane 13.
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Also consistent with the stacking of the electron-rich
naphthalene unit with the electron-poor aryl group of the
nucleophile providing the driving force for organization of the
transition state is the experimental evidence that decreasing the
electron-density of the other aromatic ring of the macrocycle
increases the enantio-selectivity of rotaxane formation (i.e. 12%
e.e. for (+)-8; 40% e.e. for (+)-11). The less electron-rich the
catechol ring is, the less it competes with the naphthalene group for
-stacking with the bis(trifluoromethyl)benzylamine and so the
greater the enantiodiscrimination in the transition state.
Figure 4. Tentative rationale for the transfer of chirality from
Euclidean point-chirality (of the leaving group) to mechanical
planar chirality (of the rotaxane). The lowest energy tetrahedral
intermediates were modelled (see Supporting Information) using
(a) electrophile 9 or (b) electrophile 12. The di(alkoxyl)naphthalene
ring of the macrocycle and bis(trifluoromethyl)benzene unit
originating from the nucleophile -stack, causing the nitro-catechol
ring to be positioned so as to cover one face of the tetrahedral center
of the intermediate. This thermodynamically favored arrangement
of components ensures the different handedness of the pseudo-
enantiomeric leaving groups is well-expressed in the
diastereomeric transition states, resulting in enantioselectivity in
the mechanically planar chiral rotaxane product. Hydrogen bonds
are indicated by black dotted lines.
CONCLUSIONS
The examples presented demonstrate that mechanically planar
chiral rotaxanes can be directly accessed in up to 50% e.e. in a
single synthetic step. The chirality of the point-chiral leaving group
is transferred into mechanically planar chirality in the rotaxane
through metal-free active template N-aminolysis. Pseudo-
enantiomeric cinchona alkaloids allow either rotaxane enantiomer
to be accessed. X-Ray crystallography and molecular modelling
suggest that the origin of the enantioselectivity lies in -stacking of
an electron-rich aromatic ring on the macrocycle with an electron-
poor aryl group originating from the nucleophilic axle building
block. This positions the second aromatic ring of the macrocycle in
an orientation that blocks one face of the electrophile. Simple
methods for accessing enantioenriched mechanically planar chiral
rotaxanes should improve their availability for investigation in
applications such as asymmetric catalysis,7 chiral (bio)molecule
sensing1,6,22 and novel designs23 of molecular machinery.
ASSOCIATED CONTENT
Figure 3. (a) Circular dichroism spectra (1.0 × 10−4 M, CH2Cl2,
298 K) of (+)-11 (red) and (−)-11 (blue), baseline corrected. (b)
Chemical structure of racemic rotaxane 13. (c) X-Ray crystal
structure of racemic rotaxane 13, side-on view showing
intercomponent hydrogen bonds (in green). Hydrogen bond
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: XXXXX. Experimental procedures,
synthesis and characterization data, including circular dichroism,
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Yeung, H. Y. Radial hetero[5]catenanes: peripheral isomer sequences of the
chiral HPLC, NMR, MS, and X-ray crystallography data (PDF).
interlocked macrocycles. Angew. Chem. Int. Ed. 2019, 58, 17375–17382.
(5) Ishiwari, F.; Nakazono, K.; Koyama, Y.; Takata, T. Induction of
single handed helicity of polyacetylenes using mechanically chiral
rotaxanes as chiral sources. Angew. Chem. Int. Ed. 2017, 56, 14858−14862.
(6) Kameta, N.; Nagawa, Y.; Karikomib, M.; Hiratani, K. Chiral sensing
for amino acid derivative based on a [2]rotaxane composed of an
asymmetric rotor and an asymmetric axle. Chem. Commun. 2006,
3714−3716.
1
2
3
4
5
6
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Crystallographic data for 13 (CIF).
AUTHOR INFORMATION
Corresponding Author
*david.leigh@manchester.ac.uk
(7) Heard, A.; Goldup, S. M. Synthesis of a mechanically planar chiral
rotaxane ligand for enantioselective catalysis. Chem 2020, 6, 994−1006.
(8) Glen, P. E.; O'Neill, J. A. T.; Lee, A.-L. Synthesis of a C1-symmetric
Box macrocycle and studies towards active-template synthesis of
mechanically planar chiral rotaxanes. Tetrahedron 2013, 69, 57−68.
(9) (a) Yamamoto, C.; Okamoto, Y.; Schmidt, T.; Jӓger, R.; Vögtle, F.
Enantiomeric resolution of cycloenantiomeric rotaxane, topologically
chiral catenane, and pretzel-shaped molecules:ꢀ Observation of pronounced
circular dichroism. J. Am. Chem. Soc. 1997, 119, 10547−10548. (b)
Schalley, C. A.; Beizai, K.; Vögtle, F. On the way to rotaxane-based
molecular motors: Studies in molecular mobility and topological chirality.
Acc. Chem. Res. 2001, 34, 465−476. (c) Kameta, N.; Hiratani, K.; Nagawab,
Y. A novel synthesis of chiral rotaxanes via covalent bond formation.
Chem. Commun. 2004, 466−467. (d) Hirose, K.; Ukimi, M.; Ueda, S.;
Onoda, C.; Kano, R.; Tsuda, K.; Hinohara, Y.; Tobe, Y. The asymmetry is
derived from mechanical interlocking of achiral axle and achiral ring
components –Syntheses and properties of optically pure [2]rotaxanes.
Symmetry 2018, 10, 20. (e) Gell, C. E.; McArdle-Ismaguilov, T. A.; Evans,
N. H. Modulating the expression of chirality in a mechanically chiral
rotaxane. Chem. Commun. 2019, 55, 1576−1579. (f) Gaedke, M.; Witte, F.;
Anhäuser, J.; Hupatz, H.; Schröder, H. V.; Valkonen, A.; Rissanen, K.;
Lützen, A.; Paulus, B.; Schalley, C. A. Chiroptical inversion of a planar
chiral redox-switchable rotaxane. Chem. Sci. 2019, 10, 10003−10009.
(10) Bordolli, R.; Goldup, S. M. An efficient approach to mechanically
planar chiral rotaxanes. J. Am. Chem. Soc. 2014, 136, 4817−4820.
(11) Jinks, M. A.; de Juan, A.; Denis, M.; Fletcher, C. J.; Galli, M.;
Jamieson, E. M. G.; Modicom, F.; Zhang, Z.; Goldup, S. M. Stereoselective
synthesis of mechanically planar chiral rotaxanes. Angew. Chem. Int. Ed.
2018, 57, 14806−14810.
(12) Makita, Y.; Kihara, N.; Nakakoji, N.; Takata, T.; Inagaki, S.;
Yamamoto, C.; Okamoto, Y. Catalytic asymmetric synthesis and optical
resolution of planar chiral rotaxane. Chem. Lett. 2007, 36, 162−163.
(13) De Bo, G.; Dolphijn, G.; McTernan, C. T.; Leigh, D. A. [2]Rotaxane
formation by transition state stabilization. J. Am. Chem. Soc. 2017, 139,
8455−8457.
(14) (a) Fielden, S. D. P.; Leigh, D. A.; McTernan, C. T.; Pérez-
Saavedra, B.; Vitorica-Yrezabal, I. J. Spontaneous assembly of rotaxanes
from a primary amine, crown ether and electrophile. J. Am. Chem. Soc.
2018, 140, 6049−6052. (b) Tian, C.; Fielden, S. D. P.; Whitehead, G. F. S.;
Vitorica-Yrezabal, I. J.; Leigh, D. A. Weak functional group interactions
revealed through metal-free active template rotaxane synthesis. Nat.
Commun. 2020, 11, 744.
(15) (a) Hogan, J. C.; Gandour, R. D. Structural requirements for glyme
catalysis in butylaminolysis of aryl acetates in chlorobenzene. Identification
of -OCH2CH2OCH2CH2OCH2CH2O- as the optimal subunit for catalysis.
J. Org. Chem. 1991, 56, 2821–2826. (b) Basilio, N.; García-Río, L.; Mejuto,
J. C.; Pérez-Lorenzo, M. A. New reaction pathway in the ester aminolysis
catalyzed by glymes and crown ethers. J. Org. Chem. 2006, 71, 4280−4285.
(16) Chiral leaving groups have previously been employed in
asymmetric substitution reactions. See: Lepore, S. D.; Mondal, D. Recent
advances in heterolytic nucleofugal leaving groups. Tetrahedron 2007, 63,
5103–5122.
(17) Heller, D.; Buschmann, H.; Scharf, H.-D. Nonlinear temperature
behavior of product ratios in selection processes. Angew. Chem. Int. Ed.
Engl. 1996, 35, 1852–1854.
(18) Cinchona alkaloids in synthesis and catalysis: Ligands,
immobilization and organocatalysis; Eui Song, C., Ed.; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, 2009.
(19) (a) Hunter, C. A.; Sanders, J. K. M. The nature of π–π interactions.
J. Am. Chem. Soc. 1990, 112, 5525–5534. (b) Riwar, L.-J.; Trapp, N.; Kuhn,
B.; Diederich, F. Substituent effects in parallel displaced π–π stacking
interactions: distance matters. Angew. Chem. Int. Ed. 2017, 56, 11252–
11257.
(20) Stewart, J. J. P. Optimization of parameters for semiempirical
methods. V. Modification of NDDO approximations and application to 70
elements. J. Mol. Model. 2007, 13, 1173–1213.
Author Contributions
§These authors contributed equally.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the Engineering and Physical Sciences Research Council
(EPSRC) (EP/P027067/1), the European Research Council (ERC)
(Advanced Grant No. 786630), the China 1000 Talents Plan and
East China Normal University for funding, the University of
Manchester for a studentship (to S.D.P.F.), the Diamond Light
Source (U.K.) for synchrotron beamtime on I19, the University of
Manchester mass spectrometry service for high-resolution mass
spectrometry, the Computational Shared Facility 3 (CSF3) at the
University of Manchester for computational resources, and Jing Liu
for preliminary studies. D.A.L. is a Royal Society Research
Professor.
REFERENCES
(1) (a) Bruns, C. J.; Stoddart, J. F. The Nature of the Mechanical Bond:
From Molecules to Machines; John Wiley & Sons: Hoboken, NJ, 2017. (b)
Jamieson, E. M. G.; Modicom, F.; Goldup S. M. Chirality in rotaxanes and
catenanes. Chem. Soc. Rev. 2018, 47, 5266−5311. (c) Evans, N. H. Chiral
catenanes and rotaxanes: Fundamentals and emerging applications. Chem.
Eur. J. 2018, 24, 3101–3112. (d) Nakazono, K.; Takata, T. Mechanical
chirality of rotaxanes: Synthesis and function. Symmetry 2020, 12, 144.
(2) If a prochiral or meso thread is incorporated into a rotaxane then
chirality can arise from the position of the ring on the axle. See: (a) Alvarez-
Pérez, M.; Goldup, S. M.; Leigh, D. A.; Slawin, A. M. Z. A chemically-
driven molecular information ratchet. J. Am. Chem. Soc. 2008, 130, 1836–
1838. (b) Cakmak, Y.; Erbas-Cakmak, S.; Leigh, D. A. Asymmetric
catalysis with a mechanically point-chiral rotaxane. J. Am. Chem. Soc.
2016, 138, 1749–1751. (c) Dommaschk, M.; Echavarren, J.; Leigh, D. A.;
Marcos, V.; Singleton, T. A. Dynamic control of chiral space through local
symmetry breaking in a rotaxane organocatalyst. Angew. Chem. Int. Ed.
2019, 58, 14955–14958.
(3) Mechanical planar chirality can also result from confinement of an
unsymmetrical macrocycle to one side of a non-prochiral axle possessing
Dnh symmetry. See: (a) Mochizuki, Y.; Ikeyatsu, K.; Mutoh, Y.; Hosoya, S.;
Saito, S. Synthesis of mechanically planar chiral rac-[2]rotaxanes by
partitioning of an achiral [2]rotaxane: Stereoinversion induced by shuttling.
Org. Lett. 2017, 19, 4347−4350. (b) Corra, S.; de Vet, C.; Groppi, J.; La
Rosa, M.; Silvi, S.; Baroncini, M.; Credi, A. Chemical on/off switching of
mechanically planar chirality and chiral anion recognition in a [2]rotaxane
molecular shuttle. J. Am. Chem. Soc. 2019, 141, 9129−9133.
(4) For examples of other stereochemical consequences of threading,
see: (a) Fuller, A.-M. L.; Leigh, D. A.; Lusby, P. J. Sequence isomerism in
[3]rotaxanes. J. Am. Chem. Soc. 2010, 132, 4954−4959. (b) Talotta, C.;
Gaeta, C.; Qi, Z.; Schalley, C. A.; Neri, P. Pseudorotaxanes with self-sorted
sequence and stereochemical orientation. Angew. Chem. Int. Ed. 2013, 52,
7437−7441. (c) La Manna, P.; Talotta, C.; Gaeta, C.; Soriente, A.; De Rosa,
M.; Neri, P. Threading of an inherently directional calixarene wheel with
oriented ammonium axles. J. Org. Chem. 2017, 82, 8973−8983. (d) Cui, J.-
S.; Ba, Q.-K.; Ke, H.; Valkonen, A.; Rissanen, K.; Jiang, W. Directional
shuttling of a stimuli-responsive cone-like macrocycle on a single-state
symmetric dumbbell axle. Angew. Chem. Int. Ed. 2018, 57, 7809–7814. (e)
Zheng, L.-S.; Cui, J.-S.; Jiang, W. Biomimetic synchronized motion of two
interacting macrocycles in [3]rotaxane-based molecular shuttles. Angew.
Chem. Int. Ed. 2019, 58, 15136–15141. (f) Ng, A. W. H.; Yee, C.-C.; Au-
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(21) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
(b) Bąk, K. M.; Porfyrakis, K.; Davis, J. J.; Beer, P. D. Exploiting the
mechanical bond for molecular recognition and sensing of charged species.
Mater. Chem. Front. 2020, 4, 1052–1073.
M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara,
M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda,
Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.;
Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.;
Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell,
A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J.
M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo,
J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski,
V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels,
A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.
Gaussian 09, Revision D.01, Gaussian, Inc., Wallingford CT, 2013.
(22) (a) Lim, J. Y. C.; Marques, I.; Félix, V.; Beer, P. D. A chiral
halogen-bonding [3]rotaxane for the recognition and sensing of biologically
relevant dicarboxylate anions. Angew. Chem. Int. Ed. 2018, 57, 584–588.
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5
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(23) (a) Fu, X.; Zhang, Q.; Rao, S.-J.; Qu, D.-H.; Tian, H. One-pot
synthesis of a [c2]daisy-chain-containing hetero[4]rotaxane via a self-
sorting strategy. Chem. Sci. 2016, 7, 1696–1701. (b) Rao, S.-J.; Zhang, Q.;
Mei, J.; Ye, X.-H.; Gao, C.; Wang, Q.-C.; Qu, D.-H.; Tian, H. One-pot
synthesis of hetero[6]rotaxane bearing three different kinds of macrocycle
through a self-sorting process. Chem. Sci. 2017, 8, 6777-6783. (c) Chen, S.;
Wang, Y.; Nie, T.; Bao, C.; Wang, C.; Xu, T.; Lin, Q.; Qu, D.-H.; Gong,
X.; Yang, Y.; Zhu, L.; Tian, H. An artificial molecular shuttle operates in
lipid bilayers for ion transport. J. Am. Chem. Soc. 2018, 140, 17992–17998.
(d) Zheng, X.; Zhang, Y.; Cao, N.; Li, X.; Zhang, S.; Du, R.; Wang, H.; Ye,
Z.; Wang, Y.; Cao, F.; Li, H.; Hong, X.; Sue, A. C.-H.; Yang, C.; Liu, W.-
G.; Li, H. Coulombic-enhanced hetero radical pairing interactions. Nat.
Commun. 2018, 9, 1961.
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