Regulation of Macrocycle Shuttling Rates in [2]Rotaxanes by Amino-Acid Speed Bumps in Organic–Aqueous Solvent Mixtures

Article abstract of DOI:10.1002/ejoc.202000997

A homologous series of two-station [2]rotaxanes incorporating amino-acid units in the molecular thread has been developed. The degenerate [2]rotaxanes exhibit amino-acid specific shuttling rates between two fumaric stations related to the steric factor associated to the amino-acid side chain, as demonstrated by variable-temperature ¹H NMR spectroscopy and exchange spectroscopy (EXSY). This allows tuning of the macrocycle shuttling rate over 4 orders of magnitude, which has a relatively small solvent dependency.

Full text of DOI:10.1002/ejoc.202000997

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Regulation of Macrocycle Shuttling Rates in [2]Rotaxanes by
Amino-Acid Speed Bumps in Organic–Aqueous Solvent Mixtures
Authors: Maxime Douarre, Vicente Martí-Centelles, Cybille Rossy,
Isabelle Pianet, and Nathan McClenaghan
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000997
Link to VoR: https://doi.org/10.1002/ejoc.202000997
01/2020

10.1002/ejoc.202000997
European Journal of Organic Chemistry
FULL PAPER
Regulation of Macrocycle Shuttling Rates in [2]Rotaxanes by
Amino-Acid Speed Bumps in Organic–Aqueous Solvent Mixtures
Maxime Douarre,[a] Vicente Martí-Centelles,*[a] Cybille Rossy,[a] Isabelle Pianet,[b] and Nathan D.
McClenaghan*[a]
[a]
M. Douarre, Dr. V. Martí-Centelles, Dr. C. Rossy, Dr. N. D. McClenaghan
Institut des Sciences Moléculaires,
CNRS UMR 5255, University of Bordeaux,
33405 Talence, France.
E-mail: nathan.mcclenaghan@u-bordeaux.fr; Homepage: mcclenaghan.ism.u-bordeaux.fr
E-mail: vicente.marti-centelles@u-bordeaux.fr; Homepage: www.vmarti.es
Dr. I. Pianet
[b]
IRAMAT, CNRS UMR 5060, Maison de l’Archéologie, Université Bordeaux Montaigne,
33607 Pessac, France.
Supporting information for this article is given via a link at the end of the document.
Abstract:
A
homologous series of two-station [2]rotaxanes
A family of interest are Leigh’s rotaxanes, assembled in
one synthetic step and facilitated by hydrogen bond pre-
organisation evoking a tetraamide macrocycle and fumaramide
or succinamide station on the thread.[20–23] In these systems,
polar solvents have a significant effect on the shuttling rate,
especially water,[17,24] producing an increase of the shuttling rate
as a consequence of disrupting hydrogen bonding between the
macrocycle and the station, on providing competitive H-bonding
interactions with the solvent. Despite the easy synthetic
accessibility, the control of shuttling rate of the macrocycle has
not been well-established and is highly dependent on the
polarity solvent. Achieving this control in aqueous solvent
mixtures, and ideally in water, is needed for developing
operational rotaxanes for potential biological applications. Yet,
few examples of rotaxane shuttles in water have been reported
with limited ring shuttling kinetic information.[25–28] While water is
shown to accelerate ring movement in hydrogen-bonding
rotaxanes, full control implies the ability to slow ring movement
and even render it solvent independent to a large degree. For
this purpose, introducing a custom steric barrier on the thread
that the macrocyclic can only pass over slowly, can produce the
desired shuttling rate reduction.
incorporating amino-acid units in the molecular thread has been
developed. The degenerate [2]rotaxanes exhibit amino-acid specific
shuttling rates between two fumaric stations related to the steric
factor associated to the amino-acid side chain, as demonstrated by
variable-temperature 1H NMR spectroscopy and exchange
spectroscopy (EXSY). This allows tuning of the macrocycle shuttling
rate over 4 orders of magnitude, which further has a relatively small
solvent dependency.
Introduction
Rotaxanes are the most commonly used systems for
constructing artificial molecular machines.[1] Indeed a variety of
effective methods for the synthesis of rotaxanes has been
established through numerous synthetic strategies.[2–5] Among a
wide diversity of reported interlocked structures, molecular
shuttles comprising a mobile macrocycle threaded on a two-
station axle, is one of the most emblematic types of architecture,
which serves as an excellent platform for bottom-up studies of
dynamic properties.[6–8] With sub-molecular movement being
integral to potential function in molecular machines, regulation of
dynamics, both spontaneous and stimulus-induced, is essential
and intimately linked with molecular design.[9–12] Developing
methods to control the shuttling rate could unlock pioneering
applications in the field of catalysis, as exemplified by rotating
catalysts where the rotation speed had a direct influence in their
performance.[13]
Despite the central importance of the ring shuttling rate in
rotaxanes, only a relatively small number of studies have
focused on detailed kinetic analyses providing key structure-
property information.[14–16] Relevant works include the discovery
of the key role of water lubricating hydrogen-bonded molecular
machines by Leigh,[17] Stoddart,[18] and Harada.[19] The
development of systems with steric barriers for unidirectional
movement by Stoddart,[6] and the null impact of the rotaxane
axle length on the ring shuttling reported by Hirose.[14] These
contributions are central to understanding the effect of the
different macrocycle-thread interactions on the shuttling rate and
incorporate such structural parameters in the design of
rotaxanes with specific shuttling dynamics.
The selection of the steric barrier size is critical, as just one
methyl difference may completely block the ring shuttling, as
highlighted by macrocycle dethreading experiments in rotaxanes
with stoppers of different sizes.[29] In this work we developed
designer rotaxane systems building on a benchmark system,
namely Leigh’s fumaramide rotaxane (Figure
1 top), by
incorporating steric barriers to control the macrocycle shuttling
rate in both non-polar organic solvents and organic aqueous
mixtures.[30,31] For this propose, we synthesized degenerate
molecular shuttles containing specific amino-acid units in the
thread which are able to act as speed bumps to control the
macrocycle shuttling speed (Figure 1, bottom) and sought to
generalize this approach for a range of amino-acid units. In
these systems, which have two identical stations, the
macrocycle would have an equal probability of residing on each
station and stochastic macrocycle shuttling would be operational.
These degenerate [2]rotaxanes systems provide an appropriate
platform to measure the shuttling process by dynamic NMR
spectroscopy using variable temperature 1H NMR and EXSY
NMR.
1
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10.1002/ejoc.202000997
European Journal of Organic Chemistry
FULL PAPER
molecular thread to act as speed bumps in our prototype
rotaxane model (Figure 1, bottom). In particular, amino-acid
speed bumps with R = Me, Et and iPr (using the amino acids Ala,
Abu and Val, respectively) have an ideal size to act as steric
speed bumps for the macrocycle employed. The wide variety of
commercially-available natural and non-natural amino acids
affords a selection of side chains with the appropriate size and
simplifies the synthesis of the corresponding axles. Among
different possible stations, the fumaramide station was selected
as it has the larger hydrogen bonding affinity towards the
macrocycle it favours the positioning of the macrocycle over the
station in polar solvents. Whereas the strongly hydrogen bond
disrupting solvent DMSO displaces the macrocycle from the low
affinity dipeptide stations,[32] the fumaramide station is still
occupied by the macrocycle for at least 85% of the time in
DMSO.[33] Stopper 6 (Figure 2) was designed to impart water
solubility of the rotaxanes in water upon hydrolysis of the tert-
butyl groups. Furthermore, the tert-butyl groups enhanced the
solubility of thread 2 and rotaxane 1 in organic solvents.
Figure 1. Representation of Leigh’s degenerate 2-station [2]rotaxane (from
Ref [21]) and the analogues developed in this project incorporating amino-acid
speed bumps and water solubilizing groups on the stopper.
The synthesis of these structures was carried out as
described in Figure 2. Amide bond formation on reacting 1,12-
diaminododecane with the activated Boc-Aaa-OH followed by
deprotection yielded compound 3 in 80–90% yield over two
Results and Discussion
steps. Stopper
6 was prepared according to a literature
procedure by condensation of tris(hydroxymethyl)aminomethane
(TRIS) with tert-butyl acrylate.[34] Amide bond formation with
monomethyl fumarate followed by deprotection in basic
conditions yielded 4 in 61% yield over two steps. Peptidic
coupling of 3 with 4 yielded thread 2 in 40–50% yields. The final
rotaxane formation reaction was performed by simultaneously
separate addition of chloroform solutions of p-xylylenediamine
The prototype 2-station molecular machine design developed by
Leigh and coworkers (Figure 1 top),[20] which comprises a
tetraamide macrocycle and two-fumaramide stations, has a
typical energy barrier of 16.2 kcal/mol to ring displacement
corresponding to a shuttling speed of 8 times per second in
CDCl3 at 25 ºC.[21] This barrier is greatly affected by polar
solvents such as water that weaken the hydrogen-bond strength
between the macrocycle and the station. This results in a
reduction of the energy barrier and consequently an
enhancement of the shuttling rate.[17,24] In the current design
(Figure 1 bottom), we integrated a multi-ester stopper that can
be hydrolyzed to obtain six negatively charged carboxylate
groups offering enhanced solubility in polar solvents, including
water. Additionally, amino-acid units were integrated into the
and of isophthaloyl dichloride to that of thread
2 and
triethylamine in chloroform during 2 h via a syringe pump. The
target rotaxanes 1 were successfully isolated in 10–16% yield
after column chromatography purification. Hydrolysis of rotaxane
1a in neat formic acid yielded rotaxane 1a-WS quantitatively.
The rotaxanes were characterized by 1H, 13C, 2D NMR and high
resolution mass spectrometry.
Figure 2. Synthesis of the [2]rotaxanes. Stopper 6 and valine amide 3a were prepared using literature procedures.[34–36]
2
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10.1002/ejoc.202000997
European Journal of Organic Chemistry
FULL PAPER
1
Initial analysis of the H NMR of rotaxane 1a in CDCl3 at room
Observation of cross peaks between the two fumaramide
protons confirmed the chemical exchange of signals S1 and S2,
which is consistent with spontaneous macrocycle shuttling
between the two similar stations (Figure 4).
temperature showed two sets of signals for the fumaramide
protons, which could be assigned to the free and occupied
stations. Whereas the free station fumaramide proton
resonances (S2) had the same chemical shift observed in the
thread, the presence of the macrocycle produced a Δδ > 1 ppm
upfield shift in the fumaramide signals S2 attributed to the
deshielding produced by the macrocycle phenyl rings (Figure 3).
The dynamic nature of ring movement within the rotaxane was
determined by EXSY 1H NMR. EXSY allows direct measurement
of dynamic process in equilibrated systems as cross peaks
between the two signals that undergo exchange during the
mixing time of the experiment.[37]
A
similar spectrum was obtained for rotaxane 1b,
comprising an ethyl appendage rather than an isopropyl group,
two sets of signals at room temperature for the fumaramide
protons being observed. In contrast, further downsizing to a
methyl appendage in rotaxane 1c resulted in a single set of
broad signals for the fumaramide protons, indicating a relatively
fast exchange between the signals of the two stations on the
NMR timescale (Figure 5). This observation qualitatively
confirms that the macrocycle undergoes a rapid shutting in this
case.
To evaluate the effect of the amino-acid speed bump on
the macrocycle shuttling, variable temperature (VT) 1H NMR
experiments in TCE-d2 were performed (600 MHz spectrometer).
Whereas no signal coalescence was observed for rotaxane 1a in
the 25–105 °C temperature range, we could observe
coalescence for rotaxanes 1b and 1c. This showed spontaneous
shuttling on the ms–µs timescale at higher temperature. The tBu
signals (Δδ ≈ 0.045 ppm) of the stopper has a coalescence
temperature > 105 °C for 1a, 75 °C for 1b and –10 °C for 1c,
showing a direct effect of the steric bulk on the shuttling rate, the
larger the substituent (iPr > Et > Me) the lower the rate. A similar
trend was observed for the fumaramide signals (Δδ ≈ 1 ppm). In
this case we only observed a coalescence of the fumaramide
signals for rotaxane 1c (Figure 5). Although no coalescence was
reached for the fumaramide signals in rotaxanes 1a and 1b,
signal broadening indicated the slow dynamics of the
macrocycle shuttling in these systems. Overall, the differences
observed in coalescence temperatures reflect a reduction of the
ring shuttling rate by the increase in amino-acid unit steric size
from 1c to 1a (Table 1).
Figure 3. 1H NMR in CDCl3 at rt, 300 MHz: (a) Rotaxane 1a, (b) thread 2a.
Fumaramide protons labelled as S1 for occupied station and S2 for free
station.
Table 1. Coalescence temperatures in TCE-d2, 600 MHz. Signal width at half-
height in brackets at the temperature displayed in the table for protons not
reaching coalescence. Fumaramide signals Δδ ≈ 1 ppm (600 Hz). tBu signals
Δδ ≈ 0.045 ppm (27 Hz).
Rotaxane
Fumaramide
Stopper tBu
> 105 °C
(7 Hz)
> 105 °C
(8 Hz)
1a
> 95 °C
(20 Hz)
1b
1c
75 °C
25 °C
–10 °C
Figure 4. EXSY 1H NMR of rotaxane 1a in TCE-d2 at 85 °C, 600 MHz, 250 ms
mixing time.
3
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10.1002/ejoc.202000997
European Journal of Organic Chemistry
FULL PAPER
In order to rationalize the significant changes in the shuttling
rates introduced by the amino-acid speed bumps, we evaluated
the precise steric hindrance introduced in each case. To this end,
we used the steric parameter S0 of the Me, Et and iPr groups to
determine if there is a direct relation between sterics vs energy
barrier.[30,40] The steric parameter S0, derived empirically from
the quaternization rate constant of methylation reactions of
ortho-substituted pyridines, has been proposed as a quantitative
scale in the evaluation the steric bulk of substituents in the
shuttling behavior of [2]rotaxanes.[30] A plot of ΔG‡ vs S0 shows a
linear relation showing the direct relation and preponderant
nature of the steric parameter on the process. This data
suggests that the speed bump does not significantly affect the
complementary hydrogen bonding interactions between the
tetraamide macrocycle and the fumaramide stations. Therefore,
the energy levels of S1 and S2 would remain unchanged and
the speed bumps only affects the energy of the transition state
that connects stations S1 and S2 as schematized in Figure 7b.
We further considered the CPK substituent volume as an
alternative parameter that can be used to evaluate the steric
bulk of amino-acid side chain.[41] The CPK volumes offer a good
linearity with the observed experimental shuttling energy barrier
(see Figure 7d and Supporting Information). We envisage that
CPK volumes could be a useful tool to select appropriate speed
bumps in rotaxane systems. As cited above, the parameter S0
provides a good description of the overall steric bulk in systems
for small groups such as Me, Et and iPr groups. However, S0
does not describe accurately the overall steric bulk of larger
groups, while the use of the relative CPK volume of the
amino-acid side chain with regard to the macrocycle cavity size
provides a better description of the speed bump steric size (see
Supporting information). Analysis of the macrocycle cavity
showed a diameter of 4.88 Å, corresponding to a spherical void
volume of 61 Å3. The overall size of the speed bump was
obtained as the CPK volume giving a value of 49 Å3, 67 Å3, and
85 Å3 for Ala, Abu, and Val, respectively (see Figure 7d and
Supporting Information). A plot of ΔG‡ vs CPK volume shows a
Figure 5. VT 1H-NMR of alanine-containing rotaxane 1c with the signals
displaying coalescence marked in blue (600 MHz in TCE-d2). Solvent
impurities are marked in grey.
From the VT 1H NMR experiments it is possible to obtain further
information on the dynamics of the process. Increasing the
temperature produces an increment of the exchange rate,
producing a broadening of the signals until coalescence is
achieved when the exchange rate approaches the frequency
difference between the two signals. Further heating produces a
fast exchange and a spectrum with individual signals at the
average frequency of the signals in this symmetrical molecule.
This phenomenon can be used to extract quantitative
information of the dynamic process by performing a dynamic
NMR lineshape fitting.[14,38,39] The results show that the
amino-acid speed bump has a direct influence in the shuttling
rate, spanning the measured kex over 4 orders of magnitude
(Figure 6 and Table 2). For the three rotaxanes 1a, 1b and 1c,
EXSY 1H NMR experiments showed cross peaks connecting the
different fumaramide and the tBu protons allowing determination
of the associated kex (see Figure 6 and supporting information
for further details).
linear relation (Figure 7d), therefore providing
a
good
representation of the overall steric bulk. This analysis also
provides a physical meaning by comparing the relative size of
the cavity of the macrocycle and the CPK volume of the speed
bump, which can be readily estimated in analogy to Rebek’s
55% optimal occupancy rule.[42] The Ala CPK volume is smaller
than the macrocycle cavity (speed bump factor = VAla/VCavity
=
0.80), and therefore the steric speed bump effect will be
relatively small or negligible. The Abu CPK volume is similar to
that of the macrocycle cavity (speed bump factor = VAbu/VCavity
=
1.10) showing a medium steric speed bump effect, and the Val
CPK volume is significantly larger than the macrocycle cavity
(speed bump factor = VVal/VCavity = 1.39) showing larger speed
bump effect (Figure 7d). Overall, the relative speed bump CPK
volume with regard to the macrocycle cavity, defined as speed
bump factor = VVal/VCavity, analysis described here represents the
observed experimental speed bump effect. We envisage that the
use of speed bump factors can be a useful tool in estimating
custom macrocycle shuttling rates in designer systems. (Note:
variants with significantly faster or slower ring shuttling rates
than the examples measured herein are incompatible with NMR
analysis).
Figure 6. Exchange rate constants determined for rotaxanes 1a, 1b and 1c in
TCE-d2 at different temperatures by lineshape analysis (squares, triangles and
circles) and EXSY (crosses) 1H NMR, 600 MHz.
4
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10.1002/ejoc.202000997
European Journal of Organic Chemistry
FULL PAPER
Table 2. Shuttling constants (kex) and the corresponding ΔG‡
values for the rotaxanes 1a, 1b, 1c and 1a-WS in different polar
solvent mixtures at 25 °C, 600 MHz
ΔG‡
Solvent
rotaxane
kex (s–1
)
(kcal/mol)
TCE-d2
1a[a]
0.07
4.6
19.1
16.5
13.4
>19.3
18.6
17.5
TCE-d2
1b[a]
TCE-d2
1c[a]
980
TCE-d2/MeOD 95:5
CDCl3/MeOD/D2O 45:45:10
MeOD/D2O 9:1
1a[b]
<0.05
0.14
0.97
1a[b]
1a-WS[b]
[a] Determined by lineshape fitting VT 1H NMR and extrapolated at 25 °C. [b]
Determined by EXSY 1H NMR.
Conclusion
A family of degenerate 2-station [2]rotaxanes incorporating
amino-acid units in conjunction with fumaramide stations is
reported. In these systems the appendages on the amino-acid
units act as speed bumps, which serve to slow down (up to 4
orders of magnitude) ring shuttling in accordance with a linear
dependence on the appendage steric factor or CPK volume. In
this regard a degree of predictability in shuttling rates is possible,
profiting from a range of commercially-available amino acids
with appendages presenting different steric factors. Equally
noteworthy, the effect of aqueous solvents on ring shuttling is
relatively small (<10) for the range of different solvent mixtures
assayed, compared to the predominant steric influence.
Figure 7. (a) Cartoon representation of the degenerate 2-station [2]rotaxanes
developed in this project. (b) Schematic representation of the amino-acid
speed bump effect on the ring-on-thread energy profile. (c) Experimental
[30,40]
shuttling energy barrier vs steric parameter S0 (see refs
for definition of
S0). (d) Experimental shuttling energy barrier vs amino-acid side chain CPK
volume. Atoms used to determine the amino-acid speed bump volume and
representation of the macrocycle cavity. Ala = alanine, Abu = 2-aminobutanoic
acid, Val = Valine. Experimental data in TCE-d2 at 25 ºC.
Further evidence of the small/negligible alanine steric speed
bump effect can be obtained by comparing the 13.4 kcal/mol
free energy of activation in rotaxane 1c with more weakly
binding stations - typically 11–12 kcal/mol,[12,20–22,32,43] and 16.2
kcal/mol for the high affinity fumaramide station (Figure 1).[21]
The activation energy found for rotaxane 1c is already limited by
bond breaking between macrocycle and initial station and chain
folding. Therefore, the size of the alanine speed bump is
effectively not significantly hindering the shuttling rate.
Experimental Section
Materials and methods
All chemicals and solvents were obtained from commercial sources and
used without further purification unless specified. Mass spectra and NMR
were performed in the CESAMO analytical facilities (Bordeaux, France).
NMR: 1H and 13C NMR spectra were recorded in a Bruker Avance 300 or
Bruker Avance III 600 spectrometer. Chemical shifts are reported in ppm
and referenced to the solvent residual peaks. Mass spectrometry: Field
desorption spectra (FD) were recorded on a AccuTOF (JEOL) mass
spectrometer using an FD emitter with an emitter voltage of 10 kV. The
sample (1–2 µL) was deposited on a 13 µm emitter wire. Electrospray
Having measured processes in a non-competitive solvent, we
further evaluated the effect of polar and protic solvents in the
macrocycle shuttling rate in rotaxane 1a. While addition of 5%
MeOD to TCE-d2 did not produce any measurable acceleration,
the more polar mixture CDCl3/MeOD/D2O 45:45:10 v/v produced
an increase of the shuttling rate from ca. 0.05 s–1 to 0.14 s–1.
Then we hydrolysed the rotaxane 1a to obtain the hexa-anionic
rotaxane 1a-WS. Unfortunately, attempts to dissolve 1a-WS in
pure D2O at the concentrations required for 1H NMR
spectroscopy were unsuccessful. Full solubilisation was
achieved in MeOD/D2O solutions when high proportions of
MeOD were employed, i.e. MeOD/D2O 9:1, v/v. The determined
shuttling rate in this solvent mixture was 0.97 s–1, highlighting
the lesser effect of polar solvents on the shuttling rate in these
systems, compared with steric influences (Table 2).
spectra (ESI) were recorded on
a
Qexactive (Thermo) mass
spectrometer. The instrument is equipped with an ESI source and
spectra were recorded in positive mode. The spray voltage was
maintained at 3200 V and capillary temperature set to 320 °C. Samples
were introduced by injection through a 20 µL loop into a 300 µL/min flow
of methanol from the LC pump.
Synthetic procedures
Rotaxanes were prepared using the synthetic scheme described in
Figure 2. The TRIS based stopper 6 was prepared using a literature
procedure.[34] Compounds 3a, 3b, and 3c were prepared using literature
procedures.[35,36] Signal labels used in the assignment and 1H and 13C
NMR spectra are provided in the Supporting Information.
5
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10.1002/ejoc.202000997
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FULL PAPER
Synthesis of rotaxane 1a: A solution of p-xylylenediamine (35 mg, 0.255
mmol, 4 eq.) in chloroform (10 mL) and a solution of isophthaloyl
dichloride (52 mg, 0.255 mmol, 4 eq.) in chloroform (10 mL) were
simultaneously added at room temperature with a syringe pump during
2h to a solution of thread 2a (100 mg, 0.0637 mmol, 1 eq.) and dry
triethylamine (71 µL, 0.510 mmol, 8 eq.) in chloroform (20 mL). The
reaction mixture was stirred at room temperature overnight under N2
atmosphere. The reaction mixture was filtered through a Celite® pad.
The filtrate was washed successively with a sodium bicarbonate solution
(10%), water and brine. The organic layer was dried over magnesium
sulfate, filtered and concentrated in vacuo. Purification by silica gel
column chromatography (cyclohexane/i-PrOH, 90:10 to 84:16, v/v)
afforded 1a as a colourless solid (13 mg, 10% yield). 1H NMR (600 MHz,
TCE-d2) δ 8.55 (s, 2H, Hu), 8.20 (t, J = 7.6 Hz, 4H, Hs), 7.68 (m, 2H, Hv or
Hv’), 7.63 (t, 2H, J = 7.8 Hz, Ht), 7.61 (m, 2H, Hv or Hv’), 7.10 (psq, J = 7.9
Hz, 8H, Hx), 6.94 (m, 1H, Hh or Hh’), 6.88 (d, J = 15.0 Hz, 1H, Hg or Hf),
6.87 (s, 1H, He’), 6.80 (d, J = 15.1 Hz, 1H, Hg or Hf), 6.56 (d, J = 8.6 Hz,
1H, Hh or Hh’), 6.49 (s, 1H, He), 6.06 (m, 1H, Hl), 5.84 (d, J = 14.6 Hz, 1H,
Hf’ or Hg’), 5.69 (brs, 1H, Hl’), 5.58 (d, J = 14.6 Hz, 1H, Hf’ or Hg’), 4.60 (m,
4H, Hw), 4.40 – 4.18 (m, 5H, Hw + Hi), 3.71 (m, 7H, Hi’ + Hd), 3.68 (m, 6H,
Hd’), 3.64 (t, J = 6.3 Hz, 12H, Hc), 3.41 – 3.03 (m, 4H, Hm), 2.45 (m, 12H,
Hb), 2.11 – 2.06 (m, 1H, Hj), 1.88 – 1.81 (m, 1H, Hj’), 1.50 – 1.44 (m, 4H,
Hn), 1.43 (s, 27H, Ha), 1.39 (s, 27H, Ha’), 1.33 – 1.19 (m, 16H, Ho-r), 0.97
– 0.74 (m, 12H, Hk + Hk’). 13C NMR (151 MHz, TCE-d2) δ 170.95, 170.83,
170.17, 169.11, 166.03, 164.90, 164.69, 163.97, 163.71, 136.85, 136.75,
134.47, 133.54, 133.42, 131.77, 131.55, 131.30, 129.29, 129.25, 129.18,
124.33, 80.64, 80.46, 68.71, 68.60, 67.07, 66.95, 61.21, 60.09, 59.36,
58.57, 44.09, 39.71, 39.52, 36.03, 35.99, 31.11, 29.61, 29.33, 29.27,
29.03, 28.96, 27.99, 27.92, 19.14, 18.03 (1 signal overlapping/missing).
HRMS (ESI): m/z calcd for C112H168N10O28+Na+: 2124.19218 [M+Na]+;
found: 2124.19153.
triethylamine (74 µL, 0.528 mmol, 8 eq.) in chloroform (20 mL). The
reaction mixture was stirred at room temperature overnight under N2
atmosphere. The reaction mixture was filtered through a Celite® pad.
The filtrate was washed successively with a sodium bicarbonate solution
(10%), water and brine. The organic layer was dried over magnesium
sulfate, filtered and concentrated in vacuo. Purification by silica gel
column chromatography (cyclohexane/i-PrOH, 9:1 to 8:2, v/v) afforded 1c
as a colourless solid (16 mg, 12% yield). 1H NMR (600 MHz, 85 °C, TCE-
d2) δ 8.51 (s, 2H, Ht), 8.24 (m, 4H, Hr), 7.64 (m, 2H, Hs), 7.57 (m, 4H, Hu),
7.18, (s, 8H, Hw), 6.53 (m, 2H, Hh), 6.35 (m, 2H, He), 6.28 (m, 4H, Hf +
Hg), 5.84 (m, 2H, Hk), 4.53 (m, 8H, Hv), 4.23 (m, 2H, Hi), 3.74 (m, 12H,
Hd), 3.70 (m, 12H, Hc), 3.32 – 3.11 (m, 4H, Hl), 2.48 (m, 12H, Hb), 1.71 –
1.49 (m, 10H, Hj + Hm), 1.47 (s, 54H, Ha), 1.41 – 1.20 (m, 16H, Hn-q). 13
C
NMR (151 MHz, TCE-d2) δ 170.91, 166.16, 164.07, 136.88, 133.58,
131.35, 129.19, 124.34, 80.55, 68.64, 67.00, 60.57, 49.09, 44.08, 39.62,
36.00, 31.32, 30.07, 29.61, 29.21, 29.17, 28.93, 27.95 (5 signals
overlapping/missing). HRMS (ESI): m/z calcd for C108H160N10O28+Na+:
2068.12957 [M+Na]+; found: 2068.12963.
Synthesis of water soluble rotaxane 1a-WS: The valine-containing
rotaxane 1a (14 mg, 6.66 µmol) was dissolved in formic acid (1 mL) and
stirred at room temperature for 6h. Volatiles were removed in vacuo.
Methanol (0.9 mL) and a solution of sodium bicarbonate (3.4 mg, 40.0
µmol, 6 eq.) in water (0.1 mL) were added successively to the residue.
Rotaxane 1a-WS was obtained upon removal of the volatiles in vacuo as
a colourless solid (quantitative yield). 1H NMR (600 MHz, MeOD/D2O 9:1,
v/v) δ 8.75 (s, 2H, Hq), 8.14 (dm, 4H, Ho), 7.70 (t, J = 7.8 Hz, 2H, Hp),
7.16 (s, 8H, Hs), 6.97 (d, J = 15.4 Hz, 1H, Hd or He), 6.91 (d, J = 15.4 Hz,
1H, Hd or He), 5.97 (d, J = 15.0 Hz, 1H, Hd’ or He’), 5.83 (d, J = 15.0 Hz,
1H, Hd’ or He’), 4.53 – 4.36 (m, 8H, Hr), 4.19 (d, J = 7.3 Hz, 1H, Hf), 3.86
(d, J = 8.7 Hz, 1H, Hf’), 3.77 (s, 6H, Hc), 3.69 (t, J = 6.8 Hz, 6H, Hb), 3.67
– 3.60 (m, 12H, Hc’ + Hb’), 3.25 – 3.00 (m, 4H, Hi), 2.42 (t, J = 6.9 Hz,
12H, Ha), 2.13 (m, 1H, Hg), 1.95 (m, 1H, Hg’), 1.49 (m, 4H, Hj), 1.44 (m,
16H, Hk-n), 1.04 – 0.90 (m, 12H, Hh + Hh’). 13C NMR (151 MHz,
MeOD/D2O 9:1, v/v) δ 180.37, 180.04, 173.40, 173.06, 169.14, 169.10,
167.25, 167.18, 167.06, 166.91, 161.35, 137.63, 137.56, 135.42, 134.94,
134.90, 132.80, 132.56, 132.46, 132.43, 130.59, 130.56, 130.36, 129.86,
126.95, 70.25, 70.15, 70.12, 70.07, 62.69, 62.02, 60.98, 45.16, 40.43,
39.38, 39.29, 30.50, 30.15, 19.68, 19.63 (3 signals overlapping/missing).
Synthesis of rotaxane 1b: A solution of p-xylylenediamine (35 mg, 0.259
mmol, 4 eq.) in chloroform (10 mL) and a solution of isophthaloyl
dichloride (53 mg, 0.259 mmol, 4 eq.) in chloroform (10 mL) were
simultaneously added at room temperature with a syringe pump during
2h to a solution of thread 2b (100 mg, 0.0649 mmol, 1 eq.) and dry
triethylamine (72 µL, 0.519 mmol, 8 eq.) in chloroform (20 mL). The
reaction mixture was stirred at room temperature overnight under N2
atmosphere. The reaction mixture was filtered through a Celite® pad.
The filtrate was washed successively with a sodium bicarbonate solution
(10%), water and brine. The organic layer was dried over magnesium
sulfate, filtered and concentrated in vacuo. Purification by silica gel
column chromatography (cyclohexane/i-PrOH, 9:1 to 8:2, v/v) afforded
1b as a colourless solid (21 mg, 16% yield). 1H NMR (600 MHz, TCE-d2)
δ 8.54 (s, 2H, Hu), 8.18 (t, J = 8.0 Hz, 4H, Hs), 7.72 (m, 2H, Hv or Hv’),
7.67 (m, 2H, Hv or Hv’), 7.62 (t, J = 7.8 Hz, 2H, Ht), 7.21 (m, 2H, Hh’), 7.11
(s, 8H, Hx), 6.88 (d, J = 14.7 Hz, 1H, Hf or Hg), 6.87 (s, 1H, He’), 6.79 (d, J
= 14.9 Hz, 1H, Hf or Hg), 6.72 (d, J = 7.8 Hz, 1H, Hh), 6.52 (s, 1H, He),
6.25 (m, 1H, Hl or Hl’), 5.84 (d, J = 14.9 Hz, 1H, Hf’ or Hg’), 5.82 (m, 1H, Hl
or Hl’), 5.61 (d, J = 14.6 Hz, 1H, Hf’ or Hg’), 4.61 (m, 4H, Hw), 4.35 (m, 1H,
Hi), 4.30 (m, 4H, Hw), 3.87 (m, 1H, Hi’), 3.71 (s, 6H, Hd), 3.69 (m, 6H, Hd’),
3.64 (m, 12H, Hc), 3.34 – 3.03 (m, 4H, Hm), 2.45 (m, 12H, Hb), 1.92 –
1.61 (dm, 4H, Hj), 1.50 – 1.45 (m, 4H, Hn), 1.43 (s, 27H, Ha or Ha’), 1.39
HRMS (ESI): m/z calcd for (C88H114N10O28
[M+4H+2Na]2+; found: 905.40192.
)
6–+4(H+)+2(Na+): 905.40290
Synthesis of thread 2a: To a solution of valine 3a (199 mg, 0.5 mmol, 1
eq.), fumaric acid stopper 4 (604 mg, 1 mmol, 2 eq.), DMAP (147 mg, 1.2
mmol, 2.4 eq.) and triethylamine (0.17 mL, 1.2 mmol, 2.4 eq.) in
dichloromethane (16 mL), EDCI·HCl (230 mg, 1.2 mmol, 2.4 eq.) was
added in one portion at room temperature. The reaction mixture was
stirred at room temperature for 16h under N2 atmosphere. The reaction
mixture was diluted with dichloromethane and washed successively with
a citric acid solution (10%), a sodium bicarbonate solution (10%), water
and brine. The organic layer was dried over magnesium sulfate, filtered
and concentrated in vacuo. Purification by silica gel column
chromatography (DCM/MeOH, 100:0 to 96:4, v/v) afforded 2a as a
colourless sticky solid (336 mg, 43% yield). 1H NMR (300 MHz, CDCl3) δ
6.96 (d, J = 15.0 Hz, 2H, Hf or Hg), 6.88 (d, J = 15.0 Hz, 2H, Hf or Hg),
6.82 (d, J = 8.8 Hz, 2H, Hh), 6.60 (s, 2H, He), 6.20 (t, J = 5.7 Hz, 2H, Hl),
4.25 (pst, J = 8.9 Hz, 2H, Hi), 3.74 (s, 12H, Hd), 3.64 (t, J = 6.3 Hz, 12H,
Hc), 3.23 (m, 4H, Hm), 2.44 (t, J = 6.1 Hz, 12H, Hb), 2.13 (m, 2H, Hj), 1.53
– 1.46 (m, 4H, Hn), 1.44 (s, 54H, Ha), 1.34 – 1.19 (m, 16H, Ho-r), 0.95 (d,
J = 6.8 Hz, 6H, Hk or Hk’), 0.93 (d, J = 6.8 Hz, 6H, Hk or Hk’). 13C NMR
(151 MHz, CDCl3) δ 171.04, 170.82, 164.62, 164.26, 134.74, 132.33,
80.65, 69.03, 67.21, 60.51, 59.30, 39.63, 36.25, 31.00, 29.53, 29.34,
29.13, 28.24, 26.87, 19.42, 18.51. HRMS (ESI): m/z calcd for
C80H140N6O24+Na+: 1591.98112 [M+Na]+; found: 1591.98344.
(s, 27H, Ha or Ha’), 1.33 – 1.16 (m, 16H, Ho-r), 0.93 – 0.78 (m, 6H, Hk
+
Hk’). 13C NMR (151 MHz, CDCl3) δ 171.13, 171.10, 171.04, 170.22,
166.71, 166.62, 165.30, 165.11, 164.45, 164.18, 137.06, 134.81, 133.88,
133.80, 132.05, 131.74, 131.51, 129.53, 129.49, 129.28, 124.78, 80.92,
80.73, 69.10, 68.96, 67.34, 67.24, 61.44, 60.48, 55.55, 54.79, 44.53,
44.47, 39.91, 39.75, 36.27, 36.26, 31.58, 30.33, 29.84, 29.57, 29.43,
28.26, 28.20, 26.04, 25.71, 10.15, 10.00 (1 signal overlapping/missing).
HRMS (ESI): m/z calcd for C110H164N10O28+Na+: 2096.160888 [M+Na]+;
found: 2096.160868 .
Synthesis of rotaxane 1c: A solution of p-xylylenediamine (36 mg, 0.264
mmol, 4 eq.) in chloroform (10 mL) and a solution of isophthaloyl
dichloride (54 mg, 0.264 mmol, 4 eq.) in chloroform (10 mL) were
simultaneously added at room temperature with a syringe pump during
2h to a solution of thread 2c (100 mg, 0.0661 mmol, 1 eq.) and dry
Synthesis of thread 2b: To a solution of valine 3b (185 mg, 0.5 mmol, 1
eq.), fumaric acid stopper 4 (604 mg, 1 mmol, 2 eq.), DMAP (147 mg, 1.2
mmol, 2.4 eq.) and triethylamine (0.17 mL, 1.2 mmol, 2.4 eq.) in
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000997
European Journal of Organic Chemistry
FULL PAPER
dichloromethane (16 mL), EDCI·HCl (230 mg, 1.2 mmol, 2.4 eq.) was
added in one portion at room temperature. The reaction mixture was
stirred at room temperature for 24h under N2 atmosphere. The mixture
was diluted with dichloromethane and washed successively with a citric
acid solution (10%), a sodium bicarbonate solution (10%), water and
brine. The organic layer was dried over magnesium sulfate, filtered and
concentrated in vacuo. Purification by silica gel column chromatography
(DCM/MeOH, 100:0 to 96:4, v/v) afforded 2b as a colourless sticky solid
(372 mg, 48% yield). 1H NMR (300 MHz, CDCl3) δ 6.95 (d, J = 15.0 Hz,
2H, Hf or Hg), 6.84 (d, J = 15.0 Hz, 2H, Hf or Hg), 6.76 (d, J = 8.0 Hz, 2H,
Hh), 6.61 (s, 2H, He), 6.23 (t, J = 5.7 Hz, 2H, Hl), 4.39 (q, J = 7.1 Hz, 2H,
Hi), 3.74 (s, 12H, Hd), 3.65 (t, J = 6.3 Hz, 12H, Hc), 3.23 (m, 4H, Hm), 2.44
(t, J = 6.3 Hz, 12H, Hb), 1.99 – 1.61 (dm, J = 71.3 Hz, 4H, Hj), 1.54 – 1.47
(m, 4H, Hn), 1.44 (s, 54H, Ha), 1.34 – 1.20 (m, 16H, Ho-r), 0.92 (t, J = 7.4
Hz, 6H, Hk). 13C NMR (101 MHz, CDCl3) δ 171.16, 171.04, 164.55,
164.23, 134.75, 132.20, 80.66, 69.09, 67.23, 60.52, 54.91, 39.67, 36.27,
29.56, 29.38, 29.17, 28.25, 26.85, 25.62, 10.09 (1 signal
overlapping/missing). HRMS (ESI): m/z calcd for C78H136N6O24+Na+:
1563.94982 [M+Na]+; found: 1563.95145.
sodium bicarbonate solution (10%), water and brine. The organic layer
was dried over magnesium sulfate, filtered and concentrated in vacuo.
Purification by silica gel column chromatography (cyclohexane/EtOAc,
7:3, v/v) afforded methyl ester 5 as a colourless oil (951 mg, 78% yield).
1H NMR (300 MHz, CDCl3) δ 7.10 (d, J = 15.4 Hz, 1H, Hf or Hg), 6.88 (s,
1H, He), 6.74 (d, J = 15.4 Hz, 1H, Hf or Hg), 3.76 (s, 3H, Hh), 3.75 (s, 6H,
Hd), 3.65 (t, J = 6.2 Hz, 6H, Hc), 2.44 (t, J = 6.2 Hz, 6H, Hb), 1.45 (s, 27H,
Ha). 13C NMR (76 MHz, CDCl3) δ 171.26, 166.22, 163.73, 138.19, 129.24,
80.78, 69.15, 67.26, 60.54, 52.04, 36.18, 28.24. HRMS (ESI): m/z calcd
for C30H51NO12+H+: 618.34840 [M+H]+; found: 618.34733.
Dynamic NMR
Line-broadening dynamic NMR (DNMR) fittings were performed using
the DNMR module in Bruker TopSpin 4.0.6. The fumaramide and tBu
signals were suitable to perform the fittings to obtain the experimental
exchange rate constants (kex).[44] The first-order exchange rate constants
(kex) were obtained from the intensities of the EXSY diagonal peaks (IAA
and IBB) and the EXSY cross peaks (IAB and IBA) at different mixing times
(tmix) as described in the literature to obtain a straight line with slope
[45,46]
Synthesis of thread 2c: To a solution of valine 3c (171 mg, 0.5 mmol, 1
eq.), fumaric acid stopper 4 (604 mg, 1 mmol, 2 eq.), DMAP (147 mg, 1.2
mmol, 2.4 eq.) and triethylamine (0.17 mL, 1.2 mmol, 2.4 eq.) in
dichloromethane (16 mL), EDCI·HCl (230 mg, 1.2 mmol, 2.4 eq.) was
added in one portion at room temperature. The reaction mixture was
stirred at room temperature for 24h under N2 atmosphere. The mixture
was diluted with dichloromethane and washed successively with a citric
acid solution (10%), a sodium bicarbonate solution (10%), water and
brine. The organic layer was dried over magnesium sulfate, filtered and
concentrated in vacuo. Purification by silica gel column chromatography
(DCM/MeOH, 100:0 to 96:4, v/v) afforded 2c as a colourless sticky solid
(375 mg, 50% yield). 1H NMR (300 MHz, CDCl3) δ 6.96 (d, J = 15.0 Hz,
2H, Hf or Hg), 6.87 (m, 2H, Hh), 6.82 (d, J = 15.2 Hz, 2H, Hf or Hg), 6.64 (s,
2H, He), 6.37 (t, J = 5.7 Hz, 2H, Hk), 4.53 (m, 2H, Hi), 3.74 (s, 12H, Hd),
3.64 (t, J = 6.3 Hz, 12H, Hc), 3.23 (q, J = 6.7 Hz, 4H, Hl), 2.44 (t, J = 6.2
Hz, 12H, Hb), 1.56 – 1.46 (m, 4H, Hm), 1.44 (s, 54H, Ha), 1.39 (d, J = 6.9
Hz, 6H, Hj) 1.33 – 1.17 (m, 16H, Hn-q). 13C NMR (101 MHz, CDCl3) δ
171.85, 171.07, 164.41, 164.20, 134.85, 132.05, 80.68, 69.10, 67.23,
60.51, 49.21, 39.71, 36.26, 29.52, 29.39, 29.18, 28.25, 26.83, 18.20 (1
kex
.
Further details and sample spectra are provided in the
Supporting Information.
Molecular Modelling
Basic modelling was carried out to evaluate the steric size of the
amino-acid speed bumps. Molecular modelling was carried out with the
Spartan ‘18 software using the MMFF force field.[47] See Supporting
information for further details.
Acknowledgements
This project has received funding from the European Union’s
Horizon 2020 research and innovation programme under the
Marie Skłodowska-Curie grant agreement No 796612. Equally,
financial support from the Agence Nationale de la Recherche
(project ANR-16-CE29-0011) and CNRS is gratefully
acknowledged.
signal
overlapping/missing).
HRMS
(ESI):
m/z
calcd
for
C76H132N6O24+Na+: 1535.91852 [M+Na]+; found: 1535.92002.
Synthesis of 4: To a solution of methyl ester 5 (920 mg, 1.49 mmol, 1
eq.) in a mixture of THF (100 mL) and water (12 mL), a solution of
LiOH·H2O (118 mg, 4.47 mmol, 3 eq.) in water (5 mL) was added. The
reaction mixture was stirred under reflux for 30 min and the reaction
progression was monitored by TLC (cyclohexane/EtOAc 1:1). THF was
evaporated in vacuo. The aqueous solution was acidified with a 1M HCl
solution to pH ≈ 1 and extracted with dichloromethane. The organic layer
was washed with brine, dried over magnesium sulfate, filtered and
concentrated in vacuo. Purification by silica gel column chromatography
(cyclohexane/EtOAc, 9:1 + 0.05% AcOH, v/v) afforded fumaric acid
stopper 4 as a thick colourless oil (699 mg, 78% yield). 1H NMR (300
MHz, CDCl3) δ 7.21 (d, J = 15.4 Hz, 1H, Hf or Hg), 7.03 (s, 1H, He), 6.73
(d, J = 15.4 Hz, 1H, Hf or Hg), 3.76 (s, 6H, Hd), 3.65 (t, J = 6.1 Hz, 6H, Hc),
Keywords: rotaxanes • molecular shuttles • dynamics • EXSY
NMR • hydrogen bonding
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10.1002/ejoc.202000997
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Key Topic: Rotaxane dynamics
A family of degenerate 2-station [2]rotaxanes incorporating amino-acid units in conjunction with fumaramide stations is reported in
aqueous and pure organic solvents. Appendages on the amino-acid units act as speed bumps, which serve to slow down (up to 4
orders of magnitude) ring shuttling in accordance with a linear dependence on the appendage steric factor and/or CPK volume.
Institute and/or researcher Twitter usernames:
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