Triggering a [2]rotaxane molecular shuttle through hydrogen sulfide

Article abstract of DOI:10.1007/s11426-017-9104-x

A novel chemically-controlled [2]rotaxane molecular shuttle was successfully designed and synthesized. A H₂S-responsive bulk barrier was introduced between the two identical recognition stations of the [2]rotaxane to prevent dynamic shuttling of the macrocycle. Upon addition of H₂S, the complete intramolecular cascade reaction occurs in a controllable manner, resulting in removal of the bulk barrier and the shuttling motion of the macrocycle between the two stations recovers.

Full text of DOI:10.1007/s11426-017-9104-x

SCIENCE CHINA
Chemistry
doi: 10.1007/s11426-017-9104-x
• ARTICLES •
Triggering a [2]rotaxane molecular shuttle through
hydrogen sulfide
Shun Yang, Zhoulin Luan, Chuan Gao, Jingjing Yu & Dahui Qu*
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology,
Shanghai 200237, China
Received May 18, 2017; accepted June 27, 2017; published online August 11, 2017
A novel chemically-controlled [2]rotaxane molecular shuttle was successfully designed and synthesized. A H2S-responsive bulk
barrier was introduced between the two identical recognition stations of the [2]rotaxane to prevent dynamic shuttling of the
macrocycle. Upon addition of H2S, the complete intramolecular cascade reaction occurs in a controllable manner, resulting in
removal of the bulk barrier and the shuttling motion of the macrocycle between the two stations recovers.
rotaxane, molecular shuttle, chemically-controlled, hydrogen sulfide, stimuli-responsive
Citation:
Yang S, Luan Z, Gao C, Yu J, Qu D. Triggering a [2]rotaxane molecular shuttle through hydrogen sulfide. Sci China Chem, 2017, 60, doi: 10.1007/
s11426-017-9104-x
1 Introduction
taxanes have been reported, such as steric hindrance strategy
[13] and varied identical station strategy [14]. These intelli-
gent driving modes triggering the molecular shuttling motion
can broaden the strategies for the construction of multi-level
molecular machines and the application of molecular ma-
chines in biological systems. Nowadays, molecular machines
are progressively applied in biology, employing the bioactive
molecules as external triggers directly to stimulate molecu-
lar machines [15]. The advantage of this novel strategy is to
prevent the biological damage from chemical reagents. How-
ever, it is still a tremendous challenge to build a biomimetic
molecular machine which can sense the biomolecular signal.
Hydrogen sulfide (H2S), which is considered to be a toxic
gas in the atmosphere, is an important neuromodulator and
cell signaling molecule. In cells, H2S can be produced by
decomposition of L-cysteine via cystathionine γ-lyase (CSE)
mediated [16]. O-azido-methylbenzoate (AzMB), known as
a sensitive self-cleavable precursor, can be reduced into ben-
zylamine by H2S, leading to the formation of indolin-1-one
after a series of intramolecular cascade reactions [17]. Al-
though AzMB has been widely developed for protection of
Biomolecular machines have attracted increasing attention,
because their linear or rotational motion could implement the
various functions in biology [1]. Rotaxanes [2], catenanes
[3], and motors [4] have been created and developed as arti-
ficial molecular machines to mimic the biological motors by
synthetic chemists. Among these molecular machines, rotax-
anes, known as a kind of mechanically interlocked molecules
(MIMs) [5], in which macrocycle is encircled onto a dumb-
bell-shaped thread, have been proved to be versatile as molec-
ular switches [6], molecular muscles [7], nano-pumps [8] and
nano-valves [9]. These functional applications are mostly
based on bistable rotaxane molecular shuttles, in which the
macrocycles can be switched to move between different sta-
tions by chemical [10], electrochemical [8a] and photochemi-
cal inputs [11]. However, there are few reports on the molecu-
lar shuttles controlled by chemical small-molecules [12]. Re-
cently, some novel strategies for chemically controlled ro-
*Corresponding author (email: dahui_qu@ecust.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2017
chem.scichina.com link.springer.com

2
Yang et al. Sci China Chem
the hydroxyl and amino in nucleosides [18], no effort was
made for the construction of chemically-controlled rotaxanes.
We foresee that the successful introduction of the bioactive
group such as AzMB group would significantly develop and
enrich the chemically controlled rotaxane systems.
1.2ꢀmmol), the 2-(chloromethyl) benzoic acid methyl ester 6
(637ꢀmg, 3.6ꢀmmol), and 4-dimethylaminopyridine (DMAP)
(147ꢀmg, 1.2ꢀmmol) in dimethylformamide (DMF, 15 mL)
was added EDCI (917ꢀmg, 4.8ꢀmmol) at 25ꢀ°C. After the solu-
tion was stirred at 25 °C for 12ꢀh, the solution was diluted with
water (250ꢀmL), and filtered through a Buchner funnel. The
filter cake was washed with dichloromethane (DCM), then
Herein we report, for the first time, a successful triggering
the shuttling motion of macrocycle in a degenerate [2]rotax-
ane via intramolecular cascade reaction induced by H2S, as
shown in Figure 1. In this design, the H2S responsive group
AzMB is introduced and covalent-bonded into the middle of
two identical sites of dumbbell-shaped thread as a bulky bar-
rier to limit the movement of macrocycle, indicating a “gated”
state that the macrocycle is localized on the one of the sta-
tions. Upon addition of H2S, complete cascade reaction oc-
curs in a controllable method, leading to the removal of the
bulky barrier, meaning an “open” state that the balanced shut-
tling motion of the macrocycle between two identical stations
recovers.
1
dried in vacuum to give compound 3 (1.19ꢀg, 1.2ꢀmmol). H
NMR (DMSO-d6, 400ꢀMHz, 298 K), δ (ppm): 8.81 (d,
J=8.0ꢀHz, 2H), 8.30 (t, J1=4.0ꢀHz, J2=8.0ꢀHz, 2H), 7.85
(d, J=8.0ꢀHz, 1H), 7.66 (t, J1=J2=8.0ꢀHz, 1H), 7.56 (d,
J=8.0ꢀHz, 1H), 7.50 (t, J1=J2=8.0ꢀHz, 1H), 7.33–7.21 (m,
20H), 7.16 (d, J=8.0ꢀHz, 4H), 6.92 (d, J=12.0ꢀHz, 4H),
6.11 (d, J=8.0ꢀHz, 2H), 5.70–5.65 (m, 1H), 4.77 (s,
2H), 4.41–4.34 (m, 4H), 4.18 (d, J=8.0ꢀHz, 4H), 2.49 (t,
J1=J2=8.0ꢀHz, 4H), 2.39 (t, J1=J2=8.0ꢀHz, 4H). 13C NMR
(DMSO-d6, 100ꢀMHz, 298 K), δ (ppm): 171.2, 170.7, 165.8,
157.0, 142.6, 136.2, 132.9, 132.2, 130.5, 129.1, 128.5,
128.2, 127.2, 126.8, 114.42, 71.2, 66.2, 55.8, 51.8, 41.4,
30.8. HRMS (ESI) (m/z): [M+Na]+ calcd for C59H57N7O8Na,
1014.4166; found, 1014.4169. m.p. 175.8–177.9 °C.
2 Experimental
2.1 Materials and apparatus
2.3 Synthesis of [2]rotaxane1
2-(Chloromethyl) benzoic acid methyl ester
6 [18],
2-(azidomethyl) benzoic acid 5 [19] and the dumbbell-shaped
thread 4 [11b] were prepared according to the previously
reported procedure. All solvents were reagent grade, which
were dried and distilled prior to use according to standard
procedures. The molecular structures of the unknown com-
Compound 2 (200ꢀmg, 0.202ꢀmmol) and Et3N (652ꢀmg,
6.45ꢀmmol) in anhydrous CHCl3 (500ꢀmL) were
stirred vigorously whilst solutions of p-xylylene-
diamine (329ꢀmg, 2.42ꢀmmol) in anhydrous CHCl3
(50ꢀmL) and the corresponding isophthaloyl dichloride
(491ꢀmg, 2.42ꢀmmol) in anhydrous CHCl3 (50ꢀmL) were si-
multaneously added over a period of 5ꢀh using syringe pumps.
After a further 4ꢀh stirring, MeOH (10ꢀmL) was added, the
resulting suspension was filtered through a celite pad, and
the filtrate was evaporated to dryness. The resulting solid
was purified by preparative TLC (SiO2, DCM:MeOH=20:1)
to yield [2]rotaxane 1 (44ꢀmg, 0.0283ꢀmmol, 14%) as a
yellow solid. 1H NMR (DMSO-d6, 400ꢀMHz, 298K), δ
(ppm): 8.94 (d, J=8.0ꢀHz, 1H), 8.81 (d, J=8.0ꢀHz, 1H),
8.41–8.37 (m, 6H), 8.29 (t, J1=8.0ꢀHz, J2=4.0ꢀHz, 1H), 8.14
(t, J1=8.0ꢀHz, J2=4.0ꢀHz, 1H), 8.02 (d, J=8.0ꢀHz, 4H), 7.83
(d, J=8.0ꢀHz, 1H), 7.65–7.59 (m, 3H), 7.53 (d, 8.0ꢀHz, 1H),
7.46 (t, J1=4.0ꢀHz, J2=8.0ꢀHz, 1H), 7.40–7.22 (m, 20H), 7.14
(d, J=8.0ꢀHz, 2H), 6.90 (s, 12H), 6.82 (d, J=8.0ꢀHz, 2H),
6.11 (d, J=8.0ꢀHz, 1H), 5.98 (d, J=8.0ꢀHz, 1H), 5.67–5.63
(m, 1H), 4.74 (s, 2H), 4.31 (t, J1=12.0ꢀHz, J2=4.0ꢀHz, 8H),
4.21 (t, J1=4.0ꢀHz, J2=12.0ꢀHz, 6H), 3.86 (d,
J=4.0ꢀHz, 2H), 2.49 (t, J1=4.0ꢀHz, J2=8.0ꢀHz, 2H), 2.39 (t,
J1=4.0ꢀHz, J2=8.0ꢀHz, 2H), 1.33 (t, J1=J2=8.0ꢀHz, 2H), 1.15
(t, J1=J2=8.0ꢀHz, 2H). 13C NMR (DMSO-d6, 100ꢀMHz, 298
K), δ (ppm): 177.4, 177.0, 176.4, 175.9, 171.1, 171.0,
162.3, 162.2, 147.89, 147.3, 142.4, 139.7, 135.9, 135.7,
134.0, 133.7, 133.6, 133.5, 132.6, 132.5, 132.0, 119.6, 76.4,
71.5, 61.0, 57.0, 48.3, 47.0, 46.6, 36.0. HRMS (ESI) (m/z):
1
pounds were confirmed via H NMR, 13C NMR and high
resolution-electronic spray ionization mass spectroscopy
(HR-ESI MS). 1H NMR and 13C NMR spectra were recorded
on a Brücker AM400 spectrometer (Germany). The ESI
MS were tested on a LCT Premier XE mass spectrometer
(Wasters, USA).
2.2 Synthesis of compound 3
A stirred solution of the dumbbell-shaped thread 4 (1.0ꢀg,
Figure 1 The schematic representation of the two modes of the [2]rotaxane
before and after addition of H2S (color online).

Yang et al. Sci China Chem
3
[M+Na]+ calcd for C91H85N11O12Na, 1546.6277; found,
1546.6285.
In order to confirm the interlocked structure of the [2]rotax-
ane 1, 1H NMR experiments was investigated. The 1H NMR
spectra of dumbbell-shaped thread 3 and [2]rotaxane 1 were
compared, as shown in Figure 2, respectively. The protons
of [2]rotaxane 1 were rationally assigned, and the chemical
shifts at δ=8.02, 7.62, 6.90, 8.39, and 4.31ꢀppm are attributed
to the protons on benzene (Ha–c, f), amide (Hd), benzyl (He)
of benzylic amide macrocycle, respectively. The signals of
the protons on AzMB (HA–E) and most peaks of protons on
the thread 3 were split into two parts. Significantly, the sig-
nals of methylene protons H7 and H8 on the succinamide sta-
tion of dumbbell-shaped thread 3 were split and shifted up-
field (Δδ=−1.24ꢀppm), due to the introduction of the macro-
3 Results and discussion
3.1 Design of a H2S-responsive [2]rotaxane 1
As shown in Scheme 1, we chose the benzylic amide macro-
cycle to investigate the shuttling motion and a H2S-sensitive
group (AzMB) 5 as a stopper to prevent the shuttling motion
of the macrocycle. The thread component 3, which contains a
dumbbell-shaped thread 4 with two succinamide recognition
sites and AzMB group, is designed and synthesized. Sub-
sequently, three-component clipping reaction resulted in the
formation of [2]rotaxane 1. The structure of this target [2]ro-
cycle. Additionally, other similar shielding signals from H3–6
,
H10 to proton H3′–6′, H10' can be found in Figure 2(b), as well.
However, the protons H11 on the phenyl stoppers and H9 on
the thread 3 shifted downfield (Δδ=−0.09ꢀppm), attributing
to the deshielding effects of the aromatic rings of macrocycle.
In principle, [2]rotaxane 1 should exists four stereoisomers,
however, we did not observed the signals of four stereoiso-
1
taxane 1 was confirmed with H NMR, 13C NMR spectro-
scopies and the HR-ESI mass spectrometry. The mass spec-
trum showed a signal peak at m/z 1546.6285, corresponding
to the specie [M+Na]+, which is consistent with the calculated
value of 1546.6277 for [C91H85N11O12Na].
1
mers according to the H NMR, as shown in Figure 2(b),
which is consistent with previously result [11b]. Moreover, a
1H NOESY spectrum (DMSO-d6, 400ꢀMHz, 298 K) of [2]ro-
taxane 1 shown nOe correlations between the amide protons
(Hd), the methylene-group protons (He) of macrocycle and
methylene-group protons (H5, H7′, and H8′) of thread, confirm-
ing that the ring was interlocked mechanically in the thread
(for details, see the Supporting Information online). There-
fore, all these results proved that the interlocked structure of
the target [2]rotaxane 1 has been successfully synthesized by
three-component clipping reaction, in which the two recog-
nition sites showed different chemical environments because
of the encircling of the macrocycle into one of the two recog-
nition site, indicating the gated state of rotaxane 1.
3.2 Triggering the shuttling motion of H2S-responsive
[2]rotaxane 1
The H2S-responsiveness of the [2]rotaxane 1 was detected by
1H NMR spectrum, as shown in Figure 3. 2 eq. NaSH (a stan-
dard source for hydrogen sulfide) was added to the DMSO-d6
of [2]rotaxane 1 and the reaction result was investigated by
1H NMR spectroscopy after 20ꢀmin [20]. Obviously, after
20ꢀmin, the key signals at δ=7.46, 7.53, 7.61, and 4.74ꢀppm of
HB-E on the H2S-responsive group AzMB in [2]rotaxane 1,
shifted to 7.14, 7.68, 7.48, and 4.38ꢀppm of HB′–E′ in [2]ro-
taxane 1 correspondingly, and these chemical shifts of HB'−E'
were similar to the protons on indolin-1-onedue due to the
addition of NaSH, which indicates that the bulky group has
been successfully cleaved upon the addition of NaSH. Sig-
nificantly, the signals (δ=5.65ꢀppm) of the H1 proton on the
axel of [2]rotaxane 1 disappeared, and a new signals (δ =
4.06ꢀppm) simultaneously appeared, which can be explained
Scheme 1 Synthetic routes of the target [2]rotaxane 1, the dumbbell-shaped
thread compounds 3, 4 and the H2S-responsive reaction of [2]rotaxane 1 to
yield degenerate [2]rotaxane 2 (color online).

4
Yang et al. Sci China Chem
Figure 4 1H NMR spectra (400ꢀMHz, DMSO-d6, 298ꢀK) of (a) [2]rotaxane
1, (b) an “open” [2]rotaxane 2, (c) dumbbell-shaped thread 4 (color online).
Figure 2 1H NMR spectra (400ꢀMHz, DMSO-d6, 298ꢀK) of (a) dumbbell-
shaped thread 3 and (b) [2]rotaxane 1. See Scheme 1 for proton assignments
(color online).
for H7 and H8 in rotaxane 2 in Figure 4(b), respectively, which
proved that the chemical environments of the protons on two
succinamide recognition sites were identical in [2]rotaxane 2
because of the fast shuttling dynamic motion induced by the
removal of the bulky middle stopper. Additionally, the sig-
nals of H3′, H4′, H5′, H10′ in rotaxane 1 (Figure 4(a)) to H3,
H4, H5, H10 in rotaxane 2 (Figure 4(b)) can also be found as
the same change tendency as well. These obvious changes of
chemical shifts showed that the macrocycle was characterized
by fast shuttling between the two stations along the thread in
[2]rotaxane 2, and the shuttling rate (ks) and free energy of
activation (∆G≠) are consistent with those in our previous re-
sult [11b]. Finally, in order to prove that a similar shuttling
motion still occurs in the H2S-triggered mode, the compara-
tion between Figure 3(b) (mixture sample) and Figure 4(b)
(pure sample) was investigated. We found that two 1H NMR
spectra were similar, which certified that the [2]rotaxane 2
was successfully formed after addition of H2S, leading to the
shuttling motion.
Figure 3 1H NMR spectra (400ꢀMHz, DMSO-d6, 298ꢀK, 1.24×10−2 M) of
(a) H2S-responsive process of [2]rotaxane 1 at 0ꢀmin, and (b) [2]rotaxane 2
after 20ꢀmin (color online).
as the break of carbonic ester in [2]rotaxane 1 indicating for-
mation of hydroxyl group in [2]rotaxane 2. These observa-
tions directly show the efficient and complete H2S-induced
self-cleavable reaction of the AzMB group, releasing a hy-
droxyl group in the obtained [2]rotaxane 2 in a chemically-
controlled mode, as shown in Scheme 1.
4 Conclusions
In conclusion, a novel [2]rotaxane in its gated state has been
successfully synthesized and demonstrated via the introduc-
tion of H2S-responsive group as a removable bulk barrier.
The binding behavior and shuttling motion upon addition of
NaSH have been investigated through 1H NMR spectroscopy.
The results showed that H2S can motivate a controlled motion
of the rotaxane by site-specific cleavage of the AzMB groups.
This work could enrich the biochemistry-controlled modes
for the motion of molecular shuttle. We envision that this
novel H2S-responsive strategy will afford an efficient method
for construction of bioresponsive rotaxanes and advance the
study artificial molecular machines.
To further confirm the final product of H2S-responsive
cascade reaction of [2]rotaxane 1, the “open” [2]rotax-
ane 2 was purified for further analysis and investigation.
1
Compared with the H NMR spectra of [2]rotaxane 1, as
shown in Figure 4(a), the chemical shift of the methyne
protons (H1) in [2]rotaxane 2 (Figure 4(b)) was shielded
(Δδ=−1.59ꢀppm), and a new peak at 5.41ꢀppm of HOH was
1
appeared, these changes were identical with the H NMR
spectra shown in Figure 3, which attributed to the fracture
of AzMB. Furthermore, we found that the chemical shifts
at δ=2.49, 2.39, 1.33, 1.15ꢀppm of H7, H7′, H8, H8′ on the
[2]rotaxane 1 (Figure 4(a)) were shifted to δ=1.96, 1.81ꢀppm
Acknowledgments This work was supported by the National Natural Sci-
ence Foundation of China (21672060), the Fundamental Research Funds for

Yang et al. Sci China Chem
5
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Conflict of interest
The authors declare that they have no conflict of
interest.
Supporting information The supporting information is available online
at http://chem.scichina.com and http://link.springer.com/journal/11426.
The supporting materials are published as submitted, without typesetting
or editing. The responsibility for scientific accuracy and content remains
entirely with the authors.
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