Synthesis of a pH-Sensitive Hetero[4]Rotaxane Molecular Machine that Combines [c2]Daisy and [2]Rotaxane Arrangements

Article abstract of DOI:10.1002/chem.201600453

The synthesis of a novel pH-sensitive hetero[4]rotaxane molecular machine through a self-sorting strategy is reported. The original tetra-interlocked molecular architecture combines a [c2]daisy chain scaffold linked to two [2]rotaxane units. Actuation of the system through pH variation is possible thanks to the specific interactions of the dibenzo-24-crown-8 (DB24C8) macrocycles for ammonium, anilinium, and triazolium molecular stations. Selective deprotonation of the anilinium moieties triggers shuttling of the unsubstituted DB24C8 along the [2]rotaxane units.

Full text of DOI:10.1002/chem.201600453

DOI: 10.1002/chem.201600453
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Supramolecular Chemistry |Hot Paper|
Synthesis of a pH-Sensitive Hetero[4]Rotaxane Molecular Machine
that Combines [c2]Daisy and [2]Rotaxane Arrangements
Philip Wael›s, Benjamin Riss-Yaw, and FrØdØric Coutrot*[a]
Abstract: The synthesis of a novel pH-sensitive hetero[4]ro-
taxane molecular machine through a self-sorting strategy is
reported. The original tetra-interlocked molecular architec-
ture combines a [c2]daisy chain scaffold linked to two [2]ro-
taxane units. Actuation of the system through pH variation
is possible thanks to the specific interactions of the dibenzo-
24-crown-8 (DB24C8) macrocycles for ammonium, anilinium,
and triazolium molecular stations. Selective deprotonation of
the anilinium moieties triggers shuttling of the unsubstitut-
ed DB24C8 along the [2]rotaxane units.
Introduction
The field of interlocked molecular machines appeared about
twenty years ago, when the motion of one element with re-
spect to another in a sole molecule was successfully achieved
with control. Various more or less complicated interlocked mo-
lecular architectures have been reported to date. In the rotax-
ane series, doubly interlocked rotaxanes (i.e., [c2]daisy chain[1])
attracted chemists because of their peculiar interwoven archi-
tecture. In 2000, J.-P. Sauvage[2] was the first to report the syn-
thesis of a metal-based doubly interlocked rotaxane that was
able to act as a stimulus-responsive molecular machine.[3] This
novel molecular machine was termed a “molecular muscle”[4]
by the author, in reference to the contractile motion that
occurs in human muscles. Indeed, such a molecular architec-
ture can adopt different co-conformations from a stretched to
a contracted state through the gliding of the macrocycles
along the encircled threads (Figure 1).
Figure 1. Representation of a [c2]daisy-chain-containing molecular muscle in
a) the stretched state and b) the contracted state.
were likened to cyclic molecular muscles.[6] The challenging
synthesis of new multi-interlocked[7] molecular architectures is
of interest because it could lead to a wide variety of molecular
motions in a single molecule. Herein, we report on the synthe-
sis and study of an appealing pH-sensitive tetra-interlocked
molecular machine I (Figure 2b). The molecular architecture
consists of a [c2]daisy chain scaffold that is linked to two [2]ro-
taxane units. The molecular machinery, which is inherent to
this hetero[4]rotaxane architecture, should allow for different
possible co-conformational states (I, J, and K) that are a conse-
quence of the gliding of the different interlocked components
with respect to each other.
Following this inspiring pioneer work, only a few teams had
reported original molecular-muscle systems.[5] In 2008, we re-
ported a straightforward chemical route to a pH-sensitive mo-
lecular muscle, which was based on ammonium and N-methyl-
triazolium stations for the dibenzo-24-crown-8 (DB24C8).[5a]
Later, we synthesized several two- and three-station-based mo-
lecular muscles that adopted numerous co-conformational
states, for which many induced conformational changes could
be controlled.[5d] Daisy-chain precursors were also used by our
group to prepare unique double-lasso rotamacrocycles that
Until now, such a tetra-interlocked chemical architecture has
been the subject of only one very recent publication by Tian,
Qu et al. (Figure 2a).[8] They proposed a self-sorting strategy[9]
that relies on the use of macrocycles with different sizes. The
very well designed molecular precursors allow the various
macrocycles to bind the ammonium template moieties that
are present on the two different axles selectively. The self-sort-
ing strategy is driven by the favorable daisy-chain arrangement
and by the fact that the small macrocycles (in yellow) cannot
thread the hermaphrodite molecule due to the presence of
a too-hindering group on its axle. Moreover, in the final inter-
locked architecture, the small macrocycles act as stoppers for
the DB24C8 (in red) and, therefore, prevent the [c2]daisy ar-
rangement from disassembling. Herein, we propose a different
self-sorting strategy for precursors A, B, and C by using differ-
ent templates (ammonium and anilinium) for analogous
DB24C8 macrocycles. On mixing A, B, and C, some supra-
molecular arrangements were formed preferentially from
[a] P. Wael›s, B. Riss-Yaw, Dr. F. Coutrot
Supramolecular Machines and ARchitectures Team
Institut des BiomolØcules Max Mousseron (IBMM) UMR 5247 CNRS
UniversitØ Montpellier, ENSCM, case courrier 1706
Bâtiment Chimie (17), 3›me Øtage, FacultØ des Sciences
Place Eug›ne Bataillon 34095 Montpellier cedex 5 (France)
E-mail: Frederic.coutrot@univ-montp2.fr
Homepage: http://www.glycorotaxane.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201600453.
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Results and Discussion
Synthesis of pH-sensitive hetero[4]rotaxane molecular Ma-
chine 3/4 and molecular muscles 6, 7, and 8
The chemical design (i.e., macrocycle and molecular stations)
of targeted hetero[4]rotaxane molecular machine I (compound
3) is based on the system we published in 2008;[5a,11b] it con-
tains ammonium, anilinium, and triazolium templates for
DB24C8 macrocycles (Scheme 1). Because the ammonium
moiety is a good template for DB24C8,[10] the presence of
these two motifs in the same molecule (1 is a hermaphrodite)
results in the formation of a doubly interlocked rotaxane
through a meso [c2]daisy supramolecular arrangement.[6b] The
encircled molecular axles of the daisy chain scaffold have been
chosen so that they also each include a N-methyltriazolium
unit, which is known to be a site of interactions of poorer affin-
ity than the ammonium site. They also have di-tert-butylanilini-
um molecular stations at the end of the axles, which prevent
disassembly of the structure and allow us to drive the extra
[2]rotaxane interlocking at each extremity of the [c2]daisy scaf-
fold. The affinity of the anilinium group for DB24C8 is better
than the triazolium station[11] but poorer than the ammonium
group, which confers interesting shuttling behavior on the mo-
lecular target.
Figure 2. Two self-sorting strategies to give the targeted tetra-interlocked
molecular architecture: a) self-sorting through selective recognition based
on the use of different macrocycles for identical templates[8] and b) self-sort-
ing strategy, reported herein, that relies on the selective recognition of dif-
ferent templates for analogous macrocycles and that could result in different
possible co-conformational states. Benzylammonium template: dark green;
anilinium template: light green; aniline: orange; triazolium: blue; DB24C8:
red.
Targeted molecular machine 3 was synthesized in an overall
yield of 65% from previously synthesized azido-containing her-
maphrodite compound 1, alkynanilinium 2, and DB24C8
(Scheme 1). In the hydrogen-bond-promoting solvent CH2Cl2,
the mixed components were self-sorted according to their af-
finities, and mainly self-assembled into two distinct supra-
molecular assemblies:
a quite stable doubly interlocked
[c2]daisy chain that quantitatively consumed 1 due to the two
strong complementary interactions between the two hermaph-
rodite monomers, and a semi-rotaxane from compounds 2 and
DB24C8 that both remain in solution.[12] The linkage between
the two supramolecular arrangements was carried out in situ
through a two-step sequence that started with a copper(I)-cat-
alyzed Huisgen[13] alkyne–azide 1,3-dipolar cycloaddition,[14] fol-
lowed by subsequent N-methylation of the triazole. The depro-
tonation of isolated hetero[4]rotaxane 3 was then studied to
investigate its propensity to act as a molecular machine. Wash-
ing rotaxane 3 with an aqueous solution of sodium hydroxide
(1m) resulted in the sole deprotonation of the anilinium mo-
lecular stations, which triggered shuttling of the DB24C8 from
the anilinium to the triazolium stations. No contraction of the
[c2]daisy-chain-containing molecule, which would arise from
among the multiple different possible ones. Ammonium-con-
taining hermaphrodite molecule C selectively assembled into
an interwoven [c2]daisy chain G, rather than being encircled
by either a free DB24C8 or another substituted macrocycle C
to give [2]rotaxane species D or E. Similarly, hermaphrodite
molecule C did not thread anilinium-containing axle A to give
F in a preponderant fashion. On one hand, these results arise
from the much greater affinity of the DB24C8 for the benzy-
lammonium moiety than for the anilinium one. On the other
hand, the possibility to achieve two binding sites between the
templates and the macrocycles in a single molecule (i.e., the
[c2]daisy chain) is favored in term of enthalpy with respect to
the formation of single [2]rotaxanes in which interaction takes
place at only one site. As a result, hermaphrodite molecule C
could be entirely converted into [c2]daisy arrangement G,
whereas excess DB24C8 B threaded chemical axle A quantita-
tively to give semi-rotaxane H. The subsequent chemical con-
nection afforded tetra-interlocked architecture I and allowed
for the incorporation of an extra unoccupied molecular station.
The molecular machinery of this hetero[4]rotaxane was investi-
gated by changing the pH.
1
a molecular-muscle actuation, was observed. H NMR spectros-
copy evidence relating to the actuation of the molecular ma-
chinery is discussed in detail below. The deprotonation of the
anilinium is not a surprise if one considers its higher acidity
with respect to the ammonium in the daisy arrangement.
Moreover, deprotonation of the ammonium involved in the
DB24C8-based [c2]daisy chain is obviously tougher than in
a single ammonium-containing [2]rotaxane because twice the
number of interactions exist between the ammonium groups
and the DB24C8, all things being equal. However, what is very
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Scheme 1. Preparations of pH-sensitive hetero[4]rotaxane molecular machines 3/4 and pH-sensitive molecular muscles 6/7/8.
specific here is the impossibility of deprotonating the ammoni-
um of the daisy-chain arrangement in the singular tetra-inter-
locked architecture regardless of the excess of NaOH used and
the experimental conditions used.[15] This problem was not ex-
pected because deprotonation of analogous (albeit only bis-in-
terlocked) synthesized molecular muscles 6 and 8[16] could be
easily achieved under the same experimental conditions,
which trigger with efficacy contracted state 7 (Scheme 1). In
bis-interlocked molecular muscle 8, we assume that the free N-
methyltriazolium molecular station may assist the deprotona-
tion of the ammonium in the daisy arrangement. Certainly, in
this case, the free triazolium site can be partially occupied by
the daisy-DB24C8, although in a very minimal fashion in the
protonated state. However, this possibility for the daisy-
DB24C8 to move slightly from its more stable site is sufficient
to help the deprotonation of the daisy ammonium due to ther-
modynamic factors. Indeed, it is known that an ammonium
group encircled by a crown ether has a lower acidity than
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a free ammonium group due to stabilization of the cationic
species.[17] Therefore, in structure 8, the possibility for the tria-
zolium sites to be minimally occupied by the crown ethers of
the daisy arrangement allows the ammonium groups to be
much less hindered (i.e., in a very small population of proton-
ated contracted co-conformers) and, therefore, more subject
to deprotonation. In contrast, when the triazolium sites are oc-
cupied by the extra DB24C8 (as in 4 because of the easy and
fast deprotonation of the anilinium moieties), the deprotona-
tion of the ammonium-containing daisy chain is highly affect-
ed. With respect to 8, the localization of the extra DB24C8
around the triazolium groups in 4 obviously decreases the
population of a possible minimal ratio of a contracted proton-
ated daisy scaffold due to the competitive interactions be-
tween the triazolium and, respectively, the extra DB24C8 or
the daisy-DB24C8.
downfield shift of H1, H3, and to a lesser extent H4 (Dd=0.41,
0.43 and 0.06 ppm, respectively) that belong to the ammoni-
um sites. These chemical shift displacements are due to hydro-
gen-bond interactions with the oxygen atoms of DB24C8. Se-
lective deprotonation of the anilinium moieties of 6 led to mo-
lecular muscle 8, which remains in the same extended co-con-
formation. This was confirmed by a direct comparison of the
1H NMR spectra of 6 and 8 (Figure 3b–c). Indeed, in 8 all the
NMR signals remained unchanged, with the exception of the
hydrogen atoms that are close to the anilinium sites. Only hy-
drogen atoms H11’, H12’, H8’, and to a lesser extent H7’ are shift-
ed upfield in 8 (Dd=À0.45, À0.47, À0.16, and À0.09 ppm, re-
spectively) because of the deprotonation of the anilinium.
Fully deprotonated molecular muscle 7 could be obtained
from either 6 or 8 by using an aqueous solution of sodium hy-
droxide. The contracted co-conformation of 7 was shown by
the comparison of NMR spectra of 8 and 7 (Figure 3c–d). In
this state (7), the DB24C8 units are localized around the triazo-
lium stations. Obviously, H1, H3, and H4 are shifted upfield in 7
(Dd=À0.87, À0.94, and À0.32 ppm, respectively) as a result of
the deprotonation of the ammoniums of the daisy chain. More
interestingly, the hydrogen atoms H1’, H14, H3’, and H16’ that
belong to the triazolium station are now highly affected by the
new localization of DB24C8. Indeed, on one hand, H1’, H3’, and
H14 are all shifted downfield in 7 (Dd=0.77, 0.59, and
0.45 ppm, respectively) because of their hydrogen-bonding in-
teractions with the oxygen atoms of DB24C8. On the other
hand, methyl hydrogen atoms H16’ are shielded in 7 (Dd=
À0.41 ppm) because they experience the shielding effect of
the aromatic rings of DB24C8. Eventually, the contracted con-
formational state of molecular muscle 7 could be confirmed
through the direct comparison of its 1H NMR spectrum with
that of uncomplexed analogue 7u (Figure 3d–e). In that case,
the same trend in chemical shift displacements was observed
for the hydrogen atoms of the triazolium station (H1’, H3’, H14,
and H16’; Dd=0.79, 0.61, 0.48, and À0.40 ppm, respectively).
This trend corroborates the new localization of DB24C8 around
the triazolium stations in 7, whereas the splitting of the meth-
ylene hydrogen atoms of DB24C8 in 7 accounts for the doubly
interlocked molecular architecture.
Interestingly, in the bis-interlocked molecular-muscle series,
the selective diprotonation of contracted molecular muscle 7
was possible by washing with an aqueous solution of the
weak acid NH4PF6. This very easy selective protonation of
amine-containing [c2]daisy chain 7 triggers the extension of
the molecular muscle and corroborates the high difference in
pKa observed between an anilinium-containing [2]rotaxane and
an ammonium-including [c2]daisy chain. Moreover, the com-
plete protonation of contracted molecular muscle 7 allowed
isolation of molecular muscle 6, which lies in an exclusive ex-
tended co-conformation and thus demonstrates the high pref-
erence of the daisy-DB24C8 for the benzylammonium com-
pared with the anilinium stations. It is also worth noting that
selective deprotonation of the anilinium moieties was possible
for extended fully protonated molecular muscle 6 by washing
with an aqueous saturated solution of sodium hydrogen car-
bonate, which again corroborates the high difference in pKa
observed between an anilinium-containing [2]rotaxane and an
ammonium-including [c2]daisy chain.
1H NMR spectroscopy evidence of the molecular machinery
observed in molecular muscles 6, 7, and 8
The co-conformations adopted by molecular muscles 6, 7, and
1
8 are shown by comparison of their H NMR spectra with those
of their non-interlocked analogues (Figure 3).
1H NMR spectroscopy evidence for the molecular machinery
in hetero[4]rotaxanes 3/4
The direct comparison between the 1H NMR spectrum of
doubly interlocked compound 6 with that of its non-inter-
locked analogue 6u demonstrates the extended co-conforma-
tion of molecular muscle 6 (Figure 3a–b). In compound 6, the
methylene hydrogen atoms of the DB24C8, HG–L and HS–X, are
all split because they are facing the two nonsymmetrical ends
of the threaded axle. Moreover, the aromatic hydrogen atoms
of the DB24C8, and in particular HE, are all shifted upfield in
the interlocked structure because they each experience the
shielding effect of the other aromatic rings of the daisy ar-
rangement. The upfield shift of HE[5a,5d,19] is typical of the
[c2]daisy arrangement in the stretched co-conformation of the
molecular muscle because it indicates the sandwich-type con-
formation adopted by the aromatics of the two DB24C8 units.
The extended co-conformation of 6 is corroborated by the
The molecular machinery observed upon a change in pH for
1
hetero[4]rotaxanes 3/4 was shown by using H NMR spectros-
copy through a comparison of the spectra of the examined in-
terlocked molecules with their non-interlocked analogues
(Figure 4).
The direct comparison between specifically diprotonated
molecular muscle 8 and its non-interlocked analogue 8u[18] re-
veals both the doubly interlocked [c2]daisy arrangement and
the extended co-conformation (Figure 4a,b). Indeed, the meth-
ylene hydrogen atoms of the daisy-chain macrocycles are all
very split in 8 because they are facing the two nonsymmetrical
ends of the [c2]daisy chain. Moreover, the hydrogen atoms of
the aromatic ring of DB24C8 and, more particularly, HE are
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Figure 3. 1H NMR spectra (CD3CN, 298 K, 600 MHz) of a) fully protonated uncomplexed thread 6u, b) tetra-protonated extended molecular muscle 6, c) specifi-
cally diprotonated extended molecular muscle 8, d) fully deprotonated molecular muscle 7, e) fully deprotonated uncomplexed thread 7u. The numbering
and color of the signals correspond to those indicated in Scheme 1.
shielded in 8 (Dd=À0.55 ppm) because they undergo the
shielding effect of the two aromatic rings of the other DB24C8
unit. The stretched doubly interlocked co-conformation is con-
firmed in 8 by the downfield shift of the hydrogen atoms that
belong to the ammonium station H1, H3, and to a lesser extent
H4 (Dd=0.62, 0.64, and 0.17 ppm, respectively) due to their hy-
drogen-bonding interactions with the oxygen atoms of the
crown ether. No other chemical shift variation is noticed for
the other hydrogen atoms between 8u and 8, which corrobo-
rates the structure drawn for 8 in Scheme 1. The direct com-
parison between molecular muscle 8 and hetero[4]rotaxane
molecular machine 4 allows us to localize the extra DB24C8
around the triazolium station and the stretched state of molec-
ular muscle 4 (Figure 4b,c). First, note the appearance in 4 of
a new set of signals for the hydrogen atoms HA’–E’ from the
extra DB24C8. Moreover, the stretched state of the [c2]daisy
chain is indicated by the absence of any variation in the signals
of HE, H1, H3, H4, which accounts for the daisy chain as dis-
cussed above. However, the hydrogen atoms of the triazolium
station are now affected by the presence of the extra DB24C8
units. Indeed, H1’, H3’, and H14 are all shifted downfield in 4
(Dd=0.64, 0.63, and 0. 48 ppm, respectively) because of their
hydrogen-bonding interactions with the oxygen atoms of the
extra DB24C8. Concomitantly, the hydrogen atoms H16’, H4’–6’
,
and H10–12 experience the shielding effect of the extra DB24C8
(Dd=À0.10–À0.39 ppm). The pH-sensitive molecular machi-
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Figure 4. 1H NMR spectra (CD3CN, 298 K, 600 MHz) of a) specifically mono-protonated uncomplexed thread 8u, b) specifically diprotonated molecular muscle
8, c) specifically diprotonated hetero[4]rotaxane molecular machine 4, d) tetra-protonated hetero[4]rotaxane molecular machine 3, e) tetra-protonated molec-
ular muscle 6, f) diprotonated uncomplexed thread 6u. The numbering and color of the signals correspond to those indicated in Scheme 1.
nery between specifically diprotonated hetero[4]rotaxane mo-
lecular machine 4 and tetra-protonated hetero[4]rotaxane mo-
lecular machine 3 was demonstrated by the direct comparison
of their 1H NMR spectra (Figure 4c,d). No variation in the chem-
ical shifts of the hydrogen atoms of the daisy arrangement (in
particular HE, H1, and H3–4) was noted, which reveals a stretched
co-conformation for both compounds. In protonated com-
pound 3, the localization of the extra DB24C8 around the anili-
nium is highlighted by the very high chemical shift of H9’ (i.e.,
NH2) and by the downfield shifts of H8’, H11’, H12’, and to
a lesser extent H7’ of the anilinium site (Dd=1.10, 0.98, 0.69,
and 0.12 ppm, respectively), which are due to their implication
in hydrogen bonding with the extra DB24C8. This matches per-
fectly with the upfield shifts observed in 3 for the hydrogen
atoms of the triazolium station H1’, H3’, and to a lesser extent
H14 and H4’ (Dd=À0.77, À0.95, À0.47, and À0.17 ppm) as
a result of the displacement of the extra DB24C8 away from
the triazolium groups. Finally, HE’–E’’ of the extra DB24C8 are
slightly shifted upfield in 3 due to their localization in the
shielding region of the anilinium aromatic ring. The localization
of the macrocycles in 3 was confirmed by the direct compari-
son with tetra-protonated molecular muscle 6 (Figure 4d,e).
Briefly, in tetra-protonated compound 6, the molecular muscle
lies in an extended state, which reveals that the ammonium
station has a better affinity for DB24C8 than the anilinium
group. Indeed, the sandwich-type arrangement of DB24C8 is
also observed (see the particular upfield chemical shift for HE).
The main difference in 3 resides in the downfield shift in the
chemical shifts of the hydrogen atoms H8’, H11’, and H12’ of the
anilinium station due to their hydrogen bonding with the
extra DB24C8 and the shielding of H3’–4’–5’ due to their localiza-
tion in the shielding cavity of the extra DB24C8. These compar-
isons between 3 and 6 illustrate the localization of DB24C8
around the anilinium site in 3 and the extended state of the
muscle. This last extended co-conformation is finally corrobo-
1
rated by a direct comparison between the H NMR spectra of 6
and its non-interlocked analogue 6u[15] (Figure 4e,f), for which
exactly the same trend in the displacement of chemical shifts
can be observed between 6 and 6u as between 8 and 8u.
Conclusion
We report the self-assembled synthesis of a novel molecular ar-
chitecture that contains a [c2]daisy scaffold linked to two [2]ro-
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(4 mL) was added to the solution and the mixture was stirred at RT
for 72 h. The solution was then evaporated and the residue was di-
luted in Milli-Q water (2 mL). Ammonium hexafluorophosphate
(39 mg, 6 equiv, 0.246 mmol) was introduced and CH2Cl2 (2 mL)
was added to the solution. The resulting bilayer solution was vigo-
rously stirred at RT for 30 min. After separation, the aqueous layer
was extracted with CH2Cl2 (3”15 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under vacuum
to obtain fully protonated triazolium-containing hetero[4]rotaxane
molecular machine 3 as a brown solid (yield: 146 mg, 94%). Rf:
taxane units. The combination of different molecular stations
(ammonium, anilinium, and triazolium) with DB24C8 units al-
lowed for the molecular shuttling of the extra DB24C8 in the
two rotaxane units. Nevertheless, the molecular muscle could
not be actuated because of the impossibility of deprotonating
the ammonium station regardless of the conditions. This result
was unexpected because deprotonation of analogous molecu-
lar muscles, albeit only bis-interlocked and thus devoid of the
extra DB24C8 on the axle linked to the daisy scaffold, could be
protonated and deprotonated easily, to give at will an extend-
ed or a contracted co-conformational state. Chemical access to
such tetra-interlocked molecular architectures now paves the
way to the possibility of generating multiple different motions
in a single molecule.
1
0.60 (CH2Cl2/CH3OH 9:1); H NMR (600 MHz, CD3CN, 298 K): d=8.55
(brs, 4H; H9’), 7.99 (s, 2H; H1’), 7.43 (s, 2H; H12’), 7.35 (s, 4H; H11’),
7.04–6.94, 6.67 (m, 4H; H2), 6.94–6.84 (m, 16H; HA’ HB’), 6.82 (d,
3J(HD,HE)=8.2 Hz, 2H; HD), 6.79–6.71 (m, 10H; HB HN HO HP HQ), 6.44
(d, 3J(HE,HD)=8.2 Hz, 2H; HE), 4.59–4.41 (m, 4H; H1), 4.47 (t,
3J(H14,H13)=7.3 Hz, 4H; H14), 4.21–3.38 (m, 48H; HG HH HI HJ HK HL
HS HT HU HV HW HX), 4.21–4.06 (m, 16H; HC’), 4.17 (m, 4H; H8’), 4.04
(s, 6H; H16’), 3.89–3.72 (m, 16H; HD’), 3.65–3.58 (m, 8H; HE’’), 3.46–
3
3.38 (m, 12H; H3 HE’), 2.51 (t, J(H3’,H4’)=7.8 Hz, 4H; H3’), 1.94 (m,
Experimental Section
3
4H; H13), 1.71 (quint., J(H4,H3)=3J(H4,H5)=7.8 Hz, 4H; H4), 1.67 (m,
Hetero[4]rotaxane 3
3J(H7’,H6’)=3J(H7’,H8’)=7.5 Hz, 4H; H7’), 1.41–1.35 (m, 4H; H4’), 1.41–
1.17 (m, 40H; H5 H5’ H6 H6’ H7 H8 H9 H10 H11 H12), 1.20 ppm (s, 36H;
H15’); 13C NMR (151 MHz, CD3CN, 298 K): d=153.9, 148.6, 147.1,
145.6, 136.2, 128.5, 126.4, 123.7 (CA CC CF CM CR C2’ C10’ C13’ C14’),
125.1 (C12’), 122.4, 122.3, 121.7, 114.3, 113.6, 113.5, 113.1, 112.8 (CA’
CB CB’ CD CE CN CO CP CQ), 121.7 (C1’), 117.9 (C11’), 73.1, 71.6, 71.5,
71.3, 71.2, 69.8, 69.3, 69.1, 68.6, 68.3, 68.2, 68.1 (CG CH CI CJ CK CL CS
CT CU CV CW CX), 71.7 (CE’ CE’’), 71.2 (CD’), 69.3 (CC’), 54.7 (C14), 52.9
(C1), 51.7 (C8’), 49.9 (C3), 38.3 (C16’), 31.5 (C15’), 30.4, 30.3, 30.2, 30.0,
29.3, 28.3, 27.4, 26.7, 26.5 (C4’ C5 C5’ C6 C6’ C7 C8 C9 C10 C11 C12), 29.7
(C13), 27.4 (C4 C7’), 23.7 ppm (C3’); HRMS (ESI): m/z calcd for
[C168H260N10O32]6+: 488.3171 [MÀ6PF6]6+; found: 488.3181.
Step 1
Alkynanilinium 2 (55 mg, 2 equiv, 0.12 mmol) and dibenzo-24-
crown-8 (135 mg, 5 equiv, 0.3 mmol) were added to
a flask
(volume: 5 mL) and dissolved in dry, degassed CH2Cl2 (1 mL). After
stirring for 15 min at RT, hermaphrodite molecule 1 (100 mg,
2 equiv, 0.12 mmol) was added to the solution, followed by
Cu(CH3CN)4PF6 (22 mg, 1 equiv, 0.06 mmol) and a drop of 2,6-luti-
dine. The mixture was stirred at RT for 72 h. The residue was then
diluted with CH2Cl2 (15 mL) and washed with aqueous disodium
ethylenediaminetetraacetate dihydrate (0.1m; 2”40 mL). The com-
bined aqueous layers were extracted with CH2Cl2 (3”20 mL). The
organic layers were combined, dried over MgSO4, filtered, and con-
centrated under vacuum. The crude product was purified by using
chromatography on a lipophilic Sephadex LH-20 column (solvent
elution: CH2Cl2) to afford the pure hetero[4]rotaxane intermediate
as a brown solid (yield: 143 mg, 69%). Rf: 0.55 (CH2Cl2/CH3OH 9:1);
1H NMR (600 MHz, CDCl3, 298 K): d=8.48 (brs, 4H; H9’), 7.45 (s, 2H;
H1’), 7.33 (s, 4H; H11’), 7.31 (s, 2H; H12’), 6.93–6.74 (m, 16H; HA’ HB’
Hetero[4]rotaxane 4
A solution of tetra-protonated triazolium-containing hetero[4]rotax-
ane molecular machine 3 (42 mg, 1 equiv, 0.011 mmol) in CH2Cl2
(15 mL) was washed with aqueous sodium hydroxide (1m; 2”
15 mL). The aqueous layer was extracted with CH2Cl2 (3”15 mL),
then the combined organic layers were dried over MgSO4, filtered,
and concentrated under vacuum to obtain selectively dideproto-
nated triazolium-containing hetero[4]rotaxane molecular muscle 4
quantitatively as a brown solid (yield: 38 mg). Rf: 0.53 (CH2Cl2/
3
3
HN HO HP HQ), 6.88 (d, J(HD,HE)=8.1 Hz, 2H; HD), 6.65 (d, J(HD,HE)=
8.1 Hz, 2H; HE), 6.64 (s, 2H; HB), 4.52–4.35 (m, 4H; H1), 4.52–3.55
(m, 48H; HG HH HI HJ HK HL HS HT HU HV HW HX), 4.33 (t, J(H14,H13)=
3
7.3 Hz, 4H; H14), 4.24–4.17 (m, 8H; HC’’), 4.13–4.08 (m, 8H; HC’), 4.12
(m, 4H; H8’), 3.87–3.79 (m, 16H; HD’), 3.68–3.63 (m, 8H; HE’’), 3.55–
1
CH3OH 9:1); H NMR (600 MHz, CD3CN, 298 K): d=8.76 (s, 2H; H1’),
3.35 (m, 12H; H3 HE’), 2.54 (t, J(H3’,H4’)=7.6 Hz, 4H; H3’), 1.94–1.84
3
6.68–6.92, 6.67 (m, 4H; H2), 6.92–6.75 (m, 10H; HB HN HO HP HQ),
(m, 4H; H13), 1.74–1.64 (quint., J(H3,H4)=3J(H4,H5)=7.6 Hz, 4H; H4),
3
3
6.87–6.79 (m, 16H; HA’ HB’), 6.81 (d, J(HD,HE)=8.2 Hz, 2H; HD), 6.74
1.64–1.53 (m, 4H; H7’), 1.42 (quint., 3J(H4’,H3’)=3J(H4’,H5’)=7.6 Hz,
4H; H4’), 1.37–1.28 (m, 8H; H5 H12), 1.37–1.10 (m, 24H; H6 H7 H8 H9
H10 H11), 1.28–1.10 (m, 8H; H5’ H6’), 1.19 ppm (s, 36H; H15’); 13C NMR
(101 MHz, CDCl3, 298 K): d=152.7, 147.7, 147.6, 147.5, 146.4, 146.2,
135.3 (CA CC CF CM CR C2’ C10’ C13’ C14’), 123.5 (C12’), 121.6 (C1’), 121.1,
121.0, 112.9, 112.8, 112.4, 111.8 (CA’ CB CB’ CD CE CN CO CP CQ), 117.0
(C11’), 72.2, 72.0, 70.9, 70.8, 70.3, 70.4, 68.4, 68.2, 67.5, 67.1, 66.9 (CG
CH CI CJ CK CL CS CT CU CV CW CX), 70.9 (CE’ CE’’), 70.3 (CD’), 68.2 (CC’
CC’’), 52.2 (C1), 50.9 (C8’), 50.2 (C14), 49.9 (C3), 31.3 (C15’), 30.5 (C13),
29.5, 29.4, 29.3, 29.2, 29.1, 29.0, 26.6, 25.9 (C4’ C5 C5’ C6 C6’ C7 C8 C9
C10 C11 C12), 27.7 (C7’), 26.7 (C4), 25.6 ppm (C3’); HRMS (ESI): m/z
calcd for [C166H254N10O32]4+: 724.9639 [MÀ4PF6]4+; found: 724.9652.
(brt, 2H; H12’), 6.47 (brd, 4H; H11’), 6.44 (d, 3J(HE,HD)=8.2 Hz, 2H;
HE), 4.94 (brs, 4H; H14), 4.59–4.41 (m, 4H; H1), 4.18–3.61 (m, 48H;
HG HH HI HJ HK HL HS HT HU HV HW HX), 4.15–4.06 (m, 8H; HC’’), 4.06–
3.98 (m, 8H; HC’), 3.82–3.76 (m, 8H; HD’’), 3.76–3.69 (m, 8H; HD’),
3.65 (s, 6H; H16’), 3.62–3.55 (m, 8H; HE’’), 3.55–3.47 (m, 8H; HE’),
3
3.47–3.37 (m, 8H; H3 H3’), 3.07 (t, J(H8’,H7’)’ =6.4 Hz, 4H; H8’), 1.96–
3
1.89 (m, 4H; H13), 1.72 (quint., J(H4,H3)=3J(H4,H5)=7.9 Hz, 4H; H4),
1.61–1.49 (m, 8H; H4’ H7’), 1.49–0.96 (m, 40H; H5 H5’ H6 H6’ H7 H8 H9
H10 H11 H12), 1.27 ppm (s, 36H; H15’); 13C NMR (151 MHz, CD3CN,
298 K): d=152.5, 149.7, 148.8, 148.6, 147.3, 147.1, 126.4 (CA CC CF
CM CR C2’ C10’ C13’ C14’), 129.8 (C1’), 123.7, 123.2, 122.5, 121.8, 121.7,
114.3, 113.6, 113.1, 112.8, 112.1 (C12’ CA’ CB CB’ CD CE CN CO CP CQ),
108.2 (C11’), 73.1, 71.9, 71.7, 71.6, 71.5, 71.4, 71.2, 71.1, 70.9, 70.3,
70.2, 70.0, 69.2, 68.6, 68.3, 68.2, 68.1 (CC’ CC’’ CD’ CD’’ CE’ CE’’ CG CH CI
CJ CK CL CS CT CU CV CW CX), 54.5 (C14), 52.9 (C1), 49.9 (C3’), 49.9 (C3),
44.5 (C8’), 31.8 (C15’), 37.1 (C16’), 31.9, 31.6, 31.5, 31.4, 30.4, 30.3, 30.1,
30.0, 29.9, 29.7, 29.5, 27.5, 27.4, 27.2 ppm (C4 C4’ C5 C5’ C6 C6’ C7 C7’
Step 2
The previously isolated intermediate (143 mg, 1 equiv, 0.041 mmol)
was dissolved in dry CH2Cl2 (0.5 mL). An excess of iodomethane
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C8 C9 C10 C11 C12 C13); HRMS (ESI): m/z calcd for [C168H260N10O32]5+
614.9733 [MÀ3PF6 +2H]5+, found: 614.9746.
:
1.87 (m, 4H; H13), 1.72 (quint., J(H4,H3)=3J(H4,H5)=7.3 Hz, 4H; H4),
1.67 (quint., 3J(H4’,H3’)=3J(H4’,H5’)=7.6 Hz, 4H; H4’), 1.51 (quint.,
3J(H7’,H6’)=3J(H7’,H8’)=7.3 Hz, 4H; H7’), 1.42–1.17 (m, 40H; H5 H5’ H6
H6’ H7 H8 H9 H10 H11 H12), 1.39 (s, 18H; H9’), 1.31 ppm (s, 36H; H15’);
13C NMR (151 MHz, CD3CN, 298 K): d=155.6, 152.3, 148.8, 147.3,
147.1, 145.7, 143.2 (CA CC CF CM CR C2’ C10’ C13’ C14’), 128.6 (C1’), 123.7,
122.5, 121.7, 114.3, 113.1, 112.8 (CB CD CE CN CO CP CQ), 122.5 (C11’),
120.8 (C12’), 73.1, 73.0, 71.6, 71.5, 71.3, 71.1, 68.6, 68.3, 68.2, 68.1 (CG
CH CI CJ CK CL CS CT CU CV CW CX), 54.6 (C14), 52.9 (C1), 50.6 (C8’), 49.9
(C3), 38.2 (C16’), 31.7 (C15’), 30.3, 29.9, 29.7, 29.6, 29.1, 28.9, 27.5, 27.4,
26.9, 26.7 (C4 C4’ C5 C5’ C6 C6’ C7 C7’ C8 C9 C10 C11 C12), 30.2 (C13), 28.7
3
Extended molecular muscle 6
Step 1
Carbamoylated compound 5 (49 mg, 2 equiv, 0.12 mmol) was dis-
solved in dry and degassed CH2Cl2 (2.5 mL), then hermaphrodite
molecule 1 (100 mg, 2 equiv, 0.12 mmol) was added to the solu-
tion, followed by Cu(CH3CN)4PF6 (22 mg, 1 equiv, 0.06 mmol) and
a drop of 2,6-lutidine. The reaction mixture was stirred at RT for
48 h, then CH2Cl2 (15 mL) was added to the mixture. The solution
was washed with aqueous disodium ethylenediaminetetraacetate
dihydrate (0.1m; 3”30 mL). The combined aqueous layers were ex-
tracted with CH2Cl2 (3”20 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated under vacuum. The
crude product was purified by using chromatography on a silica
gel column (solvent elution: CH2Cl2/CH3OH 100:0 to 98:2) to afford
the pure di-N-carbamoylated triazole-containing molecular muscle
as a white solid (yield: 96 mg, 65%). Rf: 0.60 (CH2Cl2/CH3OH 95:5);
1H NMR (400 MHz, CD3CN, 298 K): d=7.45 (s, 2H; H1’), 7.30 (brt,
(C9’), 23.7 ppm (C3’); HRMS (ESI): m/z calcd for [C130H210N10O20]4+
588.1439 [MÀ4PF6]4+; found: 588.1444.
:
Step 3
The previously isolated triazolium-containing molecular muscle
(63 mg, 1 equiv, 0.021 mmol) was dissolved in dry CH2Cl2 (0.5 mL).
An excess of hydrogen chloride (2m) in diethyl ether (15 mL) was
added to the solution and the mixture was stirred at 08C for 2 h.
The solution was evaporated, and the residue was then diluted
with Milli-Q water (2 mL). Ammonium hexafluorophosphate
(25 mg, 6 equiv, 0.15 mmol) was introduced and CH2Cl2 (2 mL) was
added to the solution. The resulting bilayer solution was vigorously
stirred at RT for 30 min. After separation, the aqueous layer was ex-
tracted with CH2Cl2 (3”15 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated under vacuum to
obtain protonated molecular muscle 6 quantitatively as a beige
solid. Rf: 0.66 (CH2Cl2/CH3OH 9:1); 1H NMR (600 MHz, CD3CN,
298 K): d=8.12 (s, 2H; H1’), 7.21 (s, 2H; H12’), 6.97–6.87, 6.67 (m,
4H; H2), 6.92 (s, 4H; H11’), 6.81 (dd, 4J(HD,HB)=1.7 Hz, 3J(HD,HE)=
8.2 Hz, 2H; HD), 6.79–6.72 (m, 10H; HB HN HO HP HQ), 6.44 (d,
3J(HE,HD)=8.2 Hz, 2H; HE), 4.57–4.41 (m, 4H; H1), 4.46 (t,
3J(H14,H13)=7.2 Hz, 4H; H14), 4.19–3.60 (m, 48H; HG HH HI HJ HK HL
HS HT HU HV HW HX), 4.09 (s, 6H; H16’), 3.47–3.37 (m, 4H; H3), 3.26 (t,
4
4J(H12’,H11’)=1.3 Hz, 2H; H12’), 7.03 (d, 4H; J(H11’,H12’)=1.3 Hz, H11’),
6.97–6.85, 6.68 (m, 4H; H2), 6.85–6.71 (m, 10H; HB HN HO HP HQ),
6.82 (d, 3J(HD,HE)=8.2 Hz, 2H; HD), 6.44 (d, 3J(HE,HD)=8.2 Hz, 2H;
HE), 4.59–4.41 (m, 4H; H1), 4.27 (t, 3J(H14,H13)=7.1 Hz, 4H; H14),
4.19–3.65 (m, 48H; HG HH HI HJ HK HL HS HT HU HV HW HX), 3.60 (t,
3J(H8’,H7’)=7.2 Hz, 4H; H8’), 3.49–3.35 (m, 4H; H3), 2.60 (t,
3J(H3’,H4’)=7.5 Hz, 4H; H3’), 1.82 (quint., 3J(H13,H14)=3J(H13,H12)=
7.1 Hz, 4H; H13), 1.72 (quint., 3J(H4,H3)=3J(H4,H5)=7.2 Hz, 4H; H4),
1.65–1.53 (m, 4H; H4’), 1.53–1.43 (m, 4H; H7’), 1.40 (s, 18H; H9’),
1.42–1.17 (m, 40H; H5 H5’ H6 H6’ H7 H8 H9 H10 H11 H12), 1.30 ppm (s,
36H; H15’); 13C NMR (101 MHz, CD3CN, 298 K): d=155.5, 152.2,
148.8, 148.5, 147.2, 147.0, 143.3 (CA CC CF CM CR C2’ C10’ C13’ C14’),
123.6, 121.7, 114.2, 113.0, 112.8 (CB CD CE CN CO CP CQ), 122.5 (C11’),
122.0 (C1’), 120.7 (C12’), 73.1, 71.6, 71.5, 71.3, 71.1, 68.6, 68.3, 68.1,
68.0 (CG CH CI CJ CK CL CS CT CU CV CW CX), 52.9 (C1), 50.7 (C8’), 50.6
(C14), 49.9 (C3), 31.7 (C15’), 31.0 (C13), 30.2, 30.1, 30.0, 29.7, 29.6, 29.5,
29.1, 27.3, 27.1 (C4’ C5 C5’ C6 C6’ C7 C7’ C8 C9 C10 C11 C12), 27.7 (C9’),
27.3 (C4), 26.2 ppm (C3’); HRMS (ESI): m/z calcd for [C128H205N10O20]3+
: 734.5121 [MÀ2PF6 +1H]3+, found: 734.5139.
3J(H8’,H7’)=7.4 Hz, 4H; H8’), 2.78 (t, J(H3’,H4’)=7.6 Hz, 4H; H3’), 1.97–
3
1.88 (m, 4H; H13), 1.76–1.63 (m, 12H; H4 H4’ H7’), 1.49–1.41
(brquint., 8H; H5’ H6’), 1.40–1.14 (m, 32H; H5 H6 H7 H8 H9 H10 H11
H12), 1.30 ppm (s, 36H; H15’); 13C NMR (101 MHz, CD3CN, 298 K): d=
153.7, 148.7, 147.2, 147.0, 145.7 (CA CC CF CM CR C2’ C10’ C13’ C14’),
128.6 (C1’), 119.0 (C12’), 114.2, 113.1, 112.8, 112.7 (CB CD CE CN CO CP
CQ), 113.4 (C11’), 73.0, 71.6, 71.5, 71.3, 71.1, 68.5, 68.3, 68.1, 68.0 (CG
CH CI CJ CK CL CS CT CU CV CW CX), 54.6 (C14), 52.9 (C1), 49.9 (C3), 49.5
(C8’), 38.2 (C16’), 31.5 (C15’), 30.3, 30.2, 30.1, 29.9, 29.6, 29.0, 28.0,
26.8, 26.7 (C5 C5’ C6 C6’ C7 C8 C9 C10 C11 C12), 29.6 (C13), 27.4 (C4 C4’
Step 2
The previously isolated di-N-carbamoylated triazole-containing mo-
lecular muscle (96 mg, 1 equiv, 0.039 mmol) was dissolved in dry
CH2Cl2 (0.5 mL) and an excess of iodomethane (3 mL) was added
to the solution. The reaction mixture was stirred at RT for 72 h,
then the solution was evaporated and the residue was diluted in
Milli-Q water (2.5 mL). Ammonium hexafluorophosphate (38 mg,
6 equiv, 0.234 mmol) was introduced and CH2Cl2 (2.5 mL) was
added to the solution. The resulting bilayer solution was vigorously
stirred at RT for 1 h. After separation, the aqueous layer was ex-
tracted with CH2Cl2 (3”15 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated under vacuum to
obtain the triazolium-containing molecular muscle as a white solid
(yield: 100 mg, 92%). Rf: 0.30 (CH2Cl2/CH3OH 95:5); 1H NMR
C7’), 23.6 ppm (C3’); HRMS (ESI): m/z calcd for [C120H195N10O16]5+
406.6957 [MÀ6PF6ÀH]5+; found: 406.6957.
:
Contracted molecular muscle 7
Extended molecular muscle 6 (61 mg, 1 equiv, 0.021 mmol) was
dissolved in CH2Cl2 (15 mL) and washed with aqueous sodium hy-
droxide (1m; 2”10 mL), then the aqueous layer was extracted
with CH2Cl2 (3”15 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated under vacuum to obtain
the deprotonated contracted molecular muscle 7 quantitatively as
1
a brown solid (yield: 49 mg). Rf: 0.60 (CH2Cl2/CH3OH 9:1); H NMR
4
(600 MHz, CD3CN, 298 K): d=8.11 (s, 2H; H1’), 7.32 (t, J(H12’,H11’)=
(600 MHz, CD3CN, 298 K): d=8.89 (s, 2H; H1’), 6.95–6.75 (m, 14H;
4
4
1.7 Hz, 2H; H12’), 7.04 (d, J(H11’,H12’)=1.7 Hz, 4H; H11’), 6.91, 6.67 (m,
HB HD HE HN HO HP HQ), 6.73 (t, J(H12’,H11’)=1.6 Hz, 2H; H12’), 6.46 (d,
4H; H2), 6.84–6.79 (m, 2H; HD), 6.84–6.71 (m, 10H; HB HN HO HP HQ),
6.44 (d, 3J(HE,HD)=8.2 Hz, 2H; HE), 4.56–4.42 (m, 4H; H1), 4.46 (t,
3J(H14,H13)=7.2 Hz, 4H; H14), 4.19–3.65 (m, 48H; HG HH HI HJ HK HL
4J(H11’,H12’)=1.6 Hz, 4H; H11’), 6.45 (brs, 2H; H9’), 4.91 (brs, 4H; H14),
4.11–3.46 (m, 48H; HG HH HI HJ HK HL HS HT HU HV HW HX), 3.68 (s,
6H; H16’), 3.63 (m, 4H; H1), 3.46–3.30 (m, 4H; H3’), 3.06 (t,
3J(H8’,H7’)=6.5 Hz, 4H; H8’), 2.54–2.43 (m, 4H; H3), 2.05–1.95 (m, 4H;
H13), 1.77–1.59 (m, 4H; H4’), 1.59–1.51 (m, 4H; H7’), 1.46–1.35 (m,
3
HS HT HU HV HW HX), 4.07 (s, 6H; H16’), 3.61 (t, J(H8’,H7’)=7.3 Hz, 4H;
3
H8’), 3.47–3.37 (m, 4H; H3), 2.76 (t, J(H3’,H4’)=7.6 Hz, 4H; H3’), 1.97–
Chem. Eur. J. 2016, 22, 6837 – 6845
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4H; H4), 1.46–0.80 (m, 40H; H5 H5’ H6 H6’ H7 H8 H9 H10 H11 H12),
1.26 ppm (s, 36H; H15’); 13C NMR (101 MHz, CD3CN, 298 K): d=
152.4, 149.9, 149.7, 148.7, 148.6, 147.4 (CA CC CF CM CR C2’ C10’ C13’
C14’), 122.2 (C1’), 121.8, 114.9, 112.9, 108.1 (CB CD CE CN CO CP CQ),
112.0 (C12’), 108.1 (C11’), 71.9, 71.7, 70.9, 70.6, 70.0, 69.9, 69.0 (CG CH
CI CJ CK CL CS CT CU CV CW CX), 54.4 (C1), 54.0 (C14), 50.0 (C3’), 49.9
(C3), 44.4 (C8’), 39.6, 37.3, 30.9, 30.4, 30.2, 29.9, 29.7, 29.5, 29.2, 28.2,
27.5, 27.3, 26.9, 23.6 (C4 C4’ C5 C5’ C6 C6’ C7 C7’ C8 C9 C10 C11 C12 C13),
35.4 (C16’), 31.7 ppm (C15’); HRMS (ESI): m/z calcd for
[C120H195N10O16]5+: 406.4951 [MÀ2PF6+3H]5+; found: 406.4951.
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Keywords: daisy chain
synthesis · rotaxanes · template synthesis
· molecular devices · biomimetic
[12] The 1H NMR spectroscopy evidence for the self-sorting strategy is re-
ported in the Supporting Information. In particular, the [c2]daisy chain
(i.e., the supramolecular interwoven dimer of hermaphrodite com-
pound 1; 1 equiv) proved to be very stable in the presence of anilinium
thread 2 (2 equiv) and/or the extra DB24C8 (3 and even 5 equiv),
whereas anilinium-containing thread 2 was entirely encircled by the
excess DB24C8.
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Received: January 30, 2016
Published online on April 6, 2016
Chem. Eur. J. 2016, 22, 6837 – 6845
www.chemeurj.org
6845
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