Slipping synthesis of cucurbit[7]uril-based [2]rotaxane in organic environment

Article abstract of DOI:10.1016/j.tetlet.2012.09.073

A dumbbell molecule with one naphthalimide and one isophthalic acid stoppers was synthesized and could fold into the cavity of cucurbit[7]uril (CB[7]) in formic acid to form a 1:1 complex. Once the solution of the complex was heated, the CB[7] ring would slip over the isophthalic acid unit, producing a stable [2]rotaxane. The energy barrier (H^?) of this slippage was estimated as 109 kJ mol^-1.

Full text of DOI:10.1016/j.tetlet.2012.09.073

Tetrahedron Letters 53 (2012) 6414–6417
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Slipping synthesis of cucurbit[7]uril-based [2]rotaxane in organic environment
⇑
Xinghua Huang, Shiyao Huang, Baoqi Zhai, Yu Zhang, Yanan Xu, Qiaochun Wang
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science & Technology, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2012
Revised 4 September 2012
Accepted 11 September 2012
Available online 22 September 2012
A dumbbell molecule with one naphthalimide and one isophthalic acid stoppers was synthesized and
could fold into the cavity of cucurbit[7]uril (CB[7]) in formic acid to form a 1:1 complex. Once the solution
of the complex was heated, the CB[7] ring would slip over the isophthalic acid unit, producing a stable
[2]rotaxane. The energy barrier (4Hà) of this slippage was estimated as 109 kJ molꢀ1
.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Rotaxane
Cucurbiturils
Slippage
Formic acid
Rotaxanes are interlocked molecular systems where one or
more macrocycles are trapped by a dumbbell-shaped molecule.
Resulting from the possibility of the macrocycles to conduct linear
movements along the dumbbell-shaped molecule, rotaxanes have
found applications in areas of molecular switches,1 logic gates,2
memories,3 machines,4 and catalytic systems,5 and thus have at-
tracted the attention of an ever-increasing group of researchers.
Cucurbiturils (CBs) are a series of barrel-shaped macrocycles that
are obtained from the acid-catalyzed cyclization between glycolu-
ril and formaldehyde. Owing to their easy synthesis, high stability,
and strong binding affinities with cationic guests, CBs are one of
the superior macrocyclic candidates in constructing rotaxanes.6
CB-based rotaxanes are usually obtained using the capping strat-
egy which involves a threading process between the CB ring and
a linear guest and the consequent stopping by bulky ends. Because
these threading processes occur only in aqueous environments,
water-soluble organic intermediates and aqueous organic reac-
tions are demanded, and as a result, there are only a few methods
reported in the construction of CB-based rotaxanes, namely Click
cycloaddition,7 dinitrophenyl stopping,8 amide-bond formation,9
and coordinating stopping.10 Herein we demonstrate a slipping
strategy to synthesize a CB-based [2]rotaxane in an organic acid,
which is simple with good-yield, and suitable for non-water solu-
ble guest. This methodology might open a new way toward the
supramolecule fabrication of CBs.
overcome the activation energy to slip over the dumbbell’s stop-
per. When the solution is cooled down, the rotaxane was formed
because the re-dissociation into the components becomes impossi-
ble as a result of the energy barrier. In this work, cucurbit[7]uril
(CB[7]) was chosen as the ring component for its appropriate cavity
for adopting a wide range of guests, as well as for the relative large
choice of the stoppers for the slippage. The dumbbell molecule 2
consists of one linear alkyl viologen unit linked by two stop-
pers—one 1,8-naphthalimide group and one isophthalic acid
(Scheme 1). The alkyl viologen unit can bind firmly with CB[7],11
and its location between the two stoppers would greatly stabilize
the formed [2]rotaxane by increasing the dissociation energy bar-
rier. The distance between the two carbonyls on the isophthalic
acid is about 7.0 Å (optimized by MM2, Fig. S4, Supplementary
data), which is greater than the annular diameter (5.4 Å) but smal-
ler than the equatorial width (7.3 Å) of CB[7],12 and would be suit-
able for the CB[7] slippage.
The dumbbell molecule 2 was synthesized from the bromo-
hexylation of 4-amino-1,8-naphthalimide 2c (Scheme S1, Supple-
mentary data), followed by the mono-quaternization with 4,4-
bipyridine, and finally linked with the isophthalic stopper.
Although there is cationic viologen on the axle, 2 could hardly dis-
solve in water, whereas it has a good solubility in organic solvents
of strong polarity, such as CH3OH, DMSO, and HCOOH. The solution
of 2 in formic acid presents a yellowish-green color but turns pale
with the addition of CB[7], indicating the existence of binding
behavior between them. Job’s plot curve (Fig. S5, Supplementary
data) reveals that 2 forms a 1:1 complex with CB[7] (2@CB) and
the binding constant K was determined as 500 Mꢀ1 (Fig. S6, Sup-
plementary data).
The slippage strategy for rotaxane is usually carried out by mix-
ing the macrocycle and the dumbbell together in a certain solvent
and then heating at a high temperature that the macrocycle could
The 1H NMR spectroscopy is a useful technique for the binding
mode identification of CB-based inclusion complexes. It has been
⇑
Corresponding author. Tel.: +86 21 64252756; fax: +86 21 64252288.
E-mail address: qcwang@ecust.edu.cn (Q. Wang).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.073

X. Huang et al. / Tetrahedron Letters 53 (2012) 6414–6417
6415
Scheme 1. The formation of 2@CB and R2 in 95% HCOOH.
Figure 1. 1H NMR spectra (400 MHz, 95% DCOOD, 298 K) of (a) 2@CB (20 mM of 2
and 40 mM of CB[7]) with 10 equiv of AD after 7 days; (b) 2@CB (20 mM of 2 and
40 mM of CB[7]); (c) 2 (20 mM); (d) R2 (20 mM); (e) R2 (20 mM) with 10 equiv of
AD after 7 days (⁄ peaks of CB[7], # solvent residual signal).
found that the guest protons inside the hydrophobic cavity of
cucurbituril lie in a magnetic shielding region and their NMR sig-
nals undergo an upfield shift; on the contrary, the outside ones un-
dergo deshielding effects and have downfield-shifted signals,
whereas those near the carbonyl rim are scarcely affected.13
Figure 1 shows the 1H NMR signals of 2 (20 mM) and its mixing
with 2.0 equiv. of CB[7] (the ratio of 2@CB was estimated as 91.6%
by the binding constant K of 2 and CB[7] in 95% HCOOH, Fig. S6,
Supplementary data) in 95% deuterated HCOOH at 298 K. Com-
pared with the dumbbell molecule, the viologen proton Hn and
all the hexyl protons on 2@CB undergo shielding effects
ever, there are no distinct NOEs that could be found between the
two ends of the hexyl unit in R2 under the same situation as
2@CB (Fig. S8, Supplementary data). These phenomena indicate
that R2 is a [2]rotaxane where the CB[7] ring resides over the hexyl
group and one of the positive charge of the viologen unit
(Scheme 1).
To further confirm the co-conformations of 2@CB and R2,
10 equiv of adamantane ammonium hydrochloride (AD), which is
of high affinity with CB[7] (K > 1012 Mꢀ1),14 were added respec-
tively and the 1H NMR spectra were recorded after 7 days
(Fig. 1a and 1e). In the 2@CB + AD system, the encircled 2 was
found to become free, indicating that CB7 was caught by AD
(AD@CB). By contrast, the signals of R2 remained unaffected after
the addition of AD. These results prove the fact that 2@CB is a
pseudorotaxane and R2 is a true [2]rotaxane.
It has been found that the pKa value of an amine would increase
when entering into the cavity of CBs.15 The measurement of the
pKa values of the 4-amino naphthalimide in 2 and R2 was then car-
ried out, as shown in Figures S9 and S10 (Supplementary data). The
pKa value of the 4-amino in 2 was 1.16 and that in R2 was found to
be 1.37. Although the pKa shift is relatively small, the amino group
linked to the naphthalimide unit remains intact in 2 but would be-
come protonated in R2 in 95% HCOOH, which is of a pH value of
1.17. The UV/Vis absorption measurements of R2 and 2 in 95%
HCOOH at 298 K are shown in Figure S11 (Supplementary data).
The maximum absorption wavelength of 2 in 95% HCOOH is
454 nm and the color of the solution is yellowish-green, while that
of R2 is about 340 nm and turns colorless. These facts are coinci-
dent with the absorption of 4-amino naphthalimide before and
after protonization.16
(
D
D
dHn = ꢀ0.17,
dHj = ꢀ0.73,
naphthalimide and other protons on the viologen unit show down-
field-shifted signals dHb = 0.51, dHc = 0.26, dHd = 0.22,
dHp = 0.12, dHq = 0.25, dHr = 0.01). These facts reveal that the
D
dHg = ꢀ0.12,
D
dHh = ꢀ0.65,
D
dHi = ꢀ0.61,
D
dHk = ꢀ0.74, dHm = ꢀ0.35); the protons on the
D
(
D
D
D
D
D
D
CB[7] ring encircles the hexyl group with the naphthalimide and
viologen units sticking out from the openings of CB[7]. Further
2D 1H NOESY NMR measurement (Fig. S7, Supplementary data)
shows the proximity of Hg to Hi/Hk, indicating that 2@CB adopts
a conformation where the middle hexyl chain of 2 folds into the
cavity of CB[7] (Scheme 1).
The slipping experiment was then conducted by mixing 2 with
1.1 equiv of CB[7] in formic acid and the mixture was heated under
reflux for 48 h. TLC analysis (ethanol:water:40% HBr solu-
tion = 25:10:1) displayed a new product (Rf = 0.1). This is different
from 2@CB, which dissociates into two parts and only 2 can be
found when analyzed by TLC. The solution was then cooled and
concentrated by evaporation, the resulting solid was purified by
chromatography and the new product (R2) was found as a yellow
solid. The solid was proved to be a [2]rotaxane through the fol-
lowed identification, and the obtained yield was 57%.
The 1H NMR spectroscopy of R2 in 95% deuterated HCOOH is
shown in Figure 1d. Similar to 2@CB, the hexyl protons on R2 un-
dergo shielding effects, and the protons on the naphthalimide and
the viologen ones (Hp, Hq, Hr) conducts de-shielding effects. How-
The equilibrium constant (Ke) of the slipping process was inves-
tigated by monitoring the UV/Vis absorption of 2 and CB[7] mix-

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X. Huang et al. / Tetrahedron Letters 53 (2012) 6414–6417
then calculated as 1.2 ꢁ 107 Mꢀ1, which is much large than
1 ꢁ 105 Mꢀ1. It can thus be deemed that once CB[7] jumps over
the isophthalic acid stopper, it will be firmly fixed on the linear
axle and the slipping of CB[7] into 2 is not irreversible in 95%
HCOOH.
Among the slipping process, CB[7] and 2 must obtain appropri-
ate energy (4Hà) to form the activated complex [2+CB[7]]à, and
generate the final product R2. It is clear that the rate constants
kon are not only dependent on the activation enthalpy 4Hà, but re-
lated to the activation entropy 4Sà from Eyring equation (Supple-
mentary data). The slipping process was then carried out at four
different temperatures (348 K, 353 K, 358 K, 368 K) to obtain the
thermodynamic parameters. The rate constants kon can be easily
determined by the second order kinetic plot (kon = 0.98
mol3 Lꢀ1 sꢀ1
,
1.67 mol3 Lꢀ1 sꢀ1
,
2.27 mol3 Lꢀ1 sꢀ1
,
8.25
mol3 Lꢀ1 sꢀ1, Fig. 3a). The value of the activation enthalpy 4Hà,
the activation entropy 4Sà, and the free activation enthalpy 4Gà
(298 K, 4Gà = 4Hà ꢀT4Sà) are evaluated as 109 kJ molꢀ1
,
66.4 J Kꢀ1molꢀ1, and 89.2 kJ molꢀ1, respectively (Fig. 3b). Com-
pared with the ground state (CB[7] and 2), a positive value of
4Sà means that the activated complex [2+CB[7]]à is highly disor-
dered and is favorable to the slipping process.
Figure 2. The absorption spectra of 2 and CB[7] mixed in 95% HCOOH (both
5 ꢁ 10ꢀ5 M) heated at 358 K for different time (from 0 to 33.5 h) and immediately
cooled to 298 K. The inset shows the corresponding calculated concentration of R2
at 454 nm.
In summary, [2]rotaxane R2 was synthesized by heating the
mixture of a dumbbell compound and the CB[7] ring. The ring
slipped over the isophthalic stopper of the dumbbell molecule
and was trapped by the hexyl-viologen axle. It should be noted that
the construction of this simple CB-based rotaxane was conducted
in formic acid using non-water soluble guests, thus may arouse
expanding interests on the supramolecular chemistry of CBs.
Acknowledgments
This work was financially supported by the NSFC/ China
(21072058),
National
Basic
Research
973
Program
(2011CB808400), and the Fundamental Research Funds for the
Central Universities.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.
073.
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