Selective synthesis of a [3]rotaxane consisting of size-complementary components and its stepwise deslippage

Article abstract of DOI:10.1021/ol300578q

An α-cyclodextrin-based size-complementary [3]rotaxane with an alkylene axle was selectively synthesized in one pot via an end-capping reaction with 2-bromophenyl isocyanate in water. Thermal degradation of the [3]rotaxane product yielded not only the ori

Full text of DOI:10.1021/ol300578q

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2226–2229
Selective Synthesis of a [3]Rotaxane
Consisting of Size-Complementary
Components and Its Stepwise Deslippage
Yosuke Akae,† Hisashi Okamura,† Yasuhito Koyama,† Takayuki Arai,†,‡ and
Toshikazu Takata*,†
Department of Organic and Polymeric Materials, Tokyo Institute of Technology, 2-12-1
(H-126), Ookayama, Meguro, Tokyo 152-8552, Japan, and Research Laboratory,
LINTEC Corporation, 5-14-42, Nishiki-cho, Warabi-shi, Saitama 335-0005, Japan
ttakata@polymer.titech.ac.jp
Received March 6, 2012
ABSTRACT
An R-cyclodextrin-based size-complementary [3]rotaxane with an alkylene axle was selectively synthesized in one pot via an end-capping
reaction with 2-bromophenyl isocyanate in water. Thermal degradation of the [3]rotaxane product yielded not only the original components but
also the [2]rotaxane. Thermodynamic studies suggested a stepwise deslippage process.
Size-complementary rotaxanes,1 which contain a wheel,
an axle, and a size-complementary group to end-cap the
wheel cavity, are unique rotaxanes.2 The rotaxane struc-
ture is kinetically stabilized enough to be isolated under
normal conditions, but it can be dissociated into its
components when certain conditions are satisfied. The
dynamic properties of rotaxanes have been utilized to
develop polymers capable of undergoing reversible poly-
merization3 and network polymers that are degradable and
recyclable under specific stimuli in order to avoid damage
to the trunk polymer due to the lack of covalent bond
breaking at the cross-linking points.4,5 While such achieve-
ments have been made with crown ether/ammonium and
crown ether/paraquat rotaxane systems,3ꢀ5 no cyclodex-
trin (CD)-based size-complementary [3]rotaxane has been
reported, except the one described by Harada, probably
because of the synthetic challenges.6 We have recently
disclosed the one-pot high-yielding synthesis of CD-based
† Tokyo Institute of Technology.
‡ LINTEC Corporation.
(1) (a) Ashton, P. R.; Baxter, I.; Fyfe, M. C. T.; Raymo, F. M.;
Spencer, N.; Stoddart, J. F.; White, A. J. P.; Williams, D. J. J. Am. Chem.
Soc. 1998, 120, 2297–2307. (b) Tachibana, Y.; Kihara, N.; Furusho, Y.;
Takata, T. Org. Lett. 2004, 6, 4507–4509. (c) Makita, Y.; Kihara, N.;
Takata, T. J. Org. Chem. 2008, 73, 9245–9250.
(2) For selected reviews, see: (a) Gibson, H. W.; Bheda, M. C.;
Engen, P. T. Prog. Polym. Sci. 1994, 19, 843–945. (b) Nepogodiev, S. A.;
Stoddart, J. F. Chem. Rev. 1998, 98, 1959–1976. (c) Sauvage, J. -P.;
Dietrich-Buchecker, C. Molecular Catenanes, Rotaxanes, and Knots;
WileyꢀVCH: New York, Weinheim, 1999. (d) Harada, A. Acta Polym.
1998, 49, 3–17. (e) Harada, A. Acc. Chem. Res. 2001, 34, 456–464. (f)
Takata, T. Polym. J. 2006, 38, 1–20. (g) Frampton, M. J.; Anderson,
H. L. Angew. Chem., Int. Ed. 2007, 46, 1028–1064. (h) Ito, K. Polym. J.
2007, 39, 489–499. (i) Araki, J.; Ito, K. Soft Matter 2007, 3, 1456–1473.
(j) Li, J.; Loh, X. J. Adv. Drug Delivery Rev. 2008, 60, 1000–1017. (k) Yui,
N.; Katoono, R.; Yamashita, A. Adv. Polym. Sci. 2009, 222, 55–77. (l)
Harada, A.; Hashizume, A.; Yamaguchi, H.; Takashima, Y. Chem. Rev.
2009, 109, 5974–6023. (m) Harada, A.; Takashima, Y.; Yamaguchi, H.
Chem. Soc. Rev. 2009, 38, 875–882. (n) van de Manakker, F.; Vermonden,
T.; van Nostrum, C. F.; Hennink, W. E. Biomacromolecules 2009, 10,
3157–3175. (o) Supramolecular Polymer Chemistry; Harada, A., Ed.;
Wiley-VCH: Weinheim, 2012. (p) Huang, F.; Gibson, H. W. Prog. Polym.
Sci. 2005, 30, 982–1018.
(3) (a) Yamaguchi, N.; Gibson, H. W. Angew. Chem., Int. Ed. 1999,
38, 143–147. (b) Oku, T.; Furusho, Y.; Takata, T. J. Polym. Sci., Part A:
Polym. Chem. 2003, 41, 119–123. (c) Gibson, H. W.; Yamaguchi, N.;
Hamilton, L. M.; Jones, J. W. J. Am. Chem. Soc. 2002, 124, 4653–4665.
(d) Gibson, H. W.; Yamaguchi, N.; Jones, J. W. J. Am. Chem. Soc. 2003,
125, 3522–3533. (e) Huang, F.; Gibson, H. W. J. Am. Chem. Soc. 2004,
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J. W.; Rheingold, A. L.; Zakharov, L. N. J. Polym. Sci., Polym. Chem.
Ed. 2010, 48, 975–985.
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Takata, T. Macromolecules 2008, 41, 8496–8503.
r
10.1021/ol300578q
Published on Web 04/20/2012
2012 American Chemical Society

polyrotaxanes in water.7 We expected that this synthetic
protocol would be applicable to simple rotaxanes, and
because a simple alkylene axle-containing R-CD-based
rotaxane has not been reported to date, we have studied
the synthesis and properties of such a rotaxane.7,8 In this
paper, we report the synthesis and unique deslipping behav-
ior of a size-complementary R-CD-based [3]rotaxane.
Prior to the synthesis of the size-complementary
[3]rotaxane, we examined both the size of the end-cap
group and the length of the axle component by Corey,
Pauling, and later improved by Kultun (CPK) model
studies. It was found that the 2-bromophenyl group serves
as an end-cap group that is size-complementary to R-CD
and that dodecamethylene has an appropriate axle length.
The one-pot synthesis of [3]rotaxane was carried out
according to our previously reported method for CD-
based polyrotaxanes.8 The threading complexation of
1,12-diaminododecane and R-CD in refluxing water for 1 h
to form pseudo[3]rotaxane gave a heterogeneous mixture
to which 2-bromophenyl isocyanate was added at 0 °C.
The resulting mixture was allowed to stand for 1 h to
end-cap the axle termini (Scheme 1). Standard workup
afforded corresponding [3]rotaxane 1 in 73% yield. Two
remarkable results were achieved: (i) the yield was excep-
tionally high in spite of the heterogeneous system and (ii)
no [2]rotaxane was formed.9 Meanwhile, neither phenyl-
nor 2-methylphenyl isocyanate could be used as the end-
cap group, both yielding only a dumbbell-shaped product.
It is interesting that subtle differences in the size and
electronic properties of the end-cap group markedly af-
fected the end-cap function.
1
[3]Rotaxane 1 was sufficiently stable to carry out H
NMR measurements in DMSO-d6 at rt. The spectrum was
consistent with the structure of 1 (Figure 1A). To examine
the size-complementarity of the components of 1, a solu-
tion of 1 in DMSO-d6 was heated at 100 °C for 2.5 h. A
clear spectral change occurred just after heating at 100 °C
and progressed based on the heating time, indicating the
prompt thermal degradation of 1. Analysis of the product
supported the formation of not only [2]rotaxane 2 but also
dumbbell-shaped molecule 3, both of which were easily
Scheme 1. One-Pot Synthesis of [3]Rotaxane 1 from 1,12-Dia-
minododecane and R-CD via the Urea End-Capping Method
Scheme 2. Thermal Degradation of [3]Rotaxane 1 to
[2]Rotaxane 2 and a Dumbbell Molecule 3 via the Deslippage of
R-CD
Figure 1. 1H NMR spectra of (A) 1, (B) 2, (C) 3, and (D) R-CD (400 MHz, DMSO-d6, 298 K).
Org. Lett., Vol. 14, No. 9, 2012
2227

purified by reversed phase column chromatography
(Scheme 2). This result indicated the occurrence of thermal
deslipping of R-CD from 1 as well as 2, which is consistent
with the initial prediction that 1 consists of size-complemen-
tary components. The isolation of [2]rotaxane 2 (54% yield)
indicated that (i) deslipping from 2 to 3 is slower than that
from 1 to 2, and (ii) [2]rotaxane, which is difficult to syn-
thesize by the typical synthetic procedure, is readily
obtained,9,10 although it was not predicted on the basis of
the structural characteristics of 1 and 2.
Figure 1 shows the 1H NMR spectra of 1, 2, and 3, which
coincide well with their structures. In spectrum A, the
simple signal pattern that was observed around the urea
NꢀH signals (e and f: δ = 6.50 ppm) and the R-proton
signals (g: δ = 3.00ꢀ2.86 ppm) suggested structural
symmetry. Therefore, 1 is expected to have a symmetrical
head-to-head CD arrangement, judging from previous
reports that the secondary hydroxyl groups of the CD face
each other.7,11 On the other hand, in spectrum B, the split
signals around both the axle termini and alkylene chain
were consistent with the unsymmetrical structure of 2,
whose lack of symmetry originates from the unsymmetri-
cal nature of the R-CD moiety (Figure 1B). In this spec-
trum, the pairs of NꢀH protons (e, e0: δ = 7.81 and 7.78
ppm, f, f0: δ = 7.00 and 6.96 ppm) and the protons at the
R-position (g, g0: δ = 3.06 and 2.99 ppm) of the urea groups
appeared separately. The chemical shifts of the OH pro-
tons at the 2-, 3-, and 6-positions and the CꢀH proton at
the 1-position of the CDs were diagnostic for 1, 2, and 3
because of the large differences in chemical shift. In addi-
tion the high resolution mass spectral data of 1 and 2
strongly supported their structures.12
DMSO-d6 at 373 K as an example. The spectrum of the
reaction mixture distinctly exhibited the intermediary for-
mation of 2 and ultimately converged to a 1:2 molar ratio
mixture of 3 and R-CD after 1100 min.
The yieldꢀtime course curves 1ꢀ3 are shown in Figure 3.
The formation of [2]rotaxane 2 started soon after heating
began, while 3 appeared more gradually. The yield of 2
reached its maximum value (ca. 80%) after 1.4 h. With the
assumption that these deslippage reactions obeyed first-
order kinetics, the rate constants were determined from
the time vs ln([rotaxane]/[rotaxane]0) plots using the integral
1
ratios from the H NMR spectra (Table 1).12 Table 1
summarizes the reaction rate constants (k) of the deslippage
and the half-lives (τ) of 1and 2. The deslippage rate constant
of 2 (k2) was ∼10 times smaller than that of 1 (k1) at all
temperature levels, leading to the remarkable difference in
Figure 3. Time course curves of the formation of 1 (b), 2 (2), and
3 (0). The reaction was carried out with 1 (5.1 μmol) in DMSO-
d6 (0.6 mL) at 373 K. These plots are fitted with the theoretical
curves estimated from the kinetic parameters.
Since [2]rotaxane 2 could be isolated, a kinetic profile of
the deslippage of both 1 and 2 was investigated to elucidate
the features of the reaction. A solution of 1 in DMSO-d6
was heated at arbitrary temperatures (333, 353, 373, and
393 K) and subjected to 1H NMR measurements. Figure 2
shows the time-dependent NMR spectral changes of 1 in
Table 1. Rate Constants (k) for The Two-Step Deslippage
Reaction of [3]Rotaxane 1 (1 f 2 f 3) and Half-Lives (τ) of 1
and 2a
temp/K
k1/sꢀ1
τ1/h
k2/sꢀ1
τ2/h
333
353
373
393
2.1 ꢁ 10ꢀ5
6.5 ꢁ 10ꢀ5
5.0 ꢁ 10ꢀ4
9.2
2.4 ꢁ 10ꢀ6
6.6 ꢁ 10ꢀ6
5.2 ꢁ 10ꢀ5
2.8 ꢁ 10ꢀ4
80
3.0
29
3.7
0.68
0.39
b
b
ꢀ
ꢀ
a The reaction was carried out with 1 (5.1 μmol) in DMSO-d6
(0.6 mL). The terms k1 and τ1 are for the reaction 1 f 2, and k2 and
τ2, for 2 f 3. b Not determined.
Table 2. Thermodynamic Parameters of Deslippage of 1 and 2
activation
activation
activation
entropy (ΔS‡)b/
J molꢀ1 Kꢀ1
energy (E)a/
enthalpy (ΔH‡)b/
rotaxane
kJ molꢀ1
kJ molꢀ1
3
3
3
3
[3]rotaxane
[2]rotaxane
81
88
78
85
ꢀ101
ꢀ99
Figure 2. Time-dependent NMR spectral changes around the
8.0ꢀ4.5 ppm region (400 MHz, DMSO-d6, 298 K) during the
deslippage reaction of 1. The reaction was carried out with a
solution of 1 (5.1 μmol) in DMSO-d6 (0.6 mL) at 373 K. The
diagnostic peaks are marked as 1 (b), 2 (2), and 3 (0).
a The activation energy was determined using an Arrhenius plot.
b The activation enthalpy and entropy were determined using an Eyring
plot.
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Org. Lett., Vol. 14, No. 9, 2012

To evaluate the stability of 2, we acquired a NOESY
NMR spectrum (Figure 4). The protons of the axle end
group (a and b) have NOE cross peaks with the protons
O(3)H of R-CD. This indicates the localization of the
R-CD wheel at the one end group by forming an inclu-
sion complex with the R-CD cavity from its head side.
This complexation would contribute to the stability of 2
(Scheme 2), being in good accordance with the large ΔH‡
of 2, as shown in Table 2. On the other hand, the result
suggests that the tail face of CD does not effectively form
such an inclusion complex. Therefore, the CD moieties in 1
with the head-to-head structure undergo deslippage more
rapidly than those in 2.
In conclusion, the present study has provided several
crucial insights and a scientific basis for rotaxane and
polyrotaxane studies from the following results: (i) a
selective synthesis of new size-complementary [3]rota-
xane in 73% yield, (ii) the discovery of the unique deslip-
ping behavior of CD, (iii) an evaluation of the stabilization
effect of [2]rotaxane based on the structural features, and
(iv) formation of a simple alkylene axle-containing CD-
based [2]rotaxane with a covalently capped end for the first
time. The results and insights obtained in this study will be
utilized in a variety of rotaxane-based systems and materi-
als such as rotaxane switches and degradable and recycl-
able cross-linked polymers, some of which are currently
underway.
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research from MEXT,
Japan (No. 22750101).
Figure 4. NOESY NMR spectrum of 2 (400 MHz, DMSO-d6,
298 K).
Supporting Information Available. Full experimental
1
the half-lives. These results clearly suggest the stepwise
deslippage of 1, including the fast formation of 2 and its
slow decomposition to 3, facilitating the isolation of 2.
The thermodynamic parameters of the deslippage pro-
cesses are summarized in Table 2. The activation energy
(E) was determined from a plotof1/T vs lnk,12 whereas the
activation enthalpy (ΔH‡) and activation entropy (ΔS‡)
were derived from a plot of 1/T vs ln(k/T). As a result, it
was found that the deslippage process depends mainly on
the enthalpy term (ΔH‡) rather than the entropy term
(TΔS‡). The activation enthalpy of the deslippage of 2 is
much larger than that of the deslippage of 1, implying a
thermodynamically stable structure of 2.
details for all new compounds, including H NMR, 13C
NMR, IR spectra, and details of the kinetic and thermo-
dynamic parameters are provided. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(7) Akae, Y.; Arai, T.; Hayashi, M.; Takagi, N.; Okamura, H.;
Koyama, Y.; Hayashi, Y.; Kawauchi, S.; Takata, T. Submitted for
publication.
(8) (a) Arai, T.; Takata, T. Chem. Lett. 2007, 36, 418–419. (b) Arai,
T.; Hayashi, M.; Takagi, N.; Takata, T. Macromolecules 2009, 42, 1881–
1887. (c) Nakazono, K.; Takashima, T.; Arai, T.; Koyama, Y.; Takata,
T. Macromolecules 2010, 43, 691–696.
(9) Details on the synthesis of alkylene axle-containing CD-based
rotaxanes will be discussed elsewhere (e.g., ref 7).
(10) Ogino, H. J. Am. Chem. Soc. 1981, 103, 1303–1304.
(11) (a) Noltemeyer, M.; Saenger, W. Nature 1976, 259, 629–632. (b)
Harata, K.; Hirayama, F.; Uekama, K.; Tsoucaris, G. Chem. Lett. 1988,
17, 1585–1588.
(6) Reversible slipping and deslipping reactions of CD-based rotax-
anes having methylpyridinium end-cap groups have been reported; see:
(a) Oshikiri, T.; Takashima, Y.; Yamaguchi, H.; Harada, A. J. Am.
Chem. Soc. 2005, 127, 12186–12187. (b) Oshikiri, T.; Takashima, Y.;
Yamaguchi, H.; Harada, A. Chem.;Eur. J. 2007, 13, 7091–7098.
(12) See Supporting Information.
The authors declare no competing financial interest.
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