Rational Design for Rotaxane Synthesis through Intramolecular Slippage: Control of Activation Energy by Rigid Axle Length

Article abstract of DOI:10.1002/chem.201600429

We describe a new concept for rotaxane synthesis through intramolecular slippage using π-conjugated molecules as rigid axles linked with organic soluble and flexible permethylated α-cyclodextrins (PM α-CDs) as macrocycles. Through hydrophilic-hydrophobic interactions and flipping of PM α-CDs, successful quantitative conversion into rotaxanes was achieved without covalent bond formation. The rotaxanes had high activation barrier for their de-threading, so that they were kinetically isolated and derivatized even under conditions unfavorable for maintaining the rotaxane structures. ¹H NMR spectroscopy experiments clearly revealed that the restricted motion of the linked macrocycle with the rigid axle made it possible to control the kinetic stability by adjusting the length of the rigid axle in the precursor structure rather than the steric bulkiness of the stopper unit.

Full text of DOI:10.1002/chem.201600429

DOI: 10.1002/chem.201600429
Full Paper
&
Supramolecular Chemistry
Rational Design for Rotaxane Synthesis through Intramolecular
Slippage: Control of Activation Energy by Rigid Axle Length
Hiroshi Masai, Jun Terao,* Tetsuaki Fujihara, and Yasushi Tsuji[a]
Abstract: We describe a new concept for rotaxane synthesis
through intramolecular slippage using p-conjugated mole-
cules as rigid axles linked with organic soluble and flexible
permethylated a-cyclodextrins (PM a-CDs) as macrocycles.
Through hydrophilic–hydrophobic interactions and flipping
of PM a-CDs, successful quantitative conversion into rotax-
anes was achieved without covalent bond formation. The ro-
taxanes had high activation barrier for their de-threading, so
that they were kinetically isolated and derivatized even
under conditions unfavorable for maintaining the rotaxane
structures. 1H NMR spectroscopy experiments clearly re-
vealed that the restricted motion of the linked macrocycle
with the rigid axle made it possible to control the kinetic
stability by adjusting the length of the rigid axle in the pre-
cursor structure rather than the steric bulkiness of the stop-
per unit.
Introduction
Rotaxanes have gained great importance as functionalized ma-
terials since the macrocycles enhance the threading axle prop-
erties,[1,2] and the development of their new synthetic method-
ologies would be a significant advancement. Rotaxanes are
typically synthesized through the construction of “dynamic”
entwining structures of axles and macrocycles using noncova-
lent interactions (Figure 1a, step 1), for example, coordination,
p–p interactions, hydrophilic–hydrophobic interactions, and
hydrogen bonds. Subsequently, these threading structures are
fixed to form stable rotaxanes via covalent-bond formation in
the axle or macrocycle (step 2).[2,3] The step 2 process, howev-
er, must be carried out under reaction conditions that allow
for the formation of the noncovalent interactions required for
entwining in step 1, which restricts the scope of reactions for
rotaxane synthesis.
Figure 1. Illustration of synthetic methodologies for rotaxanes.
entwining process (step 1’) without a covalent bond formation
process (step 2). Moreover, after isolation, these structures can
be kinetically utilized, even under conditions that are unfavora-
ble for the entwining processes (step 1’). In spite of these ad-
vantages, expanded p-conjugated axles, which could be ap-
plied to various functional materials, have rarely been reported
by using slippage synthesis. Such synthetic difficulty is derived
from the low solubility of the individual p-conjugated axles
and from the low efficiency for their encapsulation, resulting in
synthetic problems such as harsh reaction conditions and low
yields.[6] Accordingly, insulated conjugated systems have been
classically synthesized by simultaneous entwining and covalent
bonding reactions (Figure 1a)[1] or by construction of cyclic
side chains orthogonal to the conjugated axles.[7]
As an exceptional methodology to evade such problems, ki-
netically stable rotaxanes were successfully synthesized only
by heating solutions of macrocycles and dumbbell-shaped
axles in appropriate solvents (Figure 1b).[4] Macrocycles with
sizes similar to those of the stoppers of the dumbbell unit (Rꢀ
r) could mechanically pass over the stoppers at high tempera-
ture, thus exceeding the activation energy derived from the
steric barrier between the macrocycles and stoppers. In this
methodology, which is classified as “slippage”,[5] all covalent
bonds in the components are fully constructed in the previous
steps. The kinetically stable rotaxane structures, therefore, can
be formed only under conditions that are appropriate for the
[a] H. Masai, Dr. J. Terao, Dr. T. Fujihara, Dr. Y. Tsuji
Department of Energy and Hydrocarbon Chemistry
Graduate School of Engineering, Kyoto University, Kyoto, 615-8510 (Japan)
E-mail: terao@scl.kyoto-u.ac.jp
In our studies on the synthesis of highly insulated p-conju-
gated molecules,[8] we focused on a transition state in the en-
twining process of [1]rotaxanes, where the cyclic molecules are
linked with the axle (Figure 2). Conventional [1]rotaxane pre-
cursors,[9] including our previous work,[8] had low activation
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201600429.
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barriers for self-inclusion processes using noncovalent interac-
tions (Figure 2a, step 1) due to their short or flexible axles (R>
a or b). Thus, the resultant rotaxanes were dynamic pseudoro-
taxanes that could be fixed to form [1]rotaxanes through cova-
lent-bond formation with the axle (step 2) under the same
condition as those in step 1. We report herein that rigid p-con-
jugated axles (b>Rꢀa) were successfully entwined with their
linked macrocycles to form kinetically stable rotaxanes (Fig-
ure 2b, step 1’), namely, through “intramolecular slippage”.
Owing to the linkage between the axle and macrocycle, this
methodology has the advantages of high solubility of the ex-
panded p-conjugated axles and entropically assisted insulation,
which results in efficient transformation under mild conditions
when compared with classical (intermolecular) slippage. More-
over, the linkage defines the motion area of the macrocycle
around the rigid axle (Figure 2b, pink circle), which controls
the threading direction and barrier. The rigid p-conjugated
axle with length Rꢀa could thread only at high temperatures.
In contrast to classical [1]rotaxane systems, this relationship
(Rꢀa) is maintained in p-conjugated rotaxanes because of the
axle rigidity. Thus, the entwining structures could be sterically
fixed at ambient temperature and kinetically isolated without
the introduction of three-dimensional bulky stoppers on the
axle unit. Consequently, the rotaxanes formed through intra-
molecular slippage could be isolated and derivatized to form
further functionalized and thermally stable rotaxanes, even
under conditions in which maintaining the rotaxane structure
is thermodynamically unfavorable. This method completely
separates the entwining-structure formation (step 1’) and cova-
lent-bond formation processes (step 2) for p-conjugated rotax-
ane synthesis. In this study, we describe the design, versatility,
expansibility, and mechanism of this new method for rotaxane
synthesis using intramolecular slippage.
Results and Discussion
Molecular design
As a precursor for intramolecular slippage, 1 consisted of
a rigid and linear axial oligo(phenylene ethynylene) (OPE)
linked with permethylated a-cyclodextrin (PM a-CD), which
has high organic solubility and a deep cavity (Figure 3). The
PM a-CD in 1 could not thread into the linked OPE axle on the
right side because of steric bulk, as is evident from the geo-
metric relation R<b.[8c] In PM a-CD, all the hydroxyl groups of
native a-CD are methylated, which inhibit intramolecular hy-
drogen bonds. Therefore, the glucopyranose units in PM a-CD
derivatives can fully rotate around the 1,4-glucopyranose
bonds with a high activation barrier. Although this process is
well known as “flipping”,[10] as shown in Figure 3a, the [1]rotax-
anes synthesized by flipping have been dynamic with un-
threaded precursors, which were categorized by their flexible
or short axles (R>a or b; Figure 2a). On the other hand, using
the flipping process, the linked PM a-CD in 1 could thread on
the left side of the rigid OPE axle to form rotaxane 1’ (Fig-
ure 3b). Concomitantly, since the motion of PM a-CD in 1 is re-
stricted owing to its linkage with the axle, the substituent (X)
on the OPE can control axial length (a; Figure 2b) and can effi-
ciently act as a steric barrier for insulation by flipping (steps D–
F in Figure 3b).[11] Consequently, this process involving flipping
of linked PM a-CD is expected to have a high activation
energy for transformation and to yield kinetically stable p-con-
jugated rotaxanes, that is, intramolecular slippage.
Reversible interconversion via intramolecular slippage
Intramolecular slippage by full rotation of one glucopyranose
1
unit in PM a-CD (flipping) was confirmed by H NMR analysis
of 1a with different polar solvents. Uninsulated 1a was dis-
solved in CD3OD/D2O (2:1), a high polarity solvent (Figure 4a).
The time course of the changes in chemical species at 608C
1
was followed in H NMR spectroscopy, as shown in Figure 4b–
d and g. The aromatic proton peaks corresponding to uninsu-
lated 1a gradually diminished and could no longer be detect-
ed after 2 h. Accordingly, those corresponding to insulated 1a’
gradually appeared and predominated at longer times, indicat-
ing quantitative conversion of 1a to 1a’ due to hydrophilic–
hydrophobic interactions. In DOSY NMR spectrum of 1a’,
a single band at logD=À9.33 was observed, which is a similar
value to that of 1a (logD=À9.36). The DOSY NMR experi-
ments indicated that the transformation from 1a to 1a’ was
an intramolecular process without any oligomerization of 1a.
The thus-formed 1a’ possessed high stability and could be
kinetically isolated by extraction, even when using low polarity
organic solvents, as confirmed by the 1H and ROESY NMR spec-
tra (Figure 4e),[12,13] because the slightly exposed substituent
(X) on the rigid OPE axle acted as an efficient stopper for rotax-
ane 1a’. Insulated 1a’ maintained its structure after 24 h at
room temperature, even in thermodynamically unfavorable sol-
vents, such as deuterated CHCl3 and THF (Figure S11 in the
Supporting Information), which indicated the kinetic stability
Figure 2. Illustration of synthetic methodologies for [1]rotaxanes. The pink
circle in (b) is the restricted motion area of a cyclic molecule; the threading
direction and barrier are determined by the geometric relation, b>Rꢀa, be-
tween the pink circle and gray rigid axle.
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Figure 3. a) Structure and flipping of PM a-CD. b) Threading mechanism by PM a-CD flipping of 1 to 1’.
of 1a’. Similarly, 1a’ was quantitatively converted into 1a and
isolated by heating in THF, which is a low polarity solvent (Fig-
ure 4 f and h, and Figure S10 in the Supporting Information).
These results demonstrated the reversible slippage intercon-
version between 1a and 1a’ through PM a-CD flipping.
formation). The non-conversion of 1d, which has a bulkier
acetyl moiety (a>R in Figure 2b) in place of the amino group
(aꢀR) of 1a, indicates that entwining by flipping at the amino
group side in the conversion from 1a and 1a’ occurs as shown
in Figure 3.
Quantitative slippage conversions into insulated structures
were demonstrated for a variety of p-conjugated axles. All the
p-conjugated structures in precursors 2–5 (Table 1) were con-
Scope of substrates for intramolecular slippage
Amine-substituted and iodo-substituted OPEs (1a and 1b, re-
spectively) showed quantitative conversion into their insulated
counterparts (1a’ and 1b’, respectively) by heating in MeOH/
H2O=1:1, and were isolated with high yields (84 and 83%, re-
spectively; Table 1) without requiring any removal process for
uninsulated substrates; no evidence of the uninsulated sub-
Table 1. Scope of substrates.
1
strates was found by H NMR analysis of the products (Figures
S1–S7 in the Supporting Information). In contrast, substitution
of OPE with an electron-withdrawing nitro group (1c) prevent-
ed quantitative conversion in CD3OD/D2O=1:1 because the ef-
ficiency of insulation by CDs was influenced by the electron
density on the axle unit.[14] However, 1c fully converted into its
insulated structure 1c’ in a higher polarity solvent (MeOH/
H2O=1:2) and was isolated in 87% yield. Namely, quantitative
intramolecular slippage transformations of 1a–c could be per-
formed by simple adjustments in solvent polarity regardless of
the electronic character of the substituents because of the en-
tropically assisted insulation due to the linkages. On the other
hand, acetyl-substituted 1d did not undergo intramolecular
slippage, with no changes observed by heating in CD3OD/
D2O=2:1 as a polar solvent (Figure S12 in the Supporting In-
[a] Yields after extraction with organic solvents. [b] MeOH/H2O (1:2) was
used as reaction solvent. [c] MeOH/H2O (5:4) at 658C was used as reac-
tion condition.
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1
Figure 4. Partial H NMR (500 MHz) spectra of: a) 1a (CD3OD/D2O=2:1, RT). Time course of 1a (CD3OD/D2O=2:1, 608C): b) 5 min, c) 15 min, and d) 2 h. e) Iso-
lated product (1a’) after heating 1a in CH3OH/H2O=2:1 (CDCl3, RT), and f) isolated product (1a) after heating 1a’ in THF (CDCl3, RT); * indicated the residual
1
CHCl3 peak. Kinetic trace from H NMR spectra for the transformation of: g) 1a into 1a’ in CD3OD/D2O=2:1 at 608C, and h) 1a’ into 1a in [D8]THF at 608C.
structed using general synthetic procedures for covalent bond
formations before the intramolecular slippage process. Various
p-conjugated units could be applied to this highly efficient in-
sulation procedure. Electron-withdrawing (2’), electron-donat-
ing (3’), and largely extended (4’) p-conjugated systems all un-
derwent intramolecular slippage, although their steric and
electronic states strongly influenced the insulation efficiency
and axial solubility. Moreover, perfect intramolecular slippage
was obtained with an oligothiophene backbone (5’). This
quantitative intramolecular slippage conversion completely re-
moves the need for covalent-bond formation during the rotax-
ane-formation process and will be a powerful strategy for the
construction of various functionalized material with insulated
p-conjugated units.
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Derivatization of products
Kinetic experiment of intramolecular slippage
The kinetic stability and synthetic utility of the intramolecular
slippage method were clarified by further derivatization of p-
conjugated rotaxanes (Scheme 1). Compounds 1a’ and 1b’
were successfully applied to subsequent molecular transforma-
tions, even in low polarity solvent systems. Amino-substituted
1a’ could be modified by amidation (6) or azidation followed
by a Huisgen cycloaddition (7) to yield functionalized p-conju-
gated rotaxanes. Iodo-substituted 1b’ was derivatized by
Suzuki–Miyaura coupling (8 and 9) or Sonogashira coupling
(10) to form further expanded p-conjugated rotaxanes. It is no-
table that no corresponding uninsulated structures were ob-
served in the 1H NMR spectra for any of the asymmetrically
functionalized p-conjugated rotaxanes without a purification
process to remove the uninsulated products, demonstrating
sufficient kinetic stability of 1a’ and 1b’ on the reaction time-
scale for derivatization (Figures S8 and S9 in the Supporting In-
formation). In addition, derivatization accompanied by elonga-
tion of the axle enhanced the thermal stability of the rotaxane
structure, as the insulation structures were retained even in
CDCl3 at 608C (Figures S13–17 in the Supporting Information).
In order to examine the mechanism of intramolecular slippage
transformation between 1a–c and 1a’–c’, detailed thermody-
1
namic and kinetic parameters were determined from H NMR
experiments in CD3OD as a lower polarity solvent, in which
mixtures of uninsulated 1a–c and insulated 1a’–c’ were ther-
modynamically formed, whereas in higher polarity CH3OH/H2O
(1:1) quantitative conversion to 1a’–c’ was obtained, as shown
in Table 1. The temperature dependence of the kinetic con-
stants (Table S1 in the Supporting Information), which were de-
termined by fitting the time course of the existence ratio of
the insulated and uninsulated units at 40, 50, and 608C, gave
the thermodynamic and kinetic parameters for association and
activation (Table S2 in the Supporting Information).[15]
Figure 5 summarizes the association and activation energies
at 258C. On increasing the electron densities of the p-conju-
gated guest unit by changing the substituent (X),[16] the associ-
ation energies increased (1c<1b<1a). This indicates that the
driving force for inclusion was CÀH···p interactions between
the p-conjugated units in the axles and the inner protons of
PM a-CDs. On the other hand, the activation energies were
Scheme 1. Derivatization of kinetically stable rotaxanes.
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Figure 5. Kinetic and thermodynamic data for 1 and 11 at 258C.
high enough to allow the product to be kinetically isolated
(103–108 kJmolÀ1, Figure 5) and were influenced by the size of
the substituent (NH2 <I<NO2, see Figure S46 in the Support-
ing Information), which is also supported by the significant dif-
page method for the synthesis of various insulated p-conjugat-
ed materials.
ference in the kinetic constants for different substituents (Table Experimental Section
S1 in the Supporting Information). These results clearly demon-
Experimental details are provided in Supporting Information.
strated that the enlarged activation barriers owing to the rigid
axles (length a in Figure 2b) linked with PM a-CD are responsi-
ble for the kinetic stability of rotaxanes formed through intra-
molecular slippage. The units 11 a–c bearing shorter OPE axles
(b<R in Figure 2b), where the linked PM a-CD threads
through on the terminal alkyne sides,[8a] had smaller activation
energies (91.4–91.8 kJmolÀ1) that were independent of the
substituent, whereas the association energies showed a trend
similar to that observed for 1a–c.[17] These results further sup-
port the influence on the activation energies of 1a–c by steric
effects of the substituents, rather than by electronic effects.
Acknowledgements
This research was supported by the Funding Program for JSPS
Research Fellow and Grant-in-Aid for Scientific Research (B)
and Scientific Research on Innovative Areas (“Molecular Archi-
tectonics” and “Soft Molecular Systems”) from MEXT, Japan.
This research was also supported by Tokuyama Science Foun-
dation and CREST, JST.
Keywords: cyclodextrins · host-guest systems · rotaxanes ·
Conclusions
supramolecular chemistry
In conclusion, a new synthetic strategy for kinetically stable p-
conjugated rotaxanes through intramolecular slippage of
linked PM a-CDs was successfully developed. This was ach-
ieved by restricting motion between the axle and macrocycle
and by adjusting the length of the p-conjugated rigid axle
without the introduction of three-dimensional bulky terminal
stopper groups. The effective transformation was supported
by the linkage between the axle and macrocycle, making it
possible to separate formation of the entwining structure (step
1’ in Figure 2) from covalent bond formation processes (step 2)
in p-conjugated rotaxane synthesis. These results indicate the
versatility and remarkable tolerance of this intramolecular slip-
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[12] The chemical shifts of the aromatic protons in the H NMR spectrum of
1a’ indicated the formation of a rotaxane; see reference [8a].
[13] The formation of an insulated structure was also supported by the con-
sistency of the 1H NMR spectra with that of 1a’ synthesized through
a conventional procedure, that is, simultaneous dynamic rotaxane pre-
cursor formation (step 1) and covalent-bond formation (step 2); see the
Supporting Information.
[14] The CÀH···p interaction is known as a driving force for association be-
tween CDs and aromatic compounds: M. Nishio, CrystEngComm 2004,
6, 130.
[15] Detailed procedures are shown in the Supporting Information (Figures
S84–S100).
[16] C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165.
[17] The ÀDG values of 1a–c slightly decreased compared with those of
corresponding 11 a–c due to the electron-withdrawing pyridyl group.
Received: February 3, 2016
Published online on March 29, 2016
Chem. Eur. J. 2016, 22, 6624 – 6630
www.chemeurj.org
6630
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