Highly selective and high-yielding rotaxane synthesis via aminolysis of prerotaxanes consisting of a ring component and a stopper unit

Article abstract of DOI:10.1021/ol070999w

A highly rotaxane-selective synthesis via aminolysis of prerotaxanes, which were composed of a phenolic pseudo-crown ether as a ring component and a bulky stopper unit, was developed. The best result was obtained in the case of aminolysis of 3b with 3,5-d

Full text of DOI:10.1021/ol070999w

ORGANIC
LETTERS
2007
Vol. 9, No. 16
2969-2972
Highly Selective and High-Yielding
Rotaxane Synthesis via Aminolysis of
Prerotaxanes Consisting of a Ring
Component and a Stopper Unit
Keiji Hirose,* Keiji Nishihara, Naoki Harada, Yamato Nakamura, Daisuke Masuda,
Masami Araki, and Yoshito Tobe
DiVision of Frontier Materials Science, Graduate School of Engineering Science,
Osaka UniVersity, 1-3 Machikaneyama, Toyonaka, Osaka 563-8531, Japan
hirose@chem.es.osaka-u.ac.jp
Received April 28, 2007
ABSTRACT
A highly rotaxane-selective synthesis via aminolysis of prerotaxanes, which were composed of a phenolic pseudo-crown ether as a ring
component and a bulky stopper unit, was developed. The best result was obtained in the case of aminolysis of 3b with 3,5-dimethylbenzylamine
which proceeded quantitatively with ca. 100% rotaxane selectivity forming the corresponding rotaxane 5b. The rotaxanes were formed by
kinetically controlled attack of the amine from the backside of the ring component of the prerotaxanes.
Several synthetic methods for the preparation of interlocked
molecules have been reported. A pioneering work for
preparing rotaxanes via covalently bonded intermediates was
reported by Schill during the 1960s.1 However, covalent
methods were not thought to be versatile because the
synthetic process is complicated and requires many reaction
steps resulting in very low yields of interlocked molecules.
Recently, high-yielding syntheses of interlocked molecules
by a stepwise covalent method were reported2 including
Kawai’s rotaxane synthesis using dynamic covalent bonds
between the axle and ring components. Among the stepwise
covalent methods, Hiratani reported a unique method based
on simultaneous cleavage of an ester linkage and formation
of an amide linkage via aminolysis of prerotaxanes having
ester linkages composed of ring and axle components.3 This
was not only useful because of an experimentally simple
method but also a milestone which might guide us to realize
a perfect rotaxane synthesis.
Here, we developed a highly rotaxane-selective synthetic
method via aminolysis of prerotaxanes, which were com-
posed of a phenolic pseudo-crown ether as a ring component
and a bulky benzoyl group as a stopper unit. The rotaxane
selectivity is defined here as a ratio of rotaxane produced
over all products by an aminolysis, namely, rotaxane over
the sum of a rotaxane and a dumbbell. Scheme 1illustrates
our method for preparing rotaxanes. If the aminolysis
proceeds via the nucleophilic attack of amine 4 from the
backside of the crown ether ring of prerotaxanes 3a-e, as
shown in Scheme 1, the corresponding rotaxanes 5a-f would
be obtained. To study the scope and limitation of this method,
six prerotaxanes 3a-f having either different ring sizes or
different substituents on the ring components and/or the
stopper group were synthesized and aminolyses with 3,5-
dimethylbenzylamine were investigated. This versatile method
is convincingly simple, consisting of two steps: first,
esterification of a phenolic crown ether with an acid chloride;
second, aminolysis with an amine compound having a bulky
(1) Schill, G.; Zollenkopf, H. Liebigs Ann. Chem. 1969, 721, 53-74.
(2) For rotaxane synthesis, see: (a) Kawai, H.; Umehara, T.; Fujiwara,
K.; Tsuji, T.; Suzuki, T. Angew. Chem., Int. Ed. Engl. 2006, 45, 4281-
4286. (b) Hiratani, K.; Kaneyama, M.; Nagawa, Y.; Koyama, E.; Kanesato,
M. J. Am. Chem. Soc. 2004, 126, 13568-13569. (c) Kameta, N.; Hiratani,
K.; Nagawa, Y. Chem. Commun. 2004, 466-467. For catenane syntheses,
see: (d) Godt, A. Eur. J. Org. Chem. 2004, 1639-1654.
(3) Hiratani, K.; Suga, J.; Nagawa, Y.; Houjou, H.; Tokuhisa, H.; Numata,
M.; Watanabe, K. Tetrahedron Lett. 2002, 43, 5747-5750.
10.1021/ol070999w CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/07/2007

Scheme 1. Preparation and Aminolysis of Prerotaxanes 3a-f
group. Several rotaxanes were readily synthesized in moder-
ate to good yields by this method.
Prerotaxanes 3a-f were prepared by acylation of crown
ethers 1a-e4 with benzoyl chloride 2a or 2b in the presence
of KOtBu in THF. As reference compounds, acyclic esters
7 and 8 were also prepared (Figure 1).
of 3b and 3d-f having a pseudo-24-crown-8 structure with
amine 4 proceeded to give the corresponding rotaxanes in
good selectivities. The 1H NMR signals of the prerotaxane,
rotaxane, and dumbbell at low magnetic fields are simple
and are conclusively assigned. Therefore, the efficiency of
the reaction was easily monitored by 1H NMR measurement
1
of the reaction mixture. In Figure 2, H NMR monitoring
spectra of a reaction mixture of aminolysis of 3b in different
solvents are shown as examples. In polar solvent DMF-d7,
the signals due to rotaxane 5b (blue) and dumbbell 6a (red)
are clearly observed in a 3:2 ratio. In less polar solvents,
however, the dumbbell signals are greatly diminished to
negligible extent especially in C6D6, indicating a remarkable
effect of solvent on the rotaxane selectivity. No product other
than rotaxane 5b, dumbbell 6a, and crown ether 1b was
detected; the aminolyses took place quantitatively in C6D6.
Indeed, 5b was isolated in high yield (82%). The selectivities
and isolated yields of the rotaxanes are summarized in Table
1.
Figure 1. Reference compounds 7 and 8.
The structures of rotaxanes 5b and 5d-f were character-
ized by spectral data. For example, H NMR spectra of
rotaxane 5b and the corresponding dumbbell 6a are shown
in Figure 3with assignments. A significant downfield shift
of the signal due to the amide proton He of the axle in
The reaction procedure from prerotaxanes 3a-f to the
corresponding rotaxanes 5a-f was very simple.5 A mixture
of a prerotaxane and amine 4 in an appropriate solvent was
stirred at room temperature. The residue after removal of
the solvent was subjected to column chromatography on
silica gel to give the rotaxane, the dumbbell compound, and
the crown ether.
In the aminolyses of 3a and 3c having pseudo-21-crown-7
and pseudo-27-crown-9 substructures, respectively, no ro-
taxane was isolated because the size of the rings was not
suited (either too small or too large) for rotaxane formation.
Only the corresponding dumbbell compound 6a and crown
ether 1a or 1c were formed. On the contrary, the reactions
1
(5) Representative procedure of aminolysis: Into a solution of 3b (52.9
mg, 78.7 µmol) in dry C6H6 (5 mL) was added amine 4 (13.1 mg, 97.0
µmol) in dry C6H6 (2 mL). After stirring for 3 days at room temperature,
the solvent was removed under reduced pressure. The residue was purified
by chromatography on SiO2 (ethyl acetate) to afford 5b (51.9 mg, 82%
yield) as a pale brown solid. Recrystallization from hexane-CHCl3 gave
colorless plates (mp 131.0-132.0 °C): 1H NMR (270 MHz, CDCl3, 30
°C) δ 2.31 (s, 6H), 2.56-2.63 (m, 2H), 2.99-3.05 (m, 2H), 3.09-3.15
(m, 2H), 3.20-3.27 (m, 2H), 3.33-3.42 (m, 4H), 3.44-3.78 (m, 12H),
4.10 (d, J ) 10.7 Hz, 2H), 4.56 (d, J ) 5.5 Hz, 2H), 4.59 (d, J ) 10.7 Hz,
2H), 6.87 (s, 1H), 6.88 (s, 2H), 7.06 (s, 2H), 8.25 (t, J ) 5.5 Hz, 1H), 8.79
(t, J ) 2.0 Hz, 1H), 9.28 (d, J ) 2.0 Hz, 2H); 13C NMR (100 MHz, CDCl3,
30 °C) δ 21.3 (p), 44.6 (s), 68.4 (s), 70.2 (s), 70.3 (s), 70.3 (s), 70.5 (s),
70.6 (s), 70.7 (s), 112.3 (q), 119.2 (t), 126.9 (t), 128.5 (t), 128.6 (q), 131.2
(t), 131.3 (t), 137.3 (q), 138.0 (q), 138.5 (q), 146.9 (q), 152.4 (q), 164.3
(q). IR (KBr, cm-1) 3324, 3087, 2902, 2875, 1646, 1538, 1465, 1343, 1247,
1215, 1107, 953, 846, 731; MS (FAB) m/z 808 (M + H)+, HRMS (FAB)
calcd for C36H47O13N3Br (M + H)+ 808.2292; found, 808.2280.
(4) Compounds 1a-f were synthesized according to the same procedures
reported in the following literature. Spectral data are found in the Supporting
Information. (a) Hirose, K.; Fujiwara, A.; Matsunaga, K.; Aoki, N.; Tobe,
Y. Tetrahedron Lett. 2002, 43, 8539-8542. (b) Hirose, K.; Fujiwara, A.;
Matsunaga, K.; Aoki, N.; Tobe, Y. Tetrahedron: Asymmetry 2003, 14, 555-
566.
2970
Org. Lett., Vol. 9, No. 16, 2007

Figure 3. 1HNMR (270 MHz, CDCl3) spectra of (a) rotaxane 5b
and (b) dumbbell 6a. The descriptors refer to the signals represent-
ing rotaxane and dumbbell protons shown in Scheme 1.
Figure 2. Partial 1H NMR (270 MHz, CDCl3) spectra of the
reaction mixture of aminolysis of 3b with 4 in (a) C6D6 ([3b] )
7.1 µmol, [4] ) 10.3 mmol), (b) CDCl3 ([3b] ) 6.8 µmol, [4] )
9.6 mmol), (c) CD3CN ([3b] ) 6.9 µmol, [4] ) 10.4 mmol), and
(d) DMF-d7 ([3b] ) 6.8 µmol, [4] ) 10.5 mmol).
Table 1. Selectivities and Yields of Rotaxanes in the Reaction
of Prerotaxanes 3a-f with Amine 4 at 30 °C
prerotaxane amine 4
time
(h)
yielda selectivityc
(10-3 M)
(10-3 M) solvent
(%)
(%)
3a (4.9)
3b (7.1)
3b (6.8)
3b (6.9)
3b (6.8)
3c (4.9)
3d (4.9)
3e (5.0)
3e (4.9)
3f (4.9)
3f (4.9)
3f (4.9)
(10.0)
(10.3)
(9.6)
(10.4)
(10.5)
(10.0)
(9.9)
CDCl3
C6D6
36
28
244
24
36
37
36
0.70
2
60
160
240
0
82
-
-
0d
100
96
b
CDCl3
CD3CN
DMF-d7
CDCl3
C6D6
C6D6
CDCl3
C6D6
Figure 4. Views of the rotaxane 5b. Broken lines represent
intramolecular hydrogen bonds and π-π stacking.
b
95
b
-
67
0
81
81
-
-
0d
94
89
85
40
12
68e
carbonyl oxygen is 2.78 Å, in accord with the presence of
hydrogen bonding. The 3,5-dimethylphenyl group is located
away from the phenol moiety of the ring component, whereas
the 3,5-dinitrophenyl group is located above the phenolic
moiety of the ring component with an interring distace of
3.32 Å.
To confirm the absence of a slippage mechanism8 for
the formation of rotaxanes 5b and 5d-f, a solution of 5b
in CDCl3 was held at 30 °C for 10 days. No dumbbell
was detected. In addition, the mixture of 1b and 6a was
held at 30 °C for 10 days. No rotaxane was detected.
(9.9)
b
(10.0)
(10.0)
(10.0)
(9.9)
b
b
CDCl3
C6H12
-
52
a
b
c
Isolated yield. Not isolated. Selectivity of rotaxane ()rotaxane/
(rotaxane + dumbbell)) determined by 1H NMR. d Only the dumbbell and
crown ether were formed. Selectivity of rotaxane determined by HPLC.
e
rotaxane 5b was observed relative to the corresponding signal
of dumbbell 6a (δ 6.50-8.30), indicating the formation of
hydrogen bonding between the amide hydrogen and the
oxygen atoms of the crown ether of 5b. The aromatic protons
Ha of one of the stopper units shifted downfield from 8.9 to
9.4, implying that the aromatic group of the ring component
is closely located to Ha. On the other hand, the corresponding
aromatic protons Hc of the other stopper unit did not shift,
suggesting that this unit is located away from the phenol
(6) Mercury: visualization and analysis of crystal structures. Macrae,
C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor,
R.; Towler, M.; van de Streek, J. J. Appl. Crystallogr. 2006, 39, 453-457.
(7) Crystallographic data for 5b: C36H46BrN3O13, Mr ) 808.68, triclinic,
space group P-1, a ) 11.553(3), b ) 13.301(3), c ) 14.853(4) Å, R )
65.085(10), â ) 71.700(10), γ ) 66.440(7)°, V ) 1868.1(8) Å3, Z ) 2,
Fcalcd ) 1.438 g/cm-3, µ(Mo KR) ) 11.73 cm-1, T ) 173.2 K, colorless
prism, 0.80 × 0.50 × 0.50 mm, R1 ) 0.0501 [I > 2σ(I)], wR2 ) 0.1185
(all data), GOF ) 1.108.
(8) (a) Ashton, P. R.; Belohradsky, M.; Philp, D.; Stoddart, J. F. Chem.
Commun. 1993, 1269-1274. (b) Ashton, P. R.; Ballardini, R.; Balzani, V.;
Belohradsky, M.; Gandolfi, M. T.; Philp, D.; Prodi, L.; Raymo, F. M.;
Reddington, M. V.; Spencer, N.; Stoddart, J. F.; Venturi, M.; Williams, D.
J. J. Am. Chem. Soc. 1996, 118, 4931-4951. (c) Asakawa, M.; Ashton, P.
R.; Ballardini, R.; Balzani, V.; Belohradsky, M.; Gandolfi, M. T.; Kocian,
O.; Prodi, L.; Raymo, F. M.; Stoddart, J. F.; Venturi, M. J. Am. Chem.
Soc. 1997, 119, 302-310.
1
ring. In addition to the H NMR spectrum, X-ray crystal-
lographic structure analysis of rotaxane 5b revealed the
spatial arrangement of the ring and axle units as shown in
Figure 4.6,7 The distance between the nitrogen atom of the
amide group and the oxygen atom of the crown ether ring is
3.02 Å, and the distance between the OH oxygen and the
Org. Lett., Vol. 9, No. 16, 2007
2971

Because no deslippage of axle 6a out of the ring 1b and no
slippage of 6a into 1b was detected, the above possibility
was ruled out. Hence the formation of rotaxanes 5b and 5d-f
should result from the attack of stopper amine 4 from the
backside of the benzoyl group of prerotaxanes 3b and 3d-f
through the crown ether ring.
Regarding the effect of substituents on the rotaxane
selectivities, the selectivities of 3b and 3e were similar (100%
and 89%) in C6D6, as were those for 3b and 3d (100% and
94%). Therefore, the effects of both substituents at the
different positions on the ring component are minor. How-
ever, in the case of aminolysis of prerotaxane 3f having the
3,5-dimethylbenzoyl group as a stopper unit, the rotaxane
selectivity dropped significantly to 12% in CDCl3 and to 40%
in C6D6 (cf. 85% and 89%, respectively, for 3e). In less polar
C6H12, the rotaxane selectivity of 3f recovered up to 68%. It
turned out that the substituents on the axle unit of the
prerotaxanes exerted a significant effect on the rotaxane
selectivity.
To study the effect of the crown ether ring on reaction
rates of the aminolysis, the rate constants were determined
by following the consumption of 3a-c, 7, and 8 by 1H NMR
at 30 °C in CDCl3. The rate constants of the aminolyses of
prerotaxanes 3a-c were determined to be 1.7 × 10-3, 3.2
× 10-3, and 2.8 × 10-3 M-1 s-1, respectively, whereas both
of those of 7 and 8 were too small to be determined precisely
at this temperature (<3 × 10-5 M-1 s-1). These results
clearly indicate that the presence of the crown ether ring
significantly accelerates the aminolysis, presumably because
it stabilizes the tetrahedral intermediates by hydrogen bond-
ing.9 On the other hand, the size of the crown ether ring
exerts little effect on the rates of consumption of 3a-c, even
though the products were different (dumbbell 6a from 3a
and 3c, rotaxane 5b from 3b), indicating that both rotaxane
and dumbbell formation takes place through similar transition
states. Consequently, it is deduced that the high rotaxane
selectivity of this method results from the acceleration of
aminolysis from the backside through the ring component
by participation of the crown ether ring.10
In conclusion, we developed an efficient method of
rotaxane synthesis based on the aminolysis of prerotaxanes
which proceeded with moderate to excellent selectivities and
yields. We also found that the rotaxane selectivity was
significantly influenced by the substituents on the stopper
units and the solvents of the reactions.
Acknowledgment. This work was partially supported by
the SUNBOR foundation from the Suntory Institute for
Bioorganic Research.
Supporting Information Available: Crystallographic
data of rotaxane 5b and experimental procedures for the
preparation of 3a-f, reference compound 8, rotaxanes 5d-
f, and dumbbells 6a and 6b. This material is available free
of charge via the Internet at http://pubs.acs.org.
(9) (a) Hogan, J. C.; Gandour, R. D. J. Org. Chem. 1992, 57, 55-61.
(b) Basilio, N.; Garc´ıa-R´ıo, L.; Mejuto, J. C.; Pe´rez-Lorenzo, M. J. Org.
Chem. 2006, 71, 4280-4285.
(10) To elucidate the effect of the crown ring, the substituents, and
solvents on the selective formation of the rotaxanes, a detailed kinetic study
on the aminolysis is underway.
OL070999W
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Org. Lett., Vol. 9, No. 16, 2007