Efficient solvent-free syntheses of [2]- and [4]rotaxanes

Article abstract of DOI:10.1002/anie.200800530

(Figure Presented) Waste not want not: A [2]rotaxane has been generated in 49% yield through the direct grinding of solid macrocyclic, threadlike, and stoppering components. The same solid-state ball-milling reactions of solids of pseudorotaxanes and stoppers produced both [2]- and [4]rotaxanes in high yield (see picture). The approach relies on solid-state condensations and is convenient and waste-free (water is the only by-product).

Full text of DOI:10.1002/anie.200800530

Communications
DOI: 10.1002/anie.200800530
Host–Guest Chemistry
Efficient Solvent-Free Syntheses of [2]- and [4]Rotaxanes**
Sheng-Yao Hsueh, Kuang-Wei Cheng, Chien-Chen Lai, and Sheng-Hsien Chiu*
Rotaxanes have potential applicability as molecular actuators
and switches within mesoscale molecular electronic devices.[1]
Among the protocols devised for preparing rotaxanes,
threading followed by stoppering[2] has attracted the most
attention. Nevertheless, synthesizing rotaxanes in high yields
by this approach can be challenging because several factors
affect the formation of the precursor pseudorotaxanes in
solution—for example, low association constants for the
interactions between the thread- and beadlike components,
the use of competing solvents and/or elevated temperatures,
and the formation of interfering by-products during the
stoppering process.[3] Although solvent-free conditions[4]
would, in theory, minimize the degree of dissociation of the
pseudorotaxane complexes during the stoppering reaction
and allow high-order rotaxanes to be generated more
efficiently, a new challenge arises in choosing a suitable
stoppering reaction that can be performed by grinding a well-
mixed solid phase. To the best of our knowledge, only two
types of rotaxanes have been synthesized through solid-to-
solid grinding: one through the reaction of a mixture of bis-p-
phenylene[34]crown-10, a benzyl bromide derivative incor-
porating a bipyridinium recognition site, and a pyridine-
containing stopper,[5] and the other through ball-milling of
polypseudorotaxane complexes—comprising a-cyclodextrin
and poly(tetrahydrofuran) components—with isocyanate
stoppers.[6] Both of these cases gave low-to-moderate yields
of their desired products (< 45%), thus suggesting that these
reactions are not suitable for the efficient syntheses of higher-
order rotaxanes. Herein, we report a new solid-state ball-
milling reaction that produces both [2]- and [4]rotaxanes
efficiently and in high yield.
turned our attention toward the formation of hexahydropyr-
imidines by condensing carbonyl compounds with 1,3-dia-
mines.[8] We chose 1,8-diaminonaphthalene (3) as a suitable
diamine for the reaction with a threadlike moiety terminated
with a formyl group because of its steric bulk and the stability
of the resulting dihydropyrimidine stopper units.[9]
Previously, we reported that the oxygen-deficient macro-
cycle 1 forms a complex with a dibenzylammonium (DBA)
ion in CD3CN (Ka = 200mÀ1).[10] Thus, as the first step toward
preparing a [2]rotaxane under solvent-free conditions from
such components, we concentrated an equimolar mixture of
the macrocycle 1 and the dialdehyde 2-H·PF6 in CH3CN
under reduced pressure to afford a white solid, which we
assumed to contain predominantly the [2]pseudorotaxane
complex [1·2-H][PF6] (Scheme 1). After dissolving portions of
the solids in CD3CN, we used 1H NMR spectroscopy to
monitor the ball-milling reaction of a 1:2 mixture of the
[2]pseudorotaxane complex [1·2-H][PF6] and 1,8-diamino-
naphthalene at ambient temperature. A new set of signals
appeared with increasing intensity over time (Figure 1). After
1 h, these signals were predominant (Figure 1e), so we
subjected the mixture to column chromatography and iso-
lated the [2]rotaxane 4-H·PF6 in 80% yield.[11] The yield
increased to 87% when we increased the ratio of the
macrocycle 1 and the dialdehyde thread 2-H·PF6 in the solid
mixture to 1.2:1. The solution reaction of 1, 2-H·PF6, and
diamine 3 (50:50:100 mm) in CH3CN did not proceed as
efficiently as it did through ball-milling: traces of 2-H·PF6
1
remained detectable by TLC after 24 h. The use of H NMR
spectroscopy to monitor a slightly more dilute mixture
(20:20:40 mm) in CD3CN indicated that the reaction was
complete after 24 h, and provided the [2]rotaxane 4-H·PF6 in
48% yield.
The formation of imines through the dehydration of
aldehydes and primary amines can be achieved in high yield
by solid-state ball-milling.[7] As imines are in general easily
hydrolyzed, we were not inclined to use this condensation
reaction to construct higher-order rotaxanes. Instead, we
When we mixed 1, 2-H·PF6, and 3 as solids in a 1:1:2 ratio
without first generating the solid [2]pseudorotaxane complex
[1·2-H][PF6], the same ball-milling conditions afforded a
mixture of the [2]rotaxane 4-H·PF6 and the dumbbell-like salt
5-H·PF6 (Figure 2b) in yields of 49 and 44%, respectively. To
the best of our knowledge, this process is by far the most
efficient synthesis of a rotaxane by direct grinding of the
macrocyclic, threadlike, and stoppering components as inde-
pendent solids.[5] Although this result indicates that the
threading of the macrocycle 1 around the threadlike dialde-
hyde 2-H·PF6 could occur during the grinding process,
preforming the [2]pseudorotaxane [1·2-H][PF6] as a solid
substantially increased the yield of the reaction.
To prove that this solid-state rotaxane synthesis occurred
through threading followed by stoppering, rather than by
slippage,[12] we dissolved the [2]rotaxane 4-H·PF6 in
CD3SOCD3 and monitored its 1H NMR spectra at 323 K
over time. We detected no signals of the free components in
the 1H NMR spectrum recorded after 3 h, which suggests that
[*] S.-Y. Hsueh,[+] K.-W. Cheng,[+] Prof. S.-H. Chiu
Department of Chemistry, National Taiwan University
No. 1, Sec. 4, Roosevelt Road, Taipei (Taiwan, ROC)
Fax: (+886)2-3366-1677
E-mail: shchiu@ntu.edu.tw
Homepage: http://www.ch.ntu.edu.tw/english/efaculty/people/
chiu-eng.html
Prof. C.-C. Lai
Institute of Molecular Biology, National Chung Hsing University
and Department of Medical Genetics, China Medical University
Hospital, Taichung(Taiwan, ROC)
[+] These authors contributed equally to this study.
[**] This study was supported by the National Science Council, Taiwan
(NSC-95-2113M-002-016-MY3).
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angew. Chem. Int. Ed. 2008, 47, 4436 –4439

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Chemie
the terminal dihydropyrimidine groups are
true stopper units for the macrocycle 1 and
that the [2]rotaxane 4-H·PF6 was not the
product of a slippage synthesis.[13]
As solid-state ball-milling was such an
efficient method of synthesizing the [2]rotax-
ane 4-H·PF6, we turned our attention toward
the syntheses of higher-order rotaxanes. We
prepared the trisammonium salt 6-H3·3PF6
(Scheme 2) from 1,3,5-tris(p-formylphenyl)-
benzene[14] as a suitable guest species (see the
Supporting Information).
We assumed that the solid obtained after
concentrating a solution of the macrocycle 1
and 6-H3·3PF6 (4:1) in CH3CN contained
mainly the [4]pseudorotaxane [13·6-H3]-
[3PF6], which we subsequently ball-milled
with the diamine 3 (4 equiv relative to 6-
H3·3PF6) under ambient conditions. 1H NMR
spectroscopic analysis suggested that the
[4]rotaxane 7-H3·3PF6 was the predominant
product (Figure 3b) in the solid mixture after
1 h of ball-milling; 7-H3·3PF6 was isolated in
65% yield after column chromatography.[15]
The electrospray ionization (ESI) mass spec-
trum of 7-H3·3PF6 revealed intense signals at
m/z 1288.1 and 810.4, which correspond to [7-
H3·PF6]2+ and [7-H3]3+, respectively. The good matches
between the observed and calculated isotope patterns (see
the Supporting Information) for these ions support the
successful synthesis of the [4]rotaxane 7-H3·3PF6.
To prove the generality of this approach, we applied the
same ball-milling process to the solid obtained after mixing
the diamine 3 (4 equiv relative to 6-H3·3PF6) with the solid
obtained after concentrating a solution of dibenzo[24]crown-
8 (DB24C8) and 6-H3·3PF6 (4:1) in CH3CN;[16] the corre-
Scheme 1. Solid-state synthesis of the [2]rotaxane 4-H·PF6.
Figure 1. Partial 1H NMR spectra (400 MHz, CD3CN, 298 K) displaying
the formation of the [2]rotaxane 4-H·PF6 from the pseudorotaxane
[1·2-H][PF6] after solid-state ball-millingfor a) 1, b) 5, c) 10, d) 30, and
e) 60 min. #: Signals from the pseudorotaxane [1·2-H][PF6].
Figure 2. Partial 1H NMR spectra (400 MHz, CD3CN, 298 K) of a) the
isolated [2]rotaxane 4-H·PF6, b) the solid mixture obtained from direct
ball-millingof the solid mixture of 1, 2-H·PF6, and 3 (1:1:2) for 1 h,
and c) the dumbbell 5-H·PF6. #: Signals from the free macrocycle 1.
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molecules such as [2]- and [4]rotaxanes. We believe that
this approach will also be useful for constructing other
complicated interlocked molecules, several of which
are currently under investigation in our laboratory.
Experimental Section
General methods for the ball-milling process: The ball-
milling was performed using a Retsch MM 200 swing-mill
containing two 5 mL stainless-steel cells and two stainless-
steel balls (diameter: 7 mm). The mill was operated at a
frequency of 22.5 Hzat room temperature.
[2]Rotaxane 4-H·PF6 (ball-milling of preformed pseu-
dorotaxane): Macrocycle 1 (43 mg, 0.10 mmol) and dialde-
hyde 2-H·PF6 (40 mg, 0.10 mmol) were dissolved in CH3CN
(0.5 mL). The solvent was evaporated under reduced pres-
sure to afford a white solid, which was mixed with 1,8-
diaminonaphthalene (3; 33 mg, 0.21 mmol) and ball-milled at
room temperature for 1 h. The resulting solid was purified by
chromatography (SiO2; MeOH/CH2Cl2, 2:98) to afford the
[2]rotaxane 4-H·PF6 (88 mg, 80%) and the dumbbell 5-H·PF6
(11 mg, 16%). 4-H·PF6: m.p. > 2708C (decomp); 1H NMR
(400 MHz, CD3CN): d = 2.00–2.25 (m, 4H), 2.95–2.98 (m,
4H), 3.54–3.56 (m, 4H), 4.03 (s, 4H), 5.30 (s, 4H), 5.51 (s,
6H), 6.58–6.61 (m, 8H), 6.71–6.75 (m, 8H), 7.12 (d, J = 8 Hz ,
4H), 7.23 (t, J = 8 Hz, 4H), 7.46 (s, 4H), 7.40–7.45 (brs, 2H),
7.62 ppm (d, J = 8 Hz, 4H); 13C NMR (100 Hz, CD3CN): d =
51.3, 67.5, 68.4, 69.8, 71.4, 74.5, 106.2, 114.1, 116.9, 117.6,
128.0, 128.4, 128.7, 129.2, 131.8, 132.0, 135.8, 138.3, 143.3,
143.4, 158.2 ppm (one signal is missing, possibly because of
signal overlap); HRMS (FAB): m/z calcd for [4-H]+
(C62H60N5O5): 954.4594; found: 954.4576. 5-H·PF6: m.p. >
Scheme 2. Solid-state syntheses of the [4]rotaxanes 7- and 8-H3·3PF6.
1
2208C (decomp); H NMR (400 MHz, CD3CN): d = 4.26 (s,
4H), 5.37–5.42 (brs, 4H), 5.48 (s, 2H), 6.54 (d, J = 7 Hz, 4H), 7.11 (d,
J = 7 Hz, 4H), 7.21 (t, J = 7 Hz, 4H), 7.49 (d, J = 8 Hz, 4H), 7.65 ppm
(d, J = 8 Hz, 4H); 13C NMR (100 Hz, CD3CN): d = 52.2, 67.5, 106.2,
113.9, 117.6, 127.9, 129.1, 131.1, 131.6, 135.6, 143.1, 144.0 ppm; HRMS
(FAB): m/z calcd for [5-H]+ (C36H32N5): 534.2658; found: 534.2681;
calcd for [5+Na]+ (C36H31N5Na): 556.2472; found: 556.2420.
[2]Rotaxane 4-H·PF6 (direct ball-milling): The macrocycle 1
(43 mg, 0.10 mmol), the dialdehyde 2-H·PF6 (40 mg, 0.10 mmol), and
1,8-diaminonaphthalene (3; 33 mg, 0.21 mmol) were mixed and then
ball-milled at room temperature for 1 h. The crude product was
purified by chromatography (SiO2; MeOH/CH2Cl2, 2:98) to afford
the [2]rotaxane 4-H·PF6 (54 mg, 49%) and the dumbbell 5-H·PF6
(30 mg, 44%).
Figure 3. Partial 1H NMR spectra (400 MHz, CD3CN, 298 K) of a) the
isolated [4]rotaxane 7-H3·3PF6 and b) the solid obtained after directly
ball-millinga mixture of the putative [4]pseudorotaxane [ 13·6-H3][3PF6]
and the diamine 3 (1/6-H3·3PF6/3=4:1:4) for 1 h. #: Signals from the
free macrocycle 1.
[4]Rotaxane 7-H3·3PF6: Macrocycle 1 (42 mg, 0.10 mmol) and
the trialdehyde 6-H3·3PF6 (30 mg, 25 mmol) were dissolved in CH3CN
(0.5 mL). The solvent was then evaporated under reduced pressure to
afford a white solid, which was mixed with 1,8-diaminonaphthalene
(3; 16 mg, 0.10 mmol) and ball-milled at room temperature for 1 h.
The crude product was purified by chromatography (SiO2; CH3CN/
CH2Cl2, 1:9) to afford the [4]rotaxane 7-H3·3PF6 as a light-brown
solid (47 mg, 65%). M.p. > 2508C (decomp); 1H NMR (400 MHz,
CD3NO2): d = 1.80–1.90 (m, 6H), 2.63–2.75 (m, 6H), 3.28–3.45 (m,
12H), 3.76 (s, 12H), 4.09 (d, J = 9 Hz, 6H), 4.24 (d, J = 9 Hz, 6H), 5.26
(s, 6H), 5.36 (s, 12H), 5.57 (s, 3H), 6.42 (dd, J = 8, 2 Hz, 6H), 6.54 (d,
J = 8 Hz, 6H), 6.61 (d, J = 8 Hz, 6H), 6.67 (dd, J = 8, 2 Hz, 6H), 6.86
(dd, J = 8, 2 Hz, 6H), 6.93 (dd, J = 8, 2 Hz, 6H), 7.14–7.18 (m, 12H),
7.24–7.26 (m, 6H), 7.54 (s, 12H), 7.67 (d, J = 8 Hz, 6H), 7.70–7.80
(brs, 6H), 8.08 (d, J = 8 Hz, 6H), 8.23 ppm (s, 3H); 13C NMR (100 Hz,
CD3NO2): d = 49.7, 50.9, 67.3, 67.6, 69.6, 70.8, 73.9, 105.8, 113.5, 115.2,
116.7, 117.2, 125.5, 127.2, 127.5, 127.8, 128.7, 130.1, 131.4, 131.6, 131.8,
131.9, 135.1, 137.8, 141.6, 142.0, 142.5, 157.5, 157.6 ppm; HRMS
(ESI): m/z calcd for [7-H3·PF6]2+ (C159H156N9O15PF6): 1288.0682;
found: 1288.0699; calcd for [7-H3]3+ (C159H156N9O15): 810.3907; found:
810.3921.
sponding [4]rotaxane 8-H3·3PF6 was isolated in 78% yield.[17]
The ESI mass spectrum of 8-H3·3PF6 revealed intense peaks
at m/z 2806.0, 1330.1, and 838.4, which correspond to [8-
H3·2PF6]+, [8-H3·PF6]2+, and [8-H3]3+, respectively. In con-
trast, the reaction between DB24C8, 6-H3·3PF6, and 3
(40:10:40 mm) in CD3CN took 24 h to reach completion;
1H NMR spectroscopy revealed that the yield of the [4]rotax-
ane 8-H3·3PF6 was 39%.
The solid-state condensations occurring in ball-milled
mixtures of 1,8-diaminonaphthalene and benzaldehyde deriv-
atives are convenient, waste-free (water is the only by-
product), and efficient reactions for preparing interlocked
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[4]Rotaxane 8-H3·3PF6: DB24C8 (45 mg, 0.10 mmol) and the
trialdehyde 6-H3·3PF6 (30 mg, 25 mmol) were dissolved in CH3CN
(0.5 mL). The solvent was then evaporated under reduced pressure to
afford a white solid, which was mixed with 1,8-diaminonaphthalene
(3; 16 mg, 0.10 mmol) and ball-milled at room temperature for 1 h.
The crude product was purified by chromatography (SiO2; CH3CN/
CH2Cl2, 1:4) to afford the [4]rotaxane 8-H3·3PF6 as a white solid
(58 mg, 78%). M.p. > 2658C (decomp); 1H NMR (400 MHz,
CD3CN): d = 3.50–3.62 (m, 24H), 3.62–3.82 (m, 24H), 3.98–4.10 (m,
24H), 4.69–4.82 (m, 12H), 5.26 (s, 6H), 5.36 (s, 3H), 6.54 (d, J = 8 Hz ,
6H), 6.80 (s, 24H), 7.09 (d, J = 8 Hz, 6H), 7.19 (t, J = 8 Hz, 6H), 7.41
(s, 12H), 7.43 (d, J = 8 Hz, 6H), 7.47 (d, J = 8 Hz, 6H), 7.54 (s, 3H),
7.64 ppm (brs, 6H); 13C NMR (100 Hz, CD3CN): d = 48.6, 48.7, 62.8,
64.4, 66.6, 67.1, 101.6, 108.8, 109.5, 113.0, 117.5, 121.4, 123.4, 123.5,
124.1, 126.0, 126.3, 128.0, 128.7, 131.1, 137.1, 137.6, 138.6, 138.9,
143.8 ppm; HRMS (ESI): m/z calcd for [8-H3·PF6]2+
(C153H168N9O24PF6): 1330.0921, found: 1330.0910; calcd for [8-H3]3+
(C153H168N9O24): 838.4067, found: 838.4075.
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[11] When using the immediate solvent evaporation method (ISEM),
that is, dissolving
1 (38 mmol), 2-H·PF6 (38 mmol), and 3
(76 mmol) in CH3CN (0.5 mL) and then evaporating the solvent
under reduced pressure, we found that the [2]rotaxane 4-H·PF6
was also generated in the resulting thin film. According to
1H NMR spectroscopy, the reaction was finished after 5 h with a
maximum yield of 64%, as determined from integration of the
signals of the interlocked and free macrocycles (see the
Supporting Information). By using the ball-milling approach,
the same mixture gave a yield of 87% after 1 h of grinding, as
determined by integration of the 1H NMR signals. These results
show that the yield of 4-H·PF6 from the ball-milling reaction was
higher. For details of the ISEM approach, see A. Orita, G.
Uehara, K. Miwa, J. Otera, Chem. Commun. 2006, 4729 – 4731
and Ref. [5].
Received: February 1, 2008
Published online: April 29, 2008
Keywords: dihydropyrimidines · host–guest systems ·
.
interlocked molecules · rotaxanes · solvent-free synthesis
[12] a) M. Asakawa, P. R. Ashton, R. Ballardini, V. Balzani, M.
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process is believed to lower the yields of several rotaxane
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[13] We did not detect any signals for 4-H·PF6 in the 1H NMR
spectrum of a ball-milled equimolar mixture of the solid
dumbbell 5-H·PF6 and the macrocycle 1, which suggests that it
was unlikely that this [2]rotaxane was generated through
slippage.
[14] a) E. Weber, M. Hecker, E. Koepp, W. Orlia, M. Czugler, I.
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[15] 1H NMR spectroscopy indicated that direct ball-milling of a
mixture of 1, 6-H3·3PF6, and 3 as solids in a 4:1:4 ratio—without
prior generation of the putative solid [4]pseudorotaxane com-
plex [13·6-H3][3PF6]—did not yield the [4]rotaxane 7-H3·3PF6.
[16] For a discussion of the self-assembly of DB24C8 and DBA+, see
a) M. C. T. Fyfe, J. F. Stoddart, Adv. Supramol. Chem. 1999, 5, 1 –
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pairing in this recognition system, see b) W. J. Jones, H. W.
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[17] The [4]rotaxane 8-H3·3PF6 could also be generated by dissolving
DB24C8 (50 mmol), 6-H3·3PF6 (13 mmol), and 3 (50 mmol) in
CH3CN (1 mL) and then evaporating the solvent under reduced
pressure. According to 1H NMR spectroscopy, this ISEM
reaction required 5 h to reach completion; the yield was 52%
based on integration of signals of the aromatic protons of the
interlocked and free DB24C8 moieties (see the Supporting
Information). By using the ball-milling approach, the corre-
sponding reaction afforded the [4]rotaxane in 82% yield
(1H NMR spectroscopy) after 1 h. The yields of the isolated
[4]rotaxanes from the ISEM and ball-milled approaches were 50
and 78%, respectively; thus, the latter approach was superior.
[5] The corresponding [2]rotaxane was synthesized in 85% yield
from the film obtained after evaporating a solution of all three
components. This elegant approach takes advantage of bringing
the reactants together to generate the film, and thus may not be
classified as a true solid/solid reaction. Directly grinding the
three individual solids together gave the [2]rotaxane in only
11% yield; see A. Orita, J. Okano, Y. Tawa, L. Jiang, J. Otera,
Angew. Chem. 2004, 116, 3810 – 3814; Angew. Chem. Int. Ed.
2004, 43, 3724 – 3728.
[6] a) N. Kihara, K. Hinoue, T. Takata, Macromolecules 2005, 38,
223 – 226; b) R. Liu, T. Maeda, N. Kihara, A. Harada, T. Takata,
J. Polym. Sci. Part A 2007, 45, 1571 – 1574.
Angew. Chem. Int. Ed. 2008, 47, 4436 –4439ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 4439