Rapid and efficient solvent-free synthesis of cyclophanes based on bipyridinium under mechanical ball milling

Article abstract of DOI:10.1039/c2ra22802e

We reported here the first rapid and solvent-free template-directed preparation of cyclophanes based on bipyridinium, which was achieved using mechanical ball milling. The method affords a new strategy for construction of diverse substituted CBPQT·4PF₆, which greatly shortens the reaction period, rendering this methodology practical in the field of supermolecular chemistry.

Full text of DOI:10.1039/c2ra22802e

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Rapid and efficient solvent-free synthesis of
cyclophanes based on bipyridinium under mechanical
ball milling3
Cite this: RSC Advances, 2013, 3, 691
Received 7th November 2012,
Accepted 8th November 2012
Hai-Tao Xi,* Ting Zhao, Xiao-Qiang Sun, Chun-Bao Miao, Ting Zong and Qi Meng
DOI: 10.1039/c2ra22802e
www.rsc.org/advances
We reported here the first rapid and solvent-free template-
directed preparation of cyclophanes based on bipyridinium,
which was achieved using mechanical ball milling. The method
affords a new strategy for construction of diverse substituted
CBPQT?4PF6, which greatly shortens the reaction period, render-
ing this methodology practical in the field of supermolecular
chemistry.
using liquid–liquid extraction. Recently, Stoddart’s group found
that a pH-sensitive derivative of 1,5-diaminonaphthalene could
displace the template and eliminate the need for the lengthy
liquid–liquid extraction step.10
Using the traditional methods, a series of novel CBPQT?4PF6
with different substituents were reported.11 However, CBPQT?4PF6
containing electron-withdrawing groups are seldom reported or
obtained in yields greater than 5–35%.11,12 Previously, our work
12
The cyclophanes based on the general structure represented by
cyclobis(paraquat-p-phenylene) (CBPQT4+) comprise one of the
most important molecules in contemporary supermolecular
chemistry.1 Their photophysical, photochemical and electroche-
mical properties have recently been reported on pseudorotaxanes,
cantenanes and rotaxanes, respectively.2 Hu¨nig and co-workers
first reported the synthesis of the cyclophanes based on two 4,4’-
bipyridinium moieties linked via different o- or m-xylene bridges.3
In 1988, Stoddart and co-workers first synthesized CBPQT?4PF6
with a yield of only 12% using MeCN as solvent.4 Thereafter, with
the rapid development of supermolecular chemistry, considerable
attention was given to the synthesis of these supermolecular
compounds using molecular templates.5 Several templates, such
focused on synthesizing diverse substituted CBPQT?4PF6 and
studying the interactions between these cyclophanes and phenyl
ether derivatives.13 In light of our recent success in this area, we
attempted to synthesize novel cyclophanes 4a and 4b via the
traditional methodology (see ESI ) as depicted in Schemes 1 and 2.
3
Nevertheless, the two preparative methods require a long term (in
practice, more than three weeks) and consume large quantities of
solvent, respectively. To avoid these disadvantages, there has been
an urgent need to develop a new rapid, convenient and
environmentally friendly method to produce cyclophane com-
pounds.
In recent years, solvent-free organic reactions have drawn
considerable attention due to their environmentally benign
protocols, short reaction time, favorable yields, convenient means
of product purification and occasionally-enhanced selectivity.14
From a practical point of view, the mechanical ball milling
technique has been considered as a powerful tool in promoting
various organic transformations under solvent-free conditions,
as
1,4-bis[2-(2-hydroxyethoxy)ethoxy],6
1,4-bis[2-2(2-hydro-
xythoxy)],7 1,5-bis[2-(2-hydroxyethoxy)ethoxy]naphth-alene8 and
1,5-bis[2-(2-methoxyethoxy)ethoxy]naphthalene9 have been devel-
oped to increase the yields of CBPQT?4PF6. In addition to
employing templates, it was also discovered that the efficiency of
the reactions could be improved by changing the reaction solvent
from MeCN to DMF and carrying out the reaction at ultra-high
pressure (12–15 kbar).9 Higher yields were obtained under
different reaction conditions, which are not strictly comparable
and the ultra-high pressure conditions present potential safety
risks. Purification of the CBPQT?4PF6 product requires the
removal of the molecular template from the reaction mixture
School of Petrochemical Engineering, Changzhou University, Changzhou, Jiangsu,
213164, P.R. China. E-mail: xihaitao@yahoo.cn; Fax: (+86) 519 86330257;
Tel: (+86) 519 86330257
Scheme 1 Reagents and conditions: (a) 98% H2SO4, 65% HNO3, 210 uC, 69%,
(b) NBS, AIBN, CCl4, reflux, 10 h, 14%; (c) (i) 4,4’-bipyridine, MeCN, reflux; (ii) NH4PF6,
74%; (d) (i) 1,5-bis[2-(2-hydroxyethoxy)ethoxy]naphthalene 6, 1,4-bis(bromo-
methyl)benzene 2c, MeCN, r.t., three weeks; (ii) NH4PF6, 24%.
Electronic Supplementary Information (ESI) available. CCDC 890901 and 890902.
3
For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2ra22802e
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 691–694 | 691

View Article Online
Communication
RSC Advances
Table 1 Optimization of reaction conditions for the synthesis of 4aa
Scheme 2 Reagents and conditions: (a) LiAlH4, AlCl3, Et2O, 0 uC, 85%; (b) (i) 4,4’-
bipyridine, MeCN, reflux; (ii) NH4PF6, 65%; (c) (i) 2c, 6, MeCN, r.t., 2 months; (ii)
NH4PF6, 19%.
including organocatalysis,15 oxidative aminations of aldehydes,16
dehydrogenation of c-terpinene,17 Mn(OAc)3-mediated cycloaddi-
tions,18 metal-mediated cross-couplings19 and the synthesis of aryl
chlorides and bromides.20 For example, Chiu and co-workers have
synthesized rotaxanes by ball milling with a high isolation yield
(81%),21 more efficient than solution-based reactions.22
To the best of our knowledge, the use of mechanical milling
techniques to prepare CBPQT?4PF6 has not been described in the
literature. In view of the limitation of the existing methods, we
report here a practical methodology for preparing different
substituted CBPQT?4PF6 under ball milling conditions.
Yield (%)b
Entry
Template
Additives
Pre-assemblyc
One-stepd
1
2
3
4
5
6
7
8
9
5
5
5
5
5
6
6
6
6
6
—
5
—
5
10
10
13
—
15
21
22
trace
trace
trace
trace
trace
4
trace
7
7
PEG 400
NaCl
Al2O3
SiO2
—
PEG 400
NaCl
Al2O3
SiO2
10
7
a
The reaction mixture of 1,4-bis(bromomethyl)benzene 2c (1.0
Initially, we chose the reaction of 3a with 1,4-bis(bromo-
methyl)benzene 2c as the model reaction. Typically, a mixture of
2c (0.2 mmol), 3a (0.2 mmol) and 5 or 6 (0.6 mmol) was directly
milled vigorously at room temperature (Table 1). The vibration
frequency was set at the highest (30 Hz). After 30 min, only trace
products were observed without any additives (Table 1, entry 1).
Prolonging the reaction time to 60 min resulted in no improve-
ment in yield. Normally the kinetic energy generated by the action
of the milling balls is transferred to the reaction mixture, which
drives the reaction. Then, we tried adding various additives such
as NaCl to the reaction system. After all, we did find that the yield
could be improved slightly from 4–7% by adding SiO2, Al2O3 or
NaCl to dilute the concentration of the reaction (Table 1, entries 8–
10), but yield was still poor. In general, we found that reaction of
half-cyclophane 3a with 2c in the absence of a template yielded
poor self-assembly of the desired product 4a with many oligomer
and linear polymer byproducts. Employing a molecular template
could force the half-cyclophane compounds to interact with the
templates and the bipyridinium units resulting in a cis conforma-
tion.6 This would be beneficial to the cyclization step.
Subsequently, we conducted a series of pre-assembled experi-
ments. At first, 3a was dissolved in anhydrous MeCN (5 mL), and
then various templates 5 or 6 and additives were added to the
solution. Next, the mixture was refrigerated at 210 uC for 60 min,
followed by the removal of the solvent in vacuo at room
temperature. Last, the solid mixture was transferred to the ball
milling vessel and milled with 2c for 30 min at rt. As shown in
Table 1, template 6 proved to be more effective than 5 for the
cyclization reaction step. Perhaps because of their structures, the
naphthalene ring should be more polarizable and could place
more electrons of its p surface inside the CBPQT?4PF6 than the
latter.23 In addition, the yield using SiO2 and Al2O3 was higher
than that using NaCl. This maybe was due mainly to the function
equiv), 3a (1.0 equiv), template 6 (3.0 equiv) and additives (1.0 equiv)
b
was milled at 30 Hz for 30 min. Isolated yields obtained by silica
c
gel column chromatography. 3a and template 6 were assembled
d
before the reaction. 3a, template 6 and 2c were milled directly.
of SiO2 and Al2O3 in that they acted as dispersing agents and also
provided effective molecular adsorption, thereby maintaining the
configuration of the self-assembly. By contrast, NaCl was merely a
reaction diluent and offered poor molecular adsorption. The pre-
assembled solvent-free cyclization reaction in SiO2 using template
6 resulted in the best yield of 4a in 22% (Table 1, entry 10), which
was similar to the reaction performed in an organic solvent (24%).
Having defined the optimal reaction, we proceeded to explore
the scope and generality of this transformation using various
bipyridinium precursors 3 and dibromides 2. The results of these
experiments are listed in Table 2. As shown, a series of cyclophane
products 4 were achieved in 15–25% in a very short period
compared with the conventional method. Moreover, the relatively
low yield of 4b (Table 2, entries 2, 3) might be due to the steric
hindrance of the substitution on the cyclophane. As a result, the
yields of cyclophanes containing a nitro group and fluorine atoms,
were higher than the yields using cyclophanes containing electron-
donating groups or the classic cyclophanes. Compared to the
traditional methods, our method sharply reduces the reaction
period from more than 2 weeks to 1.5 h, giving similar yields.
The identification of new compounds was fully confirmed by
their MALDI-TOF-MS, 1H NMR and 13C NMR. The structures of 4a
and 4b were further confirmed by X-ray crystallography. As
presented in Fig. 1, rigid rectangular box-like conformations with
two paraquat units forming the longer sides, with the two opposite
phenylene residues forming the shorter sides, were adopted. The
twist angles relating the mean planes of the two pyridinium rings
692 | RSC Adv., 2013, 3, 691–694
This journal is ß The Royal Society of Chemistry 2013

View Article Online
RSC Advances
Communication
Table 2 The comparative synthesis of different substituted CBPQT?4PF6
Condition Aa
Time (min)
Condition Bb
Entry
1
R
R9
Product
Yield (%)c
20
Time (day)
21
Yield (%)c
23
4a
30
2
3
4b
30
17
15
60
90
19
16
30
8
4
5
4c
30
30
19
25
12
14
23
12a
4d
28
a
The reaction mixture of 2 (1.0 equiv), 3 (1.0 equiv), template 6 (3.0 equiv) and silica gel (1.0 equiv) was milled at 30 Hz for 30 min. In
b
addition, 3 and template 6 were assembled before the reaction. The reaction mixture 2 (1.0 equiv), 3 (1.0 equiv), template 6 (3.0 equiv) and a
catalytic amount of NaI was dissolved in anhydrous MeCN. Isolated yields obtained by chromatography on silica gel.
c
in the bipyridinium units of 4a and 4b change remarkably in
comparison to the distortion of different substituted CBPQT?4PF6,
The authors are grateful for the financial support from the
which have been reported.4,12a Furthermore, the interactions
Acknowledgements
National Natural Science Foundation of China (No. 20872051
and 21202011) and the Priority Academic Program
between 4a or 4b and various p-electron-rich donors will be well
studied in our further investigations.
Development of Jiangsu Higher Education Institutions.
In summary, a novel rapid and efficient protocol for the
synthesis of various substituted cyclobis(paraquat-p-phenylene)
tetracations in acceptable yields using a mechanical milling
References
process is reported. Particularly noteworthy is the fact that this
1 (a) T. T. Goodnow, M. V. Reddington, J. F. Stoddart and A.
solvent-free procedure makes the synthesis of cyclophane
compounds more efficient, economical and ecologically-friendly,
rendering this methodology useful in the field of supermolecular
chemistry.
E. Kaifer, J. Am. Chem. Soc., 1991, 113, 4335; (b) R. Hernandez,
H.-R. Tseng, J. W. Wong, J. F. Stoddart and J. I. Zink, J. Am.
Chem. Soc., 2004, 126, 3370; (c) R. Klajn, L. Fang, A. Coskun, M.
A. Olson, P. J. Wesson, J. F. Stoddart and B. A. Grzybowski, J.
Am. Chem. Soc., 2009, 131, 4233; (d) Q. Li, C.-H. Sue, S. Basu, A.
K. Shveyd, W. Zhang, G. Barin, L. Fang, A. A. Sarjeant, J.
F. Stoddart and O. M. Yaghi, Angew. Chem., Int. Ed., 2010, 49,
6751; (e) L. Fang, C. Wang, A. C. Fahrenbach, A. Trabolsi, Y.
Y. Botros and J. F. Stoddart, Angew. Chem., Int. Ed., 2011, 50,
1805.
2 (a) B. K. Juluri, A. S. Kumar, Y. Liu, T. Ye, Y.-W. Yang, A.
H. Flood, L. Fang, J. F. Stoddart, P. S. Weiss and T. J. Huang,
ACS Nano, 2009, 3, 291; (b) R. S. Forgan, C. Wang, D.
C. Friedman, J. M. Spruell, C. L. Stern, A. A. Sarjeant, D. Cao
and J. F. Stoddart, Chem.–Eur. J., 2012, 18, 202; (c) B. Brough, B.
H. Northrop, J. J. Schmidt, H.-R. Tseng, K. N. Houk, J.
Fig. 1 An ORTEP diagram of compounds 4a and 4b.
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 691–694 | 693

View Article Online
Communication
RSC Advances
F. Stoddart and C.-M. Ho, Proc. Natl. Acad. Sci. U. S. A., 2006,
103, 8583; (d) H. Yu, Y. Luo, K. Beverly, J. F. Stoddart, H.-
R. Tseng and J. R. Health, Angew. Chem., Int. Ed., 2003, 42, 5706.
3 W. Geuder, S. Hu¨nig and A. Suchy, Angew. Chem., Int. Ed. Engl.,
1983, 22, 489.
4 B. Odell, M. V. Reddington, A. M. Z. Slawin, N. Spencer, J.
F. Stoddart and D. J. Williams, Angew. Chem., Int. Ed. Engl.,
1988, 27, 1547.
5 (a) R. Ballardini, V. Balzani, M. T. Gandolfi, L. Prodi,
M. Venturi, D. Philp, H. G. Ricketts and J. F. Stoddart, Angew.
Chem., Int. Ed. Engl., 1993, 32, 1301; (b) M. Asakawa, P.
R. Ashton, S. E. Boyd, C. L. Brown, S. Menzer, D. Pasini, J.
F. Stoddart, M. S. Tolley, A. J. P. White, D. J. William and P.
G. Wyatt, Chem.–Eur. J., 1997, 3, 463; (c) M. Asakawa, P.
R. Ashton, C. L. Broewn, M. C.T. Fyfe, S. Menzer, D. Pasini,
C. Scheuer, N. Spencer, J. F. Stoddart, A. J. P. White and D.
J. Williams, Chem.–Eur. J., 1997, 3, 1136; (d) R. Hoss and
12 (a) H.-T. Xi, T.-T. Yi and and X.-Q. Sun, Chin. Chem. Lett., 2009,
21, 633; (b) H.-T. Xi, X.-Q. Sun and H.-W. Hu, Chin. J. Org.
Chem., 2007, 27, 1; (c) H.-T. Xi, X.-Q. Sun, J. Chen, Q. Meng,
Y. Pan and H.-W. Hu, Chem. Res. Chin. Univ., 2007, 23, 745.
13 X.-J. Dong, H.-T. Xi, C.-B Miao, X.-Q. Sun, Q. Meng and Y. Jiang,
Supramol. Chem., 2012, 24, 665.
14 (a) F. Toda, Acc. Chem. Res., 1995, 28, 480; (b) K. Tanaka and
F. Toda, Chem. Rev., 2000, 100, 102; (c) F. Yu, S. Yan, R. Huang,
Y. Tang and J. Lin, RSC Adv., 2011, 1, 596; (d) M. S. Singh and
S. Chowdhury, RSC Adv., 2012, 2, 4547; (e) Y.-F. Wang, R.-
X. Chen, K. Wang, B.-B. Zhang, Z.-B. Li and D.-Q. Xu, Green
Chem., 2012, 14, 893; (f) T.-H. Zhang, G.-W. Wang, P. Lu, Y.-J. Li,
R.-F. Peng, Y.-C. Liu, Y. Murata and K. Komatsu, Org. Biomol.
Chem., 2004, 2, 1698.
15 (a) S. Toma, R. Sebesta and M. Meciarova, Curr. Org. Chem.,
2011, 15, 2257; (b) A. Bruckmann, A. Krebs and C. Bolm, Green
´
Chem., 2008, 10, 1131; (c) B. Rodrıguez, A. Bruckmann and
´
C. Bolm, Chem.–Eur. J., 2007, 13, 4710; (d) B. Rodrıguez,
¨
F. Vogtle, Angew. Chem., Int. Ed. Engl., 1994, 33, 375.
T. Rantanen and C. Bolm, Angew. Chem., Int. Ed., 2006, 45,
6924.
6 C. L. Brown, D. Philp and J. F. Stoddart, Synlett, 1991, 462.
7 P. L. Anelli, P. R. Ashton, R. Ballardini, V. Balzani, M. Delgado,
M. T. Gandolfi, T. T. Goodnow, A. E. Kaifer, D. Philp,
M. Pietraszkiewicz, L. Prodi, M. V. Reddington, A. M.
Z. Slawin, N. Spencer, J. F. Stoddart, C. Vicent and D.
J. Williams, J. Am. Chem. Soc., 1992, 114, 193.
16 J. Gao and G.-W. Wang, J. Org. Chem., 2008, 73, 2955.
17 T. Szuppa, A. Stolle, B. Ondruschka and W. Hopfe, Green Chem.,
2010, 12, 1288.
18 G.-W. Wang, Y.-W. Dong, P. Wu, T.-T. Yuan and Y.-B. Shen, J.
Org. Chem., 2008, 73, 7088.
19 (a) R. Thorwirth, A. Stolle, B. Ondruschka, A. Wild and U.
S. Schubert, Chem. Commun., 2011, 47, 4370; (b) R. Schmidt,
R. Thorwirth, T. Szuppa, A. Stolle, B. Ondruschka and H. Hopf,
Chem.–Eur. J., 2011, 17, 8129; (c) R. Thorwirth, A. Stolle and
B. Ondruschka, Green Chem., 2010, 12, 985; (d) D. A. Fulmer, W.
C. Shearouse, S. T. Medonza and J. Mack, Green Chem., 2009,
11, 1821; (e) F. Schneider, T. Szuppa, A. Stolle, B. Ondruschka
and H. Hopf, Green Chem., 2009, 11, 1894; (f) F. Schneider,
A. Stolle, B. Ondruschka and H. Hopf, Org. Process Res. Dev.,
2009, 13, 44.
20 (a) R. Schmidt, A. Stolle and B. Ondruschka, Green Chem., 2012,
14, 1673; (b) G.-W. Wang and J. Gao, Green Chem., 2012, 14,
1125.
21 C.-C. Hsu, N.-C. Chen, C.-C. Lai, Y.-H. Liu, S.-M. Peng and S.-
H. Chiu, Angew. Chem., Int. Ed., 2008, 47, 7475.
22 S.-H. Chiu and J. F. Stoddart, J. Am. Chem. Soc., 2002, 124, 4174.
23 R. Castro, K. R. Nixon, J. D. Evanseck and A. E. Kaifer, J. Org.
Chem., 1996, 61, 7298.
8 C. L. Brown, D. Philp, N. Spencer and J. F. Stoddart, Isr. J.
Chem., 1992, 32, 61.
´
9 M. Asakawa, W. Dehaen, G. L’abbe, S. Menzer, J. Nouwen, F.
M. Raymo, J. F. Stoddart and D. J. Williams, J. Org. Chem., 1996,
61, 9591.
10 C.-H. Sue, S. Basu, A. C. Fahrenbach, A. K. Shveyd, S. K. Dey, Y.
Y. Botros and J. F. Stoddart, Chem. Sci., 2010, 1, 119.
11 (a) A. C. Benniston and A. Harriman, Synlett, 1993, 233; (b) C.-
Q. Fan, Y.-H. Yu, Y. Xia, B. Tu and Z.-T. Li, J. Fluorine Chem.,
2000, 106, 147; (c) A. Margotti, C. Casati, M. Lucarini and
E. Mezzina, Tetrahedron Lett., 2008, 49, 4784; (d) P. R. Ashton,
R. Ballardini, V. Balzni, S. E. Boyd, A. Credi, M. T. Gandolfi,
´
´
M. Gomez-Lopez, S. Iqbal, D. Philp, J. A. Preece, L. Prodi, H.
G. Ricketts, J. F. Stoddart, M. S. Tolley, M. Venturi, A. J. P. White
and D. J. Williams, Chem.–Eur. J., 1997, 3, 152; (e) M. A. Olson,
A. B. Braunschweig, T. Ikeda, L. Fang, A. Trabolsi, A. M.
Z. Slawin, S. I. Khan and J. F. Stoddart, Org. Biomol. Chem.,
2009, 7, 4391.
694 | RSC Adv., 2013, 3, 691–694
This journal is ß The Royal Society of Chemistry 2013