Template synthesis of [2]rotaxanes with large ring components and tris(biphenyl)methyl group as the blocking group. The relationship between the ring size and the stability of the rotaxanes

Article abstract of DOI:10.1021/jo060829h

We synthesized a series of macrocyclic phenanthrolines 3a-e and a tris(biphenyl)methyl derivative 4. [2]Rotaxanes with large ring components (10a,b) were synthesized by the template method, and the stability of the rotaxanes was examined. The study reveal

Full text of DOI:10.1021/jo060829h

Our recent interest in the chemistry of rotaxanes prompted
us to study the synthesis of a rotaxane which has a larger ring
component and a larger blocking group by the template method.
Though some large blocking groups, such as fullerenes,10 por-
phyrins,11 calixarenes,12 and dendrimers,8b,13 have been utilized
for the synthesis of the rotaxanes, the chemical stability and/or
the availability of these blocking groups would be rather limited.
We designed and synthesized a series of 33-53-membered
macrocyclic phenanthrolines and a larger stopper (tris(biphenyl)-
methyl group) which would be a very stable, large, and versatile
blocking group. Herein we report the synthesis and stability of
the rotaxanes prepared by the reactions of these components.
Polyether macrocyclic phenanthrolines are widely used
components for the template synthesis of rotaxanes.1 We
prepared a variety of macrocyclic phenanthrolines 3 from 2,9-
bis(4-hydroxyphenyl)-1,10-phenanthroline 114 and various di-
Template Synthesis of [2]Rotaxanes with Large
Ring Components and Tris(biphenyl)methyl
Group as the Blocking Group. The Relationship
between the Ring Size and the Stability of the
Rotaxanes
Shinichi Saito,* Kazuko Nakazono, and Eiko Takahashi
Department of Chemistry, Faculty of Science, Tokyo UniVersity
of Science, Kagurazaka, Shinjuku, Tokyo, Japan 162-8601
ssaito@rs.kagu.tus.ac.jp
ReceiVed April 20, 2006
(1) Reviews: (a) Catenanes, Rotaxanes, and Knots; Schill, G., Ed.;
Academic Press: New York, 1971. (b) Molecular Catenanes, Rotaxanes
and Knots; Dietrich-Buchecker, C. O., Sauvage, J. P., Eds.; Wiley-VCH:
New York, 1999. (c) Sauvage, J. P. Acc. Chem. Res. 1990, 23, 319-327.
(d) Hoss, R.; Vo¨gtle, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 375-384.
(e) Amabilino, D. B.; Stoddart, J. F. Chem. ReV. 1995, 95, 2725-2828. (f)
Ja¨ger, R.; Vo¨gtle, F. Angew. Chem., Int. Ed. Engl. 1997, 36, 930-944. (g)
Nepogodiev, S. A.; Stoddart, J. F. Chem. ReV. 1998, 98, 1959-1976. (h)
Sauvage, J. P. Acc. Chem. Res. 1998, 31, 611-619. (i) Raymo, F. M.;
Stoddart, J. F. Chem. ReV. 1999, 99, 1643-1663. (j) Tian, H.; Wang, Q.-
C. Chem. Soc. ReV. 2006, 35, 361-374.
We synthesized a series of macrocyclic phenanthrolines 3a-e
and a tris(biphenyl)methyl derivative 4. [2]Rotaxanes with
large ring components (10a,b) were synthesized by the
template method, and the stability of the rotaxanes was
examined. The study revealed that the tris(biphenyl)methyl
group is an effective blocking group for the rotaxanes with
up to a 33-membered ring. Even a rotaxane with a 37-
membered macrocyclic phenanthroline (10b) could be iso-
lated. The dissociation of 10b occurred at 60 °C.
(2) Dietrich-Buchecker, C. O.; Sauvage, J. P.; Kintzinger, J. P. Tetra-
hedron Lett. 1983, 24, 5095-5098.
(3) Harrison, I. T.; Harrison, S. J. Am. Chem. Soc. 1967, 89, 5723-5724.
(4) Harrison, I. T. J. Chem. Soc., Chem. Commun. 1972, 4, 231-232.
(5) Schill, G.; Beckmann, W.; Schweickert, N.; Fritz, H. Chem. Ber.
1986, 119, 2647-2655.
(6) Harrison, I. T. J. Chem. Soc., Perkin Trans. 1 1974, 301-304.
(7) Schill, G.; Zo¨llenkopf, H. Justus Liebigs Ann. Chem. 1969, 721,
53-74.
(8) (a) Heim, C.; Affeld, A.; Nieger, M.; Vo¨gtle, F. HelV. Chim.
Acta 1999, 82, 746-759. (b) Hu¨bner, G. M.; Nachtsheim, G.; Li, Q.-Y.;
Seel, C.; Vo¨gtle, F. Angew. Chem., Int. Ed. 2000, 39, 1269-1272. (c)
Affeld, A.; Hu¨bner, G. M.; Seel, C.; Schally, C. A. Eur. J. Org. Chem.
2001, 2877-2890. (d) Felder, T.; Schalley, C. A. Angew. Chem., Int. Ed.
2003, 42, 2258-2260.
(9) (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) Raymo, F. M.; Houk, K. N.; Stoddart, J. F. J. Am.
Chem. Soc. 1998, 120, 9318-9322. (c) Tachibana, Y.; Kihara, N.; Furusho,
Y.; Takata, T. Org. Lett. 2004, 6, 4507-4509.
[2]Rotaxane is an important class of mechanically interlocked
molecules, which is composed of a ring component and an axle
component. A number of methodologies have been reported for
the efficient synthesis of rotaxanes.1 Among them, the template
method utilizing the transition metal-ligand bond, which was
developed in the 1980s,2 has been widely used.
(10) See, for example: (a) Diederich, F.; Dietrich-Buchecker, C. O.;
Nierengarten, J.-F.; Sauvage, J. P. J. Chem. Soc., Chem. Commun. 1995,
781-782. (b) Armaroli, N.; Diederich, F.; Dietrich-Buchecker, C. O.;
Flamigni, L.; Nierengarten, J.-F.; Sauvage, J. P. Chem.sEur. J. 1998, 4,
406-416. (c) Nepal, D.; Samal, S.; Geckeler, K. E. Macromolecules 2003,
36, 3800-3802. (d) Sasabe, H.; Kihara, N.; Furusho, Y.; Mizuno, K.;
Ogawa, A.; Takata, T. Org. Lett. 2004, 6, 3957-3960.
To prevent the dissociation of a [2]rotaxane, it is necessary
to use a sufficiently large blocking group compared to the size
of the ring. The stability of [2]rotaxanes with various blocking
groups has been studied. Triphenylmethyl group was the block-
ing group which was used for the synthesis of a rotaxane with
a C30 macrocycle.3 It was observed that the triphenylmethyl
group did not pass through a C29 macrocycle at rt, but the dis-
sociation occurred at 120-130 °C.4-6 When the blocking group
was changed to a bis(cyclohexyl)methyl group, a [2]rotaxane
with a C28 macrocycle was isolated as a stable compound.6
When a tris(4-tert-butylphenyl)methyl group was introduced as
the blocking group, the rotaxane with an up to 33-membered
cyclic olefin turned out to be stable.6 1,3,5-Tris(p-tolyl)phenyl
group was used as the blocking group for the “directed”
synthesis of a rotaxane with a 26-membered macrocycle.7 The
stability and kinetics of the deslipping reactions of amide
rotaxanes8 and polyether rotaxanes9 have been studied in depth.
(11) See, for example: (a) Chambron, J.-C.; Dietrich-Buchecker, C. O.;
Heitz, V.; Nierengarten, J.-F.; Sauvage, J. P.; Pascard, C.; Guilhem, J. Pure
Appl. Chem. 1995, 67, 233-240. (b) Chambron, J.-C.; Chardon-Noblat,
S.; Harriman, A.; Heitz, V.; Sauvage, J. P. NATO ASI Ser., Ser. C, Math.
Phys. Sci. 1995, 456, 215-234. (c) Li, K.; Schuster, D. I.; Guldi, D. M.;
Herranz, M. AÄ .; Echegoyen, L. J. Am. Chem. Soc. 2004, 126, 3388-3389.
(d) Schuster, D. I.; Li, K.; Guldi, D. M.; Ramey, J. Org. Lett. 2004, 6,
1919-1922. (e) Sandanayaka, A. S. D.; Watanabe, N.; Ikeshita, K.-I.; Araki,
Y.; Kihara, N.; Furusho, Y.; Ito, O.; Takata, T. J. Phys. Chem. B 2005,
109, 2516-2525.
(12) Fischer, C.; Nieger, M.; Bo¨hmer, V.; Ungaro, R.; Vo¨gtle, F. Eur.
J. Org. Chem. 1998, 155-161.
(13) Amabilino, D. B.; Ashton, P. R.; Balzani, V.; Brown, C. L.; Credi,
A.; Fre´chet, J. M. J.; Leon, J. W.; Raymo, F. M.; Stoddart, J. F.; Venturi,
M. J. Am. Chem. Soc. 1996, 118, 12012-12020.
(14) Dietrich-Buchecker, C.; Sauvage, J. P. Tetrahedron 1990, 46, 503-
512.
10.1021/jo060829h CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/19/2006
J. Org. Chem. 2006, 71, 7477-7480
7477

SCHEME 1
SCHEME 2
TABLE 1. Examination of the Reaction Conditions for the
Macrocyclization of 1 with 2
bromides derived from resorcinol. We expected that the meta-
substituted structure would stabilize the cyclic conformation,
preventing the “shrinking (narrowing of the cavity)” of the
ring.15 We selected the reaction of 1 with 2d as the model
reaction and examined the optimum condition for the macro-
cyclization. The results are summarized in Table 1. On the basis
of previous studies,16 we chose anhydrous DMSO as the solvent
and carried out the reaction in the presence of an excess of K2-
CO3 and 1.5 equiv of the dibromide 2d (n ) 10). When the
concentration of 1 was 30 mM, the yield of 3d was very low,
and a large amount of oligomeric products were isolated (entry
1). On the other hand, the yield of 3d increased to 34% when
the reaction was carried out under highly diluted conditions
(entry 2). Though 1 equiv of 2d was sufficient for this reaction,
we noticed that the yield of 3 was not reproducible when
anhydrous DMSO was used as the solvent (entry 3). Further
examination of the reaction conditions revealed that 3 was
isolated in a higher and reproducible yield in comparison to
concn of
2d
yield
(%)
entry
solvent
1 (mM)
(equiv)
1
2
3
anhydrous DMSO
anhydrous DMSO
anhydrous DMSO
20
5
5
1.5
1.5
1
5
34
38a
43
42
37
4
99% DMSO-1% H2O
95% DMSO-5% H2O
99% DMSO-1% H2O
5
5
5
1
1
1
5
6b
a The yield was not reproducible (see text). b CsCO3 was used as the base.
7478 J. Org. Chem., Vol. 71, No. 19, 2006

1
FIGURE 1. Dissociation of 10b monitored by H NMR at 60 °C in CDCl3.
TABLE 2. Examination of the Reaction Conditions for the
Macrocyclization of 1 with 2
TABLE 3. Synthesis of Rotaxanes 10 from 3
ring
size
yield of
10 (%)
yield of
11 (%)
recovery
of 3 (%)
entry
3
1
2
3
4
3a
3b
3c
3d
33
37
41
45
62 (10a)
17
45
62
69
27
63
100
72
34 (10b)a
0
0
a Slow dissociation (deslipping) was observed (see text).
in a DMSO/water mixture has accelerated the reaction. Though
we carried out this reaction in the presence of CsCO3 instead
of K2CO3, the yield of 3d did not improve (entry 6).
We used this optimized condition for the synthesis of a series
of macrocyclic phenanthrolines (3), and the results are summa-
rized in Table 2. The effect of the ring size on the yield of 3
was small when the alkyl chain was shorter (n ) 6-10, entries
1-3), and compounds 3a-c were isolated in ca. 40% yields.
On the other hand, the yields of larger macrocyclic phenan-
throlines slightly decreased (entries 4 and 5).
entry
n
product
yield (%)
1
2
3
4
5
6
3a
3b
3c
3d
3e
41
42
43
26
37
8
10
12
16
the result shown in entry 3 by the addition of a small amount
of water to the reaction mixture (entry 4). The addition of a
larger amount of water had little effect on the yield (entry 5).
We assume that the higher solubility of the potassium salt of 1
We selected a tris(biphenyl)methyl group as a large and stable
blocking group, and the synthesis of 4 is summarized in Scheme
J. Org. Chem, Vol. 71, No. 19, 2006 7479

1. Thus, tris(biphenyl)carbinol (6)17 was prepared by the reaction
of the Grignard reagent prepared from 5 and diethyl carbonate.
The procedure18 reported for the synthesis of triarylmethyl deriva-
tives was followed, and the alcohol 6 was subjected to reduction
by formic acid to yield 719 in 61% yield. Compound 7 was
further converted to alcohol 8. Iodination20 of 8 gave 4 in 90%
yield.
To estimate the size of the tris(biphenyl)methyl group, we
chose the template method21 for the synthesis of rotaxanes and
examined the relationship between the size of 3 with the yield
of the rotaxane 10. The syntheses of the rotaxanes 10a,b are
shown in Scheme 2. Thus, macrocycle 3 and bis(hydroxyphen-
yl)phenanthroline 1 were reacted with a Cu(I) salt, and the macro-
cyclic Cu(I) complex 9 was prepared in situ.22 Compound 9 was
reacted with 4 in the presence of Cs2CO3, the Cu(I) ion was
removed, and the products were isolated. The results are
summarized in Table 3.
When the reaction was carried out with 3a (33-membered ring),
the corresponding rotaxane 10a was isolated in 62% yield, along
withasmallamountof1123 andtherecoveredmacrocyclicphenan-
throline 3 (entry 1). The result indicates that the tris(biphenyl)-
methyl group is large enough to prevent the deslipping reaction
(dissociation of 10a into 11 and 3a). Though the reaction of a
larger phenanthroline (3b, 37-membered ring) also proceeded,
the yield of 10b was much lower (34%, entry 2). The corres-
ponding rotaxane was not isolated when 3c (41-membered ring)
or 3d (45-membered ring) was chosen as the cyclic component.24
To understand the observed lower yield of 10b, we further
examined the stability of 10b and found that the dissociation of
10b occurred at 60 °C. Compound 10b was dissolved in CDCl3,
and the dissociation was monitored by heating the solution at
60 °C. The time course of the dissociation (deslipping) is shown
in Figure 1. The kinetics of the deslipping reaction was analyzed
at 70-90 °C, and the rate constants and thermodynamic
parameters were calculated as follows: ∆Gq(353 K) ) 116 kJ/
mol, ∆Hq ) 65.0 kJ/mol, ∆Sq ) -144 J/mol.25 The very high
entropic contribution would reflect the rigid structure of the
blocking group and the requirement of the particular conforma-
tion of 10b for the progress of the reaction.8c The lower yield
of 10b (Table 3, entry 2) would be explained in terms of the
partial dissociation of 10b during the work up and/or purifica-
tion.23,26 On the other hand, no dissociation of 10a was observed
when a solution of 10a in CDCl3 was heated at 60 °C for 30 h.
From these results, it is clear that the tris(biphenyl)methyl group
would be large enough for the formation of 10a. On the other
hand, the stability of 10b is rather limited at rt, and the tris-
(biphenyl)methyl group slowly passes through the 37-membered
ring formed by 3b at elevated temperature (60 °C).
In summary, we synthesized a series of cyclic phenanthrolines
3a-e and a tris(biphenyl)methyl derivative 4. Larger rotaxanes
10a,b were synthesized by the template method, and the stability
of the rotaxanes was examined. The study revealed the size of
the tris(biphenyl)methyl group, which is an effective blocking
group for the rotaxanes with up to a 33-membered ring. We also
succeeded in the synthesis and isolation of a larger rotaxane
with a 37-membered ring which dissociated at elevated tempera-
ture. The synthesis of larger blocking groups, which would be
suitable for the synthesis of much larger rotaxanes, is ongoing.
Experimental Section
A Representative Procedure for the Synthesis of Rotaxanes.
Synthesis of 10a. To a solution of Cu(CH3CN)4PF6 (37 mg, 0.1
mmol) in dry CH2Cl2 (5 mL) was added 3a (0.1 mmol) at rt. After
5 min, the solution was added to a suspension of 1 (36 mg, 0.1
mmol) in dry CH3CN (5 mL), and the mixture was stirred at rt for
1 h. The solvent was removed under reduced pressure, and to the
residue were added iodide 4 (127 mg, 0.2 mmol), dry DMF (2 mL),
and Cs2CO3 (130 mg, 0.4 mmol). The reaction mixture was kept
stirring at 60 °C for 2 days, and the solvent was removed in vacuo.
To the residue were added CH3CN (10 mL), CH2Cl2 (5 mL), H2O
(5 mL), and KCN (33 mg, 0.5 mmol). The mixture was stirred at
rt for 14 h. The organic layer was separated, washed with water,
dried over Na2SO4, and concentrated in vacuo. The residue was
purified by silica gel column chromatography using hexane/CH2-
Cl2 (1/1, v/v) as the eluent to give 10a (131 mg, 62%) and 1125
(25 mg, 17%). Compound 3a25 was also recovered (17 mg, 27%).
Compound 10a: colorless amorphous, 1H NMR (300 MHz, CDCl3)
δ 8.41 (d, J ) 10.5 Hz, 4H), 8.38 (d, J ) 8.38 Hz, 4H), 8.16 (d,
J ) 9.0 Hz, 2H), 8.12 (d, J ) 8.4 Hz, 2H), 8.00 (d, J ) 8.4 Hz,
2H), 7.96 (d, J ) 8.4 Hz, 2H), 7.66 (d, J ) 8.4 Hz), 7.55 (d, J )
7.2 Hz, 12H), 7.48 (d, J ) 8.4 Hz, 12H), 7.40-7.24 (m, 30H),
7.11 (t, J ) 8.1 Hz, 1H), 7.04 (d, J ) 8.7 Hz, 4H), 6.91 (s, 1H),
6.47 (d, J ) 8.1 Hz, 2H), 3.97-3.81 (m, 8H), 3.74 (t, J ) 7.2 Hz,
4H), 2.67-2.52 (m, 4H), 1.79-1.56 (m, 12H), 1.50-1.09 (m, 20H);
13C NMR (150 MHz, CDCl3) δ 160.4, 160.4, 160.2, 156.4, 156.2,
146.5, 146.1, 145.9, 140.5, 138.4, 136.6, 132.0, 131.8, 129.8, 129.6,
128.9, 128.6, 127.4, 127.0, 126.9, 126.4, 125.5, 125.4, 119.3, 114.7,
114.6, 106.8, 101.4, 67.9, 67.7, 56.0, 40.3, 30.3, 29.5, 29.0, 26.1,
25.9, 25.8, 25.6; IR (KBr) 2938, 2870, 2363, 1604, 1586, 1491,
1473, 1288, 1252, 1179, 1151, 1020, 835 cm-1. Anal. Calcd for
(15) The rigid phenanthroline moiety prevents the alkyl groups of the ring
component to come closer, so that the cavity of the macrocycle would not
become narrow. We expected a similar effect by introducing the resorcinol
moiety.
(16) Lu¨ning, U.; Mu¨ller, M.; Gelbert, M.; Peters, K.; von Schnering, H.
G.; Keller, M. Chem. Ber. 1994, 127, 2297-2306.
(17) Broser, W.; Kurreck, H.; Niemeier, W. Tetrahedron 1976, 32,
1183-1187.
(18) Gibson, H. W.; Lee, S.-H.; Enger, P. T.; Lecavalier, P.; Sze, J.;
Shem, Y. X.; Bheda, M. J. Org. Chem. 1993, 58, 3748-3756.
(19) Bredereck, H.; Gompper, R.; Bitzer, D. Chem. Ber. 1959, 92,
1139-1145.
(20) (a) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem. Commun.
1979, 978-980. (b) Garegg, P. J.; Regberg, T.; Stawinski, J.; Stoemberg,
R. J. Chem. Soc., Perkin Trans. 2 1987, 271-274.
(21) Dietrich-Buchecker, C.; Sauvage, J. P. Chem.sEur. J. 2000, 46,
503-512.
(22) Though we confirmed the formation of 9 by the NMR analysis of
the crude mixture, we could not isolate 9 in pure form. See Supporting
Information for the NMR spectra of 9a.
C152H134N4O6: C, 86.41; H, 6.39; N, 2.65. Found: C, 86.39; H,
(23) The formation of 11 might occur if the conformation of 9 was not
suitable for the formation of the rotaxane when the C-O bond forming
reaction proceeded. Incomplete formation of 9 might also result in the
formation of 11.
(24) Attempted detection of the rotaxane in the crude mixture by GPC
or NMR analysis failed. Since the formation of the rotaxane from 9e was
less likely, the reaction was not carried out.
6.49; N, 2.63.
Acknowledgment. We thank Yamada Science Foundation
for financial support.
Supporting Information Available: Detailed experimental
procedures and spectral data of 2e, 3a-e, 4, 8, 9a, 10a,b, and 11.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(25) See Supporting Information.
(26) The calculated t1/2 for the reaction of 10b at 27 °C was ca. 200 h.
Considering the time required for the decomplexation and purification,
we assume that the partial dissociation took place. In solid state, 10b could
be stored in a freezer (-20 °C) for a couple of months without dissoci-
ation.
JO060829H
7480 J. Org. Chem., Vol. 71, No. 19, 2006