Dynamic combinatorial library for fullerene receptors based on metal-assisted self-assembly

Article abstract of DOI:10.1016/j.tetlet.2006.09.002

A dynamic combinatorial library was prepared by the metal-induced self-assembly of phenanthroline derivatives having a guest binding unit. The binding assay using ESI mass spectrometry found out the effective combination of guest binding units for fullere

Full text of DOI:10.1016/j.tetlet.2006.09.002

Tetrahedron Letters 47 (2006) 7915–7918
Dynamic combinatorial library for fullerene receptors based
on metal-assisted self-assembly
Takeharu Haino,* Hisashi Mitsuhashi, Yoshiko Ishizu and Yoshimasa Fukazawa*
Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739, Japan
Received 1 August 2006; revised 31 August 2006; accepted 1 September 2006
Available online 25 September 2006
Abstract—A dynamic combinatorial library was prepared by the metal-induced self-assembly of phenanthroline derivatives having a
guest binding unit. The binding assay using ESI mass spectrometry found out the effective combination of guest binding units for
fullerene binding.
Ó 2006 Published by Elsevier Ltd.
R
The demand for the discovery of new drugs as well as
new materials is the driving force for the development
R
NH
O
HN
O
of new combinatorial libraries.1 Parallel and split-pool
methods on a solid support are the effective techniques
to find target compounds with combinatorial chemis-
try.2 These methods require the optimization of reaction
conditions and the development of new synthetic ways
for library construction on solid supports. In contrast,
permutation–combination-based combinatorial synthe-
sis could greatly simplify the generation of diverse
library;3 however, the resulting library faces serious
problems, which involve unequal amounts of products
and difficulties for their identification and
characterization.
Ag+
N
N
N
N
O
N
N
HN
R
Ar
Ar
C7H15
O
Ha
1•Ag+ 1
1a: R = n-Bu
OH
1d: R =
1e: R =
CH2
OH OH OH OH
Ph
1b: R =
Me
HN
N
Me
Me Me
Ph
N
NH
1c: R = CH2Ph
Ph
Permutation–combination-based dynamic combinato-
rial chemistry has recently emerged.4 The dynamic
equilibrium among library members, formed via
permutation and combination of subunits, has many
advantages for supramolecular chemistry. The amplifi-
cation of a desired member by the templation of a guest
is a characteristic feature in the dynamic library.5 The
guest recognizes and stabilizes a desired member of the
library. This selective molecular recognition event
induces a shift of the equilibrium toward the formation
of the desired member, and away from others not to be
involved in the recognition event. Thus, the desired
member is amplified, and easier to identify it in the
diverse library.
We have reported that calix[5]arene derivatives and dou-
ble-calix[5]arenes are good hosts for C60 and C70.6,7 In
our recent study, calix[5]arenes possessing a bipyridine
unit assemble via silver coordination to form a dimeric
complex, which equilibrates with its monomer in chloro-
form solution.8 We envisioned to utilize the metal-
assisted self-assembly for the construction of the
dynamic library for fullerene receptors.9 In this letter,
we report the preparation and screening of a permuta-
tion–combination-based dynamic combinatorial library
of fullerene receptors via self-assembly of phenanthro-
lines 1a–e possessing fullerene binding units through
metal-coordination.
The synthesis of phenanthrolines is outlined in Scheme
1. The treatment of phenanthroline with 4-heptyloxy-
phenyllithium, prepared from 4-heptyloxybromo-
benzene, followed by oxidation with manganese dioxide
*
Corresponding authors. Tel.: +81 82 424 7403; fax: +81 82 424 0724
(T.H.); e-mail: haino@sci.hiroshima-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.09.002

7916
T. Haino et al. / Tetrahedron Letters 47 (2006) 7915–7918
nated at 5.9 ppm (Fig. 1b). When these complexes were
a
b
mixed in a 1:1 ratio, the triplet and doublet signals split
to give rise to the new signals, pointed by the arrows
(Fig. 1c). Saturation transfer experiments revealed that
the new signals exchange with their parents, a fact which
suggests the formation of heterodimer [1aÆAg+Æ1b]TfOÀ.
These results indicate that a sizable energetic barrier
exists in the equilibrium among the heterodimer and
the homodimers (Fig. 1c). The ESI mass spectrum of
the mixture and the peak intensities of 1H NMR
confirmed the formation of the heterodimer and the
homodimers in a ratio of 1:2:1 (Fig. 2).
N
N
N
N
N
N
O
O
2
3
4
C7H15
O
C7H15
O
R-NH2
6
a-e, e
c, d
N
N
1
a–e
COOH
C7H15
O
5
6a: R = n-Bu
6d: R =
6e: R =
CH2
OH OH OH OH
OH
6b: R =
Me
Ph
N HN
NH N
Me
Me Me
Ph
6c: R = CH2Ph
Ph
Upon the addition of diethyl 1,2-methano[60]fullerene-
61,61-dicarboxylate 7 (Fig. 3) to a solution of the
mixture, the aromatic signal of [1bÆAg+Æ1b]TfOÀ quickly
disappeared, and a new signal emerged at 6.2 ppm
(Fig. 1d), which is consistent with the formation of 7
ꢀ [1bÆAg+Æ1b]TfOÀ (Fig. 1e) with the consumption of
[1bÆAg+Æ1b]TfOÀ (Fig. 1d). Interestingly, the intensities
of the aromatic protons of the heterodimer decreased
upon the addition of 7, indicating that the equilibrium
was shifted toward homodimer 7 ꢀ [1bÆAg+Æ1b]TfOÀ
by the addition of 7. This clearly suggested that the
complex having the effective guest binding units was
amplified via dynamic equilibrium.
Scheme 1. Reagents and conditions: (a) 4-heptyloxybromobenzene,
t-BuLi, THF, À78 °C, and then MnO2 48%; (b) 2-(3-bromophenyl)-
5,5-dimethyl-1,3-dioxane, t-BuLi, THF, À78 °C, and then MnO2 76%;
(c) aqueous 10% HCl, THF, 40 °C 99%; (d) TBAMnO4, pyridine,
THF, 91%; (e) EDCI, HOAt, DMF (1a: 65%, 1b: 45%, 1c: 61%, 1d:
15%, 1e: 55%).
provided 3. The aryllithium, prepared from 2-(3-bromo-
phenyl)-5,5-dimethyl-1,3-dioxane,10 reacted with 3 and
the subsequent oxidation afforded 4. The deprotection
of 4, followed by the oxidation of the resultant aldehyde
group gave carboxylic acid 5. The condensation reactions
between 5 and amino derivatives 6a–e furnished 1a–e
.
The study of noncovalently bound complexes by electro-
spray ionization mass spectrometry11 has rapidly gained
momentum. A large number of reports have dealt with
the mass spectrometric characterization of noncovalent
complexes, such as supramolecular metal complexes.12
ESI-MS spectrometry has proven to be an indispensable
tool in supramolecular chemistry. The silver cation
labeling of the self-assembling complexes [1ÆAg+Æ1]TfOÀ
Self-assembled dimers [1ÆAg+Æ1]TfOÀ quickly formed
when a half amount of silver triflate was added to a solu-
tion of 1 in dichloromethane at room temperature. The
aromatic proton Ha of the heptyloxyphenyl group of
complex [1aÆAg+Æ1a]TfOÀ appeared at 6.3 ppm, and the
amide N–H resonance showed up at 6.6 ppm as a triplet
(Fig. 1a). Proton Ha of complex [1bÆAg+Æ1b]TfOÀ reso-
Figure 2. ESI mass spectrum of a 1:1 mixture of [1aÆAg+Æ1a]TfOÀ and
[1bÆAg+Æ1b]TfOÀ in chloroform.
COOEt
EtOOC
Figure 1. 1H NMR spectra (500 MHz) of: (a) [1aÆAg+Æ1a]TfOÀ
(5.0 mmol/L), (b) [1bÆAg+Æ1b]TfOÀ (5.0 mmol/L), (c) a 1:1 mixture of
[1aÆAg+Æ1a]TfOÀ and [1bÆAg+Æ1b]TfOÀ, (d) after addition of 1.6 equiv 7,
(e) 7 [1bÆAg+Æ1b]TfOÀ in chloroform-d at 298 K.
Figure 3. The structure of diethyl 1,2-methano[60]fullerene-61,61-
dicarboxylate 7.

T. Haino et al. / Tetrahedron Letters 47 (2006) 7915–7918
7917
Table 1. Binding constants (Ka/MÀ1
)
of [1bÆCu+Æ1b]PF
,
À
was the advantage for ESI-MS measurements in non-
polar aprotic solvents.
6
[1eÆCu+Æ1e]PF À, and 7 for C60 and C70 in 1,1,2,2-tetrachloroethane
6
at 298 K
Ka
A permutation–combination-based dynamic library was
prepared via self-assembly of 1b–e upon the addition of
silver triflate. The dynamic equilibrium gives rise to
the 10 discrete library members. As expected, ESI mass
measurement of the library gave the 10 peaks, assignable
to the discrete library members (Fig. 4a). Upon the addi-
tion of C60 into a solution of the library, four new peaks
appeared, and they were assigned to four newly formed
complexes C60 ꢀ [1bÆAg+Æ1b–e] (Fig. 4b). As a result, the
calix[5]arene moiety is crucial to take up a C60 molecule.
As we noted in our previous reports, the cavity of a
calix[5]arene is complementary to the exterior of a C60
molecule, and shows the strong binding ability to it.7
Thus, the result is quite convincing. Competition exper-
iment between C60 and C70 should give information of
their relative binding affinities toward the library mem-
bers. C70 bound only to the two discrete hosts: one is
made up of a calix[5]arene and a porphyrin ring, the
other has two porphyrin rings, which gave the com-
plexes C70 ꢀ [1bÆAg+Æ1e] and C70 ꢀ [1eÆAg+Æ1e]. Their
peak intensities are close to those of C60 ꢀ [1bÆAg+Æ1b]
and C60 ꢀ [1bÆAg+Æ1e] (Fig. 4c). Since C70 is known as
a better electron acceptor than C60, C70 perhaps showed
the preferential binding to the porphyrin-based hosts
through charge transfer interaction.13
C60
C70
[1bÆCu+Æ1b]PF6À
13,000 700
9600 800
4900 200
15,000 600
4900 300
5000 200
À
[1eÆCu+Æ1e]PF6
8
O
O
H
H
O
H
H
O
O
H
O
H
H
O
H
H
O
H
O
O
Me
Figure 5. The structure of host 8.
[1eÆCu+Æ1e]PF were prepared as a stable tetrahedral
À
6
complex in solution. Their binding constants for C60
and C70 were determined by standard UV–vis titration
(Table 1).14 These hosts showed much greater binding
abilities than 8 (Fig. 5).7 The binding trends are slightly
different from those given by ESI mass spectrometry.
The mass peaks attributable to C60 ꢀ [1eÆAg+Æ1e] and
To verify the binding abilities of the given hosÀts for
C60 and C70, self-assembled hosts [1bÆCu+Æ1b]PF and
6
C70 ꢀ [1bÆAg+Æ1b] were not observed; however, the
corresponding Cu complexes [1bÆCu+Æ1b]PF
and
À
6
[1eÆCu+Æ1e]PF showed a strong binding to C60 and C70.
À
6
This may come from the difference between the struc-
tural flexibilities of the complexes 1ÆCu+Æ1 and 1ÆAg+Æ1.
In summary, we found the new hosts showing strong
binding to fullerene via a permutation–combination-
based combinatorial library, which was prepared by
metal-coordination driven self-assembly. This method
permits a quick generation of diverse combinatorial
library from a mixture of discrete subunits.
Acknowledgements
We gratefully acknowledge the financial support of this
work by a Grant-in-Aid (Nos. 14654114 and 12740348)
for Scientific Research from the Ministry of Education,
Science, Sports, and Culture, Japan.
References and notes
1. Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555–
600.
2. Wilson, S. R.; Czarnik, A. W. Combinatorial Chemistry:
Synthesis and Application; John Wiley & Sons: New York,
1997.
3. Balkenhohl, F.; von dem Bussche-Hunnefeld, C.; Lansky,
A.; Zechel, C. Angew. Chem., Int. Ed. 1996, 35, 2289–2337;
Carell, T.; Winter, E. A.; Bashir-Hashemi, A.; Rebek, J.,
Jr Angew. Chem., Int. Ed. Engl. 1994, 33, 2059–2061;
Figure 4. ESI mass spectra of the combinatorial library: (a) without a
guest, (b) with C60, (c) with a 1:1 mixture of C60 and C70 in 1,1,2,2-
tetrachloroethane.

7918
T. Haino et al. / Tetrahedron Letters 47 (2006) 7915–7918
Carell, T.; Winter, E. A.; Rebek, J., Jr. Angew. Chem., Int.
Ed. Engl. 1994, 33, 2061–2064.
11. Przybylski, M.; Glocker, M. O. Angew. Chem., Int. Ed.
1996, 35, 806.
4. Ziegler, M.; Miranda, J. J.; Andersen, U. N.; Johnson, D.
W.; Leary, J. A.; Raymond, K. N. Angew. Chem., Int. Ed.
2001, 40, 733–736; Brisig, B.; Sanders, J. K. M.; Otto, S.
Angew. Chem., Int. Ed. 2003, 42, 1270–1273.
5. Lehn, J.-M. Chem. Eur. J. 1999, 5, 2455–2463; Otto, S.;
Furlan, R. L. E.; Sanders, J. K. M. Drug Discov. Today
2002, 7, 117–125; Huc, I.; Lehn, J.-M. Proc. Natl. Acad.
Sci. USA 1997, 94, 2106–2110.
6. Haino, T.; Yanase, M.; Fukazawa, Y. Angew. Chem., Int.
Ed. 1998, 37, 997–998; Haino, T.; Yanase, M.; Fukazawa,
Y. Angew. Chem., Int. Ed. 1997, 36, 259–260; Haino, T.;
Yanase, M.; Fukazawa, Y. Tetrahedron Lett. 1997, 38,
3739–3742.
12. Jacopozzi, P.; Dalcanale, E. Angew. Chem., Int. Ed. 1997,
36, 613; Stang, P. J.; Cao, D. H.; Chen, K.; Gray, G. M.;
Muddiman, D. C.; Smith, R. D. J. Am. Chem. Soc. 1997,
119, 5163; Piguet, C.; Hopfgartner, G.; Bocquet, B.;
Schaad, O.; Williams, A. F. J. Am. Chem. Soc. 1994, 116,
´
9092; Bitsch, F.; Dietrich-Buchecker, C. O.; Khemiss,
A.-K.; Sauvage, J.-P.; Dorsselaer, A. V. J. Am. Chem. Soc.
1991, 113, 4023; Vincenti, M.; Dalcanale, E.; Soncini, P.;
Guglielmetti, G. J. Am. Chem. Soc. 1990, 112, 445;
´
Schalley, C. A.; Martın, T.; Obst, U.; Rebek, J. Jr. J. Am.
Chem. Soc. 1999, 121, 2133; Schalley, C.; Castellano, R.
K.; Brody, M. S.; Rudkevich, D. M.; Siuzdak, G.; Rebek,
J., Jr. J. Am. Chem. Soc. 1999, 121, 4568.
7. Haino, T.; Yanase, M.; Fukunaga, C.; Fukazawa, Y.
Tetrahedron 2006, 62, 2025–2035.
8. Haino, T.; Araki, H.; Yamanaka, Y.; Fukazawa, Y.
Tetrahedron Lett. 2001, 42, 3203–3206.
9. Goodman, M. S.; Jubian, V.; Linton, B.; Hamilton, A. D.
J. Am. Chem. Soc. 1995, 117, 11610–11611.
10. Neef, G.; Wiechert, R.; Ottow, E.; Rohde, R.; Beier, S.;
Elger, W.; Henderson, D. Eur. Pat. Appl. 1986, 55.
13. Zheng, J.-Y.; Tashiro, K.; Hirabayashi, Y.; Kinbara, K.;
Saigo, K.; Aida, T.; Sakamoto, S.; Yamaguchi, K. Angew.
Chem., Int. Ed. 2001, 40, 1858–1861; Wang, M.-X.; Zhang,
X.-H.; Zheng, Q.-Y. Angew. Chem., Int. Ed. 2004, 43, 838–
842.
14. Connors, K. A. Binding Constants; John Wiley & Sons:
New York, 1987.