Synthesis of Disubstituted Cucurbit[6]uril and Its Rotaxane Derivative

Article abstract of DOI:10.1021/ol025749o

(Matrix Presented) Synthesis of diphenyl cucurbit[6]uril (CB[6]) has been achieved via co-oligomerization of diphenyl glycoluril and unsubstituted glycoluril. The unsymmetrically substituted CB[6], Ph₂CB[B], was further converted to a rotaxane incorporating bis(dinitrophenyl)spermine.

Full text of DOI:10.1021/ol025749o

ORGANIC
LETTERS
2
002
Vol. 4, No. 8
287-1289
Synthesis of Disubstituted
Cucurbit[6]uril and Its Rotaxane
Derivative
1
Hiroyuki Isobe, Sota Sato, and Eiichi Nakamura*
Department of Chemistry, The UniVersity of Tokyo, Bunkyo, Hongo,
Tokyo 113-0033, Japan
nakamura@chem.s.u-tokyo.ac.jp
Received February 20, 2002
ABSTRACT
Synthesis of diphenyl cucurbit[6]uril (CB[6]) has been achieved via co-oligomerization of diphenyl glycoluril and unsubstituted glycoluril. The
unsymmetrically substituted CB[6], Ph CB[6], was further converted to a rotaxane incorporating bis(dinitrophenyl)spermine.
2
6
Almost a century has passed since the first synthesis of
cucurbit[n]uril (CB[n]) was reported.1,2 CB[n] is a cyclic
oligomer of n units of glycoluril (GU, 4) linked by 2n
methylene bridges derived from formaldehyde. Several
symmetrical homologues of CB[n] have been synthesized
by homo-oligomerization of unsubstituted GU 4 or substi-
use in molecular machines. Our interest in the development
of chemical substances that control biological activities
7
,8
through DNA targeting directed us to investigate the
synthesis of substituted CB[6]. After unsuccessful attempts
to synthesize the cyclic homohexamer, dodecasubstituted
CB[6], from disubstituted GU, we envisioned that the
persubstituted homohexamer may suffer from steric strain
between substituents. Indeed, recently Kim showed that
although a symmetrical persubstituted CB[6] is obtainable
in a certain case, the yield of the product is far less than
satisfactory. In addition, it has not been demonstrated
whether this cyclic homo-oligomer can form a rotaxane by
inclusion of a polyamine molecule. As the result of extensive
optimization studies, we found that the disubstituted cyclic
hexamer forms more readily than unsubstituted CB[6]. We
report herein the first synthesis of unsymmetrically substi-
3
,4
tuted GU. Cyclic hexamer CB[6] (1, n ) 6, R ) H) is
uniquely important because of its ability to take up a
molecule of linear polyamine in the internal cavity. The result
is the formation of pseudorotaxane,2 which is interesting
not only purely for its intriguing shape but also for possible
,5
4
b
(
1) Behrend, R.; Meyer, E.; Rusche, F. Liebigs Ann. Chem. 1905, 339,
1
-37.
(
2) (a) Freeman, W. A.; Mock, W. L.; Shih, N.-Y. J. Am. Chem. Soc.
1
981, 103, 7367-7368. (b) Mock, W. L. In ComprehensiVe Supramolecular
Chemistry; V o¨ gtle, F., Ed.; Pergamon: Oxford, 1996; Vol. 2, p 477.
(3) (a) Kim, J.; Jung, I.-S.; Kim, S.-Y.; Lee, E.; Kang, J.-K.; Sakamoto,
S.; Yamaguchi, K.; Kim, K. J. Am. Chem. Soc. 2000, 122, 540-541. (b)
Day, A. I.; Blanch, R. J.; Arnold, A. P.; Lorenzo, S.; Lewis, G. R.; Dance,
I. Angew. Chem., Int. Ed. 2002, 41, 275-277.
(6) Acc. Chem. Res. 2001, 34, 409-522 (Molecular Machines special
issue).
(7) Isobe, H.; Tomita, N.; Lee, J. W.; Kim, K.; Nakamura, E. Angew.
Chem., Int. Ed. 2000, 39, 4257-4260.
(8) (a) Nakamura, E.; Isobe, H.; Tomita, N.; Sawamura, M.; Jinno, S.;
Okayama, H. Angew. Chem., Int. Ed. 2000, 39, 4254-4257. (b) Isobe, H.;
Sugiyama, S.; Fukui, K.-i.; Iwasawa, Y.; Nakamura, E. Angew. Chem., Int.
Ed. 2001, 40, 3364-3367. (c) Isobe, H.; Tomita, N.; Jinno, S.; Okayama,
H.; Nakamura, E. Chem. Lett. 2001, 1214-1215.
(
4) (a) Flinn, A.; Hough, G. C.; Stoddart, J. F.; Williams, D. J. Angew.
Chem., Int. Ed. Engl. 1992, 31, 1475-1477. (b) Zhao, J.; Kim, H.-J.; Oh,
J.; Kim, S.-Y.; Lee, J. W.; Sakamoto, S.; Yamaguchi, K.; Kim, K. Angew.
Chem., Int. Ed. 2001, 40, 4233-4235.
(
04.
5) Jeon, Y.-M.; Whang, D.; Kim, J.; Kim, K. Chem. Lett. 1996, 503-
5
1
0.1021/ol025749o CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/16/2002

Unlike CB[5] derivatives whose internal cavity is very
1
0
2
small, Ph CB[6] 2 was found to form a pseudorotaxane
with polyamine. Full structural characterization of 2 was
achieved by further conversion to rotaxane 6 made by end-
5
capping with bulky dinitrophenyl groups. The rotaxane 6
was isolated as a trifluoroacetic acid salt by reverse-phase
chromatography and characterized by electron spray mass
1
13
19
and H, C, and F NMR spectra (Figure 2 and Supporting
Information). Molecular formula of C70 20 for di-
cationic rotaxane was obtained by ESI-MS spectra [(M -
74 32
H N O
-
2+
2CF
3
CO
2
) , m/z 842.295; found 842.294], which confirmed
the structure of the desired rotaxane composed of Ph
2
CB[6]
and bis(dinitrophenyl)spermine. The “bead and thread”
structure of 6 was evident from the significantly upfield-
shifted signals of the methylene protons enclosed in the CB
1
1
cavity (circled a and b in Figure 2). Further analysis of the
1
H NMR signals of the spermine moiety in 6 revealed that
c
g
the internal amine atoms (N ) bear two protons and the N
atoms bear only one proton on each nitrogen atom, indicating
that only the N atoms are protonated. All H and C NMR
signals of the spermine moiety including those in the
dinitrophenyl groups have been assigned. The C and
NMR analyses showed the presence of CF
Figure 1. (a) Structure of cucurbit[n]uril. (b) Structure of Ph
CB[6] 2. (c) AM1 optimized structure of rotaxane dication part of
. CB moiety is shown in a CPK model, and bis(dinitrophenyl)-
2
-
c
1
13
6
1
3
19
F
spermine is shown in a stick model (C ) gray, H ) white, N )
-
CO
2
counter-
blue, O ) red).
3
anion in 6.
2
tuted cucurbit[6]uril, Ph CB[6] (2, Figure 1), by co-oligo-
merization of substituted GU 3 and unsubstituted GU 4. The
molecule that we synthesized is capable of forming pseu-
dorotaxane and rotaxane with polyamine.
Scheme 1a
2
The optimized synthesis of Ph CB[6] 2 is very simple,
requiring only near stoichiomeric amounts of necessary
reactants. Thus, we heated a mixture composed of 1 equiv
9
of Ph
2
GU 3, 5 equiv of GU 4, 14 equiv of formaldehyde,
and 3.0 equiv of ammonium sulfate in 6.7 M aqueous sulfuric
acid first at 70 °C for 24 h and then at 95 °C for 12 h and,
after purification with gel permeation chromatography,
obtained the desired co-hexamer 2 in 30% isolated yield
together with unsubstituted CB[6] 1 in ca. 30% yield. There
formed a small amount of tetraphenyl cucurbituril (Ph CB[6])
4
as detected by mass spectral analysis of the crude reaction
mixture but none of the more substituted cohexamers or
a
Reagents and conditions: (a) H O, 25 °C, 1 h; (b) 2,4-
2
dinitrophenyl fluoride, 2,6-lutidine, H
purification (0.1% TFA in MeCN/H O).
2
O, 25 °C, 19 h; (c) HPLC
2
decaphenyl CB[5], a product expected by analogy with the
3
The most characteristic feature of the CB moiety of 6 is
previous synthesis of homopentamers. The desired Ph
2
CB-
1
13
C
2V symmetry, and hence the majority of the H and
C
[6] 2 exhibits characteristic signals at δ 4.99 observed in
NMR signals integrate twice as much as those located in
D
2
O containing 6 M H SO and 0.8 M trifluoroacetic acid
2
4
1
13
planes of the symmetry, whose H and C signals integrate
for two atoms. The connectivity for hydrogen and carbon
atoms in the CB skeleton of 6 has been determined by
as the result of the shielding effect of the phenyl group (vide
infra).
1
13
(
9) Butler, A. R.; Leitch, E. J. Chem. Soc., Perkin Trans. 2 1980, 103-
09.
10) Jansen, K.; Buschmann, H.-J.; Wego, A.; D o¨ pp, D.; Mayer, C.;
HMBC correlations (Figure 2). Assignment of H and
C
1
NMR signals was made first for the phenyl groups. Starting
(
Drexler, H.-J.; Holdt, H.-J.; Schollmeyer, E. J. Inclusion Phenom. Macro-
cyclic Chem. 2001, 39, 357-363.
(11) Mock, W. L.; Shih, N.-Y. J. Org. Chem. 1986, 51, 4440-4446.
Org. Lett., Vol. 4, No. 8, 2002
1288

Figure 2. 1H NMR spectrum (500 MHz) of rotaxane 6 in DMSO-d
. Atom labels and key HMBC correlations are shown in the molecular
6
structures. Structures of CB and spermine are shown separately for clarity. CB moiety is viewed along the spermine molecule and only the
front half of the molecule is shown. 13C NMR and 2D spectra are reported in Supporting Information.
from the C2
methylene proton, HMBC correlations through
H4
9
10
I
O
, H , and H atoms located right above the phenyl group
3
2
J
C,H established the connectivity in the CB framework from
(Figure 3). In contrast, H located in the deshielding region
undergoes marked downfield shift. The shielding increment
(∆δ) relative to the chemical shift of the corresponding
rotaxane of unsubstituted CB[6] is in good agreement with
I
1
7
the C carbonyl carbon to the most distant carbonyl C
2
carbon. The most characteristic is the upfield shift of H
O
,
5
the theoretical calculations assuming restricted rotation of
1
2
the phenyl groups. The synthesis of unsymmetrically
substituted cucurbit[6]uril and its rotaxane derivative 6 has
thus been achieved. Since the phenyl group may be amenable
to further elaboration and the synthetic route is simple and
flexible, we expect that the present synthesis will lead the
cucurbituril chemistry toward new directions.
Acknowledgment. We thank Dr. T. Yamagaki for HRMS
measurement. This work was supported by Grants-in-Aid
for Scientific Research on Priority Areas “Targeted Pursuit
of Challenging Bioactive Molecules” (to H.I.) and Specially
Promoted Research (to E.N.) from the Ministry of Education,
Culture, Sports, Science and Technology.
Supporting Information Available: Experimental pro-
cedures and details of mass and NMR spectra analyses. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 3. Upfield and downfield shifted chemical shift values (∆δ)
1
observed in the H NMR spectrum of rotaxane 6. Hydrogens colored
in green shifted upfield and those in yellow shifted downfield.
Chemical shift increments and decrements are relative to the
rotaxane complex of 1.5
OL025749O
(12) Martin, N. H. Allen, N. W., III; Moore, K. D.; Vo, L. THEOCHEM
1
998, 454, 161-166.
Org. Lett., Vol. 4, No. 8, 2002
1289