Unusually stable molecular capsule formation of a tetraphenyleneurea cavitand

Article abstract of DOI:10.1021/ol048446y

(Chemical equation presented) An unusually stable molecular capsule was formed by heating phenyleneurea-spanned resorcinarene cavitand with 4-methyl-N-p-tolylbenzamide. The molecular capsule behaved as a discrete molecular entity showing a cylindrical D_4d structure and showed no guest exchange in toluene-d₈ even at 100°C.

Full text of DOI:10.1021/ol048446y

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4431-4433
Unusually Stable Molecular Capsule
Formation of a Tetraphenyleneurea
Cavitand
Heung-Jin Choi,* Yeon Sil Park, Chan Sik Cho, Kwangnak Koh,†
Sung-Hong Kim,‡ and Kyungsoo Paek§
Department of Applied Chemistry, Kyungpook National UniVersity,
Daegu 702-701, Korea, College of Pharmacy, Pusan National UniVersity,
Busan 609-735, Korea, Korea Basic Science Institute, Daegu Branch,
Deagu 702-701, Korea, and CAMDRC and Department of Chemistry,
Soongsil UniVersity, Seoul 156-743, Korea
choihj@knu.ac.kr
Received August 5, 2004
ABSTRACT
An unusually stable molecular capsule was formed by heating phenyleneurea-spanned resorcinarene cavitand with 4-methyl-N-p-tolylbenzamide.
The molecular capsule behaved as a discrete molecular entity showing a cylindrical D4d structure and showed no guest exchange in toluene-
d8 even at 100 °C.
Self-assembled molecular capsules held together by hydrogen
bonds or metal-ligand interaction have attracted much
interest.1-3 The successful application of the complementary
hydrogen-bonding theme was first introduced by the groups
of Rebek and de Mendoza for self-assembling glycoluril-
derived capsules such as “tennis balls” and “softballs”.4-10
Cavitand 1 reported by Rebek and co-workers self-
assembled to form a cylinder-shape capsule 1‚1 by eight
bifurcated hydrogen bonds between an imide hydrogen atom
in a cavitand with two neighboring carbonyl oxygen atoms
as shown in Figure 1.11-23 Capsule 1‚1 can accommodate
various guests such as 4-methyl-N-p-tolylbenzamide 4 in a
† Pusan National University.
‡ Korea Basic Science Institute.
§ Soongsil University.
(1) For reviews, see: (a) Hof, F.; Craig, S. L.; Nuckolls, C.; Rebek, J.,
Jr. Angew. Chem., Int. Ed. 2002, 41, 1489. (b) Conn, M. M.; Rebek, J., Jr.
Chem. ReV. 1997, 97, 1647.
(2) (a) Vysotsky, M. O.; Pop, A.; Broda, F.; Thondorf, I.; Bo¨hmer, V.
Chem. Eur. J. 2001, 7, 4403. (b) Chapman, R. G.; Olovsson, G.; Trotter,
J.; Sherman, J. C. J. Am. Chem. Soc. 1998, 120, 6252. (c) MacGillivray, L.
R.; Atwood, J. L. Nature 1997, 389, 469. (d) Zadmard, R.; Junkers, M.;
Schrader, T.; Grawe, T.; Kraft, A. J. Org. Chem. 2003, 68, 6511
(3) (a) Holliday, B. J.; Mirkin, C. A. Angew. Chem., Int. Ed. 2001, 40,
2022. (b) Fochi, F.; Jacopozzi, P.; Wegelius, E.; Rissanen, K.; Cozzini, P.;
Marastoni, E.; Fisicaro, E.; Manini, P.; Fokkens, R.; Dalcanale, E. J. Am.
Chem. Soc. 2001, 123, 7539. (c) Levi, S. A.; Guatteri, P.; van Veggel, F.
C. J. M.; Vancso, G. J.; Dalcanale, E.; Reinhoudt, D. N. Angew. Chem.,
Int. Ed. 2001, 40, 1892. (d) Ikeda, A.; Udzu, H.; Zhong, Z.; Shinkai, S.;
Sakamoto, S.; Yamaguchi, K. J. Am. Chem. Soc. 2001, 123, 3872.
(4) Wyler, R.; de Mendoza, J.; Rebek, J., Jr. Angew. Chem., Int. Ed.
1993, 32, 1699.
(5) Branda, N.; Wyler, R.; Rebek, J., Jr. Science 1994, 263, 1267.
(6) Meissner, R. S.; Rebek, J., Jr.; de Mendoza, J. Science 1995, 270,
1485.
(7) Kang, J.; Rebek, J., Jr. Nature 1996, 382, 239.
(8) Conn, M. M.; Rebek, J., Jr. Chem. ReV. 1997, 97, 1647.
(9) Mart´ın, T.; Obst, U.; Rebek, J., Jr. Science 1998, 281, 1842.
(10) Rebek, J., Jr. Acc. Chem. Res. 1999, 32, 278.
(11) Heinz, T.; Rudkevich, D. M.; Rebek, J., Jr. Nature 1998, 394, 764.
(12) Heinz, T.; Rudkevich, D. M.; Rebek, J., Jr. Angew. Chem., Int. Ed.
1999, 38, 1136.
10.1021/ol048446y CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/23/2004

Cavitand 2 was directly prepared as reported by de
Mendoza,24 and the intermediates, i.e., the corresponding
octanitro cavitand and octaamino cavitand reported by
Rebek23,25-27 were similarly prepared by the method reported
by Cram et al.28
At room temperature, cavitand 2 was barely soluble in
CH2Cl2, CHCl3, toluene, or mesitylene but reasonably soluble
in DMF or DMSO, as reported by de Mendoza.24 However,
at elevated temperature it became soluble in these nonpolar
solvents and then stayed in homogeneous solution at room
temperature.
The encapsulation studies of cavitand 2 and 4-methyl-N-
p-tolylbenzamide 4 were performed in mesitylene as devised
by Rebek.12,13 A mixture of cavitand 2 and guest 4 in
mesitylene remained as a heterogeneous mixture at room
temperature even after 5 days, but at above 100 °C the
mixture was slowly homogenized. The encapsulation com-
plex 4@2‚2 was prepared by heating the mixture under reflux
until it became homogeneous and then removing the solvent
by vacuum distillation at 70 °C. The solid residue was dried
at 100 °C under vacuum. The solid complex 4@2‚2 is then
soluble in CDCl3, DMSO-d6, or toluene-d8 at room temper-
ature.
An equimolar mixture of cavitand 2 and guest 4 (1.67 mM:
1.67 mM) in mesitylene gave a soluble complex in a
relatively short period (30 min at 170 °C), but incomplete
encapsulation was observed by 1H NMR spectroscopy, which
showed three different chemical shifts of the N-H of urea
moieties for cavitand 2 (10.35, 10.36, and 10.40 ppm). The
chemical shift of the N-H of cavitand 2 was a good indicator
of whether the encapsulation complex 4@2‚2 was formed
completely or partially: the chemical shift of 2‚2 in toluene-
d8 was observed at 10.35 ppm.
A complete encapsulated complex 4@2‚2 was prepared
from a mixture of cavitand 2 and guest 4 (1.67 mM:6 mM,
respectively) in mesitylene by heating under reflux for 30
min. The 1H NMR spectrum of 4@2‚2 in toluene-d8 at 100
°C showed the chemical shifts for guest 4 at 5.41 (d, Hc),
5.20 (d, He), 3.29 (d, Hb), 3.14 (d, Hf), -2.33 (s, Hg), and
-2.41 (s, Ha) ppm (Figure 2 and Table 1). Like the
isomorphous cavitand 1‚1,11 the large upfield chemical shifts
of encapsulated guest 4 in capsule 2‚2 are observed up to
4.50 ppm for the methyl group (Ha, 2.09 ppm) of free 4 in
the 1H NMR spectrum as a result of the shielding by aromatic
ring current of capsule 2‚2. Compared to the chemical shifts
(∆δ1) for 4 in 1‚1, those (∆δ2) in 2‚2 are slightly smaller
(∆∆δ ) 0.40, 0.37 for Ha and Hg, respectively), which is
consistent with the molecular dimensions (17.21 vs 17.43 Å
through the long C4 axis of 1‚1 and 2‚2, respectively)
calculated using semiempirical AM1.
Figure 1. Hydrogen bonding modes of self-assembled pyrazin-
imide capsule 1‚1 and phenyleneurea capsule 2‚2. The bond lengths
were calculated from the energy-minimized structures (Spartan 04,
V1.0.1, AM1 semiempirical).
nonpolar mesitylene-d12. The inclusion complexes G@1‚1
show interesting guest-exchange phenomena and unprec-
edented isomerism.11-23
Phenyleneurea cavitands 2, 3, and other analogues were
first reported by de Mendoza et al.24 These cavitands
aggregated, forming different self-organized structures such
as vesicles or filaments, depending on the nature and length
of the four alkyl feet. Cavitand 2 formed large reverse
vesicles through side to side extensive stacking. In contrast,
cavitand 3 formed dimeric capsules with carboxylic acids.
We report the observation of the unusually stable capsule
formation of cavitand 2. At elevated temperature guest
molecules could template cavitand 2 to form a dimeric
capsule 2‚2 by reorganizing the intermolecular hydrogen
bonds of the aggregate of cavitand 2.
(13) Ko¨rner, S. K.; Tucci, F. C.; Rudkevich, D. M.; Heinz, T.; Rebek,
J., Jr. Chem. Eur. J. 2000, 6, 187.
(14) Craig, S. L.; Lin, S.; Chen, J.; Rebek, J., Jr. J. Am. Chem. Soc.
2002, 124, 8780.
(15) Shivanyuk, A.; Rebek, J., Jr. Angew. Chem., Int. Ed. 2003, 42, 684.
(16) Shivanyuk, A.; Rebek, J., Jr. J. Am. Chem. Soc. 2002, 124, 12074.
(17) Scarso, A.; Shivanyuk, A.; Hayashida, O.; Rebek, J., Jr. J. Am.
Chem. Soc. 2003, 125, 6239.
(18) Shivanyuk, A.; Scarso, A.; Rebek, J., Jr. Chem. Commun. 2003,
1230.
(19) Shivanyuk, S.; Rebek, J., Jr. Chem. Commun. 2002, 2326.
(20) Hayashida, O.; Shivanyuk, A.; Rebek, J., Jr. Angew. Chem., Int.
Ed. 2002, 41, 3423.
(21) Chen, J.; Ko¨rner, S.; Craig, S. L.; Lin, S.; Rudkevich, D. M.; Rebek,
J., Jr. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 2593.
(22) Hof, F.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 4775.
(23) Far, A. R.; Shivanyuk, A.; Rebek, J., Jr. J. Am. Chem. Soc. 2002,
124, 2854.
The two different chemical shifts of the N-H of urea
moieties for cavitand 2 (10.40 and 10.36 ppm) confirm that
(25) Rudkevich, D. M.; Hilmersson, G.; Rebek, J., Jr. J. Am. Chem. Soc.
1997, 119, 9911.
(26) Rudkevich, D. M.; Hilmersson, G.; Rebek, J., Jr. J. Am. Chem. Soc.
1998, 120, 12216.
(27) Tucci, F. C.; Rudkevich, D. M.; Rebek, J., Jr. J. Org. Chem. 1999,
64, 4555.
(24) Ebbing, M. H. K.; Villa, M.-J.; Valpuesta, J.-M.; Prados, P.; de
Mendoza, J. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 4962.
(28) Cram, D. J.; Choi, H.-J.; Bryant, J. A.; Knobler, C. B.J. Am. Chem.
Soc. 1992, 114, 7748.
4432
Org. Lett., Vol. 6, No. 24, 2004

Capsular complexes with smaller guests such as p-xylene
were prepared by heating cavitand 2 in p-xylene. In the
toluene-d8, p-xylene escaped rapidly as a result of the
dynamic equilibrium with toluene-d8 by mass law (t1/2 ) 37
min at 50 °C).
It is obvious that the hydrogen bonding mode in the self-
assembly 2‚2 is superior to that in 1‚1, which has been
already observed by de Mendoza.24 For molecular capsule
2‚2, two sets of lone pair electrons in the sp2 hybridized
carbonyl oxygen complementarily hydrogen bond with two
adjacent H-N protons, which consumes all of the potential
hydrogen bond donors and acceptors. However, in the self-
assembly 1‚1 only one set of lone pair electrons of the
carbonyl oxygen hydrogen bonds to the adjacent H-N
proton, as shown in Figure 1.
Figure 2. 1H NMR spectrum of encapsulation complex 4-methyl-
N-p-tolylbenzamide@2‚2 in toluene-d8 at 100 °C.
The unusual stability of capsule 4@2‚2 in toluene-d8
without exchanging guest 4 with solvent even at 100 °C
suggests that, in addition to the exceptional tight hydrogen
bond between two cavitands 2, van der Waals interaction
between guest 4 and capsule 2‚2 and the dipolar attraction
or hydrogen bond between the amide group of guest 4 and
the urea groups of the capsule 2‚2 are efficiently operating.
However, in polar solvents such as DMSO-d6 the guest 4
in capsular complex 4@2‚2 escaped rapidly at room tem-
perature. The polar DMSO-d6 molecules compete for the
hydrogen bond acceptors in the dimeric capsule 2‚2, which
weakens the stability of capsule 2‚2 and allows the fast
escape of guest 4 and/or the fast exchange of guest 4 with
solvent. The observed vase conformation of 2 in DMSO-d6
confirms that cavitand 2 still exists as a dimeric capsule
DMSO-d6@2‚2 because monomeric cavitand 4 could only
exist as rectangular kite conformation as a result of the
repulsion between adjacent urea groups.28
two chemically nonequivalent methyl groups of guest 4
occupy each cavitand of the dimeric capsule and the guest’s
head-to-tail rotation is tightly restricted on the 1H NMR time
scale even at 100 °C.
The capsular complex 4@2‚2 was unusually inert in
nonpolar solvents such as toluene-d8. No guest exchange with
the solvent molecule was observed in toluene-d8 at 100 °C
for 24 h. However, in polar solvents such as DMSO-d6 the
guest 4 in capsular complex 4@2‚2 escaped rapidly at room
temperature.
1
Table 1. Comparison of H NMR Chemical Shifts (ppm) of
4-Methyl-N-p-tolylbenzamide 4 and Encapsulation Complexes
a
4@1‚1 and 4@2‚2 in Toluene-d8
In summary, the solvent- and/or guest-assisted molecular
capsule formations G@2‚2 were observed and characterized
by heating a mixture of cavitand 2 and guests in a nonpolar
solvent at the elevated temperature.
protons
Ha
2.09 6.96(d) 7.54(d)
4@1‚1b -2.81
∆δ1 4.90
Hb
Hc
Hd
He
Hf
Hg
Acknowledgment. This work was supported by grant
R05-2001-000-00225-0 (2003) from the Basic Research
Program of the Korea Science & Engineering Foundation.
free 4
d
c
7.40(d) 6.92(d)
2.12
-2.70
4.82
c
c
c
c
4@2‚2 -2.41 3.29(d) 5.41(d) 4.54 5.20(d) 3.14(d) -2.33
∆δ2
∆∆δ
4.50 3.67
0.40
2.13
2.20
3.78
4.45
0.37
Supporting Information Available: Synthetic proce-
dures, encapsulation experiments, molecular modeling, and
selected NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
a ∆δ1 ) δ of free 4 - δ of 4@1‚1, ∆δ2 ) δ of free 4 - δ of 4@2‚2.
∆∆δ ) ∆δ1 - ∆δ2. b In mesitylene-d12 at 295 K.11 c Not reported.
d Obscured with solvent peak.
OL048446Y
Org. Lett., Vol. 6, No. 24, 2004
4433