Singly bridged double resorcin[4]arene bearing sixteen hydroxyl groups. Formation of capsular-type inclusion complexes in methanol

Article abstract of DOI:10.1016/j.tetlet.2003.08.049

The Sc(OTf)₃-catalyzed mixed cyclocondensation of bis-1,2-(2,6-dihydroxyphenyl)ethane and 2-hexylresorcinol gave a singly bridged double-resorcinarene bearing sixteen hydroxyl groups at the peripheral positions. In methanol, the double-resorcinarene binds quaternary ammonium ions to form capsular-type 1:1 complexes.

Full text of DOI:10.1016/j.tetlet.2003.08.049

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7425–7427
Singly bridged double resorcin[4]arene bearing sixteen hydroxyl
groups. Formation of capsular-type inclusion complexes
in methanol
Hisatoshi Konishi,* Osamu Morikawa, Kazuhiro Kobayashi, Kazuyuki Abe and Atsushi Ohkubo
Department of Materials Science, Faculty of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
Received 30 April 2003; revised 7 August 2003; accepted 11 August 2003
Dedicated to Emeritus Professor Soichi Misumi on the occasion of his 77th birthday
Abstract—The Sc(OTf)3-catalyzed mixed cyclocondensation of bis-1,2-(2,6-dihydroxyphenyl)ethane and 2-hexylresorcinol gave a
singly bridged double-resorcinarene bearing sixteen hydroxyl groups at the peripheral positions. In methanol, the double-resor-
cinarene binds quaternary ammonium ions to form capsular-type 1:1 complexes.
© 2003 Elsevier Ltd. All rights reserved.
benzyl bromide 112 with magnesium in THF gave
Calixarenes and resorcinarenes are bowl-shaped
the MOM ether derivative 2† in 42% yield. Removal
[14]metacyclophane compounds and versatile building
blocks for the construction of molecular capsules.1–4 In
of the MOM function of 2 was easily accomplished
by treatment with HCl in methanol to give 3‡ in 89%
particular, a number of double metacyclophanes have
been assembled from two metacyclophane units. Their
structural mobility and efficiency in molecular recogni-
tion processes are largely dependent upon the nature,
length, geometry, and number of bridging groups. In a
system linked by a single covalent bond, it is presumed
that the two subunits are free to rotate about the
bridge. However, they mostly form a 1:1 complex with
quaternary ammonium ions and pyridinium ions in a
capsular conformation,5–8 indicating the cooperative
action of the two macrocycles and the efficiency of the
cation-p9 and CH-p interaction.10,11 These observations
prompted us to synthesize the double resorcinarene 4,
bearing sixteen phenolic hydroxyl groups at the periph-
eral position. Since strong electron-donating hydroxyl
groups increase the p-basicity, 4 should show an
enhanced inclusion ability for organic ammonium
cations. We now report the synthesis and inclusion
properties of the singly bridged double resorcinarene 4.
yield. The mixed cyclocondensation of 3 and 2-hexyl-
resorcinol (molar ratio 1:18) with an excess of
† (2): A solution of 1,3-bis(methoxymethoxy)-2-bromomethylbenzene
1 (1.35 g, 4.64 mmol) in dry THF (8 ml) was added into a
suspension of magnesium powder (0.15 g, 6.0 mmol) in dry THF
(20 ml) under an argon atmosphere. The mixture was stirred for 0.5
h and then iodine (10 mg) was added. After 3 h stirring at 40°C, the
solvent was removed in vacuo. The residue was triturated with
diethyl ether, and the ether soluble fraction was separated and
concentrated. The residue was recrystallized from ethanol to give
the MOM ether 2 as white prism; yield 42%. Mp 98–99°C. 1H
NMR (270 MHz, CDCl3, 30°C): l 2.97 (s, 4H, ArCH2), 3.45 (s,
12H, OCH3), 5.02 (s, 8H, OCH2O), 6.73 (d, 4H, ArH, J=8.2 Hz),
7.01 (t, 2H, ArH, J=8.2 Hz). IR (KBr, cm−1) 2999, 1598, 1474,
1143, 1094. Anal. calcd for C22H30O8: C, 62.55: H, 7.16. Found: C,
62.39: H, 7.07.
‡ (3): The MOM ether (0.124 mg, 0.29 mmol) was dissolved in
methanol (10 ml). To this solution was added two drops of concd
HCl with stirring. The solution was heated to reflux for 1 h, diluted
with water, and then extracted with ethyl acetate (3×20 ml). The
combined organic phase was concentrated to leave white solid,
which was recrystallized from water to produce 3 in 89%. Mp
231–237°C (dec.). 1H NMR (270 MHz, DMSO-d6, 50°C) l 2.65 (s,
4H, ArCH2), 6.27 (d, 4H, ArH, J=7.9 Hz), 6.75 (t, 2H, ArH,
J=8.1 Hz), 8.77 (s, 4H, OH). IR (KBr, cm−1) 3272, 1654, 1618,
1592. Anal. calcd for C14H14O4: C, 68.28: H, 5.73. Found: C, 67.98:
H, 5.90. FAB-MS calcd for C14H14O4, 246.1. Found: 246.2.
We employed bis-1,2-(2,6-dihydroxyphenyl)ethane 3 as
a key compound in this synthetic pathway (Scheme 1).
Debrominated coupling of 2,6-bis(methoxymethoxy)-
Keywords: resorcinarene; inclusion complex; capsular molecule; qua-
ternary ammonium ion.
* Corresponding author. Tel./fax: +81-857-31-5262; e-mail: konis@
chem.tottori-u.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.049

7426
H. Konishi et al. / Tetrahedron Letters 44 (2003) 7425–7427
Scheme 1. Synthesis of the double-resorcinarene 4.
diethoxymethane in acetonitrile using Sc(OTf)3 as a
catalyst,13 produced the double resorcinarene 4§ and
resorcinarene 514 in 29 and 42% yields, respectively. The
glets for the ArCH2Ar protons in the 1H NMR
spectrum. In addition, the broadening of these signals
could not be observed at −60°C. Furthermore, the
chemical shifts of all the protons in 4 are very similar to
those of the corresponding protons of 5; the differences
are within 0.03 ppm. Therefore, it is concluded that 4 is
a very flexible molecule and there is no interaction
between the two resorcinarene units in this solvent.
1
structure of 4 was unambiguously proved by H NMR
spectroscopy and FAB mass spectrometry. Its 1H NMR
spectrum (CD3OD) exhibits two singlets (1:1 ratio) for
the bridging methylene protons of the resorcinarene
skeleton (ArCH2Ar), and three singlets (1:2:1 ratio) for
the aromatic protons in accordance with the expected
pattern for a monosubstituted resorcinarene. In addi-
tion, the four protons of the ethano bridge are seen as
a singlet. Finally the dimeric nature of 4 was confirmed
by a molecular ion peak at m/z=1506.9 (calcd 1506.8).
The binding property of the double resorcinarene 4 to
tetraethylammonium (TEA) chloride and 4-tert-butyl-
N-methylpyridinium (BMP) iodide in CD3OD was
1
measured by H NMR titration. For comparison, the
complexation property of resorcinarene 5 was also
studied. The stoichiometry of the complexes was evalu-
In CD3OD solution at 30°C, both the double resor-
cinarene 4 and the resorcinarene 5 showed sharp sin-
§ Double resorcin[4]arene (4): The diphenylethane 3 (46 mg, 0.19
mmol), 2-hexylresorcinol (0.65 g, 3.30 mmol) and diethoxymethane
(1.50 g, 14.0 mmol) were dissolved in acetonitrile (25 ml). The
solution was stirred and Sc(OTf)3 (30 mg, 0.06 mmol) was added.
After stirring for 3 h at 80°C, the solution was concentrated. The
residue was dissolved in ethyl acetate and washed with water. The
solvent was removed and the residue was purified by recycle-type
HPLC. The double-resorcin[4]arene 4 (87 mg, 29%) and resor-
cin[4]arene 5 (42%) were isolated as pure materials. 4: mp 220°C
1
(dec.). IR (CDCl3, cm−1) 3598, 3394. H NMR (270 MHz, CD3OD,
30°C) l 0.78 (m, 18H, CH3), 1.19–1.47 (m, 48H, CH2(CH2)2CH2),
2.56 (m, 4H, Ar CH2), 2.60 (m, 12H, Ar CH2), 3.70 (s, 8H, bridge
CH2), 3.74 (s, 8H, bridge CH2), 7.02 (s, 2H, ArH), 7.03 (s, 4H,
ArH), 7.07 (s, 2H, ArH). Anal. calcd for C94H122O16: C, 8.15: H,
Figure 1. Association constants Kass and complex induced
shifts (CIS, ppm) for 1:1 complex for host 4 in CD3OD. The
values in parentheses are for the complexes with 5.
74.87. Found: C, 8.27: H, 74.73. FAB-MS calcd for C94H122O16
1506.9. Found 1506.8.
,

H. Konishi et al. / Tetrahedron Letters 44 (2003) 7425–7427
7427
deeply bound in the host cavity through an N-methyl-p
interaction. Therefore, it was reasonably expected that
each of the resorcinarene units of host 4 should include
MBP molecule to form a 1:2 complex. However, as seen
in Figure 3, the Job’s plot evidently confirmed the 1:1
complex formation between 4 and MBP. More remark-
able is the large CIS values of all the protons of 4. On
the basis of these results, it can be presumed that the guest
molecule is included in an equatorial orientation between
two cavities as shown in Figure 2 (B). The Kass for the
complex of 4 with MBP was 580 M−1, which is greater
by 3.6-fold than that of 5. This enhancement in Kass is
attributed to the addition of four CH-p interactions
between the acidic pyridinium CH bonds with two
p-basic resorcinarene cores.17
Figure 2. Schematic representation for the complexes of the
double-resorcinarene 4 with (A) TEA and with (B) MBP. The
hexyl groups and hydrogen atoms are omitted for clarity.
In conclusion, we have demonstrated the usefulness of
the mixed cyclocondensation of resorcinols for the syn-
thesis of a double-resorcinarene bearing sixteen hydroxyl
groups, which behaves as a molecular capsule in the
presence of quaternary ammonium ions. The double-
resorcinarene can be considered as a versatile molecular
platform for the design of carcelands. Further work in
this direction is currently underway in our laboratory.
References
1. Asfari, Z.; Weiss, J.; Vicens, J. Synlett 1993, 719–725.
2. Cram, D. J.; Cram, J. M. Container Molecules and Their
Guests; The Royal Society of Chemistry: Cambridge,
1994.
3. Bo¨hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713–
745.
4. Saadoui, M.; Bo¨hmer, V. In Calixarenes 2001; Asfari, Z.;
Bo¨hmer, V.; Harrowfield, J.; Vicens, J., Eds.; Kluwer
Academic: Dordrecht, 2001; Chapter 7.
5. Araki, K.; Hisaichi, K.; Kanai, T.; Shinkai, S. Chem.
Lett. 1995, 569–570.
Figure 3. A Job’s plot for the double-resorcinarene 4 and MBP.
Total concentration: 5.0×10−3 mol/l.
6. Lhota´k, P.; Shinkai, S. Tetrahedron Lett. 1996, 37, 645–
648.
7. Neri, P.; Bottino, A.; Cunsolo, F.; Piattelli, M.; Gavuzzo,
E. Angew. Chem., Int. Ed. Engl. 1998, 37, 166–169.
8. Arduini, A.; Pochini, A.; Secchi, A. Eur. J. Org. Chem.
2000, 2325–2333.
9. Ma, J. C.; Dougherty, D. A. Chem. Rev. 1997, 97,
1303–1324.
ated by the Job’s plot analysis (Fig. 1). Next, the
association constants (Kass) of these complexes and the
complex induced shifts (CIS) of the guest molecules were
determined by a computer-assisted nonlinear least
square-analysis.15
10. Fujimoto, T.; Yanagihara, R.; Kobayashi, K.; Aoyama,
Y. Bull. Chem. Soc. Jpn. 1995, 68, 2113–2124.
11. Nishio, M.; Hirota, M.; Umezawa, Y. The CH/p Interac-
tion; Wiley-VCH: New York, 1998.
12. Konishi, H.; Inoue, T.; Kobayashi, K.; Morikawa, O.
Synth. Commun. 1999, 29, 227–234.
13. Konishi, H.; Sakakibara, H.; Kobayashi, K.; Morikawa,
O. J. Chem. Soc., Perkin Trans. 1 1999, 2583–2584.
14. Konishi, H.; Morikawa, O. J. Chem. Soc., Chem. Com-
mun. 1993, 34–35.
The spherical TEA molecule is effectively bound by both
host resorcinarenes. Thus, the 4: TEA 1:1 complex has
a Kass=850 M−1, while for the 5: TEA 1:1 complex, a
value of Kass=490 M−1 was determined. Moreover, the
CIS values of TEA observed for 4 are 1.6 times greater
than those for 5. These data strongly suggest that TEA
is encapsulated into a capsular that is cooperatively
formed by two resorcinarne units as shown in Figure 2
(A).
15. Hirose, K. J. Incl. Phenom. Macrocycl. Chem. 2001, 39,
193–209.
16. Araki, K.; Shimizu, H.; Shinkai, S. Chem. Lett. 1993,
205–208.
17. Araki, K.; Watanabe, T.; Oda, M.; Hayashida, H.; Yasu-
take, M.; Shinmyouzu, T. Tetrahedron Lett. 2001, 42,
7465–7468.
Next, we examined the complexation of MBP, a bulkier
N-methylpyridinium ion, with 4 and 5. It is well known
that the N-methyl groups of pyridinium ions are selec-
tively included into the cavity of metacyclophane core.16
By analysis of the CIS value of MBP observed for the
complexation with 5, it is also concluded that MBP is