First Calix[8]arene with Regioselectively Functionalized Upper Rim. Apparent Observation of Intramolecular Hydrogen-Bond Flipping

Full text of DOI:10.1021/jo9804947

4866
J . Org. Chem. 1998, 63, 4866-4867
Communications
F ir st Ca lix[8]a r en e w ith Regioselectively
F u n ction a lized Up p er Rim . Ap p a r en t
Obser va tion of In tr a m olecu la r
Hyd r ogen -Bon d F lip p in g
Hirohito Tsue,* Makiko Ohmori, and Ken-ichi Hirao
Division of Material Science, Graduate School of Environmental
Earth Science, Hokkaido University, Sapporo 060-0810, J apan
Received March 17, 1998
“Calixarene” is a general term for a series of macrocyclic
phenol condensates connected with methylene bridges and
holds a significant position in host-guest chemistry together
with crown ether and cyclodextrin.1 Especially, calix[8]arene
serves as a fascinating candidate for supramolecular chem-
istry because of its inherent large diameter of 8.6 Å and the
noticeable properties such as the double incorporation of
metal ions,2a C60 isolation from fullerene soot,2b,c and the
formation of ion-sensing film.2d Chemical modifications of
the framework enable us to control the static and dynamic
natures of the molecule.1a,b However, the great difficulty
in achieving regioselective functionalization of the frame-
work, mainly due to the complete equivalence of the reactive
sites, has hampered the growth of its chemistry compared
with the smaller calixarenes. As for the lower rim, Neri has
recently reported regioselective control with the aid of weak
inorganic base.3 On the other hand, modification at the
upper rim has so far been performed only by the introduction
of eight uniform substituents, and therefore, the regioselec-
tive functionalization at the upper rim is unprecedented to
date. Here, we report a convenient and general method for
constructing the calix[8]arene regioselectively modified at
the upper rim, followed by the successful preparation of 1
and 2, which serve as building blocks for supramolecules
because the regioselectively introduced ester moieties are
easily functionalizable. In addition, we also report the
variable-temperature NMR showing a novel dynamic process
of which observation was intrinsically impossible in the
highly symmetrical p-tert-butylcalix[8]arene 3. To the best
of our knowledge, 1 and 2 are the first examples of calix[8]-
arene derivatives carrying different substituents at the
upper rim.
6 was synthesized in 35% yield by acid-catalyzed condensa-
tion between p-tert-butylphenol condensate 45 and bisalcohol
5.6 Subsequent acid-promoted ring closure using equimo-
lecular amounts of the “7” fragment 6 and “1” fragment 5
afforded calix[8]arene 2 in 9.1% yield. The fairly low yield
reflects the fact that this “7 + 1” condensation was associated
with the formation of various linear and cyclic byproducts.
Very interestingly, one of them was found to be a ring-
shrunken calix[6]arene 7 (7.3%). Mendoza reported a
similar side reaction that involved direct transformation
from a calix[6]arene to a calix[4]arene under acidic condi-
tions.7 However, the formation of 7 is not likely to be via
the direct [8]-to-[6] pathway because no changes of 2 were
detected under the same conditions used for the 5 + 6 f 2
reaction. Finally, an additional calix[8]arene 1 was prepared
by transesterification of 2 with methanol in an autoclave
(32%).
To accomplish regioselective modification at the upper
rim, Bo¨hmer’s “3 + 1” methodology,4 which successfully
yielded asymmetric calix[4]arenes, was extended for the
preparation of calix[8]arenes 1 and 2 and designated as
convergent “7 + 1” fragment condensation. The “7” fragment
(1) (a) Gutsche, C. D. Calixarenes, Monographs in Supramolecular
Chemistry; Stoddart, J . F., Ed.; Royal Society of Chemistry: Cambridge,
1989; Vol. 1. (b) Calixarenes: A Versatile Class of Macrocyclic Compounds;
Vicens, J ., Bo¨hmer, V., Eds.; Kluwer: Dordrecht, 1991. (c) Shinkai, S.
Tetrahedron 1993, 49, 8933. (d) Takeshita, M.; Shinkai, S. Bull. Chem. Soc.
J pn. 1995, 68, 1088.
(2) (a) Shinkai, S.; Araki, K.; Manabe, O. J . Am. Chem. Soc. 1988, 110,
7214. (b) Atwood, J . L.; Koutsantonis, G. A.; Raston, C. L. Nature 1994,
368, 229. (c) Suzuki, T.; Nakashima, K.; Shinkai, S. Chem. Lett. 1994, 699.
(d) Mlika, R.; Ouada, H. B.; Hamza, M. A.; Gamoudi, M.; Guillaud, G.;
J affrezic-Renault, N. Synth. Met. 1997, 90, 173.
(3) (a) Neri, P.; Battocolo, E.; Cunsolo, F.; Geraci, C.; Piattelli, M. J . Org.
Chem. 1994, 59, 3880. (b) Neri, P.; Geraci, C.; Piattelli, M. J . Org. Chem.
1995, 60, 4126. (c) Neri, P.; Consoli, G. M.; Cunsolo, F.; Geraci, C.; Piattelli,
M. New J . Chem. 1996, 20, 433.
(4) See, for example: (a) Bo¨hmer, V.; Marschollek, F.; Zetta, L. J . Org.
Chem. 1987, 52, 3200. (b) Zetta, L.; Wolff, A.; Vogt, W.; Platt, K.-L.; Bo¨hmer,
V. Tetrahedron 1991, 47, 1911. (c) No, K.; Kim, J . E.; Kwon, K. M.
Tetrahedron Lett. 1995, 36, 8453.
Dynamic NMR spectra of calix[8]arenes 1 and 2 were
measured in a sealed tube using chloroform-d as solvent.
Although both compounds revealed almost the same spectral
changes over the range of -50 to +90 °C, ethyl ester 2 was
found to be unsuitable for extensive analyses because of the
complicated superposition of the methylene signals of the
(5) Dhawan, B.; Gutsche, C. D. J . Org. Chem. 1983, 48, 1536.
(6) Zinke, A.; Ott, R.; Leggewie, E.; Hassanein, A.; Zankl, G. Monatsh.
Chem. 1956, 87, 552; Chem. Abstr. 1957, 51, 2845c.
(7) de Mendoza, J .; Nieto, P. M.; Prados, P.; Sa´nchez, C. Tetrahedron
1990, 46, 671.
S0022-3263(98)00494-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/29/1998

Communications
J . Org. Chem., Vol. 63, No. 15, 1998 4867
Sch em e 1. Dir ection a l Ch a n ge of th e Cyclic Ar r a y
of In tr a m olecu la r Hyd r ogen Bon d s
The depicted intramolecular hydrogen bond array was
confirmed by an IR signal of 3237 cm-1 and the phase-
sensitive ROESY spectra.13 J udging from the sharp signals
of the hydroxyl and tert-butyl groups, such directional
flipping between clockwise and counterclockwise arrays was
frozen at -50 °C, while it was facilitated with a rise in
temperature. Here, it is worth noting that only protons
attached to the B and D rings were exposed to chemical
exchange and those of the A and C rings remained un-
changed. In other words, hydroxyl functionalities of the A
and C rings form hydrogen bonds only to adjacent p-tert-
butylphenol residues irrespective of the direction, whereas
those of the B and D rings are very sensitive to the direction
that switches the hydrogen bond acceptors with different
electron density, that is, p-tert-butylphenol or p-hydroxy-
benzoate residues. Therefore, only the B and D rings are
anticipated to be exchangeable. The ∆Gq for the hydrogen
bond reversal was calculated to be 14.1 kcal/mol from the
spectral changes in the hydroxyl region (Tc 30 °C and ∆δ
201 Hz).14 This relatively large ∆Gq in comparison with that
of a calix[6]arene derivative (10.6 kcal/mol)15 suggests that
the strength of the hydrogen bond should play a crucial role
in the conformational stability of calixarenes.
F igu r e 1. Enlarged 1H NMR spectra (400 MHz) of 1 at relevant
temperatures in CDCl3: (a) hydroxyl, (b) aromatic, (c) benzylic and
CO2Me, and (d) tert-butyl regions. The intensity scales are different
for each region.
ethyl groups and the benzylic bridges. Alternatively, methyl
ester 1 had enough separation to investigate the dynamic
process of the calix[8]arene in detail. On increasing the
temperature from -50 to +90 °C, drastic and gradual
changes in the signal shape were observed in the phenolic
hydroxyl, benzylic, and tert-butyl regions as shown in Figure
1. The hydroxyl groups appeared as four singlets at -50
°C, but with a rise in temperature two of them were
subjected to chemical exchange (Tc 30 °C), whereas another
two remained unaltered (Figure 1a). As can be seen from
Figure 1c, the benzylic region at -50 °C, which was assigned
to be four pairs of AB doublets from the resolution-enhanced
spectrum by a mathematical treatment of the FID signal,
turned into a broadened singlet (Tc 58 °C).8 Moreover, three
singlets in 1:1:1 ratio of the tert-butyl groups changed to two
singlets in a 2:1 ratio as shown in Figure 1d.
Comparison of the dynamic NMR spectra of 1 and 3
revealed large differences such that the spectral changes of
1 opened from -30 °C while that of 3 was almost undetect-
able up to 10 °C.9 Thorough assignments with the aid of
2D NMR experiments at -50 °C (COSY and phase-sensitive
ROESY) led to the conclusion that the temperature-depend-
ent spectra of 1 were rationally interpreted by a combination
of two kinds of dynamic processes, i.e., (1) macrocyclic ring
inversion of the pleated loop conformation10 of calix[8]arene
and (2) directional change of the intramolecular hydrogen
bond array.11 The activation energy (∆Gq) of the former
process was estimated from the changes in the benzylic
region to be 15.2 kcal/mol,12 which agrees very closely with
that of the parent calix[8]arene 3 (15.7 kcal/mol).9 At -50
°C, the appearance of the four sharp singlets of the hydroxyl
groups along with the three singlets of the tert-butyl groups
implied the presence of a C2 axis perpendicular to the
molecular plane, which classified the aromatic systems into
four types denoted as A, B, C, and D as shown in Scheme 1.
Although the presence of hydrogen-bond flipping in the
known calix[8]arenes has so far been unobserved due to the
intrinsic symmetrical reason, the present compounds 1 and
2 with lower symmetry shed some light on the nature for
the first time in calix[8]arene chemistry. The host ability
of 1 and 2 as well as the transformation into supramolecules
using these compounds as building blocks are being inves-
tigated in our laboratory.
Ack n ow led gm en t. This work was supported partially
by Grants-in-Aid for Scientific Research from the Ministry
of Education, Sports, and Culture of J apan. Also, we
gratefully acknowledge the Sasagawa Scientific Research
Grant for financial support.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures, characterization data, spectral data for all new products,
and the dynamic NMR spectra of compounds 1 and 2 (25 pages).
J O9804947
(8) Two singlets rather than a broadened singlet are expected for the
structurally different methylene bridges. Two singlets were observed at room
temperature when pyridine-d5 was used as solvent.
(9) (a) Gutsche, C. D.; Bauer, L. J . J . Am. Chem. Soc. 1985, 107, 6052.
(b) Gutsche, C. D.; Bauer, L. J . Tetrahedron Lett. 1981, 48, 4763.
(10) Gutsche, C. D.; Gutsche, A. E. J . Inclusion Phenom. 1985, 3, 447.
(11) Hydrogen-bond reversal can be induced either by disrupting the
hydrogen bonds sequentially or by a tunneling mechanism as mentioned
in ref 15.
(13) In the phase-sensitive ROESY spectra at -50 °C, each of the
hydroxyl groups showed NOEs with the two neighboring ones.
(14) The activation energy for the hydrogen-bond flipping was also
estimated from the spectral changes in the tert-butyl region (∆Gq ca. 14
kcal/mol, Tc ca. -20 °C, and ∆δ 2.2 Hz). The reviewer of this paper pointed
out that the energy barrier was too high. The calix[8]arene skeleton may
adopt the appropriate conformation for the formation of hydrogen bonding,
but we cannot further specify the exact reason only on a basis of the NMR
data at present.
(12) Almost the same ∆Gq values were obtained from the four pairs of
benzylic AB doublets (Tc 58 °C) of which parameters were as follows: (a)
∆Gq 15.2 kcal/mol, ∆δ 275 Hz, and J ) 13.3 Hz, (b) 15.2 kcal/mol, 277 Hz,
14.0 Hz, (c) 15.1 kcal/mol, 321 Hz, 13.1 Hz, and (d) 15.1 kcal/mol, 315 Hz,
13.3 Hz.
(15) Molins, M. A.; Nieto, P. M.; Sa´nchez, C.; Prados, P.; de Mendoza,
J .; Pons, M. J . Org. Chem. 1992, 57, 6924.