Synthesis and conformational property of tannin-like p-tert-butylcalix[4]arene 1,3-diesters stabilized by intramolecular hydrogen bonds

Article abstract of DOI:10.1021/jo015780o

Tannin-like p-tert-butylcalix[4]arene 1,3-digallate was synthesized, and its conformational property was investigated by dynamic ¹H NMR and X-ray crystallography. It was found that the 3-OH (or 5-OH) group of the galloyl group in p-tert-butylcalix[4]arene 1,3-digallate is placed at the position where an unusual nonbonded close contact is observed between the OH group and the aromatic ring of the galloyl group facing each other. The calixarene 1,3-diesters of various hydroxybenzoic acids were also prepared, and the conformational properties of those calixarenes were compared with that of p-tert-butylcalix[4]arene 1,3-digallate. A significant contribution of the 3- and 5-OH groups in pendant groups toward the close contact was found. It was suggested that the conformation of p-tert-butylcalix[4]arene 1,3-digallate was stabilized by intramolecular hydrogen bonds including OH···O and OH-π interactions.

Full text of DOI:10.1021/jo015780o

8030
J . Org. Chem. 2001, 66, 8030-8036
Syn th esis a n d Con for m a tion a l P r op er ty of Ta n n in -lik e
p-ter t-Bu tylca lix[4]a r en e 1,3-Diester s Sta bilized by In tr a m olecu la r
Hyd r ogen Bon d s
Eisaku Nomura,* Asao Hosoda, and Hisaji Taniguchi
Industrial Technology Center of Wakayama Prefecture, 60 Ogura, Wakayama 649-6261, J apan
nomura@wakayama-kg.go.jp
Received May 21, 2001
Tannin-like p-tert-butylcalix[4]arene 1,3-digallate was synthesized, and its conformational property
1
was investigated by dynamic H NMR and X-ray crystallography. It was found that the 3-OH (or
5-OH) group of the galloyl group in p-tert-butylcalix[4]arene 1,3-digallate is placed at the position
where an unusual nonbonded close contact is observed between the OH group and the aromatic
ring of the galloyl group facing each other. The calixarene 1,3-diesters of various hydroxybenzoic
acids were also prepared, and the conformational properties of those calixarenes were compared
with that of p-tert-butylcalix[4]arene 1,3-digallate. A significant contribution of the 3- and 5-OH
groups in pendant groups toward the close contact was found. It was suggested that the conformation
of p-tert-butylcalix[4]arene 1,3-digallate was stabilized by intramolecular hydrogen bonds including
OH‚‚‚O and OH-π interactions.
In tr od u ction
preliminary report, p-tert-butylcalix[4]arene 1,3-digallate
3a as a synthetic tannin was synthesized and a selective
binding property of this compound toward Ag+ ion was
studied.7 One of the OH groups in the galloyl group was
placed at the position where significant nonbonded
contact is observed between the OH group and the
aromatic ring of the galloyl group facing each other. This
nonbonded contact makes it possible to exert an OH-π
interaction.8 The selective binding property of 3a was
explained by this specific geometry of 3a . These observa-
tions prompted us to undertake a systematic study on
the fundamental significance of the galloyl group in the
calixarene to provide valuable information regarding the
functional group in tannin.
In this paper, we report a high-yield synthesis of the
calixarene 1,3-diesters having various hydroxybenzoyl
groups and the conformational properties of these mol-
ecules by means of dynamic 1H NMR and X-ray crystal-
lography. The contribution of the hydroxyl groups in the
pendant groups to conformational stability of the calix-
arenes was examined in solution and solid state.
Considerable attention has been paid to the synthesis
and properties of functionalized calixarenes because of
their potential utility as molecular receptors and iono-
phores.1 The design of calixarenes having desired proper-
ties requires the control of their conformation, which
possibly is achieved by the use of intramolecular hydro-
gen bonding interaction between substituents on the
calixarene skeleton.2
Gallic acid is a component of plant tannin and funda-
mental structures of hydrolyzable tannins are condensed
compounds of gallic acids with core compounds such as
glucose, quinic acid, and so on.3 These tannins exhibit a
variety of chemical and biological properties that include
pharmacological activity4 and also binding abilities to
proteins5 and metal ions.6 Three hydroxyl groups of gallic
acid play an important role in these propaties.4,5 In a
* To whom correspondence should be addressed. Phone: +81-73-
477-1271. Fax: +81-73-477-2880.
(1) (a) Gutsche, C. D. Calixarenes, Monographs in Supramolecular
Chemistry; Stoddart, J . F., Ed.; The Royal Society of Chemistry:
Cambridge, 1989. (b) Gutsche, C. D. Calixarenes Revisited, Monographs
in Supramolecular Chemistry; Stoddart, J . F., Ed.; The Royal Society
of Chemistry: Cambridge, 1998. (c) Calixarenes: A Versatile Class of
Macrocyclic Compounds; Bo¨hmer, V., Ed.; Kluwer Academic Pub:
Dordrecht, 1991.
Resu lts a n d Discu ssion
Syn th esis of th e Ca lixa r en es 3a -e. The selective
1,3-esterification of p-tert-butylcalix[4]arene 1 was es-
tablished,9 and the synthetic route was outlined in
Scheme 1. The calixarene 1,3-diesters 2a -e were pre-
pared by the reaction of 1 with O-acetylbenzoyl chlorides
in CH2Cl2 in the presence of base in high yields. For 2a ,
2c, and 2e, deacetylation was performed by using hy-
drazine monohydrate at room temperature to give 3a ,
3c, and 3e in high yields. The removal of acetyl groups
(2) (a) Nomura, E.; Takagaki, M.; Nakaoka, C.; Uchida, M.; Tani-
guchi, H. J . Org. Chem. 1999, 64, 3151. (b) Nomura, E.; Takagaki, M.;
Nakaoka, C.; Taniguchi, H. J . Org. Chem. 2000, 65, 5932. (c) Pink-
hassik, E.; Sidorov, V.; Stibor, I. J . Org. Chem. 1998, 63, 9644. (d)
Castellano, R. K.; Rebek, J ., J r. J . Am. Chem. Soc. 1998, 120, 3657.
(e) Rudkevich, D.; Hilmersson, M. G.; Rebek, J ., J r. J . Am. Chem. Soc.
1997, 119, 9911. (f) Scheerder, J .; Vreekamp, R. H.; Engbersen, J . F.
J .; Verboom, W.; v. Duynhoven, J . P. M.; Reinhoudt, D. N. J . Org.
Chem. 1996, 61, 3476.
(3) Plant Polyphenols; Hemingway, R. W., Laks, P. E., Eds.; Plenum
Press: New York, 1992.
(4) Economic and Medicinal Plant Research; Wagnner, H., Farns-
worth, N. R., Eds.; Academic Press: New York, 1991; Vol. 5.
(5) Okuda, T. Mori, K.; Hatano, T. Chem. Pharm. Bull. 1985, 33,
1424.
(6) Okuda, T.; Mori, K.; Shiota, M.; Ida, K. Yakugaku Zasshi 1982,
102, 735.
(7) Nomura, E.; Hosoda, A.; Taniguchi H. Org. Lett. 2000, 2, 779.
(8) For OH-π interaction between H2O and aromatic π electrons,
see: Atwood, J . L.; Hamada, F.; Robinson, K. D.; Orr, G. W.; Vincent,
R. L. Nature 1991, 349, 683.
(9) See, K. A.; Fronczek, F. R.; Watson, W. H.; Kashyap, R. P.;
Gutsche, C. D. J . Org. Chem., 1991, 56, 7256.
10.1021/jo015780o CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/02/2001

Properties of Tannin-like p-tert-Butylcalix[4]arene 1,3-Diesters
J . Org. Chem., Vol. 66, No. 24, 2001 8031
Sch em e 1
1
F igu r e 1. Temperature-dependent H NMR spectra of 3a (400
MHz, THF-d8).
for 2f and 2g was not achieved under the same condi-
tions. Hydrolytic cleavage for the benzoate esters was
preferred to that for the acetyl esters under any basic
conditions. Therefore, chloroacetyl ester as a protective
group, which is hydrolyzed much faster than the acetyl
group,10 was introduced to hydroxybenzoic acids instead
of the acetyl group. The calixarene 1,3-diesters 2b and
2d were prepared under the same conditions described
above in high yields. Chloroacetyl groups in 2b and 2d
were removed by using hydrazine monohydrate at room
temperature to give products 3b and 3d in high yields.
1H NMR Stu d ies. The 1H NMR spectra of 3a -e in
THF-d8 at 20 °C were obtained as simple patterns. A pair
of singlet signals arising from the tert-butyl protons and
a pair of doublet signals from the ArCH2Ar methylene
protons strongly suggest that these compounds have a
C2 symmetry and a cone conformation.11
The 3-OH and 5-OH proton signals of the galloyl
groups in 3a gave the same resonance at 8.36 ppm. This
indicates that the galloyl groups in 3a undergoes rapid
rotation on a NMR time scale at 20 °C. The chemical
shifts of the OH proton signals of the galloyl groups and
the calixarene skeleton varied with loss of temperature
(Figure 1). The signal arising from the 3-OH and 5-OH
protons at 8.36 ppm at 20 °C shifted downfield upon
cooling to -40 °C and then upfield until reaching to -70
°C. This signal separated into two signals that appeared
at 8.64 and 8.32 ppm at -100 °C. The separated upfield
signal of the OH proton at 8.32 ppm suggests that the
F igu r e 2. Temperature dependence of chemical shifts for the
OH protons at the 3- and 5-positions of the benzoyl groups of
3a -d (400 MHz, THF-d8). Error bars represent signal widths
at half-maxima.
OH group is situated at the position where it is affected
by a ring current effect associated with the facing galloyl
group. The aromatic proton signals of the galloyl groups
were also observed as two separated signals at 8.24 and
7.13 ppm at -100 °C. The temperature dependence of
the 3-OH and 5-OH proton signals for the benzoyl groups
in 3a -d was summarized in Figure 2. The signal arising
from the 3-OH and 5-OH protons of the benzoyl groups
of 3b appeared at 8.54 ppm at 20 °C and shifted
downfield upon cooling to -70 °C and then upfield
without separating such as 3a . The 3-OH proton signals
for 3c and 3d shifted downfield continually until reaching
to -100 °C. These results show that the OH groups at
the 3- and 5-positions of the benzoyl groups suppress the
rotation of the pendant groups on a NMR time scale and
(10) Reese, C. B.; Stewart, C. M.; van Boom, J . H.; de Leeuw, H. P.
M.; Nagel, J .; de Rooy, J . F. M. J . Chem. Soc., Perkin Trans. 1 1975,
934.
(11) Mogck, O.; Bo¨hmer, V.; Furguson, G.; Vogt, W. J . Chem. Soc.,
Perkin Trans. 1 1996, 1711.

8032 J . Org. Chem., Vol. 66, No. 24, 2001
Nomura et al.
F igu r e 5. MM2-optimized geometry of 3a in the cone con-
formation.
F igu r e 3. Temperature dependence of chemical shifts for the
OH protons at the 4-position of the benzoyl groups of 3a ,c,e
(400 MHz, THF-d8).
groups form strong hydrogen bonds with the neighboring
ether oxygen atoms11 because the facing galloyl groups
must be situated in positions that permit close contact.
From these observations based on the temperature-
1
dependent H NMR, the galloyl group seems to play an
important role to stabilize the conformation of 3a .
To substantiate the low-temperature conformer of 3a
in solution, theoretical calculations were performed using
the MM2 force field.12 There are three types of possible
conformers of 3a because conformational inversion through
the annulus for the galloyl group larger than ethyl are
prohibited,13 i.e., cone, 1,3-alternate (two tert-butylphenol
units are a reverse direction), and partial cone (one tert-
butylphenol unit is a reverse direction). The starting
geometry of 3a for the calculations was taken from the
optimized cone conformation of p-tert-butylcalix[4]arene.
It is the structure that allows the formation of hydrogen
bonds between phenolic hydroxyl groups and proximal
ether oxygen atoms in the cone conformation, in ac-
1
cordance with the H NMR data of 3a . The result shows
that the two galloyl groups of 3a are more or less parallel
and the 3-OH group is above the other side of the aryl
ring (Figure 5). In this connection, it is particularly
noteworthy that the cone conformation of 3a is the lowest
energy conformer in the calculations.14
F igu r e 4. Temperature dependence of chemical shifts for the
OH protons at the calixarene skeleton of 3a -e (400 MHz,
THF-d8).
Sin gle-Cr ysta l X-r a y Diffr a ction . When compounds
3a and 3b were recrystallized from acetone, prism
crystals that include acetone molecules inside the crystals
were obtained, and on standing the crystals changed
gradually from clear to opaque crystals with a loss of
acetone molecules. The crystal structures of 3a and 3b
were determined by single-crystal X-ray analysis (Figure
6). The calixarenes 3a and 3b were found to have a
similar cone conformation with a C2 symmetry and to
form a 1:5 clathrate with acetone molecules. Four acetone
molecules are captured in the channel of the crystal
lattice, and one acetone molecule is held inside the
molecular cavity of both 3a and 3b with the CH3 group
that the existence of the OH group at the 4-position
enhances the effect. The chemical shifts for the 4-OH
proton of 3a , 3c, and 3e at variable temperatures are
shown in Figure 3. The signals arising from the 4-OH
protons at 8.60, 8.96, and 9.35 ppm at 20 °C for 3a , 3c,
and 3e shifted downfield in parallel upon cooling to -100
°C. The 3-OH or 5-OH proton signals for 3a -d , also
appeared at downfield in the same order. It seems likely
to reflect the magnitude of a ring current effect of the
facing pendant group.
The chemical shifts for the OH proton signals in
calixarene skeleton of 3a -e also varied with loss of
temperature as shown in Figure 4. The OH proton signals
for 3a -e shifted downfield upon cooling from 20 to -100
°C. In particular, the signals for 3a shifted drastically
downfield under -40 °C. This suggests that the OH
(12) Allinger, N. L. J . Am. Chem. Soc. 1977, 99, 8127.
(13) Iwamoto, K.; Araki, K.; Shinkai, S. J . Org. Chem. 1991, 56,
4955.
(14) Relative potential energies (kcal/mol) for three conformers:
cone, 0; 1,3-alternate, +7.0; partial cone, +3.56.

Properties of Tannin-like p-tert-Butylcalix[4]arene 1,3-Diesters
J . Org. Chem., Vol. 66, No. 24, 2001 8033
F igu r e 6. X-ray crystallographic structure of 3a (a) and 3b (b). Hydrogen atoms have been omitted for clarity. Two acetone
molecules in the channel of the crystal lattice for 3a and 3b have been omitted for clarity.
pointing into the cavity.15 The acetone molecules within
the cavities exist at the position where a CH3-π inter-
action is possible to operate between one of the CH3
groups of acetone and the aromatic ring of the calix-
arenes.16 In fact, the CH3 carbon of acetone is situated
at distances of 3.54(4) and 3.55(3) Å above the center of
the phenyl ring of 3a and 3b, respectively. There are two
intramolecular OH‚‚‚O hydrogen bonds between the
phenolic hydroxyl groups of the calixarene ring in 3a and
the proximal ether O atoms in which the distances of
O(1)‚‚‚O(2) and O(1*)‚‚‚O(2) are the same length of
2.871(5) Å. On the other hand, for 3b, the distances of
O(1)‚‚‚O(2) and O(1*)‚‚‚O(2) are 2.803 and 2.887 Å,
respectively. These hydrogen bonds were found in com-
mon for calix[4]arenes.17 There is possible weak hydrogen
bonding between the OH groups at the 4-position of
facing galloyl groups in 3a and the distance of O(5)‚‚‚O(5*)
is 3.224(8) Å. Furthermore, the OH group at the 3- or
5-position of the galloyl group in 3a is placed at the
position where significant nonbonded contact is observed
between the OH group and the aromatic ring of the
galloyl groups facing each other, which is consistent with
ated at the position, which is 3.247(7) Å above the least-
squares plane of the facing phenyl ring of the galloyl
group. This close contact makes it possible to exert an
OH-π interaction.8 For 3b in which there is no contribu-
tion to the hydrogen bonding between the 4-OH groups
of facing pendant groups, the OH group at the 3- (or 5-)
position is also placed at the position where the non-
bonded contact are observed. The hydroxyl oxygen O(5)
is situated at 3.412(7) Å above the least-squares plane
of the facing phenyl ring. It suggests that the OH-π
interaction may still exert on keeping the close contact
in 3b. Additionally, the intermolecular hydrogen bonds
between hydroxyl groups of the pendant groups and
acetone molecules exist for 3a and 3b, and the distances
are as follows: O(6)‚‚‚O(8) ) 2.760(7) Å, O(4)‚‚‚O(9) )
2.74(1) Å for 3a ; O(4)‚‚‚O(8) ) 2.732(8) Å, O(5)‚‚‚O(7) )
2.859(6) Å for 3b.
The molecular structure of 3c was not obtained by a
single-crystal X-ray analysis because the crystals were
extremely small and fragile. The crystals of 3d and 3e
were obtained as colorless prisms from methanol/water
and chloroform (ethanol free), respectively. Fortunately,
further observation for 3d and 3e came from the X-ray
spectroscopy.
1
the model predicted from the H NMR spectral data and
the MM2 calculation. The hydroxyl oxygen O(6) is situ-
There are two independent molecules of 3d in the
asymmetric unit, and these molecules are in the same
cone conformation with a slight difference between the
two molecules (Figure 7).18 Obviously, there is no close
contact between pendant groups and these groups are
on the approximately same plane. This conformation is
(15) For calixarene-acetone clathrates, see: Ungaro, R.; Pochini,
A.; Andreetti, G. D.; Sangermano, V. J . Chem. Soc., Perkin Trans. 2
1984, 1979.
(16) For CH3-π interactions between the methyl groups of the host
and the aromatic moiety of pyridine, see: Andreetti, D.; Ori, O.;
Ugozzoli, F.; Alfieri, C.; Pochini, A.; Ungaro, R. J . Inclusion Phenom.
1988, 6, 523.
(17) (a) Bo¨hmer, V.; Ferguson, G.; Gallagher, J . F.; Lough, A. J .;
Mckervey, M. A.; Madigan, E.; Moran, M. B.; Fhillips, J .; Williams, G.
J . Chem. Soc., Perkin Trans. 1 1993, 1521. (b) Collins, E. M.; Mckervey,
M. A.; Madigan, E.; Moran, M. B.; Owens, M.; Ferguson, G.; Harris,
S. J . J . Chem. Soc., Perkin Trans. 1 1991, 3137.
(18) Groenen, L. C.; van Loon, J .-D.; Verboom, W.; Harkema, S.;
Casnati, A.; Ungaro, R.; Pochini, A.; Ugozzoli, F.; Reinhoudt, D. N. J .
Am. Chem. Soc. 1991, 113, 2385.

8034 J . Org. Chem., Vol. 66, No. 24, 2001
Nomura et al.
F igu r e 7. X-ray crystallographic structure of 3d . There are
two independent molecules in a unit cell. Hydrogen atoms and
water molecules outside the cavities have been omitted for
clarity. Intermolecular hydrogen bonds (Å): O(7)‚‚‚O(14),
2.75(1); O(6)‚‚‚O(15), 2.74(1) Å.
F igu r e 8. X-ray crystallographic structure of 3e. Hydrogen
atoms have been omitted for clarity. Two chloroform and one
water molecule outside the cavities have been omitted for
clarity.
found in common for 1,3-substituted calix[4]arenes.10 No
molecule is included inside the calixarene cavity of 3d .
The tert-butylphenol units in 3d are more flattened than
those in 3a and 3b, and the two ester unit are more
parallel to each other. The distances of possible intra-
molecular OH‚‚‚O hydrogen bonds between the phenolic
hydroxyl group of the calixarene ring and the proximal
ether O atoms are follows: O(1)‚‚‚O(2) ) 3.11(1) Å,
O(2)‚‚‚O(3) ) 3.082(9) Å, O(3)‚‚‚O(4) ) 3.01(1) Å,
O(4)‚‚‚O(1) ) 3.068(9) Å. The possible hydrogen bond is
also observed between the facing phenolic hydroxyl
groups of the calixarene ring and the distance is
O(1)‚‚‚O(3) ) 3.056(9) Å. In addition, the OH group of
pendant group of 3d forms an intermolecular hydrogen
bond with the CdO groups of the neighboring molecules
and the distance of O(7)‚‚‚O(14) is 2.75(1) Å. The CdO
group of 3d also forms an intermolecular hydrogen bond
with the OH groups of the neighboring molecules and
the distance of O(6)‚‚‚O(15) is 2.74(1) Å.
Furthermore, the molecular structure of 3e no longer
has a cone but a partial-cone conformation as shown in
Figure 8. The crystal 3e captures two chloroform and two
water molecules in the crystal lattice, and some of these
molecules were highly disordered. One water molecule
was bound between the hydroxyl groups at the p-position
of the benzoyl groups and the distances of O(7)‚‚‚O(9) and
O(8)‚‚‚O(9) are 2.75(1) and 2.94(1) Å. This water molecule
also forms an intermolecular hydrogen bond with the OH
group of the neighboring molecules of 3e and the distance
of O(9)‚‚‚O(3) is 2.878(8) Å. In addition, one of the OH
groups of the benzoyl group in 3e forms an intermolecular
hydrogen bond with the CdO group of the neighboring
calixarene and the distance of O(8)‚‚‚O(6) is 2.785(5) Å.
There are possible intramolecular OH‚‚‚O hydrogen
bonds between the hydroxyl group of the tert-butylphenol
unit and the proximal ether O atoms in which the
distances of O(1)‚‚‚O(2) and O(1)‚‚‚O(4) are 3.01(1) and
2.90(1) Å, respectively.
hydrogen bond between the calixarene molecules. The
crystal structures of 3d and 3e, however, show that
intermolecular hydrogen bonds are preferentially formed
between the pendant groups of adjacent calixarenes.
Con clu sion
Tannin-like p-tert-butylcalix[4]arene 1,3-diesters 3a -e
have been synthesized. The galloyl groups in 3a are
placed near each other at a position where an unusual
nonbonded close contact is observed by means of dynamic
1H NMR and X-ray crystallography. This contact makes
it possible to exert an OH-π interaction between the OH
group and the aromatic ring of the galloyl group facing
each other. This close contact was also observed in 3b.
The 3-OH and 5-OH groups of the pendant groups in the
calixarene show a significant contribution to the close
contact. We believe that the function of galloyl group in
the calixarene must provide significant information
regarding functional groups in plant tannin. It is ex-
pected that the availability of the tannin-like calixarenes
will allow further exploitation of their biological activities.
Studies in this direction are in progress.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were uncorrected. 1H
NMR spectra were recorded on a 400 MHz spectrometer using
residual solvent as an internal standard. Mass spectra were
recorded using ESI-TOF apparatus. Calculations were per-
formed with MM2 force field in the program CAChe Work-
System released 3.8.19
Acetylation for hydroxyl groups of benzoic acids was per-
formed by using acetic anhydride in aqueous NaOH. Chloro-
acetylation20 for 3,5-dihydroxybenzoic acid and 3-hydroxy-
benzoic acid was carried out by the reaction with chloroacetyl
chloride in anhydrous THF in the presence of pyridine.
These crystallographic structures of 3a ,b,d ,e demon-
strated that the calixarenes 3a and 3b are specific for
intramolecular hydrogen bonding, rather than inter-
molecular hydrogen bonding. There is no intermolecular
(19) CAChe WorkSystem release 3.8 1995, CAChe Scientific, Inc.
(20) Naruto, M.; Ohno, K.; Naruse, N.; Takeuchi, H. Tetrahedron
Lett. 1979, 251.

Properties of Tannin-like p-tert-Butylcalix[4]arene 1,3-Diesters
J . Org. Chem., Vol. 66, No. 24, 2001 8035
O-Acylbenzoic acids were converted to acid chlorides by using
thionyl chloride in the presence of pyridine and a small amount
of DMF.
(s, 18H), 3.40 (d, 4H), 3.99 (d, 4H), 5.19 (s, 2H), 6.54 (t, 2H),
6.84 (s, 4H), 7.12 (s, 4H), 7.28 (d, 4H), 8.54 (s, 4H); 13C NMR
(THF-d8, 20 °C) δ 31.4, 31.9, 33.0, 34.4, 34.6, 108.9, 109.4,
126.1, 126.3, 129.3, 131.9, 132.8, 143.0, 144.5, 148.5, 151.3,
159.7, 165.4; MS (ESI-TOF) calcd for C58H65O10 921.46, found
921.54 [M + H]+. Anal. Calcd for C58H64O10‚2H2O: C, 72.78;
H, 7.16. Found: C, 72.39, H, 7.09.
5,11,17,23-Tet r a -ter t-b u t yl-25,27-d ih yd r oxy-26,28-b is-
[(3,4,5-t r ia cet oxyb en zoyl)oxy]ca lix[4]a r en e (2a ). To a
solution of 1 g (1.54 mmol) of p-tert-butylcalix[4]arene and 1.25
g (12.4 mmol) of triethylamine in anhydrous CH2Cl2 (30 mL)
was added 3.9 g (12.4 mmol) of 3,4,5-triacetoxybenzoyl chlo-
ride. The mixture was stirred for 5 h at room temperature
under nitrogen. The reaction mixture was washed with water
and dried over MgSO4. After removal of the solvent, the
product was purified through a SiO2 column (CHCl3/hexane
) 10/2) to afford 1.68 g (87%) of product that was recrystallized
from CHCl3/hexane and dried under reduced pressure to give
1.2 g of crystals: mp ) 299-306 °C; IR (KBr) ν 3562, 1782
5,11,17,23-Tet r a -ter t-b u t yl-25,27-d ih yd r oxy-26,28-b is-
[(3,4-d ia cetoxyben zoyl)oxy]ca lix[4]a r en e (2c). To a solu-
tion of 2 g (3.08 mmol) of p-tert-butylcalix[4]arene and 2.49 g
(24.7 mmol) of triethylamine in 30 mL of anhydrous CH2Cl2
was added 3.16 g (12.3 mmol) of 3,4-diacetylbenzoyl chloride.
The mixture was stirred for 3 h at room temperature under
nitrogen. The reaction mixture was washed with water and
dried over MgSO4. The solvent was evaporated, and methanol
was added to produce of precipitates of the product (2.52 g,
75%). Recrystallzed from CHCl3/MeOH gave crystals: mp )
309-313 °C; IR (KBr) ν 3566, 3526, 1778, 1736 cm-1; 1H NMR
(CDCl3, 20 °C) δ 0.95 (s, 18H), 1.20 (s, 18H), 2.26 (s, 6H), 2.33
(s, 6H), 3.45 (d, 4H), 3.92 (d, 4H), 5.09 (s, 2H), 6.85 (s, 4H),
7.03 (d, 4H), 7.36 (d, 2H), 8.14 (d, 2H), 8.26 (dd, 2H); 13C
NMR (CDCl3, 20 °C) δ 20.5, 20.8, 31.0, 31.5, 32.9, 33.9,
34.0, 124.6, 125.5, 126.1, 127.7, 127,8, 128.4, 131.7, 142.6,
142.8, 146.8, 149.0, 150.1, 163.5, 167.5, 168.0; MS (ESI-TOF)
calcd for C66H73O14 1089.50, found 1089.57 [M + H]+. Anal.
Calcd for C66H72O14: C, 72.77; H, 6.66. Found: C, 72.69, H,
6.68.
5,11,17,23-Tet r a -ter t-b u t yl-25,27-d ih yd r oxy-26,28-b is-
[(3,4-d ih yd r oxyben zoyl)oxy]ca lix[4]a r en e (3c). To a solu-
tion of 0.5 g (0.46 mmol) of 2c in 20 mL of CH2Cl2 was added
0.09 g (1.8 mmol) of hydrazine monohydrate. The mixture was
stirred for 10 min at room temperature.Two milliliters of 1 M
HCl was added. The organic potion was washed with water
(30 mL × 2) and dried over MgSO4. After removal of the
solvent, the product was purified through a SiO2 column
(CHCl3/MeOH ) 40/1) to afford 0.26 g of product (61%) that
was recrystallized from MeOH/H2O to give plates: mp ) 222-
230 °C; IR (KBr) ν 3570, 3280, 1740, 1700 cm-1; 1H NMR (THF-
d8, 20 °C) δ 0.99 (s, 18H), 1.25 (s, 18H), 3.40 (d, 4H), 3.98 (d,
4H), 5.44 (s, 2H), 6.86 (s, 4H), 6.97 (d, 2H), 7.11 (s, 4H), 7.69
(d, 2H), 7.90 (dd, 2H), 8.66 (s, 2H), 8.96 (s, 2H); 13C NMR (THF-
d8, 20 °C) δ 31.4, 31.9, 33.1, 34.4, 34.6, 116.2, 117.9, 121.4,
124.2, 126.1, 129.0, 133.0, 142.7, 144.4, 146.2, 148.4, 151.4,
152.1, 165.0; MS (ESI-TOF) calcd for C58H65O10 921.46, found
921.49 [M + H]+. Anal. Calcd for C58H64O10‚2H2O: C, 72.78;
H, 7.16. Found: C, 72.43, H, 7.04.
5,11,17,23-Tet r a -ter t-b u t yl-25,27-d ih yd r oxy-26,28-b is-
[(3-ch lor oa cetoxyben zoyl)oxy]ca lix[4]a r en e (2d ). To a
solution of 2 g (3.08 mmol) of p-tert-butylcalix[4]arene and 1.95
g (25 mmol) of pyridine in 30 mL of anhydrous CH2Cl2 was
added 2.89 g (12.4 mmol) of 3-chloroacetyloxybenzoyl chloride.
The mixture was stirred for 2 h at room temperature under
nitrogen. HCl (1 M) was added to the mixture. The reaction
mixture was washed with water and dried over MgSO4. The
solvent was evaporated, and methanol was added to produce
a precipitate of the product (2.3 g, 70%) that was recrystallized
from CHCl3/MeOH to give crystals: mp ) 273-279 °C; IR
(KBr) ν 3568, 1784, 1742 cm-1; 1H NMR (CDCl3, 20 °C) δ 0.96
(s, 18H), 1.19 (s, 18H), 3.46 (d, 4H), 3.94 (d, 4H), 4.21 (s, 4H),
5.09 (s, 2H), 6.86 (s, 4H), 7.03 (d, 4H), 7.49 (d, 4H), 8.10 (s,
2H), 8.25 (t, 2H); 13C NMR (CDCl3, 20 °C) δ 31.0, 31.5, 33.0,
33.9, 34.0, 40.7, 123.3, 125.6, 126.1, 126.7, 127.8, 128.0, 130.2,
131,2, 131.6, 142.8, 142.9, 149.0, 150.2, 150.6, 163.9, 165.6;
MS (ESI-TOF) calcd for C62H67O10Cl2 1041.41, found 1041.49
[M + H]+. Anal. Calcd for C62H66O10Cl2‚H2O: C, 70.17; H, 6.16.
Found: C, 70.24, H, 6.47.
5,11,17,23-Tet r a -ter t-b u t yl-25,27-d ih yd r oxy-26,28-b is-
[(3-h yd r oxyben zoyl)oxy]ca lix[4]a r en e (3d ). To a solution
of 0.5 g (0.48 mmol) of 2d in 20 mL CH2Cl2 was added 0.048
g (0.96 mmol) of hydrazine monohydrate. The mixture was
stirred for 20 min at room temperature. 1 M HCl and ethyl
acetate (50 mL) was added. The organic potion was washed
with water (30 mL X 2) and saturated aqueous NaCl (20 mL),
and dried over MgSO4. The solvent was evaporated, and
methanol was added to produce a precipitate of the product
1
cm-1; H NMR (CDCl3, 20 °C) δ 0.87 (s, 18H), 1.30 (s, 18H),
2.05 (s, 12H), 2.30 (s, 6H), 3.39 (d, 4H), 3.95 (d, 4H), 5.38 (s,
2H), 6.75 (s, 4H), 7.11 (s, 4H), 8.29 (s, 4H); 13C NMR (CDCl3
20 °C) δ 20.2, 30.8, 31.6, 31.8, 34.0, 122.8, 125.4, 125.7, 127.0,
128.4, 131.3, 139.6, 142.2, 143.1, 144.2, 148.9, 149.9, 163.4,
166.4, 167.6; MS (ESI-TOF) calcd for C70H77O18 1205.51, found
1205.58 [M + H]+. Anal. Calcd for C70H76O18: C, 69.75; H, 6.36.
Found: C, 69.43, H, 6.33.
5,11,17,23-Tet r a -ter t-b u t yl-25,27-d ih yd r oxy-26,28-b is-
[(3,4,5-tr ih yd r oxyben zoyl)oxy]ca lix[4]a r en e (3a ). To a
solution of 1 g (0.8 mmol) of 2a in CH3CN (60 mL) was added
0.24 g (4.8 mmol) of hydrazine monohydrate. The mixture was
stirred for 30 min at room temperature. Acetic acid (0.27 mL)
and water (20 mL) were added. The organic potion was
extracted with ethyl acetate (50 mL × 2), washed with water
(30 mL × 2) and saturated aqueous NaCl, and dried over
MgSO4. The organic solvent was evaporated, and acetone was
added to produce precipitates. The precipitates were filtrated
and washed with acetone to afford 0.58 g (76%) of white solid
that was recrystallized and dried under reduced pressure to
give prisms: mp ) 225-229 °C; IR (KBr) ν 3535, 3300, 3700-
1
3740 cm-1; H NMR (THF-d8, 20 °C) δ 0.96 (s, 18H), 1.28 (s,
18H), 3.38 (d, 4H), 4.01 (d, 4H), 5.34 (s, 2H), 6.80 (s, 4H), 7.13
(s, 4H), 7.43 (s, 4H), 8.36 (s, 4H), 8.60 (s, 2H); 13C NMR (THF-
d8, 20 °C) δ 31.4, 31.9, 32.8, 34.4, 34.5, 111.0, 120.1, 125.9,
126.2, 129.3, 132.9, 140.5, 142.9, 144.4, 146.1, 148.3, 151.3,
165.4; MS (ESI-TOF) calcd for C58H65O12 953.45, found 953.47
[M + H]+. Anal. Calcd for C58H64O12‚2H2O: C, 70.43; H, 6.93.
Found: C, 70.23, H, 6.90.
5,11,17,23-Tet r a -ter t-b u t yl-25,27-d ih yd r oxy-26,28-b is-
[(3,5-d ich lor oa cetoxyben zoyl)oxy]ca lix[4]a r en e (2b). To
a solution of 1.2 g (1.8 mmol) of p-tert-butylcalix[4]arene and
1.17 g (15 mmol) of pyridine in 20 mL of anhydrous CH2Cl2
was added 2.34 g (12.3 mmol) of 3,5-dichloroacetyloxybenzoyl
chloride. The mixture was stirred for 4 h at room temperature
under nitrogen. The reaction mixture was washed with water
(30 mL × 3) and dried over MgSO4. The solvent was evapo-
rated, and methanol was added to produce the precipitate of
the product (1.71 g, 79%), which was recrystallzed from CHCl3/
MeOH to give crystals: mp ) 223-226 °C; IR (KBr) ν 3566,
1775, 1743 cm-1; 1H NMR (CDCl3, 20 °C) δ 0.88 (s, 18H), 1.29
(s, 18H), 3.40 (d, 4H), 3.95 (d, 4H), 4.05 (s, 8H), 5.32 (s, 2H),
6.75 (s, 4H), 7.11 (d, 4H), 7.36 (t, 2H), 8.22 (d, 4H); 13C NMR
(CDCl3, 20 °C) δ 30.8, 31.6, 31.9, 34.0, 40.5, 120.2, 121.1, 125.5,
125.8, 128.3, 131.2, 132.1, 142.3, 143.2, 149.1, 149.9, 150.8,
163.4, 165.3; MS (ESI-TOF) calcd for C66H69O14Cl4 1225.34,
found 1225.48 [M + H]+. Anal. Calcd for C66H68O14Cl4: C,
64.60; H, 5.59. Found: C, 64.59, H, 5.51.
5,11,17,23-Tet r a -ter t-b u t yl-25,27-d ih yd r oxy-26,28-b is-
[(3,5-d ih yd r oxyben zoyl)oxy]ca lix[4]a r en e (3b). To a solu-
tion of 0.5 g (0.43 mmol) of 2b in 20 mL of CH2Cl2 was added
0.086 g (1.7 mmol) of hydrazine monohydrate. The mixture
was stirred for 5 min at room temperature. HCl (1 M) and
ethyl acetate (50 mL) were added. The organic potion was
washed with water (30 mL × 2) and saturated aqueous NaCl
(20 mL) and dried over MgSO4. The solvent was evaporated
and chloroform (ethanol free) was added to produce 0.33 g of
crystals (75%) that were recrystallized from MeOH/H2O to give
fine needles: mp ) 303-305 °C; IR (KBr) ν 3572, 3563, 3344,
1736, 1723 cm-1; 1H NMR (THF-d8, 20 °C) δ 0.98 (s, 18H), 1.26

8036 J . Org. Chem., Vol. 66, No. 24, 2001
Nomura et al.
(0.395 g, 93%) that was recrystallized from MeOH/H2O to give
tropically. Hydrogen atoms except OH groups were included
at calculated positions.
needles: mp > 260 °C dec; IR (KBr) ν 3566, 1740 cm-1 1H
;
Cr ysta l d a ta for C58H64O12‚5(C3H6O) (3a ):7 M ) 1243.54,
tetragonal, a ) b ) 13.9382(3) Å, c ) 35.3234(8) Å, V )
6862.4(3) Å3, T ) -100 °C, space group P41212 (no. 92), Z ) 4,
µ (Cu KR) ) 6.89 cm-1, Dc ) 1.204 g cm-3, 69 324 reflections
measured, 1216 unique (Rint ) 0.039). Full-matrix least-
squares refinement was based on 2652 observed reflections (I
> 2.00σ(I)) and 408 variable parameters. R ) 0.069, Rw )
0.109, GOF ) 1.18.
NMR (THF-d8, 20 °C) δ 1.01 (s, 18H), 1.21 (s, 18H), 3.45 (d,
4H), 3.96 (d, 4H), 5.29 (s, 2H), 6.92 (s, 4H), 7.11 (s and d, 6H),
7.44 (t, 2H), 7.69 (s, 2H), 7.89 (d, 2H), 8.77 (s, 2H); 13C NMR
(THF-d8, 20 °C) δ 31.4, 31.8, 33.4, 34.4, 34.6, 117.5, 121.5,
122.0, 126.2, 126.4, 128.9, 131.0, 131.6, 132.9, 142.9, 144.4,
148.7, 151.4, 158.9, 165.1; MS (ESI-TOF) calcd for C58H65O8
889.47, found 889.55 [M + H]+. Anal. Calcd for C58H64O8‚
H2O: C, 76.79; H, 7.33. Found: C, 76.83, H, 7.13.
Cr ysta l d a ta for C58H64O10‚5(C3H6O) (3b): M ) 1211.54,
tetragonal, a ) b ) 13.8980(4) Å, c ) 35.933(1) Å, V )
6940.7(3) Å3, T ) -40 °C, space group P41212 (no. 92), Z ) 4,
µ(Cu KR) ) 6.46 cm-1, Dc ) 1.159 g cm-3, 38 480 reflections
measured, 3703 unique (Rint ) 0.011). Full-matrix least-
squares refinement was based on all observed reflections (I >
0.00σ(I)) and 399 variable parameters. R ) 0.101, Rw ) 0.075,
GOF ) 0.70.
5,11,17,23-Tet r a -ter t-b u t yl-25,27-d ih yd r oxy-26,28-b is-
[(4-a cetoxyben zoyl)oxy]ca lix[4]a r en e (2e). To a solution
of 2 g (3.1 mmol) of p-tert-butylcalix[4]arene and 2.49 g (24.7
mmol) of triethylamine in 30 mL of anhydrous CH2Cl2 was
added 2.46 g (12.4 mmol) of 4-acetylbenzoyl chloride. The
mixture was stirred for 2 h at room temperature under
nitrogen. The reaction mixture was washed with water (30 mL
× 3) and dried over MgSO4. The solvent was evaporated, and
the product was purified through SiO2 column (CH2Cl2) to
afford 2.52 g of product (84%). Recrystallzed from CHCl3/
MeOH gave crystals: mp ) 318-323 °C; IR (KBr) ν 3557,
1767, 1732 cm-1; 1H NMR (CDCl3, 20 °C) δ 0.97 (s, 18H), 1.17
(s, 18H), 2.37 (s, 6H), 3.46 (d, 4H), 3.92 (d, 4H), 5.13 (s, 2H),
6.87 (s, 4H), 7.01 (d, 4H), 7.25 (d, 4H), 8.35 (d, 4H); 13C NMR
(CDCl3, 20 °C) δ 21.2, 31.0, 31.5, 33.2, 33.8, 34.0, 122.4, 125.5,
126.0, 126.7, 127.7, 131.8, 132.0, 142.7, 143.0, 148.9, 150.2,
155.0, 164.2, 168.6. Anal. Calcd for C62H68O10‚H2O: C, 75.13;
H, 7.12. Found: C, 74.85, H, 6.79.
Cr ysta l d a ta for C58H64O8‚2(H2O) (3d ): M ) 925.17,
monoclinic, a ) 31.883(2) Å, b ) 43.077(2) Å, c ) 22.629(2) Å,
â ) 134.279(2)°, V ) 22251(2) Å3, T ) -20 °C, space group
C2/c (no.15), Z ) 16, µ(Cu KR) ) 5.98 cm-1, Dc ) 1.105 g cm-3
,
62 616 reflections measured, 20 034 unique (Rint ) 0.034). Full-
matrix least-squares refinement was based on 8445 observed
reflections (I > 1.00σ(I)) and 1208 variable parameters. R )
0.134, Rw ) 0.184, GOF ) 1.16.
Cr ysta l d a ta for C58H64O8‚2H2O‚2(CHCl3) (3e): M )
1163.92, monoclinic, a ) 41.675(1) Å, b ) 12.9899(3) Å, c )
26.7527(6) Å, â ) 119.4351(8)°, V ) 12613.2(5) Å3, T ) -80
°C, space group C2/c (no. 15), Z ) 8, µ(Cu KR) ) 29.14 cm-1
,
5,11,17,23-Tet r a -ter t-b u t yl-25,27-d ih yd r oxy-26,28-b is-
[(4-h yd r oxyben zoyl)oxy]ca lix[4]a r en e (3e). To a solution
of 0.5 g (0.48 mmol) of 2e in 5 mL of CH2Cl2 and 20 mL of
CH3CN was added 0.05 g (1.0 mmol) of hydrazine mono-
hydrate. The mixture was stirred for 30 min at room temper-
ature. The solvent was evaporated, and methanol was added
to produce a precipitate of the product (0.29 g, 63%) that was
recrystallized from CHCl3 (ethanol free) to give needles: mp
> 250 °C dec; IR (KBr) ν 3565, 3310, 1700-1740 cm-1; 1H NMR
(THF-d8, 20 °C) δ 1.00 (s, 18H), 1.24 (s, 18H), 3.42 (d, 4H),
3.97 (d, 4H), 5.45 (s, 2H), 6.90 (s, 4H), 6.94 (d, 4H), 7.11 (s,
4H), 8.26 (d, 4H), 9.35 (s, 2H); 13C NMR (THF-d8, 20 °C) δ
31.4, 31.9, 33.2, 34.4, 34.6, 116.4, 121.3, 126.1, 126.3, 128.9,
133.1, 133.4, 142.8, 144.3, 148.6, 151.4, 163.6, 164.7; MS (ESI-
TOF) calcd for C58H65O8 889.47, found 889.55 [M + H]+. Anal.
Calcd for C58H64O8‚H2O: C, 76.79; H, 7.33. Found: C, 76.69,
H, 7.25.
Dc ) 1.226 g cm-3, 66 675 reflections measured, 11 247 unique
(Rint ) 0.049). Full-matrix least-squares refinement was based
on 6938 observed reflections (I > 2.00σ(I)) and 704 variable
parameters. R ) 0.126, Rw ) 0.186, GOF ) 1.59.
Ack n ow led gm en t. This research was performed
through Special Coordination Funds for Promoting
Science and Technology (Leading Research Utilizing
Potential of Regional Science and Technology) of the
Ministry of Education, Culture, Sports, Science and
Technology of the J apanese Government. We also
acknowledge Dr. M. Shiro and Mr. K. Sasaki (Rigaku
Corp.) for helpful advice on X-ray measurements.
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data and structure refinement details for 3b,d ,e. This material
is available free of charge via the Internet at http://pubs.acs.org.
Sin gle-Cr ysta l X-r a y Diffr a ction . All the crystals were
mounted on glass fibers and were coated with nail polish to
keep solvents included. The single-crystal X-ray data was
collected on a Rigaku R-AXIS RAPID Imaging plate diffrac-
tometer. All calculations were performed with the crystal-
lographic software package teXsan (Molecular Structure Cor-
poration, 1985&1999). The structure was solved by direct
method (SHELXS-97)21 and expanded using Fourier tech-
niques (DIRDIF94).22 Non-hydrogen atoms were refined aniso-
J O015780O
(21) Sheldric, G. M. Program for the solution of crystal structure,
University of Goettingen, Germany, 1997.
(22) Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.;
de Gelder, R.; Israel, R.; Smits, J . M. M. The DIRDIF-94 program
system; Technical Report of the Crystallography Laboratory, Univer-
sity of Nijmegen, The Netherlands, 1994.