Singly Bridged Calix[8]crowns

Article abstract of DOI:10.1021/jo0002036

Crowned calix[8]arenes are obtained by direct alkylation of p-tert-butylcalix[8]arene (1) with poly-(ethylene glycol) ditosylates in the presence of various bases. K₂CO₃ promotes the preferential formation of 1,3-calix[8]crowns. Cs₂CO₃ mainly gives the 1,5-isomers, which are selectively obtained in high yields when shorter chains are used (1,5-crown-2, 88%; 1,5-crown-3, 78%). NaH affords the 1,4-isomers in yields up to 46%, often as the sole crown derivative, besides unreacted 1. 1,2-Calix-[8] crowns are also obtained in appreciable amount in some instances. The observed regioselectivity is rationalized in terms of preferential formation of specific anions in dependence of the base strength. Dynamic NMR and modeling studies prove that the polyether chain, depending on its bridging mode, may significantly reduce the available space for the through the annulus passages leading to derivatives conformationally blocked (on the NMR time scale).

Full text of DOI:10.1021/jo0002036

J . Org. Chem. 2000, 65, 5143-5151
5143
Sin gly Br id ged Ca lix[8]cr ow n s
Corrada Geraci, Mario Piattelli, Gianni Chessari, and Placido Neri *,§
†
†
†,‡
Dipartimento di Chimica, Universit a` di Salerno, Via S. Allende, I-84081 Baronissi (SA), Italy,
Istituto per lo Studio delle Sostanze Naturali di Interesse Alimentare e Chimico-Farmaceutico,
C.N.R., Via del Santuario 110, I-95028 Valverde (CT), Italy
neri@unisa.it.
Received February 14, 2000
Crowned calix[8]arenes are obtained by direct alkylation of p-tert-butylcalix[8]arene (1) with poly-
(
ethylene glycol) ditosylates in the presence of various bases. K
formation of 1,3-calix[8]crowns. Cs CO mainly gives the 1,5-isomers, which are selectively obtained
in high yields when shorter chains are used (1,5-crown-2, 88%; 1,5-crown-3, 78%). NaH affords the
,4-isomers in yields up to 46%, often as the sole crown derivative, besides unreacted 1. 1,2-Calix-
8]crowns are also obtained in appreciable amount in some instances. The observed regioselectivity
2 3
CO promotes the preferential
2
3
1
[
is rationalized in terms of preferential formation of specific anions in dependence of the base
strength. Dynamic NMR and modeling studies prove that the polyether chain, depending on its
bridging mode, may significantly reduce the available space for the through the annulus passages
leading to derivatives conformationally blocked (on the NMR time scale).
In tr od u ction
while crowns-4, in the partial-cone conformation, possess
a reverted Na /K preference.6
+
+
In the past decade particular attention has been paid
1
These successes have sparked a general interest in
calixcrowns, leading to all the possible regio- and atrop-
to the combination of calixarene frameworks with crown-
ether2 moieties, which affords a class of compounds
3
-7
3
isomers of single- and double-crowned calix[4]arenes
collectively named calixcrowns. By changing calixarene
8
and to the synthesis of a few examples of calix[5]crowns
and calix[6]crowns.9 As concerns calix[8]crowns, the
majority of the work has been carried out in our labora-
tory10 and unexpectedly led to cesium-selective iono-
size and number and length of the polyether chains, a
large variety of macropolycycles with different physico-
3
chemical properties are obtained. Of prominent interest
is their complexing ability toward cations, often displayed
with very remarkable and unparalleled selectivity. For
phores.11 All of these results have been reported in
preliminary communications,1
1-13
and we give here full
+
+
+
+
instance, high Cs /Na and K /Na selectivities have
been observed for 1,3-alternate calix[4]crowns-6 iono-
experimental data on the synthesis and characterization
of singly bridged calix[8]crowns (calix[8]mono-crowns),
while calix[8]bis-crowns and their complexing properties
will be reported in forthcoming papers.
4
5
phores and the corresponding crowns-5, respectively,
*
Ph: +39-089-965262. Fax: +39-089-965296.
Istituto Studio Sostanze Naturali, C.N.R.
Presently at Institute de Biologie de Lille, Pasteur Institute of Lille
†
‡
(
France).
(6) Yamamoto, H.; Shinkai, S. Chem. Lett. 1994, 1115.
(7) For recent additional examples, see: Lamare, V.; Dozol, J . F.;
Ugozzoli, F.; Casnati, A.; Ungaro, R. Eur. J . Org. Chem. 1998, 1559.
Asfari, Z.; Thuery, P.; Nierlich, M.; Vicens, J . Aust. J . Chem. 1999,
52, 343. Asfari, Z.; Thuery, P.; Nierlich, M.; Vicens, J . Tetrahedron
Lett. 1999, 40, 499. Ferguson, G.; Lough, A. J .; Notti, A.; Pappalardo,
S. J . Org. Chem. 1999, 63, 9703. Arnaud-Neu, F.; Ferguson, G.;
Fuangswasdi, S.; Notti, A.; Pappalardo, S.; Parisi, M. F.; Petringa, A.
J . Org. Chem. 1999, 63, 7770.
§
Universit a` di Salerno.
1) For comprehensive reviews on calixarenes see: Calixarenes, a
(
Versatile Class of Macrocyclic Compounds; Vicens, J ., B o¨ hmer, V., Eds.;
Kluwer: Dordrecht, 1991. B o¨ hmer, V. Angew. Chem., Int. Ed. Engl.
1
995, 34, 713. Ikeda, A.; Shinkai, S. Chem. Rev. 1997, 97, 1713.
Gutsche, C. D.; Calixarenes Revisited; The Royal Society of Chemis-
try: Cambridge, 1998.
(2) Pedersen, C. J . Angew. Chem., 1988, 100, 1053. Gokel, G. Crown
Ethers and Cryptands; Royal Society of Chemistry: Cambridge, 1991.
Dietrich, B.; Viout, P.; Lehn J .-M. Macrocyclic Chemistry, Aspects of
Organic and Inorganic Supramolecular Chemistry; VCH: Weinheim,
(8) (a) Kraft, D.; Arnecke, R.; B o¨ hmer, V.; Vogt, W. Tetrahedron
1993, 49, 6019. (b) Gordon, J . L. M.; B o¨ hmer, V.; Vogt, W. Tetrahedron
Lett. 1995, 36, 2445. (c) Cacciapaglia, R.; Mandolini, L.; Arnecke, R.;
B o¨ hmer, V.; Vogt, W. J . Chem. Soc., Perkin Trans. 2 1998, 419. (d)
Caccamese, S.; Notti, A.; Pappalardo, S.; Parisi, M. F.; Principato, G.
Tetrahedron 1999, 55, 5505.
(9) Casnati, A.; J acopozzi, P., Pochini, A.; Ugozzoli, F.; Cacciapaglia,
R.; Mandolini, L.; Ungaro, R. Tetrahedron 1995, 51, 591. Li, J . S.; Chen,
Y. Y.; Lu, X. R. Tetrahedron 1999, 55, 10365. Chen, Y. Y.; Li, J . S.;
Xin, J .; Zhong, Z. L.; Gong, S. L.; Lu, X. R. Synth. Commun. 1999, 29,
705.
1
993.
3) Alfieri, C.; Dradi, E.; Pochini, A.; Ungaro, R.; Eretti, G. D. J .
(
Chem. Soc., Chem. Commun., 1983, 1075. (b) Asfari, Z.; Wenger, S.;
Vicens, J . J . Incl. Phenom. 1994, 19, 137 and references therein.
(4) Ungaro, R.; Casnati, A.; Ugozzoli, F.; Pochini, A.; Dozol, J .-F.;
Hill, C.; Rouquette, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 1506.
Asfari, Z.; Harrowfield, J . M.; Sobolev, A. N.; Vicens, J . Aust. J . Chem.
1
994, 47, 757. Casnati, A.; Pochini, A.; Ungaro, R.; Ugozzoli, F.;
Arnaud, F.; Fanni, S.; Schwing, M.-J .; Egberink, R. J . M.; de J ong, F.;
Reinhoudt, D. N. J . Am. Chem. Soc. 1995, 117, 2767. Sachleben, R.
A.; Urvoas, A.; Bryan, J . C.; Haverlock, T. J .; Hay B. P.; Moyer B. A.
Chem. Commun. 1999, 1751. J i, H. F.; Brown, G. M.; Dabestani, R.
Chem. Commun. 1999, 609. Lamare, V.; Dozol, J . F.; Fuangswasdi,
S.; Arnaud-Neu, F.; Thuery, P.; Nierlich, M.; Asfari, Z.; Vicens, J . J .
Chem. Soc., Perkin Trans. 2 1999, 271. Asfari, Z.; Lamare, V.; Dozol,
J . F.; Vicens, J . Tetrahedron Lett. 1999, 40, 691.
(10) Neri P., Geraci C., Piattelli M. In Recent Research Developments
in Organic Chemistry; Pandalai, S. G., Ed.; Transworld Research
Network: Trivandrum, 1997; Vol. 1, pp 285-297.
(11) Geraci, C.; Chessari, G.; Piattelli, M.; Neri, P. Chem. Commun.
1997, 921.
(12) (a) Geraci, C.; Piattelli, M.; Neri, P. Tetrahedron Lett. 1995,
36, 5429. (b) Geraci, C.; Piattelli, M.; Neri, P. Tetrahedron Lett. 1996,
37, 7627. (c) Caccamese, S.; Principato, G.; Geraci, C.; Neri, P. Tetra-
hedron: Asymmetry 1997, 8, 1169.
(5) Casnati, A.; Pochini, A.; Ungaro, R.; Bocchi, C.; Ugozzoli, F.;
Egberink, R. J . M.; Struijk, H.; Lugtenberg, R.; de J ong, F.; Reinhoudt,
D. N. Chem. Eur. J . 1996, 2, 436.
(13) Geraci, C.; Piattelli, M.; Neri, P. Tetrahedron Lett. 1996, 37,
3899.
1
0.1021/jo0002036 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/21/2000

5
144 J . Org. Chem., Vol. 65, No. 17, 2000
Geraci et al.
Ch a r t 1
Ta ble 1. Yield of Ca lix[8]cr ow n -n in Dir ect Alk yla tion of
Alk yla t ion of p -ter t-Bu t ylca lix[8]a r en e in t h e
P r esen ce of Ak a li Ca r bon a tes. As summarized in
Table 1, reactions in the presence of cesium, potassium,
and sodium carbonates were performed in refluxing
acetone using a stoichiometric amount of tri(ethylene
glycol) ditosylate. Under these conditions sodium carbon-
ate was unable to promote calix[8]crown formation even
when present in large excess and with protracted reaction
time (72 h).
a
1
w ith TsO(CH2CH2O)m Ts (1 equ iv) in th e P r esen ce of
Va r iou s Ba ses (8 equ iv)
time
(h)
compound
(yield %)
entry
m
base
CO
solvent (temp)
1
2
3
4
5
6
7
8
9
3
3
1
2
3
3
3
4
5
K
2
3
Me
Me
2
2
CO (refl)
CO (refl)
47
22
12
7
2
2
5
5
2
4
4
4
4
4
4
2
3
4
4
4
5
6
(5), 3
(7), 4
(88)
(78)
(8), 4
(35)
(46)
(31)
(25)
4
4
(12), 6
(8), 5
4
4
(6)
(10)
Cs
Cs
Cs
2
2
2
CO
CO
CO
3
3
3
DMF (60 °C)
DMF (60 °C)
KH
THF/DMF 10:1 (refl) 17
THF/DMF 10:1 (refl)
THF/DMF 10:1 (refl) 17
4
(28)
NaH
NaH
NaH
NaH
3
K
2
CO
tosylpolyether 6
time to 47 h, 1,2-calix[8]crown-4 2
were also obtained in 5% and 12% yield, respectively
Table 1, entry 1).
The use of Cs CO
crown-4 2 (7%), and in addition two new compounds
were obtained, 1,4-calix[8]crown-4 4 (8%) and 1,5-calix-
[8]crown-4 5 (10%) (Table 1, entry 2). Thus, using two
3
was moderately efficient, and after 4 h mono-
was obtained. Extending the reaction
and 1,3-calix[8]crown-
THF/DMF 10:1 (refl)
THF/DMF 10:1 (refl)
3
3
4
4
4
(
3
4
a
In the case of entries 3 and 4, 2 equiv of alkylating agent was
used.
2
3
increased the yield of 1,2-calix[8]-
Resu lts a n d Discu ssion
4
4
The synthesis of calix[8]crowns was carried out by
direct alkylation of p-tert-butylcalix[8]arene 1 with an
oligo(ethylene glycol) ditosylate in the presence of a
base.13 In this reaction four different singly bridged
4
different bases it was possible to obtain all the four
possible calix[8]crown-4 regioisomers, although in poor
yields.
regioisomers can form, which we refer to as 1,2- (2
), 1,4- (4 ), or 1,5-calix[8]crown-n (5 ), where n rep-
resents the number of oxygen atoms in the bridge (Chart
). Since the experiments (Table 1) showed the crucial
role of the base in the regiochemical outcome, the
results will be discussed in accordance with the base
used.
n
), 1,3-
An impressive increase in calix[8]crowns yield was
observed when shorter chain ditosylates were used, with
(
3
n
n
n
Cs
conditions 1,5-calix[8]crown-3 5
1,5-crown-2 5 were formed in 78 and 88% yield, respec-
2 3
CO as the base in DMF at 60 °C. Under these
1
1
1
3
and the corresponding
1
3
2
tively (Table 1, entries 3 and 4). It is worth noting that
under identical conditions the longer chain derivatives

Singly-Bridged Calix[8]crowns
J . Org. Chem., Vol. 65, No. 17, 2000 5145
4
are still formed in rather lower yields (5 , 15%), indicat-
ing that the chain shortness is mainly accountable for
the higher yield of 5 and 5
3
2
.
Alk yla t ion of p -ter t-Bu t ylca lix[8]a r en e in t h e
P r esen ce of Alk a li Hyd r id es. Alkylation of 1 with tri-
(
ethylene glycol) ditosylate was extended to the stronger
bases NaH and KH, in refluxing anhydrous THF/DMF
10:1). KH showed much better efficiency and selectivity
than alkaline carbonates, and after 17 h compounds 2
and 4 were formed in 8% and 28% yield, respectively
Table 1, entry 5). Further improvement was obtained
with NaH, which gave 4 as the sole crown derivative in
5% yield in 3 h (Table 1, entry 6), besides unreacted 1.
(
4
4
(
4
3
1
4
The yield reached 46% after 17 h (Table 1, entry 7).
Considering the high efficiency and selectivity obtained
for crown-4, the same conditions were applied to tetra-
and penta(ethylene glycol) ditosylate. 1,4-crown-5 4
5
and
1
,4-crown-6 4 were thus obtained in 31% and 25% yield,
6
respectively (Table 1, entries 8 and 9). The preparative
value of the NaH-promoted reactions was increased by
suspending the crude reaction mixture in acetonitrile and
filtering off the unreacted calix[8]arene. Almost pure 1,4-
crown-n 4 derivatives could be thus obtained in pre-
n
parative scale without resorting to chromatographic
methods.
Str u ctu r e Assign m en t. The structures of calix[8]-
1
13
crowns were determined by NMR analysis ( H, C, and
D NMR), once the molecular weight had been confirmed
2
by FAB(+) measurements. The elementary analyses are
in accordance with the molecular formula of the com-
pounds. Discrimination among the four bridging modes
(1,2, 1,3, 1,4, and 1,5) was mainly based on molecular
symmetry as evidenced by the NMR signal patterns
expected for conformationally mobile derivatives (see
below).15
1
n
,3-Ca lix[8]cr ow n -n (3 ). Among the four regioiso-
mers, 1,3-crowns are characterized by a single binary
1
13
symmetry element bisecting opposite aromatic rings (Ar-
F igu r e 1. Portion of the H- C long-range HETCOR NMR
Ar symmetry).15 This should be reflected by the appear-
spectrum of 1,4-crown-4 4 . The structurally relevant correla-
4
tions between bridgehead aromatic carbons (B-CH
2
) and
ance of a typical five-signal pattern (1:2:2:2:1) for the tert-
ArCH
2
Ar protons (A-B, B-C) are indicated. For comparison,
butyl groups of the five types of aromatic rings. Indeed,
the expected correlations for 1,2 or 1,4 isomer are also
indicated in the structure drawings.
1
in the H NMR spectrum of compound 3
4
the expected
five singlets were seen at δ 1.18, 1.23, 1.24, 1.26, and
.27 (1:2:1:2:2). In addition, the symmetry was confirmed
by the presence of 10 resonances in the 140-155 ppm
1
1,4-Ca lix[8]cr ow n -n (4
are both characterized by a 2-fold symmetry element
bisecting opposite ArCH Ar groups (CH -CH sym-
metry). Consequently, their NMR spectra should display
a four-singlet pattern (1:1:1:1) for t-Bu groups and eight
signals for C-O and C-Bu quaternary carbons. Therefore,
discrimination between these two bridging modes re-
quired additional information.
n
). 1,4- and 1,2-intrabridging
1
3
region of the C NMR spectrum (see Experimental
Section) due to the quaternary aromatic carbons bearing
oxygen atoms or tert-butyl groups.
2
2
2
1
n
,5-Ca lix[8]cr ow n -n (5 ). 1,5-Crown derivatives pos-
sess the highest symmetry (double Ar-Ar) producing
simple NMR spectra, characterized by a three-resonance
1
pattern (1:2:1) for tert-butyls in the H NMR spectra and
As an example, the CH
evidenced by four H NMR signals at δ 1.17, 1.97, 1.22,
and 1.25 (1:1:1:1) related to tert-butyl groups and eight
2
2 4
-CH symmetry of 4 was
six signals in the low field region of the 13C NMR spectra.
These features were both observed in the three 1,5-
1
1
3
crowns (5
2
, 5
3
, and 5
4
) isolated in the present work. For
C NMR peaks for quaternary carbons in the low field
1
instance, in the H NMR spectrum of compound 5
3
,
region of the spectrum. Discrimination between 1,2- and
1,4-bridging patterns was achieved by a combination of
2D HETCOR and 2D Long-Range HETCOR NMR ex-
acquired at 330 K, the three tert-butyl singlets were
clearly seen at δ 1.12, 1.28, and 1.31 (1:2:1).
6 6
periments, performed in C D at 310 K in order to
(
14) (a) Under similar conditions NaH promoted the 1,4-bridging
sufficiently resolve the methylene signals. Using the
correlations observed in these spectra in conjunction with
chemical shift arguments all the low-field C NMR
signals were assigned. In particular the bridgehead
aromatic carbons of the alkylated rings (rings B in Figure
of p-tert-butylcalix[8]arene with some bis(bromomethyl)arene deriva-
tives: Ikeda, A.; Akao, K.; Harada, T.; Shinkai, S. Tetrahedron Lett.
996, 37, 1621. (b) The 1,4-bridging with an acridone-based linker was
also reported: Tsantrizos, Y. S.; Chew, W.; Colebrook, L. D.; Sauriol,
F. Tetrahedron Lett. 1997, 38, 5411.
1
3
1
(
15) The general principle of this approach has been detailed in ref
0 and in: Neri, P.; Consoli, G. M. L.; Cunsolo, F.; Geraci, C.; Piattelli,
M. New J . Chem. 1996, 20, 443.
1
) were clearly identified at 133.4 and 133.6 ppm, because
1
of the downfield displacement produced by the O-alky-

5
146 J . Org. Chem., Vol. 65, No. 17, 2000
Geraci et al.
lation.16 The presence of cross-peaks between these two
carbons and two ArCH Ar singlets of 4 H intensity (δ 4.04
2
and 4.08) revealed the 1,4-bridging (Figure 1), since the
alternative 1,2-crown-4 structure requires these cross-
peaks between two singlets of 4 and 2 H intensity,
respectively.
Structure assignment of 1,4-calix[8]crown-5 4 was
5
based on analogous 2D NMR studies.
1
,2-Ca lix[8]cr ow n -4 (2
4
). From NMR analysis it was
-CH symmetry
evident that 2 possesses the same CH
4
2
2
as the 1,4-regioisomer, since the typical four 18 H singlets
for t-Bu groups were seen at δ 1.20, 1.23, 1.237, and 1.24,
as well as the eight signals for quaternary aromatic
carbons in the 140-155 ppm region of the 13C NMR
spectrum. At this point, since 1,4-crown-4 had been
already identified, the 1,2-crown-4 structure was im-
F igu r e 2. 1H NMR chemical shift (see Experimental Section)
of OH groups of selected calix[8]crowns. The different types
of hydroxyls are indicated as follows: ( ) isolated, b ) singly
bonded, 9 ) singly bonded involved in “semicircular” H-bond,
mediately assigned to 2
,4-Ca lix[8]cr ow n -6 (4
the case of 1,4-calix[8]crown-6 4
4
by exclusion.
). OH Ch em ica l Sh ifts. In
, the additional informa-
2
) doubly bonded.
1
6
6
are seen at distinctly lower field (8.85 and 9.04 ppm) with
respect to those at positions 2 and 3 (8.35 and 8.20 ppm),
singly bonded only to each other. An examination of Table
tion to discriminate between 1,2- or 1,4-bridging was
1
derived from H NMR chemical shifts of the phenolic
hydroxyls.17 In fact, it is now well documented that in
calixarene family the strength of intramolecular hydro-
gen bonds increases with increasing the number of
consecutive hydroxyls, to reach a maximum in the closed,
1
shows that this cooperativity effect is present in all
compounds having at least three consecutive hydroxyls
and leads to a chemical shift not lower than 8.66 ppm.
On this basis, the occurrence of a resonance at 8.36 ppm
for 4 was considered diagnostic of the relegated singly
6
bonded hydroxyls characteristic of 1,4-bridging.
On th e Regioch em ica l Ou tcom e in th e Syn th esis
of Ca lix[8]m on o-cr ow n s. The regiochemical prefer-
ences in the reaction that leads to singly bridged calix-
“
circular H-bond” of the parent calixarenes.18 This is
reflected in the concomitant increase of OH groups
chemical shift, reaching values up to more than 10 ppm
for the closed systems.18 Generalization of these observa-
tions leads to the following conclusions: “isolated” OH
groups usually resonate at δ < 7.7; “singly bonded”
[8]crowns can be explained mainly in terms of strength
hydroxyls give signals at 7.7 < δ < 8.7; “doubly bonded”
of the base. A first deprotonation of 1 followed by
nucleophilic attack to the oligo(ethylene glycol) ditosylate
OH groups resonate at δ > 8.7.1
6,19
These limits move to
lower field if stronger cooperativity occurs.16
initially affords the open-chain monotosyl derivative 6
Scheme 1). This can then give rise, after deprotonation,
n
Consideration of hydroxyl chemical shifts for calix[8]-
crowns with unambiguously assessed structures (Figure
(
to a ring closure reaction at one of the four different
phenolic rings, originating the four calix[8]crowns regio-
isomers. Obviously, the second deprotonation is crucial
in determining the regiochemical outcome.13
2
) showed that the above empirical rules hold also for
them. For instance, 1,3-crown-4 displays four distinct OH
signals attributable to the isolated (δ 7.65, 1 H), singly
bonded (δ 8.66, 2 H), and doubly bonded (δ 9.01 and 9.24,
In the presence of excess strong base, such as NaH or
KH, a multiple deprotonation of open-chain derivative
2
and 1 H) hydroxyls.
Therefore, we confidently used the chemical shifts of
6
n
has to be expected.20 Very likely, a 2,4,6,8-tetraanion
OH groups as an aid in the structure determination of
and 4 , in which a fair distinction was possible within
of type 8 (Scheme 1) is formed wherein the repulsive
charge interaction is minimized and the hydrogen-bond
stabilization maximized.21 The subsequent closure step
4
4
5
the singly bonded OH groups on the basis of the down-
field shift produced by the cooperativity effect of the
n
would lead to 1,4-bridged calix[8]crowns 4 . In the case
“
semicircular” H-bond.16 For both compounds the singly
of the KH-promoted reaction, the concurrent 1,2-bridging
is likely due to metal template effect exerted by the
potassium cation.22
bonded hydroxyls involved in the “semicircular” H-bond
phenolic rings at positions 5 and 8 of the macrocycle)
(
In the case of the weaker base K
mono-deprotonation at position 3 of 6
give anion 9 (Scheme 1). In fact, previous studies had
shown that alkylation of 1 proceeds through the alternate
pathway,23 with the intermediate formation of monoan-
ions stabilized by proximal hydrogen bonds. Conse-
2
CO
n
3
a preferential
should occur to
(
16) The validity of this “downfield displacement” rule and the
comparison of OH chemical shift in a series of partial methoxycalix-
8]arenes have been discussed in: Cunsolo, F.; Consoli, G. M. L.;
Piattelli, M.; Neri, P. J . Org. Chem. 1998, 63, 6852.
17) For other examples of the use of OH chemical shift as a
[
(
structural probe, see refs 8a, 16, and: Neri, P.; Battocolo, E.; Cunsolo,
F.; Geraci, C.; Piattelli, M. J . Org. Chem. 1994, 59, 3880.
(18) Gutsche, C. D. Acc. Chem. Res. 1983, 16, 161. Keller, S. W.;
n
quently, in this instance 1,3-crowns 3 are preferentially
Schuster, G. M.; Tobiason, F. L. Polym. Mater. Sci. Eng. 1987, 57, 906.
The OH chemical shift in “large” calix[n]arenes (n ) 9-20) has been
comparatively discussed in: Stewart, D. R.; Gutsche, C. D. J . Am.
Chem. Soc. 1999, 121, 4136.
(20) Rogers, J . S.; Gutsche, C. D. J . Org. Chem. 1992, 57, 3152.
Kanamathareddy, S.; Gutsche, C. D. J . Org. Chem. 1992, 57, 3160.
(21) For a discussion on the behavior of a preformed calix[8]arene
trianion, see: Neri, P.; Consoli, G. M. L.; Cunsolo, F.; Rocco, C.;
Piattelli, M. J . Org. Chem. 1997, 62, 4236.
(22) This template effect has also been invoked to explain the
formation of 1,2-calix[4]crown: Yamamoto, H.; Sakaki, T.; Shinkai,
S. Chem. Lett. 1994, 469.
(19) For a discussion on the OH chemical shift in partial alkoxycalix-
[
4]arenes, see: Araki, K.; Iwamoto, K.; Shinkai, S.; Matsuda, T. Bull.
Chem. Soc. J pn. 1990, 63, 3480. Groenen, L.; Steinwender, E.; Lutz,
B.; van der Maas, J .; Reinhoudt, D. N. J . Chem. Soc., Perkin Trans. 2
1
992, 1893. Similarly, for the partial alkoxycalix[6]arene series, see:
Otsuka, H.; Araki, K.; Shinkai, S. J . Org. Chem. 1994, 59, 1542.
J anssen, R. G.; Verboom, W.; Lutz, B. G.; van der Maas, J . H.; Maczka,
M.; van Duynhoven, J . P. M.; Reinhoudt, D. N. J . Chem. Soc., Perkin
Trans. 2 1996, 1869.
(23) Neri, P.; Geraci, C.; Piattelli, M. J . Org. Chem. 1995, 60, 4126.
Consoli, G. M. L.; Cunsolo, F., Neri, P. Gazz. Chim. Ital. 1996, 126,
791.

Singly-Bridged Calix[8]crowns
Sch em e 1
J . Org. Chem., Vol. 65, No. 17, 2000 5147
formed in the closure step. Again, the presence of
potassium template effect could explain the concomitant
formation of 1,2-crowns.22
In the reaction promoted by Cs
or trianion has to be anticipated, since this base in
organic solvent has intermediate strength between K
and NaH.24 In the case of triple deprotonation a
CO
,5,7-trianion like 10 should be formed (Scheme 1), more
2
CO3, formation of a di-
1
-
F igu r e 3. Comparison of the methylene region of H NMR
2
spectra of 1,4-calix[8]crown-4 derivatives at pertinent tem-
peratures.
3
3
stabilized by hydrogen bonding with respect to other
trianions. As a result of the high mobility of the calix[8]-
arene macrocycle, the 3,5,7-trianion can adopt a confor-
mation characterized by the spatial proximity of dia-
crowns are conformationally mobile derivatives, as indi-
cated by the presence in their room temperature H NMR
spectrum of broad signals for ArCH Ar groups which
2
sharpen at higher temperatures (Figures 3a,b and 4a,b).
This mobility is even higher than that of calix[8]arene
1
2
5
metrical 1 and 5 positions, such as the pinched and the
chairlike26 ones recently characterized by X-ray crystal-
1
, because the polyether chain breaks the stabilizing
lography, which explain the preferential 1,5-bridging.
This consideration is supported by the finding that under
identical conditions shorter chains give 1,5-bridged de-
1
8
circular hydrogen bond in the parent compound. How-
ever, the remaining H-bonds still contribute to reduce
mobility.28 Their suppression following methylation of the
free OH groups leads to the corresponding hexamethoxy
rivative 5
3
and 5
2
with yields (78% and 88%, respectively)
, 15%).
remarkably higher than the longer ones (e.g., 5
4
4
derivative 4 a , highly mobile on the NMR time scale, as
Notably, this explains the apparent contradiction with
evidenced by the appearance of sharp singlets for ArCH
Ar groups (Figure 3c).
2
-
the intuitive concept that farther positions requires
longer bridges.27
An additional effect of the presence of the polyether
chain is the reduction of available space for the ring
inversion process, which may occur either by the oxygen
or tert-butyl through the annulus pathway (Figure 5).
This finding suggests that the appendage of sufficiently
bulky groups at the lower rim should inhibit the oxygen
through the annulus route while the alternative tert-butyl
through the annulus passage, although quite encum-
Con for m a tion a l F ea tu r es. As mentioned in the
structure assignment section, singly bridged calix[8]-
(24) Dijkstra, G.; Hruizinga, W. H.; Kellogg, R. M. J . Org. Chem.
1
4
987, 52, 4230. Iwamoto, K.; Araki, K.; Shinkai, S. Tetrahedron 1991,
7, 4325. Shinkai, S. Tetrahedron 1993, 49, 8933 and references
therein.
(25) Clague, N. P.; Clegg, W.; Coles, S. J .; Crane, J . D.; Moreton, D.
J .; Sinn, E.; Teat S. J .; Young, N. A. Chem. Commun. 1999, 379. This
conformation was first suggested by Gutsche: Gutsche, C. D.; Bauer,
L. J . Tetrahedron Lett. 1981, 22, 4763.
29
bered, in principle could not be excluded. Consequently,
(
26) Czugler, M.; Tisza, S.; Speier, G. J . Incl. Phenom. Mol. Recognit.
Chem. 1991, 11, 323.
27) Shinkai and co-workers similarly observed a preference for 1,4-
bridging with longer and 1,5-bridging with shorter spacer in the
(28) For
a discussion on the conformational restriction by the
(
residual hydrogen bonding in mono-O-substituted calix[6]arenes, see:
Magrans, J . O.; Rincon, A. M.; Cuevas, F.; Lopez-Prados, J .; Nieto, P.
M.; Pons, M.; Prados, P.; de Mendoza, J . J . Org. Chem. 1998, 63, 1079.
1
4a
alkylation of 1 with bis(bromomethyl)arenes.

5
148 J . Org. Chem., Vol. 65, No. 17, 2000
Geraci et al.
computer models30 of 4
b, which show that indeed p-tert-
4
butylbenzyl groups quite effectively inhibit the oxygen
through the annulus inversion and probably also the
passage of the calixarene tert-butyls through the annulus.
Obviously, this conformational behavior is entirely as-
cribable to the presence of the polyether chain, since
unbridged octakis(p-tert-butylbenzyl)-calix[8]arene 7 is
completely mobile at room temperature. Similar conclu-
sions can be drawn from the CPK computer models of
4
hexakis(p-tert-butylbenzyl)-1,3-crown-4 3 b, which also
contains temperature-independent AX systems for ArCH
2
-
Ar groups.31
On moving to hexakis(p-tert-butylbenzyl)-1,2-crown-4
1
2
4
b a different situation is observed, since its H NMR
2
spectrum shows five singlets for ArCH Ar groups indicat-
ing a high conformational mobility (Figure 4c). Again,
this can be understood using computer models which
show that upon 1,2-bridging a large portion of the calix-
[8]arene annulus remains available for conformational
conversion (Figure 6), which may take place as easily as
in the related octabenzylcalix[8]arene 7.
Com p lexa tion Tests. In analogy to calix[4]crowns,3
the presence of a polyether chain in calix[8]mono-crowns
above-described suggests a potential complexing ability
toward alkali cations. To test this potentiality two-phase
-7
1
F igu r e 4. Comparison of the methylene region of H NMR
spectra of 1,2-calix[8]crown-4 derivatives at pertinent tem-
peratures.
32
1
picrate extraction and H NMR experiments were
performed. In both cases, none of compounds 2 -5 , 4 a ,
and 2 b-4 b showed complexing properties worthy of
note for Li , Na , K , Rb , or Cs . This could be explained
in terms of poor preorganization of any ionophoric cavity
probably because of the residual mobility of both calix-
n
n
4
4
4
+
+
+
+
+
[8]arene macrocycle and polyether chain. More effectively
preorganized calix[8]bis-crown-3 derivatives show quite
1
1
interesting size-dependent complexing properties.
Con clu sion s
Intramolecular bridging is considered of central rel-
evance for the preparation of calix[8]arene-based new
preorganized hosts. In this respect, the results reported
in this paper constitute the groundwork for the use of
polyether chains as bridging elements. It is here dem-
onstrated that direct alkylation of p-tert-butylcalix[8]-
arene with oligo(ethylene glycol) ditosylate gives the four
possible calix[8]mono-crown regioisomers in yields and
selectivity sometime quite surprising. The observed re-
gioselectivity is amenable to rationalization in terms of
preferential formation of specific anions, dependent on
the base strength, shedding new light on the intricacies
of calix[8]arene chemistry.
From the conformational viewpoint, the introduction
of a single polyether chain does not significantly affect
the intrinsic mobility of calix[8]arene macrocycle. How-
ever, its presence may significantly reduce the available
space for the through the annulus passages leading to
conformationally blocked (at least on the NMR time scale)
derivatives when sufficiently bulky groups are attached
F igu r e 5. Pathways for conformational interconversion in
p-tert-butylcalix[8]arenes and in their mono-crown derivatives.
any eventual conformational conversion could proceed
only by the second mechanism, whose occurrence should
be strongly dependent on the regioisomeric position of
the bridging chain.
To verify these considerations we prepared the hexa-
substituted tert-butylbenzyl derivatives of calix[8]crowns
2 3
by exhaustive alkylation in the presence of Cs CO (see
Experimental Section), and their conformational mobility
was investigated by dynamic NMR. Interestingly, the
1
methylene region of the H NMR spectrum of hexakis-
(
p-tert-butylbenzyl)-1,4-crown-4 4
and two AB systems for ArCH Ar groups, which do not
give any hint of coalescence by heating to 350 K (Figure
d). This demonstrates that in 4 b conformational inter-
4
b displays three AX
2
3
4
conversions are prevented, at least on the NMR time
scale. This finding can be understood on the basis of CPK
(
30) Molecular modeling was performed with the MacroModel V4.5
(
29) It is worth to recall here that the tert-butyl through the annulus
computer program: Mohamadi, F.; Richards, N. G. J .; Guida, W. C.;
Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still,
W. C. J . Comput. Chem. 1990, 11, 440.
(31) On the basis of computer models this conclusions should also
be applicable to the corresponding 1,5-crown-4 derivative. However,
in this case the difficulty encountered in obtaining a sufficiently pure
compound impeded the experimental NMR confirmation.
(32) Arduini, A.; Pochini, A.; Reverberi, S.; Ungaro, R.; Andreetti,
G. D.; Ugozzoli, F. Tetrahedron 1986, 42, 2089.
passage in unbridged p-tert-butylcalix[8]arenes is always operating as
demonstrated by the fact that it occurs even in the smaller p-tert-
butylcalix[6]arenes: Otsuka, H.; Araki, K.; Sakaki, T.; Nakashima,
K.; Shinkai, S. Tetrahedron Lett. 1993, 34, 7275. van Duynhoven, J .
P. M.; J anssen, R. G.; Verboom, W.; Franken, S. M.; Casnati, A.;
Pochini, A.; Ungaro, R.; de Mendoza, J .; Nieto, P. M.; Prados, P.;
Reinhoudt, D. N. J . Am. Chem. Soc. 1994, 116, 5814. Kanamathareddy,
S.; Gutsche, C. D. J . Org. Chem. 1994, 59, 3871.

Singly-Bridged Calix[8]crowns
J . Org. Chem., Vol. 65, No. 17, 2000 5149
of Catania. Column chromatography was performed using
silica gel (Kieselgel 60, 63-200 µm, Merck). All chemicals were
reagent grade and were used without further purification.
Anhydrous THF and DMF were purchased from Aldrich.
3
4
p-tert-Butylcalix[8]arene (1) was prepared as reported.
Gen er a l P r oced u r es for th e Syn th esis of Ca lix[8]-
cr ow n s. A. A solution of 1 (0.5 g, 0.385 mmol) in Me CO (30
mL) was stirred in the presence of Cs CO (1.0 g, 3.08 mmol)
or K CO (0.425 g, 3.08 mmol) for 30 min at reflux. Tri(ethylene
glycol) ditosylate (0.176 g, 0.385 mmol) dissolved in Me CO (1
2
2
3
2
3
2
mL) was then slowly added, and the mixture stirred under
reflux for 22-47 h according to the base used. After concentra-
tion under vacuum the residue was triturated with 100 mL of
HCl, collected by filtration, washed with MeOH, and dried.
The crude product was suspended in acetonitrile, and the
insoluble starting material removed by filtration. The filtrate
containing the calix[8]crowns was taken to dryness, and the
residue purified by chromatography on silica gel.
B. To a solution of 1 (0.5 g, 0.385 mmol) in THF/DMF (30/3
mL) was added NaH (or KH) (3.08 mmol) under stirring. The
mixture was refluxed for 30 min, and then the oligo(ethylene
glycol) ditosylate (0.385 mmol) in THF (2 mL) was added
dropwise. The reaction was refluxed under stirring for 3-17
h (Table 1). Workup of the reaction mixture followed procedure
A.
2 3
C. Cs CO (1.0 g, 3.08 mmol) was added under stirring to a
solution of 1 (0.5 g, 0.385 mmol) in DMF (70 mL). The mixture
was kept at 60-70 °C for 20 min, and then a solution of mono-
or di(ethylene glycol) ditosylate (0.77 mmol) in DMF (4 mL)
was added dropwise. The reaction was stirred at 60-70 °C
for 7 or 12 h for compounds 5
concentration under vacuum the residue was triturated with
00 mL of HCl, collected by filtration, washed with MeOH,
3 2
and 5 , respectively. After
1
and dried. The crude product was purified by chromatography
on silica gel.
Op en -ch a in m on otosylca lix[8]cr ow n -4 6
entry 1, Table 1, purification by column chromatography (SiO
gradient AcOEt/cyclohexane) white powder (6%), mp 178-182
4
: procedure A,
2
,
1
°
1
4
C; H NMR (CDCl
3
, 295 K) δ 1.26, 1.27, 1.29, 1.30 (s, 36 H,
8 H, 9 H, 9 H), 2.23 (s, 3 H), 3.30, 3.53 (br t, 2 H each), 3.60-
.23 (overlapped, 24 H), 6.96-7.36 (overlapped, 18 H), 7.68
1
3
(
d, 2H, J ) 8.0 Hz), 8.96, 9.22, 9.42 (br s, 2 H, 2 H, 3 H);
C
NMR (CDCl , 295 K) δ 30.4, 31.6, 32.2, 32.6 (t), 31.5, 34.0 (q),
3
3
1
1
1
1
4.0, 34.3 (s), 68.5, 69.0, 70.2, 70.6, 70.7, 74.7 (t), 125.2, 125.4,
25.6, 125.7, 125.8, 126.6, 127.6, 127.8, 129.6 (d), 125.9, 126.9,
27.4, 127.7, 127.9, 133.1, 133.5, 143.1, 144.3, 144.5, 144.6,
46.6, 147.0, 147.1, 147.9, 148.4, 150.3 (s); FAB(+) MS m/z
583 (MH) . Anal. Calcd for C101
+
130
H O13S: C, 76.48; H, 8.26;
F igu r e 6. Polytube (top) and CPK (bottom) computer model
S, 2.02. Found: C, 76.51; H, 8.28; S, 2.00.
1,2-Ca lix[8]cr ow n -4 2 : procedure B, entry 5, Table 1,
purification by column chromatography (SiO , gradient AcOEt/
cyclohexane) white powder (8%), mp 196-198 °C; H NMR
(CDCl , 295 K) δ 1.24, 1.25, 1.26 (s, 36 H, 18 H, 18 H), 3.70-
4.35 (overlapped, 28 H), 7.00-7.27 (overlapped, 16 H), 8.69,
of 2
4
b showing that the polyether chain does not inhibit the
4
tert-butyl through the annulus passage.
2
1
at the lower rim. Of course, this influence can be altered
by controlling the bridging mode and the length of the
polyether chain.
As demonstrated in preliminary studies, the introduc-
tion of additional bridges in calix[8]mono-crowns leads
to truly preorganized derivatives able to host suitable
guests.11 In these instances, intriguing stereochemical
problems could be associated,12b,c,33 and sophisticated
topological implications could also be evidenced.
3
1
8
1
2
7
1
.97, 9.13 (br s, 2 H each). H NMR ((CD
3
)
2
CO), 324 K) δ 1.20,
, 295 K) δ
.23, 1.237, 1.24 (s, 18 H each); 13C NMR (CDCl
3
8.0, 29.7, 31.3, 32.1, 32.3 (t), 31.5 (q), 34.0, 34.3 (s) 70.1, 71.5,
4.8 (t), 125.4, 125.7, 126.4 (d), 127.0, 127.6, 127.9, 132.9,
43.3, 143.7, 143.9, 147.2, 147.4, 147.6, 148.3, 150.5 (s); FAB-
+
(+) MS m/z 1411 (MH) . Anal. Calcd for C94
H
122
O
10: C, 79.96;
H, 8.71. Found: C, 79.91; H, 8.68.
1,3-Ca lix[8]cr ow n -4 3
purification by column chromatography (SiO
cyclohexane) white powder (12%), mp 199-202 °C; H NMR
CDCl , 295 K) δ 1.18, 1.23, 1.24, 1.26, 1.27 (s, 9 H, 18 H, 9 H,
4
: procedure A, entry 1, Table 1,
2
, gradient AcOEt/
1
Exp er im en ta l Section
(
3
Gen er a l Com m en ts. Melting points are uncorrected. NMR
18 H, 18 H), 3.65-4.35 (overlapped, 28 H), 7.01, 7.14-7.18
1
13
(overlapped, 16 H), 7.65, 8.66, 9.01, 9.24 (br s, 1 H, 2 H, 2 H,
spectra were taken at 250.13 ( H) and 62.9 ( C) MHz, using
Me Si as internal standard. FAB MS measurements were
1 H); 13C NMR (CDCl
, 295 K) δ 30.4, 31.2, 32.2, 32.3 (t), 31.5
4
3
performed at the I.C.T.M.P.-C.N.R. (Catania) using 3-ni-
trobenzyl alcohol as matrix. Elemental analyses were obtained
from the Department of Pharmaceutical Sciences, University
(q), 34.0, 34.3 (s), 69.5, 70.8, 74.1 (t), 124.7, 125.1, 125,5, 125.6,
125.8, 126.2, 127.0 (d), 127.4, 127.5, 127.6, 128.1, 132.7, 133.5,
142.6, 143.4, 143.8, 144.0, 147.4, 147.6, 147.7, 148.2, 148.8,
+
1
C
50.9 (s); FAB(+) MS m/z 1411 (MH) . Anal. Calcd for
94
H
122
O
10: C, 79.96; H, 8.71. Found: C, 79.85; H 8.78.
(
33) Ikeda, A.; Suzuki, Y.; Shinkai, S. Tetrahedron: Asymmetry
998, 9, 97. Geraci, C.; Bottino, A.; Piattelli, M.; Gavuzzo, E.; Neri, P.
J . Chem. Soc., Perkin Trans. 2 2000, 185.
1
(34) Munch, J . H.; Gutsche, C. D. Org. Synth. 1989, 68, 243.

5
150 J . Org. Chem., Vol. 65, No. 17, 2000
Geraci et al.
1
,5-Ca lix[8]cr ow n -4 5
purification by column chromatography (SiO
cyclohexane) white powder (10%), mp 230-233 °C; H NMR
CDCl
4
: procedure A, entry 2, Table 1,
132.3, 132.7, 142.8, 143.1, 143.7, 147.6, 147.6, 147.9, 148.9,
150.5 (s); FAB(+) MS m/z 1499 (MH) . Anal. Calcd for
98 130
C H O12: C, 78.47; H, 8.73. Found: C 78.55; H, 8.78.
+
2
, gradient AcOEt/
1
(
3
, 295 K) δ 1.24, 1.32, 1.35 (s, 36 H, 18 H, 18 H), 3.65-
.35 (overlapped, 28H), 7.12 (d, 8 H, J ) 1.5 Hz), 7.22, 7.29 (s,
H each), 8.99, 9.65 (br s, 4 H, 2 H); C NMR (CDCl , 295 K)
3
δ 26.8, 32.9 (t), 31.4, 31.5, 31.6 (q), 34.0, 34.3 (s), 70.4, 71.9,
5.1 (t), 125.0, 125.5, 126.2, 126.6 (d), 127.1, 127.2, 127.3,
33.1, 143.0, 143.5, 147.9, 148.3, 148.6, 150.1 (s); FAB(+) MS
m/z 1411 (MH) . Anal. Calcd for C94
Found: C, 79.80; H, 8.68.
4
Hexa m eth oxy-1,4-ca lix[8]cr ow n -4 4 a . A mixture of 1,4-
calix[8]crown-4 (70 mg, 0.050 mmol) and NaH (38 mg, 1.6
mmol) in anhydrous THF (30 mL) was refluxed under stirring
4
4
1
3
3
for 30 min. CH I (0.1 mL, 1.6 mmol) was then added, and the
7
1
reaction mixture was refluxed for 30 h. Evaporation under
vacuum left a residue that was suspended in 1 N HCl, collected
by filtration, dried, and purified by column chromatography
+
122
H O10: C, 79.96; H, 8.71.
(
SiO
2
, increasing concentrations of AcOEt in cyclohexane as
a (40 mg, 53%): white powder,
, 295 K) δ 1.06, 1.07, 1.11,
.32 (s, 18 H each), 2.76 (br s, 4 H), 2.80, 2.95 (br t, 4 H each),
.43, 3.54, 3.72 (s, 6 H each), 4.00, 4.03 (br s, 4 H, 12 H), 6.69
1
,5-Ca lix[8]cr ow n -2 5
white powder (88%), purification by column chromatography
SiO , gradient AcOEt/petroleum ether), mp > 280 °C (dec);
H NMR (CDCl , 330 K) δ 1.11, 1.25, 1.33, (s, 18, 18, 36 H),
.81, 3.89 (br s, 8 H each), 5.20 (br s, 4 H), 6.96, 7.12 (s, 4 H
each), 7.17 and 7.19 (AB system, 8 H, J ) 1.5 Hz), 8.62, 8.99
2
: procedure C, entry 3, Table 1,
the eluting system) to give 4
4
1
mp 142-144 °C; H NMR (CDCl
1
3
3
(
2
1
3
3
(
)
7
d, 2 H, J ) 2.2 Hz), 6.82 (d, 2 H, J ) 2.2 Hz), 6.87 (d, 2 H, J
2.3 Hz), 6.98 (d, 2 H, J ) 2.2 Hz), 7.04 (d, 2 H, J ) 2.3 Hz),
.09 (d, 2 H, J ) 2.3 Hz), 7.12 (d, 2 H, J ) 2.4 Hz), 7.22 (d, 2
1
3
(
s, 4 H, 2 H); C NMR (CDCl
2.3 (t), 34.0, (s), 70.9 (t), 125.7, 126.5, (d), 127.3, 128.2, 133.0,
43.4, 149.0, 151.6, 152.6 (s); FAB(+) MS m/z 1345 (MNa) .
Anal. Calcd for C90
H, 8.72.
3
, 330 K) δ 31.1, 31.5, 31.7 (q),
3
1
+
H, J ) 2.4 Hz); FAB(+) MS m/z 1495 (MH) . Anal. Calcd for
C
+
100
H
134
O
10: C, 80.28, H, 9.03. Found: C, 80.06; H 9.00.
Gen er a l P r oced u r e for Ben zyla tion of Ca lix[8]cr ow n s.
CO (400 mg, 1.23 mmol) was added to a suspension of the
CO (30
114 8
H O : C, 81.71; H, 8.68. Found: C, 81.35;
Cs
2
3
1
,5-Ca lix[8]cr ow n -3 5
3
: procedure C, entry 4, Table 1,
calix[8]crown-4 of choice (50 mg, 0.035 mmol) in Me
2
white powder (78%), purification by column chromatography
mL), and the mixture was stirred under reflux for 20 min.
Then, a solution of 4-(tert-butyl)benzyl bromide (0.052 mL,
1
(
SiO
2
, gradient AcOEt/cyclohexane), mp > 280 °C (dec); H
, 330 K) δ 1.12, 1.29, 1.31, (s, 18, 36, 18 H), 3.83
br s, 8 H), 3.95, 4.27 (br t, 4 H each), 4.67 (br s, 8 H), 7.00 (s,
NMR (CDCl
3
0
2
.283 mmol) in Me CO (2 mL) was added, and stirring was
(
4
maintained under reflux for 22 h. The solvent was evaporated
under vacuum, and the residue was suspended in 1 N HCl
H), 7.09, 7.17 (AB system, 4 H each, J ) 2.2 Hz) 7.21 (s, 4
H), 7.17 and 7.19 (AB system, 8 H, J ) 1.5 Hz), 8.57, 8.65 (s,
(
50 mL), collected by filtration, dried, and purified by prepara-
tive TLC (silica gel plates Kieselgel 60 F254, 1 mm, Merck, CH
Cl /petroleum ether 7:13).
H exa k is(p -ter t-b u t ylb en zyl)-1,2-ca lix[8]cr ow n -4 2
1
3
2
3
1
1
3
H, 4 H); C NMR (CDCl , 295 K) δ 31.2, 32.4 (t), 31.5 (q),
2
-
3.9, 34.2 (s), 69.7, 74.7 (t), 125.3, 125.4, 125.9, 127.0 (d), 143.1,
2
43.8, 147.7, 148.1, 148.1, 148.9, 149.4 (s); FAB(+) MS m/z
367 (MH) . Anal. Calcd for C92
+
4
b :
, 325
K) δ 0.90, 0.97, 1.06, 1.15, 1.25, 1.29, 1.31 (s, 18 H each), 2.76
br s, 8 H), 3.15 (br t, 4 H), 4.01, 4.06, 4.12, 4.13, 4.14 (s, 2 H,
2 H, 4 H, 4 H, 4 H), 4.64, 4.76, 4.82 (s, 4 H each), 6.7-7.6
overlapped, 40 H); 13C NMR (CDCl
, 295 K) δ 28.2, 29.1, 29.7,
0.7 (t), 31.4 (q), 34.1, 34.4 (s), 69.3, 70.4, 72.3, 74.5, 74.8, 77.2
t), 125.2, 125.7, 126.3, 127.1, 127.3, 128.1(d), 132.3, 133.1,
33.3, 133.4, 133.42, 133.6, 133.7, 134.7, 145.1, 145.9, 146.3,
150.5, 150.6, 152.5, 152.7, 152.8, 153.3 (s); FAB(+) MS m/z
118 9
H O : C, 80.78; H, 8.69.
1
white powder (42%), mp 158-162 °C; H NMR (CDCl
3
Found: C, 80.55; H, 8.62.
,4-Ca lix[8]cr ow n -4 4
purification by column chromatography (SiO
cyclohexane) white powder (46%), mp 229-232 °C; H NMR
CD CO, 295 K) δ 1.17, 1.97, 1.22, 1.25 (s, 18 H each), 3.70-
1
4
: procedure B, entry 7, Table 1,
, gradient AcOEt/
(
2
1
(
3
(
1
3
(
3 2
)
4
.10 (overlapped, 28 H), 7.06 (d, 2 H, J ) 2,2 Hz), 7.12 (d, 2 H,
J ) 2.2 Hz), 7.16 (d, 2 H, J ) 2.4 Hz), 7.18 (d, 2 H, J ) 2.3
Hz), 7.28 (d, 2 H, J ) 2.0 Hz), 7.30 (d, 2 H, J ) 2.5 Hz), 7.34
1
(
d, 2 H, J ) 2.3 Hz), 8.35, 8.85, 9.05 (br s, 2 H each); H NMR
+
2
287 (MH) . Anal. Calcd for C160
Found: C, 83.70; H 9.10.
H exa k is(p -ter t-b u t ylb en zyl)-1,3-ca lix[8]cr ow n -4 3 b :
206
H O10: C, 83.94; H, 9.07.
(C
6
D
6
, 307 K) δ 1.20, 1.25 (s, 18 H each), 1.26, (s, 36 H), 3.82,
3
4
3
7
.85, 3.87 (br s, 4 H, 2 H, 6 H), 3.97, 4.04, 4.08 (br s, 8 H, 4 H,
1
3
H), 7.10-7.30 (overlapped, 16 H); C NMR (C
0.5, 31.2, 32.4, 32.6, 32.8 (t), 31.5, 31.8 (q), 34.1, 34.4 (s), 70.5,
1.5, 75.1 (t), 125.1, 125.7, 126.0, 126.3, 126.6, 127.0, 128.3
6
D
6
, 307 K) δ
4
1
white powder (72%), mp > 280 °C (dec); H NMR (CDCl
K) δ 0.70, 0.86, 1.00, 1.19, 1.26, 1.31, 1.32, 1.35, 1.37 (s, 9 H,
H, 18 H, 18 H, 18 H, 9 H, 9 H, 18 H, 18 H), 2.40, 2.61, 2.65,
2.77 (m, 12 H), 3.67 and 4.64 (AX system, 4 H, J ) 16.6 Hz),
.68 and 4.67 (AX system, 4 H, J ) 16.6 Hz), 3.78 and 4.74
3
, 320
9
(
1
d), 129.1, 133.4, 133.6, 143.0, 143.4, 144.0, 147.9, 148.5, 149.3,
+
49.7, 151.5 (s); FAB(+) MS 1411 (MH) . Anal. Calcd for
10: C, 79.96; H; 8.71. Found: C, 79.89, H, 8.62.
,4-Ca lix[8]cr ow n -5 4 : procedure B, entry 8, Table 1,
purification by column chromatography (SiO , gradient AcOEt/
cyclohexane), white powder (31%), mp 197-199 °C; H NMR
CDCl , 306 K) δ 1.24, 1.28, 1.32, 1.34 (s, 18 H each), 3.84 (br
s, 8 H), 3.91, 3.94 (s, 2 H each), 3.95, 4.01, 4.11 (s, 4 H each),
3
(
94 122
C H O
1
AX system, 4 H, J ) 15.1 Hz), 4.00 and 4.40 (AB system, 4
5
H, J ) 16.1), 4.98, 5.03 (s, 12 H), 6.59 (s, 2 H), 6.66 (s, 2 H),
2
1
6.80 and 7.07 (AX system, 4 H, J ) 2.0 Hz), 7.04 (d, 2 H, J )
2
.2 Hz), 7.10-7.60 (overlapped, 30 H); 13C NMR (CDCl
, 295
3
(
3
K) δ 29.2, 29.9, 30.1 (t), 31.4, 31.5 (q), 34.0, 34.3, 34.5, 34.6
(
s), 68.8, 72.9, 73.2, 74.0, 74.7 (t), 122.7, 123.6, 123.8, 124.6,
4
2
2
8
3
7
1
1
.13, 4.36 (br t, 4 H each), 7.06 (d, 2 H, J ) 2.2 Hz), 7.14 (d,
H, J ) 2.3 Hz), 7.17 (d, 4 H, J ) 2.1 Hz), 7.20 (d, 4 H, J )
.3 Hz), 7.21 (d, 2 H, J ) 2.4 Hz), 7.23 (d, 2 H, J ) 2.4 Hz),
1
1
25.2, 125.3, 127.1, 127.5, 127.6, 127.8, 128.0, 128.2, 128.8 (d),
31.5, 132.5, 132.7, 133.0, 133.5, 134.0, 134.1, 134.3, 134.7,
.20, 9.04, 9.73 (br s, 2 H each); 13C NMR (CDCl3, 306 K) δ
135.3, 145.3, 145.5, 146.0, 146.1, 146.2, 150.7, 150.8, 151.9,
+
1
52.7, 152.8, 153.0, 154.3 (s); FAB(+) MS m/z 2287 (MH) .
0.6, 30.9, 31.7, 31.9, 32.8 (t), 31.3, 31.6 (q), 34.0, 34.3 (s) 70.1,
1.0, 71.5, 74.9 (t), 125.3, 125.7, 125.9, 126.2, 126.3, 126.4 (d),
26.5, 126.9, 127.1, 127.4, 127.7, 132.4, 132.9, 142.9, 143.0,
Anal. Calcd for C160
H 9.01.
206
H O10: C, 83.94; H, 9.07. Found: C 83.81,
43.7, 147.9, 148.0, 148.8, 150.2 (s); FAB(+) MS m/z 1455
MH) . Anal. Calcd for C96
C, 79.30, H, 8.73.
H exa k is(p -ter t-b u t ylb en zyl)-1,4-ca lix[8]cr ow n -4 4
4
b :
+
1
(
H
126
O
11: C, 79.18; H, 8.72. Found:
white powder (43%), mp 164-168 °C; H NMR (CDCl
3
, 324
K) δ 0.97, 1.06, 1.09, 1.26, 1.32, 1.33, 1.36 (s, 18 H each), 2.05,
2.24, 2.28, 2.36 (m, 2 H each), 2.73 (br t, 4 H), 3.42 and 4.96
(AX system, 2 H, J ) 14.4 Hz), 3.67 and 4.47 (AX system, 4 H
J ) 17.1 Hz), 3.75 and 4.45 (AX system, 4 H, J ) 16.5 Hz),
3.93 and 4.30 (AB system, 2 H, J ) 15.4 Hz), 4.60 and 4.68
(AB system, 4 H, J ) 11.2 Hz), 4.87, 4.89, 4.76 (s, 4 H each),
1
,4-Ca lix[8]cr ow n -6 4
6
: procedure B, entry 9, Table 1,
, gradient AcOEt/
cyclohexane), white powder (25%); H NMR (CDCl , 293 K) δ
.18, 1.23, 1.27, 1.28 (s, 18 H each), 3.69 (br s, 4 H), 3.77, 3.83
purification by column chromatography (SiO
2
1
3
1
(
(
m, 4 H each), 3.86, 3.90, 4.00, 4.10 (br s, 4 H each), 4.11, 4.26
m, 4 H each), 7.00 (d, 2 H, J ) 1.9 Hz), 7.08 (d, 2 H, J ) 2.5
6.5-7.5 (overlapped, 40 H); 13C NMR (CDCl
, 295 K) δ 27.6,
3
Hz), 7.14-7.23 (overlapped, 12 H), 8.36, 9.14, 9.83 (br s, 2 H
29.1, 30.3 (t), 31.4, 31.6 (q), 34.06, 34.1, 34.2, 34.4, 34.5 (s),
69.1, 72.3, 74.5, 74.3 (t), 123.8, 125.0, 125.2, 125.3, 125.6, 125.9,
127.8, 128.1, 128.2 (d), 132.0, 132.1, 132.6, 133.1, 133.6, 134.0,
134.4, 134.5, 134.8, 145.3, 145.9, 150.1, 150.5, 150.7, 152.2,
1
3
each); C NMR (CDCl
3
, 306 K) δ 30.7, 31.2, 32.7 (t), 31.3, 31.5
(
1
q), 34.0, 34.3 (s), 70.7, 70.8, 71.8, 75,0 (t), 125.2, 125.6, 125.7,
25.9, 126.2, 126.4 (d), 126.6, 126.9, 127.1, 127.3, 127.6, 128.7,

Singly-Bridged Calix[8]crowns
J . Org. Chem., Vol. 65, No. 17, 2000 5151
+
1
52.5, 152.7, 154.0 (s); FAB(+) MS 2287 (MH) . Anal. Calcd
10: C, 83.94; H, 9.07. Found: C, 83.89; H 9.10.
(I.C.T.M.P., C.N.R., Catania) for FAB MS measure-
ments and to Mrs. C. Rocco (I.S.S.N., C.N.R., Valverde)
for NMR spectra acquisition.
for C160
206
H O
Ack n ow led gm en t. Financial support from the ital-
ian MURST (Supramolecular Devices Project) is grate-
fully acknowledged. Thanks are due to Mr. R. Rapisardi
J O0002036