Synthesis and conformational studies on hexa-O-alkyl p-unsubstituted calix[6]arenes

Article abstract of DOI:10.1021/jo0516638

In this article we describe the selective O-benzylation of para-unsubstituted calix[6]arene 1 in rings 1 and 4 (2a-c) and the subsequent alkylation of phenol groups with a-haloesters (methyl esters 3a, 3c, and 3e; tert-butyl esters 3b, 3d, and 3f) to determine the effect of these groups on their conformational behavior. 2D NMR studies at 188 K reveal that compounds 2a-c, 3b, 3d, and 3f are less flexible, showing a 1,2,3-alternate conformation. The same conformation has been observed in the solid state.

Full text of DOI:10.1021/jo0516638

Synthesis and Conformational Studies on Hexa-O-alkyl
p-Unsubstituted Calix[6]arenes
Jose´ C. Iglesias-Sa´nchez,† Beatriz Souto,† Ce´sar J. Pastor,† Javier de Mendoza,*,†,‡ and
Pilar Prados*,†
Departamento de Quı´mica Orga´nica and Servicio Interdepartamental de Investigacio´n (SIdI),
Universidad Auto´noma de Madrid, Cantoblanco, E-28049 Madrid, Spain, and
Institute of Chemical Research of Catalonia (ICIQ), E-43007 Tarragona, Spain
jmendoza@iciq.es
Received August 8, 2005
In this article we describe the selective O-benzylation of para-unsubstituted calix[6]arene 1 in rings
1 and 4 (2a-c) and the subsequent alkylation of phenol groups with R-haloesters (methyl esters
3a, 3c, and 3e; tert-butyl esters 3b, 3d, and 3f) to determine the effect of these groups on their
conformational behavior. 2D NMR studies at 188 K reveal that compounds 2a-c, 3b, 3d, and 3f
are less flexible, showing a 1,2,3-alternate conformation. The same conformation has been observed
in the solid state.
Introduction
groups larger than ethyl to the phenol OHs at the narrow
rim,3 conformational restriction by O-alkylation has
proven more difficult for larger cyclic oligomers, although
several conformationally restricted O-functionalized p-tert-
butylcalix[6]arenes have been reported. For instance,
mono-O-benzylation causes a slow inversion of the ring,
due to the simultaneous presence of the substituent and
the hydrogen-bonded network arising from the remaining
five OH groups which prevents rotation of the ring from
either side.4 This is also observed for 1,4-di- and 1,2,4,5-
tetra-O-benzyl derivatives.5 Another strategy to restrict
cone-cone inversion is based on bridging several phenol
rings by suitable linkers.6
Calixarenes constitute useful platforms to anchor
functional groups for molecular recognition, catalysis, and
capsule formation through self-assembly.1 However, to
fully benefit from these capabilities the flexibility of these
macrocycles should be restrained or “frozen” into the
cavity-shaped cone conformation.2 While this is easily
achieved in cyclic tetramers by simply attaching alkyl
* To whom correspondence should be addressed. Phone: +34-
977920220. Fax: +34-977920226.
† Universidad Auto´noma de Madrid.
‡ Institute of Chemical Research of Catalonia (ICIQ).
(1) (a) Pochini, A.; Ungaro, R. In Comprehensive Supramolecular
Chemistry; Atwood, J. L., Davis, J. E. D., MacNicol, D. D., Vo¨gtle, F.,
Eds.; Pergamon Press: New York, 1996; Vol. 2. (b) de Namor, A. F.
D.; Cleverly, R. M.; Zapata-Ormachea, M. L. Chem. Rev. 1998, 98,
2495-2525. (c) Hof, F.; Craig, S. L.; Nuckllos, C.; Rebek, J., Jr. Angew.
Chem., Int. Ed. 2002, 41, 1488-1508. (d) Rudkevich, D. M. Angew.
Chem., Int. Ed. 2004, 43, 558-571.
p-Unsubstituted calix[6]arenes are far more flexible
than their p-tert-butyl homologues. This is clearly ob-
(3) Shinkai, S. Tetrahedron 1993, 49, 8933-8968.
(4) Magrans, J. O.; Rinco´n, A. M.; Cuevas, F.; Lo´pez-Prados, J.;
Nieto, P. M.; Pons, M.; Prados, P.; de Mendoza, J. J. Org. Chem. 1998,
63, 1079-1085.
(5) (a) Kanamathareddy, S.; Gutsche, C. D. J. Org. Chem. 1992, 57,
3160-3166. (b) Numbers 1-6 refer to the corresponding phenol
positions.
(6) Chen, Y.; Gong, S. J. Inclusion Phenom. Macrocyclic Chem. 2003,
45, 165-184 and references therein.
(2) (a) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713-745.
(b) Gutsche, C. D. Calixarenes Revisited; The Royal Society of Chem-
istry: Cambridge, U.K., 1998. (c) Sansone, F.; Segura, M.; Ungaro, R.
In Calixarenes 2001; Asfari, Z., Bo¨hmer, V., Harrowfield, J., Vicens,
J., Eds.; Kluwer Academic Publishers: Dordrecht, The Netherlands,
2001; pp 496-512.
10.1021/jo0516638 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/16/2005
10400
J. Org. Chem. 2005, 70, 10400-10407

Hexa-O-alkyl p-Unsubstituted Calix[6]arenes
FIGURE 1. 1H NMR spectra (CDCl3, 298 K) of (a) compounds 3a, 3c, and 3e (4 ) O-CH2-C6H4-R(p); 0 ) ArCH2Ar; O )
O-CH2CO2Me) and (b) compounds 3b, 3d, and 3f (4 ) O-CH2-C6H4-R(p); 0 ) ArCH2Ar; O ) O-CH2CO2tBu).
served by 1H NMR, where protons of methylene bridges
linking the aryl rings (ArCH2Ar) are observed as sin-
glets.7 The conformation can only be restrained by
bridging.8 To the best of our knowledge, only one example
of an hexa-O-(diethoxyphosphoryloxy)calix[6]arene, which
shows a partially rigid structure at -68 °C in d6-acetone,
has been reported so far.9
In this work, we describe the selective O-benzylation
of p-unsubstituted calix[6]arene 1 at rings 1 and 4
(compounds 2a-c) and the subsequent alkylation of the
remaining phenols with R-haloesters of different steric
hindrance (methyl esters 3a, 3c, and 3e; tert-butyl esters
3b, 3d, and 3f) to determine the effect of these groups
on the restriction of the conformational equilibrium. Both
1D and 2D NMR spectroscopic methods were employed
to determine the preferred conformations. X-ray diffrac-
tion structures for compounds 3a, 3b, and 3d provided
additional support to our studies in solution.
Results and Discussion
Synthesis. Di-O-alkylation of calix[6]arene 1 was
performed under the conditions described for p-tert-
butylcalix[6]arene,5a that is, KOSiMe3 and the corre-
sponding p-substituted benzyl derivative (6 mol equiv)
in THF/DMF (9:1), to afford derivatives 2a-c in 78-89%
yields. Alkylation of the remaining phenol positions was
achieved with potassium carbonate and the correspond-
ing R-haloester,7 giving rise to compounds 3a-f in
73-80% yields.
(7) Nam, K. C.; Kang, S. O.; Lee, K. H.; Jeon, S.; Cho, H. J.; Chang,
S.-K. Bull. Korean Chem. Soc. 1998, 19, 279-281.
(8) (a) Nam, K. C.; Choi, Y. J.; Kim, D. S.; Kim, J. M.; Chun, J. C.
Conformational Study. 1H NMR spectra of com-
pounds 2a-3f in CDCl3 at room temperature reveal a
flexible structure for all of them. Methylene (ArCH2Ar)
calixarene protons are displayed as two singlets, account-
ing for a rapid interconversion of the macrocycle. Indeed,
J. Org. Chem. 1997, 62, 6441-6443. (b) Ko, S. W.; Lee, S. H.; Park,
K.-M.; Lee, S. S.; Nam, K. C. Supramol. Chem. 2003, 15, 117-125.
(9) Markovsky, L. N.; Kalchenko, V. I.; Vysotsky, M. A.; Pirozhenko,
V. V.; Simonov, Y. A.; Dvorkin, A. A.; Iatsenko, A. V.; Lipkowski, J.
Supramol. Chem. 1997, 8, 85-91.
J. Org. Chem, Vol. 70, No. 25, 2005 10401

Iglesias-Sa´nchez et al.
TABLE 1. Comparative Study of the Methylene
ppm (p-bromo 3c or p-iodobenzyl 3e, respectively) (Figure
1a). Shielding is more pronounced in bulkier esters, such
as 3b, 3d, and 3f: 4.10 ppm for p-tolylmethyl derivative
3b but 3.48 ppm for bromo and iodo derivatives 3d and
3f. Thus, tert-butyl esters induce a 0.7 ppm upfield shift
with respect to the methyl ester analogues (Figure 1b).
The above results seem to indicate that bulk O-benzyl
p-substituents and bulky esters cause a substantial
degree of congestion at the calixarene narrow rim, forcing
the benzyl methylene groups to get inside the cavity,
which explains the unusual NMR shielding. On the other
hand, 13C NMR spectra and HMQC experiments for
2a-3f showed two signals around 30 ppm for the
methylene carbons (ArCH2Ar), which accounts for an
equilibrium between two cone conformations (Table 1).10
Above room temperature (C2D2Cl4, 393 K), all 1H NMR
signals are sharp for 3a and 3d. Methylene (ArCH2Ar)
protons appear as two singlets, and benzyl (OCH2Ar) pro-
tons of 3a do not show any significant shift with respect
to the spectrum at room temperature. On the contrary,
the OCH2Ar protons of compound 3d are deshielded by
0.5 ppm (δ ) 4.03 ppm) with respect to room tempera-
(ArCH2Ar) 13C NMR Data of Compounds 2a-3f and 5a
chemical shifts (ppm)
compound
CDCl3 (293 K)
CD2Cl2 (188 K)
2a
2b
2c
3a
3b
3c
3d
3e
3f
31.5, 31.7
31.6, 31.8
31.6, 31.8
29.7, 31.0
30.8, 31.2
29.7, 30.6
29.7, 30.2
29.7, 30.6
29.7, 30.2
29.6, 30.8
29.5, 32.3
30.0, 33.0
28.3, 30.2
28.1, 30.8
27.1, 30.8
29.1, 31.6
30.0, 33.0
5aa
a Data for this compound were obtained at 248 K.
some differences in the chemical shifts are observed,
depending on the substitution. For methyl esters 3a,
3c, and 3e, methylene protons of benzyl substituents
[O-CH2-C6H4-R(p)] are increasingly shielded as the
size of the para-substituent also increases. For example,
it shifts from 4.79 ppm (p-tolylmethyl 3a) to 4.15 and 4.20
FIGURE 2. 1H NMR spectra (CD2Cl2) of (a) compound 3a (4 ) O-CH2-C6H4-R(p); 0 ) ArCH2Ar; O ) O-CH2CO2Me) and (b)
compound 3d (4 ) O-CH2-C6H4-R(p); 0 ) ArCH2Ar; O ) O-CH2CO2tBu).
TABLE 2. 1H NMR Dataa (CD2Cl2, 188 K) of Compounds 2a,b, 3a-d, 3f, and 5a
chemical shifts (ppm)
compound
ArHb
ArCH2Ar
CH2CO2R
OCH2Ar
4.99
CO2Me
CO2tBu
2a
para (2)
meta (3)
para (2)
meta (3)
para (3)
meta (5)
3.82-3.49 (AB)
3.46 (s)
2b
3a
3.61-3.84 (AB)
3.53 (s)
4.85
4.89
4.32-3.43 (o)c
4.12-3.43
4.76-4.32
2.68-2.45
3.82
2.26
3.81-3.75 (*)c
4.33-3.43 (AB)
3.85 (s)
3b
3c
3d
3f
para (2)
meta (3)
para (2)
meta (3)
para (2)
meta (3)
para (2)
meta (3)
meta (6)
4.62-4.15
4.69-4.36
4.58-4.15
4.60-4.18
2.86
2.67
2.64
2.77
4.89
1.51
4.32-3.39 (AB)
3.77 (s)
2.25
4.32-3.42 (AB)
3.79 (s)
1.48
1.51
4.33-3.43 (AB)
3.84 (s)
5a
4.57-3.52 (o)
4.57-3.38
4.50-4.36
3.92-3.45
3.83
2.19
3.95-3.87 (*)
a Protons were assigned by COSY and HMQC experiments. b Number of signals in parentheses. c Exchangeable protons in the ROESY
experiment (see text).
10402 J. Org. Chem., Vol. 70, No. 25, 2005

Hexa-O-alkyl p-Unsubstituted Calix[6]arenes
FIGURE 3. (a) Most significant ROE contacts in compound 3a. (b) Schematic representation of the equilibrium between several
1,2,3-alternate conformations (A/A′ and B/B′) of compound 3a.
ture. This indicates that, despite a rapid cone-cone
inversion in both cases, the tert-butyl ester derivative has
a different behavior than the methyl ester analogue 3a.
Moreover, at 188 K, 1H NMR spectra of compound 3a
are different from those of the other derivatives. Three
AB systems are observed for the calixarene methylene
bridges (ArCH2Ar) in 1:1:1 ratio, as well as eight signals
for the aromatic protons. Remarkably, signals corre-
sponding to one of the CH2CO2Me chains are strongly
shielded, a sign of inclusion of this leg into the cavity.
On the contrary, O-CH2Ar signals do not move. In the
tert-butyl ester series (3b, 3d, and 3f), the calixarene
ArCH2Ar signals appear as an AB system and a singlet
(2:1 ratio) and only five signals for the aromatic protons
are observed. On the other hand, the OCH2CO2R signals
At low temperatures (CD2Cl2), the distinct behavior of
tert-butyl and methyl esters was again observed. Whereas
derivatives 3a, 3c, and 3e coalesced at 233 K, compounds
2a-c, 3b, 3d, and 3f did it at a slightly higher temper-
ature, namely around 243 K. Below these coalescence
temperatures, compounds 3a, 3c, and 3e showed well-
defined spectra only at 188 K, whereas signals for
2a-c, 3b, 3d, and 3f were sharp at 213 K or below this
temperature (Figure 2).
J. Org. Chem, Vol. 70, No. 25, 2005 10403

Iglesias-Sa´nchez et al.
are at their expected position and the benzyl methylenes
(OCH2Ar) are abnormally shielded, indicating their
1
inclusion (Table 2). In the H NMR spectra of methyl
esters 3c and 3e, two conformations are observed, the
majority one showing a signal pattern similar to that
found for compounds 3b, 3d, and 3f, while the minority
one presents a signal pattern similar to that of 3a.
Finally, for compounds 2a-c, benzyl protons do not shift
significantly at room or at low temperature. These results
indicate that compound 3a is in a conformation display-
ing only one element of symmetry, whereas two sym-
metry elements are present in 2a-c and 3b-f (Table 2).
To have a better insight into the conformation of these
p-unsubstituted calix[6]arenes, 2D NMR experiments
(HMQC and ROESY) were performed at 188 K on
compounds 2a, 3a, and 3f. In the HMQC spectrum of 3a
three signals are visible for the calixarene methylene
bridges, which correspond to the two AB systems in the
1H NMR spectrum (see Table 1); two at ca. 30 ppm and
the other at ca. 33 ppm. In compound 3f, these carbon
signals are present at ca. 30 ppm (which correlates with
the AB system) and ca. 32 ppm (which correlates with
the singlet). Compared to the spectra at room tempera-
ture, one carbon is not affected whereas the other is
shifted downfield. Although the observed values (ca. 32
or 33 ppm) are away from the 37 ppm standard shift to
confirm an anti arrangement of the bridged aromatic
rings,10 it has been reported (for calix[4]arenes) that large
deviations from the usual 31 and 37 ppm values for
“pure” syn or anti arrangements, respectively, may be
interpreted either as a distorted conformation or as a fast
equilibrium between syn and anti forms.11
FIGURE 4. (a) Most significant ROE contacts in compound
3f. (b) Schematic representation of the equilibrium between
two identical 1,2,3-alternate conformations (A and A′) of
compound 3f.
A ROESY experiment on compound 3a (188 K,
CD2Cl2) revealed exchange peaks between similar pro-
tons, involving axial and equatorial protons of each AB
system, but also between the protons of the system at
3.75-3.81 ppm and the protons of the one at 3.43-4.32
ppm. Considering the symmetry of the compound (inver-
sion center) and the observed ROESY peaks (Figure 3a),
we can conclude that an equilibrium between several
1,2,3-alternate conformations of lower symmetry operates
as a result of the inclusion from the two opposite rings
carrying ester groups that are more shielded and close
to the AB system at 3.75-3.81 ppm (H* in Figure 3b).
This accounts for the exchanges observed between H*
and H° in the ROESY spectrum (Table 2) and the fact
that the 13C NMR chemical shift for one of the methylene
carbons lies midway between syn and anti conformations
(Table 1).
Compound 3f, given its symmetry, could be either in
a 1,2,3- or in a 1,4-alternate conformation. ROE contacts
between H3 and H4 protons with the tert-butyl group of
the ester and with the CH2 of the benzyl group rule out
the latter structure and indeed point to the symmetric
1,2,3-alternate conformation (Figure 4a).
Exchange between axial and equatorial positions of the
AB system, as well as between OCH2CO2R protons,
indicates exchange between the two identical 1,2,3-
alternate conformations, even at 188 K (Figure 4b). The
inversion occurs at the methylene carbon showing a
singlet in the 1H NMR (H*), as the result of the inclusion
of the aromatic ring carrying a benzyl inside the cavity.
This fact would justify the 13C NMR midway position of
the signal between anti and syn orientations.
To verify if this behavior was a consequence of the lack
of a substituent in the para positions, we tried to pre-
pare the tert-butyl analogues of compounds 3a and 3f,
namely 5a and 5b. O-Alkylation of 45a with methyl
R-bromoacetate, under the conditions described above,
afforded 4a in 90% yield. However, we were unable to
prepare 5b under the same and various other conditions,
probably due to the steric hindrance of the alkylating
agent.
Coalescence was observed at room temperature in the
1H NMR spectrum of 5a in CD2Cl2 for all signals but the
OBn residue, although a pattern similar to compound 3a
resulted at 248 K (Tables 1 and 2). The ROESY spectrum
at 248 K is also similar to 3a (i.e., exchange between axial
and equatorial protons AB calixarene systems; Figure 3).
Therefore, we could conclude that the differences in the
conformation of 3a or 3f are not due to the higher
flexibility of the former, lacking bulky tert-butyl groups
in para positions, but to the steric congestion created at
the lower rim of the calixarene, depending on the size of
the ester. The different behavior observed for 3a with
respect to the rest of the methyl esters (3c and 3e), in
which the benzyl group is located inside the cavity, could
be attributed to electronic effects caused by the para
substituent of the benzyl residue (Br or I).
(10) (a) For the 13C NMR rule in calix[4]arenes, see: Jaime, C.; de
Mendoza, J.; Prados, P.; Nieto, P. M.; Sa´nchez, C. J. Org. Chem. 1991,
56, 3372-3376. (b) Kanamathareddy, S.; Gutsche, C. D. J. Org. Chem.
1994, 59, 3871-3879.
(11) Magrans, J. O.; de Mendoza, J.; Pons, M.; Prados, P. J. Org.
Chem. 1997, 62, 4518-4520.
10404 J. Org. Chem., Vol. 70, No. 25, 2005

Hexa-O-alkyl p-Unsubstituted Calix[6]arenes
FIGURE 5. X-ray structure of compound 3a. Hydrogen atoms have been omitted for clarity. Displacement ellipsoids are drawn
at the 50% probability level.
X-ray crystal structures of p-tert-butylcalix[6]arenes
have been reported under three different conforma-
tions: “pinched cone”,12a-d “1,2,3-alternate”,12e and “1,2,4,5-
alternate”.13 Unfortunately, most of the scarce structures
published for unsubstituted calix[6]arenes refer to metal
complexes of their anions, displaying flattened cone14 or
1,2,3-alternate conformations,14a bis-crowned derivatives
in cone,15 1,2,3-16 or 1,4-alternate conformations,17 or a
mono-O-substituted calix[6]arene in cone conformation.18
Single crystals of 3a, 3b, and 3d were obtained from
chloroform/methanol. Crystals of 3d were of poorer
quality than those of 3a or 3b due to difficulties in
crystallization, which resulted in twinned crystals of low
diffraction intensity. However, the goodness-of-fit on F2
was 1.049, indicating a correct resolution, although the
R values were slightly high probably due to the thermal
vibration of the lateral chain involving the ester group.
In the solid state, compounds 3a, 3b, and 3d display
1,2,3-alternate conformations in all cases, in agreement
with our studies in solution at low temperature (Figure
5, see Supporting Information). The structures of the
three compounds are very similar, with torsion angles
for the rings accounting for a u,u,u,d,d,d conformation.19
The only significant difference was the dihedral angle
between the calixarene aromatic ring endowed with
O-benzyl and the substituents themselves [151.3(2) for
3a; -172.78(14) for 3b; and -179.9(4) for 3d].
Conclusions
1
The H NMR studies performed at room temperature
have shown a high conformational flexibility for all the
calix[6]arenes synthesized. Nevertheless, at low temper-
atures, the 1,4-di-O-benzyl calix[6]arenes endowed with
groups in para positions (methyl, bromo, or iodo) of the
pending sidearms, and O-alkylated with R-haloesters in
the remaining phenols (3a-f), possess less conforma-
tional mobility, showing a 1,2,3-alternate conformation
both in the solid state and in solution. To the best of our
knowledge, these constitute the first examples of this
kind of calix[6]arenes where the conformational equilib-
rium has been partly restricted.
Experimental Section
General Procedure A. 1,4-Di-O-alkylation. To a solution
of 1 (200 mg, 0.31 mmol) in anhydrous THF (90 mL) and DMF
(10 mL) was added KOMe3Si (239 mg, 1.86 mmol), and the
reaction was cooled to 0 °C for 15 min. A solution of the
corresponding halide (1.86 mmol) in THF (10 mL) was added,
and the mixture was stirred at room temperature for 4 h. The
solvent was removed under reduced pressure, and the residue
was triturated with 1 N HCl, affording a solid that was filtered.
The crude product was purified by crystallization with CHCl3/
MeOH (3:1).
37,40-Bis[(4-methylbenzyl)oxy]-38,39,41,42-tetra-
hydroxycalix[6]arene (2a). This compound was prepared
(227 mg, 87%) by general procedure A, from 1 and 4-methyl-
benzyl bromide (348 mg). mp 136-138 °C; 1H NMR (500 MHz,
CDCl3) δ 2.34 (s, 6H, CH3), 3.80 (s, 4H, ArCH2Ar), 3.95 (s, 8H,
ArCH2Ar), 5.02 (s, 4H, OCH2Ar), 6.76 (t, J ) 7.5 Hz, 4H, ArH),
6.99-7.06 (m, 18H, ArH), 7.26 (d, J ) 7.9 Hz, 4H, ArH), 8.05
(s, 4H, OH); 13C NMR (125 MHz, CDCl3, DEPT) δ 21.3 (CH3),
31.5, 31.7 (ArCH2Ar), 77.6 (OCH2Ar), 120.2, 125.7, 128.4,
128.7, 129.0, 129.2, 129.4 (ArCH), 127.0, 127.4, 132.4, 133.4,
138.4, 151.8, 152.6 (ArC); MALDI-TOF MS m/z 845.3 [M +
H]+, 867.3 [M + Na]+, 889.3 [M + K]+. Anal. Calcd for
C58H52O6‚2CHCl3: C, 66.49; H, 5.02. Found: C, 66.09; H, 5.12.
(12) (a) Andreetti, G. D.; Calestani, G.; Ugozzoli, F.; Arduini, A.;
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J. Org. Chem, Vol. 70, No. 25, 2005 10405

Iglesias-Sa´nchez et al.
37,40-Bis[(4-bromobenzyl)oxy]-38,39,41,42-tetra-
hydroxycalix[6]arene (2b). This compound was prepared
(269 mg, 89%) by general procedure A, from 1 and 4-bro-
37,40-Bis[(4-bromobenzyl)oxy]-38,39,41,42-tetrakis-
[(methoxycarbonylmethyl)oxy]calix[6]arene (3c). This
compound was prepared (555 mg, 80%) by general procedure
B, from 2b (500 mg) and methyl bromoacetate (0.4 mL). mp
203-205 °C; 1H NMR (500 MHz, CDCl3) δ 3.62 (s, 12H, OCH3),
3.99 (s, 12H, ArCH2Ar), 4.15 (s, 4H, OCH2Ar), 4.21 (s, 8H,
OCH2CO), 6.73 (t, J ) 7.4 Hz, 4H, ArH), 6.81 (d, J ) 7.4 Hz,
4H, ArH), 6.88 (t, J ) 7.4 Hz, 2H, ArH), 7.01 (d, J ) 7.2 Hz,
4H, ArH), 7.02 (d, J ) 8.1 Hz, 4H, ArH), 7.10 (d, J ) 7.4 Hz,
4H, ArH), 7.38 (d, J ) 8.1 Hz, 4H, ArH); 13C NMR (125 MHz,
CDCl3, DEPT) δ 29.7, 30.6 (ArCH2Ar), 51.9 (OCH3), 69.7
(OCH2CO), 73.5 (OCH2Ar), 124.0, 124.6, 128.8, 129.5, 129.6,
129.8, 131.4 (ArCH), 121.4, 133.67, 133.76, 133.79, 136.5,
154.4, 154.7 (ArC), 169.5 (CO); MALDI-TOF MS m/z 1283.1
[M + Na]+, 1299.1 [M + K]+. Anal. Calcd for C68H62Br2O14‚
2MeOH: C, 63.35; H, 5.32. Found: C, 63.15; H, 5.51.
37,40-Bis[(4-bromobenzyl)oxy]-38,39,41,42-tetrakis[(tert-
butoxycarbonylmethyl)oxy]calix[6]arene (3d). This com-
pound was prepared (625 mg, 80%) by general procedure B,
from 2b (500 mg) and tert-butyl bromoacetate (0.65 mL). mp
210-213 °C; 1H NMR (500 MHz, CDCl3) δ 1.55 [s, 36H,
C(CH3)3], 3.48 (br s, 4H, OCH2Ar), 4.06 (br s, 12H, ArCH2Ar),
4.37 (s, 8H, OCH2CO), 6.58 (br s, 8H, ArH), 6.71 (br m, 4H,
ArH), 7.01 (br s, 6H, ArH), 7.21 (d, J ) 8.0 Hz, 4H, ArH), 7.31
(br s, 4H, ArH); 13C NMR (125 MHz, CDCl3, DEPT) δ 28.2
[C(CH3)3], 29.7, 30.2 (ArCH2Ar), 70.9 (OCH2CO), 73.0 (OCH2-
Ar), 81.9 [C(CH3)3], 123.7, 124.5, 127.6, 129.6, 129.8, 131.1
(ArCH), 121.0, 133.6, 133.7, 134.4, 136.5, 154.4, 154.7 (ArC),
168.2 (CO); MALDI-TOF MS m/z 1451.7 [M + Na]+, 1467.7
[M + K]+. Anal. Calcd for C80H86Br2O14‚MeOH: C, 66.48; H,
6.20. Found: C, 65.86; H, 6.28.
37,40-Bis[(4-iodobenzyl)oxy]-38,39,41,42-tetrakis-
[(methoxycarbonylmethyl)oxy]calix[6]arene (3e). This
compound was prepared (94 mg, 78%) by general procedure
B, from 2c (100 mg) and methyl bromoacetate (0.07 mL). mp
208-211 °C; 1H NMR (500 MHz, CDCl3) δ 3.62 (s, 12H, OCH3),
3.99 (s, 12H, ArCH2Ar), 4.20 (s, 12H, OCH2Ar, OCH2CO), 6.74
(t, J ) 7.5 Hz, 4H, ArH), 6.81 (d, J ) 7.3 Hz, 4H, ArH), 6.88
(m, 6H, ArH), 6.98 (d, J ) 6.9 Hz, 4H, ArH), 7.09 (d, J ) 6.9
Hz, 4H, ArH), 7.58 (d, J ) 8.0 Hz, 4H, ArH); 13C NMR (125
MHz, CDCl3, DEPT) δ 29.7, 30.6 (ArCH2Ar), 51.9 (OCH3), 69.7
(OCH2CO), 73.6 (OCH2Ar), 124.0, 124.6, 128.9, 129.6, 129.7,
137.3 (ArCH), 93.2, 133.7, 133.76, 133.78, 137.4, 154.7 (ArC),
169.5 (CO); MALDI-TOF MS m/z 1379.3 [M + Na]+, 1395.3
[M + K]+. Anal. Calcd for C68H62I2O14: C, 60.19; H, 4.61.
Found: C, 60.57; H, 4.72.
37,40-Bis[(4-iodobenzyl)oxy]-38,39,41,42-tetrakis[(tert-
butoxycarbonylmethyl)oxy] calix[6]arene (3f). This com-
pound was prepared (104 mg, 76%) by general procedure B,
from 2c (100 mg) and tert-butyl bromoacetate (0.11 mL). mp
189-194 °C; 1H NMR (500 MHz, CDCl3) δ 1.55 [s, 36H,
C(CH3)3], 3.49 (br s, 4H, OCH2Ar), 4.06 (br s, 12H, ArCH2Ar),
4.37 (s, 8H, OCH2CO), 6.59 (br s, 12H, ArH), 6.95-7.10 (br
m, 6H, ArH), 7.31-7.39 (m, 8H, ArH); 13C NMR (125 MHz,
CDCl3, DEPT) δ 28.2 [C(CH3)3], 29.7, 30.2 (ArCH2Ar), 70.9
(OCH2CO), 73.2 (OCH2Ar), 81.9 [C(CH3)3], 123.7, 124.6, 127.6,
129.8, 130.6, 137.1 (ArCH), 92.9, 133.59, 133.63, 134.4, 154.4,
154.7 (ArC), 168.2 (CO); MALDI-TOF MS m/z 1547.1 [M +
Na]+, 1563.1 [M + K]+. Anal. Calcd for C80H86I2O14: C, 62.99;
H, 5.68. Found: C, 63.15; H, 5.51.
1
mobenzyl bromide (470 mg). mp 170-175 °C; H NMR (500
MHz, CDCl3) δ 3.77 (s, 4H, ArCH2Ar), 3.96 (s, 8H, ArCH2Ar),
4.97 (s, 4H, OCH2Ar), 6.76 (t, J ) 7.5 Hz, 4H, ArH), 7.07 (d, J
) 7.5 Hz, 4H, ArH), 7.08-7.11 (m, 10H, ArH), 7.23 (s, 4H,
ArH), 7.31 (s, 4H, ArH), 8.14 (s, 4H, OH); 13C NMR (125 MHz,
CDCl3, DEPT) δ 31.6, 31.8 (ArCH2Ar), 76.5 (OCH2Ar), 120.4,
126.0, 128.8, 129.2, 129.3, 129.4, 131.7 (ArCH), 122.5, 127.0,
127.4, 133.3, 134.3, 151.5, 152.5 (ArC); MALDI-TOF MS m/z
973.2 [M + H]+, 995.2 [M + Na]+, 1011.2 [M + K]+. Anal. Calcd
for C56H46Br2O6‚3MeOH: C, 66.17; H, 5.46. Found: C, 66.05;
H, 4.88.
37,40-Bis[(4-iodobenzyl)oxy]-38,39,41,42-tetrahy-
droxycalix[6]arene (2c). This compound was prepared (258
mg, 78%) by general procedure A, from 1 and 4-iodobenzyl
bromide (552 mg). mp 190-193 °C; 1H NMR (500 MHz, CDCl3)
δ 3.78 (s, 4H, ArCH2Ar), 3.97 (s, 8H, ArCH2Ar), 4.97 (s, 4H,
OCH2Ar), 6.76 (t, J ) 7.5 Hz, 4H, ArH), 7.09-7.11 (m, 18H,
ArH), 7.44 (d, J ) 8.1 Hz, 4H, ArH), 8.17 (s, 4H, OH); 13C NMR
(125 MHz, CDCl3, DEPT) δ 31.6, 31.8 (ArCH2Ar), 76.6 (OCH2-
Ar), 120.4, 126.1, 128.8, 129.3, 129.4, 129.5, 137.7 (ArCH), 94.3,
127.1, 127.5, 133.3, 135.0, 151.6, 152.4 (ArC); MALDI-TOF MS
m/z 1069.1 [M + H]+, 1091.1 [M + Na]+. Anal. Calcd for
C56H46I2O6‚2MeOH: C, 61.49; H, 4.80. Found: C, 61.74; H,
4.29.
General Proceduce B. O-Alkylation with Alkyl Bro-
moacetate. A suspension of the corresponding calix[6]arene
(0.11 mmol) and K2CO3 (0.66 mmol) in acetone (10 mL) was
heated at 60 °C for 1 h. The alkyl bromoacetate (0.88 mmol)
was added, and the mixture was refluxed for 6 days. The
solvent was removed at reduced pressure, and the residue was
partitioned between EtOAc and 1 N HCl. The organic layer
was washed with H2O, dried (MgSO4), and evaporated to
dryness. The residue was purified by precipitation with CHCl3/
MeOH (3:1).
37,40-Bis[(4-methylbenzyl)oxy]-38,39,41,42-tetra-
kis[(metoxycarbonylmethyl)oxy]calix[6]arene (3a). This
compound was prepared (518 mg, 75%) by general procedure
B, from 2a (500 mg) and methyl bromoacetate (0.45 mL).
mp 201-204 °C; 1H NMR (500 MHz, CDCl3) δ 2.40 [s, 6H,
Ar-CH3(p)], 3.43 (s, 12H, OCH3), 3.90 (s, 8H, OCH2CO),
3.99 (s, 8H, ArCH2Ar), 4.00 (s, 4H, ArCH2Ar), 4.79 (s, 4H,
OCH2Ar), 6.77 (t, J ) 7.2 Hz, 2H, ArH), 6.80 (t, J ) 7.2 Hz,
4H, ArH), 6.92 (d, J ) 7.2 Hz, 4H, ArH), 6.97 (d, J ) 7.2 Hz,
4H, ArH), 7.01 (d, J ) 7.2 Hz, 4H, ArH), 7.22 (d, J ) 7.9 Hz,
4H, ArH), 7.33 (d, J ) 7.9 Hz, 4H, ArH); 13C NMR (125
MHz, CDCl3, DEPT) δ 21.3 [Ar-CH3(p)], 29.7, 31.0 (ArCH2-
Ar), 51.7 (OCH3), 69.5 (OCH2CO), 74.8 (OCH2Ar), 124.1,
124.3, 128.0, 128.9, 129.1, 129.3, 130.0 (ArCH), 133.6,
133.9, 134.2, 134.6, 137.5, 154.7, 154.9 (ArC), 169.4 (CO);
MALDI-TOF MS m/z 1155.5 [M + Na]+, 1171.4 [M + K]+.
Anal. Calcd for C70H68O14: C, 74.19; H, 6.05. Found: C, 73.68;
H, 6.35.
37,40-Bis[(4-methylbenzyl)oxy]-38,39,41,42-tetrakis-
[(tert-butoxycarbonylmethyl)oxy]calix[6]arene (3b). This
compound was prepared (550 mg, 73%) by general procedure
B, from 2a (500 mg) and tert-butyl bromoacetate (0.7 mL). mp
190-193 °C; 1H NMR (500 MHz, CDCl3) δ 1.51 [s, 36H,
C(CH3)3], 2.34 [s, 6H, Ar-CH3(p)], 4.04 (s, 8H, ArCH2Ar), 4.11
(s, 8H, ArCH2Ar, OCH2Ar), 4.26 (s, 8H, OCH2CO), 6.52 (t, J
) 7.5 Hz, 4H, ArH), 6.58 (d, J ) 7.5 Hz, 4H, ArH), 6.75 (m,
4H, ArH), 6.83 (s, 2H, ArH), 6.95 (d, J ) 7.5 Hz, 4H, ArH),
7.02 (d, J ) 7.5 Hz, 4H, ArH), 7.08 (m, 4H, ArH); 13C NMR
(125 MHz, CDCl3, DEPT) δ 21.3 [Ar-CH3(p)], 28.1 [C(CH3)3],
30.8, 31.2 (ArCH2Ar), 70.7 (OCH2CO), 74.2 (OCH2Ar), 81.6
[C(CH3)3], 123.7, 124.4, 127.8, 128.2, 128.8, 129.5 (ArCH),
129.7, 133.7, 134.3, 134.8, 136.6, 154.7, 155.2 (ArC), 168.4
(CO); MALDI-TOF MS m/z 1323.7 [M + Na]+, 1339.7 [M +
K]+. Anal. Calcd for C82H92O14‚1.5 CHCl3‚MeOH: C, 67.09; H,
6.50. Found: C, 66.58; H, 6.35.
5,11,17,23,29,35-Hexa-tert-butyl-37,40-bis[(4-methyl-
benzyl)oxy]-38,39,41,42-tetrakis[(methoxy carbonylmeth-
yl)oxy]calix[6]arene (5a). This compound was prepared (115
mg, 90%) by general procedure B, from 4 (100 mg) and methyl
bromoacetate (0.07 mL). mp 200-202 °C; 1H NMR (500 MHz,
CDCl3) δ 1.20 [s, 18H, C(CH3)3], 1.61 [s, 36H, C(CH3)3], 2.40
[s, 6H, Ar-CH3(p)], 3.46-3.54 (br s, 12H, OCH3), 3.82-4.15
(br s, 12H, ArCH2Ar), 4.38-4.68 (br s, 8H, OCH2CO), 4.92 (s,
4H, OCH2Ar), 7.03-7.20 (br s, 8H, ArH), 7.23 (d, J ) 7.8 Hz,
4H, ArH), 7.38 (s, 4H, ArH), 7.53 (d, J ) 7.8 Hz, 4H, ArH);
13C NMR (125 MHz, CDCl3, DEPT) δ 21.2 [Ar-CH3(p)], 31.3
[C(CH3)3], 30.1, 31.4 (ArCH2Ar), 51.7 (OCH3), 70.1 (OCH2CO),
10406 J. Org. Chem., Vol. 70, No. 25, 2005

Hexa-O-alkyl p-Unsubstituted Calix[6]arenes
75.1 (OCH2Ar), 80.7 [C(CH3)3], 128.5, 128.9, 129.1, 129.3
(ArCH), 127.9, 133.9, 133.1, 134.5, 137.8, 146.0, 146.5, 152.7
(ArC), 169.5 (CO); MALDI-TOF MS m/z 1492.7 [M + Na]+,
1508.7 [M + K]+. Anal. Calcd for C94H116O14: C, 76.81; H, 7.95.
Found: C, 77.10; H, 8.15.
confirmed using the structure solution. The structure was
solved by direct methods (SHELXS-97),24 completed with
difference Fourier syntheses, and refined with full-matrix
2
least-squares using SHELXL-9725 minimizing ω(Fo - Fc2)2.
Weighted R factors (Rw) and all goodness of fit S are based on
F2; conventional R factors (R) are based on F. All non-hydrogen
atoms were refined with anisotropic displacement parameters.
All scattering factors and anomalous dispersions factors are
contained in the SHELXTL 6.10 program library.
Crystallographic data for the structural analyses of 3a, 3b,
and 3d have been deposited within the Cambridge Crystal-
lographic Data Centre (CCDC) as 285296, 285297, and 285298,
respectively. Copies of this information may be obtained from
The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ,
U.K. (Fax: +44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk)
or http//www.ccdc.cam.ac.uk.
Crystallographic Studies of Compounds 3a, 3b, and
3d. The samples were mounted on a glass fiber and transferred
to a Bruker SMART20 6K CCD area-detector three-circle
diffractometer with a Rigaku rotating anode (Cu KR radiation,
λ ) 1.54178 Å) generator equipped with Goebel mirrors at
settings of 50 kV and 100 mA. X-ray data were collected at
296 K, with a combination of six runs at different æ and 2θ
angles, 3600 frames. The data were collected using 0.3° wide
ω scans (10 s/frame at 2θ ) 40° and 20 s/frame at 2θ ) 100°
for compound 3a, 3 s/frame at 2θ ) 40°, and 10 s/frame at 2θ
) 100° for compound 3b, and 30 s/frame at 2θ ) 40° and 100
s/frame at 2θ ) 100° for compound 3d) with a crystal-to-
detector distance of 4.0 cm. The substantial redundancy in
data allows empirical absorption corrections (SADABS)21 to
be applied using multiple measurements of symmetry-
equivalent reflections. The raw intensity data frames were
integrated with the SAINT22 program, which also applied
corrections for Lorentz and polarization effects. Crystal-
lographic details for each compound are reported in Table S1
(see Supporting Information).
Acknowledgment. CYCIT (project BQU2002-03536)
and ICIQ Foundation are kindly acknowledged for
financial support. J.C.I.-S. acknowledges the Ministerio
de Educacio´n y Ciencia of Spain for a predoctoral
fellowship.
The software package SHELXTL23 version 6.10 was used
for space group determination, structure solution, and refine-
ment. The space group determination was based on a check
of the Laue symmetry and systematic absences and was
Supporting Information Available: General methods;
X-ray crystallographic data of compounds 3a, 3b, and 3d;
VT-1H NMR spectra (298-188 K) of compounds 2a, 3a-f, and
5a; VT-1H NMR spectra (403-298 K) of compounds 3a and
3d; HMQC spectra of compounds 2a,b, 3a-d, 3f, and 5a;
ROESY spectra of compounds 3a, 3f, and 5a. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) SMART v 5.625, Area-Detector Software Package; Bruker
AXS: Madison, WI, 1997-2001.
(21) Sheldrick, G. M. SADABS: A Program for Empirical Absorption
Correction, version 2.03; University of Go¨ttingen: Go¨ttingen, Germany,
1997-2001.
JO0516638
(22) SAINT+ NT: SAX Area-Detector Integration Program, version
6.04; Bruker AXS: Madison, WI, 1997-2001.
(24) Sheldrick, G. M. Acta Crystallogr., Sect. A 1990, 46, 467-473.
(25) Sheldrick, G. M. SHELXL-97: Program for Crystal Structure
Refinement; University of Go¨ttingen: Go¨ttingen, Germany, 1997.
(23) SHELXTL: Structure Determination Package, version 6.10;
Bruker AXS: Madison, WI, 2000.
J. Org. Chem, Vol. 70, No. 25, 2005 10407