Bridge-disubstituted calix[4]arenes obtained via a new preparative route. Synthesis and structural study

Article abstract of DOI:10.1016/j.tet.2011.05.087

A series of calix[4]arenes bearing various substituents including alkyl, p-bromobenzyl, carboxy and allyl at opposite methylene bridges has been synthesized via successive metallation followed by nucleophilic substitution. In a first step, mono-lithiated

Full text of DOI:10.1016/j.tet.2011.05.087

Tetrahedron 67 (2011) 5656e5662
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Bridge-disubstituted calix[4]arenes obtained via a new preparative route.
Synthesis and structural study
*
Conrad Fischer, Guisheng Lin, Wilhelm Seichter, Edwin Weber
€
€
Institut fur Organische Chemie, Technische Universitat Bergakademie Freiberg, Leipziger Str. 29, D-09596 Freiberg/Sachs., Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 April 2011
Received in revised form 18 May 2011
Accepted 19 May 2011
Available online 27 May 2011
A series of calix[4]arenes bearing various substituents including alkyl, p-bromobenzyl, carboxy and
allyl at opposite methylene bridges has been synthesized via successive metallation followed by
nucleophilic substitution. In a first step, mono-lithiated calix[4]arenes react with terminal bro-
moalkanes to give 2-alkylated calix[4]arenes or with CO2 the respective calixarene-2-carboxylic acid in
good yields. A second lithiation step of the monosubstituted products with subsequent attachment of
both polar and non-polar substituents yields several new diametrally bridge-disubstituted calix[4]
arenes. 2D-NMR measurements establish the disubstituted calixarenes to predominantly adopt the 1,2-
alternate conformation in solution. First examples of X-ray crystal structures of the new type of di-
substituted calix[4]arenes are described featuring the calix[4]arene also in the rare 1,2-alternate
conformation.
Keywords:
Calixarenes
Bridge disubstitution
Allyl compounds
Conformational study
X-ray crystallography
Ó 2011 Published by Elsevier Ltd.
1. Introduction
Calix[n]arenes are well known macrocyclic molecules of defined
size promising for versatile supramolecular and biological appli-
cations due to their multiple availability for chemical modification
within a concentrated space.1e3 In the special case of a calix[4]
arene, there are 12 possible sites for substitution, eight of them
located on the upper rim and lower rim sites of the calixarene and
further four located at the connecting methylene bridges (Fig. 1).
Dependent on the orientation of the arene units with regard to the
central plane including the four sp3-methylene carbons, there are
four basic conformational isomers designated as ‘cone’, ‘partial
cone’, ‘1,3-alternate’ and ‘1,2-alternate’. They are found in a trans-
formational equilibrium if the lower rim of the calix[4]arene is
substituted with residues smaller than ethyl.4
The chemistry of the vertical substitution of the calix[4]arene is
already intensively studied and the resulting products are charac-
terized with reference to their conformational behaviour or in-
clusion properties.1e3 By way of contrast, only a small number of
publications are engaged in the impact of a lateral modification of
one of the methylene bridges.5,6 We recently demonstrated that the
lateral attachment of neither a single polar carboxy group7 nor non-
polar alkyl chains of different length8 significantly hamper the
conformational equilibrium of the tetramethoxycalix[4]arene, being
Fig. 1. Reactive centers of the basic calix[4]arene.
beneficial for the preservation of the inclusion behaviour of the
chalice. Exceeding a potential use of the bridge-monosubstitution of
a calixarene for the lateral attachment to a solid support, laterally
disubstituted calixarenes will open further new structural possi-
bilities for a calixarene to act as bifunctional building block for the
design of more complex coordination type or covalently linked su-
pramolecular constructions. However, till now the chemistry of
bridge-disubstituted calixarenes is rather poorly developed and
often associated with low yields regarding their synthesis, attrib-
utable to multi-step reaction sequences that have been used to in-
troduce two bridge substituents to opposite methylene bridges.
They include the famous spirodienone route,9e11 a procedure via
anionic ortho-Fries-rearrangement12 and fragment condensation
methods.13 In the present paper, we describe a convenient two-step
synthesis for bridge diametrally disubstituted calix[4]arenes and
report on the promising structural properties of this type of
calixarenes.
* Corresponding author. E-mail address: edwin.weber@chemie.tu-freiberg.de
(E. Weber).
0040-4020/$ e see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tet.2011.05.087

C. Fischer et al. / Tetrahedron 67 (2011) 5656e5662
5657
2. Results and discussion
In this connection, it seemed also interesting to us to convert the
carboxylic acid 5 to the corresponding methyl ester 6. Usual acidic
esterification with methanol and catalytic amounts of sulfuric acid
(Scheme 2(a)) gave the respective ester 6 in moderate yield (59%).
The conformational composition of 6 coincides with the other
bridge-monosubstituted compounds 2e5, preferably exhibiting
a partial cone conformation in CDCl3 solution.
In another attempt, we tested a possibility to directly introduce
the ester function into a single bridge position by reaction with
methyl chloroformate (Scheme 2(b)). Using this reagent together
with 1.05 equiv n-BuLi under ambient conditions easily yielded 76%
of the methyl ester 6 in high purity. Hence, we found a smart one-
step reaction offering also an appreciated alternative for the syn-
thesis of higher ester homologues known for their potential to
switch the calixarene conformationally from the partial cone to the
cone form.15
Fortunately, we succeeded in growing crystals of the bridge
monoallyl substituted calixarene 3, enabling us to validate the
conformational influence of the substituent also in the solid state.
In accordance with known structures of bridge-monosubstituted
tetramethoxycalix[4]arenes,7,8,16e18 compound 3 also adopts the
partial cone conformation, bearing the allyl substituent equatorial
between syn orientated arene units (Fig. 2).
Earlier attempts to succeed with a simultaneous twofold or
multiple bridge-disubstitution of the tetramethoxycalix[4]arene 1
(Scheme 1) following an alkylation reaction under the condition of
excess n-BuLi failed, yielding only monoalkylation product. This can
be deduced from the literature data5 and has similarly been expe-
rienced by us. Although, until now, there is no entirely plausible
explanation for this unusual behaviour, hampered multisite lith-
iation or steric hindrance caused by particular lithium complexa-
tion might be seen potential reasons. However, this drawback has
now been overcome by using a sequential lithiationealkylation
process as described below. Following this new preparative route,
in a first sequence the bridge-monosubstituted calixarenes 2e5
(Scheme 1) were obtained via lithiation of a single methylene
bridge of 1 and subsequent addition of corresponding electrophiles
according to a previous description.6 All isolated products exhibit
a clear predominance of the partial cone conformation with an
equatorial arrangement of the bridge-substituent14 between syn
orientated arene units in CDCl3 solution, being already described in
the literature.7,8 This particular conformation is also preferred of
the new allyl-compound 3. Nevertheless, addition of small amounts
NaI and acetonitrile-d3 (1/10 v/v) fixes the bridge-monosubstituted
calix[4]arenes 2e5 in the cone conformation, caused by the com-
plexation of the sodium ion with the methoxy groups.
Obviously, only long and sufficiently rigidified lateral residues
fix the calixarene core in the prominent cone conformation, as
shown for a bridge-monosubstituted n-propoxycarbonyl15 as well
as an aminoalkyl tethered calix[4]arene.6 Due to the absence of
hydrogen donor substituents, no intramolecular interactions are
observed. The packing is only stabilized by weak van der Waals
contacts, e.g., involving the allyl substituent (C51eH51B/H19),
ꢀ
ꢀ
2.290 (2) A, 171 , Table S1].
Returning to the preparative route, i.e., conversion from the
bridge-monosubstituted to bridge-disubstituted calix[4]arenes,
a subsequent lithiation and substitution step is applied (Scheme 3).
To avoid side-reactions with the first bridge substituent, the syn-
theses of the compounds 7e14 were performed under kinetically
driven conditions (ꢁ78 ꢀC) with a high excess of n-BuLi (6 equiv).
Scheme 1. Formula structures of the parent calixarene 1 and bridge-monosubstituted
compounds 2e5.
Scheme 2. Different pathways for the synthesis of the bridge-monoester calixarene 6.

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C. Fischer et al. / Tetrahedron 67 (2011) 5656e5662
opposite site of the calixarene core, resulting in the formation of the
diallyl derivative 11 as well as the allyl substituted carboxylic acid
12 on the reaction with allyl bromide or CO2, respectively. However,
the reaction of the calixarene monoester 6 with n-BuLi remarkably
failed to yield the desired bridge-disubstituted carboxylic acid ester
derivative. From NMR analysis, a signal at 77.1 ppm indicates that
a reduction of the ester function to a tertiary alcohol has occurred.
In connection with the C]O signal at 179.0 ppm and the result of
the mass spectra, this new compound was identified as 15.
The presence of two substituents on opposite methylene bridges
can be concluded from different signals of the remaining methine
protons in the 1H NMR-spectra. Some of the synthesized products
(11 and 15) exhibit a clear 1H NMR spectrum with a highly limited
number of signals, whereas for all the other compounds additional
signals can be found, e.g., in the methoxy as well as the tert-butyl
group region. This suggests the predominance of a single conformer
at 294 K in CDCl3 solution for 11 and 15, while the other compounds
should exist in at least two conformations. Following the symmetry
of the compounds (C2h for 11 and Cs for 15), a singlet of the
remaining methylene protons in 11 and two closely arranged
doublets in a 1:1 ratio for 15 indicates their isoclinal arrangement
between anti orientated arene units. Considering the results of the
ROESY spectra for 11 and 15, showing crosspeaks for the methine
protons exclusively with the neighbouring methoxy groups as well
as a 4J coupling of the Ha and Hi protons (Fig. 3) in the COSY spectra
for this single conformer, the 1,2-alternate conformation can be
assigned, which is a very uncommon conformation in solution state
calix[4]arene chemistry.19
Fig. 2. Molecular structure of the monoallyl calixarene 3 in the partial cone confor-
mation. Thermal ellipsoids are drawn at the 50% probability level. H atoms as well as
a disordered position of one tert-butyl group are omitted for clarity.
Due to the high conformational flexibility at room temperature,
a conformational assignment for all the other compounds is not
possible under ambient conditions. Therefore we performed de-
tailed 2D NMR measurements at 265 K. Following the specific
correlations in the HSQC, HMBC, COSY and ROESY spectra (see ESD
part), the aforementioned resonances indicate also the presence of
the 1,2-alternate conformer in the other compounds in a greater
amount than normally observed for calix[4]arenes, increasing with
the length and bulkiness of the two bridge substituents (Table 1).
The respective fractions of the 1,2-alternate conformer have been
calculated by comparison of the methoxy signals of this specific
conformer (located in all compounds between 2.78 and 3.11 ppm)
to all occurring methoxy signals (see ESD Fig. S9eS26).
This behaviour may explain the high 1,2-alternate fraction in
compounds 11 and 15, both possessing voluminous bridge sub-
stituents. Interestingly, addition of NaI and the more polar aceto-
nitrile-d3 did not cause a conformational interconversion to a pure
cone conformation, as observed for the bridge-monosubstituted
calix[4]arenes. This seems reasonable because a successive rota-
tion of two arene units would lead to an axial arrangement of at
least one bridge substituent, which is avoided for steric reasons.14
Scheme 3. Formula structures of the laterally disubstituted calixarenes 7e15 obtained
from subsequent substitution of the monosubstituted calix[4]arenes 2e4 and 6.
Noteworthy, in spite of the excess of n-BuLi, there is only one
substitution in the diametral bridge position showing similar be-
haviour as for the monosubstitution of 1. As before, the existence of
only one distinct lithiated intermediate can be assumed.
Moreover, the allylic protons in 3 obviously show a lower kinetic
acidity compared to the methylene H-atoms located on the
Fig. 3. 1H NMR spectrum of compound 11 at 265 K indicating a high fraction of the 1,2-alternate conformer. Inset: Cut-out of the COSY spectrum of 11 showing the 4J coupling of Ha
and Hi protons.

C. Fischer et al. / Tetrahedron 67 (2011) 5656e5662
5659
Table 1
Beside the conformational difference, one of the methoxy
groups (C19) in 11 points inside the cavity, leading to a compact
molecular structure stabilized by an intramolecular CeH/p-con-
Fractions of the 1,2-alternate conformer and position of the methoxy proton signal(s)
from NMR measurements in CDCl3 at 265 K
Compound 1,2-Alternate 1H CH3O-signal(s) (1,2-alternate fraction, ppm)
tact22 (Table S1). The high symmetry of the molecule enables
a linear arrangement along the crystallographic c-direction with
trans orientation of the lateral residues (Fig. S28). The compact
structure of the crystal is reflected by a high KPI index,23 indicating
a closed packed structure and thus in combination with the nar-
rowed host-cavity that any solvent incorporation is avoided.
Increasing the polarity and donor-acceptor behaviour of the
molecule by exchange of the bridge allyl residue for a carboxylic
function preserves again the 1,2-alternate conformation, but addi-
tionally enables the inclusion of solvent molecules as found in the
crystals of compound 12 (Fig. 4(b)). An interesting hydrogen bonded
architecture is observed involving two opposite methoxy oxygen
atoms coordinated via further two solvent molecules with the next
calixarene molecule along the crystallographic a-direction (Fig. S29).
Remarkably, different CeO bond lengths in the two guest molecules
are observed leading one to assume the coexistence of correspond-
ing acid/base pairs, i.e., CH3COOH/H2O and CH3COOꢁ/H3Oþ in this
network (Table S1). Compared to a related structure of the bridge-
monofunctionalized carboxylic acid 5 including EtOH and water,
the presence of a second bridge-substituent in 12 not only changes
the basic conformation of the chalice from cone to 1,2-alternate,
but due to the exo orientation of all methoxy groups expands the
calixarene cavity. This special geometry allows the incorporation
of a water and a hydroxonium ion moderating the channel-like
arrangement of solvent molecules. The carboxylic function itself
maintains a hydrogen bond to the acid molecule resulting in
a crosslink of the channels along the crystallographic c-direction
(Fig. S29).
fraction (%)
4
7
8
9
10
11
12
13
14
15
7
33
39
31
38
75
42
18
36
88
3.07
3.08
3.04
3.03
3.05
3.02
2.96
3.02
3.09
3.04
2.96
2.97
3.01
2.77
3.04
d
2.94
d
2.97
2.95
Since there are no reports on crystal structures of bridge-di-
substituted tetramethoxycalix[4]arenes yet, the question arises,
whether this conformational switch from a preferred partial cone
conformation to 1,2-alternate by the addition of a second bridge
substituent can also be found in the solid state. For related bridge-
disubstituted tetrahydroxycalix[4]arenes, the cone conformation
was determined as the preferred one in the solid state,14,20 and only
in one special case the calixarene is shown in the 1,2-alternate form
attributed to two extremely bulky mesityl groups, located iso-
clinally at opposite methylene bridges.21 X-ray analysis of three
single crystals of the present bridge-disubstituted tetramethoxy-
calixarenes (11, 12 and 15), reveal the calixarene core in the 1,2-
alternate conformation proving our before mentioned assumption.
The difference in the conformational behaviour between the crys-
tallized monoallyl calixarene 3 and its diallyl pendant 11 is obvious
(Fig. 4(a)) and can be easily comprehended by comparison of the
metrical data (Table 2).
Fig. 4. X-ray crystal structures of the bridge-disubstituted calix[4]arenes 11 (a), 12 (b)and 15 (c). Non-relevant H-atoms have been omitted for clarity. O1W and O2W denote two
water molecules inside the calixarene cavity of molecule 12 moderating the hydrogen-bond network.
Although crystals of 15 also feature the calixarene core in the
1,2-alternate conformation (Fig. 4(c)), the presence of the bulky
lateral tertiary alcohol residue obtained by nucleophilic attack of an
Table 2
ester function results in a certain deviation of the metrical pa-
Selected conformational parameters of compounds 3, 11, 12 and 15 and their cal-
rameters of the calixarene core (Table 2). Moreover, the bulky al-
culated packing indices (KPIs). Compounds 15 and 15a denote two crystallograph-
coholic substituent forces a neighbouring methoxy group (C33) to
ically independent molecules in this structure
point inside the cavity locking the cavity for any solvent inclusion.
3
11
12
15/15a
The packing is characterized by molecular strands along the crys-
tallographic c-axis, linking the calixarene molecules alternately by
a hydrogen bond involving the carboxylic function of one molecule
and the OH-function of the next one (Fig. S30). Interestingly, the
conformational behaviour in the solid state is only slightly affected
by the donor-acceptor interactions between the bridge substituents
and guest molecules, thus indicating the intrinsic conformational
influence of the two bridge substituents.
Interplanar angle (ꢀ)
A/mpla
B/mpla
C/mpla
D/mpla
A/C
88.0 (1)
78.2 (1)
64.9 (1)
78.2 (1)
64.9 (1)
0
68.3 (1)
67.9 (1)
68.7 (1)
67.0 (1)
0.6 (1)
1.0 (1)
65.7
67.8/62.4 (1)
86.2/89.5 (1)
88.1/87.9 (1)
48.3/48.2 (1)
20.3/25.5 (1)
38.1/42.8 (1)
65.5
36.0 (1)
88.0 (1)
86.6 (1)
3.6 (1)
50.6 (1)
64.1
B/D
KPI
0
67.9

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C. Fischer et al. / Tetrahedron 67 (2011) 5656e5662
3. Conclusions
983, 951, 911, 897, 869, 810, 795, 716, 637, 598, 560. m/z (CI) 744.9
(MHþ). Elemental analysis calculated for C51H68O4: C, 82.21; H, 9.20.
Found: C, 82.06; H, 9.17.
A novel direct and short route for the synthesis of bridge-di-
substituted calix[4]arenes, including the application of a successive
lithiation and substitution sequence is demonstrated, yielding
diametrally bridge-substituted calixarenes in high quantity and
purity. Compared to related bridge-monosubstituted calixarenes,
the twofold substituted pendants exhibit an increased fraction of
the 1,2-alternate conformer in solution. X-ray analysis of com-
pounds bearing the diametral substitution pattern prove this rare
conformation to be the preferable one also in the solid state, in-
dependent of further hosteguest-interactions. Therefore, for the
first time a conformationally conducting influence of the bridge
residues on the calixarene core is demonstrated. The obtained
compounds feature significantly different polarities at their oppo-
site lateral arms, being beneficial for further synthetic steps, in-
cluding lateral attachment, polymerization or surface active
applications. Whereas the diametral substitution pattern seems to
be useful for the lateral aggregation of the calixarene core, the
observed conformational adaptation upon successive lateral sub-
stitution may be of interest for the design of novel supramolecular
receptors.24,25
4.3. Esterification of the calixarenecarboxylic acid 5
Usual acidic esterification with dry methanol and catalytic
amounts of sulfuric acid was carried out following the described
protocol (method A).15 Alternatively, direct lithiation of the tetra-
methoxycalix[4]arene 1 and subsequent reaction with methyl
chloroformate also yielded the desired methyl ester 6 (method B).
4.3.1. Methyl-5,11,17,23-tetra-tert-butyl-25,26,27,28-tetramethoxycalix
[4]arene-2-carboxylate (6). A: reagents: 5 (1.15 g, 1.5 mmol); metha-
nol (20 mL); concd H2SO4 (3 mL). Yield 0.7 g (59%). B: reagents: 1
(0.71 g, 1.0 mmol); n-BuLi (1.6 M in hexane, 1.1 mL, 1.05 mmol);
methyl chloroformate (81 mL, 0.1 g, 1.05 mmol). Yield 0.6 g (76%).
4.4. General procedure for the synthesis of the bridge-
disubstituted calixarenes 7e15
For the preparation of compounds 7e15, a solution of n-BuLi
(6 equiv, 1.6 M in hexane) and TMEDA (7 equiv) in 30 mL dry THF is
cooled to ꢁ78 ꢀC. After 30 min, the respective bridge-
monosubstituted calixarene is added via syringe and the resulting
blood-red solution is allowed to warm up to room temperature.
After 40 min the electrophile (alkyl halide or CO2) is added, turning
the colour of the solution immediately to yellow. After another
hour, the volatiles are removed under reduced pressure and the
crude products are dissolved in CH2Cl2. This solution is washed
with brine (3ꢂ) [the carboxylated compounds 10, 12, 14 and 15
were additionally pre-washed with 2 M aqueous hydrochloric acid
(2ꢂ)], dried over MgSO4 and evaporated to obtain white powders,
which were recrystallized from MeOH/CHCl3 (2:1). While com-
pounds 11 and 15 exhibit interpretable NMR spectra, the con-
formationally more flexible calixarenes 7e10 and 12e14 show only
a few interpretable peaks (as indicated in Table 1). Most of the
peaks in these compounds are broad and indistinguishable and are
not assigned in the analysis part. Respective NMR spectra of these
compounds, with an assignment of the MeO group signals of the
different coexisting conformers can be found in the ESD part
(Fig. S9eS26). For the compounds 11 and 15 only the resonances of
the predominately existing 1,2-alternate fraction are assigned.
4. Experimental
4.1. General
Melting points were determined on a microscope heating stage
PHMK Rapido (VEB Dresden Analytik) and are uncorrected. IR
spectra were measured on a Nicolet FT-IR 510 as KBr pellets. NMR
spectra were recorded on a Bruker Avance DRX 500 spectrometer at
500.1 MHz (1H-NMR) and 125.7 MHz (13C-NMR), respectively, in
CDCl3 solution. Chemical shifts
d are reported in parts per million
relative to the internal reference TMS. For the bridge mono-
substituted allyl-compound 3 the addition of small amounts of NaI
and acetonitrile-d3 fixes the calixarene in the cone conformation
(Fig. S7 and S8). Mass spectra were measured on a Varian 320 MS.
Elemental analyses were performed on a Heraeus CHN-Rapid An-
alyzer. Reagents and chemicals for the synthesis were used as
purchased from chemical suppliers. The solvents used were puri-
fied or dried according to common literature procedures. The
5,11,17,23-tetra-tert-butyl-25,26,27,28-tetramethoxycalix[4]arene
(1) was prepared from commercially available 5,11,17,23-tetra-
tert-butyl-25,26,27,28-tetrahydroxycalix[4]arene according to
the published procedure.26
4.4.1. 5,11,17,23-Tetra-tert-butyl-2-ethyl-25,26,27,28-tetra-methoxy-
14-methylcalix[4]arene (7). Reagents: 2 (0.44 g, 0.6 mmol); n-BuLi
(2.2 mL, 3.6 mmol); TMEDA (0.6 mL, 0.5 g, 4.2 mmol); methyl iodide
(0.3 mL, 0.68 g, 4.8 mmol). Yield: 0.35 g (78%). IR (cmꢁ1): 2958,
2928, 2869, 2819, 1601, 1478, 1460, 1391, 1287, 1245, 1203, 1128,
1023, 941, 869, 793, 745, 728, 646, 543. m/z (CI) 747.4 (MHþ). Ele-
mental analysis calculated for C51H70O4: C, 81.99; H, 9.44. Found: C,
81.46; H, 9.38.
4.2. Synthesis of bridge-monosubstituted calixarenes 2e5
The synthesis followed the procedure described by Scully5 and
Hertel,6 using a solution of 1 in 50 mL dry THF and 4 equiv n-BuLi
(1.6 M in hexanes). The analytical data of compounds 2, 4 and 5 are
in accordance with the literature.5
4.2.1. 2-Allyl-5,11,17,23-tetra-tert-butyl-25,26,27,28-tetramethoxycalix
[4]arene (3). Reagents: 1 (2.13 g, 3.0 mmol); n-BuLi (1.6 M in hexane,
7.5 mL, 12.0 mmol); allyl bromide (1.45 g, 1.05 mL, 12.0 mmol). Yield:
4.4.2. 2-Allyl-5,11,17,23-tetra-tert-butyl-14-ethyl-25,26,27,28-tetra-
methoxycalix[4]arene (8). Reagents: 2 (0.37 g, 0.5 mmol); n-BuLi
(1.9 mL, 3.0 mmol); TMEDA (0.55 mL, 0.41 g, 3.5 mmol); allyl
bromide (0.35 mL, 0.48 g, 4.0 mmol). Yield: 0.30 g (77%). IR (cmꢁ1):
2957, 2932, 2870, 2820, 1640, 1601, 1478, 1461, 1429, 1391, 1360,
1284, 1243, 1202, 1128, 1021, 998, 948, 908, 868, 797, 749, 714, 645,
569, 549, 510. m/z (CI) 773.5 (MHþ). Elemental analysis calculated
for C53H72O4: C, 82.34; H, 9.39. Found: C, 81.95; H, 9.30.
4
1.8 g (80%). 1H NMR:
d
¼7.24 (d, 2H, HeAr, JHH¼2.1 Hz), 7.17 (s, 4H,
4
HeAr), 7.15 (d, 2H, HeAr, JHH¼2.1 Hz), 5.75 (m, 1H, CH2CH]CH2),
3
5.11 (d, 1H, CH2CH]CH2, JHH¼17.0 Hz), 5.00 (d, 1H, CH2CH]CH2,
3JHH¼10.0 Hz), 4.73 (t, 1H, CHCH2CH]CH2, 3JHH¼8.4 Hz), 4.30 (d, 3H,
CH2, 2JHH¼12.4 Hz), 4.19 (s, 6H, OCH3), 4.15 (s, 6H, OCH3), 3.41 (d, 3H,
2
3
CH2, JHH¼12.4 Hz), 2.89 (t, 2H, CH2CH]CH2, JHH¼8.4 Hz); 1.21 (s,
36H, C(CH3)3); 13C NMR:
d
¼150.7 (2C), 148.7, 137.4, 136.0, 134.5 (2C),
4.4.3. 2-(p-Bromobenzyl)-5,11,17,23-tetra-tert-butyl-14-ethyl-
25,26,27,28-tetramethoxycalix[4]arene (9). Reagents: 2 (0.37 g,
0.5 mmol); n-BuLi (1.9 mL, 3.0 mmol); TMEDA (0.55 mL, 0.41 g,
3.5 mmol); p-bromobenzyl bromide (1.0 g, 4.0 mmol). Yield: 0.2 g
134.4, 125.9, 125.6, 122.5, 117.6, 65.2, 65.0, 38.4, 35.7, 34.4, 34.2, 31.3,
31.1 (2C), 30.0. IR (cmꢁ1): 2960, 2929, 2869, 2818, 1640, 1600, 1479,
1461, 1431, 1391, 1360, 1313, 1283, 1227, 1203, 1175, 1128, 1116, 1025,

C. Fischer et al. / Tetrahedron 67 (2011) 5656e5662
5661
(40%). IR (cmꢁ1): 2953, 2929, 2868, 2821, 1601, 1587, 1479, 1462,
1429, 1391, 1361, 1286, 1245, 1200, 1176, 1127, 1071, 1020, 1012, 949,
870, 850, 802, 757, 627, 547, 512. m/z (CI) 903.2 (MHþ). Elemental
analysis calculated for C57H73O4Br: C, 75.89; H, 8.16. Found: C,
75.60; H, 8.05.
997, 957, 909, 892, 872, 814, 781, 743, 708, 640, 624, 591, 556. m/z (CI)
789.3 (MHþ). Elemental analysis calculated for C52H68O6: C, 79.15; H,
8.69. Found: C, 78.65; H, 8.60.
4.4.7. 5,11,17,23-Tetra-tert-butyl-25,26,27,28-tetramethoxy-2,14-
dimethylcalix[4]arene (13). Reagents: 4 (0.8 g, 1.1 mmol); n-BuLi
(4.1 mL, 6.6 mmol); TMEDA (1.2 mL, 0.9 g, 7.7 mmol); methyl iodide
(0.55 mL,1.25 g, 8.8 mmol). Yield: 0.5 g (60%). IR (cmꢁ1): 2957, 2931,
2870, 2821, 1601, 1479, 1460, 1428, 1392, 1361, 1271, 1245, 1230,
1199, 1173, 1121, 1021, 1000, 937, 873, 810, 791, 783, 746, 700, 651,
638, 598, 509. m/z (CI) 733.4 (MHþ). Elemental analysis calculated
for C50H68O4: C, 81.92; H, 9.35. Found: C, 81.91; H, 9.30.
4.4.4. 5,11,17,23-Tetra-tert-butyl-14-ethyl-25,26,27,28-tetramethoxycalix
[4]arene-2-carboxylic acid (10). Reagents: 2 (0.6 g, 0.8 mmol); n-BuLi
(3 mL, 4.8 mmol); TMEDA (0.85 mL, 0.65 g, 5.6 mmol); CO2 (excess).
Yield: 0.45 g (74%). IR (cmꢁ1): 2954, 2930, 2868, 2821, 1710, 1598, 1478,
1460, 1431, 1392, 1361, 1286, 1255, 1242, 1201, 1130, 1111, 1017, 997, 952,
932, 891, 870, 816, 806, 781, 737, 708, 663, 628, 592, 558, 509. m/z (CI)
777.4 (MHþ). Elemental analysis calculated for C51H68O6: C, 78.83; H,
8.82. Found: C, 79.11; H, 8.73.
4.4.8. 5,11,17,23-Tetra-tert-butyl-25,26,27,28-tetramethoxy-14-
methylcalix[4]arene-2-carboxylic acid (14). Reagents: 4 (1.08 g,
1.5 mmol); n-BuLi (5.6 mL, 9 mmol); TMEDA (1.6 mL, 1.23 g,
10.6 mmol); CO2 (excess). Yield: 0.8 g (70%). IR (cmꢁ1): 2951, 2929,
2868, 2822, 1706, 1600, 1479, 1461, 1430, 1409, 1392, 1361, 1287,
1243, 1202, 1173, 1123, 1018, 998, 956, 940, 892, 874, 810, 782, 742,
698, 643, 626, 591, 539. m/z (CI) 763.5 (MHþ). Elemental analysis
calculated for C50H66O6: C, 78.70; H, 8.72. Found: C, 78.80; H, 8.73.
4.4.5. 2,14-Diallyl-5,11,17,23-tetra-tert-butyl-25,26,27,28-tetramethoxy-
calix[4]arene (11). Reagents: 3 (0.54 g, 0.7 mmol); n-BuLi (2.6 mL,
4.2 mmol); TMEDA (0.74 mL, 0.57 g, 4.9 mmol); allyl bromide (0.5 mL,
0.7 g, 5.8 mmol). Yield: 0.45 g (82%). 1H NMR:
d
¼7.11 (d, 4H,
4JHH¼2.1 Hz), 7.05 (d, 4H, 4JHH¼2.1 Hz), 5.82 (m, 2H, CHCH2CH]CH2),
3
5.06 (d, 2H, CHCH2CH]CH2, JHH¼17.1 Hz), 4.93 (d, 2H, CHCH2CH]
3
3
CH2, JHH¼10.3 Hz), 4.60 (t, 2H, JHH¼8.0 Hz), 3.85 (s, 4H, CH2), 3.04
3
(s, 12H, OCH3), 2.78 (t, 4H, CH2CH]CH2, JHH¼8.0 Hz), 1.26 (s, 36H,
4.4.9. 14-(5-Hydroxynonan-5-yl)-5,11,17,23-tetra-tert-butyl-
25,26,27,28-tetramethoxycalix[4]arene-2-carboxylic acid (15). Reag-
ents: 6 (0.40 g, 0.52 mmol); n-BuLi (2.0 mL, 3.2 mmol); TMEDA
(0.55 mL, 0.42 g, 3.6 mmol); CO2 (excess). Yield: 0.28 g (60%). 1H NMR:
C(CH3)3); 13C NMR:
d
¼155.1, 154.2, 144.3, 138.3, 137.3, 137.7, 137.5,
132.7, 132.4, 126.0, 125.6, 122.6, 115.9, 115.6, 60.3, 45.6, 39.2, 37.6, 37.5,
35.3, 34.1, 34.0, 31.7, 31.5, 31.4. IR (cmꢁ1): 2954, 2929, 2867, 2821,1640,
1600, 1477, 1444, 1430, 1392, 1360, 1314, 1290, 1277, 1241, 1224, 1199,
1172, 1131, 1112, 1091, 996, 958, 908, 891, 874, 863, 810, 798, 781, 754,
721, 670, 643, 608, 593, 547, 526, 509. m/z (CI) 785.4 (MHþ). Elemental
analysis calculated for C54H72O4: C, 82.61; H, 9.24. Found: C, 82.35; H,
9.23.
d
¼7.81 (s, 2H, HeAr), 7.11 (s, 6H, HeAr), 5.40 (s,1H, CHCOOH), 4.78 (s,
1H, CHC(C4H9)2OH), 3.97 (d, 2H, CH2, 2JHH¼15.9 Hz), 3.80 (d, 2H, CH2,
2JHH¼15.9 Hz), 3.04 (s, 6H, OCH3), 2.95 (2s, 6H, OCH3), 1.61 (m, 4H,
CHC(CH2CH2CH2CH3)2OH), 1.40 (m, 4H, CHC(CH2CH2CH2CH3)2OH),
1.29 (s, 18H, C(CH3)3), 1.23 (s, 18H, C(CH3)3), 0.85 (m, 4H,
CHC(CH2CH2CH2CH3)2OH), 0.76 (t, 6H, CHC(CH2CH2CH2CH3)2OH,
4.4.6. 14-Allyl-5,11,17,23-tetra-tert-butyl-25,26,27,28-tetramethoxycalix
[4]arene-2-carboxylic acid (12). Reagents: 3 (0.42 g, 0.56 mmol); n-
BuLi (2.2 mL, 3.5 mmol); TMEDA (0.6 mL, 0.46 g, 4 mmol); CO2 (ex-
cess). Yield: 0.34 g (77%). IR (cmꢁ1): 2951, 2928, 2867, 2822, 1709,
1641, 1599, 1478, 1460, 1431, 1392, 1361, 1286, 1242, 1199, 1123, 1016,
3JHH¼7.1 Hz); 13C NMR:
¼179.0,154.9,154.4,144.9,143.8,134.6,132.7,
d
132.1, 126.8, 126.7, 126.4, 124.5, 77.1, 60.4, 60.0, 53.4, 42.0, 41.4, 38.1,
37.6, 34.1, 34.0, 31.5, 31.4, 25.4, 23.1, 13.9. IR (cmꢁ1): 2953, 2868, 2821,
1713, 1601, 1480, 1464, 1431, 1393, 1362, 1286, 1245, 1201, 1178, 1120,
1069, 1019, 998, 949, 874, 809, 775, 733, 664, 629, 542. m/z (CI) 891.2
Table 3
Crystallographic and structure refinement data of the compounds studied
Compound
3
11
12
15
Empirical formula
Formula weight (g/mol)
Crystal system
C
51H68O4
C54H72O4
785.12
Triclinic
Pꢁ1
C56H80O12
945.20
Monoclinic
Pc
15.3738 (4)
15.9383 (4)
11.7944 (3)
90.00
111.2710 (10)
90.00
C60H86O9
951.29
Monoclinic
P21/c
18.4188 (5)
23.1823 (6)
26.0905 (6)
90.00
91.2990 (10)
90.00
745.05
Monoclinic
P21/n
14.1884 (4)
14.2039 (4)
22.5528 (6)
90.00
91.9070 (10)
90.00
Space group
ꢀ
a (A)
9.2499 (3)
9.7830 (3)
13.6256 (5)
84.574 (2)
82.2730 (10)
68.4730 (10)
1135.21 (7)
1
ꢀ
b (A)
ꢀ
c (A)
a
b
g
(ꢀ)
(ꢀ)
(ꢀ)
3
ꢀ
V (A )
4542.6 (2)
4
2693.13 (12)
2
11137.5 (5)
8
Z
F (000)
Dc (mgmꢁ3
(mmꢁ1
1624
1.089
0.067
428
1.148
0.070
1024
1.166
0.080
4144
1.135
0.074
)
m
)
Temperature (K)
153 (2)
100 (2)
100 (2)
100 (2)
No. of collected reflections
42,902
28,956
45,823
188,516
1.11e26.10
ꢁ22/22, ꢁ28/28, ꢁ32/32
22,120
Within the
q
limit (ꢀ)
1.67e28.10
ꢁ18/10, ꢁ18/18, ꢁ29/29
11,040
1.5e29.1
ꢁ12/12, ꢁ13/13, ꢁ18/18
6093
1.28e27.10
ꢁ19/19, ꢁ20/20, ꢁ15/15
5956
Index ranges ꢃh, ꢃk, ꢃl
No. of unique reflections
No. of refined parameters
547
270
634
1284
No. of F values used [I>2
s
(I)]
8379
5407
5198
17,336
R(¼Sj
D
Fj/SjF0j)
0.0516
0.1490
1.060
ꢁ0.445/0.47
0.0402
0.1286
1.10
ꢁ0.28/0.32
0.0604
0.1719
1.080
ꢁ0.46/0.87
0.0625
0.1848
1.173
ꢁ0.50/0.43
wR on F2
S (¼Goodness of fit on F2)
ꢀꢁ3
Final Drmax
/Drmin (e A
)

5662
C. Fischer et al. / Tetrahedron 67 (2011) 5656e5662
(MHþ). Elemental analysis calculated for C58H82O7: C, 78.16; H, 9.27.
Found: C, 77.81; H, 9.18.
structures 3, 11, 12 and 15 (Table S1 and S11eS14) can be found in
the online version of this paper at, doi:10.1016/j.tet.2011.05.087.
4.5. Crystallography
References and notes
1. Gutsche, C. D. CalixarenesdAn Introduction, 2nd ed.; The Royal Society of
Table 3 summarizes the crystal and structure refinement data of
the obtained crystal structures 3, 11, 12 and 15. Single crystals of the
compounds suitable for X-ray diffraction study, were obtained by
slowcrystallizationfrom acetone(3,11) andmixed chloroform/acetic
acid(1:1; 12,15). The intensity datawere collectedona Kappa APEXII
Chemistry: Cambridge, UK, 2008.
€
2. Asfari, M. Z.; Bohmer, V.; Harrowfield, J.; Vicens, J. Calixarenes 2001; Kluwer
Academic: Dordrecht, 2001.
3. Baklouti, L.; Vicens, J.; Harrowfield, J. Calixarenes in the Nanoworld; Springer:
Dordrecht, 2007.
4. Gutsche, C. D.; Dhawan, B.; Levine, J. A.; No, K. H.; Bauer, L. J. Tetrahedron 1983,
39, 409e426.
5. Scully, P. A.; Hamilton, T. M.; Bennett, J. L. Org. Lett. 2001, 3, 2741e2744.
6. Hertel, M. P.; Behrle, A. C.; Williams, S. A.; Schmidt, J. A. R.; Fantini, J. L. Tetra-
hedron 2009, 65, 8657e8667.
7. Gruber, T.; Gruner, M.; Fischer, C.; Seichter, W.; Bombicz, P.; Weber, E. New J.
Chem. 2010, 34, 250e259.
8. Gruner, M.; Fischer, C.; Gruber, T.; Weber, E. Supramol. Chem. 2010, 22,
256e266.
diffractometer (Bruker-AXS) with graphite-monochromated Cu K
a
ꢀ
radiation (l¼0.71073 A) using
u- and
4-scans. Reflections were
corrected for background, Lorentz and polarization effects. Pre-
liminary structure models were derived by application of direct
methods27 and were refined by full-matrix least-squares calculation
based on F2 for all reflections. An empirical absorption correction
based on multiple scanswas applied byusing theSADABSprogram.28
With exception of the disordered solvent molecules all non-
hydrogen atoms were refined anisotropically. All hydrogen atoms
were refined as being constrained to bonding atoms. Crystallo-
graphic data for the respective structures have been deposited at the
Cambridge Crystallographic Data Centre under CCDC-819560 (3),
CCDC-819559 (11), CCDC-819557 (12) and CCDC-819558 (15) and
can be obtained free of charge at www.ccdc.cam.ac.uk/data_request/
cif [or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, fax:
þ44 (0) 1223 336033, e-mail: deposit@ccdc.cam.ac.uk].
9. Agbaria, K.; Biali, S. E. J. Am. Chem. Soc. 2001, 123, 12495e12503.
10. Kuno, L.; Seri, N.; Biali, S. E. Org. Lett. 2007, 9, 1577e1580.
11. Kuno, L.; Biali, S. E. Org. Lett. 2009, 11, 3662e3665.
12. Middel, O.; Greff, Z.; Taylor, N. J.; Verboom, W.; Reinhoudt, D. N.; Snieckus, V. J.
Org. Chem. 2000, 65, 667e675.
€
13. Bohmer, V. Liebigs Ann./Recl. 1997, 2019e2030 and references therein.
€
€
14. Biali, S. E.; Bohmer, V.; Cohen, S.; Ferguson, G.; Gruttner, C.; Grynszpan, F.;
Paulus, E. F.; Thondorf, I.; Vogt, W. J. Am. Chem. Soc. 1996, 118, 12938e12949.
15. Fischer, C.; Gruber, T.; Seichter, W.; Weber, E. Org. Biomol. Chem. 2011, 9,
4347e4352.
16. Fischer, C.; Lin, G.; Seichter, W.; Weber, E. Acta Crystallogr. 2009, E65, o1704.
17. Fischer, C.; Seichter, W.; Weber, E. Struct. Chem. Commun. 2010, 1, 43e45.
18. Fischer, C.; Lin, G.; Bombicz, P.; Seichter, W.; Weber, E. Struct. Chem. 2011, 22,
433e439.
ꢁ
ꢁ
19. Lhotak, P.; Bíla, A.; Budka, J.; Pojarova, M.; Stibor, I. Chem. Commun. 2008,
1662e1664 and references thein.
Acknowledgements
€
€
20. Bohmer, V.; Ferguson, G.; Gruttner, C.; Vogt, W. Acta Crystallogr. 1997, C53,
469e472.
The authors are grateful for generous financial support to this
work from the German Federal Ministry of Economics and Tech-
nology (BMWi) under grant No. 16IN0218 ‘ChemoChips’.
21. Simaan, S.; Biali, S. E. J. Org. Chem. 2004, 69, 95e98.
22. Nishio, M.; Umezawa, Y.; Honda, K.; Tsuboyama, S.; Suezawa, H. Cryst. Eng.
Commun. 2009, 11, 1757e1788.
23. Kitaigorodskii, A. L. Molecular Crystals and Molecules; Academic: New York, NY,
1973.
Supplementary data
24. Gruber, T.; Fischer, C.; Felsmann, M.; Seichter, W.; Weber, E. Org. Biomol. Chem.
2009, 7, 4904e4917.
25. Bondy, C. R.; Gale, P. A.; Loeb, S. J. J. Am. Chem. Soc. 2004, 126, 5030e5031.
26. Gutsche, C. D.; Iqbal, M.; Steward, D. J. Org. Chem. 1986, 51, 742e745.
27. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112e122.
Supplementary data including 2D NMR spectra of compound 14
(S1-S6), NMR spectra of compounds 3 (S7, S8) and 7e15 (S9, S26) as
well as crystallographic data of the herein described X-ray crystal
€
28. Sheldrick, G. M. SADABS; University of Gottingen: Germany, 2004.