Homothiacalix[4]arenes: Synthetic exploration and solid-state structures

Article abstract of DOI:10.1002/chem.201101690

Homothiacalix[n]arenes have been largely underexposed compared with related (homo)heteracalixarenes, although their inherent structural features are particularly attractive for supramolecular host-guest chemistry. In this contribution, the synthetic macro

Full text of DOI:10.1002/chem.201101690

FULL PAPER
DOI: 10.1002/chem.201101690
Homothiacalix[4]arenes: Synthetic Exploration and Solid-State Structures
Joice Thomas,[a] Kristof Van Hecke,[b] Koen Robeyns,[b, d] Wim Van Rossom,[a]
Mahendra P. Sonawane,[a] Luc Van Meervelt,[b] Mario Smet,[a] Wouter Maes,*[a, c] and
Wim Dehaen*[a]
Abstract: Homothiacalix[n]arenes have
been largely underexposed compared
with related (homo)heteracalixarenes,
although their inherent structural fea-
tures are particularly attractive for
supramolecular host–guest chemistry.
In this contribution, the synthetic mac-
rocyclization protocols that afford ho-
mothiacalix[n]arenes have been rein-
vestigated and optimized, providing
straightforward access to the parent
homothiacalix[4]arene skeleton. More-
over, inner-rim (bis and tetrakis) ester
functionalization and dimethylenethia
bridge oxidation were successfully per-
formed as well. Solution-phase (varia-
ble-temperature) NMR spectroscopy
studies and solid-state X-ray structures
provided complementary information
on the conformational features of the
novel macrocycles.
Keywords: calixarenes · conforma-
tion analysis · macrocyclic ligands ·
solid-state structures
AHCTUNGTREGmNNUN olecular chemistry
·
supra-
Introduction
ixarenes in which CH2XCH2 bridges (X=O, NR, S, Se)
partly or completely replace the methylene bridges between
the aromatic units of the classical carbon-bridged calix[n]ar-
enes or the heteroatoms of regular heteracalixarenes.[2–9]
The dimethylenehetera linkages impose an increased cavity
size, as well as conformational mobility, and provide addi-
tional (potentially cooperative) binding sites through the
heteroatoms. These features are beneficial for supramolec-
ular binding of a suitable guest in an induced-fit fashion.
Homooxacalix[n]arenes[2,5] and their derivatives have
been thoroughly studied as crown-like receptor molecules
for the binding of alkali, alkali earth, transition metal, heavy
metal, and lanthanide cations. The coordination complexes
of these homoheteracalixarenes with Ti and V have been ex-
plored as catalytically active substances.[5i,j] They were also
very efficient host molecules for the inclusion of both
charged (tetramethylammonium) and neutral (fullerene) or-
ganic molecules. The cation- and anion-sensing receptor
properties of homoazacalix[n]arene analogues have also
scarcely been reported during the last decade.[6] On the
other hand, although thiacalixarenes[4a–d] are among the
most widely accepted and powerful (calixarene) host mole-
cules for the recognition of organic molecules, as well as
metal ions, homothiacalixarenes have received very little at-
tention. There are only a few examples of homothiacalix-
[n]arenes[8] and related cyclophanes,[10] and their host–guest
properties have only been explored to a minor extent. Ho-
mothiacalixarenes were initially reported to be formed in
trace amounts during the synthesis of dithia-
In recent decades, calixarenes have attracted wide interest
as potential (scaffolds for) supramolecular receptors because
of their capability to form complementary three-dimensional
cavities. Moreover, easy functionalization at the upper and
lower rim enables smooth access to a variety of site-specific
functional host molecules.[1] Homoheteracalixarenes consti-
tute a specific subclass of the various types of known “calix-
arenoid” cyclophanes. They are expanded analogues of cal-
[a] J. Thomas, Dr. W. Van Rossom, M. P. Sonawane, Prof. Dr. M. Smet,
Prof. Dr. W. Maes, Prof. Dr. W. Dehaen
Molecular Design and Synthesis, Department of Chemistry
Katholieke Universiteit Leuven (KUL)
Celestijnenlaan 200F, 3001 Leuven (Belgium)
Fax : (+32)16327990
E-mail: wim.dehaen@chem.kuleuven.be
[b] Dr. K. Van Hecke, Dr. K. Robeyns, Prof. Dr. L. Van Meervelt
Biomolecular Architecture, Department of Chemistry
Katholieke Universiteit Leuven (KUL)
Celestijnenlaan 200F, 3001 Leuven (Belgium)
[c] Prof. Dr. W. Maes
Design & Synthesis of Organic Semiconductors (DSOS)
Institute for Materials Research (IMO), Hasselt University
Agoralaan - Building D, 3590 Diepenbeek (Belgium)
Fax : (+32)11268299
E-mail: wouter.maes@uhasselt.be
[d] Dr. K. Robeyns
Present address: Institute of Condensed Matter
and Nanosciences (IMCN)
Universitꢀ Catholique de Louvain (UCL), Bꢁtiment Lavoisier
Place Louis Pasteur 1 (Bte 3), 1348 Louvain-la-Neuve (Belgium)
AHCTUNGTRENNUNG
[3.3]metacyclophanes.[8a,b] More recently, the synthesis of
hexahomotrithiacalix[3]arenes[8d,e] and homothiaisocalix-
naphthalenes,[8f] starting directly from monomeric precur-
sors, has been reported and the complexation abilities of the
latter have been investigated.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101690. It includes additional
1
experimental and characterization data, H (VT) and 13C NMR spec-
tra for all novel macrocycles and precursors, HRMS (ESI+) isotopic
patterns for the homothiacalix[n]arenes, and extra figures for the X-
ray crystallographic structures.
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10339

In general, in spite of their potential richness and versatil-
ity as ligands, combining the specific features of cyclophanes
and thiacrown ethers, the synthetic and supramolecular
knowledge on homothiacalixarenes is very limited relative
to thiacalixarenes or other structurally related homohetera-
calixarenes (notably oxa). Moreover, solid-state structural
studies of homothiacalixarenes are unknown in any context
to date. Therefore, herein we report a systematic investiga-
tion of the (selective) synthesis of (“all-homo”[1b]) parent ho-
mothiacalix[4]arene 4 (Scheme 1) and analogous macrocy-
chloromethyl)-5-tert-butyl-2-methoxybenzene and its corre-
sponding dithiol derivative 2 with KOH base in EtOH/ben-
zene (see Scheme 1). Gheorghiou and co-workers only ob-
tained metacyclophane 3 (38%), starting from precursors 1
and 2 under similar conditions.[12] The first goal of our study
was to direct the synthetic protocol towards an optimum
yield of cyclic tetramer 4 rather than [1+1] adduct 3. A
thorough search for the optimum macrocyclization condi-
tions was conducted by different combinations of solvent,
base, temperature, and high-dilution conditions to find a
particular combination of these variants to optimize the for-
mation of target macrocycle 4.
As summarized in Table 1, the reaction between precur-
sors 1 and 2 (1:1 molar ratio; Scheme 1) was strongly influ-
enced by the base and solvent used and all of the reactions
Table 1. Effect of solvent and base on the macrocyclization outcome.[a]
Entry
Base
Solvent
Yield
Yield
of 3 [%]
of 4 [%]
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
EtOH
DMF
CH3CN
toluene
1,4-dioxane
THF
THF
THF
THF
50
54
17
22
15
27
[b]
[b]
–
–
–
–
[b]
[b]
5
2
62[c]
41
[b]
[b]
–
–
–
[b]
[b]
9
DIPEA
–
10
11
12
NaH
THF
THF
THF
12
32
12
29
27
52
K2CO3 +[18]crown-6
K2CO3 +NaBH4
Scheme 1. Synthetic pathway towards homothiacalix[4]arene 4.
[a] The reaction was conducted at 708C under high-dilution conditions
(employing a syringe pump). Product 3 is the [1+1] product and product
4 is the [2+2] product. DIPEA=diisopropylethylamine. [b] An unidenti-
fied mixture of inseparable oligomers was obtained. [c] The rest of the re-
action mixture probably consisted of polymeric material.
cles by a straightforward one-pot macrocyclization approach
that involves substitution reactions of 1,3-bis(mercaptome-
thyl)benzene nucleophiles on 1,3-bis(bromomethyl)benzene
derivatives under basic conditions. Our interest in (homohe-
tera)calixarenes previously led us to discover a new class of
homocalixarene macrocycles, containing CH2SeCH2 bridging
units, with a ring size varying from three to eight monomeric
building blocks.[9] A precursor enabling high solubility for
all homoselenacalix[n]arenes (n=3–8) was chosen in this
previous study. Therefore, we envisaged to use the same
building block, 1,3-bis(bromomethyl)-5-tert-butyl-2-methox-
ybenzene (1), as an electrophile and its corresponding di-
thiol derivative 2 as the nucleophilic component (see
Scheme 1). This substitution pattern also allows direct com-
parison with the related homooxa- and homoselenacalixar-
enes.[5,9]
were carried out under high-dilution conditions (employing
a syringe pump) at 708C. The addition of both substrates at
once increased the degree of polymer formation. The combi-
nation of K2CO3 with a rather polar solvent, such as ethanol
or DMF, afforded 50 and 54% of [1+1] coupling product 3,
respectively, along with 22 and 15% of [2+2] coupling
product 4, respectively (Table 1, entries 1 and 2). The mac-
rocycles were efficiently separated and purified by column
chromatography (on silica gel). The same reaction in aceto-
nitrile afforded a slightly higher amount of homothiaca-
lix[4]arene 4 (27%), with a concurrent decrease in thiacyclo-
phane formation (17%; Table 1, entry 3). The reaction out-
come could hence be reversed, in the sense that the [2+2]
macrocyclization product was favored under these condi-
tions. When the reaction was carried out in more apolar sol-
vents, such as toluene or 1,4-dioxane, in the presence of
K2CO3 as a base, a mixture of inseparable oligomers was ob-
tained (Table 1, entries 4 and 5). On the other hand, the
yield of 4 improved drastically to 62% when the reaction
was performed in THF (Table 1, entry 6). The dithiacyclo-
phane adduct 3 was only obtained as a minor side product
Results and Discussion
Synthesis and characterization: In 1981, Tashiro and Yamato
described the occurrence of a cyclic tetramer,[8b] which can
be regarded as an octahomotetrathiacalix[4]arene (p-tert-bu-
tyloctahomotetrathiacalix[4]arene tetramethyl ether 4),[11] as
a side product (7%) during the synthesis of dithiacyclo-
phane 3 (56%) by a cyclocondensation reaction of 1,3-bis(-
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Homothiacalix[4]arenes
FULL PAPER
(5%) under these conditions. Upon changing to other bases
(Cs2CO3, Na2CO3, DIPEA or NaH; Table 1, entries 7–10),
yields of cyclotetramer 4 were systematically lower, al-
though the preference for the homothiacalix[4]arene was re-
tained for Cs2CO3 and NaH. A possible template effect of
the K+ counterions was analyzed by comparison with a re-
action in which [18]crown-6 was added (Table 1, entry 11).
The yield of [1+1] coupling product 3 increased to 32%
along with a concurrent decrease in the yield of [2+2] cy-
clooligomer 4 to 27%, suggesting a templating effect of K+
towards the formation of the cyclic tetramer.[5a] To suppress
the possible in situ formation of the disulfide of precursor 2
during the course of the reaction, an equimolar amount of
NaBH4 was added to the reaction, resulting in a small de-
crease in the yield of 4 (to 52%; Table 1, entry 12), possibly
due to competition between the Na+ and K+ ions.
Figure 1. Upfield shift for the OCH3 protons of homothiacalix[4]arene 4
(upon decreasing T).
These experimental observations indicated convincingly
that both the base and the solvent played an important role
in facilitating and directing macrocyclization outcome. By
careful optimization of the reaction parameters, the ratio of
the macrocyclic products formed could be completely re-
versed and the desired homothiacalix[4]arene 4 could be
prepared in good yield (62%).[13] When the reaction was re-
peated with larger reagent quantities (3.9 mmol) and a
higher concentration (10 mm), analytically pure macrocycle
4 was obtained in 53% yield. None of the larger cyclo-
lix[4]arenes in solution, and corresponds to the observed
1,2-alternate solid-state structure (see Figure 2). The same
observations were previously made for the homoselenaca-
lix[4]arene homologue.[9] To gain further insight into the
conformational behavior of homothiacalix[4]arene 4 in solu-
1
tion, variable-temperature (VT) H NMR spectra were re-
A
corded. No signal splitting was observed for temperatures
down to 230 K, while further shielding of the methoxy pro-
NMR spectroscopy (1H, 13C) and high-resolution (HR) MS
and showed good solubility in a variety of (medium polari-
ty) organic solvents, such as CH2Cl2, ethyl acetate, and THF.
The H NMR spectrum of 4 was very straightforward and
showed sharp singlet signals for each of the protons. The ab-
sence of coupling for the geminal protons of the benzylic
methylene groups (due to diastereotopicity, as observed for
thiacyclophane 3) suggested fast conformational intercon-
version in solution (on the 1H NMR spectroscopy time-
scale). As for classical methylene-bridged calix[4]arenes,
four fundamental conformations—cone, partial cone, 1,2-al-
ternate and 1,3-alternate—should be taken into account, as
determined by the relative orientation (parallel or antiparal-
lel) of the aromatic subunits. For similar octahomotetraoxa-
calix[4]arenes, it was reported that non-cone conformations
(1,2- or 1,3-alternate) were probably preferred.[5a,f,k] This in-
terpretation was based on the upfield shift of the intraannu-
lar methoxy substituents with respect to the acyclic precur-
sors. A similar but more extensive upfield shift was observed
for the methoxy protons of homothiacalix[4]arene 4. The
protons of the OCH3 signal appeared at d=3.15 ppm at RT
(Figure 1), about 0.65 ppm upfield with respect to the stan-
dard value (d=3.80 ppm). This indicated that the conforma-
tions in which the methoxy protons faced the rings of neigh-
boring aromatic units were more likely to be populated in
this case, and hence, reduced the chance of having a fixed
cone conformation with deep cavities and facing aromatic
rings. This assignment is in agreement with a 1,2- or 1,3-al-
ternate conformation for 4, such as that for homooxaca-
Figure 2. Molecular structure (with the atom labeling scheme of the
asymmetric unit) of homothiacalix[4]arene 4, with thermal displacement
ellipsoids drawn at the 50% probability level. For clarity, hydrogen
atoms are not shown.
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10341

W. Dehaen, W. Maes et al.
tons was noted, ranging from d=3.15 ppm at RT to d=
2.87 ppm at 220 K (Figure 1).
atoms of homothiacalix[n]arenes, which may impose specific
host–guest properties, has not yet been reported. The pres-
ence of sulfur atoms in the linkers enables a novel derivati-
zation pathway for these molecules, which is not applicable
to the homooxa- or homoazacalixarene subclasses, that is,
oxidation to sulfinyl and sulfonyl moieties. These com-
pounds may be of interest for the design of new receptors,
according to well-established thiacalixarene chemistry.[4a–d,14]
The synthetic strategy for the preparation of the tetrasulfon-
yl analogue was based upon complete oxidation of homo-
thiacalix[4]arene 4 by treatment with a 12-fold excess of m-
chloroperbenzoic acid (m-CPBA), affording the desired tet-
rasulfonylcalix[4]arene 11 in 84% yield (Scheme 3).[8d,14a]
Studies on the effect of intra- and extraannular aryl sub-
stituents on the macrocyclization outcome for homoselena-
calix[4]arenes indicated that the methoxy groups on the
inner rim played a crucial role for the selective formation of
the cyclic tetramer.[9] Hence, we decided to carry out similar
studies for homothiacalix[4]arenes. Reaction of 1,3-bis(mer-
captomethyl)-5-tert-butyl-2-methoxybenzene (2) and 1,3-
bis(bromomethyl)benzene (5) under the previously opti-
mized conditions (K2CO3, THF, 6 h reflux, high dilution) af-
forded dimeric dithiaACTHNUGRTENUNG[3.3]metacyclophane 7 (46%) as the
major compound, together with 22% of homothiacalix[4]ar-
ene 8 (Scheme 2). This indicates that the absence of the me-
1
The H NMR spectrum of 11 exhibited only one set of sig-
nals for the benzylic protons. Both the methoxy and methyl-
ene protons appeared slightly downfield (at d=3.49 and
Scheme 3. Oxidation of the bridging sulfur atoms.
4.17 ppm, respectively, at RT) compared with the parent ho-
mothiacalix[4]arene 4 (see the Supporting Information). At-
tempts to produce the tetrasulfinyl derivative were carried
out with a smaller amount of oxidant, based on previous
conversions of thiacalixarenes, and the best result was ob-
tained with hydrogen peroxide in glacial acetic acid.[14c]
However, purification of the tetrasulfinylcalix[4]arene was
not successful due to the presence of overoxidized products.
Towards further functionalization of octahomothiaca-
lix[4]arene 4 on the lower rim, deprotection of the methoxy
groups was initially pursued by using BBr3 or trimethylsilyl
iodide (TMSI) under different conditions. However, this ap-
proach was not successful because it was difficult to selec-
tively deprotect the methoxy groups without affecting the
macrocycle. Therefore, the introduction of the intraannular
substituents should be preferentially performed prior to
macrocyclization. We opted for the introduction of (tert-
butyl) ester functions, since this enabled further modifica-
tion on the inner rim at a later stage. The synthesis of func-
tionalized precursors 14 and 15 was carried out in a relative-
ly straightforward approach, as outlined in Scheme 4. (5-tert-
Butyl-2-hydroxy-1,3-phenylene)dimethanol (12) was treated
with tert-butyl 2-bromoacetate in the presence of K2CO3 to
afford tert-butyl ester 13, which was then brominated with
NBS/PPh3, yielding the corresponding bis(benzyl bromide)
14. Treatment of 14 with thiourea followed by hydrolysis in
Scheme 2. Exploration of the thiacyclophane size.
thoxy group ortho to the benzylic positions favors [1+1] cy-
clocondensation. On the other hand, the reaction of 2-me-
thoxy-1,3-bis(mercaptomethyl)benzene (6), which is a nucle-
ophile lacking the tert-butyl moiety, and 1,3-bis(bromometh-
yl)-5-tert-butyl-2-methoxybenzene
(1)
under
similar
conditions as those described above gave [2+2] cyclocon-
densation product 10 (44%) as the main macrocycle along
with 8% of [1+1] cyclocondensed product 9. The above ob-
servations indicate that, as in homoselenacalixarenes, the
inner-rim methoxy groups also play a crucial role for the
higher selectivity of the [2+2] coupling product in the ho-
mothiacalixarene series.
The 1H NMR spectra of A2B2-type octahomotetrathia-
ACHTUNGTRENNUNGcalix[4]arenes 8 and 10 likewise showed shielded signals for
the methoxy protons (at d=3.46 and 3.26/3.23 ppm, respec-
tively, at RT), indicating once more a preference for non-
cone conformations in solution (see the Supporting Informa-
tion).
The introduction of specific functional groups onto the
lower rim, or further derivatization of the bridging sulfur
the presence of ethylenediamine gave bis
pound 15. The optimized procedure for the synthesis of 4
ACHTUNGTREN(NGNU mercapto) com-
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Homothiacalix[4]arenes
FULL PAPER
methoxy-functionalized precursors. Tetracarboxyl derivative
20 was obtained in 90% yield by treating the corresponding
tetraester 18 with trifluoroacetic acid (TFA), and was solu-
ble in water. This compound can be used for further chemi-
cal transformations by coupling various functional groups to
the carboxyl moieties towards preparation of modified re-
ceptors. Similar inner-rim functionalized homotrioxacalix[3]-
arenes were previously explored as receptors for alkali, al-
kaline earth, transition, and heavy metal ions, and lantha-
nide cations.[5k]
Temperature-dependent 1H NMR spectroscopy was ap-
plied to analyze the conformational preferences of the func-
tionalized homothiacalix[n]arenes 16–20 in the liquid state
1
(see the Supporting Information). The H NMR spectrum of
homothiacalix[4]arene 16 at room temperature in CDCl3
displayed eight AB-type pairs of doublets for the bridging
methylene protons and individual signals for each of the
tert-butyl, methoxy, and side-chain methylene groups. In ad-
dition, four singlets were observed in the aromatic region.
These observations indicated restricted rotation imposed by
the bulky inner-rim tert-butyl acetate moieties, hindering ro-
ꢀ
tation of the aryl groups around their C2 C6 axis (O-alkyl
through-the-annulus rotation). On the other hand, a simpli-
fied set of two (broad) signals for the aromatic region and
three signals for the (two distinct sets of) tert-butyl groups
were observed at 328 K, which could be explained by the
fastened conformational dynamics at higher temperature
(on the 1H NMR spectroscopy timescale). The 1H NMR
spectrum recorded in [D6]DMSO at 353 K showed very
sharp signals for most of the protons; the only exception
was one of the bridging methylene moieties. The two inner-
rim methoxy groups showed upfield-shifted resonances (at
d=3.16 and 3.11 ppm at 300 K), which seemed to preclude a
large contribution of cone conformations. In the solid state,
Scheme 4. Synthesis of inner-rim functionalized homothiacalix[n]arenes
16–20. NBS=N-bromosuccinimide.
was then used for the synthesis of macrocycles with ester
groups on the lower rim. The [2+2] coupling reaction of 14
and 2 gave the corresponding unsymmetrical homothiaca-
lix[4]arene 16 in 28% yield, with concomitant formation of
homothiacalix[6]arene 17 in 6% yield. The presence of acy-
clic oligomers in the reaction mixture indicated the need for
a longer reaction time. An optimized yield of 16 (51%) and
17 (10%) was obtained by refluxing the reaction mixture for
two days in THF. Changing the concentration of the re-
agents and avoiding high-dilution conditions resulted in a
significant drop in the yield and the calixarenes could only
be obtained in negligible amounts. However, none of the
above optimized procedures worked well for the coupling of
14 and 15 towards the analogous tetrasubstituted ester de-
rivative. Fortunately, the replacement of THF by the higher
boiling solvent 1,4-dioxane resulted in the formation of the
desired [2+2] coupling product 18 in 46% yield, along with
[3+3] coupling product 19 in 16% yield. It is worth noting
that all macrocycles obtained in the two reactions men-
tioned above were easily separated and efficiently purified
by column chromatography (on silica gel). As anticipated,
none of the [1+1] cyclophane products were obtained in
any of these reactions because of the sterically demanding
tert-butyl ester groups. The same steric features might also
explain the formation of the enlarged homothiacalix[6]arene
homologues in this case,[15] whereas they were not observed
(in reasonable amounts) when starting from the inner-rim
a
1,2-alternate molecular structure was identified (see
Figure 3). The singlet signals observed for the bridging
methylene groups of enlarged homothiacalix[6]arene homo-
logue 17 indicated enhanced flexibility and a faster confor-
mational interconversion at room temperature. For tetrasub-
stituted ester derivative 18, extensive broadening of the
1H NMR signals was observed for each of the protons at
300 K, which could be ascribed to a slower interconversion
of the conformers due to the presence of four substituents
at the lower rim. Extensive signal splitting for all of the pro-
tons was observed while going from room temperature to
230 K; this was indicative of the presence of multiple con-
formers. The signals were noticeably sharper at 328 K and
very sharp singlets were again observed at 353 K (in
[D6]DMSO). In this case, a 1,3-alternate molecular structure
was observed by X-ray diffraction (see Figure 4). Enhanced
flexibility was once more observed for the cyclic hexamer
19. The analogous tetracarboxyl derivative 20 seemed to be
somewhat more conformationally flexible. However, some
broadening was still observed for the dimethylenesulfide
bridges and the methylene groups at the intraannular posi-
tions at 300 K. At 328 K all signals were sharper and well
defined.
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W. Dehaen, W. Maes et al.
In a manner similar to that used to prepare the monocy-
clic homothiacalix[4]arene compounds, bicyclic analogue 22
was synthesized in 23% yield through a single-step reaction
of a trifunctional electrophile, 1,3,5-tris(bromomethyl)-2,4,6-
trimethoxybenzene (21), with bisnucleophile 2 (Scheme 5)
Scheme 5. Synthetic pathway towards bicyclohomothiacalix[4]arene 22.
Figure 3. Molecular structure (with the atom labeling scheme of the
asymmetric unit) of inner-rim difunctionalized homothiacalix[4]arene 16,
with thermal displacement ellipsoids drawn at the 50% probability level.
For clarity, hydrogen atoms and disorder of the tert-butyl groups are not
shown.
in a 2:3 molar ratio. Higher polycyclic or cyclic oligomers
might be formed, but we did not detect (ESI-MS) or isolate
any of these species. High-dilution conditions were essential
to prevent extensive polymer formation. Application of a
solvent and base other than THF and K2CO3 did not result
1
in the desired product. The very simple H NMR spectrum
of macrobicycle 22 indicated a symmetrical structure in solu-
tion. The upfield shift observed for the intraannular me-
thoxy protons (d=3.07 ppm) of the dithiol precursor part in
the bicyclic structure, in comparison with the other methoxy
protons (d=3.76 ppm), indicated a diamagnetic shielding
effect of the neighboring aromatic rings. This observation
suggested that the methoxy groups of the nucleophilic com-
ponent pointed (on average) more directly into the formed
cavity, whereas the methoxy groups of the electrophilic com-
ponent pointed more outwards (in solution). From the solid-
state structure, it can be seen that (only) one of the methoxy
groups of the nucleophilic precursor is self-included (see
Figure 5). Cage compound 22, which can be seen as a homo-
thiacalix[4]arene with an additional phenyl cap, can possibly
be applied to bind specific guest molecules. Three-dimen-
sionally preorganized bicyclic ligands often provide a better
steric fit for guests. An analogous bicyclic hexaazahomoca-
lixarene has recently been synthesized and showed dual rec-
ognition (both cavity and cleft binding) of guest molecules
(e.g., acetone).[6f]
Figure 4. Molecular structure (with the atom labeling scheme of the
asymmetric unit) of inner-rim tetrafunctionalized homothiacalix[4]arene
18, with thermal displacement ellipsoids drawn at the 50% probability
level. For clarity, hydrogen atoms and disorder of the tert-butyl groups
are not shown.
Solid-state structural elucidation: To confirm the structures
and analyze the conformations of the synthesized macrocy-
cles in the solid state, high-quality single crystals of com-
pounds 4, 16, 18, and 22 were obtained by vapor diffusion of
methanol (4, 18 and 22) or pentane (16) in solutions of the
calixarenes in chloroform. X-ray diffraction analysis thus al-
10344
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Chem. Eur. J. 2011, 17, 10339 – 10349

Homothiacalix[4]arenes
FULL PAPER
and neighboring aryl units
(CH···phenyl centroid distances
of 2.61 and 2.84 ꢃ).
Homothiacalix[4]arene
16
likewise adopted a 1,2-alternate
solid-state conformation and
was also situated on an inver-
sion centre (Figure 3). A least-
squares plane could be calculat-
ed through the centroids of the
aryl rings (deviation 0.06/
0.09 ꢃ). The enclosed cavity,
defined by the distances be-
tween the aryl centroids, was
almost a square (7.16ꢄ7.66 ꢃ;
see the Supporting Informa-
tion). As in macrocycle 4, the
bond configuration around the
S atoms was V shaped, with
bond lengths of 1.82 ꢃ and an
angle of 101.6 or 101.78, which
was close to expected values.
The torsion angles around the
bridging S atoms were alternat-
ing in the anti/gauche confor-
mation (179.5/84.98) or in the
anti/anti conformation (161.0/
Figure 5. Molecular structure (with the atom labeling scheme) of bicyclohomothiacalix[4]arene 22, with ther-
mal displacement ellipsoids drawn at the 50% probability level. Only one out of three molecules in the asym-
metric unit is shown. For clarity, hydrogen atoms are not shown.
lowed us to examine the structures in the solid state. An evi-
dent but important feature of the solid-state molecular
structures is the rigidity of the macrorings, which simplifies
conformational analysis, in contrast to the liquid state.
176.88). All of the tert-butyl substituents were directed out-
wards and they all showed twofold disorder. The inner-rim
substituents were all directed inwards and further enclosed
the cavity. An intermolecular close CH···p contact (2.72 ꢃ)
was observed between the tert-butyl protons of a methoxy-
phenyl moiety and the centroid of a phenyl ring with a self-
included ester moiety.
Homothiacalix[4]arene 4 adopted a 1,2-alternate confor-
mation in the solid state (Figure 2), which resembled analo-
gous homooxacalix[4]arene structures,[5b,c] but was notably
different from the (highly distorted) 1,3-alternate structure
obtained for the corresponding homoselenacalix[4]arene.[9]
The cyclic structure of 4 was positioned on an inversion
center, with two opposing sulfur atoms pointing inwards,
whereas the remaining two atoms pointed outwards. The
torsion angles C-C-S-C and C-S-C-C were in the anti/anti
conformation (173.3 and ꢀ177.88) for the former and in the
gauche/gauche conformation (ꢀ64.6 and ꢀ52.48) for the
For inner-rim tetrafunctionalized homothiacalix[4]arene
18, the asymmetric unit consisted of one quarter of the total
cyclic structure, which was constructed around a fourfold ro-
toinversion axis, and the macrocycle adopted a 1,3-alternate
conformation (Figure 4). As in the crystal structures of 4
and 16, the bond configuration around the S atoms was V
shaped, with all sulfur atoms pointing outwards. The torsion
angles C-C-S-C and C-S-C-C were all (because of symmetry
reasons) in the anti/anti (ꢀ/+167.2 and ꢀ/+97.48) confor-
ꢀ
latter. The C S distances (1.80–1.82 ꢃ) and the C-S-C
ꢀ
angles (96.6 and 100.28) were within the expected range.
The bond configuration around the S atoms was V shaped.
The rectangular enclosed cavity, defined by the distances be-
tween the aryl centroids, was 5.39ꢄ7.92 ꢃ (see the Support-
ing Information). These centroids were situated on the same
plane, with deviations of 0.16 ꢃ. In the packing, a 3.45 ꢃ
contact was observed between two neighboring S atoms.
Another close (2.60/2.74 ꢃ) contact was observed between a
hydrogen atom of a bridging methylene group and the cent-
roid of a neighboring aryl ring. All methoxy groups were di-
rected inwards (self-inclusion), which may have correlated
mations. The S C bond lengths and C-S-C angles all
equaled 1.83 ꢃ and 102.48, respectively. A square was
formed by the aryl centroids, with a side of 6.99 ꢃ (see the
Supporting Information). These centroids were situated on
the same plane (deviations of 0.56 ꢃ). Two of the inner-rim
tert-butyl acetate moieties were directed outwards on one
side of the aryl plane, whereas the remaining two opposing
moieties were also pointing outwards, but in the opposite di-
rection on the other side of the plane. All tert-butyl groups,
as well those of the acetate groups as those directly on the
phenyl rings, were disordered. In the packing, a potential
hydrogen bond was observed between the C5(H) atom of
one calixarene molecule and the S1 atom of symmetry-
equivalent molecules (C(H)···S distance of 3.77 ꢃ), linking
1
to the observed shielding effect in the H NMR spectrum of
4. Intramolecular CH···p interactions were observed be-
tween the protons of the self-included methoxy moieties
Chem. Eur. J. 2011, 17, 10339 – 10349
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10345

W. Dehaen, W. Maes et al.
the calixarene molecules together in the [100] and [010] di-
rections.
tetrasubstituted derivative 18 showed a distorted 1,3-alter-
nate conformation in the crystalline state. The solid-state
structures were complemented with a view on the conforma-
Bicyclohomothiacalix[4]arene 22 crystallized in the cen-
1
¯
trosymmetric space group P1, with an asymmetric unit con-
tional mobility in solution, as established by (VT) H NMR
sisting of three complete calixarene molecules. One calixar-
ene molecule contained five aryl moieties: three tert-butyl
acetate substituted (precursor 2) and two trimethoxy-substi-
tuted (precursor 21) building blocks (Figure 5). All three
calixarene molecules exhibited the same bicyclic configura-
tion, that is, a first macrocycle was formed by two tert-butyl
acetate and two trimethoxy building blocks, whereas a
second macrocycle was formed by an additional tert-butyl
acetate precursor positioned on top of the first macrocycle.
As in the crystal structures of 4, 16, and 18, the bond config-
uration around the sulfur atoms was V shaped, with all S
atoms pointing outwards. For the first macrocycle, the tor-
sion angles C-C-S-C and C-S-C-C alternated between
gauche/anti (range of 53.6 to 72.08 and ꢀ164.2 to 177.68) and
anti/gauche (range of ꢀ166.6 to 179.5 and ꢀ59.7 to ꢀ66.88)
conformations, respectively. For the second macrocycle, the
torsion angles C-C-S-C and C-S-C-C were in the gauche/anti
(range of 71.0 to ꢀ83.98 and 158.5 to ꢀ164.48) conformation.
spectroscopy conformational analysis. Cone conformations
appeared to be generally disfavored. The synthetic results
obtained in this work enable homothiacalixarenes to (re)-
claim their justified position among related powerful recep-
tor molecules in host–guest chemistry. Our current research
efforts are addressed towards this issue.
Experimental Section
General experimental methods: (Temperature-dependent) NMR spectra
were acquired on commercial instruments (Bruker Avance 300 MHz,
Bruker AMX 400 MHz, or Bruker Avance II+ 600 MHz) and chemical
shifts (d) are reported in parts per million (ppm) referenced to tetrame-
thylsilane (1H) or the internal (NMR) solvent signals (13C). Mass spectra
were run by using an HP5989A apparatus (CI and EI, 70 eV ionization
energy) with an Apollo 300 data system or a Thermo Finnigan LCQ Ad-
vantage apparatus (ESI). Exact mass measurements were acquired on a
Kratos MS50TC instrument (performed in the EI mode at a resolution of
10000) or a Bruker Daltonics Apex2 FT-ICR instrument (performed in
the ESI mode at a resolution of 60000). IR spectra were recorded on a
Bruker-Alpha T FTIR spectrometer with universal sampling module.
Melting points were determined by using a Reichert Thermovar appara-
tus. For column chromatography, 70–230 mesh silica gel 60 (Merck) was
used as the stationary phase. Chemicals received from commercial sour-
ces were used without further purification. Reaction solvents (THF, etha-
nol) were used as received from commercial sources. Additions in (high-
dilution) macrocyclization reactions were performed at a constant rate
with the aid of an infusion pump.
ꢀ
The S C bond lengths and C-S-C angles ranged from 1.77
to 1.84 ꢃ and from 93.7 to 100.58, respectively. Intermolecu-
lar close contacts (2.59/2.86/2.99 ꢃ) were observed between
the hydrogen atoms of the methylene bridges and neighbor-
ing phenyl rings. The protons of a self-included methoxy
group (on the nucleophilic component) showed an intramo-
lecular CH···p interaction with the neighboring aryl unit
(CH···phenyl centroid distance of 2.96 ꢃ). One CHCl3 sol-
vent molecule could be unambiguously observed, contacting
two S atoms within one calixarene molecule (Cl···S distances
of 3.44 and 3.35 ꢃ).
General procedure for [2+2]/
procedure outlined is applicable for the synthesis of homothiacalix[4]ar-
enes 4, 8, and 10 and the dimeric dithia[3.3]metacyclophanes 3, 7, and 9.
ACHTUNGTRENUN[NG 1+1] cyclooligomerization reactions: The
AHCTUNGTRENNUNG
Separate degassed solutions of the respective bis(bromomethyl)benzene
(1 equiv, 0.78 mmol) and bis(mercaptomethyl)benzene (1 equiv,
0.78 mmol) precursors in THF (12 mL) were collected in syringes and
added dropwise (with the aid of a syringe pump) to a stirred degassed
mixture of K2CO3 (5 equiv, 3.9 mmol) in THF (150 mL) at reflux temper-
ature over a period of 5 h. After complete addition, the mixture was
stirred at reflux for an additional 10 h period after which time the mix-
ture was cooled to RT and evaporated to dryness. The crude residue was
redissolved in a mixture of CH2Cl2 and water. The organic fraction was
separated, washed with water, dried over MgSO4, filtered, and evaporat-
ed to dryness. Purification by column chromatography (silica gel, eluent
CH2Cl2/hexane/diethyl ether mixtures) afforded the corresponding mac-
rocycles as off-white solids.
Conclusion
An optimized one-pot procedure for the synthesis of homo-
thiacalix[4]arenes was presented. Careful screening of the
macrocyclization conditions enabled a spectacular increase
in yield from 7 (previous literature) to 62%, with a concom-
itant decrease in dithiacyclophane formation. The presence
of intraannular methoxy groups was crucial to direct the
macrocyclization outcome to the cyclic tetramer rather than
the cyclic dimer. The procedure could easily be extended to
lower-rim tert-butyl ester functionalized homothiacalix[4]ar-
enes and smooth conversion to the tetracarboxyl derivative
was achieved as well. Moreover, oxidation of the bridging
sulfur atoms afforded the tetrasulfonylcalix[4]arene ana-
logue. We also demonstrated that a simple extension of this
approach resulted in the synthesis of a conformationally
more-rigid macrobicyclic homothiacalix[4]arene cage com-
pound. All homothiacalixarene macrocycles were complete-
ly characterized, including single-crystal X-ray analysis of
homothiacalix[n]arenes 4, 16, 18, and 22. Among the mono-
cyclic homothiacalix[4]calixarenes, compounds 4 and 16
showed a 1,2-alternate solid-state conformation, whereas the
Compounds 3 and 4: A mixture of K2CO3 (0.539 g, 3.9 mmol, 5 equiv), 1
(0.273 g, 0.78 mmol, 1 equiv), and 2 (0.200 g, 0.78 mmol, 1 equiv) was
used. Purification by column chromatography (silica gel, eluent CH2Cl2/
hexane/diethyl ether 57.5:40:2.5) afforded 3 (0.017 g, 5%) and 4 (0.215 g,
62%) as off-white solids.
Compound 4:[8b] M.p. 245.5–246.58C; 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.20 (s, 8H; ArH), 3.66 (s, 16H; CH2), 3.16 (s, 12H; OCH3),
1.30 ppm (s, 36H; tBu); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=
154.2, 146.6, 130.7, 127.0 (CH), 61.3 (OCH3), 34.4, 31.5 (CH3), 30.6 ppm
(CH2); IR (ATR): n˜max =2952, 2865, 2828, 1480, 1462, 1361, 1248, 1200,
1098, 1000, 885, 813, 635 cmꢀ1; MS (ESI+): m/z: 911.6 [M+Na]+; HRMS
(ESI+): m/z calcd for C52H72O4S4Na [M+Na]+: 911.4206; found:
911.4214.
Compound 3: M.p. 225.5–226.58C; 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.29 (s, 4H; ArH), 3.78 (d, 2J
ACHTUNGTRENNUNG
(d, 2J
ACHTUNGTRENNUNG
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Chem. Eur. J. 2011, 17, 10339 – 10349

Homothiacalix[4]arenes
FULL PAPER
tBu); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=156.5, 146.0, 127.9,
127.7 (CH), 60.8 (OCH3), 34.4, 31.5 (CH3), 27.1 ppm (CH2); IR (ATR):
n˜max =2952, 2865, 2828, 1482, 1431, 1248, 1200, 1098, 1000, 885, 813,
650 cmꢀ1; MS (EI): m/z: 444 [M]+; HRMS (EI): m/z calcd for C26H36O2S2
[M]+: 444.2157; found: 444.2121.
Compound 13: tert-Butyl 2-bromoacetate (3.63 g, 18.6 mmol, 1.1 equiv)
was added to a mixture of 12 (3.56 g, 17.0 mmol) and K2CO3 (6.13 g,
84.8 mmol, 5 equiv) in dry CH3CN (50 mL). The mixture was stirred at
RT for 3 d and then concentrated under reduced pressure. The crude res-
idue was redissolved in a mixture of CH2Cl2 and water. The organic frac-
tion was separated, washed with water, dried over MgSO4, filtered, and
evaporated to dryness. Pure compound 13 was obtained by precipitation
from heptane, filtering, and drying in vacuo (3.07 g, 56%). M.p. 147–
1488C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.29 (s, 2H; ArH),
Compounds 7 and 8: A mixture of K2CO3 (0.539 g, 3.9 mmol, 5 equiv), 5
(0.205 g, 0.78 mmol, 1 equiv) and 2 (0.200 g, 0.78 mmol, 1 equiv) was
used. Purification by column chromatography (silica gel, eluent CH2Cl2/
hexane/diethyl ether 47:47:6) afforded 7 (0.128 g, 46%) and 8 (0.062 g,
22%) as off-white solids.
4.70 (d, 3J
(H,H)=6.0 Hz, 4H; CH2-OH), 4.56 (s, 2H; OCH2), 2.93 (t, 3J-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Compound 7: M.p. 183.5–184.58C; 1H NMR (300 MHz, CDCl3, 258C,
13C NMR (75 MHz, CDCl3, 258C, TMS): d=169.7 (CO), 153.9, 147.7,
132.9, 126.8 (CH), 83.0 (O-tBu), 71.7 (OCH2), 61.9 (CH2OH), 34.4 (tBu),
31.4 (CH3), 28.1 ppm (CH3); IR (ATR): n˜max =3442, 3388, 2952, 2820,
1736, 1484, 1432, 1363, 1242, 1202, 1120, 1057, 1033, 1008, 963, 886, 831,
792, 546 cmꢀ1; MS (ESI+): m/z: 347 [M+Na]+; HRMS (ESI+): m/z calcd
for C18H28O5Na [M+Na]+: 347.1834; found: 347.1825.
TMS): d=7.04 (s, 1H; ArH), 6.94 (s, 2H; ArH), 6.88 (s, 3H; ArH), 4.26
(d, 2J
3.69 (s, 3H; OCH3), 3.68 (d, 2J
ACHTUNGTRENNUNG
(H,H)=14.3 Hz, 2H; CH2), 1.12 ppm (s, 9H; tBu); 13C NMR (75 MHz,
ACHTUNGTRENNUNG ACHTUNGTRENNUNG
(H,H)=14.3 Hz, 2H; CH2), 3.78 (d, 2J
AHCTUNGTRENNUNG
CDCl3, 258C, TMS): d=154.2, 146.5, 137.9, 130.2, 129.4 (CH), 128.7
(CH), 126.7 (CH), 126.5 (CH), 62.2 (OCH3), 38.0 (CH2), 34.2, 31.4
(CH2), 31.2 ppm (CH3); IR (ATR): n˜max =2947, 2854, 2826, 1604, 1478,
1435, 1255, 1203, 1100, 1004, 885, 822, 635 cmꢀ1; MS (EI): m/z: 358 [M]+;
HRMS (EI): m/z calcd for C21H26OS2 [M]+: 358.1425; found: 358.1443.
Compound 14: A degassed solution of 13 (0.865 g, 2.66 mmol) and N-
bromosuccinimide (1.14 g, 6.41 mmol, 2.4 equiv) in CH2Cl2 (40 mL) was
prepared in a 100 mL flask and cooled to 08C. The solution became
slightly green after 5 min.
A solution of PPh3 (1.67 g, 6.41 mmol,
1
Compound 8: M.p. 171–1738C; H NMR (300 MHz, CDCl3, 258C, TMS):
2.4 equiv) in CH2Cl2 (10 mL) was added dropwise by using a syringe
pump over 1 h with vigorous stirring. Upon addition of the phosphine,
the solution turned colorless and was stirred for an additional 1 h at 08C.
The reaction mixture was quenched with ice water (50 mL) and extracted
with CH2Cl2 (50 mL), dried over MgSO4, filtered, and evaporated to dry-
ness to afford the crude product. Purification by column chromatography
(silica gel, eluent CH2Cl2/hexane 7:2) afforded 14 as an off-white solid
(0.81 g, 67%). M.p. 143–1448C; 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.35 (s, 2H; ArH), 4.68 (s, 2H; OCH2), 4.63 (s, 4H; CH2Br),
1.55 (s, 9H; O-tBu), 1.31 ppm (s, 9H; tBu); 13C NMR (75 MHz, CDCl3,
258C, TMS): d=168.2 (CO), 153.4, 148.6, 131.4, 129.4 (CH), 82.5 (O-
tBu), 71.3 (OCH2), 34.5, 31.3 (CH3), 28.5 (CH2), 28.3 ppm (CH3); IR
(ATR): n˜max =2965, 2867, 2825, 1753, 1482, 1436, 1365, 1264, 1243, 1214,
1199, 1153, 1098, 1047, 943, 885, 852, 747, 564 cmꢀ1; MS (EI): m/z: 450
[M]+; HRMS (EI): m/z calcd for C18H26Br2O3 [M]+: 450.0228; found:
450.0240.
d=7.27–7.07 (m, 12H; ArH), 3.65 (s, 8H; CH2), 3.62 (s, 8H; CH2), 3.46
(s, 6H; OCH3), 1.27 ppm (s, 18H; tBu); 13C NMR (100 MHz, CDCl3,
258C, TMS): d=154.3, 147.0, 138.6, 130.5, 129.6 (CH), 128.8 (CH), 127.6
(CH), 127.0 (CH), 62.0 (OCH3), 36.6 (CH2), 34.5, 31.5 (CH3), 30.5 ppm
(CH2); IR (ATR): n˜max =2957, 2922, 1610, 1481, 1433, 1249, 1206, 1099,
1000, 885, 649 cmꢀ1; MS (EI): m/z: 716 [M]+; HRMS (EI): m/z calcd for
C42H52O2S4 [M]+: 716.2850; found: 716.2835.
Compounds 9 and 10: A mixture of K2CO3 (0.688 g, 5.0 mmol, 5 equiv), 1
(0.349 g, 0.99 mmol, 1 equiv) and 6 (0.200 g, 0.99 mmol, 1 equiv) was
used. Purification by column chromatography (silica gel, eluent CH2Cl2/
hexane/diethyl ether 48:48:4) afforded 9 (0.031 g, 8%) and 10 (0.170 g,
44%) as off-white solids.
1
Compound 9: M.p. 105–1078C; H NMR (300 MHz, CDCl3, 258C, TMS):
3
d=6.98–6.91 (m, 4H; ArH), 6.63 (t, J
A
2J(H,H)=14.5 Hz, 4H; CH2), 3.51 (s, 6H; OCH3), 3.35 (d, 2J
ACHTUNGTRENNUNG ACHTUNGTRENNUNG
14.3 Hz, 4H; CH2), 1.19 ppm (s, 9H; tBu); 13C NMR (75 MHz, CDCl3,
258C, TMS): d=157.1, 155.1, 145.7, 130.9, 129.7, 129.3 (CH), 126.6 (CH),
124.6 (CH), 62.31/62.27 (OCH3), 34.3, 31.4 (CH3), 30.6 (CH2), 30.2 ppm
(CH2); IR (ATR): n˜max =2954, 2855, 2823, 1479, 1430, 1260, 1207, 1101,
1006, 874, 811, 636 cmꢀ1; MS (EI): m/z: 388 [M]+; HRMS (EI): m/z calcd
for C22H28O2S2 [M]+: 388.1531; found: 388.1538.
Compound 15: A solution of 14 (0.425 g, 0.944 mmol) and thiourea
(0.179 g, 2.36 mmol, 2.5 equiv) in THF (20 mL) was stirred for 20 h at
508C under an argon atmosphere. After the reaction mixture was cooled
to RT, THF was removed under reduced pressure. The resulting bis(iso-
thiouronium) salt was hydrolyzed by treating a suspension of the salt in
dioxane/water (4:1 v/v; 35 mL) with ethylenediamine (0.180 g,
2.99 mmol) for 20 h at RT, followed by neutralization with 6n HCl
(1.2 mL) at 08C. The reaction mixture was extracted with CH2Cl2
(50 mL), dried over MgSO4, filtered, and evaporated to dryness to afford
the crude product. Purification by column chromatography (silica gel,
eluent CH2Cl2/hexane 65:35) afforded 15 as an off-white solid (0.201 g,
59%). M.p. 95–978C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.20
Compound 10: M.p. 70–728C; 1H NMR (300 MHz, CDCl3, 258C, TMS):
3
d=7.22–7.15 (m, 8H; ArH), 7.01 (t, J
N
8H; CH2), 3.66 (s, 8H; CH2), 3.26 (s, 6H; OCH3), 3.23 (s, 6H; OCH3),
1.29 ppm (s, 18H; tBu); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=
156.5, 154.2, 146.7, 131.6, 130.6, 130.1 (CH), 127.0 (CH), 124.0 (CH),
61.54/61.48 (OCH3), 34.4, 31.5 (CH3), 30.7 (CH2), 30.3 ppm (CH2); IR
(ATR): n˜max =2958, 2863, 2821, 1485, 1431, 1264, 1208, 1101, 1000, 871,
812, 640 cmꢀ1; MS (EI): m/z: 776 [M]+; HRMS (EI): m/z calcd for
C44H56O4S4 [M]+: 776.3061; found: 776.3117.
(s, 2H; ArH), 4.55 (s, 2H; OCH2), 3.81 (d, 3J
CH2SH), 1.91 (t, 3J
(H,H)=7.3 Hz, 2H; SH), 1.54 (s, 9H; O-tBu),
ACHTUNGTREN(NGNU H,H)=7.4 Hz, 4H;
AHCTUNGTRENNUNG
1.30 ppm (s, 9H; tBu); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=168.4
(CO), 152.2, 148.3, 134.2, 126.4 (CH), 82.4 (O-tBu), 72.1 (OCH2), 34.6
(tBu), 31.5 (CH3), 28.3 (CH3), 23.9 ppm (CH2); IR (ATR): n˜max =2965,
2867, 2820, 2562, 1753, 1484, 1432, 1369, 1250, 1199, 1120, 1050, 1025,
1002, 967, 880, 830, 780, 540 cmꢀ1; MS (EI): m/z: 356 [M]+; HRMS (EI):
m/z calcd for C18H28O3S2 [M]+: 356.1480; found: 356.1465.
Compound 11: m-CPBA (0.667 g, 3.87 mmol, 12 equiv) and MgSO4
(0.906 g, 7.74 mmol) were mixed together in CH2Cl2 (10 mL) and stirred
for 1 h at RT. Subsequently, homothiacalix[4]arene 4 (0.28 g, 0.31 mmol,
1 equiv) was added and the mixture was stirred at RT for 12 h (under
Ar). The resulting solution was filtered, diluted with MeOH (20 mL),
and CH2Cl2 was carefully evaporated in vacuo, resulting in the formation
of a white crystalline solid, which was filtered off and washed carefully
with MeOH to afford 11 as an off-white solid (0.270 g, 84%). M.p.
>3358C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.56 (s, 8H;
ArH), 4.17 (s, 16H; CH2), 3.49 (s, 12H; OCH3), 1.30 ppm (s, 36H; tBu);
13C NMR (100 MHz, CDCl3, 258C, TMS): d=155.7, 148.3, 131.0 (CH),
Compounds 16 and 17: A suspension of K2CO3 (0.770 g, 5.55 mmol,
5 equiv) in dry THF (70 mL) was degassed with argon for 10 min. A solu-
tion of precursors
2 (0.284 g, 1.11 mmol, 1 equiv) and 14 (0.500 g,
1.11 mmol, 1 equiv) in dry THF (10 mL) was added and the mixture was
stirred at reflux temperature for 2 d, after which time the mixture was
cooled to RT and evaporated to dryness. The crude residue was redis-
solved in a mixture of CH2Cl2 and water. The organic fraction was sepa-
rated, washed with water, dried over MgSO4, filtered, and evaporated to
dryness. Separation of the homothiacalixarenes by column chromatogra-
phy (silica gel, eluent CH2Cl2/hexane/diethyl ether 48.5:48.5:3) afforded
16 (0.310 g, 51%) and 17 (0.060 g, 10%) as off-white solids.
121.2, 63.2 (OCH3), 52.6 (CH2), 34.7, 31.4 ppm (CH3); IR (ATR): n˜max
=
2946, 2860, 2820, 1487, 1439, 1319, 1248, 1203, 1154, 1121, 1000, 893, 814,
550 cmꢀ1; MS (ESI+): m/z: 1039 [M+Na]+; HRMS (ESI+): m/z calcd for
C52H72O12S4Na [M+Na]+: 1039.3804; found: 1039.3818.
Chem. Eur. J. 2011, 17, 10339 – 10349
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10347

W. Dehaen, W. Maes et al.
Compound 16: M.p. 180–1828C; 1H NMR (600 MHz, CDCl3, 258C,
TMS): d=7.32 (s, 2H; ArH), 7.31 (s, 2H; ArH), 7.19 (s, 2H; ArH), 7.17
(s, 2H; ArH), 4.46 (s, 2H; OCH2), 4.38 (s, 2H; OCH2), 4.15–4.07 (m,
1191, 1142, 1105, 1051, 1005, 942, 820, 796, 648 cmꢀ1; MS (ESI+): m/z:
1088 [M+Na]+.
Compound 22: Separate degassed solutions of 2 (0.171 g, 0.667 mmol,
1.5 equiv) and 21 (0.200 g, 0.447 mmol, 1 equiv) in THF (12 mL) were
collected in syringes and added dropwise (with the aid of a syringe
pump) to a stirred degassed mixture of K2CO3 (0.460 g, 3.33 mmol,
5 equiv) in THF (200 mL) at reflux over a period of 5 h. After complete
addition, the mixture was stirred at reflux for an additional 10 h, after
which time the mixture was cooled to RT and evaporated to dryness. The
crude residue was redissolved in a mixture of CH2Cl2 and water. The or-
ganic fraction was separated, washed with water, dried over MgSO4, fil-
tered, and evaporated to dryness. Purification by column chromatography
(silica gel, eluent CH2Cl2/hexane/diethyl ether 55:36:9) afforded 22 as an
off-white solid (0.061 g, 23%). M.p. 248–2498C; 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=7.23 (s, 8H; ArH), 3.76 (s, 18H; OCH3), 3.70 (s,
12H; CH2), 3.62 (s, 12H; CH2), 3.07 (brs, 9H; OCH3), 1.27 ppm (s, 27H;
tBu); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=158.5, 154.4, 147.1,
130.9, 126.9 (CH), 121.9, 63.5 (OCH3), 61.2 (OCH3), 34.4, 31.6 (CH3),
30.8 (CH2), 25.1 ppm (CH2); IR (ATR): n˜max =2951, 2865, 2821, 1578,
1480, 1459, 1410, 1249, 1198, 1159, 1091, 1002, 895, 816, 640 cmꢀ1; MS
(ESI+): m/z: 1200 [M+Na]+; HRMS (ESI+): m/z calcd for C63H84O9S6Na
[M+Na]+: 1199.4337; found: 1199.4355.
4H; CH2), 3.80 (d, 2J
CH2), 3.54 (d, 2J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
3H; OCH3), 1.48 (s, 9H; O-tBu), 1.47 (s, 9H; O-tBu), 1.33 (s, 9H; tBu),
1.31 (s, 9H; tBu), 1.28 (s, 9H; tBu), 1.27 ppm (s, 9H; tBu); 13C NMR
(75 MHz, CDCl3, 258C, TMS): d=168.6 (CO), 168.4 (CO), 154.5, 154.3,
153.3, 153.1, 147.1, 147.0, 131.7, 131.3, 129.9, 127.4 (CH), 127.3 (CH),
127.0 (CH), 126.9 (CH), 82.0 (O-tBu), 72.0 (OCH2), 71.9 (OCH2), 61.8
(OCH3), 61.6 (OCH3), 34.5, 34.4, 32.1 (CH2), 31.8 (CH2), 31.6 (CH2), 31.5
(CH3), 30.7 (CH2), 30.2 (CH2), 28.3 ppm (CH3); IR (ATR) n˜max =2951,
2905, 2868, 2825, 1756, 1478, 1437, 1364, 1223, 1191, 1152, 1102, 1051,
1004, 887, 837, 789, 647 cmꢀ1; MS (ESI+): m/z: 1112.1 [M+Na]+; HRMS
(ESI+): m/z calcd for C62H88O8S4Na [M+Na]+: 1111.5260; found:
1111.5274.
Compound 17: M.p. 87–888C; 1H NMR (300 MHz, CDCl3, 258C, TMS):
d=7.26 (s, 6H; ArH), 7.14 (s, 6H; ArH), 4.48 (s, 6H; OCH2), 3.80 (s,
12H; CH2), 3.70 (s, 12H; CH2), 3.49 (s, 9H; OCH3), 1.48 (s, 27H; O-
tBu), 1.26 (s, 27H; tBu), 1.21 ppm (s, 27H; tBu); 13C NMR (75 MHz,
CDCl3, 258C, TMS): d=168.5 (CO), 154.3, 153.4, 147.1, 147.0, 131.2,
130.5, 127.0 (CH), 126.9 (CH), 81.9 (O-tBu), 72.1 (OCH2), 61.8 (OCH3),
35.5, 34.5, 31.5 (CH3), 30.8 (CH2), 28.3 ppm (CH3); IR (ATR): n˜max
=
Crystallographic data: Data collection was performed by using CuKa radi-
ation (l=1.54178 ꢃ, crossed Goebel mirrors) and phi and omega scans
on a Bruker diffractometer equipped with a SMART 6000 CCD detector.
Prior to the diffraction experiment, the crystals were flash-cooled at
100 K. Cell refinement and data reduction were carried out by the pro-
gram SAINT.[17] The structures were solved by direct methods and re-
fined by full-matrix least squares on jF2 j using the SHELXTL program
package.[18] Non-hydrogen atoms were anisotropically refined and the hy-
drogen atoms were placed on calculated positions with temperature fac-
tors fixed at 1.2 times Ueq of the parent atoms and 1.5 times Ueq for
methyl groups.
2957, 2864, 2820, 1749, 1479, 1434, 1363, 1226, 1197, 1152, 1104, 1053,
1005, 884, 846, 791, 644 cmꢀ1; MS (ESI+): m/z: 1657.2 [M+Na]+; HRMS
(ESI+): m/z calcd for C93H132O12S6Na [M+Na]+: 1656.7973; found:
1656.8061.
Compounds 18 and 19: A suspension of K2CO3 (0.326 g, 2.36 mmol) in
dry 1,4-dioxane (170 mL) was degassed with argon for 10 min. A solution
of precursors 15 (0.168 g, 0.47 mmol) and 14 (0.212 g, 0.47 mmol) in dry
1,4-dioxane (10 mL) was added and the mixture was stirred at reflux for
3 d, after which time the mixture was cooled to RT and evaporated to
dryness. The crude residue was redissolved in a mixture of CH2Cl2 and
water. The organic fraction was separated, washed with water, dried over
MgSO4, filtered, and evaporated to dryness. Separation of the homothia-
calixarenes by column chromatography (silica gel, eluent heptane/diethyl
ether 80:20) afforded 18 (0.140 g, 46%) and 19 (0.050 g, 16%) as off-
white solids.
Compound 18: M.p. 182–1848C; 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.20 (brs, 8H; ArH), 4.09 (brs, 16H; CH2), 3.50 (brs, 12H;
OCH2), 1.44 (brs, 36H; tBu), 1.25 ppm (brs, 36H; tBu); 13C NMR
(100 MHz, CDCl3, 258C, TMS): d=168.5 (CO), 153.8, 147.0, 130.4, 127.1
(CH), 81.6 (O-tBu), 71.8 (OCH2), 34.4, 31.5 (CH3), 30.7 (CH2), 28.2 ppm
(CH3); IR (ATR) n˜max =2964, 2870, 1751, 1478, 1430, 1392, 1304, 1225,
1193, 1151, 1105, 1053, 1009, 944, 846, 795, 637 cmꢀ1; MS (ESI+): m/z:
1312 [M+Na]+; HRMS (ESI+): m/z calcd for C72H104O12S4Na [M+Na]+:
1311.6308; found: 1311.6321.
CCDC-822950 (4), 822951 (16), 822952 (18), and 822953 (22) contain the
supplementary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Compound 4: Crystallization from methanol/CHCl3; C52H72O4S4; Mr =
¯
889.34; triclinic; space group P1; a=11.276(9), b=11.1465(8), c=
12.0862(9) ꢃ; a=73.305(4), b=89.965(4), g=63.103(3)8; V=
1265.81(17) ꢃ3; T=100(2) K; Z=1; 1calcd =1.167 gcmꢀ3
(CuKa)=
2.040 mmꢀ1; 2qmax =70.398; F
(000)=480; crystal dimensions 0.28ꢄ0.18ꢄ
;
mACHTUNGTRENNUNG
AHCTUNGTRENNUNG
0.12 mm; 4720 independent reflections (Rint =0.0586); final R=0.0608 for
3906 reflections with I>2s(I) and wR2 =0.1826 for all data.
Compound 16: Crystallization from pentane/CHCl3; C62H88O8S4; Mr =
1089.56; orthorhombic; space group Pbca; a=12.1055(7), b=
19.5739(11), c=26.1194(15) ꢃ; V=6189.0(6) ꢃ3; T=100(2) K; Z=4;
ACTHNUGTRENNUGN ACHTUNGTRENNNUG
1calcd =1.169 gcmꢀ3; m(CuKa)=1.806 mmꢀ1; 2qmax =69.208; F
Compound 19: M.p. 73–758C; 1H NMR (300 MHz, CDCl3, 258C, TMS):
d=7.14 (s, 12H; ArH), 4.41 (s, 12H; CH2), 3.79 (s, 24H; OCH2), 1.46 (s,
54H; tBu), 1.20 ppm (s, 54H; tBu); 13C NMR (100 MHz, CDCl3, 258C,
TMS): d=168.4 (CO), 153.5, 147.2, 130.9, 127.0 (CH), 81.8 (O-tBu), 72.1
=
0.0921); final R=0.0700 for 4517 reflections with I>2s(I) and wR2 =
0.1700 for all data.
(OCH2), 34.4, 31.5 (CH3), 31.4 (CH2), 28.3 ppm (CH3); IR (ATR): n˜max
=
Compound 18: Crystallization from methanol/CHCl3; C72H104O12S4; Mr =
2959, 2867, 2810, 1751, 1479, 1458, 1390, 1306, 1224, 1194, 1151, 1101,
1054, 1003, 944, 845, 788, 640 cmꢀ1; MS (ESI+): m/z: 1957 [M+Na]+;
HRMS (ESI+): m/z calcd for C108H156O18S6Na [M+Na]+: 1956.9541;
found: 1956.9676.
¯
1289.83; tetragonal; space group I42d (no. 122); a=b=13.435(3), c=
41.067(9) ꢃ; V=7413(3) ꢃ3; T=100(2) K; Z=4; 1calcd =1.156 gcmꢀ3; m-
ACHUTNGRENNUG CAHTUNGTREN(NNGU 000)=2784; crystal dimensions
(CuKa)=1.622 mmꢀ1; 2qmax =141.688; F
0.4ꢄ0.3ꢄ0.2 mm; 3543 independent reflections (Rint =0.0627); final R=
0.0516 for 3267 reflections with I>2s(I) and wR2 =0.1356 for all data.
Compound 20: A solution of 18 (0.100 g, 0.077 mmol) in CH2Cl2 (4 mL)
was added to a round-bottomed flask containing a mixture of CH2Cl2
and TFA (3:1 ratio; 8 mL) and the resulting mixture was heated at reflux
for 12 h, after which time the mixture was cooled to RT and evaporated
to dryness. Pure macrocycle 20 was obtained by precipitation from hep-
tane, filtering, and drying in vacuo (0.074 g, 90%). M.p. 154–1568C;
1H NMR (600 MHz, CDCl3, 258C, TMS): d=7.16 (s, 8H; ArH), 4.45
(brs, 8H; OCH2), 3.74 (brs, 16H; CH2), 1.25 ppm (s, 36H; tBu);
13C NMR (100 MHz, CDCl3, 258C, TMS): d=172.6 (CO), 151.7, 148.5,
130.4, 127.5 (CH), 71.1 (OCH2), 34.5, 32.0 (CH2), 31.5 ppm (CH3); IR
(ATR): n˜max =2954, 2871, 2815, 1748, 1715, 1480, 1430, 1395, 1363, 1228,
Compound 22: Crystallization from methanol/CHCl3; C190H253Cl3O27S18
;
¯
Mr =3652.55; triclinic; space group P1 (no. 2); a=16.829(6), b=
20.088(8), c=31.970(13) ꢃ; a=97.794(12), b=97.718(12), g=97.520(9)8;
V=10488(7) ꢃ3; T=100(2) K; Z=2; 1calcd =1.157 gcmꢀ3
2.548 mmꢀ1; 2qmax =133.188; F
ACHTUNGTRENNUNG
; mACHTUNGTRENNUNG
0.1 mm; 35409 independent reflections (Rint =0.0966); final R=0.1086
for 22718 reflections with I>2s(I) and wR2 =0.2204 for all data. Disor-
dered solvent molecules (total electron count of 404) in solvent accessible
voids (total of 1326 ꢃ3) were squeezed out.[19]
10348
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 10339 – 10349

Homothiacalix[4]arenes
FULL PAPER
[7] Wang and co-workers recently reported a number of bis- and tetra-
homoheteracalix[2]arene[2]triazines (oxa/aza), see: Y. Chen, D.-X.
Wang, Z.-T. Huang, M.-X. Wang, J. Org. Chem. 2010, 75, 3786.
[8] For homothiacalixarenes, see: a) R. H. Mitchell, V. Boekelheide, J.
Am. Chem. Soc. 1974, 96, 1547; b) M. Tashiro, T. Yamato, J. Org.
Chem. 1981, 46, 1543; c) T. Takido, M. Toriyama, K. Ogura, H.
Kamijo, S. Motohashi, M. Seno, Phosphorus Sulfur Silicon Relat.
Elem. 2003, 178, 1295; d) K. Kohno, M. Takeshita, T. Yamato, J.
Chem. Res. 2006, 251; e) M. Ashram, J. Inclusion Phenom. Macrocy-
clic Chem. 2006, 54, 253; f) H.-A. Tran, P. E. Georghiou, New J.
Chem. 2007, 31, 921.
Acknowledgements
We thank the FWO (Fund for Scientific Research, Flanders), the KU
Leuven, and the Ministerie voor Wetenschapsbeleid for continuing finan-
cial support.
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[2] a) Y. Nakamura, T. Fujii, S. Inokuma, J. Nishimura in Calixarenes
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[3] We prefer the term heteracalixarenes to distinguish this class of het-
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[10] For homothiacalixarenes partially bridged by CH2SCH2 groups, see:
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[11] Alternative denotations: tetrathia
ACHTUNGTRENN[UNG 3.3.3.3]calixarene or 2,11,20,29-
tetrathia[3.3.3.3]metacyclophane (cyclophane nomenclature).
AHCTUNGTRENNUNG
[5] For homooxacalixarenes, see: a) B. Masci, M. Finelli, M. Varrone,
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[12] M. Ashram, D. O. Miller, J. N. Bridson, P. E. Georghiou, J. Org.
Chem. 1997, 62, 6476.
[13] The exact oxygenated analogue was obtained by Masci et al. in a
slightly lower yield (53%) by a Williamson ether reaction of similar
precursors (1 and 1,3-bis(hydroxymethyl)-5-tert-butyl-2-methoxyben-
zene).[5a]
[14] a) G. Mislin, E. Graf, M. W. Hosseini, A. De Cian, J. Fischer, Chem.
Commun. 1998, 1345; b) N. Iki, H. Kumagai, N. Morohashi, K.
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[15] Small amounts of the respective homothiacalix[8]arenes were also
observed by ESI-MS.
[16] M. Tashiro, T. Yamato, K. Kobayashi, T. Arimura, J. Org. Chem.
1987, 52, 3196.
[17] SAINT, Manual Version 5/6.0, Bruker Analytical X-ray systems,
Madison, WI, 1997.
[18] a) SHELXTL-NT, Manual Version 5.1, Bruker Analytical X-ray Sys-
tems, Madison, Wisconsin, 1997; b) G. M. Sheldrick, Acta Crystal-
logr. A 2008, 64, 112.
[19] A. L. Spek, Acta Crystallogr. D 2009, 65, 148.
Received: June 2, 2011
Published online: August 3, 2011
Chem. Eur. J. 2011, 17, 10339 – 10349
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10349