Synthesis of a deep-cavity thiacalix[4]arene

Article abstract of DOI:10.1016/j.tetlet.2003.09.048

A novel thiacalix[4]arene derivative bearing four phenyl groups on the upper rim was prepared by the direct condensation of biphenyl-4-ol with elemental sulphur. As revealed by X-ray diffraction analysis, this compound adopts the cone conformation in the solid state, thus creating a cavity with an extended π-aromatic system potentially applicable for solid-state inclusion of suitable molecules. Subsequent alkylation (RI/K₂CO ₃/acetone, R=Me, Et, Pr) yielded tetraalkylated derivatives, which were studied for their conformational preferences using ¹H NMR spectroscopy. While the Me or Et derivatives are conformationally mobile and exhibit thermodynamic equilibria of several conformers in solution (CDCl ₃ or CD₂Cl₂), the corresponding propoxy derivative is infinitely stable at room temperature.

Full text of DOI:10.1016/j.tetlet.2003.09.048

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8093–8097
Synthesis of a deep-cavity thiacalix[4]areneꢀ
a,
a
a
b
b
&
Pavel Lhota´k, * Toma´sˇ Smejkal, Ivan Stibor, Jaroslav Havl´ıcˇek, Marcela Tkadlecova´ and
Hana Petrˇ´ıcˇkova´c
aDepartment of Organic Chemistry, Institute of Chemical Technology, Technicka´ 5, 166 28 Prague 6, Czech Republic
bDepartment of Analytical Chemistry, Institute of Chemical Technology, Technicka´ 5, 166 28 Prague 6, Czech Republic
cDepartment of Solid State Chemistry, Institute of Chemical Technology, Technicka´ 5, 166 28 Prague 6, Czech Republic
Received 11 July 2003; revised 26 August 2003; accepted 5 September 2003
Abstract—A novel thiacalix[4]arene derivative bearing four phenyl groups on the upper rim was prepared by the direct
condensation of biphenyl-4-ol with elemental sulphur. As revealed by X-ray diffraction analysis, this compound adopts the cone
conformation in the solid state, thus creating a cavity with an extended p-aromatic system potentially applicable for solid-state
inclusion of suitable molecules. Subsequent alkylation (RI/K2CO3/acetone, R=Me, Et, Pr) yielded tetraalkylated derivatives,
which were studied for their conformational preferences using 1H NMR spectroscopy. While the Me or Et derivatives are
conformationally mobile and exhibit thermodynamic equilibria of several conformers in solution (CDCl3 or CD2Cl2), the
corresponding propoxy derivative is infinitely stable at room temperature.
© 2003 Elsevier Ltd. All rights reserved.
Thiacalix[4]arenes have become easily accessible in
multi-gram scales recently using simple synthetic proce-
dures.1 Because of the presence of four sulphur atoms,
the system has many novel features if compared with
classical calixarenes,2 and thiacalixarenes represent very
promising building blocks or molecular scaffolds for
the synthesis of more complicated supramolecular sys-
tems.3 Despite some recently described procedures for
thiacalix[4]arene derivatisation,4,5 the chemistry of these
compounds is still rather underdeveloped. If we con-
sider the basic thiacalix[4]arene skeleton, only a few
basic derivatives 1a–d are accessible so far.1,6
One of the major goals of calixarene chemistry has been
the design of novel receptors possessing properties suit-
able for separation science and/or molecular recogni-
tion. Therefore, the construction of calixarenes with
larger cavities is of interest, as these compounds can
potentially find applications in neutral guest recogni-
tion.2,3 Due to its rigid hydrophobic cavity, the thia-
calix[4]arene with extended p-systems 1f could be a very
attractive host molecule for host–guest chemistry. In
this paper we report the first synthesis and characterisa-
tion of thiacalix[4]arenes with deep aromatic cavities.
It is known from the chemistry of classical calixarenes
that the deep-cavity calix[4]arene 1e is virtually inacces-
sible by the direct condensation reaction of biphenyl-4-
ol with formaldehyde.1,7 So far, this compound has
been prepared either by a stepwise procedure8 or by
coupling reactions starting from the corresponding tet-
rahalocalix[4]arenes.9 As the tetrabromo- or tetra-
iodothiacalix[4]arenes are not available, we focused our
attention on the direct condensation of biphenyl-4-ol
with elemental sulphur.
Unfortunately, heating (200–230°C) biphenyl-4-ol with
sulphur in the presence of NaOH in tetraethylene glycol
dimethyl ether, i.e. similar conditions to those used for
the preparation of thiacalix[4]arene 1a,1 led to very
complicated reaction mixtures, which gave the required
product only in very low yields after complicated isola-
tion procedures (repeated column chromatography).
Keywords: thiacalixarenes; X-ray crystallography; alkylation; confor-
mational analysis.
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/j.tetlet.2003.09.048
* Corresponding author. Tel.: +420-2-2435-4280; fax: +420-2-2435-
4288; e-mail: lhotakp@vscht.cz
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.048

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P. Lhota´k et al. / Tetrahedron Letters 44 (2003) 8093–8097
This extensive study revealed several important facts: (i)
the most suitable solvent is diphenyl ether; (ii) the
temperature profile used throughout the reaction seems
to be of critical importance for the yield of the conden-
sation; (iii) the deep-cavity calixarene 1f can be isolated
using a simple precipitation/crystallisation procedure
on a multi-gram scale.10 In a typical procedure, starting
from 140
g
of biphenyl-4-ol the p-phenylthia-
calix[4]arene 1f was isolated as an off-white solid (mp
>300°C) in approx. 22% yield (ca. 35 g).
Figure 1. ORTEP drawing of 1f.
1
The structure of 1f was confirmed by H NMR spec-
troscopy and mass spectrometry. The spectrum in
CDCl3 shows a typical splitting pattern with C4v sym-
metry corresponding to the cone conformation. The
high resolution TOF ESI MS in acetonitrile revealed
the molecular mass of 800.108 (exact mass=800.118)
with a splitting pattern matching exactly an isotopic
model. As no higher mass was observed, we can con-
Thiacalixarene 1f was alkylated using the procedure
described for the alkylation4d,12 of 1a,b (RI/K2CO3/ace-
tone, reflux) yielding the corresponding tetraalkoxy
derivatives 2–4 in good yields (55–77%) (Scheme 1).
The conformational behaviour of the tetramethoxy
1
derivative 2 was studied using dynamic H NMR spec-
troscopy in the range of 173–298 K with CD2Cl2 as a
solvent. This revealed that the simple set of signals at
room temperature (e.g. the singlet at l=3.80 ppm for
the methoxy groups) is due to the fast chemical
exchange of several conformers (2a–d). As demon-
strated in Figure 2, lowering of the temperature leads to
the appearance of new signals. However, the large line
width of the resonances and overlapping nature of these
signals did not allow us to prove exactly the structures
and ratios of the corresponding conformers. The rela-
tively low coalescence temperature indicated the much
higher mobility of the thiacalixarene skeleton as com-
clude that compound 1f prefers intramolecular (lOH
=
9.66 ppm in CDCl3) instead of intermolecular hydrogen
bonds.
The final evidence for the structure of 1f was demon-
strated using single crystal X-ray diffraction analysis11
(single crystals were obtained by slow evaporation of an
EtOAc/CHCl3 solution). The molecule adopts a cone
conformation held together by intramolecular hydrogen
bonds on the lower rim (Fig. 1), thus representing a
deep cavity suitable for inclusion.
Scheme 1. Preparation of 1f and subsequent alkylation reactions: (i) S8, diphenyl ether, 230°C, 6 h (22%); (ii) RI/K2CO3/acetone,
24 h to 2 days reflux [R=Me, 2 (77%); R=Et, 3 (75%); R=Pr, 4a (55%); 4b (10%)].

P. Lhota´k et al. / Tetrahedron Letters 44 (2003) 8093–8097
8095
Consequently, two main products were obtained by
column chromatography: the 1,3-alternate 4c (55%
yield) and the partial cone 4b (10%). This situation with
the gradual freezing of conformers (Me“Et“Pr)
resembles the behaviour of tert-butyl-thiacalix[4]arene
1a where the same general trend was found.13
In conclusion, we have prepared
a novel thia-
calix[4]arene derivative bearing four phenyl groups on
the upper rim by a direct condensation of biphenyl-4-ol
with elemental sulphur. This compound represents an
interesting deep-cavity thiacalixarene with an extended
p-aromatic system, and is potentially useful for solid-
state inclusion of suitable molecules. The subsequent
utilisation of this compound for the construction of
more elaborate structures is currently under
investigation.
Acknowledgements
Figure 2. 1H NMR spectra of 2 (CD2Cl2, 300 MHz) acquired
at: (a) rt, (b) −40°C, (c) −90°C. Signal at approx. 5.3 ppm is
solvent.
This research was partially supported by the Grant
Agency of the Czech Republic (GA 203/03/0926) and
by the grant of Ministry of Education, Youth and
Sports of the Czech Republic (MSM 223400008).
pared with classical calixarenes.2 Similarly, the 1H
NMR spectrum of 3 at room temperature confirmed
that several possible conformers were present in solu-
tion under slow exchange conditions (see Fig. 3). By
means of conventional one- and two-dimensional NMR
experiments (COSY, NOESY, etc.) the main signals
were assigned as the partial cone 3b and 1,3-alternate 3c
conformers in an approximate 45:55 ratio. The spec-
trum probably contains minor signals (less than 5%)
due to other conformers 3a and/or 3d, but their accu-
rate assignment was prevented by overlapping with
stronger signals.
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c=partial cone 3b.

8096
P. Lhota´k et al. / Tetrahedron Letters 44 (2003) 8093–8097
(g) Akdas, H.; Jaunky, W.; Graf, E.; Hosseini, M. W.;
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black colour. The temperature was elevated to 170°C
over the next 30 min and the reaction mixture was
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reaction mixture was then warmed up to 230°C over 1 h
and this temperature was maintained for a further 3 h.
During this time the reaction mixture became thick and
a precipitate appeared accompanied by a colour change
from black to red to yellow. The reaction mixture was
cooled to rt, diluted with 1.5 L of CHCl3 and acidified
by the addition of hydrochloric acid (50 ml conc. HCl+
250 ml water). Insoluble material was removed by filtra-
tion, the two-phase mixture was separated and the
aqueous layer was extracted with 200 ml of CHCl3. The
organic fractions were collected, washed with water and
the chloroform was removed on a rotary evaporator. To
this liquid residue ethyl acetate (175 ml) was added and
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filtered off and washed with ethyl acetate to yield 36 g
(22%) of raw product as off-white crystals. Higher
purity product can be obtained by crystallisation from
dioxane and subsequent precipitation from a CHCl3–
diethyl ether mixture. Mp >350°C with decomp. 1H
NMR (CDCl3, 298 K, 300 MHz) l (ppm): 9.66 (s, 4H,
OH), 7.89 (s, 8H, ArH), 7.55–7.28 (m, 20H, ArH); IR
(CHCl3) wmax (cm−1): 3311 (OH); EA calcd. for
C48H32O4S4: C, 71.97; H, 4.03; S, 16.01%. Found C,
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Lett. 2002, 43, 5153–5156; (b) The synthesis of 1f was
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EP 731102 A1 11 (1996) CA 125:275921. Unfortunately,
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11. X-Ray data for 1f: C48H32O4S4, M=801.018, monoclinic
system, space group P1 21/c 1, a=12.577(2), b=
,
30.428(4), c=10.582(1) A, i=103.61(1)°, V=3935.9(9)
3
A , Z=4, Dcalcd=1.35 g cm−3, v(Cu Ka)=25.85 cm−1
,
,
crystal dimensions of 0.1×0.2×0.5 mm. Data were mea-
sured at 293 K on an Enraf-Nonius CAD4 diffractome-
ter with graphite monochromated Cu Ka radiation
,
(u=1.54180 A). The structure was solved by direct
methods14 and anisotropically refined by full matrix
least-squares on F values15 to final R=0.098, Rw=0.098
and S=1.173 with 245 parameters using 1514 indepen-
dent reflections (qmax=59.97°). Hydrogen atoms were
located from expected geometry (see supplementary
data). Crystallographic data were deposited in CSD
under CCDC registration number 213637.
formaldehyde yielding
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13. Alkylation example: 5,11,17,23-tetraphenyl-25,26,27,28-
tetrapropoxythiacalix[4]arene (4): A mixture of derivative
1f (5 g, 6.25 mmol), potassium carbonate (20 g, 145
mmol) and propyl iodide (12 ml, 195 mmol) was stirred
under reflux in 150 ml of dry acetone for 48 h. The
solvent was evaporated under reduced pressure and the
residue was poured into dilute hydrochloric acid and
extracted with chloroform. The organic layer was
washed with water, dried over MgSO4 and evaporated
to yield the crude product. Recrystallisation from ethyl
acetate gave 2.40 g of pure derivative 4c (40%) as white
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10. Preparation of 5,11,17,23-tetraphenylthiacalix[4]arene
(1f): A mixture of biphenyl-4-ol (140 g, 0.823 mol) and
elemental sulphur (51 g, 1.594 mol) was dissolved in 100
ml of diphenyl ether at 140°C in a 1000 ml three-necked
flask. The mixture was stirred on a heating mantle
equipped with magnetic stirring. The reaction flask was
purged by a slow stream of nitrogen during the whole
reaction to remove the evolving hydrogen sulphide.
Solid NaOH (16 g) was added to the yellow solution
and the mixture was maintained for 2 h at a tempera-
ture of 140–145°C. During this time the reaction mix-
1
crystals, mp 236–237°C. H NMR (CDCl3, 300 MHz) l
(ppm): 7.54 (s, 8H, ArH), 7.52–7.28 (m, 20H, ArH), 3.9
(t, 8H, OCH2), 1.4 (m, 8H, C-CH2-C), 0.54 (t, 12H,
CH3). The mother liquor after crystallisation was evapo-
rated and purified by column chromatography (silica

P. Lhota´k et al. / Tetrahedron Letters 44 (2003) 8093–8097
8097
gel, eluent petroleum ether–CH2Cl2=4:1) to yield an
additional 0.9 g (overall 55%) of 4c and 0.59 g of 4b
(10%) as a white crystalline solid, mp 211–212.5°C. 1H
NMR (CDCl3, 300 MHz) l (ppm): 8.06 (s, 2H, ArH),
7.85 (s, 2H, ArH), 7.72 (d, 2H, ArH, J=2 Hz), 7.11 (d, 2,
ArH, J=2 Hz), 7.72 (m, 2H, ArH), 7.65 (m, 2H, ArH),
7.47 (m, 4H, ArH), 7.37 (m, 2H, ArH), 7.05 (m, 2H,
ArH), 6.94 (m, 8H, ArH), 4.2–4.1 (m, 4H, OCH2), 3.8–
3.62 (m, 4H, OCH2), 2.1–1.9 (m, 6H, CH2), 1.36–1.22 (m,
2H, CH2), 1.12 (t, 6H, CH3, J=7.33 Hz), 1.03 (t, 3H,
CH3, J=7.33 Hz), 0.34 (t, 3H, CH3, J=7.33 Hz).
14. Altomare, A.; Cascarano, G.; Giacovazzo G.; Guagliardi
A.; Burla M. C.; Polidori, G.; Camalli, M. SIR-92—A
Program for Automatic Solution of Crystal Structures by
Direct Methods. J. Appl. Crystallogr. 1994, 27, 435.
15. Watkin, D. J.; Prout, C. K.; Carruthers, J. R.; Betteridge,
P. W.; Cooper, R. I. (2001) CRYSTALS, Issue 11. Chem-
ical Crystallography Laboratory: Oxford, UK.