Synthesis and properties of a mixed thiophene-octahomotetraoxacalixarene

Article abstract of DOI:10.1016/j.tetlet.2009.05.023

The synthesis of a mixed thiophene unit containing octahomotetraoxa[2]thiophenecalix[2]arene is described. Its single-crystal X-ray structure and a preliminary solution complexation study are reported herein.

Full text of DOI:10.1016/j.tetlet.2009.05.023

Tetrahedron Letters 50 (2009) 4289–4292
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Tetrahedron Letters
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Synthesis and properties of a mixed thiophene-octahomotetraoxacalixarene
*
Hassan Al-Saraierh , Louise N. Dawe, Paris E. Georghiou
Department of Chemistry, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada A1C 2Z1
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a mixed thiophene unit containing octahomotetraoxa[2]thiophenecalix[2]arene is
Received 10 April 2009
Revised 5 May 2009
Accepted 12 May 2009
Available online 18 May 2009
described. Its single-crystal X-ray structure and a preliminary solution complexation study are reported
herein.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Calixarenes
Homooxacalixarenes
Heterocyclic-containing calixarenes
Thiophene
Fullerenes
1. Introduction
could produce a potential new host for C60- or C70-fullerene
(Fig. 3). Although such a molecule would have a large degree of
Due to their potentially useful chemical properties and their
applications, heterocyclic-based calixarenes such as, 1,1 2,2 3,3 44
and 5,5 have gained considerable attention recently from many re-
search groups. These heterocycle-based calixarenes (Fig. 1), respec-
tively, incorporate pyridine, furan, thiophene, indole or pyrrole
units instead of the conventional phenolic units in the construction
of the macrocyclic compound.
In some cases, more than one type of heterocyclic unit have
been used, as in calix[2]bipyrrole[2]furan (6) and calix[2]bipyr-
role[2]thiophene (7) (Fig. 2). Sessler et al.6 have shown that the
mixed heterocycle-containing compounds, 6 and 7, for example,
selectively bind with specific anions, such as acetate and benzo-
ate, with high binding constant values. Among other mixed hete-
rocalixarenes some containing imidazolium units within the
frameworks of the calixarene (not shown) have also been synthe-
sized and these compounds were found also to be good anion
receptors.7
rotational flexibility due to the presence of four (–CH2–O–CH2–)
ether units linking the phenyl and thiophenyl units together,
molecular modelling studies indicated that this compound could
have a well-defined cavity which could embrace these fullerenes.
Indeed, based on some of our previous experiences,8b,c it was
hypothesized that the presence of the four ether oxygen atoms
and the two sulfur atoms within the cavity could play an important
role and could potentially enhance its complexation ability to-
wards C60 and/or C70 or other guests. Furthermore, molecular
mechanics modelling10 suggested that there could be additional
favourable
p-CH3 interactions resulting from the embracing tert-
butyl groups8b on the phenyl units.
In this Letter, the synthesis of the mixed thiophene unit contain-
ing ‘octahomotetraoxa[2]thiophenecalix[2]arene’ (8) is described.
As well, its single-crystal X-ray structure and a preliminary solution
complexation study are reported.
As part of our on-going studies concerned with the supramolec-
ular binding abilities of diverse bowl-shaped compounds with neu-
tral guest molecules, in particular, fullerenes8 or with other guest
species,9 we anticipated that the replacement of a single, or of
two of the benzene rings in octahomotetraoxacalix[4]arene with
thiophene rings, to form new derivatives such as 8 (Scheme 1)
2. Results and discussion
The synthesis of macrocycle 8, was achieved11 in 21% overall
yield by base-mediated condensation of 9 with 2,6-bis(bromo-
methyl)-4-tert-butylanisole (10) as outlined in Scheme 1. The reac-
tion was conducted by slowly adding an equimolar solution of 9
and 10 in THF to a mixture of NaH in THF at reflux temperature.
The precursor compound, 2,5-bis(hydroxymethyl)thiophene (9)12
was easily derived via LiAlH4 reduction of dimethyl thiophene-
2.5-dicarboxylate (11) which in turn, was readily obtained by
esterification of commercially available 2,5-thiophenedicarboxylic
* Corresponding author. Tel.: +1 709 737 8517; fax: +1 709 737 3702.
E-mail address: parisg@mun.ca (P.E. Georghiou).
Present address: Chemistry Department, Tafila Technical University, Tafila,
Jordan.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.023

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H. Al-Saraierh et al. / Tetrahedron Letters 50 (2009) 4289–4292
HO
OH
R
N
R
OH
HO
N
O
S
S
N
O
O
S
S
OH
O
HO
R
R
HO
N
OH
1
2
3
MeO
OMe
R
R
N
H
HN
NH
NH
HN
MeO
H
N
H
OMe
N
MeO
R
OMe
4
5
Figure 1.
N
H
N
H
N
H
N
H
S
O
S
O
H
H
H
H
N
N
N
N
6
7
Figure 2.
OCH3
S
O
O
R
R1
tBu
OCH3
+
tBu
R
R
CH3O
S
tBu
O
O
9 R = CH2OH
S
10 R = R1 = CH2Br
13 R = R1 = H
11 R = CO2CH3
12 R = CO2H
14 R = CH2OH; R1 = CH2Br
15 R = H; R1 = CH2Br
8
Scheme 1.
acid (12). The other precursor, 10, was synthesized13 in 68% yield,
by bis-bromomethylation of p-tert-butylanisole (13) which also
afforded the undesired side-products 14 and 15, in ꢀ10% and
20% yields, respectively.
2.1. NMR spectroscopy
The 1H and 13C NMR spectra of 8 were in agreement with the
expected product and its simplicity indicated that this compound

H. Al-Saraierh et al. / Tetrahedron Letters 50 (2009) 4289–4292
4291
Figure 3. Side- and top views of computer-generated space-filling models of a
hypothetical 1:1 supramolecular complex of C60 with 8.
is highly symmetrical. The 1H NMR spectrum shows two signals at
low field, one corresponding to the protons of the aryl units and
the other for the protons of the thiophenyl units. The bridging
methylene protons appeared as two sharp singlet signals, one at
d ꢀ4.51 and one at ꢀ4.75 ppm in the 1H NMR spectrum, showing
that this compound is highly flexible at the ambient temperature.
This confirms the hypothesis stated earlier, that a factor contribut-
ing to this flexibility is likely due to the presence of four ether
bridges which link the aryl and thiophenyls.
Figure 5. POV-ray rendering of 8 (hydrogen atoms omitted for clarity) showing one
chain of macrocycles.
The 13C NMR spectrum was also consistent with the structure of
8, showing only six carbon signals at the low field region corre-
sponding to the aryl and thiophenyl carbons and five signals at
higher field for the remaining carbon atoms in the molecule.
2.2. X-ray crystallography
Colourless crystals of 8 which were suitable for single-crystal
X-ray diffraction analysis were obtained from a methanol/dichlo-
romethane solution. The single-crystal X-ray structure (Fig. 4)14
revealed that there are two molecules in the asymmetric unit. A
similar supramolecular solid state ‘dimer’, not commonly found
in calixarenes in general, was previously observed by us in a
calix[4]naphthalene.15
In the present case, the two molecules are packed in such a way
that one of the phenyl units is situated within the hydrophobic
cavity of the second molecule. One of the tert-butyl groups of each
molecule is situated above a phenyl ring of the second molecule
with the aromatic carbon to hydrogen of the tert-butyl group hav-
ing a contact van der Waals distance of 2.73 Å, thus indicating sig-
Figure 6. POV-ray rendered structures of the two individual molecules present in
the asymmetric unit of the X-ray structure of 8. The top structure shows the ‘partial
cone’ conformation in which the two thiophene units and one of the phenolic units
are syn while the bottom structure shows the ‘1,2-alternate’ conformation in which
the two thiophene units are anti.
nificant
p-CH3 interactions being present. Short HÁ Á ÁO contacts of
2.438 and 2.62 Å can also be seen between protons in each of the
nestled phenyl groups and oxygen atoms of the bridging –
CH2OCH2-group. These interactions lead to the formation of helical
chains that run parallel to the a-axis (Fig. 5). Figure 6 shows the
conformations of each molecule present in the asymmetric unit.
Figure 6a reveals a nearly-‘partial cone’ conformation in which
the two thiophene units and one of the phenolic units are all syn,
while Figure 6b reveals a nearly-‘1,2-alternate’ conformation in
which the two thiophene units are anti.
2.3. Complexation studies
Solutions of 8 in either toluene-d8, benzene-d6 or CS2, solvents
which are usually employed for NMR titration complexation stud-
ies with fullerenes were treated with C60 or C70. In all of the cases
examined however, no colour changes which are normally associ-
ated with these complex-formation experiments were observed,
nor were there any complexation-induced chemical shift changes
in the 1H NMR spectra.
In summary, the synthesis of the mixed thiophene-based ca-
lix[4]arene 8, using a [2+2] fragment condensation reaction is de-
scribed.
A single-crystal X-ray structure revealed that this
compound forms a ‘dimer’ in the solid state. Titration experiments
with several guest including C60, C70 however failed to reveal any
evidence of complex formation.
Acknowledgements
Figure 4. POV-ray rendered asymmetric unit of 8 in which hydrogen atoms have
been omitted for clarity, showing: (a: left) 30% probability ellipses; and (b: right)
showing (blue-coloured atoms) the proximity of a tert-butyl group of one molecule
with the phenyl ring of its dimer mate.
This work was supported by Memorial University of Newfound-
land and the National Sciences and Engineering Research Council

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H. Al-Saraierh et al. / Tetrahedron Letters 50 (2009) 4289–4292
bis(hydroxymethyl) thiophene (9) (100 mg, 0.69 mmol) and 2,6-bis(bromo-
methyl)-4-tert-butylanisole (11) (241 mg, 0.69 mmol) in anhydrous THF
(50 mL) by syringe-pump over 3 h. The reaction mixture was stirred at reflux
temperature for an additional 24 h. The reaction mixture was then cooled to
room temperature and washed with water (2 Â 25 ml). The organic layers were
combined, dried over MgSO4 and filtered. The solvent was evaporated on a
rotary evaporator and the residue was purified by PLC (1:4 ethyl acetate/
hexanes) to give 8 (92 mg, 21%) as a colourless solid: mp 253–255 °C; 1H NMR
d 1.35 (s, 18H), 3.66 (s, 6H), 4.51 (s, 8H), 4.75 (s, 8H), 6.90 (s, 4H), 7.36 (s, 4H);
13C NMR d 31.7, 34.5, 63.8, 67.4, 68.1, 126.3, 128.7, 130.5, 141.9, 146.7, 156.2.
MS (APCI+) m/z calcd for C38H48NaO6S2 687.3, found 687.2 (M+Na)+.
12. Block, E.; Page, J.; Toscano, J. P.; Wang, C.-X.; Zhang, X.; DeOrazio, R.; Guo, C. X.;
Sheridan, R. S.; Towers, G. H. N. J. Am. Chem. Soc. 1996, 118, 4719–4720.
13. Zeecheng, R. K. Y.; Podrebarac, E. G.; Menon, C. S.; Cheng, C. C. J. Med. Chem.
1979, 22, 501–505.
of Canada (NSERC). David O. Miller of M.U.N. is thanked for the ini-
tial X-ray crystallographic data collection.
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10. Molecular modelling was conducted using SPARTAN’08 (Windows version)
Molecular Modelling Software. Molecular mechanics (MMFF94) calculations
were conducted on the optimized geometry of the host and/or complexes.
11. Octahomotetraoxacalix[2]arene[2]thiophene (8): To a mixture of NaH (51.4 mg,
2.14 mmol) in anhydrous THF (30 mL) at reflux was added a solution of 2,5-
14. X-ray crystallography and crystal data for 8. Monoclinic, Cc (no. 9),
a = 41.256(3),
V = 7042.7(7) Å3, Z = 8,
for I > 2 (I), wR2 = 0.1011 for all data. The intensity data were recorded on a
b = 10.1714(5),
c = 17.4177(10) Å,
b = 105.5160(10)°,
q
calcd = 1.254 g cmÀ3
, l
= 1.96 cmÀ1, final R1 = 0.0375
r
Rigaku AFC8-Saturn 70 system with MoKa radiation (k = 0.71070 Å) at
173(2) K. The structure was solved by direct methods and refined by full-
matrix least-squares analysis on F2 by using SHELXL. Collection, solution and
refinement proceeded normally. Hydrogen atoms were introduced in
calculated positions with isotropic thermal parameters set twenty percent
greater than those of their bonding partners. All hydrogen atoms were refined
on the riding model. All other atoms were refined anisotropically. CCDC
730543 contains the supplementary crystallographic data for this Letter. These
can be obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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