2,14-Dithiacalix[4]arene and its homooxa analogues: Synthesis and dynamic NMR study of conformational behaviour

Article abstract of DOI:10.1039/c5cc00819k

A simple and scalable synthesis of 2,14-dithiacalix[4]arene with alternating bridges (-CH₂- and -S-) is reported. Proper selection of the bisphenol-based starting building blocks can provide not only the title compound (58%) but also yet unrepo

Full text of DOI:10.1039/c5cc00819k

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2,14-Dithiacalix[4]arene and its homooxa
analogues: synthesis and dynamic NMR study
Cite this:DOI: 10.1039/c5cc00819k
of conformational behaviour†
Received 28th January 2015,
Accepted 12th March 2015
Michal Hucko,a Hana Dvorakova,b Vaclav Eignerc and Pavel Lhotak*a
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˘´
´
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DOI: 10.1039/c5cc00819k
www.rsc.org/chemcomm
A simple and scalable synthesis of 2,14-dithiacalix[4]arene with thiacalix[4]arenes using SEAr reactions (nitration, formylation,
alternating bridges (–CH2– and –S–) is reported. Proper selection halogenation) yields the meta-substituted products (with respect
of the bisphenol-based starting building blocks can provide not to the phenolic oxygen),6 whereas the same reactions with
only the title compound (58%) but also yet unreported homooxa classical calix[4]arenes afford the para-substituted products. As
analogues possessing three different bridging units (–CH2–, –S– a result, it would be very interesting to know the chemistry and
and –CH2–O–CH2–) in the molecule. These systems exhibit inter- conformational behaviour of calixarene systems possessing both
esting conformational behaviour allowing for the study of flip-flop sulfur and CH2 bridges within one molecule. Such mixed (S/CH2)
motion of the circular hydrogen bond arrays using dynamic NMR systems could retain the properties of both parent macrocycles
techniques.
which could find many applications in supramolecular chemistry,
including the design of novel receptor types.
Calixarenes1 play an important role in contemporary supra-
To the best of our knowledge, there have been only two
molecular chemistry. Due to their pre-organized skeletons with papers that have reported the preparation of 2,14-dithiacalix[4]-
tuneable size and even 3D shapes of their cavities, they are very arene (Scheme 1). The first approach is based on the step-by-
popular as molecular scaffolds in the design of novel receptors step formation of a linear tetraphenolic precursor with the key
and self-assembly systems.2 The well-established chemistry of cyclization taking place under acidic conditions in the final
classical calixarenes can be surprisingly complicated by the step (route A).7 This method is time consuming and gives very
introduction of heteroatoms in lieu of the usual CH2 bridging low overall yield. The second strategy (route B) employs the 2+2
units. The introduction of four sulfur atoms leads to the formation condensation of bisphenol with formaldehyde leading to a
of thiacalixarenes,3 which are very promising members of the mixture of the analogues with 4, 6 and 8 phenolic units.8
so called heteracalixarene family.4 Similarly, one can find azacalix- Although, the reported yield is acceptable (16%), this method
arenes, oxacalixarenes or even selenacalixarenes,5 all of them is unsuitable for larger scale preparation.
possessing very much different properties when compared to the
parent classical calixarenes.
In this communication we report on a simple and scalable
preparation of calixarene system 5 possessing the alternating
As recently reviewed,3a the presence of sulfur atoms invokes S and CH2 bridging moieties (2,14-dithiacalix[4]arene) and its
a dramatic change not only in the complexation behaviour and yet unreported homooxa derivatives 6 and 7 which were easily
conformational preferences, but also in the basic chemistry of obtained from slightly modified starting compounds.
such compounds. Consequently, derivatization of alkylated
a Department of Organic Chemistry, Institute of Chemical Technology Prague
(ICTP), Technicka 5, 166 28, Prague 6, Czech Republic. E-mail: lhotakp@vscht.cz;
Fax: +420-220444288; Tel: +420-220445055
b Laboratory of NMR Spectroscopy, ICTP, Czech Republic.
E-mail: dvorakoh@vscht.cz
c Department of Solid State Chemistry, ICTP, Czech Republic.
E-mail: eignerv@vscht.cz
† Electronic supplementary information (ESI) available: Synthetic details, NMR
spectra, dynamic NMR measurements and crystallographic details. CCDC
1032387 and 1032388. For ESI and crystallographic data in CIF or other electronic
Scheme 1 The two known approaches to access 2,14-dithiacalix[4]arene.
format see DOI: 10.1039/c5cc00819k
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Scheme 2 Synthesis of thiacalixarene analogues. (i) SCl2/CH2Cl2 (91%);
(ii) 1 equiv. CH2O/NaOH/water (64%); (iii) excess CH2O/KOH/water (97%);
(iv) TsOH/CHCl3 (58%); (v) TsOH/CHCl3 (27%); (vi) TsOH/CHCl3 (34%).
The synthesis was based on the preparation of suitable linear
building blocks 2–4 (Scheme 2). Although their preparation has
been reported previously,9 the original procedure failed to provide
the required products in satisfactory yields in our hands, necessi-
tating some improvements and modifications. Using the original
Fig. 1 (a) X-ray structure of compound 6 showing the OÁ Á ÁH distances
procedure, the formation of dimer 2 was always accompanied by of HB array; (b) X-ray structure of 7 with HB array; (c) site view of 7.
a substantial amount of the corresponding trimer – in 55% and
23% yield, respectively. The trimer could be removed only by
column chromatography on a silica gel, which complicates large
scale experiments. Fortunately, the condensation of SCl2 with
similar reaction conditions (1 equiv. TsOH in CHCl3, 5 days
an excess of starting phenol 1 resulted in easier isolation of
essentially pure 2 in 91% yield. This dimer represented the key
derivative 6 in 27% yield. This compound represented a completely
intermediate for hydroxymethyl derivatives 3 and 4. Again, optimi-
zation of reaction conditions led to monosubstituted compound 3
in 64% yield and disubstituted compound 4 in 97% yield.
The condensation reaction between 2 and 4 was carried out
in benzene using p-toluene sulfonic acid (TsOH) as a catalyst.
using single crystal X-ray crystallography (Fig. 1a). Compound 6
Interestingly, as shown in Table 1, a short screening of reaction
conditions confirmed that the reaction is very sensitive to the
amount of acid. Thus, 0.25 equiv. of TsOH led to a mixture of two
a circular array of intramolecular hydrogen bonds between
macrocyclic products, 5 and 7, in an B33:77 ratio. However, in
macrocycle 7, belonging to the so called tetrahomodioxadithia-
calixarene family,10 in 34% yield. Analogously, under very
at 30 1C) a mixture of 3 and 4 gave the corresponding dihomooxa
novel thiacalixarene derivative, so far unknown in the literature,
possessing three different types of bridging units within the
molecule: –S–, –CH2–O–CH2– and –CH2–.
Unequivocal evidence for structures 6 and 7 was obtained
crystallizes in the monoclinic system, space group P21/a. The
macrocycle adopted the cone conformation which was held by
four OH phenolic units and oxygen from the homooxa moiety
(Fig. 1a). The situation thus resembled the hydrogen bonding
an excess of acid (2 or 4 equiv.) only required thiacalixarene 5 was
isolated in 24% yield. Solvent choice proved to be crucial as well.
Reaction running in toluene did not provide any of the expected
product 5, however, using chloroform led smoothly to calixarene 5
Compound 7 crystallized in the triclinic system, space group
in 58% isolated yield on a 0.5 g scale.
array of the parent macrocycles – the respective OÁ Á ÁH distances
varied from 1.843 Å to 1.975 Å.
%
P1, and, contrary to compound 6, it adopted the 1,2-alternate
Due to the unexpected formation of unreported by-product 7
in the previous reaction, we focused on optimizing its inten-
tional preparation. The best reaction conditions (cat. TsOH in
CHCl3, 7 days at 35 1C) applied to building block 4 afforded
conformation. The possible circular HB array corresponding to
the cone conformation was broken into two independent halves
that were located on the opposite sites of the macrocyclic main
plane (Fig. 1b and c). The longer OÁ Á ÁH distances (1.933 Å and
2.063 Å) also indicated the higher mobility of larger macrocycle
7 when compared to smaller compound 6.
Table 1 Cyclization reactiona of compounds 2 and 4
As the conformational behavior of macrocyclic compounds
is of great importance for their possible applications, thiacalix-
arene analogues 5–7 were studied using temperature depen-
dent 1H NMR spectroscopy. This revealed that all three
compounds exhibited complex dynamic behavior where two
different dynamic processes were recognized: flip-flop motion
of the circular hydrogen bond arrays and the cone–inverted cone
Entry
Equiv. of TsOHb
Product 5c (%)
Product 7 (%)
1
2
3
4
5
0.25
0.50
1.00
2.00
4.00
33
58
82
100
100
77
42
18
0
0
a
b
Reaction conditions: benzene, 50 1C, 48 h. Equivalents of TsOH for
c
starting 2 and 4. Ratio of both products in calixarene fraction (NMR). equilibrium (Fig. 2).
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Fig. 3 Partial 1H NMR spectrum of 6 in the range of 213–313 K, CDCl3,
500 MHz (methylene part of the spectrum).
In conclusion, a simple and scalable synthesis of 2,14-
dithiacalix[4]arene with alternating bridges (–CH2– and –S–) is
reported. Interestingly, using the same bisphenol-based start-
ing building blocks under modified reaction conditions, novel
homooxa analogues possessing three different bridging units
(–CH2–, –S– and –CH2–O–CH2–) in the molecule could be
isolated selectively. These systems exhibited interesting con-
formational behaviour enabling study of the flip-flop motion of
the circular HB arrays using dynamic NMR techniques.
This research was supported by the Czech Science Founda-
tion (P207/12/2027).
Fig. 2 (a) Partial 1H NMR spectrum of 5 in the range of 213–273 K, CDCl3,
500 MHz (aromatic and hydroxy part of the spectrum), (b) partial 1H NMR
spectrum of 5 in the range of 213–298 K in CDCl3 and 313–363 K in
C2D2Cl4, 500 MHz (methylene part of the spectrum).
These two processes could be clearly demonstrated on
macrocycle 5 possessing the smallest cavity. Thus, by cooling
down the temperature to 213 K, the broad time-averaged signal
of methylene bridges split under slow exchange conditions into
two doublets (at 4.26 and 3.61 ppm) typical for axial and
equatorial methylene bridges of the cone conformation. The
coalescence temperature (Tc E 298 K) of this motion enabled
us to calculate the activation free energy DG* of the cone–cone
equilibrium of 57 kJ molÀ1, which was in good accordance with
the published data.7
An unexpected conformational behaviour was revealed for
the hydroxyl and aromatic protons. As can be seen (Fig. 2a),
the time-averaged signals (10.00 ppm for OH, 7.50 ppm and
7.25 ppm for the H–Ar atom (with meta coupling J = 2.4 Hz)) were
visibly doubled at the lowest temperature (213 K). This behaviour
can be attributed to the flip-flop motion of the circular HB arrays
where the direction of the hydrogen bonds leads to non-equivalent
signals of the OH groups and the aromatic protons. As this splitting
of signals is not possible for common thiacalix[4]arene, due to the
symmetry, the presence of mixed bridges made our systems ideal
candidates for a model study of this phenomenon which could be
seen even in 13C aromatic resonances (see ESI†). The DG* value for
5 (50 kJ molÀ1, Tc E 240 K for OH protons, Tc E 230 K for H–Ar)
corresponded with that published for the parent thiacalix[4]arene
(43 kJ molÀ1).11
Notes and references
1 C. D. Gutsche, Calixarenes an Introduction, The Royal Society of
Chemistry, Thomas Graham House, Cambridge, 2008.
2 (a) Calixarenes in the Nanoworld, ed. J. Vicens, J. Harrowfield and
L. Backlouti, Springer, Dordrecht, 2007; (b) L. Mandolini and
R. Ungaro, Calixarenes in Action, Imperial College Press, London,
2000.
3 For recent reviews on thiacalixarenes see: (a) R. Kumar, Y. O. Lee,
V. Bhalla, M. Kumar and J. S. Kim, Chem. Soc. Rev., 2014, 43, 4824;
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4 The term ‘‘heteracalixarene’’ indicates the presence of heteroatoms
in the bridging positions (instead of common CH2 groups), while
‘‘heterocalixarene’’ shows that calixarene walls are built up from
heterocycles instead of phenols (e.g. calixpyrroles).
5 For some recent reviews or papers, see e.g.: (a) H. Tsue, K. Ishibashi,
T. Koichi and R. Tamura, Top. Heterocycl. Chem., 2008, 17, 73;
(b) W. Maes and W. Dehaen, Chem. Soc. Rev., 2008, 37, 2393;
(c) J. Thomas, W. Van Rossom, K. Van Hecke, L. Van Meervelt,
M. Smet, W. Maesac and W. Dehaen, Chem. Commun., 2012, 48, 43.
¨
6 (a) O. Kundrat, I. Cisarova, B. Bohm, M. Pojarova and P. Lhotak,
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75, 8372; (d) J. Lukasek, S. Bohm, H. Dvorakova, V. Eigner and
´
The same dynamic processes were also observed for 6, but
due to its larger cavity the flip-flop motion of the circular
hydrogen bond arrays with DG* E 40 kJ molÀ1 (Tc E 203 K)
was not so obvious (see ESI†). Similarly to 5, the methylene
resonances (A = CH2–O–CH2, B = CH2) clearly exhibited the
cone–inverted cone equilibrium with DG* = 50 kJ molÀ1 (Tc E
263 K) (Fig. 3). The lower DG* values for both processes
reflected the expanded cavity of 6. Unfortunately, due to the
increased flexibility of macrocycle 7, it was not possible to prove
the above described effects unambiguously.
P. Lhotak, Org. Lett., 2014, 16, 5100.
7 T. Sone, Y. Ohba, K. Moriya, H. Kumada and K. Ito, Tetrahedron,
1997, 53, 10689.
8 N. Kon, N. Iki, Y. Yamane, S. Shirasaki and S. Miyano, Tetrahedron
Lett., 2004, 45, 207.
9 Y. Ohba, K. Moriya and T. Sone, Bull. Chem. Soc. Jpn., 1991, 64, 576.
10 See e.g.: (a) B. Dhawan and C. D. Gutsche, J. Org. Chem., 1983,
48, 1536; (b) B. Masci, Tetrahedron, 2001, 57, 2841; (c) B. Masci, in
¨
Calixarenes 2001, ed. Z. Asfari, V. Bohmer, J. Harrowfield and
J. Vicens, Kluwer Academic Publishers, Dordrecht, 2001, p. 235.
11 The DG* for the flip-flop motion of hydrogen bonds was assessed by
means of measurements of nuclear spin relaxation: J. Lang,
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K. Vagnerova, J. Czernek and P. Lhotak, Supramol. Chem., 2006, 18, 371.
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