Homoselenacalix[n]arenes

Article abstract of DOI:10.1021/ol901044m

A novel family of homoselenacalix[n]arenes (n = 3-8), with bridging CH ₂SeCH₂ groups connecting the aryl subunits, has been synthesized via two different approaches employing nucleophilic Se species. The macrocycles are adequately ch

Full text of DOI:10.1021/ol901044m

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3040-3043
Homoselenacalix[n]arenes
Joice Thomas,† Wouter Maes,† Koen Robeyns,‡ Margriet Ovaere,‡
Luc Van Meervelt,‡ Mario Smet,*,† and Wim Dehaen*,†
Molecular Design and Synthesis and Biomolecular Architecture, Department of Chemistry,
Katholieke UniVersiteit LeuVen, Celestijnenlaan 200F, 3001 LeuVen, Belgium
mario.smet@chem.kuleuVen.be; wim.dehaen@chem.kuleuVen.be
Received May 14, 2009
ABSTRACT
A novel family of homoselenacalix[n]arenes (n ) 3-8), with bridging CH2SeCH2 groups connecting the aryl subunits, has been synthesized
via two different approaches employing nucleophilic Se species. The macrocycles are adequately characterized, including single-crystal X-ray
structures for the homoselenacalix[4]- and homoselenacalix[6]arene homologues. The combined features of a calixarene-like macrocyclic
scaffold and the presence of multiple selenium atoms create appealing (biomimetic) supramolecular opportunities.
Over the past 3 decades, the design and synthesis of a variety
of calixarene macrocycles has emerged as an essential part
of supramolecular chemistry, providing high versatility in
forming three-dimensional cavities which can selectively
form host-guest complexes with neutral molecules or ions.1
Besides the extensively explored classical carbon-bridged
calix[n]arenes, several other families of “calixarenoid”
macrorings with particular properties have been developed
and the chemistry of some of these calixarene-like metacy-
clophanes has been rejuvenated in recent years. Among those,
heteracalixarenes, in which the traditional methylene linkages
between the aromatic units are replaced by heteroatoms (e.g.,
S, NR or O),2 and homoheteracalixarenes, calixarene ana-
logues in which one or more methylene units are expanded
to CH2XCH2 groups (X ) O, NR or S),3-6 are particularly
attractive since they introduce heteroatoms which might
provide additional binding sites.
(4) Homooxacalixarenes: (a) Masci, B.; Finelli, M.; Varrone, M.
Chem.sEur. J. 1998, 4, 2018. (b) Shokova, E. A.; Kovalev, V. V. Russ. J.
Org. Chem. 2004, 40, 607. (c) Shokova, E. A.; Kovalev, V. V. Russ. J.
Org. Chem. 2004, 40, 1547. (d) Masci, B.; Mortera, S. L.; Persiani, D.;
Thue´ry, P. J. Org. Chem. 2006, 71, 504. (e) Choi, J. K.; Lee, A.; Kim, S.;
Ham, S.; No, K.; Kim, J. S. Org. Lett. 2006, 8, 1601. (f) Kohmoto, S.;
Someya, Y.; Masu, H.; Yamaguchi, K.; Kishikawa, K. J. Org. Chem. 2006,
71, 4509. (g) Notestein, J. M.; Andrini, L. R.; Kalchenko, V. I.; Requejo,
F. G.; Katz, A.; Iglesia, E. J. Am. Chem. Soc. 2007, 129, 1122. (h) Redshaw,
C.; Rowan, M. A.; Warford, L.; Homden, D. M.; Arbaoui, A.; Elsegood,
M. R. J.; Dale, S. H.; Yamato, T.; Casas, C. P.; Matsui, S.; Matsuura, S.
Chem.sEur. J. 2007, 13, 1090. (i) Marcos, P. M.; Ascenso, J. R.; Segurado,
† Molecular Design and Synthesis.
‡ Biomolecular Architecture.
(1) (a) Calixarenes 2001; Asfari, Z., Bo¨hmer, V., Harrowfield, J., Vicens,
J., Eds.; Kluwer Academic Publishers: Dordrecht, The Netherlands, 2001.
(b) Gutsche, C. D. Calixarenes: An Introduction, 2nd ed.; Stoddart, J. F.,
Ed.; Royal Society of Chemistry: Cambridge, UK, 2008.
(2) (a) Ko¨nig, B.; Fonseca, M. H. Eur. J. Inorg. Chem. 2000, 2303. (b)
Lhotak, P. Eur. J. Org. Chem. 2004, 1675. (c) Morohashi, N.; Narumi, F.;
Iki, N.; Hattori, T.; Miyano, S. Chem. ReV. 2006, 106, 5291. (d) Tsue, H.;
Ishibashi, K.; Tamura, R. In Heterocyclic Supramolecules I; Matsumoto,
K., Ed.; Topics in Heterocyclic Chemistry; Springer-Verlag: Berlin Heidel-
berg, Germany, 2008; Vol. 17, pp 73-96. (e) Wang, M.-X. Chem. Commun.
2008, 4541. (f) Maes, W.; Dehaen, W. Chem. Soc. ReV. 2008, 37, 2393.
(3) (a) Nakamura, Y.; Fujii, T.; Inokuma, S.; Nishimura, J. In Calix-
arenes 2001; Asfari, Z., Bo¨hmer, V., Harrowfield, J., Vicens, J., Eds.;
Kluwer Academic Publishers: Dordrecht, The Netherlands, 2001; pp
219-234. (b) Masci, B. In Calixarenes 2001; Asfari, Z., Bo¨hmer, V.,
Harrowfield, J., Vicens, J., Eds.; Kluwer Academic Publishers: Dordrecht,
The Netherlands, 2001; pp 235-249.
M. A. P.; Bernardino, R. J.; Cragg, P. J. Tetrahedron 2009, 65, 496
.
(5) Homoazacalixarenes: (a) Takemura, H. J. Inclusion Phenom. Mac-
rocyclic Chem. 2002, 42, 169. (b) Ito, K.; Noike, M.; Kida, A.; Ohba, Y.
J. Org. Chem. 2002, 67, 7519. (c) Kaewtong, C.; Fuangswasdi, S.;
Muangsin, N.; Chaichit, N.; Vicens, J.; Pulpoka, B. Org. Lett. 2006, 8,
1561. (d) Khan, S.; Singh, J. D.; Mahajan, R. K.; Sood, P. Tetrahedron
Lett. 2007, 48, 3605. (e) Kaewtong, C.; Jiang, G.; Park, Y.; Fulghum, T.;
Baba, A.; Pulpoka, B.; Advincula, R. Chem. Mater. 2008, 20, 4915. (f)
Arunachalam, M.; Ravikumar, I.; Ghosh, P. J. Org. Chem. 2008, 73, 9144
.
10.1021/ol901044m CCC: $40.75
Published on Web 06/12/2009
 2009 American Chemical Society

The presence of additional methylene units (and possibly
heteroatoms) in homocalixarenes results in an enlarged cavity
size as well as conformational flexibility, features that might
be advantageous for binding guests in an induced-fit fash-
ion.3-6 Within the subgroup of homoheteracalixarenes, the
oxygenated analogues have been studied most intensively.3,4
Different combinations and permutations of CH2 and
CH2OCH2 groups have afforded various macrocyclic ho-
mooxacalixarene frameworks. Hexahomotrioxacalixarenes,
the most available symmetrical homologues within this
family, have been applied as efficient synthetic hosts for both
metal and organic (quaternary ammonium) ions, and
fullerenes,3,4 while an oxovanadium complex has recently
been shown to be a superior olefin polymerization catalyst.4h
The synthesis and host-guest properties of homoaza- and
homothiacalixarenes have also been explored, although to a
lesser extent.5,6 However, to date, there have been no reports
of an extension of (homo)heteracalixarene chemistry to the
corresponding third or fourth-row “isologues” of the chal-
cogen series.7
Organoselenium compounds are of great interest from a
biological and pharmaceutical point of view. Inspired by the
importance of natural selenoproteins, synthetic organosele-
nium derivatives have been designed as glutathione peroxi-
dase (GPx) mimics and antithyroid drugs, and applied for
cancer prevention, inflammation protection, immune re-
sponses, and photodynamic tumor therapy.8,9 A number of
macrocycles containing selenium atoms within the ring
system have been synthesized over the years.10 The com-
plexation chemistry of selenoethers as versatile σ-donor
ligands for transition metals and their charge-transfer com-
plexation with electron acceptors are well-established. The
easy (reversible) conversion of selenides to selenoxides and
selenones enables Se-based macrocycles to bind different
guest molecules in its different oxidation states.
From the above, it is evident that (homo)calixarene
macrocycles containing Se atoms are attractive target mol-
ecules. Herein, we report convenient and versatile synthetic
procedures toward hitherto unknown homoselenacalix[n]are-
nes (n ) 3-8).7
Synthetic strategies toward homothiacalixarenes usually
involve substitution reactions of 1,3-bis(mercaptomethyl)-
benzene nucleophiles on 1,3-bis(bromomethyl)benzene de-
rivatives.6 Unfortunately, selenols are not as easy to prepare
and handle as the corresponding thiols, and readily oxidize
to diselenides. The required selenium bisnucleophiles can,
however, in situ be generated from bis(bromomethyl)ben-
zenes and sodium hydroselenide (NaSeH) or, alternatively,
1,3-bis(selenocyanato)benzene derivatives can be used.
Our first trial toward the formation of homoselenacalix-
arenes involved reaction of 1,3-bis(bromomethyl)benzene and
NaSeH (1:1 ratio) in THF under high dilution conditions.
Analysis of the crude reaction mixture by electrospray mass
spectrometry (ESI-MS) pointed toward the formation of
macrocycles containing 2-10 dimethyleneselena links, but
poor solubility hampered efficient purification of the homo-
logues. For this reason, another monomer enforcing favorable
solubility to the macrocycles, 1,3-bis(bromomethyl)-5-tert-
butyl-2-methoxybenzene (1), was envisaged. Moreover, this
substitution pattern allows direct comparison with related
(homo)calixarenes and might enable modification of the
lower rim at a later stage. Dropwise addition of 1 equiv of
NaSeH in ethanol (freshly prepared by reaction of a 1:2 molar
ratio of Se powder and NaBH4 suspended in ethanol) into a
flask containing 1 equiv of 1 in THF at room temperature
over 15 min resulted in the formation of a (kinetic) mixture
of homoselenacalix[n]arenes (n ) 3-7) in 86% total yield
with a 37:20:14:8:7 product ratio of 3-7, respectively
(Scheme 1). The rest of the reaction mixture consisted of
(6) Homothiacalixarenes: (a) Tashiro, M.; Yamato, T. J. Org. Chem.
1981, 46, 1543. (b) Kohno, K.; Takeshita, M.; Yamato, T. J. Chem. Res.
2006, 251. (c) Ashram, M. J. Inclusion Phenom. Macrocyclic Chem. 2006,
54, 253. (d) Tran, H.-A.; Georghiou, P. E. New J. Chem. 2007, 31, 921.
(7) Mitchell described the occurrence of a cyclic trimer, which can be
regarded as a hexahomotriselenacalix[3]arene, as a side product (8%) during
the synthesis of 2,11-diselena[3.3]cyclophanes: (a) Mitchell, R. H. Tetra-
hedron Lett. 1975, 16, 1363. (b) Mitchell, R. H. Can. J. Chem. 1980, 58,
1398.
Scheme 1. Synthetic Pathways toward
Homoselenacalix[n]arenes 3-8
(8) (a) Mugesh, G.; du Mont, W.-W.; Sies, H. Chem. ReV. 2001, 101,
2125. (b) Soriano-Garcia, M. Curr. Med. Chem. 2004, 11, 1657. (c)
Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. ReV. 2004, 104, 6255.
(d) Roy, G.; Mugesh, G. J. Am. Chem. Soc. 2005, 127, 15207. (e) Weng,
X.; Ren, L.; Weng, L.; Huang, J.; Zhu, S.; Zhou, X.; Weng, L. Angew.
Chem., Int. Ed. 2007, 46, 8020
.
(9) GPx mimics: (a) Back, T. G.; Moussa, Z.; Parvez, M. Angew. Chem.
Int. Ed. 2004, 43, 1268. (b) Zade, S. S.; Singh, H. B.; Butcher, R. J. Angew.
Chem., Int. Ed. 2004, 43, 4513. (c) Zhang, X.; Xu, H.; Dong, Z.; Wang,
Y.; Liu, J.; Shen, J. J. Am. Chem. Soc. 2004, 126, 10556. (d) Xu, H.; Gao,
J.; Wang, Y.; Wang, Z.; Smet, M.; Dehaen, W.; Zhang, X. Chem. Commun.
2006, 796. (e) Metanis, N.; Keinan, E.; Dawson, P. E. J. Am. Chem. Soc.
2006, 128, 16684. (f) Bhabak, K. P.; Mugesh, G. Chem.sEur. J. 2007, 13,
4594
.
(10) (a) Batchelor, R. J.; Einstein, F. W. B.; Gay, I. D.; Gu, J.-H.;
Johnston, B. D.; Pinto, B. M. J. Am. Chem. Soc. 1989, 111, 6582. (b)
Levason, W.; Orchard, S. D.; Reid, G. Coord. Chem. ReV. 2002, 225, 159.
(c) Pietschnig, R.; Scha¨fer, S.; Merz, K. Org. Lett. 2003, 5, 1867. (d)
Shimizu, T.; Kawaguchi, M.; Tsuchiya, T.; Hirabayashi, K.; Kamigata, N.
J. Org. Chem. 2005, 70, 5036. (e) Patel, U.; Singh, H. B.; Butcher, R. J.
Eur. J. Inorg. Chem. 2006, 5089. (f) Werz, D. B.; Fischer, F. R.; Kornmayer,
S. C.; Rominger, F.; Gleiter, R. J. Org. Chem. 2008, 73, 8021. (g) Levason,
W.; Manning, J. M.; Nirwan, M.; Ratnani, R.; Reid, G.; Smith, H. L.;
Webster, M. Dalton Trans. 2008, 3486. (h) Gonza´lez-Calera, S.; Eisler,
D. J.; Morey, J. V.; McPartlin, M.; Singh, S.; Wright, D. S. Angew. Chem.,
Int. Ed. 2008, 47, 1111.
polymeric material (and possibly higher cyclooligomers). All
homoselenacalixarenes 3-7 show good solubility in a variety
Org. Lett., Vol. 11, No. 14, 2009
3041

of (medium polarity) organic solvents such as CH2Cl2, ethyl
acetate, and THF. The calixarenes were separated by column
chromatography (silica) and the macrocycle size was easily
deduced by ESI-MS. An extension of the reaction time over
a longer period has the advantage of increasing the yield of
homoselenacalix[4]arene 4 (∼45%, ∼30% 3), but at the same
time the reaction is troubled by the oxidation of a small
amount of NaSeH to sodium selenide (Na2Se2), which in
turn results in the insertion of diselenide bridges, rendering
this approach less attractive. The use of an excess of NaSeH
has no profound influence on the calixarene ratio. The
addition of NaSeH at once into a solution of dibromide 1
increased the content of polymer formation.
δ 3.22 ppm at room temperature to 2.95 ppm at -60 °C,
was noticed.3-6 The 77Se NMR spectra for 3-8 contain only
one signal arising from the bridging Se atoms, confirming
the uniformity of all selenium atoms. A minor downfield
77Se chemical shift is observed with increasing cavity size.
To confirm the structure and analyze the conformations
of the synthesized macrocycles in the solid state, single
crystals of 4 and 6 were grown.12 The solid-state conforma-
tions determined for these homoselenacalix[n]arenes differ
from the structures reported for analogous homooxa and
homoaza derivatives (Figure 1).4,5 Homoselenacalix[4]arene
A more selective synthesis of p-tert-butyloctahomotetra-
selenacalix[4]arene tetramethylether 411 could be achieved
through a [2 + 2] reductive coupling protocol starting from
dibromide 1 and bisselenocyanate 2 (Scheme 1), easily
prepared by reaction of 1 and KSeCN. An excess of NaBH4
(3 equiv), suppressing diselenide formation, was added
dropwise to a mixture of 1 and 2 (1:1 ratio) in THF using
high dilution conditions, affording homoselenacalix[4]arene
4 in 67% yield and homoselenacalix[6]arene 6 in 18% yield,
while additionally affording homoselenacalix[8]arene 8 (9%
yield). When the reaction was repeated with a larger quantity
and higher concentration of reactants (5 mmol 1 and 2, ∼10
mM in THF), even larger macrocycles (n ) 10, 12, 14) were
obtained, but these could not efficiently be separated
chromatographically. Homoselenacalix[4]arene 4 could al-
ternatively be purified by selective crystallization from a
CHCl3-pentane solvent mixture. Additional advantages of the
[2 + 2] cyclocondensation are the absence of odd-numbered
calixarenes, simplifying purification, and the opportunity to
prepare asymmetrical homoselenacalixarenes.
Homoselenacalix[n]arenes 3-8 were completely charac-
terized by NMR spectroscopy (1H, 13C and 77Se) and ESI-
1
MS. The H NMR spectra of all calixarenes are easily
interpreted and show only singlet signals. The absence of
coupling for the geminal protons of the methylene groups
(due to diastereotopicity) indicates conformational flexibility
in solution.3-6 Except for the tert-butyl groups, all other
protons show a distinct chemical shift depending on the
macrocycle size. The protons of the intraannular methoxy
substituents are shifted upfield considerably with respect to
the acyclic precursors and this effect is most pronounced
for homoselenacalix[4]arene 4. This indicates that a confor-
mation in which the protons of the methoxy groups face the
rings of neighboring aromatic units is likely more populated
Figure 1. ORTEP representations of homoselenacalix[n]arenes 4
(top) and 6 (bottom), determined by X-ray crystallography (top
view). Thermal ellipsoids are set at 50% probability.13
4 adopts a heavily twisted (distorted) 1,3-alternate conforma-
tion with 4-fold symmetry, with the bridging Se atoms
oriented inside the cavity. Two crystallographic independent
homoselenacalix[4]arene entities, with similar structural
features, can be distinguished in the crystal structure. The
methoxy groups on the intraannular rim are directed inward,
properly arranged so as to minimize steric hindrance. Two
of the methoxy hydrogens show weak hydrogen interactions
with neighboring Se atoms, while the third hydrogen atom
is involved in a weak CH-π interaction with a phenyl ring.
The latter interaction seems to correspond well with the
1
in this case. Hence, analysis of the H NMR spectrum of
the crude reaction mixture can provide a reliable quantitative
insight on the respective calixarenes produced (via integration
of the methoxy signals). The chemical shift differences for
the aromatic and methylene protons are much smaller.
1
Variable temperature H NMR spectra of 4 give additional
information on the conformational behavior. No signal
splitting was observed for temperatures down to -60 °C
while further shielding of the methoxy protons, ranging from
(12) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as suppl.
publ. no. CCDC-729034 and CCDC-729035. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
(11) Alternative denotations: tetraselena[3.3.3.3]calixarene or 2,11,20,29-
tetraselena[3.3.3.3]metacyclophane.3-6
3042
Org. Lett., Vol. 11, No. 14, 2009

1
observed shielding effect in the H NMR spectrum. On the
diselena[3.3]metacyclophane (13, 59%) as the main com-
pound, together with 13% of homoselenacalix[4]arene 14.
This indicates that the absence of an interior methoxy group
favors [1 + 1] cyclocondensation. In contrast, the coupling
reaction between 1 and bisselenocyanate 11 (lacking the tert-
butyl moiety) under similar reaction conditions afforded
homoselenacalix[4]arene 15 (40%) as the major product
(Scheme 2). No diselena[3.3]cyclophane product was de-
tected in this reaction (as for cyclocondensation of 1 and 2).
The above observations indicate that the methoxy group on
the inner rim is not only a useful diagnostic tool to determine
the ring size by NMR and enables postmacrocyclization
modifications, but also plays a crucial role for the selective
formation of the cyclic tetramers.
other hand, a 1,3,5-alternate conformation is observed for
the expanded homoselenacalix[6]arene 6. The bridging Se
atoms are directed outside the cavity and facing phenyl rings
are oriented antiparallel. The methoxy substituents are partly
included in the cavity and partly directed outward. The two
self-included methoxy groups show weak CH-π interactions
with the opposing phenyl rings, while two of the outward
directed methoxy groups show weak hydrogen interactions
with Se.
To vary the substitution pattern of the homoselenacalix-
arenes, substituent-free (at the 2- and 5-position) precursors
9 and 10 were initially combined under reductive conditions
(Scheme 2). However, [1 + 1] coupling product 12 was
In summary, a series of homoselenacalix[n]arenes of
different ring size (n ) 3-8), containing bridging dimeth-
yleneselena units connecting the aryl parts, has been syn-
thesized and the macrocycles were completely characterized,
including X-ray structures for the calix[4]- and calix[6]arene
homologues. Se-bridged calixarene macrocycles not only
represent an addition to the expanding field of organosele-
nium chemistry, but can evolve into an important family of
potential receptor molecules in which the Se atoms impose
specific complexation patterns and provide an additional
probe to monitor interactions (via 77Se NMR). Further
elaboration of the synthetic chemistry of (homo)selenacalix-
arenes and their supramolecular applications are currently
actively being pursued within our group.
Scheme 2. Exploration of the Selenacyclophane Size
Acknowledgment. We thank the FWO (Fund for Scien-
tific Research - Flanders), the KU Leuven and the Ministerie
voor Wetenschapsbeleid for continuing financial support.
Supporting Information Available: Experimental pro-
cedures and data, NMR (1H, 13C, 77Se) spectra of the novel
macrocycles and precursors, and additional information
regarding the X-ray structures of 4 and 6. X-ray data for 4
and 6 in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
obtained almost quantitatively (94%). Hence, we decided to
perform a preliminary study on the effect of intra- and
extraannular substituents on the macrocyclization outcome.
Reaction of 5-tert-butyl-2-methoxy-bisselenocyanate 2 and
9 under identical conditions gave again the dimeric
OL901044M
(13) H atoms, disorder (t-Bu in 6) and incorporated solvent (CHCl3 in
4) are omitted for clarity.
Org. Lett., Vol. 11, No. 14, 2009
3043