A new approach to inherent chirality through the N/S ratio and/or the position in mixed heterocalix[4]arenes

Article abstract of DOI:10.1039/c1cc13390j

Fine control of the N/S ratio and/or the position of the bridged heteroatoms in mixed heterocalix[4]arenes leads to a new approach to generate inherent chiral scaffolds and represents a new challenge to fine-tune cooperative properties.

Full text of DOI:10.1039/c1cc13390j

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COMMUNICATION
A new approach to inherent chirality through the N/S ratio and/or the
position in mixed heterocalix[4]arenesw
Jean-Manuel Raimundo,* Zhongrui Chen and Olivier Siri*
Received 8th June 2011, Accepted 24th July 2011
DOI: 10.1039/c1cc13390j
Fine control of the N/S ratio and/or the position of the bridged
heteroatoms in mixed heterocalix[4]arenes leads to a new
approach to generate inherent chiral scaffolds and represents a
new challenge to fine-tune cooperative properties.
functionalities5 (e.g. size, conformational freedom, host–guest
complexation) in comparison with the methylene linkages
found in ‘‘classical’’ calix[n]arenes.
For instance, thiacalix[4]arenes 1 have received great atten-
tion from the supramolecular community mainly due to their
synthetic availability, engendering a wide range of uncommon
properties.5d More recently, azacalix[4]arenes6 2 have become
a focus of interest because of the presence of nitrogen bridges,
which should allow not only direct interactions with guest
species, but also the introduction of coordinating functions on
the bridge that might be used for complexation6i (in the
following sections, the term ‘‘heterocalixarenes’’ is used to
indicate nitrogen or sulfur bridged calix[4]arene analogues
with a [14]metacyclophane skeleton).
The access to chiral calix[4]arenes continues to spur active
investigations due to the remarkable properties of this class of
receptors in supramolecular chemistry.1 These calixarenes—
bearing chiral residues on the phenyl ring(s)—have been
described and widely used in enantioselective recognition or
asymmetric catalysis.2 The non-planarity of calixarenes offers
the possibility to prepare inherently chiral systems by introduction
of achiral residues suitably disposed in order to generate an
asymmetric array. The term ‘‘inherent chirality’’ was first
introduced by Bohmer et al.4a to indicate chiral calixarenes
Curiously, the preparation of related mixed heterocalix[4]-
arenes which combine aza- and thia-bridges is hitherto
unknown whereas the possible marriage of concomitant
properties of both classes in a single molecule appears very
attractive. More specifically, the possibility to readily control
the N/S ratio and/or the position of the heteroatoms in these
molecular frameworks represents a new challenge to fine-tune
the cooperative properties and to gain a better insight into the
structure–property relationships. Among them, the access to
heterocalix[4]arenes with ‘‘inherent chirality’’ generated by the
nature of the bridge would then become possible. Herein, we
report the high yield stepwise fragment coupling synthesis of
unprecedented mixed N,S-bridged heterocalix[4]arenes. This
metal-free preparation allowed a fine control of the N/S ratio
and of their position on the molecular scaffold which enabled
the first ‘‘inherent chirality’’ that originated from the bridge
(i.e. not by the substituent of the bridge).
¨
which belong to the C1 group of symmetry. To this end, two
general strategies have been employed: (i) by asymmetric
modification of the bridges3a,b or the aromatic rings3c–h
(i.e. substitution reaction), and (ii) by cyclizing an aromatic
monomer lacking an internal plane of symmetry.4 A new
approach that would allow an efficient, controlled and easier
introduction of ‘‘inherent chirality’’ is obviously of consider-
able interest in order to enlarge the scope of this family of
compounds.
Previous
works
reported
that
introduction
of
heteroatoms as bridging units can impart novel properties and
Our group and others have recently shown that nucleophilic
aromatic substitutions (SNAr) are effective reactions to pro-
vide heterocalix[4]arenes in good yields6 in contrast to the
palladium catalyzed coupling reactions.7 Accordingly, the
syntheses of related N,S-mixed systems were carried out
through an iterative pathway from readily available starting
compounds according to a puzzle-based construction. The
synthesis of the target compounds 8–10 is depicted in
Scheme 1. Intermediate 4 was first prepared as described in the
literature6d and then further reacted, in the presence of NaH,
with 3-aminothiophenol (1 equiv.) giving the unsymmetrical
triaryl 6 as a yellow solid in 94% yield. It is noteworthy that
the reaction could be also performed without the addition of
Centre Interdisciplinaire de Nanoscience de Marseille (CINaM),
´
913, 13288 Marseille cedex 09, France. E-mail: siri@univmed.fr,
jean-manuel.raimundo@univmed.fr; Fax: +33 (0)491 418 916;
Tel: +33 (0)491 829 367
w Electronic supplementary information (ESI) available: Detailed
experimental section, crystallographic data and supramolecular views.
CCDC 818496–818497. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1cc13390j
UPR CNRS 3118 Aix-Marseille Universite, 163 Ave de Luminy case
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10410 Chem. Commun., 2011, 47, 10410–10412
This journal is The Royal Society of Chemistry 2011

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N–HÁÁÁO2N intramolecular H-bonds—as already shown for
azacalix[4]arenes6h—but also by electrostatic interactions8
between the sulfur atom (d+, due to its conjugation with the
dinitrobenzene ring) and the oxygen atom (dÀ, in the adjacent
NO2 group) in the case of sulfur-bridged intermediates 5–7.
Macrocycles 8–10 were fully characterized by X-ray diffraction
in the case of 8 and 9. Their structure determination indicates a
1,3-alternate conformation in which all the bridging nitrogen
atoms conjugate with the dinitrobenzene rings rather than the
two other phenyl rings because of the electron-withdrawing
nature of the NO2 groups.9 As a result, the two C–N bond
lengths in the C–N(H)–C moieties are not equivalent [for
instance, C(2)–N(3) = 1.399(9) vs. C(23)–N(3) = 1.469(8) A
in 8 and C(11)–N(1) = 1.458(4) vs. C(2)–N(1a) = 1.384(4) A
in 9 (Fig. 1 and 2)]. Interestingly, the C(13)–N(1) bond
distance in
8
is strongly elongated compared with
C(15)–N(2) (1.486(10) vs. 1.393(9) A). This observation can
be explained by geometric constraints due to the presence of
one sulfur bridge which induces a lengthening of the bonds in
the C(11)–N(1)–C(13) moieties (the C–S bond distances are
much longer than the C–N bonds). The angles around the
bridging nitrogen are mainly about 1201. These data suggest a
sp2 character which induces a quasi-planar geometry of the
bridges (the nitrogens are pyramidal in azacalix[4]arenes
without NO2 substituents).6f
Scheme 1 Synthetic route for the preparation of the mixed
heterocalix[4]arenes 8–10. (a) 1,3-Diaminobenzene, ethanol, 0 1C,
3 hours, 86%;6d (b) 3-aminothiophenol, ethanol, 0 1C, 2 hours,
71%; (c) 3-aminothiophenol, NaH, THF, 0 1C to rt, 3 hours 94%;
(d) 3, THF, 0 1C, 1 hour, then rt, overnight, 61%; (e) 3, CH3CN,
reflux, overnight 80%; (f) CH3CN, reflux, overnight, 52%;
(g) 3-mercaptothiophenol, NaH, THF 0 1C to rt, 3 hours, 71%.
base with nearly the same yield. Similarly, intermediate 5 was
prepared by condensation of
3 and 3-aminothiophenol
Fig. 1 Crystal structure of the racemate 8 and ORTEP diagram of
one of the enantiomers (red: O; blue: N; green: S; black: C; orange: H).
(1 equiv.) in EtOH in 71% yield. Subsequent reaction of
5 with 3 affords the precursor 7 after purification by column
chromatography (61% yield). The macrocyclization step was
achieved by condensation of the intermediate 6 with 3 in
refluxing MeCN in the presence of N(iPr)2Et. The precipitate
obtained was then isolated by filtration and carefully washed
with hot water and ethanol affording the heterocalix[4]arene
8 in 80% yield. Macrocycle 9 was obtained in 52% via
self-condensation in refluxing MeCN in the presence of
N(iPr)2Et. Lastly, macrocycle 10 was synthesized by reacting
the difluorotriaryl intermediate 7 with 3-mercapto-thiophenol
(1 equiv.) in the presence of NaH in THF from 0 1C to room
temperature for 3 hours. As already pointed out, the formation
of the macrocycles does not require high dilution conditions
due to the preorganization of the intermediates, which prevent
the formation of polymers (C E 4 Â 10À2 mol lÀ1).3f,6d
Interestingly, this preorganization is not only controlled by
Importantly, the presence of two different heteroatoms
allows fine-tuning of the shape and size of the molecular plane
defined by the four bridges. For instance, 9 has a shape and
cavity whose dimensions (5.185 Â 5.180 A) are very close to
those of a lozenge whereas 8 revealed a rectangle molecular
plane (5.200 Â 4.941 A) (Fig. 1 and 2).
Examination of the non-covalent intramolecular interactions
in 8 and 9 revealed the presence of H-bonds between the oxygen
atoms of the NO2 groups and the N–H protons of the bridges
(2.013 o d(N–HÁÁÁO2N) o 2.022 A). The presence of electrostatic
interactions between the oxygen and sulfur atoms was clear from
the SÁ Á ÁO2N distances (2.539 o d(SÁ Á ÁO2N) o 2.624 A) which
are significantly shorter than the sum of the van der Waals
radii of sulfur and oxygen (3.25 A) (Fig. 1 and 2).
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Notes and references
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Fig. 2 Crystal structure of the racemate 9 and ORTEP diagram of
one of the enantiomers (red: O; blue: N; green: S; black: C; orange: H).
Macrocycles 8–10 are obtained in a racemic form due to the
enantiomerization process which occurs at room temperature.
The high conformation mobility of the above heterocalixarenes
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building block
9
forms 3D-supramolecular channels—
assembled through C–HÁÁÁO and C–HÁÁÁN and interactions—
that might be used for complexation of guests (see ESIw, Fig. S2).
In conclusion, a stepwise fragment coupling strategy has
allowed the access to the first mixed N/S heterocalix[4]arenes.
The synthetic pathway turned out to be crucial to generate
inherent chiral properties originating from the bridge by a
ready control of the N/S ratio and/or the heteroatom position.
Although, inherently chiral derivatives have been obtained in
their racemic form, derivatizations of the starting materials
should allow the synthesis of resolvable enantiomers (for
instance by introduction on the phenyl rings of steric hindered
and/or hydrogen bonding substituents). Additionally, this new
class of calixarenes (8–10) offers the possible concomitant
properties of the thiacalixarenes 15d (regio, stereo or chemoselective
oxidation of the sulfur bridge) and the aza5f–g,6 analogues 2 (as host
and/or robust high spin stable polyradicals), that should open new
perspectives in calixarene chemistry owing to the presence of hard
and soft heteroatoms around the same cavity.
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This work was supported by the Centre National de la
Recherche Scientifique and the Ministere de l’Enseignement
Superieur et de la Recherche. We also thank M. Giorgi (Spectro-
´
9 Y. Yasukawa, K. Kobayashi and H. Konishi, Tetrahedron Lett.,
2009, 50, 5130.
pole, Marseille) for the crystal structure determinations.
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10412 Chem. Commun., 2011, 47, 10410–10412
This journal is The Royal Society of Chemistry 2011