Highly efficient construction of large molecular cavity using 1,3-alternate tetraoxacalix[2]arene[2]triazine as a platform

Article abstract of DOI:10.1039/b805293j

In the presence of K₂CO₃ in refluxing THF, dichloro-substituted tetraoxacalix[2]arene[2]triazine, a readily available macrocyclic compound from cyanuric acid chloride and benzyl 1,3- dihydroxybenzoate, underwent highly efficient nucleophilic displacement reactions with bis-nucleophilic reagents of different geometry, length and chirality in a 2+2 fashion to produce large and size-tunable cavity bis-tetraoxacalix[2]arene[2]triazines in good to excellent yields. The Royal Society of Chemistry.

Full text of DOI:10.1039/b805293j

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Highly efficient construction of large molecular cavity using 1,3-alternate
tetraoxacalix[2]arene[2]triazine as a platformw
Bao-Yong Hou, Qi-Yu Zheng, De-Xian Wang, Zhi-Tang Huang and
Mei-Xiang Wang*
Received (in Cambridge, UK) 31st March 2008, Accepted 2nd May 2008
First published as an Advance Article on the web 23rd June 2008
DOI: 10.1039/b805293j
In the presence of K2CO3 in refluxing THF, dichloro-substituted
tetraoxacalix[2]arene[2]triazine, a readily available macrocyclic
compound from cyanuric acid chloride and benzyl 1,3-dihydroxy-
benzoate, underwent highly efficient nucleophilic displacement reac-
tions with bis-nucleophilic reagents of different geometry, length and
chirality in a 2+2 fashion to produce large and size-tunable cavity
bis-tetraoxacalix[2]arene[2]triazines in good to excellent yields.
Although the syntheses and the structures of a number of
heteroatom bridged calixaromatics have been documented,
functionalization and application studies of these novel hosts
are just emerging.6k,6l,7d–f,12 Being analogous to calixarenes,
heteroatom bridged calixaromatics can act as platforms for
the construction of functionalized and more sophisticated
molecular architectures. Dichloro-substituted heteroatom
bridged calix[2]arene[2]triazines, which were readily obtained
from cyanuric chloride and different aromatic bisnucleophilic
agents, for instance, have indeed been chemically modified at
the positions of both the triazine ring12 and the nitrogen
bridge.5k We report herein the highly efficient construction
of a larger and size-tunable molecular cavity by the nucleo-
philic displacement reaction of dichlorotetraoxacalix[2]are-
ne[2]triazine 1 with bis-nucleophilic reagents 2 of varied
geometry and length in a 2+2 fashion.
We started our investigation by examining the reaction of 16a
with 1,3-bis(aminomethyl)benzene 2a under various conditions.
As summarized in Table 1, the use of di(isopropyl)ethylamine
(DIPEA) (entry 1) or Cs2CO3 (entries 2–4) as a base did not give
the desired product. The combination of K2CO3 with a polar
solvent including dimethylsulfoxide (DMSO) and N,N-dimethyl-
formamide (DMF) afforded a mixture of inseparable oligomers
(entries 5 and 6). When the reaction was carried out in dry
acetonitrile, a small amount of bis-tetraoxacalix[2]arene[2]triazine
3 was isolated from oligomers (entry 7). Gratifyingly, the chemical
yield of 3 was improved drastically to 90% when the reaction was
refluxed in dry tetrahydrofuran (THF) (entry 8). It is evident that
both the base and the solvent play an important role in facilitating
the macrocyclization reaction. The efficient formation of macro-
cycle 3 in K2CO3–THF suggests the polarity of the reaction
medium and the template effect of potassium ion are most likely
in favor of intramolecular cyclization over oligomerization.
Encouraged by the highly efficient and high-yielding synthesis
of 3 from 1 and 2a, other bis-nucleophiles of different geometry,
length and chirality were employed in order to obtain macro-
cyclic molecules with a size-tuned cavity. Under conditions
identical to those for the synthesis of 3, the reaction between 1
and benzyl 3,5-dihydroxybenzoate 2b proceeded equally well to
furnish resorcinol-connected cavity molecule 4 in excellent yield
(Fig. 1). N,N0-Dimethylethylenediamine 2c, a secondary diamine
species with the shortest aliphatic chain, was also able to react
with 1 in a 2+2 fashion, yielding a rigid macrocyclic cavity 5 in
an acceptable yield (41%) (Fig. 1). The chiral molecules can also
be incorporated into the macrocyclic bis-tetraoxacalix[2]are-
ne[2]triazine cavity. Thus, the interaction between enantiomeri-
cally pure 1R,2R-1,2-diphenylethylenediamine 2d and 1R,2R-
1,2-cyclohexanediamine 2e with 1 afforded the corresponding
For more than three decades, calix[n]arenes have been one of the
most important and attractive macrocyclic host molecules in the
study of supramolecular chemistry owing to their easy prepara-
tion and functionalization, various conformational structures and
powerful binding ability towards different guest species.1–3 Along
with the rapid development of calix[n]arenes, recent years have
also witnessed a fast growing interest in heteroatom bridged
calix(hetero)aromatics.4–8 In comparison with calix[n]arenes1–3
and calixheteroarenes such as calixpyrroles,9 calixpyridines10
and other calixaromatics,11 in which the (hetero)arene units are
linked by methylenes, introduction of heteroatoms into the
bridging positions has generated a number of novel macrocyclic
molecules.4–8 Based on the fragment coupling strategy, for ex-
ample, we6a,6k,6l,7d,7e have efficiently synthesized aza- and/or oxa-
calix[2]arene[2]triazines and azacalix[m]arene[n]pyridines (m = 0,
n = 4, 5, 8, 10; m = n = 2, 4, 5), while Katz6b–d,6m and
others6e,6f,6j,6n reported the preparation of symmetrically substi-
tuted oxacalix[4]aromatics using a very convenient one-pot reac-
tion method. Because of the different electronic nature of
heteroatoms from carbon, the heteroatom bridged calix(heter-
o)aromatics exhibit interesting structural and molecular recogni-
tion properties.4–8 It has been demonstrated that the cavity of aza-
and/or oxa-calix[2]arene[2]triazines can be regulated by using
different combinations of heteroatoms6a or varied substituents
on the bridging nitrogen atoms.6k It has also been shown that, due
to the intrinsic nature of nitrogen which can adopt sp2 and/or sp3
electronic configurations to form or not form conjugation with
its adjacent aromatic rings, azacalix[n]pyridines and
azacalix[m]arene[n]pyridines are able to pre-organize into different
conformational and cavity structures to interact with metal ions,7f
anions,7e fullerenes7d,e and both aromatic and aliphatic diols and
monools.7l
Beijing National Laboratory for Molecular Sciences, Laboratory of
Chemical Biology, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China. E-mail: mxwang@iccas.ac.cn; Fax:
+8610-6256-4723; Tel: +8610-6256-5610
w Electronic supplementary information (ESI) available: Synthesis
and characterization of compounds 3–7. Crystallographic data in
CIF or other electronic format (CCDC 682855). See DOI: 10.1039/
b805293j
ꢀc
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3864 | Chem. Commun., 2008, 3864–3866

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Table 1 Reaction of dichlorotetraoxacalix[2]arene[2]triazine 1 with
1,3-phenylenedimethanamine 2aa
Fig. 1 Structures of larger and size-tunable cavity molecules prepared.
(dC30–C33 = 8.818 A, dC43–C46 = 8.747 A) in two of the 1,3-
alternate tetraoxacalix[2]arene[2]triazine units in 5 decreased while
the distance between two benzenes (dC9–C15 = 5.867 A, dC49–C63
= 6.122 A) increased. The distance between two 1,3-alternate
tetraoxacalix[2]arene[2]triazines, which are slightly twisted, is 6.668
A (dC18–C66) to 7.104 A (dC12–C52). It is interesting to note that the
cavity in 5 is formed by four electron-deficient triazine walls.
Furthermore, in the solid state, two bis-tetraoxacalix[2]arene[2]-
triazine molecules form a non-covalently bonded dimer structure
with each large cavity including one of the benzyl moieties of the
other molecule. As judged from the distances between the included
benzene ring and benzene and triazine rings of the large cavity,
there are multiple C–H–p interactions between host and guest (see
CIF of 5 and structure in ESIw). Moreover, there is an apparent
p–p stacking interaction between two benzene rings of each bis-
tetraoxacalix[2]arene[2]triazine, as the distance between two ben-
zene planes was 3.395 A (Fig. 3).
Entry
Conditions
Oligomer
3 (%)b
1
2
3
4
5
6
7
8
a
DIPEA, 1,4-dioxane, reflux, 24 h
Cs2CO3, DMSO, reflux, 24 h
+
+
+
+
+
+
+
ꢁ
—
—
—
—
—
—
19
90
Cs2CO3, 1,4-dioxane, reflux, 24 h
Cs2CO3, THF (dry), reflux, 24 h
K2CO3, DMSO, rt to reflux, 24 h
K2CO3, DMF, rt to reflux, 24 h
K2CO3, CH3CN (dry), reflux, 24 h
K2CO3, THF (dry), reflux, 24 h
The construction of stable cavity molecules of tunable sizes is of
great importance in materials and life sciences. The functionalized
cavity hosts have been widely used in molecular recognition,
enzyme mimics and supramolecular assemblies. The bis-tetraox-
acalix[2]arene[2]triazine compounds synthesized in this study have
distinct structural features. By using bis-nucleophilic reagents of
different structures, for example, the macrocyclic cavity can be
A mixture of 1 (1 mmol) and 2a (1 mmol) was stirred or refluxed in
b
solution (880 mL). Isolated yield.
chiral cavity molecules 6 and 7, respectively, in good yields
(Fig. 1).
The structures of bis-tetraoxacalix[2]arene[2]triazines 3–7 were
supported by their spectroscopic data and microanalyses (see
Supporting Informationw). Both mass spectrometry and elemental
analysis indicated a 2+2 reaction between dichloro-substituted
tetraoxacalix[2]arene[2]triazine 1 and a bis-nucleophilic reactant 2
with the loss of two equivalents of HCl. To understand the cavity
structure on the molecular level, a single crystal of 5z was
cultivated from the slow evaporation of the solvent from its
solution in a mixture of methanol and chloroform. Since the X-
ray diffraction analysis was performed at room temperature,
disorder of the atoms of the benzyl moieties was observed (see
CIF of 5w). As illustrated in Fig. 2, the larger cavity in 5 is
composed of two 1,3-alternate tetraoxacalix[2]arene[2]triazine seg-
ments which are head-to-head (upper-rim-to-upper-rim) con-
nected by two N,N0-dimethyl-ethylenediamine moieties.
Fig. 2 X-ray structure of 5 (top view). 50% Thermal ellipsoids are
shown for the non-hydrogen atoms. Selected atomic distances:
dC30–C33 = 8.818 A; dC43–C46 = 8.747 A; dC9–C15 = 5.867 A;
dC49–C63 = 6.122 A; dC18–C66 = 6.668 A; and dC12–C52 = 7.104 A.
Compared
with
its
parent
1,3-alternate
tetraoxa-
calix[2]arene[2]triazine,12b the distance between two triazine rings
ꢀc
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Fig. 3 X-ray structure of a non-covalently bonded dimer formed in
the solid state, with one molecule at (x,y,z) being shown in spacefill
and the other at (1ꢁx, ꢁy, 1ꢁz) in capped sticks. All hydrogen atoms
are omitted for clarity. While two bis-tetraoxacalix[2]arene[2]triazine
molecules interact with each other through p–p stacking interaction
between two benzene rings (d = 3.395 A), each large cavity includes
one benzyl group of the other molecule.
tuned in size. In addition, the macrocyclic framework contains
multiple triazine and secondary amine moieties, which are poten-
tial hydrogen bond acceptors and donors, respectively. Most
noticeably, the cavity of bis-tetraoxacalix[2]arene[2]triazines such
as 4 is composed of all four electron-deficient triazine walls. It
might be useful in complexation with highly electron-rich species.
In summary, we have shown that dichloro-substituted tetra-
oxacalix[2]arene[2]triazine 1, a readily available macrocyclic scaf-
fold, is a useful building block for the construction of the higher
level polytopic macrocycles. The treatment of 1 with different bis-
nucleophilic reagents including chiral diamines in the presence of
K2CO3 in refluxing THF afforded bis-tetraoxacalix[2]arene[2]tria-
zines in good to excellent yields. In the solid state, a dimeric
structure was formed through the p–p stacking interaction and
mutual inclusion complexation between two large macrocyclic
molecules 5. The electron-deficient triazine-walled large cavity of
tunable size, the presence of multiple hydrogen-bonding sites and
the incorporated chirality would render the bis-tetraoxacalix[2]-
arene[2]triazines obtained unique and interesting receptors in
molecular recognition and supramolecular assembly. Their appli-
cations in molecular recognition are being actively investigated in
this laboratory.
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´ ´
We thank the National Natural Science Foundation of China,
Ministry of Science and Technology, Chinese Academy of
Sciences for financial support.
´
Notes and references
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ꢀc
This journal is The Royal Society of Chemistry 2008
3866 | Chem. Commun., 2008, 3864–3866