Synthesis of electron-deficient oxacalix[2]arene[2]triazines and their isomeric analogs from a one-pot reaction of perfluorinated dihydroxybenzenes with dichlorotriazines

Article abstract of DOI:10.1021/ol401959d

Efficient synthesis of tetraoxacalix[2]perfluoroarene[2]triazines and their isomeric analogs from a one-pot macrocyclic condensation reaction of methoxy- and amino-substituted dichlorotriazines with tetrafluorobenzene-1,3-, -1,4-, and -1,2-diols was developed. X-ray analysis demonstrates that they adopt drastically different 1,3-alternate conformations in the crystalline state while in solution they undergo very fast conformational changes relative to the NMR time scale.

Full text of DOI:10.1021/ol401959d

ORGANIC
LETTERS
2013
Vol. 15, No. 17
4414–4417
Synthesis of Electron-Deficient
Oxacalix[2]arene[2]triazines and Their
Isomeric Analogs from a One-Pot Reaction
of Perfluorinated Dihydroxybenzenes with
Dichlorotriazines
Chi Yang,† Yin Chen,‡ De-Xian Wang,*,‡ Liang Zhao,† and Mei-Xiang Wang*,†
The Key Laboratory of Bioorganic Phosphorous Chemistry & Chemical Biology
(Ministry of Education), Department of Chemistry, Tsinghua University,
Beijing 100084, China, and Beijing National Laboratory for Molecular Sciences,
CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100190, China
dxwang@iccas.ac.cn; wangmx@mail.tsinghua.edu.cn
Received July 11, 2013
ABSTRACT
Efficient synthesis of tetraoxacalix[2]perfluoroarene[2]triazines and their isomeric analogs from a one-pot macrocyclic condensation reaction of
methoxy- and amino-substituted dichlorotriazines with tetrafluorobenzene-1,3-, -1,4-, and -1,2-diols was developed. X-ray analysis demonstrates
that they adopt drastically different 1,3-alternate conformations in the crystalline state while in solution they undergo very fast conformational
changes relative to the NMR time scale.
Heteracalixaromatics, or heteroatom-bridged calix(het)-
arenes, are a new generation of macrocyclic host molecules
in supramolecular chemistry.1 By means of the fragment
coupling approach (FCA)1,2 and one-pot macrocyclic
condensation reaction,1,3 a wide variety of heteracalixaro-
matics, including functionalized and both symmetrically
and unsymmetrically substituted ones, have been success-
fully synthesized from simple and easily available starting
materials.4À6 Because of the easy chemical manipula-
tions on both aromatic units and bridging heteroatoms,
heteracalixaromatics provide versatile platforms for the
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Dehaen, W. Org. Lett. 2006, 8, 4161. (b) Katz, J. L.; Selby, K. J.; Conry,
R. R. Org. Lett. 2006, 8, 2755. (c) Bizier, N. P.; Vernamonti, J. P.; Katz,
J. L. Eur. J. Org. Chem. 2012, 2303. (d) Hao, E.; Fronczek, F. R.;
Vicente, M. G. H. J. Org. Chem. 2006, 71, 1233. (e) Chen, C.-F. Chem.
Commun. 2011, 47, 1674.
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L. V.; Smet, M.; Dehaen, W. Org. Lett. 2009, 11, 3040. (b) Wang, Q.-Q.;
Wang, D.-X.; Ma, H.-W.; Wang, M.-X. Org. Lett. 2006, 8, 5967. (c)
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9, 2847.
† Tsinghua University.
‡ Chinese Academy of Sciences.
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Dehaen, W. Chem. Soc. Rev. 2008, 37, 2393. (c) Tsue, H.; Ishibashi, K.;
Tamura, R. Top. Heterocycl. Chem. 2008, 17, 73. (d) Wang, M.-X. Acc.
Chem. Res. 2012, 45, 182.
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Ed. 2004, 43, 838. (b) Wang, M.-X.; Yang, H.-B. J. Am. Chem. Soc. 2004,
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r
10.1021/ol401959d
Published on Web 08/27/2013
2013 American Chemical Society

construction of sophisticated macrocycles7 and high-level
molecular architectures.8 Due to the electronic and steric
effects of heteroatoms in the linking positions, heteracalix-
aromatics adopt interesting conformational structures in
which various conjugational systems between heteroatoms
and aromatic rings are formed.2,9,5b The interplay between
heteroatoms and their adjacent aromatic rings also plays a
very important role not only in fine-tuning the structure
and size of the macrocyclic cavity but also in regulating the
electronic features and therefore the molecular recognition
properties of the resulting macrocyclic hosts. It is particu-
larly worth addressing that various heteracalixaromatics
have found diverse applications ranging from recognition
of metal ions,11 anions,12 neutral organic molecules13 includ-
ing fullerenes2,9,14 and chiral molecules,15 fabrications of
HPLC stationary phases for analysis of complex samples16
and of LangmuirÀBlodgett films for voltammetric analysis,17
discrete coordination cages,18 organometallic clusters,19
and infinite metalÀorganic frameworks.20 Azacalixar-
enes have also been shown as promising CO2 absor-
bents21 and spin-electronic materials.22
As a member of heteracalixaromatics, oxacalix[2]arene-
[2]triazine2a shows powerful capability to selectively com-
plex various anions of different geometries and shapes.12
As revealed by the X-ray crystallography, two triazine
rings embedded in a macrocycle form a tunable electron-
deficient cleft, chelating an anion through typical anionÀπ
interaction and lone-pair electronÀπ interaction. It has
also been demonstrated theoretically and experimentally
that the presence of electron-withdrawing groups enhances
triazine’s power to complex an anion species.12a Our
interest in the supramolecular chemistry of heteracalixaro-
matics1 and anionÀπ interactions12 led us to undertake the
current study. We envisioned that the replacement of
benzene units in oxacalix[2]arene[2]triazine by perfluoro-
benzene moieties would result in a more electron-deficient
macrocycle. To understand the bridging pattern on the
conformational structures, macrocycles that are com-
posed of triazine and tetrafluorobenzene-1,2- or -1,4-
diols were also included in our study. We disclose
herein the efficient synthesis of oxacalix[2]perfluoro-
arene[2]triazines and their isomeric analogs from a
one-pot macrocyclic condensation reaction of meth-
oxy- and amino-substituted dichlorotriazines with tet-
rafluorobenzene-1,3-, -1,4-, and -1,2-diols. Conforma-
tional structures of the resulting macrocycles in the
solid state and in solution phase are also reported.
We initiated our study with the synthesis of oxygen-
bridged calix[2]perfluoroarene[2]triazine 4a by means of a
stepwise fragment coupling approach2 (Scheme 1). In the
presence of K2CO3 as a base, tetrafluorobenzene-1,3-diol 1
reacted efficiently with 2 equiv of 2,4-dichloro-6-methoxy-
1,3,5-triazine 2a at ambient temperature in dry acetone to
afford intermediate 3a. The intermediate 3a was very
reactive and underwent decomposition upon purification.
To our delight, however, without isolation and purifica-
tion, intermediate 3a, formed in situ, reacted with another
equivalent of 1 in refluxing acetone in 1.5 h to produce
desired macrocycle 4a as the sole product in an excellent
yield. Replacement of methoxy-substituted dichlorotria-
zine 2a with 2-dimethylamino-4,6-dichloro-1,3,5-triazine
2b led to a sluggish reaction because of the lower electro-
philicity of the latter. For example, in the presence of a
stronger base such as Cs2CO3 at 30 °C, the formation of 3b
from the reaction between 1 and 2b required 8 h. It took
another 38 h to convert 3b into a macrocyclic product. The
one-pot synthesis furnished, nevertheless, oxacalix[2]per-
fluoroarene[2]triazine 4b in 54% yield.
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Org. Lett., Vol. 15, No. 17, 2013
4415

for the synthesis of 7b, the reaction of 8 and 2a proceeded
rapidly to yield expected product 10a in 47% yield,
whereas the same reaction between 8 and 2b took a much
longer time to go to completion giving the corresponding
macrocyclic product 10b in a slightly diminished chemical
yield. Isolation of trimeric intermediates 9 was not success-
ful in these cases due to probably their instability.
Scheme 1. Synthesis of 4
Scheme 3. Synthesis of 10
Scheme 2. Synthesis of 7
All macrocyclic products synthesized are crystalline
compounds, and their structures are established on the
basis of their spectroscopic data and microanalysis results.
To understand the conformation structures of oxacalix-
[2]perfluoroarene[2]triazines 4 and their isomeric analogs
7 and 10, single crystals of 4a, 4b, 7a, and 10a were
cultivated and their X-ray molecular structures were
determined.
Encouraged by the facile synthesis of oxacalixaromatics
from simple operations in a one-pot reaction manner, we
thenattempted the preparation of macrocyclic compounds
7 and 10 that have conceivably varied conformational and
cavity structures. Illustrated in Scheme 2 are the syntheses
of oxygen-bridged cyclophanes from perfluorinated hy-
droquinone 5 and dichlorotriazines 2. Similar to the
synthesis of 4a, a one-pot reaction between 2a and 5 took
place efficiently to give product 7a in a high yield. Under
the conditions for the preparation of 4b, only 30% of
product 7b was obtained from the reaction of 5 with 2b.
Interestingly, the use of a small amount of water (acetone/
water = 15:1) in the second step macrocyclization reaction
led to the increase of chemical yield of 7b to a 41% yield.
When isolated linear trimer 6b was employed to react with
5, macrocycle 7b was obtained in 65% yield. It should be
noted that further optimization of the reaction conditions
using other bases, solvents, and the ratio of acetone over
water unfortunately did not improve the formation of
macrocyclic product 7b (see Supporting Information
Table S2).
The one-pot reaction strategy was extended to the
construction of another type of isomeric analogs, viz.
vicinal oxygen linked cyclophanes 10 using perfluorinated
catechol 8 as a building block (Scheme 3).10 We found that
the purity of reactant 8, which was prepared from the
reaction of perfluorobenzene and ethylene glycol followed
by AlCl3-mediated dealkylation,23 was critical to the
synthesis of 10. Since catechol 8 also undergoes a sponta-
neous auto-oxidation reaction under atmospheric condi-
tions, it was beneficial to conduct the synthesis under an
inert atmosphere. By applying the optimized conditions
AsdepictedinFigure1, dimethoxy-substituted oxacalix-
[2]perfluoroarene[2]triazine 4a adopts a slightly twisted
1,3-alternate conformation, which is similar to its non-
fluorinated counterpart.25 The averaged bond lengths (see
captions of Figure S1) of the bridging oxygen to the carbon
of triazine (dOÀC(triazine)) and to the carbon of tetrafluor-
˚
obenzene (dOÀC(tetrafluorobenzene)) are 1.36 and 1.38 A,
respectively. The smaller bond length difference indicates
the formation of conjugation of bridging oxygen atoms
with both triazine and tetrafluorobenzene rings, with the
former being slightly stronger. The variation of a substi-
tuent on the triazine ring does not affect the conforma-
tional structure. This has been exemplified by the X-ray
molecular structure of amino-substituted oxacalix[2]perfluo-
roarene[2]triazine 4b which shows a highly symmetric 1,3-
alternate conformation with C2v symmetry (Figure S2).
The interaction of macrocycles with CH2Cl2 molecules
in the crystalline state was worth noting. As illustrated in
Figure 1B, two CH2Cl2 molecules are included in between
two electron-deficient tetrafluorobenzene rings of 4a. One
of the chloride atoms of each CH2Cl2 interacts with
tetrafluorobenzene rings through σ-type ClÀC (dCl1ÀC9
=
˚
3.36 A) interactions. Interestingly, the other chloride
atom of CH2Cl2 locates above the triazine ring of another
4a molecule. The short contact distance between chloride
˚
and the plane of triazine is 3.42 A (dCl2‑plane), indicating
weak lone-pair electronÀπ interaction.
(24) Chen, Y.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. J. Org.
Chem. 2010, 75, 3786.
(25) Li, S.; Fa, S.-X.; Wang, Q.-Q.; Wang, D.-X.; Wang, M.-X.
(23) Burdon, J.; Damodaran, V. A.; Tatlow, J. C. J. Chem. Soc. 1964,
763.
J. Org. Chem. 2012, 77, 1860.
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Org. Lett., Vol. 15, No. 17, 2013

Figure 3. Crystal structure of 10a. Top (A) and side (B) views.
It was noteworthy that all macrocyclic compounds
obtained exhibit one set of proton, fluorine, and carbon
resonance signals in their 1H, 19F, and 13C NMR spectra
(Figures S5ÀS25), respectively. For instance, only one
sharp singlet signal corresponding to a methoxy or di-
methylamino group was observed in their 1H NMR spec-
tra, while fluorine signals in accordance to 1,3,4,5-, 1,2,4,5-,
and 1,2,3,4-tetraflurinated benzene moieties were evi-
denced in the 19F NMR spectra of 4, 7, and 10, respec-
tively. The NMR spectroscopic features suggest that oxacalix-
[2]perfluoroarene[2]triazines 4 and their isomeric macro-
cycles 7 and 10 in solution may not retain their solid state
conformation structures. It is most likely that all macro-
cycles are fluxional and they undergo very fast conforma-
tional changes in solution relative to the NMR time scale.
In summary, we have provided an effective and practical
one-pot reaction method for the synthesis of perfluori-
nated oxacalix[2]arene[2]triazines and their isomeric
macrocyclic analogs starting from readily available mate-
rials. Synthesized macrocycles adopt drastically different
1,3-alternate conformations in the crystalline state while in
solution they undergo very fast conformational changes at
rt relative to the NMR time scale. The highly electron-
deficient nature of the macrocycles would render them
intertesting hosts for the recognition of anion species,
which is being actively investigated in this laboratory.
Figure 1. Crystal structure of 4a. Top view (A) of the macrocycle
and side view (B) of the complex of 4a with dichloromethane.
Figure 2. Crystal structure of 7a. Top (A) and side (B) views.
As we expected, when fluorinated phenylene units are
para- or ortho-linked to triazines by the bridging oxygen
atoms, the resulting macrocycles adopt different conformational
structures. For example, 7a adopts a macrocyclic struc-
ture in which the two fluorinated benzene rings are face-
to-face paralleled whereas the two triazine rings are edge-
to-edge aligned (Figure 2). In the case of compound 10a,
macrocycle gives another type of 1,3-alternate conforma-
tion. It is worth addressing that the cavity formed by two
triazine rings in 10a is narrower (Figure 3) than that in 4a
and 4b. The upper rim distance between two triazine rings
Acknowledgment. We thank the NSFC (21072197,
91127008, 21272239, 21132005, 21121004), MOST (2011-
CB932501, 2013CB834504), and Tsinghua University for
financial support.
˚
in 10a (Figure S4) is, for instance, 5.56 A (dC(33)ÀC(29)),
while, in 4a and 4b, distances of 8.87 and 9.15 A are
˚
observed, respectively in the solid state (Figures S1 and S2).
Different macrocyclic conformations derived from per-
fluorinated meta-, para-, and ortho-benzene diols indicate
the effect of linkage of or the substitution pattern of
benzene units on the structures. The general 1,3-alternate
alignment of four aromatic rings in each macrocycle is
most probably attributable to the dipoleÀdipole repulsion
between neighboring aromatic rings.24
Supporting Information Available. Experimental de-
1
tails; H, 13C, and 19F NMR spectra of products; X-ray
structures (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 17, 2013
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