Synthesis and structure of oxacalix[2]arene[2]triazines of an expanded π-electron-deficient cavity and their interactions with anions

Article abstract of DOI:10.1021/jo2024448

Novel macrocyclic anion receptors based on the principle of anion-π interactions were reported. By means of both post-macrocyclization modification protocol and the stepwise fragment coupling approach, functionalized oxacalix[2]arene[2]triazines bearing two other electron-deficient (hetero)aromatic rings on the lower rim were efficiently synthesized. The resulting oxacalix[2]arene[2]triazine macrocyclesadopt 1,3-alternate conformation, yielding therefore an expanded electron-deficient cavity or space consisting of two triazine rings and two appending aromatic rings. Spectroscopic titration study showed the selective interaction of the pentafluorophenyl- substituted oxacalix[2]arene[2]triazine with azide and fluoride in solution with the binding constants (K_1:1) ranging from 1.33 × 10 ³ to 3.52 × 10³ M^-1.

Full text of DOI:10.1021/jo2024448

Article
pubs.acs.org/joc
Synthesis and Structure of Oxacalix[2]arene[2]triazines of an Expanded
π-Electron-Deficient Cavity and Their Interactions with Anions
Sen Li,† Shi-Xin Fa,† Qi-Qiang Wang,† De-Xian Wang,*,† and Mei-Xiang Wang*,†,‡
†Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
‡The Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, China
S
* Supporting Information
ABSTRACT: Novel macrocyclic anion receptors based on
the principle of anion−π interactions were reported. By means
of both post-macrocyclization modification protocol and the
stepwise fragment coupling approach, functionalized
oxacalix[2]arene[2]triazines bearing two other electron-deficient
(hetero)aromatic rings on the lower rim were efficiently syn-
thesized. The resulting oxacalix[2]arene[2]triazine macrocycles
adopt 1,3-alternate conformation, yielding therefore an expanded
electron-deficient cavity or space consisting of two triazine rings and two appending aromatic rings. Spectroscopic titration study
showed the selective interaction of the pentafluorophenyl-substituted oxacalix[2]arene[2]triazine with azide and fluoride in
solution with the binding constants (K1:1) ranging from 1.33 × 103 to 3.52 × 103 M−1.
molecules, are able to strongly and selectively interact with
halides in solution.8c Remarkably, using its electron-deficient
V-shaped cleft of two triazine rings, oxacalix[2]arene[2]triazine
forms ternary complexes with a halide and a water molecule
in the solid state through simultaneous typical anion−π inter-
action between halide and one triazine ring and lone-pair
electrons−π (lpe−π) interaction between the included water
oxygen and the other triazine ring. Very recently, we have
studied the interaction between halides and a conformationally
rigid bis(oxacalix[2]arene[2]triazine) cage molecule.8g Astonish-
ingly, a weak σ interaction motif between chloride and the triazine
ring is observed in the host−guest complex in the crystalline state.
As revealed by the powerful isothermal titration calorimetry (ITC)
titration technique, there is anion−π interaction in the solution
phase, albeit the binding appears very weak.
One of the salient structural features of heteroatom-bridged
calix[2]arene[2]triazines is the formation of the shape-persistent
1,3-alternate conformation. A number of tetraoxacalix[2]arene-
[2]triazines, for example, give 1,3-alternate conformational struc-
tures in which two triazine rings form a V-shaped cleft, whereas
two benzene rings are almost face-to-face paralleled.9 The unique
conformational structures render tetraoxacalix[2]arene[2]-
triazines the useful platforms for the fabrication of sophisticated
molecular architectures.10,11 On the basis of the V-shaped cleft
of tetraoxacalix[2]arene[2]triazines, we envisioned therefore the
construction of a π-electron-deficient cavity or space by intro-
ducing two extra electron-deficient aromatic rings on the lower
rim positions of the benzene rings (Figure 2). The resulting
INTRODUCTION
■
The design and synthesis of efficient receptors for anion recog-
nition are challenging in supramolecular chemistry because
anions, which differ from cations, have varied geometries, low
charge density/radius ratios, and high free energies of solvation
and a narrow pH window.1 Among the anion receptors reported,2
the binding between the host molecules and anions is dominated
by the electrostatic interaction,3 hydrogen bonding,4 and Lewis
acid−base interaction.5 Recent years have witnessed a growing
interest in intriguing anion−π interactions6 since the theoret-
ical studies which propose the noncovalent anion−π interac-
tions between an anion and electron-deficient aromatics such as
N-heterocycles and benzenes bearing perfluoro, nitro, and cyano
substituents.7 On the basis of DFT calculations, four different
anion−π interaction motifs, viz. typical anion−π interaction, weak and
strong σ interactions, and hydrogen bonding, have been suggested
(Figure 1).6d,7d However, experimental evidence for unambiguous
Figure 1. Different anion−π interaction motifs proposed by Hay and
co-workers.
anion−π interactions between an anion and a charge-neutral electron-
deficient arene is very rare. Moreover, only few examples of the
anion−π interactions in solution have been reported.8
We have shown recently that oxacalix[2]arene[2]triazines, a
type of conformation and cavity tunable macrocyclic host
Received: December 1, 2011
Published: January 25, 2012
© 2012 American Chemical Society
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Scheme 1. Preparation of Dihydroxylated
Tetraoxacalix[2]arene[2]triazine 5b
Figure 2. Construction of macrocyclic hosts of an expanded π-
electron-deficient cavity.
cavity enabling multiple anion−π interactions would provide
the spacious microenvironment for anion species of larger sizes
(Figure 2). We report herein the synthesis of electron-deficient
aromatic ring-appending tetraoxacalix[2]arene[2]triazine host
molecules by means of both fragment coupling approach and
post-macrocyclization functionalization protocol. The function-
alized macrocycles adopt 1,3-alternate conformation, giving
indeed an expanded electron-deficient cavity on the lower rim
position of benzene rings. The interaction of the synthetic host
molecules with anions will also be discussed.
removal of O-benzyl, producing dihydroxylated tetraoxacalix[2]-
arene[2]triazine 5b in 82% yield.
Macrocyclic compounds 5 provided a useful platform for the
fabrication of sophisticated molecular architectures because of
the versatile reactivity of two hydroxyl groups that append on
the lower rim position. To construct a highly π-electron-defi-
cient cavity, aromatic components such as triazinyl, 2,4-dinitro-
phenyl, and pentafluorophenyl were introduced. As depicted in
Scheme 2, in the presence of K2CO3 as an acid scavenger,
interaction of 5a with 2,4-dichloro-6-methoxyltriazine 2b at
room temperature furnished the formation of 8a in a yield of
53%. Similar reaction took place smoothly between macrocycle
5b and 2b in refluxing acetone, yielding the corresponding
product 8b, albeit in a slightly lower yield. To introduce the 2,4-
dinitrophenyl group into the macrocycle, we first examined the
reaction of 5 with 1-chloro-2,4-dinitrobenzene. The reaction
outcomes were largely influenced by the conditions employed.
Under various conditions screened (see Scheme S1 and Table
S2 in Supporting Information), however, the highest yields of
products 9a and 9b did not exceed 33 and 23%, respectively.
When 1-iodo-2,4-dinitrobenzene 6 was applied, the aromatic
nucleophilic substitution reaction proceeded effectively at 50−
80 °C in N,N-dimethylformamide (DMF), and the chemical
yields of 9a and 9b were improved to 48 and 37%, respectively.
We then attempted synthesis of pentafluorophenyl-substituted
tetraoxacalix[2]arene[2]triazines by means of nucleophilic
substitution reaction of 5 with perfluorobenzene. Unfortu-
nately, no desired reaction was observed under a wide variety of
reaction conditions (see Table S3 in Supporting Information).
RESULTS AND DISCUSSION
■
Synthesis of Functionalized Tetraoxacalix[2]arene[2]-
triazines. We initiated our study with the synthesis of tar-
get molecules based on the strategy of post-macrocyclization
functionalization.10 We have reported previously the facile syn-
thesis of the lower rim dihydroxylated tetraoxacalix[2]arene[2]-
triazine 5a in which the triazine ring is arylated by a p-tolyl
group.10 To avoid the possible hydrogen bonding between
arene C−H and the anion, a methoxy group was introduced in-
stead of a p-tolyl group. Scheme 1 illustrates the preparation of
tetraoxacalix[2]arene[2]triazine 5b following our well-estab-
lished fragment coupling approach.10 The reaction between
aromatic diol 1 and 2,4-dichloro-6-methoxytriazine 2b in the
presence of K2CO3 in acetone at ambient temperature pro-
ceeded smoothly to yield intermediate 3 in 76%. After opti-
mization of the reaction conditions, varying bases, solvents,
reaction temperature, and time (see Table S1 in Supporting
Information), it was found that, under basic conditions, inter-
mediate 3 underwent efficient macrocyclization reaction with 1
in hot acetonitrile to afford product 4 in good yield. Catalytic
hydrogenolysis of 4 in methanol at room temperature led to the
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Scheme 2. Synthesis of Oxacalix[2]arene[2]triazine Products 8 and 9 by Means of Post-macrocyclization Functionalization
Methods
In some cases, the reaction led to the decomposition of macro-
cyclic structure.
conditions generated efficiently fragments 12 in 65 to 82%
yields. Further treatment of the intermediates 12 with 11 in
refluxing acetonitrile with the aid of K2CO3 resulted in the macro-
cyclic products 10a and 10b in moderate yields (Scheme 3).
Structure of Functionalized Tetraoxacalix[2]arene[2]-
triazines. The structure of all functionalized oxacalix[2]arene-
[2]triazine compounds synthesized was established on the
basis of spectroscopic data and microanalyses (see Supporting
Information Figures S25−S54). To shed light on the confor-
mational behaviors of the macrocycles, single crystals were
cultivated and X-ray molecular structures of 8a, 8b, and 10b
were determined. As a comparison, oxacalix[2]arene[2]triazine
13 devoid of aryloxy groups on the lower rim position of
the benzene rings was also synthesized (see Scheme S3 in
Supporting Information) and its X-ray molecular structure was
included. As shown in Figures 3−5 and Figures S1−S5 in
Supporting Information, the O-aryloxylated oxacalix[2]arene-
[2]triazines 8 and 10 and parent oxacalix[2]arene[2]triazine 13
appear very similar to other oxacalix[2]arene[2]triazine
compounds documented in the literature,9 adopting generally
1,3-alternate conformation in the solid state. Evidenced by the
bond lengths and angles (captions in Figures 3−5 and Figures
S1−S5), all bridging oxygen atoms form conjugation with the
neighboring triazine rather than benzene ring. Careful scrutiny
of the structures revealed that the introduction of two electron-
deficient aromatic rings on the lower rim leads to the variation
of cavity size. In comparison with the nonfunctionalized
oxacalix[2]arene[2]triazine 13 in which the upper rim distance
between two triazine rings is 10.22 Å, the V-cleft formed by two
triazines becomes narrowed with the upper rim distance being
9.44 Å (8a), 8.98 Å (8b), and 8.87 Å (10b). Concomitantly, the
lower rim distance between two benzene rings changes from
4.41 Å (13) to 4.53 Å (8a), 4.47 Å (8b), and 4.32 Å (10b). As
we expected, the introduction of two electron-deficient aromatic
rings on the hydroxy groups on the lower rim position of
benzene rings tuned the V-cleft formed by two triazine rings of
the macrocycle into an expanded cavity or space, although the
To obtain target molecules 10a and 10b, the fragment
coupling synthetic method9a was then utilized (Scheme 3). The
Scheme 3. Fragment Coupling Approach to Functionalized
Oxacalix[2]arene[2]triazine Products 10
two directional aromatic nucleophilic substitution reactions of
methyl 3,5-dihydroxy-4-perfluorophenylbenzoate 11, which
was prepared in multiple steps starting from gallic acid methyl
ester and perfluorobenzene (see Scheme S2 in Supporting
Information), with 2,4-dichlorotriazine derivatives 2 under mild
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Figure 3. Molecular structure of 8b with side view (A,C) and top view
(B). Selected bond lengths [Å]: C2−O1 1.401, O1−C7 1.345, C9−
O2 1.348, O2−C10 1.422, C14−O3 1.397, O3−C16 1.344, C18−O4
1.344, O4−C6 1.409. Selected angles: ∠C13−C14−O3 120.53°,
∠C14−O3−C16 116.26°, ∠O3−C16−N4 118.01°. The upper and
lower rim distances [Å]: C8···C17 8.980, C4···C12 4.585, C1···C15
4.465, N3···N4 4.554, C21···C23 7.430. The probability is 25%.
Hydrogen atoms were omitted for clarity.
Figure 4. Molecular structure of 10b with side view (A,C) and top
view (B). Selected bond lengths [Å]: C4−O1 1.398, O1−C2 1.346,
C8−O2 1.387, O2−C10 1.357, C12−O3 1.350, O3−C13 1.401,
C15−O4 1.389, O4−C3 1.360. Selected angles: ∠C18−C13−O3
119.14°, ∠C13−O3−C12 118.84°, ∠O3−C12−N6 119.30°. The
upper and lower rim distances [Å]: C1···C11 8.871, C6···C17 5.754,
C9···C14 4.323, N2···N6 4.571. The probability is 25%. Hydrogen
atoms were omitted for clarity.
introduced two aromatic rings do not orientate in such a way to
give an ideal cavity due to most probably packing effect in the
crystalline state. In both the crystal structures of 8a and 8b, for
example, each of the two introduced triazine rings tends to be
perpendicular to the benzene ring with a dihedral angle of
around 80 and 70°, respectively. Furthermore, these triazine
rings orientate outward of the cavity, allowing therefore the favor-
able formation of intermolecular π−π stacking with the triazine
rings of two neighboring molecules (Figure S1). In the case of
pentafluorophenyl-substituted oxacalix[2]arene[2]triazine 10b, two
pentafluorophenyl moieties intrude into the cavity (Figure 4),
and molecular packing therefore enables multiple intermolecular
interactions (Figures S4 and S5).
Figure 5. Molecular structure of 13. Selected bond lengths [Å]: C5−
O3 1.518, O3−C3 1.421, C2−O2 1.349, O2−C6 1.489, C5−O3
1.518, O3−C3 1.421, C2−O2 1.349, O2−C6 1.489. Selected angles:
C9−C5−O3 117.82°, ∠C5−O3−C3 122.77°, ∠O3−C3−N3 117.87°.
The upper and lower rim distances [Å]: C1···C1 10.217, N2···N2
4.963, C10···C10 4.410, C8···C8 5.728. The probability is 25%.
Hydrogen atoms were omitted for clarity.
It is important to address that all functionalized oxacalix[2]-
arene[2]triazine products 8−10 showed a single set of signals
in their NMR spectra at ambient temperature (see Supporting
Information). Since the free rotation of individual aromatic
rings within a macrocycle is prohibited because of the presence
of bulky substituents, both 1H and 13C NMR spectroscopic data
may indicate the shape-persistent symmetric 1,3-alternate con-
formational structure in solution. To shed light on the orien-
tation of two introduced aromatic rings, such as being inward
or outward of the V-cleft formed by two triazine rings, in solu-
tion phase, compound ethyl 4-(2,4-dinitrophenoxy)benzoate
included in the cleft between two triazine rings of the macro-
cycle. It may also imply the generation of a π-electron-deficient
cavity consisting of two triazine rings of macrocycle and two
aromatic rings attached to the oxygen atoms on the lower rim
position of benzene rings in solution.
Interactions between Functionalized Oxacalix[2]-
arene[2]triazines and Anions. Having had the functional-
ized oxacalix[2]arene[2]triazines with an expanded π-electron-
deficient cavity in hand, we then examined their interactions
with anions by means of spectroscopic titrations. Pentafluoro-
phenyl-substituted macrocyclic hosts 10a and 10b were chosen
because they do not contain any aromatic C−H moiety and
therefore exclude the possible hydrogen bonding interaction
was prepared12 and its H NMR spectrum was compared
1
with that of 9b. Almost identical chemical shift values of
aromatic protons were observed (see Figure S22 in Supporting
Information), indicating that aromatic rings appending on the
lower rim position do not experience shielding effect. In other
words, these introduced aromatic rings are most likely not
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Figure 6. UV−vis spectroscopic titration (left) of 10b (8.94 × 10−5 M in 1 mL of acetonitrile) upon the addition of Bu4N+N3− (0, 4.60, 9.20, 13.7,
18.3, 22.9, 27.5, 32.1, 36.6, 41.2, 45.8, 50.4, 55.0 × 10−5 M), respectively. The inset is the Job’s plot of 10b and azide with a total concentration being
8 × 10−4 M. Fluorescence titration (right) of 10b (0.80 × 10−4 M in 1 mL of acetonitrile) upon the addition of Bu4N+N3− (0, 4.10, 5.13, 6.16, 7.18,
8.21, 9.23, 10.26, 11.29, 12.31, 14.36 × 10−4 M), respectively. The excitation wavelength was 253 nm, excitation and emission slits were all 10 nm,
the scan speed was 240 nm/min, and voltage was 400 V.
between anions and C−H of the hosts. Unfortunately, no
spectral changes were evidenced when both host molecules were
titrated with most anion species including halides, thiocyanate,
nitrate, and phosphate (Figures S7−S10). Interestingly, the
interaction of both 10a and 10b with tetrabutylammonium azide
led to the emerging of new absorption bands at 322 and 365 nm
(Figure 6 and Figure S11). Job’s plot experiments showed that
hosts 10a and 10b formed a 1:1 complex with azide, and the
association constants, which were calculated from the titration
curves using a Hyperquad 2003 software,13 are 1.47 × 103 M−1
for [10a·N3]− and 1.33 × 103 M−1 for [10b·N3]−, respectively.
The interaction of macrocyclic compounds with azide also
resulted in the quenching of fluorescence emission of 10a and
10b at 385 and 335 nm, respectively (Figure 6 and Figure S12).
The association constants calculated using fluorescence titra-
tion data are 2.15 × 103 M−1 ([10a·N3]−) and 3.52 × 103 M−1
([10b·N3]−), respectively, which are comparable with that
obtained from UV−vis titration measurement. It should be
noted that, based on fluorescence titrations, hosts 10a and 10b
also formed complexes with fluoride in solution, giving the
association constants of 2.21 × 103 M−1 ([10a·F]−) and 1.90 ×
103 M−1 ([10b·F]−), respectively. The formation of the com-
plexes [10a·N3]−, [10b·N3]−, [10a·F]−, and [10b·F]− was
further supported by ESI mass spectrometry, which gave mass
and triazine, and the resulting intermediate 14 underwent intra-
molecular cyclization to furnish methyl 6,7,8,9-tetrafluoro-4-
hydroxydibenzo[b,e][1,4]dioxine-2-carboxylate 15 (Scheme 4;
for the synthesis of 15, see Scheme S4).
Scheme 4. Formation of 15 from the Reaction of
Tetrabutylammonium Azide with 10a
1
peaks corresponding to the complexes (Figures S14−S17). H
NMR spectroscopy was used to investigate the anion−π inter-
actions. As illustrated in Figures S18−S21, no variation at all in
1
the H NMR spectra of 10a and 10b occurred upon the
addition of anions, indicating the change of UV−vis absorbance
and the quench of fluorescence emission of the macrocycles are
the result of anion−π interaction, the results being in
agreement with our previous reports.8c,g
Concerning the possible reaction rather than noncovalent
interaction between 10 and azide during spectroscopic titration
which gave a new absorption band at 322 and 365 nm (supra
vide), we examined the UV−vis spectra of compound 15
(Figure S13). The maximum absorption band of 15 was ob-
served, however, at 298 nm, completely different from the UV−
vis spectrum of host molecule 10. In addition, the mixture of
azide and 10 in acetonitrile, which was taken from spectros-
copic titration experiments, was analyzed by means of HPLC
analysis. No new peak corresponding to 15 was observed, and
the retention time and integral peak area of 10 remained intact
(Figures S23 and S24). These results excluded the possibility
of reaction of host 10a with azide guest and validated the
formation of host−guest complex during titration. It is most
To reveal the anion−π interaction between 10 and azide at
molecular level, a single crystal of the complex was cultivated by
slow evaporation of a solution of 10 and tetraethylammonium
azide in a mixture of methanol and chloroform. Surprisingly,
the single crystal obtained from the solution of 10a and azide
was not a host−guest complex as we expected. The X-ray dif-
fraction analysis showed instead a fused ring structure 15
(Figure S6). Apparently, the interaction of perfluorophenyl-
substituted oxacalix[2]arene[2]triazine 10a with an excess
amount of azide (1:5) during the process of crystallization
caused cleavage of C−O bonds between the bridging oxygen
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MS (MALDI-TOF) m/z 583.2 [M + H]+ (61), 605.2 [M + Na]+
(100%), 621.2 [M + K]+ (11). Anal. Calcd for C24H18N6O12·CH3OH: C,
48.87; H, 3.61; N, 13.68. Found: C, 48.56; H, 3.44; N, 13.79.
likely that the presence of an excess amount of azide and high
concentration under the crystallization conditions facilitated the
reaction of azide toward oxacalix[2]arene[2]triazine. Although
the molecular details of noncovalent anion−π interaction
remain unclear at current stage, the outcomes of the reaction
observed may imply the σ complexation of azide with the
carbon of triazine.
Synthesis of 8a. To a mixture 2b (162 mg, 0.9 mmol) and anhyd-
rous potassium carbonate powder (62 mg, 0.45 mmol) in acetone
(20 mL) was added dropwise a solution of 5a10 (211 mg, 0.3 mmol) in
acetone (100 mL) during 3 h. The resulting mixture was kept stirring
at room temperature for another 12 h. After filtration, the filtrate was
concentrated and the residue was chromatographed on a silica column
eluted with a mixture of petroleum ether, dichloromethane, and ethyl
acetate (1:1:0.2, v/v/v) as the mobile phase to give pure 8a (157 mg,
53%) as a white solid: mp 271−272 °C; 1H NMR (CDCl3/300 MHz)
δ 8.36 (d, J = 8.4 Hz, 4H), 7.75 (s, 4H), 7.30 (d, J = 8.4 Hz, 4H), 3.93
(s, 6H), 3.91 (s, 6H), 2.45 (s, 6H); 13C NMR (CDCl3/75 MHz) δ
177.5, 173.4, 172.8, 172.1, 171.0, 164.4, 144.9, 144.5, 140.6, 131.2, 129.6,
129.5, 129.2, 122.7, 56.4, 52.7, 21.8; IR (KBr) ν 1732, 1574, 1526, 1371
cm−1; MS (MALDI-TOF) m/z 989.3 [M + H]+ (10), 991.4 [M + H +
2]+ (6), 1011.3 [M + Na]+ (100%), 1013.3 [M + Na + 2]+ (80), 1015.3
[M + Na + 4]+ (10), 1027.3 [M + K]+ (44), 1029.3 [M + K + 2]+ (38),
1031.3 [M + K + 4]+ (5). Anal. Calcd for C44H30Cl2N12O12·H2O: C,
52.44; H, 3.20; N, 16.68. Found: C, 52.24, H, 3.10, N, 16.25.
Synthesis of 8b. To a mixture of 2b (720 mg, 4 mmol) and
anhydrous potassium carbonate powder (415 mg, 3 mmol) in acetone
(20 mL) was added dropwise a solution of 5b (1.165 g, 2 mmol) in
acetone (20 mL) during 1.5 h. The resulting mixture was kept stirring
at room temperature for another 5 h. After filtration, the filtrate was
concentrated and the residue was chromatographed on a silica gel
column eluted with a mixture of petroleum ether, dichloromethane,
and ethyl acetate (1:1:1, v/v/v) as the mobile phase to give pure 8b
(540 mg, 31%) as a white solid: mp 167−168 °C; 1H NMR (CDCl3/
300 MHz) δ 7.68 (s, 4H), 4.08 (s, 6H), 3.97 (s, 6H), 3.92 (s, 6H); 13C
NMR (CDCl3/75 MHz) δ 174.8, 173.4, 172.7, 172.6, 170.9, 164.3, 144.4,
140.2, 129.1, 122.7, 56.5, 56.3, 52.8; IR (KBr) ν 1733, 1571, 1356 cm−1;
MS (MALDI-TOF) m/z 907.1 [M + K]+ (100%), 909.1 [M + K + 2]+
(89), 911.1 [M + K + 4]+ (5). Anal. Calcd for C32H22Cl2N12O14: C,
44.20; H, 2.55; N, 19.33. Found: C, 44.12; H, 2.66; N, 19.22.
Synthesis of 9a. A mixture of 5a (70 mg, 0.1 mmol), 1-iodo-2,4-
dinitrobenzene 6 (118 mg, 0.4 mmol), and anhydrous potassium
carbonate powder (28 mg, 0.2 mmol) in DMF (3 mL) was stirred at
80 °C for 3 h. After cooling to room temperature, hydrochloric acid
(0.5 mL, 10%) and water (10 mL) were added, and the resulting
mixture was extracted with ethyl acetate (5 × 50 mL). The combined
organic phase was dried with anhydrous Na2SO4. After filtration, the
filtrate was concentrated with a rotary evaporator to give crude
product. After washing with ethyl acetate, pure 9a (50 mg, yield 48%)
was obtained as a pale yellow solid: mp 214−215 °C; 1H NMR
(CDCl3/300 MHz) δ 8.75 (d, J = 2.7 Hz, 2H), 8.37 (dd, J = 9.2,
2.7 Hz, 2H), 8.25 (d, J = 8.1 Hz, 4H), 7.86 (s, 4H), 7.24 (d, J = 8.4 Hz,
2H), 7.00 (d, J = 9 Hz, 2H), 3.95 (s, 6H), 2.41 (s, 6H); 13C NMR
(CDCl3/75 MHz) δ 177.4, 172.0, 164.2, 153.9, 144.9, 144.8, 142.5,
141.7, 137.8, 131.0, 129.9, 129.6, 129.5, 123.2, 123.0, 117.4, 53.0, 21.8;
IR (KBr) ν 1732, 1576, 1530, 1370, 1337 cm−1; MS (MALDI-TOF)
m/z 1035.1 [M + H]+ (21), 1057.0 [M + Na]+ (100%). Anal. Calcd
for C48H30N10O18: C, 55.71; H, 2.92; N, 13.54. Found: C, 55.89; H,
3.07; N, 13.60.
CONCLUSION
■
In summary, we have synthesized a number of functionalized
oxacalix[2]arene[2]triazine compounds using both the post-
macrocyclization functionalization protocol and the fragment
coupling approach. The introduction of an electron-deficient
aromatic ring at the lower rim position of each benzene ring
resulted in the macrocycles of an expanded π-electron-deficient
cavity or space. The perfluorophenyl-appending oxacalix[2]-
arene[2]triazine host molecules formed 1:1 noncovalent anion−
π complexes with azide and fluoride in dilute acetonitrile
solution, giving association constants in the range of 1.33 × 103
to 3.52 × 103 M−1.
EXPERIMENTAL SECTION
■
Synthesis of 3. While keeping stirring at room temperature, a
solution of methyl 4-(benzyloxy)-3,5-dihydroxybenzoate 1 (2.74 g, 10
mmol) in acetone (40 mL) was added dropwise to a mixture of 2,4-
dichloro-6-methoxy-1,3,5-triazine 2b (3.60 g, 20 mmol) and potassium
carbonate (3.46 g, 25 mmol) in acetone (60 mL) during 3 h. The
resulting mixture was stirred for another 5 min, until the reactants
were consumed (TLC). After the solid was removed by filtration, the
filtrate was concentrated and the residue was chromatographed on a
silica gel column eluted with a mixture of petroleum ether,
dichloromethane, and ethyl acetate (1:1:0.2, v/v/v) as the mobile
phase to give pure product 3 (4.25 g, yield 76%) as a white solid: mp
133−134 °C; 1H NMR (CDCl3/300 MHz) δ 7.83 (s, 2H), 7.25−7.23
(m, 3H), 7.15−7.12 (m, 2H), 5.07 (s, 2H), 3.96 (s, 6H), 3.91 (s, 3H);
13C NMR (CDCl3/75 MHz) δ 173.2, 172.7, 171.7, 164.8, 146.8, 144.8,
135.6, 128.32, 128.30, 127.3, 126.0, 122.5, 75.8, 56.4, 52.6; IR (KBr) ν
1728, 1565, 1540, 1506, 804 cm−1; MS (CI) m/z 560.1 [M+] (100%),
561.1 [M + H]+ (79), 562.1 [M + 2]+ (86), 563.1 [M + H + 2]+ (52),
564.1 [M + 4]+ (22), 565.1 [M + H + 4]+ (10). Anal. Calcd for C23H18-
Cl2N6O7: C, 49.21; H, 3.23; N, 14.97. Found: C, 49.35; H, 3.28; N,
14.70.
Synthesis of 4. A solution of methyl 4-(benzyloxy)-3,5-dihydro-
xybenzoate 1 (960 mg, 3.5 mmol) and 3 (1.965 g, 3.5 mmol) in aceto-
nitrile (200 mL) was added dropwise to a hot suspension of anhydrous
potassium carbonate powder (605 mg, 4.375 mmol) in acetonitrile
(200 mL) during 2 h. The resulting mixture was refluxed for another
20 min. After cooling down to room temperature and removal of solid
by filtration, the filtrate was concentrated and the residue was chro-
matographed on a silica gel column eluted with a mixture of petroleum
ether, dichloromethane, and ethyl acetate (5:5:0.1, v/v/v) as the
mobile phase to give pure 4 (1.89 g, yield 71%) as a white solid: mp
189−190 °C ; 1H NMR (CDCl3/300 MHz) δ 7.56 (s, 4H), 7.19−7.05
(m, 10H), 4.93 (s, 4H), 4.04 (s, 6H), 3.85 (s, 6H); 13C NMR
(CDCl3/75 MHz) δ 174.5, 172.8, 164.7, 146.9, 144.9, 135.8, 128.1,
128.0, 127.4, 125.5, 122.0, 75.4, 55.9, 52.3; IR (KBr) ν 1728, 1567,
1365, 1325 cm−1; MS (MALDI-TOF) m/z 763.2 [M + H]+ (100%),
785.1 [M + Na]+ (97). Anal. Calcd for C38H30N6O12: C, 59.84; H,
3.96; N, 11.02. Found: C, 59.70; H, 3.99; N, 11.16.
Synthesis of 5b. Under hydrogen (balloon), a mixture of 4 (3.813 g,
5 mmol) and Pd/C (300 mg, 10%) in methanol (60 mL) was stirred at
room temperature for 5 h. After removal of catalyst and solvent,
recrystallization of residue in a mixture of ethyl acetate and methanol
gave colorless crystalline product 5b (2.401 g, 82%): mp 226−227 °C;
1H NMR (acetone-d6/300 MHz) 7.48 (s, 4H), 4.09 (s, 6H), 3.79 (s,
6H); 13C NMR (acetone-d6/75 MHz) δ 175.7, 174.0, 165.5, 147.3,
141.2, 122.6, 121.7, 56.2, 52.3; IR (KBr) ν 3479, 1722, 1569, 1361 cm−1;
Synthesis of 9b. A mixture of 5b (116 mg, 0.2 mmol), 1-iodo-2,4-
dinitrobenzene 6 (236 mg, 0.8 mmol), and anhydrous potassium
carbonate powder (55 mg, 0.4 mmol) in DMF (3 mL) was stirred at
50 °C for 29 h. After addition of water (15 mL), product precipitated
from the solution. Filtration and washing with ethyl acetate gave pure
1
9b (68 mg, yield 37%) as a pale yellow solid: mp 279−280 °C; H
NMR (CDCl3/300 MHz) δ 8.86 (d, J = 2.7 Hz, 2H), 8.34 (dd, J = 9.3,
2.7 Hz, 2H), 7.82 (s, 4H), 6.93 (d, J = 9.3 Hz, 2H), 4.01 (s, 6H), 3.96
(s, 6H); 13C NMR (CDCl3/75 MHz) δ 174.7, 172.5, 164.1, 153.8,
144.7, 142.5, 141.4, 137.8, 129.8, 129.5, 123.1, 117.3, 56.3, 53.0; IR
(KBr) ν 1731,1608, 1560, 1340 cm−1; MS (MALDI-TOF) m/z 937.3
[M + Na]+ (100%). Anal. Calcd for C36H22N10O20: C, 47.28; H, 2.42;
N, 15.31. Found: C, 47.24; H, 2.59; N, 15.39.
General Procedure for the Synthesis of 12a and 12b. To a
mixture of 2a or 2b (4.4 mmol) and potassium carbonate (691 mg,
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Article
5 mmol) in acetone (15 mL) was added dropwise a solution of 11
(700 mg, 2 mmol) in acetone (5 mL) during 1 h at room temperature
while stirring. After stirring for another 15−30 min, the mixture was
filtrated. The filtrate was concentrated to give a residue which was
chromatographed on silica gel column eluted with a mixture of
petroleum ether, chloroform, and acetone as the mobile phase to give
pure product.
the solvent, the residue was chromatographed on a silica gel column
with a mixture of petroleum ether and ethyl acetate (12:1, v/v) as the
mobile phase to give pure 6s (1.209 g, yield 46%) as a white solid: mp
111−112 °C; 1H NMR (CDCl3/300 MHz) δ 7.41 (s, 2H), 7.36−7.26
(m, 10H), 5.08 (s, 4H), 3.91 (s, 3H); 13C NMR (CDCl3/75 MHz) δ
166.2, 150.4, 142.2 (dm), 139.0 (dm), 138.8, 134.3 (dm, J = 260 Hz),
128.6, 128.4, 127.6, 126.6, 108.1, 71.3, 52.4; IR (KBr) ν 1710, 1516,
1108 cm−1; MS (MALDI-TOF) m/z (%) 553.2 [M + Na]+ (100%).
Anal. Calcd for C28H19F5O5: C, 63.40; H, 3.61. Found: C, 63.35; H, 3.48.
Synthesis of 11. Under hydrogen (balloon), a mixture of 6s
(1.036 g, 1.95 mmol) and Pd/C (104 mg, 10%) in methanol (20 mL)
was stirred at room temperature for 6 h. The resulting mixture was
filtered, and the filtrate was chromatographed on a silica gel column
with a mixture of petroleum ether and ethyl acetate (4:1, v/v) as the
mobile phase to give pure 11 (600 mg, yield 88%) as a white solid: mp
192−193 °C; 1H NMR (acetone-d6/300 MHz) δ 9.12 (s, 2H); 7.18 (s,
2H); 3.86 (s, 3H); 13C NMR (CDCl3/100 MHz) δ 166.5, 150.1, 143.3
(dm), 140.1 (dm), 137.1, 136.7 (dm), 128.2, 110.0, 52.4; IR (KBr) ν
3484, 3356, 1686, 1518, 996 cm−1; MS (ESI) m/z (%) 329.0 [M − HF
− H]− (100%), 349.1 [M − H]− (24). Anal. Calcd for C14H7F5O5: C,
48.02; H, 2.01. Found: C, 48.08; H, 2.12.
1
12a (65%) as a white solid: mp 120−121 °C; H NMR (CDCl3/
300 MHz) δ 8.24 (d, J = 8.4 Hz, 4H), 8.02 (s, 2H), 7.22 (d, J = 8.1 Hz,
4H), 3.96 (s, 3H), 2.42 (s, 6H); 13C NMR (CDCl3/100 MHz)
δ 175.8, 173.1, 170.6, 164.6, 145.6, 144.0, 143.0, 141.8 (dm), 139.5
(dm), 137.0 (dm), 130.9 (dm), 130.5, 129.8, 127.6, 123.4, 53.0, 21.9;
IR (KBr) ν 1734, 1549, 1516, 1352 cm−1; MS (MALDI-TOF) m/z
757.1 [M + H]+ (80), 758.2 [M + 2]+ (30), 759.2 [M + H + 2]+ (69),
760.2 [M + 4]+ (23), 761.2 [M + H + 4]+ (12), 779.1 [M + Na]+
(100%), 781.2 [M + Na + 2]+ (74), 783.2 [M + Na + 4]+ (8). Anal.
Calcd for C34H19Cl2F5N6O5: C, 53.91; H, 2.53; N, 11.10. Found: C,
54.05; H, 2.72; N, 10.86.
1
12b (82%) as a white solid: mp 47−48 °C; H NMR (CDCl3/300
MHz) δ 7.92 (s, 2H); 4.03 (s, 6H); 3.94 (s, 3H); 13C NMR (CDCl3/
100 MHz) δ 173.5, 172.8, 171.3, 164.2, 143.7, 141.7 (dm), 139.4 (dm),
136.9 (dm), 130.8 (dm), 127.7, 123.1, 56.6, 52.8; IR (KBr) ν 1731, 1566,
1538, 1347 cm−1; MS (ESI) m/z 637.1 [M + H]+ (100%), 638.1 [M +
2]+ (24), 639.1 [M + H + 2]+ (58), 640.1 [M + 4]+ (14), 641.1 [M + H
+ 4]+ (13), 659.1 [M + Na]+ (73), 661.2 [M + Na + 2]+ (63), 663.2 [M
+ Na + 4]+ (17). Anal. Calcd for C22H11Cl2F5N6O7: C, 41.46; H, 1.74; N,
13.19. Found: C, 41.20; H, 1.90; N, 13.06.
Synthesis of 13. A mixture of 2b (360 mg, 2 mmol), resorcinol
(220 mg, 2 mmol), and anhydrous potassium carbonate (345 mg,
2.5 mmol) in acetonitrile (20 mL) was allowed to reflux for 24 h. After
filtration and removing the solvent of the filtrate, the residue was
chromatographed on a silica gel column with a mixture of petroleum
ether and ethyl acetate (2:1, v/v) as the mobile phase to give pure
Synthesis of 10a. A mixture of 12a (222 mg, 0.3 mmol), 11
(105 mg, 0.3 mmol), and anhydrous potassium carbonate powder
(52 mg, 0.375 mmol) in acetonitrile (60 mL) was refluxed for 6 h.
After cooling down to room temperature, the mixture was filtrated and
the filtration cake was collected. The filtrate was concentrated, and the
resulting residue was mixed with acetonitrile (10 mL). After 15 min,
the solution was filtered. The combined filtration cake was mixed with
dichloromethane (15 mL) and washed with water (3 × 10 mL). The
organic phase was dried with anhydrous Na2SO4. After removal of
organic solvent, the residue was chromatographed on a silica gel
column eluted with a mixture of petroleum ether, chloroform, and
ethyl acetate (6:1:0.1, v/v/v) as the mobile phase to give the pure 10a
1
13 (371 mg, yield 86%) as a white solid: mp 234−238 °C; H NMR
(300 MHz, CDCl3) δ 7.23 (2H, t, J = 8.2 Hz), 6.85 (4H, dd, J1 =
8.2 Hz, J2 = 2.2 Hz), 6.71 (2H, t, J = 2.2 Hz), 4.12 (6H, s); 13C NMR
(300 MHz, CDCl3) δ 174.7, 173.4, 152.0, 130.1, 119.2, 116.6, 55.9; IR
(KBr) ν 2956, 1586, 1483, 1427, 1371, 1267, 1201, 1146 cm−1; MS
(MALDI-TOF) m/z 435.1 (M + H+) (100%), 457.1 (M + Na+) (50),
473.1 (M + K+) (10). Anal. Calcd for C20H14N6O6: C, 55.30; H, 3.25;
N, 19.35. Found: C, 55.20; H, 3.27; N, 19.25.
Synthesis of 15. A mixture of anhydrous potassium carbonate
(1.382 g, 10 mmol), methyl 3,4,5-trihydroxybenzoate (1.84 g, 10 mmol),
and perfluorobenzene (1.86 g, 10 mmol) in DMF (25 mL) was stirred for
5 h at 100 °C. After cooling to room temperature, 10% HCl was used
to neutralize the resulting mixture. The mixture was extracted with
ethyl acetate, and the organic phase was dried with anhydrous Na2SO4
and filtered. The filtrate was chromatographed on a silica gel column
with a mixture of petroleum ether and ethyl acetate (8:1, v/v) as the
mobile phase to give pure 15 (607 mg, yield 18%) as a white solid: mp
1
(170 mg, 55%) as a white solid: mp >300 °C; H NMR (CDCl3/400
MHz) δ 8.36 (d, J = 8 Hz, 4H), 7.74 (s, 4H), 7.33 (d, J = 7.6 Hz, 4H),
3.91 (s, 6H), 2.46 (s, 6H); 13C NMR (CDCl3/100 MHz) δ 177.6,
172.1, 164.4, 145.0, 144.7, 143.2, 141.8 (dm), 139.5 (dm), 137.0
(dm), 131.1, 129.6, 129.5, 127.7, 122.9, 52.7, 21.8; IR (KBr) ν 1734,
1576, 1520, 1372 cm−1; MS (MALDI-TOF) m/z 1035.4 [M + H]+
(100%), 1057.5 [M + Na]+ (38). Anal. Calcd for C48H24F10N6O10: C,
55.72; H, 2.34; N, 8.12. Found: C, 55.79; H, 2.51; N, 8.00.
1
253−254 °C; H NMR (acetone-d6/300 MHz) δ 7.35 (d, J = 1.8 Hz,
1H), 7.14 (d, J = 1.8 Hz, 1H), 3.87 (s, 3H); 13C NMR (acetone-d6/
100 MHz) δ 164.8, 145.8, 140.6, 138.5 (dm), 136.0 (dm), 132.5, 128.7
(dm), 126.6, 114.5, 108.4, 51.8; IR (KBr) ν 3366, 1708, 1522 cm−1; MS
(CI) m/z (%) 331.0 [M + H]+ (100%). Anal. Calcd for C14H6F4O5: C,
50.93; H, 1.83. Found: C, 50.68; H, 2.00.
Synthesis of 10b. A suspension of anhydrous potassium carbonate
powder (173 mg, 1.25 mmol) in acetonitrile (20 mL) was heated to
reflux. A mixture of 12b (637 mg, 1 mmol) and 11 (350 mg, 1 mmol)
in acetonitrile (80 mL) was then added dropwise during 1.5 h. The
resulting mixture was refluxed for another 0.5 h. After cooling down to
room temperature, the solid was removed by filtration. The filtrate was
concentrated, and the residue was chromatographed on a silica gel
column eluted with a mixture of petroleum ether, dichloromethane,
and ethyl acetate (1:1:0.2, v/v/v) as the mobile phase to give pure 10b
(324 mg, 35%) as a white solid: mp 193−194 °C; 1H NMR (CDCl3/
300 MHz) δ 7.68 (s, 4H), 4.08 (s, 6H), 3.90 (s, 6H); 13C NMR
(CDCl3/100 MHz) δ 175.2, 172.8, 163.9, 144.6, 143.4, 142.0 (dm),
139.6 (dm), 137.1 (dm), 131.3 (dm), 127.7, 122.9, 55.8, 52.2; IR (KBr) ν
1734, 1585, 1561, 1519, 1360, 1332 cm−1; MS (MALDI-TOF) m/z 915.3
[M + H]+ (100%), 937.3 [M + Na]+ (32). Anal. Calcd for C36H16-
F10N6O12: C, 47.28; H, 1.76; N, 9.19. Found: C, 47.52; H, 2.15; N, 8.84.
Synthesis of 6s. To a mixture of NaH (144 mg, 6 mmol) and
DMF (10 mL) was added slowly methyl 3,5-bis(benzyloxy)-4-
hydroxybenzoate (1.822 g, 5 mmol). After stirring at room tempera-
ture for 3 h, perfluorobenzene (1.395 g, 7.5 mmol) was added. The
mixture was allowed to reflux for another 6 h. The resulting mixture
was poured on ice slowly and extracted with ethyl acetate. The organic
phase was dried with anhydrous Na2SO4 and filtered. After removing
Procedure of Spectroscopic Titrations. UV−vis and fluores-
cence titration experiments were performed with the concentration of
10a and 10b maintained constantly, and the spectral changes were
recorded with the increase of the anion concentration. The spectros-
copic titration data were fitted by a Hyperquad 2003 program to
calculate the association constants.13
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental details and characterizations of products, H and
13C NMR spectra of products, UV−vis and fluorescence
1
titration spectra, H NMR spectra of 10a and 10b upon the
addition of anions, ESI-MS spectra of 10a and 10b upon the
addition of anions, cif documents of the crystal structures. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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The Journal of Organic Chemistry
Article
2002, 124, 6274. (d) Berryman, O. B.; Bryantsev, V. S.; Stay, D. P.;
Johnson, D. W.; Hay, B. P. J. Am. Chem. Soc. 2007, 129, 48. (e) Kim,
D.; Tarakeshwar, P.; Kim., K. S. J. Phys. Chem. A 2004, 108, 1250.
AUTHOR INFORMATION
Corresponding Author
*E-mail: dxwang@iccas.ac.cn, wangmx@mail.tsinghua.edu.cn.
Notes
■
̀
(f) Estarellas, C.; Frontera, A.; Quinonero, D.; Deya, P. M. Angew.
̃
Chem., Int. Ed. 2010, 50, 415.
(8) For representive examples, see: (a) Rosokha, Y. S.; Lindeman,
S. V.; Rosokha, S. V.; Kochi, J. K. Angew. Chem., Int. Ed. 2004, 43, 4650.
(b) Berryman, O. B.; Hof, F.; Hynes, M. J.; Johnson, D. W. Chem.
Commun. 2006, 506. (c) Wang, D.-X.; Zheng, Q.-Y.; Wang, Q.-Q.;
Wang, M.-X. Angew. Chem., Int. Ed. 2008, 47, 7485. (d) Chifotides,
H. T.; Schottel, B. L.; Dunbar, K. R. Angew. Chem., Int. Ed. 2010, 49,
7202. (e) Berryman, O. B.; Sather, A. C.; Hay, B. P.; Meisner, J. S.;
Johnson, D. W. J. Am. Chem. Soc. 2008, 130, 10895. (f) Gil-Ramírez,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank National Natural Science Foundation of China
(20875094, 21072197, 20972161, 21121004, 21132005), Ministry
of Sciences and Technology (2011CB932501, 2007CB808005),
Chinese Academy of Sciences, and Tsinghua University for
financial support.
́
G.; Escudero-Adan, E. C.; Benet-Buchholz, J.; Ballester, P. Angew.
Chem., Int. Ed. 2008, 47, 4114. (g) Wang, D.-X.; Wang, Q.-Q.; Han, Y.;
Wang, Y.; Huang, Z.-T.; Wang, M.-X. Chem.Eur. J. 2010, 16, 13053.
(h) Guha, S.; Saha, S. J. Am. Chem. Soc. 2010, 132, 17674.
(9) (a) Wang, M.-X.; Yang, H.-B. J. Am. Chem. Soc. 2004, 126, 15412.
for other examples of 1,3-alternate conformations of heteracalixar-
omatics, see (b) Wang, M.-X. Chem. Commun. 2008, 4541. (c) Maes,
W.; Dehaen, W. Chem. Soc. Rev. 2008, 37, 2393. (d) Tsue, H.;
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