Synthesis, structure, and fullerene-complexing property of azacalix[6]aromatics

Article abstract of DOI:10.1021/jo5003714

Synthesis, structure, and fullerene-binding property of azacalix[6]aromatics were systematically studied. By means of [3 + 3] and [2 + 2 + 2] fragment coupling protocols, a number of azacalix[6]aromatics containing different combinations of benzene, pyridine, and pyrimidine rings and various substituents on the bridging nitrogen atoms were synthesized conveniently in moderate to good yields. The resulting macrocycles adopt in the solid state symmetric and heavily distorted 1,3,5-alternate conformations depending on the aromatic building units, whereas, in solution, they exist as a mixture of conformers that undergo rapid interchanges relative to the NMR time scale. All macrocycles were able to form 1:1 complexes with C₆₀ and C ₇₀ in toluene with the association constants up to 7.28 × 10⁴ M^-1. In the crystalline state, azacalix[6]aromatics form complexes with C₆₀ and C₇₀ with 2:1, 1:1, and 1:2 stoichiometric ratios between host and guest. Azacalix[6]aromatics interact with fullerene by forming mainly the sandwich structure in which C₆₀ or C₇₀ is sandwiched by two macrocycles. X-ray molecular structures revealed that multiple π-π and CH-π interactions between concave azacalix[6]aromatics and convex fullerenes C₆₀ and C₇₀ contribute a joint driving force to the formation of host-guest complexes.

Full text of DOI:10.1021/jo5003714

Article
pubs.acs.org/joc
Synthesis, Structure, and Fullerene-Complexing Property of
Azacalix[6]aromatics
Shi-Xin Fa,† Li-Xia Wang,† De-Xian Wang,† Liang Zhao,‡ 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
‡Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing
100084, China
S
* Supporting Information
ABSTRACT: Synthesis, structure, and fullerene-binding property of azacalix-
[6]aromatics were systematically studied. By means of [3 + 3] and [2 + 2 + 2]
fragment coupling protocols, a number of azacalix[6]aromatics containing
different combinations of benzene, pyridine, and pyrimidine rings and various
substituents on the bridging nitrogen atoms were synthesized conveniently in
moderate to good yields. The resulting macrocycles adopt in the solid state
symmetric and heavily distorted 1,3,5-alternate conformations depending on the
aromatic building units, whereas, in solution, they exist as a mixture of
conformers that undergo rapid interchanges relative to the NMR time scale. All
macrocycles were able to form 1:1 complexes with C60 and C70 in toluene with
the association constants up to 7.28 × 104 M−1. In the crystalline state,
azacalix[6]aromatics form complexes with C60 and C70 with 2:1, 1:1, and 1:2
stoichiometric ratios between host and guest. Azacalix[6]aromatics interact with
fullerene by forming mainly the sandwich structure in which C60 or C70 is sandwiched by two macrocycles. X-ray molecular
structures revealed that multiple π−π and CH−π interactions between concave azacalix[6]aromatics and convex fullerenes C60
and C70 contribute a joint driving force to the formation of host−guest complexes.
ation capability and to improve possibly the selectivity,
functionalized and cavity-confined receptors based on the
aforementioned motifs have been developed. For example,
Mendoza et al.10 have devised a tripodal exTTF-CTV host that
strongly binds C60 and C70 in chlorobenzene with an
association constant log Ka(1:1) of 5.3 and 6.3, respectively.
While a double cancave host composed of two corannulene
moieties behaves as a hydrocarbon “buckycatcher”,11 metal-
loporphyrin-derived macrocycles have been shown to exhibit
strong and selective encapsulation of higher fullerenes.12 Very
recently, a cycloparaphenylene ring,13 a member of a fascinating
type of macrocycles, has been shown to bind C60 and C70 highly
selectively.
Heteracalixaromatics, or heteroatom-bridged calixaromatics,
are a new generation of macrocyclic host molecules.14 In
contrast to the methylene linkages in conventional calixarenes,
heteroatoms such as nitrogen can adopt different electronic
configurations and, more importantly, form various conjugation
systems with their adjacent aromatic rings to give different
bond lengths and angles.15 As a result, heteracalixaromatics are
able to self-regulate their conformational structures and to fine-
tune their cavity sizes when interacting with guest species. In
addition to this, the presence of different substituents on the
INTRODUCTION
■
Because of their unique structures and interesting physiochem-
ical properties, fullerenes have attracted great attention since
their discovery. Along with the tremendous development of the
study of chemical reactivity and modification of fullerenes,
particularly C60, in the hope of finding practical applications in
the field of materials and biology, supramolecular fullerene
chemistry, the study of noncovalent interactions between
fullerenes with synthetic hosts or receptors, has also emerged as
an important interdisciplinary subject.1 Highly selective
recognition and manipulation of fullerenes of varied sizes and
geometries would provide not only efficient methods of
separation and purification of ball-shaped fullerene isomers
but also pave the ways to the fine fabrications and molecular
self-assemblies of fullerene-based materials and devices in order
to achieve the best performances of these distinctive carbon
materials.
Since the milestone works of Atwood et al.2 and Nakashima
and Shinkai3 in 1994 when they independently reported
selective isolation of fullerenes C60 and C70 from fullerite using
t
conventional Bu-calix[8]arene, other macrocyclic host mole-
cules, including calix[n]arenes and their derivatives,4 calixre-
sorcinarenes,5 cyclotriveratrylenes (CTV),6 crown ethers,7
homooxacalix[3]arene,8 and γ-cyclodextrin,9 have been shown
to form host−guest complexes with fullerenes due to the
concave−convex complementarity. To increase the complex-
Received: February 15, 2014
Published: March 24, 2014
© 2014 American Chemical Society
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bridging nitrogen atoms would also play a role in tuning the
cavity of heteracalixaromatics owing to their electronic and
steric effects.16 Because of the ease of introducing diverse
aromatic moieties into the macrocyclic scaffolds, interplay
between heteroatoms and aromatic rings allows the con-
struction of molecular cavities of varied electronic features. For
example, azacalix[4]pyridines are powerful and selective hosts
for transition-metal ions17 and for hydrogen bond donors,18
whereas oxacalix[2]arene[2]triazines utilize their π-electron-
deficient cleft to form complexes with anions of various
geometries and shapes through cooperative anion−π and lone-
pair electrons−π interactions.19
Scheme 1. Synthesis of α,ω-Dihalo Linear Trimers 3a−3g
a
and α,ω-Diamino Linear Trimers 4a−4e
Although the past decade has witnessed tremendous
development of heteracalixaromatics, the majority of the
studies are concentrated on heteroatom-bridged calix[4](het)-
arenes, the macrocycles that contain four (hetero)aromatic
rings. The scarcity of research on larger macrocyclic
homologues20−22 may be partly due to the synthetic difficulty
as almost all one-pot macrocyclic condensation reactions
reported to date between aromatic dinucleophiles and
dielectrophiles produce heteracalix[4]aromatics as the thermo-
dynamically stable products.14,20b,23 Only using the stepwise
fragment coupling approaches, a few heteracalixaromatics
containing more than five aromatic rings have been
constructed.21,22 On the other hand, it has been reported22b
that larger heteracalixaromatics such as azacalix[n]pyridines (n
= 5 −10) are powerful monomacrocyclic receptors to interact
with fullerenes C60 and C70, yielding 1:1 complexes in toluene
with the association constants in the range of 2.6 × 104 to 1.3 ×
105 M−1. However, the nature of the interaction between these
macrocycles and fullerenes remains unknown. It appears
formidable and challenging to elucidate the effect of the
interplay between bridging segments and aromatic rings on the
molecular recognition property of heteracalixaromatics. As a
continuation of the research program, our interests in
developing the synthetic methods for large heteracalixaromatics
and in understanding their structures and binding property led
us to undertake the current work. We report herein in detail a
systematic study of the synthesis, structure, and selective
fullerene-binding property of a series of N-substituted azacalix-
[6]aromatics containing varied combinations of benzene,
pyridine, and pyrimidine rings.24
a
Conditions: i. Pd2(dba)3 (15 mol %), dppp (30 mol %), 1,4-dioxane,
reflux; ii. NaH (4 equiv), THF, reflux; iii. CH3NH2 (5 equiv), CuI (10
mol %), L-proline (20 mol %), K2CO3, H2O, DMSO, 100 °C; iv.
MeNH2 or EtNH2 (5 equiv), H2O in a sealed tube, 120 °C.
with methylamine under the catalysis of CuI in the presence of
L-proline or simply nucleophilic aromatic substitution reaction
of 3 with methylamine or ethylamine led to the formation of
targeted diamine products 4 in excellent yields.
With all necessary dielectrophilic and dinucleophilic frag-
ments in hand, synthesis of azacalix[6]aromatics was
implemented. Under the standard conditions of Pd-catalyzed
C−N bond-forming reaction,15a,25 the [3 + 3] fragment
coupling reactions between 3a and 4a, and between 3b and
4b, resulted in the formation of azacalix[6]arene 5a in 23%
yield and azacalix[6]pyridine 5b in 31% yield. While azacalix-
[3]arene[3]pyridine 5d was obtained in a comparable yield
(30%) from the similar [3 + 3] macrocyclization reaction from
4d and 3e, trimer 4e underwent efficient cross-coupling
reaction with trimer 3f to furnish the formation of azacalix[3]-
pyridine[3]pyrimidine 5e in 73% yield24 (Scheme 2). Without
using any transition-metal catalysts, a [3 + 3] macrocyclic
condensation reaction between 4c and 3c with the aid of NaH
produced azacalix[6]pyrimidine 5c in an acceptable yield
(Scheme 3). It is worth addressing that azacalix[6]arene 5a
was isolated in only 2% yield from Pd-catalyzed macrocyclic
oligimerization of 3-bromo-N-methylaniline,26 while reaction
between 2,6-dibromopyridine and 2,6-bis(methylamino)-
pyridine gave azacalix[6]pyridine in 10% yield.27
RESULTS AND DISCUSSION
■
Synthesis of Azacalix[6]aromatics. Retrosynthetically,
azacalix[6]aromatics might be prepared by various methods.
After considering the availability of starting materials and the
shortest possible synthetic steps, a [3 + 3] fragment coupling
approach15a,b was employed in the first place. As illustrated in
Scheme 1, dielectrophilic linear trimeric fragments 3 were
readily prepared from two directional arylation of aromatic
diamines 1 with 1,3-dihalo-substituted aromatic reactants 2 in
one-pot reaction fashion. It should be noted that the unreactive
1,3-dibromobenzene 2a underwent the palladium-catalyzed
cross-coupling reaction with 1,3-phenylene diamine 1a or 2,6-
diaminopyridine 1b in refluxing 1,4-dioxane to give product 3a
or 3e, respectively, in moderate chemical yields. In the case of
reactive substrates, such as 2,6-dibromopyridine 2b and 4,6-
dichloropyrimidine 2c, nucleophilic aromatic substitution
reaction with dinucleophiles 1 proceeded effectively in the
presence of NaH to afford the corresponding trimers 3 in the
yields ranging from 69% to 92%. Further cross-coupling
reaction of the resulting α,ω-dihalo-bearing linear trimers 3
The formation of azacalix[3]pyridine[3]pyrimidine 5e in an
exceedingly high yield from efficient macrocyclic cross-coupling
reaction between trimer fragments 3f and 4e was fascinating.
Although the exact reason is not clear at this stage, the
thermodynamic stability may contribute a decisive driving
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Scheme 2. Synthesis of Azacalix[6]aromatics 5a, 5b, 5d, and
5e
Scheme 5. Synthesis of Azacalix[3]pyridine[3]pyrimidines
5e−5o
Scheme 3. Synthesis of Azacalix[6]pyrimidine 5c
force. Nevertheless, the outcomes promoted us to test the
synthesis of 5e using smaller and simpler fragments. Under the
identical catalytic conditions, the reaction of 4,6-diaminopyr-
imidine 1d with equimolar 2,6-dibromopyridine 2b proceeded
effectively. The desired product 5e was obtained in 37% yield
along with the formation of larger macrocyclic homologues. To
our delight, macrocyclic cross-coupling reaction of dimer 8a
itself, that was conveniently obtained starting from 2-amino-6-
bromopyridine 6a and 2c (Scheme 4), yielded azacalix[3]-
pyridine[3]pyrimidine 5e in 54% yield (Scheme 5). Taking
advantage of the highly efficient macrocyclization reaction from
a dimeric fragment, we then synthesized a number of
azacalix[3]pyridine[3]pyrimidine derivatives 5. As summarized
in Scheme 5, all dimers containing diverse substituents on the
bridging and terminal nitrogen atoms underwent desired
macrocyclic head-to-tail cross-coupling reaction to afford
products in good yields. It is worth addressing that the method
provided a straightforward route to functional azacalix[3]-
pyridine[3]pyrimidines installed with either identical or two
different substituents on the linking nitrogen atoms.
Scheme 4. Synthesis of Dimers 8a−8l
Structure of Azacalix[6]aromatics. All azacalix[6]-
aromatics synthesized are crystalline compounds, and recrystal-
lization gave high-quality single crystals suitable for X-ray
diffraction analysis. The X-ray molecular structures, which are
illustrated in Figures 1−5 and Figures S27 and S28 (Supporting
Information), allow us to understand the conformation of
macrocycles in the solid state. It is interesting to note that, in
comparison to the smaller macrocyclic homologues azacalix-
[4]aromatics that generally give similar 1,3-alternate con-
formations, azacalix[6]aromatics adopt varied conformations.
More importantly, the conformational structures of azacalix-
[6]aromatics are strongly influenced by the nature of the
aromatic rings.
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Figure 1. X-ray crystal structure of azacalix[6]arene 5a: (a) top view and (b) side view. All hydrogen atoms are omitted for clarity. Selected bond
lengths (Å): C(10)−N(2) 1.428, N(2)−C(13) 1.390, C(17)−N(3) 1.393, N(3)−C(20) 1.436, C(4)−N(1) 1.392, N(1)−C(6) 1.418.
Figure 2. X-ray crystal structure of azacalix[6]pyrimidine 5c: (a) top view and (b) side view. The disorders of C(31), C(32), C(33), C(34), N(12),
N(15), and all hydrogen atoms are omitted for clarity. Selected bond lengths (Å): C(3)−N(3) 1.385, N(3)−C(5) 1.406, C(7)−N(6) 1.383, N(6)−
C(9) 1.411, C(11)−N(9) 1.380, N(9)−C(13) 1.408, C(5)−N(12) 1.393, N(12)−C(17) 1.411, C(19)−N(15) 1.459, N(15)−C (21) 1.426,
C(23)−N(18) 1.382, N(18)−C(1) 1.413.
Figure 3. X-ray crystal structure of azacalix[3]arene[3]pyridine 5d: (a) top view and (b) side view. All hydrogen atoms are omitted for clarity.
Selected bond lengths (Å): C(3)−N(1) 1.425, N(1)−C(6) 1.396, C(10)−N(3) 1.415, N(3)−C(12) 1.413, C(14)−N(4) 1.422, N(4)−C(19)
1.389.
As shown in Figure 1, azacalix[6]arene 5a adopts a 1,3,5-
alternate conformation with a C2 symmetry. Careful scrutiny of
the bond lengths and bond angles of all bridging nitrogen
atoms revealed that the macrocycle can be regarded as
consisting of three different segments including conjugated
meta-bis(methylamino)benzene and (methylamino)benzene,
and isolated benzene. It was also worth noting that one of
the methyl substituents on nitrogen of the conjugated meta-
bis(methylamino)benzene is s-cis-configured while the other is
s-trans-positioned. As a result, two s-trans-configured methyl
groups are orientated inwardly to the cavity of the macrocyclic
ring. In the case of azacalix[6]pyridine 5b (Figure S27,
Supporting Information) and azacalix[6]pyrimidine 5c (Figure
2), macrocycles show heavily distorted 1,3,5-alternate con-
formations. Noticeably, one of the pyridine rings in 5b and one
of the pyrimidine rings in 5c orientate inwardly to the
macrocyclic cavity. The bond length between linking nitrogen
atoms and carbon atoms of their adjacent pyridine rings in 5b
varies from 1.39 to 1.43 Å, while azacalix[6]pyrimidine 5c gives
Nbridge−Cpyrimidine bond lengths in the range of 1.38−1.46 Å.
Judged on the basis of the bond lengths and angles of the
nitrogen linkages, different conjugation systems, such as
aminopyridine, dipyrid-2-ylamine, and 2,6-diaminopyridine
segments, were observed in azacalix[6]pyridine 5b. However,
macrocycle 5c was mainly composed of aminopyrimidine units.
Being different from azacalix[6]arene 5a, azacalix[6]pyridine
5b, and azacalix[6]pyrimidine 5c, azacalix[6]aromatics con-
stituted by two different aromatic rings adopt a more symmetric
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Figure 4. X-ray crystal structure of 5l: (a) top view and (b) side view. Selected bond lengths (Å): C(1)−N(3) 1.368, N(3)−C(6) 1.417, C(10)−
N(5) 1.415, N(5)−C(3) 1.376.
Figure 5. X-ray crystal structure of 5n: (a) top view and (b) side view. Selected bond lengths (Å): C(1)−N(15) 1.416, N(15)−C(41) 1.378, C(2)−
N(5) 1.422, N(2)−C(9) 1.376, C(11)−N(5) 1.383, N(5)−C(16) 1.414, C(20)−N(7) 1.418, N(7)−C(24) 1.386, C(26)−N(10) 1.396, N(10)−
C(31) 1.406, C(35)−N(12) 1.414, N(12)−C(39) 1.394.
1,3,5-alternate conformation in the crystalline state. This has
been exemplified convincingly by the X-ray single crystal and
molecular structures of azacalix[3]arene[3]pyridine 5d (Figure
3) and azacalix[3]pyridine[3]pyrimidines 5l (Figure 4), 5n
(Figure 5), and 5o (Figure S28, Supporting Information). A
few interesting structural features are worth addressing. First of
all, both azacalix[3]arene[3]pyridine and azacalix[3]pyridine-
[3]pyrimidines have bowl-shaped structures. Apparently, three
alternate benzene rings in 5d or pyrimidine rings in 5l, 5n, and
5o are procumbent, lying almost on the same plane defined by
bridging nitrogen atoms. On the other hand, three alternate
pyridine rings in all macrocycles tend to be perpendicular to the
plane with dihedral angles of about 51−62°, forming a
concavity. Second, bond lengths and angles of bridging
nitrogen atoms observed in the X-ray molecular structures
indicated interesting conjugation systems. In the case of
azacalix[3]arene[3]pyridine 5d, different conjugation systems,
such as 2,6-diamonopyridine and aminopyridine segments,
were observed while all benzene rings are relatively isolated.
However, macrocycles 5l, 5n, and 5o seemed to be composed
of conjugated aminopyrimidine and partially conjugated
aminopyridine and aminopyrimidine. In 5n, there is also a
conjugated diaminopyrimidine segment. It is apparent that
bridging nitrogen atoms tend to conjugate with the more
electron-deficient aromatic ring. Furthermore, cavity size varies
depending on the aromatic components involved. For azacalix-
[3]arene[3]pyridine 5d, the average distances between the
upper-rim carbon atoms of benzene rings and between the
lower-rim nitrogen atoms of pyridine rings are around 11.87
and 7.17 Å, respectively. Azacalix[3]pyridine[3]pyrimidine
rings appeared to have slightly shrinked cavities as the average
distances between the upper-rim carbon atoms of pyrimidine
rings and between the lower-rim nitrogen atoms of pyridine
rings are around 11.32 and 7.00 Å, respectively. Finally, all six
substituents directly connected to the bridging nitrogen atoms
are cisoid-positioned. Noticeably, three 4-cyanophenyl groups
in compound 5l are orthogonal to the plane formed by bridging
nitrogen atoms, yielding an expanded cavity, whereas six phenyl
groups in compound 5o turn around to the other direction.
Such orientation of six N-benzyl groups is most probably due to
the avoidance of repulsion among N-benzyl groups.
All macrocyclic compounds in solution may not be able to
retain their conformational structures found in the crystalline
state. This has been evidenced clearly by the observation of one
1
single set of simple proton and carbon signals in their H and
13C NMR spectra, respectively, in CDCl3 (see the Supporting
Information). For example, the 1H NMR spectrum of
azacalix[6]pyrimidine 5c exhibits, in addition to ethyl proton
signals, two singlet peaks at 8.57 and 7.04 ppm corresponding
to protons at 2- and 5-positions of pyrimidine, respectively. In
its 13C NMR spectrum, only five carbon signals were observed.
Although all azacalix[6]aromatics may adopt a highly
symmetric macrocyclic structure like azacalix[3]pyridine[3]-
pyrimidines 5e−5o, we accounted, however, the highly
fluxional conformational structures in solution to the simplicity
1
of H and 13C NMR spectra. It is most likely that different
conformational structures undergo very rapid interconversions
in solution at room temperature relative to the NMR time scale.
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Figure 6. Fluorescence titration of azacalix[6]arene 5a (λex = 308 nm) with C60 (left) and C70 (right). Upper insertions are variations of fluorescence
intensity Fo/Fcal of 5a with increasing C60 and C70 concentrations, and lower insertions are Job’s plot.
To shed light on the interplay between bridging units and
aromatic rings assembled in macrocycles, the H NMR spectra
understand the capability of synthesized azacalix[6]aromatics in
complexing fullerenes, interactions between synthetic hosts and
C60 and C70 in toluene were investigated following an
established fluorescence titration method.28 As illustrated in
Figure 6 and Figures S3−S26 in the Supporting Information,
titration of macrocyclic host molecules 5a−5o with C60 and C70
led to the gradual quenching of fluorescence emissions. The
Job’s plot experiments, inserted in Figure 6 and Figures S3−
S26, indicated distinctly a 1:1 stoichiometry of the complex
formed between an azacalix[6]aromatic receptor and a fullerene
guest. On the basis of the fluorescence titration data, the
association constants for the 1:1 complexes at room temper-
ature in toluene between azacalix[6]aromatics and fullerenes
were calculated using the Hyperquad 2000 program.29
As indicated by the results compiled in Table 1, all
azacalix[6]aromatics synthesized showed expectedly strong
binding ability toward fullerenes C60 and C70. The association
constants for 1:1 complexation between macrocyclic hosts and
fullerenes C60 and C70 ranged from 3.05× 104 to 7.28 × 104
M−1 in toluene at room temperature. To the best of our
knowledge, as monomacrocyclic species, azacalix[6]aromatics
are very powerful fullerene-complexing host molecules.
Depending on the nature of aromatic rings and of, to a less
degree, N-substituents, azacalix[6]aromatics displayed different
capability and selectivity in forming fullerene complexes. For
example, when complexing with C60, azacalix[6]pyridine 5b
gave a larger Ka (6.62 × 104 M−1) than other azacalix[6]-
aromatics (entries 1−5, Table 1). Azacalix[3]arene[3]pyridine
5d acted as the strongest receptor toward C70 in comparison to
its macrocyclic analogues (entries 1−5, Table 1). Variation of
N-methyl group to N-arylmethyl and N-allyl groups in
azacalix[3]pyridine[3]pyrimidine derivatives 5e−5o led to the
enhancement of C60-binding power (entries 5−15, Table 1),
with macrocycle 5j being the strongest host (entry, 10, Table
1). Introduction of groups other than methyl into the bridging
nitrogen atoms of azacalix[3]pyridine[3]pyrimidines 5e−5o
caused, on the contrary, a slight decrease of interaction with C70
in most cases (entries 5−15, Table 1). Although not
remarkable, selectivity in forming complexes with C60 and C70
was observed for some azacalix[6]aromatics. For instance,
azacalix[6]arene 5a was found to bind C70 (Ka = 7.06 × 104
M−1) more than 2-fold stronger than to bind C60 (3.05 × 104
M−1) (entry 1, Table 1).
1
of azacalix[6]aromatics were investigated (Figure S1 and Table
S1, Supporting Information). In comparison to the chemical
shift of protons of parent benzene, pyridine, and pyrimidine,
varied upfield shifts (Δδ = 0.18−1.19 ppm) of all protons of
aromatic rings of compounds 5 were observed, substantiating
the formation of conjugation between bridging nitrogen atoms
with their adjacent aromatic rings. The Δδ values of
azacalix[6]aromatics that contain two different aromatic rings
were especially worth addressing. In the case of azacalix[3]-
arene[3]pyridine 5d, the benzene moiety showed Δδ of 0.18−
0.44 ppm, while the pyridine ring gave Δδ in a range of 0.26−
1.19 ppm. A much stronger shielding effect (Δδ = 0.58−0.87
ppm) on the pyrimidine ring than on the pyridine ring (Δδ =
0.21−0.60 ppm) was observed in 5e−5o. The outcomes
revealed convincingly the tendency of the linking nitrogen atom
to form a stronger conjugation system with pyridine than with
benzene in 5d, and with pyrimidine than with pyridine in 5e−
5o. As a result, the π-electron density of pyridine was higher
than that of benzene in 5d, while the pyrimidine ring appeared
electron-richer than the pyridine ring in 5e−5o. It should also
be noted that, in azacalix[3]pyridine[3]pyrimidine derivatives
5e−5o, the substituents on the bridging nitrogen atoms also
influenced the chemical shift of aromatic protons. Experience of
the change of chemical shifts of pyrimidine (Δδ = 0.13 ppm)
and pyridine (Δδ = 0.28 ppm) reflected a much stronger
electronic effect of the substituents on the pyridine ring than
that on the pyrimidine ring.
The formation of conjugation between aromatic rings and
bridging nitrogen atoms was also evidenced by electronic
spectroscopy (see the Supporting Information). In UV−visible
spectra, macrocyclic compounds 5 gave maximum absorption
bands in the regions of 297−333 nm, respectively, with the
molar extinction coefficient (ε) ranging from 4.9 × 104 to 7.4 ×
104 except N-pyrenylmethyl-substituted azacalix[3]pyridine[3]-
pyrimidine 5j, which gave characteristic absorption bands at
342 and 349 nm. The obvious red shift of absorption bands in
all of the above cases revealed the presence of conjugation of
the bridging nitrogen atoms with their adjacent aromatic rings,
which is in agreement with the conclusion drawn from NMR
spectroscopic data.
Fullerene-Recognition Property of Azacalix[6]-
aromatics. The bowlic cavity of azacalix[6]aromatics render
these macrocycles excellent receptors for ball-shaped fullerene
guests on the basis of the principle of complementarity. To
To understand the interactions between azacalix[6]aromatics
and fullerenes at the molecular level by revealing the host−
guest structures, single crystals of the complexes between
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Table 1. Association Constants for the 1:1 Complexation of Azacalix[6]aromatics 5a−5o with Fullerenes C60 and C70 at 298 K
a
in Toluene
entry
1
macrocyclic host
Ka (1:1 complexation with C60)
Ka (1:1 complexation with C70)
5a
5b
5c
5d
5e
5f
(3.05 0.06) × 104
(6.62 0.22) × 104
(4.44 0.13) × 104
(5.22 0.11) × 104
(4.93 0.10) × 104
(6.36 0.09) × 104
(5.86 0.11) × 104
(6.56 0.15) × 104
(5.70 0.11) × 104
(7.28 0.21) × 104
(5.59 0.15) × 104
(6.28 0.15) × 104
(6.26 0.14) × 104
(6.29 0.07) × 104
(6.15 0.09) × 104
(7.06 0.15) × 104
(6.24 0.19) × 104
(6.96 0.19) × 104
(7.27 0.02) × 104
(6.66 0.17) × 104
(6.52 0.15) × 104
(5.86 0.18) × 104
(6.08 0.16) × 104
(5.79 0.11) × 104
(6.56 0.20) × 104
(6.26 0.14) × 104
(6.55 0.11) × 104
(5.92 0.11) × 104
(6.72 0.10) × 104
(6.25 0.12) × 104
b
2
3
4
c
5
6
7
5g
5h
5i
8
9
10
11
12
13
14
15
5j
5k
5l
5m
5n
5o
a
b
c
Association constants were calculated on the fluorescence titration data with the Hyperquad 2000 program. Data was taken from ref 22b. Data
was taken from ref 24.
Figure 7. X-ray crystal structure of [5n2·C60]: (a) side view, (b) top view, and (c) π−π interaction between C60 and one host molecule. All hydrogen
atoms are omitted for clarity. The green and cyan balls indicate the centroids of six-membered and five-membered rings of C60, respectively.
Figure 8. X-ray crystal structure of [5n2·C70]: (a, b) side views and (c) π−π interaction between C70 and one host molecule. All hydrogen atoms are
omitted for clarity. The green and cyan balls indicate the centroids of six-membered and five-membered rings of C70, respectively.
macrocycles 5 and fullerenes were prepared carefully by
controlled slow mutual diffusion of fullerene solution in
toluene and macrocycle solution in chloroform at ambient
temperature. To our delight, high-quality single crystals of the
complexes of 5d, 5f, 5j, and 5n with C60 and of 5n with C70
were obtained, and their molecular structures were determined
unambiguously by X-ray diffraction analysis. Very interestingly,
as X-ray crystallography unveils, complexes of varied host−
guest stoichiometric ratios were obtained depending on the
structures of macrocyclic hosts. For example, while interaction
of methylazacalix[3]arene[3]pyridine 5d with C60 gave a [5d·
C60)2] complex, N-pyrenyl-substituted azacalix[3]pyridine[3]-
pyrimidine 5j complexed with C60 to afford [5j·C60] complex.
In other cases, the 2:1 complexes between other azacalix[3]-
pyridine[3]pyrimidine derivatives 5f, 5n and fullerenes C60 and
C70 crystallized from the host−guest interactions.
Although complexes of different stoichiometries resulted
from crystallization, one noteworthy common feature of almost
all complexes is the formation of nearly identical capsule-like
structures in which a fullerene guest such as C60 or C70 is
sandwiched by two interdigitated azacalix[6]aromatics hosts.
This has been well-illustrated by the X-ray molecular structures
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of [5n2·C60], [5n2·C70], [5f2·C60], and [5d·(C60)2], which are
depicted in Figures 7−9 and Figure S29 (Supporting
Information), respectively.
pyrimidine rings and the planes of their nearest six-membered
ring of C70 is 3.30 Å. On the other hand, the contacts of the
five-membered rings of the C70 with one pyrimidine and one
pyridine of the other macrocycle were observed. During the
meantime, the remaining four aromatic rings of the macrocycle
interact with the six-membered ring of the C70. The average
distances of the pyridine nitrogen atoms and the lower-rim
carbon atoms of pyrimidine rings to their nearest aromatic ring
of C70 are in the range of 3.19−3.32 Å (Figure 8). In addition
to the multiple π−π interactions between the concave of the
host and the convex of the guest, N-allyl groups appeared
important. The three cis-orientated 1,3,5-alternating allyl
substituents not only created an expanding concave of
heteracalix[6]aromatics 5n, which fits more favorably the
curvature of C70, but also interacted nicely with C70 by
means of weak π−π interactions between the alkene moieties
and C70 as the β-carbon atom of the allyl group is positioned to
the nearest carbon atom of C70 with a mean distance of 3.43 Å.
The outcomes of the aforementioned molecular structures
indicate the versatility of azacalix[6]aromatics in forming
macrocycle−fullerene complexes. Even with nearly similar
1,3,5-alternate conformations, they are able to fine-tune the
concave structure to achieve maximum contacts with fullerenes
of different symmetry.
As an exception, the 1:1 complex [5j·C60] formed between
N-pyrenylmethyl substituted azacalix[3]pyridine[3]pyrimidine
5j and C60 did not involve the sandwiched structure as that
observed in other heteracalix[6]aromatics−fullerene complexes.
Instead, as indicated by the short interatomic distances in
Figure 9, the bottom of the C60 guest molecule remains in close
contact with the macrocyclic surface of one azacalix[3]pyridine-
[3]pyrimidine 5j through the aforementioned multiple π−π
and CH−π interactions. Out of our expectation, none of the
three 1,3,5-alternating pyrenes substituted on the bridging
nitrogen atoms interacts with the same macrocycle ring-
complexed C60. The complexed C60 was actually surrounded by
three other pyrenes of three neighboring azacalix[3]pyridine-
[3]primidines. Furthermore, the top of the complexed C60
forms a short contact with the upper-rim carbon atoms of
pyridine rings of another azacalix[3]pyridine[3]pyrimidine
molecule. If we examined the host molecule in the crystal
structure, it is very clear that each N-pyrenylmethyl-substituted
azacalix[3]pyridine[3]primidine 5j interacts with five C60
molecules using its concave, upper-rim pyridine C−H and
three pyrene moieties. Remarkably, the molecular packing gives
rise to the array of regular hexagram channels with diameters of
their incircles being around 7.80 Å (Figures S33 and S34,
Supporting Information). Being an electron-rich aromatic
system, pyrene exhibits a beneficial effect in forming a complex
with fullerenes. In the formation of 1:1 complex [5j·C60], the
designedly introduced pyrene moieties in 5j did not
cooperatively participate in the interactions with the same
macrocycle ring-complexed C60. It is most probably the
bulkiness of pyrenylmethyl groups that prohibits the favorable
all-cis-orientation that is a prerequisite for cooperative
interactions.
Figure 9. X-ray crystal structure of [5f·C60]: (a) top view, (b) side
view. All hydrogen atoms are omitted for clarity.
Some interesting points are worth addressing. Taking the
structure of [5n2·C60] as a representive example (Figure 7), the
macrocyclic host in the complex adopts a highly symmetric
1,3,5-altenate conformation with the upper-rim interatomic
distances being 11.29 and 4.45 Å in order to achieve maximum
contact with the convex of the buckball C60. Each pyrimidine
ring of azacalix[3]pyridine[3]pyrimidine interacts with the six-
membered ring of the included C60, while each pyridine ring
points toward the five-membered ring of the complexed C60.
The distances of the lower-rim carbon atom of the pyrimidine
ring to the plane of and the centroid of the six-membered ring
of C60 are 3.22 and 3.24 Å, respectively. The pyridine nitrogen
atom is located above the five-membered ring of C60 with a
distance to the plane and the centroid being 3.18 and 3.19 Å,
respectively. All distances are shorter than the sum of van der
Waals radii, indicating strong and multiple π−π interactions
between azacalix[3]pyridine[3]pyrimidines and the sandwiched
C60. In addition, three alternating methylene units directly
connected to the bridging nitrogens also interact with the
included C60 through weak CH−π interactions, as their
distances to the nearest C60 carbon atoms are around 3.51 Å.
Apart from the macrocyclic scaffold, substituents on the
bridging nitrogen atoms provide further noncovalent binding
sites to interact with fullerene guest, contributing extra driving
force to stabilize host−guest complexes. For instance, as
evidenced by the distance of the β-carbon atom of the N-allyl
group to the nearest carbon atom of C60, which equals 3.49 Å,
three ethenyl groups form weak π−π interactions with C60 in
complex [5n2·C60].
As C70 has a lower symmetric structure than C60, formation
of [5n2·C70] complex along with its X-ray structure
determination were significant.30 It is the first supramolecular
structure of a heteracalixaromatics-C70 complex reported to
date, allowing elucidation of molecular details of noncovalent
bond interactions between heteracalixaromatics and C70. Being
different from high symmetric [5n ·C ] in the space group R3,
̅
2
60
[5n ·C ] crystallizes in a triclinic symmetry of P1. The
̅
2
70
In the case of [5d·(C60)2], the only complex having a 1:2
ratio between host and guest, the same sandwiched complex-
ation patter was also observed (Figure S29, Supporting
Information). Interestingly, each sandwiched C60 was contacted
by six C60 molecules in a hexagonal manner with the shortest
distance between peripheral C60 molecules being 3.28 Å and
the distance between peripheral C60 and the sandwiched C60
sandwiched C70 reclines between two macrocycle hosts and
interacts with them in strikingly different modes. One of the
macrocycles uses its pyrimidines and pyridines to interact with
the six- and the five-membered rings of C70, respectively. The
average distance of the pyridine nitrogen atoms to the planes of
their nearest five-membered ring of C70 is 3.33 Å, while the
average distance between the lower-rim carbon atoms of
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toluene and macrocycle solution in chloroform at ambient temper-
ature.
molecules being 3.29 Å (Figure S32, Supporting Information).
In other words, in the crystalline state of [5d·(C60)2], C60
molecules assemble into layers that are separated by macro-
cyclic hosts that form sandwich complexs with hexagonally
arranged C60 (Figure S32).
Preparation of 3a. Under argon protection, a mixture of 1a (680
mg, 5 mmol) and m-dibromobenzene 2a (2.95 g, 12.5 mmol),
Pd2(dba)3 (690 mg, 0.75 mmol), dppp (615 mg, 1.5 mmol), and
sodium t-butoxide (1.44 g, 15 mmol) in anhydrous 1,4-dioxane (100
mL) was refluxed for 10 h. The reaction mixture was cooled down to
room temperature and filtered through a Celite pad. The filtrate was
concentrated under vacuum. The residue was dissolved in dichloro-
methane (100 mL) and washed with brine (3 × 25 mL). The aqueous
phase was re-extracted with dichloromethane (3 × 20 mL), and the
combined organic phase was dried over anhydrous MgSO4. After
removal of solvent, the residue was chromatographed on a silica gel
column with a mixture of petroleum ether and ethyl acetate (v:v = 8:1)
as the mobile phase to give product 3a (876 mg, 39%) as a white
powder: mp 85−86 °C; IR (KBr) ν 1593, 1576, 1556, 1483, 1352
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.26 (t, J = 7.8 Hz, 1H), 7.12−
7.06 (m, 4H), 6.98 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 7.5 Hz, 2H), 6.78
(s, 2H), 6.75 (d, J = 1.8 Hz, 1H), 3.27 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 150.1, 149.3, 130.4, 130.3, 123.1, 123.0, 121.3, 117.2, 116.9,
116.5, 40.2; MS (CI) m/z (%) 448 [M + 4]+ (58), 446 [M + 2]+
(100), 444 [M]+ (51), 365 [M − Br]+ (51). Anal. Calcd. for
C20H18Br2N2: C, 53.84; H, 4.07; N, 6.28. Found: C, 53.69; H, 4.11; N,
6.20.
As revealed convincingly by the X-ray molecular structures,
multiple π−π interactions are the dominant noncovalent bond
interactions between concave azacalix[6]aromatics and convex
fullerenes. Both the CH−π and the π−π interactions between
substituents on the bridging nitrogen atoms and fullerenes also
contribute to the formation of host−guest complexes. The
details of the structures of azacalix[6]aromatics−fullerene
complexes in solution are hard to know at this stage.
Nevertheless, it is the multiple π−π and CH−π interactions
between sterically complementary concave and convex that
contribute a joint driving force to promote the formation of
azacalix[6]aromatics−fullerene complexes in solution. It is most
probably that all azacalix[6]aromatics 5, irrespective of their
compositions, adopt nearly identical 1,3,5-altenate conforma-
tions to form similar 1:1 complexes with C60 or C70 in solution;
the association constants, therefore, have the same order of
magnitude (see Table 1). Slight variations of association
constants shown in Table 1 reflect most likely the different
electronic effect that resulted from the interplay between varied
aromatic rings and the bridging nitrogen atoms. The effect of
N-substituents on host−guest binding appeared subtle.
Although there is no correlation between binding and N-
substituent, introduction of N-pyrenylmethyl has a beneficial
effect to enhance the interaction with C60 (see entry 10, Table
1).
Preparation of 3c. To a solution of 4,6-di(ethylamino)pyrimidine
1c (1.66 g, 10 mmol) in dry THF (60 mL) at room temperature was
added NaH (0.96 g, 40 mmol) slowly, and the mixture was heated to
reflux. After 10 h, 4,6-dichloropyrimidine 2c (5.96 g, 40 mmol) was
added to the mixture slowly, and the reaction mixture was refluxed for
another 6 h. The reaction mixture was then cooled down to room
temperature, and water (1 mL) was added slowly. The solvent was
removed under reduced pressure, and the residue was dissolved in
dichloromethane (200 mL). The organic solution was washed with
brine (3 × 50 mL) and dried over anhydrous MgSO4. After removal of
solvent, the residue was chromatographed on a silica gel column with a
mixture of petroleum ether and ethyl acetate (v:v = 8:1) as the mobile
phase to give pure 3c (2.71 g, 70%) as a colorless solid: mp 157−158
CONCLUSION
■
In summary, using [3 + 3] and [2 + 2 + 2] fragment coupling
approaches, we have synthesized a number of azacalix[6]-
aromatics containing different combinations of benzene,
pyridine, and pyrimidine rings and various substituents on
bridging nitrogen atoms. In the solid state, they form symmetric
to heavily distorted 1,3,5-alternate conformers depending on
the nature of aromatic building units, whereas, in solution, they
exist probably as a mixture of conformers that undergo rapid
interchanges relative to the NMR time scale. By means of
fluorescence titration, all macrocycles synthesized were found
to form 1:1 complexes with C60 and C70 in toluene with the
association constants in the range of 3.05 × 104 to 7.28 × 104
M−1. Crystallization gave complexes of a 2:1, 1:1, or 1:2
stoichiometric ratio between host and guest. X-ray crystallog-
raphy revealed in all cases that multiple π−π and CH−π
interactions between concave azacalix[6]aromatics and convex
fullerenes C60 and C70 contribute a joint driving force to the
formation of host−guest complexes. The outcomes of the study
would provide guidelines for the future design and fabrication
of heteracalixaromatics that are powerful and selective receptors
in the recognition of diverse fullerenes.
1
°C; IR (KBr) ν 1598, 1550, 1442, 1005 cm−1; H NMR (300 MHz,
CDCl3) δ 8.81 (s, 1H), 8.71 (s, 2H), 7.38 (s, 1H), 7.31 (s, 2H), 4.30
(q, J = 7.2 Hz, 4H), 3.33 (t, J = 6.9 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 161.7, 161.1, 161.0, 158.4, 158.3, 108.4, 104.2, 42.8, 13.0;
MS (CI) m/z (%) 419 [M + 29]+ (22), 392 [M + 2]+ (35), 391 [M +
1]+ (100), 390 [M]+(15). Anal. Calcd. for C16H16Cl2N8: C, 49.12; H,
4.12; N, 28.64. Found: C, 48.90; H, 4.16; N, 28.67.
Preparation of 3e. Compound 3e was prepared from 2,6-
bis(methylamino)pyridine 1b (685 mg, 5 mmol) following a similar
procedure as that for the synthesis of 3a. The product was obtained as
a white solid (876 mg, 39%): mp 97−98 °C. IR (KBr) ν 3062, 1571,
1456, 1338, 1157 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.39 (s, 2H),
7.21−7.06 (m, 7H), 5.96 (d, J = 8.1 Hz, 2H), 3.35 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 157.0, 148.3, 138.3, 130.3, 128.6, 127.3, 124.1,
122.5, 98.9, 38.0; MS (CI) m/z (%) 449 [M + 2]+ (7), 447 [M]+ (11),
445 [M − 2]+ (5). Anal. Calcd. for C19H17Br2N3: C, 51.03; H, 3.83; N,
9.40. Found: C, 50.86; H, 3.82; N, 9.06.
Preparation of 4a. A mixture of 3a (2.23 g, 5 mmol),
methylamine aqueous solution (25−30%) (3 mL), CuI (0.95 g, 0.5
mmol), L-proline (0.115 g, 1 mmol), and K2CO3 (2.07 g, 15 mmol) in
DMSO (15 mL) was stirred in a sealed tube at 100 °C for 24 h. After
the mixture was cooled to room temperature, the mixture was
partitioned between ethyl acetate (50 mL) and water (50 mL). The
organic layer was separated, and the aqueous layer was extracted with
ethyl acetate (2 × 25 mL). The combined organic layers were washed
with brine and dried over anhydrous Na2SO4. After removal of solvent,
the residue was chromatographed on a silica gel column with a mixture
of petroleum ether and ethyl acetate (v:v = 2:1) as the mobile phase to
give pure 4a as a red oil (1.74 g, 100%): IR (KBr) ν 1593, 1576, 1556,
1483, 1352 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.14 (t, J = 8.1 Hz,
1H), 7.08 (t. J = 8.1 Hz, 2H), 6.73 (t, J = 2.1 Hz, 1H), 6.61 (dd, J =
8.1, 2.1 Hz, 2H), 6.39 (dd, J = 8.1, 1.8 Hz, 2H), 6.30 (s, 2H), 6.23 (dd,
J = 8.1, 1.5 Hz, 2H), 3.26 (s, 6H), 2.79 (s, 6H); 13C NMR (75 MHz,
EXPERIMENTAL SECTION
■
General Information. Compounds 1a,15a 1b,22b 1c,31 1d,24 3b,22b
3d,15a 3f-3g,24 4b,22b 4e,24 5b,22b 5e,24 and 6a22b were prepared
following the reported procedures. All new products were charac-
terized by means of spectroscopic data and microanalysis.
Fluorescence titration of azacalix[6]aromatics with fullerenes C60
and C70 was conducted according to the literature.22b,28 Single crystals
of the complexes between azacalix[6]aromatics and fullerenes C60 and
C70 were cultivated by slow mutual diffusion of fullerene solution in
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CDCl3) δ 150.2, 150.1, 149.9, 129.8, 129.4, 113.5, 112.9, 110.1, 105.9,
104.9, 40.2, 30.9; MS (CI) m/z (%) 375 [M + 29]+ (18), 347 [M]+
(100). Anal. Calcd. for C22H26N4: C, 76.27; H, 7.56; N, 16.17. Found:
C, 76.31; H, 7.51; N, 16.15.
solution was washed with brine (3 × 50 mL) and dried over anhydrous
MgSO4. After removal of solvent, the residue was chromatographed on
a silica gel column using a mixture of petroleum ether and ethyl acetate
(v:v = 10:1) as the mobile phase to give pure products.
7a. Compound 7a was obtained as a white solid (8.01 g, 89%): mp
112−114 °C; IR (KBr) ν 1588, 1574, 1557, 1523, 1489, 1435, 1376,
1162, 1113, 1098, 979, 943 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.55
(s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.36−7.32 (m, 2H), 7.00 (s, 1H),
3.59 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.2, 160.4, 158.1,
155.5, 140.3, 140.0, 124.7, 117.2, 105.7, 36.2; MS (APCI) m/z 280 [M
+ H]+. Anal. Calcd. for C17H16BrN5: C, 55.15; H, 4.36; N, 18.92.
Found:C, 54.95; H, 4.37; N, 18.52.
7b. Compound 7b was obtained as a white solid (8.31 g, 72%): mp
69−70 °C; IR (KBr) ν 1585, 1557, 1463, 1432, 1412, 1392, 1334,
1232, 1101 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 0.8 Hz,
1H), 7.58 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 8.4
Hz, 1H), 6.97 (d, J = 0.8 Hz, 1H), 5.97−5.88 (m, 1H), 5.20−5.15 (m,
2H), 4.77 (dt, J = 4.8 Hz, J = 1.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 161.9, 160.5, 158.2, 154.8, 140.3, 140.2, 132.4, 124.9, 117.5,
117.3, 106.2, 50.9; MS (APCI) m/z 325 [M + H]+. Anal. Calcd. for
C12H10BrClN4: C, 44.27; H, 3.10; N, 17.21. Found: C, 44.66; H, 3.14;
N, 17.09.
7c. Compound 7c was obtained as a white solid (11.24 g, 81%): mp
135−136 °C; IR (KBr) ν 1562, 1523, 1430, 1223, 1100, 977, 929
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.53 (t, J = 7.8 Hz,
1H), 7.40−7.18 (m, 7H), 6.99 (s, 1H), 4.53 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 162.2, 160.5, 158.3, 154.8, 140.5, 140.3, 136.9, 128.8,
127.6, 127.3, 125.1, 117.4, 106.3, 51.7; MS (APCI) m/z 375 [M +
H]+. Anal. Calcd. for C16H12BrClN4: C, 51.16; H, 3.22; N, 14.91.
Found: C, 51.20; H, 3.24; N, 14.97.
General Procedure for the Synthesis of Dimers 8a−8c and
8i−l. An autoclave equipped with a magnetic stir bar was charged with
7a−7c (10 mmol), water (10 mL), and amines (20 mmol) or aqueous
methylamine (33%, 1.88 mL, 20 mmol) or 15 mL of aqueous
ammonia solution (25−28%). It was then heated at 120 °C for 10 h
(or at 170 °C for 24 h in the case of synthesis of 8l). After the mixture
was cooled to room temperature, dichloromethane (50 mL) was
added, and the organic phase was washed with brine (3 × 50 mL). The
aqueous phase was re-extracted with dichloromethane (3 × 20 mL),
and the combined organic phase was dried over anhydrous MgSO4.
After removal of solvent, the residue was chromatographed on a silica
gel column with a mixture of petroleum ether and ethyl acetate (v:v =
1:1) as the mobile phase to give products. For 8l, a mixture DCM and
ethyl acetate (v:v = 1:1) was used.
8a. Compound 8a was obtained as a white solid (2.12 g, 72%): mp
115−116 °C; IR (KBr) ν 3246, 3112, 3007, 1614, 1439, 1300, 1152,
798, 783 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.40 (t, J
= 8.0 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 5.99
(s, 1H), 5.46 (br. s, 1H), 3.53 (s, 3H), 2.86 (d, J = 5.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 164.1, 161.8, 157.4, 156.5, 139.4, 122.0,
115.9, 86.2, 35.6, 28.4; MS (ESI) m/z (%) 294 [M + H]+ (100), 296
[M + 3]+ (94). Anal. Calcd. for C11H12BrN5: C, 44.92; H, 4.11; N,
23.81. Found: C, 44.99; H, 4.11; N, 23.51.
Preparation of 4c. An autoclave equipped with a magnetic stir bar
was charged with 3c (1.95 g, 5 mmol) and 5 mL of ethylamine
aqueous solution (55−60%). Then it was heated at 120 °C for 10 h.
After the mixture was cooled to room temperature, dichloromethane
(100 mL) was added, and the organic phase was washed with brine (3
× 50 mL). The aqueous phase was re-extracted with dichloromethane
(3 × 20 mL), and the combined organic phase was dried over
anhydrous MgSO4. After removal of solvent, the residue was
chromatographed on a silica gel column with a mixture of petroleum
ether and ethyl acetate (v:v = 2:1) as the mobile phase to give pure 4c
(2.0 g, 99%) as a white solid: mp 200−201 °C; IR (KBr) ν 3258, 1622,
1
1566, 1449 cm−1; H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H), 8.33
(s, 2H), 7.07 (s, 1H), 6.17 (s, 2H), 4.87 (s, br, 2H), 4.20 (q, J = 6.9
Hz, 4H), 3.36−3.27 (m, 4H), 1.29−1.23 (m, 12H); 13C NMR (75
MHz, CDCl3) δ 163.4, 161.44, 161.38, 158.1, 158.0, 99.9, 91.0, 42.3,
36.3, 14.6, 13.4; MS (CI) m/z (%) 437 [M + 29]+ (35), 409 [M +
1]+(100), 408 [M]+(18), 379 [M − C2H5]+ (28). Anal. Calcd. for
C20H28N10: C, 58.80; H, 6.91; N, 34.29. Found: C, 58.32; H, 6.89; N,
34.49.
Preparation of 4d. Compound 4d was prepared from 3d (2.25 g,
5 mmol) following a similar procedure as that for the synthesis of 4a.
The product was obtained as a brown oil (1.74 g, 100%): IR (KBr) ν
1
3428, 1577, 1466, 1407, 1121 cm−1; H NMR (300 MHz, CDCl3) δ
7.31 (t, J = 8.1 Hz, 1H), 7.21−7.16 (m, 3H), 7.03 (dd, J = 8.1, 2.1 Hz,
2H), 5.96 (d, J = 8.1 Hz, 2H), 5.76 (d, J = 7.8 Hz, 2H), 4.32 (s, br,
2H), 3.42 (s, 6H), 2.88 (d, J = 5.1 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 158.8, 157.9, 148.0, 138.4, 129.7, 123.3, 121.7, 98.1, 94.5,
37.9, 29.2; MS (CI) m/z (%) 377 [M + 29]+ (100), 349 [M + 1]+
(100). Anal. Calcd for C20H24N6: C, 68.94; H, 6.94; N, 24.12. Found:
C, 68.78; H, 6.82; N, 24.01.
General Procedure for the Synthesis of 2-Amino-6-
bromopyridines 6b and 6c. An autoclave equipped with a magnetic
stir bar was charged with 2,6-dibromopyridine (94.8 g, 400 mmol) and
excess amine as solvent (150 mL for 6b, 100 mL for 6c). It was then
heated at 150 °C for 5 h. After cooling to room temperature, the
solvent was removed under reduced pressure, and the residue was
dissolved in ether acetate (400 mL). The organic solution was washed
with brine (3 × 150 mL), and the organic phase was dried over
anhydrous Na2SO4. After removal of solvent, the residue was
chromatographed on a silica gel column using a mixture of petroleum
ether and ethyl acetate (v:v = 20:1) as the mobile phase to give pure
product.
6b. Compound 6b was obtained as an orange oil (70.60 g, 83%): IR
(KBr) ν 3303, 1605, 1594, 1528, 1450, 918, 770 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.20 (t, J = 8.0 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.25
(d, J = 8.0 Hz, 1H), 5.84 (m, 1H), 5.32−5.16 (m, 2H), 5.14−5.08 (m,
1H), 3.86 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 159.0, 140.2,
139.7, 134.4, 116.4, 115.9, 104.6, 44.7. HRMS (FTMS-ESI) calcd. for
C8H9BrN2: [M + H]+ 213.00274. Found: 213.00270.
8b. Compound 8b was obtained as a white solid (2.72 g, 85%): mp
6c. Compound 6c was obtained as a white solid (47.62 g, 48%): mp
1
80−81 °C; IR (KBr) ν 3286, 1597, 1431, 1094, 769 cm−1; H NMR
132−133 °C; IR (KBr) ν 3227, 3103, 3005, 1606, 1574, 1554, 1478,
1
1441, 1163, 798, 786 cm−1; H NMR (400 MHz, CDCl3) δ 8.29 (s,
(400 MHz, CDCl3) δ 7.40−7.23 (m, 5H), 7.19 (t, J = 7.8 Hz, 1H),
6.74 (d, J = 7.3 Hz, 1H), 6.25 (d, J = 8.2 Hz, 1H), 5.38 (br. s, 1H),
4.48 (d, J = 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 158.9, 140.3,
139.7, 138.5, 128.8, 127.5, 127.4, 116.2, 104.7, 46.4; MS (APCI) m/z
263 [M + H]+. Anal. Calcd. for C12H11BrN2: C, 54.77; H, 4.21; N,
10.65. Found: C, 54.89; H, 4.22; N, 10.76.
1H), 7.44 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 7.6
Hz, 1H), 6.03 (s, 1H), 5.94−5.85 (m, 1H), 5.27 (dd, J1 = 17 Hz, J2 =
1.4 Hz, 1H), 5.20−5.17 (m, 2H), 3.89 (t, J = 5.6 Hz, 2H), 3.55 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 163.3, 161.9, 157.7, 156.6,
139.6, 139.1, 134.0, 122.1, 116.8, 115.9, 87.1, 44.1, 35.6; MS (APCI)
m/z 320 [M + H]+. Anal. Calcd. for C13H14BrN5: C, 48.76; H, 4.41; N,
21.87. Found: C, 48.65; H, 4.30; N, 21.69.
General Procedure for the Synthesis of Dimers 7a−7c. To a
solution of 2-amino-6-bromopyridine 6a−6c (30 mmol) in dry THF
(60 mL) at room temperature was added NaH (1.44 g, 60 mmol)
slowly, and the mixture was heated to reflux. After 10 h, 4,6-
dichloropyrimidine (8.94 g, 60 mmol) was added slowly, and the
reaction mixture was refluxed for another 6 h. The reaction mixture
was then cooled down to room temperature, and water (1 mL) was
added slowly. The solvent was removed under reduced pressure, and
the residue was dissolved in dichloromethane (200 mL). The organic
8c. Compound 8c was obtained as a white solid (3.08 g, 84%): mp
145−147 °C; IR (KBr) ν 3209, 2987, 1602, 1569, 1423, 1409, 1277,
1
1118, 1096, 696 cm−1; H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H),
7.37−7.27 (m, 6H), 7.19 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H),
5.98 (s, 1H,) 5.40 (br.s, 1H), 4.46 (d, J = 6.0 Hz, 2H), 3.52 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 163.2, 161.9, 157.8, 156.5, 139.6,
139.1, 138.0, 128.9, 127.7, 127.4, 122.1, 115.8, 87.2, 45.8, 35.5; MS
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(APCI) m/z 370 [M + H]+. Anal. Calcd. for C17H16BrN5: C, 55.15; H,
4.36; N, 18.92. Found: C, 54.95; H, 4.37; N, 18.52.
139.1, 134.0, 133.1, 131.4, 129.0, 128.6, 126.7, 126.1, 126.0, 125.5,
123.3, 122.2, 115.9, 87.3, 43.8, 35.6; MS (APCI) m/z 420 [M + H]+.
Anal. Calcd. for C21H18BrN5: C, 60.01; H, 4.32; N, 16.66. Found: C,
59.60; H, 4.38; N, 16.77.
8i. Compound 8i was obtained as a white solid (3.30 g, 83%): mp
162−163 °C; IR (KBr) ν 3212, 1600, 1570, 1512, 1424, 1246, 792
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.37 (t, J = 8.0 Hz,
1H), 7.24−7.21 (m, 3H), 7.11 (d, J = 6.8 Hz, 1H), 6.87 (dt, J1 = 8.8
Hz, J2 = 2.6 Hz, 2H), 5.98 (d, J = 0.8 Hz, 1H), 5.36 (br.s, 1H), 4.39 (d,
J = 5.6 Hz, 2H), 3.80 (s, 3H), 3.52 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 163.0, 161.9, 159.2, 157.6, 156.5, 139.6, 139.1, 129.9, 128.7,
122.1, 115.8, 114.3, 87.2, 55.4, 45.3, 35.6; MS (APCI) m/z 400 [M +
H]+. Anal. Calcd. for C18H18BrN5O: C, 54.01; H, 4.53; N, 17.50.
Found: C, 54.01; H, 4.52; N, 17.29.
8f. Compound 8f was obtained as a white solid (863 mg, 35%): mp
192−193 °C; IR (KBr) ν 3212, 1598, 1567, 1423, 845 cm−1; 1H NMR
(400 MHz, CDCl3) δ 8.38 (s, 1H), 8.01−8.00 (m, 1H), 8.15−8.12 (m,
2H), 8.09−8.00 (m, 4H), 7.16−7.09 (m, 2H), 6.94 (dd, J1 = 7.0 Hz, J2
= 1.0 Hz, 1H), 6.08 (d, J = 0.8 Hz, 1H), 5.35 (br.s, 1H), 5.17 (d, J =
4.8 Hz, 2H), 3.50 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.1,
162.0, 157.8, 156.5, 139.6, 138.9, 131.4, 131.3, 130.89, 130.86, 128.9,
128.3, 127.6, 127.4, 126.4, 126.2, 125.5, 125.4, 125.2, 124.91, 124.88,
122.5, 122.0, 115.6, 87.6, 44.0, 35.5; MS (APCI) m/z 494 [M + H]+.
Anal. Calcd. for C27H20BrN5: C, 65.59; H, 4.08; N, 14.17. Found: C,
65.45; H, 4.07; N, 13.97.
8j. Compound 8j was obtained as a white solid (2.94 g, 85%): mp
68−69 °C; IR (KBr) ν 3231, 3104, 3078, 3004, 1602, 1571, 1551,
1
1435, 1328, 1220, 1164, 1136, 931, 918, 781 cm−1; H NMR (400
8g. Compound 8g was obtained as a white solid (785 mg, 35%):
mp 97−98 °C; IR (KBr) ν 3247, 1601, 1576, 1553, 1478, 1430, 1409,
1163, 796 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.45 (t,
J = 7.8 Hz, 1H), 7.36−7.30 (m, 3H), 7.24−7.20 (m, 3H), 7.14 (d, J =
7.2 Hz, 1H), 6.02 (s, 1H), 4.87 (br.s, 1H), 3.54−3.51 (m, 5H),2.92 (d,
J = 7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 163.1, 161.9, 157.7,
156.6, 139.6, 139.2, 138.7, 128.9, 128.8, 126.7, 122.1, 115.9, 87.1, 42.8,
35.64, 35.56; MS (APCI) m/z 384 [M + H]+. Anal. Calcd. for
C18H18BrN5: C, 56.26; H, 4.72; N, 18.22. Found: C, 56.20; H, 4.78; N,
18.21.
8h. Compound 8h was obtained as a white solid (630 mg, 35%):
mp 142−143 °C; IR (KBr) ν 3222, 2227, 1601, 1570, 1425, 1409
cm−1; 1H NMR (400 MHz, CDCl3) δ8.28(s, 1H), 7.62 (d, J = 8.0 Hz,
2H), 7.43−7.38 (m, 3H), 7.21 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 7.2
Hz,1H), 6.04 (s, 1H), 5.53 (br.s, 1H), 4.58 (d, J = 5.6 Hz, 2H), 3.50 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 163.0, 161.7, 157.8, 156.4,
144.1, 139.6, 139.3, 132.6, 127.8, 122.5, 118.8, 115.8, 111.4, 87.4, 45.1,
35.7; MS (APCI) m/z 395 [M + H]+. Anal. Calcd. for C18H15BrN6: C,
54.70; H, 3.83; N, 21.26. Found: C, 54.63; H, 3.86; N, 21.33.
General Procedure for the Synthesis of Methylazacalix[6]-
aromatics 5a and 5d. Under argon protection, a mixture of 3a (1
mmol) and 4a (1 mmol) or a mixture 3e (1 mmol) and 4d (1 mmol),
Pd2(dba)3 (138 mg, 0.15 mmol), dppp (123 mg, 0.3 mmol), and
sodium t-butoxide (288 mg, 3 mmol) in anhydrous 1,4-dioxane (200
mL) was refluxed for 24 h. The reaction mixture was cooled down to
room temperature and filtered through a Celite pad. The filtrate was
concentrated under vacuum, and the residue was dissolved in
dichloromethane (100 mL) and washed with brine (3 × 25 mL).
The aqueous phase was re-extracted with dichloromethane (3 × 20
mL), and the combined organic phase was dried over anhydrous
MgSO4. After removal of solvent, the residue was chromatographed on
a silica gel column using a mixture of petroleum ether and ethyl acetate
(v:v = 1:1) as the mobile phase to give the products.
MHz, CDCl3) δ 8.28 (s, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 8.0
Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.05 (s, 1H), 5.99−5.84 (m, 2H),
5.26−5.12 (m, 5H), 4.76 (d, J = 5.2 Hz, 2H), 3.87 (t, J = 4.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 163.3, 161.5, 157.8, 155.8, 139.6,
139.3, 134.0, 133.7, 122.3, 116.8, 116.6, 116.1, 87.5, 50.2, 44.2; MS
(APCI) m/z 346 [M + H]+. Anal. Calcd. for C15H16BrN5: C, 52.04; H,
4.66; N, 20.23. Found: C, 52.04; H, 4.66; N, 20.01.
8k. Compound 8k was obtained as a white solid (1.94 g, 87%): mp
155−156 °C; IR (KBr) ν 3211, 1603, 1589, 1419, 1217, 1190 cm−1;
1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.53−7.18 (m, 11H),
7.14 (d, J = 7.6 Hz, 2H), 7.10 (d, J = 8.0 Hz, 1H), 5.96 (s, 1H), 5.79
(br.s, 1H), 5.38 (s, 2H), 4.39 (d, J = 6.6 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 163.3, 161.7, 157.9, 155.8, 139.7, 139.3, 138.3, 128.9,
128.6, 127.6, 127.4, 127.2, 127.0, 122.4, 116.1, 87.8, 51.0, 45.8; MS
(APCI) m/z 446 [M + H]+. Anal. Calcd. for C23H20BrN5: C, 61.89; H,
4.52; N, 15.69. Found: C, 61.66; H, 4.22; N, 15.63.
8l. Compound 8l was obtained as a white solid (1.43 g, 83%): mp
185−186 °C; IR (KBr) ν 3198, 1664, 1604, 1579, 1533, 1439, 784
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.48 (t, J = 8.0 Hz,
1H), 7.38 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.10 (d, J = 0.8
Hz, 1H), 4.80 (br.s, 2H), 3.55 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 163.4, 162.1, 157.9, 156.4, 139.7, 139.3, 122.6, 116.5, 88.3, 35.7; MS
(APCI) m/z 280 [M + H]+. Anal. Calcd. for C10H10BrN5: C, 42.88; H,
3.60; N, 25.00. Found: C, 42.90; H, 3.73; N, 24.73.
General Procedure for the Synthesis of Dimers 8d−8h. To a
solution of 8l (1.40 g, 5 mmol) in dry THF (50 mL) at room
temperature was added NaH (180 mg, 7.5 mmol) slowly, and the
mixture was heated to reflux. After 10 h, arylmethylene bromide (5.5
mmol) was added to the mixture slowly, and the reaction mixture was
refluxed for another 3 h. The reaction mixture was then cooled down
to room temperature, and water (0.5 mL) was added slowly. The
solvent was removed under reduced pressure, and the residue was
dissolved in dichloromethane (50 mL). The organic solution was
washed with brine (3 × 20 mL) and dried over with anhydrous
MgSO4. After removal of solvent, the residue was chromatographed on
a silica gel column using a mixture of petroleum ether and ethyl acetate
(v:v = 1:1) as the mobile phase to give pure products.
5a. Compound 5a was obtained as a white solid (144 mg, 23%):
1
mp > 300 °C; IR (KBr) ν 3074, 1589, 1572, 1487, 1115 cm−1; H
NMR (300 MHz, CDCl3) δ 7.13 (t, J = 7.8 Hz, 6H), 6.63 (t, J = 1.8
Hz, 6H), 6.57 (dd, J = 8.1 Hz, J = 2.1 Hz, 12H), 3.21 (s, 18H); 13C
NMR (75 MHz, CDCl3) δ 149.5, 129.7, 113.02, 113.00, 40.2; MS
(MALDI-TOF) m/z 631 [M + H]+. Anal. Calcd. for C42H42N6: C,
79.97; H, 6.71; N, 13.32. Found: C, 79.62; H, 6.74; N, 13.13. Slow
evaporation of the solvent from a mixture of CH2Cl2 and acetone gave
a single crystal suitable for X-ray diffraction analysis.
5d. Compound 5d was obtained as a colorless block (191 mg,
30%): mp 296−297 °C; IR (KBr) ν 1594, 1575, 1558, 1455, 1158
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.38 (t, J = 7.8 Hz, 3H), 7.18 (s,
3H), 7.03 (t, J = 7.8 Hz, 3H), 6.92 (dd, J1 = 8.1 Hz, J2 =1.8 Hz, 6H),
6.05 (d, J = 8.1 Hz, 6H), 3.43 (s, 18H); 13C NMR (75 MHz, CDCl3) δ
157.8, 148.4, 136.8, 130.5, 122.0, 119.0, 101.3, 37.8; MS (MALDI-
TOF) m/z 634 [M + H]+. Anal. Calcd. for C39H39N9: C, 73.91; H,
6.20; N, 19.89. Found: C, 73.72; H, 6.19; N, 19.77. Slow evaporation
of the solvent from a mixture of CH2Cl2 and methanol gave a single
crystal suitable for X-ray diffraction analysis.
8d. Compound 8d was obtained as a white solid (960 mg, 46%):
mp 153−155 °C; IR (KBr) ν 3222, 3094, 2990, 1600, 1569, 1423,
1
1406, 1323, 1117, 983 cm−1; H NMR (400 MHz, CDCl3) δ 8.33 (s,
1H), 7.85−7.77 (m, 3H), 7.73 (s, 1H), 7.51−7.46 (m, 1H) 7.43 (dd, J
= 8.6 Hz, J = 1.8 Hz, 1H), 7.03−6.96 (m, 3H), 5.98 (s, 1H), 5.58 (br.s,
1H), 4.62 (d, J = 5.6 Hz, 2H), 3.50 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 163.2, 161.9, 157.9, 156.4, 139.6, 139.0, 135.5, 133.5, 132.9,
128.8, 127.8, 126.5, 126.1, 125.8, 125.3, 122.1, 115.6, 87.5, 46.0, 35.5;
MS (APCI) m/z 420 [M + H]+. Anal. Calcd. for C21H18BrN5: C,
60.01; H, 4.32; N, 16.66. Found: C, 60.12; H, 4.36; N, 16.31.
8e. Compound 8e was obtained as a white solid (1.21g, 58%): mp
154−155 °C; IR (KBr) ν 3220, 1600, 1570, 1472, 1421, 1397 cm−1;
1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.26−8.20 (m, 3H),
7.91−7.89 (m, 1H), 7.83 (d, J = 8.0 Hz, 1H) 7.56−7.42 (m, 4H), 7.31
(t, J = 7.8 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H),
6.03 (s, 1H), 5.42 (br.s, 1H), 4.91 (d, J = 5.2 Hz, 2H), 3.51 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 163.1, 161.8, 157.8, 156.4, 139.6,
Preparation of Ethylazacalix[6]pyrimidine 5c. To a solution of
4c (390 mg, 1 mmol) in dry THF (30 mL) at room temperature was
added NaH (180 mg, 7.5 mmol) slowly, and the mixture was heated to
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reflux. After 12 h, the dry toluene (150 mL) and 3c (408 mg, 1 mmol)
were added, and the resulting mixture was refluxed for another 48 h.
The reaction mixture was then cooled down to room temperature, and
water (1 mL) was added slowly. The solvent was removed under
reduced pressure, and the residue was dissolved in CH2Cl2 (200 mL).
The organic solution was washed with brine (3 × 50 mL) and dried
over anhydrous MgSO4. After removal of solvent, the residue was
chromatographed on a silica gel column using a mixture of petroleum
ether and ethyl acetate (v:v = 1:1) as the mobile phase to give pure 5c
(182 mg, 25%) as a white solid: mp 279−280 °C; IR (KBr) ν 1574,
1537, 1470, 1407, 1209 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.55 (s,
6H), 7.02 (s, 6H), 4.22 (q, J = 6.9 Hz, 12H), 1.29 (t, J = 6.9 Hz, 18H);
13C NMR (75 MHz, CDCl3) δ 161.6, 158.2, 100.1, 43.0, 13.3; MS
J = 8.0 Hz), 7.83 (d, 3H, J = 8.0 Hz), 7.69 (d, 3H, J = 7.6 Hz), 7.54−
7.46 (m, 6H), 7.37 (d, 3H, J = 6.4 Hz), 7.32−7.27 (m, 6H), 6.79 (d,
3H, J = 7.6 Hz), 6.75 (d, 3H, J = 8.0 Hz,), 6.56 (s, 3H), 5.95 (s, 6H),
3.36 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 162.0, 159.0, 156.2,
155.1, 138.2, 133.8, 133.7, 131.3, 128.8, 127.5, 126.1, 125.7, 125.3,
124.7, 123.3, 112.9, 112.1, 92.2, 18.2, 34.9; MS (MALDI-TOF) m/z
1019 [M + H]+. Anal. Calcd. for C63H51N15: C, 74.32; H, 5.05; N,
20.63. Found: C, 73.93; H, 5.10; N, 20.25.
5j. Compound 5j was obtained as a white powder (290 mg, 35%):
mp 226−227 °C; IR (KBr) ν 3037, 1599, 1566, 1526, 1436, 1220, 843
1
cm−1; H NMR (400 MHz, CDCl3) δ 8.58 (s, 3H), 8.46 (d, 3H, J =
8.8 Hz), 8.16 (m, 6H), 8.10 (d, 3H, J = 9.2 Hz), 8.02−7.95 (m, 15H),
7.16 (t, 3H, J = 7.8 Hz), 6.71 (d, 3H, J = 8.0 Hz), 6.65 (d, 3H, J = 8.0
Hz,), 6.51 (s, 3H), 6.20 (s, 6H), 3.37 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 162.2, 162.1, 158.8, 156.3, 155.0, 138.2, 132.0, 131.4, 130.9,
130.5, 128.7, 127.6, 127.4, 127.1, 126.1, 125.9, 125.14, 125.07, 124.95,
124.9, 124.6, 123.0, 113.1, 112.0, 92.4, 48.4, 35.0; MS (MALDI-TOF),
neg m/z 1238 [M − H]−. Anal. Calcd for C81H57N15: C, 78.43; H,
4.63; N, 16.94. Found: C, 78.17; H, 4.70; N, 16.75.
(MALDI-TOF) m/z 727 [M + H]+. Anal. Calcd for C36H42N18: C,
59.49; H, 5.82; N, 34.69. Found: C, 59.35; H, 5.78; N, 34.83. Slow
evaporation of the solvent from a mixture of petroleum ether and ethyl
acetate gave a single crystal suitable for X-ray diffraction analysis.
General Procedure for the Synthesis of Azacalix[3]pyridine-
[3]pyrimidines 5e−5o. Under argon protection, a mixture of 8a−8k
(2 mmol) and Pd2(dba)3 (138 mg, 0.15 mmol), dppp (123 mg, 0.3
mmol), and sodium t-butoxide (288 mg, 3 mmol) in anhydrous 1,4-
dioxane (200 mL) was refluxed for 3 h. The reaction mixture was
cooled down to room temperature and filtered through a Celite pad.
The filtrate was concentrated under vacuum, and the residue was
dissolved in dichloromethane (100 mL) and washed with brine (3 ×
25 mL). The aqueous phase was re-extracted with dichloromethane (3
× 20 mL), and the combined organic phase was dried over anhydrous
MgSO4. After removal of solvent, the residue was chromatographed on
a silica gel column using a mixture of petroleum ether and ethyl acetate
(v:v = 1:1) as the mobile phase to give products 5e−5o.
5k. Compound 5k was obtained as a white solid (249 mg, 41%):
mp 280−282 °C; IR (KBr) ν 3030, 2956, 1601, 1566, 1526, 1477,
1
1435, 1419, 1265, 1233, 1187, 1161, 982 cm−1; H NMR (400 MHz,
CDCl3) δ 8.69 (s, 3H), 7.41 (t, 3H, J = 8.0 Hz), 7.30−7.17 (m, 15H),
6.79 (d, 3H, J = 8.0 Hz), 6.71 (d, 3H, J = 8.0 Hz,), 6.52 (s, 3H), 4.44
(t, 6H, J = 7.6 Hz), 3.66 (s, 9H), 3.04 (t, 6H, J = 7.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 162.5, 161.9, 159.2, 156.2, 155.8, 139.5, 137.4,
129.0, 128.4, 126.2, 111.7, 111.3, 93.0, 49.0, 35.2, 34.7; MS (MALDI-
TOF) m/z 910 [M + H]+. Anal. Calcd. for C54H51N15: C, 71.27; H,
5.65; N, 23.09. Found: C, 70.95; H, 5.79; N, 22.75.
5l. Compound 5l was obtained as a colorless block (201 mg, 32%):
mp 182−184 °C; IR (KBr) ν 2940, 2227, 1601, 1567, 1527, 1440,
5e. Compound 5e was obtained as colorless needles (229 mg,
1
54%): mp > 300 °C; IR (KBr) ν 1601, 1565, 1525, 1429 cm−1; H
1
1220, 1166, 983, 964 cm−1; H NMR (400 MHz, CDCl3) δ 8.56 (s,
NMR (300 MHz, CDCl3) δ 8.61 (d, J = 0.6 Hz, 3H), 7.38 (t, J = 8.1
Hz, 3H), 6.77 (d, J = 8.1 Hz, 6H), 6.47 (s, 3H), 3.57 (s, 18H); 13C
NMR (75 MHz, CDCl3) δ 162.1, 158.8, 156.2, 137.8, 111.6, 92.3,
34.9; MS (MALDI-TOF) m/z 662 [M + Na]+, 640 [M + H]+. Anal.
Calcd. for C33H33N15: C, 61.96; H, 5.20; N, 32.84. Found: C, 61.99; H,
5.20; N, 32.80.
5f. Compound 5f was obtained as a colorless block (263 mg, 55%):
mp > 300 °C; IR (KBr) ν 1600, 1566, 1523, 1471, 1425, 1224, 1157
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 3H), 7.40 (t, 3H, J = 7.8
Hz), 6.80−6.77 (m, 6H), 6.49 (s, 3H), 6.01−5.91 (m, 3H), 5.16 (dd,
3H, J1 = 17.2 Hz, J2 = 1.6 Hz), 5.06 (dd, 3H, J = 10.2 Hz, J = 1.4 Hz),
5.82 (d, 6H, J = 5.6 Hz), 3.56 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
162.5, 161.8, 159.1, 156.2, 155.4, 137.7, 134.4, 116.6, 111.8, 111.6,
92.9, 49.4, 34.8; MS (MALDI-TOF) m/z 719 [M + H]+. Anal. Calcd.
for C39H39N15: C, 65.25; H, 5.48; N, 29.27. Found: C, 65.23; H, 5.54;
N, 29.16.
3H),7.54−7.42 (m, 15H), 6.81−6.79 (m, 6H), 6.57 (s, 3H), 5.47 (s,
6H), 3.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 162.6, 161.7,
159.2, 156.3, 155.2, 144.8, 137.9, 132.2, 128.4, 118.9, 111.9, 111.6,
110.8, 92.9, 50.0, 34.7; MS (MALDI-TOF) m/z 943 [M + H]+. Anal.
Calcd. for C54H42N18: C, 68.78; H, 4.49; N, 26.74. Found: C, 68.78; H,
4.57; N, 26.46. Slow diffusion of benzene into CCl4 solution gave a
single crystal suitable for X-ray diffraction analysis.
5m. Compound 5m was obtained as a white powder (294 mg,
46%): mp 151−152 °C; IR (KBr) ν 2948, 2936, 2834,1600, 1565,
1525, 1512, 1436, 1425, 1396, 1246, 1218, 1160 cm−1; 1H NMR (400
MHz, CDCl3) δ 8.61 (d, 3H, J = 0.8 Hz), 7.35−7.30 (m, 9H), 6.77−
6.72 (m, 9H), 6.68 (d, 3H, J = 7.6 Hz), 6.47 (s, 3H), 6.36 (s, 6H), 3.73
(s, 9H), 3.52 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 162.4, 161.9,
159.0, 158.6, 156.1, 155.5, 137.8, 131.0, 129.4, 113.6, 112.0, 111.6,
93.2, 55.3, 49.7, 34.9; MS (MALDI-TOF) m/z 958 [M + H]+. Anal.
Calcd. for C54H51N15O3: C, 67.70; H, 5.37; N, 21.93.Found: C, 67.92;
H, 5.49; N, 21.69.
5n. Compound 5n was obtained as a colorless block (244 mg,
46%): mp 282−283 °C; IR (KBr) ν 1598, 1567, 1525, 1475, 1444,
1421, 1212, 1157 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 3H),
7.43 (t, 3H, 8.0 Hz), 6.80(d, 6H, J = 8.0 Hz), 6.52 (s, 3H), 6.00−5.90
(m, 3H), 5.13 (dd, 6H, J = 17.0 Hz, J = 1.4 Hz), 5.05 (dd, J = 10.2 Hz,
J = 1.4 Hz), 4.79 (d, 12H, J = 4 Hz), 3.73 (s, 9H), 3.52 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 162.0, 159.3, 155.5, 137.7, 134.4, 116.6,
111.9, 93.2, 49.3; MS (MALDI-TOF) m/z 796 [M + H]+. Anal. Calcd
for C45H45N15: C, 67.90; H, 5.70; N, 26.40. Found: C, 67.64; H, 5.60;
N, 26.24. Slow evaporation of the solvent from a mixture of petroleum
ether and ethyl acetate gave a single crystal suitable for X-ray
diffraction analysis.
5g. Compound 5g was obtained as a white solid (301 mg, 52%):
mp 161−162 °C; IR (KBr) ν 1600, 1566, 1526, 1437, 1220, 1158
1
cm−1; H NMR (400 MHz, CDCl3) δ 8.59 (s, 3H), 7.37−7.32 (m,
9H), 7.23−7.16 (m, 9H), 6.74 (d, 3H, J = 8.0 Hz), 6.69 (d, 3H, J = 7.6
Hz), 6.51 (s, 3H), 5.43 (s, 6H), 3.49 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 162.5, 162.0, 159.1, 156.2, 155.5, 139.0, 137.8, 128.3, 127.9,
126.9, 111.9, 111.6, 93.1, 50.3, 34.8; MS (MALDI-TOF) m/z 869 [M
+ H]+. Anal. Calcd. for C51H45N15: C, 70.57; H, 5.23; N, 24.2. Found:
C, 70.44; H, 5.32; N, 23.88.
5h. Compound 5h was obtained as a white solid (292 mg, 43%):
mp 168−169 °C; IR (KBr) ν 3054, 1600, 1565, 1526, 1429, 1400,
1
1220 cm−1; H NMR (400 MHz, CDCl3) δ 8.61 (s, 3H), 7.79−7.70
(m, 12H), 7.55 (dd, 3H, J = 8.4 Hz, J = 1.6 Hz), 7.43−7.38 (m, 6H),
7.34 (t, 3H, 8.0 Hz), 6.77−6.74 (m, 6H), 6.57 (s, 3H), 5.60 (s, 6H),
3.51 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 162.6, 162.1, 159.1,
156.3, 155.5, 137.8, 136.6, 133.4, 132.7, 127.9, 127.7, 127.6, 126.8,
126.3, 125.9, 125.5, 112.1, 111.7, 93.0, 50.5, 34.8; MS (MALDI-TOF)
m/z 1019 [M + H]+. Anal. Calcd. for C63H51 shyN15: C, 74.32; H,
5.05; N, 20.63. Found: C, 74.08; H, 5.04; N, 20.59.
5o. Compound 5o was obtained as a white powder (244 mg, 61%):
mp 268−269 °C; IR (KBr) ν 3033, 1598, 1565, 1525, 1474, 1440,
1
1278, 1206, 1162 cm−1; H NMR (400 MHz, d6-DMSO) δ 8.45 (s,
3H), 7.69 (t, 3H, J = 7.6 Hz), 7.18−7.09 (m, 36H), 6.48 (s, 3H), 5.30
(s, 12H); 13C NMR (100 MHz, CDCl3) δ 162.3, 159.4, 138.8, 137.5,
128.3, 127.7, 126.9, 111.9, 93.4, 50.1; MS (MALDI-TOF) m/z 1096
[M + H]+. Anal. Calcd for C69H57N15: C, 75.59; H, 5.24; N, 19.16.
Found: C, 75.19; H, 5.31; N, 19.16. Slow evaporation of the solvent
5i. Compound 5i was obtained as a white solid (312 mg, 46%): mp
268−269 °C; IR (KBr) ν 3046, 1599, 1567, 1525, 1474, 1437, 1397,
1221 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 3H), 8.17 (d, 3H,
3570
dx.doi.org/10.1021/jo5003714 | J. Org. Chem. 2014, 79, 3559−3571

The Journal of Organic Chemistry
Article
from a mixture of petroleum ether and ethyl acetate gave a single
crystal suitable for X-ray diffraction analysis.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Fluorescence titration; X-ray crystallographic files of 5a−5d, 5l,
5n, 5o, [5d·(C60)2], [5f2·C60], [5j·C60], [5n2·C60], and [5n2·
C70]; UV−vis spectra of 5a−5o; and 1H and 13C NMR spectra
of new products. This material is available free of charge via the
Internet at http://pubs.acs.org.
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H.-W.; Zheng, Q.-Y.; Wang, M.-X. Chem.Eur. J. 2006, 12, 9262.
(d) Van Rossom, W.; Ovaere, M.; Van Meervelt, L.; Dehaen, W. Org.
Lett. 2009, 11, 1681.
AUTHOR INFORMATION
■
Corresponding Author
(16) Wang, Q.-Q.; Wang, D.-X.; Ma, H.-W.; Wang, M.-X. Org. Lett.
2006, 8, 5967.
*E-mail: wangmx@mail.tsinghua.edu.cn.
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Tetrahedron 2009, 65, 87 and references cited therein.
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Q.-Y.; Wang, M.-X. Chem.Eur. J. 2006, 12, 9262. (b) Gong, H.-Y.;
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2007, 13, 7791.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Yang Liu, En-Xuan Zhang, and Zi-Tian Wang for
their assistance in doing experiments. We also thank the
National Natural Science Foundation of China (21320102002,
21121004, 91127008, 21272239), the Ministry of Science and
Technology (2011CB932501, 2013CB834504), Tsinghua
University, and the Chinese Academy of Sciences for financial
support.
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