Methylazacalixpyridines: Remarkable bridging nitrogen-tuned conformations and cavities with unique recognition properties

Article abstract of DOI:10.1002/chem.200600377

Methylazacalix[n]pyridines (n = 4, 8) and methylazacalix[m]arene[n] pyridines (m = n = 2, 4) have been synthesized by a convenient fragment coupling approach starting from 2,6-dibromopyridine, 2,6-diaminopyridine, and benzene-1,3-diamine. Thanks to the in

Full text of DOI:10.1002/chem.200600377

DOI: 10.1002/chem.200600377
Methylazacalixpyridines: Remarkable Bridging Nitrogen-Tuned
Conformations and Cavities with Unique Recognition Properties
Han-Yuan Gong, Xiao-Hang Zhang, De-Xian Wang, Hong-Wei Ma, Qi-Yu Zheng, and
[
a]
Mei-Xiang Wang*
Abstract: Methylazacalix[n]pyridines
n = 4, 8) and methylazacalix[m]are-
ne[n]pyridines (m = n = 2, 4) have
been synthesized by a convenient frag-
ment coupling approach starting from
Whilst in solution it is fluxional, in the
solid state methylazacalix[4]pyridine
adopts a 1,3-alternate conformation
with a C2v symmetry in which every
two bridging nitrogen atoms conjugate
with one pyridine ring. After protona-
tion, the methylazacalix[4]pyridinium
each protonated methylazacalix[4]pyri-
dine, however, varies finely to accom-
modate guest species of different size
and geometry, such as planar DMF or
(
ꢀ
ꢀ
HO CCO ion, a twisted HO CCO
2
2
2
2
ꢀ
2,6-dibromopyridine, 2,6-diaminopyri-
ion, and a tetrahedral ClO4 ion. As
giant macrocyclic hosts, both methyl-
azacalix[8]pyridine and methylazaca-
lix[4]arene[4]pyridine interact efficient-
ly with fullerenes C60 and C70 through
van der Waals forces. Their ease of
preparation, versatile conformational
structures, and recognition properties
make these multinitrogen-containing
calixarenes or cyclophanes unique and
powerful macrocyclic hosts in supramo-
lecular chemistry.
dine, and benzene-1,3-diamine. Thanks
to the intrinsic electronic nature ofni-
species has
a different conjugation
2
trogen, which can adopt mainly sp hy-
system ofits ofur bridging nitrogen
atoms, yielding the similar twisted 1,3-
alternate conformations with an ap-
bridization, allowing it variously to
conjugate, partially conjugate, or not
conjugate with the adjacent one or two
pyridine rings, the resulting nitrogen-
bridged calixpyridine derivatives act as
a unique class ofmacrocyclic host mol-
ecules with intriguing conformational
structures offering fine-tunable cavities
and versatile recognition properties.
proximate S symmetry. The cavity of
4
Keywords: anion
azacalixarenepyridines
calixpyridines
recognition
·
aza-
·
·
A
H
R
U
G
·
cavity
A
H
R
U
G
Introduction
therefore to alter and improve their selectivities towards
[4]
recognition ofvarious guest molecules. This has in fact re-
sulted in a few intriguing macrocycles such as calixpyr-
[
1]
Since Gutscheꢀs milestone work in the 1970s, calixarene
chemistry has developed to become an indispensable part of
[
5]
[6]
[7]
roles, calixpyridines, and other calixheteroaromatics. In
[2]
[5]
supramolecular chemistry. Whilst efforts in derivatizing
particular, calixpyrroles have been shown by Sessler to be
[
3]
the basic calixarene skeletons are proliferating, one ofthe
more recent developments in this field is the construction of
new calixarenes by replacing their phenol units with other
heteroarene species, in order to tune their cavities and
powerful anion receptors. In contrast with these prepara-
tions of coarsely tuned macrocyclic molecules, construction
ofcalixarenes with finely tunable cavities, through substitu-
tion oftheir methylene bridges with heteroatoms, has until
[4]
recently remained largely unexplored because ofsynthetic
[8]
obstacles, except in the case oftetrathiacalix[4]arenes.
[
a] H.-Y. Gong, X.-H. Zhang, D.-X. Wang, H.-W. Ma, Q.-Y. Zheng,
Prof. Dr. M.-X. Wang
Beijing National Laboratory for Molecular Sciences
Laboratory ofChemical Biology, Institute ofChemistry
Chinese Academy ofSciences, Beijing 100080 (China)
Fax : (+86)10-6256-4723
Nevertheless, treatment of1,3-dichloro-4,6-dinitrobenzene
with resorcinol, for example, gave a 13% yield of a tetrani-
[9]
II
tro-substituted tetraoxocalix[4]arene, whilst both the Pd -
catalyzed cyclic oligomerization of3-bromo- N-methylani-
[10]
0
line
and the Pd -catalyzed condensation ofbenzene-1,3-
E-mail: mxwang@iccas.ac.cn
[11]
diamine and 1,3-dibromobenzene derivatives
produced
Supporting information (experimental section, optimization of the
1
13
mixtures ofazacalix[ n]arenes (n = 3–8) in very low yields.
Silicon-bridged calixarenes have been synthesized by cou-
pling ofphenol or 1,3-dibromobenzene with dichlorodimeth-
syntheses of 10, 11, 13, and 14 and their H/ C NMR and UV/Vis
spectra, X-ray structure of 10) for this article is available on the
WWW under http://www.chemeurj.org/ or from the author.
9262
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 9262 – 9275

FULL PAPER
[
12]
ylsilane in 16% or 12% yields, respectively,
and a few
forded a mixture of methylazacalix[4]pyridine (1.5%) and
[17]
heteroatom-bridged calixheteroaromatics have also been
prepared by incorporating further heteroatoms into hetero-
aromatics. Among these, silicon-bridged calix[n]phospha-
arenes are notable because they act as ligands with strong
p-acceptor properties. In almost all cases, however, very
low and impractical chemical yields (<20%) were obtained
for heteroatom-bridged macrocyclic compounds.
Over a year ago we communicated an effective synthesis
ofazacalix[ m]arene[n]pyridines (m = n = 2, 4) through
stepwise coupling reactions between benzene-1,3-diamine
The fragment cou-
pling strategy was later successfully applied in the efficient
and practical synthesis ofa number ofoxygen- and/or nitro-
methylazacalix[6]pyridine (10%).
Having considered the
importance ofthe development ofmolecular diversity of
macrocyclic receptors and the success ofthe synthesis of
[4]
[19]
A
C
H
T
R
E
U
N
G
aza- and/or oxa-bridged calix[2]arene[2]triazines,
we im-
[13]
plemented a fragment coupling approach starting from the
simple 2,6-dibromopyridine and 2,6-diaminopyridine or ben-
zene-1,3-diamine. Condensation of2,6-diaminopyridine ( 1)
or benzene-1,3-diamine (2) with 2,6-dibromopyridine (3) in
the presence ofa large excess (5–10 equivalents) ofa strong
base such as potassium tert-butoxide afforded the linear
trimer products 4 or 5 in good to excellent yields. The use of
smaller amounts ofpotassium tert-butoxide (e.g., 2.4 equiva-
lents) had a detrimental effect on the formation of 4 or 5,
[12–17]
[18]
and 2,6-dibromopyridine fragments.
[19]
2
gen-bridged calix[2]arene[2]triazines.
Following a similar
fragment coupling approach, two Japanese groups have very
always yielding the dimers N -(6-bromopyridin-2-yl)pyri-
1
dine-2,6-diamine or N -(6-bromopyridin-2-yl)benzene-1,3-
recently reported the syntheses of N-methylazacalix[4]ar-
diamine as the major products. Further treatment of 4 or 5
[
20]
[21]
ene
and N-(p-tolyl)azacalix[3]pyridine
derivatives in
with methyl iodide under basic conditions resulted in the
2
6
moderate to good yields.
high-yielding formation of N ,N -bis(6-bromopyridin-2-yl)-
[19]
2
6
1
3
As demonstrated in our previous report, the combina-
tion of the electronic and steric effects of the bridging
oxygen and nitrogen atoms regulates the cavities of1,3-al-
ternate conformers of aza- and/or oxa-bridged calix[2]ar-
N ,N -dimethylpyridine-2,6-diamine (6) and N ,N -bis(6-
1
3
bromopyridin-2-yl)-N ,N -dimethylbenzene-1,3-diamine (7)
(see Supporting Information). The preparation of 6 and 7
can be facilitated in a simple one-pot operation: coupling
between aromatic diamines 1 or 2 and 2,6-dibromopyridine
(3), followed straightforwardly—without isolation and puri-
fication of 4 or 5—by the methylation reaction with methyl
iodide produced the desired 6 or 7 in yields of84% or 78%,
respectively (Scheme 1).
A
C
H
T
R
E
U
N
G
ene[2]triazines. We envisaged that the introduction ofhet-
eroatoms, particularly amino nitrogen groups, as the bridge
linkages in calixpyridines should give rise to different con-
formations with finely bridge-tunable macrocyclic cavities,
since the bridging amino nitrogen atoms might adopt either
2
3
sp or sp hybrid configurations, thus allowing them either to
enter into or not to enter into conjugation with the neigh-
boring pyridines. As multinitrogen-containing macrocyclic
molecules, the resulting azacalixpyridines might also exhibit
novel and unique recognition properties that would be sub-
ject to pH regulation. As part ofour study ofthe supramo-
lecular chemistry ofheteroatom-bridged calixaromatics or
cyclophanes, we report here a convenient fragment coupling
method for the synthesis of methylazacalix[n]pyridines (n =
To synthesize methylazacalix[4]pyridine 10, a macrocyclic
coupling reaction between trimer 6 and 2,6-bis(methylami-
no)pyridine (8) by the palladium-catalyzed aryl amination
[
22]
[23]
procedure developed by Buchwald and Hartwig was at-
0
tempted. Pd -catalyzed cyclocondensation between 6 and 8
indeed proceeded smoothly to give methylazacalix[4]pyri-
dine 10. Interestingly, in addition to the designed 1+1 cou-
pled product 10, the methylazacalix[8]pyridine cyclic homo-
logue 11 was also isolated. The formation of product 11 was
interpreted as the result ofthe macrocyclic coupling reac-
tion between linear trimer 6 and the pentamer intermediate
12, which was also isolated from the reaction mixture. At
this stage, however, it is hard to rule out another possible re-
action pathway that comprises a double cross-coupling reac-
tion between diamine 8 and two units oflinear trimer 6 (1+
2) to give a dibromo-substituted linear heptamer, followed
by its macrocyclic coupling reaction with another unit ofdi-
amine 8. To optimize the formation of azacalix[n]pyridine
products, the reaction conditions were screened in terms of
catalyst, base, substrate concentration, reactant ratio, sol-
vent, reaction temperature, and reaction period (see Table 1
and Table 1 in the Supporting Information). It was found
that the reaction outcomes were strongly dependent upon
the conditions employed: to achieve an effective macrocy-
4, 8) and methylazacalix[m]arene[n]pyridines (m = n = 2,
4) and show for the first time that the bridging amino nitro-
gen atoms can indeed form different conjugation systems
with their adjacent pyridines to provide finely tunable cavity
structures in the absence and in the presence ofa guest spe-
cies. It is also demonstrated in detail that the larger macro-
cyclic host molecules methylazacalix[8]pyridine and methyl-
azacalix[4]arene[4]pyridine are powerful spectrophotometric
detection agents for the recognition of fullerenes C60 and
C .
70
Results and Discussion
Synthesis: Retrosynthetically, azacalixpyridines might be
synthesized by several routes: cyclic oligomerization of2-
bromo-6-(methylamino)pyridine in the presence ofa palla-
dium catalyst, for example, gave methylazacalix[6]pyridine
clic coupling reaction, the combination of[Pd (dba) ] (dba=
A
T
E
G
2 3
trans,trans-dibenzylideneacetone, 1,3-bis(diphenylphosphi-
no)propane (dppp), and NaOtBu in 1,4-dioxane at 80–
1028C appeared favorable (Scheme 1). As summarized in
Table 1, a total yield of53.1%—33.8% ofmethylazacalix[4]-
0
in 8% yield, whilst a Pd -catalyzed condensation between
2,6-dibromopyridine and 2,6-bis(methylamino)pyridine af-
Chem. Eur. J. 2006, 12, 9262 – 9275
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9263

M.-X. Wang et al.
Scheme 1. Synthesis ofcalix[ n]pyridines 10 (n = 4) and 11 (n = 8) and calix[m]arene[n]pyridines 13 (m = n = 2) and 14 (m = n = 4).
[
a]
Table 1. Synthesis ofmethylazacalixpyridines 10 and 11.
to an increased yield of 14
(39.5%), whilst a higher cata-
lyst loading resulted in the se-
lective formation of 13 (see
Table 2 in the Supporting In-
formation). Apart from the
higher chemical yields, the
fragment coupling approaches
developed in our study have
the advantage over other
[
b]
[b]
[c]
[c]
[c]
Entry Catal. (%)
dppp [%]
Solvent
Temp. [8C] Time [h] 10 [%]
11 [%]
12 [%]
1
2
3
4
5
6
A
C
H
T
R
E
U
N
G
[Pd
[Pd
[Pd
[Pd
PdCl
Pd
2
A
C
H
T
R
E
U
N
G
(dba)
(dba)
(dba)
(dba)
3
3
3
] (10) 20
] (15) 30
] (15) 30
] (20) 40
50
toluene
reflux
1,4-dioxane reflux
1,4-dioxane 80
1,4-dioxane reflux
1,4-dioxane reflux
1,4-dioxane reflux
32
2.5
24
2.5
24
4.5
20.5
33.8
16.9
35.8
31.5
6.4
18.4
19.3
20.4
15.4
16.0
3.3
13.8
11.7
8.4
4.3
10.6
48.5
A
C
H
T
R
E
U
N
G
2
A
C
H
T
R
E
U
N
G
A
C
H
T
R
E
U
N
G
2
ACHTREUNG
A
C
H
T
R
E
U
N
G
2
A
C
H
T
R
E
U
N
G
3
2
(50)
A
C
H
T
R
E
U
N
G
(OAc)
2
(30)
30
[
[
a] NaOtBu (30%) was used as a base. [b] Percentage relative to reactants 6 and 8, which were in a 1:1 ratio.
c] Yield ofisolated product.
methods ofconstructing
a
pyridine 10 and 19.3% ofmethylazacalix[8]pyridine 11—
was obtained in 1,4-dioxane at reflux (Table 1, entry 2). A
higher catalyst loading (20%) slightly increased the chemi-
cal yield of 10 (35.8%, Table 1, entry 4), whilst a lower reac-
tion temperature favored the formation of 11 (Table 1,
structurally diverse range ofnovel heteroatom-bridged calix-
aromatics or cyclophanes.
[10,11,17]
Structures: Methylazacalix[n]pyridines 10 and 11 and meth-
ylazacalix[m]arene[n]pyridines 13 and 14 are crystalline
products, readily giving single crystals suitable for X-ray dif-
fraction analysis. This allowed us to study their structures in
the solid state (Table 2). In contrast with the solid-state
entry 3). PdCl , a cheaper and readily available palladi-
2
um(II) catalyst, was also able to effect the macrocyclic cou-
pling reaction, yielding 10 and 11 in acceptable yields, al-
though a higher catalyst loading (50%) was necessary
[10a]
structures ofazacalix[4]arene
and calix[4]pyridine[6],
(
Table 1, entry 5). Under identical conditions, however, Pd-
methylazacalix[4]pyridine 10 has a 1,3-alternate conforma-
tion with an approximate C2v symmetry (Figure 1). Several
intriguing structural features of 10 can be noted:
ACHTREUNG
(OAc) afforded the linear pentamer 12 as the major prod-
2
uct (Table 1, entry 6). The macrocyclic coupling reaction be-
1
3
tween linear trimer 7 and N ,N -dimethyl-benzene-1,3-di-
amine (9) proceeded equally well in boiling 1,4-dioxane, to
furnish methylazacalix[m]arene[n]pyridines 13 (m = n = 2)
and 14 (m = n = 4) in 21% and 22.5% yields, respective-
1) A pair of opposite pyridine rings is almost face-to-face
o
parallel, like a clip, with a dihedral angle of21.9 . The
N(1) and N(1A) and C(3) and C(3A) distances between
the two parallel pyridines are 4.620 Š and 3.422 Š, re-
[
18]
ly. Again, a lower reaction temperature (808C) gave rise
9264
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ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 9262 – 9275

Methylazacalixpyridines
FULL PAPER
Table 2. X-ray crystallographic data for macrocyclic host molecules and their complexes.
Compound 10·CH
3
CN
11
10·HClO
4
·DMF 10·2HClO
4
10·HClO
4
·H
2
Bi(OH)Cl
4
10·2HO
2
CCO
2
H
13·HClO
4
·CH
2
Cl
2
2 2
13·2HI·I ·CH OH
2
·H O
empirical
formula
C
26
H
27
N
9
C
24
H
24
N
8
C
27
H
32ClN
9
O
5
C
24
H
26Cl
2
N
8
O
8
C
24
H
28BiCl
5
N
8
O
5
C
28
H
28
N
8
O
9
C
27
H
29
C
l3
N
6
O
4
27 32 4 6
C H I N O
M
r
465.57
424.51
598.07
625.43
894.77
620.58
607.91
964.19
crystal size 0.40”0.37”0.32 0.77”0.69”0.11 0.37”0.25”0.04 0.52”0.49”0.11 0.61”0.14”0.09
0.33”0.28”0.14 0.37”0.10”0.08
0.51”0.35”0.27
3
[
mm ]
crystal
system
space
group
a [Š]
b [Š]
c [Š]
a [8]
orthorhombic
orthorhombic
triclinic
monoclinic
monoclinic
triclinic
orthorhombic
triclinic
¯
¯
Pmmn
Pccn
P1
P2(1)/n
P2(1)/c
P1
Pna2(1)
P1
11.7199(7)
16.6292(9)
6.1808(4)
90
90
90
1204.59(12)
1.284
2
12.0387(5)
33.9080(6)
10.406(2)
90
90
90
4247.8(9)
1.328
8
9.6632(4)
11.0917(7)
14.0602(6)
83.5930(17)
70.534(3)
85.995(2)
1411.12(12)
1.408
13.7975(6)
13.7100(6)
14.4855(8)
90
91.0020(10)
90
2739.7(2)
1.516
4
10.700(2)
11.606(2)
26.268(5)
90
96.14(3)
90
3243.5(11)
1.832
4
9.5691(19)
11.747(2)
13.787(3)
69.43(3)
82.24(3)
75.44(3)
1402.6(5)
1.469
15.774(3)
13.473(3)
13.507(3)
90
90
90
2870.7(10)
1.407
4
9.1832(18)
11.184(2)
16.038(3)
97.71(3)
92.98(3)
91.33(3)
1629.3(6)
1.965
b [8]
g[8]
V [Š ]
3
ꢀ
3
1
[gcm ]
Z
2
2
2
T [K]
293(2)
0.0506
0.150
0.0677
0.1
293(2)
0.0683
0.1900
0.1028
0.2057
1.018
293(2)
0.0697
0.1987
0.0957
0.2131
1.044
293(2)
0.0516
0.0564
0.1887
0.0623
0.830
293(2)
0.0392
0.0740
0.0769
0.0967
0.980
293(2)
0.0827
0.2064
0.1708
0.2477
1.006
293(2)
0.0610
0.0659
0.2300
0.0864
0.742
293(2)
0.0414
0.1304
0.0507
0.1373
1.063
R1, wR2
I>2s(I)
R1, wR2
(
all data)
quality of
fit
0.9
spectively, indicating weak p–p interaction between
these two nearly aligned pyridine rings. The other two
pyridine rings, however, have an edge-to-edge orienta-
tion with a dihedral angle of79.5 8. The N(2)ꢀN(2A) and
C(6)ꢀC(6A) distances are 4.853 and 9.063 Š, respective-
It is also worth noting that, in the crystallographic cell
(see Figure 1 in Supporting Information) molecules 10 ar-
range with high symmetry. The parallel array is assembled
layer-by-layer, yielding two types ofchannels: one is the
endo channel, or inherent channel, formed by the internal
surface of 10, while the other, the exo channel, is surround-
ed by the external surfaces of four 10 units. In each exo
channel, one solvent molecule (acetonitrile) is included. The
ly.
2
3
4
) All four pyridine nitrogens and the four bridging nitro-
gens lie nearly in a plane. The distance between the two
neighboring pyridine nitrogen atoms is 3.353 Š, and re-
pulsion between the two lone pairs ofelectrons on two
nitrogen atoms is avoided.
2
same sp electronic configuration of the bridging nitrogens
and the same conjugation systems were observed in the crys-
tal structure ofmethylazacalix[2]arene[2]pyridine 13, which
adopts a twist 1,3-alternate conformation with two isolated
benzene rings in a nearly parallel arrangement and two
edge-to-edge orientated conjugated 2,6-bis(methylamino)-
) Each bridging amino moiety adopts a near-planar config-
uration, with the sum ofthe three C-N-C angles being
3
53.18 and the offset distance of nitrogen and the C-C-C
[18]
plane being 0.219 Š, indicating that these four nitrogens
pyridine [-2-N(Me)-Py-6-N(Me)-] segments.
While methylazacalix[4]arene[4]pyridine 14 adopts
double-ended spoon conformation with large oval
2
have each adopted an approximate sp configuration.
a
) The four methyl groups on the bridging amino groups
can be divided into two pairs, each ofwhich is nearly co-
planar with one ofthe two fl attened-orientated pyridines
and s-trans-configured with respect to the pyridine nitro-
gens (the torsion angle ofC(7)-N(3)-C(4)-N(2) is 20.8 8).
As a result, the lone pairs ofelectrons on the fo ur bridg-
ing nitrogens conjugate with the two flattened-orientated
pyridines (CringꢀN = 1.389 Š) and do not enter into con-
a
[18]
cavity, methylcalix[8]pyridine 12 gives a pleated loop with
a Ci symmetry in the solid state. Unlike in 11, 13, and 14—
in which every two bridging amino nitrogens conjugate with
one pyridine ring to form the conjugated 2,6-bis(methylami-
no)pyridine [-2-N(Me)-Py-6-N(Me)-] unit—the bridging ni-
trogens in 12 produce different types of conjugation: some
bridging nitrogens, including N(2), N(6), N(2A), and N(6A),
for example, are partially conjugated with their two adjacent
pyridine rings, meaning that all NꢀC bond lengths are in the
jugation with the two parallel pyridine rings (C ꢀN =
ring
1
.436 Š). In other words, the cavity of 10 in its crystal
structure can be viewed as the product ofa cyclic array
oftwo isolated pyridine rings and two conjugated 2,6-
bis(methylamino)pyridine [-2-N(Me)-Py-6-N(Me)-] seg-
ments arranged in a 1,3-alternate fashion.
1.401–1.408 Š range, whilst on the other hand, other bridg-
ing nitrogens, such as N(4), N(8), N(4A), and N(8A), each
conjugate with only one ofthe neighboring pyridine rings,
with the bond lengths ranging from 1.386 Š to 1.394 Š. No-
Chem. Eur. J. 2006, 12, 9262 – 9275
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9265

M.-X. Wang et al.
Figure 2. Crystal structure ofmethylazacalix[8]pyridine 11. Top view. Se-
lected bond lengths [Š]: C(5)ꢀN(2) 1.408 A, N(2)ꢀC(6) 1.401, C(10)ꢀ
N(4) 1.394, N(4)ꢀC(11) 1.436, C(15)ꢀN(6) 1.403, N(6)ꢀC(16) 1.402,
C(20)ꢀN(8) 1.386, N(8a)ꢀC(1) 1.414; selected interatomic [Š]:
N(5A)···N(5) 12.777, C(13)···C
C(24)···C(24A) 3.743.
A
H
R
U
G
AHCTREUNG
very fluxional in solution, and that the rates of interconver-
sion ofvarious co no frmational structures might be very
rapid relative to the NMR timescale. The high conforma-
tional mobility (relative to conventional calix[n]arenes de-
rived from p-tert-butylphenol and formaldehyde) of the aza-
calixpyridines is most probably due to the lack ofsteric hin-
drance and the intramolecular hydrogen bonds, both being
key factors in stabilizing conformational structures of calix-
[2]
[
n]arenes in solution. The stability gained from the conju-
gation effect of the bridging nitrogen atoms with their
neighboring aromatic rings seems to be insufficient to pre-
vent the rotation ofaromatic rings (both pyridine and ben-
zene rings) around the meta–meta axes or through the annu-
lus. Such molecular flexibility might offer great advantages
in the self-regulation of the conformation and cavity through
dynamic adjustment ofthe bridging nitrogens ’ electronic
configurations and conjugations when they are allowed to
interact with or recognize the guest species (vide infra).
Figure 1. Crystal structure ofmethylazacalix[4]pyridine 10: A) top view
and B) side view. Selected bond lengths [Š]: C(1)ꢀN(3) 1.436, C(4)ꢀN(3)
1
.389; selected interatomic distances [Š]: C(3)···C(3A) 3.422,
N(1)···N(1A) 4.620, N(2)···N(2A) 4.835, C(6)···C(6A) 9.063, N(1)···N(2)
.353.
3
tably, methyl groups C(24) and C(24A) on the bridging ni-
A
H
R
N
trogens N(8) and N(8A) are s-cis-configured with respect to
the pyridine nitrogens N(7) and N(7A), respectively, and
they are positioned towards the middle ofthe loop. The dis-
Protonation of azacalixpyridines: As multiple-nitrogen-con-
taining macrocyclic receptors, azacalix[n]pyridines were ex-
pected to exhibit binding properties towards cations. To un-
derstand the structural properties ofazacalixpyridines under
different environments, and also as a prelude to studying
their molecular recognition properties, we first investigated
the protonation of 10, 11, 13, and 14 by spectrophotometric
titration.
tance between C(24) and C(24A) is short (3.743 Š) and
A
H
R
U
G
these two methyl groups virtually divide the cavity ofthe
molecule into two identical parts (Figure 2).
Although in the solid state methylazacalixpyridines 10, 11,
13, and 14 exist in certain conformations, with different con-
jugation systems ofbridging nitrogens being observed, these
azacalixpyridines may not be able to retain these stable con-
1
1
formational structures in solution. In both the H and the
In H NMR titration experiments, significant downfield
13
C NMR spectra, only one set ofproton and carbon reso-
shifts of almost all proton signals were observed when sam-
ples 10, 11, 13, and 14 were treated with different concentra-
tions ofCF CO D (Figure 3). The deshielding effect is con-
nance signals was observed in each case. Each product, for
example, gives one sharp singlet peak in the d=3.17–
3
2
3
.49 ppm range corresponding to all methyl protons, whilst
the protons on all its pyridine moieties resonate at d=7.37–
.42 ppm and d=6.36–7.03 ppm as a triplet and a doublet,
sistent with protonation on the pyridine nitrogen atoms. In
addition, in most cases, no new sets ofresonance signals ap-
peared under different acidic conditions at room tempera-
ture: in other words, in the solution phase the proton charg-
e(s) seem(s) to be delocalized over all the pyridine nitrogen
7
respectively. No signal splits were observed when the meas-
uring temperature was decreased to ꢀ1058C, which suggests
that all the calixpyridine macrocycles prepared are probably
1
atoms. This H NMR spectroscopic behavior might also indi-
9266
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ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 9262 – 9275

Methylazacalixpyridines
FULL PAPER
1
Figure 3. H NMR spectra of 10 (A), 11 (B), 13 (C), and 14 (D) in CDCl
3
in the absence and in the presence ofCF
3
CO
2
D at 293 K.
cate a rapid process ofproton exchanges between an unpro-
tonated pyridine ring and a protonated one and, more im-
portantly, very rapid interconversion ofcon of rmations of
the protonated azacalixpyridine species on the NMR time-
scale. It should be pointed out, however, that under one spe-
To measure the protonation constants, the protonation
equilibria ofazacalixpyridines were also studied by UV/visi-
[24,25]
ble spectroscopic titrations.
All azacalixpyridine com-
pounds gave highly pH-dependent absorption (Figure 4; see
also Figure 2 in the Supporting Information). From the UV/
visible spectroscopic titration data, protonation constants
ꢀ
2
cific set of circumstances ([CF COOD]
=
6.4”10 m),
methylazacalix[8]pyridine 11 gave about three sets ofsignals
Figure 3B), whilst methylazacalix[4]pyridine 10 exhibited
two sets ofsignals when 2.2 m ofCF COOD were present
3
[24,25]
(logK values) were obtained
and these are listed in
(
Table 3. The azacalixpyridine molecules display interesting
protonation behavior: depending on the numbers ofpyri-
dine rings present, the azacalixpyridine macrocycles 10, 11,
13, and 14 can accommodate up to four, eight, two, and four
protons, respectively. The more pyridine units present within
3
(
Figure 3A). Since the proton exchange proceeds very rapid-
ly at room temperature, the observation ofmore than two
sets ofproton signals in these cases is most probably due to
the formation of more than two relatively stable conforma-
tional structures in solution. It is also interesting to observe
that in the cases ofthe larger macrocycles—azacalix[8]pyri-
dine 11 and azacalix[4]arene[4]pyridine 14—the methyl
group proton signals shifted upfield under certain conditions
a macrocycle, the larger the logK value, which can be ex-
i
plained by considering the extensive delocalization ofposi-
tive charge(s) into other pyridine nitrogens and the better
minimization ofthe electrostatic repulsion between proto-
nated pyridine nitrogens. Azacalix[4]pyridine 10, with the
same number ofpyridine units, however, in general showed
(
Figure 3B and D), which might reflect the existence of pos-
sible conformers in which the bridging methyl groups are
buried in the shielding regions ofaromatic rings, such as
that illustrated by the crystal of 11 (see Figure 2).
a logK value greater than that ofazacalix[4]arene[4]pyri-
dine 14. This is most probably due to easier and more rapid
delocalization ofthe charge(s) in the of rmer macrocyclic
i
Chem. Eur. J. 2006, 12, 9262 – 9275
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9267

M.-X. Wang et al.
Figure 4. pH dependence ofthe spectra ofmethylazacalix[4]pyridine 10
ꢀ5
(
[10] = 2.223”10 m, I = 0.1m). Insert: absorption at 311 nm (black
square dots) and molar fractions of the protonated forms of 10 (dashed
lines).
Table 3. Logarithms ofprotonation constants ofazacalixpyridines. ( I =
0
.100m Me
4
NCl, T = 20.08C)
logK
13
i
Reaction
10
11
14
7.1(7)
4.9(0)
2.8(9)
1.0(1)
–
–
–
+
+
L + H Ð [HL]
8.4(2)
5.5(7)
3.4(2)
0.9(2)
–
–
–
–
9.9(3) 5.84(8)
7.6(9) 1.3(0)
+
+
2+
[
HL] + H Ð [H
2
L]
+
+
3+
A
C
H
T
R
E
U
N
G
[H
[H
[H
[H
[H
[H
2
3
4
5
6
7
L] + H Ð [H
L] + H Ð [H
L] + H Ð [H
L] + H Ð [H
L] + H Ð [H
L] + H Ð [H
3
4
5
6
7
8
L]
6.1(1)
5.0(7)
3.7(3)
2.2(3)
1.6(4)
1.3(6)
–
–
–
–
–
–
+
+
4+
5+
6+
7+
8+
A
C
H
T
R
E
U
N
G
L]
L]
L]
L]
L]
+
+
A
C
H
T
R
E
U
N
G
+
+
A
C
H
T
R
E
U
N
G
+
+
A
C
H
T
R
E
U
N
G
+
+
A
C
H
T
R
E
U
N
G
–
ꢀ
logK
i
18.3(3) 37.7(6) 7.1(5)
15.9(8)
Figure 5. Molecular structure ofmonoprotonated methylazacalix[4]pyri-
molecule because ofthe proximal arrangement ofthe of ur
pyridine rings. Because of the conjugated effect and the
steric hindrance, the bridging nitrogens exhibit low basicity
and no further protonation on the bridging nitrogen atoms
was observed in the pH range investigated.
ꢀ
dine [H10]ClO
4
·DMF: A) top view and B) side view (ClO
4
omitted for
clarity). Selected bond lengths [Š]: C(5)ꢀN(2) 1.423, N(2)ꢀC(6) 1.375,
C(10)ꢀN(4) 1.436, N(4)ꢀC(11) 1.346, C(15)ꢀN(6) 1.414, N(6)ꢀC(16)
1
.393, C(20)ꢀN(8) 1.423, N(8)ꢀC(1) 1.381; selected interatomic distances
[
Š]: N(1)···N(3) 3.005, N(5)···N(7) 3.012, N(5)···O(5) 2.659, C(8)···C(18)
.345.
7
To gain deeper insight into the interactions ofazacalixpyr-
idines with proton(s), the solid-state structures ofprotonat-
ed methylazacalixpyridines were studied. Fortunately, after
investigating various crystallization conditions, we obtained
X-ray quality crystals corresponding to the mono-, di-, and
triprotonated methylazacalix[4]pyridine salts (Table 2).
From the bond lengths and the intra- and intermolecular hy-
drogen bonds, all protonations were found to occur exclu-
sively on the pyridine nitrogens. Notably, all protonated
macrocyclic rings change their conformations from a 1,3-al-
ternate form with C2v symmetry (Figure 1) into the distorted
cies, unlike that ofthe parent methylazacalix[4]pyridine 10
(Figure 1), are composed o of fu r repeating conjugated
planar methylaminopyridine segments [-6-Py-2-N(CH )-] in
A
H
R
U
G
3
a distorted 1,3-alternate fashion (Figure 5 to Figure 8). All
the pyridine nitrogen atoms lie nearly in a plane, while the
bridging nitrogen atoms are located alternately on both
sides ofthe plane, with of ur methyl groups oriented in a
trans configuration (rtct). No intramolecular hydrogen bond-
ing between pyridinium protons and the bridging nitrogens
was observed. Instead, there are weak hydrogen bonding in-
teractions between the protonated pyridines and the neigh-
boring unprotonated pyridine nitrogens, as indicated by the
short NꢀH···N distances, ranging from 2.948 to 3.060 Š
1,3-alternate conformation with approximate S4 symmetry
(
Figure 5, Figure 6, Figure 7, and Figure 8). From the bond
lengths and angles, each bridging nitrogen was judged to
2
adopt the sp hybrid configuration, conjugating with one of
its adjacent pyridine rings. The cavities ofprotonated spe-
(Figure 5– Figure 8), reflecting a beneficial role played by
9268
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Chem. Eur. J. 2006, 12, 9262 – 9275

Methylazacalixpyridines
FULL PAPER
Figure 6. Molecular structure ofdiprotonated methylazacalix[4]pyridine
ꢀ
[
H
2
10]2ClO
4
: A) top view and B) side view (one ClO
4
omitted for clari-
Figure 7. Molecular structure oftriprotonated methylazacalix[4]pyridine
ty). Selected bond lengths [Š]: C(6)ꢀN(3) 1.319, N(3)ꢀC(8) 1.427,
[
3 4 4
H 10]ClO · OH·BiCl : A) top view and B) side view. Selected bond
C(12)ꢀN(5) 1.380, N(5)ꢀC(14) 1.397, C(18)ꢀN(7) 1.373, N(7)ꢀC(20)
lengths [Š]: C(5)ꢀN(2) 1.387, N(2)ꢀC(7) 1.397, C(11)ꢀN(4) 1.348, N(4)ꢀ
C(13) 1.420, C(17)ꢀN(6) 1.390, N(6)ꢀC(19) 1.399, C(23)ꢀN(8) 1.343,
N(8)ꢀC(1) 1.436; selected interatomic distances [Š]: N(1)···N(7) 2.955,
N(1)···N(3) 3.063, N(3)···N(5) 2.964, N(3)···O(3) 3.086, N(7)···O(4) 2.965,
O(4)···O(5) 2.875, O(5)···Bi(1) 2.710, C(3)···C(15) 8.417.
1
[
3
.418, C(24)ꢀN(1) 1.385, N(1)ꢀC(2) 1.395; selected interatomic distances
Š]: N(2)···N(4) 2.987, N(2)···N(8) 3.032, N(6)···N(4) 3.026, N(6)···N(8)
.040, N(6)···O(4) 2.916, N(2)···O(3) 3.033, C(10)···C(22) 8.283.
the proximal pyridine rings in stabilizing the positive charge
on the pyridinium unit in the distorted 1,3-alternate confor-
mation.
5.146 Š range. In other words, there is no interaction be-
tween the two pyridine units in the protonated methylazaca-
lix[2]arene[2]pyridine species because oftheir distal loca-
tions in the macrocyclic structure.
Single crystals ofmono- and diprotonated azacalix[2]ar-
ene[2]pyridine salts were also obtained and their solid-state
structures were determined by X-ray diffraction analysis. In-
triguingly, both mono- and diprotonated azacalix[2]arene[2]-
pyridines adopt 1,3-alternate conformations with approxi-
mate C2v symmetry (Figure 9 and Figure 10), a conformation
Differently protonated methylazacalix[4]pyridine species
behave like host molecular clips of different size to form
sandwich-type complexes with an anion or a solvent mole-
cule in the solid state. In the case ofmonoprotonated 10, f or
example, a DMF solvent molecule is included in the cavity
through an intermolecular hydrogen bond—N(5)ꢀH···O(5)
[18]
slightly different from their parent structure 13 but similar
to that ofazacalix[4]pyridine 10 in the solid state (Figure 1).
2
Furthermore, no bridging nitrogens, which are sp -config-
(Figure 5)—whilst the diprotonated 10 forms an inclusion
complex with one ofthe perchlorate anions through two in-
tramolecular hydrogen bonds: N(2)ꢀH···O(3) and N(6)ꢀ
ured, change their conjugation pattern in the protonated
methylazacalix[4]pyridine, remaining in conjugation with the
pyridine rings rather than conjugating with benzene rings.
Neither stabilization effects between protonated and unpro-
tonated pyridine rings in monoprotonated methylazaca-
lix[2]arene[2]pyridine 13 nor repulsion between two proto-
nated pyridines in diprotonated methylazacalix[2]arene[2]-
pyridine 13 were observed, the distances between two pyri-
dine nitrogen atoms in these two salts being in the 5.080–
H···O(4) (Figure 6). In the presence of different guest
anions, the conformationally similar triprotonated methyla-
zacalix[4]pyridine species form varied cavities to include
anions of different sizes and different geometries. As shown
in Figure 7, for example, triprotonated methylazacalix[4]pyr-
idine gives, through the of rmation ofa pair ofintermolecu-
lar bonds, a complex with a perchlorate anion that is further
Chem. Eur. J. 2006, 12, 9262 – 9275
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9269

M.-X. Wang et al.
Figure 8. Molecular structure of 10·HO
2
CCO
2
H·H
2
O: A) top view and B) side view ofthe complex ofthe triprotonated methylazacalix[4]pyridine with a
ꢀ
ꢀ
planar HO
2
CCO
2
. C) Top view and D) side view ofthe triprotonated methylazacalix[4]pyridine with a twisted HO
2
CCO
2
. E) Side view ofa heterodi-
meric structure. Selected bond lengths [Š]: C(5)ꢀN(3) 1.410, N(3)ꢀC(7) 1.379, C(11)ꢀN(5) 1.352, N(5)ꢀC(13) 1.332, C(17)ꢀN(7) 1.400, N(7)ꢀC(19)
1
.304, C(23)ꢀN(1) 1.427, N(1)ꢀC(1) 1.303, C(47)ꢀN(9) 1.418, N(9)ꢀC(25) 1.406, C(29)ꢀN(11) 1.378, N(11)ꢀC(31) 1.441, C(35)ꢀN(13) 1.435, N(13)ꢀ
C(37) 1.430, C(41)ꢀN(15) 1.308, N(15)ꢀC(43) 1.446; selected interatomic distances [Š]: N(4)···N(6) 2.995, N(8)···N(2) 3.050, N(8)···O(10) 2.679,
N(4)···O(12) 2.704, C(3)···C(15) 7.387, N(12)···N(14) 2.997, N(16)···N(10) 2.953, N(14)···O(16) 2.734, N(10)···O(15) 2.921, C(33)···C(45) 7.413,
O(11)···O(13) 2.572, O(11)···O(2W) 2.571.
ꢀ
hydrogen-bonded with a hydroxy moiety. It is worth noting
that the embedding ofa perchlorate anion in the cavity of
triprotonated methylazacalix[4]pyridine is almost identical
to the inclusion ofa perchlorate anion in a diprotonated
methylazacalix[4]pyridine (Figure 6 and Figure 7). More in-
triguingly, the interaction between methylazacalix[4]pyridine
and oxalic acid gives two types ofinclusion complexes, due
to different intermolecular hydrogen bond formation. In the
solid state, one ofthe triprotonated methylazacalix[4]pyri-
dines forms a pair of strong intermolecular hydrogen bonds
2.921 Š, respectively. Notably, the included HO CCO2
2
anion is heavily twisted, and the dihedral angle between the
ꢀ
planes of ꢀCO and ꢀCO H is around 568 (Figure 8c and
2
2
d). The two discrete inclusion complexes are linked by an
intermolecular hydrogen bond—O(11)ꢀH···O(13)—giving
rise to a heterodimeric structure (Figure 8e). It is also inter-
ꢀ
ꢀ
2
esting to note that two other O CCO anions form a cyclic
dimer through intermolecular hydrogen bonding with two
water molecules in the crystal structure (Figure 8e).
2
The ability ofmethylazacalix[4]pyridine 10 in its different
protonated forms to include guest species of different sizes
and different geometries—such as a planar DMF molecule
ꢀ
with two vicinal oxygen atoms ofa planar HO 2CCO2
moiety, with the N(8)ꢀH···O(10) and N(4)ꢀH···O(12) distan-
ces being 2.679 Š and 2.704 Š, respectively (Figure 8A and
B). In the other inclusion complex, triprotonated methylaza-
calix[4]pyridine forms hydrogen bonds with the carboxylic
ꢀ
ꢀ
or planar HO CCO ion, a heavily twisted HO CCO
2
2
2
2
ꢀ
anion, and a tetrahedral ClO4 ion—is unique. This is partic-
ularly intriguing when the similar 1,3-alternate conforma-
tional structures ofall the protonated macrocyclic hosts are
considered. Careful scrutiny of the bond lengths between
ꢀ
group (ꢀCO H) ofanother HO CCO ion, and the N(14)ꢀ
2
2
2
H···O(16) and N(10)···HꢀO(15) distances are 2.734 Š, and
9270
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Chem. Eur. J. 2006, 12, 9262 – 9275

Methylazacalixpyridines
FULL PAPER
Figure 10. Molecular structure ofdiprotonated methylazacalix[2]arene[2]-
ꢀ
pyridine 13·2HI·I
CH
2
·CH
3
OH: A) top view and B) side view (I
3
and
OH omitted for clarity). Selected bond lengths [Š]: C(8)ꢀN(2) 1.423,
3
N(2)ꢀC(5) 1.347, C(1)ꢀN(6) 1.336, N(6)ꢀC(25) 1.430, C(21)ꢀN(5) 1.435,
N(5)ꢀC(18) 1.349, C(14)ꢀN(3) 1.353, N(3)ꢀC(12) 1.432; selected inter-
atomic distances [Š]: C(7)···C(20) 4.657, C(10)···C(23) 3.590, N(1)···N(4)
Figure 9. Molecular structure ofmonoprotonated methylazacalix[2]ar-
4ꢀ
A
C
H
T
R
E
U
N
G
ene[2]pyridine 13·HClO
4 2 2
·CH Cl : A) top view and B) side view (ClO
and CH Cl
2
2
omitted for clarity). Proton may be located on either pyri-
dine ring. Selected bond lengths [Š]: C(5)ꢀN(2) 1.327, N(2)ꢀC(7) 1.452,
C(11)ꢀN(3) 1.428, N(3)ꢀC(14) 1.362, C(18)ꢀN(5) 1.402, N(5)ꢀC(20)
5.146, C(3)···C(16) 10.017.
1
.528, C(24)ꢀN(6) 1.336, N(6)ꢀC(1) 1.297; selected interatomic distances
[
Š]: N(1)···N(4) 5.080, C(3)···C(16) 9.809, C(9)···C(22) 3.510,
dines are able to preorganize in solution into the most favor-
able conformations with tailor-made cavities to recognize
different guest species during the crystallization process. It
might also be speculated that the interaction—or mainly in-
termolecular hydrogen bonding—ofan anion or a neutral
molecule with a protonated methylazacalix[4]pyridine indu-
ces the latter to adopt a specific conformation through the
sel f- adjustment ofthe conjugation systems ofall bridging ni-
trogens.
C(12)···C(25) 4.633.
each bridging nitrogen and its adjacent aromatic carbon (see
the captions for Figure 5, Figure 6, Figure 7, and Figure 8),
however, allowed us to establish that the degree ofconjuga-
tion ofeach bridging nitrogen with its neighboring pyridine
varies from one protonated form to another, and differs
from one bridging nitrogen to another even within a host
molecule. In other words, it is the intrinsic nature ofthe ni-
trogen atom to adopt various degrees ofconjugation with its
adjacent aromatic ring that results in the generation ofa
number o fi fn e-tuned cavities in protonated methylazaca-
lix[4]pyridines. For example, the cavity ofa protonated
methylazacalix[4]pyridine species—as defined by the dis-
tance between two 4-carbon atoms ofthe two oppositely
Complexation with fullerenes: Much attention has been
given to supramolecular fullerene chemistry because of its
potential applications in chemistry, biology, and materials
[26]
sciences. In the past decade, a few macrocyclic host mole-
[
26b,27]
cules, including calix[n]arenes,
homooxacalix[3]ar-
[28]
[29]
[30]
ene,
cyclotriveratrylene,
b-cyclodextrin
and crown
[31]
positioned pyridine rings on the upper rim—ranges from
ethers, and porphyrins and metalloporphyrins with planar
+
7
.345 Š (d
in [H10] , Figure 5A), 7.387 Š (d
p surfaces, have been shown to be able to interact with full-
C(8)–C(18)
+
C(3)–C(15)
3+
3
[32]
in [H 10] , Figure 8A), 7.413 Š (d
, in [H 10] , Fig-
in [H 10] , Figure 6A), to
erenes. With macrocyclic host molecules 10, 11, 13, and 14
3
C(33)–C(45)
3
2
+
ure 8C), 8.283 Š (d
to hand, we examined their recognition capabilities towards
fullerene guests. The methylazacalixpyridine compounds
were found to exhibit size-dependent complexation behavior
C(10)–C(22)
2
3
+
8.417 Š (dC(3)–C(15) in [H 10] , Figure 7 A). Taking the previ-
3
ously discussed spectroscopic behavior ofprotonated meth-
ylcalix[4]pyridines into account, it is most probably the case
that, through the combination of different degrees of conju-
gation of fo ur bridging nitrogens with their neighboring pyr-
idines, the highly flexible protonated methylazacalix[4]pyri-
with fullerenes C60 and C . Neither methylazacalix[4]pyri-
70
dine 10 nor methylcalix[2]arene[2]pyridine 13, for example,
is capable of fo rming a complex with C
or C , most proba-
70
6
0
bly due to the small cavities ofthe host molecules. In con-
Chem. Eur. J. 2006, 12, 9262 – 9275
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9271

M.-X. Wang et al.
ꢀ
1
trast, their larger homologues methylazacalix[8]pyridine 11
and methylazacalix[4]arene[4]pyridine 14 interact effectively
with C60 and C70 molecules. Most notably, interaction be-
tween 11 or 14 and C60 was evidenced by a color change of
a fullerene solution in toluene from its characteristic purple
to light brown. As indicated by the Job plot (see Figures 4–
s
Table 4. Stability constants K [m ] for the complexation of 11 and 14
[
a]
with C60 and C70
.
C
60
C
70
methylazacalix[8]pyridine 11
methylazacalix[4]arene[4]pyridine 14
46050ꢁ1590
70680ꢁ2060
109590ꢁ2150
136620ꢁ3770
[
33]
0
[a] Calculated from plots of F /Fcal versus fullerene concentration.
11 in the Supporting Information), both 11 and 14 form 1:1
complexes with fullerenes C60 or C . The stability constants
for the complexation of 11 and 14 with fullerenes C60 or C70
were calculated by fluorescence titration (Figure 11 and
70
ꢀ
1 [27d,f,g]
and -[6]arene derivatives (Ks = 87–2120m )
homooxacalix[3]arene (Ks = (35ꢁ5)m ),
and for
indicating a
ꢀ
1
[27d]
clear advantage ofthe introduction ofamino groups into the
bridging positions ofthe calixarenes. To the best ofour
knowledge, azacalixpyridine derivatives 11 and 14 are prob-
ably the strongest monomacrocyclic receptors to data to in-
teract with fullerenes C60 and C . It is also interesting to
70
note that azacalix[4]arene[4]pyridine 14 shows a higher af-
finity than azacalix[8]pyridine 11 in interaction with both
C60 and C , and that both 11 and 14 bind more strongly
70
with C70 than with C . The former can be ascribed mainly
60
to the electronic effect, as the all-pyridine-based azacalix[8]-
pyridine 14 provides a less electron-rich surface than the
azacalix[4]arene[4]pyridine 11. The stronger affinities of 11
and 14 towards C70 than towards C60 are most probably at-
tributable to steric effects: that is, to the oval-shaped giant
cavities ofthe host molecules.
In order to understand the interactions ofazacalixpyri-
dines 11 and 14 with fullerenes at the molecular level, we at-
tempted to determine the solid-state structures of 11/ and
ꢀ
6
ꢀ3
Figure 11. Emission spectra (lexc = 351 nm) of 11 (9.022”10 moldm
)
in the presence ofC 60 in toluene at 258C. The concentrations ofC 60 for
curves a–k (from top to bottom) are 0.0, 2.705, 4.509, 5.410, 6.312, 7.214,
.017, 9.919, and 10.82 (”10 moldm ). Inset: Variation of lf uorescence
1
4/fullerene complexes. Unfortunately, no crystals could be
1
ꢀ6
ꢀ3
obtained. No salient changes were observed in the H and
9
1
3
intensity of 11 with increasing C60 concentration.
C NMR spectra ofthe complexes in solution. Because nei-
ther new absorption nor new emission peaks were observed
in spectrophotometric titrations, the strong interaction of
azacalixpyridines with fullerenes is not due to the formation
ofcharge-trans ef r complexes. Although the precise reason
for efficient complexation of fullerenes by azacalixpyridines
still remains unclear, it is most probably explicable in terms
of the van der Waals forces between sterically fitted concave
and convex p surfaces. The introduction of electron-donat-
ing amino groups as the bridging units increases the electron
densities ofthe benzene and pyridine rings, and might there-
fore further enhance the interactions between the curved
surfaces of the macrocyclic receptors and the electron-defi-
cient fullerenes.
Figure 12), from plots of F /F versus fullerene concentra-
0
cal
[
33]
tion and are tabulated in Table 4. The K values obtained
s
for both 11 and 14 are much higher than those for calix[5]-
Conclusion
We have developed a convenient and efficient fragment cou-
pling approach to the synthesis ofnitrogen-bridged calixpyr-
idine macrocyclic host molecules. In the presence ofexcess
potassium tert-butoxide, 2,6-diaminopyridine (1) and ben-
zene-1,3-diamine (2) both underwent coupling reactions
with 2,6-dibromopyridine (3) and subsequent N-methylation
with methyl iodide in a one-pot fashion to give the corre-
ꢀ
6
ꢀ3
Figure 12. Emission spectra (lexc = 351 nm) of 11 (7.894”10 moldm
)
in the presence ofC 70 in toluene at 258C. The concentrations ofC 70 for
curves a–j (from top to bottom) are 0.0, 0.792, 1.584, 2.376, 3.168, 3.96,
.752, 5.544, 6.336, and 7.128”10 moldm ). Inset: Variation of fl uores-
cence intensity F /Fcal of 11 with increasing C70 concentration.
2
6
ꢀ
6
ꢀ3
sponding linear trimers N ,N -bis(6-bromopyridin-2-yl)-
4
2
6
1
3
0
N ,N -dimethylpyridine-2,6-diamine (6) and N ,N -bis(6-
9272
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 9262 – 9275

Methylazacalixpyridines
FULL PAPER
1
3
bromopyridin-2-yl)-N ,N -dimethylbenzene-1,3-diamine (7)
in high yields. Macrocyclic coupling reactions between the
linear trimers 6 and 7 and 2,6-diaminopyridine (1) and ben-
Experimental Section
Melting points are uncorrected. Elemental analyses were performed at
the Analytical Laboratory ofthe Institute. All chemicals were dried or
purified by standard procedures prior to use.
zene-1,3-diamine (2), catalyzed by [Pd (dba) ]/dppp under
A
H
R
U
G
2 3
basic conditions, proceeded smoothly and efficiently at
reflux in 1,4-dioxane to afford good yields of methylazaca-
lix[n]pyridines (n = 4, 8) and methylazacalix[m]arene[n]pyr-
idines (m = n = 2, 4), respectively. The fragment coupling
approach developed in this study should have generality in
2
6
2
6
Preparation of N ,N -bis(6-bromopyridin-2-yl)-N ,N -dimethylpyridine-
1
3
1
3
2
,6-diamine (6) and N ,N -bis(6-bromopyridin-2-yl)-N ,N -dimethylben-
zene-1,3-diamine (7): Under argon protection and at room temperature,
a mixture ofa fi ne powder of2,6-diaminopyridine ( 1) or benzene-1,3-dia-
mine (2) (20 mmol), 2,6-dibromopyridine (3) (60 mmol), and potassium
tert-butoxide (200 mmol) was stirred vigorously for 0.5 h. Dry THF
the
(hetero)aromatics, including unsymmetric ones if different
fragments are used.
synthesis
ofvarious
nitrogen-bridged
calix-
(
180 mL) was added rapidly to the resulting pale yellow-brown mixture,
ACHTREUNG
and an exothermic reaction took place immediately, to give a dark green
solution. (Caution! Vigorous stirring is necessary. Otherwise there may be
an explosion due to the heat generated.) After ca. 1.5 h, the reaction mix-
ture was warmed to 60–708C and a solution ofmethyl iodide (80 mmol)
in dry THF (20 mL) was added slowly and the resulting mixture was kept
stirring for another 1.5 h. The solvent was then removed under reduced
pressure, and the residue was dissolved in ethyl acetate (500 mL). The or-
ganic solution was washed with brine (3”150 mL) and dried over anhy-
drous magnesium sulfate. After removal of solvent, the residue was chro-
matographed on a silica gel column with a mixture ofpetroleum ether
The introduction ofnitrogen atoms into all the bridging
positions in calix[n]pyridines and in calix[m]arene[n]pyri-
dines has resulted in a unique class ofmacrocyclic host mol-
ecules with intriguing conformational structures and versa-
tile recognition properties. Thanks to their intrinsic electron-
2
ic natures, the bridging nitrogens can adopt mainly sp hy-
bridization to produce conjugation, partial conjugation, and/
or non-conjugation with their one and/or two adjacent pyri-
dine rings. As a consequence, in solution these highly fluxio-
nal macrocyclic azacalixpyridine species are able to adopt
specific conformations with fine-tuned cavities in order to
recognize or to accommodate guest species through the for-
mation ofhydrogen bonds. For example, whilst in solution it
is very fluxional, in the solid state methylazacalix[4]pyridine
2
6
and ethyl acetate (5:1) as the mobile phase to give pure N ,N -bis(6-bro-
2
6
mopyridin-2-yl)-N ,N -dimethylpyridine-2,6-diamine (6, 7.54 g, 84%) or
1
3
1
3
N ,N -bis(6-bromopyridin-2-yl)-N ,N -dimethylbenzene-1,3-diamine (7,
.98 g, 78%).
6
2
6
2
6
N ,N -Bis(6-bromopyridin-2-yl)-N ,N -dimethylpyridine-2,6-diamine (6):
m.p. 109–1108C (pale yellow crystals from a mixture of petroleum ether
1
and ethyl acetate (4:1)); H NMR (300 MHz, [D
6
]DMSO): d = 7.71 (t, J
=
8.0 Hz, 1H), 7.54 (t, J = 7.9 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 7.11
d, J 7.5 Hz, 2H), 6.95 (d, J 8.0 Hz, 2H), 3.45 (s, 6H) ppm;
C NMR (75 MHz, [D ]DMSO): d = 157.3, 155.3, 140.4, 140.1, 138.9,
19.9, 112.9, 109.0, 36.2 ppm; MS (EI): m/z: 449 (100), 447 [M] (56),
291 (51), 277 (36), 264 (40); elemental analysis calcd (%) for
(
=
=
1
0 adopts a 1,3-alternate conformation with a C2v symmetry
13
6
in which each pair ofbridging nitrogen atoms conjugates
with one pyridine ring. Through the formation of different
types ofconjugation between the bridging nitrogens and
pyridine rings, methylazacalix[8]pyridine 11 gives a pleated
loop with a Ci symmetry in the crystal structure. After pro-
tonation on the pyridine nitrogen(s), the methylazacalix[4]-
pyridine species changes the conjugation systems ofits of ur
bridging nitrogen atoms to yield similar twisted 1,3-alternate
+
1
C
17
H
15
N
5
Br
2
: C 45.46, H 3.37, N 15.59; found: C 45.56, H 3.35, N 15.53.
1
3
1
3
N ,N -Bis(6-bromopyridin-2-yl)-N ,N -dimethylbenzene-1,3-diamine (7):
m.p. 124–1258C (pale yellow crystals from a mixture of petroleum ether
1
and ethyl acetate (5:1)); H NMR (300 MHz, CDCl
3
): d = 7.45 (t, J =
7
2
.9 Hz, 1H), 7.20 (t, J = 7.7 Hz, 2H), 7.18 (s, 1H), 7.13 (dd, J = 8.0,
.0 Hz, 2H), 6.80 (d, J = 7.4 Hz, 2H), 6.54 (d, J = 8.3 Hz, 2H), 3.48 (s,
1
3
6H) ppm; C NMR (75 MHz, CDCl ): d = 158.4, 147.1, 140.0, 138.9,
3
conformations with an approximate S symmetry. The cavity
ofeach protonated methylazacalix[4]pyridine, however,
varies finely to accommodate, through the formation of hy-
130.9, 124.0, 123.2, 116.5, 107.1, 38.5 ppm; MS (EI): m/z: 450 (49), 449
4
+
(
48), 448 (100), 447 (70), 446 [M] (50), 445 (31), 369 (32), 367 (42), 287
(
1
35); elemental analysis calcd (%) for C18
2.50; found: C 48.32, H 3.54, N 12.50.
16 4 2
H N Br : C 48.24, H 3.60, N
drogen bonds, guest species of different sizes and different
General procedure for the synthesis of methylazacalix[n]pyridines and
methylazacalix[m]arene[n]pyridines: Under argon protection, a mixture
ꢀ
geometries, such as a planar DMF or HO CCO ion, a
2
2
ꢀ
ꢀ
twisted HO CCO2 ion, and a tetrahedral ClO4 ion. To the
oftrimer 6 or 7 (1 mmol), diamine 8 or 9 (1 mmol), [Pd2
0.1 mmol), dppp (82 mg, 0.2 mmol), and sodium tert-butoxide (288 mg,
mmol) in anhydrous 1,4-dioxane (250 mL) was warmed (or heated at
reflux) for a period of time (Table 1 and Supporting Information). When
or 7 was consumed, as monitored by TLC, the reaction was quenched
A
H
R
U
G
3
(dba) ] (92 mg,
2
best ofour knowledge, this is probably the if rst example in
which the cavity ofa calixarene species is sel -f regulated by
the bridging nitrogens through their conjugation systems. It
has also been shown that the macrocycles synthesized under-
go size-dependent interactions with fullerenes through van
der Waals forces. Both methylazacalix[8]pyridine 11 and
methylazacalix[4]arene[4]pyridine 14 are powerful spectro-
photometric host molecules for sensing fullerenes C60 and
C , with stability constants (K ) as high as 46050ꢁ1590 to
3
6
by cooling down to room temperature and the mixture was filtered
through a Celite pad. The filtrate was acidified to pH 7–8 with aqueous
hydrochloric acid (2m). After removal of the solvent, the residue was dis-
solved in dichloromethane (45 mL) and washed with brine (3”15 mL),
the aqueous phase was re-extracted with dichloromethane (3”20 mL),
and the combined organic phase was dried over anhydrous sodium sul-
fate. Basic aluminium oxide column chromatography, with elution with a
mixture ofpetroleum ether and ethyl acetate (10:1) to a mixture ofpe-
troleum ether and ethyl acetate (2:1) with 0.2% ofammonium, gave
pure products 10, 11, and 12, or 13 and 14.
7
0
s
ꢀ
1
1
36620ꢁ3770m . The ease ofpreparation, versatile con of r-
mational structures, and potential recognition properties
should make these novel multinitrogen-containing calixar-
enes or cyclophanes unique and powerful macrocyclic hosts
in supramolecular chemistry. We are currently exploring
their molecular recognition ofboth cations and anions and
will report the results in due course.
1
Methylazacalix[4]pyridine 10: m.p. 263–2648C; H NMR (600 MHz,
CD
1
3
2
Cl
2H) ppm; C NMR (75 MHz, CDCl
6.6 ppm; MS (MALDI-TOF): m/z: 425.3 [M+H] ; elemental analysis
: C 67.90, H 5.70, N 26.40; found: C 67.89, H 5.72,
2
): d = 7.42 (t, J = 7.8 Hz, 4H), 6.40 (d, J = 7.8 Hz, 8H), 3.24 (s,
13
3
): d = 159.1, 138.4, 108.5,
+
calcd (%) for C24
24 8
H N
Chem. Eur. J. 2006, 12, 9262 – 9275
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9273

M.-X. Wang et al.
N 26.41. Recrystallization from acetonitrile gave single crystals suitable
for X-ray diffraction analysis.
Acknowledgements
1
Methylazacalix[8]pyridine 11: m.p. 117–1188C; H NMR (600 MHz,
The work was supported by funds from the National Natural Science
Foundation ofChina, the Ministry ofScience and Technology ofChina,
and the Chinese Academy ofSciences. We thank Pro ef ssor Yun-Dong
Wu of Beijing University for helpful discussions.
CD
2
Cl
2
): d = 7.43 (t, J = 7.8 Hz, 8H), 6.76 (d, J = 8.4 Hz, 16H). 3.52
1
3
(
s, 24H) ppm; C NMR (75 MHz, CDCl
3
): d
6.1 ppm; MS (MALDI-TOF): m/z: 848.8 [M+1] ; elemental analysis
16: C 67.90, H 5.70, N 26.40; found: C 67.66, H
.71, N 26.37. Slow evaporation ofsolvent rf om the solution of 11 in a
= 156.0, 139.0, 107.2,
+
3
calcd (%) for C48
48
H N
5
mixture ofhexane and ethyl acetate (6:1) gave X-ray quality single crys-
tals.
[1] C. D. Gutsche, B. Dhawan, K. H. No, R. Muthukrishnan, J. Am.
Chem. Soc. 1981, 103, 3782.
[2] For reviews, see: a) Calixarenes 2001 (Eds.: Z. Asfari, V. Bçhmer, J.
Harrowfield, J. Vicens, M. Saadioui), Kluwer, The Netherlands,
1
Linear pentamer 12: m.p. 72–738C; H NMR (300 MHz, CDCl
3
): d =
7
J
6
1
2
.30–7.39 (m, 5H), 6.73–6.81 (m, 6H), 6.52 (d, J = 7.9 Hz, 2H), 5.98 (d,
7.9 Hz, 2H), 4.47 (s, 2H), 3.60 (s, 6H), 3.56 (s, 6H), 2.90 (s,
2
001; b) C. D. Gutsche, Calixarenes Revisited, Royal Society of
=
1
3
Chemistry, Cambridge, 1998; c) Calixarenes in Action (Eds.: L. Man-
dolini, R. Ungaro), Imperial College Press, London, 2000; d) G. J.
Lumetta, R. D. Rogers, A. S. Gopalan, Calixarenes for Separation,
ACS, Washington, 2000; e) C. D. Gutsche, Calixarenes, Royal Soci-
ety ofChemistry, Cambridge, 1989.
H) ppm; C NMR (75 MHz, CDCl
3
): d = 158.9, 156.9, 156.5, 156.4,
56.3, 138.6, 137.6, 137.6, 106.2, 106.1, 105.9, 103.6, 98.4, 35.6, 35.6,
ꢀ1
9.2 ppm. IR (KBr): nˇ = 3285, 1599, 1562, 1408 cm ; HRMS (FT-ICR):
+
found 562.3141 [M+H] ; C31
Methylazacalix[2]arene[2]pyridine 13: m.p. 245–2468C;
300 MHz, CDCl ): d = 7.42 (t, J = 8.0 Hz, 2H), 7.05 (t, J = 7.8 Hz,
H), 6.74 (d, J = 7.9 Hz, 4H), 6.66 (s, 2H), 6.02 (d, J = 8.0 Hz, 4H),
36
H N11 requires 562.3149.
1
H NMR
[
3] For recent examples, see: a) R. Zadmard, T. Schrader, J. Am. Chem.
Soc. 2005, 127, 904; b) U. Darbost, M.-N. Rager, S. Petit, I. Jabin, O.
Reinaud, J. Am. Chem. Soc. 2005, 127, 8517; c) O. Seneque, M.-N.
Rager, M. Giorgi, T. Prange, A. Tomas, O. Reinaud, J. Am. Chem.
Soc. 2005, 127, 14833; d) C. Gaeta, M. O. Vysotsky, A. Bogdan, V.
Bçhmer, J. Am. Chem. Soc. 2005, 127, 13136; e) B.-T. Zhao, M.-J.
Blesa, N. Mercier, F. Le Derf, M. Salle, J. Org. Chem. 2005, 70,
6254; f) H. Al-Saraierh, D. O. Miller, P. E. Geroghiou, J. Org. Chem.
(
3
2
3
1
2
1
1
3
.18 (s, 12H) ppm; C NMR (75 MHz, CDCl
26.6, 128.9, 138.8, 148.9, 158.3 ppm; MS (EI): m/z: 422 [M] (100%),
3
): d = 38.9, 95.0, 124.9,
+
11 (24); elemental analysis calcd (%) for C26
9.89; found: C 74.25, H 6.30, N 19.85.
H
26
N
6
: C 73.91, H 6.20, N
1
Methylazacalix[4]arene[4]pyridine 14: m.p. 209–2108C;
H NMR
2
005, 70, 8273; g) E.-H. Ryu, Y. Zhao, Org. Lett. 2005, 7, 1035;
h) S. K. Kim, J. H. Bok, R. A. Bartsch, J. Y. Lee, J. S. Kim, Org. Lett.
005, 7, 4839.
(
(
(
300 MHz, CDCl
m, 12H), 5.97 (d, J
75 MHz, CDCl ): d
3
): d = 7.46 (t, J = 8.0 Hz, 4H), 7.35 (s, 4H), 7.07–7.13
1
3
=
8.0 Hz, 8H), 3.49 (s, 24H) ppm; C NMR
2
3
= 38.9, 98.8, 122.7, 125.2, 131.1, 138.8, 148.6,
[
[
4] For a useful overview of heteroatom-bridged calixarenes, see: B.
Kçnig, M. H. Fonseca, Eur. J. Inorg. Chem. 2000, 2303.
1
58.2 ppm; MS (MALDI-TOF): m/z: 845.8 [M+1]; elemental analysis
calcd (%) for C52 12: C 73.91, H 6.20, N 19.89; found: C 74.16, H
.30, N 20.07.
52
H N
5] a) P. A. Gale, J. L. Sessler, V. Krꢂl, Chem. Commun. 1998, 1; b) S.
Depraetere, M. Smet, W. Dehaen, Angew. Chem. 1999, 111, 3556;
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M. Kapon, K. Suwinska, Y. Eichen, Chem. Commun. 2001, 13; d) C.
Bucher, R. S. Zimmerman, V. Lynch, V. Krꢂl, J. L. Sessler, J. Am.
Chem. Soc. 2001, 123, 2099; e) G. Cafeo, F. H. Kohnke, G. L. La
Torre, M. F. Parisi, R. P. Nascone, A. J. P. White, D. J. Williams,
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2001, 222, 57.
6
Preparation of X-ray quality single crystals: Single crystals ofmonopro-
tonated 10 were obtained by diffusing diethyl ether vapor into a solution
of 10 (10 mg) and Fe
A
C
H
T
R
E
U
N
G
(ClO
4
)
3
(10 mg) in DMF (2 mL) at 15–208C, while
single crystals of 10·2HClO
4
were cultivated simply by evaporating the
4
solvent from a clear solution of 10 in aqueous HClO solution (2m) at
room temperature.
3 4
BiCl (10 mg) and aqueous HClO solution (1m, 15 mL) were added con-
secutively to a solution of 10 (10 mg) in acetonitrile (10 mL). The mixture
was warmed for 5 min and was then filtered. Slow evaporation of solvent
from the clear solution at 208C afforded single crystals of triprotonated
[6] a) V. Krꢂl, P. A. Gale, P. Anzenbacher, K. Jursikovꢂ, V. Lynch, J. L.
Sessler, Chem. Commun. 1998, 9; b) J. L. Sessler, W.-S. Cho, V.
Lynch, V. Krꢂl, Chem. Eur. J. 2002, 8, 1134; c) G. R. Newkome, Y. J.
Joo, F. R. Fronczek, J. Chem. Soc. Chem. Commun. 1987, 854.
1
0.
For the preparation ofmethylazacalix[4]pyridine complex with oxalic
acid, 10 (20 mg) was first dissolved in dichloromethane (5 mL). Titanium
oxalate (20 mg) and methanol (15 mL) were added, and the resulting
mixture was warmed for 5 min and filtered. Hexane (10 mL) was then
added to the filtrate to give a clear solution. Slow evaporation of the sol-
[
7] a) R. G. Ackman, W. H. Brown, G. F. Wright, J. Org. Chem. 1955,
2
0, 1147; b) W. H. Brown, H. Sawatsky, Can. J. Chem. 1956, 34,
1
147; c) R. E. Beals, W. H. Brown, J. Org. Chem. 1956, 21, 447;
d) M. de Sousa Healy, A. J. Rest, J. Chem. Soc. Chem. Commun.
981, 149; e) F. H. Kohnke, G. L. La Torre, M. F. Parisi, Tetrahedron
1
vent at 208C gave single crystals of 10·2HO
Single crystals of[Cu 10](PF ·0.5CH Cl were obtained by treatment of
0 (25 mg, 0.06 mmol) with [Cu(NCCH ]PF (22 mg, 0.06 mmol) in a
2 2 2
CCO H·H O.
Lett. 1996, 37, 4593; f) P. Fonte, F. H. Kohnke, M. F. Parisi, Tetrahe-
dron Lett. 1996, 37, 6201; g) P. Fonte, F. H. Kohnke, M. F. Parisi, Tet-
rahedron Lett. 1996, 37, 6205; h) J. Guillard, O. Meth-Cohn, C. W.
Rees, A. J. P. White, D. J. Williams, Chem. Commun. 2002, 232; i) M.
Ahmed, O. Meth-Cohn, J. Chem. Soc. C 1971, 2104; j) E. Vogel, P.
Rçhrig, M. Socken, B. Knipp, A. Herrmann, M. Pohl, H. Schmick-
ler, J. Lex, Angew. Chem. 1989, 101, 1683; Angew. Chem. Int. Ed.
Engl. 1989, 28, 1651; k) E. Vogel, M. Pohl, A. Herrmann, T. Wiss, C.
Kçnig, J. Lex, M. Gross, J. P. Gisselbrecht, Angew. Chem. 1996, 108,
A
C
H
T
R
E
U
N
G
6
)
2
2
2
1
A
H
R
U
G
3
)
4
6
mixture ofdichloromethane and methanol. A tf er having been heated at
reflux overnight, the solution was cooled down to room temperature.
Slow evaporation of solvent at room temperature afforded red crystals.
To cultivate single crystals ofmonoprotonated methylazacalix[2]arene[2]-
pyridine [H·13]ClO
4 2 2
·CH Cl , 13 (10 mg) was first dissolved in dichloro-
methane (5 mL). After addition of methanol (5 mL) and aqueous HClO
solution (1m, 5 mL), n-hexane (10 mL) was added. Slow evaporation of
solvent at 8–108C gave crystals suitable for X-ray diffraction analysis.
4
1
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6
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ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: March 17, 2006
Published online: July 18, 2006
Chem. Eur. J. 2006, 12, 9262 – 9275
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9275