Exhaustively methylated azacalix[4]arene: Preparation, conformation, and crystal structure with exclusively CH/π-controlled crystal architecture

Article abstract of DOI:10.1021/ol050493i

(Chemical Equation Presented) Described are the preparation, conformation, and crystal structure of exhaustively methylated azacalix[4]arene involving nitrogen atoms as bridging units. NMR and X-ray crystallographic analysis have demonstrated that this no

Full text of DOI:10.1021/ol050493i

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2165-2168
Exhaustively Methylated
Azacalix[4]arene: Preparation,
Conformation, and Crystal Structure
with Exclusively CH/
Architecture
π-Controlled Crystal
Hirohito Tsue,*,†,‡ Koichi Ishibashi,‡ Hiroki Takahashi,‡ and Rui Tamura†,‡
Graduate School of Global EnVironmental Studies and Graduate School of Human and
EnVironmental Studies, Kyoto UniVersity, Kyoto 606-8501, Japan
tsue@ger.mbox.media.kyoto-u.ac.jp
Received March 8, 2005
ABSTRACT
Described are the preparation, conformation, and crystal structure of exhaustively methylated azacalix[4]arene involving nitrogen atoms as
bridging units. NMR and X-ray crystallographic analysis have demonstrated that this novel azacalix[4]arene adopts a 1,3-alternate conformation
both in solution and in the solid state. The crystal structure has been characterized solely by intermolecular CH/
π interactions, by which the
azacalix[4]arenes mutually interact with each other outside the cavity to furnish a two-dimensional network structure.
The name “calixarene” was initially coined for a family of
macrocyclic phenol condensates linked via methylene
bridges.1-3 In recent years, the name has been gradually
extended to express structurally related compounds desig-
nated as “heterocalixarenes”,3 in which aromatic systems
other than phenol are incorporated into the [1n]metacyclo-
phane skeleton. More recently, much attention has been
attracted to the preparation of “heteroatom-bridged calix-
arenes”,3,4 in which methylene bridges are replaced by
heteroatoms such as silicon, boron, germanium, tin, nitrogen,
oxygen, phosphorus, and sulfur. Among these, only silicon-,
sulfur-, and oxygen-bridged calixarenes5,6a,7 incorporate phe-
nols as building blocks, whereas others consist of benzene
rings and/or heteroaromatics rather than phenol.3,4a
Very recently, Tanaka,8a,b Yamamoto,8c and Wang8d,e
independently succeeded in preparing nitrogen-bridged deoxy-
calixarenes, which exhibited intriguing structure-property
relationships reflecting the introduction of nitrogen atoms
as bridging units. These calixarene analogues consist of
aromatic systems other than phenol, while we are interested
† Graduate School of Global Environmental Studies.
‡ Graduate School of Human and Environmental Studies.
(1) (a) Gutsche, C. D. In Calixarenes; Stoddart, J. F., Ed.; Royal Society
of Chemistry: Cambridge, 1989. (b) Gutsche, C. D. In Calixarenes
ReVisited; Stoddart, J. F., Ed.; Royal Society of Chemistry: Cambridge,
1998.
(2) Calixarenes: A Versatile Class of Macrocyclic Compounds; Vicens,
J., Bo¨hmer, V., Eds.; Kluwer: Dordrecht, 1991.
(3) Calixarenes 2001; Asfari, Z., Bo¨hmer, V., Harrowfield, J., Vicens,
J., Saadioui, M., Eds.; Kluwer: Dordrecht, 2001.
(5) Ko¨nig, B.; Ro¨del, M.; Bubenitschek, P. J. Org. Chem. 1995, 60, 7406.
(6) (a) Kumagai, H.; Hasegawa, M.; Miyanari, S.; Sugawa, Y.; Sato,
Y.; Hori, T.; Ueda, S.; Kamiyama, H.; Miyano, S. Tetrahedron Lett. 1997,
38, 3971. (b) Lhota´k, P.; Himl, M.; Stibor, I.; Sykora, J.; Lang, J.; Petrickova´,
H. Tetrahedron 2003, 59, 7581.
(7) Katz, J. L.; Feldman, M. B.; Conry, R. R. Org. Lett. 2005, 7, 91.
(8) (a) Ito, A.; Ono, Y.; Tanaka, K. New J. Chem. 1998, 779. (b) Ito,
A.; Ono, Y.; Tanaka, K. J. Org. Chem. 1999, 64, 8236. (c) Miyazaki, Y.;
Kanbara, T.; Yamamoto, T. Tetrahedron Lett. 2002, 43, 7945. (d) Wang,
M.-X.; Zhang, X.-H.; Zheng, Q.-Y. Angew. Chem., Int. Ed. 2004, 43, 838.
(e) Wang, M.-X.; Yang, H.-B. J. Am. Chem. Soc. 2004, 126, 15412.
(4) For a review on heteroatom-bridged calixarenes: (a) Ko¨nig, B.;
Fonseca, M. H. Eur. J. Inorg. Chem. 2000, 2303. (b) Lhota´k, P. Eur. J.
Org. Chem. 2004, 1675.
10.1021/ol050493i CCC: $30.25
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in employing phenol rings as aromatic motifs because of the
attractive prospect that the incorporation of phenol rings
would enhance conformational stability due to the formation
of intramolecular hydrogen-bonding cyclic array.1,9 With this
in mind, to develop a new and versatile host molecule, we
have designed a novel calix[4]arene 1 consisting of phenol
rings and nitrogen bridges, by which additional hydrogen-
bonding and functionalization sites would be provided. In
addition, the bridging nitrogen atoms may conjugate with
aromatic rings to increase the electron density of the π cloud.
From the synthetic point of view, the fully methylated
derivative 2 rather than 1 has been preliminarily selected as
a target molecule in the present study to establish the
synthetic pathway leading to the construction of the basic
skeleton. As an eventual outcome, azacalix[4]arene 2 in a
1,3-alternate conformation could be prepared from readily
available starting materials. Moreover, X-ray crystallographic
analysis clearly revealed that molecules of 2 mutually
interacted outside the cavity to furnish an unique crystal
structure solely stabilized by virtue of the intermolecular
CH/π interactions. In this paper, we report the synthesis and
structural features of the novel phenol-derived azacalix[4]-
arene 2 involving nitrogen atoms as bridging units.
Scheme 1. Preparation of Azacalix[4]arene 2
presence of 20 mol % Pd(dba)2, 16 mol % P(t-Bu)3, and 2
equiv of t-BuONa to give azacalix[4]arene 2 in 30% yield.
1
FD MS, H NMR, 13C NMR, and elemental analysis fully
confirmed the structure of this new azacalix[4]arene 2.
In the 1H NMR spectrum of 2 (Figure 1), only four sharp
After our numerous attempts to prepare this novel azacalix-
[4]arene 2, the convergent, stepwise approach shown in
Scheme 1 was finally devised.10 Buchwald-Hartwig aryl
amination reaction11 of dibromoanisole 512a with m-phenyl-
enediamine 612b by using Pd(OAc)2 as a catalyst in the
presence of bis[2-(diphenylphosphino)phenyl] ether
(DPEphos)12c and t-BuONa gave nitrogen-bridged linear
trimer 7 in moderate yield (66%). The same palladium-
catalyzed aryl amination reaction was again applied for the
cross-coupling reaction of the trimer 7 with monoprotected
m-phenylenediamine 8 to furnish linear tetramer 9 in 54%
yield. Treatment of the resultant 9 with methyl iodide in the
presence of NaH, followed by the removal of the Boc group
with TFA, cleanly afforded linear tetramer 10 in 81% yield
in two steps. The final cyclization reaction of 9 was achieved
by heating 10 under reflux in anhydrous toluene in the
Figure 1. 1H NMR spectrum (500 MHz, CDCl3) of azacalix[4]-
arene 2 at 25 °C.
(9) Tsue, H.; Ohmori, M.; Hirao, K. J. Org. Chem. 1998, 63, 4866.
(10) A simpler [3 + 1] cyclization of 6 with 7 afforded a complicated
reaction mixture under essentially the same reaction conditions as those
used for the cross-coupling reactions 5 + 6 f 7 and 7 + 8 f 9.
(11) For reviews on the palladium-catalyzed aryl amination: (a) Wolfe,
J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc. Chem. Res. 1998,
31, 805. (b) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (c) Hartwig, J.
F. Angew. Chem., Int. Ed. 1998, 37, 2046. (d) Muci, A. R.; Buchwald, S.
L. Top. Curr. Chem. 2002, 219, 133.
(12) (a) Wolbers, M. P. O.; van Veggel, F. C. J. M.; Snellink-Rue¨l, B.
H. M.; Hofstraat, J. W.; Geurts, F. A. J.; Reinhoudt, D. N. J. Am. Chem.
Soc. 1997, 119, 138. (b) Breitfelder, S.; Cirillo, P. F.; Regan, J. R.
(Boehringer Ingerlheim Pharmaceuticals, Inc.). PCT Int. Appl. WO
200283642, 2002; Chem. Abstr. 2002, 137, 325421. (c) Kranenburg, M.;
van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Organometallics 1995, 14, 3081.
singlet signals appeared at δ 1.29, 2.83, 3.29, and 6.66 ppm
for the tert-butyl, methoxy, N-methyl, and aromatic hydro-
gens, respectively, suggesting that azacalix[4]arene 2 adopts
either a cone or 1,3-alternate conformation. The chemical
shift of the methoxy protons was used as a diagnostic for
elucidating the conformation of 2 in solution. Methoxy
hydrogens of 2 at δ 2.83 ppm experienced an upfield shift,
as compared with that of a reference compound, 4-tert-butyl-
2,6-bis(methylamino)anisole, at δ 3.68 ppm. A similar
upfield shift is reported for the carbocyclic calix[4]arene 3;13
2166
Org. Lett., Vol. 7, No. 11, 2005

Figure 2. ORTEP19 drawing of azacalix[4]arene 2. The displace-
ment ellipsoids are drawn at the 50% probability level. Hydrogen
atoms are omitted for clarity.
the methoxy protons characteristic of the cone and 1,3-
alternate conformations appear at δ 3.8 and 2.9 ppm,
respectively,13b whereas that of 4-tert-butyl-2,6-dimethyl-
anisole at 3.71 ppm.14 The upfield shift observed in 2
(∆δ ) -0.85 ppm15) agrees well with that of 1,3-alternate
3 (∆δ ) -0.8 ppm15) rather than that of cone 3 (∆δ )
+0.1 ppm15), clearly indicating that azacalix[4]arene 2 adopts
a 1,3-alternate conformation with D2d symmetry. Whether
the conformation is frozen or not in solution remains unclear
at this moment because the NMR spectral pattern shown in
Figure 1 was virtually independent of both the solvent and
the temperature (see Figure S4 in Supporting Information).
Nontheless, conclusive evidence for the conformational
preference for the 1,3-alternate conformation over the others
was provided by NOE measurements (Figure S5) as well as
X-ray crystallography.
A single-crystal suitable for X-ray crystallographic analy-
sis16 was obtained by slow crystallization from CH2Cl2.
Unsolvated azacalix[4]arene 2 crystallizes in a monoclinic
form, space group C2/m (Z ) 4). Just from appearance
(13) (a) Gutsche, C. D.; Dhawan, B.; Levine, J. A.; No, K. H.; Bauer,
L. J. Tetrahedron 1983, 39, 409. (b) Harada, T.; Rudzinski, J. M.; Shinkai,
S. J. Chem. Soc., Perkin Trans. 2 1992, 2109. (c) Grootehuis, P. D. J.;
Kollman, P. A.; Groenen, L. C.; Reinhoudt, D. N.; van Hummel, G. J.;
Ugozzoli, F.; Andreetti, G. D. J. Am. Chem. Soc. 1990, 112, 4165.
(14) Armitage, B. J.; Kenner, G. W.; Robinson, M. J. T. Tetrahedron
1964, 20, 723.
(15) Plus and minus signs indicate downfield and upfield shifts,
respectively, compared to the chemical shift of the relevant reference
compound.
Figure 3. Crystal structure of azacalix[4]arene 2 viewed down
(a) the a axis and (b) the b axis. The carbon, nitrogen, and oxygen
atoms are represented by open, closed, and shaded circles,
respectively. The two-dimensional structure on the ab plane is
schematically illustrated in panel c, where aromatic rings A, B,
and C are represented by open circles with lettering.
(16) X-ray data were collected on a Rigaku RAXIS RAPID imaging
plate area detector. The crystal structure was solved by direct methods and
refined by full-matrix least-squares. All non-hydrogen atoms were refined
anisotropically, and hydrogen atoms were refined using the riding model.
All calculations were performed using a crystallographic software package,
CrystalStructure version 3.6.0.20 Crystal data for 2: Mr ) 765.09,
monoclinic, space group C2/m, a ) 23.64(1), b ) 16.890(6), c ) 12.682-
(5) Å, â ) 116.40(3)°, V ) 4535(3) Å3, Z ) 4, Fcalc ) 1.120 g cm-3, 2θmax
) 57.4°, Mo KR (λ ) 0.71075 Å), µ ) 0.71 cm-1, θ - ω scans, T ) 173
K, 25 100 independent reflections, 6370 observed reflections (I > 3.0σ(I)),
340 refined parameters, R ) 0.092, Rw ) 0.136, ∆Fmax ) 2.38 e Å-3, ∆Fmin
) -2.26 e Å-3; CCDC 263006. See Supporting Information for crystal-
lographic data in CIF format.
(Figure 2; see also Figure S6), azacalix[4]arene 2 is in a
highly symmetrical 1,3-alternate conformation that is similar
to that reported for thiacalix[4]arene 44b,6b rather than that
for the carbocyclic analogue 3.2,13c On the other hand, this
conformation of 2 is in striking contrast to those reported
for analogous nitrogen-bridged calixarenes incorporating
benzene rings and/or heteroaromatics in place of phenol; for
example, “clip-like” and almost flat conformational structures
Org. Lett., Vol. 7, No. 11, 2005
2167

were reported for tetrazacalix[2]arene[2]triazine8e and benzene-
derived deoxyazacalix[4]arene,8a respectively. To be more
accurate, conformation of 2 is slightly distorted from the ideal
1,3-alternate conformation with D2d symmetry to one with
Cs symmetry. There exists only one symmetry plane bisecting
the two opposite aromatic units, eventually lowering the
symmetrical arrangement of the aromatic systems to three
different types designated as A, B, and C (Figure 2; see also
Figure S6). Indeed, the dihedral angles between the aromatic
rings A, B, and C and the mean plane defined by the four
nitrogen bridges are 56.7, 64.2, and 61.9°, respectively.
Moreover, the bond alternation of the N-C(sp2) bonds was
observed, of which the distances were 1.407, 1.417, 1.416,
and 1.425 Å for N4-C23, N4-C6, N5-C2, and N5-C15,
respectively. Nonuniform packing forces arising from the
unique crystal structure of 2 (vide infra) must be a reason
for the observed decline in the symmetry of 2 from D2d to
Cs in the solid state.
Of further interest is that the crystal structure is solely
characterized by three types of intermolecular CH/π interac-
tions between azacalix[4]arenes 2; the first one is formed
between the methoxy groups located on the rings A and the
centroid of the rings A belonging to the nearest molecules
(type R, C‚‚‚centroid, 3.616 Å; CH‚‚‚centroid, 3.121 Å and
114.30°; H‚‚‚centroid‚‚‚C4, 103.79°; Figure 3a), the second
one between the tert-butyl groups bound to the rings B and
the centroid of the rings B of another neighboring 2 (type â,
C‚‚‚centroid, 4.005 Å;17 Figure 3b), and the third one between
the tert-butyl groups of the rings C and the centroid of the
rings C of another adjacent molecules (type γ, C‚‚‚centroid,
4.072 Å;17 Figure 3b). By virtue of the intermolecular CH/π
interactions of type R, a one-dimensional infinite chain
structure is formed along the b axis in an antiparallel
direction, as shown in Figure 3a. Besides, the one-
dimensional chains interact with each other along the a axis
by a combination of the CH/π interactions of types â and γ,
as depicted in Figure 3b. As a consequence of these
intermolecular interactions, a two-dimensional sheet structure
of 2 is eventually formed on the ab plane, as schematically
illustrated in Figure 3c (see also Figures S7-S9).
hydrogen bonding interactions in the former and by the
cooperation of intermolecular π/π and halogen/nitrogen
interactions in the latter. Likewise, a combination of π/π and
CH/π interactions was reported to build up the crystal
structure of thiacalix[4]arene 4.6b On the other hand, the
crystal structure of 2 is established exclusively by the
intermolecular CH/π interactions of 2, which behaves as both
CH/π donor and acceptor at once. From this experimental
result, it is reasonable to presume that the incorporation of
nitrogen atoms as bridging units increases the π-basic
character of the aromatic rings, thereby allowing the promi-
nent contribution of intermolecular CH/π interactions to the
control of the crystal structure of 2.
In summary, we have described the synthesis of the novel
phenol-derived azacalix[4]arene 2 in four steps from readily
1
available starting materials. H NMR and X-ray crystal-
lographic analysis clearly demonstrated that azacalix[4]arene
2 adopts a 1,3-alternate conformation both in solution and
in the solid state. In the crystal, azacalix[4]arene 2 was found
to enjoy its simultaneous role as both CH/π donor and
acceptor in the formation of the two-dimensional crystal
structure as a result of the enforced π-basic character of
aromatic rings. Our ongoing preliminary study for preparing
completely demethylated azacalix[4]arene 1 has revealed that
demethylation of 2 and the synthetic precursors is feasible,
though partial at this moment for the former. Further work
aimed at synthesizing 1, a perfect analogue of p-tert-
butylcalix[4]arene, is currently underway in our laboratory
in order to construct a versatile and efficient host molecule.
Acknowledgment. Financial support from Sasakawa
Grants for Science Fellows to H.T. is gratefully acknowl-
edged.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds
(including NMR spectra and crystal structure for azacalix-
[4]arene 2) (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
Similar two-dimensional network structures have precedent
in azacalix[2]arene[2]triazine8e and the clathrate complex of
a pyridine-appended p-tert-butylcalix[4]arene,18 in which
two-dimensional structures are formed by intermolecular
OL050493I
(18) Messina, M. T.; Metrangolo, P. M.; Pappalardo, S.; Parisi, M. F.;
Pilati, T.; Resnati, G. Chem. Eur. J. 2000, 6, 3495.
(19) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
(20) CrystalStructure, version 3.6.0; Rigaku and Rigaku/MSC: The
Woodlands, TX, 2004.
(17) CH‚‚‚centroid distance and angle are omitted for the positional
disorder of tert-butyl groups.
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