New upper rim pyridine-bridged calix[4]arenes: Synthesis and complexation properties toward neutral molecules and ammonium ions in organic media

Article abstract of DOI:10.1021/jo960937b

A new series of calix[4]arenes, diametrically bridged at the upper rim with pyridino systems, has been synthesized. The shape, rigidity, and chemical structure of the bridge influence the host-guest complexation properties of these systems in solution toward several neutral molecules having acidic C-H bonds. Additionally, selective complexation of methylammonium tosylate in comparison with other ammonium salts has been observed and the strength of this complexation enhanced by electron-donor ability of the p-substituent on the pyridine moiety of the calixarene host. X-ray crystal structures of endo complexes of host 5 with malononitrile and nitromethane have been resolved, verifying specific C-H bonding with the hard oxygen and nitrogen atoms of the bridge and the soft aromatic ring of the calixarene.

Full text of DOI:10.1021/jo960937b

J . Org. Chem. 1996, 61, 6881-6887
6881
New Up p er Rim P yr id in e-Br id ged Ca lix[4]a r en es: Syn th esis a n d
Com p lexa tion P r op er ties tow a r d Neu tr a l Molecu les a n d
Am m on iu m Ion s in Or ga n ic Med ia
Arturo Arduini,† William M. McGregor,† Andrea Pochini,*,† Andrea Secchi,†
Franco Ugozzoli,‡ and Rocco Ungaro†
Dipartimento di Chimica Organica ed Industriale, Universita` di Parma, Viale delle Scienze,
43100 Parma, Italy, and Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica,
Chimica Fisica and Centro di Studio per la Strutturistica Diffrattometrica del CNR, Universita` di
Parma, Viale delle Scienze, 43100 Parma, Italy
Received May 20, 1996X
A new series of calix[4]arenes, diametrically bridged at the upper rim with pyridino systems, has
been synthesized. The shape, rigidity, and chemical structure of the bridge influence the host-
guest complexation properties of these systems in solution toward several neutral molecules having
acidic C-H bonds. Additionally, selective complexation of methylammonium tosylate in comparison
with other ammonium salts has been observed and the strength of this complexation enhanced by
electron-donor ability of the p-substituent on the pyridine moiety of the calixarene host. X-ray
crystal structures of endo complexes of host 5 with malononitrile and nitromethane have been
resolved, verifying specific C-H bonding with the hard oxygen and nitrogen atoms of the bridge
and the soft aromatic ring of the calixarene.
In tr od u ction
diametrically bridged calix[4]arenes with a xylyl or a 2,4-
hexadiynyl moiety to complex neutral molecules in the
gas phase.3
Calix[4]arenes are cyclic molecules containing a hy-
drophobic cavity, extensively used in the study of host-
guest interactions.1 The formation of stable endo-cavity
complexes with neutral molecules had been observed in
the solid state1,2 and subsequently studied by us in the
gas phase3 and in solution.4 In particular, restriction of
the conformational mobility of calix[4]arenes in solution
leads to increased affinity toward neutral guests.4 In
fact, it has been recently shown that even cone tetra-
alkoxycalix[4]arenes are not completely blocked in solu-
tion, but instead experience residual conformational
mobility between two C2v flattened cone structures,5
which adversely affects the molecular recognition proper-
ties of the cavitands. The reduction of conformational
mobility and the preservation of the cone structure has
been achieved as follows: (a) by functionalization at the
lower rim with short ethereal bridges to immobilize the
calixarene in a “rigid” cone conformation4,5b and (b) by
introducing, at the upper rim, rigid bridges containing
aromatic or other π-donor groups.3,6
These cavitands showed high complexation efficiency
and selectivity toward neutral guests containing acidic
C-H groups. Our attempts to evaluate the complexation
properties of the cavitands 1 and 2 in organic media
toward neutral molecules, by 1H NMR spectroscopy, were
unsuccessful, probably because the type of interactions
involved were too weak to overcome the solvation effects.
Therefore, we decided to improve the complexation ability
of this type of cavitands by introducing an additional
binding site in the bridge, using a pyridine ring instead
of xylyl or bisacetylenic groups.
In previous work we used mass spectrometric tech-
niques to study the ability of a series of upper rim
Pyrido-crown ethers have already been extensively
used to complex, for example, ammonium salts.7 Typi-
cally, the basic pyridine nitrogen and two of the oxygen
atoms in the crown system are involved in the complex-
ation of ammonium ions. Although there is a general
interest in the complexation of ammonium ions (espe-
cially quaternary8) because of their relevance to biological
processes,9 only recently some work on their complexation
in organic media by calixarenes has been published.4,10,11
† Dipartimento di Chimica Organica ed Industriale.
‡ Dipartimento di Chimica Generale ed Inorganica.
X Abstract published in Advance ACS Abstracts, September 1, 1996.
(1) Gutsche, C. D. Calixarenes, Monographs in Supramolecular
Chemistry; Stoddart, J . F., Ed.; The Royal Society of Chemistry:
Cambridge, 1989.
(2) Vicens, J ., Bo¨hmer, V., Eds. Calixarenes: a Versatile Class of
Macrocyclic Compounds; Kluwer Academic Publishers: Dordrecht,
1991.
(3) Arduini, A.; Cantoni, M.; Graviani, E; Pochini, A.; Secchi, A.;
Sicuri, A. R.; Ungaro, R.; Vincenti, M. Tetrahedron 1995, 51, 599-
606.
(4) Arduini, A.; McGregor, W. M.; Paganuzzi, D.; Pochini, A.; Secchi,
A.; Ugozzoli, F.; Ungaro, R. J . Chem. Soc., Perkin Trans. 2 1996, 839-
846.
(7) See, e.g.: (a) Bell, T. W.; Sahni, S. K. In Inclusion Compounds;
Atwood, J . L., Davies, J . E. D., MacNicol, D. D., Eds.; Oxford University
Press: New York, 1991; Vol. 4, pp 325-390. (b) Wang, T.; Bradshaw,
J . S.; Izatt, R. M. J . Heterocycl. Chem. 1994, 31, 1097-1114 and
references therein. (c) Nazarenko, A. Y.; Huszthy, P.; Bradshaw, J .
S.; Lamb, J . D.; Izatt, R. M. J . Incl. Phenom. Mol. Rec. Chem. 1995,
20, 13-22.
(5) (a) Ikeda, A.; Tsuzuki, H.; Shinkai, S. J . Chem. Soc., Perkin
Trans. 2 1994, 2073-2080. (b) Arduini, A.; Fabbi, M.; Mantovani, M.;
Mirone, L.; Pochini, A.; Secchi, A.; Ungaro, R. J . Org. Chem. 1995, 60,
1454-1457.
(6) Arduini, A.; Casnati, A.; Fabbi, M.; Minari, P.; Pochini, A.; Sicuri,
A. R.; Ungaro, R. Supramolecular Chem. 1993, 1, 235-246.
S0022-3263(96)00937-1 CCC: $12.00 © 1996 American Chemical Society

6882 J . Org. Chem., Vol. 61, No. 20, 1996
Arduini et al.
Sch em e 1
Sch em e 2
Resu lts a n d Discu ssion
Syn th esis of th e Hosts. The major aim of this work
was to investigate the cooperative effect of the lipophilic
calixarene cavity and a basic group in close proximity,
on the complexing ability of the hosts toward neutral
molecules and ammonium ions.
9
The new upper rim bridged hosts 5-7, having pyridine
units of varying basicities,12 were synthesized from the
readily available diol 36 and pyridino diacid chlorides13
in high dilution conditions. For comparison, the synthe-
sis of a corresponding isophtalic derivative 4 was also
realized (Scheme 1).
As a final structural modification of these hosts one
or two polarizable iodine atoms were introduced on the
para position of the unbridged aromatic nuclei by iodi-
nation of 5 with iodine and silver trifluoracetate.14 The
extent of iodination was controlled by choosing the
appropriate reagent molar ratio and by varying the
solvent. In this way the monoiodo derivative 8 was
obtained in 30% yield with a substantial recovery of
starting material by using 1.5 equiv of iodine in CHCl3,
whereas the diiodo compound 9 was produced in 65%
yield, operating in CH2Cl2 with 2 equiv of the reagent
(see Scheme 2).
1
solvents, were performed by H NMR spectroscopy. In
these experiments, fast exchange conditions were ob-
served, and therefore, the stability constants were easily
calculated, having verified through continuous variation
methods (J ob plot)15 a 1:1 stoichiometry for the com-
plexes. 1H NMR experiments also provide useful infor-
mation on the structure of the complexes. A significant
upfield shift on the methyl and methylene protons of the
guest is observed on complexation, which implies that
the acidic protons of the guest interact with the π-elec-
trons of the host cavity. In fact, any interaction of these
protons, involving only the nitrogen of the pyridine
moiety and the oxygen atoms present in the bridge,
should result in a downfield shift of these signals.
The values of the stability constants are listed in Table
1. As expected, the isophthalic derivative 4 shows no
complexation for any of these guests, clearly demonstrat-
ing that the presence of the pyridine nitrogen in the
bridge is essential.
Com p lexa tion Stu d ies. The complexation studies of
some neutral molecules containing acidic C-H groups
such as CH3CN, CH3NO2, and CH2(CN)2 with the dia-
metrically bridged calixarenes, 4-9, in various apolar
To rationalize the value distribution of the stability
constants several factors that can affect complexation
phenomena must be taken into account: the acidity,
shape and size of the guest, the basicity of the nitrogen
of the pyridine ring, the accessibility of the host cavity,
and the polarity of the solvent.
The influence of the solvent and the acidity of the guest
on the extent of complexation has been extensively
described by other authors using different hosts.16 As
expected, the stability of the complexes is higher in the
less polar solvent CCl4 and increases with the acidity of
the guests17 (malononitrile > nitromethane > acetoni-
trile). Moreover, our previous results4 using some rigidi-
fied calix[4]arene cavitands as hosts showed a strong
dependence of the complexation efficiency on the steric
bulkiness of the guest (malononitrile > nitromethane >
acetonitrile).
(8) (a) Dougherty, D. A.; Kearney, P. C.; Mizoue, L. S.; Kumpf, R.
A.; Forman, J . E.; McCurdy, A. In Computational Approaches in
Supramolecular Chemistry; Wippf, G., Ed.; Kluwer Academic Publish-
ers: Dordrecht, The Netherlands, 1994; p 301-309. (b) Kim, K. S.;
Lee, J . Y.; Lee, S. J .; Ha, T.-K.; Kim, D. H. J . Am. Chem. Soc. 1994,
116, 7399-7400. (c) Caldwell, J . W.; Kollman, P. A. J . Am. Chem. Soc.
1995, 117, 4177-4178.
(9) Sussman, J . L.; Harel, M.; Frowlow, F.; Oefner, C.; Goldman,
A.; Tiler, L.; Silman, I. Science 1991, 253, 872-879.
(10) See, e.g.: Casnati, A.; J acopozzi, P.; Pochini, A.; Ugozzoli, F.;
Cacciapaglia, R.; Mandolini, L.; Ungaro, R. Tetrahedron 1995, 51, 591-
598 and references therein.
(11) (a) De Iasi, G.; Masci, B. Tetrahedron Lett. 1993, 34, 6635-
6638. (b) Masci, B. Tetrahedron 1995, 51, 5459-5464.
(12) For the basicity of pyridine derivatives in the gas phase see,
e.g.: Speranza, M. In Advances in Heterocyclic Chemistry; Katritzky,
A. R., Ed.; Academic Press: New York, 1986; Vol. 40, pp 25-96.
(13) (a) Markees, D. G.; Kidder, G. W. J . Am. Chem. Soc. 1956, 78,
4131-4135. (b) Kuttaka, A.; Sugano, Y.; Otsuka, M.; Ohno, M.
Tetrahedron 1988, 44, 2821-2833. (c) Suga, A.; Sugiyama, T.; Otsuka,
M.; Ohno, M. Sugiura, Y.; Maeda, K. Tetrahedron 1991, 47, 1191-
1204. The new compounds were prepared by refluxing the correspond-
ing diacid for 4 h in CCl4 with an excess of oxalyl chloride under a
nitrogen atmosphere, cooling and evaporating the product to dryness
under reduced pressure to give, in quantitative yield, the diacid
chloride, which could be stored for a few days at 0-5 °C under nitrogen.
(14) (a) Timmerman, P.; Verboom, W.; Reinhoudt, D. N.; Arduini,
A.; Grandi, S.; Sicuri, A. R.; Pochini, A.; Ungaro, R. Synthesis 1994,
185-189. (b) Arduini, A.; Pochini, A.; Sicuri, A. R.; Secchi, A.; Ungaro,
R. Gazz. Chim. Ital. 1995, 124, 129-132.
(15) Connors, K. A. Binding Constants: The Measurements of
Molecular Complex Stability; J ohn Wiley & Sons: New York, 1987.
(16) (a) de Boer, J . A. A.; Reinhoudt, D. N.; Harkema, S.; van
Hummel, G. J .; de J ong, F. J . Am. Chem. Soc. 1982, 104, 4073-4076.
(b) van Staveren, C. J .; Aarts, V. M. L. J .; Grootenhuis, P. D. J .; van
Eerden, J .; Harkema, S.; Reinhoudt, D. N. J . Am. Chem. Soc. 1986,
108, 5271-5276.
(17) (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463. (b)
Abraham, M. H. Chem. Soc. Rev. 1993, 73-83.

Upper Rim Pyridine-Bridged Calix[4]arenes
J . Org. Chem., Vol. 61, No. 20, 1996 6883
Ta ble 1. Associa tion Con sta n ts K1:1 (L m ol-1) of th e Com p lexes of Hosts 4-9 w ith Sever a l Gu est Molecu les in Va r iou s
Or ga n ic Solven ts a t 300 Ka
cavitands
guests
4d
5
6
7
8
9
CH3CN (CCl4)
CH3NO2 (CCl4)
CH2(CN)2 (CDCl3)
CH3NH3OTs (CDCl3)
n
n
n
n
36 ( 10
57 ( 5c
79 ( 20
131 ( 40
13 ( 2
124 ( 10c
50 ( 4
b
b
30 ( 14
47 ( 22
77 ( 46
142 ( 39
25 ( 2
29 ( 5
18 ( 2
n
37 ( 2
1970 ( 277
310 ( 55
a
b
No complexation was observed for di-, tri-, or tetramethylammonium tosylate. The calixarene host was not appreciably soluble.
c Negligible complexation in CDCl3. n indicates negligible complexation.
d
F igu r e 2. Plot of association constants for the complexation
of methylammonium tosylate by hosts 4-9 in CDCl3.
F igu r e 1. Plot of association constants for the complexation
of neutral molecules by hosts 4-9 in various organic solvents.
Cavitand 8 shows the same complexing efficiency as
host 5 (see Figure 1). These results reveal that one side
of the receptor cavity, not hindered by the iodine atom,
is still available for complexation. On the contrary,
cavitand 9 experiences very poor complexing ability with
a reversed selectivity, showing that the predominant
steric effect of the two iodine atoms reduces access to the
host cavity.
ability of the p-substituent on the pyridine moiety of the
host. The structure of the methylammonium complexes
of hosts 5-8 seems to be different from that observed
previously with other calixarene cavitands;4 in fact, the
tosylate counterion changes its chemical shift and CH3-
+
NH3 signals broaden upon complexation. These data
indicate that the ion pair breaks down and that the
complex exists as a ligand-separated ion pair, probably
through the interaction of the ligating sites with the
Substituted methylammonium tosylates, which are
sufficiently soluble in CDCl3 to allow binding studies,4
were also used as guests. No interaction was observed
between dimethyl-, trimethyl-, and tetramethylammo-
nium tosylates and any of our host molecules 4-9 (see
Table 1).
NH3 group.18
+
X-r a y Stu d ies. The structures of the complexes 5 ⊂
CH2(CN)2 and 5 ⊂ CH3NO2 obtained from the crystal-
lographic study are reported in Figure 3a,b and in Figure
3c,d, respectively.
Interestingly, methylammonium tosylate is the only
guest complexed by our receptors. This remarkable
selectivity is ascribed to the reduced dimension of the
host cavity, which is too small to complex alkylammo-
nium tosylate ion pairs larger than CH3NH3+OTs-, in
agreement with our previous studies.4 The most efficient
host is the p-dimethylamino derivative 7 (K ) ca. 2 ×
103 L mol-1), which, on the other hand, shows very little
affinity toward neutral guests having acidic C-H groups,
such as malononitrile (see Table 1).
Only the isophthaloyl derivative 4 and the diiodopy-
ridino derivative 9 do not complex the methylammonium
ion pair: the former because there is no nitrogen atom
in the bridge and the latter because the two bulky iodine
atoms prevent the access to the binding site. Figure 2
emphasizes the complexation trend of methyl ammonium
on varying the pyridino-calix structure. As expected, the
stability constants increase with the electron-donating
In both complexes the host molecule shows common
general features. It possesses a “C2 - like distorted cone
conformation” with the pseudo 2-fold axes passing through
N(1*) of the pyridine ring and to the center of mass of
the methylene bridges of the calix[4]arene. The two
opposite phenolic subunits A and C are almost orthogonal
to each othersdihedral angles between their least-
squares planes, 105.2(1) and 90.2(2)°swhereas the rings
B and D are tilted away from each other with angles of
14.7(1) and 19.7(2)° in 5 ⊂ CH2(CN)2 and 5 ⊂ CH3NO2,
respectively.
Table 2 provides a quantitative description of the calix-
[4]arene moiety conformations as a list of the dihedral
angles between the least-squares planes of the phenolic
rings and that through the four CH2 bridging carbon
(18) For complexation at the methyl group of a methylammonium
cation see ref 4.

6884 J . Org. Chem., Vol. 61, No. 20, 1996
Arduini et al.
F igu r e 3. Perspective views of the complexes 5 ⊂ CH2(CN)2 (a and b) and 5 ⊂ CH3NO2 (c and d). The hydrogen atoms of the
guest only have been reported for clarity.
atoms taken as molecular reference plane R19 and from
the Conformational Parameters,20 respectively. For both
complexes the Symbolic Representation of the confor-
mation of the calix[4]arene is therefore C1 + -,+ -,+ -,
+ -.
In the complex 5 ⊂ CH2(CN)2 the calix[4]arene is
blocked in the observed “C2 - like conformation” by the
biscarbonyl pyridine bridge that links the two phenolic
subunits B and D and whose plane is almost perpen-
dicular to them and to the reference plane R (dihedral
angles Py-B, 91.9(1)°, Py-D, 90.3(1)° and Py-R, 83.39-
(8)°). Such orientation of the pyridine bridging group
with respect to the aromatic nuclei of the calix[4]arene
allows the host to act as “tongs” toward the malononitrile
guest molecule, which is complexed via a trifurcate
hydrogen bond involving the hydrogen atoms H(1G) of
the malononitrile and the O(1*), N(1*), O(3*) acceptor
atoms of the biscarbonyl pyridine bridge. The malono-
nitrile guest forms a weaker bifurcate hydrogen bond21
(19) Perrin, M.; Hoeler, D. In ref 2, pp 65-85.
(20) Ugozzoli, F.; Andreetti, G. D. J . Incl. Phenom. Mol. Rec. Chem.
1992, 13, 337-348.

Upper Rim Pyridine-Bridged Calix[4]arenes
J . Org. Chem., Vol. 61, No. 20, 1996 6885
Ta ble 2. Con for m a tion a l P a r a m eter s (Deg) of th e
Ca lix[4]a r en e Moiety a n d Dih ed r a l An gles (Deg) betw een
th e Lea st-Squ a r es P la n es th r ou gh th e P h en olic Rin gs
a n d th e Refer en ce P la n e R
donor groups of the bridge and the “soft” aromatic cavity.
Specific complexation of methylammonium tosylate has
been observed, and the stability of this complex was
improved by structural modification of the calixarene
host.
5 ⊂ CH2(CN)2
5 ⊂ CH3NO2
æ
κ
æ
κ
Exp er im en ta l Section
A-D
D -C
C -B
B -A
110.7(4)
66.2(4)
105.9(4)
68.9(4)
-70.5(4)
-104.4(4)
-70.5(4)
98.8(8)
70.2(9)
97.7(9)
69.6(9)
-68.5(9)
-99.7(9)
-63.9(9)
-100.8(8)
Gen er a l P r oced u r es. All reactions were carried out under
nitrogen. Dichloromethane was distilled and stored over 3 Å
molecular sieves before use. All other reagents and solvents
were of reagent grade quality, obtained from commercial
suppliers, and used without further purification. NMR spectra
were recorded in CDCl3 unless otherwise indicated. Chemical
shifts (δ) are expressed in ppm relative to internal tetram-
ethylsilane (TMS). Mass spectra were determined in the CI
mode (CH4). Melting points are uncorrected. Elemental
analyses were obtained from Dipartimento Farmaceutico at
the University of Parma. The results with calixarenes are very
often inaccurate;23 however, the spectral data adequately
confirm the structure of these new compounds (also see the
supporting information). The calixarenes 1,3 2,3 and 36 were
synthesized according to literature procedures.
Gen er a l Meth od for th e Syn th esis of Up p er Rim
Br id ged Ca lix[4]a r en es 4-7. To a solution of appropriate
diacid chloride (0.7 mmol) in 300 mL of CH2Cl2 were added
2,6-di-tert-butylpyridine (0.5 g, 2.6 mmol) and compound 3 (0.5
g, 0.65 mmol). The reaction mixture was stirred for 24 h and
then quenched with water (100 mL). The organic layer was
separated, washed twice with distilled water (2 × 100 mL),
evaporated under reduced pressure, and dried in vacuo to
remove the excess of 2,6-di-tert-butylpyridine entirely.
Isop h th a loyl Der iva tive 4. Purification of the pale yellow
residue by column chromatography (hexane:ethyl acetate )
70:30) and recrystallization from methanol afforded 120 mg
(20% yield) of 4 as a white solid, mp 105 °C. 1H NMR (300
MHz) δ: 1.22 and 1.26 (2t, 12H, J ) 6.9 Hz); 3.22 (d, 4H, J )
12.6 Hz); 3.57 and 3.59 (2q, 8H); 3.77 (t, 4H, J ) 4.8 Hz); 3.98
(t, 4H); 4.09 (t, 4H, J ) 6.3 Hz); 4.42 (t, 4H); 4.59 (d, 4H); 4.81
(s, 4H); 6.71 (s, 4H); 6.77 (t, 2H, J ) 7.5 Hz); 7.07 (d, 4H); 7.49
(t, 1H, J ) 7.8 Hz); 7.91 (s, 1H); 8.18 (d, 2H). 13C (75 MHz) δ:
15.2, 15.4, 33.7, 66.3, 66.5, 66.8, 69.4, 69.6, 72.0, 74.7, 123.2,
128.4, 128.7, 128.9, 130.0, 131.3, 133.4, 133.7, 135.9, 155.0,
156.6, 165.5. Mass spectrum m/ e: 903 (M + H)+. Anal.
Calcd for C54H62O12: C, 71.82; H, 6.92. Found: C, 70.51; H,
6.48.
-108.9(4)
dihedral angles (deg)
A-R
144.65(7) 135.8(2)
B-R
C-R
D-R
98.74(9)
140.54(8)
95.96(9)
99.0(2)
135.1(2)
100.7(2)
between H(2G) and the π orbitals on C(4A) and C(5A)
atoms on the phenolic ring A.22 Bond distances and
angles of the H bonds are reported in Table 3.
The structural properties of the 5 ⊂ CH3NO2 complex
are significantly different. The calix[4]arene host shows
a more symmetric and less flattened cone conformation
(see Table 2), whereas the biscarbonyl pyridine group is
more flexed on the reference plane R of the calix[4]arene
(dihedral angles Py-B, 95.5(2)°, Py-D, 90.9(2)°, Py-R,
79.2(2)°). The complexation of the guest occurs mainly
via a bifurcated hydrogen bond involving the H(3G) of
the nitromethane and the two acceptor atoms O(3*) and
N(1*) of the biscarbonyl pyridine bridge as reported in
Table 3. The guest is thus blocked in the observed
positionswith the two hydrogen atoms H(1G), H(2G)
“astride” the phenolic unit Asby the hydrogen bonding21
involving H(2G) and the π orbital on the C(3A) (see Table
3).22 In both complexes the complexed guest is almost
parallel to the phenolic unit A: the dihedral angles
between the non-hydrogen atoms of the guest and the
phenolic ring A are 3.9(2)° and 2.6(5)° for the malononi-
trile and nitromethane complexes, respectively, even if
the interplane distances do not reveal specific stacking
interactions.
The comparison of the molecular structure of the two
complexes reveals that both guests are held by the host
via the cooperation of two different hydrogen bonding
mode: one “multifurcated” with the pyridine bridge and
the other one with the aromatic ring of the calixarene
via a CH-π interaction.22 However, the contribution of
the two different hydrogen bonding modes is different in
the two complexes: the more acidic malononitrile shows
a stronger multifurcated interaction with pyridine bridge,
whereas the nitromethane shows a stronger CH-π
interaction.
P yr id in e-2,6-d ica r boxyla te Der iva tive 5. Purification
of the pale yellow residue by recrystallization from methanol
afforded 290 mg (50% yield) of 5 as a white solid, mp 170-
171 °C. 1H NMR (300 MHz) δ: 1.19 and 1.25 (2t, 12H, J )
7.2 Hz); 3.17 (d, 4H, J ) 12.6 Hz); 3.54 and 3.58 (2q, 8H); 3.77
(t, 4H, J ) 6.0 Hz); 3.95 (t, 4H); 4.04 (t, 4H, J ) 6.6 Hz); 4.40
(t, 4H); 4.55 (d, 4H); 4.98 (s, 4H); 6.62 (s, 4H); 6.64 (t, 2H, J )
7.5 Hz); 7.00 (d, 4H); 7.97 (t, 1H, J ) 9.0 Hz); 8.25 (d, 2H). 13
C
(75 MHz) δ: 15.2, 15.4, 30.9, 66.2, 66.4, 66.9, 69.4, 69.6, 72.0,
74.6, 123.0, 127.2, 128.7, 128.9, 129.8, 133.2, 135.8, 137.8,
147.6, 154.8, 156.8, 165.0. Mass spectrum m/ e: 904 (M + H)+.
Anal. Calcd for C53H61O12N: C, 70.41; H, 6.80; N, 1.55.
Found: C, 69.01; H, 6.71; N, 1.38.
4-Meth oxypyr idin e-2,6-dicar boxylate Der ivative 6. Pu-
rification of the pale yellow residue by recrystallization from
methanol afforded 300 mg (50% yield) of 6 as a white solid,
mp 194-195 °C. 1H NMR (300 MHz) δ: 1.20 and 1.25 (2t,
12H, J ) 6.9 Hz); 3.18 (d, 4H, J ) 12.6 Hz); 3.54 and 3.58 (2q,
8H); 3.77 (t, 4H, J ) 5.1 Hz); 3.95 (t, 4H); 3.97 (s, 3H); 4.04 (t,
4H, J ) 7.2 Hz); 4.40 (t, 4H); 4.55 (d, 4H); 4.94 (s, 4H); 6.62 (s,
4H); 6.68 (t, 2H, J ) 7.5 Hz); 7.02 (d, 4H); 7.74 (s, 2H). 13C
(75 MHz) δ: 15.2, 15.4, 30.9, 66.2, 66.5, 66.6, 69.5, 69.6, 72.0,
74.6, 113.1, 123.0, 128.7, 129.2, 129.6, 133.2, 135.8, 149.3,
154.8, 156.8, 165.0. Mass spectrum m/ e: 934 (M + H)+. Anal.
Calcd for C54H63O13N: C, 69.44; H, 6.80; N, 1.50. Found: C,
68.40; H, 6.57; N, 1.21.
Con clu sion s
This new series of calix[4]arenes, diametrically bridged
at the upper rim with pyridine units, shows interesting
recognition properties toward molecules containing acidic
C-H and N-H bonds. The strength of complexation is
influenced by the acidity, shape, and size of the guest
and by the presence of nitrogen in the bridge and the
accessibility of the host cavity. X-ray crystal structures
of the complexes 5 ⊂ CH2(CN)2 and 5 ⊂ CH3NO2 confirm
the participation in the binding process of both “hard”
(21) For the van der Waals radii see: Bondi, A. J . Phys. Chem. 1964,
68, 441-451.
(22) For the CH-π interactions see, e.g.: Nishio, M; Umezawa, Y;
Hirota, M; Takeuchi, Y. Tetrahedron 1995, 51, 8665-8701.
(23) Bo¨hmer, V.; J ung, K.; Schon, M.; Wolff, A. J . Org. Chem. 1992,
57, 790-792. Gutsche, C. D.; See, K. A. J . Org. Chem. 1992, 57, 4527-
4539.

6886 J . Org. Chem., Vol. 61, No. 20, 1996
Arduini et al.
Ta ble 3. In ter a tom ic Dista n ces (Å) a n d An gles (Deg) of th e In ter m olecu la r Host-Gu est Hyd r ogen Bon d s
donor‚‚‚acceptor (Å)
H‚‚‚acceptor (Å)
5 ⊂ CH2(CN)2
donor-H‚‚‚acceptor (Deg)
C(1G)‚‚‚O(1*)
3.370(4)
3.173(5)
3.255(4)
3.501(5)
3.608(5)
H(1G)‚‚‚O(1*)
2.753(2)
2.401(4)
2.578(2)
2.857(4)
2.875(4)
C(1G)-H(1G)‚‚‚O(1*)
120.2(2)
133.3(2)
124.8(2)
122.8(2)
130.8(2)
C(1G)‚‚‚N(1*)
C(1G)‚‚‚O(3*)
C(1G)‚‚‚C(4A)
C(1G)‚‚‚C(5A)
H(1G)‚‚‚N(1*)
H(1G)‚‚‚O(3*)
H(2G)‚‚‚C(4A)
H(2G)‚‚‚C(5A)
C(1G)-H(1G)‚‚‚N(1*)
C(1G)-H(1G)‚‚‚O(3*)
C(1G)-H(2G)‚‚‚C(4A)
C(1G)-H(2G)‚‚‚ (5A)
5 ⊂ CH3NO2
C(1G)‚‚‚N(1*)
C(1G)‚‚‚O(3*)
C(1G)‚‚‚C(3A)
3.31(1)
3.24(1)
3.65(1)
H(3G)‚‚‚N(1*)
H(3G)‚‚‚O(3*)
H(2G)‚‚‚C(3A)
2.68(1)
2.32(1)
2.71(1)
C(1G)-H(3G)‚‚‚N(1*)
C(1G)-H(3G)‚‚‚O(3*)
C(1G)-H(2G)‚‚‚C(3A)
121.1(1)
151.4(9)
157.0(1)
4-(Dim eth yla m in o)p yr id in e-2,6-d ica r boxyla te Der iva -
tive 7. Purification of the pale yellow residue by recrystalli-
zation from methanol afforded 245 mg (40% yield) of 7 as a
white solid, mp 205-207 °C. 1H NMR (300 MHz) δ: 1.20 and
1.25 (2t, 12H, J ) 7.2 Hz); 3.10 (s, 6H); 3.18 (d, 4H, J ) 12.6
Hz); 3.54 and 3.58 (2q, 8H); 3.77 (t, 4H, J ) 5.4 Hz); 3.95 (t,
4H); 4.04 (t, 4H, J ) 6.9 Hz); 4.41 (t, 4H); 4.55 (d, 4H); 4.90 (s,
4H); 6.64 (s, 4H); 6.73 (t, 2H, J ) 7.5 Hz); 7.04 (d, 4H); 7.42 (s,
2H). 13C (75 MHz) δ: 15.2, 15.4, 30.9, 39.5, 66.2, 66.4, 69.4,
69.6, 72.0, 74.5, 109.3, 123.1, 128.7, 129.3, 129.8, 133.1, 135.7,
147.9, 154.7, 156.8, 165.7. Mass spectrum m/ e: 948 (M + H)+.
Anal. Calcd for C55H66O12N2: C, 69.57; H, 7.02; N, 2.96.
Found: C, 67.32; H, 7.06; N, 2.03.
Com p lexa tion Stu d ies. CDCl3 and CCl4 were dried and
stored over 3 Å molecular sieves before use. The NMR
titrations with neutral molecules were performed at 300 K
using published methods.16 The ammonium tosylates are
easily synthesized using known procedures.24,25
The NMR titrations with ammonium salts ((5.00 ( 0.05) ×
10-3 M) in CDCl3 were performed at 300 K using methods
reported elsewhere.4 Fast exchange between complexed and
free guest was observed, giving a single signal averaged
between the two forms, the chemical shift of which varies with
the ratio between host and guest. Stability constants were
calculated using nonlinear regression analysis of the induced
shifts on the low field protons of the tosylate counterion,
because the methyl group of the ammonium ion becomes broad
on complexation.
X-r a y Cr ysta llogr a p h y. The X-ray measurements were
carried out on a Siemens AED diffractometer using graphite-
monochromatized Cu KR radiation (1.541 78 Å) (5 ⊂ CH2(CN)2)
and on a Philips PW1100 diffractometer using graphite-
monochromatized Mo KR radiation (0.710 73 Å) (5 ⊂ CH3NO2).
The crystal data and the most relevant experimental param-
eters used in the X-ray measurements and in the crystal
structure analyses are reported in Table 4. All the intensities
were calculated by profile analyses according to the Lehmann
and Larsen method.26 For both complexes during the system-
atic data collection the intensity of one standard reflections,
collected every 100, showed no significant fluctuations. The
intensities were corrected for Lorentz and polarization but not
for absorption effects. The approximate coordinates of all non-
hydrogen atoms of the host molecule were obtained, for both
compounds, from direct methods using SIR92.27 The guest
molecule was located in the subsequent cycles of the Fourier
∆F map. The crystal structure was refined by blocked full-
matrix least-squares methods on F using SHELX76.28 In both
complexes parameters refined were as follows: the overall
scale factor and the atomic coordinates and anisotropic thermal
parameters for all the non-hydrogen atoms except the ni-
tromethane, which was treated with isotropic temperature
factors. All the hydrogen atoms in 5 ⊂ CH2(CN)2 were placed
at their calculated positions with the geometrical constraint
C-H 1.0 Å and refined “riding” on their corresponding carbon
atoms, whereas in 5 ⊂ CH3NO2 the hydrogen atoms were
found in the final Fourier ∆F map and refined with isotropic
temperature factors, with the exception of those of the ether
chains, which were placed at their calculated positions and
refined, with a common temperature factor, “riding” on their
corresponding carbon atoms. The atomic scattering factors of
the non-hydrogen atoms were taken from Cromer and Waber;29
Up p er Rim Br id ged Ca lix[4]a r en e P yr id in e-2,6-d ica r -
boxyla te Iod o Der iva tives 8 a n d 9. Mon oiod o Der iva tive
8. Compound 5 (0.17 mmol, 0.15 g) was dissolved in CHCl3
(100 mL), and CF3COOAg (0.25 mmol, 0.055 g) was added.
The reaction mixture was refluxed for 30 min with vigorous
stirring, and then iodine (0.25 mmol, 0.064 g) was added. After
2 h the precipitated AgI was filtered off and the organic
solution treated with a 20% w/v Na2S2O5 solution until the
violet color had disappeared. The separated organic layer was
then washed twice with distilled water and evaporated under
reduced pressure to afford a crude product that was purified
by column chromatography (hexane:ethyl acetate ) 50:50); 75
mg (50%) of the starting reagent 5 and 52 mg (30% yield) of 8
1
as pale yellow solid were recovered. 8. Mp: 181-183 °C. H
NMR (300 MHz) δ: 1.16-1.26 (m, 12H); 3.09 and 3.18 (2d,
4H, J ) 12.9 and 12.6 Hz); 3.50-3.60 (m, 8H); 3.72-3.76 (m,
4H); 3.92-4.05 (m, 8H); 4.35-4.43 (m 4H); 4.51 and 4.53 (2d,
4H); 4.87 and 5.17 (2d, 4H, J ) 11.4 Hz); 6.60 and 6.65 (2d,
4H, J ) 1.8 Hz); 6.73 (t, 1H, J ) 7.5 Hz); 7.05 (d, 2H); 7.30 (s,
2H); 7.97 (t, 1H, J ) 7.8 Hz); 8.27 (d, 2H). 13C (75 MHz) δ:
15.2, 29.7, 30.5, 30.9, 32.2, 62.7, 66.2, 66.4, 69.4, 69.6, 71.9,
72.2, 74.7, 123.1, 125.0, 127.4, 128.8, 129.4, 129.7, 129.9, 132.5,
133.2, 135.7, 137.1, 138.0, 138.5, 147.5, 154.8, 157.0, 164.6.
Mass spectrum m/ e: 1031 (M + H)+. Anal. Calcd for
C53H60O12NI: C, 61.81; H, 5.87; N, 1.36. Found: C, 60.54; H,
5.32; N, 1.18.
Diiod o Der iva tive 9. Compound 5 (0.17 mmol, 0.15 g) was
dissolved in CH2Cl2 (200 mL), and CF3COOAg (0.37 mmol,
0.083 g) was added. The reaction mixture was refluxed for
30 min with vigorous stirring, and then iodine (0.37 mmol,
0.094 g) was added. After 4 h the precipitated AgI was filtered
off and the solution treated with a 20% w/v Na2S2O5 solution
until the violet color had disappeared. The separated organic
layer was then washed twice with distilled water, dried over
Na2SO4, and evaporated under reduced pressure to afford a
crude product that was purified by column chromatography
(hexane:ethyl acetate ) 50:50) and recrystallized from metha-
nol to afford 127 mg (65% yield) of 9 as white solid, mp 181-
183 °C. 1H NMR (300 MHz) δ: 1.18 and 1.23 (2t, 12H, J )
7.2 Hz); 3.09 (d, 4H, J ) 12.6 Hz); 3.51 and 3.55 (2q, 8H); 3.72
(t, 4H, J ) 6.0 Hz); 3.91 (t, 4H); 3.97 (t, 4H, J ) 6.0 Hz); 4.38
(t, 4H); 4.48 (d, 4H); 5.07 (s, 4H); 6.61 (s, 4H); 7.32 (s, 4H);
7.99 (t, 1H, J ) 7.8 Hz); 8.29 (d, 2H). 13C (75 MHz) δ: 15.2,
15.4, 30.4, 39.5, 66.0, 66.3, 66.5, 69.4, 69.6, 72.2, 74.8, 86.3,
127.4, 129.5, 130.1, 132.4, 137.2, 138.1, 138.5, 147.8, 154.8,
157.0, 164.8. Mass spectrum m/ e: 1157 (M + H)+. Anal.
Calcd for C53H59O12NI2: C, 55.07; H, 5.14; N, 1.21. Found:
C, 55.05; H, 5.30; N, 1.03.
(24) (a) Cocivera, M. J . Am. Chem. Soc. 1966, 88, 672-676. (b)
French, C. M.; Tomlinson, R. C. B. J . Chem. Soc. 1961, 311-320.
(25) In a representative example, dry methylamine gas was bubbled
through a concentrated solution of p-toluenesulfonic acid in diethyl
ether, under nitrogen flow. The resultant precipitate was washed with
ether and dried to give N-methylammonium p-toluenesulfonate
(49%): 1H NMR (300 MHz, CDCl3) δ 2.37 (3H, s), 2.41 (3H, bs, NCH3),
7.19 (2H, d, J ) 7.7 Hz), 7.65 (3H, bs), 7.75 (2H, d, J ) 7.7 Hz).
(26) Lehmann, M. S.; Larsen, F. K. Acta Crystallogr. 1974, A30,
580-584.
(27) SIR92: Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.;
Giacovazzo, C.; Guagliardi, A.; Polidori, G. J . Appl. Crystallogr. 1994,
27, 435.
(28) Sheldrick, G. SHELX76, Program for Crystal Structure Deter-
minations; University of Cambridge: England, 1976.

Upper Rim Pyridine-Bridged Calix[4]arenes
J . Org. Chem., Vol. 61, No. 20, 1996 6887
Ta ble 4. Exp er im en ta l Da ta for th e X-r a y Diffr a ction Stu d ies
5 ⊂ CH2(CN)2
5 ⊂ CH3NO2
formula
crystal syst
space group
cell param at 295 Ka
a (Å)
C53H61NO12‚C3H2N2
C53H61NO12‚CH3NO2
monoclinic
triclinic
P21/n
P1h
15.838(4)
12.831(3)
b (Å)
18.318(4)
11.979(3)
c (Å)
17.894(3)
19.264(3)
R (deg)
90
93.01(2)
90
5184(2)
88.31(2)
88.25(2)
61.82(2)
2608(1)
â (deg)
γ (deg)
V (Å3)
Z
4
2
Dcalcd (g cm-3
F(000)
)
1.243
2064
1.229
1028
mol wt
970.127
7.131
965.105
0.886
linear abs coeff, cm-1
scan type
θ/2θ
θ/2θ
scan speed (deg/min)
scan width (deg)
2θ range, deg
reflcns measd
3 ÷ 12
3 ÷ 9.6
[θ - 0.65], [θ + 0.65 + ∆λλ-1tg θ]
[θ - 0.6], [θ + 0.6 + ∆λλ-1tg θ]
6 ÷ 140
(h,+k,+l
10497
6 ÷ 52
(h,(k,(l
10554
total data measd
criterion for obsd
obsd data measd
I g 2σ(I)
7355
I g 2σ(I)
3324
unique obsd data
agreement between equiv obsd reflns
no. of variablesb
7020
0.009
241, 241, 178
0.07
0.069
3211
0.007
273, 273, 176
0.08
0.061
max ∆/σ on last cycle
R ) ∑|∆F|/Σ|Fo|
Rw ) ∑w1/2|∆F|/∑w1/2|Fo|
0.069
1.769
0.061
1.714
2
GOF ) [∑w1/2|∆F| /(NO - NV)]1/2
a
Unit cell parameters were obtained by least-squares analysis of the setting angles of 30 carefully centered reflections found in a
b
random search in reciprocal space. In the blocked full-matrix least-squares refinement.
the values of ∆F′ and ∆F′′ were those of Cromer and Ibers.30
Mobility Programme, Network (contract no. CHRX-
The geometrical calculations were obtained by PARST.31 All
the calculations were carried out on the Gould Encore91 of
the Centro di Studio per la Strutturistica Diffrattometrica of
C.N.R., Parma.
CT940484), and INTAS programme (contract no. IN-
TAS-94.1914) and developed within Cost Action D7 and
INTAS. We are grateful to C.I.M. (Centro Interdipar-
timentale di Misure “G. Casnati”) for NMR and mass
measurements.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
all new compounds 4-9 (6 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of this journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
Ack n ow led gm en t. This work was partly supported
by C.N.R. Progetto Strategico Tecnologie Chimiche
Innovative - Sottoprogetto A, Human Capital and
(29) Cromer, D. T.; Waber, J . J . In International Tables for X-Ray
Crystallography; Ibers, J . A., Hamilton W. C., Eds.; The Kynoch
Press: Birmingham, England, 1974; Vol. 4, Table 2.2.B.
(30) See ref 29, Table 2.3.1.
(31) PARST: Nardelli, M. Comput. Chem. 1983, 7, 95-102.
J O960937B