Heterocalixarenes. 1. Calix[2]uracil[2]arene: Synthesis, X-ray Structure, Conformational Analysis, and Binding Character

Article abstract of DOI:10.1021/jo990085q

1,3-Bis[(1-uracilyl)methyl)]benzene derivatives 3, formed by selective N-1 alkylation of 1,3-bis(trimethylsilyloxy)pyrimidine with 1,3-bis(bromomethyl)benzene derivatives 2, on cyclization with the same or different derivative of 2, provide calix[2]uracil

Full text of DOI:10.1021/jo990085q

J . Org. Chem. 1999, 64, 7717-7726
7717
Heter oca lixa r en es. 1. Ca lix[2]u r a cil[2]a r en e: Syn th esis, X-r a y
Str u ctu r e, Con for m a tion a l An a lysis, a n d Bin d in g Ch a r a cter
Subodh Kumar,* Geeta Hundal, Dharam Paul, Maninder Singh Hundal, and Harjit Singh*
Department of Chemistry, Guru Nanak Dev University, Amritsar - 143005, India
Received J anuary 19, 1999
1,3-Bis[(1-uracilyl)methyl)]benzene derivatives 3, formed by selective N-1 alkylation of 1,3-bis(tri-
methylsilyloxy)pyrimidine with 1,3-bis(bromomethyl)benzene derivatives 2, on cyclization with the
same or different derivative of 2, provide calix[2]uracil[2]arenes 4. Their conformations, investigated
through X-ray, variable temperature 1H NMR, and molecular modeling MM2 calculations, are found
to depend on the nature of substituent(s) on the position 2 of 1,3-phenylene rings. 4a exists in
equilibrium between various conformations, and 4b, 4d -4i adopt an inward flattened partial cone
conformation. In 4j, the equilibrium is restricted to two conformations at -60 °C, but the 4j‚ethanol
complex (2:1), in the solid state, has a cone conformation with ethanol being a H-bond donor through
H of OH and CH2 and an acceptor through O of OH. 4d , 4j, and 4k exhibit significant preferences
toward alkaline earth metal ions over alkali metal ions though overall bindings are poor.
Calixarenes1 constitute π-electron-rich cavities that are
responsible for their binding with aromatic,2 ammonium,3
and metal ion4 guests through π-π and π-cation inter-
actions. Heterocalixarenes,5-10 constituted by replace-
ment of arylene unit(s) of calixarenes with heterocyclic
moieties, depending on the electron-deficient6 or rich5
nature of a heterocyclic unit(s), encompass numerous new
opportunities for π-π interactions with electron-rich and
electron-deficient π systems. The protonizable H and
heteroatom of the heterocyclic constituent could also
induce H-bonding interactions with anionic and acidic H
substrates. Thus, pyrrole5,7 and pyridinium cation6a based
calix[4]arenes exhibit binding character toward halide
ions and alcohols, etc., and carboxylate ions, respectively.
A COOH-functionalized appendage at a methylene bridge
in calix[4]pyrrole shows unique self-assembling proper-
ties.7 The heterocalixarenes possessing cyclic urea8-10
based heterocycles such as benzimidazol-2-one, 1,3,5-
triazinone, and ethylene/propylene urea along with phe-
nolic units also show unique conformational and inclusion
properties, unprecedented in homocyclic calixarenes.
* Corresponding author. E-mail: chemistry@gndu.ernet.in. Fax:
091-183-258820.
(1) (a) Gutsche, C. D. Calixarenes, Monographs in Supramolecular
Chemistry; Stoddart, J . F., Ed.; The Royal Society of Chemistry:
Cambridge, 1989; Vol. 1. (b) Vicens, J .; Bohmer, V. Calixarenes:
A
Versatile Class of Macrocyclic Compounds; Kluwer: Dordrecht, 1990.
(c) Bohmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713. (d) Shinkai,
S. Tetrahedron 1993, 49, 8933. (e) Ikeda, A.; Shinkai, S. Chem. Rev.
1997, 97, 1713-34.
(2) (a) Andreetti, G. D.; Pochini A.; Ungaro, R. J . Chem. Soc., Perkin
Trans. 2, 1983, 1773. (b) Ungaro, R.; Pochini, A.; Andreeti G. D.;
Domiano, P. J . Chem. Soc., Perkin Trans. 2 1985, 197. (c) Andreetti,
G. D.; Ori, O.; Ugozzoli, F.; Alfieri, C.; Pochini A.; Ungaro, R. J .
Inclusion Phenom. Mol. Recogn. 1988, 6, 523. (d) Andreetti, G. D.;
Ungaro R.; Pochini, A. J . Chem. Soc., Chem. Commun. 1979, 1005. (e)
Araki, K.; Matsuda, T.; Shinkai, S.; Nishiyama, N.; Ikeda, H.; Takusu,
I.; Iwamoto, M. J . Am. Chem. Soc. 1990, 112, 9053.
(3) Araki, K.; Shimizu, H.; Shinkai, S. Chem. Lett. 1993, 205.
(4) (a) Iwamoto, K.; Ikeda, A.; Araki, K.; Harada, T.; Shinkai, S.
Tetrahedron 1993, 49, 609. (b) Shinkai, S.; Ikeda, A. J . Am. Chem.
Soc. 1994, 116, 3102. (c) Koh, K. N., Araki, K.; Shinkai, S.; Asfari, Z.;
Vicens, J . Tetrahedron Lett. 1995, 36, 6095. (d) Ikeda, A.; Tsudera, T.;
Shinkai, S. J . Org. Chem. 1997, 62, 3568. (e) Ikeda, A.; Tsuzuki, S.;
Shinkai, S. J . Chem. Soc., Perkin Trans. 2 1994, 2073. (f) McCarrick,
M.; Wu, B.; Harris, S. J ., Diamond, D.; Barrett, G.; McKervey, M. A.
J . Chem. Soc. Chem. Commun. 1992, 1287.
(5) (a) Gale, P. A.; Sessler, J . L.; Allen, W. E.; Tvermoes N. A.; Lynch,
V. J . Chem. Soc. Chem. Commun. 1997, 665. (b) Allen, W. E.; Gale, P.
A.; Brown, C. T.; Lynch, V. M.; Sessler, J . L. J . Am. Chem. Soc. 1996,
118, 12471. (c) Allen, W. E.; Gale, P. A.; Tvermoes, N. A.; Lynch, V.
M.; Sessler, J . L. J . Chem. Soc. Chem. Commun. 1997, 665. (d) Gale,
P. A.; Sessler, J . L.; Sansom. P. I.; Lynch, V. Tetrahedron Lett. 1996,
37, 7881.
Despite the significance of uracil and its derivatives
toward complexation with H+ and other biological cations
in RNA strands11 and in other catalytic functions,12 the
uracil-based synthetic cyclic receptors have scarcely been
studied.13 In addition, inbuilt subheterocyclic urea oxy-
gen, present in the macrocycles, is known to be directed
toward the cavity, sterically less hindered, and better
binding than ether or ester oxygens.14 We have now
developed a facile two-step synthesis of uracil-based
heterocalix[4]arenes possessing two uracil and two simi-
larly or differently substituted 1,3-phenylene units.15
X-ray crystal structure, 1H NMR, and molecular modeling
studies show that these calix[2]uracil[2]arenes (4), de-
pending on the nature of the substituents on 2-position
of 1,3-phenylene rings, attain an inward flattened partial
cone, a cone, or other flexible structures.
(6) (a) Shinoda, S.; Tadokoro, M.; Tsukube, H.; Arekewa, R. J . Chem.
Soc., Chem. Commun. 1998, 181. (b) Newkome, G. R.; J oo, Y. J .;
Fronczek, F. R. J . Chem. Soc., Chem. Commun. 1987, 854. (c) Kral,
V.;. Gale, P. A.; Anzenbacher, P. J r., J ursikova, K.; Lynch V.; Sessler,
J . L. J . Chem. Soc., Chem. Commun. 1998, 9.
(7) Gale, P. A.; Lynch, V. M.; Sessler, J . L. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2782.
(8) (a) Weber, E.; Trepte, J .; Gloe, K.; Piel, M.; Czugler, M.; Kravtsov,
V. C.; Simonov, Y. A.; Lipkowski, J .; Ganin, E. V. J . Chem. Soc., Perkin
Trans. 2 1996, 2359. (b) Weber, E.; Trepte, J .; Gloe, K.; Czugler, M. J .
Chem. Soc., Perkin Trans. 2 1997, 1461.
(9) (a) Dave, P. R.; Doyle, G. J . Org. Chem. 1995, 60, 6946. (b) Dave,
P. R.; Doyle, G. Tetrahedron Lett. 1992, 33(8), 1021.
(10) Pratt, J . A. E.; Sutherland, I. O. J . Chem. Soc., Perkin Trans.
1, 1988, 13.
(11) Stryer, L. Biochemistry; W. H. Freemann & Company: New
York, 1981; p 512.
(12) Pyle, A. M. Science 1993, 261, 709.
(13) Htay, M. M.; Meth-Cohn, O. Tetrahedron Lett. 1976, 469.
(14) Stewart, K. D.; Meish, M.; Knobler, C. B.; Maverick, E. F.;
Cram, D. J . J . Org. Chem. 1986, 51, 4327.
(15) Kumar, S.; Paul, D.; Singh, H. Tetrahedron Lett. 1997, 38(20),
3607.
10.1021/jo990085q CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/24/1999

7718 J . Org. Chem., Vol. 64, No. 21, 1999
Kumar et al.
Sch em e 1. P r ojection of Syn th etic Ap p r oa ch es for th e Ta r get Ca lix[2]u r a cil[2]a r en es
Sch em e 2. Syn th esis of Ca lix[2]u r a cil[2]a r en es
Syn th esis
4a -k
The uracil-based calix[4]arene models, possessing two
uracil and two 1,3-phenylene units, due to nonequiva-
lence of uracil N1 and N3 positions and possibility of
similar and different substitution pattern in 1,3-phe-
nylene units, are composed of the four structures A-D
(Scheme 1). Their synthesis through single-step 2:2
stoichiometric alkylation (Scheme 1, path I) of uracil with
a 1,3-bis(bromomethyl)benzene derivative would provide
a product mixture of two structural isomers A and B.
Using a mixture of two 1,3-bis(bromomethyl)benzene
derivatives, all the possible four structures could be
formed. However, the alkylation (path I) of uracil with
2a under phase-transfer catalytic conditions (K2CO3-
CH3CN-tetrabutylammonium hydrogensulfate) or in a
DMF-NaH mixture gave a multiple-component reaction
mixture, which could not be separated even by repeated
column chromatography.
An alternate two-step approach (path II, Scheme 1),
requiring selective N1 alkylation of uracil followed by
subsequent cyclization of the intermediate product (Z)
with the same or a different 1,3-bis(bromomethyl)benzene
derivative, would provide calix[2]uracil[2]arene deriva-
tives A or C selectively (Scheme 1). Thus, 1,3-bis(trim-
ethylsilyloxy)pyrimidine (1) on refluxing with 2a in 1,2-
dichloroethane by using I2 as catalyst16 provides 3a (60%),
mp 268 °C, M+ m/z 326. The cycloalkylation of 3a with
2a under phase-transfer catalytic conditions (K2CO3-
CH3CN-tetrabutylammonium hydrogensulfate) provides
4a , a heterocalix[4]arene of type A (24%), mp 287-90 °C,
M+ m/z 428. The latter approach though involves two
steps and provides only one calix[2]uracil[2]arene in good
yield. So, for procuring 4a -4k only the two-step approach
has been used.
4d , 4g-i in 20-30% yields (Scheme 2). The cycloalky-
lations of 3a with 2b, 3b with 2a , 3b with 2c, and 3c
with 2b provide respective type C (U-symm, P-unsymm)
calix[2]uracil[2]arene derivatives 4c, 4b, 4e, and 4f. To
evaluate the complexation of dihydroxycalix[2]uracil[2]-
arenes with alkali and alkaline earth metal using UV
spectrophotometric techniques, we have synthesized the
calix[2]uracil[2]arene 4k , having a chromogenic NO2
group. The cycloalkylation of 3c with 2f forms a non-
separable product mixture which on hydrolysis (HCl:
EtOH) provides pure calix[2]uracil[2]arene 4k (10%).
1,3-Bis(bromomethyl)benzene derivatives 2b-e react
with 1 to give acyclic products 3b-e which on subsequent
cyclization with the same dibromoalkyl derivatives 2b-e
provide type A (U-symm, P-Symm) calix[2]uracil[2]arenes
Con for m a tion a l An a lysis
The 1H NMR and off-resonance 13C NMR spectra of
compounds 3 exhibit NCH2 as a singlet and a triplet,
1
(16) Singh, H.; Aggarwal, P.; Kumar, S. Synthesis 1990, 6, 520.
respectively. In the H NMR spectra of calix[2]uracil[2]-

Heterocalixarenes
J . Org. Chem., Vol. 64, No. 21, 1999 7719
F igu r e 2. Diagram showing the numbering system of the 2:1
complex of 4j‚ethanol.
F igu r e 1. Diagram showing the numbering system of 4g.
Sch em e 3. Icon ogr a p h ic Rep r esen ta tion s of
Con for m a tion s
between N-3 positions of uracil units has a dihederal
angle of 105.3(1)° with the plane of methylene carbons.
The larger dihedral angle of the phenylene ring linked
between N-1 positions of uracil units places the corre-
sponding acetyl-substitued O1 directed inward to the
cavity of calix[2]uracil[2]arene 4g to form an inward
flattened partial cone conformation (Scheme 3). The
interplanar angles between oppositely placed phenylene
and uracil rings are 36.7(2)° and 12.6(2)°. Therefore, both
the uracil rings are parallel to each other about the cone
axis with their respective carbonyl units at C-2 pointing
in the same direction, but the phenylene rings are not
parallel, again due to above-mentioned flattening. Also,
the O-acetyl unit of the 1,3-phenylene ring (m) (Scheme
2) faces the π-cloud of the other phenylene ring placed
between N-3 positions of the uracils. The 3.362(1) Å
distance between OCOCH3 and phenylene ring shows the
presence of CH3-π interactions which might be respon-
sible for stabilization of inward flattened conformation.
Both the acetyl groups are planar and rotated with
respect to the phenylene rings through angles of 86.6(2)°
and 79.1(2)°, respectively.
The X-ray crystal structure of 2:1 complex of 4j‚ethanol
shows the presence of two crystallographically indepen-
dent types of molecules (X and Y) in the unit cell. The
environment around the two types of molecules is dif-
ferent; therefore, they show slight variation in their bond
lengths and bond angles. There are eight calix[2]uracil[2]-
arene and four ethanol molecules per unit cell thus giving
a 2:1 stoichiometric calix:ethanol complex. Ethanol is
H-bonded to 4j (Figure 2) and acts as a H-bond donor
through alcoholic oxygen O13H and methylene H at C54,
giving two intramolecular contacts (O13-H13A‚‚‚O12,
O13‚‚‚O12 2.87(4) Å, O13-H13A‚‚‚O12 137(5)°; C54-
H54A‚‚‚O12, C54‚‚‚O12 2.19(3) Å, C54-H54A‚‚‚O12
129(3)°) to one of calix[2]uracil[2]arene molecule (Y) while
it behaves as a H-bond acceptor due to the presence of
an intermolecular H-bond (C21-H21A‚‚‚O13(i), C21..O13
3.02(4) Å, C21-H21A‚‚‚O13 147(2)° where i ) x - 1, y
- 1, z) to the second calix[2]uracil[2]arene molecule (X).
The small-sized alcohols such as methanol, ethanol,
propanol, etc., which lack large hydrocarbon surfaces
necessary for efficient hydrophobic interactions, show
only weak OH-induced H-bondings with the receptors.17
So in these cases, only oxygen of alcohol is involved in
binding with acidic protons of the host. Here, in case of
the 4j:ethanol complex, ethanol shows an unusual bind-
ing, where in addition to OH of ethanol, the adjacent CH
proton also undergoes H-bonding with the C4dO of the
arene 4, N1-CH2 (4H) and N3-CH2 (4H) units appear
as combinations of (i) two singlets (4a ) or (ii) sharp
singlet-broad signal (4j, 4k ) or (iii) one singlet-one AB
quartet (4c) or (iv) two AB quartets (4b, 4d -i), depending
on the presence/absence and nature of the substituents
on the position 2 of the two 1,3-phenylene units. Evi-
dently, heterocalix[4]arenes 4, depending on the substit-
uents on 1,3-phenylene rings, exhibit various conforma-
tions. The four distinct conformations of calix[4]areness
cone, partial cone, 1,3-alternate, and 1,2-alternateshave
been recognized (first row, Scheme 3). The flattening of
one of the rings either inward or outward the cavity can
lead to four additional conformations9 (second row,
Scheme 3). The structures of calix[2]uracil[2]arenes (4)
have been assigned by 1H NMR in solution, single-crystal
X-ray crystallography in two cases, and by force field
energy minimization studies.
A. X-r a y Str u ctu r a l Stu d ies. Single-crystal X-ray
structural studies show that 4g adopts an inward flat-
tened partial cone conformation (Figure 1). The torsion
angles ø and φ around C10, C15, C25, and C30 ArCH
bonds are 104.4(5)°, -62.0(6)°; 117.1(5)°, 126.8(5)°;
-131.4(5)°, -116.4(5)°; and 66.1(5)°, -106.7(5)°, respec-
tively. Both the phenylene rings are planar whereas the
uracil rings are almost planar with a maximum deviation
of 0.06 Å of C14 and C29 carbons. The four methylene
carbons lie almost in a plane (( 0.06 Å), and two uracil
rings make interplanar angles of 95.6(1)° and 83.1(1)°
with the plane of methylene carbons. The phenylene ring
(C2-C3-C4-C5-C6-C7) placed between N-1 positions
of uracil units forms a dihedral angle of 141.9(1)°, and a
phenylene ring (C16-C17-C18-C19-C20-C21) placed

7720 J . Org. Chem., Vol. 64, No. 21, 1999
Kumar et al.
uracil units. As a result, ethanol shows a unique three-
center H-bonding with the uracil units of heterocalix 4j.
In the 4j‚ethanol complex, both heterocalixarene units
have a cone conformation characterized by a continual
change of sign (+,-) of the torsion angles about the
ArCH2 bonds.18 As the two independent molecules have
different environments so their torsion angles also vary.
These torsion angles about C7, C12, C19, C24 are 85(2),
-100(2); 94(2), -73(2); 80(2), -98(2); and 90(2), -75(2)
and about C33, C38, C45, C50 are 77(2), -97(2); 104(2),
-85(2); 74(2), -83(2); and 96(2), 88(2) for X and Y units,
respectively. The interplanar angles between two phe-
nylene and two uracil rings are 46(2)°, 97(1)° and 50(1)°,
101(2)°, respectively, for molecules X and Y. Thus, uracil
rings are almost perpendicular, but phenylene rings are
nearly parallel in both molecules X and Y. The interpla-
nar angles found between the best plane fitted to the
connecting methylene C-atoms and the uracil rings of two
molecules are 47(1)°, 50(1)° and 47(2)°, 54(2)°, between
this plane and phenylene rings lying between N-1 posi-
tions of the uracil units are 116(1)°, 113(3)° whereas
between this plane and phenylene rings placed between
N-3 positions of uracil are 67(1)°, 63(1)°, respectively, for
molecules X and Y. Thus, in both the molecules, the
phenylene rings placed between N-1 positions of uracils
are more flattened inward as in comparison to the one
placed between N-3 positions of uracils. Both molecules
show intramolecular H-bonding involving hydroxy groups
and the corresponding carbonyl oxygens at the positions
C-2 of the uracil rings which stabilize the cone conforma-
tion [O1-H1A‚‚‚O3, with O1..O3 2.64(2) Å, O1-
H1A‚‚‚O3 121(1)°; O4-H4A‚‚‚O5, O4‚‚‚O5 2.77(2) Å,
O4-H4A‚‚‚O5, 116(1)°; O7-H7A‚‚‚O11, O7‚‚‚O11 2.60(2)
Å, O7-H7a‚‚‚O11 120(1)°; O10-H10A‚‚‚O9, O10‚‚‚O9
2.63(1) Å, O10‚‚‚H10A‚‚‚O9 115(1) Å]
F igu r e 3. Packing diagram of 4j‚ethanol showing H-bonding
and π-π interaction.
3.80, 5.46 (J ) 14 Hz) and 4.20, 5.79 (J ) 14 Hz). The
correlation between AB quartets have been established
by decoupling experiments. The 13C NMR spectrum
exhibits the expected two signals for NCH2 carbons at δ
42.30 and 46.86. Its 1H NMR spectrum shows two
singlets each due to COCH3 (δ 1.50 and 2.01) and Ar-
CH3 (δ 2.33 and 2.41) protons. In consonance with X-ray
structure, the signal at δ 1.50 could be due to COCH3 on
the 1,3-phenylene (m) which faces the π-cloud of phe-
nylene ring n (Scheme 2) and is shifted upfield to the
other COCH3 signals (δ 2.01) due to π ring currents.
The average O‚‚‚O distance in molecules X and Y are
2.821(2) Å and 2.793(2) Å, respectively, with lengthening
of 0.2 Å with respect to those observed in the normal
calix[4]arenes.18 Crystal packing (Figure 3) shows exten-
sive π-π interactions between the various rings. The
molecules are packed in alternate layers of centrosym-
metrically related pairs of molecules X and Y along [010]
plane. The uracil ring (N1-C8-C9-C10-N2-C11) of
molecule X is showing intramolecular π-π interaction
with the phenylene ring (C39 to C44) placed between N-1
positions of molecule Y (distance between the centers of
these two rings being 4.162(2) Å). This may be considered
as a donor-acceptor π-π interaction, uracil being an
electron-deficient ring. At the same time the other
phenylene ring (C27 to C32) and H-bonded uracil ring
(N7-C46-C47-C48-N8-C49) of molecule Y are show-
ing π-π interaction with their symmetry-related coun-
terparts having a center-to-center distance of 3.881(2) Å
and 4.390(3) Å, respectively.
Like 4g, other U-symm, P-symm calix[2]uracil[2]arenes
1
4d , 4h , and 4i in their H NMR spectra exhibit two AB
quartets due to N1-CH2 and N3-CH2 protons, and one
of the methoxy (in case of 4d ) or acetoxy (in case of 4h
and 4i) singlets is shifted upfield by 0.5-1.00 ppm.
Therefore, replacement of the acetoxy groups with less
bulky methoxy units in 4d or the replacement of methyl
units of the phenylene ring with H in 4i or tert-butyl in
4h does not affect the conformation of these calix[4]arenes.
The force field energy minimization19 studies on these
calix[2]uracil[2]arenes show them to attain either cone
or the partial cone nonconvertible conformations and
more appropriately to be designated as configurations.
The cone configurations are in general more stable than
the partial cone ones. In case of partial cone configura-
tions the phenylene ring placed between N1 positions of
uracils undergoes inward flattening in the cavity to
provide an inward flattened partial cone configuration
(Figures 4 and 5) as shown by the X-ray crystal structure
of 4g and 1H NMR studies. The cone configuration as
deduced by energy minimization studies does not envis-
age any 1H NMR upfield shift of the signal for the
substituent at 2-position of one of the phenylene rings.
B. 1H NMR a n d F or ce F ield En er gy Min im iza tion
1
Stu d ies. In the H NMR spectrum of 4g in CDCl3, eight
methylene protons appear as two 4H AB quartets at δ
(17) (a) Mendez, L.; Singleton, R.; Slawin, A. M. Z.; Stoddart, J . F.;
Williams, D. J .; Williams, M. K. Angew. Chem., Int. Ed. Engl. 1992,
31, 478. (b) Allwood, B. L.; Mendez, L.; Stoddart, J . F.; Williams, D.
J .; Williams, M. K. J . Chem. Soc., Chem. Commun. 1992, 331. (c)
Huang, C.-Y.; Cabell, L. A.; Anslyn, E. V. J . Am. Chem. Soc. 1994,
116, 2778. (d) Cochran, J . E.; Parrott, T. J .; Whitlock, B. J .; Whitlock,
H. W. J . Am. Chem. Soc. 1992, 114, 2269.
1
Therefore, a combination of H NMR and energy mini-
(18) (a) Ghidine, E.; Ugozzoli, F.; Ungaro, R.; Harkima, S.; El-Fadl,
A. A.; Reinhoudt, D. N., J . Am. Chem. Soc. 1990, 112, 6979. (b)
Takeshita, M.; Shinkai, S., Bull Chem. Soc. J pn. 1995, 68, 1088.
(19) The energy minimization studies have been performed by Using
PCMODEL, provided by Serena Software.

Heterocalixarenes
J . Org. Chem., Vol. 64, No. 21, 1999 7721
F igu r e 6. 1H NMR spectra of 4a at (a) 27 °C and (b) -60 °C
in CDCl3 at 500 MHz.
(CDCl3, DMSO-d6, or TFA) unlike the conventional p-tert-
butylcalix[4]arene.18 The latter due to the presence of
intramolecular H-bonding forms a stable cone conforma-
tion, but its tetra-O-methyl and O-ethyl derivatives,20
depending on the polarity of the solvent, exist as different
conformational isomers, and the increase in bulk in case
of tetra-O-propyl derivative restricts this free intercon-
version between different conformers. However, in these
calix[2]uracil[2]arenes, even the presence of two methoxy
groups along with less bulky uracil oxo units, restricts
the conformational interconversion. The X-ray crystal
structure of 4j, elaborated subsequently, shows that in
case of calix[2]uracil[2]arene, due to shorter N-C dis-
tances in comparison with C-C distances, the distance
between two phenylene units is decreased to 6.0-6.2 Å
units in comparison to > 7 Å units in case of conventional
calix[4]arenes. These smaller cavities of calix[2]uraci[2]-
arenes in comparison with conventional calix[4]arenes
could also be responsible for inhibition of conformational
interconversions and thereby stabilization of one of the
conformers.
The 1H NMR of 4a in CDCl3 at 27 °C exhibits both
NCH2 signals as broad singlets at δ 4.96 and 5.16 (Figure
6a) which on lowering the temperatures to 0 °C or -25
°C undergo further broadening. Its 1H NMR spectrum
at -60 °C shows two pairs of distorted AB quartets
(Figure 6b) (3:2), but the signals are not well defined.
Therefore, 4a , which lacks any substituent on 1,3-
phenylene rings, even at -60 °C, undergoes interconver-
sion between two conformers. In the case of calix[2]-
uracil[2]arene 4c, the presence of two NCH2 signals as
one singlet and one AB quartet shows that in the solution
phase 4c also has a semiflexible conformation.
F igu r e 4. Energy-minimized structures of 4g and 4d .
F igu r e 5. Energy-minimized structures of 4b and 4c.
mization studies can assist in assignment of configura-
tions to these calixarenes, which is in consonance with
X-ray crystal structure. The energy minimization studies
of the compounds 4d (Figure 4), 4h and 4i, corroborate
either cone configuration or inward flattened partial cone
configuration, in parallel with 4g. The upfield shift of the
methyl or acetyl substituents present at the 2-position
of phenylene ring can be explained only by inward
flattened partial cone configurations.
The U-symm, P-unsymm type calix[2]uracil[2]arenes
1
4b, 4e, and 4f in their H NMR spectra exhibit two AB
quartets due to N1-CH2 and N3-CH2 protons. In case
of 4b and 4e, it is the signal for the methoxy group that
is shifted upfield, whereas in 4f, the acetoxy group signal
is shifted upfield. In the 1H NMR spectrum of 4c in
CDCl3, four methylene protons appear as one sharp
singlet at δ 4.01, four methylene protons appear as one
AB quartet at δ 4.49, 5.12 (J ) 14 Hz), and the methoxy
signal appears as singlet at δ 3.67 (normal position). It
may be concluded that, in these calix[2]uracil[2]arenes
4b, 4d -i, the susbtituent present at the 2-position of 1,3-
phenylene ring placed between N-1 of the two uracils is
Due to presence of circular hydrogen bonding, the
conventional calix[4]arenes derived from the para-
substituted phenol and formaldehyde exist in a cone
conformation, whereas the conformations of O-alkylated
calix[4]arenes depend on the nature and number of the
alkoxy groups. So, we envisaged that such hydrogen
bonding could be invoked in a calix[2]uracil[2]arene
constituted by the phenylene rings having hydroxy
groups at 2-position. The acid-catalyzed (HCl:EtOH)
hydrolysis of 4g provides 4j (90%), which crystallizes from
1
shifted upfield in their H NMR spectra. These observa-
tions lead to a conformation with the phenylene ring
placed between N-1 of uracils flattened inward and both
phenylene rings in anti configuration, i.e., flattened
inward partial conelike conformation as found in case of
4g (X-ray).
(20) (a) Nagasaki, T.; Sisido, K.; Arimura, T.; Shinkai, S. Tetrahe-
dron 1992, 48, 797. (b) Araki, K.; Shimizu, H.; Shinkai, S. Chem. Lett.
1993, 205. (c) Iwamoto, K.; Araki, K.; Shinkai, S. J . Org. Chem. 1991,
56, 4955. (d) Dijkstra, P. J .; Brunink, J . A. J .; Bugge, K.-E.; Reinhoudt,
D. N.; Harkema, S.; Ungaro, R.; Ugozzoli, F.; Ghidini, E. J . Am. Chem.
Soc. 1989, 111, 7567.
The 1H NMR spectra of 4g, 4d -i show only one
conformation which remains unaffected by solvents

7722 J . Org. Chem., Vol. 64, No. 21, 1999
Kumar et al.
Ta ble 1. Extr a ction (%) a n d Tr a n sp or t P r ofile (m ol/24 H × 10-8) of Ca lix[2]u r a cil[2]a r en es 4d a n d 4j
Li+
Na+
K+
Tl+
Mg2+
Ca2+
Sr2+
Ba2+
Pb2+
Ag+
extraction
4d
4j
0.01
0.01
0.02
0.01
0.01
0.01
0.03
0.02
0.00
0.01
0.26
0.00
0.23
0.00
-
-
0.22
0.06
0.01
0.01
transport rates
4d
9
23
17
98
9
341
266
22
-
38
only one additional endothermic peak at 176-213 °C and
50-141 °C, respectively. In thermogravimetric analysis,
4j‚ethanol/4j‚methanol complexes show a respective loss
of ethanol and methanol between 178 and 250 °C which
is in consonance with DSC results. However, in case of
the 4j‚ethylene glycol complex, no loss of ethylene glycol
in the 50-141 °C range could be observed, and finally
ethylene gycol is lost above 200 °C, i.e, at its boiling point.
Therefore, ethylene gylcol forms a weaker complex which
is cleaved below 140 °C whereas methanol and ethanol
complexes are cleaved at a much higher temperature
range of 178-210 °C.
In conclusion, calix[2]uracil[2]arenes 4 with (i) both
phenylene rings n and m para-disubstituted or (ii)
phenylene ring n para-disubstituted and m unsubsti-
tuted, have a very unique inward flattened partial
conelike conformation. The analogue of category i, pos-
sessing phenolic rings n and m, because of H-bonding,
constitute a conelike conformation which undergoes fast
interconversions between various conformers in solution
phase. In 4, with ring n being unsubstituted and ring m
being para-disubstituted and both phenylene rings n and
m being unsubstituted, the calix[4]arenes have a flexible
conformation. Since the uracil moieties in all these
heterocalix[4]arenes are placed similarly, their conforma-
tions depend on the substitution pattern of phenylene
rings and their placement at N1, N1 or N3, N3 positions
of uracil.
F igu r e 7. 1H NMR spectra of 4j at (a) 27 °C and (b) -60 °C
in CDCl3 at 500 MHz.
ethanol as a 2:1 4j‚ethanol complex. Calix[2]uracil[2]arene
4j on crystallization from methanol and ethylene glycol
provides 2:1 4j‚methanol/ethylene glycol complexes but
in case of higher alcohols 4j‚alcohol complexes are not
formed.
The X-ray crystal structure of 4j shows its cone
1
conformation in solid state, but in its H NMR spectrum
(27 °C) recorded on a 200 Mz instrument, the appearance
of one of the 4H (NCH2) signals at δ 4.85 as a broad
singlet indicates that the molecule exists as a mixture
of a number of conformers which undergo fast intercon-
version to provide the average signals. However, on
recording the spectrum on a 500 MHz instrument at 25
°C, in addition to broad signals for both N-1 and N-3 CH2
at δ 4.85 (4H) and δ 5.12 (4H), a number of small signals
(<10% intensity) appear (Figure 7a). On recording the
spectrum at 0 °C, further broadening of these signals
occurs and two OH broad singlets at δ 8.00 and 8.25 also
appear as one broad singlet. At -25 °C, a number of
broad signals appear in the region δ 4.00-6.00, which
undergo further splitting at -45 °C. Further lowering of
the temperature to -60 °C provides a well-defined 1H
NMR spectrum, which shows four sets of AB quartets.
The U-5H and U6-H appear as two sets of doublets at δ
5.80 and 5.95 (2:1) and at δ 7.35 and 7.50 (2:1), respec-
tively (Figure 7). Similarly, two OH groups appear in two
sets of singlets (δ 7.80, 7.92) and (δ 8.82, 9.16) in a 1:2
ratio. Therefore, 4j at -60 °C (Figure 7b) exists as a
mixture of two conformers which undergoes quite slow
interconversion at least on an NMR time scale.
The binding capacities of 4j with methanol, ethanol,
and ethylene glycol could be observed from differential
scanning calorimetry. The uncomplexed 4j, obtained by
crystallization of the 4j‚methanol complex from tert-butyl
alcohol, exhibits only a small endothermic peak at 216-
258 °C along with an endothermic melting peak at 295
°C. The 4j‚methanol/ethanol/ethylene glycol complexes
exhibit these as common peaks along with following
additional peaks. The 4j‚ethanol complex shows one
exothermic and one endothermic peak at 65-102 °C (6.74
kJ mol-1) and 178-209 °C (2.99 kJ mol-1), respectively.
4j‚methanol and 4j‚ethylene glycol complexes exhibit
Recogn ition Beh a vior
Calix[2]uracil[2]arenes (4d -i) constituted by the phe-
nylene rings having substituents other than hydroxy
group at the 2-position have similar inward flattened
partial cone conformations, and out of these, the repre-
sentative case of calix[2]uracil[2]arene 4d was selected
for study of extraction and transporation of metal pi-
crates. Calixarenes 4d show both extraction and trans-
portation (Table 1), preference for Ca2+, Sr2+, Ba2+, and
Pb2+ picrates over Li+, Na+, K+, Tl+, Ag+, and Mg2+
picrates.
The calix[2]uracil[2]arene 4k , having the chromogenic
nitrophenol unit as one of the binding sites, on addition
of alkali metal (Li+, Na+, K+) and Tl+ acetate shows only
a marginal change in absorbance, but on the addition of
alkaline earth metal (Mg2+, Ca2+, Sr2+, Ba2+) acetates,
the absorbances are significantly increased (Figure 8),
though the λmax value remains unchanged. The titration
of 4k against metal acetates shows the formation of 1:1,
4k ‚metal acetate complexes with nearly 80-100 times
the preference for alkaline earth metal cations over alkali
metal cations (Table 2).
The calix[2]uracil[2]arene 4j undergoes fast equilibra-
tion between the various conformers (as seen by variable
1
temperature NMR), and its H NMR spectrum exhibits
two signals (δ 8.31, 7.97) due to OH protons, and NCH2
protons appear as one broad (δ 4.80) and one sharp
singlet (δ 5.14). The addition of malonitrile to a solution

Heterocalixarenes
J . Org. Chem., Vol. 64, No. 21, 1999 7723
°C; MS m/z 376, 378, 380 (1:2:1, M+); 1H NMR (200 MHz,
CDCl3): δ 1.33 (9H, s, 3 × CH3), 2.44 (3H, s, COCH3), 4.35
(4H, s, 2 × CH2), 7.37 (2 H, s, ArH); 13C NMR (normal/DEPT-
135) (50 MHz, CDCl3): δ 20.60 (+ve, CH3), 27.98 (+ve, CH3),
28.61 (absent, C), 30.70 (-ve, CH2), 126.10 (absent, ArC),
128.15 (+ve, ArCH), 130.09 (absent, ArC), 149.64 (absent,
ArC), 168.48 (absent, CdO); IR νmax/cm-1 (KBr): 1710 (CdO).
1,3-Bis(br om om eth yl)-2-a cetoxy-5-n itr oben zen e (2f). A
mixture of 2,6-bis(bromomethyl)-4-nitrophenol22 (3.23 g, 0.01
mol) and acetic anhydride (10 mL) containing a catalytic
amount of H2SO4 was heated on water bath for 30 min, and
the solvent was removed under vaccum. The residue was
dissolved in 25 mL of ether solvent and washed with aqueous
sodium bicarbonate. The organic layer was dried (Na2SO4) and
evaporated under vaccum and used without further purifica-
tion (80%): mp 81 °C (hexane + ether); MS m/z 365, 367, 369
1
(1:2:1, M+); H NMR (200 MHz, CDCl3): δ 2.50 (3H, s, CH3),
4.41 (4H, s, 2 x CH2), 8.32 (2 H, s, ArH); 13C NMR (normal/
DEPT-135) (50 MHz, CDCl3): δ 20.58 (+ve, CH3), 25.79 (-ve,
CH2), 126.19 (+ve, ArCH), 133.05 (absent, ArC), 145.42
(absent, ArC), 151.94 (absent, ArC), 167.46 (absent, CdO); IR
ν
max/cm-1 (KBr): 1700 (CdO).
Syn th esis of 1,3-Bis(1-u r a cilylm eth yl)a r yl Der iva tives
3(a -e). Gen er a l P r oced u r e. A solution of 2,4-bis(trimeth-
ylsilyloxy)pyrimidine 1 (1.96 g, 0.01 mol), 2a 23 (1.32 g, 0.005
mol), and I2 (20 mg) in 1,2-dichloroethane (20 mL) was heated
to reflux, and the progress of the reaction was monitored by
TLC. After completion of the reaction, the mixture was cooled
to 5 °C, and methanol (15 mL) was added. After couple of
minutes the separated solid was filtered and recrystallized
from methanol to get pure 3a . Similarly, reactions of dihalides
2b,24 2c,25 2d and 2e26 with 1 gave compounds 3b, 3c, 3d , and
3e, respectively.
F igu r e 8. Spectra of 4k and 4k + metal acetates.
Ta ble 2. Sta bility Con sta n ts of Ca lixa r en e 4k w ith Meta l
Aceta tes
stability
no.
additive
constant (mol-1 L)
1
2
3
4
5
6
7
lithium acetate
sodium acetate
0
1.59 × 102
2.81 × 102
6.18 × 103
1.62 × 104
1.61 × 104
1.78 × 104
potassium acetate
magnesium acetate
calcium acetate
strontium acetate
barium acetate
1,3-Bis(1-u r a cilylm eth yl)ben zen e (3a ): 60%, 48 h; mp
268 °C (AcOH + H2O); MS m/z 326 (M+); 1H NMR (200 MHz,
CDCl3 + TFA): δ 5.18 (4H, s, 2 × NCH2), 6.21 (2 H, d, J ) 7.8
Hz, C5-H), 7.23-7.43 (4H, m, ArH), 7.52 (2H, d, J ) 7.8 Hz,
C6-H); 13C NMR (normal/DEPT-135) (50 MHz, CDCl3
+
DMSO-d6): δ 49.68 (-ve, NCH2), 101.28 (+ve, C5-H), 126.49
(+ve, ArCH), 128.42 (+ve, ArCH), 135.82 (absent, C), 140.05
(+ve, ArCH), 143.60 (+ve, C6-H), 150.34 (absent, C), 163.18
(absent, C); IR νmax/cm-1 (KBr): 3200 (NH), 1700 (CdO), 1658
(CdO). Anal. Calcd for C16H14O4N4: C 58.90, H 4.29, N 17.18.
Found: C 58.55, H 4.02, N 17.57.
1,3-Bis(1-u r a cilylm e t h yl)-2-m e t h oxy-5-m e t h ylb e n -
zen e (3b): 90%, 36 h; mp 263 °C (MeOH); MS m/z 370 (M+);
1H NMR (200 MHz, CDCl3 + DMSO-d6): δ 2.28 (3H, s, CH3),
3.82 (3H, s, OCH3), 4.92 (4H, s, 2 × NCH2), 5.61 (2 H, dd, J 1
) 7.8 Hz, J 2 ) 1.8 Hz, C5-H), 6.99 (2H, s, ArH), 7.29 (2H, d,
J ) 7.8 Hz, C6-H), 7.58 (1H, s, NH), 11.08 (1H, s, NH); 13C
NMR (normal/DEPT-135) (50 MHz, CDCl3 + DMSO-d6): δ
19.25 (+ve, CH3), 44.36 (-ve, NCH2), 59.90 (+ve, OCH3),
101.06 (+ve, C5-H), 127.53 (+ve, ArCH), 127.95 (absent, C),
132.49 (absent, C), 144.02 (+ve, C6-H), 149.60 (absent, C),
152.11 (absent, C), 162.69 (absent, C); IR νmax/cm-1 (KBr):
3205 (NH), 1710 (CdO), 1695 (CdO), 1675 (CdO), 1644(CdO).
Anal. Calcd for C18H18O5N4: C 58.38, H 4.86, N 15.14. Found:
C 58.37, H 4.85, N 15.58.
1,3-B is (1-u r a c ily lm e t h y l)-2-a c e t o x y -5-m e t h y lb e n -
zen e (3c): 70%, 48 h; mp 272 °C (AcOH); MS m/z 398 (M+);
1H NMR (200 MHz, CDCl3 + TFA): δ 2.38 (3H, s, CH3), 2.44
(3H, s, OAc), 4.90 (4H, s, 2 × NCH2), 6.11 (2 H, d, J ) 7.9 Hz,
C5-H), 7.20 (2H, s, ArH), 7.46 (2H, d, J ) 7.9 Hz, C6-H), 10.83
(2H, s, 2 × NH); 13C NMR (normal/DEPT-135) (50 MHz, CDCl3
+ TFA): δ 20.39 (+ve, CH3), 37.98 (+ve, OAc), 47.19 (-ve,
NCH2), 103.20 (+ve, C5-H), 127.60 (absent, C), 131.63 (+ve,
of 4j in CDCl3 shifts the OH protons upfield from δ 8.31
to 7.97. The H NMR spectrum of 4j‚malonitrile (1:40)
1
exhibits only one singlet at δ 7.97, and one NCH2 singlet
at δ 4.80 becomes sharp and a second NCH2 at δ 5.14
becomes broad, in comparison with that observed in 4j.
So, malonitrile binds weakly with 4j (K ) 6.5 + 0.5
mol-1). A similar effect is observed with acetonitrile, but
addition of nitromethane does not effect the 1H NMR
spectrum of 4j.
Exp er im en ta l Section
For general experimental details, see ref 21.
1,3-Bis(b r om om e t h yl)-2-a ce t oxy-5-(t er t -b u t yl)b e n -
zen e (2d ). To a mixture of p-tert-butylphenol (28.0 g, 0.185
mol) and K2CO3 (30.0 g, 0.217 mol) in 300 mL of water stirred
under N2 at 70 °C was added 37% aqueous formaldehyde
solution (60 mL, 0.74 mol), and it was stirred at 65-70 °C for
5 h. The CO2 was bubbled through the reaction mixture until
the yellow solution turned very cloudy. The mixture was
extracted with ethyl acetate, and the organic layer was dried
over Na2SO4 (anhydrous). The solvents were removed under
vaccum, and the residue was added to the cooled solution of
37% HBr in acetic acid (60 mL) and stirred for 30 min at room
temperature and then heated to 50 °C for another 30 min.
Acetic anhydride (120 mL) was added to the reaction mixture
very carefully, and the reaction mixture was heated on water-
bath for 1 h. The solvent was removed under vaccum, and the
residue was dissolved in ether solvent and washed with
aqueous NaHCO3 solution. The organic layer was separated
and dried (Na2SO4). The solvent was evaporated, and the
residue was sublimed under vaccum to get 2e (55%): mp 61
(22) Mendoza, J .; Nieto, P. M.; Prados, P.; Sanchez, C. Tetrahedron
1990, 6(2), 671.
(23) Wilhelm, W. J . Org. Chem. 1952, 17, 523.
(24) Koeing, K. E.; Lein, G. M.; Stuckler, P.; Kaneda, T.; Cram, D.
J . J . Am. Chem. Soc. 1979, 101, 3553.
(25) Zawadowski, T. Rocz. Chem. 1968, 42, 297.
(26) Wieder, W.; Naetscher, R.; Voeglte, F. J ustus Liebigs Ann.
Chem. 1976, 5, 924.
(21) Kumar, S.; Hundal, M. S.; Hundal, G.; Singh, P.; Bhalla, V.;
Singh, H., J Chem. Soc. Perkin Trans. 2 1998, 925.

7724 J . Org. Chem., Vol. 64, No. 21, 1999
Kumar et al.
ArCH), 139.62 (absent, C), 144.96 (+ve, C6-H), 146.78 (absent,
C), 152.42 (absent, C), 162.27 (absent, C), 173.47 (absent, C);
IR νmax/cm-1 (KBr): 1758 (CdO), 1713 (CdO), 1676 (CdO).
Anal. Calcd for C19H18O6N4: C 57.29, H 4.52, N 14.07. Found:
C 57.39, H 4.39, N 13.86.
102.32 (+ve, C5-H), 123.99 (+ve, ArCH), 127.58 (+ve, ArCH),
128.91 (+ve, ArCH), 129.51 (absent, C), 132.62 (absent, ArC),
137.55 (absent, C), 141.37 (+ve, C6-H), 151.55 (absent, C),
155.48 (absent, C), 162.40 (absent, C); IR νmax/cm-1 (KBr):
1710 (CdO), 1670 (CdO). Anal. Calcd for C26H24O5N4: C 66.10,
H 5.08, N 11.86. Found: C 66.40, H 485, N 11.92.
2,6-Bis(1-u r a cilylm eth yl)-1-a cetoxy-4-(ter t-bu tyl)ben -
zen e (3d ): 70%, 48 h; mp 271-273 °C (AcOH); MS m/z 440
4d : 18%, 24 h; mp > 340 °C (CHCl3 + MeOH); FAB MS
1
1
(M+); H NMR (200 MHz, CDCl3 + DMSO-d6): δ 1.30 (9H, s,
m/z 517 (M+ + 1); H NMR (200 MHz, CDCl3): δ 2.32 (3H, s,
3 × CH3), 2.36 (3H, s, OAc), 4.78 (4H, s, 2 × NCH2), 5.56 (2 H,
dd, J 1 ) 8.0 Hz, J 2 ) 2.0, C5-H), 7.18 (2H, d, J ) 8.0 Hz, C6-
H), 7.32 (2H, s, ArH); 13C NMR (normal/DEPT-135) (50 MHz,
CDCl3 + DMSO-d6): δ 25.90 (+ve, CH3), 36.09 (+ve, OAc),
39.37 (absent, C), 50.66 (-ve, NCH2), 106.66 (+ve, C5-H),
132.07 (absent, C), 134.02 (absent, C), 150.09 (+ve, C6-H),
153.95 (absent, C), 156.10 (absent, C), 168.61 (absent, C),
174.32 (absent, C); IR νmax/cm-1 (KBr): 1753 (CdO), 1716
(CdO), 1672 (CdO). Anal. Calcd for C22H24O6N4: C 60.00, H
5.45, N 12.72. Found: C 60.35, H 5.11, N 12.86.
CH3), 2.33 (3H, s, CH3), 2.86 (3H, s, OCH3), 3.65 (3H, s, OCH3),
3.74, 5.74 (4H, AB quartet, J ) 14 Hz, NCH2), 4.20, 5.87 (4H,
AB quartet, J ) 14 Hz, NCH2), 5.50 (2 H, d, J ) 7.8 Hz, C5-
H), 6.62 (2H, d, J ) 7.8 Hz, C6-H), 7.01 (2H, s, ArH), 7.26
(2H, s, ArH); 13C NMR (normal/DEPT-135) (50 MHz, CDCl3):
δ 15.69 (+ve, CH3), 29.80 (-ve, NCH2), 41.78 (-ve, NCH2),
47.04 (-ve, NCH2), 61.21 (+ve, OCH3), 61.83 (+ve, OCH3),
101.62 (+ve, C5-H), 129.75 (absent, C), 130.90 (absent, C),
131.47 (absent, C), 132.46 (+ve, ArCH), 133.81 (absent, C),
134.13 (+ve, ArCH), 139.48 (+ve, C6-H), 150.98 (absent, C),
156.46 (absent, C), 162.37 (absent, C); IR νmax/cm-1 (KBr):
1710 (CdO), 1700 (CdO), 1657 (CdO). Anal. Calcd for
2,6-Bis(1-u r a cilylm eth yl)-1-a cetoxyben zen e (3e): 70%,
48 h; mp 258-62 °C (MeOH); MS m/z 384 (M+); 1H NMR
(CDCl3 + TFA): δ 2.46 (3H, s, OAc), 4.95 (4H, s, 2 × NCH2),
6.08 (2 H, d, J ) 8.0 Hz, C5-H), 7.26-7.45 (5H, s, ArH, C6-H),
13C NMR (normal/DEPT-135) (CDCl3 + TFA): δ 20.59 (+ve,
OAc), 47.06 (-ve, NCH2), 103.21 (+ve, C5-H), 128.10 (+ve,
ArCH), 128.42 (absent, ArC), 130.97 (+ve, ArCH), 146.24 (+ve,
ArCH), 152.05 (absent, ArC), 166.97 (absent, CdO), 166.62
(absent, CdO), 171.79 (absent, CdO); IR νmax/cm-1 (KBr): 1770
(CdO), 1700 (CdO), 1670 (CdO). Anal. Calcd for C18H16O6N4:
C 56.25, H 4.16, N 14.58. Found: C 56.45, H 4.01, N 14.36.
Syn th esis of Ca lix[2]u r a cil[2]a r en es (4a -i). A suspen-
sion of 3a (3.26 g, 0.01 mol) in acetonitrile (1000 mL)
containing dibromide 2a (3.168 g, 0.012 mol), K2CO3 (10 g),
and TBA-HSO4 (20 mg) was heated to reflux, and the progress
of the reaction was monitored by TLC. After completion of
reaction, K2CO3 was filtered off and washed with acetonitrile.
The filtrate and washings were combined, the solvent was
distilled off, and the residue was column chromatographed on
silica gel (60-120 mesh) using ethyl acetate:chloroform (20:
80) as eluent to isolate product 4a . Similar reactions of 3a with
2b and 3b with 2a , 2b, and 2c gave calix[4]arenes 4c, 4b, 4d ,
and 4e. The reactions of 3c with 2b and 2c, 3d with 2d , and
3e with 2e gave calix[4]arenes 4f, 4g, 4h , and 4i, respectively.
4a : 24%, 30 h; mp 287-290 °C (CHCl3); MS m/z 428 (M+);
1H NMR (200 MHz, CDCl3): δ 4.97 (4H, s, 2 × NCH2), 5.16
(4H, s, 2 × NCH2), 6.16 (2 H, d, J ) 8.0 Hz, C5-H), 7.21-7.46
(10H, m, ArH and C6-H); 13C NMR (normal/DEPT-135) (50
MHz, CDCl3): δ 45.51 (-ve, NCH2), 53.95 (-ve, NCH2), 102.13
(+ve, C5-H), 126.94 (+ve, ArCH), 128.65 (+ve, ArCH), 129.10
(+ve, ArCH), 129.84 (+ve, ArCH), 129.98 (absent, C), 135.39
(absent,C), 136.00 (absent,C), 144.83 (+ve, C6-H), 152.08
(absent, C), 166.36 (absent, C); IR νmax/cm-1 (KBr): 1700
(CdO), 1660 (CdO), 1652 (CdO). Anal. Calcd for C24H20O4N4:
C 67.29, H 4.67, N 13.48. Found: C 67.02, H 4.37, N 13.86.
4b: 20%, 24 h; mp 297 °C decomp (CHCl3 + MeOH); MS
m/z 472 (M+); 1H NMR (200 MHz, CDCl3): δ 2.31 (3H, s, CH3),
2.95 (3H, s, OCH3), 3.91, 5.50 (4H, AB quartet, J ) 15 Hz, 2
× NCH2), 4.75, 5.82 (4H, AB quartet, J ) 15 Hz, 2 × NCH2),
5.59 (2 H, d, J ) 7.8 Hz, C5-H), 6.65 (s, 1H, ArH), 6.73 (2H, d,
J ) 7.8 Hz, C6-H), 7.06 (2H, s, ArH), 7.27 (3H, s, ArH); 13C
NMR (normal/DEPT-135) (50 MHz, CDCl3): δ 20.59 (+ve,
CH3), 43.75 (-ve, NCH2), 47.62 (-ve, NCH2), 61.27 (+ve,
OCH3), 101.40 (+ve, C5-H), 122.37 (+ve, ArCH), 127.19 (+ve,
ArCH), 127.66 (+ve, ArCH), 130.78 (absent, C), 132.42 (+ve,
ArCH), 134.26 (absent, C), 137.34 (absent, C), 140.46 (+ve,
C6-H), 151.42 (absent, C), 155.71 (absent, C), 162.65 (absent,
C); IR νmax/cm-1 (KBr): 1707 (CdO), 1660 (CdO), 1652 (CdO).
Anal. Calcd for C26H24O5N4: C 66.10, H 5.08, N 11.86. Found:
C 65.87, H 4.88, N 11.56.
C
28H28O6N4: C 65.12, H 5.43, N 10.85. Found: C 64.81, H 5.09,
N 11.16.
4e: 27%, 24 h; mp > 340 °C decomp (CHCl3 + MeOH); FAB
MS m/z 545 (M+ + 1); 1H NMR (200 MHz, CDCl3): δ 2.15 (3H,
s, OAc), 2.32 (3H, s, CH3), 2.37 (3H, s, CH3), 2.91 (3H, s, OCH3),
3.78, 5.75 (4H, AB quartet, J ) 14 Hz, 2 × NCH2), 4.22, 5.68
(4H, AB quartet, J ) 14 Hz, 2 × NCH2), 5.56 (2 H, d, J ) 7.8
Hz, C5-H), 6.76 (2H, d, J ) 7.8 Hz, C6-H), 7.04 (2H, s, ArH),
7.36 (2H, s, ArH); 13C NMR (normal/DEPT-135) (50 MHz,
CDCl3): δ 20.57 (+ve, 2 × CH3), 21.99 (+ve, OAc), 41.79 (-ve,
NCH2), 47.07 (-ve, NCH2), 61.12 (+ve, OCH3), 101.97 (+ve,
C5-H), 129.24 (absent, C), 130.50 (absent, C), 132.64 (+ve,
ArCH), 133.88 (absent, C), 134.10 (absent, C), 134.19 (+ve,
ArCH), 140.53 (+ve, C6-H), 146.20 (absent, C), 150.86 (absent,
C), 156.35 (absent, C), 162.34 (absent, C), 170.37 (absent, C);
IR νmax/cm-1 (KBr): 1750 (CdO), 1712 (CdO), 1675 (CdO),
1592 (CdC). Anal. Calcd for C29H28O7N4: C 63.97, H 5.15, N
10.29. Found: C 64.35, H 4.87, N 10.25.
4f: 20%, 24 h; mp > 340 °C decomp (CHCl3 + MeOH); FAB
MS m/z 545 (M+ + 1); 1H NMR (200 MHz, CDCl3): δ 1.47 (3H,
s, OAc), 2.29 (3H, s, CH3), 2.40 (3H, s, CH3), 3.54 (3H, s, OCH3),
3.76, 5.43 (4H, AB quartet, J ) 14 Hz, 2 × NCH2), 4.21, 5.97
(4H, AB quartet, J ) 14 Hz, 2 × NCH2), 5.58 (2 H, d, J ) 7.8
Hz, C5-H), 6.74 (2H, d, J ) 7.8 Hz, C6-H), 7.16 (2H, s, ArH),
7.20 (2H, s, ArH); 13C NMR (normal/DEPT-135) (50 MHz,
CDCl3): δ 20.37 (+ve, CH3), 20.64 (+ve, CH3), 42.17 (-ve,
NCH2), 46.77 (-ve, NCH2), 62.53 (+ve, OCH3), 102.00 (+ve,
C5-H), 130.05 (absent, C), 132.37 (+ve, ArCH), 132.94 (absent,
C), 133.40 (+ve, ArCH), 136.49 (absent, C), 139.91 (+ve, C6-
H), 150.50 (absent, C), 162.45 (absent, C); IR νmax/cm-1 (KBr):
1740 (CdO), 1707 (CdO), 1662 (CdO). Anal. Calcd for
C
29H28O7N4: C 63.97, H 5.15, N 10.29. Found: C 64.42, H 4.87,
N 10.12.
4g: 28%, 20 h; mp > 340 °C decomp (CHCl3 + MeOH); FAB
MS m/z 573 (M+ + 1); 1H NMR (200 MHz, CDCl3): δ 1.50 (3H,
s, OAc), 2.01 (3H, s, OAc), 2.33 (3H, s, CH3), 2.41 (3H, s, CH3),
3.80, 5.46 (4H, AB quartet, J ) 15 Hz, 2 × NCH2), 4.20, 5.79
(4H, AB quartet, J ) 15 Hz, 2 × NCH2), 5.63 (2 H, d, J ) 8.0
Hz, C5-H), 6.87 (2H, d, J ) 7.8 Hz, C6-H), 7.18 (2H, s, ArH),
7.26 (2H, s, ArH); 13C NMR (normal/DEPT-135) (50 MHz,
CDCl3): δ 20.40 (+ve, CH3), 20.44 (+ve, CH3), 20.64 (+ve,
OAc), 21.67 (+ve, OAc), 42.30 (-ve, NCH2), 46.86 (-ve, NCH2),
101.60 (+ve, C5-H), 130.55 (absent, C), 130.68 (absent, C),
132.45 (+ve, ArCH), 133.39 (+ve, ArCH), 135.48 (absent, C),
136.73 (absent, C), 140.71 (+ve, C6-H), 146.01 (absent, C),
150.27 (absent, C), 156.35 (absent, C), 162.33 (absent, C),
169.50 (absent, C), 170.04 (absent, C); IR νmax/cm-1 (KBr):
1753 (CdO), 1710 (CdO), 1660 (CdO), 1672 (CdO). Anal.
4c: 15%, 30 h; mp 276 °C (CHCl3); MS m/z 472(M+); 1H
NMR (200 MHz, CDCl3): δ 2.33 (3H, s, CH3), 3.67 (3H, s,
OCH3), 4.01 (4H, s, 2 × NCH2), 4.49, 5.76 (4H, AB quartet, J
) 14 Hz, 2 × NCH2), 5.58 (2 H, d, J ) 8.0 Hz, C5-H), 6.92
(2H, d, J ) 8.0 Hz, C6-H), 7.21-7.40 (6H, m, ArH); 13C NMR
(normal/DEPT-135) (50 MHz, CDCl3): δ 20.66 (+ve, CH3),
42.15 (-ve, NCH2), 51.16 (-ve, NCH2), 62.37 (+ve, OCH3),
Calcd for C30H28O8N4: C 62.94, H 4.89, N 9.79. Found:
62.65, H 4.61, N 10.06.
C
4h : 18%, 20 h; mp > 340 °C (decomp) (CHCl3); FAB MS
1
m/z 657 (M+ + 1); H NMR (200 MHz, CDCl3): δ 1.34 (9H, s,
3 × CH3), 1.37 (9H, s, 3 × CH3), 1.39 (3H, s, OAc), 1.97 (3H,
s, OAc), 3.85, 5.57 (4H, AB quartet, J ) 14.4 Hz, 2 × NCH2),
4.25, 5.82 (4H, AB quartet, J ) 14.4 Hz, 2 × NCH2), 5.66 (2

Heterocalixarenes
J . Org. Chem., Vol. 64, No. 21, 1999 7725
Ta ble 3. Cr ysta l Da ta Collection a n d Refin em en t
P a r a m eter s for Ca lix[2]u r a cil[2] Ar en es 4g a n d
4j‚Eth a n ol (2:1)
H, d, J ) 8.0 Hz, C5-H), 6.84 (2H, d, J ) 7.8 Hz, C6-H), 7.33
(2H, s, ArH), 7.42 (2H, s, ArH); 13C NMR (normal/DEPT-135)
(50 MHz, CDCl3): δ 21.18 (+ve, OAc), 21.66 (+ve, OAc), 31.36
(+ve, CH3), 34.34 (absent, C), 34.61 (absent, C), 42.71 (-ve,
NCH2), 47.22 (-ve, NCH2), 101.52 (+ve, C5-H), 128.68 (+ve,
ArCH), 129.26 (+ve, ArCH), 130.20 (absent, C), 140.84 (+ve,
C6-H), 145.65 (absent, C), 146.61 (absent, C), 148.40 (absent,
C), 150.24 (absent, C), 162.46 (absent, C), 169.31 (absent, C),
170.99 (absent, C); IR νmax/cm-1 (KBr): 1753 (CdO), 1710
(CdO), 1660 (CdO), 1672 (CdO). Anal. Calcd for C36H40O8N4:
C 65.85, H 6.09, N 8.54. Found: C 65.63, H 5.87, N 8.37.
4i: 16%, 36 h; mp > 340 °C (decomp) (CHCl3); MS m/z 544
(M+); 1H NMR (CDCl3): δ 1.46 (3H, s, OAc), 2.01 (3H, s, OAc),
3.87, 5.49 (4H, AB quartet, J ) 14.4 Hz, 2 × NCH2), 4.26, 5.83
(4H, AB quartet, J ) 14.4 Hz, 2 × NCH2), 5.62 (2 H, d, J )
8.0 Hz, C5-H), 6.85 (2H, d, J ) 7.8 Hz, C6-H), 7.20-7.49 (6H,
m, ArH); 13C NMR (normal/DEPT-135) (50 MHz, CDCl3): δ
20.19 (+ve, OAc), 21.68 (+ve, OAc), 34.34 (absent, C), 43.21
(-ve, NCH2), 446.91 (-ve, NCH2), 101.70 (+ve, C5-H), 125.93
(+ve, ArCH), 126.76 (+ve, ArCH), 131.14 (absent, C), 131.96
(+ve, ArCH), 132.73 (+ve, ArCH), 139.75 (+ve, C6-H), 148.23
(absent, C), 149.32 (absent, C), 150.28 (absent, C), 162.31
4g
4j‚ethanol (2:1)
empirical formula
MW
crystal system
space group
C
30H28N4O8
C54H54N8O13
1023.05
monoclinic
p21/c
572.56
monoclinic
p21/c
a/Å
b/Å
c/Å
9.5660(10)
18.271(2)
15.602(2)
93.750(10)
2721.1(5)
4
11.346(3)
17.125(3)
25.281(5)
102.63(2)
4743(2)
4
â/deg
V/Å3
Z
crystal size/mm
0.3 × 0.3 × 0.2
0.4 × 0.3 × 0.3
µ(Mo KR)/cm-1
1.03
1.03
θ
max/deg
2.13 to 20°
1.45 to 20.00°
4404
no. of measured reflections 2629
no. of unique reflections
2433
4105
Rint
0.0267
0.0976
no. observations [I > 3σ(I)] 2211
3140
416
R1 ) 0.0979
wR2 ) 0.2262
no. of variables
residuals: R
379
R1 ) 0.0494
wR2 ) 0.1147
(absent, C), 169.29 (absent, C), 170.80 (absent, C); IR νmax
/
max and min residual
electron density/e Å-3
goodness of fit (GOOF)
0.203 and -0.204 0.362 and -0.255
1.056 1.015
cm-1 (Kbr). Anal. Calcd for C28H24O8N4: C 61.76, H 4.41, N
10.29. Found: C 61.92, H 4.13, N 10.12.
4j. A suspension of 4g (0.57 g, 0.001 mol) in HCl-ethanol
(1:1) (300 mL) was refluxed, and the progress of hydrolysis
was monitored by TLC. After the completion of hydrolysis, the
reaction mixture was concentrated under vaccum, and the
separated solid was filtered and recrystallized from ethanol-
chloroform to get 4j‚ethanol (2:1) complex (80%) (20 h), mp
279 °C (CHCl3 + MeOH). The crystalline product upon heating
at approximately 200 °C, due to a loss of trapped solvent,
became an amorphous powder: MS m/z 488 (M+); 1H NMR
(CDCl3): δ 2.16 (3H, s, CH3), 2.22 (3H, s, CH3), 5.12 (4H, bs,
2 × NCH2), 5.29 (4H, s, 2 × NCH2), 5.74 (2 H, d, J ) 7.8 Hz,
C5-H), 6.90 (2H, s, ArH), 7.17 (2H, d, J ) 7.8 Hz, C6-H), 7.22
(2H, s, ArH), 7.97 (1H, bs, OH), 8.34 (1H, bs, OH); 13C NMR
(normal/DEPT-135) (CDCl3): δ 20.36 (+ve, CH3), 40.53 (-ve,
NCH2), 50.27 (-ve, NCH2), 101.17 (+ve, C5-H), 123.39 (absent,
C), 123.91 (absent, C), 128.84 (absent, C), 130.14 (absent, C),
131.92 (+ve, ArCH), 133.08 (+ve, ArCH), 142.14 (+ve, C6-H),
151.40 (absent, C), 152.78 (absent, C), 162.56 (absent, C); IR
crystals of 4g and 4j‚ethanol suitable for X-ray diffraction work
were obtained by recrystallization from acetonitrile and etha-
nol, respectively. The unit cell parameters were determined
from a least-squares fit of setting angles of 25 reflections in
the range 20 e 2θ e 25°. Three standard reflections were
measured every 100 reflections and showed no significant
intensity variation during the data collection. The data were
corrected for Lorentz and polarization effects. No absorption
corrections were applied. The structures were solved by direct
methods. Full matrix least squares refinement was employed
with anisotropic thermal parameters for the non hydrogen
atoms. The hydrogen atoms placed at calculated positions were
refined isotropically with fixed thermal parameters and in-
cluded in structure factor calculations. Crystal data and
parameters for data collection and refinements are sum-
marized in Table 3.
Extr a ction Mea su r em en ts.28 For the extraction experi-
ments, metal picrate solutions (0.01 mol dm-3) were prepared
in deionized, distilled water. The solutions of macrocycles (0.01
mol dm-3) were prepared in chloroform (A.R. grade).
ν
max/cm-1 (KBr): 1753 (Cd O), 1710 (CdO), 1660 (CdO), 1672
(CdO). Anal. Calcd for C26H24O6N41/2C2H5OH: C 62.92, H 5.62,
N 10.48. Found: C 62.45, H 5.31, N 10.36.
An aqueous solution (2 cm3) of metal picrate (0.01 mol dm-3
)
4k . The phase transfer catalyzed cyclocondensation of 3c
with 2f, as described above for synthesis of 4a -i, gave a
mixture of products which was refluxed in HCl-ethanol (1:1)
for 24 h. After removal of solvent under vaccum, the residue
was column chromatographed using chloroform-ethyl acetate
(8:2) as eluent to get pure 4k (12%) (36 h), mp 295 °C (CHCl3
and a chloroform solution (2 cm3) of the macrocycle (0.01 mol
dm-3) were shaken in a cylindrical tube closed with a septum
for 5 min and kept at 27 ( 1 °C for 3-4 h. An aliquot of the
chloroform layer (1 cm-3) was withdrawn with a syringe and
diluted with acetonitrile to 10 cm-3. The UV absorption was
measured against CHCl3-CH3CN (1:9) solution at 374 nm.
Extraction of metal picrate has been calculated as the percent-
age of metal picrate extracted in the chloroform layer, and the
values reported here are the mean of three independent
measurements which were within (2% error (Table 1).
Tr a n sp or t Mea su r em en ts.29 The transport experiments
were carried out at constant temperature (27 ( 1 °C) in a
cylinderical glass cell consisting of outer and inner jackets by
using (i) metal picrate (0.01 mol dm-3) in water (3 cm3) in the
inner phase; (ii) water (10 cm3) in the outer phase; (iii) ligand
(10 mmol dm-3) in the chloroform layer (15 cm3) with stirring
(150 ( 5 rpm) at 27 ( 1 °C. After stirring for 6 h, the picrates
transported in the aqueous receiving phase were determined
from the UV absorptions at 355 nm. Each value is a mean of
three experiments which are consistent (10% (Table 1). Before
1
+ MeOH); MS m/z 519 (M+); H NMR (200 MHz, CDCl3): δ
2.21 (3H, s, CH3), 4.90 (4H, bs, 2 × NCH2), 5.19 (4H, s, 2 ×
NCH2), 5.79 (2 H, d, J ) 7.8 Hz, C5-H), 6.94 (2H, s, ArH),
7.25 (2H, d, J ) 7.8 Hz, C6-H), 8.05 (1H, bs, OH), 8.31 (2H, s,
ArH), 9.20 (1H, bs, OH); 13C NMR (normal/DEPT-135) (50
MHz, CDCl3): δ 20.24 (+ve, CH3), 40.45 (-ve, NCH2), 50.06
(-ve, NCH2), 103.17 (+ve, C5-H), 123.30 (absent, C), 123.56
(absent, C), 128.75 (absent, C), 130.08 (absent, C), 132.08 (+ve,
ArCH), 139.94 (absent, ArC), 142.37(+ve, C6-H), 151.28
(absent, C), 152.80 (absent, C), 159.70 (absent, C), 162.24
(absent, C); IR νmax/cm-1 (KBr): 1750 (CdO), 1709 (CdO), 1658
(CdO), 1676 (CdO). Anal. Calcd for C25H21O8N5: C 57.80, H
4.05, N 13.49. Found: C 58.13, H 4.00, N 13.17.
X-r a y Str u ctu r e An a lysis of Ca lix[2]u r a cil[2]a r en es 4g
a n d 4j‚Eth a n ol (2:1). All intensity data measurements were
carried out on a Siemens P4 four circle diffractometer with
graphite monochromatic Mo-KR radiation (λ ) 0.71069 Å).
All structures were solved and refined using the SHELXTL
software27 package on a Siemens Nixdorf computer. The
(28) (a) Moore, S. S.; Tarnowski, T. L.; Newcomb, M.; Cram, D. J .
J . Am. Chem. Soc. 1977, 99, 6398. (b) Koeing, K. E.; Lehn, G. M.;
Stuckler, P.; Kaneda, T.; Cram, D. J . J . Am. Chem. Soc. 1979, 101,
3553.
(29) (a) Maruyama, K.; Tsukube, H.; Akai, T. J . Am. Chem. Soc.
1980, 102, 3246. (b) Maruyama, K.; Tsukube, H.; Akai, T. J . Chem.
Soc., Dalton Trans. 1981, 1486.
(27) Sheldrick, G. M. SHELXT-PC Verian 5.03, Siemens Analytical
Instruments Inc., Madison, WI, 1995.

7726 J . Org. Chem., Vol. 64, No. 21, 1999
Kumar et al.
the transport rates were determined, blank experiments were
performed in the absence of the carrier macrocycle in the
chloroform layer to check the leakage of metal picrates. The
only significant leakage was observed in the case of Pb2+, and
so, transport of Pb2+ was not determined.
Sp ectr op h otom etr ic Deter m in a tion of Sta bility Con -
sta n ts.30 The complexation (1:1) of metal cation M by a ligand
L in solution can be represented by the equilibrium
calix[2]uracil[2]arene 2j (10-3 M) and metal acetates (10-2 M)
were prepared in a methanol:deionized water (95:5) mixture.
The titrations were carried out by addition of known volumes
of metal acetate stock solutions to 1 mL of calix[2]uracil[2]arene
2j stock solutions in 10 mL measuring flasks and diluted up
to the mark with a methanol:deionized water (95:5) mixture
and recording the absorption spectra of these solutions. On
plotting the absorption against the metal acetate concentra-
tions, we observed a monotonic dependence, thus indicating a
constant 1:1 stoichiometry of complexation. The limiting value
of complexation was determined by recording absorption of 2j
in the presence of 2 equiv of NaOH. The stability constants
were calculated according to the method described in the
literature.30
M + L h ML
which is controlled by the stability constant
KS ) [ML]/[M][L]
Ack n ow led gm en t. We thank DST (SP/SI/G-28/97)
and UGC, New Delhi, for financial assistance.
expressing the degree of stability of the complex in given
solvent and temperature conditions.
The absorption spectra were recorded on a UV-visible
Su p p or tin g In for m a tion Ava ila ble: Crystal data for 4g
and 4j‚ethanol. This material is available free of charge via
the Internet at http://pubs.acx.org.
spectrophotometer at 25 ( 1 °C. The stock solutions of
(30) Bourson, J .; Pouget, J .; Voleur, B. J . Phys. Chem. 1993, 97,
4552.
J O990085Q