Squaramido-based receptors: Design, synthesis, and application to the recognition of tetraalkylammonium compounds

Article abstract of DOI:10.1021/jo9614147

A new series of tripodal receptors based on squaramido rings as unprecedented binding units has been devised. Among the different structural possibilities that this functionality offers, the ability of establishing multiple O to C-H interactions has been explored. On this basis, new receptors capable of recognizing choline, acetylcholine, and related ammonium salts have been synthesized. Association constants in the range 10³-10⁴ M^-1 have been measured by a ¹H-NMR titration method using a 1:1 model. The formation of intracavity complexes is supported by the observation of characteristic changes in the NMR spectra of the complexes, of intermolecular cross peaks in 2D ROESY experiments, and by detection of signals corresponding to the molecular weight of the complexes by positive FAB mass spectrometry.

Full text of DOI:10.1021/jo9614147

9394
J . Org. Chem. 1996, 61, 9394-9401
Squ a r a m id o-Ba sed Recep tor s: Design , Syn th esis, a n d Ap p lica tion
to th e Recogn ition of Tetr a a lk yla m m on iu m Com p ou n d s
Salvador Toma`s, Rafel Prohens, Manuel Vega, M. Carmen Rotger, Pere M. Deya`,
Pablo Ballester,* and Antoni Costa*
Departament de Quı´mica, Universitat de les Illes Balears, 07071 Palma de Mallorca, Spain
Received J uly 24, 1996X
A new series of tripodal receptors based on squaramido rings as unprecedented binding units has
been devised. Among the different structural possibilities that this functionality offers, the ability
of establishing multiple O to C-H interactions has been explored. On this basis, new receptors
capable of recognizing choline, acetylcholine, and related ammonium salts have been synthesized.
1
Association constants in the range 103-104 M-1 have been measured by a H-NMR titration method
using a 1:1 model. The formation of intracavity complexes is supported by the observation of
characteristic changes in the NMR spectra of the complexes, of intermolecular cross peaks in 2D
ROESY experiments, and by detection of signals corresponding to the molecular weight of the
complexes by positive FAB mass spectrometry.
In tr od u ction
absence of hydrophobic effects. Thus, the use of cation-π
interactions as the sole binding force has led to very
limited complexation of ammonium compounds with
artificial receptors in nonpolar organic solvents.
The cation-π interaction observed in complexes be-
tween quaternary ammonium compounds and aromatic
receptors has been recently exploited as a useful binding
An additional binding interaction arises from the
charged character of the ammonium compounds. In fact,
the R-methyl or methylene hydrogens in R4N+ cations
bear a partial positive charge9 and, therefore, can be
engaged in hydrogen bonding. This interaction can have
an important electrostatic component especially if the
hydrogen acceptor is a basic oxygen atom located in a
polar group.10 This condition can be fulfilled by oxygen
carbonyl atoms. On the basis of crystallographic data,
it has been suggested that the C-H‚‚‚O hydrogen bond
is stronger for carbonyl oxygens than for other polar
oxygen groups.11 In an attempt to expand the repertory
of forces suitable for binding a tetraalkylammonium
compound in nonpolar organic media, we rationalized
that multiple C-H‚‚‚O (OdC) interactions would be well
suited for an effective complexation of these charged
compounds within neutral receptors.
force for molecular recognition studies.1,2-4
Recent
,16
work by Dougherty1 has emphasized the importance of
this attractive force in biological systems.5 According to
his argument,6 the electrostatic interaction between a
cationic ligand and the electron-rich surface of an aro-
matic ring would play a central role in binding interac-
tions.
Fueled by these findings, several groups have studied
the extent of the cation-π or CH-π7 interaction for
molecular recognition in nonpolar organic media. Studies
on a number of suitable aromatic hosts have revealed
that the association constants measured for these model
systems are usually lower than 102 M-1 (∼2 kcal/mol),8
reflecting the weak character of these forces in the
X Abstract published in Advance ACS Abstracts, November 15, 1996.
(1) (a) Shepodd, T. J .; Petti, M. A.; Dougherty, D. A. J . Am. Chem.
Soc. 1988, 110, 1983-1985. (b) Stauffer, D. A.; Barrans, R. E., J r.;
Dougherty, D. A. J . Org. Chem. 1990, 55, 2762-2767. (c) Petti, M. A.;
Shepodd, T. J .; Barrans, R. E., J r.; Dougherty, D. A. J . Am. Chem.
Soc. 1988, 110, 6825-6840. (d) Kearney, P. C.; Mizoue, L. S.; Kumpf,
R. A.; Forman, J . A.; McCurdy, A.; Dougherty, D. A. J . Am. Chem.
Soc. 1993, 115, 9907-9919.
(2) (a) Collet, A.; Dutasta, J .-P.; Lozach, B. Bull. Soc. Chim. Belg.
1990, 99, 617-633. (b) Collet, A.; Dutasta, J . P.; Lozach, B. In Advances
in Supramolecular Chemistry; Gokel, G. W., Ed.; J AI Press Inc.:
Greenwich, CT, 1993; Vol. 3; pp 1-35.
(3) (a) Araki, K.; Shimizu, H.; Shinkai, S. Chem. Lett. 1993, 205-
208. (b) Shinkai, S. Tetrahedron 1993, 49, 8933-8968. (b) Shinkai, S.;
Araki, K.; Manabe, O. J . Am. Chem. Soc. 1988, 110, 7214-7218. (c)
Arimura, T.; Kubota, M.; Araki, K.; Shinkai, S.; Matasuda, T.
Tetrahedron Lett. 1989, 2563-2566. (d) Shinkai, S.; Araki, K.; Mat-
suda, T.; Nishiyama, N.; Ikeda, H.; Takasu, I.; Iwamoto, M. J . Am.
Chem. Soc. 1990, 112, 9053-9058. (e) Shinkai, S.; Araki, K.; Kubota,
M.; Arimura, T.; Matsuda, T. J . Org. Chem. 1991, 56, 295-300.
(4) (a) De Iasi, G.; Masci, B. Tetrahedron Lett. 1993, 6635-6638.
(b) Masci, B. Tetrahedron 1995, 51, 5459-5464.
Interestingly, C-H‚‚‚O contacts involving quaternary
ammonium compounds have been observed in crystals.12
Additional support for the hydrogen-bonding ability of
ammonium compounds comes from ab initio calculations
on the tetramethylammonium cation performed by Kim
et al.13 These authors reported the existence of σ
electronic transfer between the R-methyl hydrogens and
the electron-donating lone pairs of oxygen, thus confirm-
ing previous theoretical work on this subject.14
Although the existence of C-H‚‚‚O interactions is well
established, their practical applications in molecular
recognition are scarce.15 It is worth mentioning here that
recent work by Ungaro et al.16 describes a preferential
competitive complexation of Me4N+ to six amido carbonyl
(5) Dougherty, D. A.; Stauffer, D. A. Science 1990, 250, 1558-1560.
(6) (a) Dougherty, D. A. Science 1996, 271, 163-168. (b) Mecozzi,
S.; West, A. P., J r.; Dougherty, D. A. J . Am Chem. Soc. 1996, 118,
2307-2308.
(9) Reetz, M. T. Angew. Chem., Int. Ed. Engl., 1988, 27, 994-998.
(10) (a) Desiraju, G. R. Acc. Chem. Res. 1991, 24, 290-296. (b)
Aakero¨y, C. B.; Seddon, K. R. Acc. Chem. Res. 1993, 397-407.
(11) Steiner, T. J . Chem. Soc., Chem. Commun., 1994, 2341-2342.
(12) (a) Vazquez, C.; Calabrese, J . C.; Dixon, D. A.; Miller, J . S. J .
Org. Chem. 1993, 58, 65-81. (b) Reetz, M. T.; Hu¨tte, S.; Goddard, R.
J . Am. Chem. Soc. 1993, 115, 9339-9340.
(7) (a) Nishio, M.; Umezawa, Y.; Hirota, M.; Takeuchi, Y. Tetrahe-
dron 1995, 51, 8665-8703. (b) Nishio, M.; Hirota, M. Tetrahedron 1989,
45, 7201-7245.
(8) (a) Stauffer, D. A.; Dougherty, D. A. Tetrahedron Lett. 1988, 29,
6039-6042. (b) Takeshita, M.; Nishio, S.; Shinkai, S. J . Org. Chem.
1994, 59, 4032-4034. (c) Araki, K.; Shimizu, H.; Shinkai, S. Chem.
Lett. 1993, 205-208. (d) A.; Dalla Cort, A.; Mandolini, L. J . Org. Chem.
1995, 60, 8313-8314.
(13) Kim, K. S.; Lee, J . Y.; Lee, S. J .; Ha, T. K.; Kim, D. H. J . Am.
Chem. Soc. 1994, 116, 7399-7400.
(14) Meot-Ner, M.; Deakyne, C. A. J . Am. Chem. Soc. 1985, 107,
469-474.
S0022-3263(96)01414-4 CCC: $12.00 © 1996 American Chemical Society

Squaramido-Based Receptors
J . Org. Chem., Vol. 61, No. 26, 1996 9395
F igu r e 1. Three possible hydrogen bond patterns for squara-
mides.
groups conveniently located at the lower rim of a calix-
arene, rather to the aromatic π pool. In a previous
communication we addressed briefly this subject,17 and
the present work assesses the ability of a series of
tripodal squaramides as receptors for tetraalkylammo-
nium salts.
Resu lts a n d Discu ssion
P r elim in a r y Stu d ies. Crucial to the development of
squaramido-based receptors is an understanding and
characterization of their hydrogen-bonding patterns and
capabilities. At first glance, the two eclipsed sp2 hybrid-
ized carbonyl oxygens would allow hydrogen bonding to
take place with additional contribution from the attrac-
tive secondary hydrogen bonding.18 Secondly, in squara-
mides featuring two hydrogen bond donors (Z ) NH), a
behavior close to that observed for carboxylates and N,N′-
disubstituted ureas could be anticipated.19 Finally,
depending upon the conformational preference of mono-
alkylamino-substituted squaramides, a hydrogen bond
donor-acceptor pattern could also be expected (Figure
1). In order to test both, the validity of the proposed
hydrogen bond patterns and the conformational prefer-
ences of squaramides, preliminary experiments using
model squaramides were undertaken.
At this point, N,N′-diethylsquaramide 1 was selected
to test the squaramide hydrogen bond acceptor mode.
Titration of N,N′-diphenylurea (DPU) with 1 in chloro-
form resulted in large downfield shifts of the urea N-H
resonances (∆δ ) +1.6 ppm), consistent with the forma-
tion of a hydrogen-bonded complex. An association
constant of 120 M-1 was determined from fitting the data
to the corresponding 1:1 binding isotherm. Remarkably,
upon addition of a 10-fold excess of 1, the initially
averaged spectrum of DPU spread, showing clearly three
sets of first-order resonances for the aromatic protons of
DPU. These data can be explained by formation of a
mixed complex between 1 and a DPU molecule in the
required trans, trans form. Consistent with the locked
F igu r e 2. Partial 1H-NMR (CDCl3) spectra of uncomplexed
DPU (a) and complexation-induced shifts produced after
addition of 1 (b), 2 (c), and 10 equiv of 1 (d).
conformation of complexed DPU, the ortho aromatic
hydrogens appear at lower field under the paramagnetic
influence of the urea carbonyl group (Figure 2).
The next task was to test the hydrogen bond donor
capabilities on 3,4-monoalkylamino-substituted-3-cy-
clobutene-1,2-dione 2. Unfortunately, squaramides 2a -c
were insoluble in chloroform, precluding the determina-
tion of any association constant in this solvent.
(15) Intramolecular CH‚‚‚O interactions have been used to restrict
conformational freedom in urea-based receptors for carboxylates, see:
Smith, P. J .; Reddington, M. V.; Wilcox, C. S. Tetrahedron Lett. 1992,
33, 6085-6088.
(16) Casnati, A.; J acopozzi, P.; Pochini, A.; Ugozzoli, F.; Cacciapaglia,
R.; Mandolini, L.; Ungaro, R. Tetrahedron 1995, 51, 591-598.
(17) Toma`s, S.; Rotger, M. C.; Gonza´lez, J . F.; Deya`, P. M.; Ballester,
P.; Costa, A. Tetrahedron Lett. 1995, 36, 2523-2526.
(18) (a) J eong, K. S.; Tjivikua, T.; Muehldorf, A.; Deslongchamp, G.;
Famulok, M.; Rebek, J ., J r. J . Am. Chem. Soc. 1991, 113, 201-209.
(b) J orgensen, W. L.; Pranata, J . J . Am. Chem. Soc. 1990, 112, 2008-
2010. (c) J orgensen, W. L.; Severance, D. L. J . Am. Chem. Soc. 1991,
113, 209-216.
(19) Fan, E.; Van Arman, S. A.; Kincaid, S.; Hamilton, A. D. J . Am.
Chem. Soc. 1993, 115, 369-370. (b) Galan, A.; Andreu, D.; Echavarren,
A. M.; Prados, P.; de Mendoza, J . J . Am. Chem. Soc. 1992, 114, 1511-
1512. (c) Albert, J . S.; Hamilton A. D. Tetrahedron Lett. 1993, 34,
7363-7366. (d) Flack, S. S.; Chaumette, J .-L.; Kilburn, J . D.; Langley,
G. J .; Webster, M. J . Chem. Soc., Chem. Commun. 1993, 399-401. (e)
J airam, R.; Potvin, P. G. J . Org. Chem. 1992, 57, 4136-4141.
An important issue for the development of squaramido-
based receptors is the characterization of the conforma-
1
tional preferences of squaramides in solution.20 The H-
NMR spectra of 10-3 M solutions of model squaramido
esters 3a ,b21 in CDCl3 at room temperature showed broad
signals consistent with the existence of exchange pro-
cesses. On lowering the temperature, line broadening
disappeared and two sets of resonances were clearly
(20) MM calculations are of little assistance in this case as the
carbon atom types present in squaramides are not parametrized.
(21) For solubility reasons, the study was limited to squaramido
esters 3. Full details concerning the conformational behavior of
squaramides will be published elsewhere.

9396 J . Org. Chem., Vol. 61, No. 26, 1996
Toma`s et al.
barrier of interconversion observed for squaramides to
produce, initially, a nonpreorganized array of up to six
hydrogen-bonding acceptors. According to our hypoth-
esis, such a structure should be able of recognizing
quaternary ammonium compounds by “grasping” them
through multiple O to CH hydrogen-bonding interactions.
Our prototype would require a spacer that is large
enough to accommodate the bulky ammonium guests. On
the basis of modeling studies,27 a tripodal spacer was
synthesized, based on semirigid triarylbenzene frame-
work 9 which seemed well suited for the above purposes.
Syn th esis. The preparation of squaramido-based
tripodal receptors 10-16 would rely on the availability
of the pivotal triamines 9a ,b as outlined in Scheme 1.
The starting ester 4a was obtained in multigram scale,
observed for both the NH and ethoxy groups. At 273 K
3b exists as an apparent mixture of two isomers in a 74:
26 ratio. Coalescence occurred at ∼285-290 K, while at
300 K the spectrum showed only one set of sharp signals
corresponding to the fast exchange limit. These observa-
tions can be accounted for by rotation around the C-N
bond giving rise to a mixture of two conformers in
1
equilibrium. The assignment of the H-NMR signals for
each conformer was derived from their response toward
the presence of benzoic acid. The addition of increasing
amounts of benzoic acid to a 10-3 M solution of 3a ,b
shifted the equilibrium toward the major conformer and,
at the same time, produced a strong downfield shift of
the NH signal of this conformer. In contrast, an almost
constant chemical shift was observed for the NH of the
minor isomer in the presence of benzoic acid. These
results clearly indicate that the signals of the major
component in the equilibrium can be assigned to the cis
conformer.
Further information was obtained from the tempera-
ture dependence chemical shift coefficients22 (∆δ/∆T),
determined from variable-temperature 1H-NMR mea-
surements. In agreement with the previous assignments,
values of -5.9 and -21.9 ppb/K were calculated for the
minor and the major conformers of 3a , respectively,
indicating clearly an enhanced self-association tendency
for the major rotamer. The rates of interconversion of
both isomers were also calculated at different tempera-
tures by line shape analysis,23 and from the data, an
apparent24 free energy of activation of the rotational
barrier (∆Gq) was derived giving a value of 61.4 kJ /mol
calculated at 298 K, which is in accordance with previous
data on this subject.25 The lack of a clear conformational
preference in N-monoalkyl-substituted squaramides to-
gether with the low barrier of rotation about their C-N
bond are distinctive factors when compared to N-mono-
substituted amides whose strong preference for the E
form as well as a higher activation energy of the internal
rotation is well established.26
using the highly efficient trimerization of salicylic acid
esters promoted by SiCl4.28 In order to improve the
solubility of the receptors, a propylated triester 4b was
also prepared.
Triamines 9a ,b were synthesized uneventfully in five
steps starting from 4a ,b. Upon treatment of triamines
9a ,b with a 3-fold excess of diethyl squarate in ether at
room temperature, the key squaramido esters 10a ,b were
obtained in good yields (Scheme 1). The existence of the
squaramido rings as a mixture of conformers was de-
duced from the 1H-NMR spectra. In DMSO-d6, the
spectra of 10a ,b showed two NH signals at 9.09 and 9.31
ppm as well as two methylene resonances at 4.92 and
4.74 ppm in a 1:1 ratio (estimated by integration).
Condensation of 10a ,b with several representative
primary and secondary aliphatic amines in ethanol at
room temperature produced squaramides 11-14 in high
yields. Aryl squaramide 15 was prepared by condensa-
tion of an excess of 3-[[4-(dimethylamino)phenyl]amino]-
4-ethoxy-3-cyclobutene-1,2-dione29 with 9b . Finally,
4-[4-(dimethylamino)phenyl]-3-ethoxy-3-cyclobutene-1,2-
dione (16), featuring a direct aryl to cyclobutenedione ring
bond, was synthesized by condensation of N,N-dimethy-
laniline with diethyl squarate using TiCl4 as catalyst30
Encouraged by these results, the considerable potential
of squaramides warranted their incorporation into model
receptors for the recognition of biologically relevant
tetraalkylammonium compounds. Our receptor design
would consist of three squaramido units tethered by a
tripodal aromatic spacer, taking advantage of the low
(22) (a) Winningham, M. J .; Sogah, D. Y. J . Am. Chem. Soc.1994,
116, 11173-11174. (b) Dado, G. P.; Gellman, S. H. J . Am. Chem. Soc.
1994, 116, 1054. (c) Gellman, S. H.; Dado, G. P.; Liang, G. B. ; Adams,
B. R. J . Am. Chem. Soc. 1991, 113, 1164.
(23) DNMR5. Iterative Nuclear Magnetic Resonance Program for
Unsaturated Exchange-Broadened Bandshapes (IBM-PC version);
Program QCMP059, Quantum Chemistry Program Exchange, Indiana
University, Bloomington, IN, 1988.
(24) The value is apparent as it is affected for the dimerization of
the Z form, and it reflects not only the rotation around the C-N
squaramido bond but also the process of forming and breaking
hydrogen bonds.
(27) W. C. Still, Macromodel 3.5X, Columbia University, New York,
1990.
(28) Elmorsy, S. S.; Pelter, A.; Smith, K. Tetrahedron Lett. 1994,
32, 4175-4176.
(29) Schmidt, A. H. Synthesis 1980, 961-993.
(30) (a) Ohno, M.; Yamamoto, Y.; Shirakasi, Y.; Eguchi, S. J . Chem.
Soc., Perkin Trans. 1 1993, 263-271. (b) Law, K.-Y.; Court, F. J . Org.
Chem. 1992, 57, 3278-3286.
(25) Thorpe, J . E. J . Chem. Soc. B 1968, 435-436.
(26) Kessler, H.; Anders, U.; Schudok, M. J . Am. Chem. Soc. 1990,
112, 5908-5916.

Squaramido-Based Receptors
J . Org. Chem., Vol. 61, No. 26, 1996 9397
Sch em e 1
a
Ta ble 1. Associa tion Con sta n ts (Ka sn
)
a n d Lim itin g
and condensed with 9b. The resulting tripodal squara-
mides 11-16 were well characterized spectroscopically
and furnished correct elemental analyses. The diagnostic
IR bands31 at 1790-1800 cm-1 and 13C-NMR signals at
184-186 ppm, present in 11-16 confirmed the presence
and integrity of the squaramido moiety. 11 was in-
soluble, while 12-16, were soluble enough in CDCl3
(∼10-2 M) to be studied by NMR.
Com p lexa tion -In d u ced Sh ifts (∆δ)
receptor
NR4+ (anion)
Kasn (M-1
)
∆δ (ppm)
10b
16
12
12
12
12
13
13
13
13
14
14
15
15
TMA (AcO-)
594 ( 31
90 ( 5
-0.29
-0.41
-0.41
-0.53
-0.56
-0.55
-0.47
-0.25
-0.43
-0.42
-0.34
-0.22
-0.66
-0.52
BTAc (Br-)
TBAb (Br-)
117 ( 4
272 ( 7
324 ( 4
487 ( 24
BTAc (Br-)
BTA (AcO-)
TMA (AcO-)
The existence of at least two different conformers in
solution was evident from the splitting and broadening
BTA (Br-)
4624 ( 256
BTA (Br-)
271 ( 41d
methylpyridinium (I-)
acetylcholine (I-)
acetylcholine (I-)
acetylcholine (I-)
acetylcholine (I-)
choline (I-)
4050 ( 1091
1473 ( 59
1
of several resonances in the H- and 13C-NMR spectra of
12-16 at room temperature. In all cases, raising the
temperature to the fast exchange limit (∼340 K) reduced
the spectra to their first-order appearance, simplifying
the interpretation of the signals.
5669 ( 931
205 ( 13d
8559 ( 175
14509 ( 1403
Bin d in g P r op er t ies of Sq u a r a m id o R ecep t or s.
The new structures possess attendant rotational pos-
sibilities owing to the presence of several unrestricted
single bonds and low barriers of rotation of the squara-
mido C-NH bonds. Nevertheless, the rigid triaryl
spacer, common to all the compounds, prevents the
collapse of these structures and reduces the self-associa-
tion due to steric factors. Thus, these compounds can
accommodate tetraalkylammonium cations of different
alkyl sizes. The length and shape of the alkyl chains
modulate the aperture of the squaramidic arms of the
receptors until an effective grasping of the ammonium
guests is achieved.
a
At 21 °C in CDCl3. Calculated errors at a confidence level of
95%. Tetrabutyl ammonium. c Benzyltrimethylammonium. In
10% MeOD-d4-CDCl3.
b
d
contrast, the spectra of the receptors alone showed
considerable changes in both chemical shifts and signal
broadening, upon lowering the temperature. This be-
havior provides indirect evidence for the formation of the
intracavity complexes since binding the ammonium salt
would effectively restrict the conformational mobility of
the receptor in these complexes.
Analogously, the reverse addition of the receptor to a
solution of the ammonium guests produced consistent
and reproducible upfield shifts of the R-methyl and/or
R-methylene protons, supporting the contribution of
diamagnetic effects due to the close proximity of the aryl
and carbonyl shielding groups (see Table 1). Altogether,
these observations provide ample support for the forma-
tion of pseudosymmetric C3 complexes as depicted in
Figure 3.
Initially, complexation of ammonium compounds was
1
studied by H-NMR spectroscopy. In general, the addi-
tion of increasing amounts of different ammonium salts
to 12-16 in chloroform caused a considerable simplifica-
tion of the spectra. Upon saturation, the resulting
signals appeared sharp and well defined allowing first-
order interpretation. Moreover, the spectra of the com-
plexes were essentially temperature independent. In
The proposed C3 geometry (Figure 3) is in agreement
with the NOE intermolecular contacts32 detected on
several complexes. 2D ROESY experiments performed
(31) West, R., Ed. In Oxocarbons; Academic Press: New York, 1980.

9398 J . Org. Chem., Vol. 61, No. 26, 1996
Toma`s et al.
R-methyl hydrogens of the guests. The observation of
intermolecular NOE contacts implies a close proximity
between the receptor and the ammonium group and,
basically, demonstrates the formation of intracavity
complexes where the ammonium is deeply buried within
the receptors. The evidence already presented suggests
that the receptors bind in a “three-finger grip” to am-
monium compounds.
Next, we shifted our attention to determine whether
the relative position of the ammonium counterion could
be affected by the complexation. 1H-NMR studies carried
out by Pochapsky et al.34 revealed that tetraalkylammo-
nium salts in chloroform solution exist mainly in the form
of interpenetrated ion pairs whose van der Waals vol-
umes are smaller than the sum of the volumes of the
single ion pairs.33 In our studies, precise information on
the relative position of the counterion in one of our
receptor-ammonium complexes was deduced from the
observation of specific 1H,1H NOE interionic effects using
tetra-n-butylammonium borohydride as guest.34 ROESY
F igu r e 3. Computer-generated view of a complex between
12 and the TMA cation.
experiments performed on Bu4N+BH4 showed that the
-
-
BH4 anion and the quaternary ammonium nitrogen
were in the form of interpenetrated ion pairs, due to the
-
observation of NOE contacts between the protons of BH4
anion and mainly the R- and â-methylene hydrogens of
the alkyl chains. When the ROESY experiment was
repeated on a complex of receptor 14 with Bu4N+BH4
,
-
in addition to the above-described signals, diagnostic ion
to receptor cross peaks between protons Ha and Hc of the
receptor and the R-methylene protons of the ammonium
alkyl chain, as well as between the Ha and BH4- protons,
were detected. Since both interionic and molecule to ion
contacts were observed, it was evident that complexation
of Bu4N+BH4- did not disturb significantly the interpen-
etrated structure of the ion pair. This is also in agree-
ment with a mode of complexation that maintains the
counterion close to the ammonium ion in the open part
of the receptor.
Complex formation was also studied by FAB-MS.35
Stirring of an equimolar mixture of 11 or 12 with
tetramethylammonium acetate or 15 with acetylcholine
iodide during 1 h in CDCl3 followed by evaporation of
the solvent gave the corresponding 1:1 complexes. FAB+
mass spectra (m-nitrobenzyl alcohol as matrix) exhibited
peaks at m/ z 1134 [11 + TMA]+, 1134 [12 + TMA]+, and
1524 [15 + ACh]+ in addition to the peaks of free 11, 12,
and 15.
It is well established that in squaramides the substit-
uents of the cyclobutenedione ring are conjugated with
the nonadjacent carbonyl group by resonance delocaliza-
tion through the double bond of the ring.36 According to
this, the binding abilities of the squaramido carbonyls
can be expected to be modulated by placing adequate
substituents on the squaramidic nitrogens. We ad-
F igu r e 4. Partial ROESY spectrum showing intermolecular
contacts between Ha, Hc of 12 and TMA. Only positive peaks
are shown (above). Positive FAB+ mass spectrum showing the
presence of peaks at the m/ z of the complex (below).
(33) (a) Boche, G. Angew. Chem., Int. Ed. Engl. 1992, 31, 731-732.
(b) Abbott, A. P.; Schiffrin, J . J . Chem. Soc., Faraday Trans. 2 1990,
86, 1453-1459.
(34) (a) Pochapsky, T. C.; Stone, P. M. J . Am. Chem. Soc. 1991, 113,
1460-1462. (b) Pochapsky, T. C.; Stone, P. M. J . Am. Chem. Soc. 1990,
112, 6714-6715.
on complexes of receptor 14 and acetylcholine (ACh)
iodide (see Supporting Information) as well as with
receptor 12 and tetramethylammonium (TMA) acetate
showed (Figure 4), in both cases, cross peaks correlating
protons Ha and Hc of the receptor, but not Hb, with the
(35) (a) Rudkevich, D. M.; Brzozka, Z.; Palys, M.; Visser, H. C.;
Verboom, W.; Reinhoudt, D. N. Angew. Chem., Int. Ed. Eng. 1994, 33,
467-468. (b) Rudkevich, D. M.; Stauthamer, W. P. R. V.; Verboom,
W.; Engbersen, J . F. J .; Harkema, S.; Reinhoudt, D. N. J . Am. Chem.
Soc. 1992, 114, 9671-9673. (c) Flack, S. S.; Chaumette, J .-L.; Kilburn,
J . D.; Langley, G. J .; Webster, M. J . Chem. Soc., Chem. Commun. 1993,
399-401.
(36) (a) Sun, L.; Liebeskind, L. S. J . Org. Chem. 1995, 60, 8194-
8203. (b) Liebeskind, L. S.; Granberg, K. L.; Zhang, J . J . Org. Chem.
1992, 57, 4345.
(32) Neuhaus, D.; Williamson, M. The Nuclear Overhauser Effect
in Structural and Conformational Analysis; VCH: New York, 1989.

Squaramido-Based Receptors
J . Org. Chem., Vol. 61, No. 26, 1996 9399
dressed this point by preparing several receptors featur-
ing different squaramido substituents. The effect of these
changes can be followed through H-NMR titrations. The
formation of 1:1 complexes was deduced from the corre-
sponding J ob plots as well as by the fit of the data to the
1:1 isotherm model. From the data in Table 1, it follows
that receptors featuring a primary amino substituent in
positions 3 of the cyclobutenedione ring are more effective
than the others, as their respective association constants
are clearly higher.
Exp er im en ta l Section
Gen er a l In for m a tion . All reagents were obtained from
commercial sources and used without further purification.
Solvents were purified as follows: dichloromethane and etha-
nol were distilled from CaH2; diethyl ether, toluene, and
benzene were distilled from sodium/benzophenone; DMF was
treated with molecular sieves (3 Å). Organic solutions were
dried over Na2SO4 before being concentrated. CDCl3 (99.8%
D) was stored on molecular sieves (3 Å). Flash chromatogra-
phy was performed on E. Merck silica gel 60 (230-400 mesh).
Thin-layer chromatography was performed on E. Merck 60F-
254 precoated silica plates (0.25 mm layer thickness). Melting
points were taken on a capillary melting point apparatus. Ions
for positive FAB mass spectra were produced from a matrix
1
Replacement of the ethoxy or aryl groups as in 10b
and 16 with an alkylamino group drastically increased
the binding ability of the receptors. This is probably due
to the enhanced basicity of the carbonyl oxygen that is
under the influence of the outer amino substituents.
Receptor 12 exhibited low association constants toward
several ammonium salts, suggesting that the diethy-
lamino substituent is not able to enhance the basicity of
the carbonyl. Molecular modeling suggested that 3,4-
monoalkylamino-disubstituted squaramides can form
almost coplanar structures where both nitrogens can
remain conjugated with the cyclobutenedione ring. In
contrast, 3,4-dialkylamino-disubstituted squaramides pro-
duced unavoidable steric repulsions between the nitrogen
substituents. In fact, literature X-ray data of a 4-dialky-
lamino cyclobutenedione has shown that the coplanar
arrangement of both substituents in positions 3 and 4 of
the cyclobutenedione ring is impossible.37 If this were
the case for receptor 12, the simultaneous participation
of both nitrogen lone pairs would be impossible. In
accordance to this, larger Kasn were obtained with squara-
mides 13-15. The largest value of 14 509 ( 1403 M-1
obtained with 15 can be rationalized by considering the
participation of the 4-(dimethylamino)phenyl ring via
extended delocalization.
1
of 4-nitrobenzyl alcohol. The H- and 13C-NMR spectra were
recorded at 300 and 75 MHz, respectively, at 23 °C. Chemical
shifts are reported as parts per million (δ) and were referenced
1
to the deuterium lock solvents (δ 7.26 for H and 77.0 for 13C).
Microanalyses were conducted by Servei de Microana`lisi CID
(CSIC), Barcelona, Spain.
Titr a tion s. NMR titrations were peformed in a 5 mm o.d.
NMR tube at ambient temperature. The required 1H-NMR
spectra were taken at 300 MHz using a reverse broad-band
probe to improve proton sensitivity. In a typical titration, 500
µL of a solution ranging from 10-2 to 5 × 10-5 M ammonium
salt in CDCl3 was treated with aliquots of a solution containing
receptor and alkylammonium guest. Changes in the chemical
shifts of methyl and/or methylenic ammonium salt protons
were monitored. In the experimental conditions described
above, dimerization or other agreggation phenomena were
negligible. The HOSTEST5 package38 was used to estimate
association constants, along with the limiting chemical shifts
of each of the monitored protons. The concentrations of both
components were adjusted to achieve Weber’s p values ranging
from 20 to 80. The reported values for Kasn are the average of
the association constants obtained in three independent titra-
tions.
1,3,5-Tr is[4-b u t oxy-3-(m e t h oxyca r b on yl)-5-p r op yl-
p h en yl]ben zen e (5b). To a solution of triester 4b39 (5.2 g,
7.9 mmol) in 80 mL of acetone and 35 mL of DMF was added
Cs2CO3 (11.2 g, 33 mmol) in several portions. After stirring
for 15 min, butyl bromide (5.45g, 39.8 mmol) was added
dropwise over 20 min and the mixture was heated at reflux
for 18 h. The mixture was cooled to room temperature and
filtered through a pad of Celite; solvents were evaporated
under reduced pressure. The residue was redissolved in ether
(∼100 mL), washed with water (2 × 50 mL) and brine (1 × 40
mL), dried, and evaporated to give a yellow oil pure by NMR
(6.3 g, 97%). An analytical sample was obtained by column
chromatography (silica, hexanes AcOEt, 9:1 v/v). The purified
material solidified slowly on standing to give the tributyl ether
5b as a pale yellow solid; mp 93-94 °C. The product was
recrystallized in EtOH-benzene affording white prisms: mp
102-103 °C; 1H-NMR δ 7.91 (d, J ) 2.4 Hz, 3H), 7.66 (s, 3H),
7.62 (d, J ) 2.6 Hz, 3H), 3.94 (s, 9H), 3.92 (t, J ) 6.5 Hz, 6H),
2.71 (m, 6H), 1.83 (m, 6H), 1.66 (m, 6H), 1.55 (m, 6H), 1.01 (t,
J ) 7.4 Hz, 9H), 1.00 (t, J )7.3 Hz, 9H); 13C-NMR δ 166.0,
155.8, 140.2, 136.7, 134.9, 131.8, 126.8, 123.9, 123.7, 74.0, 51.1,
31.2, 31.0, 22.8, 18.1, 13.0, 12.8; FAB-MS (m/ z) 822 (M+,73),
Complexation studies carried out in 10% MeOD-d4/
CDCl3 mixtures gave association constants that were
roughly 20-25 times weaker than in CDCl3 alone. In
such cases, the formation of the corresponding complexes
were still evident. These results can be explained by
competitive interaction of methanol with the ammonium
salt combined with the increased polarity of the solution.
The relevant issue in these examples is that Kasn in
the range 103-104 M-1 have been routinely obtained,
thereby demonstrating the significant role that multiple
O to C-H interactions can play in molecular recognition.
Con clu sion
The most relevant result of the present work is the
introduction of squaramides as binding units for abiotic
receptor designs. The binding features of this functional-
ity and the easy incorporation within a molecular
framework allows the preparation of efficient receptors
for tetraalkylammonium compounds. In addition, the
strength of the host-guest complexes can be conveniently
modulated by modifying the external substituents of the
cyclobutenedione ring. The results outline the role of the
squaramido moiety and confirm binding of tetraalkylam-
monium ion pairs. On that basis, the synthesis of more
selective receptors to be used as molecular sensors or
catalysts can be envisaged.
791 (98), 735 (100); IR (KBr) 1730, 1260-1210, 1150, cm-1
Anal. Calcd for C51H66O9: C, 74.41; H, 8.08. Found: C, 74.32;
H, 8.16.
1,3,5-Tr is[4-b u t oxy-3-(m et h oxyca r b on yl)p h en yl]b en -
zen e (5a ). 5a was prepared in a manner analogous to that
described above starting from triester 4a .39 The product was
obtained as a viscous oil in 89% yield: 1H-NMR δ 8.09 (d, J )
2.3 Hz, 3H), 7.70 (dd, J ) 8.6, 2.3 Hz, 3H), 7.66 (s, 3H), 7.07
(d, J ) 8.7 Hz, 3H), 4.10 (t, J ) 6.4 Hz, 6H), 3.92 (s, 9H), 1.85
(m, 6H), 1.56 (m, 6H), 1.00 (t, J ) 7.3 Hz, 9H); 13C-NMR δ
.
(38) (a) Cowart, M. D.; Sucholeiki, I.; Bukownik, R. R.; Wilcox, C.
S. J . Am. Chem. Soc. 1988, 110, 6204-6210. (b) Wilcox, C. S.
HOSTEST (v5.0), University of Pittsburgh, Pittsburgh, PA, 1994.
(39) Rotger, M. C.; Costa, A.; Saa´, J . M. J . Org. Chem., 1993, 58,
4083-4087. Full details of an improved procedure for multigram
synthesis of 5a ,b will be published shortly.
(37) LePage, T.; Kazuhiro, N.; Breslow, R. Tetrahedron Lett. 1985,
26, 5919-5922.

9400 J . Org. Chem., Vol. 61, No. 26, 1996
Toma`s et al.
166.8, 158.2, 141.0, 132.7, 131.9, 130.2, 120.6, 113.5, 68.7, 52.0,
31.1, 19.1, 13.8; FAB-MS m/ z (%) 718 (M++ Na+, 18), 696 (70),
695 (M+, 100), 664 (86.6), 608 (88.0); IR (neat) 1720, 1310-
1210, 1170, 1080 cm-1. Anal. Calcd for C42H48O9: C, 72.39;
H, 6.94. Found: C, 72.45; H, 7.06.
tion. Benzene (80 mL) was added, and the mixture was
washed with water (5 × 75 mL) and brine. After drying,
solvents were evaporated at reduced pressure, affording 1.9 g
(93.7%) of 8b. An analytical sample was recrystallized from
ethanol affording transparent prisms: mp 96-98 °C; 1H-NMR
δ 7.65 (s, 3H), 7.48 (d, J ) 2.2 Hz, 3H), 7.46 (d, J ) 2.2 Hz,
3H), 4.47 (s, 6H), 3.87 (t, J ) 6.5 Hz, 6H), 2.69 (m, 6H), 1.84
(m, 6H), 1.72 (m, 6H), 1.58 (m, 6H), 1.02 (t, J ) 7.3 Hz, 9H),
1.00 (t, J ) 7.4 Hz, 9H); 13C-NMR δ 156.2, 142.4, 137.7, 137.4,
130.2, 129.8, 127.4, 125.5 75.2, 50.7, 33.1, 32.8, 24.5, 19.9, 14.8,
14.6; FAB-MS m/ z (%) 813 (M+, 17); IR (KBr) 2100 cm-1. Anal.
Calcd for C48H63N9O3: C, 70.82; H, 7.80; N, 15.48. Found: C,
70.87; H, 7.85; N, 15.25.
1,3,5-Tr is[4-bu toxy-3-(h ydr oxym eth yl)-5-pr opylph en yl]-
ben zen e (6b). Lithium aluminum hydride (LAH; 2.6 g, 69
mmol) was slowly added to a cooled (0 °C) solution of 5b (7.1
g, 8.6 mmol) in dry THF (140 mL), under argon. After stirring
on ice for 4 h, the reaction mixture was partitioned between
100 mL of saturated Na2SO4 solution and 100 mL of ether.
The organic layer was separated, washed with water (2 × 50
mL) and brine (1 × 50 mL), dried, and evaporated under
reduced pressure. The crude concentrate was purified by
column chromatography (silica, hexanes-AcOEt, 8:2 v/v) to
give the title alcohol as a white solid (5.6 g, 88%). The product
was crystallized using MeOH-water to give white needles: mp
147-148 °C; 1H-NMR δ 7.66 (s, 3H), 7.49 (d, J ) 2.3 Hz, 3H),
7.44 (d, J ) 2.3 Hz, 3H), 4.79 (d, J ) 6.2 Hz, 6H), 3.89 (t, J )
6.5 Hz, 6H), 2.68 (m, 6H), 2.26 (t, J ) 6.2 Hz, 3H), 1.85 (m,
6H), 1.85 (m, 6H), 1.67 (m, 6H), 1.60 (m, 6H), 1.02 (t, J ) 7.3
Hz, 9H), 0.99 (t, J ) 7.4 Hz, 9H); 13C-NMR δ 154.0, 140.7,
135.9, 133.2, 127.6, 124.5, 123.5, 73.1, 60.7, 31.4, 30.8, 28.5,
22.8, 18.16, 13.1, 12.8; FAB-MS m/ z (%) 737 (M+, 75), 664 (53);
IR (KBr) 3650-3100, 1170, cm-1. Anal. Calcd for C48H66O6:
C, 78.01; H, 9.01. Found: C, 78.08 H, 9.09.
1,3,5-Tr is[3-(azidom eth yl)-4-bu toxyph en yl]ben zen e (8a).
Prepared using the above procedure in 93% yield. The solid
was recrystallized from toluene: pentane (1:1 v/v) to give white
prisms of the triazide; mp 69-70 °C. 1H-NMR δ 7.64 (s, 3H),
7.62 (dd, J ) 8.5, 2.2 Hz, 3H), 7.57 (d, J ) 2.2 Hz, 3H), 6.97
(d, J ) 8.5 Hz, 3H), 4.65 (s, 6H), 4.11 (t, J ) 6.3 Hz, 6H), 1.87
(m, 6H), 1.57 (m, 6H), 1.02 (t, J ) 7.1 Hz, 9H); 13C-NMR δ
157.5, 142.3, 134.1, 129.6, 129.1, 127.2, 125.1, 124.6, 112.3,
68.7, 51.0,.31.9, 20.0, 14.5; FAB-MS m/ z (%) 687 (M+, 50), 660
(16), 645 (30); IR (KBr) 2100 cm-1
.
Anal. Calcd for
39H45N9O3: C, 68.10; H, 6.59; N, 18.33. Found: C, 68.24; H,
6.68; N, 18.25.
1,3,5-Tr is[4-bu toxy-5-p r op yl-3-[[(4-eth oxy-1,2-d ioxo-3-
cyclobu ten yl)a m in o]m eth yl]p h en yl]ben zen e. Squ a r a -
m id e Ester 10b. A solution of tripropylated triazide 8b (1.3
g, 1.6 mmol) in toluene (60 mL) was treated with Red-Al (1.5
mL of a 65 wt % solution in toluene, ∼7.7 mmol). After stirring
over a 15 min period, the reaction was quenched with water.
The organic layer was separated and washed with water (1 ×
40 mL) and brine (1 × 25 mL). Solvent was removed by rotary
evaporation, and the crude solid was triturated twice with
pentane (20 mL) to yield triamine 9b (0.97 g, 82%) as a
yellownish amorphous solid which was used directly in the
next step: 1H-NMR δ 7.66 (s, 3H), 7.42 (d, J ) 2.2 Hz, 3H),
7.40 (d, J ) 2.2 Hz, 3H), 3.93 (s, 6H), 3.85 (t, J ) 6.5 Hz, 6H),
2.68 (m, 6H), 1.84 (m, 6H), 1.69 (m, 6H), 1.58 (m, 6H), 1.02 (t,
J ) 7.3 Hz, 9H), 1.00 (t, J ) 7.4 Hz, 9H). Triamine 9b (0.97
g, 1.3 mmol) and diethyl squarate (2.0 g, 11.9 mmol) were
dissolved in ether (100 mL). The solution was stirred under
argon at room temperature overnight (20 h). Solvent was
removed under reduced pressure, and the product was purified
by column chromatography (silica, CH2Cl2-MeOH, 99:1 v/v)
to afford pure 10b (0.92 g, 52% from the azide) as an off-white,
1,3,5-T r i s [4-b u t o x y -3-(h y d r o x y m e t h y l)p h e n y l]-
ben zen e (6a ). Similar reduction gave this product as an
amorphous yellow solid in 93% yield, which was used directly
in the next reaction. An analytical sample was obtained by
crystallization in toluene-pentane (1:1 v/v): mp 124-125 °C,
1H-NMR δ 7.65 (s, 3H), 7.61 (d, J ) 2.1 Hz, 3H), 7.57 (dd, J )
8.3, 2.3 Hz, 3H), 6.98 (d, J ) 8.3 Hz, 3H), 4.78 (d, J ) 6.6 Hz,
6H), 4.09 (t, J ) 6.4 Hz, 6H), 2.44 (t, J ) 6.6 Hz, 3H), 1.84 (m,
6H), 1.54 (m, 6H), 1.00 (t, J ) 7.3 Hz, 9H); 13C-NMR δ 157.3,
142.4, 134.2, 130.2, 128.3, 128.2, 124.5, 112.1, 68.6, 63.0, 32.0,
20.0, 14.5; FAB-MS m/ z (%) 612 (M+, 100), 595 (33), 539 (41);
IR (KBr) 3650-3100, 1250, cm-1. Anal. Calcd for C39H48O6:
C, 76.44; H, 7.89. Found: C, 76.28; H, 7.92.
1,3,5-Tr is[3-(br om om eth yl)-4-bu toxy-5-p r op ylp h en yl]-
ben zen e (7b). To a solution of alcohol 6b (4.8 g, 6.5 mmol)
in toluene (200 mL) was added dropwise PBr3 (7.1 g, 26 mmol)
in toluene (40 mL). After stirring at room temperature for 2
h, and 3 h at reflux, the mixture was allowed to cool to room
temperature and 5% aqueous NaHCO3 was added slowly. The
organic layer was separated, washed with water and brine,
and evaporated at reduced pressure. The residue was tritu-
rated twice with pentane to afford the crude tribromide (5.9
g, 97%) pure enough to be used in the next step. An analytical
sample was obtained by flash chromatography (silica, hex-
anes-AcOEt, 97:3 v/v) and crystallization to yield pure tri-
bromide as small white needles: mp 146-7 °C; 1H-NMR δ 7.62
(s, 3H), 7.53 (d, J ) 2.2 Hz, 3H), 7.43 (d, J ) 2.1 Hz, 3H), 4.66
(s, 6H), 3.99 (t, J ) 6.5 Hz, 6H), 2.68 (t, J ) 7.6 Hz, 6H), 1.88
(m, 6H),1.66 (m, 6H), 1.58 (m, 6H), 1.04 (t, J ) 7.3 Hz, 9H),
1.00 (t, J ) 7.4 Hz, 9H); 13C-NMR δ 156.1, 142.3, 1337.8, 137.5,
132.3, 130.5, 128.7, 125.5, 74.8, 33.1, 32.7, 29.3, 24.5, 19.9, 14.9,
14.6. Anal. Calcd for C48H63O3Br3: C, 62.14; H, 6.84; Br,
25.85. Found: C, 62.22; H, 7.04; Br, 25.30.
1,3,5-Tr is[3-(b r om om et h yl)-4-b u t oxyp h en yl]b en zen e
(7a ). The same procedure was used as above. The crude
tribromide was recrystallized from pentane-toluene (1:1 v/v)
to give the title compound as white needless in 98% yield: mp
115-116 °C; 1H-NMR (300 MHz, CDCl3) δ 7.64 (d, J ) 2.2
Hz, 3H), 7.61 (s, 3H), 7.58 (dd, J ) 8.5, 2.3 Hz, 3H), 6.97 (d, J
) 8.5 Hz, 3H), 4.65 (s, 6H), 4.11 (t, J ) 6.3 Hz, 6H), 1.87 (m,
6H), 1.57 (m, 6H), 1.02 (t, J ) 7.1 Hz, 9H); 13C-NMR δ 157.4,
142.1, 134.1, 130.4, 129.5, 127.2, 124.6, 112.7, 68.8,.32.0, 29.8,
20.0, 14.5; FAB-MS m/ z (%) 801 (M+, 15), 800 (15), 721 (22).
Anal. Calcd for C39H45O3Br3: C, 58.44; H, 5.66. Found: C,
58.40 H, 5.66.
1,3,5-Tr is[3-(a zid om et h yl)-4-b u t oxy-5-p r op ylp h en yl]-
ben zen e (8b). A mixture of tribromide 7b (2.4 g, 2.6 mmol)
and sodium azide (1.0 g, 15.3 mmol) in 20 mL of benzene and
20 mL of DMF was heated at reflux for 3 h. After cooling at
room temperature, the organic salts were removed by filtra-
1
amorphous solid: mp 92-94 °C; H-NMR (300 MHz, DMSO-
d6) δ 9.31 and 9.08 (t, 3H), 7.77 (s, 3H), 7.64 (m, 6H), 4.93 and
4.74 (m, 6H), 4.73 (q, J ) 7.02 Hz, 6H), 3.89 (m, 6H), 2.75 (t,
J ) 6.9 Hz, 6H), 1.83 (m, 6H), 1.71 (m, 6H), 1.63 (m, 6H), 1.41
(m, 9H), 1.07 (m, 9H), 1.05 (m, 9H); FAB-MS m/ z (%) 1109
(M+, 91), 967 (17), 685 (23), 629 (100); IR (KBr) 3350-3100,
1805, 1710, 1610 cm-1. Anal. Calcd for C66H81N3O12: C, 71.52;
H, 7.37, N, 3.79. Found: C, 71.55; H, 7.40; N, 3.78.
1,3,5-Tr is[4-bu toxy-3-[[(4-eth oxy-1,2-d ioxo-3-cyclobu te-
n yl)a m in o]m eth yl]p h en yl]ben zen e. Squ a r a m id e Ester
10a . The corresponding triazide 8a was reduced as above to
yield triamine 9a as a yellow solid in 90% yield: 1H-NMR δ
7.65 (s, 3H), 7.52 (m, 6H), 6.96 (d, J ) 8.9 Hz, 3H), 4.06 (t, J
) 6.5 Hz, 6H), 3.90 (s, 6H), 2.68 (m, 6H), 1.84 (m, 6H), 1.56
(m, 12H), 1.00 (t, J ) 7.4 Hz, 9H). Triamine 9a and diethyl
squarate were condensed by using the same procedure as for
10b. Product 10a was obtained as an off-white amorphous
solid in 65% yield. This compound could not be crystallized
and was used without further purification: mp 104-105 °C.
1H-NMR (300 MHz, DMSO-d6) δ 9.20 and 9.00 (br, 3H), 7.80
(m, 9H), 7.23 (d, J ) 8.1 Hz, 3H), 4.92 (s, 3H), 4.7 (m, 9H),
4.15 (m, 6H), 1.79 (m, 6H), 1.53 (m, 6H), 1.44 (t, J ) 7.0 Hz,
9H), 1.03 (t, J ) 7.0 Hz, 9H); FAB-MS m/ z (%) 981 (M+, 3.0),
841 (5), 647 (100), 441 (95); IR (KBr) 3350-3100, 1800, 1710,
1605 cm-1. Anal. Calcd for C57H63N3O12: C, 69.71; H, 6.47,
N, 4.28. Found: C, 69.74; H, 6.61, N, 4.13.
1,3,5-Tr is[4-bu toxy-5-p r op yl-3-[[[4-(ben zyla m in o)-1,2-
d ioxo-3-cyclob u t en yl]a m in o]m et h yl]p h en yl]b en zen e.
Squ a r a m id e 13. Squaramide ester 10b (0.57 g, 0.5 mmol)
and benzylamine (0.5 g, 4.6 mmol) in EtOH (80 mL) were

Squaramido-Based Receptors
J . Org. Chem., Vol. 61, No. 26, 1996 9401
stirred at room temperature for 24 h. The solid was collected
by filtration, washed with cold ethanol, and digested in hot
methanol for 1 h. After filtration, the residue was recrystal-
lized in CHCl3-MeOH to give 0.59 g (89%) of a white powder:
1,3,5-Tr is[4-b u t oxy-5-p r op yl-3-[[[[[(4-(N,N′-d im et h y-
la m in o)p h en yl]a m in o]-1,2-d ioxo-3-cyclobu ten yl]a m in o]-
m et h yl]p h en yl]b en zen e. Sq u a r a m id e 15. Triamine 9b
(0.14 g, 0.2 mmol) and 4-[[4-(dimethylamino)phenyl]amino]-
3-ethoxy-3-cyclobutene-1,2-dione (0.21 g, 0.8 mmol) in 25 mL
of ethanol were condensed stirring at room temperature for 1
h. The mixture was filtered and washed with ethanol, and
the crude precipitatepurified by column chromatography
(silica, CH2Cl2-MeOH, 98:2 v/v) to afford 15 (0.125 g) in 48%
1
mp 253-258 °C; H-NMR (DMSO-d6) δ 7.80 (br s, 3H), 7.77
(s, 3H), 7.67 (s, 6H), 7.36 (br s, 15H), 7.33 (br s, 3H), 4.91 (m,
6H), 4.78 (m, 6H), 3.91 (t, J ) 6.3 Hz, 6H), 2.72 (m, 6H), 1.84
(m, 6H), 1.74 (m, 6H), 1.59 (m, 6H), 1.04 (t, J ) 7.3 Hz, (18H);
FAB-MS m/ z (%) 1313 (M++ Na); IR (KBr) 3400-3100, 1800,
1670, 1580 cm-1. Anal. Calcd for C81H90N6O9: C, 75.32; H,
7.02; N, 6.50. Found: C, 75.08; H, 7.01, N, 6.42.
1
yield: mp 238-242 °C dec; H-NMR (300 MHz, DMSO-d6) δ
7.67 (d, J ) 2.2 Hz, 3H), 7.60 (s, 3H), 7.56 (d, J ) 2.2 Hz, 3H),
6.95 (d, J ) 8.5 Hz, 3H), 6.07 (t, J ) 6.1 Hz, 3H), 4.97 (d, J )
6.1 Hz, 6H), 4.06 (t, J ) 6.4 Hz, 6H), 3.51 (br s, 12H), 1.78 (m,
6H), 1.51 (m, 6H), 1.20 (t, J ) 7.14 Hz, 18H), 0.99 (t, J ) 7.3
Hz, 9H); FAB-MS m/ z (%) 1392 (M+ + Na+, 9), 1379 (M+, 100),
1,3,5-Tr is[4-bu toxy-5-p r op yl-3-[[[4-[(5-h yd r oxyp en tyl)-
a m in o]-1,2-d ioxo-3-cyclobu ten yl]a m in o]m eth yl]p h en yl]-
ben zen e. Squ a r a m id e 14. Squaramide ester 10b and
5-amino-1-pentanol were condensed using the same procedure
as for 13 except that the residue was washed with ethanol
and recrystallized with CH2Cl2-ethanol to give a white solid
in 71% yield: mp 150-153 °C; 1H-NMR (300 MHz, DMSO-d6)
δ 7.78 (s, 3H), 7.70 (br, 3H), 7.69 (s, 6H), 7.44 (br, 3H), 4.92
(br s, 3H), 4.44 (t, J ) 5.0 Hz, 3H), 3.93 (t, J ) 6.1 Hz, 6H),
3.56 (m, 6H), 3.44 (obscured by residual water), 2.77 (t, J )
7.1 Hz, 6H), 1.83 (m, 6H), 1.75 (m, 6H), 1.60 (m, 12H), 1.46
(m, 6H), 1.37 (m, 6H), 1.07 (t, J ) 7.2 Hz, 18H); FAB-MS m/ z
(%) 1279 (M+, 72), 1081 (14), 664 (73); IR (KBr) 3600-3100,
895 (7), 1305 (14), 1148 (34); IR (KBr) 1790, 1675, 1590 cm-1
.
Anal. Calcd for C84H99N9O9: C, 73.18; H, 7.24; N, 9.14.
Found: C, 72.52; H, 7.29; N, 8.94.
1,3,5-Tr is[4-bu toxy-5-p r op yl-3-[[[[4-(N,N′-d im eth yla m i-
n o)p h en yl]-1,2-d ioxo-3-cyclobu ten yl]a m in o]m eth yl]p h e-
n yl]ben zen e. Squ a r a m id e 16. Triamine 9b (0.18 g, 0.24
mmol) and 4-[4-(dimethylamino)phenyl]-3-ethoxy-3-cyclobutene-
1,2-dione (0.24 g, 0.97 mmol) in 15 mL of absolute ethanol were
condensed as above. Ethanol was removed at vacuo, and the
mixture was purified by column chromatography (silica, CH2-
Cl2-MeOH, 98:2 v/v) to afford 16 (0.17 g) in 53% yield: mp
157-161 °C; 1H-NMR δ 7.72 (d, J ) 9.0 Hz, 6H), 7.56 (s, 3H),
7.49 (br s, 3H), 7.43 (d, J ) 2.1 Hz, 3H), 6.93 (br t, 3H), 6.65
(d, J ) 9.0 Hz, 3H), 5.09 (d, J ) 5.4 Hz, 6H), 3.92 (t, J ) 6.5
Hz, 6H), 3.00 (s, 18H), 2.67 (t, J ) 7.6 Hz, 6H), 1.86 (m, 6H),
1.69 (m, 6H), 1.56 (m, 6H), 1.02 (t, J ) 7.4 Hz, 9H), 0.99 (t, J
) 7.4 Hz, 9H); FAB-MS m/ z (%) 1334 (M+, 100), 1320 (18);
1118 (43); IR (KBr) 1770, 1710, 1605 cm-1. Anal. Calcd for
C84H96N6O9: C, 75.65; H, 7.26; N, 6.30. Found: C, 75.40; H,
7.41; N, 6.23.
1800, 1670, 1590 cm-1
. Anal. Calcd for C75H102N6O12: C,
70.39; H, 8.03; N, 6.57. Found: C, 70.02; H, 8.03, N, 6.51.
1,3,5-Tr is[4-bu toxy-3-[[[4-(bu tyla m in o)-1,2-d ioxo-3-cy-
clobu ten yl]a m in o]m eth yl]p h en yl]ben zen e. Squ a r a m id e
11. Squaramide ester 10a and butylamine were condensed
as described to give a white solid in 80% yield: mp 282-287
1
°C; H-NMR (300 MHz, DMSO-d6) δ 7.82 (m, 9H), 7.65 (br s,
3H), 7.40 (br, s, 3H), 7.24 (d, J ) 8.4 Hz, 3H), 4.90 (m , 6H),
4.17 (br t, 6H), 3.58 (m, 6H), 1.82 (m, 6H), 1.54 (m, 12H), 1.35
(m, 6H), 1.03 (t, J ) 7.3 Hz, 9H), 0.92 (br t, 9H); FAB-MS m/ z
(%) 1083 (M++ Na, 1.5); 1062 (M+, 1.8). Anal. Calcd for
C63H78N6O9: C, 71.14; H, 7.39; N, 7.90. Found: C, 71.04; H,
7.35; N, 7.78.
Ack n ow led gm en t. We thank the Direccio´n General
de Investigacio´n Cient´ıfica y Te´cnica (DGICYT, Project
PB92-0251) for financial support. S.T. thanks the
Fundacio´ Muntaner, M.C.R. thanks the Ministerio de
Educacio´n y Ciencia of Spain for fellowship support.
FAB mass spectra were obtained at the facilities of the
University of New Brunswick (Canada) and University
of Sheffield (U.K.). We express our gratitude to Prof.
Craig S. Wilcox for generously providing a copy of
HOSTEST (v5.0).
1,3,5-Tr is[4-bu toxy-3-[[[(4-N,N′-(d ieth yla m in o)-1,2-d i-
o x o -3-c y c lo b u t e n y l]a m in o ]m e t h y l]p h e n y l]b e n ze n e .
Squ a r a m id e 12. Squaramide ester 10a and N,N-diethy-
lamine were condensed following the standard procedure. The
crude product was purified by column chromatography (silica,
CH2Cl2-MeOH, 96:4 v/v) to afford 12 in 93% yield. An
analytical sample was obtained by crystallization in ethanol:
1
mp 173-174 °C; H-NMR δ 7.67 (d, J ) 2.2 Hz, 3H), 7.60 (s,
3H), 7.56 (d, J ) 2.2 Hz, 3H), 6.95 (d, J ) 8.5 Hz, 3H), 6.07 (t,
J ) 6.1 Hz, 3H), 4.97 (d, J ) 6.1 Hz, 6H), 4.06 (t, J ) 6.4 Hz,
6H), 3.51 (br s, 12H), 1.78 (m, 6H), 1.51 (m, 6H), 1.20 (t, J )
7.14 Hz, 18H), 0.99 (t, J ) 7.3 Hz, 9H); 13C-NMR δ 182.1, 181.0,
166.0, 165.9, 155.4, 140.1, 132.1, 127.5, 126.5, 125.6, 122.5,
110.3, 66.8, 443.6, 43.0, 30.2, 18.2, 14.0, 12.7; FAB-MS m/ z
(%) 1085 (M+ + Na+, 9.3), 1063 (M+ + H+, 6.5), 1062 (M+, 7.1),
Su p p or tin g In for m a tion Ava ila ble: ROESY spectra of
complexes and 1H-NMR spectra of tripodands 10-16 (11
pages). This material is contained in libraries on microfiche,
inmediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
895 (7); IR (KBr) 1790, 1670, 1570 cm-1
. Anal. Calcd for
C63H78N6O9: C, 71.14; H, 7.39; N, 7.90. Found: C, 69.17; H,
7.42; N, 7.23.
J O9614147