Recognition of amides by new rigid calix[4]arene-based cavitands

Article abstract of DOI:10.1021/jo005596n

The synthesis of new hosts specifically designed for the recognition of amides, characterized by two binding regions: a rigid calix[4]arene cavity and a sidearm, inserted at its rim, able to form strong hydrogen bonds, is described. The binding abilities of the new receptors toward amides of general structure R¹CONR²R³ have been investigated in CDCl₃ solution by ¹H NMR spectroscopy. When the additional binding site is the N-phenylureido group spaced by a methylene unit from the apolar cavity, binding constants up to 756 M^-1 were measured. Neither the two separate potential binding sites, nor the model host, where the calix[4]arene skeleton is flexible show detectable binding ability toward the series of guests examined. The rigidity of the calix[4]arene apolar cavity is the key control element in determining the efficiency of these molecular recognition processes. The presence of NH groups in the guest controls the efficiency and selectivity of binding.

Full text of DOI:10.1021/jo005596n

J . Org. Chem. 2000, 65, 9085-9091
9085
Recogn ition of Am id es by New Rigid Ca lix[4]a r en e-Ba sed
Ca vita n d s
Arturo Arduini, Andrea Secchi, and Andrea Pochini*
Dipartimento di Chimica Organica e Industriale, Universita` di Parma, Parco Area delle Scienze 17/ A,
I-43100, Parma, Italy
pochini@unipr.it
Received August 2, 2000
The synthesis of new hosts specifically designed for the recognition of amides, characterized by
two binding regions: a rigid calix[4]arene cavity and a sidearm, inserted at its rim, able to form
strong hydrogen bonds, is described. The binding abilities of the new receptors toward amides of
1
general structure R1CONR2R3 have been investigated in CDCl3 solution by H NMR spectroscopy.
When the additional binding site is the N-phenylureido group spaced by a methylene unit from
the apolar cavity, binding constants up to 756 M-1 were measured. Neither the two separate
potential binding sites, nor the model host, where the calix[4]arene skeleton is flexible show
detectable binding ability toward the series of guests examined. The rigidity of the calix[4]arene
apolar cavity is the key control element in determining the efficiency of these molecular recognition
processes. The presence of NH groups in the guest controls the efficiency and selectivity of binding.
In tr od u ction
Another interesting result, which confirms the impor-
tance of rigidity and, consequently, of the preorganization
of the cone conformer of calix[4]arenes in determining
their recognition ability, is obtained by the comparison
between p-tert-butylcalix[4]arene tetraamide and its
sodium picrate complex in the binding of nitromethane
in CDCl3. In fact, while the conformationally mobile
tetramide derivative does not show any significant com-
plexation, its sodium complex, which is rigid, significantly
binds CH3NO2.4
The possibility to rigidify calix[4]arene-based hosts
using different strategies based on noncovalent interac-
tions was confirmed by other authors. Stibor and co-
workers5 saw evidence of the possibility to utilize calix-
[4]arene compounds partially alkylated at the lower rim,
e.g. 1,3-dialkoxy derivative, as efficient hosts for guests
bearing acidic C-H bonds. The explanation of these
results can be found in the studies on the conformational
distribution and interconversion of lower rim partially
alkylated calix[4]arenes performed by Reinhoudt and co-
workers6 and experimentally confirmed by Bo¨hmer and
co-workers.7 In particular, the conformations of partially
methylated derivatives are far less mobile than either
the tetrahydroxy- or the tetramethoxycalix[4]arenes;
therefore, for these hosts the rigidity derives from a
combination of hydrogen bonds interactions and steric
repulsions.
The calix[4]arenes in the cone conformation present
an internal cavity which can potentially host neutral
guest molecules of complementary size. In particular the
inclusion of aromatic guest has been widely documented,1
whereas any attempt to exploit their π-donor apolar
cavity for the recognition in apolar solvents of these
aromatic molecules gave very poor results. This was
attributed to the high solvation phenomena and to the
scarce preorganization of these hosts. However, the
introduction of bulky substituents on the phenolic oxy-
gens, which prevent the cone-to-cone ring inversion,
afforded tetra-O-alkylated calix[4]arenes cone isomers
which show no complexing ability.
Moving from recent findings which show that in
solution a residual conformational mobility of these cone
isomers still exist,2 other approaches to reduce this
conformational flexibility have been pursued. After the
successful results using upper rim bridged calix[4]-
arenes,3 with the aim to exploit the aromatic cavity of
calix[4]arenes as the only binding site for neutral organic
molecules, very rigid and undistorted calix[4]arene-bis-
(crown-3) cone derivatives were obtained by the linkage
of two proximal phenol rings with short diethylene glycol
bridges, and they were able to recognize nitromethane
and malononitrile as guests in apolar organic solvents.4
Regardless the strategy followed to immobilize the cone
structure, in all the binding studies, only guests bearing
acid CH3 or CH2 groups were bound. These findings,
together with the presence of electron rich phenolic nuclei
(1) (a) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713-745.
(b) Pochini, A.; Ungaro, R. In Comprehensive Supramolecular Chem-
istry; Atwood, J . L., Davies, J . E. D., McNicol, D. D., Vo¨gtle, F., Eds.;
Pergamon: Oxford, 1996; Vol. 2, pp 103-142. (c) Gutsche, C. D.
Calixarenes Revisited - Monographs in Supramolecular Chemistry;
Stoddart, J . F., Ed.; The Royal Society of Chemistry, Cambridge, 1998;
Vol. 6.
(2) (a) Ikeda, A.; Tsuzuki, H.; Shinkai, S. J . Chem. Soc., Perkin Trans
2 1994, 2073-2080. (b) Arduini, A.; Fabbi, M.; Mantovani, M.; Mirone,
L.; Pochini, A.; Secchi, A.; Ungaro, R. J . Org. Chem. 1995, 60, 1454-
1457.
(4) Arduini, A.; McGregor, W. M.; Paganuzzi, D.; Pochini, A.; Secchi,
A.; Ugozzoli, F.; Ungaro, R. J . Chem. Soc., Perkin Trans. 2 1996, 839-
846.
(5) Smirnov, S.; Sidorov, V.; Pinkhassik, E.; Havlicek, J .; Stibor, I.
Supramol. Chem. 1997, 8, 187-196.
(3) (a) Arduini, A.; Cantoni, M.; Graviani, E.; Pochini, A.; Secchi,
A.; Sicuri, A. R.; Ungaro, R.; Vincenti, M. Tetrahedron 1995, 51, 599-
606. (b) Arduini, A.; McGregor, W. M.; Pochini, A.; Secchi, A.; Ugozzoli,
F.; Ungaro, R. J . Org. Chem. 1996, 61, 6881-6887.
(6) Van Hoorn, W. P.; Morshuis, M. G. H.; van Veggel, F. C. J . M.;
Reinhoudt, D. N. J . Phys. Chem. A 1998, 102, 1130-1138.
(7) Kusano, T.; Tabatabai, M.; Okamoto, Y.; Bo¨hmer, V. J . Am.
Chem. Soc. 1999, 121, 3789-3790.
10.1021/jo005596n CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/02/2000

9086 J . Org. Chem., Vol. 65, No. 26, 2000
Arduini et al.
Sch em e 1a
a
Reagents and conditions: (i) NBS, methyl ethyl ketone; (ii) CuCN, DMF, T ) 200 °C; (iii) B2H6, THF, reflux; (iv) TsCl, pyridine,
CH2Cl2; (v) C6H5NCX, CH2Cl2; (vi) C6H5NHCONHCH2OH, CF3COOH/CH2Cl2.
in the host skeleton, suggest the importance of specific
CH-π aromatic interactions8 to stabilize these com-
plexes. A solid state study, based on the X-ray crystal
structure of these complexes, complementary with those
performed in solution, revealed that the guest molecule
lies inside the cavity with the CH3 or CH2 groups facing
the aromatic nuclei and afforded further insights in the
role played by these weak interactions. In particular, an
interesting dependence of the complexation mode on the
nature of either the guest and host employed was
evidenced.9
The previous reported studies can be seen as iterative
processes which developed from the better understanding
of the intermolecular interactions to allow design of new
molecular receptors for specific guests useful for the
preparation of a new generation of sensing devices where
efficiency and selectivity are governed by molecular
recognition processes.
In this context, however, the recognition of neutral
species bearing specific functional groups by the calix-
arene cavity remains unexplored. This need should
encourage the tailoring of an appropriate receptor able
to bind the guest through more specific interactions. In
such cases, the aid of one or more supplementary binding
sites could be used to drive the complexation. This
strategy, though well documented for calixarenes-based
ionophores,10 has found only few applications for the
recognition of neutral molecules so far.11
In view of the current interest, particularly in biological
field, in the recognition of the amide functional group,
such as, for example, peptides and/or surface protein
recognition,12 we describe herein the synthesis of a series
of calixarene derivatives specifically designed for the
recognition of low molecular weight amides through the
cooperative action of two distinct binding sites: the rigid
calix[4]arene cavity and a hydrogen bond donor-acceptor
sidearm inserted on its wider rim.
The binding ability of these new hosts was investigated
by NMR techniques in CDCl3 toward a series of amides,
N-alkyl and N,N-dialkyl amides derived from formic,
acetic, and benzoic acids.
Resu lts a n d Discu ssion
Design a n d Syn th esis of th e Hosts. The synthesis
of new receptors 5-7 was based on the analysis of
molecular models, obtained by preliminary molecular
mechanics studies, which showed that the introduction
of methyleneamido or sulfonamido moieties (CH2NHY;
Y ) COR, SO2R) on the upper rim of the rigidified calix-
[4]arene-bis(crown-3) 1 would result in receptors having
the appropriate stereoelectronic matching to interact with
the guest carbonyl group. The precursor of these new
receptors was the methylenamino derivative 4 prepared
(10) See,for example, (a) Casnati, A.; Fochi, C.; Minari, P.; Pochini,
A.; Reggiani, M.; Ungaro, R.; Reinhoudt, D. N. Gazz. Chim. Ital. 1996,
126, 99-106. (b) Magrans, J . O.; Ortiz, A. R.; Molins, M. A.; Lebouille,
P. H. P.; Sa`nchez-Quevada, J .; Prados, P.; Pons, M.; Gago, F.; de
Mendoza, J . Angew. Chem., Int. Ed. Engl. 1996, 35, 1712-1715. (c)
Pelizzi, N.; Casnati, A.; Friggeri, A.; Ungaro, R. J . Chem. Soc., Perkin
Trans. 2 1998, 1307-1311.
(11) See e.g. Starnes, S. D.; Rudkevich, D. M.; Rebek, J ., J r. Org.
Lett. 2000, 2, 1995-1198.
(12) See,for example, Peczuh, M. W.; Hamilton, A. D. Chem. Rev.
2000, 100, 2479-2494.
(8) (a) Nishio, M.; Umezawa, Y.; Hirota, M.; Takeuchi, Y. Tetrahe-
dron 1995, 51, 8665-8701. (b) Umezawa, Y.; Tsuboyama, S.; Honda,
K.; Uzawa, J .; Nishio, M. Bull. Chem. Soc. J pn. 1998, 71, 1207-1213.
(c) Braga, D.; Grepioni, F.; Tedesco, E. Organometallics 1998, 17,
2669-2672. (d) Further information about CH-π interactions is
available in the following web site: http://www.tim.hi-ho.ne.jp/dionisio/.
(9) Arduini, A.; Nachtigall, F. F.; Pochini, A.; Secchi, A.; Ugozzoli,
F. Supramol. Chem. 2000, in press.

Recognition of Amides by Calix[4]arene Receptors
J . Org. Chem., Vol. 65, No. 26, 2000 9087
Sch em e 2a
Ch a r t 1. N-ben zyl-N′-p h en ylu r ea 11 a n d
P h en ylu r eid om eth yl-tetr a p r op oxy-ca lix[4]a r en e 12
a s Mod els of th e Su p p lem en ta r y Bin d in g a n d of
th e F lexible An a logu e of 6, Resp ectively
(5-7 and 10) toward formamide and acetamide as guests,
by 1H NMR spectroscopy in CDCl3. The starting com-
pound 1 and the model N-benzyl-N′-phenylurea 11 were
also studied to verify the cooperative effect of the two
binding sites. Finally the tetrapropoxycalix[4]arene bear-
ing the methylene-N-phenylureido group on the upper
rim (12)10a which is the flexible analogue of 6 was studied
with the aim to verify the effect of the cavity rigidity on
the recognition efficiency (Chart 1).
By adding increasing amounts of a 1 × 10-1 M solution
of the guest to a 1 × 10-2 M solution of the host in CDCl3,
several signals of the receptors and of the guests were
shifted upon complexation. In particular, with the 1:1
complex of 6 with acetamide, a downfield complexation
induced shift (CIS)17 of ca. 1.0 ppm was experienced by
both the two NH protons of the host, as expected on the
base of their involvement in hydrogen bonding with the
oxygen of the guest carbonyl group. On the contrary, the
NH2 and CH3 guest signals are upfield shifted up to 1.9
and 1.1 ppm, respectively, as a consequence of the
anisotropy shielding effects exerted by the aromatic rings
of the cavity, thus accounting for their inclusion into the
host cavity. Similar results were also obtained with the
other calixarene hosts 5, 7, and 10.
In all titration experiments the 1H NMR spectra
showed time-averaged signals for the free and complexed
species. The binding constants (Kas), based on monitoring
the NH signal of the host amidomethyl group (see Figure
1), were calculated using methods already described,18
and the results are summarized in Table 1.
The analysis of the binding constants allowed us to
make important considerations about the binding mode.
The good complexation efficiency showed by hosts 5, 6,
and 7 was the evidence that the recognition of the amide
guests can occur only when the two distinct binding sites,
the rigid calix[4]arene cavity and the additional group
having hydrogen bond ability, are present in the same
receptor. These results account for the cooperative action
a
Reagents and conditions: (i) NH2NH2‚H2O, Pd/C, C2H5OH,
reflux; (ii) C6H5NCO, CH2Cl2.
according to Scheme 1, starting from the monobromo
derivative 2 as intermediate. Careful choice of the
reaction conditions and the ratio between reagents was
chosen as the strategy for the monofunctionalization of
1. Thus, reacting NBS with an excess of 1 gave 2 in
reasonable yield (30%). This compound was then con-
verted to the corresponding aminomethyl derivative 4 in
high yield via the sequence Br/CN exchange, using
CuCN, followed by reduction of the monocyano derivative
3 with B2H6. Subsequent reaction of 4 with tosyl chloride,
phenyl isocyanate, or phenyl iso(thio)cyanate gave recep-
1
tors 5, 6, and 7. The H NMR spectra of derivatives 2-7
in CDCl3 clearly show the typical fingerprint of mono-
functionalized calix[4]arene-bis(crown-3) with the four
equatorial and the four axial methylene protons resonat-
ing as eight separated AX systems.13
For comparison, the receptor 10 having the N-phenyl-
ureido additional binding site directly attached to the
cavity, was prepared with an overall yield of 60%,
starting from the previously reported mononitro calix[4]-
arene-bis(crown-3) 813 as described in Scheme 2.
All the monosubstituted calix[4]arene-bis(crown-3) de-
rivatives are chiral molecules, nevertheless this property
was not exploited in the present study.
Having verified the good efficiency of the methylene-
N-phenylureido derivative 6 (see ahead), a simpler
synthetic approach to this host was studied. We found
that by a Tscherniac-Einhorn amidomethylation reac-
tion14 using N-hydroxymethyl-N′-phenylurea15 in a tri-
fluoroacetic-dichloromethane mixture, this receptor was
directly prepared in a 25% yield from derivative 1 in a
one-step process (see Scheme 1).16
Bin d in g Stu d ies. Preliminary binding studies were
carried out to compare the efficiency of the new hosts
(13) Arduini, A.; Pochini, A.; Secchi, A. Eur. J . Org. Chem. 2000,
2325-2334.
(14) (a) Zaugg, H. E.; Martin, W. B. In Organic Reactions; Cope, A.
C., Ed.; Wiley: New York, 1965; Vol. 14, pp 52-269. (b) Zaugg, H. E.
Synthesis 1970, 49-73. (c) Zaugg, H. E. Synthesis 1984, 85-110.
(15) Zigeneur, G.; Voglar, K.; Pitter, R. Montash. Chem. 1954, 85,
1196-1207.
(16) For the synthesis of calix[4]arene derivatives using the Tscher-
niac-Einhorn amidomethylation reaction, see van Bommel, K. J . C.;
Westerhof, F.; Verboom, W.; Reinhoudt, D. N.; Hulst, R. J . Prakt.
Chem. 1999, 341, 284-290.
(17) (a) Hunter, C. A.; Packer, M. J . Chem. Eur. J . 1999, 5, 1891-
1897. (b) Ru¨diger, V.; Schneider, H.-J . Magn. Reson. Chem. 2000, 38,
85-89 and references therein.
(18) (a) Wilcox, C. S. In Frontiers in Supramolecular Organic
Chemistry and Photochemistry; Schneider, H.-J ., Du¨rr, H., Eds.;
VCH: Weinheim, 1991; pp 123-143. (b) Tsukube, H.; Furuta, H.;
Odani, A.; Takeda, Y.; Kudo, Y.; Inoue, Y.; Liu, Y.; Sakamoto, H.;
Kimura, K. In Comprehensive Supramolecular Chemistry; Atwood, J .
L., Davies, J . E. D., MacNicol, D. D., Vo¨gtle, F., Eds.; Pergamon:
Oxford, 1996; Vol. 8, pp 123-143.

9088 J . Org. Chem., Vol. 65, No. 26, 2000
Arduini et al.
F igu r e 1. (a) Titration of host 6 with CH3CONH2 in CDCl3 (T ) 300 K, initial concentrations [60] ) 9.4 × 10-3 M, [G0] ) 9.8 ×
10-2 M), Kas ) 359 M-1 determined monitoring the downfield shift of the host NH (b) signal; (b) chemical shifts of the guest
signals recorded during the titration: NH2 (9, few signals overlapped, δ free guest ) 5.32 ppm) and CH3 (2, δ free guest ) 2.02
ppm).
Ta ble 1. Associa tion Con sta n ts (Ka s, M-1) for Hosts 1,
5-7, 10-12 w ith F or m a m id e a n d Aceta m id e Gu estsa
guest
1
5
6
7
10
80(11) 746(161) 118(20) 11(2)
12(2) 342(25) 37(4)
11 12
HCONH2
CH3CONH2
b
b
b
b
b
b
b
a
Determined by 1H NMR in CDCl3 (T ) 300 K); all values result
from at least duplicate experiments, standard deviations are in
brackets. Negligible complexation.
b
of the two binding sites in these molecular recognition
processes which has been indirectly confirmed by the lack
of complexation ability experienced by the calix[4]arene-
bis(crown-3) 1, and by N-benzyl-N′-phenylurea 11.
The presence of two NH groups in the host increases
its efficiency (5 in comparison with 6 and 7), whereas
the results obtained with host 10 support the importance
of the methylene group as spacer between the cavity and
the hydrogen bond active binding site. The lower stability
constants experienced by host 7 for both guests compared
with those showed by 6 are not easy to rationalize. In
fact it is well-known from the literature that calix[4]-
arenes,10a or calix[6]arenes19 bearing phenyl(thio)ureido
groups, are in general better complexing agents, toward,
for example, anion species, when compared with ana-
logues receptors having the phenylureido groups. This
behavior is usually justified, invoking the higher acidity20
of the NH protons of the thioureido moiety as reported
in a former work by Hamilton and co-worker,21 although
the effect of the O/S substitution on the NH acidity is
F igu r e 2. Chemical-induced shift (CIS) of proton amide
guests 13-15 measured during the titration with host 6 in
CDCl3 (T ) 300 K). aOverlapped signals; bno significant
variations of the signals.
22
far from fully understood.
its NH’s or acceptor through its CO, it is quite remark-
able to note that it is the rigid electron rich calix[4]arene
cavity which governs the recognition process by pivoting
also the receptor binding mode (see ahead).
The 1H NMR binding experiments were then extended
to a series of amides, N-alkyl and N,N-dialkyl amides
derived from formic (13a -c), acetic (14a -d ), and benzoic
acid (15a -d ) (see Figure 2). This study was carried out
using only host 6 because of its better binding efficiency.
The association constants obtained are summarized in
Table 2.
Finally, the comparison of the complexing ability of the
rigid host 6 with those of the flexible analogue 12 further
supports the importance of the cavity preorganization in
determining the recognition of neutral molecules.
Considering that the phenylureido sidearm itself could,
in principle, act as both hydrogen bond donor through
(19) Scheerder, J .; Engbersen, J . F. J .; Casnati, A.; Ungaro, R.;
Reinhoudt, D. N. J . Org. Chem. 1995, 60, 6448-6454.
(20) For the acidity of the thioamide group, see, for example,
Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.
(21) Fan, E.; Van Arman, S. A.; Kincaid, S.; Hamilton, A. D. J . Am.
Chem. Soc. 1992, 115, 369-370.
Host 6 is able to efficiently recognize amides bearing
the NH2 or NHR group (13a ,b, 14a ,b, 14d , and 15a ,b),
whereas a substantial decrease of the Kas was observed
(22) See, for example, Haushalter, K. A.; Lau, J .; Roberts, J . D. J .
Am. Chem. Soc. 1996, 118, 8891-8896.

Recognition of Amides by Calix[4]arene Receptors
J . Org. Chem., Vol. 65, No. 26, 2000 9089
Ta ble 2. Associa tion Con sta n ts (Ka s, M-1) for Host 6 w ith
Am id e Gu ests (R1CONR2R3)a
R2 ) CH3,
R3 ) H
R2 ) C6H5,
R3 ) H
R1
R2 ) R3 ) H
R2 ) R3 ) CH3
H
13a 746(161) 13b 204(8) 13c 38(7)
b
CH3 14a 342(25) 14b 261(24) 14c 56(30)
14d 198(10)
C6H5 15a 96(10)
15b 245(17) 15c < 10
15d c
Determined by 1H NMR in CDCl3 (T ) 300 K); all values result
a
from at least duplicate experiments, standard deviations are in
b
brackets. Not determined. c Negligible complexation.
F igu r e 4. Energy-minimized structures (molecular mechan-
ics, MM+ force field) of complex 6 ⊃ 14b. Hydrogen atoms
except those of the guest molecule and phenylureido group
have been omitted for clarity: (a) endo-cavity CONHCH3, (b)
endo-cavity NHCOCH3.
affected by the nature of R1 group. In fact while forma-
mide 13a is better bound than N-methylformamide 13b,
the corresponding acetamide 14a and N-methylacetamide
14b are recognized with comparable efficiency. On the
contrary, with benzoic acid derivatives 15a and 15b, a
reversed efficiency was observed. Probably with formic
derivatives the better matching of the geometrical re-
quirements which favors the formation of two strong
NH-π aromatic interactions are fulfilled. On the con-
trary, the increase of steric requirements of the R1 group
results in a strong decrease of the specific interactions
of the second NH so that the dispersion forces of the
methyl group with the host cavity become relatively
stronger.
In particular, the three amides formamide 13a , aceta-
mide 14a , and benzamide 15a showed CIS (-∆δ) of their
NH: 3.4, 1.9, and 0.6-0.9 ca. ppm, respectively (see
Figure 2), and this is due to their different interactions
with the calix[4]arene cavity. In the case of the N-
methylamide derivatives 13b, 14b, and 15b the N-methyl
group experience upfield larger than that showed by the
corresponding NH group, thus suggesting its deep en-
gulfment into the cavity of the calix.
Finally some short considerations on the energy of the
recognition process. Since it is known that amides
bearing an NH group are associated in apolar organic
solvents,25,26 the energy balance for complex formation
must overcome not only that required for the desolvation
of the interacting species, but also that required by both
host and guest self-dissociation. Thus, the energy gain
in the host-guest complex formation could be due to the
simultaneous interaction of the guest with the aromatic
cavity and the additional binding site. The rigidified
aromatic cavity interacts with the guest both by London
dispersion forces and as well as hydrogen bond acceptor.
These last intermolecular forces and in particular NH-π
F igu r e 3. 1H NMR spectra in CDCl3 (300 MHz, 300 K): (a)
free host 6; (b) 1:1.5 complex 6 ⊃ 14b. The host NH signals
are designated as 2 and 1; free guest signals as O, small open
box, and 0, whereas the complexed ones marked as b, small
solid box, and 9.
when the guest bears the N,N-dimethylamino groups
(13c, 14c, and 15c). The comparison of the binding
constants obtained with guests bearing phenyl groups
(14d , 15a , 15b, and 15d ) gives useful information on the
binding mode. Host 6 binds efficiently guests having only
one bulky phenyl group either on the amino (acetanilide
14d ) or on the carbonyl group (benzamide 15a and
N-methylbenzamide 15b), whereas the presence of two
phenyl groups in the guest (15d ) results in the complete
lack of host-guest interaction. These results strongly
support the inclusion of the CH3CONH and CH3NHCO
groups into the aromatic cavity.
On the basis of these data and from the observation
that, upon complexation, all the protons present in the
guest are substantially upfield shifted (see Figures 2 and
3), we hypothesize the existence of two complementary
binding modes. In particular R1CONH (R1 ) H or CH3)
or CONHR2 (R2 ) H or CH3) groups can interact with
the aromatic cavity of 6 probably through NH-π interac-
tions23,24 (see Figure 4).
The difference of the Kas of host 6 with amide or
N-methylamide derivatives of formic, acetic, and benzoic
acid supports the hypothesis that the binding mode and
consequently the intermolecular interactions are strongly
(23) (a) Desiraju, G. R.; Steiner, T. The Weak Hydrogen Bond, IUCr
Monographs on Cristallography Vol. 9; Oxford Science Pub.: Oxford,
1999. (b) Mitchell, J . B. O.; Nandi, C. L.; McDonald, I. K.; Thornton,
J . M.; Price, S. L. J . Mol. Biol. 1994, 239, 315-331. (c) Malone, J . F.;
Murrey, C. M.; Charlton, M. H.; Docherty, R.; Lavery, A. J . J . Chem.
Soc., Faraday Trans. 1997, 93, 3429-3436. (d) Braga, D.; Grepioni,
F.; Tedesco, E. Organometallics 1998, 17, 2669-2672. (e) Umezawa,
Y.; Suboyama, S.; Takahashi, H.; Uzawa, J .; Nishio, M. Tetrahedron
1999, 55, 10047-10056.
(25) See, for eample, Fruwert, J .; Dombrowski, D.; Geiseler, G. Z.
Physik. Chem. 1964, 227, 349.
(26) Dimerization constants for derivatives 6 and 7 (Kd ) 48 ( 4
and 15 ( 3, respectively) have been determined, assuming a dimeric
structure, through 1H NMR dilution experiments following the pro-
cedure reported by Horma, I.; Dreux, B. Helv. Chim. Acta 1984, 67,
754-764.
(24) For an application of NH-π aromatic interactions to molecular
recognition see: Adams, H.; Carver, F. J .; Hunter, C. A.; Osborne, N.
J . Chem. Commun. 1996, 2529-2530.

9090 J . Org. Chem., Vol. 65, No. 26, 2000
Arduini et al.
mixture was poured in a thick wall glass autoclave and then
heated at 200 °C overnight. After cooling to rt, the solvent was
completely evaporated in vacuo, and the sticky residue was
extracted twice with hot ethyl acetate (2 × 50 mL). The
combined organic phases were washed with brine (2 × 100
mL) and dried (Na2SO4), and the solvent was completely
evaporated in vacuo (the separated water phase was carefully
treated with aq sodium hypochlorite to destroy residual
cyanide ions). Purification of the residue by chromatography
(ethyl acetate/hexane, 50:50) gave 0.84 g (90%) of 3: mp 278-
aromatic interactions seem to determine the efficiency
and the selectivity in the recognition process of the amide.
Con clu sion s. This study demonstrates that the strat-
egy to introduce an additional binding site properly
designed onto the wider rim of the calix[4]arene cavity
can yield receptors able to recognize neutral organic
guests having specific functional groups in apolar media.
The rigidity of the calix[4]arene cavity is an essential
requisite to allow the additional sidearm to efficiently act
as binding site.
1
280 °C. H NMR (400 MHz) δ: 3.20, 3.21, 3.25, and 3.26 (4d,
4H, J 1 ) J 3 ) 12.5, J 2 ) J 4 ) 12.2 Hz); 3.8-4.0 (m, 4H); 4.1-
4.4 (m, 12H); 4.47, 4.50, 5.03, and 5.10 (4d, 4H); 6.71 (t, 1H, J
) 7.5 Hz); 6.80 (bt, 2H, J ) 7.6 Hz); 6.9-7.0 (m, 4H); 7.06 (bt,
2H, J ) 7.2 Hz); 7.23 and 7.25 (dd, 2H, J ) 2.0 Hz). 13C (75
MHz) δ: 29.4, 29.8, 30.5, 30.6, 73.6, 74.2, 74.7, 74.9, 76.0, 76.3,
76.4, 107.1, 119.3, 123.6, 123.8, 124.0, 128.0, 128.7, 128.9,
129.1, 129.5, 132.2, 133.2, 134.1, 134.5, 134.9, 135.8, 136.1,
136.9, 151.3, 155.0, 155.4, 158.9. CI(+) MS m/e: 590 [MH+].
IR(KBr) ν (cm-1): 2224 (w). Anal. Calcd for C37H35NO6‚H2O:
C, 73.13; H, 6.14; N, 2.30. Found: C, 73.52; H, 6.35; N, 2.28.
5-Am in om e t h yl-25,26-27,28-b is(cr ow n -3)-ca lix[4]-
a r en e (4). To a solution of 3 (0.93 mmol, 0.55 g) in dry THF
(20 mL) was added B2H6 (1 M solution in THF, 10 mL). The
resulting mixture was refluxed overnight under argon atmo-
sphere, cooled, treated with methanol (20 mL, CAUTION!),
and then refluxed for additional 30 min. The solvent was then
completely evaporated in vacuo and the residue taken up with
CH2Cl2 (50 mL) and saturated aq Na2CO3 solution (50 mL).
The organic layer was separated, washed with brine (2 × 100
mL), and dried (Na2SO4), and the solvent was completely
evaporated in vacuo. Purification of the residue by chroma-
tography (CH2Cl2/CH3OH, 50:50) gave 0.50 g (90%) of 4: mp
211 °C (dec). 1H NMR (300 MHz) δ: 2.46 (bs, 2H); 3.21 and
3.26 (2d, 4H, J 1 ) 12.0, J 2 ) 12.3 Hz); 3.39 (bs, 2H); 3.8-3.9
(m, 4H); 4.2-4.4 (m, 12H); 4.46, 4.50, 5.01, and 5.03 (4d, 4H,
J 1 ) J 2 ) J 3 ) J 4 ) 12.0 Hz); 6.56 (bt, 1H); 6.77 (t, 2H, J ) 6.9
Hz); 6.9-7.1 (m, 8H). 13C (25 MHz) δ: 29.7, 29.8, 30.7, 45.2,
74.6, 74.7, 76.2, 123.6, 123.7, 127.1, 127.9, 128.0, 128.8, 128.9,
129.0, 135.3, 135.4, 135.6, 154.1, 155.1. CI(+) MS m/e: 595
[MH + 1+]. Anal. Calcd for C37H39NO6‚3/2H2O: C, 71.59; H,
6.82, N, 2.26. Found: C, 71.52; H, 6.90; N 2.32.
Despite the stronger host-guest interactions with the
phenylureido group, which can be predicted on the base
of hydrogen bonding, it seems that the rigid calixarene
cavity governs the whole recognition process. This bind-
ing site seems to operate not only by London dispersion
forces but also by specific XH-π aromatic interactions.
These results could thus disclose the possibility to predict
the interaction with new guests. In fact preliminary
results show that dimethylurea is bound by host 6 with
a binding constant Kas ) 745(90) M-1 in CDCl3. Studies
are in progress to better understand whether specific
interactions of amide NH of the guest with the aromatic
cavity of calixarenes play a role in these recognition
processes and to extend this approach to the design of
new families of more complex receptors able to efficiently
and selectively recognize guests bearing specific func-
tional groups.
Exp er im en ta l Section
All reactions were carried out under nitrogen; all solvents
were freshly distilled under nitrogen and stored over molecular
sieves for at least 3 h prior to use. All other reagents were of
reagent grade quality as obtained from commercial suppliers
and were used without further purification. NMR spectra were
recorded in CDCl3 unless otherwise indicated. Mass spectra
were determined in CI mode (CH4). Melting point are uncor-
rected. As observed by other authors,27 the elemental analysis
of calixarenes are very often incorrect. Nevertheless, the
spectral data were in full agreement with the proposed
structure of these new compounds (see Supporting Informa-
tion). Compound 1,4 8,13 11,28 and 1210a were synthesized
according to literature procedures.
5-Br om o-25,26-27,28-bis(cr ow n -3)-ca lix[4]a r en e (2). To
a solution of 1 (1.77 mmol, 1.0 g) in methyl ethyl ketone (100
mL) was added NBS (1.59 mmol, 0.28 g). The resulting mixture
was stirred overnight and then diluted with ethyl acetate (100
mL) and treated with saturated aq Na2SO3 solution (100 mL).
The organic layer was separated, washed with brine (2 × 100
mL), and dried (Na2SO4), and the solvent was completely
evaporated in vacuo. Purification of the residue by chroma-
tography (ethyl acetate/hexane, 60:40) gave 0.34 g (30%) of 2:
mp > 270 °C (dec). 1H NMR (300 MHz) δ: 3.17, 3.23, 3.24,
and 3.29 (4d, 4H, J 1 ) J 2 ) J 3 ) J 4 ) 12.3 Hz); 3.8-4.0 (m,
4H); 4.2-4.3 (m, 12H); 4.46, 4.50, 5.02, and 5.04 (4d, 4H); 6.77
(t, 3H, J ) 7.5 Hz); 6.9-7.1 (m, 6H); 7.12 (bd, 2H). 13C (75
MHz) δ: 29.5, 29.7, 30.5, 30.6, 74.4, 74.7, 76.2, 76.3, 76.4,
115.8, 123.7, 123.8, 127.9, 128.0, 128.3, 128.8, 128.9, 129.2,
130.7, 131.6, 134.4, 134.6, 135.2, 135.4, 135.5, 135.7, 137.6,
137.8, 154.7, 155.0, 155.1. CI(+) MS m/e: 644 [MH+]. Anal.
Calcd for C36H35BrO6‚H2O: C, 65.36; H, 5.64. Found: C, 65.45;
H, 5.66.
5-(4-Meth ylben zen esu lfon a m id o)m eth yl-25,26-27,28-
bis(cr ow n -3)-ca lix[4]a r en e (5). To a solution of 4 (0.84
mmol, 0.5 g) in dry CH2Cl2 (25 mL) were added pyridine (4.2
mmol, 0.33 g) and TsCl (1.25 mmol, 0.24 g). The resulting
mixture was stirred for 2 h, poured into water (50 mL), and
diluted with CH2Cl2 (50 mL). The organic layer was separated,
washed with water (2 × 100 mL), and dried (Na2SO4), and
the solvent was completely evaporated in vacuo. Purification
of the residue by chromatography (ethyl acetate/hexane, 40:
60) gave 0.22 g (35%) of 5: mp 170 °C (dec). 1H NMR (300
MHz) δ: 2.43 (s, 3H), 3.10, 3.16, 3.20, and 3.26 (4d, 4H, J 1
)
12.1, J 2 ) 12.8, J 3 ) 12.6, J 4 ) 12.3 Hz); 3.7-3.9 and 3.88 (m
and d, 6H, J ) 5.9 Hz); 4.1-4.3 (m, 12H); 4.36 (bt, 1H); 4.43,
4.47, 4.97, and 5.01 (4d, 4H); 6.7-6.8 (m, 5H); 6.8-7.0 (2m,
6H); 7.30 (d, 2H, J ) 8.1 Hz); 7.73 (d, 2H). 13C (25 MHz) δ:
21.7, 30.0, 31.0, 47.3, 75.0, 76.6, 123.8, 124.0, 127.2, 128.0,
128.2, 128.9, 129.2, 129.9, 131.3, 136.0, 155.3, 155.5. CI(+) MS
m/e: 748 [MH+]. IR(KBr) ν (cm-1): 3435 (s); 1455 (s). Anal.
Calcd for C44H45NO8S‚H2O: C, 69.00; H, 6.18, N, 1.83; S, 4.19.
Found: C, 69.02; H, 6.21; N, 1.80; S 4.13.
5-Am in o-25,26-27,28-bis(cr ow n -3)-ca lix[4]a r en e (9). To
a solution of 8 (1.64 mmol, 1.0 g) in absolute C2H5OH (100
mL) were added a spatula tip of Pd/C catalyst (CAUTION!)
and NH2NH2‚H2O (16.4 mmol, 0.82 g, CAUTION!). The
resulting heterogeneous mixture was refluxed overnight and
cooled, and the palladium catalyst was filtered off on Celite
under nitrogen atmosphere. The resulting solution was com-
pletely evaporated in vacuo, and the residue was partitioned
between water (100 mL) and CH2Cl2 (100 mL). The organic
layer was separated, the water phase was further extracted
with CH2Cl2, the combined organic portions were washed twice
with brine and dried with CaCl2, and the solvent was com-
pletely evaporated to dryness. Purification of the residue by
5-Cya n o-25,26-27,28-bis(cr ow n -3)-ca lix[4]a r en e (3). To
a solution of 2 (1.56 mmol, 1.0 g) in DMF (30 mL) was added
CuCN (3.12 mmol, 0.28 g). The resulting heterogeneous
(27) (a) Bo¨hmer, V.; J ung, K.; Schon, M.; Wolff, A. J . Org. Chem.
1992, 57, 790-792. (b) Gutsche, C. D.; See, K. A. J . Org. Chem. 1992,
57, 4527-4539.
(28) Suto, M. J .; Gayo-Fung, L. M.; Palanki, M. S. S.; Sullivan, R.
Tetrahedron 1998, 58, 4141-4150.

Recognition of Amides by Calix[4]arene Receptors
J . Org. Chem., Vol. 65, No. 26, 2000 9091
chromatography (ethyl acetate/hexane, 50:50) gave 0.85 g
(90%) of 9: mp 228-230 °C. 1H NMR (300 MHz) δ: 3.09, 3.14,
3.22, and 3.27 (4d, 4H, J 1 ) J 2 ) 12.0, J 3 ) J 4 ) 12.3 Hz);
3.7-3.9 (m, 4H); 4.1-4.3 (m, 14H); 4.42, 4.50, 4.96, and 5.03
(4d, 4H); 6.31 and 6.33 (dd, 2H, J ) 2.7 Hz); 6.74 (t, 3H, J )
7.5 Hz); 6.9-7.1 (m, 6H). 13C (75 MHz) δ: 29.7, 29.8, 30.7, 74.5,
74.6, 74.7, 74.8, 76.1, 76.2, 76.4, 115.0, 116.1, 123.5, 123.6,
128.0, 128.8, 128.9, 135.3, 135.4, 135.6, 135.9, 141.4, 148.0,
155.0, 155.2. CI(+) MS m/e: 580 [MH+]. IR(KBr) ν (cm-1): 3457
(s); 3380 (s). Anal. Calcd for C36H37NO6‚1/2H2O: C, 73.45; H,
6.51, N, 2.38. Found: C, 73.78; H, 6.62; N, 2.25.
Gen er a l P r oced u r e for th e Syn th esis of Ca vita n d s 6,
7, a n d 10. A solution of the appropriate amino derivative (4
or 9, 1 mmol) in dry CH2Cl2 (25 mL) was reacted with the
proper electrophile (tosyl chloride, phenyl isocyanate, or phenyl
isothiocyanate, 1.1 mmol). The resulting mixture was stirred
for 8 h, poured into water (50 mL), and diluted with CH2Cl2
(50 mL). The organic layer was separated, washed with water
(2 × 100 mL), and dried (Na2SO4), and the solvent was
completely evaporated in vacuo.
135.8, 136.0, 154.8, 155.1, 155.2, 180.8. CI(+) MS m/e: 729
[MH+]. IR(KBr) ν (cm-1): 3390 (s), 1450 (s). Anal. Calcd for
C44H44N2O6S‚1/2H2O: C, 71.62; H, 6.15, N, 3.80, S, 4.35.
Found: C, 71.81; H, 6.15; N, 3.67; S, 3.89.
5-(N-P h en ylu r eid o)-25,26:27,28-bis(cr ow n -3)-ca lix[4]-
a r en e (10): eluent ethyl acetate/hexane, 50:50; 0.49 g (70%);
mp 205-207 °C. 1H NMR (300 MHz) δ: 3.1-3.3 (m, 4H); 3.7-
4.0 (m, 4H); 4.1-4.4 (m, 12H); 4.49, 4.50, 5.05, and 5.06 (4d,
4H, J 1 ) J 2 ) 12.2 Hz, J 3 ) J 4 ) 12.1 Hz); 6.08 (s, 1H); 6.32
(s, 1H); 6.63 (t, 1H, J ) 7.5 Hz); 6.7-6.8 (m, 2H); 6.87(bd, 2H);
6.9-7.0 and 7.1-7.2 (2m, 11H). 13C (75 MHz) δ: 29.7, 30.7,
73.8, 74.0, 75.1, 75.2, 76.2, 76.3, 120.2, 123.3, 123.4, 123.5,
123.9, 124.4, 127.8, 128.0, 128.3, 128.7, 129.0, 132.2, 135.1,
135.6, 135.7, 136.0, 136.4, 138.1, 153.7, 154.7, 155.5. CI(+) MS
m/e: 699 [MH+]. IR (KBr) ν (cm-1): 3386 (s), 1653-1598 (s).
Anal. Calcd for C43H42N2O7‚1/2H2O: C, 72.97; H, 6.12, N, 3.96.
Found: C, 73.41; H, 6.26; N, 3.75.
Dir ect Syn th esis of 5-(N′-P h en ylu r eid o)m eth yl-25,26-
27,28-bis(cr ow n -3)-ca lix[4]a r en e (6). To a solution of 1 (3.3
mmol, 1.85 g) in CH2Cl2 (60 mL) and CF3COOH (20 mL)
solvents mixture, maintained at 0 °C, was dropwise added (10
min) a solution of C6H5NHCONHCH2OH (1.98 mmol, 0.32 g)
in CH2Cl2 (20 mL). The resulting purple mixture was allowed
to stir at room temp for 1 h and then quenched with water
(100 mL). The organic phase was separated and washed with
saturated aq Na2CO3 up to neutrality and dried (Na2SO4), and
the solvent was completely removed under reduced pressure.
The solid residue was purified by chromatography (see above);
0.57 g (25%).
5-(N-P h en ylu r eid o)m et h yl-25,26-27,28-b is(cr ow n -3)-
ca lix[4]a r en e (6): eluent ethyl acetate/hexane, 40:60; 0.5 g
(70%); mp 178-180 °C. 1H NMR (300 MHz) δ: 3.19, 3.21, 3.24,
and 3.27 (4d, 4H, J 1 ) J 4 ) 12.0, J 2 ) 11.9, J 3 ) 12.3 Hz);
3.8-3.9 (m, 4H); 4.13 (d, 2H, J ) 4.8 Hz); 4.2-4.3 (m, 12H);
4.47 and 4.50 (2d, 2H); 4.75 (bt, 1H); 5.01 and 5.02 (2d, 2H);
6.16 (s, 1H); 6.6-6.7 (m, 3H); 6.9-7.1 (m, 9H); 7.1-7.2 (m,
4H). 13C (75 MHz) δ: 29.6, 29.7, 30.6, 44.2, 74.6, 74.7, 74.8,
76.3, 76.4, 120.8, 123.4, 123.7, 123.8, 127.4, 127.9, 128.1, 128.3,
128.8, 129.1, 135.4, 135.5, 135.7, 135.8, 154.8, 155.1, 155.2.
CI(+) MS m/e: 713 [MH+]. Anal. Calcd for C44H44N2O7‚H2O:
C, 72.31; H, 6.34, N, 3.83. Found: C, 72.41; H, 6.36; N, 3.75.
5-(N-P h en yl(th io)u r eido)m eth yl-25,26-27,28-bis(cr own -
3)-ca lix[4]a r en e (7): eluent ethyl acetate/hexane, 50:50; 0.58
Ack n ow led gm en t . We thank the Ministero dell’
Universita` e della Ricerca Scientifica e Tecnologica
(MURST) “Supramolecular Devices” project, for finan-
cial support and C.I.M. (Centro Interdipartimentale di
Misure “G. Casnati”) of the University of Parma for
NMR and mass measurements.
1
g (80%); mp 149-151 °C. H NMR (300 MHz) δ: 3.1-3.3 (m,
4H); 3.8-3.9 (m, 4H); 4.2-4.3 (m, 12H); 4.46 and 4.48 (2d, 2H,
J 1 ) J 2 ) 12.1 Hz); 4.6-4.7 (m, 2H); 5.01 and 5.02 (2d, 2H, J 1
) J 2 ) 12.0 Hz); 6.11 (bs, 1H); 6.6-6.7 (m, 3H); 6.88 (s, 2H);
6.9-7.0 (m, 9H); 7.11 (d, 2H, J ) 7.5 Hz); 7.2-7.4 (m, 2H);
7.56 (bs, 1H). 13C (75 MHz) δ: 29.7, 30.7, 49.3, 74.5, 74.6, 74.8,
76.3, 76.4, 123.6, 123.7, 125.1, 127.0, 127.2, 127.9, 128.0, 128.1,
128.8, 128.9, 129.0, 130.2, 131.8, 135.2, 135.4, 135.5, 135.7,
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of new compounds 2-7, 9, and 10. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O005596N