Recognition of guests bearing donor and acceptor hydrogen bonding groups by heteroditopic calix[4]arene receptors

Article abstract of DOI:10.1016/S0040-4020(03)01126-8

The synthesis of new hosts specifically designed for the recognition of neutral guests bearing donor-acceptor hydrogen bonding groups is described. These hosts are characterized by the presence of two distinct binding region in close proximity: the rigid

Full text of DOI:10.1016/S0040-4020(03)01126-8

Tetrahedron 59 (2003) 7587–7594
Recognition of guests bearing donor and acceptor hydrogen
bonding groups by heteroditopic calix[4]arene receptors
*
Arturo Arduini, Elisabetta Brindani, Giovanna Giorgi, Andrea Pochini and Andrea Secchi
`
Dipartimento di Chimica Organica e Industriale dell’Universita, Parco area delle Scienze 17/a, 43100 Parma, Italy
Received 4 April 2003; revised 23 June 2003; accepted 17 July 2003
Abstract—The synthesis of new hosts specifically designed for the recognition of neutral guests bearing donor–acceptor hydrogen bonding
groups is described. These hosts are characterized by the presence of two distinct binding region in close proximity: the rigid p-donor cavity
and the H-bond donor N-methylene-N0-phenylureido group inserted onto the upper rim of the calix[4]arene skeleton. The binding abilities of
1
these receptors were investigated toward a series of neutral ditopic organic molecules in CDCl3 solution by H NMR spectroscopy. The
results obtained show that rigidity of the calix[4]arene apolar cavity is the control element in determining efficiency. In fact, compared with
the more rigid 2, host 10, where the rigidity of the cone structure is maintained by hydrogen bonding of the OH of the lower rim, a decrease of
efficiency of almost one order of magnitude was observed. The cooperative effect of the two binding region of host 2 was verified with
different classes of ditopic guests. Good efficiency in the recognition of urea derivatives and dimethylsulfoxide was achieved.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
recognise very efficiently amides of formic, acetic and
benzoic acids.11 In particular, it w0as observed that the
introduction of aN N-methylene-N -phenylureido group
onto the upper rim of the rigid calixarene skeleton of host
1 renders receptor 2 able to interact through its NHs with the
carbonyl group of the guest. In addition the NH and/or CH
groups of the guest directly linked to the carbonyl interact
with the calix[4]arene p-donor cavity through NH-p12,13 or
CH-p9,10 interactions. As a result of the proper structural
matching between the host and the neutral guest, the
association constants measured in apolar media approached
700 M21 in some instances. It thus appears that the
synthesis of simple heteroditopic receptors able to effi-
ciently bind neutral organic molecules bearing specific
functional groups could be a powerful tool for the
comprehension not only of the role and magnitude of the
host preorganization on the binding efficiency, but also of
the nature of the weak intermolecular interactions that are
involved in biological and molecular recognition processes.
In apolar media, the binding abilities of the p-donor cavity
of calix[4]arenes1–3 are strictly related to the conformation-
al flexibility of the macrocycle. In fact, it has been verified
that, because of their residual flexibility, simple tetraalkoxy
calix[4]arenes in the cone conformation are not able to form
stable endo cavity inclusion complexes with neutral organic
molecules.4 On the contrary, calix[4]arenes held in a ‘rigid’
cone conformation through the linkage of two proximal
phenol groups with short diethyleneglycol bridges or
hydrogen bonding interactions in partially alkylated
calix[4]arenes are able to form inclusion complexes with
neutral organic guests.5–8 Regardless of the strategy adopted
to immobilize the cone structure, in all binding studies, only
guests bearing acid CH3 or CH2 groups were found to be
suitable guests, recognised with association constants that
occasionally exceed 50 M21. From the structure of these
complexes, inferred in apolar media and observed in the
solid state, it emerges that specific CH-p(aromatic)
interactions9,10 represent the main driving force for their
formation.
A possible approach to a deeper understanding of these
phenomena could derive from the extension of the study,
performed using 2 as reference host, to other classes of guest
bearing donor and acceptor hydrogen bonding groups.
Moreover, other useful information could be obtained
studying the effect of the preorganization and shape of the
calix[4]arene aromatic cavity on the recognition process. To
address these issues the synthesis of new heteroditopic hosts
held in a ‘rigid’ cone conformation through intramolecular
H-bonds was undertaken. Moreover, these more versatile
synthetic hosts could be easily modified to be employed as
More recently, attempts to enhance the efficiency of the
binding ability of rigidified calix[4]arenes as hosts, have
brought us to the synthesis of heteroditopic receptors able to
Keywords: calix[4]arenes; heteroditopic receptors; molecular recognition;
neutral organic guests.
*
Corresponding author. Tel.: þ39-0521-905408; fax: þ39-0521-905472;
e-mail: pochini@unipr.it
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01126-8

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A. Arduini et al. / Tetrahedron 59 (2003) 7587–7594
active components, bound onto appropriate surfaces, for the
preparation of new selective sensors for neutral molecules.
2. Results and discussion
2.1. Design and synthesis of the new hosts
In a previous paper11 we studied the binding ability of
receptors 1, 2, and 3 (Fig. 1) toward simple amides derived
from formic, acetic and benzoic acids. We found that the
rigid 1, where only the p donor cavity can act as a binding
site, experiences quite poor binding efficiency, comparable
with that of 3, where the hydrogen bond donor methylene-
phenylureido group is anchored to the flexible tetrapropoxy-
calix[4]arene skeleton. On the contrary 2, where the same
additional binding site was inserted onto the rigid platform
of 1, experiences quite remarkable efficiency. To give an
insight into the mutual role of both host rigidity and
additional binding site, the synthesis of the new receptor 10
was tackled.14
Scheme 1. Reagents and conditions: (i) NBS, 2-butanone, h¼45%;
(ii) CuCN, DMF, T¼2008C, h¼90%; (iii) NaH, BnBr, DMF, T¼708C,
h¼75%; (iv) B2H6, THF, T¼608C, h¼55%; (v) C6H5NCO, CH2Cl2, rt,
h¼90%; (vi) H2, Pd/C (cat.), h¼60%; (vii) C6H5NHCONHCH2OH, AlCl3,
CH2Cl2, h¼30%.
Receptor 10 is characterized by the presence of the
N-methylen-N0-phenylureido group inserted at the upper
rim of the calix[4]arene skeleton, held in a rigid cone
conformation by intramolecular hydrogen bonding between
the two distal OH groups present at its lower rim.
N0-phenylureido groups onto its upper rim. Moreover a
triethyleneglycol chain, that links the two proximal phenol
groups, could contribute, together with the formation of
intramolecular hydrogen bonding between remaining
phenolic groups, to the stiffening of the whole calixarene
skeleton.
Attempts to apply the procedure used for the synthesis of
host 2,11 based on a Tscherniac–Einhorn amidomethylation
reaction15–17 between N-hydroxymethyl-N0-phenylurea and
1, using trifluoroacetic acid as catalyst on the 25,27-
dipropoxy-calix[4]arene (4) were unsuccessful. Therefore
compound 10 was synthesized in 9% overall yield through
the reaction sequence reported in Scheme 1 that, together
with the necessary steps for functional group insertion and
transformation, also involves the protection–deprotection
steps of the calixarene OH groups, which contribute to a
decrease of the overall yield. The low overall yield
prompted us to study in more detail the direct amidomethyl-
ation reaction. The systematic investigation of the reaction
conditions brought us to the selection of AlCl3 as the
catalyst of choice for0 the direct amidomethylation of 4 with
N-hydroxymethyl-N -phenylurea that gave 10 in 30%
(Scheme 1). Using the same synthetic approach, receptor
12 was synthesized (Scheme 2) from 25,26-dihydroxy-
27,28-mono(crown-4)-calix[4]arene (11) in 55% yield. It is
characterized by the presence of two proximal N-methylen-
Both receptors 10 and 12 were fully characterized by NMR
and MS spectroscopy (see Section 4). The main features of
1
the H NMR spectrum of 10 in CDCl3 are two singlets at
d¼8.30 and 8.36 ppm for the phenolic OHs, and two
overlapped AX systems at d¼3.35, 3.37, 4.30 and 4.32 ppm
for the equatorial and axial methylene protons, respectively.
The ureido NH protons resonate at d¼5.1 and 6.5 ppm as
two broad singlets. The overall pattern of peaks is typical for
a 1,3-dialkoxy-calix[4]arene derivative mono-substituted at
the upper rim, in a flattened cone conformation on the NMR
timescale. The 1H NMR spectrum in CDCl3 of derivative 12
is rather complicated and shows broad peaks especially in
the aromatic region. A well resolved spectrum was recorded
in DMSO d6 in which all the characteristic signals of this
compound were fully assigned by means of 1H–1H 2D
1
COSY and H–13C 2D HETCOR spectroscopy.
2.2. Binding studies
Initially formamide, acetamide and their N-methyl deriva-
tives were selected as guests to compare the binding
efficiency of the new receptor 10 with that of 2.18 Therefore
1H NMR titration experiments were performed adding
increasing amounts of a 0.5–1.0£1021 M stock solution of
the guest to a 0.5–1.0£1022 M stock solution of the host in
CDCl3, by monitoring the host ureido chemical shift
variation. All the NMR spectra showed time-averaged
signals for the free and complexed species and, having
verified a 1:1 stoichiometry for the host–guest association
Figure 1.

A. Arduini et al. / Tetrahedron 59 (2003) 7587–7594
7589
nucleus functionalized with the phenylureido moiety,
indicating that during the titration a partial rearrangement
of the calixarene skeleton takes place. Analogous behavior
was also observed, although with different magnitude, with
all the other guests studied.
Owing to its higher efficiency, the binding properties of host
2 were evaluated toward different series of ditopic guests,
selected on the basis of the different extent of their hydrogen
bond donor–acceptor ability (see Fig. 3). In fact, the
common structural feature of the guests reported in Table 2
is the presence of a methyl group linked to moieties having
different electron-withdrawing and H-bond acceptor ability
(CH3–G, where G¼C(O)R1, C(S)R2, S(O)R2, S(O2)R2 with
R1¼Me, NH2, NHMe, OMe and R2¼Me, NH2). As a
consequence, these CH3 groups, having different acidity,
should be able to interact with the calixarene cavity through
‘hydrogen bond like’ C–H/p interactions, whose magnitude
could be related to their acidity.7 In addition, the higher
upfield shift experienced by the NH protons of acetamide
and thioacetamide indicates, that for these guests, NH/p
interactions with the host cavity could be the major driving
force for complex formation (see Fig. 3).
Scheme 2. Reagents and conditions: (i) C6H5NHCONHCH2OH, AlCl3,
CH2Cl2, h¼55%.
by means of continuous variation methods,19 the stability
constants (K) for the complex formation were calculated
using methods that have been previously described based on
the non-linear fitting of the experimental data.20–22 The
results are summarized in Table 1.
From the comparison of the efficiency of 2 and 10, it
emerges that the lower hydrogen bonding driven pre-
organization of the calixarene cavity of 10 results in a
general decrease of efficiency of almost one order of
magnitude. Interestingly, 10 experiences a different
selectivity order compared with 2 and a higher stability
constant was observed with the bulkiest N-methylaceta-
mide. Probably the larger flexibility of 10, that could be
responsible for this lower efficiency, could also, on the other
hand, render it more adaptable to the bulkiest guest.
By looking at the K values reported in Table 2, it emerges
that the Brønsted acidity in DMSO23–28 of the guest CH3
and/or NH2 groups, does not account, as the unique
parameter, for the efficiency order observed. In fact, methyl
acetate (entry 2) that possesses the more acid CH3 group, is
the least efficiently bound, while DMSO (entry 5), that is the
weakest acid among the guests, is the most strongly bound.
Similarly, the comparison of the NH2 acidity, for example,
of acetamide (entry 3) and methansulfonamide (entry 7)
shows that the latter, in spite of its more acid NH2 is less
strongly bound.
From the variation of the chemical shift experienced by the
protons of both the hosts and the different guests during the
titration experiments, general information on the structure
of the complexes formed can be inferred (see Fig. 2). For
example, during the titration of 10 with acetamide, a
downfield complexation induced shift of about 0.8 and
0.5 ppm was experienced by the two ureido NH protons of
the host, as expected on the basis of their involvement in
hydrogen bonding with the oxygen of the guest carbonyl
group. On the other hand, the guest NH2 and CH3 group
signals were upfield shifted up to 0.8 and 0.35 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.
Furthermore a downfield shift of about 0.2 ppm was
experienced by hydroxyl protons belonging to the aromatic
A better rationalization of the K values reported in both
Tables 1 and 2 could derive from the quantitative evaluation
of the mutual and co-operative actions of the two binding
sites of the host on the recognition of a ditopic guest that,
unfortunately, has been scarcely studied. Nevertheless we
attempted to analyze the results obtained in the present
study through the solute effective hydrogen bond basicity
and acidity scales introduced by Abraham.29,30 In these
scales the H-bond acceptor (A) and H-bond donor (B)
parameters have been defined as free energy properties that
reflect the tendency of a certain solute to accept and donate
H-bonding in aprotic chlorinated solvents, measured toward
an acid and a base taken as reference, respectively.
It should however be noted that these scales do not take into
account the H-bond acidity of aliphatic protons. Moreover,
considering the low H-bond basicity of the aromatic systems
(e.g. B for benzene is 0.14), the very weak H-bond
Table 1. Association constants (K, M21) for hosts 2 and 10 with different
amide-based guests, determined by 1H NMR in CDCl3 (T¼300 K)
Entry
Guest
2a
10
1
2
3
4
HCONH2
750(160)
204(8)
350(25)
260(25)
30(5)
25(5)
40(7)
65(5)
HCONHCH3
CH3CONH2
CH3CONHCH3
Calculated monitoring the chemical shift variation of the Ar(calix)–
CH2NH–CONHC6H5 signal. All values result from at least duplicate
experiments, standard deviations are in brackets.
Figure 2. Observed upfield CIS (Complexation Induced Shifts) for amide-
based guests during the titration with host 10 in CDCl3 (T¼300 K, [G0]/
[H0]¼0.3).
a
See Ref. 11.

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A. Arduini et al. / Tetrahedron 59 (2003) 7587–7594
Figure 3. Observed upfield CIS (Complexation Induced Shifts) of the guest proton signals for the titration experiments when receptor 2 is used as host (CDCl3,
T¼300 K, [G0]/[H0]¼0.3).
interactions, like the CH/p (aromatic), that are often
responsible for the formation of several supramolecular
complexes, are neglected in such an approach.
A further series of guests examined is represented by the
pentaatomic heterocycles; pyrrole, 1-H-pyrazole and 1-H-
imidazole (see Table 3, entries 1–3). These potential guests
are all characterized by a relatively acidic NH proton,
potentially able to interact with the host cavity of 2.
Pyrazole and imidazole could be recognized as ditopic
guests since the second nitrogen atom located in the 2 and 3
positions, respectively, could participate in the overall
recognition process by interacting with the host ureido NH.
As expected these latter guests are bound more efficiently
than the monotopic pyrrole for which negligible binding
was observed.
As a consequence, for the data analyses, only the H-bond
acidity of the NH groups present in the different guests
could be utilized. Nevertheless, considering the correlation
of the H-bond donor (A) and acceptor (B) ability with the
binding efficiency of guests having related functional
groups such as acetamide (A¼0.55; B¼0.68; K¼
350^25 M21), N-methylacetamide (A¼0.40; B¼0.71;
K¼260^25), acetone (A¼0.04; B¼0.49; K¼16^2) and
methyl acetate (A¼0.00; B¼0.45; K¼13^2), it emerges
that these parameters account for the trend of the measured
binding constants. In fact, it could be reasonable to assume
that acetone and methyl acetate because of the lack of
H-bond donor ability, can be bound by host 2 only through
their carbonyl group and hence less efficiently than
acetamide and N-methylacetamide that, because of the
H-bond donor ability of their NH, can be recognised more
efficiently by a co-operative interactions of their CO and NH
groups. However, as expected, any attempt to apply this
approach to rationalize the K values for all the different
classes of guest studied failed. It is reasonable, in fact, to
assume that, besides the H-bond parameters, other structural
properties of the guests (e.g. polarity, polarizability, shape
and size) can affect the recognition process.
Furthermore the higher efficiency exhibited by 2 toward
imidazole suggests that, for this guest, the H-donor and
acceptor atoms are in more appropriate relative positions.
These latter results, together with those obtained in the case
of amide recognition, prompted us to verify whether host 2
could be exploited for the recognition of structurally related
guests like ureas. Unfortunately, in spite of their very
effective H-bond donor and acceptor ability and the current
interest in their recognition and sensing, the study was
restricted to N,N0-dimethylurea and ethylenurea (entries 4
and 5, Table 3) for solubility reasons. Interestingly both
ureas are bound to the same extent and with a magnitude
almost identical to that of acetamide, suggesting a very
similar binding mode.
2.3. Binding mode
Table 2. Association constants (K, M21) and limiting chemical shift values
(d , ppm) for hosts 2 with neutral guests, determined by 1H NMR in CDCl3
Attempts to obtain suitable crystals for X-ray analysis of the
complexes formed by 2 with the different guests failed.
However, because of the unexpected and unprecedented
1
(T¼300 K)
Entry
Guest
pKa
K (M21
)
d(NH)1
Table 3. Association constants (K, M21), limiting chemical shift values
(d , ppm), for hosts 2 with urea and heterocycles-based guests, determined
1
2
3
4
5
6
7
CH3COCH3
26.5a
16(2)
13(2)
340(25)
5.3(0.2)
5.0(0.1)
5.8(0.2)
5.6(0.2)
CH3COOCH3 22.7b
1
1
CH3CONH2
CH3CSNH2
CH3SOCH3
CH3SO2CH3
CH3SO2NH2
35(Me)c, 25.5(NH2)d
by H NMR in CDCl3 (T¼300 K)
25.7(Me)e, 18.5(NH2)f 270(30)
K (M21
)
d(NH)1
35.1a
1250(350) 6.0(0.2)
200(20)
85(25)
Entry
Guest
31.1a
5.5(0.2)
5.2(0.2)
a
17.5(NH2)g
1
2
3
4
5
Pyrrole
–
1-H-imidazoleb
1-H-pyrazoleb
CH3NHCONHCH3
Ethylenurea
330(20)
120(15)
330(30)
340(30)
7.9(0.1)
7.1(0.1)
5.9(0.1)
6.4(0.2)
Calculated monitoring ArCH2NHCONH chemical shift variation.
a
Ref. 23.
Determined as tert-butylacetate, Ref. 24.
Determined as N,N-diethylacetamide, Ref. 24.
Ref. 25.
Determined as N,N-diethylthioacetamide, Ref. 24.
Ref. 26.
Ref. 27.
b
c
d
Calculated monitoring ArCH2NHCONH chemical shift variation, unless
otherwise stated.
e
f
a
Negligible binding.
Calculated monitoring NHCONHC6H5 signal chemical shift variation.
g
b

A. Arduini et al. / Tetrahedron 59 (2003) 7587–7594
7591
high association between 2 and DMSO, a detailed NMR
investigation on the structure of the complex was carried
out.
In the NMR spectra of the 1:1 complex (see Fig. 4(c)), the
signals of the host NHs are downfield of about 1 ppm and
resonate at d¼6.0 and 7.6 ppm, suggesting their involve-
ment in hydrogen bonding with the guest S–O. On the other
hand, the methyl groups of DMSO support an upfield shift
of 2.1 ppm and resonate at d¼0.55 ppm. This indicates that
they are in close proximity to the host aromatic cavity.
These chemical shifts variation suggest a binding mode in
which the guest SO moiety is involved in hydrogen bonding
with the NH ureido protons and it seems reasonable to
assume that this interaction pivots the orientation of at least
one methyl group of DMSO toward the p-rich calix[4]arene
cavity.
While the complete assignment of all host signals was
1
obtained from H–1H 2D NMR DQF-COSY experiments,
the structure of the complex was inferred through NOESY
spectra.31 The main feature of these latter spectra are the
NOE cross-peaks between the methyl protons of DMSO
with the aromatic and NH protons of the host.32 In particular
large cross-peak volumes were observed for the guest
protons with H-5, 7, 11, 13 and 15 (see Fig. 5).
Figure 5. Expanded region of the NOESY spectrum of 2.DMSO complex
(1:1.25) showing negative cross-peaks corresponding to intermolecular
interactions between the methyl groups of the guest with the aromatic part
of the host (300 MHz, T¼300 K, mixing time¼0.7 ms).
These data suggest the hypothesis that, beside the formation
of classical H-bonding, a not negligible contribution to the
complex stability also derives from the interaction of the
methyl group of DMSO with the host cavity.
lower rim. The recognition properties of the new hosts was
tested toward a series of small amide derivatives having
complementary hydrogen bonding properties, and com-
pared to those experienced by a corresponding highly
preorganised calix[4]arene-biscrown-3 (2). These studies
show that the recognition of this type of guests can also be
achieved, although less efficiently, with hosts whose degree
of rigidity is only determined by intramolecular hydrogen
bonding. These findings open new possibilities to employ
these latter hosts as active components for the development
of new artificial sensors for small organic molecules. In fact,
it could be easy to realize new calix[4]arene receptors
having 1,3-dialkoxy substituents functionalized with groups
that allow the anchoring of the host onto sensor surfaces. On
the other hand, the results obtained with 2 show interesting
binding ability of this receptor toward DMSO. The stability
constant calculated for this derivative (K.103 M21) in
apolar solvents is one of the highest among those reported in
literature for other synthetic hosts where the complexation
of DMSO is driven only by hydrogen bonds5,33,34 or
mediated by metal cations.35 The NMR studies accom-
plished on this complex show that its complexation is the
result of the co-operation of the two binding sites of host 2
towards DMSO, which behaves as ditopic guest.
3. Conclusion
The present study shows an efficient route for the synthesis
of new heteroditopic calix[4]arene-based receptors having
one and two phenylureido groups at their upper rim, whose
degree of preorganization is modulated through the
formation of intramolecular hydrogen bonding at their
4. Experimental
4.1. General remarks
Figure 4. Stack plot of the titration of DMSO with host 2 in CDCl3
(T¼300 K): (a) free host; (b) [DMSO]/[2]¼0.75; (c) [DMSO]/[2]¼1.0;
(d) [DMSO]/[2]¼1.25; (X) host ureido NH signals; (W) guest Me signal;
(–-) free guest.
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

7592
A. Arduini et al. / Tetrahedron 59 (2003) 7587–7594
reagents were of reagent grade quality as obtained
from commercial suppliers and were used without
further purification. Column chromatography were per-
formed on silica gel 63–200 mesh. NMR spectra were
recorded in CDCl3 at 300 K unless otherwise
indicated. Mass spectra were determined in the CI
mode (CH4) as appropriate. Melting point are uncorrected.
N-hydroxymethyl-N0-phenylurea,36 calix[4]arenes 2,37 437
and 1138 were synthesized according to literature
procedures.
acetate (100 mL). The reaction was then quenched by
treatment with a 10% HCl solution (50 mL, CAUTION!).
The organic layer was separated, washed with a saturated
solution of Na2CO3 (100 mL), dried (Na2SO4), and
evaporated to dryness. Purification of the residue by
crystallization with hexane, gave 0.6 g (75%) of 7: mp
146–1488C. 1H NMR (300 MHz) d: 0.63 (t, 6H, J¼7.2 Hz);
1.5–1.7 (m, 4H); 3.05 and 3.15 (2d, 4H, J¼13.5 Hz); 3.7–
3.9 (m, 4H); 4.41 and 4.44 (2d, 4H, J¼13.4 Hz); 4.77 and
4.82 (2s, 4H); 6.21 (d, 2H, J¼7.5 Hz); 6.44 (s, 2H); 6.50 (t,
1H, J¼7.8 Hz); 6.92 (t, 2H, J¼7.3 Hz); 6.98 and 7.07 (2dd,
4H, J1¼7.3 Hz, J2¼1.7 Hz); 7.3–7.5 (m, 10H). 13C NMR
(75 MHz) d: 9.4, 22.8, 30.8, 31.0, 76.5, 105.9, 119.5, 122.3,
122.5, 127.6, 127.8, 128.2, 128.25, 128.3, 128.5, 128.7,
129.5, 130.0, 131.6, 133.5, 135.4, 135.9, 136.6, 136.9,
137.7, 154.6, 157.5. MS-CI(þ) m/z: 714 [MHþ]; Anal.
Calcd for C49H47NO4: C, 82.44; H, 6.64, N, 1.96. Found: C,
82.62; H, 6.70 N, 1.90.
4.1.1. 5-Bromo-25,27-dipropoxycalix[4]arene (5). To a
solution of 4 (2.0 g, 3.9 mmol) in methyl ethyl ketone
(200 mL), NBS was added (0.6 g, 3.5 mmol). After stirring
at rt for 4 h, the solution was diluted with CH2Cl2 (100 mL)
and then treated with a saturated aqueous solution of
Na2SO3 (100 mL). The organic layer was separated, washed
with brine (2£100 mL), dried (Na2SO4), and the solvent was
completely evaporated under reduce pressure. Purification
of the residue by chromatography (hexane/CH2Cl2, 60:40)
gave 0.9 g (45%) of 5 as a pale yellow solid: mp 180–1818C
(dec.). 1H NMR (300 MHz) d: 1.31 (t, 6H, J¼7.4 Hz); 2.0–
2.1 (m, 4H); 3.32, 3.38 (2d, 4H, J¼13 Hz); 3.97 (t, 4H,
J¼6 Hz); 4.28, 4.31 (2d, 4H, J¼13 Hz); 6.66 (t, 1H,
J¼7.5 Hz); 6.76 (t, 2H, J¼7.5 Hz); 6.8–6.9 (m, 4H); 7.12
(d, 2H, J¼7.5 Hz); 7.17 (s, 2H); 8.4 and 8.2 (2s, 2H). 13C
NMR (75 MHz) d: 10.8, 23.4, 29.6, 31.1, 31.3, 78.4, 110.2,
118.9, 125.3, 127.9, 128.4, 129.2, 130.1, 130.6, 132.5,
133.5, 151.8, 152.5, 153.2. MS-CI(þ) m/z: 587 [MHþ];
Anal. Calcd for C34H35BrO4: C, 69.50; H, 6.00. Found: C,
69.32; H, 6.05.
4.1.4. 5-Aminomethyl-26,28-dibenzyloxy-25,27-diprop-
oxycalix[4]arene (8). To
a solution of 7 (0.6 g,
0.84 mmol) in dry THF (30 mL), B2H6 (1 M solution in
THF, 8.4 mL) was added. The resulting mixture was
refluxed for 24 h under argon atmosphere, cooled, treated
with methanol (20 mL, CAUTION!), and then refluxed for
an additional 30 min. The solvent was then completely
evaporated under reduced pressure and the residue taken up
with CH2Cl2 (50 mL) and a saturated solution of Na2CO3
(50 mL). The organic layer was separated, washed with
brine (2£100 mL), dried (Na2SO4), and the solvent was
completely evaporated. Purification of the solid residue by
chromatography (CH2Cl2/CH3OH, 95:5) gave 0.33 g (55%)
of 8 as a white solid: mp 200–2018C (dec.). 1H NMR
(300 MHz) d: 0.65 (t, 6H, J¼7.4 Hz); 1.33 (bs, 2H); 1.7–1.8
(m, 4H); 3.14, 3.15 (2d, 4H, J¼13.3 Hz); 3.30 (s, 2H); 3.8–
3.9 (m, 4H); 4.47, 4.48 (2d, 4H, J¼13.2 Hz); 4.82 (s, 4H);
6.20 (s, 2H); 6.36 (bs, 3H); 6.88 (t, 2H, J¼7.5 Hz); 7.0 (d,
4H, J¼7.5 Hz); 7.3–7.5 (2m, 10H). 13C NMR (75 MHz) d:
9.5, 22.8, 31.0, 31.1, 45.8, 76.5, 77.4, 121.9, 126.4, 127.6,
127.8, 127.83, 128.1, 128.6, 128.7, 128.9, 129.0, 134.0,
136.3, 137.6, 137.8, 153.4, 154.9, 157.5. MS-CI(þ) m/z:
717 [MHþ]; Anal. Calcd for C49H51NO4: C, 81.98; H, 7.16,
N, 1.95. Found: C, 82.12; H, 7.20; N, 1.90.
4.1.2. 5-Cyano-25,27-dipropoxycalix[4]arene (6). To a
solution of 5 (2.0 g, 3.4 mmol) in DMF (100 mL), CuCN
(0.90 g, 10.2 mmol) was added. The resulting hetero-
geneous mixture was poured into a thick wall glass
autoclave and then heated at 2008C for 48 h under vigorous
stirring. After cooling, the solvent was completely evapor-
ated under reduced pressure. The resulting sticky residue
was extracted twice with hot ethyl acetate (2£50 mL). The
combined organic phases were then washed twice with brine
(2£100 mL), dried (Na2SO4), and the solvent was com-
pletely evaporated to dryness (the separated water phase
was carefully treated with a solution of sodium hypochlorite
to destroy the residuals cyanide ions). Purification of the
solid residue by chromatography (hexane/CH2Cl2, 50:50)
afforded 1.8 g (90%) of 6 as a white solid: mp 200–2018C
(dec.). 1H NMR (300 MHz) d: 1.31 (t, 6H, J¼7.4 Hz); 2.0–
2.1 (m, 4H); 3.37, 3.39 (2d, 4H, J¼13.1 Hz); 3.9–4.0 (m,
4H); 4.28, 4.30 (2d, 4H, J¼13 Hz); 6.6–6.7, 6.7–6.8, 6.9–
7.0, 7.0–7.1, (4m, 9H); 7.37 (s, 2H); 8.19 and 9.19 (2s, 2H).
13C NMR (75 MHz) d: 10.8, 23.4, 31.1, 31.3, 78.4, 118.9,
119.0, 125.4, 127.7, 128.3, 128.4, 128.7, 128.8, 129.2,
129.5, 131.8, 132.4, 133.6, 151.7, 153.2. MS-CI(þ) m/z:
534 [MHþ]; Anal. Calcd for C35H35NO4: C, 78.77; H, 6.61;
N, 2.62. Found: C, 78.99; H, 6.67; N, 2.53.
4.1.5. 5-(N-Phenylureido)methyl-26,28-dibenzyloxy-
25,27-dipropoxycalix[4]arene (9). To a solution of 8
(0.3 g, 0.42 mmol) in dry CH2Cl2 (25 mL), phenyl iso-
cyanate (0.05 g, 0.42 mmol) was added. After 3 h under
stirring, the mixture was poured into water (50 mL) and
diluted with CH2Cl2 (50 mL). The organic layer was
separated, washed with water (2£100 mL), dried
(Na2SO4), and the solvent was completely evaporated.
Crystallization with diethyl ether afforded 0.27 g (90%) of 9
as pure white solid: mp 116–1188C. 1H NMR (300 MHz) d:
0.62 (t, 6H, J¼7.4 Hz); 1.6–1.7 (m, 4H); 3.07, 3.11 (2d, 4H,
J¼13 Hz); 3.7–3.8 (m, 4H); 3.89 (d, 2H, J¼5.3 Hz); 4.31
(bt var, 1H); 4.40 and 4.43 (2d, 4H, J¼13.2 Hz); 4.78, 4.79
(2s, 4H); 6.03 (bs var, 1H); 6.16 (s, 2H); 6.2–6.3 (m, 3H);
6.78 (t, 2H, J¼7.4 Hz); 6.9–7.0 (m, 4H); 7.0–7.1, 7.2–7.3
(2m, 5H); 7.3–7.5 (m, 10H). 13C NMR (75 MHz) d: 10.3,
22.8, 29.5, 31.1, 32.7, 42.4, 44.1, 75.5, 120.3, 121.3, 121.96,
122.65, 124.7, 126.94, 127.3, 127.86, 128.8, 129.0, 129.4,
129.98, 131.8, 134.2, 136.2, 137.6, 154.4, 155.3, 157.4. MS-
4.1.3. 5-Cyano-26,28-dibenzyloxy-25,27-dipropoxy-
calix[4]arene (7). To a solution of 6 (0.80 g, 1.5 mmol) in
DMF (60 mL), NaH (0.22 g, 9.2 mmol) was added. The
resulting heterogeneous mixture was stirred for 30 min, then
benzyl bromide (0.65 g, 3.8 mmol) was added. The mixture
was heated at 658C for 3 h, cooled and diluted with ethyl

A. Arduini et al. / Tetrahedron 59 (2003) 7587–7594
7593
CI(þ) m/z: 836 [MHþ]; Anal. Calcd for C56H56N2O5: C,
dell’Istruzione, dell’Universita e della Ricerca (MIUR)
‘calixarene glycoconjugate’ project. We are grateful to CIM
(Centro Interdipartimentale di Misure) ‘G. Casnati’ of the
University of Parma for NMR and Mass measurements.
`
80.35; H, 6.74, N, 3.35. Found: C, 80.51; H, 6.84; N, 3.28.
4.1.6. 5-(N-Phenylureido)methyl-25,27-dipropoxy-
calix[4]arene (10). To a solution of 9 (0.27 g, 0.32 mmol)
in dry CH2Cl2 (15 mL) and MeOH (5 mL) solvents mixture,
a spatula tip of Pd/C catalyst was added (CAUTION!). The
resulting dark mixture was stirred for 24 h under atmos-
pheric hydrogen pressure, then the palladium catalyst was
filtered off, under nitrogen atmosphere, through a short pad
of celite. The filtered solution was evaporated to dryness and
the resulting solid residue was triturated with hot cyclo-
hexane to afford 0.16 g (60%) of 10 as white solid: mp 152–
154 8C. 1H NMR (300 MHz) d: 1.31 (t, 6H, J¼7.5 Hz); 2.0–
2.2 (m, 4H); 3.35, 3.37 (2d, 4H, J¼13 Hz); 3.97 (t, 4H,
J¼6.3 Hz); 4.09 (d, 2H, J¼5.3 Hz); 4.30, 4.32 (2d, 4H,
J¼12.9 Hz); 5.13 (bt var, 1H); 6.48 (bs var, 1H); 6.6–6.7
(m, 3H); 6.8–6.9 (m, 6H); 6.96 (s, 2H); 7.1–7.2 (m, 5H);
8.30 and 8.36 (2s, 2H). 13C NMR (75 MHz) d: 10.8, 23.4,
31.3, 78.3, 121.0, 127.9, 128.3, 128.9, 129.1. MS-CI(þ)
m/z: 656 [MHþ]; Anal. Calcd for C42H44N2O5: C, 76.80; H,
6.75, N, 4.26. Found: C, 77.07; H, 6.82; N, 4.20.
References
1. Gutsche, C. D. Calixarenes Revisited-Monographs in Supra-
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2. Calixarenes in Action; Mandolini, L., Ungaro, R., Eds.;
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¨
3. Calixarenes 2001; Asfari, Z., Bohmer, V., Harrowfield, J.,
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7. Arduini, A.; Giorgi, G.; Pochini, A.; Secchi, A.; Ugozzoli, F.
Tetrahedron 2001, 57, 2411–2417.
`
8. Arena, G.; Contino, A.; Magrı, A.; Sciotto, D.; Arduini, A.;
To a solution of 4 (1.0 g, 1.97 mmol) and anhydrous AlCl3
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xymethyl-N0-phenylurea (0.33 g, 1.97 mmol) in CH2Cl2
(20 mL) was added dropwise. After stirring at room
temperature for 3 h, the reaction was quenched with a
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diluted with CH2Cl2 (50 mL), separated, washed with water
(2£100 mL) up to neutrality, dried (Na2SO4), and com-
pletely evaporated. Purification of the solid residue by
chromatography (hexane/CH2Cl2, 5:5) gave 0.38 g (30%) of
10.
Pochini, A.; Secchi, A. Supramol. Chem. 2001, 13, 379–386.
9. For a recent article on CH/p interactions see e.g. Takahashi,
O.; Khono, Y.; Iwasaki, S.; Ko, S.; Iwaoka, M.; Tomoda, S.;
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12. See, e.g. Desiraju, G. R.; Steiner, T. The Weak Hydrogen
Bond, IUCr Monographs on Crystallography; Oxford Science:
Oxford, 1999; Vol. 9. and references therein.
13. For a recent paper on directionality of NH/p interaction see:
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4.2.1. 17,23-Bis-(N-phenylureido)methyl-25,26-didroxy-
27,28-mono(crown-4)-calix[4]arene (12). As reported for
the direct synthesis of 10 using the following reagents and
quantities: 11 (0.5 g, 0.9 mmol), AlCl3 (0.5 g, 3.7 mmol),
and N-hydroxymethyl-N0-phenylurea (0.31 g, 1.86 mmol)
in dry CH2Cl2 (70 mL). Purification of the residue by
crystallization from a CH2Cl2/ethyl acetate mixture gave
0.43 g (55%) of 12 as white solid: mp 241–2428C. 1H NMR
(300 MHz, DMSO-d6) d: 3.35 (bs, 1H); 3.45 (d, 3H,
J¼12.9 Hz); 3.7–3.8 (m, 3H); 3.9–4.2 (m, 20H); 4.65 (d,
1H, J¼12.3 Hz); 6.2–6.3 (m, 2H); 6.79 (t, 2H, J¼7.5); 6.88
(t, 2H, J¼7.5); 7.0–7.1 (m, 6H); 7.20 (t, 4H, J¼7.8); 7.28
(d, 2H, J¼7.5); 7.36 (d, 4H, J¼7.8); 8.25 (s, 2H); 8.54 (s,
2H). 13C NMR (75 MHz, DMSO-dd) d: 28.48, 30.62, 30.93,
42.57, 68.88, 70.39, 75.39, 117.57, 120.95, 124.57, 127.59,
128.05, 128.55, 128.74, 128.91, 129.30, 131.75, 133.99,
135.25, 140.35, 149.79, 153.40, 154.92. MS-CI(þ) m/z: 835
[MHþ]; Anal. Calcd for C50H50N4O8: C, 71.92; H, 6.04, N,
6.71. Found: C, 71.63; H, 6.14; N, 6.60.
14. To the best of our knowledge, the role played by rigidity of
calixarene receptors on their complexation efficiencies in
apolar solvents has never been systematically studied. Only a
few studies have been reported so far in the literature in which
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18. The presence of the two additional binding sites in 12, which
in principle, could cooperatively act as hydrogen bond donor,
does not substantially enhance the receptor efficiency and
experiences binding properties that parallel those of 10 (K,
M21: 28^2 for HCONH2; 49^7 for HCONHCH3; 90^15 for
CH3CONH2; 170^60 for CH3CONHCH3). A tentative
explanation of such behavior could derive from the possibility
of the two ureido sidearms to mutually interact, hence
decreasing their ability to cooperatively act as H-bond donor
groups.
Acknowledgements
This work was partly supported by Ministero

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