Bidentate urea derivatives of p-tert-butyldihomooxacalix[4]arene: Neutral receptors for anion complexation

Article abstract of DOI:10.1021/jo4026012

Three new bidentate ureidodihomooxacalix[4]- arene derivatives (phenyl 5a, n-propyl 5b, and tert-butyl 5c) were synthesized in four steps from the parent compound ptert- butyldihomooxacalix[4]arene and obtained in the cone conformation, as shown by NMR st

Full text of DOI:10.1021/jo4026012

Article
pubs.acs.org/joc
Bidentate Urea Derivatives of p‑tert-Butyldihomooxacalix[4]arene:
Neutral Receptors for Anion Complexation
Paula M. Marcos,*,†,‡ Filipa A. Teixeira,† Manuel A. P. Segurado,†,‡ Jose R. Ascenso,§ Raul J. Bernardino,∥
́
Sylvia Michel,⊥,# and Veronique Hubscher-Bruder⊥,#
́
†Centro de Cien
Portugal
‡Faculdade de Farmac
§Instituto Superior Tec
∥Laboratory of Separation and Reaction Engineering, ESTM, Instituto Politec
Apartado 126, 2524-909 Peniche, Portugal
̂ ̂
cias Moleculares e Materiais, Faculdade de Ciencias da Universidade de Lisboa, Edifício C8, 1749-016 Lisboa,
́
ia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
nico, Complexo I, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
́ ́
nico de Leiria, Santuario Na. Sra. dos Remedios,
́
́
⊥Universite
́
de Strasbourg, IPHC, 25 rue Becquerel 67087 Strasbourg, France
#CNRS, UMR7178, 67037 Strasbourg, France
S
* Supporting Information
ABSTRACT: Three new bidentate ureidodihomooxacalix[4]-
arene derivatives (phenyl 5a, n-propyl 5b, and tert-butyl 5c)
were synthesized in four steps from the parent compound p-
tert-butyldihomooxacalix[4]arene and obtained in the cone
conformation, as shown by NMR studies. The binding ability
of these neutral receptors toward spherical, linear, trigonal
planar, and tetrahedrical anions was assessed by 1H NMR and
UV−vis titrations. The structures and complexation energies
of some complexes were also studied by DFT methods. The
data showed that the association constants are strongly
dependent on the nature of the substituent (aryl/alkyl) at
the urea moiety. In general, for all the receptors, the
association constants decrease with decrease of anion basicity. Ph-urea 5a is the best anion receptor, showing the strongest
complexation for F− (log Kassoc = 3.10 in CDCl3) and also high binding affinity for the carboxylates AcO− and BzO−. Similar
results were obtained by UV−vis studies and were also corroborated by DFT calculations.
receptors. These groups provide effective and directional
hydrogen bonds. Over the last 15 years, calix[4]arene scaffolds,
incorporating one or more urea and thiourea moieties at the
lower7−11 or upper rim,12−14 have been the most studied for
anion recognition. Ureidocalix[5]arene15 and calix[6]arene16,17
derivatives have also been tested as anion receptors.
Following our previous studies on the cation binding
properties of dihomooxacalix[4]arenes (calix[4]arene analogues
in which one CH2 bridge is replaced by one CH2OCH2
group),18 we have recently extended our research into the
study of anion complexation. Dihomooxacalix[4]arenes have
cavity sizes slightly larger than those of calix[4]arenes; they are
therefore more flexible, but possess a cone conformation, being
potential hosts for larger anions. This paper reports the
synthesis, the NMR conformational analysis, and the complex-
ation properties of three new bidentate urea derivatives of p-
tert-butyldihomooxacalix[4]arene toward a large variety of
anions (spherical, linear, trigonal planar, and tetrahedrical).
INTRODUCTION
■
Calixarene-based molecules, in particular lower rim derivatives,
have been widely used in the last three decades as metal cation
binders.1a−c Conversely, the binding of anions by these
macrocycles has received less attention in the past. Selective
complexation of anions is more demanding than that of cations,
mainly because of some unique properties of anions that need
to be taken into account in the design of the receptors.
Compared to cations, anions are larger and therefore have a
lower charge to radius ratio. Consequently, they show less
effective electrostatic interactions. They present a wide range of
geometries and pH dependence, and they are more affected by
solvation. However, more recently, the study of anion receptors
based on calixarenes, as well as on other macrocycle
compounds, has gained a growing interest due to the important
role displayed by anions in biology, medicine, and environ-
mental areas.2−6
To add hydrogen bond donor groups to organic hosts has
been an important task for obtaining recognition for specific
anions. Thus, urea and thiourea binding groups have been
widely incorporated in the calixarene scaffold to produce anion
Received: November 27, 2013
© XXXX American Chemical Society
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Scheme 1. Synthetic Route for the Preparation of Bidentate Urea Derivatives 5a−c
These properties have been assessed by proton NMR and UV
absorption spectrophotometric studies. The structures and
complexation energies for some urea-anion systems were also
investigated by theoretical studies using DFT methods. The
results are compared to those obtained with closely related
calix[4]arene derivatives and discussed in terms of the nature of
the substituent (aryl/alkyl) at the urea moiety.
compounds, the cone conformation and the substitution
patterns were further confirmed by proton−proton correlations
observed in the NOESY spectra. As previously described by us
for the formation of other disubstituted dihomooxacalix[4]-
arenes,21 the preferential formation of the 1,3-disubstituted
derivative is expected. This type of substitution (Scheme 1) was
confirmed for the asymmetric compound 2 (Figure 1) through
RESULTS AND DISCUSSION
■
Synthesis and NMR Conformational Analysis. Follow-
ing our recent interest in anion binding by homooxacalixarenes
modified with substituted urea groups at the lower rim, and to
overcome the difficulties found to obtain the tetra-
[(cyanopropyl)oxy] derivatives (precursors to urea-terminated
compounds) in the cone conformation,19 we decided to try the
synthesis of bidentate urea derivatives. Thus, the parent
compound p-tert-butyldihomooxacalix[4]arene (1) was treated
with 2 equiv of 4-bromobutyronitrile and K2CO3 in refluxing
acetonitrile for 6 days (Scheme 1). This reaction afforded a
mixture composed of two disubstituted compounds. Separation
by flash chromatography gave the 1,3-dicyanodihydroxy
derivative 2 as the main product, along with a small amount
of the 3,4-dicyanodihydroxy derivative 2a.
1
The H NMR spectrum of 2 displays four singlets for the
Figure 1. Section of the NOESY spectrum of 1,3-dicyanodihydroxy
derivative 2.
tert-butyl groups, five AB quartets for the CH2 bridge protons,
four pairs of doublets for the aromatic protons, two singlets for
the OH groups, and several multiplets for the
−OCH2CH2CH2CN methylene protons. The 13C NMR
spectrum shows three ArCH2Ar resonances at 29.3, 30.0, and
32.7 ppm, indicating a cone conformation for this derivative.20
Compound 2a exhibits symmetric NMR spectra. The 1H NMR
spectrum shows two singlets for the tert-butyl groups, three AB
quartets in a 2:2:1 ratio for the CH2 bridge protons, five
multiplets for the −OCH2CH2CH2CN groups, two pairs of
doublets for the aromatic protons, and one singlet for the OH
groups. The 13C NMR spectrum displays two ArCH2Ar
resonances at δ 30.7 (one carbon atom) and δ 31.6 (two
carbon atoms), indicating a cone conformation. For both
the simultaneous observation of two NOE effects between the
OH proton at 7.12 ppm (position 30) and two axial methylene
protons at 4.42 and 4.69 ppm (positions 10 and 4,
respectively). In the case of the symmetric compound 2a
(Figure S1, Supporting Information), the 3,4-disubstituted
pattern (Scheme 1) was confirmed by two simultaneous NOE
effects observed between the OH proton (position 27) and two
axial methylene protons at 4.20 and 4.67 ppm (positions 22 and
2, respectively), as well as between the (cyanopropyl)oxy
protons (position 28) and the two axial methylene protons at
4.20 and 4.45 ppm (positions 22 and 16, respectively).
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Derivative 2 was further alkylated with n-butyl iodide and
NaH in THF/DMF, yielding dicyanodibutoxy derivative 3 in
the cone (major product) and partial cone A (Scheme 2)
7.03 ppm (position 20) and those methylene protons at 0.73
ppm (Figure S2, Supporting Information).
Reduction of the cyano groups of the cone derivative 3 with
borohydride and cobalt chloride in methanol gave the diamine
4, which reacted with aryl or alkyl isocyanate in chloroform to
give the corresponding diaryl or dialkylurea derivatives (phenyl
5a, n-propyl 5b, and tert-butyl 5c) in the cone conformation.
These compounds have no symmetry. They are inherently
chiral, as indicated by their NMR spectra. All the ureido
derivatives show clear and sharp proton NMR spectra in CDCl3
at room temperature and independent of the concentration,
indicating absence of self-aggregation.13,14 Parts a−c of Figure 2
show a section of those spectra with the two NHa and the two
NHb protons of the ureido groups at the expected chemical
shifts. When a more polar solvent like DMF was used, the NH
signals remained sharp but shifted downfield, in agreement with
the formation of intermolecular hydrogen bonds between the
ureido groups and the solvent (see, for example, n-Pr-urea 5b,
Figure 2d).
Scheme 2. Dicyanodibutoxy Derivative 3 in the Partial Cone
A Conformation
conformations. After separation of the two conformers, the 13C
NMR spectra displayed three ArCH2Ar resonances around 30
ppm for the cone conformer and three ArCH2Ar resonances,
one around 39 ppm and the other two at 30 ppm, for the partial
1
Anion-Binding Studies. H NMR Studies. The binding
affinity of bidentate ureas 5a, 5b, and 5c toward anions of
spherical (F−, Cl−, Br−, I−), trigonal planar (NO3 , AcO−,
−
cone A conformer.22 The H NMR spectrum of the latter
1
BzO−), linear (CN−, SCN−), and tetrahedral (HSO4 , H2PO4 ,
−
−
conformer displays an upfield multiplet (δ 0.73 ppm)
corresponding to four methylene protons of an inverted
group.19 According to the COSY spectrum, these protons have
no correlations with the methyl protons at 0.96 ppm, which
indicates that they belong to a (cyanopropyl)oxy group and not
to a (butyl)oxy group. Moreover, the identification of the
inverted group was further corroborated by proton−proton
correlations observed in a NOESY spectrum, mainly by the
NOE enhancement observed between the aromatic proton at
−
1
ClO4 ) geometries was investigated in CDCl3 by H NMR
titrations using tetrabutylammonium salts. The association
constants, reported in Table 1, were determined following the
urea NH chemical shift and using the WinEQNMR2
program.23 In a few cases where those protons became broad
or even completely disappeared, the binding constants were
determined from the complexation induced shifts of the
aromatic protons of the calixarene framework. The titration
1
Figure 2. Partial H NMR spectra (500 MHz, CDCl3, 22 °C) of (a) Ph-urea-5a, (b) n-Pr-urea 5b, (c) t-Bu-urea 5c, (d) n-Pr-urea 5b in DMF-d7.
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a
1
Table 1. Association Constants (log Kassoc) of Dihomooxa Bidentate Ureas 5a−c in CDCl3 at 25 °C Determined by H NMR
Experiments
spherical
linear
trigonal planar
AcO−
tetrahedral
F−
Cl−
Br−
I−
CN−
SCN−
NO3
BzO−
HSO4
H2PO4
ClO4
−
−
−
−
b
i. radius (Å)
1.33
3.10
1.65
1.38
1.81
2.73
1.57
1.21
1.96
2.23
1.35
1.02
2.20
1.59
1.34
1.18
1.91
2.71
1.61
1.28
2.13
1.90
1.46
1.20
1.79
2.42
1.54
1.00
2.32
2.88
1.59
0.90
1.90
2.58
1.40
1.05
2.00
2.69
1.21
1.17
2.40
1.65
1.56
1.13
Ph-urea 5a
n-Pr-urea 5b
t-Bu-urea 5c
2.93
1.65
0.89
a
b
Estimated error <10%. Data quoted in Marcus, I. Ion Properties; Marcel Dekker: New York, 1997; pp 50−51.
profiles obtained in all cases (see for example Figure 3) clearly
indicate the formation of 1:1 receptor−anion complexes, being
this stoichiometry also confirmed by Job plots (see as an
example the Job curve for 5a + Br−, Figure 4).
protons, clearly indicating hydrogen-bonding interactions. In all
cases, a fast exchange rate between the complexed and the free
host was observed on the NMR time scale at room
temperature. With very few exceptions, the association
constants of 5a−c with the anions decrease in the order of
the anion basicity in CHCl3 (Table 2). Although no pKa values
Table 2. Anion Basicity in CHCl3 and MeCN
geometry
spherical
anion basicity (CHCl3/MeCN)
F− > Cl− > Br− > I−
CN− > SCN−
linear
AcO− > BzO− > NO3
−
trigonal planar
tetrahedral
−
−
−
H2PO4 > HSO4 > ClO4
were found in this solvent, it is known that pKa values follow
the same trends in similar solvents.24 Thus, it is completely
justifiable to assume the same pKa order in CHCl3 as was
reported in 1,2-dichloroethane.
Figure 3. Titration curves of Ph-urea 5a with TBA salts in CDCl3.
A systematic observation of the data in Table 1 and Figure 3
reveals that in the case of the halogen anions (spherical
geometry) the addition of 2 equiv of TBA iodide to Ph-urea 5a
causes a small downfield shift for the urea NHb1 proton (0.12
ppm), which increases for Br− (0.44 ppm) and even more for
Cl− (0.83 ppm). In the case of F− a large downfield shift of 1.82
ppm can be observed, as well as another of 1.52 ppm for NHa1
proton. Small downfield shifts for the ortho protons and small
upfield shifts for the meta and para protons of the phenyl urea
groups are also observed, as mentioned before for other
analogue receptors,7,10,25 and corroborate the expected effects
for the formation of hydrogen-bonding complexes. These
effects are the result of both the increase of electron density on
the phenyl rings (through-bond) causing a shielding effect, and
the polarization of the C−H bonds (through-space) causing a
deshielding effect.5 5a displays a log Kassoc of 3.10 for F−, the
highest value obtained with these dihomooxa urea receptors. It
Figure 4. Job plot based on 1H NMR data for Ph-urea 5a + Br−; total
concentration 5 × 10−3 M in CDCl3.
−
shows some selectivity over Cl− and Br− (SF /X− = 2.3 and 7.4,
respectively). The same trend is observed for urea derivatives
5b and 5c (Kassoc decreases with decreasing of anion basicity),
except for t-Bu-urea 5c with I−, which displays a slightly higher
Kassoc than that with Br−.
The data show that the association constants for anion
binding with the receptors 5a, 5b, and 5c strongly depend on
the nature of the substituted (aryl/alkyl) at the urea moiety. In
general, arylureas are stronger anion receptors than alkylureas
because of the higher acidity of their ureido NHs.3 Ph-urea
derivative 5a is the best anion receptor, displaying moderate to
reasonably high binding ability. n-Pr-urea 5b and t-Bu-urea 5c
are weak receptors, with 5b being slightly better than 5c. The
higher flexibility and the less bulky shape of the R group in the
former receptor may lead to a conformational arrangement
more favorable to the NH hydrogen bond donation. However,
the three receptors show the same trend in the anion-binding
affinities. The addition of anions to the receptors (5a−c)
caused more or less significant downfield shifts of the NH
Our results with F− showed no evidence for the formation of
the HF2− species, either generated in situ due to trace amounts
of water26 or by deprotonation of the receptor.10,27,28 Thus, no
sigmoidal shape can be observed in the titration curve shown in
Figure 3, and the chemical shifts of the relevant protons
followed the expected variations for the formation of an H-
bond complex, namely the ortho protons of the urea phenyl
rings, as mentioned before. These protons experienced small
downfield shifts during all the titration (Δδ = 0.10 ppm with 10
equiv of F−). On the other hand, the acidity of Ph-urea 5a is
lower when compared to receptors containing electron-
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withdrawing groups, such as NO2.28 In addition, solvent
polarity plays an important role in stabilizing the H-bond
complexes. The higher the polarity of the solvent (DMSO >
MeCN > CHCl3), the lower the stability of the H-bond
complex. It was reported that in the poorly polar CH2Cl2, the
1,3-bis(4-nitrophenyl)urea gave only the H-bond complex with
F−.28 In addition, deprotonation was never reported in
CHCl3.25
In the presence of the pseudohalides CN− and SCN− (linear
geometry) a similar behavior was observed for all the receptors,
which followed the same trend observed for the halogens. The
more basic anion CN− was better complexed, mainly with Ph-
urea 5a, that exhibited a log Kassoc of 2.71 and selectivity over
SCN− of 6.5.
Concerning the trigonal planar oxoanions, Ph-urea 5a
showed a high binding affinity toward the carboxylates BzO−
and AcO− (log Kassoc of 2.93 and 2.88, respectively). In contrast
to the previous situations, the trend observed with these
oxoanions was slightly different. Receptors 5a and 5b displayed
association constants that slightly increased from AcO− to
Figure 5. Changes in the UV spectra of 5a upon addition of acetate
(CL = 1.95 × 10−4 M; 0 ≤ R = CA/CL ≤ 2) in MeCN. The arrow
indicates the increasing amounts of acetate.
BzO− and then decreased from BzO− to NO3 (as expected).
−
a
This slight inversion of the expected order for AcO− and BzO−
according to their basicities is within the experimental error,
and has no meaning if we compare the differences between the
pKa of the corresponding acids in CHCl3 [ΔpKa (AcOH →
BzOH) = 1.7 and ΔpKa (BzOH → HNO3) = 12.6].29 This
means that AcO− is a base only 50 times stronger than BzO−,
while NO3− is a base almost 4 × 1012 times weaker than BzO−!
However, as that inversion was not maintained in the UV
studies (discussed below), a possible explanation may lie in a
specific solvation mode of the urea−benzoate complexes in
chloroform. t-Bu-urea 5c is the weakest receptor, displaying a
Table 3. Association Constants (log Kassoc) of Ph-urea 5a in
MeCN at 25 °C Determined by UV−vis Experiments
−
X:L
F−
AcO−
BzO−
H2PO4
Ph-urea 5a
1:1
2:1
4.6
4.6
4.5
4.3
4.2
4.4
4.2
4.0
a
Values are the average of at least two experiments; estimated error
<10%.
can influence the stoichiometry of the species formed and also
their association constants. The more diluted solutions used in
UV studies favor the dissociation of the salts, providing a higher
concentration of the anions available for complexation, and
consequently the association constants become higher. Similar
situations were reported before with other receptors.14,15,25
However, these UV results follow the same trend observed in
the NMR studies discussed above. No positive cooperative
effect is observed, as the association constants are lower for the
second complexation step than for the 1:1 complexes (except in
the case of BzO−).
DFT Studies. The binding affinity of Ph-urea 5a was also
studied by DFT methods to give more insight into the
structures and electronic properties of the complexes.
All the structures (receptor and complexes) were fully
optimized without symmetry constraints using the Becke three-
parameter hybrid functional combined with the Lee, Yang, and
Parr correlation functional (B3LYP).30 Although the compar-
ison between gas-phase and condensed-phase structures is not
direct, all the structures were geometry optimized solvent free.
They are therefore expected to correlate primarily with gas state
complex geometries and not necessarily with NMR data, in
which the solvent will influence the anion−receptor inter-
actions and the relative complexation energies. However, they
can give some insight into the key differences between the
complexes under investigation.
−
slightly higher log Kassoc value for the smaller anion NO3 .This
may be due to steric hindrance caused by the t-Bu groups.
Finally, concerning the tetrahedral oxoanions, Ph-urea 5a
followed the anion basicity order and exhibited much higher
−
binding affinities toward H2PO4− and HSO4− than to ClO4 . In
the case of n-Pr-urea 5b the basicity order is inverted. The less
basic and largest anion ClO4− is slightly better complexed than
the others. This may be due to a suitable size complementarity
of 5b and the anion. Size-dependent binding has already been
described, mainly for the spherical halides.12 Furthermore, n-Pr-
urea should have enough flexibility to allow a good binding
environment in terms of size matching. t-Bu-urea 5c showed
again the lowest log Kassoc values, but following the basicity
order.
UV−vis Studies. The interactions between Ph-urea 5a and
−
some anions of different geometries (F−, Cl−, SCN−, NO3 ,
−
−
AcO−, BzO−, HSO4 , and H2PO4 ) as TBA salts have also
been studied by UV−vis absorption spectrophotometry in
MeCN.
Significant spectral changes were observed for 5a in the
presence of F−, AcO−, BzO−, and H2PO4 , as shown in Figure
−
5 for AcO− as an example. Very small or no spectral changes
occurred for all other systems, which could not be interpreted.
As revealed by the association constant data (Table 3), Ph-urea
5a displayed the strongest complexation for F− (log Kas−soc
=
The interactions of 5a with some anions of each geometry
4.6), closely followed by AcO−, BzO−, and H2PO4 in
agreement with the basicity order in MeCN. Compound 5a
forms 1:1 and also 2:1 complexes with all the anions and
presents higher association constants than by NMR. It should
be noted that in UV titration experiments the concentrations
are much lower than those used in NMR, and this difference
group (F−, Cl−, SCN−,CN−, AcO−, BzO−, HSO4 , and
−
−
H2PO4 ) were studied, and their minimum energy structures
were initially determined with the B3LYP/3-21G basis set.
After this minimization, single-point energy calculations were
then carried out at the B3LYP/6-31G(d,p) level, to add
polarization functions for hydrogen atoms and diffuse functions
E
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for both hydrogen and non-hydrogen atoms, to obtain a more
accurate description of the hydrogen-bonding interactions
involved in the complexation of the anions.31
The energies obtained for all the anion−receptor 1:1
complexes, either by optimization or single point, are presented
in Table 4. All of the complexation energies calculated were
negative electrostatic potential, while the blue ones correspond
to higher or more positive electrostatic potential. Three
structures are presented here: the receptor, the most stable
complex (5a-F−), and the least stable complex (5a-SCN−). In
all of the structures the oxomethylene bridge is a zone with
negative electrostatic potential as well as the oxygen atom of
the urea fragment. The presence of the anion pulls the lower
limit of the electrostatic potential further down when compared
to the free receptor. Also visible are the hydrogen bonds
between the more electronegative atoms of the anions and the
hydrogens of the NH ureido moiety. Overall, these structural
representations give insights to the electrostatic rearrangement
caused by the introduction of the anion molecules. Although
the electrostatic potentials of the complexes are similar (Figure
7, b and c), the potential energy associated with each anion is
very different, as represented by the color distribution observed.
Table 4. Total Energies E (au) and Complexation Energies
a
ΔEc (kcal mol−1) for the Systems Studied. Optimization at
B3LYP/3-21G and Single-Point at B3LYP/6-31G(d,p)
Levels
B3LYP/3-21G
B3LYP/6-31G(d,p)
a
a
E
ΔEc
E
ΔEc
5a
−3645.10924
−3744.53902
−4103.25415
−3872.46085
−4063.14083
−4341.12293
−4285.30927
−3737.51271
−4133.79539
−3665.19423
−3765.14991
−4125.53025
−3893.79082
−4085.53032
−4364.91281
−4308.83746
−3758.11448
−4156.35055
5a·F−
−175.30
−55.11
−86.72
−67.23
−69.84
−71.69
−69.88
−40.39
−126.50
−52.57
−62.56
−49.03
−41.14
−45.95
−60.07
−35.75
5a·Cl−
5a·AcO−
5a·BzO−
5a·HSO4
5a·H2PO4
5a·CN−
5a·SCN−
CONCLUSIONS
■
A new family of anion receptors based on dihomooxacalix[4]-
arenes containing two urea moieties at the lower rim via a four
carbon atom spacer, has been described. Three bidentate ureido
derivatives (phenyl 5a, n-propyl 5b, and tert-butyl 5c) were
obtained in the cone conformation and complexed anions in a
−
−
a
ΔEc corresponds to the process 5a + X− → [5a-X−], where X−
1
1:1 stoichiometry through hydrogen bonding, as shown by H
represents each one of the anions.
NMR studies. The data revealed that the substituents (Ph, n-Pr,
and t-Bu) on the urea moiety strongly influence the binding
1
negative, meaning that the complexes were thermodynamically
favorable. The relative complexation energies were, however,
very different. In general, it can be observed that independently
of the basis set used (3-21G or 6-31G(d,p)), the stability of the
complexes decrease with decreasing of anion basicity. The most
stable complex was obtained with F− with a complexation
energy double of the following one (5a-AcO−). Moreover, the
difference in energy between the two spherical anions F− and
Cl− is much higher than the difference in energy between the
two trigonal planar oxoanions AcO− and BzO− (ΔEc = 73.93
and 13.53 kcal mol−1, respectively). This is in complete
agreement with the strength of these bases in CHCl3 [ΔpKa
(HF → HCl) = 15.5 and ΔpKa (AcOH → BzOH) = 1.7].29
Figure 6 shows the optimized structures for Ph-urea 5a and
the eight complexes studied. It can be observed that the free
receptor presents a distorted cone conformation, which
becomes more symmetric upon the anion complexation,
being this more noticeable in the case of F−. It is also clear
from Figure 6 (b and c) that for the spherical F− and Cl− a cage
structure was formed with all four NH ureido groups directed
into the center of the cavity, in which the anion is included. In
the case of the linear CN− and SCN− anions (Figure 6, h and
i), the four hydrogen bonds are directed into the more
electronegative atom, while for the oxoanions they are directed
to both oxygen atoms (or to the three oxygens in the case of
ability of the receptors. H NMR, UV−vis, and DFT studies
showed that, in general, the association constants decreased
with decreasing of anion basicity. Ph-urea 5a is the best anion
receptor, showing the strongest affinity for F− (log Kassoc = 3.10
and 4.6 in CDCl3 and MeCN, respectively) and a complexation
energy double of the next more stable complex. High
complexation was also obtained for the oxoanions AcO− and
BzO− with 5a. t-Bu-urea 5c was the weakest receptor, probably
due to steric hindrance caused by the bulky tert-butyl groups.
The binding results obtained followed the same trend by both
techniques and were corroborated by DFT methods.
EXPERIMENTAL SECTION
■
Synthesis. All chemicals were reagent grade and were used without
further purification. Chromatographic separations were performed on
silica gel 60 (particle size 40−63 μm, 230−400 mesh). Melting points
1
were measured (not corrected) and FTIR spectra were recorded. H
and 13C NMR spectra were recorded using a 500 MHz spectrometer,
with TMS as internal reference. The conventional COSY 45 and the
phase-sensitive NOESY experiments were collected as 256 × 2 K
complex points. Elemental analysis was determined on a micro-
analyser.
7,13,19,25-Tetra-tert-butyl-27,29-bis[(cyanopropyl)oxy]-28,30-di-
hydroxy-2,3-dihomo-3-oxacalix[4]arene (2). A mixture of p-tert-
butyldihomooxacalix[4]arene (6.0 g, 8.85 mmol), K2CO3 (2.45 g, 17.7
mmol), and 4-bromobutyronitrile (1.81 mL, 17.7 mmol) in CH3CN
(140 mL) was refluxed and stirred under N2 for 6 days. After cooling,
the solvent was evaporated under reduced pressure and the residue
was dissolved in CH2Cl2 (250 mL) and washed with 1 M HCl (150
mL), H2O (2 × 100 mL), and brine (2 × 100 mL). The organic layer
was dried over Na2SO4 and filtered, and the solvent was removed
under reduced pressure. The crude product was subjected to flash
chromatography on silica gel (eluent CH2Cl2/MeOH, 99.5:0.5)
affording a white solid in 49% yield (3.5 g). An analytically pure
sample was obtained from recrystallization from MeOH: mp 175−177
°C; IR (KBr) 2247 cm−1 (CN); 1H NMR (CDCl3, 500 MHz) δ 1.10,
1.23, 1.25, 1.27 [4s, 36H, C(CH3)], 2.35−2.43 (m, 4H,
OCH2CH2CH2CN), 2.83−2.99 (m, 3H, OCH2CH2CH2CN), 3.15−
3.21 (m, 1H, OCH2CH2CH2CN), 3.34, 4.42 (ABq, 2H, J = 13.1 Hz,
−
HSO4 ) of the anion molecule. This is confirmed in Table 5,
where hydrogen-bond distances are listed. As expected, all the
anions interact preferably with the four hydrogen atoms of the
NH ureido groups. According to the distances NH···X− shown
in Table 5, it is evident a strong concordance between these
distances and the stability of the complexes, namely for F− and
AcO− that show the shortest distances (in average 1.69 and
1.81 Å, respectively).
To better characterize and visualize the electrostatic
equilibria in the complexes, electrostatic potential maps were
calculated over an electronic isodensity surface of ρ = 0.05 Å−3
(Figure 7). Red regions are those of relatively lower or more
F
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Article
−
Figure 6. Optimized structures for Ph-urea 5a-X− complexes: (a) 5a, (b) 5a + F− (c) 5a + Cl−, (d) 5a + BzO−, (e) 5a + AcO−, (f) 5a + HSO4 , (g)
−
5a + H2PO4 , (h) 5a + CN− and (i) 5a + SCN−. All of the hydrogen atoms were removed for clarity, except the urea NH hydrogens.
Table 5. Selected Structural Data of 5a-X− Complexes
(B3LYP/3-21G)
NMR (CDCl3, 125.8 MHz) δ 14.4, 14.5 (OCH2CH2CH2CN), 26.2,
26.7 (OCH2CH2CH2CN), 29.3, 30.0, 32.7 (ArCH2Ar), 31.1, 31.4,
31.5, 31.6 [C(CH3)], 33.9 (2C), 34.2, 34.3 [C(CH3)], 71.5, 72.4
(CH2OCH2), 72.8, 73.7 (OCH2CH2CH2CN), 119.1, 120.1 (CN),
NH···X− (Å)
123.9, 125.1, 125.4, 125.6, 126.0, 126.2, 128.0, 129.6 (ArH), 122.3,
127.2, 127.4, 128.4, 129.1, 131.9, 132.2, 135.1, 141.9, 142.4, 147.2,
147.6, 149.3 (2C), 152.5, 153.3 (Ar). Anal. Calcd for C53H68N2O5·
MeOH: C, 76.75; H, 8.59; N, 3.32. Found: C, 77.07; H, 8.51; N, 3.57.
7,13,19,25-Tetra-tert-butyl-28,29-bis[(cyanopropyl)oxy]-27,30-di-
hydroxy-2,3-dihomo-3-oxacalix[4]arene (2a). From the previous
flash chromatography, another set of fractions were combined and
chromatographed again (eluent CH2Cl2/MeOH, 99.8:0.2) yielding 2a
a1
b1
a2
b2
5a·F−
1.69
2.35
1.73
1.85
1.78
1.87
1.89
1.92
1.68
2.32
1.92
1.81
1.96
1.85
2.38
2.25
1.78
2.40
1.77
2.96
1.74
1.89
1.89
1.97
1.61
2.28
1.82
1.88
2.19
2.37
2.37
2.62
5a·Cl−
5a·AcO−
5a·BzO−
5a·HSO4
5a·H2PO4
5a·CN−
5a·SCN−
−
−
1
in low yield: mp 143−145 °C; IR (KBr) 2250 cm−1 (CN); H NMR
(CDCl3, 500 MHz) δ 1.00, 1.26 [2s, 36H, C(CH3)], 2.35 (m, 4H,
OCH2CH2CH2CN), 2.75, 2.87 (2m, 4H, OCH2CH2CH2CN), 3.45,
4.20 (ABq, 4H, J = 13.9 Hz, ArCH2Ar), 3.46, 4.45 (ABq, 2H, J = 13.5
Hz, ArCH2Ar), 4.05, 4.23 (2m, 4H, OCH2CH2CH2CN), 4.26, 4.67
(ABq, 4H, J = 10.0 Hz, CH2OCH2), 6.81, 6.86, 6.93, 7.23 (4d, 8H,
ArH), 7.53 (s, 2H, OH); 13C NMR (CDCl3, 125.8 MHz) δ 14.3
(OCH2CH2CH2CN), 26.1 (OCH2CH2CH2CN), 30.7, 31.6
(ArCH2Ar), 31.0, 31.5 [C(CH3)], 33.9, 34.0 [C(CH3)], 71.6
(CH2OCH2), 72.8 (OCH2CH2CH2CN), 119.7 (CN), 124.8, 125.1,
1 and 2 refer to the two ureido groups of 5a.
ArCH2Ar), 3.35, 4.54 (ABq, 2H, J = 12.8 Hz, ArCH2Ar), 3.53, 4.10
(ABq, 2H, J = 13.3 Hz, ArCH2Ar), 4.02−4.23 (3m, 4H,
OCH2CH2CH2CN), 4.25, 4.77 (ABq, 2H, J = 9.7 Hz, CH2OCH2),
4.43, 4.69 (ABq, 2H, J = 10.0 Hz, CH2OCH2), 6.88, 6.91, 7.01, 7.05,
7.06, 7.18, 7.28, 7.51 (8d, 8H, ArH), 7.12, 7.78 (2s, 2H, OH); 13C
G
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Figure 7. Electrostatic potential for Ph-urea 5a and two anion complexes: (a) 5a, (b) 5a + F− and (c) 5a + SCN−. The electrostatic potential (in au)
is represented over a constant electronic isodensity ρ (in Å−3) surfaces of volume Vs (in Å−3). All three figures correspond to ρ = 0.05 Å−3, and the
potential varies: (a) from B = 0.33 (dark blue) to A = −0.17 (red) for the receptor; (b) from B = 0.13 (dark blue) to A = −0.31 (red) for the
complex 5a-F− and (c) from B = 0.07 (dark blue) to A = −0.37 (red) for the complex 5a-SCN−.
126.1, 128.0 (ArH), 123.3, 128.0, 132.8, 133.3, 142.2, 147.0, 151.0,
151.7 (ArH). Anal. Calcd for C53H68N2O5: C, 78.29; H, 8.43; N, 3.45.
Found: C, 78.54; H, 8.74; N, 3.61.
39.2 (ArCH2Ar), 31.4, 31.5, 31.6 (2C) [C(CH3)], 32.1, 32.2
(OCH2CH2CH2CH3), 34.1 (2C), 34.2, 34.3 [C(CH3)], 64.6, 68.5
(CH2OCH2), 70.3, 70.4, 73.9, 75.4 (OCH2CH2CH2CN and
OCH2CH2CH2CH3), 119.7, 121.1 (CN), 125.3, 125.9, 126.2, 126.7,
126.8, 126.9, 127.0, 128.2 (ArH), 130.2, 130.6, 132.9, 133.2, 133.4,
133.44, 134.5, 143.53, 145.3, 145.4, 145.8, 146.6, 152.4, 152.9, 153.7,
154.3 (Ar). Anal. Calcd for C61H84N2O5: C, 79.18; H, 9.15; N, 3.03.
Found: C, 78.79; H, 9.06; N, 3.21.
7,13,19,25-Tetra-tert-butyl-27,29-bis[(cyanopropyl)oxy]-28,30-di-
butoxy-2,3-dihomo-3-oxacalix[4]arene (3). A mixture of 2 (1.0 g,
1.23 mmol) and 0.30 g (7.4 mmol) of NaH (60% oil dispersion) in 40
mL of THF−DMF (7:1, v/v) was stirred under an atmosphere of N2.
After 1 h, 0.85 mL (7.4 mmol) of 1-iodobutane was added, and the
mixture was refluxed and stirred for 14 h. After cooling, the solvent
was evaporated, and the residue was dissolved in CH2Cl2 (75 mL) and
washed with 1 M HCl (2 × 40 mL), NH4Cl saturated solution (3× 30
mL), and brine (40 mL). The organic layer was dried over Na2SO4
and filtered, and the solvent was removed under reduced pressure. The
crude product was subjected to flash chromatography on silica gel
(eluent gradient from n-heptane/ethyl acetate 95:5 to 90:10) to give 3
as a white solid in the cone (0.55 g, 54% yield) and partial cone A
conformations (0.14 g, 14% yield).
7,13,19,25-Tetra-tert-butyl-27,29-bis[(aminobutyl)oxy]-28,30-di-
butoxy-2,3-dihomo-3-oxacalix[4]arene (4). To a suspension of 1.0 g
(1.08 mmol) of 3 (cone conformation) and 1.54 g (6.48 mmol) of
CoCl2·6H2O in MeOH (35 mL) was slowly added 0.85 g (21.6 mmol)
of NaBH4. A black suspension was formed that was stirred at room
temperature for 24 h. Then, another portion of NaBH4 (0.85 g) was
added, and the suspension was stirred for an additional 24 h. A 25%
ammonia solution (110 mL) was added, and the mixture was stirred
overnight. The solution was extracted with CH2Cl2 (3 × 50 mL) and
dried over Na2SO4, and the solvent evaporated to dryness to afford
diamine 4 as a beige solid (88% yield), which was pure enough to be
Cone: mp 104−106 °C; IR (KBr) 2247 cm−1 (CN); 1H NMR
(CDCl3, 500 MHz) δ 0.65, 1.04, 1.23, 1.34 [4s, 36H, C(CH3)], 1.01,
1.03 (2t, 6H, J = 7.4 Hz, CH3), 1.47, 1.55 (2m, 4H,
OCH2CH2CH2CH3), 1.84 (m, 4H, OCH2CH2CH2CH3), 2.16, 2.28,
2.37, (3m, 4H, OCH2CH2CH2CN), 2.60, 2.66 (2m, 4H,
OCH2CH2CH2CN), 3.22, 4.30 (ABq, 2H, J = 13.9 Hz, ArCH2Ar),
3.23, 4.34 (ABq, 2H, J = 12.9 Hz, ArCH2Ar), 3.26, 4.32 (ABq, 2H, J =
13.0 Hz, ArCH2Ar), 3.59, 3.74, 3.85, 4.02 (4m, 8H,
OCH2CH2CH2CH3 and OCH2CH2CH2CN), 4.33, 4.65 (ABq, 2H, J
= 13.2 Hz, CH2OCH2), 4.65, 4.77 (ABq, 2H, J = 13.0 Hz, CH2OCH2),
6.28, 6.79, 6.85, 6.89, 7.10, 7.12, 7.20, 7.22 (8d, 8H, ArH); 13C NMR
(CDCl3, 125.8 MHz) δ 14.0 (2C) [O(CH2)3CH3], 14.1, 14.4, 19.3,
19.5 (OCH2CH2CH2CN and OCH2CH2CH2CH3), 26.1, 26.3
(OCH2CH2CH2CN), 29.7, 30.1, 30.5 (ArCH2Ar), 31.2 (2C), 31.5,
31.6 [C(CH3)], 32.4, 32.5 (OCH2CH2CH2CH3), 33.8, 33.9, 34.2, 34.3
[C(CH3)], 67.7, 68.2 (CH2OCH2), 71.9 (2C), 74.8, 75.6
(OCH2CH2CH2CN and OCH2CH2CH2CH3), 119.7, 120.3 (CN),
123.2, 124.3, 124.6, 125.1, 125.4, 126.5, 126.6, 127.0 (ArH), 130.0,
131.9, 132.3, 132.4, 132.6, 133.7, 133.9, 135.2,144.8, 145.3, 145.8,
145.9, 151.3, 151.9, 152.0, 152.9 (Ar). Anal. Calcd for C61H84N2O5: C,
79.18; H, 9.15; N, 3.03. Found: C, 78.92; H, 9.12; N, 3.21.
1
immediately used in the next step: H NMR (CDCl3, 500 MHz) δ
0.90, 0.99, 1.16, 1.20 [4s, 36H, C(CH3)], 1.00, 1.01 (2t, 6H, J = 7.4
Hz, CH3), 1.42−1.67, 1.77−2.05 (several m, 16H, OCH2CH2CH2CH3
a n d O C H 2 C H 2 C H 2 C H 2 N H 2 ) , 2 . 7 9 ( 2 t , 4 H ,
OCH2CH2CH2CH2NH2), 3.18, 4.38 (ABq, 2H, J = 13.2 Hz,
ArCH2Ar), 3.18, 4.40 (ABq, 2H, J = 13.2 Hz, ArCH2Ar), 3.22, 4.39
(ABq, 2H, J = 13.0 Hz, ArCH2Ar), 3.61−3.90 (several m, 8H,
OCH2CH2CH2CH3 and OCH2CH2CH2CH2NH2), 4.59, 4.64 (ABq,
2H, J = 13.1 Hz, CH2OCH2), 4.59, 4.68 (ABq, 2H, J = 13.1 Hz,
CH2OCH2), 6.62, 6.81, 6.93, 6.94, 6.97, 7.00, 7.03, 7.07 (8d, 8H,
ArH).
Procedure for the Synthesis of Ureas 5a, 5b, and 5c. To a
solution of 4 (0.90 g, 0.966 mmol) in CHCl3 (30 mL) was added 1.93
mmol of the appropriate isocyanate. The mixture was stirred at room
temperature under N2 for 4 h. Evaporation of the solvent yielded the
crude products which were purified as described below.
7,13,19,25-Tetra-tert-butyl-27,29-bis[[(N′-phenylureido)butyl]-
oxy]-28,30-dibutoxy-2,3-dihomo-3-oxacalix[4]arene (5a). Flash
chromatography (SiO2, eluent CH2Cl2/MeOH, from 99:1 to 97:3)
was followed by recrystallization from MeOH: 45% yield (0.56 g); mp
214−216 °C; IR (KBr) 3327 cm−1 (NH), 1647 cm−1 (CO); 1H NMR
(CDCl3, 500 MHz) δ 0.55, 1.08, 1.33, 1.37 [4s, 36H, C(CH3)], 0.91,
0.94 (2t, 6H, J = 7.4 Hz, CH3), 1.44 (m, 4H, OCH2CH2CH2CH3),
1.50, 1.78, 1.92, 2.27 (4m, 12H, OCH2CH2CH2CH2NHa and
OCH2CH2CH2CH3), 3.20, 4.31 (ABq, 2H, J = 14.1 Hz, ArCH2Ar),
3.21, 4.30 (ABq, 2H, J = 12.7 Hz, ArCH2Ar), 3.22, 4.38 (ABq, 2H, J =
1 2. 6 H z , A r C H2 Ar), 3. 2 1, 3. 35, 3 . 55 (3m, 4H,
OCH2CH2CH2CH2NHa), 3.47, 3.58−3.81, 3.90, 3.99 (several m,
8H, OCH2CH2CH2CH3 and OCH2CH2CH2CH3), 4.39, 4.91 (ABq,
2H, J = 13.2 Hz, CH2OCH2), 4.40, 5.15 (ABq, 2H, J = 12.6 Hz,
CH2OCH2), 5.82, 6.27 (2t, 2H, NHa), 6.13, 6.47, 6.76, 6.94, 7.12, 7.20,
7.30, 7.31 (8d, 8H, ArH), 6.96, 7.01 (2t, 2H, Ph-Hp), 7.25, 7.27 (2t,
1
Partial cone A: mp 108−110 °C; IR (KBr) 2243 cm−1 (CN); H
NMR (CDCl3, 500 MHz) δ 0.73 (m, 4H, OCH2CH2CH2CN
inverted), 0.96, 0.97 (2t, 6H, J = 7.4 Hz, CH3), 1.21, 1.25, 1.38,
1.39 [4s, 36H, C(CH3)], 1.38 (m, 4H, OCH2CH2CH2CH3), 1.66,
1.75, 1.92, 2.37 (4m, 10H, OCH2CH2CH2CH3, OCH2CH2CH2CN
and OCH2CH2CH2CN inverted), 3.30, 4.39 (ABq, 2H, J = 13.1 Hz,
ArCH2Ar), 3.31, 4.28 (ABq, 2H, J = 13.1 Hz, ArCH2Ar), 3.49−3.77
(several m, 6H, OCH2CH2CH2CH3 and OCH2CH2CH2CN), 3.81,
3.88 (ABq, 2H, J = 15.8 Hz, ArCH2Ar), 4.10, 5.05 (ABq, 2H, J = 11.9
Hz, CH2OCH2), 4.11 (s, 2H, CH2OCH2), 7.03, 7.05, 7.16, 7.22, 7.24,
7.32, 7.33 (7d, 8H, ArH); 13C NMR (CDCl3, 125.8 MHz) δ 12.2, 13.2
(OCH2CH2CH2CN inverted and OCH2CH2CH2CN), 14.0 (2C)
[O(CH2)3CH3], 19.2, 19.3 (OCH2CH2CH2CH3), 25.2, 26.1
(OCH2CH2CH2CN inverted and OCH2CH2CH2CN), 29.1, 30.1,
4H, Ph-Hm), 7.46, 7.4 (2d, 4H, Ph-Ho), 7.96, 8.05 (2s, 2H, NHb); 13
C
H
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NMR (CDCl3, 125.8 MHz) δ 13.9, 14.1 [O(CH2)3CH3], 19.3, 19.4
( O C H 2 C H 2 C H 2 C H 3 ) , 2 5 . 4 , 2 6 . 0 , 2 6 . 2 , 2 8 . 6
(OCH2CH2CH2CH2NHa), 29.2, 30.9, 31.2 (ArCH2Ar), 31.2, 31.3,
31.6, 31.7 [C(CH3)], 32.2, 32.6 (OCH2CH2CH2CH3), 33.7, 33.9,
34.19, 34.21 [C(CH3)], 39.6 (2C) (OCH2CH2CH2CH2NHa), 70.8,
71.7 (CH2OCH2), 72.3, 74.7, 75.0, 75.5 (OCH2CH2CH2CH2NHa and
OCH2CH2CH2CH3), 118.9, 119.2, 121.8, 122.7, 123.8, 124.8, 125.0,
125.2, 125.9, 126.2, 126.9, 128.5, 128.8, 129.2 (ArH), 129.1, 131.0,
132.0, 132.7, 132.9, 134.37, 134.43, 136.0, 139.6, 140.1, 144.3, 145.0
(2C), 145.5, 152.6, 153.0, 153.9, 154.5 (Ar), 156.2, 156.9 (CO). Anal.
Calcd for C75H98N4O7: C, 77.15; H, 8.46; N, 4.80. Found: C, 77.15;
H, 8.69; N, 4.79.
7,13,19,25-Tetra-tert-butyl-27,29-bis[[(n-propylureido)butyl]oxy]-
28,30-dibutoxy-2,3-dihomo-3-oxacalix[4]arene (5b). Flash chroma-
tography (SiO2, eluent CH2Cl2/MeOH, from 99:1 to 96:4) was
followed by recrystallization from CH2Cl2/n-hexane: 36% yield (0.42
g); mp 183−185 °C; IR (KBr) 3345 cm−1 (NH), 1634 cm−1 (CO);
1H NMR (CDCl3, 500 MHz) δ 0.55, 1.06, 1.29, 1.36 [4s, 36H,
C(CH3)], 0.95, 0.96, 0.97, 0.99 [4t, 12H, J = 7.3 Hz, O(CH2)3CH3
and NHbCH2CH2CH3)], 1.43−1.61, 1.68 (several m, 10H,
OCH2 CH2 CH2 CH3 , NHb CH2 CH2 CH3 and OCH2 CH2 -
C H 2 C H 2 N Ha ) , 1 . 7 2 − 1. 8 6, 1 . 9 1 , 2 . 16 ( 3 m , 1 0 H,
OCH2CH2CH2CH2NHa and OCH2CH2CH2CH3), 3.19, 4.31 (ABq,
2H, J = 13.9 Hz, ArCH2Ar), 3.20, 4.33 (ABq, 2H, J = 12.9 Hz,
ArCH2Ar), 3.21, 4.36 (ABq, 2H, J = 12.6 Hz, ArCH2Ar), 3.14−3.35,
3.42 (several m, 8H, NHbCH2CH2CH3 and OCH2CH2CH2CH2NHa),
3.49, 3.59−3.70, 3.75, 3.84, 3.91 (several m, 8H, OCH2CH2-
CH2CH2NHa and OCH2CH2CH2CH3), 4.46, 4.59 (ABq, 2H, J =
13.4 Hz, CH2OCH2), 4.50, 4.92 (ABq, 2H, J = 12.9 Hz, CH2OCH2),
5.36, 5.59 (2t, 2H, NHb) 5.51, 5.62 (2t, 2H, NHa), 6.14, 6.65, 6.76,
6.88, 7.11, 7.20, 7.21, 7.25 (8d, 8H, ArH); 13C NMR (CDCl3, 125.8
MHz) δ 11.5 (2C) (NHbCH2CH2CH3), 14.0, 14.1 [O(CH2)3CH3],
19.3, 19.4 (OCH2CH2CH2CH3), 23.7 (2C) (NHbCH2CH2CH3), 25.9,
26.4, 26.6, 28.4 (OCH2CH2CH2CH2NHa), 29.4, 30.8, 30.9
(ArCH2Ar), 31.2, 31.3, 31.6, 31.7 [C(CH3)], 32.2, 32.6
(OCH2CH2CH2CH3), 33.7, 33.9, 34.1, 34.2 [C(CH3)], 39.8, 40.0,
41.9, 42.2 (OCH2CH2CH2CH2NHa and NHbCH2CH2CH3), 69.5
(2C) (CH2OCH2), 72.6, 74.4, 74.9, 75.4 (OCH2CH2CH2CH2NHa
and OCH2CH2CH2CH3), 123.6, 124.0, 124.5, 125.0, 125.6, 126.3,
126.9, 127.4 (ArH), 129.3, 131.6, 132.2, 132.66, 132.70, 134.2 (2C),
135.9, 144.3, 145.0, 145.1, 145.3, 152.5, 152.6, 153.3, 153.8 (Ar),
159.1, 159.2 (CO). Anal. Calcd for C69H102N4O7: C, 75.37; H, 9.35;
N, 5.10. Found: C, 75.02; H, 9.29; N, 5.20.
(CO). Anal. Calcd for C71H106N4O7: C, 75.63; H, 9.47; N, 4.97.
Found: C,75.60; H, 9.30; N, 5.03.
1H NMR Titrations. The association constants (as log Kassoc) were
determined in CDCl3 by 1H NMR titration experiments. Several
aliquots (up to 10 equiv) of the anion solutions (as tetrabutylammo-
nium salts) were added to 0.5 mL solution of the receptors (2.5 × 10−3
− 5 × 10−3 M) directly in the NMR tube. The spectra were recorded
after each addition of the salts, and the temperature of the NMR probe
was kept constant at 25 °C. For each anion−receptor system titrations
were repeated at least two times. The association constants were
evaluated using the WinEQNMR2 program23 and following the urea
NH chemical shifts. When possible, Kassoc was calculated as a mean
value of the four NH chemical shifts. The Job methods were
performed keeping the total concentration in the same range as before.
UV−vis Titrations. The association constants were also
determined in acetonitrile by absorption spectrophotometry at 25.0
0.1 °C. The spectra were recorded between 260 and 310 nm, using
quartz cells with an optical path length of 1 cm. The anions studied
were provided as tetrabutylammonium salts, and were dried under
vacuum for at least 24 h before use. Twenty additions of 10 μL of the
anion solution were directly added into the cell containing 2 mL of the
receptor solution (CL from 10−5 to 2 × 10−4 M). The anion to
receptor ratios were in the range 1−10. The spectral changes were
interpreted using the SPECFIT program.32
Theoretical Methods. Computational density functional theory
(DFT) methods were used to analyze the structure and electronic
properties of all the conformers studied. All the structures were fully
optimized without symmetry constraints using the Becke three-
parameter hybrid functional combined with the Lee, Yang, and Parr
correlation functional (B3LYP)30 along with the split-valence double-ζ
Pople basis set, which is well-known to produce accurate geometries.
Following this optimization, a single-point energy calculation with the
same functional and a bigger basis was made, using 6-31G(d,p) valence
double-ζ polarized basis set.
The methods and basis sets used were those implemented in the
Gaussian 03 software package.33 The vibrational frequency calculations
were performed at the same level of theory to check that all structures
were at the global minima of the potential energy surface (denoted by
an absence of negative vibrational frequencies) and to correct the
computed energies for zero-point energies as well as translational,
rotational and vibrational contributions to the enthalpy. All the figures
and electrostatic potential surfaces were constructed using Molekel
software.34
The electrostatic potential was drawn over a surface of constant
electronic isodensity using Molekel software. All the data needed to
generate these surfaces and electrostatic potentials were calculated
with Gaussian 03 software.
For each anion several initial positions were tested, starting inside or
outside the receptor cavity.The relative complexation energies (ΔEc
corresponding to the process 5a + X− → [5a − X−], where X−
represents each one of the anions) were calculated as the energy
difference at 298 K between the final energy of the complexes and the
sum of the energies of 5a and the anion in study, at the same
theoretical level.35
7,13,19,25-Tetra-tert-butyl-27,29-bis[[(tert-butylureido)butyl]-
oxy]-28,30-dibutoxy-2,3-dihomo-3-oxacalix[4]arene (5c). Flash
chromatography (SiO2, eluent CH2Cl2/MeOH, from 99:1 to 95:5):
49% yield (0.59 g); mp 160−162 °C; IR (KBr) 3366 cm−1 (NH),
1
1638 cm−1 (CO); H NMR (CDCl3, 500 MHz) δ 0.54, 1.07, 1.30,
1.36 [4s, 36H, C(CH3)], 0.96, 0.98 [2t, 6H, J = 7.5 Hz,
O(CH2)3CH3), 1.38, 1,43 [(2s, 18H, NHbC(CH3)], 1.41−1.52 (m,
6H, OCH2CH2CH2CH3 and OCH2CH2CH2CH2NHa), 1.64−1.93,
2 . 1 9 ( s e v e r a l m , 1 0 H , O C H 2 C H 2 C H 2 C H 3 a n d
OCH2CH2CH2CH2NHa), 3.19, 4.36 (ABq, 2H, J = 12.6 Hz,
ArCH2Ar), 3.20, 4.31 (ABq, 2H, J = 12.6 Hz, ArCH2Ar), 3.21, 4.29
(ABq, 2H, J = 13.5 Hz, ArCH2Ar), 3.18−3.27, 3.48 (several m, 4H,
OCH2CH2CH2CH2NHa), 3.36, 3.57−3.80, 3.87−3.98 (several m, 8H,
OCH2CH2CH2CH2NHa and OCH2CH2CH2CH3), 4.46, 4.67 (ABq,
2H, J = 13.3 Hz, CH2OCH2), 4.47, 4.95 (ABq, 2H, J = 12.6 Hz,
CH2OCH2), 5.16, 5.58 (2s, 2H, NHb), 5.56, 5.57 (2t, 2H, NHa), 6.12,
6.62, 6.76, 6.90, 7.11, 7.20, 7.22, 7.25 (8d, 8H, ArH); 13C NMR
(CDCl3, 125.8 MHz) δ 14.0, 14.1 [O(CH2)3CH3], 19.3, 19.4
( O C H 2 C H 2 C H 2 C H 3 ) , 2 5 . 5 , 2 6 . 4 , 2 6 . 5 , 2 8 . 5
(OCH2CH2CH2CH2NHa), 29.6, 30.8, 31.1 (ArCH2Ar), 29.7, 29.8
[NHbC(CH3)], 31.2, 31.3, 31.6, 31.7 [C(CH3)], 32.3, 32.7
(OCH2CH2CH2CH3), 33.7, 33.9, 34.1, 34.2 [C(CH3)], 39.3, 39.5
(OCH2CH2CH2CH2NHa), 49.9, 50.2 [NHbC(CH3)], 69.6, 69.9
(CH2OCH2), 72.4, 74.8, 74.9, 75.4 (OCH2CH2CH2CH2NHa and
OCH2CH2CH2CH3), 123.6, 124.0, 124.5, 125.1, 125.6, 126.2, 126.9,
127.6 (ArH), 129.1, 131.5, 132.2, 132.7, 132.8, 134.1, 134.3, 136.0,
144.3, 144.9, 145.1, 145.4, 152.6, 152.7, 153.6, 153.9 (Ar), 158.4 (2C)
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra of the new compounds 2, 2a, 3
(cone), 3 (cone partial), 5a, 5b, and 5c, and 2D NOESY
spectra of compounds 2a and 3 (partial cone). Table of atom
coordinates and absolute energies. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: pmmarcos@fc.ul.pt.
■
Notes
The authors declare no competing financial interest.
I
dx.doi.org/10.1021/jo4026012 | J. Org. Chem. XXXX, XXX, XXX−XXX

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ACKNOWLEDGMENTS
■
We thank the Fundaca
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ref PTDC/QUI/69858/2006.
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