Structures of urea/thiourea 1,3-disubstituted thia[4]calixarenes and corresponding monofunctional receptors and their anion recognition properties

Article abstract of DOI:10.1007/s10847-010-9798-0

Two thiacalix[4]arenes in 1,3-alternate conformation functionalized by two (CH₂)₂NH(C=X)NHC₆H₄-NO₂-p groups (X = S,O) as well as two related monofunctional receptors MeO(CH₂)₂NH(

Full text of DOI:10.1007/s10847-010-9798-0

J Incl Phenom Macrocycl Chem (2010) 68:387–398
DOI 10.1007/s10847-010-9798-0
ORIGINAL ARTICLE
Structures of urea/thiourea 1,3-disubstituted thia[4]calixarenes
and corresponding monofunctional receptors and their anion
recognition properties
•
Carol Perez-Casas Herbert Hopfl
•
´
Anatoly K. Yatsimirsky
¨
Received: 22 February 2010 / Accepted: 28 April 2010 / Published online: 14 May 2010
Ó Springer Science+Business Media B.V. 2010
Abstract Two thiacalix[4]arenes in 1,3-alternate confor-
mation functionalized by two (CH2)2NH(C=X)NHC6H4-
NO2-p groups (X = S,O) as well as two related mono-
functional receptors MeO(CH2)2NH(C=X)NHC6H4-NO2-p
were prepared and characterized by X-ray crystal structures.
The thioureido and ureido derivatives have E,Z and E,E
conformations respectively both in monofunctional recep-
tors and thiacalixarenes. The thiacalixarene attached thio-
urea groups are well separated from each other, but
respective urea groups are much closer to each other and
have mutual parallel orientation making the bisurea deriv-
ative a better preorganized receptor as compared to bis-
thiourea. Binding of Cl-, F-, H2PO4- and AcO- anions in
chloroform and DMSO was studied by spectrophotomet-
ric and NMR titrations. In chloroform both bisurea and
bisthiourea thiacalix[4]arenes bind anions 3–5 times
stronger than corresponding monofunctional compounds in
spite of better preorganization of the urea derivative. In
DMSO simultaneous deprotonation of ureido NH groups
of receptors and hydrogen bonding reactions are observed.
(log K = 3.9). For hydrogen bonding associations the
-
binding constants of H2PO4 and AcO- with bisurea thi-
acalixarene are up to two orders of magnitude larger than
those with corresponding monofunctional receptor, but with
bisthiourea thiacalixarene the effect is less than two-fold.
Thus in this solvent in contrast to chloroform the preorga-
nization is an important factor.
Keywords Thiacalixarene ꢀ Urea ꢀ Thiourea ꢀ
Structure ꢀ Anion recognition
Introduction
Anion recognition by hydrogen bonding receptors is an
area of intensive current research [1–6]. Urea and thiourea
functionalities are often used for design of neutral anion
receptors due to their ability to form stable bidentate
complexes with anions even in relatively polar solvents
like DMSO and significant increase in affinity can be
achieved by attaching two or more urea or thiourea groups
to acyclic [7–11] or macrocyclic scaffolds [12–19].
-
Deprotonation by H2PO4 is accompanied by a strong
-
association between liberated H3PO4 and H2PO4
Typically thiourea derivatives bind anions tighter than
the respective urea derivatives due to higher acidity of the
former. However, in several instances similar or even
better binding by ureas was reported and attributed to
unfavorable E,Z conformation of some substituted thio-
ureas, which compensates the advantage of higher acidity
[20]. It seems interesting therefore to see how this con-
formational difference can be manifested in binding prop-
erties of a bifunctional receptor in comparison with its
monofunctional counterpart. To explore this aspect we
have prepared 1,3-disubstituted urea and thiourea deriva-
tives of thia[4]calixarenes 1, as well as corresponding
monofunctional receptors 2 (Scheme 1) all of which were
Electronic supplementary material The online version of this
article (doi:10.1007/s10847-010-9798-0) contains supplementary
material, which is available to authorized users.
´
C. Perez-Casas ꢀ A. K. Yatsimirsky (&)
´
Facultad de Quımica, Universidad Nacional Autonoma
de Mexico, 04510 Mexico, DF, Mexico
´
´
´
´
e-mail: anatoli@servidor.unam.mx
¨
H. Hopfl
Centro de Investigaciones Quımicas, Universidad Autonoma
´
´
del Estado de Morelos, Av. Universidad 1001,
´
62209 Cuernavaca, Mexico
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O2N
NO2
in the presence of Cs2CO3. The monofunctional receptors
2a and 2b were prepared by condensation of 2-methoxy-
ethylamine with the corresponding aryl-isothiocyanate or
aryl-isocyanate. An additional thioureido-thiacalixarene
derivative 1c lacking the nitro group in the para position of
phenyl ring was prepared, but was not used in anion binding
studies because of too low affinity.
NH
NH
HN
HN
X
X
S
t Bu
t
Bu
O
O
O
S
S
S
The molecular structures of thiacalixarenes 1 and the
monofunctional receptors 2 were determined by X-ray
diffraction analysis, Table 1.
NO2
O
X
Ph
t Bu
O
t Bu
N
H
N
H
Ph
Crystal structures of 2a, 2b are shown in Fig. 1. The
thiourea receptor 2a has E,Z (syn,anti) conformation, in
which the N–H bond adjacent to aromatic ring is syn-ori-
ented with respect to C=S bond. This is typical for many
other N-aryl-N0-alkylthiourea derivatives [32]. Such a
configuration is unfavorable for bidentate anion complex-
ation and as a result thioureas in spite of their higher
acidity are often poorer receptors for anions than ureas
[12, 20, 32], which typically are pre-organized for double
hydrogen bonding in their Z,Z conformation observed also
for 2b.
1a,b
2a,b
a X=S
b X=O
Scheme 1 Chemical structures of receptors employed
characterized by X-ray crystal structures. We chose for this
study the thiacalixarene scaffold because ureido-substituted
thiacalixarenes as well as thiacalixarenes in general attrac-
ted recently considerable interest due to their possible
improved receptor properties as compared to traditional
calixarenes [21–28]. In addition, the presence of heavy
sulfur atoms facilitates the analysis of X-ray diffraction data
for large macrocyclic molecules.
Both thiacalixarene derivatives have the expected 1,3-
alternate conformation. The thiourea derivatives 1a and 1c
have highly symmetric structures with the thiourea groups
in E,Z conformations, Fig. 2 and Fig. S1 (Supplementary
Material). The molecular structure of 1a has crystallo-
graphic C2-symmetry, in which the thiourea groups are far
separated from each other, as it can be seen from the
distance between the carbon atoms of the thiocarbonyl
Since both affinity and selectivity of anion binding by
urea receptors are solvent dependent [7, 29], we studied
interactions of receptors 1a, 1b and 2a, 2b with anions in
two solvents of strongly different polarities: DMSO and
chloroform. As is shown below the expected advantage of a
bifunctional receptor over a monofunctional one appears to
be solvent dependent.
˚
groups (10.96 A). Opposite aromatic rings of the thioca-
lixarene have approximately parallel orientations, the
interplanar angles being 3.7° for the rings carrying the
thiourea group and 7.4° for the rings bearing benzyl
t
groups. The Bu substituents fill the space between the
Results and discussion
thiourea groups, thus inhibiting close approach of the
thiourea groups, which is necessary for chelate anion
binding. All these features show that this receptor is poorly
preorganized for a potential chelation of anions by two
thioureido groups.
Synthesis and structural characterization
The tetrathiacalix[4]arene 3 in cone conformation was pre-
pared according to a published procedure [30, 31] and then
transformed into 1 as shown in Scheme 2. The change of the
conformation of thiacalixarene from cone to 1,3-alternate
occurs at the first step during reaction with bromoacetamide
Because of poor crystal quality, for thiacalixarene 1b
only data of low resolution could be measured (see
Experimental Section). However, these were of sufficiently
good quality to observe clearly the atom connectivity and
conformation of the macrocycle. In contrast to 1a the
molecular structure of 1b (Fig. 3) is asymmetric, since the
benzyl groups have different orientations with respect to
the macrocyclic ring. The urea groups have Z,Z configu-
ration, which is also observed for the respective mono-
functional receptor 2b (Fig. 1). Importantly, the urea
groups are now much closer to each other and have mutual
t Bu
tBu
OH
1. BrCH2CONH2
2. BH3/THF
3. XCNC6H4NO2-p, X=S,O
)
1a,b
(
S
S
2
O
Ph
˚
parallel orientation with a distance of 5.07 A between the
3
carbons of the carbonyl groups. At the same time the
interplanar angles between the aromatic rings are increased
Scheme 2 Synthesis of functionalized thiacalix[4]arenes
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389
Table 1 Crystallographic data for compounds 1a–1c and 2a–2b
Crystal dataa
1a
1b
1c
2a
2b
Formula
C72H78N6O8S6
1347.76
C2/c
C72H78N6O10S4, MeCN
C72H80N4O4S6
1257.76
C2/c
C10H13N3O3S
255.29
C10H13N3O4
239.23
P21/c
MW (g mol-1
Space group
Temp. (K)
)
1356.70
P21/c
P-1
100
100
100
293
293
˚
a (A)
28.766(2)
13.8975(10)
19.3330(14)
90
15.409(2)
14.953(2)
30.206(5)
90
29.2418(19)
12.5827(8)
19.8058(13)
90
4.3166(15)
9.494(3)
14.693(5)
96.871(6)
95.003(6)
101.148(6)
582.8(3)
2
4.6208(7)
28.605(4)
8.9845(13)
90
˚
b (A)
˚
c (A)
a (°)
b (°)
c (°)
117.390(1)
90
93.596(3)
90
115.009(1)
90
103.546(3)
90
3
˚
V (A )
6862.4(8)
4
6945.9(18)
4
6604.1(7)
4
1154.5(3)
4
Z
l (mm-1
calcd (g cm-3
)
0.259
0.201
0.259
0.278
0.108
q
)
1.305
1.297
1.265
1.455
1.376
Rb,c
Rdw,e
a
0.1003
0.2139
0.1527
0.3784
0.1146
0.2452
0.0780
0.0548
0.1259
0.1911
˚
kMoKa = 0.71073 A
b
c
d
e
I [ 2r(I)
R = R(F2o - Fc2)/RF2o
All data
Rw = [Rw(F2o - F2c)2/Rw(Fo2)2]‘
between the urea groups. Regarding the receptor properties
of 1b, a possible drawback in the structure might be the
observation that there is an intramolecular hydrogen
bonding interaction between the urea groups (C=OꢀꢀꢀH–
˚
N = 2.22 A), but obviously 1b is a much better preorga-
nized receptor than 1a.
The structural differences between thiacalixarenes 1a and
1b, which chemically differ just by the nature of one atom, S
instead of O in the ureido group, are unexpectedly large. In
part this can be attributed to different conformations of
N,N0-disubstituted ureas (Z,Z) and thioureas (E,Z), which
distort the macrocycle in a different manner, thus giv-
ing different spatial orientations of these groups. Another
important factor is the hydrogen bonding between ureido
groups in 1b, which is absent in 1a probably because of
lower hydrogen bond accepting ability of thiourea sulfur
atoms as compared to urea oxygen atoms. Recently similar
structural differences between urea and thiourea derivatives
of calix[6]arenes were inferred from analysis of their NMR
spectra [33].
Interactions with anions in chloroform
Fig. 1 Perspective view of the molecular structures of compounds 2a
and 2b. Ellipsoids are shown at the 30% probability level
Binding of anions to receptors 1a, 1b and 2a, 2b in chlo-
roform was studied by spectrophotometric titrations. In all
cases additions of anions induced a red shift and an
increase in intensity of the receptor absorption band around
to 44.7° for those bearing benzyl substituents and 42.1° for
those bearing urea groups. This conformational change
t
mutually separates the Bu groups, thus creating a void
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J Incl Phenom Macrocycl Chem (2010) 68:387–398
nearly linear increase at higher concentrations. Such profiles
indicate the strong binding of the first anion apparently by
chelation with two thioureido groups followed by weaker
binding of the second anion affording a complex with two
anions bound to each thioureido group separately. Fitting
curves to such a model are shown by solid lines in Fig. 5b
and the respective formation constants are given in Table 2.
For Cl- only an estimate of the upper limit of K2 was pos-
sible due to very weak binding of the second anion. The
interaction with H2PO4- (Fig. 5b) involves binding of only
one anion.
Interactions of anions with urea derivatives 2b and 1b
induced similar spectral changes, but shifted to shorter
wavelengths (Fig. S2a and b, Supplementary Material).
The fitting curves are shown in Fig. S3a and b (Supple-
mentary Material) and the respective binding constants are
given in Table 2. The 1:1 stoichiometry of binding with
both receptors was confirmed by Job plots (not shown).
Examining K1 values, which refer to the 1:1 association,
shows that generally thiourea and urea derivatives bind
anions with similar strength. Ureido thiacalixarene receptor
1b binds anions stronger than the respective monofunc-
tional receptor 2b with log K increased on average by 0.6
units and with the same low selectivity. The thioureido
thiacalixarene 1a shows however a pronounced peak
selectivity to acetate absent for the respective monofunc-
tional receptor 2a, which results from unexpectedly weak
binding of H2PO4-. Interestingly, the effect of stronger
binding with other anions for the ‘‘unorganized’’ receptor
1a is similar or even larger than that for preorganized
receptor 1b. A possible reason for this is that the hydrogen
bonding between ureido groups in 1b hampers the anion
binding, thus eliminating the advantage of better preorga-
nization of this receptor.
Fig. 2 Perspective view (a lateral and b top view) of the molecular
structure of 1a. Ellipsoids are shown at the 30% probability level
330 nm characteristic of the formation of hydrogen bonded
complexes [34].
Interactions with anions in DMSO
A typical course of the spectrophotometric titration is
illustrated in Fig. 4a with 2a and acetate as a guest. The
absorption maximum of the free receptor at 335 nm is
shifted to 368 nm with two isosbestic points at 258 and
345 nm. A similar shift was observed with dihydrogen
phosphate and fluoride anions, but with less basic chloride
anion the shift was smaller, only to 355 nm. Typical
titration curves are shown in Fig. 4a (inset) and b. Binding
constants obtained by fitting of these results are given in
Table 2.
In more polar DMSO solvent interactions of both thiourea
receptors with all anions except chloride involve more or
less pronounced deprotonation of the receptor. Both 2a and
1a form with Cl- weak hydrogen bonded complexes
manifested in red shifts of absorption bands and down-field
1
shifts of H NMR signals of ureido NH protons (Fig. S4a
and b, Supplementary Material) with equilibrium constants
given in Table 3. Both 2a and 1a undergo complete mono-
deprotonation probably of the NH group adjacent to the
aromatic ring by fluoride anions manifested in appearance
of an intense absorption band in the visible range (Fig. S5,
Supplementary Material) [35–38]. Interaction of 2a with
acetate in DMSO has been studied previously [34]. It
involves simultaneous hydrogen bonding and deprotona-
tion, Eq. 1, with equilibrium constant K3 defined by Eq. 2.
Spectrophotometric titrations of the thiacalixarene recep-
tor 1a showed a similar pattern as illustrated in Fig. 5a with
acetate as a guest. All anions induced red shifts of the band at
339 nm to the same extent as for 2a. Titration plots for Cl-,
F- and AcO- (Fig. 5b) were biphasic with rapid increase in
absorbance at low anion concentrations followed by slow
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391
Fig. 3 Perspective view of the
molecular structure of
compound 1b. a Lateral views
and b top view. Ellipsoids are
shown at the 30% probability
level
RH þ Aꢁ ꢀ Rꢁ þ HA
ð1Þ
ð2Þ
thioureido group, smaller downfield shift by 0.3 ppm of the
signal of aromatic protons in ortho positions to thioureido
group due to a through-space interaction with hydrogen
bound acetate anion and even smaller upfield shift by
0.06 ppm of the signal or aromatic protons in ortho posi-
tions to nitro group due to an inductive shielding effect of
the bound anion. The shape of titration plots for NH pro-
tons (Fig. 7) indicates the binding of two acetate anions to
one receptor molecule and the fitting agrees with inde-
pendent binding of each acetate anion to one thioureido
group of 1a with K1 = 3000 600 M-1. The reason of
why the hydrogen bonding is the predominant process in
the NMR experiment is that in this case the concentration
of receptor is 100 times higher than in UV–Vis experiment
and a large amount of acetic acid liberated during depro-
tonation shifts the equilibrium (1) to the left.
K3 ¼ ½Rꢁꢂ½HAꢂ=½RHꢂ½Aꢁꢂ
The interaction of thiacalixarene 1a with acetate quali-
tatively proceeds in the same way. Fig. 6a illustrates the
course of spectrophotometric titration of 1a by Bu4NOAc
indicating formation of a colored deprotonated form with
kmax 483 nm. The yield of the deprotonated form under
‘‘saturation’’ is less than 50% and therefore more than the
half of the receptor should be transformed simultaneously
into a hydrogen bonded complex.
The NMR titration of 1a with acetate (Fig. S6, Sup-
plementary Material) shows a behavior typical for hydro-
gen bonding [35–38]: broadening and strong downfield
shifts by 3 ppm of the signals of N–H protons of the
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Fig. 4 a Spectrophotometric titration of 4.8 9 10-5
Bu4NOAc in CHCl3. In this and following figures arrows show the
directions of spectral changes at increasing guest concentrations;
inset—titration curve at 390 nm. b Titration curves for 4.8 9 10-5
2a with Bu4NCl (lower scale), Bu4NF and Bu4NH2PO4 (upper scale)
in CHCl3. Solid lines fitting curves to the 1:1 binding isotherm
M 2a by
Fig. 5 a Spectrophotometric titration of 1.5 9 10-5
M 1a by
Bu4NOAc in CHCl3. b Titration curves for 1.5 9 10-5 M 1a
(absorbance at 390 nm) with Bu4NCl, Bu4NOAc, Bu4NF (lower
scale) and Bu4NH2PO4 (upper scale) in CHCl3
M
The deprotonation of 1a under conditions of UV–Vis
titration can be confirmed by additions of small amounts of
acetic acid, which suppress the deprotonation without
affecting the hydrogen bonding equilibrium [34]. Indeed,
the spectral course of titrations in the presence of 2–3 mM
AcOH was typical for hydrogen bonding complexation
(Fig. S7, Supplementary Material) and from these results
the value of K1 given in Table 3 was obtained. The inset in
Fig. 6b shows the profiles of absorbance at 483 nm vs.
acetate concentration in the presence of increased amounts
of acetic acid. Fitting of these profiles by Hyperquad to a
set of equations involving hydrogen bonding and depro-
tonation equilibria allowed us to estimate the value of
Table 2 Binding constants (log K) for association of anions with
receptors 1a, 1b and 2a, 2b in chloroform. Relative error in K values
10% ( 0.04 in log K)
Anion
1a
2a
1b
2b
log K1
log K2
log K1
log K1
log K1
Cl-
F-
AcO-
3.87
4.57
5.30
4.00
\1.7
2.00
3.32
3.17
3.86
4.46
4.58
4.26
4.42
4.65
4.30
3.52
3.90
4.01
3.88
-
H2PO4
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393
Table 3 Binding (log K1) and deprotonation (K3) constants for interactions of anions with receptors 1a,b and 2a,b in DMSO
Anion
1a
2a
1b
2b
log K1
K3
log K1
K3
log K1
log K1
Cl-
1.57 0.03
3.48 0.05
3.30 0.05
1.12 0.01
3.06a
1.38 0.02
4.33 0.05
4.74 0.05
1.20 0.03
3.04a
AcO-
H2PO4
a
0.32 0.05
(2.0 0.1)910-3
0.05a
(3.2 0.1)910-4
-
3.08 0.05
2.86 0.05
Ref. [34]
K3 = 0.32 0.05, which was six times larger than previ-
ously determined K3 for 2a (see Table 3). Since log K3 =
pKa(AcOH) - pKa(RH) and pKa(AcOH) = 12.3, [39] one
obtains pKa(1a) = 12.8. Thus the thiourea group of the
thiacalixarene receptor is somewhat more acid than the
thiourea group of the corresponding receptor 2a (pKa =
13.6) [34].
-
The spectral course of the titration of 2a by H2PO4
(Fig. S8, Supplementary Material) resembles that observed
with acetate. Titrations in the presence of added AcOH
were performed (a typical titration is shown in Fig. 8, solid
squares) in order to separate H-bonding and deprotonation
equilibria, which allowed us to determine the K1 value
-
given in Table 3. Since the conjugated acid for H2PO4 is
H3PO4 rather than AcOH we repeated titrations of 2a with
-
H2PO4 but in the presence of H3PO4 instead of AcOH.
The deprotonation was suppressed but the titration curves
in the range 360–400 nm, where the absorbance changes
are due to formation of the hydrogen bonded complex,
displayed clear inflection points at the ratio [H2PO4-]/
[H3PO4] = 1, Fig. 8. This means that H3PO4 suppresses
also the hydrogen bonding until an excess of the anion is
applied and the only possible reason for this effect is the
-
complexation of H2PO4 with H3PO4, Eq. 3.
AH þ Aꢁ ꢀ A2Hꢁ
ð3Þ
ð4Þ
KA2H ¼ ½A2Hꢁꢂ=½AHꢂ½Aꢁꢂ
The quantitative analysis of titration curves obtained in
the presence of phosphoric acid allowed us to estimate K3
given in Table 3 and the homoconjugation constant
log KA2H = 3.9 0.1 (Eq. 4) for the formation of com-
-
-
plex [H2PO4 ꢀ H3PO4]. Lower K3 value for H2PO4 as
compared with that for AcO- reflects lower basicity of the
former. Assuming pKa = 13.6 for 2a one obtains from this
K3 value the pKa = 10.1 for H3PO4 in DMSO. The stability
Fig. 6 a Spectrophotometric titration of 1.9 9 10-5
Bu4NOAc in DMSO. b The titration curve at 483 nm; solid line is
the fitting curve to a scheme involving simultaneous hydrogen
bonding and deprotonation of 1a; inset: titrations with added AcOH
M 1a by
-
of complex [H2PO4 ꢀ H3PO4] is much higher than that of
analogous acetic acid—acetate complex (log KA2H = 2.1
in DMSO) [34] apparently due to possibility of formation
of two instead of one hydrogen bonds between the anion
and acid. No detectable interaction was observed between
in water [40], and the respective homoconjugation complex
was found, for example, in the crystal structure of
[(g5-C5Me5)2Co][H3PO4][H2PO4] [41]. At the same time to
the best of our knowledge the homoconjugation of dihy-
drogenphosphate in DMSO has never been described. The
-
H2PO4 and acetic acid. It is worth mentioning that weak
association between H3PO4 and H2PO4- was detected even
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J Incl Phenom Macrocycl Chem (2010) 68:387–398
Fig. 7 Chemical shifts of NH protons (left axis NH group adjacent to
the aromatic ring, right axis NH group adjacent to the methylene
group) in the NMR titration of 3 mM 1a by Bu4NOAc in DMSO
Fig. 9 a Spectrophotometric titration of 5.25 9 10-5 2b by H2PO4
-
in DMSO; b Titration curves for 2b (open squares) and 2.2 9 10-5
1b (solid squares)
given in Table 3. The value of K3 agrees very well with that
calculated as log K3 = pKa(H3PO4) - pKa(1a) = -2.7.
Interactions of urea derivatives 1b and 2b with chloride
anions involved simple hydrogen bonding with K1 values
similar to those for 1a and 2a, Table 3. Fluoride anions
induced deprotonation of both 1b and 2b, but the spectral
course of titration indicated a complicated reaction mech-
anism, which we were unable to fit to any scheme: the
formation of the colored deprotonated form occurred very
sharply in a narrow concentration range of fluoride about
1 mM. Similar behavior was reported recently for the
interaction of fluoride anions with another N-nitrophenyl
urea derivative in DMSO [42].
Fig. 8 Titration curves of 4.8 9 10-5
Bu4NH2PO4 in DMSO in the presence of added acids: solid squares
AcOH, open squares and solid triangles H3PO4
M 2a at 400 nm by
-
stronger homoconjugation of H2PO4 as compared to that
of AcO- explains why this less basic anion induces the
deprotonation of 2a to approximately the same extent as
acetate. This can be attributed to the participation of two
anions in the deprotonation process in accordance with the
known mechanism when the equilibrium of deprotonation
(1) is shifted to the right by complexation of the acid lib-
erated at this step with the second anion [35–38].
-
-
Interaction of H2PO4 with 1a also involved both
Interactions of 1b and 2b with AcO- and H2PO4
deprotonation and hydrogen bonding. The similar analysis
involving titration in the presence of added AcOH was
employed to determine the true binding constant K1 for the
hydrogen bonding association and deprotonation constant K3
involve mainly the hydrogen bonding with a very small, less
then 5% formation of the deprotonated form in the case of
thiacalixarene receptor 1b (Fig. S9, Supplementary Mate-
rial). Results for 2b and AcO- were reported previously
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J Incl Phenom Macrocycl Chem (2010) 68:387–398
395
-
[34]. Spectrophotometric titrations of 1b and 2b by H2PO4
intramolecular hydrogen bonding between urea groups
offsets the advantage of cooperative anion complexation
by correctly positioned functional groups. A previously
unnoticed aspect is a strong complexation of phosphoric
were of similar type. Figure 9a illustrates the titration
experiment for 2b and Fig. 9b shows the titration profiles
for both receptors. Results for both receptor fit well to a
simple 1:1 association model with K1 given in Table 3.
The results collected in Table 3 allow us to compare the
behavior of thiacalixarene urea and thiourea receptors and
corresponding monofunctional compounds in two types of
equilibria: hydrogen bonding (K1) and deprotonation (K3).
The values of K3 increase nearly by one order of magnitude
on going from 2a to 1a. A possible reason for this is a
strong electron accepting effect of the thiacalixarene
macrocycle, which is transmitted even through the chain of
two methylenes. A structural evidence in favor of this
explanation is some elongation of the C=S bond from
-
acid by H2PO4 in DMSO, which explains why this anion
deprotonates thiourea receptors in spite of its low basicity.
Experimental section
5,11,17,23-Tetra-tert-butyl-2,8,14,20-tetrathiacalix[4]arene-
25,26,27,28-tetraol, 5,11,17,23-tetra-tert-butyl-25,27-di
[(benzyl)methoxy]-26,28-dihydroxy-2,8,14,20-tetrathiaca-
lix[4]arene (3),10 N-methoxyethyl-N0-(4-NO2-phenyl)thio-
urea (2a) and N-methoxyethyl-N0-(4-NO2-phenyl)urea (2b)
were prepared according to the reported procedure [34].
˚
˚
1.652(5) A in 2a to 1.689(5) A in 1a. Also in line with this,
signals of NH protons in 1a are shifted by 0.07 ppm
downfield as compared to their positions in 2a. The
hydrogen bonding of anions with 1a is somewhat stronger,
by a factor of 2 or less, than with 2a. The effect is similar
for all anions and most probably reflects increased acidity
of the thiourea groups in 1a, rather than a chelate com-
plexation. For the urea receptors 1b and 2b deprotonation
is observed only with the most basic fluoride anion and,
unfortunately, cannot be characterized quantitatively due to
the complexity of the system. In the hydrogen bonding
association the advantage of bisurea receptor is clearly seen
in greatly enhanced affinity of 1b as compared to 2b
towards H2PO4-. A smaller, but still significant effect is
observed with AcO-, but with Cl- the effect is small. This
selectivity of the chelate effect can be attributed to the
different geometry of anions, which must fit the cleft
between two ureido groups. Interestingly, in DMSO the
chelate effect for ureido receptor 1b is much larger than in
chloroform (cf. Table 2). A possible reason for this is that
DMSO disrupts intramolecular hydrogen bonds between
urea groups in 1b interfering with anion complexation in
chloroform. Thus better preorganization of bis-ureido thi-
acalixarene receptor as compared to bis-thioureido deriv-
ative leads to a more efficient binding only in more polar
solvent.
5,11,17,23-Tetra-tert-butyl,25,27-di[(benzyl)methoxy]-
26,28-bis(carbamoylmethoxy)-2,8,14,20-
tetrathiacalix[4]arene (4)
To a solution of 3 (1 g, 1.11 mmol) in dry acetone
(50 mL), Cs2CO3 (1.8 g, 5.55 mmol) and 2-bromoacet-
amide (76 mg, 5.55 mmol) were added and the mixture
was refluxed for 24 h under argon, cooled at room tem-
perature and concentrated under reduced pressure. The
residue was dissolved in dichloromethane and washed with
1 N HCl. The organic layer was separated, washed with
brine (2 9 15 mL) and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure and the res-
idue triturated with MeOH to give 4 (676 mg, 64%) as a
white solid. Recrystallization from CHCl3–MeOH afforded
1
6 as white solid. M.p. 175–178 °C. H NMR d (CDCl3)
0.81 (s, 18H), 1.26 (s, 18H), 4.48 (s, 4H), 5.07 (s, 4H), 6.87
(t, J = 4.98 Hz 5H), 7.01 (t, J = 4.98 Hz 5H), 7.09 (s,
4H), 7.40 (s, 4H). 13C NMR d 30.91, 31.43, 34.22,
34.58,67.48, 71.28, 127.17, 127.24, 128.12, 128.35,
128.89, 129.05, 129.52, 137.34, 147.80, 147.89, 154.94,
170.73. MS m/z: 1015.40 (M?). Anal. Calcd. for
C58H66N2O6S4: C, 68.60; H, 6.55; N 2.76. Found: C, 68.33;
H, 6.49; N, 2.75%.
Conclusions
5,11,17,23-Tetra-tert-butyl,25,27-di[(benzyl)methoxy]-
26,28-bis(2-aminoethyloxy)-2,8,14,20-
tetrathiacalix[4]arene (5)
Crystal structures of disubstituted thiacalix[4]arenes indi-
cate that the bisthiourea derivatives are especially poorly
preorganized for anion complexation, firstly, due to syn,anti
conformation of the thioureido group and, secondly, due to
the divergent arrangement of these groups. In contrast, the
bisurea derivative has a well preorganized structure. One
observes however that the effect of preorganization is sol-
vent dependent because in a low polar medium the
To a 15 mL of BH3/THF solution was added 4 (676 mg,
0.66 mmol) and the reaction mixture was stirred for 1 h at
ambient temperature, then reflux for 5 h under argon. The
mixture was allowed to cool to ambient temperature, and
an additional aliquot (10 mL) of the borane solution added.
The mixture was refluxed for an additional 15 h. The
123

396
J Incl Phenom Macrocycl Chem (2010) 68:387–398
solvent was removed under reduced pressure and the res-
idue treated with 20 mL of 1 N HCl and reflux for 1 h.
After cooling down to room temperature, 10% KOH was
added until the solution became basic and extracted with
CH2Cl2 (2 9 15 mL). The solvent was removed under
reduced pressure to give 5 (423 mg, 65%) as a white solid.
Recrystallization from CHCl3–MeOH afforded 5 as white
solid. M.P. 194–197 °C. 1H NMR d (CDCl3) 0.82 (s, 18H),
1.29 (s, 18H), 2.46 (t, J = 5.33 Hz 4H,), 3.94 (t, J =
5.35 Hz 4H), 5.04 (s, 4H), 6.86 (t, J = 4.99 Hz 5H), 7.07
(s, 4H), 7.12 (t, J = 4.99 Hz 5H), 7.38 (s, 4H). MS m/z:
987.40 (M?). 13C NMR d 29.92, 30.96, 31.56, 31.74,
41.98, 70.61, 71.31, 127.48, 128.14, 128.88, 129.40,
131.19, 143.90. Anal. Calc. For C58H70N2O4S4: C, 70.55;
H, 7.15; N, 2.84. Found: C, 70.76; H, 7.17; N, 2.85%.
MS (FAB, m/z) 1315 (M?).Anal. Calcd. for C72H78
N6O10S4 C, 65.73; H, 5.98; N 6.39. Found: C, 65.09; H,
5.89; N, 6.41%.
X-ray crystallography
X-ray diffraction studies were performed on a Bruker-APEX
diffractometer with a CCD area detector (kMoKa
=
˚
0.71073 A, monochromator: graphite). Frames were col-
lected at T = 100 K (compounds 1a,1b) and T = 293 K
(compounds 2a,2b) via x//-rotation at 10 s per frame
(SMART) [43]. The measured intensities were reduced to F2
and corrected for absorption with SADABS (SAINT-NT)
[44]. Corrections were made for Lorentz and polarization
effects. Structure solution, refinement and data output were
carried out with the SHELXTL-NT program package [45,
46]. Non hydrogen atoms were refined anisotropically, while
hydrogen atoms were placed in geometrically calculated
positions using a riding model.
5,11,17,23-Tetra-tert-butyl,25,27-di[(benzyl)methoxy]-
26,28-bis[(4-nitrophenylthioureido)ethoxy]-2,8,14,20-
tetrathiacalix[4]arene (1a)
For 1a the asymmetric unit contains one molecule halve.
Solvent molecules were present in the crystal lattice of
compound 1b (CH3CN). Although relatively large crystals
could be grown and the data collections were performed at
T = 100 K, for compound 1b the R value is somewhat
elevated. Besides the large molecular structures, for com-
pound 1b this can be attributed to the weak diffraction of
the crystals at theta angles[20°. However, the data were of
sufficient quality to determine properly the molecular and
crystal structures. It should, however, be noticed that the
low resolution of the data affects the reliability of the bond
lengths and angles, intermolecular distances and the
refinement of the anisotropic thermal parameters. In the
case of compound 1b SIMU, DELU and ISOR instructions
have been used during the refinement.
To 5 (423 mg, 0.43 mmol) in 15 mL of CH2Cl2, was added
4-nitrophenyl isothiocyanate (232 mg, 1.29 mmol) and the
mixture was stirred for overnight under nitrogen. The sol-
vent was removed under reduced pressure and the residue
triturated with MeOH and washed with hexane to give 1a
(409 mg, 65%) as a pale yellow powder. Recrystallization
from CHCl3–CH3CN afforded 1a as pale yellow crystals.
1
M.p. [200 °C. H NMR d (CDCl3) 0.83 (s, 18H), 1.21 (s,
18H), 3.81 (br t, 4H), 4.30 (br t, 4H), 4.93 (s, 4H), 7.13 (t,
J = 5.10 Hz 5H), 7.16 (s, 4H), 7.22 (t, J = 5.12 Hz 5H),
7.38 (s, 4H), 7.43 (d, J = 7.45 Hz 4H), 7.86 (br s, 2H),
7.97 (br s, 2H), 8.17 (d, J = 7.45 Hz). 13C NMR d (CDCl3)
30.96, 31.55, 34.12, 34.48, 70.86, 73.64, 122.72, 125.59,
127.34, 127.50, 127,86, 128.08, 128,59, 131.82, 132.43,
137.28, 143.61, 144.60, 146.43, 146.86, 157.31, 158.53,
180.84. MS (FAB, m/z) 1347 (M?).Anal. Calcd. for
C72H78N6O8S6 (1347.82): C, 64.16; H, 5.83; N 6.24.
Found: C, 64.09; H, 5.79; N, 6.20%.
Crystallographic data for the structures reported in this
paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publications no.
CCDC-706665-706669. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: (?44)1223-336-033;
e-mail: deposit@ccdc.cam.ac.uk, www: http://www.ccdc.
cam.ac.uk).
5,11,17,23-Tetra-tert-butyl,25,27-di[(benzyl)methoxy]-
26,28-bis[(4-nitrophenylureido)ethoxy]-2,8,14,20-
tetrathiacalix[4]arene (1b)
Similar procedure as that for 1a was applied with the yield
1
63%. Mp. [200 °C. H NMR d (CDCl3) 0.83 (s, 18H),
Spectrophotometric and 1H NMR Titrations
1.15 (s, 18H), 3.17 (br t, 4H), 4.04 (br t, 4H), 5.05 (s, 4H),
5.90 (br s, 2H), 6.95 (t, J = 5.10 Hz 5H), 7.09 (t,
J = 5.12 Hz 5H), 7.13 (s, 4H), 7.42 (d, J = 7.45 Hz 4H),
7.55 (br s, 2H), 8.07 (d, J = 7.45 Hz,4H). 13C NMR d
(CDCl3) 30.94, 31.29, 34.13, 34.45, 40.70, 70.38, 71.44,
117.96, 125.47, 127.42, 127.56, 127.91, 128.21, 128.32,
129.95, 137.20, 142.43, 145.54, 146.88, 155.45, 157.40.
The absorption spectra were recorded after additions of
aliquots of stock solutions of tetrabutylammonium salts in
respective solvents to a 10-5–10-4 M receptor solution in
DMSO or chloroform in a quartz cuvette placed in a
compartment of a diode array spectrophotometer thermo-
stated at 25 0.1 °C with a recirculating water bath. NMR
titrations were performed on a 300 MHz spectrometer with
123

J Incl Phenom Macrocycl Chem (2010) 68:387–398
397
receptor based on the calix[4]arene framework using two dif-
ferent cationic effectors. Am. Chem. Soc. 127, 5507–5511 (2005)
16. Yakovenko, A.V., Boyko, V.I., Kalchenko, V.I., Baldini, L.,
Casnati, A., Sansone, F., Ungaro, R.J.: N-linked peptidoca-
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more concentrated stock solutions in the respective deu-
terated solvents adding aliquots of them to 5–20 mM
receptor solutions in DMSO-d6 or CHCl3-d directly to
NMR tubes. In order to test possible autoassociation of
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´
Acknowledgments Carol Perez-Casas thanks DGAPA UNAM and
CONACyT for the postdoctoral fellowships and Anatoly Yatsimirsky
thanks DGAPA UNAM for Sabbatical fellowship.
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