Preferred dimerization of tetra-tolyl- and tetra-tosylurea derivatives of flexible and rigidified calix[4]arenes

Article abstract of DOI:10.1039/b410462e

The dimerization of tetratolyl- and tetratosyl-urea derivatives 1 and 2, derived from a tetrapentoxy calixarene in the cone conformation and of the corresponding tetra-urea derivatives 3 and 4, in which the cone conformation is rigidified by the two crown-3 tethers, have been studied. All six possible equimolar mixtures were examined by ¹H NMR using CDCl₃ and CD₂Cl₂ as solvents. While no heterodimers are found for the combinations 1/3 and 2/4 in either solvent, all remaining combinations lead to the (exclusive) formation of heterodimers in CD₂Cl₂. In CDCl₃ heterodimers are only observed for the combinations of 3 with 2 or 4. These results are discussed in terms of entropic and enthalpic contributions and compared with MD-simulations in a box of chloroform solvent molecules.

Full text of DOI:10.1039/b410462e

View Article Online / Journal Homepage / Table of Contents for this issue
A R T I C L E
Preferred dimerization of tetra-tolyl- and tetra-tosylurea derivatives
of flexible and rigidified calix[4]arenes†
Yuliya Rudzevich,a Myroslav O. Vysotsky,a Volker Böhmer,*a Marcus S. Brody,b
Julius Rebek, Jr.,*b Frank Brodac and Iris Thondorf*c
a
Abteilung Lehramt Chemie, Fachbereich Chemie und Pharmazie, Johannes Gutenberg-
Universität Mainz, Duesbergweg 10-14, D-55099, Mainz, Germany.
E-mail: vboehmer@mail.uni-mainz.de
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla,
b
CA 92037, USA
c
Fachbereich Biochemie/Biotechnologie, Institut für Biochemie, Martin-Luther-Universität
Halle-Wittenberg, Kurt-Mothes-Str. 3, D-06099, Halle, Germany
Received 9th July 2004, Accepted 7th September 2004
First published as an Advance Article on the web 4th October 2004
The dimerization of tetratolyl- and tetratosyl-urea derivatives 1 and 2, derived from a tetrapentoxy calix[4]arene
in the cone conformation and of the corresponding tetra-urea derivatives 3 and 4, in which the cone conformation
is rigidified by the two crown-3 tethers, have been studied. All six possible equimolar mixtures were examined by
1H NMR using CDCl3 and CD2Cl2 as solvents. While no heterodimers are found for the combinations 1/3 and
2/4 in either solvent, all remaining combinations lead to the (exclusive) formation of heterodimers in CD2Cl2. In
CDCl3 heterodimers are only observed for the combinations of 3 with 2 or 4. These results are discussed in terms of
entropic and enthalpic contributions and compared with MD-simulations in a box of chloroform solvent molecules.
We recently showed that the rigidification of the calix[4]arene
Introduction
skeleton by two short crown ether bridges in tetraureas of
type 3 led to remarkable changes of their properties. There is,
for instance, a strong increase of the thermodynamic stability
of dimers 3·3 which tolerate larger amounts of DMSO than the
analogous dimers 1·1.8 The kinetic stability expressed by the rate
of guest exchange9 is higher as well. Rather unexpected was the
observation that 1 and 3 obviously do not form heterodimers.
A mixture of both tetraureas in CDCl3 contains only the two
homo-dimers 1·1 and 3·3.
To get a better understanding of the factors which control the
homo- or hetero-dimerization of such tetraurea calix[4]arenes
we studied the dimers formed in binary mixtures of tetraureas
1–3 including the hitherto unknown rigid tetra-tosylurea 4.
It is now well established that tetraurea derivatives of
calix[4]arenes form dimeric capsules in apolar, aprotic solvents.
In chloroform or benzene these are held together by a seam of
hydrogen bonds between the urea functions attached to the
wider rim.1 The inclusion of a suitable guest, often the solvent,
is a necessary condition for this dimerization. The dimeric
1
structure, initially proposed on the basis of H NMR spectra,2
has been confirmed subsequently by several X-ray structures,3
and for cationic guests by mass spectroscopy.4
Results and discussion
The NMR spectra shown in Fig. 1 clearly show that the two
homodimers are present in the mixture of 1 with the correspond-
ing tetra tolyl urea 3, derived from the rigidified calix[4]arene.
This result can be tentatively explained on an entropic basis,
since the internal mobility of a dimer/capsule formed with 3
Chart 1 Tetraurea derivatives of calix[4]arene.
If two tetraurea derivatives of type 1 (Chart 1), where R may
be alkyl or aryl are mixed in a suitable solvent the two possible
homodimers and the heterodimer are usually formed in a (more
or less) statistical ratio of 1:2:1. This formation of heterodimers
could be considered as a strong and unambiguous proof of the
dimerization.5 Unexpected, and still not understood in detail,
was the observation, that a mixture of the tolyl urea 1 with the
tetra tosyl urea 2 contained only the heterodimer 1·G·2, if 1 and
2 are present in stoichiometric amounts, accompanied inevitably
by the respective homodimer, if one of the tetraureas is present
in excess.6 This exclusive formation of heterodimers was
successfully used to control the structure of larger assemblies.7
† Electronic supplementary information (ESI) available: Molecular
dynamics simulations and free energy analyses. See http://www.rsc.org/
suppdata/ob/b4/b410462e/
Fig. 1 Sections of the 1H NMR (400 MHz, CDCl3, 25 °C) spectra of:
a) homodimer 1·1; b) homodimer 3·3; c) mixture of 1 and 3 resulting in
two homodimers.
3 0 8 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 8 0 – 3 0 8 4
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

View Article Online
Table 1 Dimerization experiments between tetraurea calix[4]arenes 1–4
CDCl3
CD2Cl2
Entry
Mixture
Equilibrium state picture
Determining factor
Equilibrium state picture
Determining factor
I
II
III
IV
V
1 (Tol, F) + 3 (Tol, R)
2 (Tos, F) + 4 (Tos, R)
1 (Tol, F) + 2 (Tos, F)
3 (Tol, R) + 4 (Tos, R)
1 (Tol, F) + 4 (Tos, R)
3 (Tol, R) + 2 (Tos, F)
−
−
+
−
+
−
S
S
H
H
H > S
H < S
(−)
−
S
S
H
H
H > S
H > S
+
+
+
VI
+
+ indicates the exclusive formation of the heterodimer; − means that only the two homodimers are present; (−) stands for an irregular assembly; the
factor which disfavors the formation of heterodimers is designated by S (entropic factor); the factor which favors the formation of heterodimers is
designated by H (enthalpic factor).
(homo- or heterodimer) is much more restricted than that of
a homodimer of 1. Thus, the formation of heterodimers 1·G·3
would be entropically less advantageous than the exclusive
formation of homodimers 1·G·1 and 3·G·3.
This observation raises the question, which of the two
tendencies would be more pronounced, the formation of
heterodimers between tolyl and tosyl ureas, or the absence of
heterodimers in a mixture of a flexible and rigid tetra urea?
In other words, with the compounds discussed so far, are
heterodimers formed exclusively in a mixture of 2 and 3 or not?
To obtain a complete answer on this question, which might
be important for the selective construction of supramolecular
assemblies via reversible bonds, we included also the tetra-tosyl
urea 4, derived from the rigidified calix[4]arene.
a) The combination of a flexible with a rigid calixarene
disfavors the formation of heterodimers. For entries I) and II)
this is the only factor and heterodimers are not observed for tolyl
as well as tosyl ureas in both solvents.
b) The combination of tolyl with tosyl ureas favors the
exclusive formation of heterodimers. This is the only factor
in entries III) and IV) and it is working for rigid as well as
flexible calixarenes in CD2Cl2. The situation is less clear for
CDCl3 where the heterodimer is formed for flexible ureas but
not for the rigid ones. Thus we have the interesting situation
(entry IV), that the dimerization can be «switched» between
hetero (CD2Cl2) and homo (CDCl3) by the solvent, or (perhaps
better) by the guest, since most probably the/a solvent molecule
is included as guest.
As expected, all four tetraureas form homodimers in CDCl3
solutions containing only a single calixarene as evidenced by
clear 1H NMR spectra with sharp signals. Surprisingly however,
both tetratosyl ureas 2 and 4 form homodimers also in CD2Cl2,
where the spectrum of 1 shows only broad and uninterpretable
bands. Broadening of signals is also observed for 3 in CD2Cl2
but the chemical shifts are in accordance with those of the
homodimer 3·3 in CDCl3 (Fig. 2).
To study the formation of heterodimers the single calixarenes
were dissolved either in CDCl3 or in CD2Cl2 (at c = 3.08 mM),
equimolar amounts of the two solutions (containing the
respective homodimers) were mixed, and spectra were recorded
immediately, after 3 h, 20 h‡ and one week. In those cases, where
heterodimers with the rigid calixarenes 3 and 4 were formed, this
formation was slow. After 3 h usually about 50% conversion was
observed. The reaction was complete in all cases after 20 h (see
Fig. 3), and no further changes were noticed in the spectra after
one week.
In entries V) and VI) both effects are present. And in CD2Cl2
the situation is clear, the tendency of tosyl/tolyl residues to
induce the formation of heterodimers is dominant for both
combinations. In CDCl3 however, in agreement with entry IV)
the «tosyl/tolyl» effect is less pronounced than the «flexible/
rigid» effect, and heterodimers are not formed in entry VI). This
may be due to 3, the compound present in both entries IV) and
VI).
Although this is not yet a detailed explanation, it is a self-
consistent, general picture. In accordance to all observations the
mixing of 1·G·2 and 3·G·4 heterodimers together does not lead
to any changes in the spectra during 3 days.
Stereochemistry
Dimers of the tetraureas 3 and 4 are interesting also for their
stereochemistry. The single calix[4]arene has C2v symmetry,
like a calix[4]arene consisting of two different phenolic units in
alternating sequence (ABAB). However, the symmetry planes
intersect opposite methylene bridges and not opposite phenolic
units. A homodimer 3·3 or 4·4 thus has D2-symmetry, which is
reduced to C2 by the directionality of the hydrogen bonded belt.
Thus, with or without directionality, they form only one pair of
enantiomers, since the chirality is caused by the combination of
the two calixarenes and not by this directionality.
Table 1 summarizes the results obtained for all combinations
of 1 to 4 and both solvents after equilibrium was reached. They
can be rationalized by considering two factors.
‡ The rate of the dimerization depends on the amount of water in the
solvents.
Fig. 2 Selected 1H NMR spectra (400 MHz, 25 °C) of tetraureas: a) irregular aggregates of 1 in CD2Cl2; b) homodimer 2·2 in CD2Cl2; c) homodimer
4·4 in CDCl3 d) homodimer 4·4 in CD2Cl2.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 8 0 – 3 0 8 4
3 0 8 1

View Article Online
Table 2 Mean free energy and entropic term calculated for all possible
dimeric capsules
Dimer
Gtotala ± rb/kcal mol−1
−TS/kcal mol−1
1·1
2·2
3·3
4·4
1·3
2·4
1·2
3·4
1·4
2·3
−114.4 ± 2.1
−71.1 ± 2.3
−35.8 ± 2.0
−7.8 ± 2.3
−76.0 ± 1.9
−30.5 ± 2.3
−94.2 ± 2.2
−13.5 ± 2.2
−53.5 ± 2.3
−52.7 ± 2.0
−212.7
−235.6
−205.0
−244.6
−208.7
−248.6
−233.3
−225.6
−229.8
−229.8
a Average free energies from 4000 structures. b r = standard errors of the
mean energies.
replacing the ether groups (Y) and the urea groups (R) appro-
priately. To save computation time Y = Et was used for 1 and 2.
After equilibration11 MD simulations were performed for 8 ns
and snapshots were collected every 2 ps.
Fig. 3 Formation of heterodimers of 3 and 4 in CD2Cl2. 1H
NMR spectra (400 MHz, 25 °C) were recorded a) immediately after
mixing; b) 3 h after mixing; c) 20 h after mixing. The NH and calixarene
aromatic signals of dimers 3·3, 4·4 and 3·4 are represented by the blue,
red and green colours, respectively.
Unfortunately significant differences could not be found for
the averaged geometrical parameters between the ten dimers
(four homodimers and six heterodimers). For example the
pole to pole distances (between the centers of the planes of the
methylene bridge carbons) vary between 9.15 and 9.44 Å and
the volume of the capsule between 207 and 220 Å3. The NO
distances for hydrogen bonds for the amino functions attached
to the calixarene ranged from 2.25 to 2.36 Å and those for amino
functions attached to the urea residues R from 2.07 to 2.14 Å.
Significant differences are also not found for the time averaged
number of hydrogen bonds formed by the two types of NH-
groups. Occasionally NHOS hydrogen bonds were observed
in homo- and heterodimers containing the tosylureas 2 and 4.
Energetic parameters (DG, DS) for the dimerization are
collected in Tables 2 and 3. They were calculated by post-
processing of the MD trajectories using the MM-PBSA
method12 on the basis of all 4000 snapshots. As seen from the
third column of Table 3, where a negative DGtotal means, that the
heterodimer is favored over the two homodimers, these values
are in agreement with the experimental results in Table 1, with
the single exception of entry I. However, keeping in mind that
the standard errors of the mean free energy RGtotal is in the range
of 1.9–2.3 kcal mol−1 one has to state that these differences in
DGtotal, ranging between −2.2 and 3.0 kcal mol−1, are not really
significant.
The situation is different for heterodimers, which are C4v
(1·2) or C2v-symmetric (1·4, 2·3) and become chiral (C4 and
C2-symmetric, respectively) by the directionality of the hydro-
gen bonded belt. Both factors are present in heterodimers 3·4
which are C2-symmetric already by the combination of the two
calixarenes. The directionality of the H-bonded belt is added
now as an independent element of chirality (this is the case only
in heterodimers) and two diastereomeric pairs of enantiomers
(C2-symmetry) are expected, as demonstrated schematically in
Fig. 4. Indeed, these are observed in the 1H NMR spectra.
Thus, we have to conclude that the equilibrium between the
two homodimers and the respective heterodimer, e.g. 1·1 + 2·2 
2 1·2 is too delicate to be modelled by MD simulations. Larger
geometric factors of a dimeric capsule, such as the general
difference between hydrogen bonds formed by the inner and
outer NH-groups are correctly reported by the MD simula-
tions (in agreement with NMR- and X-ray data). However
the energetic differences between various dimers are obviously
too small and cannot be sufficiently explained by the simula-
tions. Although this is disappointing with respect to our initial
ambitions, we believe that this result nevertheless should be
reported.
Fig. 4 Schematic representation of the possible stereoisomers of
heterodimers 3·4. The directionality of the hydrogen bonded belt is
indicated by arrows. Without directionality I and II are identical as
well as II and I.
Molecular dynamics simulations
The tendency to form heterodimers between tolyl and tosylureas
is entirely predominant in methylene chloride, as shown by
entries III–VI (Table 1), and is the most important factor in
chloroform for entries III and V. To get a better understanding
of this phenomenon we started molecular dynamics simulations
for all combinations of tetraureas 1 to 4, since numerous
attempts to obtain diffraction quality single crystals from such
a heterodimer failed (so far).
Simulations were carried out in a chloroform box using
the AMBER 710 software package. The starting geometry of
a capsule was obtained from the known crystal structures,
placing one chloroform molecule as guest in the interior, and
Conclusions
Wide rim tetratolyl (1, 3) and tetratosyl (2, 4) ureas with a
more flexible calix[4]arene tetrapentylether (1, 2) or a rigidified
biscrown-3 ether derivative (3, 4) as basic skeleton form
homodimers in apolar solvents such as CDCl3. For mixtures
of two tetraureas there is the additional possibility to form
heterodimers. Very subtle enthalpic and entropic contributions
involving also the solvent (and guest) are obviously responsible
for the exclusive formation of either homo- or heterodimers in
stoichiometric (1:1) mixtures. This may be concluded from the
observation that for two pairs (3–2 and 3–4) the self-assembly
3 0 8 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 8 0 – 3 0 8 4

View Article Online
Table 3 Formation of homo- and heterodimers; energies in kcal mol−1
a
b
c
Entry
Mixture
Homodimer RGtotal
Heterodimer RGtotal
DGtotal
−TDS
I
II
III
IV
V
1·3
2·4
1·2
3·4
1·4
3·2
−150.3
−63.3
−185.5
−28.0
−106.7
−106.9
−152.0
−61.1
−188.5
−27.0
−107.0
−105.4
−1.7
2.2
−3.0
1.0
−0.3
1.5
0.4
1.0
−0.6
−1.9
−2.0
−1.3
VI
a Calculated as sum of Gtotal of the two homodimers. b Two times Gtotal of the heterodimer. c Column 4 − column 3.
switches from hetero- to homodimers when going from CD2Cl2
to CDCl3. Obviously these subtle effects are also the reasons why
no significant conclusions can be drawn from MD-simulations.
6.74 (1H, d, J 2.4, ArH), 4.92 (2H, d, J 11.6, ArCH2Ar), 4.36
(2H, d, J 11.6, ArCH2Ar), 4.23–3.98 (12H, m, OCH2), 3.67–3.63
(4H, m, OCH2), 3.17 (2H, d, J 11.6, ArCH2Ar), 3.12 (2H, d, J
11.6, ArCH2Ar), 2.48 (6H, s, CH3), 2.47 (6H, s, CH3); m/z (ESI)
1435.5 (M+Na, 100%).
Experimental
All solvents were of analytical quality (p. a.) and were used
without additional purification. The melting points were
uncorrected. All solvents for NMR were purchased from
Self-assembly studies
In a typical experiment tetraurea calix[4]arenes 1 (5.55 mg,
4.32 lmol) and 2 (6.68 mg, 4.32 lmol) were mixed together,
dichlormethane-d2 (0.7 mL) was added and the solution formed
(sometimes with the help of an ultrasonic bath) was transferred
in an NMR tube and 1H NMR spectra were recorded.
1
Deutero GmbH. H NMR were recorded on a Bruker Avance
DRX 400 or a Bruker AC200 instrument at 400 or 200 MHz.
13C NMR spectra were recorded on a Bruker Avance DRX
400 at 100 MHz. The solvent signals were used for calibration
of NMR spectra. Starting tetraamino tetrapentoxy 513 and
tetraamino biscrown 614 calix[4]arenes were synthesized in
accordance with the published procedures.
1
Heterodimers 1·4, 2·3 and 3·4 were prepared analogously. H
NMR spectra of the heterodimers are given below.
1·2 dH (400 MHz, CD2Cl2) NH: 10.81 (4H, s), 8.04 (4H, s),
7.96 (4H, s), 6.91 (4H, br s); ArHTos: 8.14 (8H, d, J 8.2), 7.48
(8H, d, J 8.2); ArHTol: 7.60 (8H, d, J 7.7), 6.87 (8H, d, J 7.7);
ArHcal: 7.88 (4H, s), 7.01 (4H, s), 6.96 (4H, s), 4.86 (4H, s);
ArCH2Ar: 4.58 (4H, d, J 11.7), next 4H are overlapped with
multiplet at 4.00–3.89, 3.33 (4H, d, J 11.7), 2.59 (4H, d, J 11.7);
OCH2: 4.00–3.89 (12H (from them 4H belong to ArCH2Ar), m),
3.60–3.45 (8H, m); CH3Tos: 2.50 (12H, s); CH3Tol: 2.08 (12H, s);
CH2: 1.83–1.72 (8H, m), 1.60–1.19 (40H, m); CH3alk: 0.99 (12H,
t, J 7.2), 0.90 (12H, t, J 7.2).
1·2 dH (400 MHz, CDCl3) NH: 10.52 (4H, s), 8.04 (4H, s), 8.02
(4H, s), 7.62 (4H, s); ArHTos: 8.14 (8H, d, J 8.2), 7.48 (8H, d, J
8.2); ArHTol: 7.57 (8H, d, J 8.3), 6.79 (8H, d, J 8.3); ArHcal: 7.86
(4H, d, J 2.3), 7.04 (4H, d, J 2.3), 6.87 (4H, d, J 2.3), (4H, d, J
2.3); ArCH2Ar: 4.54 (4H, d, J 11.7), 3.91 (4H, d, J 11.7), 3.37
(4H, d, J 11.7), 2.52 (4H, d, J 11.7); OCH2: 3.95–3.84 (8H, m),
3.53–3.40 (8H, m); CH3Tos: 2.48 (12H, s); CH3Tol: 2.05 (12H, s);
CH2: 1.72–1.68 (8H, m), 1.45–1.12 (40H, m); CH3alk: 0.97 (12H,
t, J 7.0), 0.88 (12H, t, J 7.0).
1·4 dH (400 MHz, CD2Cl2) NH: 10.91 (2H, br s), 10.68 (2H,
br s), 8.09 (4H, s), 7.99 (2H, s), 7.96 (2H, s), 7.09 (2H, br s),
6.95–6.90 (2H, br s); ArHTos: 8.14 (8H, d, J 8.3), 7.48 (8H, d, J
8.3); ArHTol: 7.64 (4H, d, J 8.3), 7.61 (4H, d, J 8.3), 6.93 (4H,
d, J 8.3), 6.90 (4H, d, J 8.3); ArHcal: 7.91 (2H, d, J 1.9), 7.88
(2H, d, J 1.9), 7.16 (2H, s), 7.02 (2H, d, J 1.9), 6.99 (4H, s), 4.96
(2H, s), 4.93 (2H, d, J 1.9); ArCH2Ar: 4.60 (2H, d, J 11.7), 4.59
(2H, d, J 11.7), 4.51 (2H, d, J 11.7), next 2H are overlapped
with multiplet at 4.12–3.82, 3.35 (2H, d, J 11.7), 3.34 (2H, d, J
11.7), 2.64 (2H, d, J 11.7), 2.57 (2H, d, J 11.7); OCH2: 4.12–3.82
(22H (from them 2H belong to ArCH2Ar), m), 3.48–3.40 (4H,
m); CH3Tos: 2.51 (12H, s); CH3Tol: 2.12 (12H, s); CH2: 1.51–1.40
(24H, m); CH3alk: 1.02–0.98 (12H, m).
1·4 dH (400 MHz, CDCl3) NH: 10.54 (2H, s), 10.29 (2H, s),
8.08 (2H, s), 8.06 (2H, s), 8.05 (2H, s), 8.00 (2H, s), 7.84 (2H,
s), 7.76 (2H, s); ArHTos: 8.13 (8H, d, J 8.3), 7.41 (8H, d, J 8.3);
ArHTol: 7.59 (4H, d, J 8.3), 7.56 (4H, d, J 8.3), 6.83 (4H, d, J
8.3), 6.81 (4H, d, J 8.3); ArHcal: 7.86 (4H, s), 7.04 (4H, s), 7.00
(2H, s), 6.90 (2H, s), 5.04 (2H, s), 4.92 (2H, s); ArCH2Ar: 4.55
(2H, d, J 11.7), 4.54 (2H, d, J 11.7), 4.42 (2H, d, J 11.7), next 2H
are overlapped with multiplet at 4.12–3.78, 3.37 (2H, d, J 11.7),
3.36 (2H, d, J 11.7), 2.57 (2H, d, J 11.7), 2.52 (2H, d, J 11.7);
OCH2: 4.12–3.78 (22H (from them 2H belong to ArCH2Ar), m),
3.48–3.42 (4H, m); CH3Tos: 2.46 (12H, s); CH3Tol: 2.06 (12H, s);
CH2: 1.50–1.36 (24H, m); CH3alk: 1.01–0.96 (12H, m).
5,11,17,23-Tetratosylurea-25,26,27,28-tetrapentoxycalix[4]-
arene 2
The tetraamine 5 (0.50 g, 0.65 mmol) was dissolved in CH2Cl2
(10 ml) and tosyl isocyanate (0.77 g (0.60 ml), 3.92 mmol) was
added to the solution. The reaction mixture was stirred overnight
at room temperature and then MeOH (20 ml) was added. The
precipitate was filtered, washed with MeOH (3 × 10 ml) and
dried, yielding a white powder (0.65 g, 77%); mp 216 °C; dH
(400 MHz; DMSO-d6) 10.17 (4H, s, NH), 8.42 (4H, s, NH), 7.79
(8H, d, J 7.8, ArHTos), 7.42 (8H, d, J 7.8, ArHTos), 6.60 (8H, s,
ArH), 4.20 (4H, d, J 12.5, ArCH2Ar), 3.71 (8H, t, J 7.0, OCH2),
3.01 (4H, d, J 12.5, ArCH2Ar), 2.40 (12H, s, CH3Tos), 1.80 (8H,
br s, CH2), 1.31 (16H, br s, CH2), 0.87 (12H, t, J 6.4, CH3); dH
(400 MHz, CD2Cl2) 10.11 (4H, s, NH), 7.95 (12H, m, ArH,
ArHTos), 7.76 (4H, s, NH), 7.39 (8H, d, J 7.8, ArHTos), 6.67 (4H,
s, ArH), 4.34 (4H, d, J 11.7, ArCH2Ar), 3.71 (8H, br s, OCH2),
4.34 (4H, d, J 11.7, ArCH2Ar), 2.41 (12H, s, CH3Tos), 1.90 (8H,
br s, CH2), 1.32–1.20 (16H, m, CH2), 0.87 (12H, t, J 6.8, CH3);
m/z (ESI) 1575.7 (M+Na, 100%).
5,11,17,23-Tetratosylurea-25,26-27,28-biscrown-3-calix[4]-arene 4
Tetraamine 6 (0.34 g, 0.54 mmol) was dissolved in a mixture
of THF–CHCl3 = 1:1 (50 ml) and tosyl isocyanate (1.28 g
(0.99 ml), 6.53 mmol) was added to the solution. The reaction
mixture was stirred overnight at room temperature. The solvent
was removed at reduced pressure and Et2O (30 ml) was added.
The crude product was filtered, washed with Et2O (3 × 15 ml),
MeOH (5 ml), precipitated from a CHCl3–MeOH mixture and
dried yielding a light yellow powder (0.35 g, 46%); mp > 206 °C
decomp.; dH (200 MHz; DMSO-d6) 10.47 (4H, br s, NH), 8.44
(4H, s, NH), 7.82 (8H, d, J 7.80, ArHTos), 7.41 (8H, d, J 7.80,
ArHTos), 6.90 (8H, s, ArH), 4.80 (2H, d, J 12.2, ArCH2Ar),
4.31–4.12 (14H, m, ArCH2Ar, OCH2), 3.61–3.35 (4H, m,
OCH2), 3.15–3.12 (2H, d, J 12.2, ArCH2Ar), 2.39 (12H, s, CH3);
dH (400 MHz, CD2Cl2) 10.20 (4H, br s, NH), 8.24 (1H, s, NH),
8.19 (1H, s, NH), 8.13 (1H, s, NH), 8.07 (1H, s, NH), 8.02 (4H,
d, J 8.2, ArHTos), 8.01 (4H, d, J 8.2, ArHTos), 7.97 (1H, d, J 2.4,
ArH), 7.95 (1H, d, J 2.4, ArH), 7.85 (1H, d, J 2.4, ArH), 7.83
(1H, d, J 2.4, ArH), 7.46 (8H, d, J 8.2, ArHTos), 6.82 (1H, d, J
2.4, ArH), 6.80 (1H, d, J 2.4, ArH), 6.75 (1H, d, J 2.4, ArH),
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 8 0 – 3 0 8 4
3 0 8 3

View Article Online
2·3 dH (400 MHz, CD2Cl2) NH: 10.86 (2H, s), 10.73 (2H, s),
References
1 J. Rebek, Jr., Chem. Commun, 2000, 637–643.
8.12 (4H, s), 8.04 (2H, s), 8.03 (2H, s), 7.10–6.95 (2H, br s), 6.81
(2H, br s); ArHTos: 8.14 (8H, d, J 7.7), 7.48 (8H, d, J 7.7); ArHTol
:
2 K. D. Shimizu and J. Rebek, Jr., Proc. Natl. Acad. Sci. USA, 1995,
92, 12403–12407.
3 O. Mogck, E. F. Paulus, V. Böhmer, I. Thondorf and W. Vogt, Chem.
Commun, 1996, 2533–2534; I. Thondorf, F. Broda, K. Rissanen,
M. Vysotsky and V. Böhmer, J. Chem. Soc., Perkin. Trans 2, 2002,
1796–1800; M. O. Vysotsky, M. Bolte, I. Thondorf and V. Böhmer,
Chem. Eur. J., 2003, 9, 3375–3382.
4 C. A. Schalley, R. K. Castellano, M. S. Brody, D. M. Rudkevich,
G. Siuzdak and J. Rebek, Jr., J. Am. Chem. Soc., 1999, 121,
4568–4579.
5 O. Mogck, V. Böhmer and W. Vogt, Tetrahedron, 1996, 52,
8489–8496.
6 R. K. Castellano, B. H. Kim and J. Rebek, Jr., J. Am. Chem. Soc.,
1997, 119, 12671–12672.
7 R. K. Castellano, D. M. Rudkevich and J. Rebek, Jr., Proc. Nat.
Acad. Sci. USA, 1997, 94, 7132–7137.
8 M. O. Vysotsky, O. Mogck, Y. Rudzevich, A. Shivanyuk, V. Böhmer,
M. S. Brody, Y. L. Cho, D. M. Rudkevich and J. Rebek, Jr., J. Org.
Chem., 2004, 69, 6115–6120.
9 For further examples see: M. O. Vysotsky and V. Böhmer, Org. Lett.,
2000, 2, 3571–3574; M. O. Vysotsky, I. Thondorf and V. Böhmer,
Chem. Commun., 2001, 1890–1891.
10 D. A. Case, D. A. Pearlman, J. W. Caldwell, T. E. Cheatham III,
J. Wang, W. S. Ross, C. L. Simmerling, T. A. Darden, K. M. Merz,
R. V. Stanton, A. L. Cheng, J. J. Vincent, M. Crowley, V. Tsui,
H. Gohlke, R. J. Radmer, Y. Duan, J. Pitera, I. Massova, G. L.
Seibel, U. C. Singh, P. K. Weiner and P. A. Kollman: AMBER 7,
2002, University of California, San Francisco.
7.61 (8H, br s), 7.87 (4H, d, J 8.0), 6.85 (4H, d, J 8.0); ArHcal: 7.97
(2H, d, J 1.9), 7.92 (2H, d, J 1.9), 7.10 (2H, d, J 1.9), 7.03 (2H, d,
J 1.9), 6.96 (4H, s), 4.88 (2H, s), 4.79 (2H, s); ArCH2Ar: 5.05 (2H,
d, J 11.6), 4.53 (2H, d, J 11.6), 3.98 (2H, d, J 11.1), 3.95 (2H, d,
J 11.1), 3.34 (2H, d, J 11.6), 3.31 (2H, d, J 11.6), 2.59 (2H, d, J
11.1), 2.52 (2H, d, J 11.1); OCH2: 4.40–4.17 (12H, m), 3.82–3.75
(4H, m), 3.56–3.46 (8H, m); CH3Tos: 2.50 (12H, s); CH3Tol: 2.09
(6H, s), 2.07 (6H, s); CH2: 1.79–1.74 (8H, m), 1.34–1.23 (16H,
m); CH3alk: 1.89 (6H, t, J 9.7), 0.90 (6H, t, J 9.7).
3·4 dH (400 MHz, CD2Cl2) NH: 10.93 (1H, s), 10.78 (1H, s),
10.73 (1H, s), 10.60 (1H, s), next 4H are overlapped with doublet
at 8.16, 8.11 (2H, s), 8.07 (2H, s), 7.23 (1H, s), 7.22 (1H, s), 7.07
(1H, s), 7.04 (1H, br s); ArHTos: 8.16 (12H (from them 4H belong
to NH), d, J 8.3), 7.50 (4H, d, J 8.3), 7.49 (4H, d, J 8.3); ArHTol
:
7.67–7.61 (8H, m), 6.93 (4H, d, J 8.3), 6.90 (4H, d, J 8.3); ArHcal:
8.02 (1H, d, J 2.4), 7.99 (1H, d, J 2.4), 7.95 (1H, d, J 2.4), 7.92
(1H, d, J 2.4), 7.18 (1H, s), 7.17 (1H, s), 7.12 (1H, d, J 2.4), 7.11
(1H, d, J 2.4), 7.05 (1H, d, J 2.4), 7.02 (1H, d, J 2.4), 7.01 (1H,
s), 6.99 (1H, s), 4.95 (2H, s), 4.88 (2H, s); ArCH2Ar: 5.09 (1H,
d, J 11.7), 5.07 (1H, d, J 11.7), 4.55 (2H, d, J 11.7), next 4H are
overlapped with multiplet at 4.49–3.78, 3.37 (2H, d, J 11.7), 3.43
(2H, d, J 11.7), 2.76–2.52 (4H, m); OCH2: 4.49–3.78 (32H (from
them 4H belong to ArCH2Ar), m), 3.49–3.41 (4H, m); CH3Tos
2.52 (12H, s); CH3Tol: 2.12 (12H, s).
:
11 For details of the MD simulations see the Supporting
information†.
12 P. A. Kollman, I. Massova, C. Reyes, B. Kuhn, S. Huo, L. Chong,
M. Lee, T. Lee, Y. Duan, W. Wang, O. Donini, P. Cieplak,
J. Srinivasan, D. A. Case and T. E. Cheatham, Acc. Chem. Res.,
2000, 33, 889–897.
13 R. A. Jacobi, V. Böhmer, C. Grüttner, D. Kraft and W. Vogt, New J.
Chem., 1996, 20, 493–501.
Acknowledgements
J. R. is grateful to the Skaggs Institute and the National
Institutes of General Medical Sciences for support. V. B.
and I. T. gratefully acknowledge research support from the
Deutsche Forschungsgemeinschaft (projects Bö 523/14-2 and
Th 520/5-2).
14 A. Arduini, L. Mirone, D. Paganuzzi, A. Pinalli, A. Pochini,
A. Secchi and R. Ungaro, Tetrahedron, 1996, 52, 6011–6018.
3 0 8 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 8 0 – 3 0 8 4