Cyclic triureas-synthesis, crystal structures and properties

Article abstract of DOI:10.1039/b718114k

The synthesis of 24-membered macrocycles is described, in which rigid xanthene units (X) and/or diphenyl ether units (D) as flexible analogues are linked via urea groups. All four possible combinations (XXX, XXD, XDD, DDD) have been obtained with yields of 40-72% for the cyclisation step. In two cases, the respective cyclic hexamers (XXDXXD, XXXXXX) were also isolated. Two compounds have been characterised by a single crystal X-ray analysis of the free triurea (XXD, XDD) and one example (DDD) by its complex with tetrabutylammonium chloride. It shows the chloride anion in the centre of the macrocycle, held by six NH...Cl^- hydrogen bonds. The interaction with various other anions has been studied by ¹H NMR. Complexation constants for chloride, bromide and acetate have been measured for all trimers by UV spectrophotometry. Molecular dynamics simulations have been carried out to determine the conformation of the free receptors in chloroform and acetonitrile. They show that in chloroform, intramolecular hydrogen bonding occasionally facilitated by trans→cis isomerisation of an amide bond dominates the conformation of the macrocycles while in acetonitrile (the solvent used for complexation measurements), the ligating urea NH protons are properly arranged for the complexation of anions, however, their strong solvation is counteractive to the complexation.

Full text of DOI:10.1039/b718114k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Cyclic triureas—synthesis, crystal structures and properties†
Denys Meshcheryakov,a Franc¸oise Arnaud-Neu,b Volker Bo¨hmer,*a Michael Bolte,c
Ve´ronique Hubscher-Bruder,b Emilie Jobin,b Iris Thondorfd and Sabine Wernerd
Received 22nd November 2007, Accepted 18th January 2008
First published as an Advance Article on the web 14th February 2008
DOI: 10.1039/b718114k
The synthesis of 24-membered macrocycles is described, in which rigid xanthene units (X) and/or
diphenyl ether units (D) as flexible analogues are linked via urea groups. All four possible combinations
(XXX, XXD, XDD, DDD) have been obtained with yields of 40–72% for the cyclisation step. In two
cases, the respective cyclic hexamers (XXDXXD, XXXXXX) were also isolated. Two compounds have
been characterised by a single crystal X-ray analysis of the free triurea (XXD, XDD) and one example
(DDD) by its complex with tetrabutylammonium chloride. It shows the chloride anion in the centre of
the macrocycle, held by six NH · · · Cl− hydrogen bonds. The interaction with various other anions has
been studied by 1H NMR. Complexation constants for chloride, bromide and acetate have been
measured for all trimers by UV spectrophotometry. Molecular dynamics simulations have been carried
out to determine the conformation of the free receptors in chloroform and acetonitrile. They show that
in chloroform, intramolecular hydrogen bonding occasionally facilitated by trans→cis isomerisation of
an amide bond dominates the conformation of the macrocycles while in acetonitrile (the solvent used
for complexation measurements), the ligating urea NH protons are properly arranged for the
complexation of anions, however, their strong solvation is counteractive to the complexation.
hydrogen bonding in the macrocycle. On the other hand, it is
Introduction
tempting to envisage anion receptors for the planar nitrate anion
based on a suitable cyclic arrangement of three urea groups.7 We
therefore started with the question, what would be an appropriate
spacer holding three urea groups in the optimum position, and we
tried to find some guidelines by molecular modelling.
Based on molecular modelling studies,8 the 4,5-substituted
xanthene skeleton was evaluated as an appropriate spacer
between the urea functions (Fig. 1). Along with its rigidity, it has
an additional advantage. The repulsion between the xanthene
oxygens and the urea oxygens should favour conformations in
which the urea hydrogens are oriented towards the centre of
the macrocycle. This “preorganization” should also minimise
intermolecular hydrogen bonding.
Amide groups are often used as hydrogen bond donors in synthetic
anion receptors.1 They have been combined as podands on a suit-
able platform, e.g. a calix[4]arene,2 or included into macrocyclic3
or macrobicyclic molecules.4 Urea or thiourea functions are able
to form “three centered” hydrogen bonds to an appropriate
acceptor atom.5 Consequently, various anion receptors based on
oligoureas have been described, in which the urea groups are either
arranged as podands or incorporated into a macrocycle,6 while
macrobicyclic oligourea molecules are not known.
In spite of these numerous examples, anion binding by neutral
cyclic oligoureas has not yet shown remarkable results. This may
be due to an insufficient complementarity or to intramolecular
The known 2,7-di-tert-butyl-9,9-dimethyl-4,5-diamino-xan-
thene 1 (X-unit) was chosen as a building block for the synthesis
of macrocycles, since it is easily prepared from the commercially
available dicarboxylic acid.9 This xanthene-derived spacer was al-
ready used in some simple open chain urea-based anion receptors,
which demonstrated promising results.10
In general, the receptor properties of a host molecule are
determined by a delicate balance between the prearrangement
of ligating functions due to a certain “rigidity” and the ability
to adapt to the target guest by a sufficient “flexibility”. Thus we
decided to introduce, besides the rigid xanthene units, the more
flexible diphenyl ether derivative 2 (D-unit), which could also be
prepared following relatively simple procedures.11
aFachbereich Chemie, Pharmazie und Geowissenschaften, Abteilung
Lehramt Chemie, Johannes Gutenberg-Universita¨t Mainz, Duesbergweg
10-14, D-55099 Mainz, Germany. E-mail: vboehmer@mail.uni-mainz.de;
Fax: +49 (0) 6131 3925419; Tel: +49 (0) 6131 3922319
bIPHC-DSA, ULP, CNRS, 25 rue Becquerel, F-67087 Strasbourg, France.
E-mail: farnaud@chimie.u-strasbg.fr; Fax: +333 90242747; Tel: +333
90242749
cFachbereich Chemie und Pharmazeutische Wissenschaften, Institut fu¨r
Anorganische Chemie, Johann Wolfgang Goethe-Universita¨t Frankfurt,
Marie-Curie-Straße 11, D-60439 Frankfurt/Main, Germany. E-mail:
bolte@chemie.uni-frankfurt.de; Fax: +49 (0) 69 7982 9239; Tel: +49 (0)
69 79829136
dFakulta¨t fu¨r Naturwissenschaften I—Biowissenschaften, Institut fu¨r Bio-
chemie und Biotechnologie, Martin-Luther-Universita¨t Halle-Wittenberg,
Kurt-Mothes-Straße 3, D-06099 Halle/Saale, Germany. E-mail: iris.
thondorf@biochemtech.uni-halle.de; Fax: +49 (0) 345 5527011; Tel: +49
(0) 345 5524862
Results and discussion
† Electronic supplementary information (ESI) available: Table S1: Com-
pounds used for the calculation of RESP charges and the corresponding
RESP derived charges for the constituting fragments of the macrocycles
10–13. Also given are the corresponding atom types used for the AMBER
calculations. See DOI: 10.1039/b718114k
Syntheses
The family of cyclic trimers based on these two units X and
D consists of four possible compounds 10 (XXX), 11 (XXD),
1004 | Org. Biomol. Chem., 2008, 6, 1004–1014
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Fig. 1 Cyclic triureas with rigid spacers as potential receptors for the nitrate anion.
Scheme 1 Reagents and conditions: (a) triphosgene, diisopropylethylamine, CH2Cl2, r. t., 3 h; (b) Boc-anhydride, THF, 25 ◦C, 18 h; (c) Boc-anhydride,
THF, 60 ◦C, 48 h; (d) N-acylation: p-nitrophenyl chloroformate, diisopropylethylamine, THF, 60 ◦C, 18 h; deprotection: trifluoroacetic acid, CH2Cl2, r.
t., 3 h; (e) 7 as bis-trifluoroacetate, diisocyanate 3, triethylamine, CH2Cl2, r. t., 12 h; (f) diisocyanate 4, acetonitrile, r. t., 12 h; (g) diamine 1, CH2Cl2, r. t.,
18 h; (h) diisocyanate 4, CH2Cl2, r. t, 18 h.
12 (XDD) and 13 (DDD). Their synthesis is summarised in the
general Scheme 1.
in a 2 : 1 ratio with p-nitrophenyl chloroformate in the presence of
base (Scheme 1). The subsequent deprotection with trifluoroacetic
acid yields the dimeric diamines 7 or 8. Isocyanates were preferred
over the active urethanes for the formation of urea groups in the
further reaction steps since the absence of bulky residues resulted
in better yields and higher purity of the products.
For the synthesis of cyclic trimers, we envisaged the reaction
of the diisocyanates 3 or 4 with the dimeric diamines 7 or 8.
The concentration of the reactants was kept between 2.9 mM
and 6.0 mM, but no general procedure can be given, due to their
different solubility and the different solvents used.
Both diamines 1 and 2 were prepared according to the slightly
improved literature procedures. Reaction with triphosgene in
the presence of diisopropylethylamine led to the corresponding
diisocyanates 3 and 4 in 76 and 88% yield, respectively. The
preparation of mono-protected diamines 5 and 6 was possible
by reaction with di-tert-butyl dicarbonate in THF (molar ratio 1 :
1), followed by chromatographic separation. The compounds were
isolated with yields of 55 and 42%, respectively. 5 and 6 form the
corresponding ureas almost quantitatively when they are reacted
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ethanol. The unit cell contains two molecules of 11 related by
an inversion center and four molecules of chloroform (two of
which are disordered over two positions). The urea groups linking
the diphenylether unit with the two xanthene units adopt a trans
conformation.
Their NH-protons form intramolecular hydrogen bonds to the
oxygen of the third urea group connecting the two xanthene units
˚
=
(N–H · · · ·O C distances 2.48–2.60 A). This urea is found in the
cis conformation with the H- and O-atoms pointing roughly in the
same direction. Fig. 2 shows the molecular conformation of 11
seen from two directions. The packing is best illustrated by Fig. 3.
Intermolecular hydrogen bonds are not formed.
Thus, the trimer XXD (11) was obtained in 62% yield when
the diisocyanate 4 was reacted with the diamine 7 in acetonitrile.
Interestingly, the cyclic hexamer XXDXXD (14) was formed (up
to 20% yield) in addition to 11, when the reaction was carried out
in the less polar methylene chloride.12
When the more rigid xanthene-based diisocyanate 3 was reacted
with the diamine 7 in dichloromethane under analogous condi-
tions, the corresponding hexamer XXXXXX (15), consisting of
xanthene units, appeared to be the main product with yields up to
49%, while the triurea XXX (10) was not isolated at all. In contrast
to the synthesis of the trimer 11, the change of the solvent to the
more polar acetonitrile did not lead to the preferred formation of
the trimer. A mixture of oligoureas with different chain lengths
was formed instead of the desired product. However, the trimer
10 is formed preferably and can be isolated by crystallization with
yields up to 40% when the trifluoroacetate of the diamine 7 was
used in the reaction instead of the non-protonated diamine.
The formation of side products hinders also the isolation of
the trimers XDD (12) and DDD (13), but the formation of
hexamers was not detected during attempts to synthesise these
more flexible compounds. Trimer 12 was prepared by the “reversed
2 + 1” strategy reacting the diisocyanate 9 with the diamine 1. The
reaction of the xanthene-based diisocyanate 3 with the flexible
diamine 8 produced so many byproducts, that the isolation of the
pure macrocycle 12 was nearly impossible, while the reaction of 9
with 1 allowed us to isolate the trimer with 40% yield. Probably,
the conversion of both amino groups to isocyanate groups in
9 decreases the possibility of undesired hydrogen bonding and
association in solution. The trimer 13 was prepared by the reaction
of the diamine 8 with diisocyanate 4 in THF and was isolated with
a yield of 72%.
Fig. 2 Molecular conformation of 11, seen from two different directions.
Intramolecular hydrogen bonds are indicated by dashed lines.
Fig. 3 Packing diagram of 11, seen along the c-axis.
Single crystals of 12 were formed by slow evaporation of
a solution in DMSO–methanol. The unit cell contains four
molecules of 12 related bythree two-foldscrew axes. Two molecules
of DMSO and one molecule of methanol are incorporated per
molecule of 12. Fig. 4 shows the asymmetric unit of the crystal
and illustrates the molecular conformation of 12.
X-Ray structures
Three of the four cyclic trimers were confirmed by single crystal
X-ray diffraction. Crystallographic details are collected in Table 1.
Suitable crystals of 11 where obtained by slow evaporation
of a solution in a mixture of chloroform–dichloromethane–
Table 1 Characterisation of the conformation in the crystal by interplanar angles between phenyl rings (first three columns) and between urea groups
(N–C(O)–N) and the adjacent phenyl units (last three columns)
Compound
11 (XXD)
12 (XDD)
13 (DDD)
Ph1/Ph2
Ph3/Ph4
Ph5/Ph6
Ph2–Ur–Ph3
Ph4–Ur–Ph5
Ph6–Ur–Ph1
3.0
X
4.8
X
11.4
X
72.6
D
62.2
D
62.0
D
69.9/74.9
X–X
20.2/37.4
X-D
27.2/17.3
X-D
4.8/26.0
D-D
8.9/7.3
D-X
44.6/35.0
D-X
70.3
61.8
51.9
24.1/54.0
36.2/28.7
38.0/46.4
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Fig. 4 Molecular conformation of 12 seen from two directions. Hydrogen
bonds to solvent molecules are indicated by dashed lines.
Fig. 6 Molecular conformation of (13@Cl−); the chloride anion and the
urea groups of the macrocycle are shown in a space filling representation.
All urea groups assume the trans conformation and the NH-
protons point to the center of the macrocycle forming hydrogen
bonds to the DMSO molecules. One of them is held by two
three-center hydrogen bonds from the urea groups adjacent to
the xanthene unit, while the second molecule of DMSO is bound
analogously by the third urea group and connected to another
urea also by a bifurcated hydrogen bond. The methanol molecule
is hydrogen bonded to one urea carbonyl group. Thus, again no
intermolecular hydrogen bonds exist between the molecules of 12
(Fig. 5).
inclined by angles of 20◦–28◦ with respect to the planes through
the carbonyl C- or O-atoms.
The complexed chloride anions and the tetrabutylammonium
cations are ordered alternately to columns extending along the
c-axis (Fig. 7, left). Subsequent molecules of 13 in a column are
found in enantiomeric conformation symmetry related by a glide
˚
˚
plane. Cl–N distances are 4.464 A and 4.546 A, and the distances
˚
between subsequent Cl (or N) atoms are 8.351 A. These columns
are packed in a “pseudo” hexagonal arrangement, as illustrated
by Fig. 7 (right).
+
Fig. 7 Packing of (13@Cl−)C4H9 seen from different directions.
1H NMR studies
Since the 1H NMR spectra in CDCl3 are broad for all compounds,
due to various intra- and intermolecular hydrogen bonds, DMSO-
d6 was chosen for a comparative study. Fig. 8 shows the low field
section (aromatic and urea protons). Still, the spectrum of 10
remains broad and does not show any significant sharpening upon
heating nor upon addition of anions, although a strong interaction
with such anions as chloride, fluoride or dihydrogen phosphate is
evident.
The spectrum of 11 is sharp and well resolved at room
temperature (see also Fig. 9). Three singlets for NH, four m-
coupled doublets (8.16 and 7.15 ppm) for the xanthene units, two
o-coupled doublets (8.13 and 6.92 ppm) and two o-coupled triplets
(7.12 and 7.02 ppm) for the diphenylether unit correspond to the
expected C2v symmetry.
Fig. 5 Packing diagram of 12, seen along the a-axis.
Slow evaporation of a solution of DDD (13) and tetra-
butylammonium chloride in a mixture of acetone–acetonitrile–
chloroform–dichloromethane–ethanol–ethyl acetate13 gave single
crystals containing both components in a 1 : 1 ratio. No solvent is
incorporated in the crystal lattice.
Each macrocycle includes one (spherical!) chloride anion
(Fig. 6) in the way envisaged for the planar (!) nitrate anion.
(Unfortunately all attempts to get crystals also with tetraethyl or
tetrabutyl nitrate have failed so far.) The trans urea groups form
six N–H · · · ·Cl hydrogen bonds with N–Cl distances between 2.47
˚
to 2.75 A. Their arrangement resembles a three-bladed propeller
formed by the three urea planes (–NH–C(O)–NH–), which are
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slightly shifted upfield. The addition of various anions causes
similar spectral changes as observed for 11, but smaller shifts.
The sharp, well resolved spectrum for 13 is in complete agree-
ment with the expected, time-averaged D3h symmetry, showing a
singlet for NH at low field (8.86 ppm), and two doublets (7.97
and 6.87 ppm) and two triplets (7.06 and 6.98 ppm) with o-
coupling, all with the same intensity. Based on the chemical shifts,
all protons experience practically the same environments as the
diphenylether unit in 11. Only small downfield shifts are observed
for the signals of 13 upon addition of various anions. This suggests
that the high flexibility of the macrocycle weakens any cooperative
interaction of the three urea functions with an anion.
UV spectrophotometry
Fig. 8 Sections of the 1H NMR spectra of the cyclic tri-urea compounds
10–13 in DMSO-d6. The trimer 11 is used to show the signal assignment.
The interaction of all cyclic trimers with various anions was
quantitatively studied by UV spectrophotometry. This requires
sufficient spectral changes upon complexation (for an example
see Fig. 10), which were not obtained in all cases. The spectral
variations observed for nitrate, for instance, were not sufficiently
significant to allow any interpretation. Stability constants, which
could be determined in this way, are collected in Table 2.
Addition of tetrabutylammonium salts caused no changes for
I−, NO3−, HSO3−, BF4 and SCN−, while broadened spectra
−
were obtained for H2PO4 and F−. Sharp spectra, indicating a
−
new, kinetically stable species were obtained for Cl−, Br− and
CH3COO−, as shown for Cl− in Fig. 9. The similarity of the spectral
changes observed suggests the formation of a 1 : 1 complex for the
three anions, although for acetate a fivefold excess is required to
obtain again a sharp spectrum.
Fig. 10 Experimental spectra obtained upon addition of increasing
amounts of chloride to the solution of XDD (12) (cL = 10−5 M; 0 ≤
R = cA/cL ≤ 4).
The evaluation of the spectroscopic data reveals that, in addition
to 1 : 1 complexes, 1 : 2 complexes (anion to ligand) may also be
formed. It must be kept in mind, however, that a missing constant
in Table 2 could be either due to a small value for this constant or
to a small spectral change connected with its formation.
The following trends can be extracted from Table 2:
(a) XXD (11) and DDD (13) form 1 : 1 and 1 : 2 complexes with
Cl− while XDD (12) forms only a 1 : 2 complex and XXX (10)
only a 1 : 1 complex.
(b) As shown for chloride, the values of the stability constants
obtained may depend on the counter cation.
(c) Complexes with chloride and acetate show similar stability,15
while bromide is more weakly bound.16
Fig. 9 Aromatic section of the 1H NMR spectra obtained upon stepwise
addition of tetrabutylammonium chloride to a 0.1 mM solution of 11 in
DMSO-d6.
For XDD (12) the same symmetry is expected as for XXD (11).
However, the spectrum is generally broadened and several signals
are overlapping around 7 ppm (Fig. 8). Four NH protons appear
as two peaks (at 9.14 and 8.93 ppm) and are downfield shifted
in comparison to 11 and 10, while the singlet for the remaining
two urea protons, which usually appears around 8 ppm, is not
visible in Fig. 8. The signals for aromatic protons appear generally
(d) 11 (and chloride) forms the strongest complexes (e.g. log
b = 6.1 (1 : 1 complex) and 12.9 (1 : 2 complex) with Bu4N+ as
counterion).
(e) 12 (1 : 2 complex) and 10 (1 : 1 complex) show the weakest
binding.
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Table 2 Overall stability constants (log b r) of the complexes formed by the trimers with chloride, bromide and acetate (counterion : [Na + 222]+ or
Bu4N+)14 in acetonitrile (T = 25 ◦C)
Anion
Composition (A− : L)
10 (XXX)
11 (XXD)
12 (XDD)
13 (DDD)
Cl− ([Na + 222]+)
Cl− (Bu4N+)
1 : 1
1 : 2
1 : 1
1 : 2
1 : 1
1 : 2
1 : 1
1 : 2
4.5 0.1
—
5.5 0.2
11.7 0.1
6.1 0.2
12.9 0.1
3.9 0.4
—
—
5.1 0.2
11.3 0.4
6.0 0.1
11.5 0.2
4.3 0.1
—
10.5 0.2
—
10.6 0.5
—
8.7 0.2
4.7 0.2
10.0 0.5
4.6 0.2
—
Br− (Bu4N+)
CH3COO− (Bu4N+)
npa
npa
npa
5.7 0.3
—
5.9 0.4
—
npa
a Determination was not possible.
(f) A small cooperative effect is observed for the formation of
the 1 : 2 complexes (D = log b (1 : 2 complex)–2 log b (1 : 1
complex) = 0.6–1.1) except with DDD (13) and chloride with
Bu4N+ as counterion where this effect is slightly negative. This
means that the formation of biligand complexes is usually favoured
as compared to the 1 : 1 complexes.
Microcalorimetric studies are currently being undertaken to
obtain a deeper insight by a complete set of thermodynamic data
(DG, DH, and DS).
Molecular dynamics calculations
While our design of anion hosts mostly relied on geometrical
considerations, fragment search and molecular mechanics cal-
culations, we used molecular dynamics simulations to elucidate
the flexibility and the preorganisation of the receptors for anion
recognition. In order to investigate the effect of solvent polarity
on the conformation, the four triurea hosts were simulated in a
box of chloroform and acetonitrile molecules, respectively. MD
calculations are currently being carried out for complexes with
chloride, bromide, nitrate and mesylate as models for spherical,
trigonal planar and trigonal pyramidal anions, and will be
published in due course.
The conformations17 averaged over the whole course of the
simulations are shown in Fig. 11. Differences of the structures
in chloroform and acetonitrile result from different solvation of
the macrocyclic hosts and differences in hydrogen bonding.
In the less polar chloroform, intramolecular hydrogen bonding
plays the dominant role due to the poor solvation of the hydrogen
bond donor and acceptor groups (Fig. 12). In the case of 10 and
11, a trans → cis isomerisation of one of the urea amide bonds
occurs during the first ps of the dynamics since the macrocyclic
building blocks are too rigid to enable intramolecular hydrogen
bonding without significant conformational transitions.
When the MD simulation was started from the crystal structure
of 11 (with two cis configured amide bonds), the input geometry
was stable over the time course of the calculation. Due to the
presence of more than a single diphenyl ether unit, the hosts 12 and
13 are flexible enough to enable intramolecular hydrogen bonding
without the necessity of a cis configured amide bond. Both
compounds exhibit on average a C2 symmetrical conformation,
which is characterised by an inward directed carbonyl oxygen
hydrogen bonded by four urea protons. Thus, in chloroform, the
four anion receptors do not show the expected geometry with
the urea hydrogens pointing toward the center of the macrocyclic
Fig. 11 Average structures obtained from the MD simulations in chlo-
roform (left column) and acetonitrile (right column) for the macrocycles
10–13 (from top to bottom). Nonpolar hydrogen atoms have been omitted,
the carbon atoms of the diphenylether units are drawn in yellow.
cavity. Prior to the complexation of anions, the hosts have to
rearrange to the proper geometry, which is accompanied by
considerable energetic demand (Table 3) and hence by weakening
the binding affinity.
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Fig. 12 Radial distribution functions N–H · · · CCHCl (left) and N–H · · · NCH (right) of the six NH protons.
3 CN
3
protons. This conformation is more stable by about 10 kcal mol−1
than the initial geometry and does not undergo a further transition
during the remaining simulation. The macrocycle 11 adopts a
twisted structure in which the planes of the three urea units are
stacked on top of each other. Only small conformational changes
are necessary to get a suitable structure for the complexation
of anions. Indeed, the reorganisation energies upon binding of
chloride, bromide, nitrate or mesylate (Table 3) are by far less
than for the same host in chloroform and for 12 in acetonitrile.
The same is also valid for the hosts 10 and 13, which adopt on
average nonplanar Cs and C3 structures, respectively, with all
the NH protons pointing towards the center of the macrocycle.
From the comparison of the two sets of MD simulations it can
be concluded that the strong solvation in acetonitrile results in a
better preorganisation of the host for anion binding, however, a
higher energetical price must in turn be paid for the desolvation in
the more polar solvent.
Table 3 Average reorganization energies (Ehost,complexed − Ehost,free, in kcal
mol−1) necessary for the binding of different anions
−
Cl−
Br−
NO3
Mes−
10–CHCl3
11–CHCl3
12–CHCl3
13–CHCl3
10–CH3CN
11–CH3CN
12–CH3CN
13–CH3CN
38.4
36.8
41.1
39.1
11.2
10.9
21.5
17.8
32.2
34.8
37.5
31.5
5.7
10.9
15.7
9.5
31.9
33.3
32.2
28.3
4.7
7.2
11.8
5.7
34.5
35.4
34.2
27.7
5.3
9.1
11.5
5.4
In acetonitrile (the solvent used for the determination of stability
constants), the behaviour of the receptor molecules is completely
different. The radial distribution functions illustrated for 10 as
an example in Fig. 12 reveal that the urea protons are strongly
solvated by acetonitrile (forming intermolecular hydrogen bonds)
while intramolecular hydrogen bonding was observed only in the
case of 12. The XDD receptor 12 rearranges after about 5 ns to a
structure similar to that found in chloroform in which the carbonyl
group of the urea flanked by the two diphenyl ether units points
to the center of the macrocycle, hydrogen bonded by two urea
Conclusions
Regarding the initial plan, based on rational considerations
backed by advanced molecular modelling, we have to state that the
Table 4 Summary of crystallographic dataaa CCDC reference numbers 667517–667519. For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b718114k
11 (XXD)
12 (XDD)
13·Bu4NCl (DDD)
Chemical formula
CCDC ref. numbers
M
C61H70N6O6·2CHCl3
667517
1221.97
Triclinic
¯
P1
14.2014(19)
15.4184(19)
15.7438(17)
73.389(9)
81.409(10)
66.041(9)
3016.6(6)
2
C50H50N6O6·2DMSO·CH3OH
C39H30N6O6·C16H36NCl
667519
1019.26
Orthorhombic
P212121
13.8190(8)
17.9176(10)
21.6376(10)
90
667518
956.60
Monoclinic
P21/c
Crystal system
Space group
˚
a, A
21.9730(16)
14.2644(6)
16.7013(12)
90
96.085(6)
90
5205.2(6)
4
173
˚
b, A
˚
c, A
a, ◦
b, ◦
c , ◦
V, A
Z
T, K
90
90
5357.5(5)
4
173
3
˚
173
24329
Reflections
19313
66076
Unique reflections
Rint
10411
0.0882
0.3167
—
9414
9795
0.0298
0.0859
0.02(5)
0.0866
0.1056
—
wR(F2), all data
Flack-parameter
1010 | Org. Biomol. Chem., 2008, 6, 1004–1014
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experimental results were different from our expectations. Among
the four cyclic triureas 10–13, the envisaged XXX (10) shows the
lowest affinity to a simple spherical anion such as chloride, while
the binding of the target anion nitrate is considerably weaker.
Rigidification of the linkers between the three urea groups does
not prevent their intramolecular hydrogen bonding as shown by
the crystal structure of XXD (11). A similar conformation seems to
be possible also for XXX (10) for which we have not yet obtained
single crystals. Surely the progress in supramolecular chemistry
will depend in the future, to a certain degree, on lucky chances, as
shown in the present case by the unexpected complexation of two
chloride anions12 by a cyclic hexaurea XXDXXD (14).
hexane 1 : 8 (v/v)). The monoprotected diamine 5 (6.10 g, 56%)
was isolated as a white powder; mp 173 ◦C; dH (400 MHz, DMSO-
d6): 8.86 (1 H, s, NH), 7.63 (1 H, d, J 2, ArH), 7.13 (1 H, d, J 2,
ArH), 6.64 (1 H, d, J 2.4, ArH), 6.59 (1 H, d, J 2.4, ArH), 5.21
(2 H, s, NH2), 1.53 (6 H, s, CH3), 1.49 (9 H, s, tBu), 1.27 (9 H, s,
tBu), 1.23 (9 H, s, tBu).
Mono Boc-protected amine 6. A solution of di-tert-butyl
dicarbonate (6.86 g, 31.4 mmol) in THF (150 cm3) was added
dropwise over 1 h with stirring to a solution of the diamine 2
(6.30 g, 31.4 mmol) in THF (200 cm3). After 48 h at 60 ◦C
the solvent was removed under reduced pressure. The residual
brown oil was dissolved in a mixture of toluene (2 cm3), ethyl
acetate (2 cm3) and hexane (16 cm3) and was separated by column
chromatography (silica gel 1000 cm3, ethyl acetate–hexane 1 : 5
(v/v)). The monoprotected diamine 6 (4.00 g, 42%) was isolated
as a white powder; mp 112 ◦C; dH (400 MHz, DMSO-d6,): 8.54 (1
H, s, NH), 7.64–7.57 (1 H, m, ArH), 7.00–6.87 (3 H, m, ArH),
6.78 (2 H, dd, 3J 8.0, 4J 1.6, ArH), 6.58–6.50 (2 H, m, ArH), 1.46
(9 H, s, tBu).
Experimental
Syntheses
All solvents were of analytical quality (p. a.) and were used without
additional purification. All solvents for NMR were purchased
1
from Deutero GmbH. All H NMR spectra were recorded on
a Bruker Avance DRX 400 spectrometer at 400 MHz using the
solvent signals as internal reference. Mass spectra were recorded
with the Finnigan MAT 8230 instrument. The melting points were
not corrected.
Diamine 7. A solution of 4-nitrophenyl chloroformate (1.04 g,
5.1 mmol) in THF (100 cm3) was added dropwise over 1 h
to a stirred solution of the monoprotected diamine 5 (4.65 g,
10.2 mmol) and diisopropylethylamine (1.33 g, 10.2 mmol) in THF
(100 cm3). After stirring at 60 ◦C for 18 h the solvent was removed
under reduced pressure. The residual yellow oil was dissolved in
ethyl acetate (100 cm3) and the solution was washed with 5 N
sodium carbonate solution until the yellow colour of nitrophenol
disappeared. Then, the solution was washed with distilled water
(2 × 100 cm3) and dried over MgSO4. Evaporation of the solvent
gave the protected dimeric diamine 7 as a foam-like solid. The
product was dissolved in dichloromethane (50 cm3), the solution
was cooled in an ice bath and trifluoroacetic acid (30 cm3) was
added. The mixture was allowed to reach room temperature during
the next 4 h of stirring. Then the reaction mixture was slowly
poured into a 5 M solution of sodium carbonate (300 cm3). The
pH was adjusted to 9–10; the organic layer was separated and
the aqueous layer extracted with dichloromethane (2 × 50 cm3).
The organic solutions were combined and dried over MgSO4.
Evaporation under reduced pressure yielded the dimeric diamine
7 (3.85 g, 98%) as a light-brown powder; mp >200 ◦C (decomp.);
dH (400 MHz, DMSO-d6): 8.90 (2 H, s, NH), 8.13 (2 H, d, J 2,
ArH), 7.11 (2 H, d, J 2, ArH), 6.68 (2 H, d, J 2, ArH), 6.62 (2 H,
d, J 2, ArH), 5.26 (4 H, s, NH2), 1.57 (12 H, s, CH3), 1.31 (18 H, s,
tBu), 1.26 (18 H, s, tBu); m/z (FD) 731.6 (M+, 100%).
Diisocyanate 3. A solution of the diamine 1 (818 mg,
2.5 mmol) and diisopropylethylamine (746 mg, 2.5 mmol) in
dichloromethane (20 cm3) was added dropwise under a nitrogen
flow over 1 h to a vigorously stirred solution of triphosgene
(650 mg, 5 mmol) in dichloromethane (20 cm3). After 3 h
the mixture was filtered through silica gel (100 g), which was
subsequently washed with dichloromethane (2 × 50 cm3). The
solvent was removed under reduced pressure and the crude
product was kept on the rotavap for 1 h at 80 ◦C to remove excess
triphosgene. The diisocyanate 3 (781 mg, 76%) was obtained after
cooling as a light-brown solid; mp 168 ◦C; dH (400 MHz, CDCl3):
7.22 (2 H, d, J 2.4, ArH), 7.01 (2 H, d, J 2.4, ArH), 1.62 (6 H, s,
CH3), 1.30 (18 H, s, tBu).
Diisocyanate 4.
A
solution of diamine
2
(1.48 g,
7.37 mmol) and diisopropylethylamine (1.91 g, 14.7 mmol) in
dichloromethane (50 cm3) was added dropwise under a nitrogen
flow over 1 h to a vigorously stirred solution of triphosgene
(84 mg, 0.28 mmol) in dichloromethane (50 cm3). After 3 h the
reaction mixture was filtered through silica gel (100 g), which was
subsequently washed with dichloromethane (2 × 50 cm3). The
solvent was removed under reduced pressure and the crude oily
product was kept on the rotavap for 1 h at 80 ◦C to remove excess
triphosgene. After cooling, the isocyanate 4 (1.64 g, 88%) was
obtained as a light-brown oil. The compound could be crystallised
to a light-brown solid after initiation with a small crystalline
Diamine 8. A solution of 4-nitrophenyl chloroformate (1.34 g,
6.66 mmol) in THF (100 cm3) was added dropwise over 1 h
to a stirred solution of the monoprotected diamine 6 (4.0 g,
13.3 mmol) and diisopropylethylam◦ine (1.72 g, 13.3 mmol) in
THF (100 cm3). After stirring at 60 C for 18 h the solvent was
removed under reduced pressure. Trituration of the oily residue
with methanol (100 cm3) produced a crystalline solid which was
filtered off and washed with methanol (3 × 50 cm3) to remove the
residual nitrophenol. The Boc-protected dimeric diamine 8 was
isolated as a microcrystalline powder. The product was dissolved
in dichloromethane (60 cm3), the solution was cooled in an ice
bath and trifluoroacetic acid (30 cm3) was added. The mixture was
allowed to reach room temperature during the next 4 h of stirring.
◦
particle; mp > 95 C (decomp.); dH (400 MHz, DMSO-d6): 7.25
(6 H, m, ArH), 7.01 (2 H, d, J 8.2, ArH).
Mono Boc-protected amine 5. A solution of di-tert-butyl
dicarbonate (5.26 g, 24 mmol) in THF (200 cm3) was added
dropwise over 1 h to a stirred solution of the diamine 1 (8.50 g,
24 mmol) in THF (500 cm3). After 18 h the solvent was removed
under reduced pressure. The residual yellow oil was dissolved in a
mixture of ethyl acetate (2 cm3) and hexane (18 cm3) and separated
by column chromatography (silica gel 1000 cm3, ethyl acetate–
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The reaction was stopped by slowly pouring the mixture into a
5 M solution of sodium carbonate (300 cm3). The pH was adjusted
to 9–10. The organic layer was separated and the aqueous layer
was extracted with dichloromethane (2 × 50 cm3). The combined
organic solutions were dried over MgSO4. Evaporation under
reduced pressure yielded the dimeric diamine 8 (1.83 g, 87%) as a
was isolated by column chromatography (ethyl acetate–hexane, 1
: 5) as a white powder; mp >340 ◦C (decomp.); dH (400 MHz,
DMSO-d6): 9.14 (2 H, s, NH), 8.93 (2 H, s, NH), 8.30 (2 H, d,
J 7.3, ArHdiph), 8.07 (2 H, d, J 1.5 Hz, ArHxan), 8.01 (2 H, s,
NH), 7.75 (2 H, d, J 7.3, ArHdiph), 7.25–7.13 (2 H, m, ArHdiph
,
overlapped with d at 7.17, 2 H, J 1.8, ArHxan), 7.10–6.99 (8 H, m,
ArHdiph), 6.74 (2 H, d, J 7.7, ArHdiph), 1.74 (3 H, s, CH3xan), 1.49
(3 H, s, CH3xan), 1.30 (18 H, s, tBu); m/z (ESI) 853.4 (M+ + Na,
100%).
◦
light-brown powder; mp 200 C; dH (400 MHz, DMSO-d6): 9.16
(2 H, s, NH), 8.17 (2 H, dd, 3J 8.2, J 1.5, ArH), 7.01–6.83 (6 H,
m, ArH), 6.80 (4 H, d, J 8.2, ArH), 6.59–6.50 (4 H, m, ArH), 4.97
(4 H, s, NH2); m/z (FD) 427.0 (M+, 100%).
Cyclic trimer 13. Solutions of the diisocyanate 4 (80 mg,
0.32 mmol) in dichloromethane (25 cm3) and the diamine 8
(135 mg, 0.32 mmol) in THF (25 cm3) were added simultaneously
with stirring under nitrogen over 2 h to a flask containing
dichloromethane (50 cm3). After 18 h the solvent was evaporated
under reduced pressure and the crude product was triturated with
hexane (50 cm3). The solid was filtered off and washed with hexane
(2 × 25 cm3) to yield the trimer 13 (156 mg, 72%) as a beige powder;
Diisocyanate 9. A solution of diamine 8 (1,0 g, 2.34 mmol)
and diisopropylethylamine (0.61 g, 2.34 mmol) in a mixture of
THF (10 cm3) and dichloromethane (20 cm3) was added dropwise
under nitrogen during 1 h to a vigorously stirred solution of
triphosgene (696 mg, 4.7 mmol) in dichloromethane (20 cm3).
After 3 h the mixture was filtered through silica gel (100 g), which
was subsequently washed with dichloromethane (2 × 50 cm3).
The solvent was removed under reduced pressure and the crude
product was kept on the rotavap for 1 h at 80 ◦C to remove excess
triphosgene. The diisocyanate 9 (890 mg, 79%) was obtained, after
◦
mp >184 C (decomp.); dH (400 MHz, DMSO-d6): 8.86 (6 H, s,
NH), 7.97 (6 H, dd, 3J 7.8, 4J 1.2, ArH), 7.06 (6 H, ddd, 3J 7.4, 3J
7.8, 4J 1.2, ArH), 6.98 (6 H, ddd, 3J 8.2, 3J 7.4, 4J 1.6, ArH), 6.87
(6 H, dd, 3J 8.2, 4J 1.2, ArH); m/z (ESI) 701.2 (M+ + Na, 100%).
◦
cooling, as a brownish solid; mp 205 C; dH (400 MHz, CDCl3):
8.12 (2 H, dd, 3J 8.2, 4J 1.2, ArH), 7.18–6.98 (12 H, m, NH, ArH),
6.87–6.80 (4 H, m, ArH).
Absorption spectrophotometric titrations
Cyclic trimer 10. Trifluoroacetic acid (0.3 cm3) was added to a
solution of the diamine 7 (120 mg, 0.12 mmol) in dichloromethane
(10 cm3). After 15 min of stirring, the solvent was evaporated under
reduced pressure and the residual light-brown oil was dissolved
in dichloromethane (10 cm3). A solution of the diisocyanate 3
(51 mg, 0.12 mmol) in dichloromethane (10 cm3) and triethylamine
(0.2 cm3) was added with stirring. After 12 h, the solvent was
evaporated, the oily residue was dissolved in ethyl acetate (10 cm3)
and filtered through silica gel (20 g), which was subsequently
washed with ethyl acetate (2 × 20 cm3). The yellow oil obtained
after evaporation was dissolved in hexane (10 cm3). After 2 h the
cyclic trimer 10 started to precipitate. It was filtered off, yielding
50 mg (37%) as thin white flakes; mp >340 ◦C (decomp.); dH
(400 MHz, DMSO-d6): 8.34 (6 H, s, NH), 7.50 (6 H, br.s, ArH),
7.06 (6 H, s, ArH), 1.44 (18 H, s, CH3), 1.23 (54 H, s, tBu); m/z
(FD) 1134.8 (M+, 100%).
Stability constants were determined by absorption spectropho-
tometry using a VARIAN (Cary 3) spectrophotometer equipped
with a thermoregulated cell compartment (25.0 0.1 ◦C). Small
volumes (0.02 cm3) of a solution containing the anion were added
to 2 cm3 of the ligand solution, directly in the spectrophotometric
cell of 1 cm path length.
Spectra were recorded in the wavelength range 220–300 nm after
each addition. The ratio anion : ligand (A : L), reached at the end of
the titration, was between 2 and 100 according to the ligands and
the anions studied. Preliminary kinetic studies were performed
to make sure that the equilibrium of the systems was reached.
For each system, at least two independent measurements were
performed. The software SPECFIT Global Analysis System V3.0
32 bit for Windows was used to calculate the stability constants
(log b) of the complexes formed.18
The various anions studied were provided as tetraalkylam-
monium salts: Bu4NCl (Fluka, ≥97%), Bu4NBr (Fluka, ≥99%),
Bu4NAcO (Aldrich, ≥97%), Et4NNO3 (Fluka, ≥99%). In the case
of chloride, a mixture of NaCl (SDS, ≥95.5%) + 222 (Merck,
Kryptofix) was also used to provide a bulky cation. These salts
were dried under vacuum at room temperature during 24 h.
All the solutions were prepared in acetonitrile (Riedel de Hae¨n,
≥99.5%). No supporting electrolyte was added to the solution
because of (i) the insolubility of most inert salts in this solvent
and (ii) the very small ligand and anion concentrations used (2 ×
10−5 M).
Cyclic trimer 11. The diamine 7 (120 mg, 0.164 mmol) was
dissolved in acetonitrile (25 cm3). A solution of the diisocyanate 4
(42 mg, 0.164 mmol) in acetonitrile (15 cm3) was added dropwise
over 30 min with vigorous stirring under nitrogen. After 12 h a
white prec◦ipitate of the trimer 11 (100 mg, 62%) was filtered off;
mp >280 C (decomp.); dH (400 MHz, DMSO-d6): 8.71 (2 H, s,
NH), 8.59 (2 H, s, NH), 8.36 (2 H, s, NH), 8.16 (d, 2 H, J 2.0,
ArHxan), 8.13 (2 H, d, J 7.8, ArHdiph), 7.30 (2 H, d, J 2.0, ArHxan),
7.24 (2 H, d, J 2.0, ArHxan), 7.15 (2 H, d, J 2, ArHxan), 7.12 (2 H,
t, J 7.6, ArHdiph), 7.02 (2 H, t, J 7.0, ArHdiph), 6.92 (2 H, d, J 7.8,
ArHdiph), 1.61 (12 H, s, CH3xan), 1.29 (18 H, s, tBu), 1.21 (18 H, s,
tBu); m/z (ESI) 1005.6 (M+ + Na, 100%).
Molecular modelling
Cyclic trimer 12. Solutions of the diisocyanate 9 (100 mg,
0.201 mmol) in dichloromethane (25 cm3) and the diamine 1
(73 mg, 0.201 mmol) in dichloromethane (25 cm3) were added
simultaneously with stirring under nitrogen over 2 h to a flask
containing dichloromethane (20 cm3). After 18 h the solvent was
evaporated under reduced pressure, and the trimer 12 (70 mg, 40%)
All molecular dynamics simulations were performed using the
AMBER 7 and AMBER 9 software packages and the gaff
parameter set.19 The initial geometry of the macrocycles was
obtained by manual construction with an all-trans arrange-
ment of the urea amide groups. Charges (see ESI†) were de-
rived following the standard RESP procedure20 from a 6-31G*
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electrostatic potential calculated with the Gaussian98 program21
and the molecule structures were transferred into the LEaP format.
Subsequently, a rectangular box of chloroform or acetonitrile
Notes and references
1 S. O. Kang, R. A. Begum and K. Bowman-James, Angew. Chem.,
2006, 118, 8048–8061, (Angew. Chem., Int. Ed., 2006, 45, 7882–
7894).
˚
molecules, respectively (approximately 14 A solvent layer thickness
2 Y. Morzherin, D. M. Rudkevich, W. Verboom and D. N. Reinhoudt,
J. Org. Chem., 1993, 58, 7602–7605; A. Casnati, L. Pirondini, N. Pelizzi
and R. Ungaro, Supramol. Chem., 2000, 12, 53–65; M. D. Lankshear,
A. R. Cowley and P. D. Beer, Chem. Commun., 2006, 612–614; B.
Schazmann, N. Alhashimy and D. Diamond, J. Am. Chem. Soc., 2006,
128, 8607–8614.
3 K. Choi and A. D. Hamilton, J. Am. Chem. Soc., 2003, 125, 10241–
10249; S. Kubik, R. Goddard, R. Kirchner, D. Nolting and J. Seidel,
Angew. Chem., 2001, 113, 2722–2725, (Angew. Chem., Int. Ed., 2001,
40, 2648–2651); M. A. Hossain, S. O. Kang, D. Powell and K. Bowman-
James, Inorg. Chem., 2003, 42, 1397–1399.
4 A. A. P. Bisson, V. M. Lynch, M. C. Monahan and E. V. Anslyn, Angew.
Chem., 1997, 109, 2435–2437, (Angew. Chem., Int. Ed., 1997, 36, 2340–
2342); S. O. Kang, M. A. Hossain, D. Powell and K. Bowman-James,
Chem. Commun., 2005, 328–330.
5 K. D. Shimizu and J. Rebek, Jr., Proc. Natl. Acad. Sci. USA, 1995, 92,
12403–12407; A. Shivanyuk, M. Saadioui, F. Broda, I. Thondorf, M. O.
Vysotsky, K. Rissanen, E. Kolehmainen and V. Bo¨hmer, Chem.–Eur. J.,
2004, 10, 2138–2148; Y. Rudzevich, V. Rudzevich, D. Schollmeyer, I.
Thondorf and V. Bo¨hmer, Org. Lett., 2005, 7, 613–616.
6 For a general review on anion receptor chemistry see: J. L. Sessler,
P. A. Gale, and W. Cho, in Anion Receptor Chemistry, Monographs
in Supramolecular Chemistry, ed. J. F. Stoddart, Royal Society of
Chemistry, Cambridge, UK, 2006 (for the urea-based receptors see
pp. 193–205); P. D. Beer and P. A. Gale, Angew. Chem., 2001, 113, 502–
532, (Angew. Chem., Int. Ed., 2001, 40, 486–516); for relevant examples
on macrocyclic urea-based receptors see also: S. J. Brooks, S. E. Garc´ıa-
Garrido, M. E. Light, P. A. Cole and P. A. Gale, Chem.–Eur. J., 2007,
13, 3320–3329; B. H. M. Snellink-Rue¨l, M. M. G. Antonisse, J. F. J.
Engbersen, P. Timmermann and D. N. Reinhoudt, Eur. J. Org. Chem.,
2000, 165–170; R. Herges, A. Dikmans, U. Jana, F. Ko¨hler, P. G.
Jones, I. Dix, T. Fricke and B. Ko¨nig, Eur. J. Org. Chem., 2002, 3004–
3014; D. Ranganathan and C. Lakshmi, Chem. Commun., 2001, 1250–
1251.
on each side), was added. For the chloroform solvent model, the
corresponding parameters22 of AMBER 7 and for the acetonitrile
model the parameters by Kollman et al.23 were used. Missing
parameters for the ca–oh bond length, the ca–ca–oh and ca–oh–ho
bond angles, as well as the X–ca–oh–X and ca–ca–c–oh dihedral
angles were adopted from the AMBER 7 parm98 parameter set.
The missing parameter for ca–c3–ca was taken from Kirchhoff
et al.24 The solvated structures were subjected to 5000 steps of
minimisation followed by a 30 ps belly dynamics (300 K, 1 bar, 1 fs
timestep) for solvent relaxation and a 100 ps equilibration period.
Subsequently, MD simulations were performed in a NTP (300 K,
1 bar) ensemble for at least 9 ns using a 1 fs time step. Constant
temperature and pressure conditions were achieved by the weak
coupling algorithm and isotropic position scaling. Temperature
and pressure coupling times of 0.5 ps and 1.0 ps, respectively, and
the experimental compressibility values of 100 × 10−6 bar−1 for
chloroform and of 87.1 × 10−6 bar−1 for acetonitrile were used. The
particle mesh Ewald (PME) method25 was applied to treat long-
range electrostatic interactions, and the van der Waals interactions
˚
were truncated by using a cut-off value of 9 A. Bonds containing
hydrogen atoms were constrained to their equilibrium length using
the SHAKE algorithm. Snapshots were recorded every 2 ps.
Geometrical and energetical analyses of the trajectories were
carried out with the carnal and anal modules of AMBER 7.
Graphical analysis of the results was performed with the SYBYL
program.26
7 For the complexation of nitrate by a macrocycle containing two
urea units see: P. Blondeau, J. Benet-Buchholz and J. de Mendoza,
New J. Chem., 2007, 31, 736–740.
Single-crystal X-ray diffraction
Data were collected on a STOE-IPDS-II two-circle diffrac-
tometer employing graphite-monochromated MoKa radiation
8 Manuscript in preparation.
9 B. B. C. Hamann, N. R. Branda and J. Rebek, Jr., Tetrahedron Lett.,
1993, 34, 6837–6840.
˚
(0.71073 A). Data reduction was performed with the X-Area
10 P. Bu¨hlmann, S. Nishizawa, K. P. Xiao and Y. Umezawa, Tetrahedron,
1997, 53, 1647–1654; V. Alca´zar, M. Segura, P. Prados and J. de
Mendoza, Tetrahedron Lett., 1997, 39, 1033–1036.
11 P. R. Ashton, B. Ho¨rner, O. Kocian, S. Menzer, A. J. P. White, J. F.
Stoddart and D. J. Williams, Synthesis, 1996, 8, 930–940.
12 D. Meshcheryakov, V. Bo¨hmer, M. Bolte, V. Hubscher-Bruder, F.
Arnaud-Neu, H. Herschbach, A. Van Dorsselaer, I. Thondorf and
W. M o¨gelin, Angew. Chem., 2006, 118, 1679–1682, (Angew. Chem., Int.
Ed., 2006, 45, 1648–1652).
software.27 An empirical absorption correction was performed
using the MULABS28 option in PLATON.29 Structures were
solved by direct methods with SHELXS-9030 and refined by full-
matrix least-squares techniques with SHELXL-97.31
All non-H atoms were refined with anisotropic displacement
parameters. Hydrogens were included at calculated positions and
allowed to ride on their parent atoms. The H atoms at the
urea nitrogens of 13@Bu4NCl and 12 were freely refined. One
chloroform molecule of 11 is disordered over two positions with
a ratio of the site occupation factors of 0.528(9) : 0.472(9). In
13@Bu4NCl the terminal ethyl group of a butyl side chain is
disordered over two positions with a ratio of the site occupation
factors of 0.551(8) : 0.449(8). The C–C bond lengths of this butyl
13 The complicated solvent mixture developed since, upon evaporation,
an “unsuccessful” solvent was replaced by a different one and so on,
until finally, suitable single crystals were obtained.
14 The 222 cryptand is known to be a good complexant for Na+ cation. See
for instance: M. K. Chantooni and I. M. Kolthoff, J. Solution Chem.,
1985, 14, 1–12.
15 The urea moiety should be well adapted to acetate because of its
ability to form two N–H · · · O bonds with two oxygen atoms of the
anion, see: M. Boiocchi, L. Del Boca, D. Esteban-Gomez, L. Fabbrizzi,
M. Licchelli and E. Monzani, J. Am. Chem. Soc., 2004, 126, 16507–
16514.
˚
chain were restrained to 1.50(1) A and the 1–3 C–C distances were
˚
restrained to 2.4(1) A.
Crystallographic data are summarised in Table 4.
16 The interaction via hydrogen bonds decreases for the spherical halides
with increasing radius since it leads to a decrease of their charge density
in the order Cl− > Br− > I−, see: V. Amendola, M. Boiocchi, B. Colasson
and L. Fabbrizzi, Inorg. Chem., 2006, 45, 6138–6147.
17 The macrocyclic receptors were constructed manually with an all-trans
arrangement of the urea amide groups.
Acknowledgements
Financial support from the Deutsche Forschungsgemeinschaft
(Bo¨523/17-1,2 and TH 520/6-1) and CNRS is gratefully acknowl-
edged. We thank Dr Werner Mo¨gelin for preliminary calculations
and Dr Uta Scha¨del for preliminary screening experiments.
18 H. Gampp, M. Maeder, C. J. Meyer and A. D. Zuberbu¨hler, Talanta,
1985, 32, 257–264.
19 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,
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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, University
of California, San Francisco, USA, 2002; D. A. Pearlman, D. A. Case,
J. W. Caldwell, W. S. Ross, T. E. Cheatham III, S. DeBolt, D. Ferguson,
G. Seibel and P. A. Kollman, Comput. Phys. Commun., 1995, 91, 1–
41.
E. S. Replogle and J. A. Pople, Gaussian 98, Revision A.11, Gaussian,
Inc., Pittsburgh PA, USA, 2001.
22 T. Fox and P. Kollman, J. Phys. Chem. B, 1998, 102, 8070–8079; P.
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