A macrocyclic diurea derived from diphenylether

Article abstract of DOI:10.1016/j.tetlet.2009.12.087

A new 16-membered cyclic diurea was synthesized and tested as potential receptor for fluoride. ¹H and ¹⁹F NMR spectroscopy revealed an unexpected deprotonation of both urea groups after initial 1:1 binding. A single crystal X-ray structure shows bifurcated hydrogen bonds to two DMSO molecules.

Full text of DOI:10.1016/j.tetlet.2009.12.087

Tetrahedron Letters 51 (2010) 1202–1204
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A macrocyclic diurea derived from diphenylether
Denys Meshcheryakov a, Michael Bolte b, Volker Böhmer a,
*
a Fachbereich Chemie, Pharmazie und Geowissenschaften, Abteilung Lehramt Chemie, Johannes Gutenberg-Universität Mainz, Duesbergweg 10-14, D-55099 Mainz, Germany
b Fachbereich Chemie und Pharmazeutische Wissenschaften, Institut für Anorganische Chemie, Johann Wolfgang Goethe-Universität Frankfurt,
Max-von-Laue-Str. 7, D-60438 Frankfurt/Main, Germany
a r t i c l e i n f o
a b s t r a c t
A new 16-membered cyclic diurea was synthesized and tested as potential receptor for fluoride. 1H and
19F NMR spectroscopy revealed an unexpected deprotonation of both urea groups after initial 1:1 binding.
A single crystal X-ray structure shows bifurcated hydrogen bonds to two DMSO molecules.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 28 October 2009
Revised 15 December 2009
Accepted 16 December 2009
Available online 28 December 2009
1. Introduction
2.2. Interaction with fluoride anions
Various hydrogen bond donors (podands,1 macrocyclic,2 and
macro-bicyclic3 compounds) have been proposed, synthesized,
and studied as anion receptors.4 Oligourea (or thiourea)5 deriva-
tives, able to interact via bifurcated hydrogen bonds6 with the tar-
geted anion seem especially promising. In course of our studies on
cyclic polyurea compounds composed of three,7 four,8 six,9 and
more10 urea-bridged xanthene (X) and diphenylether (D) units,
we also obtained smaller cycles, based on the more flexible D-unit.
In addition to the product of the intramolecular cyclization (‘cyclic
monomer’),11 the cyclic dimer 2, in which two diphenylether units
are connected by two urea groups via the 2,20-positions, has been
isolated. Here we report the crystal structure of this cyclic diurea
2 and its interaction with fluoride.
Since the cyclic diurea 2 might be a ligand sized for fluoride
anions, we followed its interaction with tetrabutylammonium
fluoride in DMSO-d6 by 1H NMR. The spectrum of the free dimer
2 (Fig. 1) shows a sharp singlet for the four NH protons at
8.85 ppm, two doublets (ortho-coupling, J = 7.8 Hz) for the four aryl
protons adjacent to NH and O, and a multiplet (two overlapping
triplets) for the remaining aryl protons.
Upon addition of small amounts of fluoride, the NH-signal
strongly broadens and practically disappears. Small shifts occur
for the aryl protons, 0.2 ppm downfield for the doublets and
slightly upfield for the triplets, which now are clearly separated.
Since still only one set of signals appears, the free macrocycle 2,
and its complex with fluoride must be rapidly exchanging on the
NMR-time scale. The NH-signals become sharper again, and for a
1:1 ratio (2/Fꢀ) we observe (mainly) one species, according to
the aromatic signals (2 d, 2 tr), with two (!) rather broad NH
signals. Assuming a 1:1 complex, where the Fꢀ anion is not in
the geometric center of 2, but moves between two positions, this
exchange must be ‘rapid’ for the aromatic signals, but ‘slow’ for
the NH signals. This is not unreasonable, since the chemical shift
difference should be larger for the NH-proton (close to the fluoride
anion) than for the aromatic protons.
2. Results and discussion
2.1. Synthesis
The cyclic dimer 2 is always formed when the diamine 1 is re-
acted with p-nitro chloroformate or triphosgene in the presence of
a trialkylamine (Scheme 1). Depending on the solvent, the yield
varies and reaches 20% when the reaction is carried out in ethyl-
acetate, in the presence of diisopropyl-ethylamine and when the
reagents are added slowly at room temperature (over 10 h) to
the reaction flask. Since the pure dimer precipitates from the mix-
ture and can be easily isolated in pure form simply by filtration we
did not try to improve this simple procedure. Attempts to synthe-
size the analogous urea bridged dimer of xanthene, or to incorpo-
rate at least one xanthene unit into the dimer failed, however.
* Corresponding author. Tel.: +49 (0) 6131 3923873; fax: +49 (0) 6131 3925419.
E-mail address: vboehmer@mail.uni-mainz.de (V. Böhmer).
Scheme 1. Formation of the dimeric cycle 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.087

D. Meshcheryakov et al. / Tetrahedron Letters 51 (2010) 1202–1204
1203
Figure 2. Structural view of the single molecule of 2 in the crystalline state
(thermal ellipsoids at 50% probability level).
scheme) is shown in Figure 2. The molecule assumes a conforma-
tion with ‘distorted’ C2h-symmetry, with the C2-axis passing O3
and O4 and the
r-plane intersecting the carbonyl groups. Both
urea groups are ‘exactly’ planar (the distance of the carbon atom
from the plane defined by the oxygen and the two nitrogen atoms
is 0.004 and 0.006 Å). The angle between these two planes (8.03°)
characterizes the deviation from an ideal conformation with S2-
symmetry.
Figure 1. Stepwise addition of tetrabutylammonium fluoride solution to the
solution of the dimeric cycle 2 (DMSO-d6, 25 °C); peaks for LH4Fꢀ (ꢃ) and LH2
2ꢀ
(ꢄ) are marked. The main species are indicated at the right side of the spectra.
Already before, in the presence of ꢁ0.9 mol of Fꢀ, a sharp signal
at 12.45 ppm appears, together with aromatic signals (two dou-
blets, and two triplets) for another complex species, which obvi-
ously is not in fast exchange with the first one. These doublets
(up- and downfield shifted) and triplets (both upfield shifted) are
stronger separated, than the corresponding signals of the first spe-
cies. At the ratio of about 1:2 (2/Fꢀ), both species are obviously
present in nearly equal amounts, but even with a large excess of
Fꢀ (about 10-fold), the first set of signals is still clearly visible.
This can be explained by the initial formation of a 1:1 complex,
which is in rapid equilibrium with the free cyclic ligand LH4
The two DMSO molecules15 are hydrogen bonded by the two
urea functions (bifurcated H-bonds) with Nꢂ ꢂ ꢂO-distances of
2.911 Å and 2.943 Å for O3S (to N11 and N12) and 2.906 Å and
2.847 Å for O1S (to N21 and N22), thus ‘closing’ from both sides
the hole in the 16-membered macrocycle. A third DMSO molecule
being not involved in hydrogen bonds obviously fills gaps in the
crystal lattice.
The packing is illustrated in Figure 3. The molecules of 2, sol-
vated by two hydrogen-bonded DMSO molecules form staples par-
allel to the a-axis including channels ‘filled’ by the non-hydrogen-
bonded DMSO molecules (Fig. 3).
LH4 þ Fꢀ¡LH4Fꢀ
A molecular main plane through C11, C21, C31, and C41 may be
defined to further characterize the conformation. The planes of
aromatic rings I (24.1°), II (25.9°), and III (24.8°) have very similar
angles with this plane, while it is somewhat larger (32.4°) for IV.
The conformation of the two diphenyl urea sections is also similar.
The plane defined by O1, N11, and N12 includes angles of 46.0° and
37.8° with the planes of I and III, respectively, while the corre-
sponding angles with II and IV are 37.3° and 47.5° for the plane
through O2, N21, and N22. For both pairs the difference (8–10°)
is rather similar.
Further addition of Fꢀ leads to a twofold deprotonation of the
diurea 2:
LH4Fꢀ þ 3Fꢀ¡LH22ꢀ þ 2FHFꢀ
A similar behavior (elimination of several protons from NH-
groups of a molecule by fluoride) was reported for a tripodal pyr-
role-based receptor,12 and even for a receptor with a single urea
group.13
This interpretation is in agreement with a series of 19F NMR
spectra, where the quintuplet of the LH4Fꢀ appears and increases
until one equivalent of fluoride is added. Upon further addition it
decreases again, while an increasing doublet for FHFꢀ appears
instead.
3. Conclusion
From three potential combinations of xanthene and diphenyl-
ether units only the cyclic diurea 2 with the flexible 2,20-diphenyl
ether connections is sterically possible for the 16-membered ring.
It forms a 1:1 complex with a fluoride anion in solution, which is
deprotonated to the dianion [2]2ꢀ and FHFꢀ anion when tetrabu-
tylammonium fluoride is added in excess.
2.3. Crystal structure
Crystals of 2ꢂ3 DMSO were obtained from a solvent mixture
containing dichloromethane, chloroform, and DMSO by slow evap-
oration.14 The molecular conformation (including the numbering
Although these species are stable on the NMR-time scale, the
cocrystallization with TBA fluoride was not successful. Single

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D. Meshcheryakov et al. / Tetrahedron Letters 51 (2010) 1202–1204
References and notes
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Acknowledgment
Financial support from the Deutsche Forschungs-gemeinschaft
(Bö523/17-1-3) is gratefully acknowledged.
Supplementary data
14. CCDC reference number 748328.
15. One of them is disordered with two positions for the S- and O-atoms. Discussed
is the main position.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.087.