Macrocyclic bis(ureas) as ligands for anion complexation

Article abstract of DOI:10.3762/bjoc.10.193

Two macrocyclic bis(ureas) 1 and 2, both based on diphenylurea, have been synthesized. Compound 1 represents the smaller ring with two ethynylene groups as linkers and 2 the larger ring with two butadiynylene groups. On thermal treatment to 130 °C molecule 1 splits up into two dihydroindoloquinolinone (3) molecules. Both compounds 1 and 2 form adducts with polar molecules such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) and act as complexing agents towards a series of anions (Cl-, Br-, I-, NO3 -, HSO4-). The crystal structures of 3, 2.2DMSO, 2.2DMF, and of the complex NEt4[Br.2] have been determined. Quantitative investigations of the complexation equilibria were performed via 1H NMR titrations. While 1 is a rather weak complexing agent, the large ring of 2 binds anions with association constants up to log K = 7.93 for chloride ions.

Full text of DOI:10.3762/bjoc.10.193

Macrocyclic bis(ureas) as ligands for anion complexation
Claudia Kretschmer, Gertrud Dittmann and Johannes Beck*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1834–1839.
Institute for Inorganic Chemistry, University of Bonn,
Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
doi:10.3762/bjoc.10.193
Received: 01 April 2014
Accepted: 16 July 2014
Published: 12 August 2014
Email:
Johannes Beck* - j.beck@uni-bonn.de
* Corresponding author
This article is part of the Thematic Series "Chemical templates".
Guest Editor: S. Höger
Keywords:
anion binding; macrocyclic compounds; NMR spectra; supramolecular
chemistry; template; urea
© 2014 Kretschmer et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Two macrocyclic bis(ureas) 1 and 2, both based on diphenylurea, have been synthesized. Compound 1 represents the smaller ring
with two ethynylene groups as linkers and 2 the larger ring with two butadiynylene groups. On thermal treatment to 130 °C mole-
cule 1 splits up into two dihydroindoloquinolinone (3) molecules. Both compounds 1 and 2 form adducts with polar molecules such
as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) and act as complexing agents towards a series of anions (Cl−, Br−,
I−, NO3−, HSO4−). The crystal structures of 3, 2·2DMSO, 2·2DMF, and of the complex NEt4[Br·2] have been determined. Quanti-
tative investigations of the complexation equilibria were performed via 1H NMR titrations. While 1 is a rather weak complexing
agent, the large ring of 2 binds anions with association constants up to log K = 7.93 for chloride ions.
Introduction
Supramolecular chemistry – the “chemistry beyond the mole- entity enables the formation of complex building units. Tripodal
cule” – is an area of modern chemistry, which has grown expo- tris(ureas) were synthesized, which contain tetrahedral oxoan-
nentially in the last decades [1,2]. Among the many concepts of ions like phosphate or sulfate [6,7] and ligands with three
supramolecular interactions, anion coordination chemistry has concatenated urea functions were shown to form 2:2 complexes
always been an intensively explored field, which still offers with phosphate anions [8]. Anion complexation is also possible
substantial progress [3-5].
with a rigid planar ligand, as was shown by indole-based
macrocycles [9]. This ligand system represents a stiff ring of
The urea group has proven to be an excellent anion receptor. two bis(indole) units connected via two ethynylene groups as
The ability to form two directional hydrogen bonds through the linkers. As proven by a crystal structure determination, a chlo-
highly polarized N−H groups towards different kinds of anions ride ion fits into the cavity bound via four N−H∙∙∙Cl bonds and
allows for building particular molecular arrangements. strong complexation was observed with several other anions. In
Incorporation of two or three urea groups into one molecular the 1H NMR spectra a significant dependence of the chemical
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shift of the N−H proton with the kind of bound anion was molecular shape for the bis(ureas). All attempts to obtain single
observed and the association constants as high as log K = 6.2 crystals of 1 for a structure determination failed. Crystallization
for Cl− were determined.
from solution gave only microcrystalline material. When we
tried to obtain crystals via vacuum sublimation, a complete
We achieved the synthesis of a macrocyclic planar bis(triazene), vaporisation at temperatures above 130 °C and deposition of
in which two diphenyltriazene units were linked by two colourless crystals were observed. A crystal structure analysis
ethynylene groups. On deprotonation, a dianionic planar of the deposited crystals, however, revealed that a fragmenta-
bis(triazenide) ligand is formed, which takes up several tion and rearrangement reaction had occurred. Under the
different transition metal ions, preferredly in the divalent state applied conditions 1 is completely converted to dihydroindolo-
[10]. Linking two diphenylurea groups by one ethynylene or quinolinone 3 (Scheme 2).
butadiynylene group gives a stiff arrangement but leaves one
degree of freedom in the system, since rotation around the
linking group is possible. This approach was realized by Steed
and coworkers, who showed that on adding chloride ions
planarization occurs and a rather high binding constant of
log K = 2.55 for the complexation of Cl− was determined [11].
Introducing a second bridging unit would give a ring containing
two diphenylurea units connected via two stiff linking units.
Since the urea unit N−C(O)−N and the triazenide unit N−N=N
are isosteric, we complemented our bis(triazene) ligand system
Scheme 2: Formation of dihydroindoloquinolinone 3 from 1 by vacuum
sublimation.
by cyclic bis(ureas). This opens the possibility for complexa-
tion of cations and anions with two isosteric ligands, just under
exchange of the active groups within the respective ring system.
Here we describe our results concerning macrocyclic bis(ureas) In accordance with the effortlessness of the conversion reaction,
with a rather rigid molecular entity.
the mass spectrum of 1 is dominated by the [M/2]+ signal. The
indoloquinolinone 3 forms essentially planar molecules (see
Supporting Information File 1, Figure S8). Indoloquinolinones
Results and Discussion
The synthesis of the two macrocyclic diphenylureas 1 and 2 can be synthesized by multistep procedures from suitable
proceeds straightforward from the respective 2,2’-diamino precursors [12-14]. Using thermolysis for the synthesis of
derivatives of diphenylethyne (tolane) and diphenylbuta-1,3- indoloquinolines has already been reported. Cyclization of
diyne with carbonyldiimidazole (Scheme 1).
aminophenyl substituted tolane isocyanates lead to indoloquino-
linones. The crystal structure of the N-methylated congener of 3
In both cases, the cyclization products were selectively formed has been determined [15].
in good yields. The quest for the molecular conformation is
challenging for both molecules. Since the bis(triazenide) Thermal treatment of 2 does not lead to fragmentation or subli-
congeners of 1 and 2 are planar, one can presume an analogous mation of volatile material as observed for 1. Macrocycle 2 is
Scheme 1: Synthesis of the macrocyclic bis(ureas) 1 and 2.
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soluble in dimethylformamide (DMF) or dimethyl sulfoxide
(DMSO) and can be crystallized from solution as light-yellow
crystals (see Supporting Information File 1, Figure S4). These
crystals incorporate associated solvent molecules, which are
difficult to remove and lead to discrepancies in the elemental
analyses towards the calculated compositions even after exces-
sive pumping at elevated temperatures. A bluish coloration of
the yellow material is already observed after prolonged keeping
under vacuum at ambient temperature. Thermal treatment in
vacuo at temperatures above 200 °C leaves a dark blue material
(see Supporting Information File 1, Figure S2). Dissolving the
blue material in DMF or DMSO leads to an almost complete
dissolution and a yellow solution, leaving behind only a small
portion of dark insoluble material. The nature of the yellow-to-
blue transformation is presently unclear. Partial cyclization
reactions in the solid material or formation of polymers via
radical mechanisms seem probable.
When crystallized from DMF or DMSO, 2 forms stable 1:2
adducts with these solvent molecules. Crystals were examined
by X-ray single crystal diffraction [16]. Both compounds,
2·2DMF and 2·2DMSO, are not crystallographically isotypic
but the molecular entities are completely analogous and may be
discussed jointly. In both cases the macrocyclic ring is mainly
flattened and two molecules of DMF or DMSO are coordinated
above and below the ring plane (Figure 1). A plane through all
atoms except the C and O atoms of the urea groups is rather
well fulfilled with the largest deviation found for C13 with
0.3 Å. The urea groups themselves are planar but tilted by 28°
against the main plane of the outer ring. This is caused by the
N−H∙∙∙O bonds to the O atom of the DMF molecule with H∙∙∙O
Figure 1: The molecular structure of 2·2DMF in two different views, on
top perpendicular to the plane, on bottom in the plane of the macro-
cycle. The molecular complex bears an inversion centre in the
midpoint. Thermal ellipsoids are scaled at the 50% probability level.
For a figure of the molecular structure of 2·2DMSO see Supporting
Information File 1, Figure S9.
separations of 2.00(1) and 2.07(2) Å. The somewhat lower a solution of 2 in DMSO, on slow evaporation yellow crystals
basicity of DMSO is manifested in longer N−H∙∙∙O bonds of of NEt4[Br·2] are separated. The crystal structure consists of ion
2.09(1) and 2.18(2) Å in the 2·2DMSO adduct.
pairs, tetraethylammonium cations and bromide anions, which
are located in the cavity of the macrocycle (Figure 2). The
Since immediate experimental data for the structure of the ligand is strongly tilted. The four N−H∙∙∙Br bonds, however,
unsolvated macrocyclic bis(ureas) were not obtainable, we used show uniform lengths (H1−Br, 2.72; H2−Br, 2.74; H3−Br, 2.75;
molecular mechanics calculations as implemented in the H4−Br, 2.71 Å; N−H∙∙∙O angles 149–169°). The representation
SPARTAN program suite [17] to calculate the respective struc- with space filling radii shows that the halide anion fits well into
tures. In both cases, the molecules are obtained as far from the bis(urea) ring. The ammonium ions are located in the saddle
planarity (see Supporting Information File 1, Figure S6 and shaped cavity formed by the twisted bis(urea).
Figure S7). Actually, a strong tilting is expected for both 1 and
2. According to these calculations, the small ring of 1 forces the The binding properties of 1 and 2 towards anions were studied
two urea groups into a head-to-tail arrangement with short by 1H NMR spectroscopy. As 2 was sufficiently soluble,
intramolecular hydrogen bridges. An even stronger tilting of the tetrahydrofuran (THF) turned out as a suitable solvent for the
molecule is expected for 2. Here, the distances are too large for spectroscopic investigations. On addition of tetrabutylammo-
any intramolecular N−H∙∙∙O bridging bonds.
nium salts with different anions significant changes in the
spectra emerge. The N−H proton resonances are shifted down-
As a strong anion complexing agent 2 binds halide anions even field with increasing effect in the order of I− < HSO4− < NO3−
in DMSO as solvent, despite DMSO itself is bound to the urea < Br− < Cl−. With the large complex anion PF6−, however, no
functional groups (Figure 1). If an excess of NEt4Br is added to effect was detected, indicating that no interaction occurred. The
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Beilstein J. Org. Chem. 2014, 10, 1834–1839.
Figure 3: 1H NMR spectra of 2 in THF-d8 after addition of several
different tetrabutylammonium salts. The N−H proton resonances show
a distinct dependence on the kind of the present anion.
For 1, which is in pure form soluble only in DMF or DMSO, it
was possible to record spectra in acetone-d6, since the solu-
bility was highly increased by the addition of ammonium salts
and subsequent complex formation. The effects on the N−H
proton resonances are weaker compared with 2 (see Supporting
Information File 1, Figure S11).
Figure 2: Molecular structure of the anionic complex in NEt4[Br·2].
Two different representations are given, on top with thermal ellipsoids
scaled at the 50% probability level, on bottom in a space filling repre-
sentation showing the strong twist of the macrocyclic bis(urea) ligand.
Since no signals of the free host and of the anionic complexes
phenyl proton resonances are also affected by the effect. The are simultaneously present, the exchange rate between the anion
protons at positions A, B, C (see Figure 3) are shifted slightly and the host molecules is fast compared to the NMR timescale.
upfield, while the phenyl protons in position D ortho to the urea However, the broadening of the signals by adding anion
substituents are shifted downfield for the weaker complexes amounts around 0.5 equivalents may be interpreted as a coales-
with HSO4− and NO3− but upfield for the stronger complexes cence phenomenon caused by an exchange between loaded and
formed with Br− and Cl−. The effect on the phenyl protons unloaded host. After the amount of the anion reaches a molar
amounts to maximally 0.3 ppm and is much weaker than the ratio of 1:1, the N−H proton resonance of 2 shows no further
effect on the urea protons where shifts up to 1.7 ppm are increase in the shift, indicating that a 1:1 complex has been
observed. The relatively strong influence on the resonances of formed (Figure 4). To ensure the composition of the host–guest
the ortho positioned protons may arise from the interaction with complexes Job plots were used. The function molar fraction vs
the carbonyl oxygen atom of the urea groups. This interaction is the product of molar fraction multiplied by the shift change Δδ
sensitive on the conformation of the flexible macrocyclic ring allows for the determination of the molar fractions of host and
system. Comparing the crystal structures of 2·2DMSO/DMF guest. From the maximum of the extrapolated curve the molar
with [Br·2]− shows a slight decrease of the mean O···H(ortho) fraction of the complex is obtained (see Supporting Informa-
distance from 2.32 to 2.25 Å.
tion File 1). For I−, NO3−, and Br− maxima at 0.50, 0.54, and
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Beilstein J. Org. Chem. 2014, 10, 1834–1839.
Figure 4: 1H NMR spectra of 2 in THF-d8 after addition of increasing molar equivalents of tetrabutylammonium nitrate. The N−H proton resonance
shows a distinct downfield shift depending on the concentration of the anion. The small invariant DMF signal originates from the solvent of recrystal-
lization used to purify the sample for the NMR experiments.
0.55 were found, which leads to the ratio of one host molecule mass spectrometry studies of NEt4[NO3·2] were undertaken.
and one guest molecule. For Cl−, the anion with the strongest Signals at m/z = 515.2 and 578.2 clearly indicate the masses of
shift effect, a maximum at 0.68 is present, indicating a complex the neat macrocycle 2 and the complex [NO3·2]. Signals origi-
of two bis(urea) molecules and one chloride ion. For the smaller nating from higher masses at 640.13 (2 with two molecules
macrocyclus 1 the Job plots do not show a distinct plateau after nitrate) or 1094.31 (two molecules of 2 with one molecule
addition of one equivalent of anion. Here, doubtless an inter- nitrate) could not be detected. So the 1:1 binding mode seems
action is present but apparently not a distinct host–guest com- the most plausible ratio. After evaluating the Job plots of the
plex formation.
complex of 2 and chloride, a 2:1 binding mode for the calcula-
tion of the association constants was used. Reliable association
The binding constants were determined with the help of the constants for the smaller macrocycle 1 could only be obtained
program WinEQNMR2 [18]. Table 1 contains the obtained in the case of chloride.
constants. The association constants of 2 with nitrate, bromide
and iodide were obtained by fitting the titration curves and the A short look at the binding constants reflects the amount of the
subsequent calculation to a 1:1 binding mode. This binding chemical shifts in the 1H NMR spectra. Bromide is bound
mode was already confirmed by the Job plots for all anions strongly to 2 in the 1:1 binding mode. Nitrate is bound weaker
except Cl−. Because the Job plot for the complex formation than bromide but still stronger than iodide, and chloride in the
between 2 and nitrate shows the maximum of the curve not 2:1 binding mode shows a high association constant of log K =
exactly at a molar ratio of 0.5 additional investigations via ESI 7.93. The binding constants for the known ring opened
Table 1: Binding constants of the macrocyclic bis(ureas) 1 and 2 towards different anions. All anions were used as tetrabutylammonium salts. Com-
pound 2 was dissolved in THF-d8 and 1 in DMSO-d6. All NMR spectra were taken at room temperature (298 K).
Anion
Receptor 2
Receptor 1
K
log K
K
log K
I−
1775 ± 97 M−1
3.25
4.64
6.71
7.93
NO3−
Br−
Cl−
43.556 ± 430 M−1
5.1∙106 ± 5100 M−1
8.57∙107 ± 9.21∙104 M−2
202 M−1
2.31
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Conclusion
Two macrocyclic bis(ureas) have been synthesized and exam-
ined for their anion complexation properties. The larger ring
with two butadiynylene groups as spacers turned out as a suit-
able receptor for small anions with high binding constants. The
molecule is flexible. In the complex with a bromide ion
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Angew. Chem., Int. Ed. 2008, 47, 1866–1870.
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Experimental
The procedures for the syntheses of 1, 2, and 3 and the spectro-
scopic characterizations are described in detail in Supporting
Information File 1.
10.Beck, J.; Hörner, M.; Dittmann, G. Eur. J. Inorg. Chem. 2009,
4314–4319. doi:10.1002/ejic.200900470
11.Swinburne, A. N.; Paterson, M. J.; Beeby, A.; Steed, J. W.
Chem.–Eur. J. 2010, 16, 2714–2718. doi:10.1002/chem.200903293
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doi:10.1007/BF00810008
13.Mulwad, V. V.; Lohar, M. V. Indian J. Chem., Sect. B 2003, 42,
1937–1942.
Supporting Information
14.Zhang, X.; Zhang-Negrerie, D.; Deng, J.; Du, Y.; Zhao, K.
J. Org. Chem. 2013, 78, 12750–12759. doi:10.1021/jo4023292
15.Li, H.; Yang, H.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2004, 69,
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Supporting Information File 1
Detailed experimental procedures, details of the crystal
structure determinations and spectroscopic data for 1, 2,
and 3.
16.Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112–122.
doi:10.1107/S0108767307043930
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-193-S1.pdf]
The crystal structure solutions and refinements were performed using
the Shelx programs (Shelxs93 and Shelxl93): G. M. Sheldrick,
Shelx-Programs for Crystal Structure Solution and Refinement. All
details concerning the crystal structure determinations may be found in
the Supporting Information File 1.
Supporting Information File 2
X-ray crystallographic data for 2·2DMF, 2·2DMSO,
NEt4[Br·2], 3, CCDC 993209, CCDC 993210, CCDC
993207, CCDC 993208.
17.Spartan 10, Program for Calculation of Molecular Properties;
Wavefunction Inc.: Irvine, CA, USA.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-193-S2.cif]
18.Hynes, M. J. J. Chem. Soc., Dalton Trans. 1993, 311–312.
doi:10.1039/dt9930000311
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Acknowledgements
The support of this work within the Collaborative Research
Center (Sonderforschungsbereich) SFB 624 (Project B13) of the
German Research Council (Deutsche Forschungsgemeinschaft)
is gratefully acknowledged. We thank C. Klein, Kekulé-Insti-
tute for Organic Chemistry and Biochemistry, University of
Bonn, for his help with the SPARTAN calculations.
This is an Open Access article under the terms of the
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(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
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