A bis-bisurea receptor with the R,R-cyclohexane-1,2-diamino spacer for phosphate and sulfate ions

Article abstract of DOI:10.1039/c2ob26591e

A bis-bisurea receptor (L) based on the R,R-cyclohexane-1,2-diamino scaffold forms an uncommon 2:2 complex (1) with the monohydrogen phosphate ion (HPO₄^2-) and a 1:1 complex (2) with the sulfate ion (SO₄^2-). Solution binding properties of the two anions were studied by ¹H NMR, UV-vis, and circular dichroism (CD) methods.

Full text of DOI:10.1039/c2ob26591e

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A bis-bisurea receptor with the R,R-cyclohexane-1,2-diamino spacer for
phosphate and sulfate ions†
Meiying Wei,a Biao Wu,*b Lei Zhao,c Hui Zhang,c Shaoguang Li,a Yanxia Zhaoa and Xiao-Juan Yanga
Received 10th August 2012, Accepted 24th September 2012
DOI: 10.1039/c2ob26591e
diaminocyclohexane subunit is a widely used source of chirality
because of its geometrical pre-organization nature.16 For
example, Fabbrizzi et al.17 and Albrecht et al.18 incorporated
optically pure 1,2-diaminocyclohexane into the linking unit of
bis-imino bis-quinoline or dicatechol diimine ligands, respecti-
vely, and isolated homochiral metal helicates.
A bis-bisurea receptor (L) based on the R,R-cyclohexane-1,2-
diamino scaffold forms an uncommon 2 : 2 complex (1) with
the monohydrogen phosphate ion (HPO42−) and a 1 : 1
complex (2) with the sulfate ion (SO42−). Solution binding
properties of the two anions were studied by 1H NMR,
UV-vis, and circular dichroism (CD) methods.
In the present work, the R,R-cyclohexane-1,2-diamine linker
was included in the bis-bisurea moiety (receptor L, Scheme 1) in
order to realize chiral resolution of triple anion helicates. Un-
expectedly, the assembly of L with phosphate ions did not afford
the desired 3 : 2 (host to guest) homochiral triple-stranded helicate,
but resulted in a 2 : 2 anion complex with the uncommon mono-
hydrogen phosphate ion (HPO42−), [Bu4N]4[(HPO4)2L2] (1). In
addition, a 1 : 1 complex of ligand L and the sulfate anion,
(Bu4N)2[SO4L] (2), has also been obtained.
The binding of phosphate and sulfate ions has attracted special
attention due to their ubiquitous presence in biological systems
and environments. Examples in biology include the sulfate
binding protein (SBP)1 and phosphate binding protein (PBP),2
which employ seven and twelve hydrogen bonds, respectively, to
recognize or transport the anion. In addition, phosphate and
sulfate anions are known as inorganic pollutants, which can
cause the eutrophication of waterways or problems in nuclear
waste treatment.3 Due to the large solvation energies of phos-
phate and sulfate ions, their separation is highly challenging.
Therefore, many efforts have been devoted to the design of artifi-
cial receptors for these two anions.4–12
We have recently developed a series of ortho-phenylene-
bridged oligourea ligands, whose anion coordination behavior
with the tetrahedral phosphate and sulfate anions greatly
resembles the oligo-pyridine ligands with transition metals.13
Through the self-assembly of a bis-bisurea receptor and a phos-
phate anion, the first triple anion helicate [A2L3] was obtai-
ned,13a in which the two coordinated PO43− ions adopt the same
configuration (Δ–Δ or Λ–Λ) in one helix but the compound is
racemic, consisting of both P and M enantiomers. This lack
of stereo-preference is common in the assembly by achiral
ligands.14 To modulate the relative population of the helical
structures and obtain optically pure isomers, an effective strategy
is to introduce chiral segments into the ligand.15 The chiral 1,2-
The ligand L was synthesized by the reaction of p-nitro-
phenylisocyanate and 1,1-bis-(2-aminophenyl-urea)-(1R,2R)-
cyclohexane (see ESI† for the synthesis). Slow diffusion of
diethyl ether into a THF solution of L and excess (Bu4N)H2PO4
and (Bu4N)OH afforded yellow crystals of the monohydrogen
phosphate complex (Bu4N)4[(HPO4)2L2] (1). Interestingly,
though different equivalents of (Bu4N)OH were added, only the
complex of the monoprotonated phosphate ion was isolated,
while the desired complex of the fully deprotonated phosphate
(PO43−) or other species with the dihydrogen phosphate
(H2PO4−) was not observed. Moreover, attempts to prepare the
3−
PO4 complex by using Na3PO4, K3PO4 and [K([18]crown-
6)]3PO4 have also been unsuccessful. For the sulfate anion,
aState Key Laboratory for Oxo Synthesis & Selective Oxidation,
Lanzhou Institute of Chemical Physics, CAS, Lanzhou 730000, China
bCollege of Chemistry and Materials Science, Northwest University,
Xi’an, 710069, China. E-mail: wubiao@nwu.edu.cn
cState Key Laboratory for Physical Chemistry of Solid Surfaces, and
College of Chemistry and Chemical Engineering, Xiamen University,
Xiamen 361005, China
†Electronic supplementary information (ESI) available: Experimental
details, X-ray data, NMR, UV-vis, and CD titrations, and computational
details. CCDC 895441 and 895442. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2ob26591e
Scheme 1 Structure of the receptor L.
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Fig. 2 (a) Crystal structure of the complex [(SO4)L]2− (2). (b) Hydro-
gen bonds around the SO42− ion.
Fig. 1 (a) Crystal structure of [(HPO4)2L2]4− (1; non-acidic hydrogen
atoms, Bu4N+ countercations and solvent molecules are omitted for
clarity). (b) Detailed view of the binding sites for the HPO4 dimer,
2−
monohydrogen phosphate ion is quite rare. An unusual phos-
phate dimer, [H3PO4·PO4]3−, was obtained by Jurczak et al.22
showing the 12 hydrogen bonds around each anion.
2−
Very recently, Gale et al.10a reported a similar HPO4 dimer
binding by an acyclic amido-indole decorated diindolylurea
receptor, which has eight NH hydrogen bond donors as in the
ligand L.
yellow crystals of the complex (Bu4N)2[SO4L] (2) were obtained
from the ligand L and excess (Bu4N)2SO4 in a DMSO/H2O
solution.
In the 1 : 1 sulfate complex (Bu4N)2[SO4L] (2), the receptor L
also displays a saddle shape with a “pocket” for the anion. There
are two independent molecules in the complex, whose structural
parameters are very close. All of the eight NH groups point to
the pocket and donate nine hydrogen bonds to the sulfate ion
(N⋯O distances range from 2.745 to 3.260 Å, average 2.972 Å;
N–H⋯O angles from 120° to 178°, average 154°) (Fig. 2a).
While the binding mode is similar to the amido-indole decorated
diindolylurea receptor,9a the latter shows a more “flat”, quasi-
square conformation rather than the curved L molecule in
The crystal structure of complex 1 shows a 2 : 2 binding ratio
of L and the HPO42− anion. The receptor adopts a “saddle” con-
formation and two receptor molecules are arranged in an anti-
parallel face-to-face manner, creating a cavity in which two
HPO42− ions are located. Each anion is bound strongly by one L
molecule via eight N–H⋯O hydrogen bonds (N⋯O distances
range from 2.685 to 3.083 Å, average 2.880 Å; and N–H⋯O
angles from 132° to 174°, average 154°) with all of the four urea
2−
moieties (Fig. 1 and Table S2†). The two encapsulated HPO4
2−
complex 2. Moreover, there is a Bu4N+ ion above the SO4
ions dimerize through two PvO⋯HO–P hydrogen bonds
(O–H⋯O: 2.640(5) Å, 155°, and 2.604(6) Å, 113°), and two
water molecules serve as bridges between the two anions, pro-
viding four slightly weaker O–H⋯O bonds for the anion dimer
anion, which forms additional C–H⋯O hydrogen bonds with the
anion (Fig. 2b and Table S3†). The sulfate binding mode in 2
also distinguishes from that in all the o-phenylene-bridged
tetrakis(urea) ligands, which encapsulates the sulfate ion in a
helical cavity by eight hydrogen bonds.13c
2−
(2.712(6)–2.946(6) Å, 126–164°) (Fig. 1b). Thus, each HPO4
ion indeed forms a total of twelve hydrogen bonds (eight
N–H⋯O, two PvO⋯HO–P, and two O–Hw⋯O bonds). This
coordination number (12) is consistent with the phosphate
binding protein, which also binds the monoprotonated form
(HPO42−) of phosphate by seven N–H⋯O, four O–H⋯O, and
one PO–H⋯O hydrogen bonds.2 For artificial receptors,
however, most studies have been focused on the dihydrogen
form of phosphate (H2PO4−),19–21 whereas binding of the
The solution binding behavior of L with phosphate and
sulfate anions was investigated by 1H NMR experiments. For the
−
H2PO4 anion, all of the urea NH groups showed gradual
−
downfield shifts when adding 0 to 5.0 equiv. of H2PO4 (as
Bu4N+ salt) (Fig. 3). Job’s plot pointed to a 1 : 2 binding mode,
−
and the association constants for H2PO4 were calculated to be
K1 = 1.10 × 104 M−1 and K2 = 6.39 × 101 M−1 by fitting the
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Fig. 3 1H NMR titration of L (5.0 × 10−3 M) with (Bu4N)H2PO4 in
DMSO-d6.
Fig. 5 CD spectra of L (1.5 × 10−4 M) upon addition of (Bu4N)2SO4
in CH3CN–0.5% DMSO.
2−
mode. The association constants between
L and SO4
determined by Dynafit24 were 2.81 × 104 M−1 (K1) and 3.47 ×
105 M−1 (K2).
The chirality properties of L upon addition of the above
anions were investigated by circular dichroism in CH3CN–0.5%
DMSO (1.5 × 10−4 M) (Fig. 5, Fig. S5†). The free ligand exhib-
ited strong negative CD signals at around 245 and 364 nm corre-
sponding to the phenyl and nitrophenyl segments, respectively.
−
2−
Interestingly, upon addition of H2PO4 and SO4 ions, the
Cotton effect at 245 nm reduced gradually in intensity and
finally became positive, which is attributed to the conformational
change of the receptor L (see below the DFT studies) upon
binding the anions. A similar “chirality reduction–inversion”
phenomenon has also been reported in the literature.25 Mean-
while, the signal at 364 nm began to show an exciton couplet
with the first negative and second positive Cotton effects corre-
sponding to the chromophores (λabs ≈ 355 nm) during the
addition of 1.0 equiv. of the anions.26 The intensity of this
exciton couplet decreased when adding 1.0 to 2.0 equiv. of
anions, which may be due to the increasing interchromophore
distance27 caused by the change of the ligand L from a “saddle”
shape to a stretched “S” shape to accommodate two anions as in
the previously reported sulfate complex of a related bis-bisurea
ligand.13a
As mentioned above, the initial goal of this work was to
obtain enantiomerically pure triple anion helicates. However, the
ligand adopts the bent conformations and acts as a “tetradentate”
tetrakis(urea) in both the phosphate (HPO42−) and sulfate com-
plexes rather than the desired bis-chelating bis-bisurea form.
Thus the rigidity and conformational preference of the ligand L
was studied by DFT calculations using the B3LYP/6-311++G(d,p)
method. Different from complexes 1 and 2, the optimized struc-
ture of the free ligand in the gas phase displays a twisted confor-
mation in which three urea groups converge to a cleft but the
fourth urea arm points away, with intra-molecular N–H⋯O
hydrogen bonds between the urea groups (Fig. S6†). The cyclo-
hexane-1,2-diamino spacer does not show the “anti” orientation
expected for the helical structures. The calculated N–C–C–N
torsion angle of the cyclohexylene diamine moiety in the free
ligand is −65.8°, while it is −54.3° in complex 1 and −49.5° in
Fig. 4 1H NMR titration of L (5.0 × 10−3 M) with (Bu4N)2SO4 in
DMSO-d6.
titration data with the EQNMR program (Fig. S1 and S2†).23 In
the case of sulfate ions (Fig. 4, Fig. S1†), all urea NH signals of
L also shifted gradually downfield upon titration of (Bu4N)2SO4,
2−
and the spectrum of L with 1 equiv. of SO4 resembles closely
that of complex 2. When more than 1 equiv. of sulfate ions were
added, a slow exchange process was observed, with the appear-
ance of a new set of NH signals in further downfields besides
those of complex 2 (Fig. 4e). This may be due to the conversion
of the 1 : 1 complex to the 1 : 2 (host–guest) binding mode, in
which the ligand molecule may assume an “S” shape and binds
one anion on each side, as observed for the sulfate complex of
the ethylene-bridged bis-bisurea ligand.13a The spectrum reached
saturation with 2 equiv. of the anion, and Job’s plot also gave a
1 : 2 binding stoichiometry (Fig. S1†). The downfield shifts
2−
(Δδ = 1.53–3.00 ppm) induced by 2.0 equiv. of SO4 were
larger than those observed with the H2PO4− ion, indicating stron-
2−
ger binding with SO4
.
In the UV-vis titration experiments (Fig. S3 and S4†), the
−
2−
H2PO4 and SO4 ions induced obvious bathochromic shifts
with clear isosbestic points, implying the formation of one single
complex. All absorption spectra reached saturation after addition
of 2.0 equiv. of anions, suggesting 1 : 2 (host–guest) binding
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M. B. Hursthouse and M. E. Light, Chem. Commun., 2008, 3007–3009;
(c) C. Caltagirone, J. R. Hiscock, M. B. Hursthouse, M. E. Light and
P. A. Gale, Chem.–Eur. J., 2008, 14, 10236–10243; (d) P. Dydio,
T. Zieliński and J. Jurczak, Chem. Commun., 2009, 4560–4562;
(e) J. L. Sessler, D.-G. Cho and V. Lynch, J. Am. Chem. Soc., 2006, 128,
16518–16519.
2. These values are far from those (157.2–179.6°) found in the
ethylene-bridged bis-bisurea receptor in the triple anion
helicate.13a
In conclusion, we report a chiral bis-bisurea receptor based on
the R,R-cyclohexane-1,2-diamine scaffold. Crystallization of L
with the anions resulted in the formation of a rare monohydrogen
phosphate complex 1 and the sulfate complex 2. In contrast to
the 1 : 1 binding in the solid state, the ligand displays the 1 : 2
(host to guest) binding ratio with phosphate and sulfate anions in
solution. Theoretical results demonstrated that the cyclohexane-
1,2-diamine spacer might be too rigid to form anion helicates.
Thus more flexible chiral ligands may be necessary for the con-
struction of optically pure anion helicates.
9 (a) P. A. Gale, J. R. Hiscock, C. Z. Jie, M. B. Hursthouse and
M. E. Light, Chem. Sci., 2010, 1, 215–220; (b) M. T. Huggins, T. Butler,
P. Barber and J. Hunt, Chem. Commun., 2009, 5254–5256.
10 (a) D. H. Lee, J. H. Im, S. U. Son, Y. K. Chung and J.-I. Hong, J. Am.
Chem. Soc., 2003, 125, 7752–7753; (b) S. L. Tobey, B. D. Jones and
E. V. Anslyn, J. Am. Chem. Soc., 2003, 125, 4026–4027; (c) S. L. Tobey
and E. V. Anslyn, J. Am. Chem. Soc., 2003, 125, 14807–14815;
(d) M. S. Han and D. H. Kim, Angew. Chem., Int. Ed., 2002, 41, 3809–
3811.
11 (a) C. R. Bondy, P. A. Gale and S. J. Loeb, J. Am. Chem. Soc., 2004,
126, 5030–5031; (b) R. Custelcean, V. Sellin and B. A. Moyer, Chem.
Commun., 2007, 1541–1543.
12 E. A. Katayev, Y. A. Ustynyuk and J. L. Sessler, Coord. Chem. Rev.,
2006, 250, 3004–3037.
Acknowledgements
13 (a) S. Li, C. Jia, B. Wu, Q. Luo, X. Huang, Z. Yang, Q.-S. Li and
X.-J. Yang, Angew. Chem., Int. Ed., 2011, 50, 5721–5724; (b) C. Jia,
B. Wu, S. Li, Z. Yang, Q. Zhao, J. Liang, Q.-S. Li and X.-J. Yang, Chem.
Commun., 2010, 46, 5376–5378; (c) C. Jia, B. Wu, S. Li, X. Huang and
X.-J. Yang, Org. Lett., 2010, 12, 5612–5615; (d) B. Wu, C. Jia, X. Wang,
S. Li, X. Huang and X.-J. Yang, Org. Lett., 2012, 14, 684–687.
14 (a) H. Juwarker, J.-m. Suk and K.-S. Jeong, Chem. Soc. Rev., 2009, 38,
3316–3325; (b) C. Schmuck, Angew. Chem., Int. Ed., 2003, 42, 2448–
2452.
15 (a) V. R. Naidu, M. C. Kim, J.-m. Suk, H.-J. Kim, M. Lee, E. Sim and
K.-S. Jeong, Org. Lett., 2008, 10, 5373–5376; (b) S. E. Howson and
P. Scott, Dalton Trans., 2011, 40, 10268–10277.
16 I. Alfonso, Curr. Org. Synth., 2010, 7, 1–23.
17 V. Amendola, L. Fabbrizzi, C. Mangano, P. Pallavicini, E. Roboli and
M. Zema, Inorg. Chem., 2000, 39, 5803–5806.
18 M. Albrecht, I. Janser, S. Kamptmann, P. Weis, B. Wibbeling and
R. Frohlich, Dalton Trans., 2004, 37–43.
19 V. Amendola, M. Boiocchi, D. Esteban-Gomez, L. Fabbrizzi and
E. Monzani, Org. Biomol. Chem., 2005, 3, 2632–2639.
20 P. S. Lakshminarayanan, I. Ravikumar, E. Suresh and P. Ghosh, Chem.
Commun., 2007, 5214–5216.
21 K. Calderon-Kawasaki, S. Kularatne, Y. H. Li, B. C. Noll, W. R. Scheidt
and D. H. Burns, J. Org. Chem., 2007, 72, 9081–9087.
This work was supported by the National Natural Science Foun-
dation of China (Grant Nos. 20872149 and 20973136).
Notes and references
1 J. W. Pflugrath and F. A. Quiocho, Nature, 1985, 314, 257–260.
2 H. Lueke and F. A. Quiocho, Nature, 1990, 347, 402–406.
3 (a) C. J. Fowler, T. J. Haverlock, B. A. Moyer, J. A. Shriver, D. E. Gross,
M. Marquez, J. L. Sessler, M. A. Hossain and K. Bowman-James, J. Am.
Chem. Soc., 2008, 130, 14386–14387; (b) L. R. Eller, M. Stępień,
C. J. Fowler, J. T. Lee, J. L. Sessler and B. A. Moyer, J. Am. Chem. Soc.,
2007, 129, 11020–11021.
4 C. Bazzicalupi, A. Bencini and V. Lippolis, Chem. Soc. Rev., 2010, 39,
3709–3928.
5 (a) K. M. Mullen and P. D. Beer, Chem. Soc. Rev., 2009, 38, 1701–1713;
(b) E. A. Katayev, G. D. Pantos, M. D. Reshetova, V. N. Khrustalev,
V. M. Lynch, Y. A. Ustynyuk and J. L. Sessler, Angew. Chem., Int. Ed.,
2005, 44, 7386–7390.
6 (a) S. K. Dey and G. Das, Dalton Trans., 2011, 40, 12048–12051;
(b) M. Allevi, M. Bonizzoni and L. Fabbrizzi, Chem.–Eur. J., 2007, 13,
3787–3795.
7 (a) I. Ravikumar and P. Ghosh, Chem. Soc. Rev., 2012, 41, 3077–3098;
(b) C. Jia, B. Wu, S. Li, X. Huang, Q. Zhao, Q.-S. Li and X.-J. Yang,
Angew. Chem., Int. Ed., 2011, 50, 486–490; (c) B. Wu, J. Liang, J. Yang,
C. Jia, X.-J. Yang, H. Zhang, N. Tang and C. Janiak, Chem. Commun.,
2008, 1762–1764; (d) R. Custelcean, P. Remy, P. V. Bonnesen,
D.-E. Jiang and B. A. Moyer, Angew. Chem., Int. Ed., 2008, 47, 1866–
1870; (e) Q.-Y. Chen and C.-F. Chen, Eur. J. Org. Chem., 2005, 2468–
2472.
22 P. Dydio, T. Zieliński and J. Jurczak, Org. Lett., 2010, 12, 1076–1078.
23 M. J. Hynes, J. Chem. Soc., Dalton Trans., 1993, 311–312.
24 P. Kuzmič, Anal. Biochem., 1996, 237, 260–273.
25 (a) M. Asakawa, G. Brancato, M. Fanti, D. A. Leigh, T. Shimizu,
A. M. Z. Slawin, J. K. Y. Wong, F. Zerbetto and S. Zhang, J. Am. Chem.
Soc., 2002, 124, 2939–2950; (b) J.-m. Suk, V. R. Naidu, X. Liu,
M. S. Lah and K.-S. Jeong, J. Am. Chem. Soc., 2011, 133, 13938–13941.
26 J.-M. Fang, S. Selvi, J.-H. Liao, Z. Slanina, C.-T. Chen and P.-T. Chou,
J. Am. Chem. Soc., 2004, 126, 3559–3566.
8 (a) P. A. Gale, J. R. Hiscock, S. J. Moore, C. Caltagirone,
M. B. Hursthouse and M. E. Light, Chem.–Asian J., 2010, 5, 555–561;
(b) C. Caltagirone, P. A. Gale, J. R. Hiscock, S. J. Brooks,
27 S. Matile, N. Berova, K. Nakanishi, J. Fleischhauer and R. W. Woody,
J. Am. Chem. Soc., 1996, 118, 5198–5206.
This journal is © The Royal Society of Chemistry 2012
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