Bambus[n]urils: A new family of macrocyclic anion receptors

Article abstract of DOI:10.1021/ol201515c

A recently discovered anion receptor is jointed by three related macrocycles differing in the number of glycoluril units and type of substitution. The synthesis is carried out in nonpolar solvents compared to aqueous media used in the case of the original

Full text of DOI:10.1021/ol201515c

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4000–4003
Bambus[n]urils: a New Family of
Macrocyclic Anion Receptors
Vaclav Havel,† Jan Svec,† Michaela Wimmerova,‡ Michal Dusek,§ Michaela Pojarova,§
and Vladimir Sindelar*,†,
Department of Chemistry, Masaryk University, Kamenice 5, 625 00 Brno, Czech
Republic, Central European Institute of Technology, National Centre for Biomolecular
Research and Department of Biochemistry, Masaryk University, Kamenice 5, 625 00
Brno, Czech Republic, Institute of Physics of the ASCR, v.v.i., Na Slovance 2, 182 21
Prague 8, Czech Republic, and Research Centre for Toxic Compounds in the
Environment, Masaryk University, Kamenice 3, 625 00 Brno, Czech Republic
sindelar.chemi.muni.cz
Received June 7, 2011
ABSTRACT
A recently discovered anion receptor is jointed by three related macrocycles differing in the number of glycoluril units and type of substitution.
The synthesis is carried out in nonpolar solvents compared to aqueous media used in the case of the original macrocycle. The size of macrocycle
is controlled by a template. A hexameric macrocycle with benzyl substitution binds halide anions with an affinity exceeding 109 Mꢀ1 while a
tetrameric analog does not bind any of the investigated anions.
Macrocycles are the most important class of supramo-
lecular host molecules.1 They usually consist of several
identical building blocks which are connected forming a
cyclic structure with a preorganized shape. In such an
arrangement the macrocyclic hosts bear multivalent bind-
ing sites which allow the strong and selective binding of the
guest. The nature of the binding sites determines if the
positively or negatively charged or neutral guests will form
supramolecular complexes within a macrocycle. There is a
wide range of macrocyclic compounds presented in litera-
ture. Only a few of them, however, attract substantial
attention. These macrocycles are represented by cation
receptors including crown ethers2 and calixarenes,3 anion
receptors including katapinands4 and calixpyrroles,5 and
also those receptors in which the hydrophobic effect plays
an important role in the complex formation including
(3) (a) No, K. H.; Gutsche, C. D. J. Org. Chem. 1982, 47, 2713–2719.
(b) McIIdowie, M. J.; Mocerino, M.; Ogden, M. I. Supramol. Chem.
2010, 22, 13–39. (c) Ikeda, A.; Shinkai, S. Chem. Rev. 1997, 97, 1713–
1734. (d) Bohmer, V. Angew. Chem., Int. Ed. 1995, 34, 713–743. (e)
Gutsche, C. D. Calixarenes; The Royal Society of Chemistry: Cambridge,
U.K., 1989.
† Department of Chemistry, Masaryk University.
‡ Central European Institute of Technology.
§ Institute, of Physics of the ASCR.
Research Centre for Toxic Compounds in the Environment.
(1) Steed, J. W.; Atwood, J. L. Supramolecular Chemistry;
Wiley-VCH: Weinheim, 2009.
(4) (a) Simmons, H. E.; Park, C. H. J. Am. Chem. Soc. 1968, 90, 2428–
2429. (b) Park, C. H.; Simmons, H. E. J. Am. Chem. Soc. 1968, 90, 2431–
2432.
(2) (a) Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 7017–7036. (b)
Wolf, R. E.; Hartman, J. A. R.; Storey, J. M. E.; Foxman, B. M.;
Cooper, S. R. J. Am. Chem. Soc. 1987, 109, 4328–4335. (c) Gokel, G. W.
Crown Ethers and Cryptands; The Royal Society of Chemistry: Cambridge,
U.K., 1991.
(5) (a) Gale, P. A.; Sessler, J. L.; Kral, V.; Lynch, V J. Am. Chem. Soc.
1996, 118, 5140–5141. (b) Sessler, J. L.; Camiolo, S.; Gale, P. A. Coord.
Chem. Rev. 2003, 240, 17–55. (c) Turner, B.; Botoshansky, M.; Eichen,
Y. Angew. Chem., Int. Ed. 1998, 37, 2475–2478. (d) Yoon, D. W.;
Hwang, H.; Lee, C. H. Angew. Chem., Int. Ed. 2002, 41, 1757–1759.
r
10.1021/ol201515c
Published on Web 06/28/2011
2011 American Chemical Society

cyclodextrins6 and cucurbiturils.7 In all these cases not
only a single macrocycle exists, but there are families of
macrocycles having the same structural motif but differing
in the size or in their substitution. The reasons for the
popularity of these receptors are not only their supramo-
lecular properties but also rather simple preparation of at
least some of the members within each macrocyclic family.
Recently, we have prepared a new macrocyclic com-
pound, bambus[6]uril (Figure 1), which acts as an anion
receptor with high affinity and selectivity for various
anions in both organic solvent mixtures and aqueous
media.8
deprotected, which would allow further derivatization of
the bambusuril skeleton. The starting material, 2,4-diben-
zylglycoluril, was prepared by acid catalyzed condensation
of 4,5-dihydroxyimidazolidin-2-one9 with 1,3-dibenzylur-
ea in methanol in 81% yield. The reaction between 2,4-
dibenzylglycoluril and formaldehyde, which was expected
to give the bambusuril compound, appeared to be very
sensitive to the reaction conditions. When the reaction was
carried out in the mixture of methanol and 35% HClaq (1:1),
glycoluril selectively rearranged into dibenzylhydantoin
1.10 On the other hand, in the mixture of methanesulfonic
acid and 35% HClaq (4:1), the reaction gave clip-shape-like
molecule 2 (see Scheme 1) in very good yield (85%). It
should be noted that although the crystal structure of this
molecule was reported in the literature,11 the experimental
details of its preparation are missing.
Scheme 1. Reaction between 2,4-Dibenzylglycoluril and
Formaldehyde under Different Conditions
Figure 1. Dodecamethylbambus[6]uril (Me12BU[6]).
The starting materials for the synthesis are inexpensive
ureas, glyoxal, and formaldehyde. The bambus[6]uril
synthesis is simple, as the macrocycle precipitates out from
the reaction solution as the only product. Here we show
that bambus[6]uril is not the only macrocycle of its kind
but there are related molecules consisting of the same
building block and differing in their number within the
macrocycle as well as in the substitution on the nitro-
gen atom of glycoluril units. To differentiate the original
bambus[6]uril from the new derivatives we will, from now
on, name it dodecamethylbambus[6]uril (Me12BU[6]). This
trivial name reflects the presence of 12 methyl groups and 6
glycoluril units in the macrocycle. New derivatives will be
named accordingly.
We decided to test the preparation of dodecabenzyl-
bambus[6]uril (Bn12BU[6]) (see Scheme 1) in which the 12
methyl groups of Me12BU[6] are substituted by benzyl
groups. We envisioned that the macrocycle should be
soluble in single nonpolar solvents compared to the
Me12BU[6], which dissolved only in mixtures of solvents
when complexed to anions and does not dissolve in any
organic solvent in the absence of an anion inside its cavity.
Furthermore, benzyl groups would be subsequently
We then tested the reaction of 2,4-dibenzylglycoluril
with paraformaldehyde in chloroform in the presence of
a catalytic amount of p-toluenesulfonic acid. This reaction
finally gave the macrocyclic compound, but it was surpris-
ingly octabenzylbambus[4]uril (Bn8BU[4]) containing
four glycoluril units connected by four methylene bridges
(Scheme 1). We were able to obtain the crystal structure of
Bn8BU[4]. Figure 2A clearly shows that the methine carbon
atoms of the glycoluril units point to the center of the
macrocycle and the glycoluril units adopt an alternate
conformation. Clearly the structural features of Bn8BU[4]
are similar to those of previously published Me12BU[6].
Thus Bn8BU[4] represents the first bambusuril derivative
of its older relative differing in (a) the number of glycoluril
units and (b) the 2,4-substituents on glycoluril units.
(6) (a) Cyclodextrins and Their Complexes: Chemistry, Analytical
Methods; Dodziuk, H., Ed.; Wiley-VCH: Weinheim, 2009. (b) Szejtli, J.
Chem. Rev. 1998, 98, 1743–1753. (c) Takahashi, K. Chem. Rev. 1998, 98,
2013–2033. (d) Connors, K. A. Chem. Rev. 1997, 97, 1325–1357.
(7) (a) Lee, J.; Samal, S.; Selvapalam, N.; Kim, H.; Kim, K. Acc.
Chem. Res. 2003, 36, 621–630. (b) Lagona, J.; Mukhopadhyay, P.;
Chakrabarti, S.; Isaacs, L. Angew. Chem., Int. Ed. 2005, 44, 4844–
4870. (c) Modern Supramolecular Chemistry: Strategies for Macrocycle
Synthesis; Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.; Wiley-VCH:
Weinheim, 2008.
(9) (a) Vail, S. L.; Barker, R. H.; Mennitt, P. G. J. Org. Chem. 1965,
30, 2179–2182. (b) Grillon, E.; Gallo, R.; Pierrot, M.; Boileau, J.;
Wimmer, E. Tetrahedron Lett. 1988, 29, 1015–1016.
(10) (a) Ulgheri, F.; Giunta, D.; Spanu, P. Tetrahedron 2008, 64,
11768–11775. (b) Ulgheri, F.; Orru, G.; Crisma, M.; Spanu, P. Tetra-
hedron Lett. 2004, 45, 1047–1050.
(8) (a) Svec, J.; Necas, M.; Sindelar, V. Angew. Chem., Int. Ed. 2010,
49, 2378–2381. (b) Svec, J.; Dusek, M.; Fejfarova, K.; Stacko, P.; Klan,
P.; Kaifer, A. E.; Li, W.; Hudeckova, E.; Sindelar, V. Chem.;Eur. J.
2011, 17, 5605–5612.
ꢀ
(11) Hu, Y.; Zhou, B.; Cao, L. Acta Crystallogr. 2007, E63, o4480.
Org. Lett., Vol. 13, No. 15, 2011
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Figure 2. Crystal structures (top and side views) of (A) Bn8BU[4]:2 CH3CN complex, (B) Bn12BU[6]:2 Clꢀ complex, and (C) Pr12BU[6]:
Iꢀ complex. Color coding: C, gray; N, blue; O, red; Clꢀ, green; Iꢀ, purple.
The supramolecularpropertiesofBn8BU[4] were studied
in the solid state and in solution. In the crystal, obtained by
slow crystallization from acetonitrile solution, each of both
portals defined by the benzyl substituents is occupied by
one molecule of acetonitrile (Figure 2A). This 2:1 complex
is stabilized by van der Waals interactions. On the other
hand, we did not observe such a complexation in solution.
Furthermore, we investigated the interaction between halide
presence of TBACl. Figure 2B shows that in the solid state
a 2:1 complex is formed in which each of the two portals of
Bn12BU[6] is occupied by one chloride anion. This is in
contrastwith thepreviously obtained1:1complex between
Me12BU[6] and chloride, in which the anion is located in
the center of the cavity.
To evaluate the affinity of Bn12BU[6] toward halide
anions we first had to isolate the macrocycle without an
encapsulated anion. Anion-free Bn12BU[6] was obtained
by boiling of the complex between Bn12BU[6] and a
chloride anion in an excess of methanol, filtration of the
solid, and drying under vacuum. Compared to anion-free
Me12BU[6], which did not dissolve in any of the investi-
gated solvents, Bn12BU[6] was readily soluble in chloro-
form. We, therefore, investigated the affinity of Bn12BU[6]
1
anions and Bn8BU[4] in CD3Cl using H NMR spectro-
scopy. In contrast with Me12BU[6], which forms very
stable complexes with halide anions, Bn8BU[4] did not
show any affinity toward anions. The reason is most likely
the small cavity of the macrocycle which is not able to
include even a fluoride anion.
Bn8BU[4] did not act as a receptor for anion binding. We
therefore continued in our synthetic effort to prepare bam-
busuril with a larger internal cavity. We found that when
2,4-dibenzylglycoluril reacts with paraformaldehyde in
chloroform or toluene in the presence of a template anion,
the formation of the cyclic tetramer Bn8BU[4] was sup-
pressed and the hexameric analog Bn12BU[6] was detected
as the major product (Scheme 1). Among all tested halide
templates, the best yield of Bn12BU[6] (65%) was achieved
when tetrabutylammonium iodide (TBAI) was used. A
lower yield of Bn12BU[6] (53%) was obtained in the pre-
sence of TBACl. This is indeed in agreement with the
previously published results,8 which showed that the affi-
nity of Me12BU[6] toward halide anions decreases in the
order Iꢀ > Brꢀ > Clꢀ > Fꢀ. Good quality monocrystals
of Bn12BU[6] were obtained by the slow evaporation of the
chloroform from the solution of the macrocycle in the
1
toward halide anions in this nonpolar solvent using H
NMR spectroscopy (Figure 3). For instance, addition of
0.5 equiv of TBACl into Bn12BU[6] solution led to the
appearance of a new set of signals. In the presence of 1.0
equiv of TBACl the original signals of Bn12BU[6] were no
longer present and only new signals were detected in the
spectra. Further addition of TBA salt no longer influenced
the appearance of the Bn12BU[6] spectrum. These experi-
ments showed that (a) the complexation between Bn12BU-
[6] and the chloride anion is slow on the NMR time scale,
(b) the formation of the 1:1 complex takes place in the
solution instead of the 2:1 complex observed in the solid
state, and (c) complex stability is too high which precludes
the determination of the association constant (Ka) of the
complex using 1H NMR spectroscopy. We further inves-
tigated the remaining halide anions and found that all of
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Org. Lett., Vol. 13, No. 15, 2011

them interact with Bn12BU[6] in the same manner as the
chloride anion. The formation of 1:1 complexes was con-
firmed by the observation of a major signal corresponding
to the m/z value of the complex between Bn12BU[6] and
each anion in the ESI mass spectrum.
HCl. Therefore, we investigated if some other bambusuril
derivatives could be prepared in aqueous media. We
selected the reaction between 2,4-dipropylglycoluril and
formaldehyde in 5.4 M HCl. MALDI-TOF MS revealed
that the reaction at room temperature gave only a mixture
of water-soluble acyclic oligomers. However, raising the
temperature up to 100 °C resulted in the formation of a
precipitate of dodecapropylbambus[6]uril (Pr12BU[6]).
The binding behaviors of Pr12BU[6] were similar to those
of Me12BU[6]. For instance, the Pr12BU[6] formed strong
1:1 complexes with iodide anion in the solution and also in
the solid state (see Figure 2C).
In conclusion, we have prepared new bambusuril deri-
vatives Bn8BU[4], Bn12BU[6], and Pr12BU[6]. Thus we
have demonstrated that Me12BU[6] is not the only macro-
cycle of its kind, but part of a new family of macrocyclic
compounds, the bambusuril family. Bambusuril homolo-
gues differ significantly in their supramolecular and phy-
sical properties. Bn8BU[4], with a small internal cavity, did
not behave as a receptor of anions. On the other hand,
Bn12BU[6] was able to bind halide anions with an affinity
as high as 3.8 ꢁ 109
M
ꢀ1. In contrast to previously
published anion-free Me12BU[6], which does not dissolve
in any organic solvent,8b Bn12BU[6] is soluble in chloro-
form even in the absence of complexed anions. We are
currently exploring the possibility of the bambusuril deri-
vatives with even larger internal cavities as well as the
modification of the already reported macrocycles.
Figure 3. 1H NMR spectra (300 MHz, CDCl3) of Bn12BU[6] in
the absence (A) and in the presence of 0.5 equiv (B), 1.1 equiv
(C), and 2.2 equiv (D) of TBAþClꢀ.
As direct measurement from 1H NMR spectra was not
possible we determined equilibrium association constant
(Ka) values of the complexes using isothermal titration
calorimetry (ITC). ITC experiments in classical arrange-
ments allowed us to characterize the complexation of Fꢀ
and Clꢀ with Bn12BU[6]. Competitive calorimetric titra-
tion was used to measure the binding between Brꢀ and Iꢀ
and the macrocycle because of the high affinity of these
complexes. Ka values of 8.6 ꢁ 105, 3.0 ꢁ 106, 3.0 ꢁ 108, and
3.8 ꢁ 109 Mꢀ1 were found for the complexes formed
between Bn12BU[6] and Fꢀ, Clꢀ, Brꢀ, and Iꢀ. These valeus
show that Bn12BU[6] is one of the most potent neutral
receptors for halide anions. Despite the overall high
Acknowledgment. Support for this work was provided
by the Grant Agency of the Czech Republic (P207/10/
0695; V.S.), the project “CEITEC - Central European
Institute of Technology” (CZ.1.05/1.1.00/02.0068; MW),
and the projectCETOCOEN (no. CZ.1.05/2.1.00/01.0001;
V.S.) from the European Regional Development Fund,
and the Ministry of Education, Youth and Sports of the
Czech Republic (MSM0021622413; M.W). The crystal-
lographic part was supported by the Institutional research
plan No. AVOZ10100521 of the Institute of Physics
and the Praemium Academiae project of the AS CR, v.
v. i. (M.D.).
stability of these complexes, Bn12BU[6] exhibits for Iꢀ
a
high selectivity of about 4400, 1200, and 12 over Fꢀ, Clꢀ,
and Brꢀ.
Supporting Information Available. Synthetic proce-
dures, full characterization and 1H and 13C NMR spectra
of all new compounds, X-ray crystallographic files (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Benzylated bambusurils Bn12BU[6] and Bn8BU[4] were
prepared in chloroform due to their insolubility in water.
On the other hand, Me12BU[6] was synthesized in diluted
Org. Lett., Vol. 13, No. 15, 2011
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