Alkali metal complexation properties of resorcinarene bis-crown ethers: effect of the crown ether functionality and preorganization on complexation

Article abstract of DOI:10.1016/j.tet.2007.11.103

The synthesis and characterization of tetramethoxy resorcinarene tribenzo-bis-crown ethers, m- and p-TBBC6, are described. The effect of the added aromatic functionality in the crown ether bridge on the alkali metal complexation properties was investigate

Full text of DOI:10.1016/j.tet.2007.11.103

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1798e1807
www.elsevier.com/locate/tet
Alkali metal complexation properties of resorcinarene bis-crown
ethers: effect of the crown ether functionality
and preorganization on complexation
*
Kirsi Salorinne, Maija Nissinen
Department of Chemistry, Nanoscience Center, University of Jyva¨skyla¨, PO Box 35, 40014 JYU, Finland
Received 23 August 2007; received in revised form 13 November 2007; accepted 29 November 2007
Available online 4 December 2007
Abstract
The synthesis and characterization of tetramethoxy resorcinarene tribenzo-bis-crown ethers, m- and p-TBBC6, are described. The effect of the
added aromatic functionality in the crown ether bridge on the alkali metal complexation properties was investigated and compared to the prop-
erties of tetramethoxy resorcinarene bis-crown-5 (BC5) by means of 1H NMR spectroscopy and X-ray crystallography. It was found that BC5 and
m-TBBC6 were capable of binding alkali metal cations (Kþ, Rbþ, and Csþ), with the highest affinity toward Csþ cation, while no binding was
observed in the case of p-TBBC6, which confirms the significance of the complementarity and preorganization for complexation affinity.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Calixcrown; Alkali metal cations; Complexation studies; Conformational analysis
1. Introduction
calixarene skeleton are united with the abilities of crown ether
to selectively bind cations.8 Inspired by this union, we sought to
take it one step further and replaced the calixarene framework
with tetramethoxy resorcinarene,9 thus, creating an assembly
with two crown ether bridges on the open end of the resorcinar-
ene cavity capable of hosting two cations in the formed crown
pockets (Scheme 1).10 Our earlier studies showed that tetrame-
thoxy resorcinarene bis-crown-5 (BC5) was able to bind Csþ
cation, but had affinity toward Kþ and Rbþ cations as well.10
As has been demonstrated earlier,11 the selectivity in cation
binding is determined by the number of oxygen atoms in the
crown ether moiety. In addition, alkali metal cations are
known to form cationep interactions with their host mole-
cule.2,12 An example of utilizing both these features is a cesium
receptor by Bryan et al.,13 which was based on the crown ether
framework and m-xylene as a donor group. Also, Vicens
et al.14 have shown that introducing aromatic spacers in the
crown bridges favored the complexation of cesium cation
over the other alkali metal cations.
The complexation of alkali metal cations and their noncova-
lent interactions with host molecules have engaged a lot of in-
terest due to their importance in chemical and biological
systems.1 A special point of interest has been cationep inter-
actions,1,2 which have been intensively studied especially in
gas phase3 and with the help of theoretical studies,4 and also
to some extent in crystalline state.2,5 In order to investigate
these interactions that prevail in the hosteguest system, the de-
sign of complementary hosteguest pairs is an important aspect
in developing new macrocyclic and macrobicyclic ligands that
are able to selectively complex a specific guest. The criteria set
for the host in molecular recognition include complementarity
in respect to size and charge, sufficient flexibility, and preorga-
nization, as well as induced fit upon guest binding.6
Calixcrowns7 are a widely studied family of compounds, in
which the properties arising from the rigid and preorganized
With this in mind, our scope was to improve the design of
the resorcinarene bis-crown ethers by introducing aromatic
functionality in the crown ether bridge with the idea that
* Corresponding author. Tel.: þ358 14 260 4242; fax: þ358 14 260 4756.
E-mail address: maija.nissinen@jyu.fi (M. Nissinen).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.103

K. Salorinne, M. Nissinen / Tetrahedron 64 (2008) 1798e1807
1799
The structures of m/p-TBBC6 and their precursors were
characterized by means of NMR (1H, 13C, and 2D NMR)
and mass (ESIþ) spectroscopies, X-ray crystallography, and
elemental analysis, which all confirmed the success of the
reactions.
MeO
O
OMe
O
O
R
R
R
R
MeO
OMe
O
2.2. Conformational studies by NMR and X-ray
crystallography
=
=
BC5
O
O
O
O
O
As the crown bridges are formed over the adjacent aromatic
rings of the resorcinarene skeleton, there no longer exist hy-
drogen bonds on the upper rim of the resorcinarene bowl
and the symmetry is reduced to adopt a boat conformation.
This can be seen in the proton NMR spectra by doubling of
the resonances arising from the resorcinarene core. Since the
conformation is locked by the crown bridges, and there cannot
be any boat-to-boat interconversions, the environment of the
upright aromatic and methoxy protons differs from the respec-
tive protons in the horizontal plane, and the resonances of
these protons in these two environments become distinctly dif-
ferent giving rise to two sets of resonances (Fig. 1).
O
O
O
O
O
O
m/p-TBBC6
Scheme 1. Schematic presentation of tetramethoxy resorcinarene bis-crown
ethers BC5 and m/p-TBBC6 (R¼C2H5).
selectivity toward Csþ cation would be enhanced over Kþ and
Rbþ cations. We report here the synthesis and characterization
of tetramethoxy resorcinarene bis-crowns m- and p-tribenzo-
bis-crown-6 (m- and p-TBBC6), both of which have three
benzene rings in the crown bridge, yet differ from one another
by the position of the central aromatic ring (Scheme 1). In ad-
dition, alkali metal binding abilities of BC5 and m/p-TBBC6
Although m- and p-TBBC6 differ only by the position of
the central benzene ring in the crown bridges, their conforma-
tions are very different from one another. The eCH2e reso-
nances belonging to the crown ether bridge, which are seen
in the 3e5 ppm area of the proton NMR spectra, are more re-
solved in the case of p-TBBC6 than in the spectra of m-
TBBC6 indicating that the crown ether bridge of p-TBBC6
is more rigid in structure and has less molecular motion.
This was also evidenced by variable temperature NMR exper-
iment. An increase of temperature from room temperature to
60 ꢀC resulted in only slight changes in the chemical shifts
of the protons in the crown bridge of m-TBBC6, whereas
the changes in the corresponding resonances of p-TBBC6
were significantly greater. The opposite was observed when
the temperature was lowered from room temperature to
ꢁ50 ꢀC as the resolution of the spectra of p-TBBC6 occurred
already at ꢁ10 ꢀC, while with m-TBBC6 the spectra did not
resolve completely until ꢁ50 ꢀC. From this it can be con-
cluded that there is more molecular motion within m-
TBBC6 due to the more flexible crown bridges (Fig. 2).
Single crystals suitable for crystal structural determination
were obtained by slow evaporation from acetonitrile and ace-
tonitrileechloroform (structures A and B for m-TBBC6, re-
spectively), and chloroformedibenzylamine (p-TBBC6)
solutions. The obtained crystal structures confirmed the boat
conformation of the resorcinarene bis-crowns m- and
p-TBBC6, and, more importantly, they revealed the very
different positions of the crown ether moieties in respect to
the resorcinarene cavity for these two host molecules. In
m-TBBC6 the crown bridge unfolds over the aromatic ring
of the resorcinarene skeleton in the horizontal plane creating
a crown pocket with an aromatic ring as the base (Fig. 3).
On the contrary, in p-TBBC6 the crown bridges are formed
by encircling the upright aromatic rings from outside and cre-
ating two loops rather than pockets as in m-TBBC6 (Fig. 4).
1
were investigated and compared by means of H NMR and
UVevis spectroscopies, and X-ray crystallography.
2. Results and discussion
2.1. Synthesis and characterization
The aromatic crown bridges (Scheme 2) were obtained by
the reaction of m/p-bis(bromomethyl)benzene with 2 equiv
of 2-(2-hydroxyethoxy)phenol in the presence of K2CO3 in ac-
etone affording 1a/b in 65 and 94% yield, respectively. Subse-
quent reaction of 1a/b with p-toluenesulfonyl chloride in the
presence of triethylamine in dichloromethane gave ditosylates
2a/b in 58 and 81% yield, respectively. Resorcinarene
bis-crowns m- and p-TBBC6 were finally accomplished by
the reaction of the appropriate ditosylate 2 with tetramethoxy
resorcinarene9 in acetonitrile or DMF using excess of Cs2CO3
as the base with yields of 18 and 42%, respectively.
Br
OH
O
O
m/p-
O
O
Br
O
K2CO3, acetone
OH
OR
OR
1a/b R=H
TsCl, Et3N
CH2Cl2
2a/b R=Ts
Scheme 2. Synthesis of aromatic crown bridges of m/p-TBBC6.

1800
K. Salorinne, M. Nissinen / Tetrahedron 64 (2008) 1798e1807
Figure 1. 1H NMR spectra of (a) m-TBBC6 and (b) p-TBBC6 in CDCl3. The chemical shifts of the resorcinarene core are indicated with letters showing the two
sets of resonances for the aromatic and methoxy protons.
The difference in flexibility between m- and p-TBBC6 ob-
served in the 1H NMR spectroscopic experiments was also ev-
ident in the obtained crystal structures. m-TBBC6 crystallized
in two distinct conformations, in which the crown bridges were
either bent over the resorcinarene cavity (structure A) or
stretched out sideways away from the cavity (structure B,
Fig. 3). In structure A, the upright aromatic rings of the resor-
cinarene core are inclined outward opening up the cavity with
an angle of 28.4ꢀ between the opposite aromatic rings, whereas
in structure B the aromatic rings were slightly bent toward one
another with an angle of ꢁ7.2ꢀ (the distances between the cen-
˚
troids of the opposite aromatic rings are 5.6 and 4.8 A in the
structures A and B, respectively). Three acetonitrile molecules
occupy the resorcinarene cavity in structure A, while in struc-
ture B the cavity is too confined to include any solvent mole-
cules, but the solvents are situated above the host via weak
interactions to host. In both of these structures the molecules
are packed in the crystal lattice in a manner, in which the
crown bridges of the neighboring molecules are interlocked
and held together through multiple CHep and pep interac-
˚
tions having distances in the range of 2.8e3.4 A (Fig. 5).
In the crystal structure of p-TBBC6, on the other hand, the
crown loops had flapped out on the side of the molecule (struc-
ture C, Fig. 4). The resorcinarene cavity opened up, having an
angle of 35.0ꢀ between the opposite upright aromatic rings
(the distance between the centroids of the opposite aromatic
˚
rings is 5.7 A) and is, therefore, able to include a part of the
neighboring molecule inside the cavity forming a sandwich-
like structure with the cavities of the two molecules facing
one another while leaving no room for solvent inclusion.
Again, multiple CHep and pep interactions between the
neighboring molecules prevail in the crystal packing with dis-
˚
tances in the range of 2.8e3.2 A.
2.3. Complexation studies
1
Figure 2. H NMR variable temperature experiment of (a) m-TBBC6 and (b)
The binding abilities of BC5 and m/p-TBBC6 toward al-
kali metal cations (Kþ, Rbþ, and Csþ) were investigated by
p-TBBC6 in CDCl3 showing the changes in the 3e5 ppm area of the spectra at
a temperature range of 60 to ꢁ40 ꢀC.

K. Salorinne, M. Nissinen / Tetrahedron 64 (2008) 1798e1807
1801
Figure 3. Ortep plot (front and side views) and VDW presentation (side view) showing the different conformations of the structures A (top) and B (bottom) of
m-TBBC6. Solvent molecules in the crystal lattice are omitted for clarity.
means of 1H NMR titration and picrate extraction experi-
ments. The titration experiments of BC5 were carried out in
acetone-d6, whereas with m- and p-TBBC6, acetonitrile-d3
or 1:3 mixture of CDCl3eCD3CN was used due to solubility
problems. Complexation-induced chemical shifts, particularly
of the crown ether resonances in the respective 1H NMR spec-
tra, were observed after the addition of RbPF6 and CsPF6 salts
in the solutions of BC5 and m-TBBC6. With BC5, the addi-
tion of KPF6 also induced changes in the crown ether region
of the spectrum, but no changes were observed with any of
the alkali metal salts in the presence of p-TBBC6 as the
host. The lack of complex formation in the case of p-
TBBC6 is explained by the rigid structure and unfavorable
conformation of the host established in the conformational
studies.
As a result of the inclusion of the cation in the crown
pocket, the fairly flexible crown bridge should adopt a more
Figure 4. Top: Ortep plot and VDW presentation of p-TBBC6 (top views).
Solvent molecules are omitted for clarity. Bottom: crystal packing of p-
TBBC6 (side view). Blue lines indicate the CHep and pep interactions be-
tween the neighboring molecules. Hydrogens and solvent molecules in the
crystal lattice are omitted for clarity.
Figure 5. Crystal packing of the structures A (top) and B (bottom) of
m-TBBC6 (top views). Blue lines indicate the CHep and pep interactions
between the neighboring molecules. Hydrogens and solvent molecules are
omitted for clarity.

1802
K. Salorinne, M. Nissinen / Tetrahedron 64 (2008) 1798e1807
Table 1
rigid form and simplify the spectrum in the crown ether re-
gion. In fact, upon increasing the amount of the added salt,
resolution of the crown ether resonances of the respective
host was observed, which was similar in pattern with the dif-
ferent cations investigated. In the case of BC5, the addition of
CsPF6 induced changes in the spectrum already with 1:1 molar
ratio of the cation, whereas with KPF6 and RbPF6 the same
changes required excess amount of the added salt. The inclu-
sion of Csþ cation in the cavity of BC5 also caused significant
changes in the chemical shifts of the aromatic protons in the
resorcinarene skeleton, which were not observed to the same
extent with the other cations. This suggests that the inclusion
of the guest in the crown pocket also causes changes in the
conformation of the resorcinarene core and in the case of
Csþ cation, there seems to be substantial interaction with the
aromatic walls of the cavity through cationep interaction.12
A similar effect was observed with m-TBBC6 as the host.
The addition of CsPF6 resulted in changes in the chemical
shifts and resolution of the resonances of the eCH2e and aro-
matic protons in the crown bridge as well as changes in the
chemical shifts of the aromatic protons in the resorcinarene
core (Fig. 6). With the addition of RbPF6 the changes in the
spectrum were smaller, requiring excess amounts of the salt
and contributed only to the changes in the chemical shifts
but not to resolution of the spectra.
Binding constants (Mꢁ1) of 1:1 complexes of BC5 and m-TBBC6 with
19
MPF6
Host
KPF6
RbPF6
CsPF6
BC5
m-TBBC6
1.7b
d
4.5b
2.2a
56.5a
35.3a
a
Errors <20%.
Error 30e40%.
b
was assumed to have a similar binding model to BC5 based
on the similarity in structure.
Since the water content of the samples in the titration ex-
periments exceeded 1 molar ratio relative to host, EQNMR
analysis18 of the titration data was fitted to a 1:1 binding
model (Table 1). The stability constant data show that both
BC5 and m-TBBC6 have one order of a magnitude higher af-
finity for Csþ cation than for Rbþ and Kþ cations. Also, BC5
has a slightly stronger binding compared to m-TBBC6. This
could be explained partly by preorganization of the crown
bridge.13 The more extended crown bridge of m-TBBC6 has
more freedom to orient in different conformations, which
may hinder the cation binding as more energy is needed to
be applied in order to reach the suitable conformation. In
BC5 the crown pocket is almost circular and has an average
10
cavity diameter of 6.05e6.31 A. With m-TBBC6 the aver-
˚
˚
age cavity diameters are 5.58e5.68 A (structure A) and
˚
6.29e6.37 A (structure B), but the cavity of the crown pocket
is elliptical in shape and the longest cavity diameters measure
Since there are two crown ether pockets in both host mol-
ecules, which can each accommodate one guest species, we
expected 1:2 host-to-guest complex formation. The stoichiom-
etry was determined by modified Job analysis of continuous
variations.15 Interestingly, it was observed in the case of
BC5 that when the intrinsic water content of the NMR solvent
was less than 0.3 molar ratio relative to host, Job plot analysis
gave a maximum corresponding to 1:2 complex formation.
Whereas with 2 molar ratio of water in relation to host, the
stoichiometry of the complex species present was observed
to be 1:1. This indicates that water plays a crucial role in com-
plex formation, whether it is due to solvation effects of the al-
kali metal cations16 or competitive binding in the crown
pocket of the host molecule.17 The stoichiometry of m-
TBBC6 could not be determined due to solubility problems
at higher concentrations of the host molecule, although it
˚
˚
up to 6.75e7.21 A (structure A) and 9.46e10.10 A (structure
B) depending on the conformation. Although m-TBBC6 has
more aromatic functionality in the crown bridge, and should
therefore increase the favorable cesiumep interactions12 in
addition to the aromatic cavity of the resorcinarene core, it
seems that the crown pocket of BC5 may provide a better
complementarity in respect to shape and size.
Alkali metal picrate extraction experiments from water into
chloroform confirmed the binding properties of the different
hosts with Kþ, Rbþ, and Csþ picrates. With p-TBBC6 as
the host, no alkali metal cations were extracted into the or-
ganic layer as was expected from the 1H NMR titration exper-
iments. In the case of m-TBBC6 only Csþ was extracted,
Figure 6. 1H NMR titration spectra of (a) BC5 with CsPF6 in acetone-d6 and (b) m-TBBC6 with CsPF6 in CDCl3eCD3CN (1:3) showing the changes in the
aromatic and crown ether area of the spectra with different hosteguest ratios.

K. Salorinne, M. Nissinen / Tetrahedron 64 (2008) 1798e1807
1803
Table 2
Alkali metal picrate extraction experimentsa
Host
Kþ
Rbþ
Csþ
BC5
1.3
0
4.8
0
6.7
3.4
0
m-TBBC6
p-TBBC6
a
0
0
Percentage (%) of picrate extracted from water into chloroform. Standard
deviation of <0.01.
whereas BC5 showed extraction ability toward all of the alkali
metal cations studied (Table 2). Similar trends in selectivity
1
were observed as in the H NMR titration experiments with
the highest affinity toward Csþ cation.
2.4. Crystal structures of the alkali metal complexes of BC5
The reaction of BC5 with RbPF6 and CsPF6 in
acetone afforded single crystals of the complexes of
BC5$2RbPF6$2Me2CO and BC5$2CsPF6.20 Both of these
structures show inclusion of one cation in each of the crown
pocket of BC5 confirming 1:2 (hosteguest) complex forma-
tion. The structures are almost isomorphous with the exception
that the structure of BC5 with RbPF6 contains solvent mole-
cules in the crystal lattice. BC5 also formed a complex with
KPF6, BC5$2KPF6$2MeCN$H2O, which has been reported
earlier.10 No crystals of the complexes of m-TBBC6 with
RbPF6 or CsPF6 have so far been obtained, which also sup-
ports the results of weaker complexation affinity.
In both of the structures of BC5 the cations are bound
tightly in the resorcinarene cavity and the angle between the
upright aromatic rings of the resorcinarene core is 17.8ꢀ and
22.8ꢀ for the BC5$RbPF6 and BC5$CsPF6 complexes, respec-
tively. The same angle in the conformation of BC5 without the
salts10 is 31.6ꢀ, which clearly shows the participation of the re-
sorcinarene core in complex formation by narrowing the cav-
ity. Both cations coordinate to four crown ether oxygens in the
crown bridge, to one methoxy oxygen, and to the aromatic
ring in the crown pocket (Table 3). Additionally, the cations
are coordinated to one of the PFꢁ6 counter anions that lies
Figure 7. Ortep plot (top and front views) and VDW presentations (bottom,
front, and top views) of the BC5$CsPF6 complex. Noncoordinating solvent
molecules are omitted for clarity.
inside the cavity between the two cations, while the other
one contributes to the crystal packing outside the host mole-
cule (Fig. 7). A similar binding of Kþ cation in the crown
pocket was also observed in the complex of BC5$KPF6 with
the exception that the PFꢁ6 counter anion was situated between
two Kþ cations of neighboring BC5$KPF6 complexes inside
the formed capsule.10 The cationep interaction in the struc-
tures of BC5$RbPF6 and BC5$CsPF6 follows the h6-coordina-
tion mode, which has been shown to be ideal in theoretical
studies,1b,12 whereas in the structure of BC5$KPF6, the Kþ
cation is slightly off-centered from the aromatic ring toward
the crown ether bridge.10 These differences in the structures
of the complexes of BC5 with KPF6 and RbPF6 or CsPF6 dem-
onstrate that the crown pocket of BC5 is adaptable enough to
accommodate guest species differing in size.
Both of the structures are packed in the crystal lattice in
a similar fashion, in which the molecules are lined up on top
of one another forming vertical piles. These stacks then pack
to form layers, in which the neighboring piles are facing in
Table 3
Selected bond lengths (A) of the alkali metal complexes of BC5
˚
BC5$KPF6x
BC5$RbPF6
BC5$CsPF6
K2/O4
K2/O43
K2/O46
K2/O49
K1/O18
K1/O54
K1/O57
K1/O60
K2/O20
K2/Ct1a
K1/Ct2a
K2/F11B
K1/F13A
K1/F16A
a
3.113(3)
2.805(3)
2.926(3)
2.799(3)
2.817(3)
3.872(3)
2.860(3)
2.853(3)
3.020(3)
3.198(2)
3.149(2)
2.838(3)
2.728(3)
2.785(3)
Rb/O6
Rb/O43A
Rb/O46A
3.080(5)
2.965(5)
3.00(2)
Cs/O6
Cs/O43
Cs/O46
3.184(3)
3.011(4)
3.186(4)
Rb/O49
3.268(6)
b
Cs/O49A
3.269(7)
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
Rb/O4
3.099(4)
3.151(3)
Cs/O4
3.177(3)
3.202(2)
Rb/Ct1a
Cs/Ct1a
b
b
b
b
Rb/F12
Rb/F14A
d
3.015(7)
3.482(4)
d
Cs/F22A
Cs/F24
d
2.973(7)
3.303(1)
d
Ct1¼CtC8eC13 and Ct2¼CtC22eC27.
b
The coordination of both cations in the crown pocket is identical due to symmetry. See crystallographic numbering in Supplementary data.

1804
K. Salorinne, M. Nissinen / Tetrahedron 64 (2008) 1798e1807
4. Experimental
4.1. General
NMR spectra were recorded on Bruker Avance DRX
1
(500 MHz for H and 126 MHz for 13C) spectrometer. ESI
mass spectra were measured with Micromass LCT ESI-TOF
instrument. Melting points were obtained with Stuart Scien-
tific SMP3 melting point apparatus and are uncorrected. Ele-
mental analyses were performed on Vario EL III apparatus.
UVevis spectra was recorded with Varian Cary 100 Conc
UVevisible spectrophotometer.
4.2. Materials
All materials were commercial and used as such unless oth-
erwise mentioned. Tetramethoxy resorcinarene was prepared
according to the literature procedure9 and BC5 as previously
described.10 RbPF6 and CsPF6 were prepared by adding a sat-
urated aqueous solution of NH4PF6 to an aqueous solution of
RbCl or CsCl, respectively, followed by filtration and drying in
Figure 8. Crystal packing of the complexes of BC5 with CsPF6 and RbPF6: (a)
sideview of BC5$CsPF6 (same for the complex of BC5$RbPF6), (b) top view
of BC5$CsPF6, and (c) top view of BC5$RbPF6. Hydrogens are omitted for
clarity.
vacuum.21 DMF was distilled and stored over Linde type 3 A
˚
different directions (Fig. 8a). The difference between the al-
most isomorphous structures of BC5$CsPF6 and BC5$RbPF6
is that with BC5$RbPF6 there are molecules of solvent acetone
packed in the crystal lattice, which make the layers diagonal to
one another, while with BC5$CsPF6 the layers are in straight
line (Fig. 8b and c).
molecular sieves prior use. Dichloromethane, acetonitrile, and
acetone were distilled over CaCl2 and stored over Linde type
˚
3 A molecular sieves prior use. K2CO3 and Cs2CO3 were dried
in the oven at 120 ꢀC and stored in a desiccator.
4.3. Synthesis
3. Conclusions
4.3.1. m/p-Bis-(2-ethoxyphenyloxy)xylene, 1a/b
In conclusion, tetramethoxy resorcinarene tribenzo-
bis-crown ethers m- and p-TBBC6 were prepared and their
binding properties with alkali metal cations were studied and
compared together with the earlier prepared BC5. The confor-
mational studies of m- and p-TBBC6 showed that preorgani-
zation provided by the resorcinarene skeleton, yet sufficient
flexibility in the binding site, is an important feature of the
host in complex formation. Of these three hosts, BC5 and
m-TBBC6 showed affinity in binding alkali metal cations
(Kþ, Rbþ, and Csþ), while no binding was observed with p-
TBBC6. The binding in m-TBBC6 was observed to be more
selective compared to BC5 since m-TBBC6 bound Csþ cation
almost exclusively, whereas BC5 was able to bind Kþ and
Rbþ cations as well. However, the binding affinity of BC5 to-
ward cesium was almost two times higher than in the case of
m-TBBC6. This indicates that the crown pocket of BC5 is
more preorganized in respect to shape and size and offers a bet-
ter fit to Csþ cation, even without the added aromatic function-
ality of m- and p-TBBC6. This again shows the importance of
host complementarity in the design of ligands in order to ob-
tain selectivity and affinity in guest binding. In our future
research, we plan to investigate the family of resorcinarene
bis-crown ethers further by introducing different functional-
ities at the crown bridges and study the effects on complex
formation.
A mixture of dibromo-m/p-xylene (4.3 g, 1.6 mmol), 2-
(2-hydroxyethoxy)phenol (5.0 g, 3.3 mmol), K2CO3 (4.5 g,
3.3 mmol), and 18-crown-6 (2 mol %) was suspended in dry
acetone (50 mL) under nitrogen atmosphere with stirring.
The reaction mixture was refluxed overnight. After cooling
to room temperature, the reaction mixture was filtered by suc-
tion and evaporated to dryness under vacuum. The resulting
white solid was dissolved in dichloromethane and washed
with water, dried over MgSO4, and evaporated to dryness un-
der vacuum. Compound 1a: recrystallization from methanol
afforded 4.2 g (65%) of white crystalline solid. 1H NMR:
(CDCl3) d 7.67 (s, 1H), 7.40e7.38 (m, 3H), 6.99e6.92 (m,
8H), 5.11 (s, 4H), 4.09 (t, J¼4.4 Hz, 4H), 3.86 (t, J¼3.3 Hz,
4H), 2.20 (br s, 2H) ppm. 13C NMR: (CDCl3) d 149.0,
148.9, 137.5, 128.8, 127.4, 127.0, 122.0, 121.9, 115.2, 115.0,
71.6, 71.5, 61.2 ppm. MS (ESI-TOF): m/z 433.09 [MþNa]þ.
Anal. Calcd for C24H26O6: C, 70.23; H, 6.39. Found C,
69.94; H, 6.21. Mp 75e77 ꢀC. Compound 1b: recrystallization
from hexaneemethanol afforded 6.3 g (94%) of white solid.
1H NMR: (CDCl3) d 7.45 (s, 4H), 6.99e6.94 (m, 8H), 5.11
(s, 4H), 4.11 (t, J¼4.5 Hz, 4H), 3.86 (t, J¼4.5 Hz, 4H) ppm.
13C NMR: (CDCl3) d 149.4, 148.9, 136.9, 127.8, 122.3,
121.9, 116.2, 115.1, 71.8, 71.3, 61.3 ppm. MS (ESI-TOF):
m/z 433.13 [MþNa]þ. Anal. Calcd for C24H26O6$0.25H2O:
C, 69.47; H, 6.44. Found C, 69.23; H, 6.22. Mp 110e112 ꢀC.

K. Salorinne, M. Nissinen / Tetrahedron 64 (2008) 1798e1807
1805
4.3.2. Ditosylate of m/p-bis-(2-ethoxyphenyloxy)xylene, 2a/b
A mixture of 1a/b (1.0 g, 2.4 mmol) and p-toluenesulfonyl
chloride (1.0 g, 5.4 mmol) was suspended in dry dichlorome-
thane (30 mL) under nitrogen atmosphere with stirring. Tri-
ethylamine (1.3 mL, 9.6 mmol) in dichloromethane was added
dropwise and the reaction mixture was stirred at room temper-
ature for 2 days. The reaction mixture was neutralized by the
addition of 2 M HCl solution. The organic layer was washed
two times with water, dried over MgSO4, and evaporated to
dryness under vacuum. Compound 2a: purification by column
chromatography on silica (CHCl3eacetone, 9:1) afforded
4.3.3.2. Method B. A mixture of tetramethoxy resorcinarene9
(0.21 g, 0.31 mmol) and Cs2CO3 (0.72 g, 2.2 mmol) in dry
DMF (25 mL) was stirred at 90 ꢀC under nitrogen atmosphere
for 20 min before the dropwise addition of ditosylate 2b
(0.44 g, 0.61 mmol) in dry DMF with vigorous stirring. The
reaction mixture was stirred at 90 ꢀC for 2 days. After cooling
to room temperature the reaction mixture was filtered by suc-
tion through a pad of Hyflo SuperÒ and solvent was removed
under vacuum. The resulting residue was partitioned between
water and dichloromethane, and acidified with 2 N HCl. The
organic layer was separated, dried over MgSO4, and evapo-
rated to dryness under vacuum. p-TBBC6: purification by col-
umn chromatography on silica (CHCl3eacetone, 9:1) afforded
1
1.0 g (58%) of opaque viscous oil. H NMR: (CDCl3) d 7.77
(m, 4H), 7.49 (s, 1H), 7.38 (d, J¼1.3 Hz, 3H), 7.25 (m, 4H),
6.93e6.83 (m, 8H), 5.09 (s, 4H), 4.35 (m, 4H), 4.22 (m,
4H), 2.39 (s, 6H) ppm. 13C NMR: (CDCl3) d 149.2, 148.3,
144.8, 137.6, 133.0, 129.8, 128.8, 127.9, 126.8, 126.1, 122.6,
121.7, 116.1, 115.5, 71.2, 68.3, 67.3, 21.6 ppm. MS (ESI-TOF):
m/z 741.10 [MþNa]þ, 757.06 [MþK]þ. Compound 2b: puri-
fication by column chromatography on silica (CH2Cl2e
1
0.18 g (42%) of white solid. H NMR: (CDCl3) d 7.13 (q,
J¼8.3, 5.2 Hz, 8H), 7.02e6.88 (m, 16H), 6.76 (s, 2H), 6.71
(s, 2H), 6.27 (s, 2H), 6.08 (s, 2H), 4.96 (dd, J¼12.0, 25.8 Hz,
4H), 4.84 (q, J¼11.0, 6.7 Hz, 4H), 4.50 (t, J¼7.6 Hz, 2H),
4.41 (t, J¼7.6 Hz, 2H), 4.29 (m, 2H), 4.22 (m, 4H), 4.15e4.08
(m, 4H), 3.98 (m, 4H), 3.83 (m, 2H), 3.43 (s, 6H), 3.20 (s, 6H),
1.83 (m, 8H), 0.85 (m, 12H) ppm. 13C NMR: (CDCl3) d 155.7,
155.5, 155.0, 149.9, 149.3, 149.2, 149.1, 136.8, 136.7, 127.8,
127.6, 127.3, 126.6, 126.5, 126.3, 125.5, 122.0, 121.8, 121.7,
121.5, 116.0, 115.5, 115.3, 114.5, 98.9, 98.8, 71.6, 71.0, 69.0,
68.7, 68.6, 68.3, 55.5, 55.1, 36.5, 36.4, 28.3, 28.1, 12.6,
12.5 ppm. MS (ESI-TOF): m/z 1428.59 [MþNa]þ. Anal. Calcd
for C88H92O16$2H2O: C, 73.31; H, 6.71. Found C, 73.62; H,
6.44. Mp 133e135 ꢀC.
1
acetone, 9:1) afforded 1.4 g (81%) of white solid. H NMR:
(CDCl3) d 7.78 (m, 4H), 7.42 (s, 4H), 7.26 (m, 4H), 6.94e
6.84 (m, 8H), 5.08 (s, 4H), 4.35 (m, 4H), 4.23 (m, 4H), 2.39
(s, 6H) ppm. 13C NMR: (CDCl3) d 149.2, 148.4, 144.8,
136.8, 133.0, 129.8, 128.0, 127.5, 122.6, 121.8, 116.1, 115.5,
71.1, 68.3, 67.3, 21.6 ppm. MS (ESI-TOF): m/z 741.20
[MþNa]þ. Anal. Calcd for C38H38O10S2$0.5H2O: C, 62.71;
H, 5.40. Found C, 62.64; H, 5.19. Mp 112e113 ꢀC.
1
4.4. H NMR titration experiments
4.3.3. Tetramethoxy resorcinarene tribenzo-bis-crown-6,
m/p-TBBC6
1H NMR titrations were performed by subsequently adding
increasing aliquots of the salt (KPF6, RbPF6, and CsPF6) in
deuterated solvent to solutions of the respective host (BC5
in acetone-d6, m-TBBC6 in 1:3 mixture of CDCl3eCD3CN,
and p-TBBC6 in acetonitrile-d3) and the spectra were re-
corded at 30 ꢀC. The obtained titration data were analyzed
by the computer program EQNMR.18 Job plot samples were
prepared with 0.5, 1, 1.5, 2, 3, and 4 equiv of the salt while
keeping the sum of host and guest concentration equal.
4.3.3.1. Method A. A mixture of tetramethoxy resorcinarene9
(0.28 g, 0.43 mmol), Cs2CO3 (1.2 g, 3.8 mmol), and di-
benzo-18-crown-6 (0.08 g, 0.22 mmol) in dry acetonitrile
(70 mL) under nitrogen atmosphere was heated to reflux.
The reaction mixture was allowed to stir for 30 min before
the dropwise addition of ditosylate 2a (0.61 g, 0.85 mmol) in
acetonitrile and refluxed for 2 days. After cooling to room
temperature the reaction mixture was filtered by suction and
the solvent was removed under vacuum. Chloroform was
added to the resulting residue and solid formed was filtered
off by suction. m-TBBC6: purification by column chromatog-
raphy on silica (chloroformeethyl acetate 95:5) afforded 0.1 g
4.5. Picrate extraction experiments
The alkali metal (Naþ, Kþ, and Csþ) picrate extraction ex-
periments were performed by using 2.5 mM host solutions of
BC5 and m- and p-TBBC6 in chloroform and 5 mM picrate
solutions in deionized water according to the procedure de-
scribed earlier.10 The absorption of the extracted picrate was
measured from the aqueous layer at 375 nm and compared
against blank solution (no host in chloroform) of the appropri-
ate picrate. The average of three samples is reported with stan-
dard deviation.
1
(18%) of white crystalline solid. H NMR: (CDCl3) d 7.61 (s,
2H), 7.31 (m, 6H), 7.12 (s, 2H), 7.06e6.86 (m, 16H), 6.46 (s,
2H), 6.06 (s, 2H), 5.97 (s, 2H), 5.06 (dd, J¼11.4, 14.7 Hz,
4H), 5.02 (s, 4H), 4.39e4.28 (m, 12H), 3.81e3.72 (m, 6H),
3.70 (s, 6H), 3.03 (overlapping m and s, 8H), 1.90 (m, 4H),
1.75 (m, 4H), 0.90 (m, 12H) ppm. 13C NMR: (CDCl3)
d 156.1, 155.7, 155.2, 155.0, 149.7, 149.2, 149.0, 148.6, 137.9,
137.5, 129.7, 129.0, 128.4, 127.4, 127.3, 126.3, 125.5, 125.4,
122.2, 121.7, 121.6, 121.5, 116.1, 115.1, 115.0, 114.7, 71.8,
71.3, 69.4, 68.4, 68.0, 67.2, 55.6, 54.9, 37.1, 36.9, 27.9, 27.4,
12.6, 12.5 ppm. MS (ESI-TOF): m/z 1427.43 [MþNa]þ,
1443.43 [MþK]þ. Anal. Calcd for C88H92O16$0.75CHCl3:
C, 71.29; H, 6.25. Found C, 71.19; H, 6.15. Mp 135e137 ꢀC.
4.6. X-ray crystallography
Data were recorded on a Nonius Kappa CCD diffractometer
with Apex II detector using graphite monochromatized Cu Ka
˚
[l(Cu Ka)¼1.54178 A] radiation at a temperature of 173.0 K.

1806
K. Salorinne, M. Nissinen / Tetrahedron 64 (2008) 1798e1807
Table 4
Crystallographic details of m-TBBC6 (structures A and B) and p-TBBC6 (structure C) and the complexes of BC5$RbPF6 and BC5$CsPF6
m-TBBC6 (structure A) m-TBBC6 (structure B) p-TBBC6 (structure C) BC5$RbPF6
Molecular formula C88H92O16$7CH3CN$0.25H2O C88H92O16$3CH3CN$CHCl3 C88H92O16$C14H15
BC5$CsPF6
N
C56H76O14$2RbPF6$2(CH3)2CO C56H76O14$2CsPF6
Formula weight
Crystal system
Space group
1697.50
1648.15
1602.89
1550.20
1528.93
Monoclinic
P21/n (no. 14)
21.3463(5)
22.1363(5)
22.0402(5)
116.115(1)
9350.2(4)
4
Monoclinic
P21/c (no. 14)
17.4834(4)
20.0800(4)
25.1202(6)
102.913(1)
8595.8(3)
4
Monoclinic
P21/n (no. 14)
16.2238(4)
30.5922(9)
18.1516(4)
109.974(2)
8467.1(4)
4
Monoclinic
P2/c (no. 13)
20.3086(9)
10.0123(4)
19.7412(6)
118.180(2)
3538.3(2)
2
Monoclinic
P2/c (no. 13)
18.2591(8)
9.8762(5)
19.8445(8)
116.541(2)
3201.4(3)
2
˚
a (A)
˚
b (A)
˚
c (A)
b (ꢀ)
3
˚
Volume (A )
Z
Dcalcd (Mg mꢁ3
)
1.206
0.659
1.274
1.522
1.257
0.674
1.455
3.043
1.586
10.188
m (mmꢁ1
)
GOF on F2
1.026
0.085/0.170
1.017
0.085/0.215
1.019
0.084/0.170
1.070
0.090/0.231
1.077
0.047/0.103
Final R indicesa
a
(I>2sI).
The data were processed with Denzo-SMN v0.97.638.22 The
structures were solved by direct methods (SHELXS-9723) and
refinements based on F2 were made by full-matrix least-squares
techniques (SHELXL-9724). The hydrogen atoms were calcu-
lated to their idealized positions with isotropic temperature fac-
tors (1.2 or 1.5 times the C temperature factor) and refined as
riding atoms, except for the amine hydrogen of dibenzoamine,
which was located from the difference Fourier map (Table 4).
Absorption correction25 was made to all structures but used
only in the final refinement of the structure of BC5$2CsPF6
since it worsened the quality of all the other structures described.
Crystallographic details of the structures are presented in Table
4. Crystallographic data (excluding structural factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication
nos. CCDC-658268, 658269, 658270, 658271, 658272, and
658273. Copiesof the datacan be obtained, free of charge, on ap-
plication to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: þ44 (0) 1223 336033 or email: deposit@ccdc.cam.ac.uk).
3. See, for example: (a) Woodin, R. L.; Beauchamp, J. L. J. Am. Chem. Soc.
1978, 100, 501e508; (b) Dunbar, R. C.; Ryzhov, V. J. Am. Chem. Soc.
1999, 121, 2259e2268.
4. For review on the subject, see Ref. 1b. For more recent work see, for ex-
ample: (a) Macias, A. T.; Norton, J. E.; Evanseck, J. D. J. Am. Chem. Soc.
2003, 125, 2351e2360; (b) Priyakumar, U. D.; Punnagai, M.; Mohan,
G. P. K.; Sastry, G. N. Tetrahedron 2004, 60, 3037e3043.
5. (a) Cametti, M.; Nissinen, M.; Dalla Cort, A.; Mandolini, L.; Rissanen, K.
˚
J. Am. Chem. Soc. 2005, 127, 3831e3837; (b) Ahman, A.; Nissinen, M.
Chem. Commun. 2006, 1209e1211.
6. Schneider, H. J.; Anmar, K. M. Receptors for Organic Guest Molecules:
General Principles. Comprehensive Supramolecular Chemistry; Atwood,
J. L., Davies, J. E. D., Macnicol, D. D., Vogtle, F., Eds.; Pergamon:
¨
Oxford, UK, 1996; Vol. 2, pp 69e101.
7. (a) Ungaro, R. Calixarenes in Action; Mandolini, L., Ungaro, R., Eds.;
Imperial College Press: London, UK, 2000; (b) Sharma, K. R.; Agrawal,
Y. K. Rev. Anal. Chem. 2004, 23, 133e158; (c) Alfieri, C.; Dradi, E.;
Pochini, A.; Ungaro, R.; Andreetti, G. D. J. Chem. Soc., Chem. Commun.
1983, 1075e1077.
8. Steed, J. W. Coord. Chem. Rev. 2001, 215, 171e221.
9. McIldowie, M. J.; Mocerino, M.; Skelton, B. W.; White, A. H. Org. Lett.
2000, 2, 3869e3871.
10. Salorinne, K.; Nissinen, M. Org. Lett. 2006, 8, 5473e5476.
11. (a) Ghidini, E.; Ugozzoli, F.; Ungaro, R.; Harkema, S.; El-Fadi, A. A.;
Reinhoudt, D. N. J. Am. Chem. Soc. 1990, 112, 6979e6985; (b) Stephan,
Acknowledgements
H.; Gloe, K.; Paulus, E. F.; Saadioui, M.; Bohmer, V. Org. Lett. 2000, 2,
¨
839e841; (c) Casnati, A.; Della Ca’, N.; Sansone, F.; Ugozzoli, F.;
Ungaro, R. Tetrahedron 2004, 60, 7869e7876.
We are grateful to Reijo Kauppinen (University of Jyvas-
¨
kyla) for his help with the NMR studies and the Academy
¨
of Finland (project 211240) for funding.
12. Fukin, G. K.; Lindeman, S. V.; Kochi, J. K. J. Am. Chem. Soc. 2002, 124,
8329e8336.
13. Bryan, J. C.; Hay, B. P.; Sachleben, R. A.; Eagle, C. T.; Zhang, C.;
Bonnesen, P. V. J. Chem. Crystallogr. 2003, 33, 349e355.
´
14. (a) Lamare, V.; Dozol, J. F.; Fuangswasdi, S.; Arnaud-Neu, F.; Thuery, P.;
Supplementary data
Nierlich, M.; Asfari, Z.; Vicens, J. J. Chem. Soc., Perkin Trans. 2 1999,
271e284; (b) Asfari, Z.; Lamare, V.; Dozol, J. F.; Vicens, J. Tetrahedron
Lett. 1999, 40, 691e694.
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2007.11.103.
15. Hirose, K. J. Incl. Phenom. Macrocyclic Chem. 2001, 39, 193e209.
16. Buschmann, H. J.; Wenz, G.; Schollmeyer, E.; Mutihac, L. Inorg. Chem.
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