Molecular engineering. Part 7. Cavitands having four aromatic sp2 nitrogens as salt binding ligands

Article abstract of DOI:10.1039/b100490p

Nine new salt binders built on resorcin[4]arene or calix[4]arene and having four aromatic sp² nitrogens as salt binding ligands were designed and characterized. Structurally rigid cavitands based on resorcin[4]arene showed much higher affinities toward metal cations compared to those based on flexible calix[4]arene. In particular, imidazolylcavitand 7 showed high affinity for alkali metal cations (-ΔG° = 7.0-10.9 kcal mol^-1) and pyrazolylcavitand 8 showed unusually high selectivity for silver cations, which are presumably due to their different binding modes, nesting vs. inclusion fashion, respectively.

Full text of DOI:10.1039/b100490p

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Molecular engineering. Part 7.1 Cavitands having four aromatic
sp2 nitrogens as salt binding ligands
Kyungsoo Paek,* Jaehyung Yoon and Yongju Suh
2
Molecular Engineering Research Laboratory and Department of Chemistry,
Soongsil University, Seoul, 156-743, Korea
Received (in Cambridge, UK) 15th January 2001, Accepted 27th March 2001
First published as an Advance Article on the web 3rd May 2001
Nine new salt binders built on resorcin[4]arene or calix[4]arene and having four aromatic sp2 nitrogens as salt binding
ligands were designed and characterized. Structurally rigid cavitands based on resorcin[4]arene showed much higher
affinities toward metal cations compared to those based on flexible calix[4]arene. In particular, imidazolylcavitand 7
showed high affinity for alkali metal cations (Ϫ∆GЊ = 7.0–10.9 kcal molϪ1) and pyrazolylcavitand 8 showed unusually
high selectivity for silver cations, which are presumably due to their different binding modes, nesting vs. inclusion
fashion, respectively.
Introduction
Selective recognition of metal cations has been one of the
central research themes for the last three decades in host–guest
chemistry, and many targets are met using either naturally-
occurring ionophores or synthetic receptors such as crown
ethers, cryptands and spherands, whose major ligating hetero-
atoms are sp3 oxygens.2
Nitrogen atoms have significant intrinsic affinities for IA and
IIA group cations as well as transition metal cations, but
compared to oxygen, they have been much less frequently
adopted in host systems for IA or IIA group cations.3 sp3
Hybridised nitrogen atoms are less effective in complexing
alkali metals than sp3 oxygen and also cannot be easily
incorporated to give a substantially preorganized binding site in
which the sp3 lone pair orbitals point directly to its center due to
steric congestion and feasible orbital inversion. Nitrogen atoms
with an sp lone pair present as an integral part of an organic
host exist only in cyano groups and its ligating properties were
well studied using octacyanand 1.4 Once this problem of design
was overcome, sp nitrogen showed much higher intrinsic
binding abilities for IA group cations than sp3 oxygen.
sp2 Hybridised nitrogen atoms can also be incorporated into
strong and selective host systems as the planar lone pair has
directionality as well as diversity in aromatic rings, even though
they are usually less feasible than sp3 oxygen in forming a
preorganized binding site. sp2 Hybridised nitrogen atoms in
imines,3 pyridine,5 phenanthroline,6 etc. have been incorporated
to give good hosts for transition metals or organic guests.
Recently, Voegtle et al. reported a macrobicyclic tripyridine
cage host 2,7 whose pyridine sp2 N cooperatively binds included
NBS bromination (80%) were reacted with an excess of imid-
guest ions in the cavity. This host turned out to be remarkably
selective for the Ag+ cation. Also Kim et al. reported that tri-
azole, pyrazole, indazole or benzimidazole in CHCl3 to give
podand 3 shows high selectivity for NH4+ by charge–dipole and
hosts 7a (55%), 7b (77%), 8 (65%), 9 (78%), or 10 (30%) in good
yields (Fig. 1). Host 11 was obtained from a tetraol 511 and
2-(chloromethyl)pyridine (85%). Cavitands 12 (50%), 13 (50%),
and 14 (46%) were obtained from tetrakis(p-chloromethyl)-
calix[4]arene 612 in CHCl3 or CH3CN with an excess of imid-
azole, pyrazole and indazole, respectively. The new hosts were
purified by washing exclusively with deionized water several
times followed by repeated recrystallizations from a mixed
solution.
cation–π interactions.8
In this paper we report the synthesis and the high affinity
to alkali cations, transition metal cations and ammonium ions
of new salt-binding cavitands that possess four aromatic sp2
nitrogens which can face inward to form a cation binding site.9
Results and discussion
1H NMR spectra of cavitands 12–14 show that they exist as
cone conformers, as structurally rigid cavitands 7–11 do, but
the binding studies of cavitands 10 and 12 cannot be pursued
due to their low solubility in CHCl3.
Synthesis of cavitands 7, 8, 9, 10, 11, 12, 13 and 14
Tetrakis(bromomethyl)cavitands 4a and 4b10 easily obtained
from the corresponding tetramethylcavitands 4 (X = CH3) by
916
J. Chem. Soc., Perkin Trans. 2, 2001, 916–922
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b100490p

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Fig. 2 1H NMR spectroscopic titration with Na+ClO4Ϫ of imidazolyl-
cavitand 7b in CDCl3–CD3CN = 3 : 1 (v/v).
The free energies of complexation (Ϫ∆GЊ in kcal molϪ1) were
determined at 22 ЊC in H2O-saturated CHCl3 by Cram’s liquid
extraction method16 on a 1 or 4 mM scale host solution binding
+
+
+
Li+, Na+, K+, Rb+, Cs+, NH4 , CH3NH3 , and (CH3)3CNH3
picrates. Among the cavitands, except cavitands 10 and 12
which are very insoluble in CHCl3, only hosts 7 showed sub-
stantial affinities for alkali or ammonium picrate and the results
are summarized in Table 1 (average of two determinations
whose difference was <0.5 kcal molϪ1). Imidazolylcavitand 7a
tends to precipitate in the organic phase (CHCl3) on the 4 mM
scale, but imidazolylcavitand 7b is soluble on the 4 mM scale.
At the 1 mM scale imidazolylcavitands 7a and 7b showed
similar tendencies for alkali and ammonium metal picrate
extraction, experimental differences being within 0.5 kcal
molϪ1
.
Fig. 4 illustrates the host–guest structure–binding relation-
ships for complexation of eight cations and imidazolylcavitand
7b. For a comparison the binding free energies of octacyanand
1 having two rigidly preorganized binding sites solely composed
of four sp nitrogens for each are also shown. It is reported that
octacyanand 1 showed 1 : 1 binding at 10Ϫ3 M solution (CHCl3)
in a perching fashion.
Imidazolylcavitand 7b showed unexpected high binding
energies of Ϫ∆GЊav = 9.2 kcal molϪ1 ranging from 7.0 for
+
(CH3)3CNH3 to 10.9 for Na+ with a maximum spread of 3.9
kcal molϪ1. Imidazolylcavitand 7b tends to bind spherical
+
+
cations better: NH4 a little better than CH3NH3 and
Fig. 1 Cavitands 4–14.
+
+
CH3NH3 somewhat better than t-BuNH3 showing a peak
binding for Na+. Imidazolylcavitand 7b has lower binding
energies [∆(Ϫ∆GЊ) = Ϫ0.5 for Li+ to Ϫ4.6 kcal molϪ1 for K+]
than octacyanand 1. Compared to octacyanand 1, imidazolyl-
cavitand 7b has a much less preorganized binding site due to the
free rotation of the imidazolylmethyl arms, which also caused
its relatively low selectivity.
Binding stoichiometry and picrate extraction experiments
Quite a few salt binders based on resorcin[4]arene have been
developed,13 because typical container hosts constructed on
resorcin[4]arene do not bind salts.14 However, quite a lot of
those based on calix[4]arene have been reported due to the
conformational and chemical diversity of calix[4]arene.15
The 1 : 1 complexation between NaClO4 and host 7b was
confirmed by solid–liquid extraction (Fig. 2) which showed the
chemical shift saturations at a 1 : 1 ratio of solid NaClO4 to
host 7b in CDCl3–CD3CN = 3 : 1 (v/v) at room temperature.
1H NMR titration experiments
Binding studies were also carried out using the chemical shift
Ϫ
change caused by incremental addition of Na+BPh4 to imid-
azolylcavitand 7a in CDCl3–MeOH-d4 (7 : 1, v/v) at 298 K. Fig.
5 shows the observed chemical shift changes of three different
hydrogens (Hm,exo, H4Ј and Hb) of 7a vs. guest–host ratio.
The H NMR data for imidazolylcaviplex 7bؒNa+ClO4 (400
MHz) suggest all four imidazolyl groups are coordinated
to sodium. Compared to the free 7b, the resonances of the
imidazole unit and methylenedioxy protons in the complex
showed large upfield chemical shifts (NCHN, 0.28 ppm, from
7.53 to 7.25 ppm; one of NCHCHN, 0.02 ppm, from 6.93
to 6.91 ppm; exo-OCH2O, 0.19 ppm, from 6.02 to 5.83 ppm;
endo-OCH2O, 0.23 ppm, from 4.20 to 3.97 ppm). A computer-
generated (HyperChem with MM+ force field) stereo view of
imidazolylcaviplex 7aؒNa+ in the gas phase (Fig. 3) shows its
nesting binding mode.
1
Ϫ
The protons whose signals were chosen for Ka determinations
exhibited a relatively large chemical shift change upon com-
plexation (>0.05 ppm). The sensitivity of H4Ј and Hm,exo were
similar to those from solid–liquid extraction, but the large
sensitivity of Hb and the weak sensitivity of Hm,endo are
unexpected. The Ka value calculated using a Benesi–Hildebrand
plot17 for cavitand 7a binding Na+ at 298 K was 541 MϪ1
.
The probable anion effect was also tested. A small quantity
of host 7a was dissolved in CDCl3–MeOH-d4 (7 : 1, v/v) to be
J. Chem. Soc., Perkin Trans. 2, 2001, 916–922
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Table 1 Apparent association constant (Ka/MϪ1) and binding free energy (Ϫ∆GЊ/kcal molϪ1) for complexation of imidazolylcavitand 7b with alkali
metal, ammonium and alkylammonium picrates in CHCl3 saturated with H2O at 25 ЊCa
+
+
+
Li+
Na+
K+
Rb+
Cs+
NH4
CH3NH3
t-BuNH3
Ka/MϪ1
3.1 × 107
10.1
1.3 × 108
11.0
1.3 × 107
9.5
1.6 × 107
9.4
5.9 × 106
9.2
6.5 × 106
9.2
2.1 × 106
8.5
1.7 × 105
7.0
Ϫ∆GЊ/kcal molϪ1
a The values are average values from organic and aqueous phases of two trials at the 4 mM scale whose difference was <0.5 kcal molϪ1
.
Fig. 3 Stereo view of the energy minimized structure of imidazolylcaviplex 7aؒNa+(Hyperchem with MM+ force field).
Table 2 Percentage extraction of metal picrates by cavitands 7a, 8, 9,
11, 13 and 14 at 298 K
Ex%a
Host
Ag+
Mg2+ Ca2+ Co2+
Ni2+
Cu2+
Zn2+
Cd2+
7a
8
100
93
22
74
20
25
43
0
0
8
0
57
0
0
10
0
0
47
0
0
5
0
47
3
11
27
0
55(56)b
9
4
30
0
0
49
0
0
9
0
31
0
0
0
0
9
11
13
14
0
0
0
0
0
a Organic phase (2 mL of CHCl3) contains cavitand (1.0 mM) and
aqueous phase (2 mL) contains picric acid (1.0 mM) and M(NO3)n
(10 mM). The two-phase mixture was stirred for 1 min and centrifuged
for 1 min and then Ex% values were determined spectrophoto-
metrically. b Ref. 18.
Fig. 4 Comparison of binding free energy (∆GЊ) between octacyanand
1 and imidazolylcavitand 7b.
Fig. 5 Observed chemical shift changes (∆δ) of the three different
hydrogens of 7a vs. [G]/[H] ratio.
about 1 mM, and its 300 MHz 1H NMR spectrum was
Ϫ
recorded. To this solution about 20 equivalents of Bu4N+BPh4
was added and then the 1H NMR spectrum was recorded.
Chemical shift changes did not occur for H-4Ј or Hm,exo but were
found for Hb. However, its change (<0.05 ppm) is very much
smaller than that with Na+BPh4 (>0.26 ppm at 5 eq.), which
Ϫ
Fig. 6 Illustration of percentage extraction of metal picrates by
cavitands 7a, 8, 9, 11, 13 and 14 at 298 K.
supports the theory that the chemical shifts were induced by
cation binding to host.
(10 mM) and picric acid (1.0 mM) was extracted with the host
solution (CHCl3, 1.0 mM).
The percentage extraction (Ex%) was calculated by measur-
ing the picrate concentration in the aqueous phase. The results
are summarized in Table 2 and Fig. 6. Imidazolylcavitand 7a
showed the highest extractabilities for IIA and transition metal
Affinities for alkaline earth and transition metal picrates
Solvent extractions of aqueous alkaline earth or transition
metal cations into H2O-saturated organic host solutions were
performed at 25 ЊC. An aqueous solution containing M(NO3)n
918
J. Chem. Soc., Perkin Trans. 2, 2001, 916–922

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Fig. 7 Stereo view of energy minimized structure of pyrazolylcaviplex 8ؒAg+(Hyperchem with MM+ force field).
cations with the highest for Ag+ (100%). The ionic radius of
Experimental
Ca2+ (0.99 Å) is very similar to that of Na+ (0.96 Å), which may
explain the higher Ex% (57 vs. 43%) for Ca2+ than for Mg2+ (the
ionic radius of Mg2+ is 0.65 Å).
General
Chemicals were reagent grade (Aldrich), and used as received,
unless otherwise noted. All anhydrous reactions were con-
ducted under an atmosphere of argon. Melting points (mp)
were measured on an electrothermal 9100 apparatus and are
Pyridinylcavitand 11 also showed a high affinity for Ag+
(74%), but overall it showed lower affinities for other metal
cations, compared to those of cavitand 7, due to its higher
flexibility. The Ex% (<25%) for Ag+ by calix[4]arene-based
cavitands 13 or 14 is insignificant, but that (93%) by pyrazolyl-
cavitand 8 was exceptional.
1
uncorrected. The H NMR spectra were run on a Gemini-300
(300 MHz) or Jeollamad-400 (400 MHz) spectrometer. Spectra
taken in CDCl3 were referenced to residual CHCl3 at 7.26 ppm,
J values are given in Hz. FAB+ MS spectra were determined on
a VG-VSEQ spectrometer with 3-nitrobenzyl alcohol as a
matrix. Infrared spectra were recorded on a Mattson 300
FT-IR spectrometer. UV–VIS absorbance readings were taken
on a Perkin-Elmer 551 spectrometer. Gravity chromatography
was performed on E. Merck silica gel 60 (70–230 mesh ASTM).
Thin-layer chromatography was carried out on plastic sheet
silica gel 60 F254 (E. Merck, 0.2 mm). The elementary analyses
were conducted at Institute of Basic Sciences of Korea.
The remarkably high selectivity by pyrazolylcavitand 8 for
Ag+ over Mg2ϩ, Ca2ϩ, Co2ϩ, Ni2ϩ, Cu2ϩ, Zn2ϩ and Cd2ϩ and the
CPK molecular model study suggest that the four lone pair
electrons of the N-2 atoms of host 8 can converge to form
a binding site for a spherical cation in an inclusion fashion.
π-Base receptors which feature cation–π interactions display
a high metal affinity,19 which is true for 8ؒNa+. Computer-
generated (HyperChem with MM+ force field) stereo views of
imidazolylcaviplex 8ؒNa+ (Fig. 7) also support its inclusion
binding mode. Pyrazolylcavitand 8 showed much more efficient
silver extraction ability (93%) than pyridine-containing cage
2 (19.5%) which complexes with a silver ion by a linear coord-
ination between the two adjacent pyridine donor atoms.7
Indazolylcavitand 9 could bind in a similar binding mode, but
compared to 8, the rotation of indazolyl arms to permit an
inclusion mode seemed to be much more sterically hindered,
which resulted in low affinities for the tested metal cations, even
for Ag+.
5,11,17,23-Tetrakis(chloromethyl)-25,26,27,28-tetrahydroxy-
calix[4]arene (6)12
To a cold solution (Ϫ10 ЊC) of 1.0 g (2.4 mmol) of calix[4]arene
and 14.4 g (81 mmol) of chloromethyl n-octyl ether in 100 mL
of CHCl3, 4.7 mL (40.3 mmol) of SnCl4 were added dropwise
over a period of about 15 min. The cooling bath was removed
and the reaction mixture was stirred at room temperature for an
additional 50 min, after which time all the calix[4]arene had
reacted (TLC, hexane–ethyl acetate = 4 : 3). Water (100 mL)
was then added slowly and the organic phase was separated.
The organic layer was washed twice with distilled water, dried
over MgSO4 and concentrated to give a residue which was
treated with n-hexane. The precipitate was filtered to give 6
(1.23 g, 80%), mp >153.5–154.6 ЊC (decomp.); νmax (KBr)/cmϪ1
3092 (OH), 1479 (C–O); δH (400 MHz, CDCl3) 3.54 (4H, br s,
exo-ArCH2Ar), 4.17 (4H, br s, endo-ArCH2Ar), 4.40 (8H, s,
ArCH2Cl), 7.09 (8H, s, ArH), 10.12 (4H, s, OH).
Conclusions
Nine new hosts based on cavitands and having four aromatic
sp2 nitrogens as potential ligands were efficiently obtained and
the largest affinities of imidazolylcavitands 7 for various metal
cations were observed. These results strongly support the
substantial intrinsic affinities of aromatic sp2 nitrogen for alkali
metal and ammonium cations when organized in a good
binding arrangement.
In particular, pyrazolylcavitand 8 showed a strong selec-
tivity for Ag+ which was embraced in the host 8. The high
affinity of sp2 nitrogen for Ag+ was known7 and the additional
Ag+–π interaction of pyrazolylcaviplex 8ؒAg+ seems to be
crucial to sustain the inclusion of Ag+, which was not possible
in case of alkali, alkaline or other transition metal cations
tested.
These results support the high intrinsic affinities of imid-
azolyl sp2 nitrogen for alkali metal and ammonium cations,
especially when they are preorganized to form a good binding
site. Also the selectivity by a cavitand can be manipulated
by controlling the direction of the lone pair of sp2 nitrogen
atoms and the secondary interactions, such as cation–π
interactions.
1,21,23,25-Tetrapropyl-7,11,25,28-tetrakis(imidazolylmethyl)-
2,20:3,19-dimethano-1H,21H,23H,25H-bis[1,3]dioxocino-
[5,4-i:5Ј,4Ј-iЈ]benzo[1,2-d:5,4-dЈ]bis[1,3]benzodioxocine (7a)
Imidazole (6.32 g, 0.093 mol, 100 eq.) was dissolved in 50 mL of
CH3CN, and stirred at rt for 30 min. Tetrakis(bromomethyl)-
cavitand 4a (1.00 g, 0.93 mmol) was added, and the mixture was
stirred for 1.5 h. The reaction mixture was concentrated, dis-
solved in CH2Cl2, and washed with basic water (3 M NaOH).
The organic phase was washed with deionized water several
times followed by repeated recrystallizations from a mixture of
methyl ethyl ketone (MEK)–CH3CN–CH2Cl2 to give 7a (52 mg,
55%), mp >243.0 ЊC (decomp.) (Found: C, 65.56; H, 6.29; N,
J. Chem. Soc., Perkin Trans. 2, 2001, 916–922
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10.96. C60H64O8N8 CH2Cl2 CH3CN requires C, 65.73; H, 6.04;
times. The solvent was evaporated to give cavitand 9 (340 mg,
N, 10.95%); νmax (KBr)/cmϪ1 1618 (C᎐N); δ (400 MHz, CDCl )
30%), mp 269.0 ЊC; νmax (KBr)/cmϪ1 1691.66 (N᎐N), 1626.09
᎐
᎐
H
3
1.00 (12H, m, CH2CH2CH3), 1.34 (8H, m, CH2CH2CH3), 2.21
(8H, m, CH2CH2CH3), 4.11 (4H, d, J 7.2, inner -OCH2O-), 4.76
(4H, m, ArCHAr), 4.87 (8H, s, ArCH2N), 5.91 (4H, d, J 7.2,
outer -OCH2O-), 6.89 (4H, d, J 7.0, imidazolyl-H5Ј), 7.02 (4H,
s, ArH), 7.20 (4H, d, J 7.2, imidazolyl-H4Ј), 7.40 (4H, s,
imidazolyl-H2Ј); FAB MS m/z 1025.27 (M + H+, 100%).
(C᎐N); δ (400 MHz, CDCl ) 1.01 (12H, m, CH CH CH ), 1.34
᎐
H 3 2 2 3
(8H, m, CH2CH2CH3), 2.22 (8H, m, CH2CH2CH3), 4.23 (4H, d,
J 7.4, inner -OCH2O-), 4.80 (4H, m, ArCHAr), 5.52 (8H, s,
ArCH2N), 5.54 (4H, d, J 7.4, outer -OCH2O-), 7.07 (4H, s,
ArH), 7.39–7.18 (8H, m, indazolyl-H), 7.47 (4H, d, J 8.5,
indazolyl-H), 7.72 (4H, d, J 7.2, indazolyl-H), 7.93 (4H, s,
indazolyl-H); FAB MS m/z 1225.4 (M+, 100%).
1,21,23,25-Tetrapentyl-7,11,25,28-tetrakis(imidazolylmethyl)-
2,20:3,19-dimethano-1H,21H,23H,25H-bis[1,3]dioxocino-
[5,4-i:5Ј,4Ј-iЈ]benzo[1,2-d:5,4-dЈ]bis[1,3]benzodioxocine (7b)
1,21,23,25-Tetrapropyl-7,11,25,28-tetrakis(benzimidazolyl-
methyl)-2,20:3,19-dimethano-1H,21H,23H,25H-bis[1,3]dioxo-
cino[5,4-i:5Ј,4Ј-iЈ]benzo[1,2-d:5,4-dЈ]bis[1,3]benzodioxocine (10)
Imidazole (5.72 g, 0.083 mol, 100 eq.) was dissolved in 50 mL of
CH3CN and stirred at rt for 30 min. Tetrakis(bromomethyl)cav-
itand 4b (1.00 g, 0.84 mM) was added and the mixture was
stirred for 3 h. The reaction mixture was concentrated, dis-
solved in CH2Cl2 and washed with basic water (3 M NaOH).
The organic phase was washed with deionized water several
times and the concentrated crude product was dissolved in
acetone, and the precipitate was filtered. The filtrate was
concentrated and the residue was recrystallized from a mixture
of CH2Cl2–CH3CN to give cavitand 7b (0.73 g, 77%), mp
207.0 ЊC (Found: C, 67.78; H, 7.01; N, 10.11. C68H80O8N8
CH2Cl2 CH3CN requires C, 67.50; H,6.78; N, 9.98%); νmax
(KBr)/cmϪ1 1610.66 (C᎐N); δ (400 MHz, CDCl3) 0.89 (12H,
m, (CH2)4CH3), 1.31 (24H, m, CH2(CH2)3CH3), 2.17 (8H, m,
CH2(CH2)3CH3), 4.07 (4H, d, J 7.03, inner-OCH2O-), 4.70 (4H,
m, ArCHAr), 4.85 (8H, s, ArCH2N), 5.88 (4H, d, J 7.03, outer
-OCH2O-), 6.87 (4H, d, J 7.0, imidazolyl-H5Ј), 6.99 (4H, d, J
7.4, imidazolyl-H4Ј), 7.16 (4H, s, ArH), 7.38 (4H, s, imidazolyl-
H2Ј); FAB MS m/z 1137.4 (M+, 100%).
Benzimidazole (11.2 g) was dissolved in 80 mL of CH3CN, and
stirred at 50 ЊC for 30 min. Tetrakis(bromomethyl)cavitand 4a
(1.0 g, 0.93 mmol) was added, and the mixture was stirred for
3 h. The solvent was evaporated, and benzimidazole was
washed out with MeOH. The precipitate was filtered, washed
with methanol several times to give cavitand 10 (89 mg, 78%) as
a white solid, mp >268.0 ЊC (decomp.); νmax (KBr)/cmϪ1 1608.73
(C᎐N); δ (400 MHz, CDCl3) 0.89 (12H, m, CH2CH2CH3),
1.22 (8H, m, CH2CH2CH3), 2.09 (8H, m, CH2CH2CH3), 4.10
(4H, d, J 5.1, inner -OCH2O-), 4.68 (4H, m, ArCHAr), 4.98
(8H, s, ArCH2N), 5.62 (4H, s, outer -OCH2O-), 7.15 (4H, s,
ArH), 7.24 (8H, m, benzimidazolyl-H), 7.48 (4H, d, J 7.8,
benzimidazolyl-H), 7.66 (4H, m, benzimidazolyl-H), 7.73 (4H,
s, benzimidazolyl-H); FAB MS m/z 1225.4 (M+, 100%).
᎐
H
᎐
H
7,11,15,28-Tetrakis(2-pyridylmethyl)-1,21,23,25-tetrapentyl-
2,20:3,19-dimethano-1H,21H,23H,25H-bis[1,3]dioxocino-
[5,4-i:5Ј,4Ј-iЈ]benzo[1,2-d:5,4-dЈ]bis[1,3]benzodioxocine
stereoisomer (11)
1,21,23,25-Tetrapropyl-7,11,25,28-tetrakis(pyrazolylmethyl)-
2,20:3,19-dimethano-1H,21H,23H,25H-bis[1,3]dioxocino-
[5,4-i:5Ј,4Ј-iЈ]benzo[1,2-d:5,4-dЈ]bis[1,3]benzodioxocine (8)
2-Picolyl chloride hydrochloride† (0.74 g) and tetraol 5 (0.20 g,
0.23 mmol) were dissolved in 30 mL of DMF, at 70 ЊC. The
mixture was stirred for 3 h and then 3 M HCl (30 mL) was
added. The mixture was extracted with CH2Cl2 and washed
with H2O, and then dried over MgSO4. The product was
crudely purified by silica gel gravity column chromatography
using 5% MeOH in CH2Cl2. The best fractions were collected
and washed with deionized water several times. The solution
was concentrated to give cavitand 12 (240 mg, 85%), mp
>215 ЊC (decomp.) (Found C, 71.89; H6.70; N, 4.85.
C76H84O12N4 H2O requires C, 72.24; H, 6.86; N, 4.43%); νmax
(KBr)/cmϪ1 1618.36 (C᎐N); δ (400 MHz, CDCl3) 0.90 (12H,
m, (CH2)4CH3), 1.35 (24H, m, CH2(CH2)3CH3), 2.19 (8H, m,
CH2(CH2)3CH3), 4.47 (4H, d, J 7.0, inner -OCH2O-), 4.72 (4H,
m, ArCHAr), 5.08 (8H, s, ArOCH2), 5.73 (4H, d, J 7.0, outer
-OCH2O-), 6.84 (4H, s, ArH), 7.18 (4H, t, J1 6.3, J2 6.11,
pyridinyl-H), 7.57 (4H, d, J 7.8, pyridinyl-H), 7.69 (4H, t, J 7.8,
pyridinyl-H), 8.52 (4H, d, J 4.2, pyridinyl-H); FAB MS m/z
1245.6 (M+, 100%).
Tetrakis(bromomethyl)cavitand 4a (0.50 g, 0.46 mmol) and
pyrazole (0.60 g) were dissolved in 50 mL of CH3CN with
K2CO3 (2.5 g) at 50 ЊC and the mixture was stirred for 3 h. The
mixture was concentrated, dissolved in CH2Cl2, washed with
water several times, and dried over MgSO4. The concentrated
crude product was purified by silica gel column chrom-
atography using EtOAc–hexane (2 : 1 to 5 : 1). The best
fractions were collected and concentrated. The residue was
dissolved in CH2Cl2 and washed with deionized water several
times. The organic phase was concentrated to give cavitand 8
(310 mg, 65%), mp 239 ЊC (Found: C, 69.05; H, 6.46; N, 10.47.
C60H64O8N8 H2O requires C, 69.08; H, 6.38; N, 10.74%);
νmax (KBr)/cmϪ1 1707.11 (N᎐N), 1637.67 (C᎐N); δ (400
᎐
H
᎐
᎐
H
MHz, CDCl3) 0.94 (12H, m, CH2CH2CH3), 1.30 (8H,
m, CH2CH2CH3), 2.10 (8H, m, CH2CH2CH3), 4.16 (4H, d,
J 7.4, inner -OCH2O-), 4.74 (4H, m, ArCHAr), 4.98 (8H, s,
ArCH2N), 5.70 (4H, d, J 7.4, outer -OCH2O-), 6.11 (4H, t,
J 2.0, pyrazolyl-H4Ј), 7.09 (4H, s, ArH), 7.31 (4H, d, J 2.1,
pyrazolyl-H5Ј), 7.34 (4H, d, J 0.8, pyrazolyl-H3Ј); FAB MS m/z
1025.48 (M+, 100%).
Tetrakis(p-imidazolylmethyl)-25,26,27,28-tetrahydroxycalix[4]-
arene 12
Tetrakis(chloromethyl)calix[4]arene 6 (100 mg, 0.16 mmol) was
dissolved in 2 mL of CHCl3, and stirred at Ϫ10 ЊC for 20 min.
Imidazole (720 mg, 10.5 mmol) was added, and the mixture was
stirred for 2 h. The reaction mixture was washed with basic
water (3 M NaOH) and then with deionized water. Undissolved
powder was filtered and washed with deionized water several
times to give cavitand 12 (60 mg, 50%), mp >170 ЊC (decomp.);
δ13C (100.4 MHz, DMF-d7) 33.30 (ArCH2Ar), 50.63 (ArCH2N),
120.01 (ArC), 127.07 (ArC), 127.92 (imidazolyl 5Ј-C), 128.89
(imidazolyl 4Ј-C), 131.61 (NCHN), 137.76 (ArC), 155.85
(ArCOH); δH (300 MHz, DMF-d7) 3.13 (4H, d, J 12.4, exo-
1,21,23,25-Tetrapropyl-7,11,25,28-tetrakis(indazolylmethyl)-
2,20:3,19-dimethano-1H,21H,23H,25H-bis[1,3]dioxocino-
[5,4-i:5Ј,4Ј-iЈ]benzo[1,2-d:5,4-dЈ]bis[1,3]benzodioxocine (9)
Tetrakis(bromomethyl)cavitand 4a (1.00 g, 0.93 mmol) and
indazole (2.2 g) were dissolved in 50 mL of CH3CN with K2CO3
(2.57 g). The mixture was refluxed for 24 h. The solvent was
evaporated, and the residue was dissolved in CH2Cl2. It was
washed with water several times and dried over MgSO4. The
concentrated crude product was purified by silica gel column
chromatography using EtOAc–hexane (2 : 1) as eluent. The best
fractions were collected and concentrated. The residue was
dissolved in CH2Cl2 and washed with deionized water several
† The IUPAC name for 2-picolyl chloride hydrochloride is 2-
(chloromethyl)pyridine hydrochloride.
920
J. Chem. Soc., Perkin Trans. 2, 2001, 916–922

View Article Online
ArCH2Ar), 4.56 (4H, d, J 12.4, endo-ArCH2Ar), 5.11 (8H, s,
ArCH2N), 7.07 (8H, s, ArH), 7.11 (4H, d, J 4.2, imidazolyl-H),
7.3 (4H, d, J 4.2, imidazolyl-H), 8.20 (4H, s, imidazolyl-H).
form layer. Each Ka and Ϫ∆GЊ value reported in Table 1 and
Fig. 4 are the average values of two independent measurements.
1H NMR spectrometric titration of imidazolylcavitand 7a with
Na+BPh4Ϫ
Tetrakis(p-pyrazolylmethyl)-25,26,27,28-tetrahydroxycalix[4]-
arene 13
These studies were conducted by monitoring chemical shift
changes in the 400 MHz 1H NMR spectra of 1.4 × 10Ϫ3 M 7a in
CDCl3–MeOH-d4 (7 : 1 v/v, containing 0.3% by volume of
TMS) by incremental guest additions. A small quantity (5–10
µL) of a guest solution (1.9 × 10Ϫ2 M) in CDCl3–MeOH-d4
(7 : 1 v/v) was added via a micro pipette directly into the NMR
tube and the 1H NMR spectrum of the solution was
redetermined. This process was repeated until the chemical shift
changes of host appeared to be reasonably well spaced.
Pyrazole (600 mg, 8.3 mmol) was dissolved in 5 mL of CH3CN,
and stirred at rt for 10 min. Tetrakis(chloromethyl)calix[4]arene
6 (100 mg, 0.16 mmol) was added, and the mixture was stirred
for 1 d. The reaction mixture was evaporated, dissolved in
CH2Cl2, washed with basic water (3 M NaOH) and deionized
water three times, and then dried over MgSO4. The solvent was
evaporated under vacuum. The residue was purified by silica gel
chromatography with 2% MeOH–CH2Cl2 as a mobile phase
to give cavitand 13 (60 mg, 50%), mp >126 ЊC; δ13C (100.4
MHz, CDCl3) 148.60 (ArCOH), 139.49 (pyrazolyl 3Ј-C),
130.39 (ArC), 129.11 (pyrazolyl 5Ј-C), 128.60 (ArC), 128.35
(ArCCH2N), 105.92 (pyrazolyl 4Ј-C), 55.24 (ArCH2N), 31.59
(ArCH2Ar); δH (300 MHz, CDCl3) 3.53 (4H, d, J 12.4, exo-
ArCH2Ar), 4.16 (4H, d, J 12.4, endo-ArCH2Ar), 5.11 (8H, s,
ArCH2N), 6.28 (4H, t, J 2.1, pyrazolyl-4Ј-H), 6.90 (8H, s, ArH),
7.28 (4H, d, J 1.2, pyrazolyl-5Ј-H), 7.33 (4H, d, J 1.7, pyrazolyl-
3Ј-H), 10.12 (4H, s, OH).
Picrate extraction experiment of alkaline earth and transition
metal picrates
A two-phase liqid–liquid extraction experiment was carried
out between an aqueous solution (2.0 mL, [picric acid] = 1.0
mM, [M(NO3)n] = 10 mM) and a chloroform solution (2.0
mL, [Host] = 1.0 mM). The two-phase mixture in a tightly-
stoppered centrifuge tube was shaken with a Voltex-Genie for
1 min at 25 ЊC and then centrifuged at 1600 rpm for 1 min. The
extractability was determined spectrophotometrically from the
decrease of the picrate ion in the aqueous phase. The extraction
percentage was given by eqn. (1)
Tetrakis(p-indazolylmethyl)-25,26,27,28-tetrahydroxycalix[4]-
arene 14
Indazole (600 mg, 5.1 mmol) was dissolved in 5 mL of CH3CN,
and stirred at rt for 10 min. Tetrakis(chloromethyl)calix[4]arene
6 (100 mg, 0.16 mmol) was added and the mixture was stirred
for 1 d. The reaction mixture was evaporated and then dissolved
in CH2Cl2. The mixture was washed with basic water (3 M
NaOH) and with deionized water three times, and then dried
over MgSO4. The solvent was evaporated under vacuum. The
residue was purified by silica gel chromatography with a 1%
MeOH–CH2Cl2 as a mobile phase to give cavitand 14 (70 mg,
46%), mp >157 ЊC (decomp.); δ13C (100.4 MHz, CDCl3)
10.02 (s, 4H, OH), 31.44 (ArCH2Ar), 56.75 (ArCH2N),
117.51(indazolyl-8Ј-C), 120.19 (indazolyl-6Ј-C), 121.81
(indazolyl-6Ј-C), 122.07 (indazolyl-4Ј-C), 122.83 (indazolyl-7Ј-
C), 126.04 (indazolyl-3Ј-C), 128.41 (ArCCH2N), 128.81 (ArC),
129.14 (ArC), 148.85 (indazolyl-8Ј-C), 148.98 (ArCOH);
δH (300 MHz, CDCl3) 3.51 (4H, d, J 12.4, exo-ArCH2Ar), 4.15
(4H, d, J 12.4, endo-ArCH2Ar), 5.33 (8H, s, ArCH2N), 6.95
(8H, s, ArH), 7.13 (4H, d, J 8.3, indazolyl-H), 7.30 (4H, d, J 8.7,
indazolyl-H), 7.63 (4H, d, J 8.4, indazolyl-H), 7.76 (4H, m,
indazolyl-H), 7.79 (4H, s, indazolyl-H).
(1)
where [Host]o is the initial host concentration in chloroform
and [Host]comp is the complexed host concentration after
mixing, which is obtained from [Gb]aq Ϫ [Gi]aq. [Gb]aq is the con-
centration of picrate ion in the aqueous phase remaining after
extraction with chloroform solution (blank test) and [Gi]aq is the
guest concentration in the aqueous phase after extraction with
host solution.
Complexometric titration18 of Cu2+
A two-phase liquid–liquid extraction experiment was carried
out between an aqueous solution (3 mL, [Cu(NO3)2] = 0.1 M)
and a chloroform solution (3 mL, [Host] = 0.05 M). The
two-phase mixture in a tightly-stoppered centrifuge tube was
shaken with a Voltex-Genie for 1 min at 25 ЊC and then cen-
trifuged at 1600 rpm for 1 min. After phase separation the
aqueous solution of Cu2+ (1 mL) was diluted to 50 mL with
water and aqueous NH4Cl (10 mL, 1 M) and murexide‡ was
added. The concentration of Cu2+ in the aqueous phase was
determined by EDTA (0.02 M) titration experiment. At the
equivalent point the colour of murexide changed from orange
to dark green. The extraction percentage was obtained from
eqn. (1).
1H NMR spectrometric titration of imidazolylcavitand 7b with
Na+ClO4Ϫ
Five NMR tubes with solution 7b (0.7 mL) (8.1 × 10Ϫ6 mol in
Ϫ
CDCl3–CD3CN = 3 : 1 v/v) were treated with solid Na+ClO4
(0.3 mg, 0.3 eq.; 0.5 mg, 0.5 eq.; 1.0 mg, 1 eq.; 3.2 mg, 3 eq. and
10.7 mg, 10 eq.), respectively. The mixtures were sonicated for
10 min at room temperature and the resulting changes in the
NMR spectra were monitored.
Acknowledgements
The financial support from the Korean Science and Engineer-
ing Foundation (No. 971-0302-011-2 and No. 1999-2-123-001-
3) is gratefully acknowledged.
Picrate extraction experiment of 7b
A two-phase liquid–liquid extraction experiment was carried
out between an aqueous solution (2.0 mL, [GPic] = 4 mM) and
a chloroform solution (2.0 mL, [Host] = 4 mM). The two-phase
mixture in a tightly-stoppered centrifuge tube was shaken with
a Voltex-Genie for 1 min at 22 ЊC and then centrifuged at 1600
rpm for 1 min. After phase separation the concentration of the
complexed picrate salt in the CHCl3 layer was determined
spectrophotometrically. For an internal check the decrease
in concentration of the picrate salt in water solution was
measured and found to be in agreement with that of the chloro-
‡ The IUPAC name for murexide is ammonium bis(2,4,6-trioxo-
hexahydropyrimidin-5-yl)amide.
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