Tetrakis(phenylamidinium)-substituted resorcin[4]arene receptors for the complexation of dicarboxylates and phosphates in protic solvents

Article abstract of DOI:10.1002/(SICI)1522-2675(20000119)83:1<93::AID-HLCA93>3.0.CO;2-5

Three bowl-type cavitand receptors (1-3), consisting of a resorcin[4]arene core with four convergent phenylamidinium groups, were prepared in gram quantities by efficient synthetic routes (Schemes 1 and 2) for the recognition of organic anions in CD₃

Full text of DOI:10.1002/(SICI)1522-2675(20000119)83:1<93::AID-HLCA93>3.0.CO;2-5

Helvetica Chimica Acta ± Vol. 83 (2000)
93
Tetrakis(phenylamidinium)-Substituted Resorcin[4]arene Receptors for
the Complexation of Dicarboxylates and Phosphates in Protic Solvents
by Lubomir Sebo and François Diederich*
Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule, ETH-Zentrum,
Universitätstrasse 16, CH-8092 Zürich
and Volker Gramlich
Laboratorium für Kristallographie, ETH-Zentrum, Sonneggstrasse 5, CH-8092 Zürich
Three bowl-type cavitand receptors (1 ± 3), consisting of a resorcin[4]arene core with four convergent
phenylamidinium groups, were prepared in gram quantities by efficient synthetic routes (Schemes 1 and 2) for
the recognition of organic anions in CD3OD and D2O. The key steps in the syntheses are the Suzuki cross-
coupling reactions between the tetraiodo cavitands 12, 13, and 23, respectively, with the m-cyanophenylboronic
ester 14 and subsequent conversion of the nitrile to amidinium groups by the Garigipati reaction. Compounds 1
and 2 displayed limited solubility in protic solvents, and evidence for stoichiometric host-guest association
between 2 and AMP (28) could only be obtained by FAB-MS analysis of a complex precipitated from MeOH
(Fig. 2). In contrast, receptor 3 with four triethyleneglycol monomethyl ether side chains was readily soluble in
the protic environments, and complexation of isophthalates and nucleotides 25 ± 37 was extensively studied by
1H-NMR titrations and Jobꢀs method of continuous variation. In CD3OD and pure D2O, isophthalates 25 and 26
formed stable 1:2 host-guest complexes (Table 1 and Fig. 3), whereas upon addition of borate (pH 9.2) or Tris/
HCl buffer (pH 8.3) to the D2O solution, the tendency for higher-order complexation vanishes. Stable 1:1
complexes formed in the buffered solutions (Fig. 4) with 5-methoxyisophthalate being selectively bound over
the 5-NO2 derivative. Complexation-induced upfield shifts of specific isophthalate 1H-NMR resonances (Fig. 5)
suggest a preferred inclusion of the methoxyphenyl ring into the receptor cavity. Cavitand 3 forms stable 1:1
host-guest complexes with nucleotides in Tris/HCl-buffered D2O. Association constants increase strongly with
increasing guest charge in the series cAMP < AMP < ADP < ATP (Table 2). Association strength is strongly
reduced in the presence of high salt (NaCl) concentration (Table 3). Receptor 3 shows a slight preference for
the complexation of AMP (Fig. 7) and analogs dAMP or e-AMP (Table 4) over nucleotides containing G
(guanine), C (cytosine), T (thymine), or U (uracil) as bases. According to the 1H-NMR analysis, only the
nucleobase adenine and derivatives thereof possess the necessary stereoelectronic complementarity for
inclusion into the bowl-type cavity. The major forces stabilizing the complexes of 3 with isophthalates and
nucleotides result from ion pairing and ionic H-bonding between the charged groups of host and guest, and from
the desolvation of these groups upon complexation. Apolar interactions and hydrophobic desolvation do not
seem to make a large contribution to the measured binding free enthalpies.
1. Introduction. ± In the directly preceding paper [1], we described the complex-
ation of dicarboxylate guests (glutarate, isophthalates) by a cleft-type bis(phenylamid-
inium) receptor in MeOH. Here, we report on the novel macrocyclic hosts 1 ± 3 which
feature a resorcin[4]arene core [2 ± 6] with four convergent phenylamidinium groups
and were designed for organic-anion recognition in H2O [7]. Similar to the cleft-type
receptors in the preceding study [1], compounds 1 ± 3 were expected to complex with
their amidinium residues organic anions by ion pairing and ionic H-bonding
interactions. Additionally, they should display enhanced binding affinity and selectivity
resulting from inclusion of complementary lipophilic segments of the anionic guests

94
Helvetica Chimica Acta ± Vol. 83 (2000)
into the bowl-type resorcinarene cavity, driven by hydrophobic desolvation and apolar
host-guest interactions [8].
Since hydrophobic bonding is most effective in H2O, good monodisperse H2O-
solubility of the resorcinarene-based anion receptors [9][10] was crucial for the success
of this work. We show that this desirable property is best obtained by introducing
triethyleneglycol monomethyl ether side chains as ꢁfeetꢀ into receptor 3. The power of
these side chains to enhance the H2O-solubility of large organic molecules became
previously apparent in our studies of dendrimers as biological mimics [11].
Anions considered in this investigation are dicarboxylates, such as isophthalates
(for references to carboxylate-anion binding by synthetic receptors, see [1]) and
phosphates, such as mononucleotides. In the past, macrocyclic and cleft-type receptors
containing ammonium or guanidinium groups have often been investigated for both
carboxylate and phosphate binding in aqueous solution. Efficient macrocyclic
nucleotide receptors include protonated azacrown ethers [12] and azacryptands [13],
tetrazonia[8.1.8.1]paracyclophanes [14], and sapphyrins [15]. Non-macrocyclic recep-
tors containing one or two guanidinium ions for phosphate and nucleotide binding have
been reported [16][17]. We found that cationic carriers, which contain two diquater-
nary 1,4-diaza[2.2.2]bicyclooctane units, undergo ion-pairing with nucleotide-5'-tri-
phosphates and strongly accelerate their transport across liquid organic membranes
[18]. Here, we show that resorcinarene 3 is a highly efficient nucleotide binder and
analyze the contributions of polar and apolar interactions to the stability of the host-
guest complexes formed in aqueous buffers.
2. Results and Discussion. ± 2.1. Synthesis. We first prepared the target compounds 1
and 2 under the assumption that the four amidinium residues would be sufficient to
provide good solubility in protic solvents. Octols 4 and 5 (Scheme 1) were prepared
according to literature procedures starting from resorcinol and the corresponding
aldehyde [19]. Subsequently, the Br substituents were introduced with N-bromosuccin-
imide (NBS) in butanone into the 2-positions of the resorcinol sub-units to yield

Helvetica Chimica Acta ± Vol. 83 (2000)
95
tetrabrominated 6 and 7, respectively [20]. These octols were bridged with ethylene-
glycol bis[p-toluenesulfonate] and Cs2CO3 in Me2SO to provide the rigidified
cavitands 8 and 9. Triply-bridged compounds 10 and 11 were also isolated in this step;
they were subsequently transformed into 8 and 9, respectively, by a second cyclization
step in MeCN. Drying of 8 and 9 was crucial for the success of the subsequent
metallation step; therefore, residual solvent included in their cavity (H2O, CH2Cl2
(1H-NMR)) was removed by slow distillation of THFand benzene from solutions of the
cavitands.
Scheme 1. Synthesis of Tetraamidinium Cavitands 1 and 2
a) NBS, butanone, 208, 1 d. b) TsO(CH2)2OTs, anh. Cs2CO3, Me2SO, 658, 40 h (8), 4 d (9). c) TsO(CH2)2OTs,
anh. Cs2CO3, MeCN, 908/1 d (10), 1208/3 d (11). d) 1. BuLi, THF, 1008, 35 min; 2. I2, 1008 ! 208, 12 h. e)
[PdCl2(PPh3)2], AsPh3, Cs2CO3, dioxane, H2O, 758, 3 h. f) MeAlNH2Cl, 1,2-dichlorobenzene, 708 ± 808, 6 d (1),
4 d (2).
Crystals of 9 were grown from CH2Cl2, and the X-ray crystal structure of the
solvate with two CH2Cl2 molecules was solved. The solid-state structure (Fig. 1) showed
interesting enclathration phenomena similar to those previously described by Cram
and co-workers [2][19][20]. One CH2Cl2 molecule is located inside the cavitand bowl
with one Cl-atom pointing deeply into the cavity. The second CH2Cl2 molecule is
embedded in a second cavity shaped by the four 2-phenylethyl legs.
Since a fourfold Suzuki cross-coupling [21][22] of tetrabrominated 8 and 9 led to
unsatisfactory conversions, the cavitands were metallated with BuLi in THF and
iodinated with I2 to give tetraiodides 12 and 13, respectively. The second component for
the Suzuki reaction, ꢁpinacol borateꢀ 14, was obtained by metallation of 3-
bromobenzonitrile with BuLi, followed by reaction with B(OMe)3 and transesterifi-
cation with pinacol. Cross-coupling between 12 or 13 and 14 yielded the tetracyano-

96
Helvetica Chimica Acta ± Vol. 83 (2000)

Helvetica Chimica Acta ± Vol. 83 (2000)
97
cavitands 15 and 16, respectively. Finally, the tetraamidinium salts 1 and 2 were
prepared from 15 and 16, respectively, by the Garigipati method [23] with MeAlNH2Cl.
The synthesis of 3 (Scheme 2) with its polar triethyleneglycol monomethyl ether
legs started from dodecaol 17, which was obtained by acid-catalyzed condensation of
resorcinol and 2,3-dihydrofuran according to the procedure published by Sherman and
co-workers [24]. Bromination with NBS afforded 18, which was transformed by
Williamson cyclization to the rigid cavitand 19 and by subsequent mesylation into 20.
Nucleophilic substitution of tetrakis[methanesulfonate] 20 with the sodium salt of
triethyleneglycol monomethyl ether (prepared with NaH) yielded 21, which, however,
was contaminated with a large amount of cavitand possessing the four triethyleneglycol
monomethyl ether feet but lacking one of the four Br-atoms. This undesirable
debromination could be avoided by using the dialkoxymagnesium derivative 22 in the
Sn2 reaction. Substitution of 20 with 22, formed from triethyleneglycol monomethyl
ether with Mg and I2, gave 21 in 78% yield. The residual conversions in the synthesis of
3 closely followed those applied in the route to 1 and 2, leading via the sequence 21 !
23 ! 24 ! 3 to the desired receptor which was obtained in gram quantities.
Scheme 2. Synthesis of the Tetraamidinium cavitand 3
a) NBS, butanone, MeOH, 208, 15 h; 77%. b) TsO(CH2)2OTs,Cs2CO3, K2CO3, 2,6-bis(1,1-dimethylethyl)-4-
methylphenol (BHT), N,N-dimethylacetamide (DMA), 208 (1 d), 458 (1 d), 658 (3 d); 42%. c) MeSO2Cl,
NEt3, dioxane, 08 ! 208, 3 h; 92%. d) Dioxane, 608, 16 h; 78%. e) 1. BuLi, THF, 1008, 30 min; 2. I2, 1008 !
208, 2 h; 97%. f) 14, Cs2CO3, [PdCl2(PhCN)2], AsPh3, dioxane, H2O, 708, 2 h; 84%. g) MeAlNH2Cl, 1,2-
dichlorobenzene, 708 ± 808, 3 d; 91%.
1
2.2. Complexation Studies. Extensive H-NMR binding studies were undertaken
with substrates 25 ± 37. It soon became apparent that the low solubility of cavitands 1
and 2 in MeOH or H2O was a major disadvantage, since no titration experiments could
be successfully performed in these protic solvents. For example, upon mixing equimolar

98
Helvetica Chimica Acta ± Vol. 83 (2000)
solutions of 2 and AMP (28) in MeOH, a precipitate formed. The analysis of the solid
by fast-atom-bombardment mass spectrometry (FAB-MS) confirmed the formation of
a 1:1 host-guest complex (Fig. 2).
In contrast, receptor 3 was readily soluble in MeOH and H2O, and all subsequent
complexation studies were executed with this cavitand.

Helvetica Chimica Acta ± Vol. 83 (2000)
99
Fig. 2. FAB Mass spectra (3-nitrobenzyl alcohol as matrix) of receptor 2 (a) and the 1:1 host-guest complex with
AMP (28), which precipitated out of MeOH (b)
1
2.2.1. Complexation of Isophthalates. In H-NMR binding titrations (500 MHz,
300 K) with 3 in CD3OD at fast host-guest exchange, the concentration of the
ammonium salt 25a was kept constant, and the data were fitted using the program
SPECFIT V. 2.11 [25]. Complexation of 25a could not be described using a simple 1:1
host-guest binding model. Instead, a good fit of the data to the 1:2 host-guest
Table 1. Association Constants and Complexation Free Enthalpies from 1H-NMR Titrations for 1 : 1 and 1 : 2
Host-Guest Complexes of Isophthalates with Receptor 3 (Tˆ 300 K) in CD3OD and D2O. Also shown are the
maximum observed complexation-induced shifts Ddmax obs
(
: upfield) of guest 1H resonances monitored during
the titrations.
b
Guest
Ka(HG)a)
DG(HG)
Ka(HG2)
)
DG(HG2)
Ddmax obs
1
1
1
1
[l mol
]
[kJ mol
]
[l mol
]
[kJ mol
]
[ppm]
In CD3ODc)
25a
350000
31.8 Æ 2.7
60000
27.3 Æ 5.7
0.145 (H C(2))
0.091 (H C(4))
In pure D2Od)
25b
14800
86000
24.0 Æ 0.3
28.3 Æ 0.4
3800
7700
20.6 Æ 1.0
22.3 Æ 1.5
‡ 0.076 (H C(2))
0.278 (H C(4))
‡ 0.139 (H C(2))
0.548 (H C(4))
26b
In D2O containing Na2B4O7 (5 mm; pH ˆ 9.2)e)
25b
4000
20.7 Æ 0.1
28.6 Æ 0.3
‡ 0.082 (H C(2))
0.268 (H C(4))
‡ 0.148 (H C(2))
0.565 (H C(4))
26b
96500
In D2O containing Tris/HCl (2.5 mm, pH ˆ 8.3)f)
25b
12200
23.5 Æ 0.2
29.2 Æ 0.4
‡ 0.094 (H C(2))
0.317 (H C(4))
‡ 0.159 (H C(2))
0.599 (H C(4))
26b
118900
a) Equilibrium constant for the 1 : 1 complexation step: H ‡ G > HG. b) Equilibrium constant for the 1 : 2
complexation step: HG ‡ G > HG2. c) [25a] ˆ 0.5 mm; [3] ˆ 0.03 ± 0.5 mm. d) Constant guest concentration:
f
0.5 mm. e) Constant guest concentration: 0.5 mm (25b), 0.2 mm (26b). ) Constant guest concentration: 0.5 mm
(25b), 0.3 mm (26b).

100
Helvetica Chimica Acta ± Vol. 83 (2000)
association model was obtained, yielding high association constants for both 1:1 and
1:2 complexation steps (Table 1).
The 1:2 stoichiometry was confirmed using Jobꢀs method of continuous variation
1
(Fig. 3), where the complexation-induced shifts of host or guest H-NMR resonances
were followed as a function of the host or guest mole fraction, respectively, keeping
their total concentration constant [26].
1H-NMR Titrations in pure D2O confirmed the results obtained in CD3OD, and a
1:2 host-guest association was again observed (Table 1). Methoxyisophthalate 26b was
found to undergo a stronger association with 3 than the derivative 25b. Although the
1:2 host-guest binding model is valid in both CD3OD and D2O, the association
geometries in the two solvents are quite different, as indicated by the different Dd
values of the guest resonances. In CD3OD, the resonance of proton H C(2) displays a
larger upfield shift than that of H C(4). In contrast, only the resonance of H C(4) is
shifted upfield in D2O (Table 1), with the shift being particularly large in the
complexation of methoxy derivative 26b (Table 1). The data suggest that complexation
in CD3OD occurs much more at the rim of the cavitand, whereas in D2O, one of the two
isophthalates is, in time average, included with the less polar segment of its phenyl ring
into the receptor cavity. These findings are in agreement with previous work which
showed that apolar cavity inclusion, driven largely by the release of solvent molecules
into the bulk, is much more favorable in D2O than in CD3OD [8].
Interestingly, higher-order association between receptor 3 and isophthalates 25b
and 26b is suppressed in deuterated aqueous borate buffer (pH 9.2), and complexation
is readily described using the 1:1 host-guest binding model. The association behavior of
the two guests in the presence of buffer is quite different. The association constant for
the 1:1 complex between 3 and methoxyisophthalate 26b in the borate buffer remains
unchanged within experimental error, when compared to the first association constant
of the 1:2 complex in unbuffered D2O. In the case of nitro derivative 25b, however, the
association constant Ka in the borate buffer drops by a factor of four. Furthermore, the
measured complexation-induced upfield shift of the resonance of H C(4) in 26b is
twice as large as the shift measured for the corresponding resonance in 25b. Apparently,
Fig. 3. Job plots for the complex formed between 3 and 25a in CD3OD at 300 K. The total concentration c0(H) ‡
c0(G) was kept constant at 2 mm. The host (H) signal H C(5') (left graph) and the guest (G) signal H C(2)
(right graph) were followed. Host molar fraction x(H) defined as c0(H)/c0(H) ‡ c0(G)); guest molar fraction
x(G) defined as c0(G)/(c0(H) ‡ c0(G)).

Helvetica Chimica Acta ± Vol. 83 (2000)
101
methoxyisophthalate 26b has a much higher stereoelectronic complementarity to the
resorcinarene cavity than nitro derivative 25b, leading to a deeper inclusion of its MeO-
substituted phenyl ring. As a result, a more stable complex is formed [9], which is less
affected by the competitive buffer anions. The 1:1 stoichiometry of the complexes in
borate buffer was confirmed using Jobꢀs method (Fig. 4).
Fig. 4. Job plots for the complex formed between 3 and 25b in D2O containing Na2B2O7 (5 mm) at 300 K, pH 9.2.
The total concentration c0(H) ‡ c0(G) was kept constant at 2 mm. The host signal H C(2') (left graph) and the
guest signal H C(4) (right graph) were followed. For further definitions, see Caption to Fig. 3.
The quality of the experimental titration data in borate buffer is documented in
Fig. 5. It is readily apparent that, with increasing receptor concentration, the signal of
H
C(2) of the guest moves downfield, whereas the signal of H C(4) moves upfield.
The fact that differential up- and downfield shifts are observed is generally an indicator
for the formation of a geometrically highly structured complex rather than unspecific
aggregation or association.
Isophthalate binding by cavitand 3 in aqueous solution was further studied in the
presence of Tris/HCl buffer at pH8.3 (Tris ˆ 2-amino-2-(hydroxymethyl)propane-1,3-
diol). The results are in good agreement with those from the study in the borate buffer.
The cationic Tris/HCl buffer (pH 8.3) was found less competitive than the anionic
borate buffer (pH 9.2), which was reflected in the increased value of the association
constant, especially in the case of nitro derivative 25b. Again, 1:1 host-guest
stoichiometry was observed exclusively.
The complexation of the two isophthalates by 3 was also investigated by computer
modeling. Results of energy minimizations (4000 steps) using the Monte Carlo multiple
minimum simulation method implemented in MacroModel V. 6.0 [27] with the
AMBER* force-field [28] and the GB/SA solvation model for H2O [29] were in
agreement with the experimentally observed formation of stable inclusion complexes.
Fig. 6 shows the energy-minimized structure of the complex formed by methoxyisoph-
thalate. The aromatic ring of 26 is embedded into the host cavity while the carboxylate
residues interact via ion pairing and ionic H-bonding with the surrounding benzamid-
inium residues. Such an inclusion geometry is supported experimentally by the
substantial complexation-induced upfield shift observed for the 1H-NMR resonance of
H
C(4) in 26a/b.

102
Helvetica Chimica Acta ± Vol. 83 (2000)
Fig. 5. Two examples of 1H-NMR titrations with isophthalates in D2O containing Na2B4O7 (5 mm) at 300 K,
pH 9.2. Left: Part of the 1H-NMR spectrum of 25b (0.5 mm) alone (a) and in the presence of receptor at [3] ˆ
0.12 (b), 0.21 (c), 0.50 (d), and 1.0 (e) mm. Right: Part of the 1H-NMR spectrum of 26b (0.2 mm) alone (a), and
in the presence of receptor at [3] ˆ 0.049 (b), 0.084 (c), 0.20 (d), and 0.41 (e) mm.
2.2.2. Complexation of Phosphates. Various nucleotides (cf. 25 ± 37) were chosen
and their complexation with receptor 3 studied in aqueous solution. All phosphates
were used as sodium salts except for dinucleotide d(AA) 33, which was used as
ammonium salt. 1H-NMR Binding titrations were executed at 300 K in D2O containing
Tris/HCl (pH 8.3), a buffer commonly used in biological studies with nucleotides [30].
Stable complex formation was observed, and all data could be fitted to the 1:1 host-
guest binding model since higher associations were not observed. The following results
were obtained:
i) In D2O containing Tris/HCl (2.5 mm), complexation strength increases with
increasing guest charge: the association constant Ka increases in the series cAMP
(30) < AMP (28) < ADP (31) < ATP (32) (Table 2). The thermodynamic data for ATP
1
binding have a high uncertainty, since they exceed the limits of the used H-NMR
technique. Similar correlations between guest charge and binding affinity had been
previously observed in the complexation of these nucleotides with protonated aza-
crown ethers [12]. The 1:1 stoichiometry of AMP complexation with 3 was confirmed
by Job-plot analysis (Fig. 7).
ii) The effects of varying buffer and salt (NaCl) concentrations on AMP (28)
binding were the subject of further studies. It was found that a fourfold increase of the
Tris/HCl buffer concentration did not significantly alter the association constant
(Table 3). On the other hand, introduction of high salt concentrations decreased the
binding constant dramatically. The buffer/salt system (10 mm Tris/HCl ‡ 150 mm

Helvetica Chimica Acta ± Vol. 83 (2000)
103
Fig. 6. Energy-minimized structure of the complex formed between receptor 3 and 5-methoxyisophthalate 26. The
calculations were performed with MacroModel V. 6.0 (4000-step Monte-Carlo multiple minimum simulation,
AMBER* force-field, GB/SA solvation model for H2O). Shown are the intermolecular H-bonding N ´´´ O
distances in the complex: a) 2.65 Š, b) 2.74 Š, c) ± e): 2.66 Š. For simplification, the (CH2)3(OCH2CH2)3OMe
chains in 3 were replaced by Me groups.
Table 2. Association Constants (Ka) and Complexation Free Enthalpies (DG) for the 1 : 1 Complexes of
Adenosine Phosphates with Receptor 3 in D2O Containing Tris/HCl (2.5 mm, pH 8.3). Tˆ 300 K. Also shown are
the maximum observed complexation-induced upfield shifts Ddmax obs of guest resonances monitored during the
titrations.
Guesta)
Ka [l mol
]
DG [kJ mol
18.1 Æ 0.2
]
Ddmax obs [ppm]
1
1
cAMP (30)
1400
0.020 (H C(2))
0.091 (H C(8))
0.066 (H C(1'))
0.412 (H C(2))
0.091 (H C(8))
0.106 (H C(1'))
0.067 (H C(8))
0.186 (H C(1'))
0.100 (H C(8))
0.202 (H C(1'))
AMP (28)
10000
23.0 Æ 0.3
ADP (31)
ATP (32)
48700
26.9 Æ 0.4
33.4 Æ 1.5
660000
a) Constant guest concentrations: 1.0 mm (30), 0.4 mm (28), 0.3 mm (31), 0.2 mm (32).

104
Helvetica Chimica Acta ± Vol. 83 (2000)
Fig. 7. Job plots for the complex formed between AMP (28) and 3 in D2O containing Tris/HCl (5 mm) at 300 K,
pH 8.3. The total concentration c0(H) ‡ c0(G) was kept constant at 2 mm. The host signal H C(2') (left graph)
and the guest signal H C(2) (right graph) were followed. For further definitions, see Caption to Fig. 3.
Table 3. Association Constants (Ka) and Complexation Free Enthalpies (DG) for the 1 : 1 Complex of AMP (28)
with Receptor 3 in Different Buffer/Salt Systems. Tˆ 300 K. Also shown are the maximum observed
complexation-induced upfield shifts Ddmax obs of guest resonancesa) monitored during the titrations.
1
1
c(Tris/HCl) [mm]
c(NaCl) [mm]
Ka [l mol
]
DG [kJ mol
23.0 Æ 0.3
]
Ddmax obs [ppm]
2.5
0
10000
0.412 (H C(2))
0.091 (H C(8))
0.106 (H C(1'))
0.358 (H C(2))
0.077 (H C(8))
0.093 (H C(1'))
0.075 (H C(2))
0.014 (H C(8))
0.020 (H C(1'))
10.0
10.0
0
9600
720
22.9 Æ 0.2
16.4 Æ 0.3
150
a) Constant guest concentration: 0.4 mm.
NaCl), being the most competitive in the presented studies, is widely used as a standard
medium in biochemistry for many DNA assays [30].
iii) Receptor 3 preferentially complexes AMP (28) over the other natural
nucleotides GMP (34), CMP (35), TMP (36), or UMP (37), although differences in
binding free enthalpy are not very large (Table 4). Substantial complexation-induced
upfield shifts, indicative of cavity inclusion of the nucleobase, were only observed for
the resonance of proton H C(8) in bound AMP. This could suggest that the slight
preference of the receptor for AMP could originate from additional apolar binding
interactions and hydrophobic desolvation, associated with cavity inclusion. Interest-
ingly, AMP (28) and its analogs dAMP (27), missing the C(2') OH group, and e-AMP
(29), with an extended tricyclic nucleobase, form complexes of similar stability with 3.
Particularly large complexation-induced upfield shifts of the resonances of H C(10)
(Ddmax
ˆ
0.619 ppm) and H C(11) (Ddmax obs
ˆ
0.805 ppm) in e-AMP (29)
obs
suggest that the additional fused imidazole ring of this guest is deeply embedded into
the shielding cavity of the cavitand. The association strength, however, is not much
affected by this cavity inclusion. Therefore, the present studies demonstrate that ion

Helvetica Chimica Acta ± Vol. 83 (2000)
105
Table 4. Association Constants (Ka) and Complexation Free Enthalpies (DG) for the 1 : 1 Complexes of
Nucleotides with Receptor 3 in D2O Containing Tris/HCl (2.5 mm, pH 8.3). Tˆ 300 K. Also shown are the
maximum observed complexation-induced upfield shifts Ddmax obs of guest resonances monitored during the
titrationsa).
1
1
Guest
Ka [l mol
]
DG [kJ mol
23.0 Æ 0.3
]
Ddmax obs [ppm]
AMP (28)b)
10000
0.412 (H C(2))
0.091 (H C(8))
0.106 (H C(1'))
0.023 (H C(8))
0.035 (H C(1'))
0.031 (H C(5))
0.021 (H C(6))
0.025 (H C(1'))
0.040 (Me)
0.021 (H C(6))
0.026 (H C(1'))
0.033 (H C(5))
0.014 (H C(6))
0.018 (H C(1'))
0.357 (H C(2))
0.053 (H C(8))
0.096 (H C(1'))
0.201 (H C(2))
0.011 (H C(8))
0.619 (H C(10))
0.805 (H C(11))
0.009 (H C(1'))
0.027 (H C(2))
0.052 (H C(8))
GMP (34)b)
CMP (35)b)
5200
3500
21.4 Æ 0.2
30.4 Æ 0.2
TMP (36)b)
UMP (37)b)
dAMP (27)b)
e-AMP (29)b)
5900
3800
9500
9200
21.6 Æ 0.3
20.6 Æ 0.3
22.9 Æ 0.2
22.8 Æ 0.3
d(AA) (33)c)
330
14.5 Æ 0.2
a) For numbering of the protons, see Formulae 25 ± 37. b) Constant guest concentration: 0.4mm. c) Buffer
concentration: 10 mm, constant guest concentration: 1.0 mm.
pairing and ionic H-bonding between the charged groups of host and guest, as well as
desolvation of these groups upon complexation [1], rather than apolar interactions and
hydrophobic desolvation, provide the major driving forces for nucleotide complexation
by 3.
iv) Dinucleotide d(AA) (33) forms a weak 1:1 complex with 3 (Table 4). Small
complexation-induced changes in chemical shift were only observed for the 1H
resonances of one of the two nucleobases (adenosine with the free C(5') OH group),
and cavity inclusion presumably is not very effective in the complex.
Nucleotide binding by 3 was also investigated by computer modeling with
MacroModel V. 6.0 (see above). In agreement with the experimental findings, AMP
was calculated to preferentially form an inclusion complex with the nucleobase
embedded into the cavity of the receptor (Fig. 8). In contrast, the smaller pyrimidine
base in UMP (37) did not show a high propensity to bind into the bowl and preferred
turning away form the cavity into the solution. The majority of the low-energy
conformations generated for complexes of the nucleotides that were studied
experimentally showed the involvement of three convergent amidinium residues in
host-guest ion pairing, while the fourth aminidium residue was extending away from
the cavity into the solution.

106
Helvetica Chimica Acta ± Vol. 83 (2000)
Fig. 8. Energy-minimized structure of the complex formed between receptor 3 and AMP (28). The calculations
were performed with MacroModel V. 6.0 (4000-step Monte-Carlo multiple-minimum simulation, AMBER*
force-field, GB/SA solvation model for H2O). Shown are the intermolecular H-bonding N ´´´ O distances in the
complex: a) 2.69 Š, b) 2.67 Š, c) 2.66 Š, d) 2.75 Š, e) 2.91 Š, f) 2.76 Š. For simplification, the
(CH2)3(OCH2CH2)3OMe chains in 3 were replaced by Me groups.
3. Conclusion. ± The tetrakis(phenylamidinium) cavitand 3 is readily prepared in
gram quantities and represents an excellent anion receptor in CD3OD and D2O. In
CD3OD and pure D2O, isophthalates 25 and 26 form stable complexes with 1:2 host-
guest stoichiometry, as revealed by 1H-NMR binding titrations and application of Jobꢀs
method of continuous variation. In aqueous buffers (borate, Tris/HCl), however, the
tendency to form higher-order complexes vanishes, and the analysis of the titration data
and Job plots confirmed the exclusive formation of 1:1 host-guest complexes. A
substantial binding selectivity is observed between the two isophthalates in buffered
D2O solutions. The 5-MeO derivative 26b forms a significantly more stable complex
than the corresponding 5-NO2 derivative 26b. Specific complexation-induced changes
in chemical shift of the aromatic guest resonances suggest that inclusion of the MeO-
substituted phenyl ring of 26b in the lipophilic receptor cavity is more favorable than
inclusion of the NO2-substituted phenyl ring of 25b. This could explain the observed
binding selectivity.
Stable host-guest complexes also form in Tris/HCl-buffered D2O between cavitand
3 and a variety of nucleotides. The 1:1 stoichiometry of all complexes was clearly
revealed by 1H-NMR titration data and Job-plot analyses. Association constants
increase strongly with increasing guest charge in the series cAMP (30) < AMP (28) <
ADP (31) < ATP (32). Aweaker complex with 1:1 host-guest stoichiometry also forms
with the dinucleotide d(AA) (33). Association strength is strongly reduced in the

Helvetica Chimica Acta ± Vol. 83 (2000)
107
presence of high salt (NaCl) concentration. The receptor shows a slight selectivity for
AMP and analogs over other nucleotides, such as GMP (34), CMP (35), TMP (36), or
UMP (37). The analysis of the complexation-induced changes in chemical shift of the
aromatic guest resonances suggests that the nucleobase in bound AMP, dAMP (27),
and e-AMP (29) is deeply embedded in the receptor cavity, which does not seem to be
the case for the nucleobases in the other nucleotides. However, the additional gain in
binding free enthalpy resulting from this cavity inclusion and, hence nucleotide
selectivity, is only small. Therefore, it can be concluded that the major forces stabilizing
the complexes of 3 with isophthalates and nucleotides result from ion-pairing and ionic
H-bonding between the charged groups of host and guest and from the desolvation of
these groups upon complexation [1]. Apolar interactions and hydrophobic desolvation
do not seem to make a large contribution to the measured binding free enthalpies. The
good synthetic availability and the excellent nucleotide-binding ability make the
tetrakis(phenylamidinium) cavitand 3 a promising building block for the construction
of oligomeric receptors that are capable of complexing oligonucleotides such as DNA
and RNA fragments. Developments in this direction are now being pursued in our
laboratory.
Experimental Part
General. See [1]. Resorcinarene cavitands were named according to [20]. An alternative name for the
unsubstituted resorcinarene cavitand skeleton (e.g., in 8 or 9, but without Br-substituents and side chain R,
Scheme 1) is: 2,5,9,12,16,19,23,26-octaoxanonacyclo[25.15.1.128,42.06,40.08,38.013,36.015,34.020,32.022,30]tetratetraconta-
1(43),6,8(38),13,15(34),20,22(30),27,31,35,39,42-dodecaene.
1H-NMR Titrations. For the preparation of 25a and 26a, see [1]. The disodium isophthalates 25b and 26b
were obtained by neutralization of MeOH solns. of the corresponding isophthalic acids with 2 equiv. of 1m aq.
NaOH. The resulting soln. was concentrated in vacuo, and the residue was recrystallized from H2O/MeOH to
give, after drying (0.01 Torr, 808, 12 h), the pure disodium salts 25b and 26b, resp. All nucleotides were
purchased from Sigma or Fluka and used without further purification. Borate buffer (pH 9.2, 5 mm) was
prepared by dissolving anh. Na2B4O7 (Aldrich) in D2O. Tris/HCl buffer (pH 8.2; 2.5 mm) was prepared from
solid Tris/HCl (Fluka) and D2O. All 1H-NMR titrations were performed with a 500-MHz Bruker AMX 500
instrument. The titrations were performed by adding a soln. of both components (11 Â 20 ± 300 ml) to the soln. of
one component in NMR tubes. The signals of the component which was kept at constant concentration were
followed. The experimental data were fitted using the program SPECFIT V. 2.11 [25].
Job Plots. A set of 11 samples was prepared with the total concentration of both components being kept
constant at 2 mm in all samples. The host-guest ratio was varied in such a way that the host molar fraction (c0(H)/
(c0(H) ‡ c0(G)) (c0 ˆ total initial concentration) increased (0, 0.10, 0.20, ... 1.00; in intervals of 0.10) and the
guest molar fraction (c0(G)/(c0(H) ‡ c0(G)) correspondingly decreased in the prepared samples. Resonances of
both components were followed on a 500-MHz Bruker AMX 500 instrument. The plots were generated using
the program proFit V. 5.0.1 [31].
Molecular Modeling. All calculations were carried out on Silicon Graphics Indigo 2 or Octane workstations.
Initial structures of host and guest were generated by a conjugate gradient minimization with the AMBER*
force-field and the BatchMin program implemented within MacroModel V. 6.0. For simplification, the
(CH2)3(OCH2CH2)3OMe chains in 3 were replaced by Me groups. Counterions of host and guest were not
included in the simulations. The guests were placed outside the resorcinarene cavity in the initial structures.
These structures were further refined by a 4000-step Monte-Carlo multiple minimum simulation, using the GB/
1
SA solvation model for H2O. All conformations within 30 kJ mol of the computed global minimum were
stored, and the representative lowest-energy structure was analyzed for intermolecular close contacts and H-
bonds.
5,11,17,23-Tetrabromo-2,8,14,20-tetraundecylpentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,5,7(28),9,11,
13(27),15,17,19(26),21,23-dodecaene-4,6,10,12,16,18,22,24-octol (all-cis-stereoisomer; 6). NBS (18.50 g, 104.00
mmol) was added portionwise at 358 to a stirred soln. of 4 (10.00 g, 9.00 mmol) in butanone (300 ml), and the
mixture was stirred at 208 for 1 d under Ar in the dark. The formed solid was removed by filtration, washed with

108
Helvetica Chimica Acta ± Vol. 83 (2000)
cold butanone, and dried in vacuo to give 6 (6.69 g, 52%). M.p. 295 ± 2968 (dec.). IR (KBr): 3396s, 2923s, 2852m,
1
1616w, 1471s, 1434m, 1313m, 1156m, 1090w. H-NMR ((CD3)2CO, 500 MHz): 8.28 (s, 8 H); 7.61 (s, 4 H); 4.44
(t, J ˆ 6.5, 4 H); 2.29 ± 2.30 (m, 8 H); 1.30 ± 1.36 (m, 8 H); 1.25 ± 1.30 (m, 64 H); 0.88 (t, J ˆ 6.9, 12 H). 13C-NMR
((CD3)2CO, 125 MHz): 149.69; 126.03; 124.47; 100.90; 34.53; 32.67; 30.52; 30.43; 30.36; 30.20; 30.05; 29.90;
29.74; 28.82; 23.33; 14.35. FAB-MS: 1421.4 (48, MH , C72H10979Br281Br2O8 ), 1342.5 (27, [M ‡ H Br] ), 1265.2
‡
‡
‡
‡
(100, [M ‡ H 2 Br] ), 1185.3 (35). Anal. calc. for C72H108Br4O8 (1421.26): C 60.85, H 7.66, Br 22.49; found:
C 60.96, H 7.57, Br 22.56.
5,11,17,23-Tetrabromo-2,8,14,20-tetrakis(2-phenylethyl)pentacyclo[19.3.1.13,7.19,13.115,19 ]octacosa-
1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,31-dodecaene-4,6,10,12,16,18,22,24-octol (all-cis-stereoisomer; 7).
NBS (185.73 g, 88.0 mmol) was added portionwise to a stirred soln. of 5 (10.00 g, 9.00 mmol) in butanone
(300 ml), and the mixture was stirred at 208 for 1 d under Ar in the dark. The formed solid was removed by filtra-
tion, washed with cold butanone, and dried in vacuo to give 7 (11.80 g, 87%). M.p. 2808 (dec.) ([32]: 2608 (dec.)).
IR (KBr): 3404s, 3024m, 2937m, 2861w, 1613m, 1473s, 1305s, 1201s, 1157s, 1098s, 749m, 699s. 1H-NMR ((CD3)2SO,
300 MHz): 9.24 (s, 8 H); 7.49 (s, 4 H); 7.10 ± 7.20 (m, 20 H); 4.39 (t, J ˆ 6.5, 4 H); 2.45 ± 2.50 (m, 16 H). 13C-NMR
((CD3)2CO/CD3OD 1:1, 125 MHz): 150.10; 143.14; 129.41; 129.30; 126.67; 126.32; 124.40; 100.48; 37.35; 36.84;
35.49. FAB-MS: 1221.0 (67, MH , C60H5379Br281Br2O8 ), 1115.5 (100, [M ‡ H C8H8] ), 1037.4 (19, [M ‡ H
‡
‡
‡
‡
C8H8 Br] ). Anal. calc. for C60H52Br4O8 (1220.68): C 59.04, H 4.29; Br 26.18; found: C 59.01, H 4.22, Br 25.97.
8,13,18,32-Tetrabromo-5,6,10,11,15,16,20,21-octahydro-1,25,27,29-tetraundecyl-2,24:3,23-dimetheno-1H,25H,
27H,29H-bis[1,4]dioxonino[6,5-j:6',5'-j']benzo[1,2-e:5,4-e']bis[1,4]benzodioxonin (all-cis-stereoisomer; 8). A
mixture of dry 6 (3.30 g, 2.32 mmol), TsO(CH2)2OTs (7.11 g, 19.20 mmol), anh. Cs2CO3 (12.12 g, 37.20 mmol),
and dry Me2SO (100 ml) was degassed and stirred under Ar at 658 for 40 h. Filtration through a pad of Celite and
concentration in vacuo left a residue which was mixed with H2O (100 ml) and extracted with CH2Cl2 (3 Â
100 ml). The combined org. layers were washed with H2O (2 Â 100 ml), dried (MgSO4), and concentrated in
vacuo. CC (SiO2; CH2Cl2) afforded 8 (1.20 g, 34%) as a colorless oil besides 10 (1.53 g, 43%) as a white solid. A
mixture of 10 (1.45 g, 965 mmol), TsO(CH2)2OTs (715 mg, 1.93 mmol), anh. Cs2CO3 (1.80 g, 5.52 mmol), and
dry MeCN (30 ml) was degassed and stirred under Ar at 908 for 1 d. Evaporation and workup as described
before yielded 8 (1.29 g, 88%). Colorless oil. IR (KBr): 2918s, 2852s, 1464s, 1439s, 1302m, 1095s, 1061s, 1040m,
881m, 862m, 622m. 1H-NMR (CDCl3, 500 MHz): 7.24 (s, 4 H); 5.26 (t, J ˆ 8.2, 4 H); 4.44 ± 4.47 (m, 8 H); 3.74 ±
3.78 (m, 8 H); 2.03 ± 2.06 (m, 8 H); 1.20 ± 1.34 (m, 72 H); 0.88 (t, J ˆ 7.0, 12 H). 13C-NMR (CDCl3, 75 MHz):
151.65; 137.10; 123.16; 113.29; 70.48; 34.89; 34.21; 31.85; 29.58; 29.55; 29.29; 27.63; 22.58; 13.99. FAB-MS: 1525.8
(100, MH , C80H11779Br281Br2O8 ). Anal. calc. for C80H116Br4O8 (1525.41): C 62.99, H 7.66, Br 20.95; found:
C63.15, H 7.54, Br 20.74.
‡
‡
8,13,18,32-Tetrabromo-5,6,10,11,15,16,20,21-octahydro-1,25,27,29-tetrakis(2-phenylethyl)-2,24:3,23-dimethe-
no-1H,25H,27H,29H-bis[1,4]dioxonino[6,5-j:6',5'-j']benzo[1,2-e:5,4-e']bis[1,4]benzodioxonin
(all-cis-stereo-
isomer; 9). A mixture of dry 7 (18.95 g, 15.52 mmol), TsO(CH2)2OTs (46.0 g, 124.2 mmol), anh. Cs2CO3
(80.9 g, 248.4 mmol), and dry Me2SO (800 ml) was degassed and stirred under Ar at 658 for 4 d. Filtration
through a pad of Celite and concentration in vacuo left a residue, which was mixed with H2O (400 ml) and
extracted with CH2Cl2 (3 Â 350 ml). The combined org. layers were washed with H2O (2 Â 350 ml), dried
(MgSO4), and concentrated in vacuo. CC (SiO2; CH2Cl2) gave 9 (6.65 g, 32%) and 11 (12.16 g, 60%) as white
solids. A mixture of 11 (12.16 g, 9.36 mmol), TsO(CH2)2OTs (7.32 mg, 19.75 mmol), anh. Cs2CO3 (14.86 g,
45.6 mmol), and dry MeCN (300 ml) was degassed and stirred under Ar at 1208 for 3 d. Evaporation in vacuo
and workup as described before yielded 9 (9.38 g, 76%). White solid. M.p. 184 ± 1868. IR (KBr): 2927m, 1774w,
1
1602w, 1496w, 1446s, 1301m, 1097s, 1060s, 881w, 751m, 700s. H-NMR (CDCl3, 500 MHz): 7.31 (s, 4 H); 7.17 ±
7.19 (m, 12 H); 7.07 ± 7.09 (m, 8 H); 5.42 (t, J ˆ 7.9, 4 H); 4.49 ± 4.52 (m, 8 H); 3.81 ± 3.85 (m, 8 H); 2.51 ± 2.55
(m, 8 H); 2.37 ± 2.40 (m, 8 H). 13C-NMR (CDCl3, 125 MHz): 151.75; 141.46; 136.85; 128.49; 128.35; 125.96;
122.87; 113.53; 70.52; 36.79; 35.33; 34.39. FAB-MS: 1325.1 (100, MH , C68H6179Br281Br2O8 ). Anal. calc. for
C68H60Br4O8 (1324.83): C 61.65, H 4.56, Br 24.13; found: C 61.76, H 4.57, Br 24.38. X-ray: see Figure 1.
8,13,18,32-Tetraiodo-5,6,10,11,15,16,20,21-octahydro-1,25,27,29-tetraundecyl-2,24:3,23-dimetheno-1H,25H,
27H,29H-bis[1,4]dioxonino[6,5-j:6',5'-j']benzo[1,2-e:5,4-e']bis[1,4]benzodioxonin (all-cis-stereoisomer; 12).
Dry 8 (4.78 g, 3.13 mmol) was dissolved in dry THF (150 ml) under Ar, and the soln. was cooled to 1008.
BuLi (1.6m in hexane, 19.6 ml, 31.4 mmol) was slowly added, and the mixture was stirred for 35 min. I2 (9.54 g,
37.6 mmol) was added, and the mixture was warmed to 208 and stirred for 12 h, concentrated in vacuo, washed
with sat. aq. NaHSO3 soln. (250 ml), and extracted with CH2Cl2 (3 Â 100 ml). The combined org. layers were
dried (MgSO4) and concentrated in vacuo. CC (SiO2; CH2Cl2) yielded 12 (4.19 g, 78%). Colorless oil, which
solidified upon standing. M.p. 1408. IR (KBr): 2923s, 2852s, 1456m, 1439s, 1094s, 1061s. 1H-NMR (CDCl3,
500 MHz): 7.29 (s,4 H); 5.26 (t, J ˆ 8.1, 4 H); 4.44 ± 4.47 (m, 8 H); 3.74 ± 3.77 (m, 8 H); 2.01 ± 2.06 (m, 8 H);
‡
‡

Helvetica Chimica Acta ± Vol. 83 (2000)
109
1.17 ± 1.35 (m, 72 H); 0.88 (t, J ˆ 7.0, 12 H). 13C-NMR (CDCl3, 125 MHz): 154.37; 136.44; 124.76; 89.86; 70.38;
‡
35.49; 34.78; 31.92; 29.67; 29.66; 29.65; 29.62; 29.38; 27.70; 22.68; 14.10. FAB-MS: 1714.1 (100, MH ). Anal. calc.
for C80H116I4O8 (1713.41): C 56.08, H 6.82, I 29.63; found: C 56.00, H 6.70, I 29.71.
8,13,18,32-Tetraiodo-5,6,10,11,15,16,20,21-octahydro-1,25,27,29-tetrakis(2-phenylethyl)-2,24:3,23-dimetheno-
1H,25H,27H,29H-bis[1,4]dioxonino[6,5-j:6',5'-j']benzo-[1,2-e:5,4-e']bis[1,4]benzodioxonin
(all-cis-stereoiso-
mer; 13). Dry 9 (11.68 g, 8.82 mmol) was dissolved in dry THF (350 ml) under Ar, and the soln. was cooled
to 1008. BuLi (1.6m in hexane, 55.1 ml, 88.2 mmol) was slowly added, and the mixture was stirred for 30 min. I2
(26.85 g, 105.8 mmol) was added, and the mixture was warmed to 208 and stirred for 12 h. The mixture was
concentrated in vacuo, washed with sat. aq. NaHSO3 soln. (300 ml), and extracted with CH2Cl2 (3 Â 200 ml).
The combined org. layers were dried (MgSO4) and concentrated in vacuo. CC (SiO2; CH2Cl2) yielded 13
(11.92 g, 89%). White solid. M.p. 304 ± 3058. IR (KBr): 3023m, 2923s, 1603m, 1496m, 1440s, 1297m, 1095s, 1060s,
862m, 749m, 699s. 1H-NMR (CDCl3, 500 MHz): 7.34 (s, 4 H); 7.17 ± 7.19 (m, 12 H); 7.05 ± 7.08 (m, 8 H); 5.42
(t, J ˆ 7.9, 4 H); 4.49 ± 4.52 (m, 8 H); 3.79 ± 3.83 (m, 8 H); 2.50 ± 2.53 (m, 8 H); 2.34 ± 2.39 (m, 8 H). 13C-NMR
(CDCl3, 125 MHz): 154.65; 141.42; 136.30; 128.49; 128.35; 125.95; 124.51; 90.20; 70.42; 37.30; 35.84; 34.41. FAB-
‡
MS: 1512.5 (100, M ). Anal. calc. for C68H60I4O8 (1512.84): C 53.99, H 4.00, I 33.55; found: C 54.14, H 4.06,
I 33.54.
3-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)benzonitrile (14). BuLi (1.6m in hexane, 30.1 ml, 48.16 mmol)
was added at 1008 under Ar to 3-bromobenzonitrile (3.50 g, 19.23 mmol) in dry THF (150 ml), and the soln.
was stirred for 15 min. B(OMe)3 (22 ml, 193.7 mmol) was added at 1008, and the mixture was slowly warmed
up and stirred for 14 h at 208. After evaporation in vacuo, pinacol (2.80 g, 23.69 mmol), NH4Cl (1 g), and PhMe
(150 ml) were added. The mixture was heated to reflux for 3 h, then concentrated in vacuo. The residue was
suspended in H2O (300 ml), acidified with 2m HCl (30 ml), and extracted with CH2Cl2 (3 Â 100 ml). The
combined org. layers were dried (MgSO4) and concentrated in vacuo. Bulb-to-bulb distillation (1008, 0.1 Torr)
yielded 14 (4.17 g, 95%). White crystals. M.p. 80 ± 818 (hexane). IR (KBr): 2976s, 2227s, 1604s, 1487m, 1421s,
1353s, 1272m, 1147s, 1091m, 966m, 879m, 847m, 804m, 700s, 672m, 560m. 1H-NMR (CDCl3, 200 MHz): 8.08
(br. s, 1 H); 8.00 (d, J ˆ 7.6, 1 H); 7.69 ± 7.74 (m, 1 H); 7.46 (t, J ˆ 7.6, 1 H); 1.34 (s, 12 H). 13C-NMR (CDCl3,
‡
50 MHz): 138.71; 138.36; 134.36; 128.36; 118.78; 112.05; 84.46; 24.81. EI-MS: 229.2 (21, M ); 214.2 (66), 143.1
(100), 130.1 (65). Anal. calc. for C13H16BNO2 (229.09): C 68.16, H 7.04, N 6.11; found: C 68.29, H 7.04, N 6.06.
3,3',3'',3'''-(5,6,10,11,15,16,20,21-Octahydro-1,25,27,29-tetraundecyl-2,24:3,23-dimetheno-1H,25H,27H,29H-
bis[1,4]dioxonino[6,5-j:6',5'-j']benzo[1,2-e:5,4-e']bis[1,4]benzodioxonin-8,13,18,32-tetrayl)tetrakis[benzonitrile]
(all-cis-stereoisomer; 15). A degassed mixture of 12 (7.00 g, 4.09 mmol), 14 (9.36 g, 40.9 mmol), Cs2CO3
(19.97 g, 61.3 mmol), [PdCl2(PPh3)2] (720 mg, 1.00 mmol), AsPh3 (2.40 g, 7.80 mmol), dioxane (180 ml), and
H2O (7.2 ml) was stirred under Ar at 758 for 3 h. After cooling to 208, H2O (200 ml) was added and the
precipitated solid was collected by filtration, washed with H2O, and dried in vacuo. CC (SiO2; CH2Cl2 ! CH2Cl2/
AcOEt 98 :2) yielded 15 (5.29 g, 80%). White solid. M.p. 237 ± 2388. IR (KBr): 2922s, 2852s, 2230m, 1603w,
1579w, 1458s, 1265m, 1095s, 1063s, 1043m, 796m. 1H-NMR (CDCl3, 500 MHz): 7.65 (td, J ˆ 7.7, 1.3, 4 H); 7.62
(s, 4 H); 7.50 (t, J ˆ 7.7, 4 H); 7.47 (br. s, 4 H); 7.41 (d, J ˆ 7.7, 4 H); 5.23 (t, J ˆ 8.1, 4 H); 3.82 ± 3.86 (m, 8 H);
3.34 ± 3.38 (m, 8 H); 2.19 ± 2.23 (m, 8 H); 1.39 ± 1.40 (m, 8 H); 1.25 ± 1.30 (m, 64 H); 0.88 (t, J ˆ 7.0, 12 H).
13C-NMR (CDCl3, 125 MHz): 151.53; 136.50; 136.37; 134.23; 133.24; 131.26; 129.00; 128.90; 124.85; 118.45;
‡
112.38; 72.25; 34.74; 33.88; 31.94; 29.74; 29.72; 29.69; 29.41; 27.93; 22.69; 14.10. FAB-MS: 1615.2 (100, MH ,
‡
C10713CH133N4O8 ). Anal. calc. for C108H132N4O8 (1614.25): C 80.36, H 8.24, N 3.47; found: C 80.25, H 8.14,
N 3.41.
3,3',3'',3'''-[5,6,10,11,15,16,20,21-Octahydro-1,25,27,29-tetrakis(2-phenylethyl)-2,24:3,23-dimetheno-1H,25H,
27H,29H-bis[1,4]dioxonino[6,5-j:6',5'-j']benzo[1,2-e:5,4-e']bis[1,4]benzodioxonin-8,13,18,32-tetrayl]tetrakis[ben-
zonitrile] (all-cis-stereoisomer; 16). A degassed mixture of 13 (6.54 g, 4.32 mmol), 14 (9.90 g, 43.2 mmol),
Cs2CO3 (21.11 g, 64.8 mmol), [PdCl2(PPh3)2] (250 mg, 0.35 mmol), AsPh3 (1.00 g, 3.25 mmol), dioxane
(170 ml), and H2O (6.8 ml) was stirred under Ar at 758 for 3 h. After cooling to 208, ice (180 g) was added,
and the solid was collected by filtration, washed with H2O, and dissolved in CH2Cl2 (250 ml). The soln. was
filtered, dried (MgSO4), and concentrated in vacuo. CC (SiO2; CH2Cl2/AcOEt 98 :2) afforded 16 (5.17 g, 85%).
White solid. M.p. 355 ± 3578. IR (KBr): 2926m, 2228m, 1602w, 1581w, 1496w, 1455s, 1442s, 1268m, 1235w, 1096s,
1063s, 864w, 800m, 751m, 699s. 1H-NMR (CDCl2CDCl2, 500 MHz): 7.66 (s, 4 H); 7.57 (d, J ˆ 7.7, 4 H); 7.43
(t, J ˆ 7.7, 4 H); 7.37 ± 7.38 (m,8 H); 7.04 ± 7.08 (m, 20 H); 5.28 (t, J ˆ 7.9, 4 H); 3.75 ± 3.76 (m, 8 H); 3.26 ± 3.28
(m, 8 H); 2.48 ± 2.52 (m, 16 H). 13C-NMR (CDCl2CDCl2, 125 MHz): 151.95; 142.02; 136.52; 136.48; 134.70;
133.54; 131.64; 129.42; 129.23; 128.83; 126.82; 126.32; 124.88; 119.15; 112.29; 72.59; 37.33; 34.86; 34.50. FAB-
‡
MS: 1413.2 (100, M ). Anal. calc. for C96H76N4O8 ´ H2O (1413.70 ‡ 18.02): C 80.54, H 5.49, N 3.91; found:
C 80.64, H 5.64, N 3.89.

110
Helvetica Chimica Acta ± Vol. 83 (2000)
3,3',3'',3'''-(5,6,10,11,15,16,20,21-Octahydro-1,25,27,29-tetraundecyl-2,24:3,23-dimetheno-1H,25H,27H,29H-
bis[1,4]dioxonino[6,5-j:6',5'-j']benzo[1,2-e:5,4-e']bis[1,4]benzodioxonin-8,13,18,32-tetrayl)tetrakis[benzamidin-
ium] Tetrachloride (all-cis-stereoisomer; 1). A suspension of NH4Cl (5.79 g, 108.2 mmol) in 1,2-dichlorobenzene
(45 ml) was slowly added at 108 under Ar to Me3Al (2m in PhMe, 50 ml, 100.0 mmol), and the mixture was
stirred at 208 for 2 h, then evaporated at 208/0.1 Torr to give MeAlNH2Cl. A suspension of 15 (5.29 g,
3.28 mmol) in a soln. of MeAlNH2Cl (2.2m in 1,2-dichlorobenzene, 45 ml, 100.0 mmol) was stirred under Ar at
708 for 1 d, additional MeAlNH2Cl (2.2m in 1,2-dichlorobenzene, 45 ml, 100.0 mmol) was added, and the
mixture was stirred at 808 for 5 d. The mixture was cooled to 08, ice (100 g) and MeOH (50 ml) were slowly
added, and the suspension was filtered through a pad of Celite. The solid was washed with MeOH (500 ml), and
the combined filtrates were concentrated in vacuo. The residue was dried in vacuo (0.01 Torr), stirred in a
mixture of acetone (200 ml) and i-PrOH (0.2 ml) at 208 for 8 h, and filtered. The solid was washed with acetone
(500 ml), dried, and washed with H2O (500 ml). Recrystallization (MeOH/Et2O 2 :3) afforded 1 (4.22 g, 70%).
White solid. M.p. >3008 (dec.). IR (KBr): 3406s, 2923s, 2853m, 1674s, 1458m, 1439m, 1093m. 1H-NMR
(CD3OD, 500 MHz): 7.84 (td, J ˆ 7.9, 1.5, 4 H); 7.78 (br. s, 8 H); 7.74 (s, 4 H); 7.66 (t, J ˆ 7.9, 4 H); 5.32 (t, J ˆ 8.1,
4 H); 3.72 ± 3.76 (m, 8 H); 3.56 ± 3.60 (m, 8 H); 2.29 ± 2.33 (m, 8 H); 1.47 ± 1.49 (m, 8 H); 1.38 (br. s, 64 H); 0.95
(t, J ˆ 7.0, 12 H). 13C-NMR (CD3OD, 125 MHz): 167.98; 153.07; 138.47; 137.41; 131.85; 130.57; 129.94; 129.07;
127.98; 125.94; 73.49; 35.52; 35.34; 33.16; 30.90; 30.87; 30.77; 30.59; 29.25; 23.80; 14.52. FAB-MS: 1682.0/1683.0
‡
‡
‡
(91/100, [M 3 H 4 Cl] ). HR-FAB-MS: 1682.1199 [M 3 H 4 Cl] , C108H145N8O8 ; calc. 1682.1185). Anal.
calc. for C108H148N8O8Cl4 ´ 1.5 CH3OH (1828.22 ‡ 24.03): C 70.10, H 8.27, N 5.97; found: C 70.11, H 8.19, N 5.99.
3,3',3'',3'''-[5,6,10,11,15,16,20,21-Octahydro-1,25,27,29-tetrakis(2-phenylethyl)-2,24:3,23-dimetheno-1H,25H,
27H,29H-bis[1,4]dioxonino[6,5-j:6',5'-j']benzo[1,2-e:5,4-e']bis[1,4]benzodioxonin-8,13,18,32-tetrayl]tetrakis[benz-
amidininium] Tetrachloride (all-cis-stereoisomer; 2). Me3Al (2m in PhMe, 50 ml, 100.0 mmol) was slowly added
to a suspension of NH4Cl (5.79 g, 108.2 mmol) in 1,2-dichlorobenzene (45 ml) at 108 under Ar, and the
mixture was stirred at 208 for 2 h, then evaporated at 208/0.1 Torr. A suspension of 16 (5.29 g, 3.74 mmol) in a
soln. of MeAlNH2Cl (2.2m in 1,2-dichlorobenzene, 45 ml, 100.0 mmol) was stirred under Ar at 808 for 1 d, then
additional MeAlNH2Cl (2.2m in 1,2-dichlorobenzene, 45 ml, 100.0 mmol) was added, and the mixture was
stirred at 808 for 3 d. After cooling to 08, ice (100 g) and MeOH (50 ml) were slowly added, and the suspension
was filtered through a pad of Celite. The solid was washed with MeOH (500 ml), and the combined filtrates were
concentrated in vacuo. The residue was dried in vacuo (0.01 Torr), stirred at 208 for 8 h with a mixture of
acetone (200 ml) and i-PrOH (0.2 ml), and filtered. The solid was washed with acetone (500 ml), dried, and
washed with H2O (500 ml). The obtained solid was recrystallized (MeOH/Et2O 1:2) to provide 2 (4.81 g, 79%).
White solid. M.p. 327 ± 3298 (dec.). IR (KBr): 3382 (br.), 3111s (br.), 1675s, 1455m, 1094m, 700m. 1H-NMR
(CD3OD, 500 MHz): 7.82 ± 7.87 (m, 16 H); 7.68 (t, J ˆ 8.0, 4 H); 7.17 ± 7.22 (m, 20 H); 5.43 (t, J ˆ 7.2, 4 H); 3.73 ±
3.77 (m, 8 H); 3.59 ± 3.64 (m, 8 H); 2.60 ± 2.64 (m, 16 H). 13C-NMR (CD3OD, 125 MHz): 167.96; 153.29; 143.35;
138.43; 137.44; 137.34; 132.01; 130.58; 129.99; 129.54; 129.51; 129.05; 128.03; 126.91; 126.04; 73.53; 38.18; 35.68;
‡
35.49. FAB-MS: 1482.6 (100, [M 3 H 4 Cl] ). Anal. calc. for C96H92Cl4N8O8 ´ 2 CH3OH (1627.64 ‡ 32.04):
C 69.66, H 5.85, N 6.63; found: C 69.48, H 5.98, N 6.55.
5,11,17,23-Tetrabromo-2,8,14,20-tetrakis(3-hydroxypropyl)pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,5,
7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-4,6,10,12,16,18,22,24-octol (all-cis-stereoisomer; 18). NBS
(11.1 g, 62.4 mmol) was added at 208 to a suspension of 17 (10.00 g, 13.9 mmol) in butanone (133 ml) and
MeOH (57 ml), and the soln. was stirred in the dark for 3 h. Additional NBS (4.93 g, 27.7 mmol) was added, and
the mixture was stirred in the dark for additional 12 h. The formed solid was isolated by filtration, washed with
cold butanone, and dried in vacuo to yield 18 (11.10 g,77%). White powder. M.p. 282 ± 2838 (dec.) ([24]: 2208
(dec.)). 1H-NMR (CD3OD, 200 MHz): 7.15 (s, 4 H); 4.50 (t, J ˆ 7.7, 4 H); 3.61 (t, J ˆ 6.4, 8 H); 2.13 ± 2.24
(m, 8 H); 1.47 ± 1.54 (m, 8 H).
3,3',3'',3'''-(8,13,18,32-Tetrabromo-5,6,10,11,15,16,20,21-octahydro-2,24:3,23-dimetheno-1H,25H,27H,29H-
bis[1,4]dioxonino[6,5-j:6',5'-j']benzo[1,2-e:5,4-e']bis[1,4]benzodioxonin-1,25,27,29-tetrayl)tetrakis[propanol] (all-
cis-stereoisomer; 19). A soln. of 18 (11.19 g, 10.8 mmol) in DMA (50 ml) was added at 208 under Ar via
syringe pump over 2 d to a mixture of TsO(CH2)2OTs (18.00 g, 48.6 mmol), anh. Cs2CO3 (45.74 g, 140.4 mmol),
and BHT (1 mg) in dry DMA (400 ml). The suspension was stirred at 208 for 1 d, additional TsO(CH2)2OTs
(12.00 g, 32.4 mmol) and anh. Cs2CO3 (40.00 g, 122.8 mmol) were added, and stirring was continued at 458 for
1 d. Additional TsO(CH2)2OTs (12.00 g, 32.4 mmol) and anh. K2CO3 (43.70 g, 316.2 mmol) were added, and the
mixture was stirred at 658 for 3 d. After evaporation in vacuo, the solid residue was stirred with H2O (1 l) at 208
for 2 d, filtered, and dried. The solid was heated to reflux in dioxane (400 ml), the insoluble part was filtered off,
and the filtrate was concentrated in vacuo. CC (SiO2; CH2Cl2/MeOH 95 :5 ! 90 :10) and recrystallization
(dioxane/PhMe/CH2Cl2 1:10 :10) afforded 19 (5.14g, 42%).White solid. M.p. 380 ± 3908. IR (Br): 3421s, 2932m,

Helvetica Chimica Acta ± Vol. 83 (2000)
111
2869m, 1447s, 1302m, 1100m, 1058s. 1H-NMR ((CD3)2SO, 500 MHz): 7.82 (s, 4 H); 5.11 (t, J ˆ 8.3, 4 H); 4.38
(t, J ˆ 5.0, 4 H); 4.29 ± 4.33 (m, 8 H); 3.69 ± 3.73 (m, 8 H); 3.40 ± 3.43 (m,8 H); 2.48 ± 2.50 (m, 8 H); 1.24 ± 1.30
(m, 8 H). 13C-NMR ((CD3)2SO, 125 MHz): 150.99; 136.60; 124.97; 112.57; 70.36; 60.27; 34.63; 30.83; 29.45.
FAB-MS: 1140.0 (53, M ), 955.5 (100). HR-FAB-MS: 1140.0150 (M , C48H5279Br281Br2O12 ; calc. 1140.0151).
8,13,18,32-Tetrabromo-5,6,10,11,15,16,20,21-octahydro-2,24:3,23-dimetheno-1H,25H,27H,29H-bis[1,4-diox-
onino][6,5-j:6',5'-j']benzo[1,2-e:5,4-e']bis[1,4-benzodioxonin]-1,25,27,29-tetrayltetrakis[propane-1,3-diyl]tetra-
kis[methanesulfonate] (all-cis-stereoisomer; 20). MsCl (2.5 ml, 32.2 mmol) was added via syringe pump over
40 min at 08 under Ar to 19 (500 mg, 438 mmol) in dry dioxane (40 ml) and Et3N (20 ml), and the suspension
was stirred for 3 h at 208. After addition of ice (100 g), the mixture was extracted with CH2Cl2 (3 Â 100 ml). The
combined org. layers were washed with sat. aq. NH4Cl soln. (100 ml), sat. aq. NaHCO3 soln. (100 ml), dried
(Na2SO4), and concentrated in vacuo. CC (SiO2; CH2Cl2/AcOEt 85 :15 ! 75 :25) yielded 20 (589 mg, 92%).
White solid. M.p. 160 ± 1658. IR (KBr): 2936m, 1461s, 1446s, 1351s, 1173s, 1102m, 1058s, 937s, 528s. 1H-NMR
(CDCl3, 500 MHz): 7.40 (s, 4 H); 5.29 (t, J ˆ 8.4, 4 H); 4.45 ± 4.48 (m, 8 H); 4.31 (t, J ˆ 6.1, 8 H); 3.76 ± 3.80
(m, 8 H); 3.06 (s, 12 H); 2.26 ± 2.31 (m, 8 H); 1.63 ± 1.67 (m, 8 H). 13C-NMR (CDCl3, 125 MHz): 151.73; 136.42;
‡
‡
‡
‡
123.32; 113.45; 70.55; 70.33; 37.42; 34.57; 29.80; 27.44. FAB-MS: 1451.7 (100, M ). HR-FAB-MS: 1449.9273
(M , C52H6079Br381BrO20S4 ; calc. 1449.9274); 1451.9249 (M , C52H6079Br281Br2O20S4 ; calc. 1451.9253).
8,13,18,32-Tetrabromo-5,6,10,11,15,16,20,21-octahydro-1,25,27,29-tetrakis(3-{2-[2-(2-methoxyethoxy)eth-
oxy]ethoxy}propyl)-2,24:3,23-dimetheno-1H,25H,27H,29H-bis[1,4]dioxonino[6,5-j:6',5'-j']benzo[1,2-e:5,4-
e']bis[1,4]benzodioxonin (all-cis-stereoisomer; 21). Mg (1.00 g, 41.1 mmol) was activated with a crystal of I2 at
2008, triethyleneglycol monomethyl ether (15 ml, 95.7 mmol) was added, and the suspension was stirred at 1408
for 1.5 h. After cooling to 208, dioxane (10 ml) was added to yield a soln. of 22. This soln. (41.1 mmol) was added
to 20 (1.20 g, 826 mmol) in dioxane (20 ml), and the mixture was stirred at 608 for 16 h. The residue obtained by
evaporation in vacuo was dissolved in AcOEt (60 ml), the resulting soln. was washed with sat. aq. NH4Cl soln.
(100 ml), and the aq. layer was extracted with AcOEt (4 Â 100 ml). The combined org. layers were washed with
sat. aq. NaHCO3 soln. (150 ml) and H2O (150 ml). The combined aq. layers were extracted with AcOEt (3 Â
80 ml). The combined org. layers were dried (MgSO4) and concentrated in vacuo, and the residue was dried at
1608 (bulb-to-bulb, 0.1 Torr). CC (SiO2; CH2Cl2/MeOH 98 :2 ! 94 :6) yielded 21 (1.11 g, 78%). Colorless,
viscous oil. IR (KBr): 2922s, 2868s, 1448s, 1349m, 1302m, 1246m, 1102s, 1056s, 934m, 862m, 623m. 1H-NMR
(CDCl3, 500 MHz): 7.19 (s, 4 H); 5.25 (t, J ˆ 8.2, 4 H); 4.38 ± 4.42 (m, 8 H); 3.70 ± 3.74 (m, 8 H); 3.48 ± 3.61
(m, 48 H); 3.44 (t, J ˆ 6.5, 8 H); 3.31 (s, 12 H); 2.08 ± 2.10 (m, 8 H); 1.43 ± 1.46 (m, 8 H). 13C-NMR (CDCl3,
125 MHz): 151.46; 136.57; 122.78; 113.17; 71.73; 70.41; 70.38; 70.35; 70.31; 70.28; 69.88; 58.82; 34.23; 30.29; 27.29.
‡
‡
‡
‡
‡
FAB-MS: 1725.4 (100, MH ).
8,13,18,32-Tetraiodo-5,6,10,11,15,16,20,21-octahydro-1,25,27,29-tetrakis(3-{2-[2-(2-methoxyethoxy)ethoxy]eth-
oxy}propyl)-2,24:3,23-dimetheno-1H,25H,27H,29H-bis[1,4]dioxonino[6,5-j:6',5'-j']benzo[1,2-e:5,4-e']bis[1,4]ben-
zodioxonin (all-cis-stereoisomer; 23). BuLi (1.6m in hexane, 13.5 ml, 21.6 mmol) was added at 1008 under Ar
to dry 21 (3.24 g, 1.88 mmol) in dry THF (100 ml), and the soln. was stirred for 30 min at 1008. I2 (6.67 g,
26.3 mmol) was added at 1008, then the mixture was slowly warmed to 208 and stirred for 2 h. Evaporation in
vacuo provided a residue which was dissolved in CH2Cl2 (100 ml). The soln. was washed with sat. aq. NaHSO3
soln. (100 ml), and the aq. layer was extracted with CH2Cl2 (4 Â 100 ml). The combined org. layers were dried
(MgSO4) and concentrated in vacuo. CC (SiO2; CH2Cl2/MeOH 98 :2 ! 95 :5) yielded 23 (3.50 g, 97%).
Colorless, viscous oil. IR (KBr): 2922s, 2868s, 1441s, 1349m, 1297m, 1104s, 1033s, 932m, 860m, 619m. 1H-NMR
(CDCl3, 500 MHz): 7.23 (s, 4 H); 5.24 (t, J ˆ 8.2, 4 H); 4.37 ± 4.41 (m, 8 H); 3.69 ± 3.71 (m, 8 H); 3.47 ± 3.61
(m, 48 H); 3.43 (t, J ˆ 6.5, 8 H); 3.31 (s, 12 H); 2.04 ± 2.09 (m, 8 H); 1.41 ± 1.44 (m, 8 H). 13C-NMR (CDCl3,
125 MHz): 154.30; 135.98; 124.40; 89.79; 71.68; 70.36; 70.33; 70.29; 70.26; 70.14; 69.82; 58.79; 34.71; 30.74; 27.25.
‡
‡
‡
FAB-MS: 1914.1 (100, MH ). HR-FAB-MS: 1913.3501 (MH , C76H109I4O24 ; calc. 1913.3488).
3,3',3'',3'''-{5,6,10,11,15,16,20,21-Octahydro-1,25,27,29-tetrakis(3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}prop-
yl)-2,24:3,23-dimetheno-1H,25H,27H,29H-bis[1,4]dioxonino[6,5-j:6',5'-j']benzo[1,2-e:5,4-e']bis[1,4]benzodiox-
onin-8,13,18,32-tetrayl}tetrakis[benzonitrile] (all-cis-stereoisomer; 24). A degassed mixture of 23 (760 mg,
397 mmol), 14 (910 mg, 3.97 mmol), Cs2CO3 (1.94 g, 5.96 mmol), [PdCl2(PhCN)2] (30 mg, 78 mmol), AsPh3
(150 mg, 490 mmol), dioxane (9.6 ml), and H2O (0.4 ml) was stirred under Ar at 708 for 2 h. The mixture was
cooled to 208 and filtered through a pad of Celite and MgSO4 (1:1) using CH2Cl2 (200 ml) and AcOEt (100 ml).
After evaporation in vacuo, CC (SiO2; CH2Cl2/MeOH 98 :2 ! 95 :5) provided 24 (607 mg, 84%). Colorless
viscous oil which solidified upon standing. M.p. 78 ± 808. IR (KBr): 2922s, 2868s, 2228m, 1457s, 1443s, 1266m,
1100s. 1H-NMR (CDCl3, 500 MHz): 7.62 (d, J ˆ 7.8, 4 H); 7.60 (s, 4 H); 7.49 (t, J ˆ 7.8, 4 H); 7.45 (s,4 H); 7.42
(d, J ˆ 7.8, 4 H); 5.25 (t, J ˆ 8.1, 4 H); 3.80 ± 3.83 (m, 8 H); 3.51 ± 3.65 (m, 64 H); 3.35 (s, 12 H); 2.24 ± 2.28
(m, 8 H); 1.54 ± 1.59 (m, 8 H). 13C-NMR (CDCl3, 125 MHz): 151.61; 136.34; 136.00; 134.28; 133.13; 131.16;

112
Helvetica Chimica Acta ± Vol. 83 (2000)
129.05; 128.88; 124.57; 118.37; 112.16; 72.16; 71.84; 70.68; 70.51; 70.49; 70.42; 69.99; 58.92; 33.32; 30.78; 27.67.
‡
‡
‡
‡
FAB-MS: 1815.0 (100, MH ). HR-FAB-MS: 1813.8656 (MH , C104H125N4O24
; calc. 1813.8684; M ,
C10313CH124N4O24 ; calc. 1813.8639).
‡
3,3',3'',3'''-{5,6,10,11,15,16,20,21-Octahydro-1,25,27,29-tetrakis(3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}prop-
yl)-2,24:3,23-dimetheno-1H,25H,27H,29H-bis[1,4]dioxonino[6,5-j:6',5'-j']benzo[1,2-e:5,4-e']bis[1,4]benzodiox-
onin-8,13,18,32-tetrayl}tetrakis[benzamidininium] Tetrachloride (all-cis-stereoisomer; 3). MeAlNH2Cl (2m in
1,2-dichlorobenzene, 30 ml, 60.0 mmol) was added to 24 (2.78 g, 1.53 mmol) in dry 1,2-dichlorobenzene (20 ml),
and the mixture was stirred under Ar at 708 for 1 d. Additional MeAlNH2Cl (2m in 1,2-dichlorobenzene, 30 ml,
60.0 mmol) was added, and stirring was continued at 808 for 2 d. After cooling to 08, ice (50 g) and MeOH
(20 ml) were slowly added, and the suspension was filtered through a pad of Celite. The solid was washed with
MeOH (500 ml), and the combined filtrates were concentrated in vacuo. The residue was dried in vacuo
(0.01 Torr), stirred with PhMe (300 ml) at 208 for 4 h, and filtered. The solid was washed with PhMe (200 ml),
dried, washed with cold 20% aq. NaOH soln. (100 ml) and H2O (800 ml). The residue was dissolved in MeOH
(50 ml), 6m ethanolic HCl soln. (3 ml) was added, and the solvents were removed in vacuo. The product was
dried in vacuo (0.05 Torr) and recrystallized (MeOH/Et2O 1:4) to afford 3 (2.83 g, 91%). White solid. M.p.
1
306 ± 3108 (dec.). IR (KBr): 3104 (br.), 2932s, 2867s, 1677s, 1521m, 1457m, 1097s. H-NMR (D2O, 500 MHz):
8.01 (s, 4 H); 7.87 (d, J ˆ 7.7, 4 H); 7.70 (t, J ˆ 7.7, 4 H); 7.63 (d, J ˆ 7.7, 4 H); 7.62 (s, 4 H); 5.25 (t, J ˆ 8.2, 4 H);
3.84 ± 3.86 (m, 8 H); 3.53 ± 3.72 (m, 64 H); 3.34 (s, 12 H); 2.45 ± 2.48 (m, 8 H); 1.61 ± 1.75 (m, 8 H). 13C-NMR
(CD3OD, 125 MHz): 167.93; 153.21; 138.45; 137.41; 137.30; 131.90; 130.62; 129.95; 129.05; 127.99; 126.08; 73.51;
72.96; 71.83; 71.63; 71.59; 71.56; 71.38; 71.30; 59.11; 34.90; 31.54; 29.16. FAB-MS: 1882.9 (100, [M 3 H
‡
‡
‡
4 Cl] ). HR-FAB-MS: 1881.9748 ([M 3H 4 Cl] , C104H137N8O24
; calc. 1881.9746). Anal. calc. for
C104H140Cl4N8O24 ´ 0.5 H2O (2028.10 ‡ 9.01): C 61.29, H 7.42, N 5.50; found: C 61.10, H 7.16, N 5.02.
X-Ray Crystal Structure of 9 ´ 2 CH2Cl2. X-Ray crystal data for C71H66Br4Cl6O8 (Mr ˆ 1579.58): monoclinic
space group P21/c, Dc ˆ 1.568 g cm 3, Z ˆ 4, a ˆ 16.853(9), b ˆ 16.312(10), c ˆ 24.37(2) Š, b ˆ 92.97(5)8, Vˆ
6691(7) Š3, MoKa radiation, l ˆ 0.71073 Š, 1.67 ꢀ q ꢀ 20.048, 2913 unique reflections, Tˆ 293 K. The structure
was solved by direct methods (SHELXS 86) and refined by full-matrix least-squares analysis (SHELXL-93).
All heavy atoms were refined anisotropically; H-atoms fixed isotropically, H-positions are based on
stereochemical considerations. Final R(F) ˆ 0.0361, wR(F2) ˆ 0.0764 for 746 parameters and 2913 reflections
with I > 2s(I). C Cl Distances of the solvent molecules are restrained to be equal. Crystallographic data
(excluding structure factors) for compound 9 ´ 2 CH2Cl2 have been deposited with the Cambridge Crystallo-
graphic Data Centre as deposition No. CCDC-137143. Copies of the data can be obtained, free of charge, on
application to the CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax: ‡ 44 (1223) 336033; e-mail:
deposit@ccdc.cam.ac.uk).
This work was supported by F. Hoffmann-La Roche AG, Basel.
REFERENCES
[1] L. Sebo, B. Schweizer, F. Diederich, Helv. Chim. Acta, 2000, 83, 80.
[2] D. J. Cram, J. M. Cram, ꢁContainer Molecules and Their Guestsꢀ, The Royal Society of Chemistry,
Cambridge, 1994.
[3] J. Rebek, Jr., Acc. Chem. Res. 1999, 32, 278.
[4] P. Timmerman, W. Verboom, D. N. Reinhoudt, Tetrahedron 1996, 52, 2663.
[5] J. C. Sherman, Tetrahedron 1995, 51, 3395.
[6] V. Böhmer, Angew. Chem. 1995, 107, 785; ibid., Int. Ed. 1995, 34, 713.
[7] P. D. Beer, P. A. Gale, D. K. Smith, ꢁSupramolecular Chemistryꢀ, Oxford University Press, New York, 1999;
F. P. Schmidtchen, M. Berger, Chem. Rev. 1997, 97, 1609; C. Seel, A. Galan, J. de Mendoza, Top. Curr. Chem.
1995, 175, 101.
[8] F. Diederich, D. B. Smithrud, E. M. Sanford, T. B. Wyman, S. B. Ferguson, D. R. Carcanague, I. Chao, K. N.
Houk, Acta Chem. Scand. 1992, 46, 205; D. B. Smithrud, T. B. Wyman, F. Diederich, J. Am. Chem. Soc.
1991, 113, 5420; D. B. Smithrud, F. Diederich, J. Am. Chem. Soc. 1990, 112, 339.
[9] D.-R. Ahn, T. W. Kim, J.-I. Hong, Tetrahedron Lett. 1999, 40, 6045.
[10] A. R. Mezo, J. C. Sherman, J. Org. Chem. 1998, 63, 6824; M. H. B. G. Gansey, F. K. G. Bakker, M. C.
Feiters, H. P. M. Geurts, W. Verboom, D. N. Reinhoudt, Tetrahedron Lett. 1998, 39, 5447.
[11] P. J. Dandliker, F. Diederich, A. Zingg, J.-P. Gisselbrecht, M. Gross, A. Louati, E. Sanford, Helv. Chim. Acta
1997, 80, 1773; T. Habicher, F. Diederich, V. Gramlich, Helv. Chim. Acta 1999, 82, 1066.

Helvetica Chimica Acta ± Vol. 83 (2000)
113
[12] B. Dietrich, M. W. Hosseini, J.-M. Lehn, R. B. Sessions, J. Am. Chem. Soc. 1981, 103, 1282; M. W. Hosseini,
A. J. Blacker, J.-M. Lehn, J. Chem. Soc., Chem. Commun. 1988, 596; M. W. Hosseini, A. J. Blacker, J.-M.
Lehn, J. Am. Chem. Soc. 1990, 112, 3896; M. Dhaenens, J.-M. Lehn, J.-P. Vigneron, J. Chem. Soc., Perkin
Trans. 2 1993, 1379.
[13] B. Dietrich, T. M. Fyles, J.-M. Lehn, L. G. Pease, D. L. Fyles, J. Chem. Soc., Chem. Commun. 1978, 934.
[14] H.-J. Schneider, T. Blatter, B. Palm, U. Pfingstag, V. Rüdiger, I. Theis, J. Am. Chem. Soc. 1992, 114, 7704.
[15] H. Furuta, M. J. Cyr, J. L. Sessler, J. Am. Chem. Soc. 1991, 113, 6677.
[16] Y. Kato, M. M. Conn, J. Rebek, Jr., J. Am. Chem. Soc. 1994, 116, 3279.
[17] P. Schiessl, F. P. Schmidtchen, J. Org. Chem. 1994, 59, 509.
[18] T. Li, F. Diederich, J. Org. Chem. 1992, 57, 3449; T. Li, S. J. Krasne, B. Persson, H. R. Kaback, F. Diederich,
J. Org. Chem. 1993, 58, 380.
[19] L. M. Tunstad, J. A. Tucker, E. Dalcanale, J. Weiser, J. A. Bryant, J. C. Sherman, R. C. Helgeson, C. B.
Knobler, D. J. Cram, J. Org. Chem. 1989, 54, 1305.
[20] D. J. Cram, S. Karbach, H.-E. Kim, C. B. Knobler, E. F. Maverick, J. L. Ericson, R. C. Helgeson, J. Am.
Chem. Soc. 1988, 110, 2229.
[21] N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457.
[22] F. Diederich, P. J. Stang (Eds.), ꢁMetal-catalyzed Cross-coupling Reactionsꢀ, Wiley-VCH, Weinheim, 1998.
[23] R. S. Garigipati, Tetrahedron Lett. 1990, 31, 1969; R. A. Moss, W. Ma, D. C. Merrer, S. Xue, Tetrahedron
Lett. 1995, 36, 8761.
[24] B. C. Gibb, R. G. Chapman, J. C. Sherman, J. Org. Chem. 1996, 61, 1505.
[25] R. A. Binstead, A. D. Zuberbühler, SPECFIT V. 2.11 for MS-DOS, Spectrum Software Associates, 1997.
[26] K. A. Connors, ꢁBinding Constants: The Measurement of Molecular Complex Stabilityꢀ, Wiley, New York,
1987.
[27] F. Mohamadi, N. G. J. Richards, W. C. Guida, R. Liskamp, M. Lipton, C. Caufield, G. Chang, T.
Hendrickson, W. C. Still, J. Comput. Chem. 1990, 11, 440.
[28] S. J. Weiner, P. A. Kollman, D. A. Case, U. C. Singh, C. Ghio, G. Alagona, S. J. Profeta, P. Weiner, J. Am.
Chem. Soc. 1984, 106, 765; D. Q. McDonald, W. C. Still, Tetrahedron Lett. 1992, 33, 7743.
[29] W. C. Still, A. Tempczyk, R. C. Hawley, T. Hendrickson, J. Am. Chem. Soc. 1990, 112, 6127.
[30] ꢁThe Merck Indexꢀ, 11th edn., S. Budavari (Ed.) Merck & Co, Rahway, 1989, Compound number 9684,
p. 1536.
[31] Quantum Soft, proFit V. 5.0.1 ppc, Cherwell Scientific Publishing, Frankfurt, 1996.
[32] J. C. Sherman, C. B. Knobler, D. J. Cram, J. Am. Chem. Soc. 1991, 113, 2194.
Received November 25, 1999