New calix[4]arene-cored peripherally functionalized dendrimers: Synthesis and conformational characteristics

Article abstract of DOI:10.1002/hlca.201400304

Abstract New calixarene-based dendrimers, containing calix[4]arene as the core and different generations of Fréchet-type poly(benzyl ether) dendrons as building blocks, which possess either Br-atoms or COO^tBu groups at their surface were synthe

Full text of DOI:10.1002/hlca.201400304

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New Calix[4]arene-Cored Peripherally Functionalized Dendrimers: Synthesis
and Conformational Characteristics
by Georgios Paraskevopoulosa), Dimitrios Alivertisb), Vassiliki Theodoroua), and
Konstantinos Skobridis*a)
a) Department of Chemistry, University of Ioannina, GR-45110 Ioannina
(phone: þ 30-265-1008598; fax: þ 30-265-1008682; e-mail: kskobrid@cc.uoi.gr)
b) Department of Biological Applications and Technology, University of Ioannina, GR-45110 Ioannina
New calixarene-based dendrimers, containing calix[4]arene as the core and different generations of
FrØchet-type poly(benzyl ether) dendrons as building blocks, which possess either Br-atoms or COOtBu
groups at their surface were synthesized and presented herein for the first time. The new calix[4]arene-
cored dendritic macromolecules were fully characterized and found to prefer strictly the cone con-
formation.
Introduction. – Since their discovery [1], dendrimers have attracted great attention
as a new line of molecular structures opening numerous innovating and promising
applications. Excellent reviews and book chapters, over the past decade, describe and
analyze the use of dendrimers in chemical applications, as well as, in the interface of
chemistry and biology [2]. Dendritic architectures can be formed following the
divergent and/or the convergent approach. The class of poly(benzyl ether) dendrimers,
which was presented for the first time by Hawker and FrØchet [3], is a prototype of the
convergent synthetic approach and can be used for the formation of dendritic shells.
The ability of peripheral modifications allows particular architectures to be optimized
in different ways and the final macromolecules to possess lipophilic, hydrophilic or
amphiphilic characteristics. The attachment of these dendrons to different cores
opened the way for expanding their applications [4]. Moreover, the combination of
dendritic molecules and other macromolecular structures as building blocks, such as
macrocyclic compounds, is considered as an attractive approach to the study of
hostÀguest chemistry [5]. These observations indicate that mono- or poly-functional-
ization of dendrimers with active moieties and/or functional groups can occur either to
the core, the branching units, the periphery or as a combination of these.
In previous publications, we reported the synthesis and the specific cation-binding
properties of poly(benzyl ether) dendritic molecules combined with crown-ether
moieties as the core [6]. Depending on the dendrimer generation, positive and negative
ꢀdendritic effectsꢁ have been assigned to the complexation behavior of the crown ether-
functionalized dendrimers [7].
In view of these results, and as part of our efforts on the design and synthesis of
functional dendrimers, we offer an extension of the concept by conjugating one of the
most versatile molecular building blocks, the calix[4]arene active core moiety.
Calixarenes are well-defined macrocycles, containing a preorganized cavity with a
ꢂ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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variety of conformations, as a consequence of the flexibility around the ArÀCH2ÀAr
groups, useful in hostÀguest chemistry and with potentially unlimited applications [8].
In calixarene-based dendrimers reported so far, calixarenes have been used as the core
in conjugation with dendritic branches or as the branching units in dendritic structures
[9]. Furthermore, the use of calixarenes as core, branching unit and surface in the same
dendritic structure has been reported [10]. To the best of our knowledge, the previously
reported calixarene-cored dendrimers functionalized with poly(benzyl ether) dendritic
branches possess p-tert-butylcalix[4]arene as core [11].
Results and Discussion. – In our approach, we used the de-alkylated derivative,
calix[4]arene 1, and the dendritic branches were functionalized with Br-atoms or
COOtBu groups at their periphery by using 4-bromobenzyl bromide (2) and tert-butyl
4-(bromomethyl)benzoate (3), respectively, as starting compounds (Fig. 1). The
peripheral modification with Br-atoms provides the final molecules with increased
lipophilicity. On the other hand, COOtBu groups are potential providers of hydrophilic
characteristics, due to their ease transformation to carboxylates when they are treated
with acids. In addition, they provide ideal cascade through the synthetic route as they
are extremely stable in basic conditions in contrast with other ester groups.
The required calix[4]arene was prepared by transforming p-tert-butylcalix[4]arene
according to literature procedures [12]. The starting compound tert-butyl 4-(bromo-
methyl)benzoate (3) was synthesized by the reaction of 4-(bromomethyl)benzoic acid
in the presence of AcOtBu and HClO4. The preparation of the poly(benzyl ether)
branches until the third generation was achieved according to FrØchetꢁs procedures
[13], except that the purification steps were modified, using 3,5-dihydroxybenzyl
alcohol for the generation growth while the periphery modifications (dendritic
substituents) were Br-atoms and COOtBu (Scheme 1).
Following the convergent procedure, the calix[4]arene-cored dendrimers have been
prepared by conjugating calix[4]arene and dendritic wedges up to the third generation
with the aforementioned functionalities at their periphery. For the synthesis of
calix[4]arene dendrimers, different reaction conditions (solvent, base, temperature)
were tested. Initially, based on phase-transfer reaction conditions bromide branches
reacted with calix[4]arene in acetone with K2CO3 as base in the presence of 18-crown-6
as catalyst. Under these conditions, calix[4]arene reacted smoothly only with zero
generation bromide branches (RÀG0ÀCH2Br), 2, and 3, under Williamson ether-
ification conditions to give the desired dendrimers 16 and 17 by tetra-etherification of
the four OH groups at the lower rim, while the 1st-, 2nd-, and 3rd-generation dendritic
Fig. 1. Structures of calix[4]arene 1 and the starting compounds 2 and 3 used for periphery modifications

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Scheme 1. Syntheses of Peripherally Functionalized FrØchet-Type Poly(benzyl ether) Dendrons

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wedges did not afford the tetra-etherificated calix[4]arene dendrimers. When THF or
dioxane or mixture of them were used as solvent, with NaH as base, the reaction was
unsuccessful, even under most forcing conditions (several days of reflux). Finally, to
our surprise when a mixture of dioxane/DMF as solvent and NaH as base were used,
progress of the reactions resulted in a remarkable change, i.e., the calix[4]arene with
1st-generation branch bromide afforded the fully conjugated lower rim calix[4]arene-
cored dendrimers 18 and 19. With the optimized reaction conditions in hand, the
synthesis of calix[4]arene dendrimers was implemented from the 1st-, to the 2nd- and
3rd-generation bromide branches. The reactions of calix[4]arene with dendrons of zero,
first, and second generation afforded the fully tetra-etherificated calix[4]arene
dendrimers (Scheme 2) in relatively good yields, ranging between 60 – 70% (for 16
and 17), 57 – 62% (for 18 and 19), and 25 – 30% (for 20 and 21). On the other hand, the
reactions of calix[4]arene with the third generation dendrons did not give similar
results. In more detail, the third generation dendrons, modified at their periphery with
COOtBu groups, afforded only two-fold substitution (compound 22) in low yield (7%),
while the third generation dendrons modified with Br-atoms under the same conditions
afforded a mixture of products which were difficult to separate. As these findings are
concerned, we believe that periphery modifications, as well as different reaction
conditions (base, solvent medium) are very important and play a critical role on the
incomplete etherification of the calixarene-core moiety.
Considering the above mentioned, we believe that the conjugation of dendrons to
the calixarenic core may proceed through different mechanisms each time, SN1 and/or
SN2, depending on the reaction conditions. Note that the use of THF or dioxane alone
or as a mixture did not afford the desired products. In fact, the higher polarity of DMF
as solvent influences the kinetics of the etherification reactions. The progress of all
reactions was monitored by thin-layer chromatography, and the crude reaction
products were purified by flash chromatography on SiO2. All final compounds
are white solids and soluble in most organic solvents. They were characterized by means
1
of H- and 13C-NMR spectroscopy as well as by mass spectroscopy (ESI, MALDI-
TOF).
In the 1H-NMR spectra of the final products, characteristic peaks of both
calix[4]arene functionalities and dendrons, could be easily identified. The signals in
all the 1H-NMR spectra of the calix[4]arene-fuctionalized dendrimers could be
grouped into three regions: the first region included signals with chemical shifts
between d(H) 6.30 and 8.00 ppm, which were due to the aromatic H-atoms of the
molecules. In this region, two doublets of the para-substituted terminal aromatic rings
as well as the absorption of the aromatic H-atoms of the calixarenic core were always
observed. The second region showed peaks with chemical shifts between d(H) 4.60 and
5.10 ppm, which were due to the benzylic H-atoms of the branches. The third region
included signals with chemical shifts between d(H) 2.80 and 4.40 ppm. All the signals in
this region were due to the benzylic H-atoms of the bridging CH2 groups of the
calixarenic core. The NMR spectra of the final products were quite simple, indicating
conclusive evidence of their conformational characteristics: the absorption as two
characteristic doublet peaks for the equatorial (2.86 – 3.29 ppm, 2J ¼ 13.00 – 14.00) and
2
axial (4.15 – 4.30 ppm, J ¼ 13.00 – 14.00) H-atoms of ArÀCH2ÀAr-groups indicated
that all the final products preferred strictly the cone conformation [14]. Furthermore,

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Scheme 2. Syntheses of Calix[4]arene-Functionalized Dendrimers via Convergent Approach

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an additional evidence for the cone conformation of the final lower rim functionalized
calix[4]arenes came from the 13C-NMR spectra, where the benzylic C-atoms of the
bridging CH2 groups of the calixarenic core absorbed only at d(C) ca. 31 ppm, and no
absorption was observed at d(C) ca. 37 ppm, showing that only a syn orientation took
place between phenoxy rings while an anti orientation was absent [15]. Finally, in the
1H-NMR spectra of the calix[4]arene-fuctionalized dendrimers with COOtBu groups at
their periphery, a single sharp peak was always noted between d(H) 1.62 and 1.53 ppm
t
1
due to the H-atoms of the Bu groups. Fig. 2 showed the H-NMR spectra of all
calix[4]arene-cored dendrimers up to the third generation, modified at their periphery
with COOtBu groups, where all the above mentioned characteristic absorptions were
presented, indicating that the calix[4]arene cores adopted, as shown in Fig. 2, the well-
defined cone conformation.
The molecular weights of all the calix[4]arene-cored dendrimers, 16 – 22, were
confirmed by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF)
and HR-ESI-MS for two of them, 17 and 19.
In Fig. 3, we show three typical MALDI-TOF mass spectra of zero-, first-, and
second-generation calix[4]arene dendrimers with Br-atoms at their surface, 16, 18, and
20, which prove the monodispersity and the high purity of the final products.
In most cases (see Exper. Part), the use of [(2E)-3-(4-tert-butylphenyl)-2-methyl-
prop-2-en-1-ylidene]malononitrile (DCTB) has been shown to be an efficient matrix
for the matrix-assisted laser desorption ionization of the calix[4]arene-cored dendritic
polyethers, afforded the [M þ Na]þ ion.
Conclusions. – In summary, a series of novel dendritic compounds which contain
calix[4]arene as the core, surrounded by periphery modified poly(benzyl ether)
dendrons of zero, first, second, and third generation have been synthesized and fully
Fig. 2. 1H-NMR Spectra (250 MHz, CDCl3) of calix[4]arene-dendrimers, functionalized with COOtBu
groups at their periphery: a) zero generation 17, b) the first generation 19, c) the second generation 21, and
d) the third generation 22

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Fig. 3. MALDI-TOF-MS Spectra of the calix[4]arene dendrimers 16, 18, and 20
characterized. The synthesis of tert-butyl ester periphery modified FrØchet-type
poly(benzyl ether) dendrimers, as well as the conjugation of FrØchet-type poly(benzyl
ether) dendrons with the de-alkylated derivative of p-tert-butylcalix[4]arene are
described herein for the first time. Additionally, as evidenced through 1H- and
13C-NMR studies, the calix[4]arene-cored dendrimers prefer strictly the well-defined
cone conformation. Taking into account the easy transformation of the COOtBu
peripheral groups to the corresponding carboxylic groups or carboxylate anions, and
considering the ability of calixarenes to bind inorganic and organic cations as well as
neutral organic molecules selectively, dendrimer compounds with new properties are
expected. Experiments involving their hostÀguest behavior are currently under
investigation.
This research was co-funded by the European Union in the framework of the program Pythagoras I
of the Operational Program for Education and Initial Vocational Training of the 3rd Community Support
Framework of the Hellenic Ministry of Education, funded 25% from national sources and 75% from the
European Social Fund (ESF). In addition, the authors would like to thank Associate Professor Georgios
Tsiotis (Department of Chemistry, University of Crete, Greece) and Dr. Andreas Springer (Department
of Chemistry, Freie Universität Berlin, Germany) for having kindly obtained HR-ESI- and MALDI-
TOF-MS spectra.
Experimental Part
1. General. All solvents were of anal. grade, and dry solvents were prepared according to procedures
described by Armarego and Perrin and used immediately after preparation [16]. All reagents were
purchased from Sigma – Aldrich, Fluka, and Merck. TLC and prep. TLC: silica gel F254 (Fluka). Flash
column chromatography (FC): 9385 silica gel F254 (Merck). M.p.: Büchi 510 apparatus; uncorrected.
1
1
NMR: Bruker AMX (250/63 MHz H/13C and 400/100 MHz H/13C); d in ppm rel. to Me4Si as internal

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standard, J in Hz. MS: Finnigan MAT-8200, Agilent 6210 ESI-TOF, or UltrafleXtreme MALDI-TOF/TOF
mass specrometers; in m/z. Elemental analysis: Heraeus CHN-Rapid Analyzer; in %.
2. Synthesis of tert-Butyl 4-(Bromomethyl)benzoate (3). To a stirred soln. of 4-(bromomethyl)ben-
zoic acid (3.0 g, 14 mmol) in AcOtBu (150 ml) in a flask was added HClO4 (1 ml, 70% aq. soln.,
12 mmol), and the flask was tapped quickly with a plastic tap. The mixture was stirred at r.t. until no solid
was observed in the flask, and washed with H2O (3 Â 100 ml) and a sat. aq. K2CO3 soln. until no bubbling
was observed. The org. layer was dried (Na2SO4), filtered, and evaporated to afford 3 (2.64 g, 70%) as
colorless liquid. 1H-NMR (250 MHz, CDCl3): 1.59 (s, Me3C); 4.49 (s, CH2Br); 7.42 (d, 3J ¼ 8.25, 2 arom.
H); 7.96 (d, 3J ¼ 8.25, 2 arom. H). 13C-NMR (63 MHz, CDCl3): 28.49; 32.68; 81.53; 129.15; 130.21; 132.41;
142.58; 165.59.
3. General Procedure for the Growth of Dendritic Branches with Br-Atoms at Their Periphery. For the
preparation of dendritic branches with Br-atoms at their periphery, the FrØchet procedure was followed,
starting from 4-bromobenzyl bromide (BrÀG0ÀCH2Br; 2). Spectroscopic data for all compounds were in
agreement with those in [13].
4. General Procedure for the Growth of Dendritic Branches with COOtBu Groups at Their Periphery.
For the preparation of dendritic branches with COOtBu groups at their periphery, the FrØchet procedure
was followed, starting from the previously synthesized tert-butyl 4-(bromomethyl)benzoate (3).
5. General Procedure for the Synthesis of Dendritic Alcohols with COOtBu Groups at Their
Periphery. Benzylic bromides (2.1 equiv.) reacted with 3,5-dihydroxybenzylic alcohol (1.0 equiv.) in the
presence of K2CO3 (2.1 equiv.) and 18-crown-6 (0.2 equiv.) in anh. acetone at refluxing temp. After
reaction completion, the solvent was evaporated under reduced pressure, and the residue was taken up in
AcOEt and washed with H2O (3 Â ) and a sat. aq. NaCl soln. (2 Â ). The org. layer was dried (Na2SO4),
filtered, and the solvent evaporated under reduced pressure. The benzylic alcohol isolated from the
resulting residue by FC as described for each compound.
Di-tert-butyl 4,4’-{[5-(Hydroxymethyl)benzene-1,3-diyl]bis(oxymethanediyl)}dibenzoate (5). Elu-
ent: hexane/AcOEt (10 :1). Yield: 83%. White solid. M.p. 107 – 1088. 1H-NMR (250 MHz, CDCl3): 1.58
4
(s, 2 Me3C); 3.02 (br. s, CH2OH); 4.58 (s, CH2OH); 5.01 (s, 2 Ar’CH2O); 6.47 (t, J ¼ 2.00, 1 arom. H
(Ar)); 6.59 (d, 4J ¼ 2.00, 2 arom. H (Ar)); 7.41 (d, 3J ¼ 8.25, 4 arom. H (Ar’)); 7.97 (d, 3J ¼ 8.25, 4 arom. H
(Ar’)). 13C-NMR (63 MHz, CDCl3): 28.33; 64.97; 69.46; 81.28; 101.38; 105.89; 126.97; 129.82; 131.59;
141.72; 144.08; 159.92; 165.72.
Tetra-tert-butyl 4,4’,4’’,4’’’-{[5-(Hydroxymethyl)benzene-1,3-diyl]bis[oxymethanediylbenzene-5,1,3-
triylbis(oxymethanediyl)]}tetrabenzoate (9). Eluent: hexane/AcOEt (8 :1). Yield: 86%. White solid.
M.p. 758. 1H-NMR (250 MHz, CDCl3): 1.60 (s, 4 Me3C); 2.33 (br. s, CH2OH); 4.60 (s, CH2OH); 4.94 (s,
2 Ar’CH2O); 5.06 (s, 4 Ar’’CH2O); 6.47 (t, 4J ¼ 2.00, 1 arom. H (Ar)); 6.53 (t, 4J ¼ 2.00, 2 arom. H (Ar’));
6.57 (d, 4J ¼ 2.00, 2 arom. H (Ar)); 6.65 (d, 4J ¼ 2.00, 4 arom. H (Ar’)); 7.45 (d, 3J ¼ 8.25, 8 arom. H (Ar’’));
7.99 (d, 3J ¼ 8.25, 8 arom. H (Ar’’)). 13C-NMR (63 MHz, CDCl3): 28.43; 65.47; 69.66; 69.97; 81.35; 101.53;
101.92; 105.90; 106.60; 127.08; 129.92; 131.77; 139.76; 141.63; 144.14; 160.08; 160.12; 165.75.
Octa-tert-butyl 4,4’,4’’,4’’’,4’’’’,4’’’’’,4’’’’’’,4’’’’’’’-([5-(Hydroxymethyl)benzene-1,3-diyl]bis{oxymethane-
diylbenzene-5,1,3-triylbis[oxymethanediylbenzene-5,1,3-triylbis(oxymethanediyl)]})octabenzoate (13).
1
Eluent: hexane/AcOEt (8 :1). Yield: 75%. White solid. M.p. 848. H-NMR (250 MHz, CDCl3): 1.60 (s,
8 Me3C); 2.19 (s, CH2OH); 4.60 (s, CH2OH); 4.95 (s, 12 H, Ar’CH2O, Ar’’CH2O); 5.05 (s, 8 Ar’’’CH2O);
6.53 (m, 7 arom. H (Ar’, Ar’’)); 6.61 (d, 4J ¼ 1.50, 2 arom. H (Ar)); 6.66 (m, 12 arom. H (Ar’, Ar’’)); 7.44
(d, 3J ¼ 8.25, 8 arom. H (Ar’’’)); 7.99 (d, 3J ¼ 8.25, 8 arom. H (Ar’’’)). 13C-NMR (63 MHz, CDCl3): 28.32;
65.43; 69.64; 70.08; 81.29; 101.55; 101.81; 101.91; 106.18; 106.67; 127.08; 129.91; 131.78; 139.63; 141.60;
144.10; 160.09; 160.20; 165.68.
6. General Procedure for the Synthesis of Dendritic Bromides with COOtBu Groups at Their
Periphery. For the preparation of the benzylic bromides, the corresponding benzylic alcohol (1.0 equiv.)
was dissolved in a minimum amount of anh. THF and reacted with CBr4 (1.25 equiv.) and Ph3P (1.25
equiv.) at r.t. under inert atmosphere (Ar). After reaction completion, AcOEt was added to the mixture
and washed with H2O (3 Â ) and a sat. aq. NaCl soln. (2 Â ). The org. layer was dried (Na2SO4), filtered,
and the solvent evaporated under reduced pressure. The benzylic bromide isolated from the resulting
residue by FC as described for each compound.

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Di-tert-butyl 4,4’-{[5-(Bromomethyl)benzene-1,3-diyl]bis(oxymethanediyl)}dibenzoate (7). Eluent:
1
hexane/AcOEt (10 :1). Yield: 73%. White solid. M.p. 123 – 1248. H-NMR (250 MHz, CDCl3): 1.60 (s,
4
4
2 Me3C); 4.38 (s, CH2Br); 5.04 (s, 2 Ar’CH2O); 6.51 (t, J ¼ 2.00, 1 arom. H (Ar)); 6.63 (d, J ¼ 2.00, 2
arom. H (Ar)); 7.44 (d, 3J ¼ 8.00, 4 arom. H (Ar’)); 8.01 (d, 3J ¼ 8.00, 4 arom. H (Ar’)). 13C-NMR
(63 MHz, CDCl3): 28.32; 33.58; 69.52; 81.13; 102.31; 108.37; 126.97; 129.82; 131.72; 140.08; 141.34; 159.87;
165.48.
Tetra-tert-butyl 4,4’,4’’,4’’’-{[5-(Bromomethyl)benzene-1,3-diyl]bis[oxymethanediylbenzene-5,1,3-
triylbis(oxymethanediyl)]}tetrabenzoate (11). Eluent: hexane/AcOEt (10 :1). Yield: 80%. White solid.
1
M.p. 768. H-NMR (250 MHz, CDCl3): 1.61 (s, 4 Me3C); 4.40 (s, CH2Br); 4.96 (s, 2 Ar’CH2O); 5.09 (s,
4 Ar’’CH2O); 6.51 (t, 4J ¼ 2.25, 1 arom. H (Ar)); 6.55 (t, 4J ¼ 2.25, 2 arom. H (Ar’)); 6.61 (d, 4J ¼ 2.25, 2
arom. H (Ar)); 6.66 (d, 4J ¼ 2.25, 4 arom. H (Ar’)); 7.45 (d, 3J ¼ 8.25, 8 arom. H (Ar’’)); 8.00 (d, 3J ¼ 8.25, 8
arom. H (Ar’’)). 13C-NMR (63 MHz, CDCl3): 28.45; 33.99; 69.71; 70.14; 81.31; 102.01; 102.32; 106.66;
108.45; 127.09; 129.95; 131.85; 139.48; 139.96; 141.60; 160.14; 160.15; 165.69.
Octa-tert-butyl 4,4’,4’’,4’’’,4’’’’,4’’’’’,4’’’’”,4’’’’’’’-([5-(Bromomethyl)benzene-1,3-diyl]bis{oxymethane-
diylbenzene-5,1,3-triylbis[oxymethanediylbenzene-5,1,3-triylbis(oxymethanediyl)]})octabenzoate (15).
Eluent: hexane/AcOEt (3 :1). Yield: 88%. White solid. M.p. 91 – 938. 1H-NMR (250 MHz, CDCl3):
1.61 (s, 8 Me3C); 4.39 (s, CH2Br); 4.96 (s, 12 H, Ar’CH2O, Ar’’CH2O); 5.07 (s, 8 Ar’’’CH2O); 6,54 (m, 7
arom. H (Ar’, Ar’’)); 6,63 (d, 4J ¼ 2.00, 2 arom. H (Ar)); 6.68 (m, 12 arom. H (Ar’, Ar’’)); 7.45 (d, 3J ¼ 8.25,
8 arom. H (Ar’’’)); 8.00 (d, 3J ¼ 8.25, 8 arom. H (Ar’’’)). 13C-NMR (63 MHz, CDCl3): 28.44; 33.94; 69.66;
70.13; 70.21; 81.29; 101.64; 101.93; 102.60; 106.70; 108.73; 127.10; 129.93; 131.82; 139.45; 139.61; 140.21;
141.60; 160.13; 160.25; 165.68.
7. General Procedure for the Synthesis of the Calix[4]arene Functionalized Dendrimers 16 – 22. To a
stirred soln. of calix[4]arene (1 equiv.) in anh. dioxane was added under Ar a suspension of NaH (5
equiv.), and the mixture was heated to reflux for ca. 30 min (purple color observed). The stirred soln. was
cooled to r.t., and the dissolved corresponding dendritic bromide of the zero, first, second, and third
generation (4.2 equiv.) in anh. DMF was added dropwise under Ar. The mixture was heated to reflux for
24 – 48 h, then allowed to cool to r.t., worked up carefully with H2O, and evaporated under reduced
pressure. H2O was added to the residue, and the resulting aq. suspension was extracted with AcOEt
(3Â ). The combined org. extracts were dried (Na2SO4), evaporated, and purified either by crystal-
lization or by FC (SiO2).
25,26,27,28-Tetrakis[(4-bromobenzyl)oxy]calix[4]arene (16). Yield: 60%. Colorless solid. M.p. 190 –
1948 (heptane). 1H-NMR (250 MHz, CDCl3): 3.05 (d, 2J ¼ 13.50, 2 ArCH2Ar); 4.20 (d, 2J ¼ 13.50,
2 ArCH2Ar); 4.89 (s, 4 ArOCH2Ar); 6.64 (m, 12 arom. H (Ar)); 7.16 (d, 3J ¼ 8.25, 8 arom. H (Ar)); 7.40
3
(d, J ¼ 8.25, 8 arom. H (Ar)). 13C-NMR (63 MHz, CDCl3): 31.57; 75.87; 122.41; 122.84; 128.67; 131.41;
131.54; 135.25; 136.69; 155.29. MALDI-TOF-MS (matrix: DCTB): 1123.457 ([M þ Na]þ,
C56H46Br4NaOþ4 ; calc. 1121.0027). Anal. calc. for C56H46Br4O4 (1102.58): C 61.00, H 4.21; found: C
60.73, H 4.40.
25,26,27,28-Tetrakis{[4-(tert-butoxycarbonyl)benzyl]oxy}calix[4]arene (17). Eluent: hexane/AcOEt
1
(10 :1). Yield: 70%. Colorless solid. M.p. 1198. H-NMR (250 MHz, CDCl3): 1.62 (s, 4 Me3C); 2.95 (d,
2
2J ¼ 13.50, 2 ArCH2Ar); 4.17 (d, J ¼ 13.50, 2 ArCH2Ar); 5.00 (s, 4 ArOCH2Ar’); 6.57 (m, 12 arom. H
(Ar)); 7.36 (d, 3J ¼ 8.00, 8 arom. H (Ar’)); 7.91 (d, 3J ¼ 8.00, 8 arom. H (Ar’)). 13C-NMR (63 MHz,
CDCl3): 28.47; 31.66; 76.05; 81.28; 122.80; 128.66; 129.51; 131.88; 135.32; 142.17; 155.27; 165.75. HR-ESI-
MS (matrix: CsCO3): 1318.4602 ([M þ Cs]þ, C76H82CsO1þ2 ; calc. 1318.4782). MALDI-TOF-MS (matrix:
DCTB): 1208.066 ([M þ Na]þ, C76H82NaO1þ2 ; calc. 1209.5704). Anal. calc. for C76H82O12 (1187.46): C
76.87, H 6.96; found: C 77.02, H 6.65.
25,26,27,28-Tetrakis({3,5-bis[(4-bromobenzyl)oxy]benzyl}oxy)calix[4]arene (18). Eluent: hexane/
CH2Cl2 (3 :1). Yield: 57%. Colorless solid. M.p. 93 – 948. 1H-NMR (250 MHz, CDCl3): 2.90 (d, 2J ¼ 13.50,
2
2 ArCH2Ar); 4.19 (d, J ¼ 13.50, 2 ArCH2Ar); 4.69 (s, 8 ArOCH2Ar’); 5.06 (s, 4 Ar’OCH2Ar’’); 6.41 (t,
4J ¼ 2.00, 4 arom. H (Ar’)); 6.59 (m, 20 arom. H (Ar’, Ar’’)); 7.06 (d, 3J ¼ 8.25, 16 arom. H (Ar’’)); 7.37 (d,
3J ¼ 8.25, 16 arom. H (Ar’’)). 13C-NMR (63 MHz, CDCl3): 31.90; 69.37; 76.17; 101.74; 108.66; 122.11;
122.69; 128.58; 129.28; 131.88; 135.45; 135.93; 140.51; 155.35; 159.59. MALDI-TOF-MS (matrix:
DCTB): 2289.341 ([M þ Na]þ, C112H90Br8NaOþ12 ; calc. 2290.1276). Anal. calc. for C112H90Br8O12
(2267.14): C 59.33, H 4.00; found: C 59.47, H 3.77.

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Helvetica Chimica Acta – Vol. 98 (2015)
25,26,27,28-Tetrakis[(3,5-bis{[4-(tert-butoxycarbonyl)benzyl]oxy}benzyl)oxy]calix[4]arene (19).
Eluent: hexane/AcOEt (10 :1). Yield: 62%. Colorless solid. M.p. 99 – 1028. 1H-NMR (250 MHz, CDCl3):
1.57 (s, 8 Me3C); 2.86 (d, 2J ¼ 13.50, 2 ArCH2Ar); 4.17 (d, 2J ¼ 13.50, 2 ArCH2Ar); 4.78 (s, 8 ArO-
4
CH2Ar’); 5.06 (s, 4 Ar’OCH2Ar’’); 6.43 (t, J ¼ 2.00, 4 arom. H (Ar’)); 6.55 – 6.58 (m, 20 arom. H (Ar’,
3
3
Ar’’)); 7.22 (d, J ¼ 8.25, 16 arom. H (Ar’’)); 7.87 (d, J ¼ 8.25, 16 arom. H (Ar’’)). 13C-NMR (63 MHz,
CDCl3): 28.49; 31.71; 69.39; 76.08; 81.12; 101.81; 108.64; 122.47; 127.08; 128.32; 129.87,131.56; 135.29;
140.32; 141.49; 155.28; 159.51; 165.52. HR-ESI-MS (matrix: CsCO3): 2567.0969 ([M þ Cs]þ,
C152H162CsOþ28
;
calc. 2568.0307). MALDI-TOF-MS (matrix: DCTB): 2459.611 ([M þ Na]þ,
C152H162CsOþ28 ; calc. 2458.1150). Anal. calc. for C152H162O28 (2436.90): C 74.92, H 6.70; found: C74.61,
H 6.62.
25,26,27,28-Tetrakis{[3,5-bis({3,5-bis[(4-bromobenzyl)oxy]benzyl}oxy)benzyl]oxy}calix[4]arene
(20). Eluent: hexane/CH2Cl2 (4 :1). Yield: 25%. Colorless solid. M.p. 77 – 798. 1H-NMR (250 MHz,
CDCl3): 2.91 (d, 2J ¼ 13.50, 2 ArCH2Ar); 4.21 (d, 2J ¼ 13.50, 2 ArCH2Ar); 4.61 (s, 8 Ar’OCH2Ar’’); 4.71
(s, 16 Ar’’OCH2Ar’’’); 5.05 (s, 4 ArOCH2Ar’’); 6.35 – 6.59 (m, 48 arom. H (Ar’, Ar’’)); 7.11 (d, 3J ¼ 8.25, 32
arom. H (Ar’’’)); 7.39 (d, 3J ¼ 8.25, 32 arom. H (Ar’’’)). 13C-NMR (63 MHz, CDCl3): 31.87; 69.37; 69.98;
101.61; 102.02; 106.64; 108.57; 122.17; 122.81; 128.47; 129.34; 131.91; 135.22; 135.87; 139.59; 140.54;
155.69; 159.64; 160.01. MALDI-TOF-MS (matrix: DCTB): 4620.687 ([M þ Na]þ, C224H178Br16NaO2þ8
;
calc. 4619.2471). Anal. calc. for C224H178Br16O28 (4596.26): C 58.53, H 3.90; found: C 58.61, H 3.77.
25,26,27,28-Tetrakis({3,5-bis[(3,5-bis{[(4-tert-butoxycarbonyl)benzyl]oxy}benzyl)oxy]benzyl}oxy)-
calix[4]arene (21). Eluent: hexane/acetone/AcOEt (12 :2 :1). Yield: 30%. Colorless solid. M.p. 107 –
1108. 1H-NMR (250 MHz, CDCl3): 1.55 (s, 16 Me3C); 2.87 (d, 2J ¼ 14.00, 2 ArCH2Ar); 4.21 (d, 2J ¼
14.00, 2 ArCH2Ar); 4.64 (s, 8 Ar’OCH2Ar’’); 4.80 (s, 16 Ar’’OCH2Ar’’’); 5.06 (s, 4 ArOCH2Ar’’); 6.35 –
3
3
6.59 (m, 48 arom. H (Ar’, Ar’’)); 7.29 (d, J ¼ 8.25, 32 arom. H (Ar’’’)); 7.89 (d, J ¼ 8.25, 32 arom. H
(Ar’’’)). 13C-NMR (63 MHz, CDCl3): 28.49; 31.81; 69.20; 69.90; 81.05; 101.59; 102.10; 106.37; 108.39;
122.47; 127.14; 128.45; 129.89; 131.64; 135.26; 139.51; 140.45; 141.32; 155.34; 159.66; 159.94; 165.55. HR-
ESI-MS (matrix: DHB): 4956.0000 ([M þ Na]þ, C304H322NaO6þ0 ; calc. 4955.2043). Anal. calc. for
C304H322O60 (4935.77): C 73.98, H 6.58; found C 73.84, H 6.65.
26,28-Bis{[3,5-bis({3,5-bis[(3,5-bis{[4-(tert-butoxycarbonyl)benzyl]oxy}benzyl)oxy]benzyl}oxy)-
benzyl]oxy}-25,27-dihydroxycalix[4]arene (22). Eluent: hexane/AcOEt (4 :1). Yield: 7%. Colorless
solid. 1H-NMR (250 MHz, CDCl3): 1.55 (s, 16 Me3C); 3.30 (d, 2J ¼ 13.00, 2 ArCH2Ar); 4.30 (d, 2J ¼ 13.00,
2 ArCH2Ar); 4.69 (s, 4 Ar’OCH2Ar’’); 4.77 (s, 8 Ar’’OCH2Ar’’’); 4.90 (s, 16 Ar’’’OCH2Ar’’’’); 5.06 (s,
ArOCH2Ar’); 6.38 – 7.00 (m, 54 arom. H (Ar’, Ar’’, Ar’’’)); 7.34 (d, 3J ¼ 8.00, 32 arom. H (Ar’’’)); 7.92 (d,
3J ¼ 8.00, 32 arom. H (Ar’’’)); 7.99 (s, 2 ArOH). 13C-NMR (63 MHz, CDCl3): 28.25; 31.69; 69.36; 69.88;
81.19; 101.52; 101.72; 105.63; 106.33; 106.61; 126.84; 128.14; 128.68; 129.68; 131.66; 133.37; 139.40;
139.60; 139.90; 141.35; 152.17; 153.45; 159.95; 160.32; 165.59. MALDI-TOF-MS (matrix: DCTB):
5197.5120 ([M þ Na]þ, C318H332NaOþ64 ; calc. 5197.2622). Anal. calc. for C318H332O64 (5178.00): C 73.76, H
6.46; found C 73.45, H 6.39.
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Received September 25, 2014