Synthesis of 1,3-alternate calix[4]-cyclen-benzo-crown-6 as a hard-soft receptor

Article abstract of DOI:10.1016/S0040-4039(00)01641-5

1,3-Alternate calix[4]-cyclen-benzo-crown-6 incorporating a cyclen subunit on one side and a benzo-crown-6 on the other side of the calix[4]arene framework has been synthesized. Preliminary complexation studies of this macropolycycle with cesium and zinc picrate salts have been carried out by means of proton nuclear magnetic resonance spectroscopy. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01641-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9167–9171
Synthesis of 1,3-alternate calix[4]-cyclen-benzo-crown-6 as a
hard–soft receptor
Buncha Pulpoka,* Matinee Jamkratoke, Thawatchai Tuntulani and
Vithaya Ruangpornvisuti
Supramolecular Chemistry Laboratory, Department of Chemistry, Faculty of Science, Chulalongkorn University,
Bangkok 10330, Thailand
Received 13 September 2000; accepted 20 September 2000
Abstract
1,3-Alternate calix[4]-cyclen-benzo-crown-6 incorporating a cyclen subunit on one side and a benzo-
crown-6 on the other side of the calix[4]arene framework has been synthesized. Preliminary complexation
studies of this macropolycycle with cesium and zinc picrate salts have been carried out by means of proton
nuclear magnetic resonance spectroscopy. © 2000 Elsevier Science Ltd. All rights reserved.
Calixarenes, calix[4]arene in particular, show their versatility as building-blocks in
supramolecular chemistry due to their ease of synthesis and well-defined structures.1–5 Further-
more, the 1,3-alternate calix[4]arene framework is of interest to the chemist because it provides
two cavities, symmetric or asymmetric, on each side of calix[4]arene platform.1–4 Since the first
double-bridge calix[4]arene in the 1,3-alternate conformation, 1,3-p-tert-butylcalix[4]-bis-crown-
ether-5,6 many 1,3-alternate calix[4]arene derivatives, i.e. 1,3-calix[4]-bis-crown-ethers7–9 and
crown-ethers with phenylene9 or pyridine10 units have been prepared. In order to enhance
stability and selectivity by increasing the number of coordination sites, the diaza-crown ether
moiety was introduced onto a 1,3-alternate calix[4]arene.11 This 1,3-calix[4]-bis-cryptand can
+
form dinuclear complexes with Na+, K+ and Rb+ and shows the oscillation of NH4 through the
p-basic benzene tunnel of the calix[4]arene framework12 as found in 1,3-calix[4]-bis-crown-5.13,14
Many 1,3-alternate calix[4]arene building-blocks incorporating different cavities have also been
synthesized. The calix[4]-uranylsalophen-crown-6 containing one anion loop and one cation
cavity on each side of 1,3-alternate calix[4]arene can simultaneously transport both a cation and
an anion, CsCl and CsNO3, through a liquid membrane.15 The 1,3-alternate calix[4]-
cryptand[2,2]-crown-616 can form heterobinuclear complexes with Na+, K+ and Cs+ in which Na+
and K+ are complexed in the cryptand cavity, whereas Cs+ is bound in the crown ether loop.12
* Corresponding author. Tel: +66 2 218 5226; fax: +66 2 254 1309; e-mail: pbuncha@chula.ac.th
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01641-5

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Moreover, this ligand can act as ‘hard–soft’ receptor due to its ‘soft’ cavity, cryptand, which can
bind soft metal ions, Ni2+ and Zn2+, and ‘hard’ binding site, crown ether loop, which can
accommodate hard metal ions such as Cs+.17
These observations led us to synthesize 1,3- alternate calix[4]-cyclen-benzo crown-6 4 consist-
ing of 1,4,7,11-tetraazacyclododecane or ‘cyclen’, which can form high stable transition-metal18
and lanthanide19 complexes and a benzo-crown ether subunit which can complex Cs+ ions
selectivity,9 linking on each side of calix[4]arene in 1,3-conformation. This novel heteroditopic
ligand is aimed to be an approach to a ‘hard–soft’ receptor,20 which could bind hard and soft
metal ions strongly and selectively and to act as molecular sensors and/or catalysts capable of
detecting or catalysing redox action on guest species.21,22
The synthesis of 4, shown in Scheme 1, began with preparation of 2-(2-bromoethoxy)benzyl
alcohol23 by reaction of 2-hydroxybenzyl alcohol with 1,2-dibromoethane according to the
literature.16 1,3-Distal disubstitution of the calix[4]arene was carried out by substitution with 3
equiv. of 2-(2-bromoethoxy)benzyl alcohol in refluxing acetonitrile in the presence of an excess
Na2CO3 as base for 7 days. After precipitation with hexane, calix[4]-di-2-ethoxybenzyl alcohol
124 was obtained as a white solid in 53%. Compound 1 existed in a cone conformation due to
the presence of two AB-systems at 4.36 and 3.42 ppm with a coupling constant of 13.0 Hz in the
1H NMR spectrum. Bridging of 1 was achieved by refluxing 1 with 1 equiv. of 1,2-bis-
(diethylene glycol tosyl)benzene25 in a suspension of 10 equiv. of K2CO3 in acetonitrile for 3
days. Calix[4]-di-2-ethoxy-benzyl alcohol-benzo-crown-6 226 was eluted from a silica gel column
as a white solid in 98% using 95:5 CH2Cl2/EtOAc as eluent. The conversion of hydroxy groups
of 2 to bromide groups was accomplished by treating 2 with PBr3 in the presence of pyridine in
dichloromethane at 0°C for 10 min to give calix[4]-di-2-ethoxy-benzyl bromide-benzo-crown-6
327 as a white solid in quantitative yield. The condensation of compound 3 with cyclen began
Scheme 1. Synthetic pathway to 1,3-alternate calix[4]-cyclen-benzo-crown-6 4. Reagents and conditions: (i) 2-(2-
bromoethoxy)benzyl alcohol, Na2CO3, CH3CN, reflux 7 days, 53%; (ii) 1,2-bis-(diethylene glycol tosyl)benzene,
K2CO3, CH3CN, reflux 3 days, 98%; (iii) PBr3, pyridine, CH2Cl2, 0°C 10 min, quantitative yield; (iv) cyclen·2H2SO4,
NaOEt, CH3CN, EtOH, H2O, reflux 24 h, 10%

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28
with the generation of cyclen in situ by treatment of cyclen·2H2SO4 dissolved in a minimum
quantity of water with ethanolic NaOEt. 1 Equiv. of 3 dissolved in acetonitrile was added and
the reaction mixture refluxed for 24 h. Calix[4]-cyclen-benzo-crown-6 429 was obtained as a white
solid in 10% after purification by alumina chromatography using 75:25 CH2Cl2:acetone as
eluent. The compounds 2, 3 and 4 were in the 1,3-alternate conformation indicated by the
presence of a singlet for the methylene bridge protons (ArꢀCH2ꢀAr) at 3.81, 3.82 and 3.79 ppm,
1
respectively, in the H NMR spectra.
Preliminary complexation studies of 4 with cesium picrate (Cs+Pic−), and zinc picrate
1
(Zn2+Pic− ) were carried out by means of H NMR spectroscopy. The stoichiometry of the
2
complexes was estimated by comparing the integration of the picrate protons versus those of
glycolic ethylene protons (OCH2) of the ligand. Compound 4 was dissolved in CDCl3 at the
concentration of 3×10−3 mol L−1 and solid picrate salts were added into each tube. After
addition, the clear solution turned yellow which indicated the formation of complexes. With the
cesium picrate, the 1:1 (Cs+:4) complex was obtained after 2 weeks. The singlet for the picrate
protons was observed at 8.78 ppm and that for benzo-crown protons shifted from 6.97 ppm in
the ligand to 6.87 ppm in the complex. Moreover, the signal for the glycolic ethylene protons of
benzo-crown loop dislocated from a multiplet at 3.79–3.72 ppm to a singlet at 3.99 ppm. The
results suggest that cesium ion probably resides in the benzo-crown cavity and the formation of
cation-p interaction with the phenylene unit occurred as found in the calix[4]-bis-benzo-crown-
6.30 For complexation with zinc picrate, the 1:1 (Zn2+:4) complex was achieved after 3 weeks of
reaction. The singlet for the picrate protons appeared at 8.74 ppm. We observed that the doublet
and the triplet of ArH of 4 at 7.48 (J=6.2 Hz) and 7.16 (J=7.2 Hz) ppm, respectively, shifted
to a multiplet at 7.38–7.29 ppm. We also noticed the migration of doublet of H2CNHCH2
protons from 2.82 (J=9.0 Hz) ppm to be a broad signal at 3.23 ppm. This implies the Zn2+ was
coordinating to the cyclen subunit. Such an upfield shift has already been observed in
tris(ZnII–cyclen)complex.31
Further studies of the complexation properties of 4 are currently under investigation and will
be presented in due course. Our complexation project will concentrate on showing evidence of
heterobinuclear complexes and investigation of binding constants toward alkali and transition
metal ions.
Acknowledgements
This work was financially supported by the Thailand Research Fund (PDF/10/2541) and
Grant for Development of New Faculty Staffs from Ratchadapisek Somphot Research. The
help rendered by Dr. Suwabun Chirachanchai for partial elemental analysis results is greatly
appreciated.
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1
23. Analytical data for 2-(2-bromoethoxy)benzyl alcohol: H NMR (200 MHz, CDCl3): l (ppm) 7.30–7.20 (m, 2H,
ArH), 6.95 (t, J=6.4 Hz, 1H, ArH), 6.80 (d, J=8.0 Hz, 1H, ArH), 4.68 (s, 2H, ArCH2), 4.28 (t, J=5.7 Hz, 2H,
ArOCH2), 3.64 (t, J=5.7 Hz, 2H, ArOCH2), 2.95 (s, 1H, ArCH2OH). Anal. found C, 46.82; H, 4.72. Calcd for
C9H11BrO2: C, 46.78; H, 4.80.
1
24. Analytical data for compound 1: (mp 213–214°C) H NMR (200 MHz, CDCl3): l (ppm) 8.87 (s, 2H, ArOH),
7.31 (dd, J=7.3, 1.7 Hz, 2H, ArH), 7.14 (dt, J=7.8, 1.7 Hz, 2H, ArH), 7.05 (d, J=7.6 Hz, 4H, ArH), 7.00 (d,
J=8.7 Hz, 4H, ArH), 6.94 (dt, J=7.9, 0.9 Hz, 2H, ArH), 6.82 (t, J=7.5 Hz, 2H, ArH), 6.70–6.60 (m, 4H, ArH),
4.62 (d, J=6.8 Hz, 4H, ArCH2), 4.36 (d (AB-system), J=13.0 Hz, 4H, ArCH2Ar), 4.33 (bs, 8H, ArOCH2), 3.42
(d (AB-system), J=13.0 Hz, 4H, ArCH2Ar). Anal. found C, 75.56; H, 6.11. Calcd for C46H44O8: C, 76.22; H,
6.12.
25. Preparation procedure of 1,2-bis-(diethylene glycol tosyl)benzene see: Abidi, R.; Asfari, Z.; Harrowfield, J. M.;
1
Nauman, V.; Sobolev, A. N.; Vicens, J. Anales de Quimica Int. Ed. 1996, 92, 51–56. Analytical data: H NMR
(200 MHz, CDCl3): l (ppm) 7.75 (d, J=8.3 Hz, 4H, ArH), 7.26 (d, J=7.9 Hz, 4H, ArH), 6.86 (d, J=2.0 Hz,
4H, ArH), 4.14 (t, J=4.7 Hz, 4H, OCH2), 4.03 (t, J=4.7 Hz, 4H, OCH2), 3.77–3.71 (m, 8H, OCH2), 2.37 (s, 6H,
ArCH3). Anal. found C, 56.45; H, 5.73; S, 10.52. Calcd for C28H34O10S2: C, 56.55; H, 5.76 S, 10.78.
1
26. Analytical data for compound 2: (Mp 72–73°C) H NMR (200 MHz, CDCl3): l (ppm) 7.32 (dd, J=7.3, 1.4 Hz,
2H, ArH), 7.21 (dt, J=7.3, 1.6 Hz, 2H, ArH), 7.10 (d, J=7.6 Hz, 4H, ArH), 7.05 (d, J=7.6 Hz, 4H, ArH), 6.99
(s, 4H, ArH), 6.96 (t, J=7.3 Hz, 2H, ArH), 6.76–6.69 (m, 6H, ArH), 4.66 (s, 4H, ArCH2OH), 4.17–4.10 (m, 4H,
ArOCH2), 3.81 (s, 8H, ArCH2Ar), 3.77–3.72 (m, 12H, OCH2), 3.61 (d, J=4.6 Hz, 4H, OCH2), 3.54 (d, J=4.6
Hz, 4H, OCH2), 2.63 (s, 2H, CH2OH). Anal. found C, 73.65; H, 6.53. Calcd for C60H62O12: C, 73.90; H, 6.41.
1
27. Analytical data for compound 3: (mp 66–67°C) H NMR (200 MHz, CDCl3): l (ppm) 7.34 (dd, J=7.4, 1.3 Hz,
2H, ArH), 7.18 (dt, J=7.8, 1.3 Hz, 2H, ArH), 7.08 (d, J=7.5 Hz, 8H, ArH), 6.98 (s, 4H, ArH), 6.89 (t, J=7.4
Hz, 2H, ArH), 6.74–6.66 (m, 6H, ArH), 4.53 (s, 4H, ArCH2Br), 4.13 (t, J=5.0 Hz, 4H, ArOCH2), 3.89–3.83 (m,
8H, ArOCH2), 3.82 (s, 8H, ArCH2Ar), 3.71 (t, J=4.9 Hz, 4H, OCH2), 3.64–3.54 (m, 8H, OCH2). Anal. found
C, 65.89; H, 6.06. Calcd for C60H60Br2O10: C, 65.46; H, 5.49.
28. Preparation procedure of cyclen·2H2SO4 see: Atkin, J. T.; Richman, J. E.; Oettle, W. F. Org. Synth, 1978, 58,
86–98.

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1
29. Analytical data for compound 4: (mp 190–200°C (dec.)) H NMR (200 MHz, CDCl3): l (ppm) 7.48 (d, J=6.2
Hz, 2H, ArH), 7.16 (t, J=7.2 Hz, 2H, ArH), 7.07 (d, J=7.8 Hz, 4H, ArH), 7.03 (d, J=8.4 Hz, 4H, ArH), 6.97
(s, 4H, ArH), 6.92 (t, J=6.9 Hz, 2H, ArH), 6.82–6.70 (m, 6H, ArH), 4.13 (t, J=4.8 Hz, 4H, ArOCH2), 3.79 (s,
8H, ArCH2Ar), 3.79–3.72 (m, 20H, NCH2 and OCH2), 3.63–3.53 (m, 8H, ArCH2N and OCH2), 3.54 (t, J=5.5
Hz, 4H, OCH2), 2.82 (d, J=9.0 Hz, 8H, HNCH2). Anal. found C, 71.32; H, 6.95. Calcd for C68H78N4O10.
2 H2O: C, 71.18; H, 7.20. ES(+)-MS, m/z 1110.30 (M+).
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