Synthesis of meso-2,2’-bipyridyl-substituted calix[4]arenes and their response to metal cations 215 D O I: 1 0. 15 82 6/ ch im te ch .2 02 0. 7. 4. 14 Moseev T. D., Khasanov A. F., Varaksin M. V., Kopchuk D. S., Kovalev I. S., Taniya O. S., M. Rahman, S. Santra, Zyryanov G. V., Chupakhin O. N., Charushin V. N. Chimica Techno Acta. 2020. Vol. 7, no. 4. P. 215–221. ISSN 2409–5613 Synthesis of meso-2,2’-bipyridyl-substituted calix[4] arenes and their response to metal cations T. D. Moseeva, A. F. Khasanovab, M. V. Varaksinab, D. S. Kopchukab, I. S. Kovaleva, O. S. Taniyaab, M. Rahmana, S. Santraa, G. V. Zyryanovab*, O. N. Chupakhinab, V. N. Charushinab a Ural Federal University named after the first President of Russia B. N. Yeltsin, 19 Mira st., Ekaterinburg, 620002, Russian Federation b I. Ya. Postovsky Institute of Organic Synthesis of RAS (Ural Branch), 22/20 S. Kovalevskoy/Akademicheskaya st., Ekaterinburg, 620990, Russian Federation *email: g.v.zyrianov@urfu.ru Abstract. A convenient synthetic approach to meso-substituted with 2,2’-bipyridine and 1-(pyridin-2-yl)isoquinoline residues calix[4]arenes is reported. This approach involves the reaction of generated in situ 2-lithio-calix[4]arene with 1,2,4-triazine precursor with the following aromatization of the obtained adduct, and the aza-Diels- Alder reaction of the 1,2,4-triazinyl-substituted calix[4]arene with 2,5-norbornadien or in-situ generated 1,2-dehydrobenzene. The UV/fluorescence response of thus obtained meso-pyridyl-substituted calix[4]arenes to metal cations is studied. Keywords: calix[4]arene; 1,2,4-triazines; aza-Diels-Alder reaction; 2,2’-bipyridines; visual cations detection Received: 16.09.2020. Accepted: 20.12.2020. Published:30.12.2020. © Moseev T. D., Khasanov A. F., Varaksin M. V., Kopchuk D. S., Kovalev I. S., Taniya O. S., M. Rahman, S. Santra, Zyryanov G. V., Chupakhin O. N., Charushin V. N., 2020 Introduction Calix[4]arenes and their de- rivatives are, probably, the mostly studied supramolecular hosts for various applica- tions for analytical chemistry [1], materials science [2], as well as environmental [3] and medicinal [4] applications. By means the proper synthetic modification various calixarene derivatives bearing extra hetero- cyclic ligand units or other receptor units at the upper or lower rim were obtained to be used for the recognition/supramo- lecular extraction of inorganic [5] and or- ganic cations [6], anions [7], as well as some neutral molecules [8]. In  this article we wish to report a method for the prepara- tion of  meso-2,2’-bipyridyl-substituted calix[4]arenes and their response to metal cations. Experimental part 1H NMR spectra were recorded on a  Bruker Avance-400 spectrom- eter (400  MHz), the  internal standard was SiMe4. Mass-spectra (ionization type — electrospray) were recorded on a  MicrOTOF-Q II instrument from Bruker Daltonics (Bremen, Germany). Elemental analysis was performed on a Perkin Elmer 216 PE 2400 II CHN analyzer. Fluorescence spectra were measured on Horiba Fluo- romax-4 spectrofluorometer. Absolute quantum yields were measured by using the  integrating sphere. UV-spectra were measured on Shimadzu UV-1800 spec- trometer. The  starting meso-triazinyl- substituted calix[4]arenes were prepared as reported [9]. Mes o-2,2’-bipy ri dy l-substitute d calix[4]arene (3). In  a  50 ml round- bottom flask to  a  solution of  2-(6-phe- nyl-3-(2-pyridyl)-1,2,4-triazin-5-yl)- 25,26,27,28-tetramethoxycalix[4]arene 2 (0.106 g, 0.15 mmol) in 10 ml of o-xylene 2,5-norbornadiene (0.15 ml) was added and the  resulting solution was heated at a temperature of 130–150 °C for 12 hours under the argon atmosphere. Then another 0.1 ml of 2,5-norbornadiene were added and the reaction mixture was heated for another 6 hours at a temperature of 130– 150  °C. o-Xylene was distilled off under reduced pressure, and the column chroma- tography (eluent — ethyl acetate) resulted in the product 3 (Rf = 0.55). Yield 69 mg (0.097 mmol, 65%), mp >250°С. NMR 1H (CDCl3, δ, ppm): 8.64 (1H, d, J=4.9 Hz, Н-6 (2-Ру)), 8.43–8.51 (1H, dd, J=8.2 Hz, J=15.1 Hz, Н-3 (Ру)), 8.33–8.37 (1Н, dd, J=2.7 Hz, J=8.2 Hz, Н-4 (Ру)), 7.67–7.76 (2Н, m, Н-3 (2-Ру)), Н-4 (2-Ру)), 7.35– 7.43 (2Н, m, Н-5 (2-Ру), Ph), 7.27–7.33 (2Н, m, Ph) 7.11–7.27 (5Н, m, Ph), 6.90– 6.97 (2Н, m, Ph), 6.80–6.86 (2Н, m, Ph), 6.67–6.77 (6Н, m, Ph), 6.28, 5.70 (1Н, s, С(2)Н), 4.25–4.32, 4.12–4.17 (2Н, m, Ar- CH2Ar), 3.72–3.77 (4Н, m, 1Н ArCH2Ar + 3Н ОМе), 3.65 (3Н, s, ОМе), 3.57 (1Н, m, ArCH2Ar), 3.42–3.48 (4Н, m, 1Н ArCH2Ar + 3Н ОМе), 3.16 (3Н, m, 3Н ОМе), 2.85 (1H, m, ArCH2Ar). Found: С 81.27%, Н 6.15%.C48H42N2O4. Calculated: С 81.10%, Н 5.96%. Meso-1-(pyridin-2-yl)isoquinolinyl- substituted calix[4]arene (4). In a 100 ml three-necked flask equipped with a reflux condense 2-(6-phenyl-3-(pyridin-2-yl)- 1,2,4-triazin-5-yl)-25,26,27,28-tetrameth- oxycalix[4]arene (0.142 g, 0.2 mmol) was dissolved and 0.1 ml of  iso-amyl nitrite (0.7 mmol) in  40 ml of  dry toluene was added at once. Under argon atmosphere the resulted solution was heated to a tem- perature of  105–110  °C, and a  solution of anthranilic acid (96 mg, 0.7 mmol) in 20 ml of 1,4-dioxane was added to dropwise for 30 minutes with an intensive stirring the reaction mixture. After that the reac- tion was kept under such conditions for 60 minutes. The reaction mixture was than cooled down to  room temperature and washed with a 30% aqueous alkali solution (4 times 50 ml each), the organic phase was separated, dried with an anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure. The product 4 was isolated by  column chromatog- raphy (dichloromethane: ethyl acetate in a ratio of 4: 1, Rf = 0.85). Yield 10 mg (0.012 mmol, 6.0%), mp >250°С. NMR 1H (CDCl3, δ, ppm): 8.89 (1H, d, J=4.9 Hz, Н-6 (2-Ру)), 8.41–8.48 (1H, dd, J=8.2 Hz, J=15.1 Hz, Н-3 (2-Ру)), 8.79–8.88 (1H, dd, J=2.7 Hz, J=8.2 Hz, Н-4 (2-Ру)), 7.59–7.66 (2Н, m, Н-5 (2-Ру), Ph), 7.46–7.55 (4Н, m, Ph), 7.39–7.46 (3Н, m,Ph), 7.08–7.18 (2Н, m, Ph), 6.89–7.04 (2Н, m, Ph), 6.83– 6.88 (2Н, m, Ph), 6.65–6.76 (5Н, m, Ph), 6.57–6.64 (2Н, m, Ph), 6.35, 5.96 (1Н, s, С(2)Н), 4.25–4.32, 4.12–4.17 (2Н, m, Ar- CH2Ar), 3.72–3.77 (4Н, m, 1Н ArCH2Ar + 3Н ОМе), 3.65 (3Н, s, ОМе), 3.57 (1Н, m, ArCH2Ar), 3.42–3.48 (4Н, m, 1Н ArCH2Ar + 3Н ОМе), 3.16 (3Н, m, 3Н ОМе), 2.85 (1H, m, ArCH2Ar). Found: С 81.91%, Н 5.77%. C52H44N2O4. Calculated: : С 82.08%, Н 5.83%. 217 Studies of  the  interactions of  calix- arenes 3–4 with cations The studies of the interactions of com- pounds 3–4 with Zn2+ and Cd2+ cations were carried out at  the  concentrations of  3–4 of  (1-9)·10–6 M (depending on the  value of  the  absorption coefficient (A  ≤ 0.1)) in  anhydrous freshly distilled THF. The concentrations of cations were 10–3–10–4 M. Results and discussion A  most common method for the  in- troducing of  (bi)pyridine moieties into the  calix[4]arenes is  the  modification of  upper or lower ring the  calixarene core with oligopyridine-attached spacer groups by means of acylation, alkylation or condensation reactions [9–17]. As an al- ternative approach our group reported the direct modification of an upper ring of calix[4]arene moiety with 3-(2-pyridyl)- 1,2,4-triazine-5(2H) — one residues [18]. For these modified calixarenes an  effec- tiveness for their transport of La3+ cations was confirmed. Additionally, we reported recently an  effective synthetic approach to  meso-substituted with 1,2,4-triazine moieties calix[4]arenes via direct modifi- cation of 5-H-1,2,4-triazines by the reac- tion with generated in situ 2-lithio-calix[4] arene and the following aromatization [9] (Scheme 1). From another hand the 1,2,4-triazines are suitable precursors for the preparation of multi-substituted (bi)pyridine ligands/ fluorophores via the inverse demand Diels- Alder/retro-Diels-Alder reaction sequence OMeOMe MeOOMe Li H OMeOMe MeOOMe H N N N Ph N OMeOMe MeOOMe H N Ph N OMeOMe MeOOMe H N Ph N 1 2 3 4 i,ii iii iv Scheme 1. Reagents and conditions: i) 1.6 M n-BuLi, TMEDA, THF, –78 °C, 1h, then 25 °C overnight; ii) DDQ (1.2 eq.), THF, 25 °C, 0.5 h; iii) 2,5-norbornadiene, o-xylene, 130–150 °C, 18 h; iv) anthranilic acid, iso-amylnitrite, 1,4-dioxane-toluene, 105–110 °C, 1.5 h. 218 with various dienophiles, such as 2,5-nor- bornadiene [20], enamines [21], acetylene equivalents [22] or aryne intermediates [23]. Keeping in  mind all the  mentioned above we decided to prepare new calix[4] arenes meso-substituted with (benzo) pyridine moieties and study their re- sponse to  selected metal cations. To  do that as a first step we prepared the corre- sponding meso-1,2,4-triazine-substituted calixarene 2 using the previously reported procedure [9]. As a next step the ID Diels- Alder reaction between 2 and 2,5-norbor- nadiene was carried out to afford smoothly meso-2,2’-bipyridyl-substituted calix[4] arene 3 in  up to  65% yield (Scheme  1). The photophysical properties of calixarene 3 are presented below (Table 1). The introduction of bipyridyl ligand/ fluorophore on the periphery of calix[4] arene caused the change in the photophysi- cal properties of product 3. Thus, in THF solution calixarene 3 has a strong absorb- ance band near 292 nm and an emission peak near 379  nm. Calculated absolute fluorescence quantum yield was 1.1%. The response of calixarene 3 to Zn2+ and Cd2+ cations is shown below. Thus, in UV- spectra the addition of 1 eq. of these cations caused a strong decrease of the absorbance peak at 292 nm (Fig. 1). The  same trend was obser ved in  the  emission spectra. Thus, upon ad- dition of  1 eq. of  Cd2+ or Zn2+ a  dra- matic fluorescence quenching was ob- served along with the bathochromic shift of  the  emission maxima by  5–20  nm. It worth to mention that, the addition of Zn2+ caused the stronger red-shift, while the ad- dition of Cd2+ caused stronger fluorescence quenching (Fig. 2). As  a  last step the  isoqinoline-substi- tuted calixarene 4 was obtained by using the reaction between 2 and benzyne gener- ated in situ as reported before [23]. The re- Table 1 Photophysical properties of calixarene 3(C3) in THF solution # λabs max a, nm λem max b, nm εM (at λabs max, 10 4 M–1 ·cm–1) Stokes shift, nm Φf, (%) c (λ ex, nm) d C3 292 379 1.60 113 1.1 (292 nm) a absorption maxima in THF at room temperature; b fluorescence maxima in THF at room temperature; c absolute photoluminescence quantum yield in THF; d excitation wavelength Fig. 1. UV-spectra of calixarene 3 in the presence of Cd2+ and Zn2+ Fig. 2. Emission spectra of calixarene 3 in the presence of Cd2+ and Zn2+ 219 action afforded as low as 6% of the desired calixarene 4, while the rest of the reaction mixture contains several non-identified products. In  preliminary experiments in  a  solution of  THF in  the  presence of even trace amounts of Cd2+ calixarene 4 exhibited a dramatic fluorescence quench- ing. 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