Synthesis and Complexation Studies of Calix[4]crown Telomers Intermolecularly Bridged with Calixarene Segments

Chinese Journal of Chemistry, 2009, 27, 130—134 Full Paper

* E-mail: [email protected]; Tel.: 0086-027-67866423; Fax: 0086-027-67867954 Received April 27, 2008; revised August 18, 2008; accepted September 22, 2008. Project supported by the National Natural Science Foundation of China (Nos. 20602015, 20772038), the Program for Distinguished Young Scientist

of Hubei Province (No. 2007ABB017) and the Program for Chenguang Young Scientist of Wuhan (No. 200750731283). † Dedicated to Professor Qingyun Chen on the occasion of his 80th birthday.

© 2009 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis and Complexation Studies of Calix[4]crown Telomers Intermolecularly Bridged with Calixarene Segments†

LI, Haibing*,a(李海兵) TIAN, Demeia(田德美) CHEN, Yuanyinb(陈远荫) GAO, Zhinong*,b(高志农)

a Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, Hubei 430079, China

bDepartment of Chemistry, Wuhan University, Wuhan, Hubei 430072, China

Three derivatived calix[4]crowns were condensed with calixarene segments: 2,6-bis(bromomethyl)-4-methylanisole (BBA) to afford their telomers TCA[4] in rational yields. The binding sites may complex metal ions or amino acids selectively. The telomers shows different metal ions selectivity in comparison with their monomers, which suggests that calixarene segment bridges play an important role in ion-binding. The liquid-liquid extraction experiment showed that telomer TCA[4]-III was excellent receptor for zwitterionic α-amino acids and soft cations Ag＋ and Pb2＋. The extraction percentage of tryptophan and histidine was as high as 87.9% and 91.5%, respec-tively.

Keywords calixarene, calixcrown, telomer, amino acid

Introduction

Calixcrowns1,2 comprise a family of calixarenes3-5 in which the phenolic oxygens are linked intramolecularly via flexible poly(oxyethylene) chains. As they possess preorganized structures and more rigid binding sites in comparison with calixarene and crown ethers, they ex-hibit superior recognition ability toward alkali metal ions and other ions by the cooperative effects of calix-arene and crown moieties. It is not surprising that many new and functionalized calixcrowns have been synthe-sized,6-11 and numerous applications of calixcrowns have been reported in various fields, for example, iono-phores in ion-selective electrodes, and ion sensitive field-effect transistors.12

Up to date, in comparison with numerous studies on monomeric calixcrowns, less attention has been paid to polymeric calixcrowns. In 1995, Zhong et al.13 firstly reported the synthesis and properties of calixcrown si-loxane oligomer. Ungaro et al.14 reported the utility of calix[4]crown bonded silica gel for the separation of Na＋ and Cs＋ in liquid chromatography. Duhart et al.15 employed a solid membrane composed of calix[4]-bis- crown-6 bonded to polysiloxane backbone to remove cesium from model nuclear waster solution. The calix[6]crown-containing organosilicon resins and their complexation toward metal ions were reported by our group.16 More recently, we synthesized p-tert-butylcalix[4]diazacrown-4 oligomer, containing both hard

and soft ion binding sites, which exhibited high selec-tivity toward cesium ions.17,18

Amino acids, the building blocks of peptides and proteins, play many vital roles in the metabolic proc-esses within living bodies.19 The ability of calixarene based molecules to form complexes with amino acids has been the central topic of many studies. Selectivity towards amino acid species can be tuned by varying the shape and size of the cavity or by modifying the sub-stituents of the upper and lower rims.20 To the best of our knowledge, few papers concerning the amino acid binding properties of polymeric calixcrown were ap-peared until now.

In the present work, we reported synthesis and ex-traction properties toward metal ions and amino acids of new calix[4]crown telomers whose lower rims were intermolecularly bridged with calixarene segments. In these telomers, the bridge and a portion of the original calix[4]crown composed a new calixarene-like subunit, which afforded a new binding site toward cations and bioorganic molecules such as amino acids.

Experimental

Sodium hydride was purchased from Aldrich. Petro-leum ether refers to the fraction with a boiling point in the range 60—90 ℃. All solvents were purified by standard procedures. All other chemicals were analyti-cally pure and used without further purification.

Calixarene Chin. J. Chem., 2009 Vol. 27 No. 1 131


Measurements

Melting points were recorded on a Gallenkamp melting point apparatus in open capillaries and are un-corrected. 1H NMR spectra were recorded on a Varian Mercury VX400 (400 MHz) instrument in which TMS was used as an internal standard for NMR. IR spectra were recorded on a Perkin Elmer 1605 FTIR spec-trometer as KBr Pellets. UV-Vis spectra were obtained on a Shimadzu 1601A UV-Vis recording spectropho-tometer. FAB-MS data were obtained from a Kratos MS80RF mass spectrometer, with m-nitrobenzyl alcohol as a matrix. Elemental analysis was performed by the Analytical Laboratory of the College of Chemistry, Central China Normal University. GPC measurements were carried out at 25 ℃ using THF as eluent with a 1.0 mL/min flow rate. The system was calibrated with polystyrene standards.

General procedure for synthesis of calix[4]crown-4 monomers CA[4]

p-tert-Butylcalix[4]crown-4 (CA[4]-I), p-tert-butylcalix[4]dioxacrown-4 (CA[4]-II) and p-tert-butylcalix[4]diazacrown-4 (CA[4]-III) were synthesized ac-cording to the reported methods in yields of 64%, 27%, and 41%, respectively.21-23

General procedure for synthesis of telomers

A mixture of calix[4]crown (0.5 mmol) and 2,6-bis- (bromomethyl)-4-methylanisole (BBA, 0.17g, 0.55 mmol) was dissolved in a minimum portion of dry di-oxane (10 mL). To this solution, 80% NaH (0.76 g, 25.2 mmol) was added slowly with continuous stirring at room temperature. The reaction mixture was stirred for 12—16 h at room temperature under N2. Then the sol-vent was evaporated, the residue was first washed with hexane and then MeOH (Caution!). After that, a portion of water was added for precipitation (Caution!). The solid material was filtered, washed with water, dried, purified by reprecipitation from a chloroform-methanol system and finally the following oligomers were thus afforded.

Telomer TCA[4]-I from CA[4]-I and BBA

Telomer TCA[4]-I was obtained in 56% yield. Mn＝

5500 Da (calcd: 5448 Da); 1H NMR (CDCl3, 400 MHz) δ: 0.75 (s, 18H, Bu-t), 1.15 (s, 18H, Bu-t), 2.18 (s, 3H, ArCH3), 3.45 (bd, J＝12.4 Hz, 4H, ArCH2Ar), 4.15—4.18 (m, 6H, CH2O), 4.26—4.50 (m, 13H, CH2O and ArOCH3 and ArCH2Ar), 5.52 (bs, 4H, ArCH2OAr), 7.00—7.53 (m, 10H, ArH); IR (KBr) ν: 3400 (—OH, H2O), 1185 (C—O) cm－1. Anal. calcd for (C60H76O7)6: C 79.26, H 8.42; found C 79.35, H 8.62.

Telomer TCA[4]-II from CA[4]-II and BBA

Telomer TCA[4]-II was obtained in yield 73%. Mn

＝4750 Da (calcd: 4680 Da); 1H NMR (CDCl3, 400 MHz) δ: 0.85—1.36 (m, 36H, Bu-t), 2.25 (s, 3H, ArCH3), 3.42 (bd, J＝14.4 Hz, 4H, ArCH2Ar), 3.60—4.50 (m, 15H, CH2O and ArCH2Ar and ArOCH3 and

COCH2O), 5.54 (s, 4H, ArCH2OAr), 7.0—7.45 (m, 10H, ArH); IR (KBr) ν: 3440 (—OH, H2O), 1756 (C＝O), 1200 (C—O) cm－1. Anal. calcd for (C60H72O9)5: C 76.89, H 7.74; found C 76.99, H 7.50.

Telomer TCA[4]-III from CA[4]-III and BBA

Telomer CA[4]-III was obtained in yield 65%. Mn＝

4680 Da (calcd: 4670 Da); 1H NMR (CDCl3, 400 MHz) δ: 1.05 (br s, 18H, Bu-t), 1.37 (br s, 18H, Bu-t), 2.20 (s, 3H, ArCH3), 3.35, 4.43 (br s, each, 4H each, ArCH2Ar), 3.43—3.72 (m, 7H, NHCH2CH2NH and ArOCH3), 4.22 (s, 4H, COCH2), 5.60 (s, 4H, ArOCH2Ar), 6.80—7.34 (m, 10H, ArH), 8.37 (s, 2H, NH); IR (KBr) ν: 3545 (—OH, H2O), 1645 (C＝O), 1204 (C—O) cm－1. Anal. calcd for (C60H74O7N2)5: C 77.06, H 7.97; found C 77.19, H 7.84.

Solvent extraction toward cations

Picrate extraction experiments were performed fol-lowing Ho’s procedure.24 A 5 mL of 5×10－3 mol/L aqueous picrate solution and 5 mL of 5×10－3 mol/L solution of calixarene in CHCl3 were vigorously agi-tated in a stoppered glass tube with a mechanical shaker for 5 min then magnetically stirred in a thermostated water-bath at 25 ℃ for 2 h, and finally left standing for an additional 30 min. The concentration of picrate ion remaining in the aqueous phase was then determined by UV spectra from the resulting absorbance at 380 nm.24 Blank experiments showed that no picrate extraction occurred in the absence of calixarene.

Solvent extraction toward amino acids25

Into each of 25 mL volumetric flasks, the aliquots of solution containing some of amino acids, 2.0 mL of pH 5.2 buffer solution, 4.0 mL of 3% ninhydrin solution and 1.5 mL of 0.3% ascorbic acid solution were added, and the mixture was diluted to the mark with water, then mixed well, heated in an 84—86 ℃ thermostatic wa-ter-bath for 40 min and immediately cooled to room temperature under tap water. The absorbances of the final solutions in 532—600 or 520—600 nm with an interval of 4 nm between every two measurements, against reagent blank (as reference solution) in 1 cm cells were recorded and used for the following calcula-tions.

Results and discussion

Calixarenes are becoming an important class of compounds in supramolecular chemistry. In particular, p-tert-butylcalix[4]arene, which is easily accessible in large quantities, is a very convenient substructure for the synthesis of molecular or cationic receptors and car-riers. It was found that the ester and amide groups played an important role in the complex formation.26 Meanwhile, the calixcrown, 1,3-bridged calix[4]arenes via polyoxyethylene on the lower rim, are novel mar-cocylic compounds (possessing both hydrophilie and lipophilie cavities), and can form complexes with metal

132 Chin. J. Chem., 2009, Vol. 27, No. 1 LI et al.


ions selectively. Thus, having chosen the ester and am-ide group-containing calix[4]crowns as the basis for derivatives that contain a hydrophobic cavity, synthetic schemes have to be developed to enable the derivatiza-tion of the molecule. Such synthetic routes are shown in Scheme 1.

The syntheses of calix[4]crown CA[4] were based on the previous procedure. Reacting p-tert-butylcalix- [4]arene 1 with bifuncional group agents in the presence of carbonate salts as base in acetontrile under a nitrogen atmosphere afforded compounds CA[4]-I, CA[4]-II and CA[4]-III in 64%, 27% and 41% yields, respectively. To the dioxane solution of CA[4], was added NaH at room temperature, followed by 1.1 equiv. of BBA with stirring and refluxing for 12—16 h. The excess of NaH was quenched by addition of a minimal quantity of methanol (caution!). Distilling off the solvent, the resi-due was treated with HCl (10%, V/V) and then with wa-ter, and recrystallized from methanol-CHCl3, telomers TCA[4] were isolated in 56%, 73% and 65%, respec-tively. Mn ＝ 5500 Da for TCA[4]-I, 4750 Da for TCA[4]-II, and 4680 Da for TCA[4]-III. As could be seen in Table 1, the polydispersities of the three te-lomers were low. Thus they were obtained with chain lengths around 5—6 calixcrown units.

Table 1 Molecular weight and polydispersity of telomers

Mn/Da Polydispersitya

TCA[4]-I 5500 1.15

TCA[4]-II 4750 1.23

TCA[4]-III 4680 1.17 a GPC in THF vs. polystyrene at 25 ℃.

All new compounds were characterized by a combi-nation of IR, 1H NMR, and elemental analysis. The conformational characterization of the calixarenes was conveniently estimated by the splitting pattern of the ArCH2Ar methylene protons in the 1H NMR spectros-copy. All monomers CA[4] adopted a cone conforma-tion.21-23 From 1H NMR data, it was deduced that the p-tert-butylcalix[4]arene units in the telomers TCA[4]s all existed in a cone conformation, which was clearly indicated by the typical AB system for the two anisot-ropic hydrogen atoms.

SEM results of the surface morphology of TCA[4]-I, TCA[4]-II and TCA[4]-III are presented in Figure 1, which shows that the surface of TCA[4]-III exhibits some porous structures, whereas TCA[4]-I and TCA[4]-II did not exhibit a silimar architecture (Fig-ures 1a and 1b).

Scheme 1 Synthetic routes of p-tert-butylcalix[4]crown monomers and their telomers

Reagents and conditions: (i) Na2CO3, TsO(CH2CH2O)2CH2CH2OsT; (ii) K2CO3/KI, (ClCH2CO2CH2)2/benzene; (iii) K2CO3/KI, (ClCH2CONH-

CH2)2/CH3CN; (iv)NaH/dioxane.

Figure 1 SEM of (a) TCA[4]-I, (b) TCA[4]-II and (c) TCA[4]-III.

Calixarene Chin. J. Chem., 2009 Vol. 27 No. 1 133


We were interested in synthesizing a type of iono-phore that could selectively extract the metal cations from the aqueous to the organic phase. Therefore, sol-vent extraction experiments were performed to see the effectiveness of the telomers TCA[4]. The results of two-phase extraction measurements are summarized in Table 2. Data obtained with monomers are included for comparison. These data were obtained by using a chlo-roform solution of these compounds to extract metal picrates from the aqueous phase. The equilibrium con-centration of picrates in the aqueous phase was deter-mined spectrophotometrically. As shown in Figure 2, p-tert-butylcalix[4]diazacrown-4 oligomer with poly-ether bridge PCA[4] reported by our previous work17

was used as reference compound to determine the in-fluence of the BBA moiety on the percent of extraction.

Figure 2 Oligomer PCA[4]: p-tert-butylcalix[4]diazacrown-4 telomer with polyether bridge.

From the data given in Table 2, on the introduction of ester and amide groups into calixcrown moiety, the transferring characteristic of telomers TCA[4]-II and TCA[4]-III were increased to some extent for transition metal cations. This could be attributed to the C＝O, or NHC＝O groups containing π bonds, which was pref-erable to complex the more polarizable transition metal ions that were known as soft metal cations due to cation-π interactions. The phenomenon might also re-flect the “Principle of hard and soft acids and bases” introduced by Ho.24 In comparison with p-tert-butylcalix[4]diazacrown-4 oligomer with polyether bridge PCA[4] (Figure 2), p-tert-butylcalix[4]-diazacrown-4

telomer with BBA TCA[4]-I showed a high selectivity towards silver cations. This could be attributed to that the BBA bridges introduced more cation-π interaction and new cavity into the oligomer frameworks.

Observation showed that the extraction ratios of Pb2＋ and Ag＋ with oligomer TCA[4]-I increased as compared to its parent monomer CA[4]-I. In the case of oligomer TCA[4]-II with ester groups, better affinity can be seen for transition metal ions, especially for Cu2＋

than its monomer CA[4]-II. And meanwhile oligomer TCA[4]-III showed a high affinity towards transition metal ions than its monomer CA[4]-III. The increased affinity of oligomers could be attributed to the effective aggregation of calix[4]arene in the oligomers and BBA bridges of the oligomers, which played an important role in extraction procedure.

The extraction percentages of a series of zwitterionic α-amino acids (see Figure 3) from water into CHCl3 are summarized in Table 3. As expected, telomers exhibited good extraction ability towards tested α-amino acids. It was worthy of noting that the extraction ability of polymeric calixcrowns for zwitterionic α-amino acids was studied for the first time, and the extraction per-centage of calix[4]diazacrown-4 telomer was out

Figure 3 List of zwitterionic amino acids.

Table 2 Percentage extraction of picrate salts in CHCl3 at 25 ℃a

Host Li＋ Na＋ K＋ Cs＋ Cu2＋ Cd2＋ Pb2＋ Ag＋ Cs＋/Na＋ Ag＋/Na＋

CA[4]-I ＜1.0 1.4 ＜1.0 ＜1.0 ＜1.0 2.0 1.3 5.6 — 4.0

CA[4]-II ＜1.0 3.2 4.6 5.6 7.2 5.8 7.5 21.0 1.75 6.6

CA[4]-III 1.4 2.9 2.5 7.8 14.2 16.2 21.6 30.5 2.69 10.5

TCA[4]-I ＜1.0 0.8 4.3 2.7 ＜1.0 2.1 9.4 15.7 3.38 19.6

TCA[4]-II 1.7 3.5 9.5 9.6 34.3 11.2 18.8 26.0 2.74 7.4

TCA[4]-III 3.5 6.7 5.3 14.5 37.6 32.5 53.8 77.5 2.16 11.6

PCA[4] 2.5 4.4 7.5 49.7 19.6 18.4 24.8 29.6 11.30 6.7 a Control experiments showed that the extraction percentage for amino acids was less than 0.2% in the absence of the host.

134 Chin. J. Chem., 2009, Vol. 27, No. 1 LI et al.


Table 3 Percentage extraction of α-amino acids in CHCl3 at 25 ℃

Host Gly Iso Met Thr Lys Pro His Try

CA[4]-I 3.2 6.2 3.8 6.8 8.4 11.5 10.7 17.8

CA[4]-II 5.8 5.0 6.3 7.4 9.3 11.3 15.6 18.5

CA[4]-III 6.5 7.9 9.3 8.7 12.5 13.8 18.5 15.6

TCA[4]-I 14.5 23.5 13.8 27.7 32.9 46.3 45.1 58.9

TCA[4]-II 23.4 16.3 20.8 35.7 41.6 48.4 56.8 68.9

TCA[4]-III 25.7 30.6 38.4 35.6 56.8 55.3 91.5 87.9

standing among all kinds of calixarene derivatives, al-though some calixarene derivatives,27 especially, aque-ous miscible or hydrophilic calixarene derivatives con-taining carboxylic acids28,29 and phosphonates30,31 were reported to bind amino acids or amino acid esters. The extraction result of telomer TCA[4]-III indicated that calix[4]diazacrown-4 telomer TCA[4]-III was an effec-tive receptor not only for metal cations, but also for bioorganic molecules, such as amino acids. The extrac-tion percentage of tryptophan and histidine was as high as 87.9% and 91.5%, respectively.

Conclusion

Three derivative calix[4]crown-4 compounds were condensed with calixarene segments: 2,6-bis(bromomethyl)-4-methylanisole (BBA) to afford their telomers, p-tert-butylcalix[4]crown-4 telomer (TCA[4]-I), p-tert-butylcalix[4]dioxacrown-4 telomer (TCA[4]-II), p-tert-butylcalix[4]diazacrown-4 telomer (TCA[4]-III) in rational yields. The binding sites may complex metal ions or amino acids selectively. The telomers are fairly good extractants for heavy metal ions in comparison with their monomers, which suggests that the calixarene segment bridges are efficient for complexing heavy metal ions. The liquid-liquid extraction experiment showed that telomer TCA[4]-I possessed a good silver ion-binding selectivity and TCA[4]-III was an excellent receptor for zwitterionic α-amino acids. The extraction percentage of tryptophan and histidine was as high as 87.9% and 91.5%, respectively. Further research on the application of calix[4]crown-4 oligomers is still under-way.

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Synthesis and Complexation Studies of Calix[4]crown Telomers Intermolecularly Bridged with Calixarene Segments