Recognition of chiral anions using calix[4]arene-based ureido receptor in the 1,3-alternate conformation

Tetrahedron 70 (2014) 477e483

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Recognition of chiral anions using calix[4]arene-based ureido receptor in the 1,3-alternate conformation
clav Eigner b, Oldrich Hude
s Vrzal c, Filip Botha a, Jan Budka a, Va cek a, Luka
k a, *
d, Pavel Lhota Ivana Císarova
5, 166 28 Prague 6, Czech Republic Department of Organic Chemistry, Institute of Chemical Technology Prague (ICTP), Technicka
5, 166 28 Prague 6, Czech Republic Department of Solid State Chemistry, ICTP, Technicka c
5, 166 28 Prague 6, Czech Republic Laboratory of NMR Spectroscopy, ICTP, Technicka d Department of Inorganic Chemistry, Charles University, Hlavova 8, 128 43 Prague 2, Czech Republic a

b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 26 August 2013 Received in revised form 29 October 2013 Accepted 12 November 2013 Available online 16 November 2013

A new type of calixarene-based receptor designed for the recognition of chiral anions was prepared by the introduction of (S)-2-methylbutan-1-ol moieties into the lower rim of calixarene. The immobilization of calixarene skeleton in the 1,3-alternate conformation enabled the construction of a cavity consisting of preorganised ureido functions and chiral substituents in close proximity. This cavity is capable of chiral discrimination of selected anions as demonstrated on D- and L-phenylalaninates. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Calixarene Alkylation NMR titration Chiral receptor Anion recognition

1. Introduction Anions are ubiquitous in various biological systems and their basic role in the functioning of living matter is well recognized. Not surprisingly, the study of the complexation/recognition of anionic species represents an important part of modern supramolecular chemistry as can be easily proven by many review articles1 and books2 focused recently on this topic. Given the importance of anions in environmental pollution or industrial processes, chemistry, biology or medicine, serious efforts have been paid for the development of synthetic receptors and sensors for recognition of anions.3 Many strategies have been developed for anion recognition in last few decades. Obviously, the major approach that has been utilized so far relied on the electrostatic interactions of anions with positively charged species like quaternary ammonium salts, polyammonium azacryptands or guanidinium cations.4 As the electrostatic attraction forces represent non-directional interactions, the role of these compounds in the deliberate design of novel receptors is rather questionable. On the other hand, the application of highly

* Corresponding author. Tel.: þ420 220 445 055; fax: þ420 220 444 288; e-mail
k). address: [email protected] (P. Lhota 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.11.030

directional hydrogen bonding interactions from neutral molecules bearing amidic, sulfonamidic, ureido/thioureido or triazole functions,5 enables the design of tailor-made receptors with precisely defined structures and mutual positions of functional groups. In this context, calix[4]arenes are frequently used as molecular scaffolds because of their well-established chemistry offering easy derivatization, and tuneable three-dimensional shapes of the cavity resulting in four basic conformations (cone, partial cone, 1,3alternate and 1,2-alternate).6 The potential choice of four different shapes (conformations) makes calix[4]arenes attractive candidates for the application in the design of novel receptors, as one can create almost limitless combinations of various functional groups with exactly defined mutual positions. Many neutral calixarene-based ligands for the complexation of anions have been reported in literature in the last decade.7,8 During our ongoing research on anion recognition we have focused mainly on receptors based on urea, thiourea or amidic functional groups,9 which are well-accessible in various conformations. We have shown that diureidocalix[4]arenes in the cone conformation,10a which is the most frequently used conformer for construction of various receptors, can be efficient ligands (Fig. 1, A) for recognition of anions possessing different binding geometries. Surprisingly, immobilization in the 1,3-alternate conformation (Fig. 1, B) makes these derivatives even more efficient as shown recently for selected

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Fig. 1. Calix[4]arene based receptors for anion recognition in the cone (A) and 1,3-alternate (B) conformation, schematic design of chiral receptors in the 1,3-alternate conformation (C).

anions.10b In this connection, we have realized that the 1,3-alternate conformation, albeit synthetically not so simply available, possesses one reasonable advantage if compared with the cone analogue. The introduction of chiral substituents into the lower rim of inverted phenolic units (Fig. 1, C) allows the construction of receptors bearing preorganized ureido cavity with a chiral surrounding nearby. In this paper we report on the preparation of this kind of receptor and its use for the recognition of chiral anions.11 2. Results and discussion The alkylation of starting calix[4]arene 1 with (S)-2methylbutan-1-ol was carried out using Mitsunobu reaction as described for thiacalixarene analogue.12 The rapid screening of the reaction conditions (Table 1) revealed that refluxing of 1 with 10 equiv of chiral alcohol in the presence of PPh3 (6 equiv) and DIAD (6 equiv) in toluene for 3 days gave distally dialkylated derivative 2 in 59% yield after simple crystallization. Small amount (1% yield) of monoalkylated calixarene 2a was also obtained as the byproduct. Compound 2 was nitrated with 65% aqueous HNO3 in DCM applying the procedure used for nitration of dipropoxycalix [4]arene.13 These conditions led regioselectively to the dinitro derivative 3 with para-nitrated free phenolic subunits in 54% yield (Scheme 1). Table 1 Optimization of Mitsunobu reactiondpreparation of derivative 2 ROHa

PPh3a

DIADa

Time

Products

10 10 10 10 10 10

1.4 1.4 3 3 6 6

1.6 1.6 3 3 6 6

2 days 3 weeks 3 days 3 weeks Overnight 3 days

Starting 1þ2a (1:1)b Starting 1þ2a (4:5)b 2 (20%)c 2 (23%)c 2 (50%)c 2 (59%)dþ2a (1%)

a

Equivalents of agents per calixarene 1. Based on the integral intensities of phenolic functions in 1H NMR spectrum of the crude reaction mixture. c Isolated by column chromatography. d Isolated by simple crystallization. b

Subsequent alkylation with hexyl iodide (longer alkyl chain was used to improve solubility in organic solvents) is the key-step of the whole reaction sequence. Unfortunately, despite extensive variations in the reaction conditions (base, solvent, reaction temperature and time) the unwanted partial cone derivative 4a was always isolated as the main stereoisomer while the desired 1,3-alternate conformer 4b was formed only as a minor byproduct. Thus, the application of KH/DMF, TMSOK/dioxane, KHMDS/THF or Cs2CO3/ acetone systems at various temperatures did not lead to meaningful yield of the 1,3-alternate conformation 4b. The best yield was finally achieved using Cs2CO3 as a base and DMF as reaction solvent at 110  C for 1 week. These conditions led to the isolation of 4b in 15% and 4a in 32% yield after column chromatography on silica gel.

The mono-substituted partial cone isomer 4c was also isolated and characterized as a minor byproduct (<1% yield). Unfortunately, the yield of the 1,3-alternate conformer 4b is reasonably influenced by the scale of reaction. Synthetically acceptable yield was achieved using 1.00 g (compound 3) scale of the reaction, all our attempts to increase the amount of starting compound led to substantially lower yields (e.g., 10% yield at 2 g scale), which makes this step a serious bottle-neck of the whole reaction sequence (Table 2). On the other hand, the partial cone isomer 4a can be selectively obtained using Mitsunobu reaction conditions where it was isolated as the sole reaction product in 52% yield. The 1,3-alternate isomer 4b was then reduced by SnCl2$2H2O in ethanol14 to give the corresponding amine 5 in almost quantitative yield (97%). The final reaction with commercial p-nitrophenyl isocyanate in DCM gave the chiral receptor 6 in 42% yield after purification. The structure and the conformation of nitro derivative 6 were confirmed using 1H NMR spectroscopy. The symmetry of 1,3-alternate conformation leads to two triplets of terminal CH3 groups (at 0.75 and 0.90 ppm in DMSO-d6) and one doublet of CH3 group from chiral unit (0.60 ppm). The splitting pattern and multiplicity of signals in aromatic part of spectrum perfectly corresponds with expected signals. Thus, two doublets at 7.65 and 8.15 ppm with typical ortho-interaction constants (J¼9.4 Hz) support the presence of p-nitrophenyl groups, while two singlets at 8.36 and 9.37 ppm originated from the ureido NeH protons. The final unambiguous structural evidence was obtained by X-ray crystallography. Single crystals were obtained by slow evaporation of acetonitrile/acetone 1:1 (v/v) solution and 6 crystallized into the triclinic system, space group P1 with two molecules in the asymmetric unit. As shown in Fig. 2, the individual molecules are interconnected via hydrogen bonding interactions between ureido NH groups and ureido carbonyl oxygen of the neighbour molecule. Every calixarene molecule includes three molecules of solvent (MeCN), the first one is located deeper in the cavity and held by CHep interactions from inverted aromatic units, the other two molecules are fixed by complicated array of hydrogen bonding (NH/N^C, aromH/N^C) and electrostatic interactions. The complexation abilities of receptor 6 towards selected chiral anions were investigated by standard 1H NMR titration experiments. The aliquots of anion were gradually added to the solution of ligand (concentration 3.0e5.0 mM) in the NMR tube to achieve different calixarene/anion ratios (1:0.3e10). To ensure the solubility of both organic ligand and ionic guests DMSO-d6 was used as a solvent. All anions were added in the form of their tetrabutylammonium salts to minimize possible unwanted interactions of calixarene cavity with counter cations. Under these conditions, the addition of anions to receptor led to remarkable down-field shifts of ureido NH signals thus indicating that the complexation phenomenon occurred under fast exchange conditions. Despite the fact that DMSO is known as a highly competitive solvent towards HB interactions, very high complexation induced chemical shifts (CIS) were observed for all anions measured. Thus, the NH signals of free receptor can be found at 8.36 and 9.37 ppm, while these signals moved to 11.44 and 12.54 ppm upon the addition of 10 equiv of D-Phe anion (CIS>3.0 ppm). This clearly indicates some hydrogen bonding interactions between anion and calixarene ligand. The complexation constants for the anions were determined by analyzing the binding isotherms (obtained from the CIS values of NH ureido protons) using the original nonlinear curve-fitting program (program OPIUM).15 Fig. 3 shows a typical titration curve constructed for 6/N-Ac-Phe-O system. All titration curves best fit with the formation of 1:1 complexes (calix/anion). The stoichiometry of the complexes was unambiguously proven by the independent Job plot analysis16 for selected anions (Fig. 4) or by Job

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479

Scheme 1. Preparation of receptor 6: (i) (S)-2-methylbutan-1-ol/DIAD/PPh3/toluene (59%); (ii) HNO3/DCM (54%); (iii) hexan-1-ol/DIAD/PPh3/toluene (4a, 52%); (iv) 1-iodohexane/ Cs2CO3/DMF (4a, 32%, 4b, 15%); (v) SnCl2$2H2O/EtOH (97%); (vi) p-nitrophenyl isocyanate/DCM (42%).

Table 2 The influence of the scale on yield of 4b (alkylation of 3) Starting amount of 3

Isolated yield of 4b

400 mg 1000 mg 2000 mg

17% 15% 10%

Fig. 3. 1H NMR titration of receptor 6 with Bu4Nþ D-/L-phenylalaninate (DMSO-d6, 300 MHz, 298 K). For details see Supplementary data.

Fig. 2. X-ray structure of receptor 6 with intermolecular hydrogen bonds, included molecules of MeCN shown as ball and stick format.

plots constructed from titration data. The 1:1 stoichiometry of complexes was also confirmed by LC/HRMSeESI technique in acetonitrile as an HB competitive solvent. The calculated binding constants are summarized in Table 3. It shows that the binding site composed of two preorganized ureido functions can bind carboxylates and possess some ability of chiral discrimination. Thus, N-Ac-D-Phe-O anion is bound by 6 (KN-Ac-D1 Phe¼348 M ) more efficiently than its L enantiomer 13 (KN-Ac-L1 ¼161 M ) leading to selectivity factor s¼2.16. Interestingly, the Phe

binding constants for D-/L-leucinate and D-/L-tryptophanate showed inverse selectivity with selectivity factors s¼1.13 and 1.52 for Lisomers, respectively. The highest complexation constant was obtained for D-phenylalaninate (KD-Phe¼636 M1), where one can find also the highest selectivity factor 2.86 for D-isomer. The comparison with R and S mandelates revealed that the presence of a-hydroxy group did not lead to any measurable chiral discrimination between both enantiomers (s¼1.01), which indicates the irreplaceable role of a-amino functional group in the recognition process. 3. Conclusions In conclusion, the introduction of chiral substituents into the immediate proximity of ureido functional groups, forming a cavity for anion recognition via hydrogen bonding interactions, leads to receptor, which is capable of chiral recognition of selected anions. While a-hydroxy substituted carboxylates did not show any chiral

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60F254 (Merck) and analyzed at 254 or 365 nm. Column chromatography was performed using Silica gel Geduram 60F254 (Merck, particle size 0.063e0.200 mm); technical grade Silica gel (Aldrich, particle size 0.040e0.063 mm, pore size 60  A) or Aluminium oxide 90 standardized (Merck, particle size 0.063e0.200 mm). Preparative TLC chromatography was carried out on 2020 cm glass plates covered by Silica gel 60GF254 (Merck). 4.2. 25,27-Bis[(S)-2-methylbutoxy]calix[4]arene-26,28-diol (2)

Fig. 4. Job plot for system 6dD-phenylalaninate (1H NMR titration, DMSO-d6, 300 MHz, 298 K). For details see Supplementary data.

Table 3 Binding constants of receptor 6 towards selected anions (1H NMR titration, 300 MHz, DMSO-d6, 298 K)a Anionb

K [M1]

Selectivityc

N-Ac-D-Phenylalaninate N-Ac-L-phenylalaninate N-Ac-L-Leucinate N-Ac-D-Leucinate N-Ac-L-Tryptophanate N-Ac-D-Tryptophanate (R)-Mandelate (S)-Mandelate D-Phenylalaninate L-Phenylalaninate

34846 16111 33916 29919 37244 24514 13120 12918 63649 22226

2.16 (for D)

a b c

1.13 (for L) 1.52 (for L) 1.01 (for R) 2.86 (for D)

Referenced for TMS. For structures of anions see Supplementary data. Selectivity factor: s¼KD/KL or KL/KD to obtain s1.

discrimination, the corresponding amino acids are recognized with selectivity factors up to 2.8 (Kd/Kl). The further exploitation of this simple approach towards chiral anion receptors based on calixarenes is currently in progress. 4. Experimental 4.1. General All chemicals were purchased from commercial sources and used without further purification. Solvents were dried and distilled using conventional methods. Melting points were measured on Heiztisch Mikroskop-Polytherm A (Wagner & Munz, Germany) and are not corrected. The IR spectra were measured on an FT-IR spectrometer Nicolet 740 in CHCl3 and/or in KBr at a spectral resolution of 4 cm1. NMR spectra were performed on Varian Gemini 300 (1H: 300 MHz, 13C: 75 MHz) and on Bruker 600 AvanceIII (1H: 600 MHz, 13C: 151 MHz) spectrometers. Deuterated solvents used are indicated in each case. Chemical shifts (d) are expressed in parts per million and are referenced to the residual peak of solvent or TMS as an internal standard; coupling constants (J) are in hertz. Signal assignment was supported by 1He1H COSY, 1He13C HMQC or 1 He13C HMBC 2D NMR and 1D 1H-DPFGSE NOE experiments using the standard pulse sequences provided by Bruker. The mass analyses were performed using ESI technique on a Q-TOF (Micromass) spectrometer. Polarimetry was performed with a Rudolph research analytical Autopol VI instrument with a Na lamp (589 nm, continuous). The purity of the substances and the courses of reactions were monitored by TLC using TLC aluminium sheets with Silica gel

Starting calix[4]arene 1 (2.544 g, 6.00 mmol), triphenylphosphine (9.45 g, 36 mmol) and (S)-2-methylbutan-1-ol (6.48 ml, 60 mmol) were dissolved in dry toluene (150 ml). The reaction mixture was cooled to 0  C and DIAD (diisopropyl azodicarboxylate, 7.50 ml, 36 mmol) was added dropwise. The mixture was stirred for 5 min at 0  C and then heated to 120  C (oil bath) for 48 h while the course of the reaction was checked by TLC (hexane/EtOAc¼16:1 v/ v). The reaction mixture was then cooled to room temperature, toluene was evaporated on vacuum evaporator and the liquid residue was precipitated by addition of hot methanol (40  C, 50 ml). The precipitate was filtered off, washed thoroughly with cold methanol and dried overnight in drying oven to yield 2.00 g (59%) of title compound17 in the form of white microcrystals. Analytical sample can be obtained by slow evaporation of benzene solution. Mp 242e244  C (benzene). Rf¼0.3e0.4 (hexane/EtOAc¼16:1 v/v). 1 H NMR (CDCl3, 300 MHz, 25  C) d (ppm): 8.11 (s, 2H, eOH), 7.06 (m, 4H, AreH), 6.89 (d, 4H, J¼7.6 Hz, AreH), 6.73 (t, 2H, J¼7.5 Hz, AreH), 6.64 (t, 2H, J¼7.5 Hz, AreH), 4.32 (m, 4H, AreCH2eAr ax), 3.82 (m, 4H, eOCH2e), 3.37 (m, 4H, AreCH2eAr eq), 2.10 (m, 2H, eCHe), 1.82 (m, 2H, eCH2e), 1.52 (m, 2H, eCH2e), 1.32 (d, 6H, J¼6.7 Hz, eCH3), 1.04 (t, 6H, J¼7.5 Hz, eCH3). 13C NMR (CDCl3, 75.4 MHz, 25  C) d (ppm): 153.5, 151.7, 133.0, 132.8, 128.9, 128.8, 128.4, 127.9, 127.7, 125.2, 118.7, 81.8, 36.0, 31.4, 31.1, 26.0, 16.7, 11.6. IR (KBr) n (cm1): 3352, 2962, 2922, 2875, 1463, 1198, 997, 755. [a]25 D þ8.9 (c 2.51, CHCl3). HRMSeESI (C38H44O4) m/z (% int.) calcd: 587.3132 [MþNa]þ, 603.2871 [MþK]þ, found: 587.3129 [MþNa]þ (100%), 603.2866 [MþK]þ (57%). 4.3. 25-[(S)-2-Methylbutoxy]calix[4]arene-26,27,28-triol (2a) This compound was obtained as byproduct from the mother liquer in previous reaction. Isolated by preparative TLC on silica gel using EtOAc/hexane 1:16 (v/v) as an eluent. White crystals, mp 214e220  C (CDCl3). Rf¼0.2e0.3 (hexane/EtOAc¼16:1 v/v). 1H NMR (CDCl3, 300 MHz, 25  C) d (ppm): 9.62 (s, 1H, eOH), 9.33 (s, 1H, eOH), 9.32 (s, 1H, eOH), 7.08e6.98 (m, 8H, AreH), 6.87e6.82 (t, 1H, J¼7.5 Hz, AreH), 6.70e6.65 (m, 3H, AreH), 4.40e4.16 (m, 4H, AreCH2eAr), 4.01e3.87 (m, 2H, eOCH2e), 3.49e3.43 (m, 4H, AreCH2eAr), 2.29e2.23 (m, 1H, eCHe), 1.85e1.76 (m, 1H, eCH2e), 1.55e1.46 (m, 1H, eCH2e), 1.36e1.33 (d, 3H, J¼6.7 Hz, eCH3), 1.11e1.06 (t, 3H, J¼7.5 Hz, eCH3). 13C NMR (CDCl3, 75,4 MHz, 25  C) d (ppm): 151.5, 151.0, 148.9, 134.0, 129.3, 128.8, 128.4, 128.3, 128.3, 128.1, 126.0, 122.1, 120.8, 120.7, 82.9, 35.8, 31.9, 31.4, 31.3, 29.7, 26.3, 17.0, 11.4. IR (KBr) n (cm1): 3318, 2924, 2872, 1465, 1386, 1247, 1194, 754. HRMSeESI (C33H34O4) m/z (% int.) calcd: 512.2795 ½M þ NH4 þ ; 517.2349 [MþNa]þ, 533.2089 [MþK]þ, 495.2530 [MþH]þ, found: 512.2798 ½M þ NH4 þ (100%), 517.2351 [MþNa]þ (40%), 533.2090 [MþK]þ (36%), 495.2532 [MþH]þ (16%). 4.4. 25,27-Bis[(S)-2-methylbutoxy]-5,17-dinitrocalix[4]arene26,28-diol (3) Calixarene 2 (7.964 g, 14.101 mmol) was dissolved in dry dichloromethane (850 ml) and 65% aqueous HNO3 (11.86 ml) was added dropwise at room temperature under an intensive stirring. The reaction mixture was then heated to reflux and the course of

F. Botha et al. / Tetrahedron 70 (2014) 477e483

reaction was carefully checked by TLC (eluent: dichloromethane/ hexane 2:1 v/v). After 15 min the reaction mixture was quenched by saturated aqueous solution of Na2CO3 (300 ml) and the mixture was stirred for 5 min. The water phase was extracted with DCM (315 ml), organic extracts were combined, washed thoroughly with distilled water and dried over MgSO4. The solvent was then evaporated, the residue dissolved in small amount of DCM and precipitated by methanol. Product 3 was obtained after drying (5.00 g, 54% yield) in the form of yellow crystals. Analytical sample can be obtained by crystallization from MeCN or DCM/i-PrOH mixture. Mp 118e120  C (acetonitrile). Rf¼0.30 (DCM/hexane¼2:1 v/v). 1H NMR (CDCl3, 300 MHz, 25  C) d (ppm): 9.24 (s, 2H, eOH), 8.04 (s, 4H, AreH), 6.96 (d, 4H, J¼7.6 Hz, AreH), 6.82 (t, 2H, J¼7.3 Hz, AreH), 4.29 (m, 4H, AreCH2eAr ax), 3.85 (m, 4H, eOCH2e), 3.50 (m, 4H, AreCH2eAr eq), 2.11 (m, 2H, eCHe),1.78 (m, 2H, eCH2e),1.54 (m, 2H, eCH2e),1.32 (d, 6H, J¼6.7 Hz, eCH3), 1.05 (t, 6H, J¼7.5 Hz, eCH3). 13C NMR (CDCl3, 75.4 MHz, 25  C) d (ppm): 159.7, 151.7, 139.7, 131.7, 131.5, 129.7, 129.6, 128.3, 128.0, 125.8, 124.5, 82.5, 35.9, 31.2, 31.0, 26.0, 16.7, 11.5. IR (KBr) n (cm1): 3252, 2962, 2928, 2875, 1590, 1515, 1460, 1334, 1264, 1209, 1099, 991, 911, 733. [a]25 þ9.5 (c 0.78, CHCl3). HRMSeESI D (C38H42N2O8) m/z (% int.) calcd: 677.2833 [MþNa]þ, 693.2573 [MþK]þ, found: 677.2804 [MþNa]þ (77%), 693.2544 [MþK]þ (30%). 4.5. 26,28-Dihexyloxy-25,27-bis[(S)-2-methylbutoxy]-5,17dinitrocalix[4]arene (1,3-alternate) (4b) and (partial cone) (4a) A mixture of diol 3 (2.0 g, 3.05 mmol) and anhydrous caesium carbonate (7.07 g, 21.7 mmol) was suspended in dry N,N-dimethylformamide (150 ml) and the reaction mixture was gradually heated to 110  C during 1 h. Hexyl iodide (3.22 ml, 21.7 mmol) was then added dropwise and the mixture was stirred at 110  C for 2 days. New portion of caesium carbonate (7.07 g, 21.7 mmol) and hexyl iodide (3.22 ml, 21.7 mmol) was added and the reaction mixture was stirred for next 12 days. The solvent (DMF) was evaporated on a vacuum evaporator, the residue was treated with 1 M aqueous HCl and extracted repeatedly with dichloromethane. The organic layers were combined and successively washed with aqueous sodium thiosulfate solution, brine and water. After drying on MgSO4 the solvent was evaporated and the crude product was purified by column chromatography on silica gel. The column was first eluted with pure hexane to remove the remaining alkylating agent, and then with DCM/hexane 1:1 (v/v) mixture to yield 260 mg (11% yield) of title compound 4b (1,3-alternate) and 800 mg (32%) of the partial cone isomer 4a. 4.5.1. Partial cone isomer 4a. Yellow glass, mp 60e70  C (DCM/ MeOH). Rf¼0.6e0.7 (DCM/hexane¼1:1 v/v). 1H NMR (CDCl3, 300 MHz, 25  C) d (ppm): 8.23 (s, 2H, AreH), 8.02 (s, 2H, AreH), 6.95 (m, 2H, AreH), 6.45 (t, 2H, J¼7.6 Hz, AreH), 6.17 (d, 2H, J¼7.0 Hz, AreH), 4.13 (m, 2H, AreCH2eAr), 3.92 (t, 2H, J¼7.1 Hz, eOCH2e), 3.77e3.67 (m, 4H, AreCH2eAr), 3.61 (m, 2H, eOCH2e), 3.42 (m, 4H, eOCH2e), 3.20 (d, 2H, J¼13.8 Hz, AreCH2eAr), 2.09e1.93 (m, 4H, eCH2e), 1.78e1.65 (m, 2H, eCHe), 1.57e1.52 (m, 4H, eCH2e), 1.45e1.23(m, 12H, eCH2e), 1.15 (t, 6H, J¼6.7 Hz, eCH3), 1.04 (m, 6H, eCH3), 0.96 (t, 3H, J¼7.0 Hz, eCH3), 0.88 (t, 3H, J¼7.2 Hz, eCH3). 13C NMR (CDCl3, 75.4 MHz, 25  C) d (ppm): 163.0, 162.9, 155.7, 142.1, 137.9, 135.2, 132.0, 130.8, 129.4, 128.8, 125.3, 124.5, 122.1, 80.6, 74.5, 74.4, 36.1, 35.0, 31.7, 31.4, 30.8, 30.7, 29.2, 26.5, 26.4, 25.8, 25.0, 22.9, 22.7, 17.0, 16.9, 14.0, 13.9, 11.3. IR (KBr) n (cm1): 2958, 2930, 2872, 1519, 1453, 1340, 1194, 1093, 996, 752. [a]25 D þ3.7 (c 5.26, CHCl3). HRMSeESI (C50H66N2O8) m/z (% int.) calcd: 845.4711 [MþNa]þ, 840.5157 ½M þ NH4 þ ; 861.4451 [MþK]þ, found: 845.4713 [MþNa]þ (100%), 840.5163 ½M þ NH4 þ (34%); 861.4451 [MþK]þ (32%). 4.5.2. 1,3-Alternate isomer 4b. White microcrystals, mp 111e113  C (DCM/MeOH). Rf¼0.2e0.3 (DCM/hexane¼1:1 v/v). 1H NMR (CDCl3, 300 MHz, 25  C) d (ppm): 7.95 (s, 4H, AreH), 7.01 (d, 4H, J¼7.3 Hz,

481

AreH), 6.69 (t, 2H, J¼7.6 Hz, AreH), 3.74e3.52 (m, 16H, AreCH2eArþeOCH2e), 2.04 (m, 2H, eCHe), 1.75 (m, 4H, eCH2e), 1.64e1.53 (m, 2H, eCH2e), 1.48e1.22 (m, 14H, eCH2e), 1.04e0.94 (m, 18H, eCH3). 13C NMR (CDCl3, 75,4 MHz, 25  C) d (ppm): 161.7, 156.3, 141.7, 134.7, 132.2, 130.2, 124.9, 124.8, 122.0, 78.8, 73.3, 36.3, 35.4, 31.7, 30.3, 26.4, 25.6, 22.6, 16.4, 14.0, 11.3. IR (KBr) n (cm1): 2957, 2931, 2871, 1523, 1452, 1342, 1195, 1096, 997, 750. [a]25 D þ0.2 (c 1.1, CHCl3). HRMSeESI (C50H66N2O8) m/z (% int.) calcd: 845.4711 [MþNa]þ, found: 845.4715 [MþNa]þ (100%). 4.6. 26,28-Dihexyloxy-25,27-bis[(S)-2-methylbutoxy]-5,17dinitrocalix[4]arene (partial cone) (4a) (alternative preparation) Starting calix[4]arene 3 (0.654 g, 1.00 mmol), triphenylphosphine (1.58 g, 6 mmol) and hexan-1-ol (1.26 ml, 10 mmol) were dissolved in dry toluene (50 ml). The reaction mixture was cooled to 0  C and DIAD (diisopropyl azodicarboxylate, 1.25 ml, 6 mmol) was added dropwise. The mixture was stirred at 0  C for 5 min and then heated to 120  C (oil bath) for 3 days. The reaction mixture was then cooled to room temperature, toluene was evaporated on vacuum evaporator, and the residue was purified by column chromatography on silica gel using EtOAc/hexane 1:16 (v/v) mixture as eluent. The title compound (435 mg, 52% yield) was obtained in the form of yellow glass. Rf¼0.5 (hexane/EtOAc¼16:1 v/v). 4.7. 26-Hexyloxy-25,27-bis[(S)-2-methylbutoxy]-5,17dinitrocalix[4]arene-28-ol (partial cone) (4c) Obtained as byproduct (1% yield) from previous reaction, white needle-shaped crystals, mp 195e196  C (i-PrOH). Rf¼0.4 (DCM/ hexane¼1:1 v/v). 1H NMR (CDCl3, 300 MHz, 25  C) d (ppm): 8.24 (s, 1H, eOH), 8.20 (s, 2H, AreH), 8.04 (s, 2H, AreH), 7.00 (d, 2H, J¼7.3 Hz, AreH), 6.90 (d, 2H, J¼7.3 Hz, AreH), 6.78 (m, 2H, AreH), 4.11e3.82 (m, 8H, 2x eOCH2eþ2x AreCH2eAr), 3.49e3.29 (m, 6H, 1x eOCH2eþ2x AreCH2eAr), 2.00e1.85 (m, 2H, eCHe), 1.64e0.80 (m, 27H, eCH2eþeCH3). 13C NMR (CDCl3, 75,4 MHz, 25  C) d (ppm): 162.30, 159.61, 154.51, 154.42, 142.07, 139.53, 135.25, 135.24, 132.18, 131.76, 131.63, 129.94, 129.87, 128.55, 128.30, 126.30, 126.24, 124.22, 124.02, 123.94, 79.79, 79.68, 71.79, 37.88, 37.82, 35.68, 35.54, 31.62, 30.95, 30.73, 29.68, 26.41, 26.05, 25.15, 22.52, 16.71, 15.96, 13.90, 11.50, 11.22. IR (KBr) n (cm1): 3261, 2959, 2927, 2873, 1516, 1455, 1335, 1267, 1205, 1099, 986, 761. [a]25 D þ3.5 (c 0.72, CHCl3). HRMSeESI (C44H54N2O8) m/z (% int.) calcd: 761.3772 [MþNa]þ, 777.3512 [MþK]þ, found: 761.3777 [MþNa]þ (73%), 777.3514 [MþK]þ (40%). 4.8. 5,17-Diamino-26,28-dihexyloxy-25,27-bis[(S)-2-methylbutoxy]calix[4]arene (1,3-alternate) (5) The dinitro derivative 4b (129.8 mg, 0.158 mmol) was suspended in a mixture of THF (5 ml) and aqueous ethanol (22 ml, 96%), and SnCl2$2H2O (1.092 g, 4.73 mmol, 30 equiv) was added. The mixture was heated to reflux for 3 days and then evaporated to dryness. The solid residue was dissolved in DCM (100 ml) and extracted repeatedly with aqueous solution of KOH (pH 12). The organic layer was washed with water and dried over MgSO4. Solvent was then removed under reduced pressure to give the title compound 5 (139 mg, 97% yield) as a yellow solid, which was used in the next reaction without any purification. 1H NMR (CDCl3, 300 MHz, 25  C) d (ppm): 7.02 (d, 4H, J¼7.6 Hz, AreH), 6.61 (t, 2H, J¼7.5 Hz, AreH), 6.50 (s, 4H, AreH), 3.72e3.40 (m, 16H, AreCH2eArþeOCH2e), 3.06 (br s, 4H, eNH2), 2.07 (m, 2H, eCHe), 1.88 (m, 4H, eCH2e), 1.70e1.50 (m, 6H, eCH2e), 1.42 (m, 10H, eCH2e), 1.26 (d, 6H, J¼6.8 Hz, eCH3), 1.04 (t, 6H, J¼7.5 Hz, eCH3), 0.96 (t, 6H, J¼7.0 Hz, eCH3). 13C NMR (CDCl3, 75.4 MHz, 25  C)

482

F. Botha et al. / Tetrahedron 70 (2014) 477e483

d (ppm): 156.2, 149.4, 140.0, 134.1, 133.3, 129.5, 121.5, 117.3, 78.4, 73.3, 36.3, 34.9, 31.8, 30.4, 29.6, 26.4, 25.9, 22.6, 17.0, 14.0, 11.5. HRMSeESI (C50H70N2O4) m/z (% int.) calcd: 763.5408 [MþH]þ, 785.5228 [MþNa]þ, 801.4967 [MþK]þ, found: 763.5405 [MþH]þ (100%), 785.5222 [MþNa]þ (26%), 801.4959 [MþK]þ (12%). IR (KBr) n (cm1): 3362, 2956, 2926, 2854, 1610, 1456, 1384, 1196, 1023, 752. 4.9. 5,17-Bis[N0 -(4-nitrophenyl)ureido]-26,28-dihexyloxy25,27-bis[(S)-2-methylbutoxy]calix[4]arene (1,3-alternate) (6) Compound 5 (92.7 mg, 0.121 mmol) was dissolved in dry DCM (15 ml) and p-nitrophenyl isocyanate (44 mg, 0.267 mmol, 2.2 equiv) was added. The reaction mixture was stirred at room temperature for 3 days and it was quenched by addition of poly(ethyleneimine) resin to remove the excess of isocyanate. After 15 min of stirring at room temperature, the solvent was removed under reduced pressure, and the residue was purified by column chromatography on alumina using DCM/MeOH¼10:1 (v/v) mixture as eluent. The final recrystallization from acetone/MeCN mixture yielded the title compound in the form of orange crystals (50 mg, 38% yield). Mp 143e145  C (CDCl3). 1H NMR (CDCl3, 300 MHz, 25  C) d (ppm): 8.48 (br s, 2H, eNHCOe), 8.11 (d, 4H, J¼9.1 Hz, AreH), 7.63 (d, 4H, J¼9.1 Hz, AreH), 7.00 (s, 2H, AreH), 6.94 (m, 6H, AreH), 6.76 (br s, 2H, eNHCOe), 6.57 (t, 2H, J¼7.5 Hz, AreH), 3.64e3.35 (m, 16H, eOCH2eþAreCH2eAr), 2.18 (m, 2H, eCHe), 1.85e0.72 (m, 38H, eCH2eþeCH3). 13C NMR (CDCl3, 125.8 MHz, 25  C) d (ppm): 155.56, 153.76, 153.26, 145.07, 142.58, 135.36, 132.79, 129.85, 129.77, 125.17, 123.05, 122.24, 118.14, 79.34, 74.17, 36.32, 34.15, 31.78, 30.75, 29.68, 26.51, 25.97, 22.86 17.03, 14.10, 1 14.07, 11.27. [a]25 D þ9.8 (c 0.7, CHCl3). IR (KBr) n (cm ): 3289, 2957, 2928, 2871, 1689, 1598, 1556, 1510, 1455, 1332, 1218, 1199, 1111, 1015. HRMSeESI (C64H78N6O10) m/z (% int.) calcd: 1113.5672 [MþNa]þ, 1129.5411 [MþK]þ, found: 1113.5656 [MþNa]þ (100%), 1129.5399 [MþK]þ (12%). 4.10. Crystallographic measurements 4.10.1. Crystallographic data for C50H66N2O8 (4b). M¼823.09 g mol1, triclinic system, space group P1, a¼16.2598 (5)  A, b¼16.5394 (5)  A,    c¼18.0901 (5) A, a¼95.488 (2) , b¼96.331 (2) , g¼99.942 (3) , Z¼4, V¼4729.8 (3)  A3, Dc¼1.156 g cm3, m(Cu Ka)¼0.62 mm1, crystal dimensions of 0.480.210.14 mm. Data were collected at 170 (2) K on a Xcalibur OnyxCCD diffractometer with graphite monochromated Cu Ka radiation. The structure was solved by chargeflipping methods18 and refined using the CRYSTALS suite of programs.19 All non-hydrogen atoms were refined anisotropically by full matrix least squares on F squared value to final R¼0.076 and Rw¼0.237 using 23,466 independent reflections (Qmax¼76.1 ), 2308 parameters and 394 restrains. The positions of disordered functional groups were found from the difference electron density maps and then placed in appropriate positions. All distances between neighbouring atoms and angles of disordered groups were fixed. Site occupancies were assigned resulting in similar thermal parameters for each of disordered groups. The hydrogen atoms were placed in calculated positions. The structure was deposited into Cambridge Structural Database under number CCDC 948583. 4.10.2. Crystallographic data for C44H54N2O8 (4c). M¼738.93 g mol1, monoclinic system, space group P21, a¼24.5098 (3)  A, b¼10.79032 (11)  A, c¼30.8946 (3)  A, b¼94.6663 (10) , Z¼8, V¼8143.57 (15)  A3, 3 1 Dc¼1.205 g cm , m(Cu Ka)¼0.67 mm , crystal dimensions of 0.500.240.15 mm. Data were collected at 150 (2) K on a Xcalbur OnyxCCD diffractometer with graphite monochromated Cu Ka radiation. The structure was solved by direct methods20 using the CRYSTALS suite of programs19 and anisotropically refined by full matrix least squares on F squared value to final R¼0.076 and

Rw¼0.233 using 33,887 independent reflections (Qmax¼77.4 ), 2270 parameters and 716 restrains. The positions of disordered functional groups were found from the electron density maps and then placed in appropriate positions. All distances between neighbouring atoms and angles were fixed. Site occupancies were assigned resulting in similar thermal parameters for each of disordered groups. The hydrogen atoms were placed in calculated positions. The structure was deposited into Cambridge Structural Database under number CCDC 948582. 4.10.3. Crystallographic data for C70H87N9O10 (6$3MeCN). M¼1214.52 g mol1, triclinic system, space group P1, a¼10.1869 (3)  A, b¼12.3519 (3)  A, c¼28.9819 (9)  A, a¼85.545 (1) , b¼84.483   (1) , g¼66.199 (1) , Z¼2, V¼3318.09 (16)  A3, Dc¼1.216 g cm3, m(Mo Ka)¼0.08 mm1, crystal dimensions of 0.510.190.10 mm. Data were collected at 150 (2) K on a Bruker SAINT diffractometer with graphite monochromated Mo Ka radiation. The structure was solved by direct methods20 using the CRYSTALS suite of programs19 and anisotropically refined by full matrix least squares on F squared value to final R¼0.088 and Rw¼0.234 using 11,711 independent reflections (Qmax¼25.0 ), 1932 parameters and 932 restrains. The positions of disordered solvent and functional groups were found from the electron density maps and then placed in appropriate positions. All distances between neighbouring atoms and angles were fixed. Site occupancies were assigned resulting in similar thermal parameters for each of disordered groups. Due to the lack of strong reflections the solvent molecules were refined isotropically. The hydrogen atoms were placed in calculated positions. The structure was deposited into Cambridge Structural Database under number CCDC 948581. 4.11. Determination of association constants and stoichiometries The aliquots of guest (anion) were gradually added (for exact intervals see Supplementary data) from stock solution to the solution of host (concentration 3.0e5.0 mM) in the NMR tube to achieve different calixarene/anion ratios (1:0.3e10), ensuring constant host concentration during the 1H NMR titration experiment in DMSO-d6.21 The complexation constants were determined by analyzing the binding isotherms (obtained from the CIS values of two NH ureido protons) using the original nonlinear curve-fitting program (program OPIUM15) assuming different stoichiometries. An LC/HRMSeESI analysis of resulting calixarene/TBAþ salt mixture was performed using acetonitrile as an HB competitive solvent. Job’s method was used to verify the stoichiometry of the complexes in DMSO-d6 for selected anions.16 All data best fit with the formation of 1:1 complexes. Acknowledgements The authors wish to thank the Czech Science Foundation (1321704S) and the Grant Agency of the Academy of Sciences of the CR (IAAX08240901) for financial support of this work. Supplementary data Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2013.11.030. These data include MOL files and InChiKeys of the most important compounds described in this article. References and notes 1. (a) Gale, P. A. Chem. Commun. 2008, 4525e4540; (b) Vilar, R. Eur. J. Inorg. Chem. 2008, 3, 357e367; (c) Dieng, P. S.; Sirlin, C. Int. J. Mol. Sci. 2010, 11, 3334e3348;

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