Synthesis of Ionizable Calix[4]arenes for Chelation of Selected Divalent Cations

Abstract

Two sets of functionalised calix[4]arenes, either with a 1,3-crown ether bridge or with an open-chain oligo ether moiety in 1,3-position were prepared and further equipped with additional deprotonisable sulfonamide groups to establish chelating systems for selected cations Sr²⁺, Ba²⁺, and Pb²⁺ ions. To improve the complexation behaviour towards these cations, calix[4]arenes with oligo ether groups and modified crowns of different sizes were synthesized. Association constants were determined by UV/Vis titration in acetonitrile using the respective perchlorate salts and logK values between 3.2 and 8.0 were obtained. These findings were supported by the calculation of the binding energies exemplarily for selected complexes with Ba²⁺.

1. Introduction

Molecular baskets based on the calixarene backbone were found to be a promising basis to search for suitable macrocyclic ligands especially for divalent metal ions. Calix[4]arenes are metacyclophanes having a hydrophobic cavity between the lower and upper rim, formed by four phenol units connected with methylene units [1,2]. Due to their numerous possibilities for functionalization on the upper as well as on the lower rim [3], this class of macromolecules is known for a wide range of applications [4,5]. Calix[4]arenes were found to act as biologically active compounds as they are used as antibacterial and even antimalarial agents or in cancer chemotherapy [6,7,8,9]. Additionally, they can interact with amino acids or show promising enzyme inhibitory effects [10]. Their ability to form inclusion compounds with neutral molecules [11] or ions [12,13,14,15,16] makes them useful as sensors [17,18], catalysts [19], ligands, or as effective separation agents for ions [20] when resin-bound [21,22,23,24]. Since calix[4]arene derivatives interact particularly strongly with heavy group 2 metals [25,26,27,28,29,30,31], one major field of application consists in their use as extraction agents for nuclear waste treatment [27,32,33,34,35].

In this regard, the calix[4]arene skeleton can be seen as an ideal platform to build an optimized chelator. Two out of the four hydroxy groups on the lower rim are possible to be functionalized with proton-ionizable groups, which leads to the formation of neutral complexes with divalent cations. The remaining two can be furnished with oligo ether groups, either open-chain or bridged, leading to the calixcrown scaffold, which is easily accessible. Using this concept, both the advantages of the electrostatic, macrocyclic, and cryptate effect are unified.

Three divalent cations Sr²⁺, Ba²⁺, and Pb²⁺ are in the focus of our interest, because they all possess radioisotopes with useful nuclear properties for various diagnostic or therapeutic applications in nuclear medicine [36], and are therefore suitable to prepare radiopharmaceuticals. The beta-emitter ⁸⁹Sr is applied as “bone seeker” [37], and ⁹⁰Sr is used for superficial brachytherapy of some cancers [38,39]. ¹³¹Ba (t_1/2 = 11.5 d) is a γ-emitter for possible diagnostic uses and is discussed as a bone-scanning agent in scintigraphy [40,41,42]. Furthermore, Ba²⁺ functions as a non-radioactive surrogate [43,44,45] for both alpha-emitters ^223/224Ra, because of their analogous chemical properties and their radii of similar range [46]. Radium-223 and radium-224, have suitable half-lives (²²³Ra: 11.4 d, ²²⁴Ra: 3.6 d) and nuclear decay properties (decay chain with four alpha and two beta particles) [47] that make them useful tools for alpha-particle therapy [48]. [²²³Ra]RaCl₂ is known as Xofigo^® and is applied in clinics for the treatment of bone metastases. Furthermore, Pb²⁺ was part of our research. On the one hand, it is the stable end product (²⁰⁷Pb and ²⁰⁸Pb) of both radium decay chains. On the other hand, ²¹²Pb is a promising β^–-emitter, and a feasible candidate for radiopharmaceutical applications, since it can also be used as an in vivo generator for ²¹²Bi, which is a strong alpha emitter [49,50]. No indications were found regarding radiopharmaceutical applications of the light alkaline earth metals beryllium, magnesium, and calcium for therapy or diagnosis.

To provide the ideal cavity for heavy group 2 metals for stable complexation, it is essential to choose a suitable oligo ether length or crown size, respectively, combined with an adequate number of donor sites. Recently, the impact of the crown-6-functionalization of two simple calix[4]crown-6 derivatives has been elaborated [29,30]. The group of R. A. Bartsch focused on extraction of alkaline earth metal cations using functionalized calixcrowns [51,52,53] and found the calix[4]arene-1,3-crown-6 derivatives to be very effective group 2 metal ion extraction agents. The additional impact of two trifluoromethylsulfonylamide groups as proton-ionizing residues was corroborated by them and our research group [26]. Furthermore, these compounds showed high selectivity for Ba²⁺ over the lighter alkaline earth metal or alkali metal ions. However, Ra²⁺ was not investigated. There are only a handful of reports dealing with Ra²⁺ and the efficiency of various ligands including calixarenes as ionophores in nuclear waste management [28,54,55]. Particularly in radiopharmacy, high stability of the complex is urgently important so that a M²⁺-release and the following accumulation in bone tissues is minimized [42,44].

The objective of this research was to evaluate and compare different open-chain and bridged p-tert-butylcalix[4]arene derivatives as possible leading compounds that could, upon further modification, yield viable chelators for the selected divalent metal ions Sr²⁺, Ba²⁺, and Pb²⁺ in radiopharmaceutical applications and provide information about comparable stability constants. The existing literature about group 2 metal ligands specifically with radium, is focused mainly on extraction studies. Therefore, the UV titration as reliable and constant method for the calculation of stability constants was used to determine association constants for the respective ions. Additionally, theoretical calculations involving Ba²⁺ as a surrogate for Ra²⁺ were accomplished to underline the results.

2. Results and Discussion

2.1. Preparation of the Functionalized Calix[4]arenes

For a better understanding of the complexation ability, two sets of calix[4]arene derivatives either with open-chain or bridged oligoethers were evaluated. The first set of chelators containing the open-chain oligo ether functions was prepared to start from the basic compound 1, which contains the same number of oxygen donor atoms as calix[4]crown-6 14a. The complete synthesis path is described in Scheme 1. Calix 1 is proposed to form complexes with Na⁺ and K⁺ [56]. For the introduction of proton-ionizable groups to improve the complexation behavior, the two remaining free OH groups were modified by alkylation with ethyl bromoacetate to yield calix 2. In the next step, calix 2 was saponified under basic conditions to yield diacid 3 in quantitative yield without further purification after precipitation with HCl. To introduce the amide functions, compound 3 was then treated with oxalyl chloride to form the dichloride 4, which was instantly reacted with morpholine or 1,4,7-trioxa-10-azacyclododecane to yield amides 5 and 6, respectively. Both amines were used for modification to raise the number of donors for complexation and the steric demand. The introduction of proton-ionizable sulfonamides to yield 7a–c follows the same procedure by using trifluoromethyl sulfonamide, perfluoroisopropyl sulfonamide, and perfluorophenyl sulfonamide, respectively, which were deprotonated prior to the reaction with dichloride 4.

To check the influence of the resulting cavity, the flexibility of the functionalized crown ether bridge on the association constant and the possibility to introduce further functional groups at the crown, the second set of chelators is prepared based on the bridging moiety like a simple crown, benzocrown or aza crown. For this purpose, the respective bridging compounds 3,6,10,13-tetraoxapentadecane-1,15-diyl ditosylate (8b) [57] and the catechol derivatives 12a and 12b [58] were prepared according to literature procedures. Additionally, ditosylates 12c,d resulting from functionalized catecholes 9b,c were prepared to allow a later functionalisation of the calix-bridge using conventional ligation reactions. The preparation procedure is outlined in Scheme 2.

For the connection of the functionalized crown ethers with the calix[4]arene skeleton, the resulting ditosylates 8a,b and 12a–d of the oligo ethers were reacted with ^tBu-calix[4]arene (13) under basic conditions using K₂CO₃ in dichloromethane (DCM) to prepare the calix-crown-6 derivatives 14a,b and the calix-benzocrown-6 derivatives 14c–f in yields of 36–81%. The complete synthesis path is described in Scheme 3. The two remaining free OH groups of the calix-crowns 14a–f were alkylated with ethyl bromoacetate to yield 15a–f. In the next step, they were saponified under basic conditions to yield the respective diacid derivatives 16a–f in mostly quantitative yields without further purification after precipitation with HCl. To introduce the proton-ionizable fluorinated sulfonamide functions, an amide coupling strategy using EDC and (Cl-)HOBt was applied. Thus, compounds 16a–f were dissolved in anhydrous acetonitrile and reacted with the respective perfluorinated sulfonamides 17–19 at ambient temperature using the aforementioned coupling agents to form calix-crowns 20–22 and the modified calix-benzocrowns 23–27 in yields of 27–97%.

2.2. The Influence of the Crown Type

The influence of lower-rim crown modifications on the metal-calixcrown-coordination was next checked. For this purpose, reaction binding energies of Ba²⁺ with four selected crown-bearing calixarenes were calculated (Figure 1). That involved calix[4]crown-6 20 and additionally benzo-crown derivative 23 with the modification on adding an aromatic six-membered ring at the bottom of the crown, propylene derivative 22 with an extended crown by a CH₂ group, and calix[4]crown-5 28 lacking an ethoxy unit (CH₂CH₂O). As the result of the calculated binding energies (corrected for basis set superposition error) shown in

Table 1. Computed binding energies of different types of calixcrowns (B3LYP-D3/def2-TZVP).

Calixarene	Crown Type	ΔE (kcal/mol)
20	Crown-6	−100.9
22	Propylene-crown-6	−93.1
23	Benzocrown-6	−90.2
28	Crown-5	−89.9

, the energetically most favored environment to host the metal ion is found for calix[4]crown-6 20, while in the other three compounds, the metal-crown binding is weakened up to about 10%. Furthermore, the lowest binding energy is found for the barium ion and calix[4]crown-5. At first glance, the crown-5 might appear to feature an optimal size to host ions like Ba²⁺, as the size of the macrocycle cavity relative to the ionic radius is often used as a common parameter to rationalize and design new ligands in host-guest chemistry [59]. Considering the geometrical parameters given in Table S1, the crown-5 cavity seems to enclose the Ba²⁺ ion better than the crown-6; however, the calculated binding energies show a reversed trend. Our calculations are in accordance with previous studies in the field of host-guest chemistry of crown ethers [60]. Islam et al., for instance, showed that Na⁺ binds more tightly to a crown-6 body although the crown-5 hole’s size matches the sodium ion radius better compared to the one of crown-6 [61].

2.3. NMR Investigations

To determine the stability constants for the complexation of Ba²⁺, Sr²⁺, and Pb²⁺, a reliable method was developed in the past by our group using ¹H NMR spectroscopy. Due to the different ¹H NMR spectra, which were recorded for the respective complexes in comparison with the ligands, a ¹H NMR titration method was established [26,29,30]. For this purpose, the compounds were dissolved in acetonitrile-d₃ and treated in portions with an acetonitrile-d₃ solution containing Ba(ClO₄)₂. It was observed, that after addition of 0.5 equivalents of Ba salt, a new set of signals appeared, belonging to the respective Ba-complex exemplarily shown for calix 24 in Figure 2. This leads to two separate species: ligand 24 and complex Ba-24 in the ¹H NMR spectrum (see, for instance, the difference of the methylene protons of the calix skeleton in the box of Figure 3). After the addition of 1 eq. of Ba(ClO₄)₂, no ligand was detectable anymore, which leads to the assumption of a complex with 1:1 stoichiometry. The situation in Figure 2 is a consequence of a slow exchange on the NMR time scale and is therefore not suitable for a logK determination by NMR titration for our calix compounds [62]. Next, a more reliable titration method based on UV/vis spectroscopy was used instead to determine the association constants.

2.4. UV Titration Studies

To determine the association constants by UV titration, the open-chain calix[4]arenes 7a,b as well as the calix[4]crowns 20–22 and benzocrown compounds 23–25 and 27 were dissolved in acetonitrile and aliquots of M(ClO₄)₂ with M = Ba, Sr, Pb in acetonitrile were added, which caused a clear change in the UV absorption. This behavior is shown in Figure 4 based on the example of compound 21 and its complexes Ba-21, Sr-21 and Pb-21. Considering one wavelength with a high change in absorption, the stoichiometry of the complex was determined from the diagram titration curve (Figure 4, exemplarily for Ba-21). All titration experiments showed the presence of a complex with a 1:1 stoichiometry, formed by functionalized calix[4]crowns with M(ClO₄)₂ except for calix 6 (see Supplementary Materials), as the slope of the graph is changing at the 1:1 molar ratio. The results from the evaluation of the association constants are summarized in

Table 2. Determined logK values using the UV titration method.

Calixarene	logK(Ba)	logK(Sr)	logK(Pb)
5	6.1 ± 0.3	3.8	5.7 ± 0.2
6	--- (a)	--- (a)	--- (a)
7a	4.4 ± 0.2	4.9 ± 0.2	5.0 ± 0.6
7b	4.6 ± 0.3	3.2 ± 0.2	5.4 ± 0.1
14a	4.6 ± 0.1 (b)	4.3 ± 0.1 (b)	3.3 ± 1 (b)
20	5.7 ± 0.1	n.d.	n.d.
21	5.0 ± 0.8	5.0 ± 0.8	5.5 ± 0.8
22	4.9 ± 0.7	5.6 ± 0.8	7.4 ± 1.5 (c)
23	6.6 ± 1.0 (c)	7.0 ± 1.4 (c)	4.0 ± 0.2
24	5.8 ± 0.9	6.4 ± 1.0 (c)	6.3 ± 0.9 (c)
25	7.5 ± 1.5 (c)	7.6 ± 1.5 (c)	8.0 ± 1.6 (c)
27	5.2 ± 0.8	7.0 ± 1.4 (c)	3.9 ± 0.1

^(a) No value available from UV titration, ^(b) see ref. [29], ^(c) Value over the upper method detection limit, n.d.—not determined.

(all UV titration experiments are expressed in the Supplementary Materials).

The association constants of the bridged derivatives 20–25 and 27 with Sr²⁺, Ba²⁺ and Pb²⁺ showing values up to 8.0 and were higher as for the basic complexes Ba-14a (logK 4.6), Sr-14a (logK: 4.3), and Pb-14a (logK 3.3) [26] without additional side functions due to the increasing number of donor atoms and the additional macrocyclic effect. Interestingly, higher association constants were obtained for the benzocrown derivatives 23–25 in comparison to the basic crown derivatives 20–22. The calix derivatives with benzocrown bridge led to more stable complexes showing higher stability constants of approximately one magnitude (e.g., Sr-21: 5.0 vs. Sr-24: 6.4 (C₃F₇) or Ba-20: 5.7 vs. Ba-23: 6.6 (CF₃)) for the group 2 metal ions. Moreover, the propylene bridge in calix 22 has only a marginal influence on the association constant regarding the respective Ba-complexes Ba-21 and Ba-22, but a strong influence when comparing the Pb-complexes (logK_(Pb-21) = 5.5 vs. logK_(Pb-22) = 7.4).

Additionally, a high value is even found for calix 5 with morpholine modification and its respective complexes with Ba²⁺ and Pb²⁺ possibly due to the higher number of donor atoms. The constants for the open-chain derivatives Ba-7a,b are lower or equal to the value found for 14a in contrast to the values found for Pb-7a,b, which were higher. Differences between the M²⁺ complexes from the same ligand arose from the different ion radii as well as from the chemical behavior (HSAB concept), as Sr²⁺ and Ba²⁺ belong to the alkaline earth metals (group 2) and Pb²⁺ is a group 4 metal ion and therefore, show a softer ion character.

3. Materials and Methods

3.1. General

All chemicals were purchased from commercial suppliers and used without further purification unless otherwise specified. Anhydrous THF was purchased from Acros, anhydrous Ba(ClO₄)₂ was purchased from Alfa Aesar, and deuterated solvents were purchased from deutero GmbH. Compounds 8b [57], 9c [63], 11a, 12a [59], 11b, 12b [64], 14a, 15a, 16a, and 20 [26] were prepared according to the literature. NMR spectra of all compounds were recorded on an Agilent DD2-400 MHz NMR or an Agilent DD2-600 MHz NMR spectrometer with ProbeOne. Chemical shifts of the ¹H, ¹⁹F, and ¹³C spectra were reported in parts per million (ppm) using TMS as an internal standard for ¹H/¹³C and CFCl₃ for ¹⁹F spectra. Mass spectrometric (MS) data were obtained on a Xevo TQ-S mass spectrometer (Waters) by electron spray ionization (ESI). The melting points were determined on a Galen III melting point apparatus (Cambridge Instruments & Leica) and are uncorrected. TLC detections were performed using Silica Gel 60 F₂₅₄ sheets (Merck, Darmstadt, Germany). TLCs were developed by visualization under UV light (λ = 254 nm). Chromatographic separations were accomplished by using an automated silica gel column chromatography system Biotage Isolera Four and appropriate Biotage KP-SIL SNAP columns. UV/Vis- measurements were realized at a Specord 50 by Analytik Jena. The calculation of the stability constants was accomplished using HypSpec 1.1.18.

3.2. The Computational Methodology

The calculations of calixcrowns were performed using Kohn-Sham DFT. The general gradient approximation functional BP86 [65,66] was used for geometry optimizations and the B3LYP [67,68] to calculate single point energies. With the latter settings, we have used a continuum solvation COSMO model for acetonitrile (dielectric constant ζ = 37.5) in order to approximately include the solvent environment used in the experiment. Ahlrichs’ triple zeta valence polarized (def2-TZVP) [69] basis set was employed as well as the resolution of identity (RI) approach and corresponding auxiliary basis sets [70], along with Grimme’s D3 dispersion correction [71]. Since the def2-TZVP was not available for radium, we have used the split valence polarized (def-SVP) basis set [72] for both Ra²⁺ and Ba²⁺ in the calculations that involved a comparison between their binding energies. Effective core potentials have been used for the heavy metals in order to account for scalar relativistic effects. The Turbomole 7.3 package [73] was used for all calculations in this study. To prevent the over-stabilization of final energies, basis set superposition error (BSSE) was considered. Binding energies were calculated as differences of electronic energies E via E(complex)-[E(calixcrown)+E(M²⁺)].

3.3. Chemical Syntheses

5,11,17,23-Tetrakis(tert-butyl)-25,27-dihydroxy-26,28-bis[2-(2-methoxyethoxy)ethoxy]calix[4]arene 1. Under Ar, tert-butylcalix[4]arene (2 g, 3.08 mmol) was dissolved in anhydrous acetonitrile (40 mL) and 2-(2-methoxyethoxy)ethyl tosylate (1.86 g, 6.78 mmol) and K₂CO₃ (1.06 g, 7.7 mmol) added. The reaction mixture was stirred at 72 °C for 4 d. After cooling, the solvent was changed to chloroform (40 mL), the insoluble ingredients were removed by filtration and the organic phase was washed with 10% aqueous HCl (2 × 30 mL) and water (2 × 30 mL). After separation, the organic phase was dried over Na₂SO₄ and the crude product was purified using column chromatography (petroleum ether:acetone = 10:1 → 5:1) to obtain 1 as colorless oil, which tends to crystallize after standing (2.31 g, 88%); mp 100 °C; R_f 0.46 (petroleum ether:acetone = 2:1); ¹H NMR (600 MHz, CDCl₃): δ 0.95 (s, 18 H, ^tBu), 1.30 (s, 18 H, ^tBu), 3.30 (d, ²J = 13.1 Hz, 4 H, CH₂Ar), 3.39 (s, 6 H, OCH₃), 3.61–3.64 (m, 4 H, OCH₂), 3.83–3.86 (m, 4 H, OCH₂), 3.96–4.00 (m, 4 H, OCH₂), 4.16–4.19 (m, 4 H), 4.36 (d, ²J = 13.1 Hz, CH₂Ar), 6.77 (s, 4 H, ArH), 7.06 (s, 4 H, ArH), 7.15 (s, 2 H, OH); ¹³C NMR (151 MHz, CDCl₃): δ 31.2 (^tBu), 31.9 (^tBu), 33.9 (C_q), 34.0 (C_q), 59.2 (OCH₃), 70.1 (OCH₂), 71.1 (OCH₂), 72.3 (OCH₂), 75.4 (OCH₂), 125.1, 125.6 (2 × CH_Ar), 128.0 (C Ar), 132.7, 141.4, 146.9, 150.0, 150.8 (6 × C_Ar) ppm; MS (ESI+) m/z = 871 (M⁺ + NH₄), 876 (M⁺ + Na), 892 (M⁺ + K).

5,11,17,23-Tetrakis(tert-butyl)-25,27-bis(2-ethoxy-2-oxoethoxy)-26,28-bis[2-(2-methoxyethoxy)ethoxy]calix[4]arene 2. Under Ar, compound 1 (1 g, 1.17 mmol) was dissolved in anhydrous THF (40 mL) and NaH (234 mg, 5.86 mmol, 60% in mineral oil) added and stirred at rt for 30 min. Afterwards, a solution of ethyl bromoacetate (978 mg, 5.86 mmol) in 5 mL of THF was added and the resulting mixture stirred at 50 °C for 2 d. After cooling to rt, the solvent was changed to chloroform (40 mL), the insoluble ingredients were removed by filtration and the organic phase was washed with 10% aqueous HCl (3 × 30 mL) and water (2 × 30 mL). After separation, the organic phase was dried over Na₂SO₄ and the crude product was purified using column chromatography (petroleum ether:acetone = 4:1) to obtain 2 as light-yellow oil (1.07 g, 89%); R_f 0.52 (petroleum ether:acetone = 2:1); ¹H NMR (400 MHz, CDCl₃): δ 1.03 (s, 18 H, ^tBu), 1.12 (s, 18 H, ^tBu), 1.29 (t, ³J = 7.1 Hz, 6 H, CH₃), 3.15 (d, ²J = 12.9 Hz, 4 H, CH₂Ar), 3.37 (s, 6 H, OCH₃), 3.53–3.57 (m, 4 H, OCH₂), 3.66–3.69 (m, 4 H, OCH₂), 3.94 (t, ³J = 5.6 Hz, 4 H, OCH₂), 4.12 (t, ³J = 5.6 Hz, 4 H, OCH₂), 4.22 (q, ³J = 7.2 Hz, 4 H, OCH₂), 4.67 (d, ²J = 12.9 Hz, 4 H, CH₂Ar), 4.77 (s, 4 H, CH₂C=O), 6.70 (s, 4 H, ArH), 6.83 (s, 4 H, ArH); ¹³C NMR (101 MHz, CDCl₃): δ 14.4, 31.5, 31.6 (3 × CH₃), 31.7 (CH₂Ar), 33.9 (C_q), 34.0 (C_q), 59.2 (OCH₃), 60.5 (OCH₂), 70.4 (OCH₂), 70.7 (OCH₂), 71.3 (CH₂C=O), 72.2 (OCH₂), 73.2 (OCH₂), 125.1 (CH_Ar), 125.5 (CH_Ar), 133.5, 134.0, 144.8, 145.2, 153.2, 153.4 (6 × C_Ar), 170.8 (C=O) ppm; MS (ESI+) m/z = 1042 (M⁺ + NH₄), 1047 (M⁺ + Na).

5,11,17,23-Tetrakis(tert-butyl)-25,27-bis(carboxymethoxy)-26,28-bis[2-(2-methoxyethoxy)ethoxy]calix[4]arene 3. Compound 2 (213 mg, 0.21 mmol) was dissolved in THF (20 mL), a solution of Me₄NOH ∙ 5 H₂O (264 mg, 1.46 mmol) in methanol (1 mL) was added and the reaction mixture was stirred at 55 °C overnight. The major part of the solvent was removed and the product was precipitated with ice-cold aqueous HCl (6 M). The solid residue was filtered and washed with water (20 mL) and dissolved in chloroform (20 mL). The organic phase was washed with brine (3 × 10 mL) and 10% aqueous HCl (2 × 10 mL). After separation, the organic phase was dried over Na₂SO₄, the solvent was removed and the product was obtained as pale-orange solid (200 mg, >99%); mp 104–106 °C; ¹H NMR (400 MHz, CDCl₃): δ 0.83 (s, 18 H, ^tBu), 1.34 (s, 18 H, ^tBu) 3.24 (d, ²J = 13 Hz, 4 H, CH₂Ar), 3.38 (s, 6H, OCH₃), 3.23–3.26 (m, 4 H, OCH₂), 3.73–3.75 (m, 4H, OCH₂), 3.83–3.85 (m, 4 H, OCH₂), 3.99–4.01 (m, 4 H, OCH₂), 4.45 (d, ²J = 13.0 Hz, 4 H, CH₂Ar), 4.75 (s, 4 H, CH₂C=O), 6.56 (s, 4 H, ArH), 7.17 (s, 4 H, ArH); ¹³C NMR (101 MHz, CDCl₃): δ 31.09 (CH₂Ar), 31.14 (CH₃), 31.8 (CH₃), 33.9 (C_q), 34.4 (C_q), 59.2 (OCH₃), 69.8 (OCH₂), 70.5 (OCH₂), 72.2 (OCH₂), 72.3 (CH₂C=O), 76.2 (OCH₂), 125.5 (CH_Ar), 126.2 (CH_Ar), 132.3, 135.0, 146.1, 147.3, 150.2, 153.3 (6 × C_Ar), 170.6 (C=O); MS (ESI−) m/z = 968 (M^– − H).

5,11,17,23-Tetrakis(tert-butyl)-26,28-bis[2-(2-methoxyethoxy)ethoxy]-25,27-bis(2-morpholino-2-oxoethyl)calix[4]arene 5. Under Ar, compound 3 (100 mg, 0.103 mmol) was dissolved in CCl₄ (5 mL), oxalyl chloride (0.75 g, 5.88 mmol) dropwise added and the reaction mixture stirred at 65 °C for 5 h. After cooling to rt, the remaining oxalyl chloride and the solvent were removed under high vacuum and anhydrous DCM (5 mL) added. After cooling the solution to 0 °C, morpholine (22 mg, 0.26 mmol) and DIPEA (40 mg, 0.31 mmol) were added to resulting mixture was allowed to come to rt and was stirred at rt overnight. Afterwards, DCM (20 mL) was added and the organic phase washed with saturated hydrogen carbonate solution (20 mL), aqueous HCl (10%, 20 mL), and brine (15 mL). After separation, the organic phase was dried over Na₂SO₄ and the crude product was purified using automated column chromatography (chloroform: methanol = 0 → 15%) to obtain 5 as colorless oil (67 mg, 59%); R_f 0.16 (chloroform:methanol = 9:1); ¹H NMR (400 MHz, CDCl₃): δ 1.04 (s, 18 H, ^tBu), 1.09 (s, 18 H, ^tBu), 3.14 (d, ²J = 12.8 Hz, 4 H, CH₂Ar), 3.34 (s, 6 H, OCH₃), 3.37–3.44 (m, 4 H, NCH₂), 3.49–3.55 (m, 8 H, OCH₂), 3.59–3.71 (m, 12 H, NCH₂, OCH₂), 3.97 (t, ³J = 5.7 Hz, 4 H, OCH₂), 4.18 (t, ³J = 5.7 Hz, 4 H, OCH₂), 4.60 (d, ²J = 12.8 Hz, 4 H, CH₂Ar), 4.78 (s, 4 H, CH₂C=O), 6.74 (s, 4 H, ArH), 6.78 (s, 4 H, ArH); ¹³C NMR (101 MHz, CDCl₃): δ 31.5 (CH₃), 31.56 (CH₃), 31.62 (CH₂Ar), 33.9 (C_q), 34.0 (C_q), 42.0 (NCH₂), 45.9 (NCH₂), 59.1 (OCH₃), 66.8 (OCH₂), 67.0 (OCH₂), 70.1 (OCH₂), 70.5 (OCH₂), 71.6 (CH₂C=O), 72.2 (OCH₂), 72.8 (OCH₂), 125.2 (CH_Ar), 125.4 (CH_Ar), 133.4, 133.9, 144.8, 145.1, 153.1, 153.6 (6 × C_Ar), 168.3 (C=O) ppm; MS (ESI+): m/z = 1130 (M⁺ + Na).

5,11,17,23-Tetrakis(tert-butyl)-26,28-bis[2-(2-methoxyethoxy)ethoxy]-25,27-[2-(1,4,7-trioxa-10-azacyclododecan-10-yl)-2-oxoethyl]calix[4]arene 6. Under Ar, compound 3 (100 mg, 0.10 mmol) was dissolved in CCl₄ (5 mL), oxalyl chloride (0.75 g, 5.88 mmol) dropwise added and the reaction mixture stirred at 65 °C for 5 h. After cooling to rt, the remaining oxalyl chloride and the solvent were removed under high vacuum and anhydrous DCM (5 mL) added. After cooling the solution to 0 °C, 1-aza-12-crown-4 (45 mg, 0.26 mmol) and DIPEA (40 mg, 0.31 mmol) were added to resulting mixture was allowed to come to rt and was stirred at rt overnight. Afterwards, DCM (20 mL) was added and the organic phase washed with saturated hydrogen carbonate solution (15 mL), aqueous HCl (10%, 15 mL), and brine (15 mL). After separation, the organic phase was dried over Na₂SO₄ and the crude product was purified using automated column chromatography (chloroform:methanol = 0 → 15%) to obtain 6 as colorless solid (103 mg, 78%); R_f 0.29 (chloroform:methanol = 85:15); ¹H NMR (400 MHz, CDCl₃): δ = 1.08 (s, 18 H, ^tBu), 1.13 (s, 18 H, ^tBu), 3.26–3.32 (m, 10 H, ArCH₂, OCH₃), 3.34–3.42 (m, 4 H, CH₂), 3.44–3.48 (m, 4 H, CH₂), 3.50–3.55 (m, 4 H, CH₂), 3.58–3.67 (m, 16 H, CH₂), 3.69–3.76 (m, 8 H, CH₂), 3.86–3.94 (m, 8 H, CH₂), 4.12–4.18 (m, 4 H, CH₂), 4.34 (d, 4 H, ²J = 12.5 Hz, CH₂Ar), 4.78 (s, 4 H, CH₂C=O), 7.05 (s, 4 H, ArH), 7.07 (s, 4 H, ArH) ppm; ¹³C NMR (101 MHz, CDCl₃): δ = 30.0 (CH₂Ar), 31.3 (CH₃), 31.4 (CH₃), 34.2 (C_q), 34.3 (C_q), 49.3 (CH₂), 50.0 (CH₂), 59.0 (OCH₃), 68.6, 68.8, 69.1, 69.5, 69.9, 70.0, 70.1, 70.9, 72.0 (9 × CH₂), 73.9 (CH₂C=O), 75.2 (CH₂), 125.7 (CH_Ar), 125.9 (CH_Ar), 134.6, 134.8, 147.7, 148.3, 148.5, 150.0 (6 × C_Ar), 170.1 (C=O) ppm.

5,11,17,23-Tetrakis(tert-butyl)-26,28-bis[2-(2-methoxyethoxy)ethoxy]-25,27-[2-(trifluoromethylsulfonamido)-2-oxoethyl]calix[4]arene 7a. Under Ar, compound 3 (100 mg, 0.10 mmol) was dissolved in CCl₄ (5 mL), oxalyl chloride (0.75 g, 5.88 mmol) dropwise added and the reaction mixture stirred at 65 °C for 5 h. After cooling to rt, the remaining oxalyl chloride and the solvent were removed under high vacuum, anhydrous DCM (5 mL) added and the solution cooled to 0 °C. In a second flask, trifluoromethanesulfonamide (39 mg, 0.26 mmol) was dissolved in anhydrous THF (2 mL) and NaH (41 mg, 1.03 mmol, 10 eq., 60% in mineral oil) was added. After stirring for 15 min, this solution was added to the DCM solution at 0 °C and the combined mixture was stirred for 1.5 h at rt. The solvent was changed to chloroform (20 mL) and the organic phase washed with saturated hydrogen carbonate solution (15 mL), aqueous HCl (10%, 15 mL), and brine (15 mL). After separation, the organic phase was dried over Na₂SO₄ and the crude product was purified using automated column chromatography (petroleum ether:ethyl acetate = 0 → 30%) to obtain 7a as colorless solid (68 mg, 54%); mp 113–115 °C; R_f 0.76 (petroleum ether:ethyl acetate = 1:1); ¹H NMR (400 MHz, CDCl₃): δ 1.04 (s, 18 H, ^tBu), 1.20 (s, 18 H, ^tBu), 3.34 (d, ²J = 12.4 Hz, 4 H, CH₂Ar), 3.34 (s, 6 H, OCH₃), 3.59 (t, ³J = 4.3 Hz, 4 H, OCH₂), 3.69–3.78 (m, 8 H, OCH₂), 4.08–4.12 (m, 4 H, OCH₂), 4.28 (d, ²J = 12.4 Hz, 4 H, CH₂Ar), 4.46 (s, 4 H, CH₂C=O), 6.99 (s, 4 H, ArH), 7.15 (s, 4 H, ArH); ¹³C NMR (101 MHz, CDCl₃): δ 30.0 (CH₂Ar), 31.2 (CH₃), 31.5 (CH₃), 34.2 (C_q), 34.3 (C_q), 59.2 (OCH₃), 68.7 (OCH₂), 70.0 (OCH₂), 70.6 (OCH₂), 76.4 (OCH₂), 76.9 (CH₂C=O), 120.5 (q, ¹J_C,F = 323 Hz, CF₃), 125.97 (CH_Ar), 126.02 (CH_Ar), 134.3, 134.7, 147.6, 148.4, 148.5, 149.6 (6 × C_Ar), 178.3 (C=O); ¹⁹F NMR (376 MHz, CDCl₃): δ − 79.0 (CF₃) ppm; MS (ESI+) m/z = 1232 (M⁺ + H), 1254 (M⁺ + Na).

5,11,17,23-Tetrakis(tert-butyl)-26,28-bis[2-(2-methoxy ethoxy)ethoxy]-25,27-[2-(heptafluoroisopropylsulfonamido)-2-oxoethyl]calix[4]arene 7b. Under Ar, compound 3 (100 mg, 0.10 mmol) was dissolved in CCl₄ (5 mL), oxalyl chloride (0.75 g, 5.88 mmol) dropwise added and the reaction mixture stirred at 65 °C for 5 h. After cooling to rt, the remaining oxalyl chloride and the solvent were removed under high vacuum, anhydrous THF (3 mL) added and the solution cooled to 0 °C. In a second flask, heptafluoroisopropylsulfonamide (64 mg, 0.26 mmol) was dissolved in anhydrous THF (2 mL) and NaH (41 mg, 1.03 mmol, 60% in mineral oil) was added. After stirring for 15 min, this solution was added to the other THF solution at 0 °C and the combined mixture was stirred for 1.5 h at rt. The solvent was changed to chloroform (20 mL) and the organic phase washed with saturated hydrogen carbonate solution (15 mL), aqueous HCl (10%, 15 mL), and brine (15 mL). After separation, the organic phase was dried over Na₂SO₄ and the crude product was purified using automated column chromatography (petroleum ether:ethyl acetate = 0 → 20%) to obtain 7b as colorless solid (53 mg, 36%); mp 113–115 °C; R_f 0.76 (petroleum ether:ethyl acetate = 1:1); ¹H NMR (400 MHz, CDCl₃): δ 1.04 (s, 18 H, ^tBu), 1.21 (s, 18 H, ^tBu), 3.35 (d, ²J = 12.5 Hz, 4 H, CH₂Ar), 3.41 (s, 6 H, OCH₃), 3.58 (t, ³J = 4.4 Hz, 4 H, OCH₂), 3.70–3.77 (m, 8 H, OCH₂), 4.06–4.11 (m, 4 H, OCH₂), 4.27 (d, ²J = 12.5 Hz, 4 H, CH₂Ar), 4.44 (s, CH₂C=O), 6.99 (s, 4 H, ArH), 7.16 (s, 4 H, ArH); ¹³C NMR (101 MHz, CDCl₃): δ 29.9 (CH₂Ar), 31.2 (CH₃), 31.5 (CH₃), 34.2 (C_q), 34.4 (C_q), 59.2 (OCH₃), 68.8 (OCH₂), 70.0 (OCH₂), 70.6 (OCH₂), 76.3 (OCH₂), 76.9 (CH₂C=O), 96.5 (dsep, ¹J_C,F = 240 Hz, ²J_C,F = 32 Hz, CF), 119.6 (dq, ¹J_C,F = 288 Hz, ²J_C,F = 26 Hz, CF₃), 126.0 (CH_Ar), 126.04 (CH_Ar), 134.3, 134.7, 147.7, 148.5, 148.52, 149.5 (6 × C_Ar), 178.0 (C=O); ¹⁹F NMR (565 MHz, CDCl₃): δ –170.5 (sep, ³J = 7.0 Hz, 1 F, CF), −71.9 (d, ³J = 7.0 Hz, 6 F, CF₃) ppm.

5,11,17,23-Tetrakis(tert-butyl)-26,28-bis[2-(2-methoxyethoxy)ethoxy]-25,27-[2-(pentafluorophenylsulfonamido)-2-oxoethyl]calix[4]arene 7c. Under Ar, compound 3 (100 mg, 0.10 mmol) was dissolved in CCl₄ (5 mL), oxalyl chloride (0.75 g, 5.88 mmol) dropwise added and the reaction mixture stirred at 65 °C for 5 h. After cooling to rt, the remaining oxalyl chloride and the solvent were removed under high vacuum, anhydrous THF (3 mL) added and the solution cooled to 0 °C. In a second flask, pentafluorophenylsulfonamide (64 mg, 0.26 mmol) was dissolved in anhydrous THF (2 mL) and NaH (41 mg, 1.03 mmol, 60% in mineral oil) was added. After stirring for 15 min, this solution was added to the other THF-solution at 0 °C and the combined mixture was stirred for 1.5 h at rt. The solvent was changed to chloroform (20 mL) and the organic phase washed with saturated hydrogen carbonate solution (15 mL), aqueous HCl (10%, 15 mL), and brine (15 mL). After separation, the organic phase was dried over Na₂SO₄ and the crude product was purified using automated column chromatography (petroleum ether:ethyl acetate = 0 → 20%) to obtain 7c as colorless solid (15 mg, 10%); mp 98–100 °C; R_f 0.76 (petroleum ether:ethyl acetate = 1:1); ¹H NMR (600 MHz, CDCl₃): δ 1.06 (s, 18 H, ^tBu), 1.18 (s, 18 H, ^tBu), 3.31 (d, ²J = 12.4 Hz, 4 H, ArCH₂), 3.39 (s, 6 H, OCH₃), 3.51 (t, ³J = 4.6 Hz, 4 H, OCH₂), 3.58 (t, ³J = 3.8 Hz, 4 H, OCH₂), 3.67 (t, ³J = 4.6 Hz, 4 H, OCH₂), 4.02 (t, ³J = 3.8 Hz, 4 H, OCH₂), 4.25 (d, ²J = 12.4 Hz, 4 H, CH₂Ar), 4.41 (s, 4 H, CH₂C=O), 7.00 (s, 4 H, ArH), 7.12 (s, 4 H, ArH); ¹³C NMR (151 MHz, CDCl₃): δ 30.0 (CH₂Ar), 31.3 (CH₃), 31.5 (CH₃), 34.2 (C_q), 34.3 (C_q), 59.3 (OCH₃), 68.3 (OCH₂), 69.7 (OCH₂), 70.4 (OCH₂), 75.9 (OCH₂), 76.9 (CH₂C=O), 125.9 (CH_Ar), 125.94 (CH_Ar), 134.5, 134.6, 147.7, 148.3, 148.9, 149.5 (6 × C_q), 177.3 (C=O); ¹⁹F NMR (564 MHz, CDCl₃): δ –160.7 (t, ³J = 20.0 Hz, 4 F, m-ArF), –150.3 (t, ³J = 20.5 Hz, 2 F, p-ArF), −130.1 (d, ³J = 20.0 Hz, 4 F, o-ArF) ppm; MS (ESI+) m/z = 1428 (M⁺ + H), 1445 (M⁺ + NH₄).

tert-Butyl 3,4-bis[2-(2-hydroxyethoxy)ethoxy]benzoate 11c. Under Ar, compound 9c (176 mg, 0.84 mmol), K₂CO₃ (578 mg, 4.19 mmol) and KI (194 mg, 4.2 mmol) were suspended in anhydrous DMF (5 mL) and 2-(2-chloroethoxy)ethanol (354 μL, 417 mg, 3.35 mmol) was added. The mixture was stirred at 75 °C overnight. After cooling to rt, the solvent was changed to DCM (15 mL) and filtered. The organic phase was washed with hydrochloric acid (10 mL, 10%), brine (10 mL) and water (10 mL). After removal of the solvent, the crude product was purified via column chromatography (ethyl acetate:methanol 99:1) to obtain 11c as colorless oil (140 mg, 43%); R_f = 0.4 (DCM:methanol = 9:1); ¹H NMR (400 MHz, CDCl₃): δ 1.58 (s, 9H, ^tBu). 2.79 (s, 2H, OH), 3.72–3.65 (m, 4H, OCH₂), 3.79–3.71 (m, 4H, OCH₂), 3.95–3.88 (m, 4H, OCH₂), 4.24–4.17 (m, 4H, OCH₂), 6.86 (d, ³J = 8.4 Hz, 1H, ArH), 7.53 (d, ⁴J = 1.9 Hz, 1H, ArH), 7.60 (dd, ³J = 8.4 Hz, ⁴J = 1.9 Hz, 1H, ArH); ¹³C NMR (101 MHz, CDCl₃): δ 28.2 (^tBu), 61.6 (OCH₂), 68.3 (OCH₂), 68.4 (OCH₂), 69.0 (OCH₂), 69.2 (OCH₂), 72.7 (OCH₂), 72.8 (OCH₂), 80.8 (C_q), 111.7 (CH_Ar), 113.9 (CH_Ar), 123.6 (CH_Ar), 125.0 (C_Ar), 147.7 (C_Ar), 151.9 (C_Ar), 165.5 (C=O) ppm; MS (ESI+): m/z = 409 (M⁺ + Na).

1,2-Bis[2-(2-hydroxyethoxy)ethoxy]-4-nitrobenzene 11d. Under Ar, 4-nitrocatechol (1.0 g, 6.45 mmol), K₂CO₃ (8.0 g, 64 mmol) and KI (1.66 g, 9.03 mmol) were suspended in anhydrous DMF (20 mL) and 2-(2-chloroethoxy)ethanol (2.72 g, 29mmol) was added. The mixture was stirred at 75 °C overnight. After cooling to rt, the solvent was changed to DCM (35 mL) and filtered. The organic phase was washed with hydrochloric acid (25 mL, 10%), brine (25 mL) and water (25 mL). After removal of the solvent, the crude product was purified via column chromatography (DCM:methanol 97:3) to obtain 11d as colorless oil (1.08 g, 52%); R_f 0.4 (DCM:methanol 9:1); ¹H NMR (600 MHz, CDCl₃): δ 3.41 (s, 2H, OH), 3.63–3.59 (m, 4H, OCH₂), 3.69–3.66 (m, 4H, OCH₂), 3.90–3.84 (m, 4H, OCH₂), 4.20–4.12 (m, 4H, OCH₂), 6.85 (d, ³J = 8.9 Hz, 1H, ArH), 7.67 (d, ⁴J = 2.6 Hz, 1H, ArH), 7.80 (dd, ³J = 8.9 Hz, ⁴J = 2.6 Hz, 1H, ArH); ¹³C NMR (151 MHz, CDCl₃): δ 61.4 (OCH₂), 61.5 (OCH₂), 68.6 (OCH₂), 68.7 (OCH₂), 68.8 (OCH₂), 68.9 (OCH₂), 72.7 (OCH₂), 72.7 (OCH₂), 108.0 (CH_Ar), 111.3 (CH_Ar), 118.0 (CH_Ar), 141.4 (C_Ar), 148.0 (C_Ar), 153.9 (C_Ar) ppm; MS (ESI+): m/z = 354 (M⁺ + Na).

tert-Butyl 3,4-bis{2-[2-(tosyloxy)ethoxy]ethoxy}benzoate 12c. Under Ar, compound 11c (459 mg, 1.2 mmol) and Et₃N (536 μL, 392 mg, 3.87 mmol) were dissolved in anhydrous DCM (15 mL), cooled to 0 °C, p-TsCl (1.40 g, 9.9 mmol) added and the reaction mixture stirred at rt overnight. Afterwards, the organic phase was washed with water (2 × 15 mL), dried over Na₂SO₄. After removal of the solvent, the crude product was purified using automated column chromatography (DCM → DCM:methanol 99:1) to obtain 12c as colorless oil (298 mg, 36%); R_f 0.6 (DCM:methanol = 99:1); ¹H NMR (400 MHz, CDCl₃): δ 1.59 (s, 9H, ^tBu), 2.42–2.39 (m, 6H, CH₃), 3.85–3.73 (m, 8H, OCH₂), 4.15–4.05 (m, 4H, OCH₂), 4.21–4.14 (m, 4H, OCH₂), 6.84 (d, ³J = 8.4 Hz, 1H, ArH), 7.32–7.25 (m, 4H, Ar_Ts), 7.48 (d, ⁴J = 2.0 Hz, 1H, ArH), 7.60 (dd, ³J = 8.4 Hz, ⁴J = 2.0 Hz, 1H, ArH), 7.78 (d, ³J = 8.0 Hz, 4H, Ar_Ts); ¹³C NMR (151 MHz, CDCl₃): δ 21.6 (CH₃), 21.6 (CH₃), 28.2 (^tBu), 68.6 (OCH₂), 68.8 (OCH₂), 68.9 (OCH₂), 69.0 (OCH₂), 69.3 (OCH₂), 69.4 (OCH₂), 69.6 (OCH₂), 69.8 (OCH₂), 80.8 (C_q), 112.6 (CH_Ar), 114.8 (CH_Ar), 123.8 (CH_Ar), 125.1 (C_Ar), 128.0 (CH_Ts), 129.8 (CH_Ts), 133.0, 144.8, 148.1, 152.4 (4 × C_Ar), 165.5 (C=O) ppm; MS (ESI+): m/z 718 (M⁺ + Na).

1,2-Bis{2-[2-(tosyloxy)hydroxyethoxy]ethoxy}-4-nitrobenzene 12d. Compound 11d (1.37 g, 4,13 mmol) was dissolved in THF and cooled to 0 °C. NaOH (500 mg, 12.4 mmol) dissolved in water (2.5 mL) and p-tosyl chloride (1.97 g, 10.3 mmol) were added and the mixture was stirred 3 h at rt. Afterwards, saturated hydrogen carbonate solution (10 mL) was added and extracted with DCM (2 × 50 mL). The organic phase was washed with water (2 × 50 mL), dried over Na₂SO₄ and the crude product was purified using automated column chromatography (DCM → DCM:methanol 50:1) to obtain 12d as yellowish oil (1.74 g, 66%); R_f 0.6 (DCM:methanol = 99:1); ¹H NMR (600 MHz, CDCl₃): δ 2.42–2.40 (m, 6H, CH₃), 3.79–3.76 (m, 4H, OCH₂), 3.87–3.81 (m, 4H, OCH₂), 4.15–4.11 (m, 2H, OCH₂), 4.20–4.15 (m, 6H, OCH₂), 6.91 (d, ³J = 8.9 Hz, 1H, ArH), 7.32–7.28 (m, 4H, Ts), 7.73 (d, ⁴J = 2.6 Hz, 1H, ArH), 7.80–7.75 (m, 4H, Ts), 7.88 (dd, ³J = 8.9 Hz, ⁴J = 2.6 Hz, 1H, ArH); ¹³C NMR (151 MHz, CDCl₃): δ 21.7 (CH₃), 21.8 (CH₃), 69.1 (OCH₂), 69.2 (OCH₂), 69.2 (OCH₂), 69.3 (OCH₂), 69.4 (OCH₂), 69.5 (OCH₂), 69.6 (CH₂), 69.7 (OCH₂), 109.0 (CH_Ar), 112.1 (CH_Ar), 118.3 (CH_Ar), 128.1 (CH_Ts), 128.2 (CH_Ts), 129.9 (CH_Ts), 130.0 (CH_Ts), 133.1, 141.7, 145.0, 145.1, 148.5, 154.5 (6 × C_Ar) ppm; MS (ESI+): m/z = 662 (M⁺ + Na).

5,11,17,23-Tetrakis(tert-butyl)-26,28-dihydroxycalix[4]arene-propylenecrown-6 14b. Under Ar, tert-butylcalix[4]arene (13, 158 mg, 0.24 mmol) and K₂CO₃ (39 mg, 0.28 mmol) were suspended in DCM (10 mL) and compound 8b (273 mg, 0.49 mmol) dissolved in 5 mL of DCM was added dropwise. The resulting mixture was stirred at 30 °C for 11 d. Afterwards, the DCM phase was washed with water (2 × 15 mL) and aqueous HCl (10%, 2 × 15 mL), dried over Na₂SO₄ and the solvent was removed. The crude product was purified via column chromatography (petroleum ether:ethyl acetate = 2:1 → 1:1) yielding compound 14b as a colourless solid (85 mg, 40%); R_f 0.2 (petroleum ether:ethyl acetate = 1:1); ¹H NMR (600 MHz, CDCl₃): δ 0.94 (s, 18H, ^tBu), 1.30 (s, 18H, ^tBu), 1.76 (p, ³J = 5.8 Hz, 2H, OCH₂), 3.30 (d, ²J = 13.0 Hz, 4H, CH₂Ar), 3.67 (t, ³J = 5.8 Hz, 4H, OCH₂), 3.75–3.78 (m, 4H, OCH₂), 3.90–3.93 (m, 4H, OCH₂), 4.00–4.03 (m, 4H, OCH₂), 4.13–4.16 (m, 4H, OCH₂), 4.37 (d, ²J = 13.0 Hz, 4 H, CH₂Ar), 6.78 (s, 4H ArH), 7.06 (s, 4H, ArH), 7.18 (s, 2H, OH); ¹³C NMR (101 MHz, CDCl₃): δ 30.4 (OCH₂), 31.1 (CH₃), 31.6 (CH₂Ar), 31.9 (CH₃), 34.0 (C_q), 34.1 (C_q), 67.5 (OCH₂), 71.0 (OCH₂), 70.1 (OCH₂), 71.3 (OCH₂), 76.1 (OCH₂), 125.1 (CH_Ar), 125.6 (CH_Ar), 128.0 (C_Ar), 132.7 (C_Ar), 141.4 (C_Ar), 146.9 (C_Ar), 150.0 (C_Ar), 150.8 (C_Ar) ppm; MS (ESI+): m/z = 883 (M⁺ + NH₄), 888 (M⁺ + Na).

5,11,17,23-Tetrakis(tert-butyl)-26,28-dihydroxycalix[4]arene-benzocrown-6 14c. Under Ar, tert-butylcalix[4]arene (13, 610 mg, 0.94 mmol) and K₂CO₃ (150 mg, 1.08 mmol) were suspended in DCM (20 mL) and compound 12a (1.12 g, 1.88 mmol) dissolved in 10 mL of DCM was added dropwise. The resulting mixture was stirred at 30 °C for 11 d. Afterwards, the DCM phase was washed with water (2 × 30 mL) and aqueous HCl (10%, 2 × 30 mL), dried over Na₂SO₄ and the solvent was removed. The crude product was purified via column chromatography (DCM:ethyl acetate = 20:1 → 10:1) yielding compound 14c as colourless solid (346 mg, 41%); mp 154 °C; R_f 0.2 (DCM:methanol = 96:4); ¹H NMR (600 MHz, CDCl₃): δ 0.93 (s, 18H, ^tBu), 1.29 (s, 18H, ^tBu), 3.29 (d, ²J = 13.1 Hz, 4H, CH₂Ar), 4.11 (t, ³J = 4.7 Hz, 4H, OCH₂), 4.15 (t, ³J = 4.7 Hz, 4H, OCH₂), 4.23 (t, ³J = 4.7 Hz, 4H, OCH₂), 4.27–4.33 (m, 8H, OCH₂, CH₂Ar), 6.77 (s, 4H, ArH), 6.91–6.94 (m, 2H, ArH), 6.97 (m, 2H, ArH), 7.05 (s, 4H, ArH), 7.18 (s, 2H, OH); ¹³C NMR (151 MHz, CDCl₃): δ 31.1 (^tBu), 31.6 (CH₂Ar), 31.9 (^tBu), 34.0 (C_q), 34.1 (C_q), 70.3 (OCH₂), 70.5 (OCH₂), 71.1 (OCH₂), 76.5 (OCH₂), 116.5 (CH_Ar), 122.2 (CH_Ar), 125.1 (CH_Ar), 125.7 (CH_Ar), 127.9, 132.6, 141.5, 147.1, 149.5, 149.9, 150.8 (7 × C_Ar) ppm; MS (ESI+): m/z = 917 (M⁺ + NH₄), 922 (M⁺ + Na).

5,11,17,23-Tetrakis(tert-butyl)-26,28-dihydroxycalix[4]arene-benzocrown-8 14d. Under Ar, tert-butylcalix[4]arene (13, 265 mg, 0.41 mmol) and K₂CO₃ (65 mg, 0.47 mmol) were suspended in DCM (20 mL) and compound 12b (557 mg, 0.82 mmol) dissolved in 5 mL of DCM was added dropwise. The resulting mixture was stirred at 30 °C for 11 d. Afterwards, the DCM phase was washed with water (2 × 20 mL) and aqueous HCl (10%, 2 × 20 mL), dried over Na₂SO₄ and the solvent was removed. The crude product was purified via column chromatography (petroleum ether:acetone = 3:1) yielding compound 14d as colourless solid (325 mg, 81%); R_f 0.2 (petroleum ether:acetone = 3:1); ¹H NMR (400 MHz, CDCl₃): δ 0.95 (s, 18H, ^tBu), 1.29 (s, 18H, ^tBu), 3.28 (d, ²J = 13.0 Hz, 4H, CH₂Ar), 3.91–3.96 (m, 8H, OCH₂), 3.97–4.05 (m, 8H, OCH₂), 4.10–4.16 (m, 8H, OCH₂), 4.35 (d, ²J = 13.0 Hz, 4H, CH₂Ar), 6.78 (s, 4H, ArH), 6.85–6.91 (m, 4H, ArH), 7.05 (s, 4H, ArH), 7.30 (s, 2H, OH) ppm; ¹³C NMR (101 MHz, CDCl₃): δ 31.2 (CH₃), 31.6 (CH₂Ar), 31.9 (CH₃), 34.0 (C_q), 34.1 (C_q), 69.6 (OCH₂), 70.1 (OCH₂), 70.4 (OCH₂), 71.4 (OCH₂), 71.5 (OCH₂), 76.1 (OCH₂), 114.2 (CH_Ar), 121.5 (CH_Ar), 125.1 (CH_Ar), 125.6 (CH_Ar), 127.9, 132.8, 141.4, 147.0, 149.2, 149.9, 150.9 (7 × C_Ar) ppm; MS (ESI+): m/z = 1009 (M⁺ + Na).

5,11,17,23-Tetrakis(tert-butyl)-26,28-dihydroxycalix[4]arene-4-tert-butoxycarbonyl-benzocrown-6 14e. Under Ar, tert-butylcalix[4]arene (13, 140 mg, 0.22 mmol) and K₂CO₃ (34 mg, 0.25 mmol) were suspended in DCM (10 mL). Compound 12e (298 mg, 0.43 mmol) dissolved in 5 mL of DCM was added dropwise. The resulting mixture was stirred at 30 °C for 11 d. Afterwards, the DCM phase was washed with water (2 × 20 mL) and aqueous HCl (10%, 2 × 20 mL), dried over Na₂SO₄ and the solvent was removed. The crude product was purified via column chromatography (petroleum ether:acetone = 4:1 → 1:1) yielding compound 14e as colourless solid (78 mg, 36%); R_f 0.5 (petroleum ether:acetone = 2:1); ¹H NMR (400 MHz, CDCl₃): δ 0.93 (s, 18H, ^tBu), 1.30 (s, 18H, ^tBu), 1.58 (s, 9H, O ^tBu), 3.30 (d, ²J = 12.7 Hz, 4H, CH₂Ar), 4.10–4.33 (m, 20H, OCH₂ + CH₂Ar), 6.76 (s, 4H, ArH), 6.90 (d, ³J = 8.1 Hz, 1H, ArH), 7.05 (s, 4H, ArH), 7.14 (s, 2H, OH), 7.59–7.64 (m, 2H, ArH); ¹³C NMR (101 MHz, CDCl₃): δ 28.4 (O^tBu), 31.6 (CH₂Ar), 31.1 (CH₃), 31.9 (CH₃), 34.0 (C_q), 34.0 (C_q), 69.8 (OCH₂), 70.3 (OCH₂), 70.5 (OCH₂), 70.6 (OCH₂), 70.8 (OCH₂), 76.4 (OCH₂), 76.5 (OCH₂), 80.8 (OC_q), 114.0 (CH_Ar), 116.9 (CH_Ar), 124.4 (CH_Ar), 125.1 (CH_Ar), 125.2 (CH_Ar), 125.7 (CH_Ar), 126.1, 127.8, 127.9, 132.6, 141.8, 141.9, 147.0, 147.1, 148.5, 150.8, 153.8 (11 × C_Ar), 165.7 C=O) ppm; MS (ESI+): m/z = 1022 (M⁺ + Na).

5,11,17,23-Tetrakis(tert-butyl)-26,28-dihydroxycalix[4]arene-4-nitrobenzocrown-6 14f. Under Ar, tert-butylcalix[4]arene (13, 882 mg, 1.36 mmol) and K₂CO₃ (220 mg, 1.56 mmol) were suspended in DCM (20 mL), and compound 12f (1.74 g, 2.72 mmol) dissolved in 10 mL of DCM was added dropwise. The resulting mixture was stirred at 30 °C for 11 d. Afterwards, the DCM phase was washed with water (2 × 30 mL) and aqueous HCl (10%, 2 × 30 mL), dried over Na₂SO₄ and the solvent was removed. The crude product was purified via column chromatography (DCM:ethyl acetate = 97:3 → 9:1) yielding compound 14f as colourless solid (870 mg, 68%); R_f 0.3 (DCM:ethyl acetate = 9:1); ¹H NMR (600 MHz, CDCl₃): δ 0.91 (s, 18H, CH₃), 1.29 (s, 18H, CH₃), 3.25–3.30 (m, 4H, ArCH₂), 4.08–4.15 (m, 8H, OCH₂, ArCH₂), 4.18–4.30 (m, 8H, OCH₂), 4.34–4.40 (m, 4H, OCH₂), 6.71–6.76 (m, 4H, ArH), 6.88–6.92 (m, 1H, ArH), 6.99 (s, 2H, OH), 7.02–7.04 (m, 4H, ArH), 7.77–7.83 (m, 2H, ArH); ¹³C NMR (151 MHz, CDCl₃): δ 31.1 (^tBu), 31.5 (ArCH₂), 31.9 (^tBu), 34.0 (C_q), 34.1 (C_q), 69.9 (OCH₂), 70.3 (OCH₂), 70.4 (OCH₂), 70.5 (OCH₂), 70.6 (OCH₂), 70.8 (OCH₂), 76.2 (OCH₂), 76.3 (OCH₂), 110.5 (CH_Ar), 113.3 (CH_Ar), 118.5 (CH_Ar), 125.1 (CH_Ar), 125.2 (CH_Ar), 125.7 (CH_Ar), 127.8, 127.9, 132.4, 132.5, 141.6, 141.9, 147.1, 149.8, 149.9, 150.7, 154.9 ppm (11 × C_Ar); MS (ESI+): m/z = 967 (M⁺ + Na), 983 (M⁺ + K).

5,11,17,23-Tetrakis(tert-butyl)-25,27-bis(2-ethoxy-2-oxoethoxy)calix[4]arene-propylenecrown-6 15b. Under Ar, compound 14b (85 mg, 0.12 mmol) was dissolved in anhydrous THF (10 mL) and NaH (23 mg, 0.58 mmol, 60% in mineral oil) was added and the mixture stirred for 30 min at rt. Next, ethyl bromoacetate (65 μL, 0.58 mmol) was added and the mixture stirred at 60 °C overnight. Afterwards, the solvent was changed to DCM (15 mL), the organic phase washed with water (2 × 15 mL) and dried over Na₂SO₄. After removal of the solvent, the crude product was purified via column chromatography (petroleum ether:ethyl acetate = 2:1 → 1:1) yielding compound 15b as colourless solid (45 mg, 37%); R_f 0.2 (petroleum ether:ethyl acetate = 2:1); ¹H NMR (600 MHz, CDCl₃): δ 0.88 (s, 18H, ^tBu), 1.26 (s, 18H, ^tBu), 1.30 (t, ³J = 7.1 Hz, 6H, CH₃), 1.83 (p, ³J = 5.7 Hz, 2H, CH₂), 3.16 (d, ²J = 12.7 Hz, 4H, CH₂Ar), 3.67 (t, ³J = 5.7 Hz, 4H, OCH₂), 3.70 (m, 4H, OCH₂), 3.75–3.78 (m, 4H, OCH₂), 4.11–4.15 (m, 4H, OCH₂), 4.21–4.28 (m, 8H, CH₂C=O, OCH₂), 4.51 (d, ²J = 12.7 Hz, 4H, CH₂Ar), 6.55 (s, 4H, ArH), 4.56 (s, 4H, OCH₂), 7.02 (s, 4H, ArH); ¹³C NMR (151 MHz, CDCl₃): δ 14.4 (CH₃), 30.5 (CH₂), 31.3 (CH₃), 31.4 (CH₂Ar), 31.8 (CH₃), 33.8 (C_q), 34.2 (C_q), 60.8 (CH 3 CH 2 OCO), 67.1 (OCH₂), 70.0 (OCH₂), 70.1 (OCH₂), 70.4 (OCH₂), 72.1 (OCH₂C=O), 72.7 (OCH₂), 125.0 (CH_Ar), 125.6 (CH_Ar), 132.4, 135.1, 145.0, 145.2, 152.3, 154.3 (6 × C_Ar), 169.9 (C=O) ppm; MS (ESI+): m/z = 1060 (M⁺ + Na).

5,11,17,23-Tetrakis(tert-butyl)-25,27-bis(2-ethoxy-2-oxoethoxy)calix[4]arene-benzocrown-6 15c. Under Ar, compound 14c (346 mg, 0.39 mmol) was dissolved in anhydrous THF (20 mL) and NaH (77 mg, 1.93 mmol, 60% in mineral oil) was added and the mixture stirred for 30 min at rt. Next, ethyl bromoacetate (214 μL, 1.93 mmol) and NaI in catalytic amounts were added and the mixture stirred at 60 °C overnight. Afterwards, the solvent was changed to DCM (20 mL), the organic phase was washed with water (2 × 20 mL) and dried over Na₂SO₄. After removal of the solvent, the product was recrystallized from hot methanol. After filtration the product was washed with cold methanol yielding compound 15c as colorless solid (238 mg, 58%); R_f 0.2 (petroleum ether: ethyl acetate = 2:1); ¹H NMR (600 MHz, CDCl₃): δ 0.92 (s, 18H, CH₃), 1.14 (t, ³J = 7.1 Hz, 6H, CH₃), 1.23 (s, 18H, CH₃), 3.17 (d, ²J = 12.7 Hz, 4H, ArCH₂), 4.00–4.07 (m, 8H, OCH₂, CH₂), 4.19–4.28 (m, 12H, OCH₂), 4.54 (d, ²J = 12.7 Hz, 4H, ArCH₂), 4.61 (s, 4H, CH₂C=O), 6.58 (s, 4H, ArH), 6.91 (s, 4H, ArH), 6.97 (s, 4H, ArH); ¹³C NMR (151 MHz, CDCl₃): δ 28.1 (CH₃), 31.2 (ArCH₂), 31.3 (^tBu), 31.7 (^tBu), 33.8 (C_q), 34.1 (C_q), 69.4 (OCH₂), 70.2 (OCH₂), 70.9 (OCH₂), 72.0, (CH₂C=O), 77.4 (OCH₂), 114.6 (CH_Ar), 121.6 (CH_Ar), 123.6 (CH_Ar), 125.1 (CH_Ar), 125.6 (CH_Ar), 128.2, 132.6, 134.7, 145.1, 149.6, 149.6 (6 × C_Ar), 170.0 (C=O) ppm; MS (ESI+): m/z = 1094 (M⁺ + Na).

5,11,17,23-Tetrakis(tert-butyl)-25,27-bis(2-ethoxy-2-oxoethoxy)calix[4]arene-benzocrown-8 15d. Under Ar, compound 14d (325 mg, 0.33 mmol) was dissolved in anhydrous THF (20 mL) and NaH (184 mg, 1.7 mmol, 60% in mineral oil) was added and the mixture stirred for 30 min at rt. Next, ethyl bromoacetate (183 μL, 1.7 mmol) and NaI in catalytic amounts were added and the mixture stirred at 60 °C overnight. Afterwards, the solvent was changed to DCM (15 mL), the organic phase was washed with brine (2 × 15 mL) and dried over Na₂SO₄. After removal of the solvent, the crude product was purified via column chromatography (DCM:methanol = 95:5) yielding compound 15d as colorless solid (170 mg, 45%); R_f 0.2 (petroleum ether:ethyl acetate = 2:1); ¹H NMR (600 MHz, CDCl₃): δ 0.87 (s, 18H, CH₃), 1.23–1.28 (m, 24H, CH₃ + OCH₂CH₃), 3.15 (d, ²J = 12.7 Hz, 4H, ArCH₂), 3.79–3.82 (m, 4H, OCH₂), 3.87–3.90 (m, 4H, OCH₂), 3.94 (t, ³J = 4.5 Hz, 4H, OCH₂CH₃), 4.10–4.33 (m, 16H, OCH₂), 4.48 (d, ²J = 12.7 Hz, 4H, ArCH₂), 4.52 (s, 4H, CH₂C=O), 6.53 (s, 4H, ArH), 6.88–6.92 (m, 4H, ArH), 7.02 (m, 4H, ArH); ¹³C NMR (151 MHz, CDCl₃): δ 14.4 (CH₃), 31.3 (^tBu), 31.6 (ArCH₂), 31.8 (^tBu), 60.9 (CH₂), 69.6 (OCH₂), 69.9 (OCH₂), 70.0 (OCH₂), 70.8 (OCH₂), 71.2 (OCH₂), 72.2 (CH₂C=O), 72.5 (OCH₂), 77.4 (OCH₂), 114.3 (CH_Ar), 121.6 (CH_Ar), 125.1 (CH_Ar), 125.6 (CH_Ar), 132.3, 135.1, 145.0, 145.2, 149.2, 152.3, 154.4 (7 × C_Ar), 169.9 (C=O) ppm; MS (ESI+): m/z = 1182 (M⁺ + Na).

5,11,17,23-Tetrakis(tert-butyl)-25,27-bis(2-ethoxy-2-oxoethoxy)calix[4]arene-4-tert-butoxycarbonyl-benzocrown-6 15e. Under Ar, compound 14e (78 mg, 0.078 mmol) was dissolved in anhydrous THF (10 mL) and NaH (16 mg, 0.39 mmol, 60% in mineral oil) was added and the mixture stirred for 30 min at rt. Next, ethyl bromoacetate (44 μL, 0.39 mmol) and NaI in catalytic amounts were added and the mixture stirred at 60 °C overnight. Afterwards, the solvent was changed to DCM (15 mL), the organic phase was washed with brine (2 × 15 mL) and dried over Na₂SO₄. After removal of the solvent, the crude product was purified via column chromatography (petroleum ether:ethyl acetate = 4:1) yielding compound 15e as colorless solid (31 mg, 34%); R_f 0.2 (petroleum ether:ethyl acetate = 2:1); ¹H NMR (400 MHz, CDCl₃): δ 0.93 (s, 18H, CH₃), 1.12 (t, ³J = 7.2 Hz, 6H, CH₂CH₃), 1.21 (s, 18H, CH₃), 1.58 (s, 9H, O^tBu), 3.17 (d, ²J = 12.8 Hz, 4H, ArCH₂), 3.97–4.07 (m, 8H, OCH₂), 4.20–4.29 (m, 12H, OCH₂), 4.50–4.58 (m, 4H, ArCH₂), 4.62 (s, 4H, CH₂C=O), 6.59 (s, 4H, ArH), 6.86 (d, ³J = 8.5 Hz, 1H, ArH), 6.95 (s, 4H, ArH), 7.52 (s, 1H, ArH), 7.60 (d, ³J = 8.5 Hz, 1H, ArH); ¹³C NMR (101 MHz, CDCl₃): δ 14.2 (CH₂CH₃), 28.4 (O^tBu), 31.4 (^tBu), 31.5 (ArCH₂), 31.7 (^tBu), 33.9 (C_q), 34.1 (C_q), 60.7 (CH₂CH₃), 69.2 (OCH₂), 69.6 (OCH₂), 70.0 (OCH₂), 70.1 (OCH₂), 71.1 (OCH₂), 71.2 (OCH₂), 71.9 (CH₂C=O), 73.5 (OCH₂), 80.8 (COOC(CH₃)₃), 112.4 (CH_Ar), 115.0 (CH_Ar), 123.8 (CH_Ar), 124.9 (C_Ar), 125.1 (CH_Ar), 125.1 (CH_Ar), 125.6 (CH_Ar), 132.7, 134.6, 134.6, 145.1, 148.6, 152.2, 153.1, 154.5, 154.6 (9 × C_Ar), 165.7 (C=O), 170.0 (C=O) ppm; MS (ESI+): m/z = 1195 (M⁺ + Na).

5,11,17,23-Tetrakis(tert-butyl)-25,27-bis(2-ethoxy-2-oxoethoxy)calix[4]arene-4-nitrobenzocrown-6 15f. Under Ar, compound 14f (870 mg, 0.92 mmol) was dissolved in anhydrous THF (40 mL) and NaH (184 mg, 4.61 mmol, 60% in mineral oil) was added and the mixture stirred for 30 min at rt. Next, ethyl bromoacetate (513 μL, 1.93 mmol) and NaI in catalytic amounts were added and the mixture stirred at 60 °C overnight. Afterwards, the solvent was changed to DCM (30 mL), the organic phase was washed with brine (2 × 30 mL) and dried over Na₂SO₄. After removal of the solvent, the crude product was purified via column chromatography (DCM → DCM:methanol = 98:2) yielding compound 15f as colorless solid (960 mg, 93%); R_f 0.5 (DCM:methanol = 95:5); ¹H NMR (600 MHz, CDCl₃): δ 0.95 (s, 18H, CH₃), 1.11 (t, ³J = 7.1 Hz, 6H, CH₂CH₃), 1.19 (br. s, 18H, CH₃), 3.17 (d, ²J = 12.8 Hz, 4H, ArCH₂), 3.98–4.03 (m, 4H, CH₂CH₃), 4.04–4.09 (m, 4H, OCH₂), 4.20–4.30 (m, 12H, OCH₂), 4.50–4.58 (m, 4H, ArCH₂), 4.65 (s, 4H, OCH₂), 6.62 (s, 4H, ArH), 6.91–6.94 (m, 1H, ArH), 6.93 (d, ³J = 8.9 Hz, 4H, ArH), 7.75 (d, ⁴J = 2.7 Hz, 1H, ArH), 7.90 (dd, ³J = 8.9 Hz, ⁴J = 2.7 Hz, 1H, ArH); ¹³C NMR (151 MHz, CDCl₃): δ 14.2 (CH₂CH₃). 31.4 (^tBu), 31.7 (ArCH₂), 31.8 (^tBu), 33.9 (C_q), 34.2 (C_q), 60.7 (CH₂CH₃), 69.8 (OCH₂), 69.9 (OCH₂), 70.0 (OCH₂), 71.3 (OCH₂), 71.4 (OCH₂), 72.0 (OCH₂CO), 73.4 (OCH₂), 73.5 (OCH₂), 109.2 (CH_Ar), 112.1 (CH_Ar), 118.1 (CH_Ar), 125.1 (CH_Ar), 125.2 (CH_Ar), 125.7 (CH_Ar), 132.8, 134.5, 134.6, 141.9, 145.2, 145.3, 152.4, 154.6, 154.7, 155.1 (10 × C_Ar), 169.9 (C=O) ppm; MS (ESI+): m/z = 1139 (M⁺ + Na).

5,11,17,23-Tetrakis(tert-butyl)-25,27-bis(carboxymethoxy)calix[4]arene-propylenecrown-6 16b. Compound 15b (45 mg, 43 μmol) was dissolved in THF (5 mL), a solution of Me₄NOH ∙ 5 H₂O (55 mg, 0.30 mmol) in methanol (2 mL) was added and the reaction mixture was stirred at 55 °C overnight. The major part of the solvent was removed and the product was precipitated with ice-cold aqueous HCl (6 M). The solid residue was filtered and washed with water (20 mL) and dissolved in DCM (10 mL). The organic phase was washed with cold water (5 mL). After separation, the organic phase was dried over Na₂SO₄, the solvent was removed and 16b was obtained as grey solid (41 mg, 95%); ¹H NMR (600 MHz, CDCl₃): δ 0.83 (s, 18H, ^tBu), 1.33 (s, 18H, ^tBu), 1.67 (p, ³J = 6.7 Hz, 2H, CH₂), 3.21 (d, ²J = 13.0 Hz, 4H, CH₂Ar), 3.58 (t, ³J = 6.7 Hz, 4H, OCH₂), 3.65–3.68 (m, 4H, OCH₂), 3.72–3.75 (m, 4H, OCH₂), 3.83–3.86 (m, 4H, OCH₂), 3.96–4.01 (m, 4H, OCH₂), 4.50 (d, ²J = 13.0 Hz, 4H, CH₂), 4.86 (s, 4H, CH₂C=O), 6.59 (s, 4H, ArH), 7.14 (s, 4H, ArH); ¹³C NMR (151 MHz, CDCl₃): δ = 29.8 (CH₂); 31.0 (CH₂Ar), 31.1 (CH₃), 31.8 (CH₃), 33.9 (C_q), 34.3 (C_q), 67.3 (OCH₂), 70.3 (OCH₂), 70.6 (OCH₂), 70.7 (OCH₂), 72.9 (CH₂C=O), 77.1 (OCH₂), 125.5 (CH_Ar), 126.1 (CH_Ar), 132.6, 135.2, 146.0, 146.9, 150.6, 153.4 (6 × C_Ar), 171.0 (C=O) ppm; MS (ESI+): m/z = 1048 (M⁺ − 2 H + 3 Na).

5,11,17,23-Tetrakis(tert-butyl)-25,27-bis(carboxymethoxy)calix[4]arene-benzocrown-6 16c. Compound 15c (446 mg, 0.435 mmol) was dissolved in THF (20 mL), a solution of Me₄NOH ∙ 5 H₂O (2.45 g, 6.85 mmol) in methanol (5 mL) was added and the reaction mixture was stirred at 55 °C overnight. After filtration, the major part of the solvent was removed and the product was precipitated with ice-cold aqueous HCl (6 M). The solid residue was filtered and washed with water (20 mL) and dissolved in DCM (30 mL). The organic phase was washed with cold water (15 mL). After separation, the organic phase was dried over Na₂SO₄, the solvent was removed and 16c was obtained as brownish solid (440 mg, >99%); ¹H NMR (400 MHz, CDCl₃): δ 0.83 (s, 18H, CH₃), 1.31 (s, 18H, CH₃), 3.19 (d, ²J = 12.8 Hz, 4H, ArCH₂), 3.80–4.28 (m, 16H, OCH₂), 4.45 (d, ²J = 12.8 Hz, 4H, ArCH₂), 4.86 (s, 4H, OCH₂CO), 6.60 (s, 4H, ArH), 6.75–6.88 (m, 4H, ArH), 7.12 (s, 4H, ArH); ¹³C NMR (101 MHz, CDCl₃): δ 30.9 (ArCH₂), 31.1 (^tBu), 31.8 (^tBu), 33.9 (C_q), 34.3 (C_q), 67.9 (OCH₂), 70.7 (OCH₂), 71.0 (OCH₂), 72.9 (OCH₂C=O), 77.4 (OCH₂), 111.5 (CH_Ar), 120.6 (CH_Ar), 125.5 (CH_Ar), 126.0 (CH_Ar), 132.6, 135.2, 145.9, 146.9, 148.4, 150.5 (6 × C_Ar), 170.1 (C=O) ppm; MS (ESI+): m/z = 1060 (M⁺ − H + 2 Na), 1082 (M⁺ − 2 H + 3 Na).

5,11,17,23-Tetrakis(tert-butyl)-25,27-bis(carboxymethoxy)calix[4]arene-benzocrown-8 16d. Compound 15d (170 mg, 0.15 mmol) was dissolved in THF (10 mL), a solution of Me₄NOH ∙ 5 H₂O (186 mg, 1.03 mmol) in methanol (2 mL) was added and the reaction mixture was stirred at 55 °C overnight. After filtration, the major part of the solvent was removed and the product was precipitated with ice-cold aqueous HCl (6 M). The solid residue was filtered and washed with water (10 mL) and dissolved in DCM (30 mL). The organic phase was washed with cold water (15 mL). After separation, the organic phase was dried over Na₂SO₄, the solvent was removed and 16d was obtained as brownish solid (134 mg, 83%); ¹H NMR (400 MHz, CDCl₃): δ 0.83 (s, 18H, CH₃), 1.33 (s, 18H, CH₃), 3.17 (d, ²J = 13.0 Hz, 4H, ArCH₂), 3.72–3.75 (m, 4H, OCH₂), 3.78–3.84 (m, 8H, OCH₂), 3.86–3.90 (m, 4H, OCH₂), 3.95–4.04 (m, 8H, OCH₂), 4.46 (d, ²J = 13.0 Hz, 4H, ArCH₂), 4.74 (s, 4H, OCH₂CO), 6.56 (s, 4H, ArH), 6.71–6.76 (m, 2H, ArH), 6.81–6.85 (m, 2H, ArH), 7.12 (s, 4H, ArH); ¹³C NMR (101 MHz, CDCl₃): δ 30.9 (ArCH₂), 31.1 (^tBu), 31.8 (^tBu), 33.9 (C_q), 34.3 (C_q), 69.1 (OCH₂), 70.1 (OCH₂), 70.5 (OCH₂), 71.1 (OCH₂), 72.4 (OCH₂CO), 77.4 (OCH₂), 115.2 (CH_Ar), 121.6 (CH_Ar), 125.5 (CH_Ar), 126.1 (CH_Ar), 132.5, 135.2, 147.1, 149.1, 150.4, 153.2 (6 × C_Ar), 170.6 (C=O) ppm; MS (ESI+): m/z = 1170 (M⁺ − 2 H + 3 Na).

5,11,17,23-Tetrakis(tert-butyl)-25,27-bis(carboxymethoxy)calix[4]arene-4-tert-butylcarboxy-benzocrown-6 16e. Compound 15e (31 mg, 27 μmol) was dissolved in THF (4 mL), a solution of Me₄NOH ∙ 5 H₂O (34 mg, 0.19 mmol) in methanol (2 mL) was added and the reaction mixture was stirred at 55 °C overnight. The solvent was removed and the crude product was dissolved in DCM (30 mL). The organic phase was washed with saturated NH₄Cl solution (15 mL) and water (15 mL). After separation, the organic phase was dried over Na₂SO₄, the solvent was removed and 16e was obtained as yellowish oil (26 mg, 87%); ¹H NMR (400 MHz, CDCl₃): δ 0.83 (s, 18H, CH₃), 1.31 (s, 18H, CH₃), 1.56 (s, 9H, OC(CH₃)₃), 3.19 (d, ²J = 12.8 Hz, 4H, ArCH₂), 3.83–4.08 (m, 12H, OCH₂), 4.26–4.31 (m, 4H, OCH₂), 4.44 (d, ³J = 12.8 Hz, 4H, ArCH₂), 4.84 (s, 4H, OCH₂CO), 6.60 (s, 4H, ArH), 6.76 (d, ³J = 8.5 Hz, 1H, ArH), 6.98 (s, 4H, ArH), 7.40 (d, ⁴J = 1.9 Hz, 1H, ArH), 7.55 (dd, ³J = 8.5 Hz, ⁴J = 1.9 Hz, 1H, ArH); ¹³C NMR (101 MHz, CDCl₃): δ 28.4 (O^tBu), 31.1 (^tBu), 31.2 (ArCH₂), 31.8 (^tBu), 33.9 (C_q), 34.3 (C_q), 68.2 (OCH₂), 68.5 (OCH₂), 70.4 (OCH₂), 70.5 (OCH₂), 70.9 (OCH₂), 71.0 (OCH₂), 72.0 (OCH₂CO), 77.4 (OCH₂), 80.6 (OC_q), 110.6 (CH_Ar), 112.2 (CH_Ar), 123.2 (CH_Ar), 125.3 (C_Ar), 125.5 (CH_Ar), 125.7 (CH_Ar), 135.2, 136.0, 143.3, 145.8, 145.9, 147.0, 147.9, 150.4, 150.5, 151.7, 152.1 (11 × C_Ar), 165.9 (COO^tBu), 172.8 (C=O) ppm; MS (ESI+): m/z = 1160 (M⁺ − H + 2 Na).

Disodium 5,11,17,23-tetrakis(tert-butyl)-25,27-bis(N-heptafluoropropane-2-sulfonylcarbamoyl-methoxy)calix[4]arene-crown-6 21. Calixarene 16a (300 mg, 0.31 mmol) was suspended in CCl₄ (6 mL), oxalyl chloride (1.5 mL) was added and the mixture was stirred for 5 h at 65 °C. After cooling to rt, the solvent and remaining oxalyl chloride was removed. Under argon, the residue was dissolved in anhydrous DCM (5 mL) and a mixture of perfluoroisopropanesulfonamide (193 mg, 0.77 mmol) and NaH (60% in mineral oil, 124 mg, 3.1 mmol) dissolved in anhydrous DCM was added. After stirring overnight at rt, the mixture was filtered, the organic phase was washed with 10% HCl, the organic phase was separated and dried over Na₂SO₄. Next, the solvent was removed and the crude product was purified by column chromatography (DCM → DCM/methanol 5:1) to yield calixarene 21 as colorless solid (254 mg, 57%). R_f 0.6 (petroleum ether:ethyl acetate = 2:1); ¹H NMR (600 MHz, CDCl₃): δ 1.11 (s, 18H, ^tBu), 1.15 (s, 18H, ^tBu), 3.38 (d, ²J = 12.3 Hz, 4H, ArCH₂), 3.71–3.74 (m, 4H, OCH₂), 3.82–3.86 (m, 4H, OCH₂), 3.86–3.92 (s, 8H, OCH₂), 4.10–4.18 (m, 8H, OCH₂+ArCH₂), 4.63 (s, 4H, CH₂C=O), 7.08 (s, 4H, m-H_Ar), 7.11 (s, 4H, m-H_Ar); ¹³C NMR (151 MHz, CDCl₃): δ 30.1 (ArCH₂), 31.3, 31.4 (2 x CH₃), 34.1, 34.3 (C_q), 69.3, 69,4, 72.1, 72.2, (4 × OCH₂), 77.0 (CH₂C=O), 78.8 (OCH₂), 125.8, 126.3 (2 × m-C_Ar), 134.1, 134.4 (2 × o-C_Ar), 147.8, 148.4 (2 × p-C_Ar), 148.3, 151.5 (2 × i-C_Ar), 176.2 (C=O); ¹⁹F NMR (565 MHz, CDCl₃): δ −169.3 (2F), −71.7 (12F) ppm; MS (MALDI-TOF): m/z = 1429 (M⁺).

Disodium 5,11,17,23-tetrakis(tert-butyl)-25,27-bis(N-heptafluoropropane-2-sulfonylcarbamoyl-methoxy)calix[4]arene-propylenecrown-6 22. Under Ar, compound 16b (41 mg, 42 μmol), 6-chloro-1-hydroxybenzotriazole (16 mg, 92 μmol), EDC · HCl (18 mg, 92 μmol), and Et₃N (13 μL, 9.3 mg, 92 μmol) was dissolved in anhydrous acetonitrile (8 mL) and stirred at 0 °C for 30 min. Afterwards, heptafluoroisopropane-2-sulfonamide (42 mg, 167 μmol) and Et₃N (12 μL, 8.4 mg, 84 μmol) dissolved in anhydrous acetonitrile (5 mL) were added and the resulting mixture stirred at rt overnight. Next, the solvent was changed to DCM (15 mL) and the organic phase was washed with brine (15 mL), saturated hydrogen carbonate solution (15 mL) and brine (15 mL), dried over Na₂SO₄ and the solvent was removed. The crude product was purified using column chromatography (petroleum ether:ethyl acetate = 4:1 → 2:1) to obtain 22 as colourless solid (24 mg, 40%); mp >350 °C; R_f = 0.6 (petroleum ether:ethyl acetate = 2:1); ¹H NMR (400 MHz, CDCl₃): δ 1.07 (s, 18H, ^tBu), 1.18 (s, 18H, ^tBu), 2.09–2.01 (m, 2H, CH₂), 3.36 (d, ²J = 12.3 Hz, 4H, CH₂Ar), 3.74–3.69 (m, 4H, OCH₂), 3.82–3.74 (m, 8H, 2 × OCH₂), 3.89–3.82 (m, 4H, OCH₂), 4.07–4.00 (m, 4H, OCH₂), 4.16 (d, ²J = 12.3 Hz, 4H, CH₂Ar), 4.58 (s, 4H, CH₂C=O), 7.04 (s, 4H, ArH), 7.13 (s, 4H, ArH); ¹³C NMR (101 MHz, CDCl₃): δ 30.0 (CH₂Ar), 30.3 (CH₂), 31.3 (CH₃), 31.5 (CH₃), 34.2 (C_q), 34.3 (C_q), 70.4 (OCH₂), 71.1 (OCH₂), 71.4 (OCH₂), 72.5 (OCH₂), 77.4 (CH₂C=O), 78.0 (OCH₂), 125.9 (CH_Ar), 126.5 (CH_Ar), 134.1, 134.5, 147.7, 148.4, 148.8, 151.0 (6 × C_Ar), 175.9 (C=O); ¹⁹F NMR (376 MHz, CDCl₃): δ −169.5 (hept, ³J = 7.5 Hz, 2F), −71.7 (d, ³J = 7.5 Hz, 12F) ppm; MS (ESI+): m/z = 1466 (M⁺ + Na).

Disodium 5,11,17,23-tetrakis(tert-butyl)-25,27-bis(N-trifluormethanesulfonylcarbamoylmethoxy)-calix[4]arene-benzocrown-6 23. Under Ar, compound 16c (100 mg, 99 μmol), 6-chloro-1-hydroxybenzotriazole (37 mg, 0.22 mmol), EDC · HCl (42 mg, 0.22 mmol), and Et₃N (30 μL, 22 mg, 0.22 mmol) were dissolved in anhydrous acetonitrile (10 mL) and stirred at 0 °C for 30 min. Afterwards, trifluoromethanesulfonamide (59 mg, 0.39 mmol) and Et₃N (27 μL, 20 mg, 0.20 mmol) dissolved in anhydrous acetonitrile (5 mL) were added and the resulting mixture stirred at rt overnight. Next, the solvent was changed to DCM (15 mL) and the organic phase was washed with water (15 mL), saturated hydrogen carbonate solution (15 mL) and water (15 mL), dried over Na₂SO₄ and the solvent was removed. The crude product was purified using column chromatography (petroleum ether:ethyl acetate = 2:1 → 3:2) to obtain 23 as yellowish solid (122 mg, 97%); mp 320 °C (decomp.); R_f 0.6 (petroleum ether:ethyl acetate = 1:1); ¹H NMR (400 MHz, CDCl₃): δ 1.13 (s, 18H, ^tBu), 1.15 (s, 18H, ^tBu), 1.10–1.16 (m, 36H, CH₃), 3.40 (d, ² J = 12.3 Hz, 4H, CH₂Ar), 3.96–4.02 (m, 4H, OCH₂), 4.04–4.21 (m, 12H, OCH₂, CH₂Ar), 4.27–4.33 (m, 4H, OCH₂), 4.64 (s, 4H, CH₂C=O), 6.88–6.98 (m, 4H, ArH), 7.07–7.14 (m, 8H, ArH) ppm; ¹³C NMR (101 MHz, CDCl₃): δ 30.3 (CH₂Ar), 31.3 (CH₃), 31.4 (CH₃), 34.2 (C_q), 34.3 (C_q), 67.0 (OCH₂), 70.6 (OCH₂), 72.6 (OCH₂), 77.4 (CH₂C=O), 78.3 (OCH₂), 111.7 (CH_Ar), 121.6 (CH_Ar), 125.8 (CH_Ar), 126.3 (CH_Ar), 134.2, 134.3, 147.0, 148.0, 148.1, 148.4, 151.6 (7 × C_Ar), 176.3 (C=O); ¹⁹F NMR (376 MHz, CDCl₃): δ − 76.6 (CF₃) ppm; MS (ESI+): m/z = 1278 (M⁺ + H), 1295 (M⁺ + NH₄), 1295 (M⁺ + Na).

Disodium 5,11,17,23-tetrakis(tert-butyl)-25,27-bis(N-heptafluoropropane-2-sulfonylcarbamoyl-methoxy)calix[4]arene-benzocrown-6 24. Under Ar, compound 16c (67 mg, 66 μmol), 6-chloro-1-hydroxybenzotriazole (20 mg, 0.15 mmol), EDC · HCl (29 mg, 0.15 mmol), and Et₃N (21 μL, 15 mg, 0.15 mmol) were dissolved in anhydrous acetonitrile (10 mL) and stirred at 0 °C for 30 min. Afterwards, heptafluoroisopropane-2-sulfonamide (66 mg, 0.26 mmol) and Et₃N (18 μL, 13 mg, 0.13 mmol) dissolved in anhydrous acetonitrile (5 mL) were added and the resulting mixture stirred at rt overnight. Next, the solvent was changed to DCM (15 mL) and the organic phase was washed with water (15 mL), saturated hydrogen carbonate solution (15 mL) and water (15 mL), dried over Na₂SO₄ and the solvent was removed. The crude product was purified using column chromatography (DCM → DCM:methanol = 74:1) to obtain 24 as colorless solid (50 mg, 50%); mp 340 °C (decomp.); R_f 0.7 (DCM:methanol = 98:2); ¹H NMR (400 MHz, CDCl₃): δ 1.10 (s, 18H, ^tBu), 1.17 (s, 18H, ^tBu), 3.41 (d, ²J = 12.4 Hz, 4H, CH₂Ar), 3.98–4.06 (m, 8H, OCH₂), 4.17 (d, ²J = 12.4 Hz, 4H, CH₂Ar), 4.20–4.25 (m, 8H, OCH₂), 4.65 (s, 4H, CH₂C=O), 6.84–6.88 (m, 2H, ArH), 6.93–6.97 (m, 2H, ArH), 7.06 (s, 4H, ArH_Calix), 7.14 (s, 4H, ArH_Calix); ¹³C NMR (101 MHz, CDCl₃): δ 30.3 (CH₂Ar), 31.4 (CH₃), 31.4 (CH₃), 34.2 (C_q), 34.3 (C_q), 66.5 (OCH₂), 70.2 (OCH₂), 72.8 (CH₂C=O), 76.8 (OCH₂), 78.1 (OCH₂), 110.9 (CH_Ar), 119.0 (dd, ¹J_C-F = 288 Hz, ³J_C-F = 26 Hz, CF), 119.5 (qd, ¹J_C-F = 288 Hz, ³J_C-F = 26 Hz, CF₃), 121.4 (CH_Ar), 125.8 (CH_Ar), 126.3 (CH_Ar), 134.1, 134.2, 146.8, 147.9, 148.0, 148.5, 151.9 (7 × C_Ar), 176.1 (C=O); ¹⁹F NMR (564 MHz, CDCl₃): δ − 72.0 (d, ³J = 7.0 Hz), −169.9 (hept, ³J = 7.0 Hz) ppm; MS (MALDI-TOF): m/z = 1499 (M⁺ + Na).

Disodium 5,11,17,23-tetrakis(tert-butyl)-25,27-bis(N-pentafluorobenzenesulfonylcarbamoylmethoxy)-calix[4]arene-benzocrown-6 25. Under Ar, compound 16c (100 mg, 99 μmol), 6-chloro-1-hydroxybenzotriazole (37 mg, 0.22 mmol), EDC · HCl (42 mg, 0.22 mmol), and Et₃N (30 μL, 22 mg, 0.22 mmol) were dissolved in anhydrous acetonitrile (10 mL) and stirred at 0 °C for 30 min. Afterwards, pentafluorobenzenesulfonamide (97 mg, 0.39 mmol) and Et₃N (27 μL, 20 mg, 0.20 mmol) dissolved in anhydrous acetonitrile (5 mL) were added and the resulting mixture stirred at rt overnight. Next, the solvent was changed to DCM (15 mL) and the organic phase was washed with water (15 mL), saturated hydrogen carbonate solution (15 mL) and water (15 mL), dried over Na₂SO₄ and the solvent was removed. The crude product was purified using column chromatography (petroleum ether:ethyl acetate = 2:1 → 3:2), dissolved again in DCM and washed with 10% HCl to obtain 25 as yellowish solid (122 mg, 97%); mp 320 °C (decomp.); R_f 0.6 (petroleum ether:ethyl acetate = 1:1); ¹H NMR (400 MHz, CDCl₃): δ 0.83 (s, 18H, CH₃), 1.24 (s, 18H, CH₃), 3.14 (d, ²J = 12.8 Hz, 4H, ArCH₂), 4.00–4.10 (m, 8H, OCH₂), 4.17–4.23 (m, 4H, OCH₂), 4.32 (d, ²J = 12.8 Hz, 4H, ArCH₂), 4.41–4.47 (m, 4H, OCH₂), 5.17 (s, 4H, OCH₂CO), 6.47 (s, 4H, ArH), 6.93 (s, 4H, ArH), 6.96–7.02 (m, 4H, ArH), 11.12 (s, 2H, C=O); ¹³C NMR (101 MHz, CDCl₃): δ 31.1 (CH₃), 31.6 (CH₃), 32.1 (ArCH₂), 33.8 (C_q), 34.2 (C_q), 68.1 (OCH₂), 70.0 (OCH₂), 70.3 (OCH₂C=O), 71.7 (OCH₂), 73.4 (OCH₂), 114.0 (CH_Ar), 122.1 (CH_Ar), 125.0 (CH_Ar), 125.4 (CH_Ar), 131.9, 135.1, 145.4, 146.1, 148.0, 151.4, 152.5 (7 × C_Ar), 168.8 (C=O); ¹⁹F NMR (376 MHz, CDCl₃): δ −138.6 (d, ³J = 20.4 Hz), −148.6 (d, ³J = 20.4 Hz), −163.5 (t, ³J = 20.4 Hz) ppm; MS (ESI +): m/z = 1474 (M⁺ + H), 1491 (M⁺ + NH₄), 1518 (M⁺ − H + 2 Na), 1534 (M⁺ − H + Na + K).

Disodium 5,11,17,23-tetrakis(tert-butyl)-25,27-bis(N-heptafluoro-2-propanesulfonylcarbamoyl-methoxy)calix[4]arene-4-tert-butylcarboxybenzocrown-6 26. Under Ar, compound 16e (26 mg, 42 μmol), 6-chloro-1-hydroxybenzotriazole (9 mg, 51 μmol), EDC · HCl (10 mg, 51 μmol), and Et₃N (7,1 μL, 5 mg, 51 μmol) were dissolved in anhydrous acetonitrile (8 mL) and stirred at 0 °C for 30 min. Afterwards, heptafluoropropane-2-sulfonamide (23 mg, 0.093 mmol) and Et₃N (6.5 μL, 5 mg, 0.084 mmol) dissolved in anhydrous acetonitrile (5 mL) were added and the resulting mixture stirred at rt overnight. Next, the solvent was changed to DCM (15 mL) and the organic phase was washed with water (15 mL), saturated hydrogen carbonate solution (15 mL) and water (15 mL), dried over Na₂SO₄ and the solvent removed. The crude product was purified using column chromatography (petroleum ether:ethyl acetate 3:1 → 2:1) to obtain 26 as colourless solid (13 mg, 35%); mp 340 °C (decomp.); R_f 0.3 (petroleum ether:ethyl acetate 2:1); ¹H NMR (400 MHz, CDCl₃): δ 1.10 (s, 18H, CH₃), 1.17 (s, 18H, CH₃), 1.61 (s, 9H, OC(CH₃)₃), 3.41 (d, ²J = 12.3 Hz, 4H, ArCH₂), 3.98–4.10 (m, 8H, OCH₂), 4.16 (d, ²J = 12.3 Hz, 4H, ArCH₂), 4.21–4.31 (m, 8H, OCH₂), 4.64 (s, 4H, OCH₂CO), 6.86 (d, ³J = 8.5 Hz, 1H, ArH), 7.06 (s, 4H, ArH), 7.14 (s, 4H, ArH), 7.50 (d, ⁴J = 1.9 Hz, 1H, ArH), 7.67 ppm (dd, ³J = 8.5 Hz, ⁴J = 1.9 Hz, 1H, ArH); ¹³C NMR (101 MHz, CDCl₃): δ 28.4 (O^tBu), 30.3 (ArCH₂), 30.4 (ArCH₂), 31.3 (^tBu), 31.4 (^tBu), 34.2 (C_q), 34.3 (C_q), 66.9 (OCH₂), 67.2 (OCH₂), 69.9 (OCH₂), 70.0 (OCH₂), 72.8 (OCH₂), 72.9 (OCH₂), 76.7 (OCH₂CO), 78.0 (OCH₂), 78.1 (OCH₂), 80.9 (OC_q), 110.2 (CH_Ar), 111.8 (CH_Ar), 124.0 (CH_Ar), 125.4 (C_Ar), 125.8 (CH_Ar), 126.3 (CH_Ar), 134.1, 134.2, 146.4, 147.9, 148.0, 148.1, 148.5, 150.3, 151.8, 151.9 (10 × C_Ar), 165.6 (C=OOtBu), 176.1 (C=ONH); ¹⁹F NMR (376 MHz, CDCl₃): δ −72.0 (m, 6F), −169.9 (hept, ³J = 7.3 Hz, 1F) ppm; MS (ESI +): m/z = 1595 (M⁺ + NH₄), 1600 (M⁺ + Na), 1616 (M⁺ + K), 1622 (M⁺ − H + 2 Na).

5,11,17,23-Tetrakis(tert-butyl)-25,27-bis(N-heptafluoro-2-propanesulfonylcarbamoyl-methoxy)calix[4]arene-benzocrown-8 27. Under Ar, compound 16d (135 mg, 0.12 mmol), 1-hydroxybenzotriazole (36 mg, 0.27 mmol), EDC · HCl (52 mg, 0.27 mmol), and Et₃N (37 μL, 27 mg, 0.27 mmol) were dissolved in anhydrous acetonitrile (20 mL) and stirred at 0 °C for 30 min. Afterwards, heptafluoropropane-2-sulfonamide (122 mg, 0.49 mmol) and Et₃N (34 μL, 25 mg, 0.24 mmol) dissolved in anhydrous acetonitrile (5 mL) were added and the resulting mixture stirred at rt overnight. Next, the solvent was changed to DCM (20 mL) and the organic phase was washed with water (20 mL), saturated hydrogen carbonate solution (20 mL) and water (20 mL), dried over Na₂SO₄ and the solvent removed. The crude product was purified using column chromatography (DCM:petroleum ether:ethyl acetate 3:8:2 → DCM:ethyl acetate 1:1) and washed with 10% aqueous HCl to obtain 27 as colourless solid (51 mg, 27%); mp 162 °C; R_f 0.25 (DCM:petroleum ether:ethyl acetate 3:8:2); ¹H NMR (400 MHz, CDCl₃): δ 0.82 (s, 18H, CH₃), 1.31 (s, 18H, CH₃), 3.22 (d, ²J = 13.0 Hz, 4H, ArCH₂), 3.77–3.79 (m, 4H, OCH₂), 3.79–3.82 (m, 8H, OCH₂), 3.98–4.00 (m, 4H, OCH₂), 4.07–4.10 (m, 4H, OCH₂), 4.20–4.23 (m, 4H, OCH₂), 4.55 (d, ²J = 13.0 Hz, 4H, ArCH₂), 5.28 (s, 4H, OCH₂CO), 6.50 (s, 4H, ArH), 6.84–6.89 (m, 2H, ArH), 6.90–6.95 (m, 2H, ArH), 7.08 (s, 4H, ArH); ¹³C NMR (151 MHz, CDCl₃): δ 33.7 (^tBu), 34.2 (^tBu), 34.7 (ArCH₂), 36.2 (C_q), 36.7 (C_q), 69.4 (OCH₂), 71.5 (OCH₂), 71.9 (OCH₂), 72.9 (OCH₂), 73.3 (OCH₂CO), 73.4 (OCH₂), 114.5 (CH_Ar), 123.7 (CH_Ar), 127.5 (CH_Ar), 128.4 (CH_Ar), 134.7, 137.8, 147.7, 148.1, 150.4, 154.0 (6 × C_Ar); ¹⁹F NMR (564 MHz, CDCl₃): δ −71.7 (d, ³J = 8.0 Hz, 6F), −168.5 (m, 1F) ppm; MS (ESI +): m/z = 1394 (M⁺ − H − NHSO₂CF(CF₃)₂ + K + Na), 1625 (M⁺ − H + K + Na).

4. Conclusions

Two sets of new functionalized calixarene ligands were prepared and analysed via UV/vis titration regarding their potential to chelate divalent cations like Ba, Sr and Pb. These ions are of high importance, e.g., as diagnostic or therapeutic radionuclides in radiopharmacy, or they are found in environmental chemistry. Thus, there exists a keen necessity for a strong complexation of these ions. In summary, the additional proton-ionizable side functions connected together with a benzocrown ether structure to the calixarene skeleton led to a considerable improvement of the complex stability resulting in high association constants. There is still room to improve the stability of these complexes for future application as chelators for radiometal ions in radiopharmacy.