The Preparation and Crystal Structures of Octaoxoketocalix[8]arene Derivatives: The Ketocalixarene Counterparts of the Largest “Major” Calixarene

Abstract

The purpose of this study was to synthesize and structurally characterize ketocalixarenes (i.e., calixarenes where the bridging methylene bridges are replaced by carbonyl groups) derived from the largest “major” calixarene, namely p-tert-butylcalix[8]arene 3a. Ketocalix[8]arenes were synthesized by the oxidation of protected p-tert-butylcalix[8]arene derivatives. Octamethoxy-p-tert-butylketocalix[8]arene 6b was prepared by the photochemical reaction of the calixarene 3b with NBS in a CHCl₃/H₂O mixture. The oxidation of the methylene groups of octaacetoxy-p-tert-butylcalix[8]arene 3c was conducted by a reaction with CrO₃ in Ac₂O/AcOH. The basic hydrolysis of the acetate groups of the oxidation product yielded octahydroxy-p-tert-butylketocalix[8]arene 6a. In the crystal, the molecule adopts a saddle-like conformation of crystallographic C₂ and idealized S₄ symmetry. Strikingly, the array of OH/OH intramolecular hydrogen bonds present in the parent 3a is completely disrupted in 6a.

1. Introduction

Calix[n]arenes are synthetic macrocycles consisting of n phenol rings interconnected by methylene units [1,2,3,4,5,6]. These systems possess a well-defined cavity capable of hosting smaller molecules or ions. During the last few decades, calixarenes have received considerable attention because of their multitude of potential applications [6]. Their preparation usually involves the base-catalyzed condensation of p-tert-butylphenol and formaldehyde. Only three calixarenes were initially synthetically accessible in both multigram scale and high yields: p-tert-butylcalix[4]arene (1a), p-tert-butylcalix[6]arene (2a) and p-tert-butylcalix[8]arene (3a) [7,8,9,10]. These systems were dubbed by Gutsche as “major calixarenes”(Scheme 1) [11]. Substituents are usually introduced at the scaffold via the electrophilic substitution of aromatic rings and/or via the alkylation or acylation of phenolic hydroxyl groups [12]. These modifications usually aim to alter the chemical properties, three-dimensional shape and rigidity of the macrocycle. A structural modification which is relatively unexplored involves the oxidation of methylene bridges to carbonyl groups.

Calixarenes where phenol rings are interconnected by carbonyl groups (“ketocalixarenes”) are of both stereochemical and synthetic interest [13]. The formal replacement of the bridging methylene groups by carbonyls changes the conformational preferences of the macrocycle. Remarkably, whereas the parent p-tert-butylcalix[4]arene (1a) adopts a cone conformation stabilized by a circular array of hydrogen bonds [14], tetrahydroxyketocalix[4]arene 4a adopts in the crystal and in solution a 1,3-alternate conformation (Figure 1) [15,16]. The carbonyl groups are not involved in intramolecular hydrogen bonding, and it was conjectured that the conformational change is due to dipole–dipole repulsion in the cone form and the increased conjugation of aryl rings with carbonyl groups in the conformation adopted [15].

Tetrahydroxyketocalix[4]arene 4a (Scheme 2) was first synthesized in 1990 by Görmar and coworkers [17]. The reaction sequence involved the acetylation of the hydroxyl groups of 1a (to protect the phenol moieties during the subsequent oxidation step), CrO₃ oxidation of the methylene groups of 1c and hydrolysis of the acetoxy groups [17,18]. Starting from hexahydroxycalix[6]arene 2a, a similar synthetic sequence was utilized for the preparation of hexahydroxyketocalix[6]arene 5a [19]. There is only a single report on the attempted oxidation of the methylenes of a derivative of calix[8]arene 3a which is the largest “classical” calixarene. In a pioneering study, Ninagawa and coworkers reported in 1985 on the CrO₃ oxidation of the methylene groups of 3c in an Ac₂O/AcOH mixture at 45 °C. A calix[8]arene derivative was obtained with three methylene bridges oxidized to carbonyls, but the identity of the structural isomer isolated was not determined [20]. The goal of this work was to synthesize and structurally characterize the derivatives of p-tert-butylcalix[8]arene, where all methylene bridges were oxidized to carbonyl groups.

2. Results

2.1. General Considerations

In all cases reported where the methylene groups of a calix scaffold were oxidized to carbonyl groups, the calixarene phenolic OH groups were protected as methyl ether (i.e., 1b, 2b) or acetoxy (1c, 2c) groups. This protection is necessary to avoid the oxidation of the phenol rings (e.g., to yield calixquinones [21] or 5,5’-bicalix[n]arenes [22]). In general, methyl ethers functionalities are considered more robust protecting groups of phenolic hydroxyls. This is of importance if, after oxidation, a further chemical modification of carbonyl bridges is planned on the protected derivative (e.g., by reaction with an organometallic reagent). For example, the reaction of tetramethoxyketocalix[4]arene 4b with PhLi [23] or MeLi [24] proceeds, readily affording the corresponding tetra-addition product. However, in our previous experience, we found that the deprotection of all the OH groups by the cleavage of the O-Me bonds in a methylene functionalized system sometimes fails, even under strenuous reaction conditions. Labile acetoxy protecting groups, although incompatible with organometallic reagents, can be readily cleaved under basic hydrolysis conditions and unmask protected OH groups.

2.2. Oxidation of Octamethylether of Calix[8]arene

In 2013, Fischer and coworkers reported on a facile method for the oxidation of the methylene groups of tetramethoxycalix[4]arene 1b. The photochemical reaction of 1b with eight equivalents of N-bromosuccinimide (NBS) in a mixture of CHCl₃/H₂O afforded ketocalix[4]arenes 4b in relatively high yields [25,26]. Presumably, the reaction involved the radical dibromination of methylenes, followed by the hydrolysis of the brominated bridges. In the case of the larger 2b, the initial experiments showed that the reaction afforded the target 5b, but a pentamethoxy ketocalix[6]arene derivative (7, Figure 2) was also obtained as a side product, presumably formed via the cleavage of an O-Me bond by the HBr generated in the reaction. The optimization of the reaction time yielded the ketocalixarene 5b in high yield [27].

The oxidation of 3b (NBS, irradiation with a spot lamp, CHCl₃/H₂O) was conducted using the optimized reaction conditions found previously for 2b (Equation (1)). An examination of the crude product by NMR indicated the formation of a single major product. After recrystallization from CHCl₃/EtOH, 6b was isolated in 36% yield.

(1)

The ¹H NMR spectrum of 6b (500 MHz, CDCl₃, rt) displayed a symmetrical pattern, with one singlet each for the aromatic, methoxy and t-Bu protons (Supplementary Materials). The observed downfield shift in the aromatic protons (δ = 7.60 ppm) is consistent with the presence of carbonyl groups at the bridges, which results in the deshielding of these protons. A symmetrical pattern was also observed in the ¹³C NMR spectrum. Both NMR spectra are consistent with a molecule possessing averaged eightfold symmetry.

2.3. Crystal Structure of Ketocalix[8]arene 6b

Single crystals of 6b were grown from a mixture of CHCl₃/EtOH. The molecule crystallized with CHCl₃ molecules (Figure 3) in a conformation of C_i symmetry. A pair of opposite methoxy groups (C(21a)-O(4a) and C(21b)-O(4b)) were disordered in two orientations: “in” (pointing towards the cavity) and “out” at a 2:1 population ratio. In their “out” arrangement, a disordered chloroform molecule was located within the calix cavity. Assuming that the preferred conformation in solution is similar to the crystal conformation, the observed eightfold symmetry observed in the NMR spectra can be ascribed to a fast dynamic process involving rotation about the carbonyl–aryl and methoxy–aryl bonds.

2.4. Demethylation of 6b with Iodocyclohexane/DMF

An iodocyclohexane/DMF mixture was introduced by Wang, Duan and coworkers as a useful reagent for the demethylation of aryl methylethers [28]. This reagent has been successfully used in the exhaustive demethylation of calixarene methyl ether derivatives [29,30]. An attractive feature of the reagent is the slow release of HI generated by an elimination reaction. We therefore attempted the demethylation of 6b by reaction with iodocyclohexane/DMF for 24, 48 and 96 h. Unfortunately, in all cases, the ¹H NMR spectrum of the crude reaction mixture displayed a complex pattern of broad signals in both the t-Bu and aromatic regions, suggesting that the demethylation did not proceed to completion (Equation (2)).

(2)

As an alternative pathway for the preparation of 6a, we also examined the CrO₃ oxidation of 3c since if the oxidation of methylenes proceeds as intended, the readily hydrolyzed acetoxy group should provide synthetic access into the octahydroxy derivative.

2.5. Oxidation of Octaacetoxy p-tert-Butyl-calix[8]arene 3c

We have previously shown that the oxidation of the 1,3-alternate form of tetracetoxycalix[4]arene 1c to the corresponding tetraoxoketocalix[4]arene can be conducted by reaction with NBS in a CHCl₃/H₂O mixture under irradiation with a 100 W lamp. Although HBr is generated in the reaction, the acetate groups were not cleaved during the oxidation step [31]. However, preliminary experiments indicated that the attempted oxidation of 3c with NBS under similar reaction conditions resulted only in decomposition products. We therefore resorted to Görmar’s reaction conditions (CrO₃ in refluxing Ac₂O/AcOH) [17]. Satisfactorily, the reaction afforded the desired octaacetoxyketocalix[8]arene 6c, albeit in low yield (12%, Scheme 3).

The ¹H NMR spectrum of 6c displayed a simple spectrum with sharp singlets for the aromatic and t-Bu groups (Figure 4). As observed for 6b, the aromatic signal was downfield shifted resonating at 7.69 ppm. Notably, the acetoxy group appeared as a broad signal at 1.65 ppm. The relative upfield shift of the acetoxy groups suggest that at least some of the acetoxy groups are under the shielding effects of the aromatic rings. The increased broadening of the acetoxy signal may be indicative of a dynamic exchange between conformers resulting in an observed time averaged signal. A similar broadening of the acetoxy signal in the ¹H NMR spectrum was previously observed for the smaller analog 5c [19].

2.6. Crystal Structure of Octaacetoxy Ketocalix[8]arene 6c

A single crystal of 6c was grown from chlorobenzene and submitted to X-ray crystallography. The solvent molecule that cocrystallized was disordered, and its hydrogen atoms were not located nor calculated. The molecule adopts in the crystal a conformation of C_i symmetry (Figure 5). The eight carbonyl groups can be divided into two types: “corner” and “edge”. The four “corner” carbonyls radiate from the center of the macrocycle. The acetoxy groups attached to four non-vicinal rings are oriented towards the cavity center, while the rest of the acetoxy groups are oriented “out”.

2.7. Preparation and Crystal Structure of Octahydroxyketocalix[8]arene 6a

The removal of the protecting acetyl groups of 6c was conducted by reaction with aq. NaOH in MeOH yielding 6a (Scheme 3). As with 6b and 6c, the ¹H NMR spectrum of 6a (500 MHz, CDCl₃, rt) showed single singlets for all groups. The OH groups resonated at low field (δ 11.01 ppm), suggesting that these groups are involved in hydrogen bonds. A single crystal of 6a was grown by the slow evaporation of an ethanolic solution and submitted to X-ray diffraction.

In contrast to 6b and 6c, 6a adopts in the crystal a saddle-like conformation of crystallographic C₂ symmetry and idealized S₄ symmetry. In general, the parent 3a displays a closed loop of hydrogen bonds where each OH serves both as a donor and acceptor of a hydrogen bond. A detailed analysis of the crystal structure of 3a cocrystallized with different solvents showed that although in some cases, a solvent molecule can disrupt the closed loop, most of the intramolecular hydrogen bonds between neighboring phenol rings remain unaffected [32]. Remarkably, the hydrogen bond pattern in 6a displays four pairs of convergent intramolecular hydrogen bonds involving carbonyl groups and a pair of geminal phenol rings (Figure 6). To the best of our knowledge, such a pattern is unprecedented for a calix[8]arene analog. The non-hydrogen-bonded carbonyls are located at the corners of the somewhat square-shaped geometry and are pointing away from the cavity center. An analysis of the crystal structures of substituted benzophenones in the literature has shown that in non-hydrogen-bonded derivatives, the C=O bond length is on the average 1.22 Å, whereas when hydrogen-bonded, this bond length increases to 1.24–1.25 Å [33]. In 6a, the C=O bond lengths of the two nonequivalent carbonyls at the corners are O(8)C(44):1.221(3) and O(4)C(22):1.224(3) Å, whereas for the hydrogen-bonded carbonyls, they are O(6)C(33):1.247(3) and O(2)C(11):1.246(3) Å, in agreement with the previous analysis.

Pairs of convergent hydrogen bonds involving carbonyl oxygens as acceptors were not observed in the crystal structure of the smaller ketocalix[4]arene 4a. It seems likely that the larger (and thus more flexible) macrocyclic scaffold in 6a allows for conformations where pairs of OH groups on geminal rings are in steric proximity to a central carbonyl. These conformations are sterically inaccessible for the lower homolog 4a.

The structure of 6a can be viewed as comprising four non-overlapping diarylketone subunits. Diarylketones prefer a helical “propeller” conformation where both rings are twisted in the same direction relative to the C-C(=O)C central plane [33,34,35]. The propeller conformation is a compromise between two opposite effects: (i) to maximize the conjugation of the aryl rings with the carbonyls by attaining a coplanar arrangement and (ii) to minimize the steric repulsion between ortho hydrogens (or substituents if present) on both rings. This propeller conformation is chiral; thus, two enantiomeric arrangements are possible. These two arrangements are depicted in Figure 7. An inspection of the crystal structure of 6a indicates that the two possible helicities alternate along the macrocycle, as expected for a conformation of idealized S₄ symmetry (Figure 7).

2.8. Low-Temperature ¹H NMR Spectra of 6a

In the crystal conformation, the unique C₂ axis is perpendicular to the main macrocyclic plane and exchanges pairs of opposite rings. However, this chiral conformation may be due to a minor distortion (due to crystal packing forces) of the more symmetric achiral conformation of S₄ symmetry. In this conformation, alternating rings (i.e., in “1,3,5,7” or “2,4,6,8” positions) are exchanged by the S₄ axis, but pairs of geminal rings are symmetry nonequivalent. Thus, it should be expected that if the conformation is “frozen” on the NMR timescale, precluding accidental isochrony, two OH signals should be observed. Upon lowering the temperature of an NMR sample in CD₂Cl₂, the OH signals broadened and decoalesced into two relatively sharp signals in a 1:1 ratio and three broad signals in a 1:1:2 ratio (Figure 8). If the two sharp singlets are assigned to a conformation of S₄ symmetry, it can be concluded that an additional conformation with C₂ or C_i symmetry is also present in solution.

3. Experimental Methods

3.1. General Information

All common reagents and solvents were used from commercial suppliers without further purification. ¹H NMR and ¹³C NMR spectra were recorded at room temperature on DRX400 (Bruker, Karlsruhe, Germany) and AVANCE II 500 (Bruker, Karlsruhe, Germany) instruments. Proton chemical shifts (δ in ppm) were referenced to the residual protium resonance of the solvent (CDCl₃, δ = 7.26 ppm) or to TMS. Carbon chemical shifts (δ in ppm) were referenced to the carbon resonances of the solvent (CDCl₃, δ = 77.2 ppm). High-resolution mass spectra (HRMS) were recorded at the Analytical Chemistry Lab (The Hebrew University) using an X500R QTOF (SCIEX, Framingham, MA, USA) instrument. Melting points were measured using a Fisher-Johns (Fischer Scientific Co., Hampton, VA, USA) melting point apparatus and were uncorrected.

3.2. Crystal Data

CCDC (Deposition Number 2363603-2363605) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/? (accessed on 28 August 2024) (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: [email protected]).

• Crystal data for 6a: empirical formula: C_98.5H₁₀₈O_21.25, formula weight: 1631.84, temperature: 150.0(1) K, crystal system: monoclinic, space group: I2/a, a: 18.4709(5) Å, b: 22.0612(6) Å, c: 23.7204(7) Å, β: 90.484(3)°, V: 9665.5(5) ų, Z: 4, ρcalc: 1.121 g/cm³, μ: 0.078 mm⁻¹, F(000): 3476.0, crystal size: 0.24 × 0.09 × 0.08 mm³, radiation: Mo Kα (λ = 0.71073), 2θ range for data collection: 4.41 to 64.572°, index ranges: −23 ≤ h ≤ 27, −32 ≤ k ≤ 28, −33 ≤ l ≤ 35, reflections collected: 44,192, independent reflections: 14328 [R_int =0.0435, R_sigma =0.0584], data/restraints/parameters: 14,328/0/606, goodness-of-fit on F²: 1.028, final R indexes [I ≥ 2σ (I)]: R₁: 0.0916, wR₂: 0. 0.2518, final R indexes [all data]: R₁: 0.1404, wR₂: 0.2827, largest diff. peak/hole/e Å⁻³ 0.80/−0.34.

• Crystal data for 6b: empirical formula: C_97.67H_113.33Cl₅O₁₆, formula weight: 1720.50, temperature: 200.0(1) K, crystal system: triclinic, space group: P-1, a: 12.4386(1)Å, b: 13.4767(2) Å, c: 14.6784(1) Å, α: 97.887(1)°, β: 93.365(1)°, γ: 96.941(1)°, V: 2412.32(4) ų, Z: 1, ρcalc: 1.184 g/cm³, μ: 0.212 mm⁻¹, F(000): 912.0, crystal size: 0.43 × 0.11 × 0.07 mm³, radiation: Mo Kα (λ = 0.71073), 2θ range for data collection: 4.174 to 64.604°, index ranges: −17 ≤ h ≤ 18, −19 ≤ k ≤ 19, −21 ≤ l ≤ 21, reflections collected: 104,881, independent reflections: 15145 [R_int = 0.0309, R_sigma = 0.0221], data/restraints/parameters: 15,145/0/631, goodness-of-fit on F²: 1.031, final R indexes [I ≥ 2σ (I)]: R₁: 0.0695, wR₂: 0.2071, final R indexes [all data]: R₁: 0.0871, wR₂: 0.2205, largest diff. peak/hole/e Å⁻³ 0.84/−0.66.

• Crystal data for 6c: empirical formula: C₁₁₆H₁₁₂Cl₂O₂₄, formula weight: 1960.95, temperature: 150.0(1) K, crystal system: triclinic, space group: P-1, a: 10.0905(1) Å, b: 15.8706(2) Å, c: 17.1177(2) Å, α: 84.812(1)°, β: 76.830(1)°, γ: 82.254(1)°, V: 2639.74(5) ų, Z: 1, ρcalc: 1.234 g/cm³, μ: 0.134 mm⁻¹, F(000): 1034.0, crystal size: 0.26 × 0.19 × 0.09 mm³, radiation: Mo Kα (λ = 0.71073), 2θ range for data collection: 4.174 to 64.798°, index ranges: −14 ≤ h ≤ 14, −22 ≤ k ≤ 23, −23 ≤ l ≤ 24, reflections collected: 94,717, independent reflections: 16,346 [R_int = 0.0412, R_sigma = 0.0312], data/restraints/parameters: 16,346/0/778, goodness-of-fit on F²: 1.027, final R indexes [I ≥ 2σ (I)]: R₁: 0.0737, wR₂: 0.1987, final R indexes [all data]: R₁: 0.0918, wR₂: 0.2101, largest diff. peak/hole/e Å⁻³ 0.57/−0.68.

3.3. Synthesis of Compounds 6a–6c

3.3.1. Preparation of 5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,51,52,53,54,55,56-octahydroxy-2,8,14,20,26,32,38,44-octaoxo-calix[8]arene (6a)

A mixture of 6c (0.5 g, 0.29 mmol), aq. NaOH (75 mL, 2 M) and methanol (50 mL) was heated to reflux for 4 h. After cooling to rt, the mixture was acidified with conc. HCl until pH = 1, and the solid was filtered by vacuum yielding 0.48 g of a yellow solid. Trituration with cold methanol afforded 0.38 g 6a (94%), mp 305–307 °C.

IR ν = 3527 (OH), 1669 (C=O) cm⁻¹. ¹H NMR (CDCl₃, 500 MHz) δ 11.01 (s, 8H, OH), 7.86 (s, 16H, ArH), 1.35 (s, 72H, t-Bu) ppm. ¹³C NMR (CDCl₃, 125 MHz) δ 198.4, 158.9, 141.6, 133.1, 124.8, 34.5, 31.3 ppm. HRMS (ESI-QTOF) m/z calcd. for C₈₈H₉₆O₁₆ + H⁺: 1409.6771. Found: 1409.6730.

3.3.2. Preparation of 5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,51,52,53,54,55,56-octamethoxy-2,8,14,20,26,32,38,44-octaoxocalix[8]arene (6b)

A mixture of octamethoxycalix[8]arene 3b (4.7 g, 4.36 mmol), NBS (19.7 g, 110.0 mmol), chloroform (90 mL) and water (2 mL) was refluxed during 3.5 h while irradiated with a spotlight (100 W). After cooling, the solution was washed successively with aq Na₂S₂O₅, water, aq NaHCO₃, water, dried over MgSO₄ and evaporated. A ¹H NMR analysis of the crude product indicated a nearly complete oxidation of the methylene groups. The crude product was recrystallized from CHCl₃/EtOH, yielding the product (1.82 g, 36% yield), mp 312 °C.

¹H NMR (CDCl₃, 400 MHz) δ 7.60 (s, 16H, ArH), 3.23 (s, 24H, OMe), 1.25 (s, 72H, t-Bu) ppm. ¹³C NMR (CDCl₃, 100 MHz) δ 195.3, 155.9, 145.9, 133.3, 130.6, 63.1, 34.5, 31.1 ppm. HRMS (ESI-QTOF) m/z calcd. for C₉₆H₁₁₂O₁₆ + H⁺: 1521.8023. Found: 1521.7952.

3.3.3. Preparation of 5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,51,52,53,54,55,56-octaacetoxy-2,8,14,20,26,32,38,44-octaoxo-calix[8]arene (6c)

To a mixture of octaacetoxycalix[8]arene 3c (3.03 g, 1.85 mmol), 200 mL acetic anhydride and 4 mL acetic acid was added CrO₃ (6.5 g, 0.065 mmol). The mixture was heated to reflux for 3h. During the heating period, the color of the reaction changed from dark orange to green. After cooling to rt, the mixture was filtered through a sintered glass filter, 200 mL of chloroform was added and the mixture was washed with water (200 mL) several times until the water phase was no longer colored. The organic phase was dried (MgSO₄) and evaporated. The residue was recrystallized from CHCl₃/MeOH, yielding 0.4 g (12%) 6c, mp 310–312 °C.

¹H NMR (CDCl₃, 500 MHz) δ 7.69 (s, 16H, ArH), 1.65 (br s, 24H, CH₃C=O), 1.28 (s, 72H, t-Bu) ppm. ¹³C NMR (CDCl₃, 125 MHz) δ 192.3, 168.5, 149.1, 144.9, 132.4, 130.8, 34.9, 31.0, 20.0 ppm. Anal. calcd. for C₁₀₄H₁₁₂O₂₄: C, 71.54, H, 6.47. Found: C, 71.54, H, 6.46. HRMS (ESI-QTOF) m/z calcd. for C₁₀₄H₁₁₂O₂₄ + H⁺: 1745.7616. Found: 1745.7603.

4. Conclusions

Octamethoxy and octaacetoxyketocalix[8]arenes can be prepared by the oxidation of the corresponding calix[8]arenes with NBS/light and CrO₃, respectively. An X-ray analysis of a crystal of octahydroxyketocalix[8]arene 6a grown from ethanol indicates that the molecule adopts a conformation of idealized S₄ symmetry where the helicities of the dihydroxybenzophenone subunits alternate along the macrocycle. The carbonyl groups disrupt all the intramolecular hydrogen bonds between phenol rings.