Synthesis, conformational properties, and molecular recognition abilities of novel prism[5]arenes with branched and bulky alkyl groups

Abstract

The direct macrocyclization to prism[5]arenes of 2,6-dialkoxynaphthalenes with branched and bulky alkyl groups has been obtained in good yields in the presence of 1,4-dihexyl-DABCO template. These novel prism[5]arenes exhibit typical D₅-symmetry and DFT calculations indicate that the homochiral all-pS (all-pR) conformation is the most stable of all the possible conformations. Prism[5]arenes crystallize as racemic mixtures (all-pS/all-pR) in centrosymmetric space groups. The eight crystal structures show C₂ point symmetry of the macrorings, with a larger opening of the cavity observed for PrS[5]^iBu, PrS[5]^MeCy and the β-form of PrS[5]^PrCy. The dynamic stereochemical inversion (from pR to pS and vice versa) of prism[5]arenes was examined by ¹H VT NMR experiments. The racemization of prism[5]arene derivatives occurs by through the-annulus-rotation of the naphthalene units. With increasing length of linear alkyl substituents from C2 to C9, the chains tend to pack at both rims, thereby diminishing the conformational freedom of the naphthalene units. The presence of branched alkyl groups at both rims of the prism[5]arenes increases the energy barrier to racemization and consequently lowers the rate of the racemization process. Prism[5]arenes bearing branched or bulky alkyl groups at both rims can form endo-cavity complexes with 1,4-dihexyl-DABCO 2²⁺ and piperazonium 3²⁺ guests. Two hosts with branched alkyl groups, PrS[5]^iPr and PrS[5]^iBu, show guest binding affinities higher than those calculated for the analogous linear PrS[5]^nPr and PrS[5]^nBu prism[5]arenes. This result can be justified on the basis of the greater conformational rigidity and preorganization of prism[5]arenes bearing branched groups.

---

Introduction

The first generation of macrocyclic hosts, such as cryptands,¹ crown ethers,² and spherands,³ were introduced in the 1960s and 1970s by Lehn, Pedersen and Cram. These hosts featured cavities decorated with oxygen atoms and were specifically designed to host spherical alkali-cations. Subsequently, between the 1980s and 1990s, calixarenes,⁴ resorcinarenes,⁵ and cucurbiturils⁶ gained significant popularity due to their facile chemical functionalisation and conformational versatility. In contrast to the first generation of hosts, calixarenes and resorcinarenes exhibit large aromatic cavities capable of hosting small organic molecules.^4,5 In 2008, Ogoshi introduced pillararenes,⁷ macrocycles formed by 1,4-dialkoxybenzene units bridged by methylene groups, marking the advent of the third generation of macrocyclic hosts. Unlike calix[4]arene, which adopts a cone-shaped structure, pillararenes feature a distinctive pillar-shaped cavity. The rigid structure of pillararenes, along with their unique supramolecular properties, paved the way for the design of a plethora of novel macrocyclic structures, including biphenarenes,⁸ oxatubarenes,⁹ saucerarenes,¹⁰ pagodarenes,¹¹ calix[2]naphth[2]arene,¹² and naphthotubes,¹³ all characterized by biomimetic deep aromatic cavities.

In this regard, in 2020 we reported a novel class of macrocyclic hosts named prism[n]arenes¹⁴PrS[n]^R (n = 5 and 6, in Fig. 1). These prismarenes are constituted by 1,5-methylene bridged 2,6-dialkoxynaphthalene units (Fig. 1). Prismarenes exhibit a deep π-electron rich aromatic cavity^14–19 and can form endo-cavity complexes with ammonium guests, both in organic^14–17 and aqueous media. These complexes are stabilized by cation⋯π and C–H⋯π interactions.¹⁸

Fig. 1 Chemical drawings of prismarene macrocycles.

As a result of these appealing properties, prismarenes have attracted significant interest in the scientific community over the last three years.^20–26 An intriguing aspect of prismarenes pertains to their chirality. Like pillararenes,^27–29 prism[n]arenes exhibit planar chirality (Fig. 2). The pS and pR conformational isomers of the permethylated prismarenes can undergo interconversion via oxygen-through-the-annulus passage of the naphthalene units, a process observed to be fast on the NMR time scale (Fig. 2).²⁴ To isolate pS- and pR-enantiomeric forms of prism[5]arenes, it becomes necessary to impede the rotational motion of the naphthalene units. Ogoshi and coworkers demonstrated^27,28 that the presence of bulky and branched groups on both rims of pillar[5]arene is essential to prevent racemization.²⁷ Their findings revealed that the size and structure of alkyl chains on the rims of pillararenes play a crucial role in this regard. More recently, the chiral and conformational features of prism[5]arenes have been exploited for the chiral recognition of aminoacids.²⁴ The complexation with chiral guests resulted in strong circular dichroism (CD) signals at the absorption band of prism[5]arenes. Notably, the CD signals induced by the chiral complexation varied with the length of the alkyl chains on the prism[5]arene rims.²⁴

Fig. 2 Planar chirality of prismarenes and racemization process by oxygen-through-the-annulus passage of naphthalene units.

Regarding the synthesis of prismarenes, we demonstrated that the direct macrocyclization of 2,6-dimethoxynaphthalene in the presence of 1,4-dihexyl-DABCO as a template yielded PrS[5]^Me (Fig. 1) as the major product (47%).¹⁴ In contrast, when attempting direct macrocyclization starting from 2,6-diethoxynaphthalene or 2,6-dipropoxynaphthalene in the presence of 1,4-dihexyl-DABCO 2²⁺, a mixture of PrS[6]^R/PrS[5]^R (R = Et or nPr) was formed.¹⁵ Differently, in the absence of 1,4-dihexyl-DABCO 2²⁺, the direct macrocyclization delivered the hexamer in very high yields (60–80%) and in short reaction times (30–40 min) in various solvents (cyclohexane, toluene, decaline, chlorocyclohexane).¹⁵ Thus, we concluded that the direct macrocyclization of 2,6-diethoxy or 2,6-dipropoxynaphthalene was driven by an intramolecular thermodynamic self-templating effect,¹⁵ resulting from the self-filling of the internal cavity of the hexamer with ethyl or propyl chains. Both PrS[6]^Et and PrS[6]^nPr assumed, in solution and in the solid state, a conformation in which four alkyl chains occupied the cavity of the macrocycle.¹⁵ This self-templating effect drives the direct macrocyclization toward the hexamer, even in the presence of 2²⁺. These considerations clearly demonstrate that the length of the alkyl chain plays a pivotal role in prismarene synthesis. Consequently, the question arises as to whether direct macrocyclization to prism[5]arene is again favoured in the presence of 1,4-dihexyl-DABCO 2²⁺ when starting from monomers bearing linear C4–C9 alkyl chains (1a–e in Scheme 1) or α–δ branched (1f–h) groups or even more bulky cyclic substituents (1j–q).

Scheme 1 Direct macrocyclization of 2,6-dialkoxynaphthalene monomers to give prism[5]arene derivatives: 1,2-DCE (5 mM), TFA (15 equiv.), paraformaldehyde (1.2 equiv.), 70 °C, 2²⁺·2I⁻ (1.0 equiv.).

In the present study, we report on the direct macrocyclization of 2,6-dialkoxynaphthalenes with alkyl groups of different lengths and structures, resulting in novel prism[5]arene derivatives. Additionally, their conformational properties and molecular recognition abilities have been investigated through NMR studies and X-ray crystallography.

Results and discussion

Synthesis of prism[5]arenes

Initially, we investigated the direct macrocyclization of 2,6-dipentoxynaphthalenes, 1b, to prism[5]arene (Scheme 1). The reaction utilized 1,4-dihexyl-DABCO 2²⁺ as a template and 1,2-dichloroethane as the solvent. Under the conditions previously reported by us,^14,15 a mixture of 2,6-dipentoxynaphthalene 1b, 1,4-dihexyl-DABCO 2²⁺ (1.0 equiv.), paraformaldehyde (1.2 equiv.) and trifluoroacetic acid (TFA, 15 equiv.) was stirred in 1,2-dichloroethane (1,2-DCE) at 70 °C for 22 h. After purification by column chromatography, the isolated product was identified as 2,6-bis(pentoxy)prism[5]arene, PrS[5]^nPe, in a yield of 25%. Notably, extending the reaction time to 72 h at 70 °C increased the yield to 35%, and further optimization resulted in a yield of 45% after 120 hours. The structure of PrS[5]^nPe was confirmed through 1D and 2D NMR analysis (ESI†), high-resolution mass spectrometry and single crystal X-ray diffraction (ESI† and vide infra). The 1D and 2D NMR spectra (CD₂Cl₂, 298 K, 600 MHz) were consistent with the D₅ symmetry previously observed for PrS[5]^Me. Specifically, the ¹H NMR spectrum revealed an AX system at 8.31 and 6.95 ppm, corresponding to the aromatic H-atoms of the macrocycle, with a singlet at 4.68 ppm attributable to the methylene-bridges. Encouraged by these results, we extended our investigations to the systematic study of direct macrocyclization of 2,6-dialkoxynaphthalene monomers as a function of alkyl chain length, adding butyl 1a, hexyl 1c, heptyl 1d, and nonyl 1e.

As indicated in Table 1 (entries 1–4), the direct macrocyclization of 1a, 1c, 1d and 1e to prism[5]arenes occurred in good yields in the presence of the template 1,4-dihexyl-DABCO 2²⁺ cation. The NMR spectral features of all these prism[5]arenes are consistent with the D₅ symmetry previously observed for other peralkylated prism[5]arene derivatives. Subsequently, a series of experiments were conducted to investigate the effects of branched alkyl groups on the efficiency of the macrocyclization outlined in Scheme 1 (Table 1, entries 6–15). Starting with 2,6-diisopropoxynaphthalene 1f, the 2,6-bis(isopropoxy)prism[5]arene, PrS[5]^iPr, was obtained in 48% yield after 24 h. In this case, the formation of the hexamer 2,6-bis(isopropoxy)prism[6]arene, PrS[6]^iPr,¹⁷ was significant, at a 36% yield even in presence of the template 1,4-dihexyl-DABCO 2²⁺ cation. In fact, the PrS[6]^iPr was formed as major product (60%) after 120 h.¹⁷ As recently reported by us,¹⁷ the isopropyl groups can stabilize the cuboid D₂-conformation of the 2,6-bis(isopropoxy)prism[6]arene, PrS[6]^iPr, through a self-filling effect.¹⁷ Starting with 2,6-diisobutoxynaphthalene 1g, a PrS[5]^iBu/PrS[6]^iBu ratio of 3/1 was observed with an overall lower yield. The formation of hexameric prismarene may be attributed to a competitive self-templated effect of the isobutyl chains. However, the situation becomes more complex in this case, as indicated by the crystallographic analysis, revealing that two methyl groups of the isobutyl chains are deeply inserted into the cavity of the pentameric prismarene (see below). The macrocyclization to prism[5]arene was selective with 2,6-diisopentoxynaphthalene 1h (Table 1, entry 8) and 2,6-diisohexyloxynaphthalene 1i (Table 1, entry 9), resulting in the formation of the respective prism[5]arene derivatives in 37% and 43% yields, respectively, with no evidence of hexamer in their crude reaction mixtures. Longer isopentyl and isohexyl chains are hypothesized to be less effective in filling the internal cavity of the prism[6]arene, allowing the template effect of 2²⁺ to prevail. Interestingly, the direct macrocyclization of 1j, bearing cyclohexylmethyl groups, delivered the prism[5]arene PrS[5]^MeCy in a 25% yield (Table 1, entry 10), while higher yields were obtained after the direct macrocyclization of 1k (Table 1, entry 11) and 1l (Table 1, entry 12) bearing cyclohexylethyl (44%) and cyclohexylpropyl (43%) groups, respectively. These results indicate that, as the cyclohexyl unit gets closer to the rims, the yield of macrocyclization drops significantly (1k, 44% → 1j, 25%). Analogous results were observed for the direct macrocyclization of 1n (R = cycloheptylmethyl, Table 1 entry 14) and 1o (R = cycloheptylethyl, Table 1, entry 15), which gave PrS[5]^MecHp and PrS[5]^EtcHp in 30% and 45% yields, respectively. Significantly, the direct macrocyclization of 1p leads to the formation of 2,6-bis(benzyloxy)prism[5]arene PrS[5]^MePh in 20% yield (Table 1, entry 16). This prismarene can be considered as a useful precursor of perhydroxylated prism[5]arene.¹⁹ In all the reactions explored in this study (Table 1), the formation of prismarenes with naphthalene units linked at positions 1,4 (confused-prism[5]arenes) was not observed. Typically, the confused-prism[5]arene skeleton adopts a conformation where the 1,4-bridged naphthalene ring is oriented inside the cavity. It is likely that in the presence of long and/or branched alkyl groups, confused-prism[5]arenes cannot be formed, primarily due to the significant steric hindrance caused by these groups within the cavity. Interestingly, the prism[5]arenes bearing long C6–C9 alkyl chains or bulky α−ε branched alkyl groups at both rims, exhibit typical D₅ NMR-patterns. Similar results were observed for prism[5]arene derivatives bearing cyclic units at both rims. Specifically, percyclohexylmethyl-prism[5]arene PrS[5]^MeCy shows an aromatic AX system at 8.24 and 6.92 ppm with a Δδ value of 1.32 ppm, a value significantly higher than that observed for the 2,6-bis(methoxy)prism[5]arene PrS[5]^Me, which has a Δδ of 1.04 ppm. Similarly, a wide aromatic spacing of 1.44 ppm was observed between the doublets of the 2,6-bis(isobutoxy)prism[5]arene PrS[5]^iBu. Prism[5]arenes bearing larger cycloheptylmethyl and cycloheptylethyl groups, show aromatic AX systems with a Δδ value of 1.30 and 1.35 ppm, respectively. Also noteworthy is the Δδ value of 1.41 ppm observed between the aromatic doublets of 2,6-bis(cyclohexylpropyl)prism[5]arene PrS[5]^PrCy. As previously reported by us,¹⁵ an aromatic Δδ value of 1.30–1.50 ppm suggests that the prism[5]arene skeleton adopts an open conformation¹⁵ in which the aromatic walls exhibit canting angle averaged values close to 90°. Consequently, these results indicate that, in solution, a greater opening of the cavity is observed for PrS[5]^iBu, PrS[5]^MeCy and PrS[5]^PrCy. In this open prismatic conformation, the aromatic H atoms move away from the cavity and experience a down-field shifting with respect to the closed conformation of PrS[5]^Me, in which a naphthalene ring is folded inside the cavity.

Table 1 Synthesis of peralkylated prism[5]arenes PrS[5]^R (Scheme 1)

Entry	PrS[5]^R	R	Time	Yield (%)
1	PrS[5]^nBu	n-Butyl	120 h	46
2	PrS[5]^nPe	n-Pentyl	120 h	45
3	PrS[5]^nHex	n-Hexyl	120 h	48
4	PrS[5]^Hp	n-Heptyl	120 h	35
5	PrS[5]^Nonyl	n-Nonyl	120 h	46
6	PrS[5]^iPr	Isopropyl	24 h	48
7	PrS[5]^iBu	Isobutyl	120 h	30
8	PrS[5]^iPe	Isopentyl	120 h	37
9	PrS[5]^iHex	Isohexyl	120 h	43
10	PrS[5]^MeCy	Cyclohexylmethyl	120 h	25
11	PrS[5]^EtCy	Cyclohexylethyl	120 h	44
12	PrS[5]^PrCy	Cyclohexylpropyl	120 h	43
13	PrS[5]^BuCy	Cyclohexylbutyl	120 h	12
14	PrS[5]^MecHp	Cycloheptylmethyl	120 h	30
15	PrS[5]^EtcHp	Cycloheptylethyl	120 h	45
16	PrS[5]^MePh	Benzyl	120 h	20
17	PrS[5]^BuPh	Phenylbutyl	120 h	27

---

Structural properties of prism[5]arenes in the solid state: the role of the alkyl chains

The crystallographic structures of PrS[5]^iPr, PrS[5]^nBu, PrS[5]^iBu, PrS[5]^nPe, PrS[5]^MeCy, PrS[5]^EtCy, and PrS[5]^PrCy (α- and β- forms) were determined (Fig. 3a). Details of data collection, structure refinements and geometrical features are reported in the ESI.† All molecules crystallize as racemic mixtures of inherent chiral pairs in centrosymmetric space groups. All prismarene molecules exhibit a similar macrocycle conformation, analogous to the one observed for PrS[5]^Me, PrS[5]^Et and PrS[5]^nPr.¹⁵ The PrS[5]^iBu, PrS[5]^EtCy and the α form of PrS[5]^PrCy show a crystallographic twofold axis passing through the methylene bridge connecting the C and C′ rings and the middle of the opposite A naphthalene moiety (Fig. S135†). The crystal structures of the other molecules show a pseudo C₂ point symmetry for the PrS[5]^R scaffold. The canting angles reported in Table S9† illustrate this situation: the dihedral angles of the B/B′ and C/C′ couples (see Fig. S135†) are supplementary angles with mean values of 68(2)°/113(2)° for B/B′ and 136(4)°/44(5)° for C/C′; while the A angle is approximately 90° with a mean value of 89(1)°. The standard deviations reported in parentheses indicate relatively larger variability in the conformation of the C/C′ couple with the most fixed position for the A naphthalene. In agreement with NMR studies in solution, a greater opening of the cavity is observed for PrS[5]^iBu, PrS[5]^MeCy and the β-form of PrS[5]^PrCy, where the C/C′ angles decrease and increase by about 6°, respectively, in comparison to the other structures (Table S9†). This greater opening is also reflected in the C/C′ dihedral angles. A mean value of 60(2)° is observed for PrS[5]^iBu, PrS[5]^MeCy and β-PrS[5]^PrCy, while a mean value of 49(1)° is observed for all the other structures. The opening observed for PrS[5]^MeCy and β-PrS[5]^PrCy can be attributed to the presence of a dichloromethane solvent molecule hosted in the prismarene cavity (Fig. 3b). In the case of PrS[5]^iBu, a self-filling of two symmetry-related methyl groups of the alkoxy chains, one from each C and C′ naphthalene moiety, is observed (Fig. 3b). The analogous PrS[5]^iPr molecule shows a more closed conformation, with the self-filling of only one methyl group (Fig. 3b). These structural differences in intramolecular interactions could be connected to the differences observed for the product distribution in the synthesis. The other structures all show comparable closed conformations, with the alkoxy chains outside the cavity (Fig. 3b).

Fig. 3 (a) Stick representation of new PrS[5]^R. X-ray structures reported in the present work. Hydrogen atoms and solvent molecules are omitted for clarity. For each structure, only one molecule with disordered alkyl groups of highest occupancy is shown. (b) Stick representation with van der Waals surfaces of PrS[5]^R structures viewed along the C₂ axis. The A naphthalene group in the foreground has been omitted to see the filling of the cavity by alkyl groups (green) or solvent molecules (magenta/cyan).

Conformational dynamics of prism[5]arenes PrS[5]^R

Analogously to pillararene macrocycles, prism[5]arenes exhibit planar chirality (Fig. 2 and 4). The pentamers PrS[5]^R can adopt 8 conformations of different planar chirality corresponding to 4 enantiomeric pairs (I–IV in Fig. 4).

Fig. 4 Schematization of four conformations with different planar chirality I–IV of a prism[5]arene. (I) = pSpSpSpSpS; (II) = pRpSpSpSpS; (III) = pRpRpSpSpS; (IV) = pRpSpRpSpS. Each conformation has an enantiomer with opposite planar chirality, which results in a total of eight distinct conformations.

As reported for pillararenes,^27–29 the chirality in these conformational isomers of prism[5]arenes can be described using the pR and pS nomenclature (Fig. 4).

The stability of the conformational isomers of peralkylated prism[5]arene derivatives was evaluated by DFT calculations at the B97D3/SVP/SVPFIT level of theory (ESI†).³⁰ The calculations for PrS[5]^nPr,¹⁵ indicate conformation I, all-pS (all-pR) (Fig. 4), as more stable than all the other possible conformations II, III, and IV by 11.8, 14.7, and 8.1 kcal mol⁻¹ (ESI†), respectively.

Analogous results were obtained for the percyclohexylethyl-prism[5]arene PrS[5]^EtCy: DFT calculations indicate conformation I as more stable compared to conformations II, III and IV, by 22.6, 22.9 and 4.4 kcal mol⁻¹, respectively. Similarly, for PrS[5]^iPr, the all-pS (all-pR) (Fig. 4), was calculated as more stable than II, III, and IV by 10.0, 11.5, and 6.5 kcal mol⁻¹ (ESI†), respectively. The conformational features of the peralkylated prism[5]arene derivatives PrS[5]^R in Scheme 1 were investigated by variable temperature ¹H NMR experiments. The 1D and 2D NMR spectra (25 °C) of the PrS[5]^R derivatives are in agreement with the D₅ symmetry of their all-pR (or all-pS) conformation I. The presence of diastereotopic resonances attributable to OCH₂ groups in the ¹H NMR spectra of 2,6-bis(ethoxy)prism[5]arene (Fig. 5a) and 2,6-bis(propoxy)prism[5]arene at 298 K (300 MHz, Toluene-d₈, ESI†) confirms their planar chirality. As reported in literature for pillar[5]arenes,^27,29,31 the separation of the OCH₂ diastereotopic resonances is a useful probe to study whether racemization of planar chiral macrocycles (Fig. 2 and 5) takes place on the NMR time scale. Racemization processes (Fig. 2) become faster on the NMR time scale as the temperature increases, leading to the coalescence of diastereotopic OCH₂ resonances due to the rapidly averaged chemical environment around OCH_aH_b protons.^27,29,31 Above the coalescence temperature (T_c), the –OCH₂– proton signals generally converge into a sharp singlet (Fig. 5a and b). The presence of diastereotopic resonances attributable to OCH₂ groups of PrS[5]^R (R = Et, n-Pr) indicates that the inversion process between their pR and pS enantiomeric forms is slow on the NMR time scale, at room temperature. On heating, the diastereotopic OCH₂ signals of PrS[5]^Et and PrS[5]^nPr coalesced at 338 K (Fig. 5a) and 348 K (Fig. 5b) (in toluene-d₈), respectively. From these values, energy barriers³² values of 16.8 and 17.4 kcal mol⁻¹ were calculated for the racemization process of PrS[5]^Et and PrS[5]^nPr, respectively. Table 2 shows the coalescence temperatures (T_c) and the energy barrier ΔG^‡ values for the racemization of prism[5]arene derivatives in Scheme 1. The data in Table 2 clearly indicate an increase in the energy barrier ΔG^‡ with the increase of the n-alkyl chain length from C3 to C9 and thus decreasing the conformational freedom of the macrocycles. Thus, 2,6-bis(nonyloxy)prism[5]arene PrS[5]^Nonyl showed a broadening of the OCH₂ signals at 383 K, in toluene-d₈ (ESI†) suggesting that rotations of the 2,6-bis(nonyloxy)naphthalene units still occur more slowly than the NMR time scale at this temperature. It seems likely that, with an increase in the length of alkyl substituents, the linear chains pack on both rims, consequently reducing the conformational freedom of the naphthalene units within these prism[5]arenes. The presence of branched alkyl groups at both rims of the prism[5]arenes increases the energy barrier to racemization (Fig. 2) and consequently lowers the rate of the process. In detail, in 2,6-bis(isopropoxy)prism[5]arene PrS[5]^iPr the diastereotopic (CH₃)_aCH(CH₃)_b signals didn't change their shape even on heating (ESI†). This result clearly indicates that the rotation of the 2,6-bis(isopropoxy)naphthalene units in PrS[5]^iPr did not take place on the NMR time scale in the temperature range investigated (298–383 K). In contrast, rotation of 2,6-bis(propoxy)naphthalene units in PrS[5]^nPr is considerably faster. On heating, the diastereotopic OCH₂ signals of PrS[5]^nPr show a coalescence temperature of 348 K (in toluene-d₈), and an energy barrier of 17.4 kcal mol⁻¹ to the racemization process. Similar results were observed for PrS[5]^iBu and PrS[5]^iPe, which show coalescence temperatures of 373 K and energy barriers of 18.9 and 18.3 kcal mol⁻¹, respectively, higher than that observed for PrS[5]^nBu and PrS[5]^nPe(see Table 2). We have previously shown¹⁷ that 2,6-bis(isopropoxy)prism[6]arene PrS[6]^iPr exhibits an energy barrier to the racemization process significantly higher than that measured for the isomer 2,6-bis(propoxy)prism[6]arene PrS[6]^nPr.¹⁵ These results clearly indicate that the presence of branched groups at the rims of prismarene macrocycles increase the energy barrier to the racemization process to a greater extent than the respective isomeric linear groups.

Fig. 5 Partial DNMR spectra of OCH₂ protons: (a) PrS[5]^Et, (b) PrS[5]^nPe, (c) PrS[5]^EtCy and (d) PrS[5]^BuPh in toluene-d₈.

Table 2 Coalescence temperatures T_C (K) and ΔG^‡ (kcal mol⁻¹) values for the oxygen-through-the-annulus rotation of the peralkylated prism[5]arenes PrS[5]^R

Entry	PrS[5]^R	R	T C (K)	ΔG^‡ (Kcal mol^−1)
a A broadening of the OCH2 diastereotopic signals was observed at 383 K. b No evidence of coalescence was observed in the temperature range investigated (298–383 K) in toluene-d8. c Deuterated chlorobenzene was used as solvent due to the accidental isochronous appearance of OCH2 signals in deuterated toluene. In chlorobenzene-d5 no evidence of coalescence was observed in the temperature range investigated (298–383 K).
1	PrS[5]^Et	Ethyl	338	16.8
2	PrS[5]^nPr	n-Propyl	348	17.4
3	PrS[5]^nBu	n-Butyl	353	17.8
4	PrS[5]^nPe	n-Pentyl	358	18.0
5	PrS[5]^nHex	n-Hexyl	363	18.5
6	PrS[5]^Hp	n-Heptyl	373	18.6
7	PrS[5]^Nonyl	n-Nonyl		>19.2
8	PrS[5]^iPr	Isopropyl		—
9	PrS[5]^iBu	Isobutyl	373	18.9
10	PrS[5]^iPe	Isopentyl	373	18.3
11	PrS[5]^iHex	Isohexyl	383	19.2
12	PrS[5]^MeCy	Cyclohexylmethyl		—
13	PrS[5]^EtCy	Cyclohexylethyl		—
14	PrS[5]^PrCy	Cyclohexylpropyl		—
15	PrS[5]^BuCy	Cyclohexylbutyl		—
16	PrS[5]^MecHp	Cycloheptylmethyl		—
17	PrS[5]^EtcHp	Cycloheptylethyl		—
18	PrS[5]^BuPh	Phenylbutyl		—

---

Prompted by these observations, we have investigated the conformational dynamics of prism[5]arenes bearing cyclohexylmethyl (PrS[5]^MeCy), cyclohexylethyl (PrS[5]^EtCy), cyclohexylpropyl (PrS[5]^PrCy), cyclohexylbutyl (PrS[5]^BuCy), cycloheptylethyl (PrS[5]^EtcHp), and phenylbutyl groups (PrS[5]^BuPh) at both rims. In all these cases, the rotation of the respective 2,6-dialkoxynaphthalene units is blocked on the NMR time scale. On heating, the diastereotopic OCH₂ signals of these derivatives didn't show any evidence of broadening in the temperature range investigated (298–383 K, Fig. 5c and d).

To gain insights into the aspect of chiral stability, chiral HPLC studies were carried out for percyclohexylethyl (and percyclohexylpropyl) substituted prism[5]arenes (ESI†). Upon injection of PrS[5]^EtCy onto a chiral HPLC column, two peaks of equal area were observed in the chromatogram (ESI†). The two enantiomers were collected and reinjected separately. Unfortunately, racemization was again observed after HPLC runs. Analogous results were observed for PrS[5]^PrCy. Therefore, the chiral prism[5]arene enantiomers are not stable at room temperature, however the chiral separation was observed. This observation is in agreement with the conclusion that the rotation of the 2,6-dicyclohexylethyloxynaphthalene and 2,6-dicyclohexylpropoxynaphthalene units is blocked on the NMR time scale.

Molecular recognition studies

As previously reported by us and others,^11–26 prismarenes form endo-cavity supramolecular complexes stabilized by secondary interactions such as cation⋯π, C–H⋯π, van der Waals and the hydrophobic effect. Specifically, the PrS[5]^R (R = Et, nPr)¹⁵ show a high binding affinity toward 1,4-dihexyl-DABCO 2²⁺ and N,N,N′,N’-tetramethylpiperazonium 3²⁺ as barfate salts (Table 3 and Fig. 6). Based on these results, we have explored the recognition abilities of some prism[5]arenes obtained in this work. Our aim was to study how the presence of long alkyl chains or branched/bulky groups in PrS[5]^R can affect the complexation abilities of these new derivatives. When 1,4-dihexyl-DABCO 2²⁺ as barfate salt^33,34 was mixed with 2,6-bis(isopropoxy)prism[5]arene PrS[5]^iPr in CD₂Cl₂ solution, the ¹H NMR spectrum of the host showed significant changes (Fig. 6a–c). The ¹H NMR titration experiment in Fig. 6a–c is indicative of an endo-cavity complexation process in which chemical exchange between free and complexed species is slow compared to the NMR time scale. In fact, when PrS[5]^iPr and 2²⁺ were mixed in a 1/0.5 ratio in CD₂Cl₂ solution, the ¹H NMR spectrum (Fig. 6b) showed the presence of both, complexed and uncomplexed species. Upon addition of 1 equiv. of 2²⁺ as a barfate salt to a CD₂Cl₂ solution of PrS[5]^iPr the ¹H NMR spectrum (Fig. 6c) showed the presence of the 2²⁺@PrS[5]^iPr complex alone, while no indication of uncomplexed species was observed. Thus, the signals at negative values of chemical shifts (−0.64 and −0.97 ppm) in Fig. 6c are attributable to 2²⁺ hosted inside the cavity of PrS[5]^iPr. In addition, the ¹H NMR spectrum of 2²⁺@PrS[5]^iPr (Fig. 6c) shows a singlet at 4.79 ppm attributable to ArCH₂Ar groups (4.67 ppm for the free host), a signal at 4.70 ppm for the OCH(CH₃)₂ groups and two diastereotopic doublets at 1.59 and 1.30 ppm attributable to methyl groups of OCH(CH₃)₂, (1.16 and 0.77 ppm, for the free host). Calculation of the binding constant of the 2²⁺@PrS[5]^iPr pseudorotaxane complex, by direct peak integration was not possible as the ¹H NMR signals (Fig. 6c) of the host PrS[5]^iPr and guest 2²⁺ in the unbound forms were undetectable. Following a procedure previously reported by us and other groups, binding constants assessment was carried out by means of a competition experiment in which 1 equiv. of 2²⁺ as a barfate salt was added to a 1 : 1 mixture of 2,6-bis(isopropoxy)prism[5]arene PrS[5]^iPr and 2,6-bis(propoxy)prism[5]arene PrS[5]^nPr (in CD₂Cl₂). The 2²⁺@PrS[5]^iPr complex was preferentially formed (ESI†), with a percentage of formation of 81% versus 19% for 2²⁺@PrS[5]^nPr. From these data and knowing the binding constant value of the 2²⁺@PrS[5]^nPr complex in CD₂Cl₂, an association constant value of 3.3 × 10⁹ M⁻¹ was calculated (Table 3), significantly higher than that observed for the formation of the 2²⁺@PrS[5]^nPr complex of 1.7 × 10⁸ M⁻¹. This result can be justified on the basis of the greater conformational rigidity and preorganization of the 2,6-bis(isopropoxy)prism[5]arene PrS[5]^iPr macrocycle compared to PrS[5]^nPr. Interestingly, the 2,6-bis(isopropoxy)prism[5]arene PrS[5]^iPr showed a greater binding affinity toward N,N,N′,N’-tetramethylpiperazonium 3²⁺ guest than 2²⁺, with a 3²⁺@PrS[5]^iPr/2²⁺@PrS[5]^iPrselectivity ratio of 3.6 (Table 3).

Fig. 6 ¹H NMR spectra (CD₂Cl₂, 600 MHz, 298 K) of: (a) PrS[5]^iPr, (b) a 1 : 0.5 mixture of PrS[5]^iPr and 2²⁺·(BArF)₂ (2.6 mM), (c) a 1 : 1 mixture of PrS[5]^iPr and 2²⁺·(BArF)₂ (2.6 mM), (d) PrS[5]^nBu, (e) a 1 : 0.5 mixture of PrS[5]^nBu and 2²⁺·(BArF)₂ (2.1 mM), (f) a 1 : 1 mixture of PrS[5]^nBu and 2²⁺·(BArF)₂ (2.1 mM), (g) PrS[5]^EtCy, (h) a 1 : 0.5 mixture of PrS[5]^EtCy and 2²⁺·(BArF)₂ (1.7 mM) and (i) a 1 : 1 mixture of PrS[5]^EtCy and 2²⁺·(BArF)₂ (1.7 mM). Marked with red circles the signals of free hosts and with blue stars the signals of complexed species.

Table 3 Binding constant values for the formation of the complexes between the ammonium 2²⁺ and 3²⁺ cations as barfate salts and PrS[5]^Et, PrS[5]^nPr, PrS[5]^nBu, PrS[5]^nPe, PrS[5]^iPr, PrS[5]^iBu, PrS[5]^iPe, PrS[5]^EtCy and PrS[5]^EtcHp

PrS[5]^R	2^2+ (Kass, M^−1)	3^2+ (Kass, M^−1)
a See ref. 15. b The binding constant obtained by NMR competition experiment is in perfect agreement with the value determined through fluorescence titration experiment. See ESI,† pages S170–173, for further details.
PrS[5]^Et	1.4 ± 0.2 × 10^8 M^−1 ^a	2.8 ± 0.4 × 10^8 M^−1 ^a
PrS[5]^nPr	1.7 ± 0.3 × 10^8 M^−1 ^a	1.4 ± 0.2 × 10^9 M^−1 ^a
PrS[5]^nBu	4.6 ± 0.6 × 10^8 M^−1	1.1 ± 0.2 × 10^9 M^−1
PrS[5]^nPe	4.3 ± 0.6 × 10^8 M^−1	7.4 ± 0.9 × 10^8 M^−1
PrS[5]^iPr	3.3 ± 0.4 × 10^9 M^−1 ^b	1.2 ± 0.2 × 10^10 M^−1 ^b
PrS[5]^iBu	9.6 ± 0.9 × 10^8 M^−1	4.3 ± 0.6 × 10^9 M^−1
PrS[5]^iPe	2.7 ± 0.4 × 10^8 M^−1	5.8 ± 0.8 × 10^8 M^−1
PrS[5]^EtCy	2.1 ± 0.3 × 10^8 M^−1 ^b	6.8 ± 0.9 × 10^8 M^−1 ^b
PrS[5]^EtcHp	2.1 ± 0.3 × 10^8 M^−1	2.8 ± 0.4 × 10^8 M^−1

---

Analogously, the 2,6-bis(isobutoxy)prism[5]arene PrS[5]^iBu gives endo-cavity complexations in the presence of 2²⁺ and 3²⁺ as barfate salt, with binding affinities higher than those observed for the analogous complexation with 2,6-bis(butoxy)prism[5]arene PrS[5]^nBu (Table 3). The structure of the endo-cavity complex 2²⁺@PrS[5]^iBu, was investigated by a 2D NOESY experiment (ESI†), revealing diagnostic dipolar couplings between the methylene signals of 2²⁺ shielded inside the cavity of PrS[5]^iBu at −0.54/−0.85 ppm and the ArH signals of PrS[5]^iBu at 8.86 and 7.21 ppm (Fig. S105, ESI†), confirming the formation of the endo-cavity 2²⁺@PrS[5]^iBu complex. High binding affinity (≈ 10⁸ M⁻¹, Table 3) toward 2²⁺ and 3²⁺ was also observed in the presence of bulky cyclohexylethyl and cycloheptylethyl groups at both rims of PrS[5]^EtCy (Fig. 6g–i†) and PrS[5]^EtcHp (ESI†), respectively (Table 3).

Conclusions

In this work we report the direct macrocyclization to prism[5]arenes of 2,6-dialkoxynaphthalenes bearing branched and bulky alkyl groups. Utilizing the 1,4-dihexyl-DABCO template, we successfully accomplish the direct macrocyclization of 2,6-dialkoxynaphthalene monomers into prism[5]arene with good yields. This process is effective in the presence of both long and branched alkyl chains. The NMR spectral characteristics of all the synthesized prism[5]arenes, are in accordance with the chiral D₅ symmetry that has been previously reported for other prism[5]arene derivatives. In all cases, DFT calculations indicate that the homochiral all-pS (all-pR) conformation of PrS[5]^R as more stable than all the other possible conformations.

The solid state structures of PrS[5]^iPr, PrS[5]^nBu, PrS[5]^iBu, PrS[5]^nPe, PrS[5]^MeCy, PrS[5]^EtCy, and PrS[5]^PrCy (α- and β- forms) were described. In the solid state, a large opening of the cavity is observed for PrS[5]^iBu, PrS[5]^MeCy and the β-form of PrS[5]^PrCy. The opening observed for PrS[5]^MeCy and β-PrS[5]^PrCy can be attributed to the presence of a dichloromethane solvent molecule hosted in the prismarene cavity. In the case of PrS[5]^iBu, a self-filling effect involving two methyl groups of the alkoxy chains is observed. All molecules crystallize as racemic mixtures of inherent chiral pairs (all-pS/all-pR) in centrosymmetric space groups. The dynamic stereochemical inversion (from pR to pS and vice versa) behaviour of prism[5]arenes was examined by variable temperature NMR experiments. These studies suggest that the racemization of prism[5]arene derivatives occurs by through-the-annulus rotation of the naphthalene units. With increasing length of linear alkyl substituents from C2 to C9, the chains tend to pack on both rims, thereby diminishing the conformational freedom of the naphthalene units.

The presence of branched alkyl groups at both rims of the prism[5]arenes increases the energy barrier to racemization and consequently lowers the rate of the process. As a result, PrS[5]^iPr and PrS[5]^iBu exhibit significantly higher energy barriers to racemization compared to those found for their analogous linear isomers PrS[5]^nPr and PrS[5]^nBu. Finally, in prism[5]arenes bearing cyclic units on both rims such as cyclohexylmethyl and cyclohexylethyl, the rotation of the respective 2,6-dialkoxynaphthalene units is blocked on the NMR time scale.

Prism[5]arene derivatives bearing branched or bulky alkyl groups on both rims can form endo-cavity complexes with 1,4-dihexyl-DABCO 2²⁺ and piperazonium 3²⁺ guests. PrS[5]^iPr and PrS[5]^iBu hosts show higher relative binding affinities toward 2²⁺ and 3²⁺ than those calculated for their linear analogues PrS[5]^nPr and PrS[5]^nBu. This result can be justified on the basis of the greater conformational rigidity and preorganization of PrS[5]^iPr and PrS[5]^iBu compared to PrS[5]^nPr and PrS[5]^nBu.

The knowledge acquired from this study, encompassing the synthesis, structural and conformational properties, as well as the molecular recognition abilities of prism[5]arenes featuring branched and bulky groups at both rims, has the potential to lay the foundation for the development of innovative functional systems based on prismarenes.

Author contributions

The manuscript was written through contributions of all authors.

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

C. G. thanks the Italian Ministero dell'Università e della Ricerca (MUR) (PRIN_PNRR P2022XHLTX_PrismaSens) for financial support.

References

1. J.-M. Lehn, Supramolecular Chemistry—Scope and Perspectives Molecules, Supermolecules, and Molecular Devices, Angew. Chem., Int. Ed. Engl., 1988, 27, 89–112.
2. C. J. Pedersen, Cyclic Polyethers and Their Complexes with Metal Salts, J. Am. Chem. Soc., 1967, 89, 7017–7036.
3. D. J. Cram, The Design of Molecular Hosts, Guests, and Their Complexes, Angew. Chem., Int. Ed. Engl., 1988, 27, 1009–1020.
4. P. Neri, J. L. Sessler and M.-X. Wang, Calixarenes and Beyond, Springer Int Publishing, 2016.
5. D. J. Cram and J. M. Cram, Container Molecules and Their Guests, The Royal Society of Chemistry, Cambridge, 1994.
6. J. Lagona, P. Mukhopadhyay, S. Chakrabarti and L. Isaacs, The Cucurbit[n]uril Family, Angew. Chem., Int. Ed., 2005, 44, 4844–4870.
7. T. Ogoshi, Pillararenes, The Royal Society of Chemistry, Cambridge, 2015.
8. H. Chen, J. Fan, X. Hu, J. Ma, S. Wang, J. Li, Y. Yu, X. Jia and C. Li, Biphen[n]arenes, Chem. Sci., 2015, 6, 197–202.
9. F. Jia, Z. He, L.-P. Yang, Z.-S. Pan, M. Yi, R.-W. Jiang and W. Jiang, Oxatub[4]arene: A Smart Macrocyclic Receptor With Multiple Interconvertible Cavities, Chem. Sci., 2015, 6, 6731–6738.
10. J. Li, H.-Y. Zhou, Y. Han and C.-F. Chen, Saucer[n]arenes: Synthesis, Structure, Complexation, and Guest-Induced Circularly Polarized Luminescence Property, Angew. Chem., Int. Ed., 2021, 60, 21927–21933.
11. (a) X.-N. Han, Y. Han and C.-F. Chen, Pagoda[4]arene and i-Pagoda[4]arene, J. Am. Chem. Soc., 2020, 142(18), 8262–8269; (b) X.-N. Han, Y. Han and C.-F. Chen, Recent advances in the synthesis and applications of macrocyclic arenes, Chem. Soc. Rev., 2023, 52, 3265–3298; (c) X.-N. Han, Q.-S. Zong, Y. Han and C.-F. Chen, Pagoda[5]arene with Large and Rigid Cavity for the Formation of 1:2 Host–Guest Complexes and Acid/Base-Responsive Crystalline Vapochromic Properties, CCS Chem., 2022, 4, 318–330.
12. R. Del Regno, P. Della Sala, A. Spinella, C. Talotta, D. Iannone, S. Geremia, N. Hickey, P. Neri and C. Gaeta, Calix[2]naphth[2]arene: A Class of Naphthalene–Phenol Hybrid Macrocyclic Hosts, Org. Lett., 2020, 22, 6166–6170.
13. L.-P. Yang, X. Wang, H. Yao and W. Jiang, Naphthotubes: Macrocyclic Hosts with a Biomimetic Cavity Feature, Acc. Chem. Res., 2020, 53, 198–208.
14. P. Della Sala, R. Del Regno, C. Talotta, A. Capobianco, N. Hickey, S. Geremia, M. De Rosa, A. Spinella, A. Soriente, A. Spinella, P. Neri and C. Gaeta, Prismarenes: A New Class of Macrocyclic Hosts Obtained by Templation in a Thermodynamically Controlled Synthesis, J. Am. Chem. Soc., 2020, 142, 1752–1756.
15. P. Della Sala, R. Del Regno, L. Di Marino, C. Calabrese, C. Palo, S. Geremia, C. Talotta, S. Geremia, N. Hickey, A. Capobianco, P. Neri and C. Gaeta, An intramolecularly self-templated synthesis of macrocycles: self-filling effects on the formation of prismarenes, Chem. Sci., 2021, 12, 9952–9961.
16. P. Della Sala, R. Del Regno, V. Iuliano, A. Capobianco, C. Talotta, S. Geremia, N. Hickey, P. Neri and C. Gaeta, Confused-Prism[5]arene: a Conformationally Adaptive Host by Stereoselective Opening of the 1,4-Bridged Naphthalene Flap, Chem. – Eur. J., 2023, 29, e202203030.
17. R. Del Regno, P. Della Sala, N. Hickey, S. Geremia, C. Talotta, P. Neri and C. Gaeta, Insights into the Self-Filling Effects of Branched Isopropyl Groups on the Conformational and Supramolecular Properties of Isopropoxyprism[6]arene, Eur. J. Org. Chem., 2023, e202300608.
18. R. Del Regno, G. D. G. Santonoceta, P. Della Sala, M. De Rosa, A. Soriente, C. Talotta, A. Spinella, P. Neri, C. Sgarlata and C. Gaeta, Molecular Recognition in an Aqueous Medium Using Water-Soluble Prismarene Hosts, Org. Lett., 2022, 24, 2711–2715.
19. R. Del Regno, P. Della Sala, D. Picariello, C. Talotta, A. Spinella, P. Neri and C. Gaeta, per-Hydroxylated Prism[n]arenes: Supramolecularly Assisted Demethylation of Methoxy-Prism[5]arene, Org. Lett., 2021, 23, 8143–8146.
20. C. Zhai and L. Isaacs, New Synthetic Route to Water-Soluble Prism[5]arene Hosts and Their Molecular Recognition Properties, Chem. – Eur. J., 2022, 28, e202201743.
21. Q. Song, K. Shang, T. Xue, Z. Wang, D. Pei, S. Zhao, J. Nie and Y. Chang, Macrocyclic Photoinitiator Based on Prism[5]arene Matching LEDs Light with Low Migration, Macromol. Rapid Commun., 2021, 42, 2100299.
22. Q. Song, K. Zhao, T. Xue, S. Zhao, D. Pei, J. Nie and Y. Chang, Nondiffusion-Controlled Photoelectron Transfer Induced by Host–Guest Complexes to Initiate Cationic Photopolymerization, Macromolecules, 2021, 54, 8314–8320.
23. D. Pei, W. Guo, P. Liu, T. Xue, X. Meng, X. Shu, J. Nie and Y. Chang, Prism[5]arene-based nonporous adaptive crystals for the capture and detection of aromatic volatile organic compounds, J. Chem. Eng., 2022, 433, 134463.
24. X. Liang, Y. Shen, D. Zhou, J. Ji, H. Wang, T. Zhao, T. Mori, W. Wu and C. Yang, Chiroptical induction with prism[5]arene alkoxy-homologs, Chem. Commun., 2022, 58, 13584–13587.
25. G. Zhang, Z. Li, Z. Pan, D. Zhao and C. Han, A facile and efficient preparation of prism[6]arene and its dual responsive complexation with 1-adamantane ammonium tetrakis[3,5-bis(trifluoromethyl)-phenyl]borate, New J. Chem., 2023, 47, 18910–18913.
26. J. Xie, Z. Xi, Y. Yang, X. Zhang, Z. Yang and M. He, Computational investigation of the structures, properties, and host-guest chemistry of prism[n]arenes, Int. J. Quantum Chem., 2023, e27253.
27. T. Ogoshi, K. Masaki, R. Shiga, K. Kitajima and T.-A. Yamagishi, Planar-Chiral Macrocyclic Host Pillar[5]arene: No Rotation of Units and Isolation of Enantiomers by Introducing Bulky Substituents, Org. Lett., 2011, 13, 1264–1266.
28. N. L. Strutt, H. Zhang and J. F. Stoddart, Enantiopure pillar[5]arene active domains within a homochiral metal–organic framework, Chem. Commun., 2014, 50, 7455–7458.
29. T. Ogoshi, K. Kitajima, T. Aoki, S. Fujinami, T.-A. Yamagishi and Y. Nakamoto, Synthesis and Conformational Characteristics of Alkyl-Substituted Pillar[5]arenes, J. Org. Chem., 2010, 75, 3268–3273.
30. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman and D. J. Fox, Gaussian 16, Revision C.01, Gaussian, Inc., Wallingford CT, 2019.
31. K. Du, P. Demay-Drouhard, K. Samanta, S. Li, T. U. Thikekar, H. Wang, M. Guo, B. van Lagen, H. Zuilhof and A. C.-H. Sue, Stereochemical Inversion of Rim-Differentiated Pillar[5]arene Molecular Swings, J. Org. Chem., 2020, 85, 11368–11374.
32. R. J. Kurland, M. B. Rubin and M. B. Wise, Inversion Barrier in Singly Bridged Biphenyls, J. Chem. Phys., 1964, 40, 2426–2427.
33. P. Della Sala, C. Talotta, T. Caruso, M. De Rosa, A. Soriente, P. Neri and C. Gaeta, Tuning Cycloparaphenylene Host Properties by Chemical Modification, J. Org. Chem., 2017, 82, 9885–9889.
34. C. Gaeta, C. Talotta, L. Margarucci, A. Casapullo and P. Neri, Through-the-annulus threading of the larger calix[8]arene macrocycle, J. Org. Chem., 2013, 78, 7627–7638.

---

Footnote

† Electronic supplementary information (ESI) available. CCDC 2251128 and 2308578–2308584. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3qo02139d

---