Manipulating stereo-communication in binaphthol-bridged α- and β-cyclodextrins to develop β-selective chiroptical pH switching and anion sensing in water

Giovanni Preda^ab, Sonia La Cognata^a, Laura Pedraza-González^c, Laurine Carlier^b, Maxime Kolb^b, Gennaro Pescitelli^c, Valeria Amendola^a, Dominique Armspach*^b and Dario Pasini*^a
aDepartment of Chemistry and INSTM Research Unit, University of Pavia, 27100 Pavia, Italy. E-mail: dario.pasini@unipv.it
^bÉquipe Confinement Moléculaire et Catalyse, Université de Strasbourg, Institut de Chimie de Strasbourg, UMR 7177 CNRS, 4 rue Blaise Pascal, CS90032, 67081 Strasbourg Cedex, France. E-mail: d.armspach@unistra.fr
^cDepartment of Chemistry and Industrial Chemistry, University of Pisa, via Moruzzi 13, 56124 Pisa, Italy

First published on 16th August 2025

---

---

Introduction

Supramolecular engineering of confined, chiral nano-spaces in the fields of sensing, optoelectronics and catalysis is a subject of growing interest.¹ In this regard, the naturally occurring and optically active cyclodextrins (CDs) are of great significance, as they can form inclusion complexes with a large variety of molecules in water by virtue of their hydrophobic cavity. This unique property has been increasingly exploited over the last century for a variety of purposes, ranging from food and pharmaceutical applications to detergents, pollutant removal and catalysis among others.²

Parallel to these developments is the growing interest in chiroptical materials, in view of their possible applications in fields such as smart optoelectronics, data encryption, and biochemical assays.^3–5 Sustainability concerns have driven the search for new strategies aiming at transferring the non-chromophoric chirality found in affordable, naturally occurring molecules of the “chiral pool”, to organic chromophores with strong chiroptical properties. In this regard, CDs have the potential to serve as excellent starting materials for developing chiral functional organic materials. However, their effectiveness in inducing chirality transfer has rarely been reported.^6–10

Recently, we demonstrated that stereo-communication between point-chiral permethylated α- and β-CDs and axially-chiral atropoisomeric biphenol bridging units (Fig. 1, top) can be highly effective.¹¹ In such two-level molecular systems, the stereochemical information of the non-chromophoric CD (point chirality) is transferred to the chromophoric biphenyl capping unit (axial chirality), imposing a single axial configuration on an otherwise stereodynamic cap.† The CDs impose either (aR) or (aS) configurations on the biaryl axis depending on the presence or absence of intramolecular hydrogen bonding. In the case of a 2,2′-dimethoxy-1,1′-biphenyl unit, where such hydrogen bonds are absent, the atropoisomeric unit adopts an (aR) configuration. On the other hand, when OH groups are present, intramolecular hydrogen bonds rigidify the 2,2′-dihydroxy-1,1′-biphenyl bridging unit, selecting the (aS) configuration on the biaryl axis.

Stereostable, axially chiral chromophoric units can also possess valuable properties in the field of chiroptical sensing. In substituted 1,1′-binaphthyl derivatives, the expression of chirality – the asymmetry induced by the stereogenic axis – is directly embedded into the two π-extended chromophoric regions. Their use in chiroptical sensing has recently been successfully exploited by our groups and others, given that only slight changes in the dihedral angle between the two naphthyl rings lead to a significant modulation of the ECD signal.¹²

We hypothesized that bridging CDs with stereostable atropoisomeric units (Fig. 1, bottom) instead of stereolabile biphenolic ones, might induce substantial chiroptical modulation in response to guest complexation and/or an external stimulus, particularly when creating a “chiral mismatch” in the two stack molecular systems. In essence, we envisioned that bridging the CDs with a stereostable (aR) 2,2′-dihydroxy-1,1′-binaphthyl would create strain in the bridged CD as it deviates from the preferred (aS) configuration.

Any release of this strain caused by a change in the binaphthyl dihedral angle would lead to a significant modulation of the ECD signal. In this article, we present the synthesis and chiroptical characterization of axially chiral, enantiostable binaphthyl-bridged α- and β-CDs and demonstrate their application as chiroptical pH switches and chiroptical sensors, selective for the ReO₄⁻ anion, in aqueous solution.

Results and discussion

Synthesis

Binaphthol-bridged CDs 1a,b and 2a,b were synthesized from permethylated A,D-diamino α- and β-CDs,^13a,b and respectively enantiopure (aR)-3,3′-diformyl-2,2′-dimethoxy-1,1′-binaphthyl and (aR)-3,3′-diformyl-2,2′-dihydroxy-1,1′-binaphthyl (Scheme 1), following the procedures optimized for their biphenol analogues. While one-pot reductive amination was used for accessing 2,2′-dimethoxy-1,1′-binaphthyl-bridged CDs 1a,b, a two-step procedure involving a condensation step followed by reduction of the diimine intermediate with NaBH₄ was necessary for synthesizing 2a,b. This difference of reactivity can be attributed to the key role played by the intramolecular hydrogen bonding of the phenolic groups in stabilizing the neighbouring imine nitrogen atoms, which makes the reduction of the diimine more challenging in the case of 2a,b.

Remarkably, the CD truncated cone is sufficiently flexible to ensure efficient bridging, even in the case of the hydroxy derivatives, where the (aR) axial configuration of the binaphthyl cap is not the most suited for the CD unit.

The cavity-free analogue 3 was synthesized from 3,3′-diformyl-2,2′-dihydroxy-1,1′-binaphthyl and methylamine by adapting a reported procedure.¹⁴ All new compounds were extensively characterized by high-resolution mass spectrometry as well as mono- and bidimensional NMR spectroscopy, confirming the expected C₂-symmetry of the α-CD derivatives (see SI). Unlike 1a and 1b, the exchangeable protons (NH and OH) could not be revealed in neither 2a nor 2b when their ¹H NMR spectra were recorded in CDCl₃. To detect these protons and gain more information on possible intramolecular OH⋯NH or/and OH⋯O hydrogen bonds, variable temperature (VT) NMR studies on both compounds were performed in CD₂Cl₂. At 298K, the spectrum of 2a displays a broad singlet at δ = 4.58 ppm integrating for four protons, consistent with both OH and NH protons (Fig. S1). Upon cooling to 283K, this signal broadens and is significantly downfield shifted (Δδ = 0.25 ppm) (Fig. S2). Instead, a CD₂Cl₂ solution of 2b does not reveal any exchangeable protons (Fig. S3) at 298 K; upon cooling, a broad singlet at δ = 10.60 ppm, integrating for about two protons and most likely corresponding to the two OH protons, emerges at 243K and is the sharpest at 223K (Fig. S4 and S5). The signal is downfield shifted from 233K to 193K (Δδ = 0.68 ppm). Furthermore, unlike all other aromatic protons, the H-8,8′ binaphthyl protons of both 2a (Fig. S6) and 2b (Fig. S7) are remarkably upfield shifted (Δδ = 0.09 ppm for 2a and 0.12 and 0.08 ppm for 2b) upon cooling. Clearly, in both compounds, intramolecular hydrogen bonds involving the NH and OH functionalities, the strength of which is temperature dependant,¹¹ have a strong impact on the binaphthyl dihedral angle (see below).

Attempts to obtain single crystals suitable for X-ray crystallography were unsuccessful, but in-depth insights into the molecular structure of the bridged CDs were gained through molecular modelling (see Computational studies below).

Optical and chiroptical characterization and pH switching behaviour

UV-vis and ECD spectra of all molecules were initially recorded in both protic (water and methanol) and aprotic (acetonitrile) solvents to assess the impact of potential intramolecular hydrogen bonds (HN⋯HO– and OH⋯O) between the two components of the bridged CDs (CD and binaphthyl units). All spectra are dominated by the binaphthyl chromophoric moiety, exhibiting maximum absorbance in the UV region at 230 nm for all compounds (Fig. S8 and S9). Regarding the methoxy derivatives 1a and 1b, where the chiral units (CD and binaphthyl) match, no significant differences in the ECD spectra were observed regardless of the solvent used (Fig. S8, S9 and Fig. 2). These compounds display the characteristic bisignate excitonic couplet centered at 230 nm, typical of the binaphthyl system. In contrast, for the hydroxyl derivatives 2a and 2b, which exhibit a “chiral mismatch”, significant differences were observed, particularly for 2b. The negative portion of the bisignate excitonic couplet in the ECD spectra of 2b, centered at 234 and 237 nm in MeOH and ACN respectively, is almost completely suppressed in H₂O (Fig. 2), while a new bisignate excitonic couplet of opposite sign emerges at 224 nm. For 2a (Fig. S2), a partial decrease in optical activity is observed, although the exciton couplet retains the same sign when switching from organic solvents to water.

We first investigated whether the protonation state of the amino groups near the binaphthyl chromophore could influence the chiroptical properties of 2b. Because of the low solubility of 2b in water near neutral pH at concentrations suitable for potentiometric studies, these titrations were conducted in an EtOH/H₂O (3:2, v/v) mixture. The distribution diagram (Fig. S10), calculated from the protonation constant values, indicates that compound 2b is predominantly (>90%) in its bis-protonated form [H₂(2b)]²⁺ between pH 2 and 4 (pK_a1 = 5.66 ± 0.08), with both amine groups near the binaphthyl moiety in the protonated form. For pH values above 5, the concentration of the mono-protonated species [H(2b)]⁺ increases, reaching its maximum abundance around pH 6.2 (pK_a2 = 7.00 ± 0.02). At approximately neutral pH, the solution contains an almost equimolar mixture of the mono-protonated and neutral forms, [H(2b)]⁺ and 2b, while the free amine species 2b predominates in solution above pH 7.5.

The effect of the protonation was further investigated by recording the ECD spectra of 2b in H₂O at varying pH values. Remarkably, as the pH increased from 3 to 9 (Fig. 3, top), the ECD spectrum underwent a nearly complete inversion. Specifically, the exciton couplet centered at 230 nm, observed at pH 3 and attributed to the bis-protonated species [H₂(2b)]²⁺, gradually diminished with increasing pH and was ultimately replaced by a new couplet of opposite sign at pH 9, where the gradual deprotonation of [H₂(2b)]²⁺ and the formation of the free base 2b occurs. The profiles of the pH-dependent UV/vis spectra (Fig. S11) revealed only a small reduction of the intensity of the main absorption band at 230 nm, confirming the absence of deprotonation of the OH groups in the pH range 3–9. It is known that the ECD spectra of binaphthyl systems are highly sensitive to the dihedral angle between the two planes defined by the naphthyl fragments. Even minor angle changes can significantly alter the ECD spectrum and may even lead to a complete sign inversion, despite the chromophore retaining its original axial configuration.¹⁵

Whereas other examples of molecular systems with pH-dependent ECD reversible modulation have been reported,^16,17 the present case represents, to our knowledge, the only example of a quasi-complete optical inversion triggered by pH changes. This behaviour is completely reversible and reproducible. Upon successive additions of concentrated acid and base solutions to the same aqueous solution of 2b, ten complete cycles of ECD inversion between pH 3 and 9 (Fig. 3, bottom) were carried out without any detectable loss of optical activity. This makes 2b one of the few known single-molecule chiroptical switch that operates in water and is capable of reversibly switching the optical activity of the binaphthyl exciton couplet in response to acid–base stimuli, in a fully reversible, hysteresis-free and non-destructive manner. The protonation state of the amine groups neighbouring the binaphthyl systems exerts a change in the dihedral angle through a buttressing effect,¹⁸ amplified by the intramolecular strain introduced by the atropoisomeric binaphthyl cap in a ‘chiral mismatch’ with the cyclodextrin cavity and by the influence of intramolecular hydrogen bonds. Indeed, as a control, the pH-dependent ECD spectra of model compound 3 (Fig. S12) showed only a modest reduction in the intensity of the excitonic couplet, with no spectral inversion.

Chiroptical sensing

The ability of CDs – whether in their native state or permethylated as in the present case – to encapsulate a wide range of organic species in aqueous solution arises from their unique structure, which features a hydrophobic inner cavity as well as a hydrophilic outer surface. The hydrophobic cavity facilitates the encapsulation of poorly water-soluble organic guests, while the hydrophilic exterior ensures the solubility of the resulting inclusion complexes in water.

We sought to explore the potential of 2b as a chiroptical sensor for anions with a known degree of hydrophobicity. Studies by Beer et al.¹⁹ on CDs equipped with halogen or hydrogen bond donors at the primary face have shown that such hosts can selectively bind the hydrophobic ReO₄⁻ anion in water. This anion is of particular interest as a non-radioactive surrogate for the radioactive pollutant TcO₄⁻.

We have recently demonstrated²⁰ that incorporating a binaphthyl moiety into a hexa-protonated azacryptand enables the resulting cage-like host to act as a selective chiroptical chemosensor for ReO₄⁻ in acidic aqueous solution.^21,22 A similar approach was employed for 2b. Anion-binding titration experiments were carried out in aqueous solution acidified to pH 2.5 to ensure full protonation of the amine groups. Under these conditions, the addition of NaReO₄ to a 0.1 mM solution of the bis-protonated host, [H₂(2b)]²⁺, led to a significant modulation of the binaphthyl exciton couplet centered around 230 nm, particularly in the regions near 234 nm and 223 nm (Fig. 4, top). Specifically, the intensities of the couplet bands decreased progressively until reaching a plateau upon addition of excess NaReO₄, and the high-energy branch split in two distinct bands. These changes support the hypothesis that perrhenate is encapsulated within the β-CD cavity, where it changes its conformation and that of the binaphthyl moiety. Analysis of the titration data, assuming a 1:1 [H₂(2b)]²⁺/ReO₄⁻ binding stoichiometry, yielded an association constant of 3.80(3) log units (inset, Fig. 4, top). Remarkably, this value is one order of magnitude higher than that observed by Beer for his best performing system.¹⁹ From the analysis of the linear portion of the titration curve, the limits of detection (LOD) and quantification (LOQ) were determined, and were found to be 18 μM and 60 μM, respectively (see the SI for details).

The chiroptical response of [H₂(2b)]²⁺ to various anions was further tested against a series of other species (ClO₄⁻, OTf⁻, NO₃⁻, Cl⁻, Br⁻, I⁻ and SO₄²⁻; see Fig. S13 and S22). Among these, only ClO₄⁻ (Fig. S13 and S14) and OTf⁻ (Fig. S15 and S16) induced notable modulation of the ECD spectrum of [H₂(2b)]²⁺ (Fig. S21). The corresponding 1:1 binding constants were found to be 2.44(5) and 2.48(1) log units for ClO₄⁻ and OTf⁻, respectively—at least one order of magnitude lower than that observed for perrhenate (Table S1). To demonstrate that the strong chiroptical response of 2b to ReO₄⁻ is directly linked to its unique structural features, we conducted control ECD studies with perrhenate on three related compounds: 1b, 2a, and 3 (Fig. S22). No chiroptical changes were observed in the ECD spectra upon the incremental addition of NaReO₄ to an aqueous solution of the cavity-free compound 3.

Furthermore, only small changes were recorded for systems featuring either a smaller cyclodextrin cavity with hydroxyl groups (2a) or a comparable β-CD cavity bearing protected hydroxyl groups (1b). These results clearly indicate that both the size of the cyclodextrin cavity and the presence of intramolecular hydrogen bonding between the CD unit and the binaphthyl bridge – which is absent in the dimethoxy host 1b – are essential for an effective chiroptical response to perrhenate in aqueous solution.

The formation of a 1:1 complex with ReO₄⁻ was also confirmed by ¹H NMR titration (Fig. 5 and Fig. S23). The association constant (3.93(7) log units) is consistent with the value obtained from ECD titration. Upon addition of NaReO₄ to an acidic solution of the host in D₂O (pD adjusted to 2.5 with TFA), the 6-OMe singlets were significantly affected: two shifted downfield, while the remaining three shifted upfield (see white and black symbols in Fig. 5, and titration profiles in Fig. S24). In addition to the 6-OMe signals, only a few other resonances were influenced by complexation—specifically, the Hε proton of the binaphthyl moiety and two of the seven anomeric (H-1) protons (Fig. S23). Given that the chemical shifts of H-1 protons are highly sensitive to conformational changes in cyclodextrins, these results suggest that ReO₄⁻ binding induces a conformational rearrangement in the two glucose units associated with the shifted H-1 protons – possibly those directly linked to the binaphthyl bridge. By using triflic acid instead of trifluoroacetic acid as the acidic medium, the binding affinity of [H₂(2b)]²⁺ with ReO₄⁻ could be confirmed through a ¹H-NMR titration experiment (Fig. S25 and S26).

The competition of OTf⁻ and Cl⁻ with ReO₄⁻ for binding to the host was also investigated through ECD titrations in aqueous solution. These experiments were carried out using either triflic acid or HCl, instead of TFA, for the preparation of both the [H₂(2b)]²⁺ (0.1 mM) and ReO₄⁻ solutions at pH 2.5. Under these conditions, the concentration of either competitor of OTf⁻ and Cl⁻ was in significant excess (∼30:1 molar ratio) relative to the [H₂(2b)]²⁺ host. However, these studies indicated that, even in presence of competing species, perrhenate binding induces significant changes in ECD spectra of the host. From the fitting of the titration profiles, we could also determine the binding constant for ReO₄⁻ under these conditions (see Table S2 and Fig. S27, S28). As expected, in OTf⁻ containing medium, the binding constant for ReO₄⁻ was about 3.5 times lower than that calculated in TFA at the same pH.

Computational studies

To interpret the ECD properties of binaphthol-bridged CDs and substantiate their anion sensing ability, a computational study was run on compound 2b and its complex with ReO₄⁻, following the same approach employed in our previous work on CD's capped with 2,2′-dihydroxy-1,1′-biphenyl units.¹¹

Classical explicit-solvent molecular dynamics (MD) simulations were carried out for [H₂(2b)]²⁺ (2b in acidic conditions) in the presence of two equivalents of either Cl⁻ (MD1) or ReO₄⁻ (MD2), enabling a comparative assessment of how these anions influence the conformational dynamics of the host. We focused on two structural parameters: (i) the dihedral angle (θ) between the naphthyl planes of the binaphthol unit, serving as a local flexibility indicator, and (ii) the root-mean-square deviation (RMSD) of the CD scaffold, as a global stability indicator.

In the presence of Cl⁻ (MD1), θ remained confined to a relatively narrow window (−75° to −95°) throughout the 1.2 μs trajectory (Fig. S29), with the system ultimately settling at −75° after ∼900 ns and remaining stable thereafter. This behavior suggests restricted torsional freedom of the binaphthol unit, consistent with a lack of directional non-covalent interactions. However, the CD scaffold itself exhibited significant conformational fluctuations, with RMSD values frequently exceeding 2.5 Å (Fig. S30), indicating limited global stabilization by Cl⁻, acting only as a charge-balancing ion.

In contrast, the behavior of [H₂(2b)]²⁺ in the presence of ReO₄⁻ (MD2) was markedly different. The inter-naphthyl angle explored a broader range (−80° to −110°) across a longer 2.0 μs simulation (Fig. 6b), revealing that ReO₄⁻ ion promotes access to binaphthyl conformers not sampled in the Cl⁻ simulation.

This enhanced local flexibility suggests a dynamic interplay between the binaphthol moiety and the ReO₄⁻ anion. Distinct structural states associated with θ values of −81°, −90°, and −110° were captured for further analysis (see colored stars in Fig. 6b).

These findings underscore the dynamic nature of the [H₂(2b)]²⁺·ReO₄⁻ complex and highlight the role of ReO₄⁻ in expanding the accessible conformational space. A key mechanistic feature appears to be water-mediated hydrogen bonding between ReO₄⁻ and the binaphthol hydroxyl groups (Fig. 6c–e). These solvent bridges form a dynamic coordination network that alleviates torsional constraints on the binaphthol moiety while maintaining overall host integrity. Despite the enhanced local motion, the [H₂(2b)]²⁺·ReO₄⁻ system exhibited significantly improved global rigidity, with RMSD values consistently below 1.5 Å (Fig. S30). This global stabilization can be attributed to the central positioning of ReO₄⁻ which is encapsulated within the β-CD cavity (Fig. 6a), where it forms multiple water-mediated contacts with the hydroxyl binaphthol linker, fostering a more compact and symmetric macrocyclic structure.

Altogether, these findings provide strong evidence that ReO₄⁻ not only induces specific conformational changes but also stabilizes the overall architecture of 2b. In contrast, Cl⁻ functions mainly as a charge-balancing counterion, exerting negligible structural influence. These insights support the conclusion that ReO₄⁻ actively contributes to the chiroptical sensing mechanism by enabling and stabilizing water-modulated conformers. Moreover, the fact that ReO₄⁻ cannot penetrate the CD cavity deeply, but barely fits its wider rim, let us infer that the selectivity observed between 2a and 2b is related to a size-exclusion effect.

ECD calculations were performed for representative structures of 2b extracted from both MD simulations: [H₂(2b)]²⁺ from MD1 and [H₂(2b)]²⁺·ReO₄⁻·H₂O complex from MD2. A chromophoric fragment composed of the binaphthol moiety, with two –CH₂–NH₂⁺–CH₃ substituents at 3,3′ positions, was extracted from several frames of MD1 corresponding to values of θ dihedral ranging from −75° to −90° (see SI). The structures were reoptimized with DFT at B3LYP/6-31G(d,p) level, including IEF-PCM solvent model for water, and keeping frozen both the value of angle θ and the coordinates of C atoms of the remote CH₃ groups to preserve the overall arrangement obtained by MD. ECD spectra were calculated with TD-DFT at CAM-B3LYP/def2-TZVP and B3LYP/def2-TZVP levels, including IEF-PCM solvent model for water. The calculated spectra for selected representatives from clusters with θ = −75° and −81° are very similar and consist of an intense negative couplet in region of ¹B_b transitions around 230 nm, and a positive band at longer wavelengths due to ¹L_a and ¹L_b transitions (Fig. S35). The representative from cluster with θ = −90° yielded a similar yet less intense ¹B_b couplet. Overall, the spectra reproduce well those measured for 2b in acidic water, with B3LYP providing the best agreement in the long-wavelength region and CAM-B3LYP in the short-wavelength region (Fig. 7 and S35). Thus, MD and ECD calculations ultimately proof the preferred conformation assumed by the (aR)-binaphthol moiety in [H₂(2b)]²⁺, with a dihedral angle around −80°.

The same procedure described above was employed for ECD calculations of [H₂(2b)]²⁺·ReO₄⁻·H₂O complex extracted from MD2. In this case, in addition to angle θ and remote C atoms, the coordinate of Re atom was also frozen; moreover, it was necessary to keep a water molecule between the BINOL moiety and ReO₄⁻ to achieve convergence. Optimizations were run with functional B3LYP, 6-31G(d,p) basis sets for all atoms except Re, SDD basis set for Re with the related MWB60 effective core potential, and including IEF-PCM solvent model for water. Calculations run on representatives from clusters with θ = −90° and −109° (Fig. 6b) showed ECD couplets of opposite sign in the ¹B_b region (Fig. S36), in agreement with the well-known dependence of the couplet sign on θ angle for 1,1′-binaphthyls.¹⁵ Therefore, the presence of a small but non-negligible conformational population with θ ≈ −110° is expected to reduce the overall intensity of the couplet.

In Fig. 7 we compare the spectra calculated on the chromophoric models extracted from MD1 and MD2 simulations. For [H₂(2b)]²⁺, the representative from the cluster with θ = −81° was used, whereas for [H₂(2b)]²⁺·ReO₄⁻·H₂O the representatives of the two clusters θ = −90° and −109° were combined with a 9:1 proportion.

Although simplified, the approach is able to capture the main changes observed in the ECD spectrum of compound 2b in acidic conditions upon complexation of ReO₄⁻ (Fig. 4, top), including a reduction of ¹B_b couplet intensity by 50% (experimentally, 45%) and substantially unchanged signal in the long-wavelength region. ECD spectra calculated on [H₂(2b)]²⁺·ReO₄⁻·H₂O clusters after removing H₂O and ReO₄⁻ units do not change appreciably (Fig. S37). Natural transition orbitals analysis (NTO) further demonstrates the similar nature of the main transitions responsible for ECD bands of the two model systems, apart from a lift of degeneracy for the two naphthalene rings in [H₂(2b)]²⁺·ReO₄⁻·H₂O (Fig. S37–S40). Therefore, the main conclusion from the computational analysis is that the major chiroptical effect of ReO₄⁻ binding to 2b is structural rather than electronic, as the widening of the upper rim makes a new family of conformations accessible to the binaphthol moiety with larger angles θ and less intense or even oppositely signed couplets.

Finally, additional MD simulations and ECD calculations were run on a neutral 2b system without counterions (MD3) as a model of basic conditions. In this case, further conformational space was accessible to the CD scaffold, witnessed by RMSD values often approaching 4 Å (Fig. S30). More importantly, angle θ assumed values between −90° to −100°, eventually stabilizing at ≈−105° (Fig. S32). ECD calculations run on snapshots with θ = −100°, −102° and −108° all yielded positive ECD couplets in the ¹B_b region (Fig. S38), on a par with the pH-dependent evolution of ECD spectra (see Fig. 3).

Conclusions

We have synthesized two-level molecular structures comprising CDs (point chirality) and binaphthyls (axial chirality) as bridging units. Unlike our previous work involving CDs capped with stereodynamic biphenyls, such structures can exhibit an unfavorable stereocommunication mode (‘chiral mismatch’), as observed in bridged β-CD 2b. This occurs because the configuration of the enantiostable binaphthyl (aR) cap opposes the preferred configuration imposed by the CD cavity when intramolecular hydrogen bonds are present. Consequently, these structures display highly responsive chiroptical behavior. Notably, 2b functions as a pH-controlled, single-molecule chiroptical switch, as the optical activity of the binaphthyl unit's exciton couplet undergoes nearly complete reversal from acidic (pH 3) to basic (pH 9) conditions in a fully reversible manner. Additionally, the same host molecule demonstrates a pronounced chiroptical response to perrhenate in aqueous solution at pH 2.5, showing excellent selectivity for this specific anion. The induced strain is confirmed upon comparison with the behaviour of the cavity-free analogue 3 under otherwise identical conditions. Computational analysis confirmed that the major chiroptical effect of ReO₄⁻ binding to 2b is structural rather than electronic, making new conformations accessible to the binaphthol moiety with a large variation of the associated dihedral angles.

These remarkable chiroptical properties rely on finely tuned stereochemical communication between the two molecular components—β-cyclodextrin and binaphthyl. We believe the principles demonstrated by these systems can inspire the design of new tailor-made, cyclodextrin-based supramolecular cavities. Moreover, they highlight how stereocommunication between point-chiral cyclodextrins and axially chiral atropoisomeric caps—an aspect previously underexplored—can enable the development of novel functional chiral organic materials, with promising potential in chemosensing. Given the outstanding chiroptical responses of the molecular systems described in this paper, and their modular supramolecular cavities, applications in programmable optical encryption and asymmetric catalysis will be explored in the near future.

Author contributions

Conceptualization: Gi. Pr., D. A and D. P. Formal analysis: Gi. Pr., S. L. C., L. P.-G., Ge. Pe. and V. A. Funding acquisition: D. A. and D. P. Investigation: Gi. Pr., S. L. C. and L. P.-G. Methodology: all authors. Project administration: D. A. and D. P. Supervision: V. A., D. A. and D. P. Writing – original draft: Gi. Pr. Writing – review & editing: Ge. Pe., V. A., D. A., and D. P.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the SI: experimental procedures for the synthesis of derivatives 1–3 and their full characterization, additional UV/vis, ECD and NMR data. See DOI: https://doi.org/10.1039/d5qo00910c.

Acknowledgements

Dario Pasini and Giovanni Preda gratefully acknowledge Regione Lombardia (POR FESR 2014-2020-Call HUB Ricerca e Innovazione, Progetto 1139857 CE4WE: Circular Economy for Water and Energy), and Ministero dell'Università e della Ricerca (MUR) through the program “Dipartimenti di Eccellenza 2023–2027” and the University of Pavia for financial support. Dario Pasini thanks the Région Grand Est and the Eurométropole de Strasbourg for the award of a Gutenberg Excellence Chair. Dominique Armspach gratefully acknowledges financial support by the “Cercle Gutenberg”. Valeria Amendola and Sonia La Cognata gratefully acknowledge financial support from the Italian Ministero dell'Università e della Ricerca (MUR) under the PRIN 2022 call (Prot. 20224HH9KP, project MUR: 20224HH9KP_002). We thank Daniele Feltri (University of Pavia) for the synthesis of model compound 3 and Dr Lorenzo Cupellini for assistance with the computations. Gennaro Pescitelli and Laura Pedraza-González gratefully acknowledge the University of Pisa for the availability of high-performance computing resources and support of the computing service at the University of Pisa. Valeria Amendola and Dario Pasini thank Teresa Recca and Barbara Mannucci of Centro Grandi Strumenti NMR and MS Facility for their support and assistance in this work.

References

1. F. Begato, G. Licini and C. Zonta, Exploiting Chirality in Confined Nanospaces, Angew. Chem., Int. Ed., 2023, 62, e202311153 CrossRef CAS PubMed .
2. G. Crini, Review: A History of Cyclodextrins, Chem. Rev., 2014, 114, 10940–10975 Search PubMed .
3. (a) L. Zhang, H.-X. Wang, S. Li and M. Liu, Supramolecular chiroptical switches, Chem. Soc. Rev., 2020, 49, 9095–9120 RSC ; (b) G. Preda and D. Pasini, One-Handed Covalent Helical Ladder Polymers: The Dawn of a Tailorable Class of Chiral Functional Materials, Angew. Chem., Int. Ed., 2024, 63, e202407495 CrossRef CAS ; (c) Y.-Y. Zhao, Z.-Q. Li, Z.-L. Gong, S. Bernhard and Y.-W. Zhong, Endowing Metal-Organic Coordination Materials with Chiroptical Activity by a Chiral Anion Strategy, Chem. – Eur. J., 2024, 30, e202400685 Search PubMed .
4. B. L. Feringa, R. A. van Delden, N. Koumura and E. M. Geertsema, Chiroptical Molecular Switches, Chem. Rev., 2000, 100, 1789–1816 CrossRef CAS PubMed .
5. (a) D. Sahoo, R. Benny, N. K. Ks and S. De, Stimuli-Responsive Chiroptical Switching, ChemPlusChem, 2022, 87, e202100322 CrossRef CAS PubMed ; (b) A. Nitti and D. Pasini, Aggregation-Induced Circularly Polarized Luminescence: Chiral Organic Materials for Emerging Optical Technologies, Adv. Mater., 2020, 32, 1908021 Search PubMed ; (c) P. T. Probst, Y. Dong, Z. Zhou, O. Aftenieva and A. Fery, Bottom-Up Assembly of Inorganic Particle-Based Chiroptical Materials, Adv. Opt. Mater., 2024, 12, 2301834 CrossRef CAS ; (d) W. Ma, H. Kuang, L. Xu, L. Ding, C. Xu, L. Wang and N. A. Kotov, Attomolar DNA detection with chiral nanorod assemblies, Nat. Commun., 2013, 4, 2689 CrossRef PubMed .
6. D. Armspach, D. Matt and N. Kyritsakas, Anchoring a Helical Handle across a Cavity: The First 2,2′-Bipyridyl-Capped α-Cyclodextrin Capable of Encapsulating Transition Metals, Polyhedron, 2001, 20, 663–668 CrossRef CAS .
7. M. Kazem-Rostami, A. Orte, A. M. Ortuño, A. H. G. David, I. Roy, D. Miguel, A. Garci, C. M. Cruz, C. L. Stern, J. M. Cuerva and J. F. Stoddart, Helically Chiral Hybrid Cyclodextrin Metal–Organic Framework Exhibiting Circularly Polarized Luminescence, J. Am. Chem. Soc., 2022, 144, 9380–9389 CrossRef CAS PubMed .
8. M. Ménand, M. Sollogoub, B. Boitrel and S. Le Gac, Hexaphyrin–Cyclodextrin Hybrids: A Nest for Switchable Aromaticity, Asymmetric Confinement, and Isomorphic Fluxionality, Angew. Chem., Int. Ed., 2016, 55, 297–301 Search PubMed .
9. (a) H. Shigemitsu, K. Kawakami, Y. Nagata, R. Kajiwara, S. Yamada, T. Mori and T. Kida, Cyclodextrins with Multiple Pyrenyl Groups: An Approach to Organic Molecules Exhibiting Bright Excimer Circularly Polarized Luminescence, Angew. Chem., Int. Ed., 2022, 61, e202114700 CrossRef CAS ; (b) S. Dash, A. Fihey, L. Favereau, C. Lagrost, R. Benchouaia, S. Blanchard, M. Ménand and S. Le Gac, Encoding and Expressing the Handedness of a Möbius π System in a Totemic Architecture, J. Am. Chem. Soc., 2025, 147, 15242–15252 Search PubMed .
10. R. Benchouaia, N. Cisse, B. Boitrel, M. Sollogoub, S. Le Gac and M. Menand, Orchestrating Communications in a Three-Type Chirality Totem: Remote Control of the Chiroptical Response of a Möbius Aromatic System, J. Am. Chem. Soc., 2019, 141, 11583–11593 CrossRef CAS PubMed .
11. G. Preda, S. Jung, G. Pescitelli, L. Cupellini, D. Armspach and D. Pasini, Enabling Stereochemical Communication and Stimuli–Responsive Chiroptical Properties, Chem. – Eur. J., 2023, 29, e202302376 CrossRef CAS PubMed .
12. (a) P. K. Baruah, R. Gonnade, P. R. Rajamohanan, H.-J. Hofmann and G. J. Sanjayan, BINOL-Based FoldamersAccess to Oligomers with Diverse Structural Architectures, J. Org. Chem., 2007, 72, 5077–5084 CrossRef CAS PubMed ; (b) L. Di Bari, G. Pescitelli and P. Salvadori, Conformational Study of 2,2′-Homosubstituted 1,1′-Binaphthyls by Means of UV and CD Spectroscopy, J. Am. Chem. Soc., 1999, 121, 7998–8004 CrossRef CAS ; (c) M. Caricato, C. Coluccini, D. Dondi, D. A. Vander Griend and D. Pasini, Nesting Complexation of C₆₀ with Large, Rigid D₂ Symmetrical Macrocycles, Org. Biomol. Chem., 2010, 8, 3272–3280 RSC ; (d) M. Caricato, N. J. Leza, K. Roy, D. Dondi, G. Gattuso, L. S. Shimizu, D. A. Vander Griend and D. Pasini, A Chiroptical Probe for Sensing Metal Ions in Water, Eur. J. Org. Chem., 2013, 6078–6083 CrossRef CAS ; (e) M. Caricato, A. Olmo, C. Gargiulli, G. Gattuso and D. Pasini, A “clicked” macrocyclic probe incorporating Binol as the signalling unit for the chiroptical sensing of anions, Tetrahedron, 2012, 68, 7861–7866 CrossRef CAS ; (f) M. Agnes, A. Nitti, D. A. Vander Griend, D. Dondi, D. Merli and D. Pasini, A chiroptical molecular sensor for ferrocene, Chem. Commun., 2016, 52, 11492–11495 RSC ; (g) C. Coluccini, D. Dondi, M. Caricato, A. Taglietti, M. Boiocchi and D. Pasini, Structurally-Variable, Rigid and Optically-Active D₂ and D₃ Macrocycles Possessing Recognition Properties towards C₆₀, Org. Biomol. Chem., 2010, 8, 1640–1649 RSC ; (h) D. Pasini and A. Nitti, Recent Advances in Chirality Sensing using Atropoisomeric Molecular Receptors, Chirality, 2016, 28, 116–123 CrossRef CAS .
13. (a) D. Armspach and D. Matt, Metal-Capped α-Cyclodextrins: Squaring the Circle, Inorg. Chem., 2001, 40, 3505–3509 CrossRef CAS ; (b) D. Armspach and D. Matt, The tris(4-tert-butylphenyl)methyl group: a bulky substituent for effective regioselective difunctionalisation of cyclomaltohexaose, Carbohydr. Res., 1998, 310, 129–133 CrossRef CAS .
14. D. Verga, M. Nadai, F. Doria, C. Percivalle, M. Di Antonio, M. Palumbo, S. N. Richter and M. Freccero, Quinone Methides Tethered to Naphthalene Diimides as Selective G-Quadruplex Alkylating Agents, J. Am. Chem. Soc., 2010, 132, 14625–14637 CrossRef CAS PubMed .
15. (a) S. F. Mason, R. H. Seal and D. R. Roberts, Optical activity in the biaryl series, Tetrahedron, 1974, 30, 1671–1682 CrossRef CAS ; (b) C. Rosini, S. Superchi, H. W. I. Peerlings and E. W. Meijer, Enantiopure Dendrimers Derived from the 1,1′-Binaphthyl Moiety: A Correlation Between Chiroptical Properties and Conformation of the 1,1′-Binaphthyl Template, Eur. J. Org. Chem., 2000, 61–71 CrossRef CAS ; (c) G. Pescitelli, ECD exciton chirality method today: a modern tool for determining absolute configurations, Chirality, 2022, 34, 333–363 CrossRef CAS PubMed .
16. (a) P. E. Reyes-Gutiérrez, M. Jirasek, L. Severa, P. Novotna, D. Koval, P. Sazelova, J. Vavra, A. Meyer, I. Cisarova, D. Saman, R. Pohl, P. Stepanek, P. Slavicek, B. J. Coe, M. Hajek, V. Kasicka, M. Urbanova and F. Teply, Functional helquats: helical cationic dyes with marked, switchable chiroptical properties in the visible region, Chem. Commun., 2015, 51, 1583–1586 RSC ; (b) W. Lu, G. Du, K. Liu, L. Jiang, J. Ling and Z. Shen, Chiroptical Inversion Induced by Rotation of a Carbon–Carbon Single Bond: An Experimental and Theoretical Study, J. Phys. Chem. A, 2014, 118, 283–292 CrossRef CAS PubMed ; (c) N. Saleh, B. Moore, M. Srebro, N. Vanthuyne, L. Toupet, J. A. G. Williams, C. Roussel, K. K. Deol, G. Muller, J. Autschbach and J. Crassous, Acid/Base-Triggered Switching of Circularly Polarized Luminescence and Electronic Circular Dichroism in Organic and Organometallic Helicenes, Chem. – Eur. J., 2015, 21, 1673–1681 CrossRef CAS .
17. (a) J. W. Canary, Redox-triggered chiroptical molecular switches, Chem. Soc. Rev., 2009, 38, 747–756 RSC ; (b) Z. Dai, J. Lee and W. Zhang, Chiroptical Switches: Applications in Sensing and Catalysis, Molecules, 2012, 17, 1247–1277 CrossRef CAS PubMed .
18. L. A. Paquette and J. M. Gardlik, Utilization of Buttressing Effects for Comparing Ring Inversion and π Bond Shifting Transition State Geometries in Cyclooctatetraenes, J. Am. Chem. Soc., 1980, 102, 5033–5035 CrossRef CAS .
19. S. P. Cornes, M. R. Sambrook and P. D. Beer, Selective perrhenate recognition in pure water by halogen bonding and hydrogen bonding alpha-cyclodextrin based receptors, Chem. Commun., 2017, 53, 3866–3869 RSC .
20. R. Mobili, G. Preda, S. La Cognata, L. Toma, D. Pasini and V. Amendola, Chiroptical sensing of perrhenate in aqueous media by a chiral organic cage, Chem. Commun., 2022, 58, 3897–3900 RSC .
21. V. Amendola, G. Bergamaschi and A. Miljkovic, Azacryptands as molecular cages for anions and metal ions, Supramol. Chem., 2018, 30, 236–242 CrossRef CAS .
22. R. Alberto, G. Bergamaschi, H. Braband, T. Fox and V. Amendola, ⁹⁹TcO₄⁻: Selective Recognition and Trapping in Aqueous Solution, Angew. Chem., Int. Ed., 2012, 51, 9772–9776 CrossRef CAS .
23. W. Humphrey, A. Dalke and K. Schulten, VMD: visual molecular dynamics, J. Mol. Graphics, 1996, 14, 33–38 CrossRef CAS .

---

Footnote

† The aryl–aryl bond in the biphenol unit is typically freely rotating at room temperature when not part of a capping unit.

This journal is © the Partner Organisations 2025