A modular family of chiral cavitand receptors: tuning the chiroptical response of achiral fullerene guests

Abstract

A new family of chiral self-folding cavitand receptors based on calix[5]arene has been developed. The cavitand synthesis is modular and highly convergent, relying on a late-stage amide formation step that allows facile diversification with different chiral amines and straightforward access to either enantiomer of the host. This strategy provides access to a set of structurally diverse and conformationally flexible cavitands that efficiently bind fullerene derivatives. The resulting host–guest complexes exhibit an induced electronic circular dichroism response in the spectral window of the achiral fullerene chromophore. The modular nature of the cavitand scaffold allows tuning of the chiroptical response of a given fullerene across the visible spectrum.

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Introduction

Fullerenes are spherical π-conjugated molecules with notable electronic, photophysical, and structural properties that have gained significant attention in materials science^1,2 and biomedicine,³ among other fields. However, practical access is mainly limited to C₆₀ and C₇₀, and the inherent symmetry of these molecules creates substantial challenges in efficiently obtaining new derivatives for fullerene-based applications. In this context, supramolecular chemistry has recently become a promising approach to overcome the intrinsic limitations of fullerene chemistry.⁴ The selective extraction of higher fullerenes using tailored synthetic hosts is a suitable strategy for accessing the least abundant carbon cages in fullerene soot.^5–13 Similarly, carefully designed synthetic hosts have been used as supramolecular “masks” that enable regioselective and/or enantioselective functionalization of fullerenes.^14–20

Finally, encapsulation in chiral hosts offers a promising method to induce chirality in achiral fullerene chromophores,^21–26 bypassing the cumbersome and highly inefficient synthetic routes typically used to produce chiral fullerenes.^27,28 Fullerenes with intrinsic chirality—originating from dissymmetric substitution of the spherical π system—are particularly promising for integration into circularly polarized light (CPL) detecting devices.²⁹ For the latter objective, practical access to synthetic receptors that can be systematically modified to fine tune the electronic structure of the host–guest complexes is crucial. However, the majority of works on the topic of fullerene molecular recognition focus on a single host structure, often with limited potential for diversification. In metal–organic cages, for instance, subtle changes in the ligand structure often result in disparate cage geometries, limiting systematic study of a given host. In addition, many of the previous studies require resolution of the host racemate by preparative chiral HPLC, which is far from ideal.

Recently, our group has developed a series of flexible cavitand receptors based on calix[5]arene that are stabilized in the folded conformation by means of cooperative hydrogen bond networks.^30–33 While receptors featuring O-methyl groups at the narrow rim favour narrow and irregularly shaped pinched conformers, analogues with free hydroxyl groups engage in additional hydrogen bonding at the lower rim, bringing about a wider and more spherical cavity that is suitable for the binding of fullerenes. Importantly, the synthesis of these receptors rests on a late-stage amide condensation reaction that makes them amenable to facile diversification. Fukazawa, Haino and co-workers have previously demonstrated that (achiral) calix[5]arene-based hosts are excellent receptors for fullerenes.^34–37 Herein, we report a new family of chiral spherical receptors 1a–e based on calix[5]arene featuring aromatic panels with a range of electronic properties (Fig. 1). We then systematically study the induction of chirality onto achiral fullerenes upon binding by 1a–e, and rationalize the resulting electronic circular dichroism (ECD) response using molecular dynamics (MD) simulations and TD-DFT.

Fig. 1 Schematic structures of the new family of tunable chiral self-folding cavitands for fullerene binding and desymmetrization, and molecular model of C₆₀⊂(S⁵)-1a.

Results and discussion

Host synthesis and characterization

The synthesis of cavitands 1a–e required the preparation of enantiomerically pure chiral amine building blocks 2a–e (Scheme 1). The parent Betti base (2a) was synthesized and resolved via classical resolution using tartaric acid, as previously described in the literature (Scheme 1A).^38,39 Enantiopure bromo-naphthalene derivative 2b was obtained following the same strategy. However, this approach proved ineffective for the preparation of amines bearing substituted phenyl rings. Amines 2c–e were prepared in optically pure form using Ellman's chiral sulfinamide auxiliary (Scheme 1B). Diastereoselective addition of phenylmagnesium bromide to sulfinylimines 6c–e followed by sequential cleavage of the O-silyl and N-sulfinyl groups provided optically pure 2c–e.⁴⁰ Both enantiomeric forms were obtained starting from either enantiomer of the Ellman auxiliary. The configuration of compound 8d was unambiguously established by single crystal X-ray diffraction (Fig. S1), corroborating the previously assigned configuration based on the induction model developed by Ellman.^40,41

Scheme 1 Synthetic route for the preparation of chiral amine building blocks 2a–e. A: Naphthol derivatives obtained through conventional resolution. B: Phenol derivatives synthesized via a chiral auxiliary strategy. Synthesis of the (S)-2c–e isomers was conducted analogously starting from (R)-2-methylpropane-2-sulfinamide. THF: tetrahydrofuran. TBSCl: tert-butyldimethylsilyl chloride. DCM: dichloromethane. TBAF: tetrabutylammonium fluoride.

The key step of the cavitand synthesis is the coupling reaction of the enantiopure amines with a suitable calix[5]arene pentacarboxylic acid precursor (11, Scheme 2). The use of a temporary protection scheme for the phenol groups was found necessary to improve the efficiency of the coupling reaction and to facilitate purification. Importantly, a small protecting group is required to provide a conformationally flexible calix[5]arene precursor that does not get conformationally locked upon successive condensation reactions (see SI).⁴² Herein, we used an allyl protecting group instead of the acetyl group featured in our previous work.³¹ The allyl group proved superior due to its greater stability and ease of cleavage under mild conditions under Pd(0)-catalysis. Thus, known pentaaldehyde intermediate 9 was per-alkylated with allyl bromide and subjected to Pinnick oxidation to yield key pentaacid 11 (Scheme 2). Subsequent amide bond formation with chiral amines 2a–e using standard peptide coupling reagents provided cavitands 12a–e in good yields, considering the 5-fold reaction. The structure of O-allyl derivative (S⁵)-12d could be determined by single crystal X-ray diffraction (Fig. S3). A molecule of solvent (toluene) was found to be bound in the cavity, demonstrating the capacity of this scaffold to adapt to the bound guest's size and shape while preserving most of the envisaged hydrogen bonding interactions. Finally, cleavage of the allyl groups under Pd(0) catalysis or base induced isomerization conditions (for 12b) furnished enantiopure cavitands 1a–e in good overall yields. The structure of (R⁵)-1a in the solid state could be determined by single crystal X-ray diffraction (Fig. S4). Two solvent molecules are accommodated in the cavity, showcasing the expansion of the binding site upon cleavage of the allyl groups. Overall, we efficiently obtained both enantiomers of 5 different cavitands in enantiopure form through a concise number of steps. The results highlight the potential of this approach to obtain chiral receptors where the electronic properties and molecular recognition abilities can be easily modulated. All hosts were fully characterized by ¹H/¹³C NMR spectroscopy, HRMS, IR spectroscopy, and polarimetry.

Scheme 2 Synthesis of cavitands 1a–e. DCM: dichloromethane. OxymaPure: ethyl cyano(hydroxyimino)acetate. EDC·HCl: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. DMF: N,N-dimethylformamide. DMBA: N,N′-dimethylbarbituric acid.

The ¹H NMR spectra of cavitands 1a–e in non-hydrogen bonding solvents such as CDCl₃ and toluene-d₈ presented the characteristic features previously observed in lower rim O-methyl analogues,³² namely: (a) separate resonances for the aromatic protons of the calix[5]arene core and the two protons of the methylene bridges, indicating restricted rotation about both the aryl-CH₂ and the aryl-CONH bonds, and (b) far downfield shifts corresponding to the OH and NH protons in the upper section of the host, indicative of a cyclic, uninterrupted intramolecular network of cooperative hydrogen bonds (Fig. 2 and Fig. S5). Overall, these features indicate the stabilization through hydrogen bonding of cone conformations that are kinetically stable in the ¹H NMR shift time scale.

Fig. 2 ¹H NMR titration of 1a with C₆₀ (toluene-d₈, [1a] = 2.05 mM, 298 K) from bottom spectrum (free 1a) to top (3.07 eq. C₆₀). The NH/OH and CH₂ regions are shown, highlighting the cooperative nature of the H-bond network and the diastereotopic methylene resonances. Green triangles and blue squares correspond to resonances of free and bound 1a, respectively. The asterisk indicates residual traces of methanol.

Fullerene binding

With cavitands 1a–e in hand, their binding ability toward C₆₀, C₇₀, and PCBM ([6,6]-phenyl-C₆₁-butyric acid methyl ester) was evaluated. We first monitored changes in the ¹H NMR spectra of 1a–e upon addition of fullerenes. As shown in Fig. 2, addition of C₆₀ to a solution of 1a in toluene-d₈ results in the formation of a new set of separate resonances, corroborating the binding event and indicating that the corresponding equilibrium is also slow relative to the ¹H NMR time scale. The same behaviour is observed for all the possible cavitand/fullerene combinations. This finding contrasts with the behaviour previously found in lower rim O-methyl analogues, which undergo fast guest exchange.³² Upon binding, all resonances of the cavitand shift downfield, which is commensurate with anisotropic deshielding by the nearby π surface of the fullerene guest. However, the NH and OH resonances experience unusually large downfield shifts, in particular those of the lower rim OH groups, which we attribute to a conformational rigidification of the assembly upon binding of the fullerene guest (Fig. S6 and S7). In order to gauge the substituent effects on the guest exchange kinetics, we systematically determined the barrier of guest exchange using EXSY experiments on solutions of cavitands 1a–e and PCBM, containing roughly equimolar concentrations of free and bound cavitand (Fig. S8–S12). Interestingly, all the barriers to guest release were found fall in a narrow range (ΔG^‡ = 17.1–17.6 kcal mol⁻¹) and no clear correlations to the electronic properties of the phenol/naphthol moiety of the upper panels could be established. This evidence suggests that the cooperativity of the hydrogen bond network is the key feature governing the conformational and guest exchange mechanisms, and that discrete effects that may increase or decrease the hydrogen bonding capability of the OH groups have a negligible effect.

We next determined the association constants (K_a) for the host–guest complexation equilibria of 1a–e with C₆₀, C₇₀ and PCBM, which were found to be in the range of 10²–10⁵ M⁻¹ (Table 1). Association constants for C₆₀ and C₇₀ were determined using UV-vis titrations (Fig. S13 and S14). For PCBM, reliable binding data could not be obtained by UV-Vis titrations. Instead, direct integration of ¹H NMR spectra was used to determine K_a, taking advantage of the slow exchange regime as previously detailed (Fig. S15–S19). Additionally, we were able to obtain the thermodynamic parameters of binding for the strongest host–guest pair (C₇₀⊂1e) using isothermal titration calorimetry (ITC, Fig. S20). The binding of C₇₀ with 1e is enthalpically favoured and entropically disfavoured (ΔH = −15.2 kcal mol⁻¹; −TΔS = 7.5 kcal mol⁻¹). The driving force for binding in the systems studied herein can be dissected in various contributions. First, attractive non-covalent π–π interactions provide an enthalpic gain. The strength of these interactions can be modulated by both the extension of the π system (naphthyl vs. phenyl panel) and the electronic effects induced by the panel substituents. Entropic contributions can in turn be broken down in various components. First, desolvation of the fullerenes upon binding has been postulated to be a positive contributor to binding of fullerenes within calixarene hosts.³⁷ In contrast, the binding event will be accompanied by a conformational selection process of the flexible cavitand structure, as well as a reduction in rotational diffusion of the fullerene, both disfavouring binding in terms of entropy. The entropic penalty to binding determined for C₇₀⊂1e is below the intrinsic entropy loss for the formation of a 1 : 1 complex, suggesting that favourable desolvation effects are indeed significant in this system. Some of these contributions to binding may even work in opposite directions. For instance, the extended π surface of naphthyl panels would provide an enhanced enthalpic gain in comparison to phenyl panels, but the latter are less conformationally restricted, which could provide a better overlap with the bound fullerene surface. Overall, the obtained data indicate a complex relationship between cavitand structure and K_a values that points at a delicate balance of factors, although some trends can be obtained. For the naphthalene based cavitands (1a–b), the electronic effect is consistent: cavitand 1b bearing the electron-withdrawing bromine substituents provides lower binding constants throughout the series of fullerenes, which feature a polarizable electron-accepting surface. On the contrary, a consistent electronic effect is not observed for the phenyl panel series (1c–e). For C₆₀, introduction of an electron-withdrawing chlorine substituent on the cavitand panels reduces binding while an electron donating methoxy group increases it, as expected (Table 1, entries 3–5), while both chlorine and methoxy groups increase binding in the case of C₇₀ and PCBM (Table 1, entries 8–10 and 13–15). In any case 1e, provides increased binding over 1d in all cases as expected from electronic effects only. We reason that the phenyl panels provide reduced non-covalent interactions to the bound fullerene with respect to the larger naphthalene π surface, making subtler conformational effects dominant in these cases. Similarly, a clear binding trend when comparing C₆₀ and C₇₀ is not observed. C₇₀ provides the higher K_a in the series (Table 1, entry 10), in good agreement with its poorer solubility in toluene. However, cavitands 1b and 1c display increased binding for C₆₀, pointing again at subtle conformational effects. As expected form our previous work,^32,33 the flexibility of the cavitands studied herein allows adaptation to different guest sizes, surpassing the guest complementarity limitations of rigid hosts. Finally, PCBM consistently displayed the lowest affinities throughout the series. While this may be due in part to electronic effects—the π system of C₆₀ is partially disrupted—entropic effects are likely as important. In comparison to C₆₀ and C₇₀, PCBM is intrinsically more soluble in toluene and its cyclopropane addend will lead to reduced rotational diffusion within the cavity. Both effects result in unfavourable entropic contributions.

Table 1 Association constants (K_a) of cavitands 1a–e with fullerenes

Cavitand	Entry	Fullerene	Ka ^a [M^−1]	Entry	Fullerene	Ka ^a [M^−1]	Entry	Fullerene	Ka ^b [M^−1]
a Obtained by UV-Vis titration experiments in toluene at 298 K; values are the average of three replicates.b Obtained by direct integration from ^1H NMR spectra in toluene-d8, 298 K.
1a	1	C60	8.8 ± 0.4 × 10^3	6	C70	1.6 ± 0.1 × 10^4	11	PCBM	4.7 ± 0.2 × 10^2
1b	2	C60	3.8 ± 0.1 × 10^2	7	C70	1.8 ± 0.1 × 10^2	12	PCBM	1.8 ± 0.1 × 10^2
1c	3	C60	1.4 ± 0.1 × 10^4	8	C70	8.6 ± 0.3 × 10^3	13	PCBM	4.5 ± 0.3 × 10^2
1d	4	C60	4.9 ± 0.3 × 10^3	9	C70	1.7 ± 0.1 × 10^4	14	PCBM	1.0 ± 0.1 × 10^3
1e	5	C60	1.4 ± 0.1 × 10^4	10	C70	1.9 ± 0.1 × 10^5	15	PCBM	2.7 ± 0.2 × 10^3

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Chirality transfer to fullerenes

To investigate the ability of the chiral cavitands to induce asymmetry in the fullerene guests, electronic circular dichroism (ECD) measurements were performed on host–guest complexes in solution. These experiments were carried out with excess host over the corresponding fullerene, and the concentrations were adjusted according to the calculated association constants (Table 1) to minimize the amount of free fullerene in solution and maximize the ECD response in the region of the spectrum where only the fullerenes absorb (λ > 400 nm). The observed induced circular dichroism (ICD) signals, quantified by the absorbance dissymmetry factor (g_abs = ΔA^R/L/A), provided insight into the extent of supramolecular induction. Fig. 3 displays the ECD spectra obtained for the complexes of C₆₀, C₇₀, and PCBM with the (S⁵) enantiomers of hosts 1a–e, highlighting the effect of cavitand structure on the ICD of a given fullerene chromophore (complete spectroscopic data available in the SI, Fig. S21–S23). Given the fact that cavitands 1a–e do not absorb in the 400–700 nm region (Fig. S24) and that the achiral fullerene molecules are ECD silent, all signals detected in this spectral range are attributable to the host–guest complex and correspond to electronic transitions of the fullerene chromophore. These findings offer clear evidence of chirality transfer from the chiral host to the various fullerene guests. Among all systems examined, the complex PCBM⊂1e produced the strongest ICD signals, displaying a maximum g_abs of 8.12 × 10⁻⁴ (λ = 515 nm). We rationalized this result on the basis of the reduced symmetry of PCBM in relation to C₆₀ and C₇₀. In addition, the alkylidene addend on PCBM limits its rotational mobility within the cavity, maximizing the symmetry breaking of the fullerene chromophore induced by the chiral environment. On the other hand, the lower association constants observed for PCBM (K_a ∼ 10² M⁻¹) indicated a weaker interaction with the aromatic panels that may result in diminished chiral induction. However, cavitands 1a and 1d bind C₇₀ in the 10⁴ M⁻¹ range while producing low g_abs values (1.44–2.07 × 10⁻⁴), indicating that the ICD response is the result of a complex interplay between binding affinity, cavity electronic structure, and guest dynamics. Remarkably, our set of cavitands allows tuning the chiroptical response, producing ECD maxima in a range of frequencies in the visible region, which may be a useful property for building tunable CPL detectors (Fig. 3a). The most salient feature of this cavitand scaffold is the ability to produce varied and complementary chiroptical response with the same fullerene chromophore. This is best illustrated by the pairs of complexes C₆₀⊂1a/C₆₀⊂1b and PCBM⊂1a/PCBM⊂1b, where nearly mirror image Cotton effects are obtained from cavitands of the same configuration, by tuning the cavitand–fullerene interactions that lead to chirality transfer through substituent electronic effects only.

Fig. 3 (a) ECD spectra of C₆₀, C₇₀ and PCBM host–guest complexes with 1a–e in toluene ([1a–e] = 10⁻³ M, [fullerene] = 10⁻⁴ M). (b) NCI plot for C₇₀⊂1e. (c) Trajectory analysis for the MD simulation of C₇₀⊂1e. (d) Experimental vs. computed (TD-DFT, B3LYP/def2-svp) ECD spectra of C₇₀⊂1e (see SI for details).

Computational studies

Theoretical calculations at different levels were carried out to rationalize the observed molecular recognition phenomena and the resulting chiral induction effects. Structures of all host–guest pairs were optimized by DFT methods, and non-covalent interaction (NCI) analyses were carried out (Fig. 3b and Fig. S25–S27). The results reveal significant favourable host–guest interactions between the surfaces of the fullerene and the aromatic panels of the host, in good agreement with the experimentally obtained binding enthalpy for C₇₀⊂1e. Frontier orbital analysis of the host guest complexes revealed that the LUMO of the host guest complexes is located exclusively on the fullerene guest (Fig. S34). On the other hand, the HOMO is distributed across the cavitand surface and the bound fullerene, resulting in breaking of the native fullerene orbital symmetry. The observed induced ECD signals correspond to the HOMO–LUMO transition, an optically forbidden transition, hence the moderate ECD signals observed. Given the innate conformational flexibility of hosts 1a–e and the potential rotational diffusion of the encapsulated fullerene guests, we carried out molecular dynamics (MD) simulations to rationalize these dynamic effects. The MD trajectories confirmed the flexibility of the receptor scaffold and revealed different degrees of motion among the fullerene guests (Fig. 3c and Fig. S31). The arrangement of PCBM with the cyclopropane addend locked between adjacent panels of the cavitands appears to be significantly stable throughout the trajectories (Fig. S31), which explains the larger g_abs values observed for this guest complexes in comparison to cases where the fullerene guest suffers from higher rotational mobility (C₆₀, C₇₀). Finally, the ECD spectra for the complexes of 1e (the cavitand exhibiting the strongest and most meaningful induced signal across all the range of guests) were simulated using TD-DFT (Fig. 3d and Fig. S33). These simulations reproduced the experimentally observed ECD signals.

Conclusions

We have obtained a new family of self-folding cavitand receptors based on calix[5]arene that allows efficient chirality transfer to bound fullerene guests. A streamlined and highly modular cavitand synthesis has been developed that allows the preparation of cavitands with varied molecular recognition properties. Remarkably, easy access to both enantiomers of these hosts is straightforward and does not require HPLC separation. Despite the cavitands’ inherent flexibility, a variety of fullerenes are efficiently bound. Upon binding of fullerenes, an induced ECD signal is obtained in the spectral region of the achiral fullerene guests, showcasing an efficient transfer of chirality in the confined space. This induced chiroptical response can be modulated across the visible region through substituent effects on the cavitand's walls. Overall, this work presents a promising approach for obtaining tailored chiroptical materials based on simple and readily accessible achiral chromophores. Such materials could find applications in the development of CPL sensors²⁹ or quantum information technologies based on the CISS effect of discrete molecular entities.⁴³

Author contributions

H. M. L. carried out the synthesis of cavitands, acquired spectroscopic and titration data, analysed and curated the data, and edited the manuscript. A. S. B and F. F. carried out computational work and curated the corresponding data. C. M.-A. and P G.-M. synthesized intermediates of cavitands 1a–e. E. P.-F. acquired and curated ECD spectroscopic data. M. S. planned and supervised computational work, analysed the data, edited the manuscript, and was responsible for funding acquisition. A. L. conceptualized the project, designed experiments, analysed and curated the data, wrote the manuscript and was responsible for funding acquisition.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting the findings of this work has been deposited in the CORA. RDR repository,⁴⁴ https://doi.org/10.34810/data2722.

Supplementary information (SI): synthesis procedures, characterization data, titration data, computational details. See DOI: https://doi.org/10.1039/d6qo00249h.

CCDC 2527221 (8d), 2527222 (9), 2533645 ((S⁵)-12d) and 2548699 ((R⁵)-1a) contain the supplementary crystallographic data for this paper.^45a–d

Acknowledgements

We are grateful for financial support from grants TED2021-130573B-I00, PID2023-146498NB-I00, PID2023-152415NB-I00, RED2024-154A8-T, REQ2021_B_05, and fellowship PREP2023-002111 (to F. F.) funded by MICIU/AEI/10.13039/501100011033 and by the European Union NextGenerationEU/PRTR. We thank AGAUR/Generalitat de Catalunya for funding (2021SGR623 and 2021SGR00487) and the Universitat de Girona for a fellowship to A. S. B. (IFUdG 68 2022). E. P. thanks ICIQ for a predoctoral contract. We thank Dr Xavier Fontrodona (Serveis Tècnics de Recerca, Universitat de Girona) for solving X-ray diffraction structures.

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