Type II porous ionic liquids could be prepared at room temperature by dissolving up to 5 wt.% of anti-cryptophane-A derivatives functionalized with alkyl or fluorinated alkyl chains in phosphonium- and pyrrolidinium-based ionic liquids. In this study, we provide the first direct experimental evidence that these molecular cages retain their internal free volume when dissolved in ionic liquids. At 303 K and 1 bar, the porous ionic liquids prepared as solutions of anti-cryptophane-A grafted with a ten-carbon alkyl chain in the ionic liquids [] (1:36), [ (1:52) and [] (1:50) absorb 3.0, 3.5 and 11 times more methane than the pure ionic liquid, respectively. The solution of anti-cryptophane-A grafted with a fluorinated alkyl chain in [] (1:73) absorbs in turn 1.8 times more methane than the pure ionic liquid. We show that 97(2)% of the cryptophane dissolved in [] can encapsulate one molecule of methane, whereas only 60(1)% of the cavities in solid cryptophane are available for gas encapsulation. The presence of permanent porosity in the liquid solution is further supported by controlled atmosphere NMR spectroscopy that allows to distinguish between free and caged methane, thus providing molecular-level evidence that the gas is encapsulated in the free cryptophane cavities.

We report the study of the two enantiomers of the water-soluble cryptophane 1 by Synchrotron Radiation Circular Dichroism (SRCD) in DMSO, LiOH/H2O, NaOH/H2O, KOH/H2O, and CsOH/H2O solutions. Interestingly, SRCD gives access to new Cotton bands that could not be detected with a conventional CD spectrometer. Our findings reveal that the low-lying excited states detected by SRCD spectroscopy are extremely sensitive to the concentration of the basic solution. In contrast, except for the thallium cation, the nature of the cationic species has only a little impact on the overall shape of the SRCD spectra in LiOH/H2O (0.1 M) solution.

Cryptophane syn-1, a compound decorated with three acetate functions and three benzyl groups, has been isolated in very small quantities from the reaction aimed at preparing functionalized syn- and anti-cryptophanes (Brotin J. Org. Chem. 2018). This new compound has been fully characterized, and its X-ray structure is reported. Compound syn-1 shows an unusual arrangement of the substituents never encountered for cryptophane derivatives. The preparation of this product in larger quantities and subsequent reactions enabled the synthesis of the chiral syn-2 compound, which is a regioisomer of the syn-cryptophane-B derivative. The two enantiomers of syn-2 have been separated by HPLC on a chiral stationary phase and isolated in small quantities. The X-ray structure of syn-2 was reported, and its chiroptical properties were determined from polarimetry, electronic (ECD), and vibrational (VCD) circular dichroism experiments. Finally, VCD combined with theoretical calculations allowed the determination of the (-)589-MP absolute configuration for syn-2.

Since the affinity of Cryptophane-A for methane was first reported in 1993, cryptophane-doped polymer films have been extensively studied as enrichment cladding layers in plasmonic, fiber-optic, and integrated waveguide-based optical sensors. While the use of cryptophane-doped layers has improved methane sensitivity compared to undoped claddings, controversy has grown over the years regarding their claimed selectivity and practical applicability. In this work, we employ Raman spectroscopy to provide direct and unambiguous evidence that Cryptophane-A exhibits measurable affinity for three major atmospheric gases (carbon dioxide, methane, and nitrogen) at room temperature, debunking old beliefs of cryptophane-methane selectivity and reformulating the role of nitrogen. Notably, carbon dioxide shows a 1.5-times stronger affinity for Cryptophane-A than methane, while nitrogen relative affinity to methane was demonstrated to be 0.4. This study underscores the value of Raman spectroscopy as a benchmark technique for investigating gas capture within host molecules at ambient conditions. It offers deeper insight into the binding behavior of Cryptophane-A and enables quantification of its relative affinities to atmospheric gases, thereby revealing both the limitations and the potential of cryptophane for future sensing applications.

Cryptophane molecules are cage-like structures consisting in two hemispheres, each made of three benzene rings. These hemispheres are bound together with three O(CH2)nOlinkers of various lengths giving rise to a plethora of cryptophane derivatives. Moreover, they are able to encapsulate neutral guests: CH2Cl2, CHCl3, …; and charged species: Cs+, Tl+, …. Finally, they exhibit chiroptical properties thanks to the anti arrangement of the linkers between the hemispheres. This work focuses on the Raman optical activity (ROA) signatures of Cryptophane-111 (n=1 for each linker). More specifically, we aim at simulating accurately its ROA spectra with and without a xenon atom inside its cavity. Experimental data (Buffeteau et al., 2017) have already demonstrated the effect of the encapsulation in the low-wavenumbers region. To generate the initial structures, we rely on the novel Conformer-Rotamer Ensemble Sampling Tool (CREST) program, developed by S. Grimme and co-workers. This is required due to the flexibility provided by the linkers. The CREST algorithm seems promising and has already been used to sample the potential energy surface (PES) of target systems before the simulation of their vibrational spectroscopies (Eikås et al., 2022). We observe large similarities between the two sets of conformers (one with and one without Xe encapsulated), demonstrating the robustness of the CREST algorithm. For corresponding structures, the presence of xenon pushed the two hemispheres slightly further apart. After optimization at the DFT level, only one unique conformer has a Boltzmann population ratio greater than 1%, pointing out the relative rigidity of the cage. Based on this unique conformer, our simulations are in good agreement with the experimental data. Regarding xenon encapsulation, the (experimental and theoretical) ROA signatures at low wavenumbers are impacted: slight shifts in wavenumbers are observed as well as a decrease in relative ROA intensity for bands around 150 cm-1. The wavenumber shifts were very well reproduced by our simulations, but the experimental decrease in the ROA intensity was unfortunately not reproduced.

An anti-cryptophane decorated with three aromatic amine and three phenol groups shows a high affinity for the cesium and thallium cations in LiOH/H2O (0.1 M). The formation of the complexes was studied by 133Cs NMR and by 205Tl NMR spectroscopy at different temperatures. Characteristic signals for caged cesium and thallium were observed at a high field with respect to the signals of the free cations present in the bulk. Isothermal titration calorimetric experiments performed in LiOH/H2O (0.1 M) and NaOH/KCl buffer (pH = 13) allowed us to determine the parameter of complexation and to ascertain the high affinity of this cryptophane for cesium and thallium. A comparison with other cryptophanes that bind these two cations shows that the introduction of nitrogen atoms into the cryptophane backbone has an effect on the binding properties. The affinity for cesium and thallium(I) ions is in the following order of substitution: OH > NH2 > OCH2COOH. This study paves the way to the design of new efficient host molecules for the extraction of these two cations in aqueous solution.

This article reports the synthesis of the two enantiomers of a water‐soluble cryptophane 3 enabling cesium and thallium complexation at neutral or basic pH. The two enantiomers of 3 were obtained in a two steps synthesis from cryptophane 4, a molecule decorated with three phenol groups and three other phenol groups protected by benzyl units. The two enantiomers of 4 were isolated from liquid chromatography using chiral stationary phase. The absolute configuration of the two enantiomers of 3 was determined by vibrational circular dichroism combined with theoretical calculations. Contrary to cryptophane 1 that present large spectroscopic changes upon cesium and thallium complexation, the electronic circular dichroism spectra of compound 3 exhibit moderate spectral changes suggesting that this compound cannot change the conformation of its linkers as easily as cryptophane 1.

Here the monocation complexes of seven anti-cryptophanes are examined with high-resolution ion-mobility mass spectrometry. The relative size of the [cation + cryptophane]+ complexes were compared based on their measured mobilities and derived collisional cross sections. A paradoxical trend of structural contraction was observed for complexes of increasing cation size. Density functional theory confirmed encapsulation occurs for cation = Na+, K+, Rb+, Cs+ and NH4+. However, cation = Li+ preferred oxygen coordination at a linker over encapsulation within the cavity, leading to a slightly larger gas phase structure overall. Protonated cryptophanes yielded much larger collision cross sections via imploded cryptophane structures. Thus, competing physical effects led to the observed non-periodic size trend of the complexes. Trends in complexation from isothermal titration calorimetry and other condensed phase techniques were borne out by the gas phase studies. Further, predicted cavity sizes compared with the gas phase experimental findings reveal more about the encapsulation mechanisms themselves.

A tetrahedral FeII4L4 cage assembled from the coordination of triangular chiral, face-capping ligands to iron(II). This cage exists as two diastereomers in solution, which differ in the stereochemistry of their metal vertices, but share the same point chirality of the ligand. The equilibrium between these cage diastereomers was subtly perturbed by guest binding. This perturbation from equilibrium correlated with the size and shape fit of the guest within the host; insight as to the interplay between stereochemistry and fit was provided by atomistic well-tempered metadynamics simulations. The understanding thus gained as to the stereochemical impact on guest binding enabled the design of a straightforward process for the resolution of the enantiomers of a racemic guest.

Self-assembly of a flexible tritopic aniline and 3-substituted 2-formylpyridine subcomponents around iron(II) templates gave rise to a low-spin FeII 4 L4 capsule, whereas a high-spin FeII 3 L2 sandwich species formed when a sterically hindered 6-methyl-2-formylpyridine was used. The FeII 4 L4 cage adopted a new structure type with S4 symmetry, having two mer-Δ and two mer-Ʌ metal vertices, as confirmed by NMR and X-ray crystallographic analysis. The flexibility of the face-capping ligand endows the resulting FeII 4 L4 framework with conformational plasticity, enabling it to adapt structurally from S4 to T or C3 symmetry upon guest binding. The cage also displayed negative allosteric cooperativity in simultaneously binding different guests within its cavity and at the apertures between its faces.

We report the synthesis and absolute configuration (AC) of a chiral isotopologue of syn-cryptophane-B. Low chiral signatures were measured by polarimetry and electronic circular dichroism, whereas most significant chiroptical effects were observed by vibrational circular dichroism (VCD) and Raman optical activity (ROA). The comparison of experimental VCD and ROA spectra with those predicted by DFT calculations allows the determination of the AC of the two enantiomers as (-)589-MP-syn-2 and (+)589-PM-syn-2.

We report the synthesis of C3-symmetric cryptophanes decorated with three aromatic amine groups on the same CTB cap and their interaction with xenon. The relative stereochemistry of these two stereoisomers syn and anti was assessed thanks to the determination of the X-ray structure of an intermediate compound. As previously observed with the tris-aza-cryptophanes analogs anti-1 and syn-2 (J. Org. Chem. 2021, 86, 11, 7648-7658), both compounds anti-5 and syn-6 show a slow in-out exchange dynamics of xenon at 11.7 T. Our work supports the idea that the presence of nitrogen atoms grafted directly onto the cryptophane backbone has a strong impact on the in-out exchange dynamics of xenon whatever their stereochemistry. This result contrasts with the case of other cryptophanes decorated solely with methoxy substituents. Finally, we demonstrate that these new derivatives can be used to design new anti/syn cryptophanes bearing suitable ligands in order to constitute potent 129Xe NMR-based sensors. An example is reported here with the synthesis of the tris-iodo derivatives anti-13 and syn-14 from compounds anti-5 and syn-6.

A new water-soluble xenon host system with great promise for the 129Xe NMR-based biosensing approach is presented: the syn-cryptophane-222-hexacarboxylate. It compares favorably with its already known anti diastereomer, on the one hand, and with cucurbit[6]uril, on the other hand, in particular in terms of xenon binding constant and xenon in-out exchange, a key parameter for the efficiency of the most sensitive HyperCEST method.

Cryptophane cages can adopt either an anti or syn configuration that present different recognition properties. While the synthesis of anti-cryptophanes is well reported, the synthesis of syn-cryptophanes remains a challenge. Herein, we demonstrate that the use of HFIP as a co-solvent during the second ring closure reaction significantly affects the regioselectivity, providing easier access to the syn-cryptophane stereomers.

Determination of stereochemistry and enantiomeric excess in chiral natural molecules is a research of great interest because enantiomers can exhibit different biological activities. Viniferin stilbene dimers are natural molecules present in grape berries and wine but also, in larger amount, in stalks of grapevine. Four stereoisomers of viniferin stilbene dimers (7aS,8aS)-E-ε-viniferin (1a), (7aR,8aR)-E-ε-viniferin (1b), (7aS,8aR)-E-ω-viniferin (2a), and (7aR,8aS)-E-ω-viniferin (2b) were isolated from grapevine stalks of Cabernet Sauvignon, Merlot and Sauvignon Blanc, using a combination of centrifugal partition chromatography (CPC), preparative and chiral HPLC. The structure elucidation of these molecules was achieved by NMR whereas the absolute configurations of the four stereoisomers were investigated by vibrational circular dichroism spectroscopy in combination with density functional theory (DFT) calculations. This study unambiguously established the (+)-(7aS,8aS) and (+)-(7aR,8aS) configurations for E-ε-viniferin and E-ω-viniferin, respectively. Finally, we show that Cabernet Sauvignon provided the quasi enantiopure (+)-(7aS,8aS)-E-ε-viniferin compound which presents the best anti-inflammatory and anti-oxidant activities.

This review addresses the synthesis of enantiopure cryptophane and the study of their chiroptical properties. Cryptophane derivatives represent an important class of macrocyclic compounds that can bind a large range of species in solution under different conditions. The overwhelming majority of these host molecules is chiral, and their chiroptical properties have been thoroughly investigated. The first part of this review is dedicated to the optical resolution and the synthesis of enantiopure cryptophane derivatives. In a second part, the study of the chiroptical properties of these molecular hosts by different techniques such as electronic and vibrational circular dichroism and Raman optical activity is detailed. These techniques allow the determination of the absolute configuration of cryptophane derivatives and provide useful information about their conformation in different conditions.

We report the synthesis and optical resolution of C3-symmetrical tris-aza-cryptophanes anti-3 and syn-4, as well as the study of their interaction with xenon via hyperpolarized 129Xe NMR. These molecular cages are close structural analogues of the two well-known cryptophane-A (1; chiral) and cryptophane-B (2; achiral) diastereomers since these new compounds differ only by the presence of three nitrogen atoms grafted onto the same cyclotribenzylene unit. The assignment of their relative (syn vs anti) and absolute configurations was made possible, thanks to the combined use of quantum calculations at the density functional theory level and vibrational circular dichroism spectroscopy. More importantly, our results show that despite the large structural similarities with cryptophane-A (1) and -B (2), these two new compounds show a very different behavior in the presence of xenon in organic solutions. These results demonstrate that prediction of the physical properties of the xenon@cryptophane complexes, only based on structural parameters, remains extremely difficult.

A detailed examination of binding thermodynamics is undertaken for the interaction between rubidium ion and a water-soluble cryptophane molecule using isothermal titration calorimetry. The equilibrium binding quotient for this host-guest pair decreases with increasing product formation. When analyzed with a thermodynamic framework that considers water explicitly in the governing equation, the shift in equilibrium is ascribed to an unfavorable change in the free energy of solvation upon formation of the inclusion complex. A van't Hoff analysis of the binding data, as well as an observation of aggregation between inclusion complexes, suggests that charge-charge interactions between rubidium ion and the phenolate groups of the cryptophane host provide the driving force for association in water that overcomes a large and unfavorable change in solvent enthalpy.