Abstract
Chirality plays a central role in molecular recognition, and systems combining multiple, interdependent chiral elements can offer enhanced enantioselectivity. Here we show that covalent tethering of a dihydroxy-pillar[5]arene with meso-2,11-dibromododecanedioate yields diastereomeric pseudo[1]catenanes that combine three stereogenic features: two point chiral centers within the aliphatic linker, a helical chirality (P/M) induced by macrocycle closure, and a planar chirality of the pillararene ring. This system exhibits dynamic stereochemical behaviour involving in/out conformational equilibria, accompanied by inversion of the planar chirality. Using NMR spectroscopy, X-ray diffraction, DFT calculations and circular dichroism, we characterize the structures and dynamics of these macrobicyclic pillararenes, including guest-induced inclusion–exclusion processes. Hydrolysis affords a dicarboxyl-functionalized receptor capable of recognizing diamines via host-to-guest proton transfer, while enantiopure derivatives act as chiroptical sensors able to discriminate between L- and D-lysine esters. These results demonstrate how coupling multiple types of chirality can be exploited for responsive molecular recognition.
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Introduction
Mechanically Interlocked Molecules (MIMs, Fig. 1)1,2,3,4,5,6,7,8,9,10 are characterized by two or more components held together by mechanical entanglement in space. When these components are covalently linked, they form a new class of compounds known as “Mechanically Self-locked Molecules” (MSMs, Fig. 1)11. Unlike MIMs and MSMs, their so-called pseudo-analogues are not held together by mechanical bonds but share similarities, such as self-inclusion of portions within their macrocyclic cavities and analogous molecular motions8. Recent literature has extensively dealt with [1]rotaxanes and pseudo[1]rotaxanes12, while pseudo[1]catenanes have surfaced more sporadically13. The latter are macrobicyclic compounds capable of threading and dethreading one macrocyclic moiety within the other by means of an in/out conformational interconversion, a motion reminiscent of the mutual rotational of one ring within the other observed in classical [2]catenanes14. Their potential was fully realized with the advent of pillararenes15 which exhibit planar chirality due to the substitution patterns on their aromatic units. Pillar[5]arenes preferentially adopt chirality-aligned all-pS and all-pR conformations due to steric hindrance16. In 2013, Ogoshi and colleagues17 described a pillar[5]arene-based pseudo[1]catenane that utilizes the conformational mobility of pillar[5]arenes18,19,20,21,22 to invert its planar chirality. This inversion occurs upon guest inclusion with the dethreading of the ancillary ring, which consists of an alkyl chain attached to one of its aromatic units. It is important to note that symmetrically connecting an achiral chain to both rims of the same aromatic unit yields a pair of non-interconvertible pseudo[1]catenane enantiomers. Each of these pseudo[1]catenane enantiomers can adopt two different conformations with opposite planar chirality, designated as in or out, depending on whether the ancillary chain is included or excluded from the pillararene macrocycle. This pioneering study also showed that the in/out conformational preference can be modulated by the choice of solvent. Those that fit well within the macrocycle, such as CH2Cl2 and CH3CN, promote the exclusion of the alkyl chain from the cavity, while solvents with lower affinity for the cavity, e.g., CHCl3 and CH3OH, cannot displace the self-included cyclic alkyl chain. Furthermore, the in/out conformations of enantiopure pseudo[1]catenanes can be monitored using circular dichroism (CD) spectroscopy, as the interconversion between the in and out conformers results in an inversion of the sign of the CD spectrum.
Top row shows mechanically interlocked molecules: [2]rotaxane and [2]catenane, compared with mechanically self-locked molecules: [1]rotaxane and [1]catenane. Bottom row shows the corresponding pseudo-systems that are not mechanically locked: pseudo[2]rotaxane, pseudo[1]rotaxane, and pseudo[1]catenane.
Chiral control is an appealing goal, as chirality plays a crucial role in determining the functional properties of biological and artificial systems23. The first pseudo[1]catenane was primarily controlled by the affinity of pillar[5]arene cavity for various solvents or guests. Subsequent studies on a similar crown ether-strapped pseudo[1]catenane showed that, in addition to the nature of the solvent24,25, temperature26 and pressure27 also influence the prevalence of the in or out conformations.
A significant advancement was achieved by incorporating specific functionalities into the ancillary chain, such as thiacrown28 or azacrown29 loops, which allowed the second macrocycle to actively influence planar chirality inversion. For instance, in a pillar[5]thiacrown pseudo[1]catenane, equipped with two sulfur atoms acting as soft metal binding sites, the presence of Hg2+ could trigger the dethreading of the ancillary cycle by nesting within the thiacrown loop28. Conversely, in a pillar[5]azacrown pseudo[1]catenane chirality switching was induced by acid/base treatment. HCl would protonate the NH groups of the self-included azacrown moiety, leading to dethreading, whereas NaOH would deprotonate the ammonium groups, restoring the initial in conformer29. Recently, a redox-controlled pillar[5]arene pseudo[1]catenane was described, reliant on the presence of a tetrathiafulvalene unit in the ancillary chain30. This unit facilitated in/out interconversion, via a two-electron redox process. The ability to control the chirality of pillararene-based pseudo[1]catenanes has led to their use as chiroptical sensors31,32,33,34,35. Chiroptical CD detection was successfully achieved for achiral guests, such as adiponitrile17,25,36 and the di-n-pentylammonium cation17. However, to date, no examples of enantioselective recognition by pillararene-based pseudo[1]catenanes have been reported.
Over the past decade, we have actively investigated the use of ionizable macrocyclic receptors for the complexation of protonable guests via proton-transfer-mediated recognition37. By strategically incorporating carboxylic acid moieties near the cavity of macrocycles such as calix[5]arenes or pillar[5]arenes, we achieved efficient and selective recognition of linear primary amines38,39, α,ω-diaminoalkanes40,41, and biogenic polyamines42. Proton transfer from the carboxyl group of the host to the amine group of the guest produces the corresponding alkylammonium ion, which is then bound within the macrocycle cavity and stabilized by additional carboxylate-ammonium ion pairing. This approach was successfully applied to the construction of calix[5]arene-43 and pillar[5]arene-based AA/BB-type supramolecular polymers, where ditopic bis-macrocycle monomers equipped with two carboxyl moieties self-assembled in the presence of α,ω-diaminoalkanes44 or imidazole-capped ditopic guests45 resulting in overall neutral, internally ion-paired supramolecular polymers46,47,48.
It is envisioned that incorporation of carboxyl groups into a pillar[5]arene-based pseudo[1]catenane, specifically, within its ancillary cyclic moiety, could yield a system capable of efficiently recognizing diamino compounds of suitable length. By precisely positioning the carboxyl groups on the ancillary chain, proton transfer from the CO2H of the host to the NH2 groups of the guest should occur. This, combined with the natural affinity of pillar[5]arenes for diaminoalkanes49, is expected to provide additional stabilization through a double salt-bridge interaction (Fig. 2).
Schematic illustrating guest inclusion into the pseudo[1] catenane cavity and key host–guest interactions.
The addition of carboxylic groups to the ancillary chain not only generates new chiral centers but also increases the stereochemical complexity of the system. We hereby report the synthesis of diastereomeric pillar[5]arene-based pseudo[1]catenanes containing two carboxylic groups. Our investigation includes an in-depth analysis both of their stereochemistry and dynamic conformational properties, as well as their potential to act as enantioselective chiroptical sensors31,50,51 for L- and D-lysine derivatives.
Results and Discussion
The synthesis of pillar[5]arene-based pseudo[1]catenanes was accomplished by reacting octamethyl-pillar[5]arene52 3 with dimethyl meso-2,11-dibromododecanedioate43,44,53 4 in the presence of K2CO3 as the base in refluxing MeCN (Fig. 3A). Unexpectedly, this cyclization reaction yielded two different pseudo[1]catenane diesters. In addition to the anticipated diastereomer rac-HETERO-1b (8%), which retains the meso relationship between the stereocenters of the alkylating agent (i.e., diester 4), a second diastereomer, rac-HOMO-1a, was isolated as the main product (16%), wherein this stereochemical relationship was lost. The relative configuration of the stereocenters of the two isomers was initially deduced from their 1H NMR spectra in CDCl3 (Fig. 3B and Supplementary Fig. S3).
Panel A shows the synthesis of diester derivatives rac-HOMO-1a and rac-HETERO-1b, and of diacid derivatives rac-HOMO-2a, and rac-HETERO-2b. Panel B shows 1H NMR spectra of the racemic diastereomer mixtures of the diester derivatives (500 MHz, 25 °C, CDCl3). * Asterisks indicate residual solvent peaks.
The spectra for both compounds display resonances in the upfield region (from 1.7 to –1.6 ppm), indicative of the intense shielding of the alkyl chain included within the aromatic cavity of the pillararene macrocycle. Consistent with earlier reports17, the use of CDCl3 as the solvent promotes the self-inclusion of the ancillary chain, resulting in 1a and 1b adopting the in conformation, while in CD2Cl2 the pseudo[1]catenanes predominantly stay in their out conformation (Supplementary Fig. S1). Notably, the NMR spectra of the two compounds display significant differences in terms of symmetry. Pseudo[1]catenane 1a exhibits five resonances in the aromatic region, whereas 1b shows ten peaks. The different symmetry is also reflected in the resonances for the highly diagnostic CHCO2Me hydrogen atoms in 1a and 1b, one (4.94 ppm) vs two (4.88 and 4.49 ppm), respectively, indicating that the two compounds possess different molecular symmetry. Considering that the only point symmetry element available for these molecules is a twofold rotation axis, it follows that 1a is a dissymmetric molecule with the same configuration (R,R or S,S) for both stereocenters (rac-HOMO-1a), while 1b is asymmetric with different configurations (R and S) for the two stereocenters (rac-HETERO-1b).
In addition to the two stereocenters, the orientation of the ancillary ring relative to the pillararene introduces a third stereogenic element characterized by right-handed/left-handed helicity, P/M (Fig. 4). Consequently, from the non-stereoconserving reaction between pillararene 3 and meso-diester 4, a maximum of eight (2n, where n = 3) diastereomers –four pairs of enantiomers– could theoretically be generated. However, considering the equivalent positions of the two stereocenters (commutative property), the HETERO configurations are identical in pairs, reducing the number of possible diastereomers to six –three pairs of enantiomers– as detailed in Fig. 4. It is important to note that in these pseudo[1]catenanes the in/out conformational change inverts their planar chirality, however the attachment of the ancillary chain in the pillar[5]arene, with its intrinsic helicity, produces P/M enantiomeric pairs that are not interconvertible (Fig. 4).
Stick and cartoon representations illustrating the relationship between in/out conformational equilibrium and configurational chirality. The mirror plane (dashed line) depicts the enantiomeric relationship. The propeller-like arrangement between the ancillary ring (red) and the pillararene core (blue) defines a stereogenic element with right-handed (P) or left-handed (M) helicity, assigned based on the minimal rotation needed to align the top with the bottom ring when viewed along the pseudo-twofold axis through the shared arene ring toward the opposite pillararene methylene bridge. The ancillary ring is designated top or bottom depending on the alkyl chain’s proximity to the observer. In/out conformational changes invert planar chirality but not helicity. The lower part shows all possible diastereomers obtained from the reaction of pillararene 3 with meso-diester 4.
Synchrotron X-ray diffraction of single cryocooled crystals, obtained using various solvents, allowed the unambiguous determination of the relative stereochemical configurations of rac-HOMO-1a and rac-HETERO-1b in both in and out conformations (Fig. 5, Supplementary Fig. S16, S17 and Supplementary Tables S1–S3). The planar chirality of the five aromatic units is aligned in all molecules with a specific relationship between the configuration of the helical chirality and those of the stereocenters (vide infra). Furthermore, all six crystal structures obtained for these two compounds are centrosymmetric and therefore these pseudo[1]catenanes crystallize as racemic mixtures (see Supplementary Information).
Top and side views of rac-HOMO-1a and rac-HETERO-1b, in both in and out conformations. In conformations were obtained in CHCl3 (and CHCl3/n-propanol for 1a), out conformations in MeCN. Only the P enantiomer is shown for each structure. Solvent molecules omitted.
The choice of the crystallization solvents is critical because, depending on the solvent affinity for the pillararene cavity, pseudo[1]catenanes in the solid state may adopt either an in or out conformation. Single crystals of rac-HOMO-1a and rac-HETERO-1b grown from CHCl3 or a CHCl3/n-propanol mixture adopt the in conformation, with the ancillary rings self-included within the pillararene cavities, while in the presence of MeCN the pseudo[1]catenanes adopt an out conformation with the solvent as guest. Furthermore, in all structures the aromatic units of the macrocycle are very regularly arranged perpendicularly with respect to the pillararene mean plane, as defined by the methylene bridges (Supplementary Figs. S16, S17 and Supplementary Table S7), indicating that the self-included alkyl moiety perfectly fits within the cavity without causing significant distortions to the pentagonal pillar-shaped conformation of the macrocycle.
The X-ray analysis confirmed the relative configurations of the two stereocenters (HOMO/HETERO), as deduced from symmetry considerations based on 1H NMR spectra. In addition, the structures established the specific relationship between the helical chirality and the stereocenters in rac-HOMO-1a: all four X-ray structures show the presence of two enantiomeric pairs, P-(S,S)/M-(R,R) (Supplementary Fig. S16). This relationship between the stereogenic elements is also observed in the host-guest complex rac-HOMO-1a@MeCN, in which the aligned planar chirality is inverted with respect to the in conformation of the other three structures (Fig. 5). Interestingly, the other potential HOMO enantiomeric pair from the macro-bicyclization reaction, M-(S,S)/P-(R,R) was not observed (Fig. 4). Pseudo[1]catenane rac-HETERO-1b was found to exist as the racemic mixture P-(R,S)/M-(S,R) with a commutative property of the two stereocenters (Fig. 4 and Supplementary Fig. S17). It is worth noting that for a purely statistical process this secondary product should be the most abundant product (Fig. 4). As illustrated in Fig. 6, the product distribution can be rationalized in terms of formation of pseudo[1]rotaxane intermediates (see below).
Structures of pseudo[1]rotaxanes proposed as intermediates during pseudo[1]catenane formation. The combination of the eversion and self-inclusion/dethreading equilibria provides the basis to understand the product distribution.
In-depth observation of the solid-state data provides further interesting evidence regarding the tri-dimensional arrangement of the CO2Me groups with respect to the pillararene macrocycle. When the ester groups are connected to an (S) methine carbon atom connected in turn to a P pillararene (or conversely, (R) methine to an M pillararene), the carboxymethyl group is arranged in a perpendicular fashion with respect to the pentagon shape, with a trans conformation around the alkoxy-methine O–C bond, whereas when it is connected to an (R) methine (or conversely, (S) methine to an M-pillararene), the carboxymethyl group points away from the pillararene cavity, with a clinal conformation around the alkoxy-methine O–C bond (Supplementary Table S8). As a consequence, in the rac-HOMO-1a enantiomers, P-(S,S)/M-(R,R), there is a symmetrical arrangement of the CO2Me groups (hence the higher symmetry seen in the 1H NMR spectrum), whereas in the rac-HETERO-1b enantiomers, P-(R,S)/M-(S,R), the two ester groups adopt a less symmetrical arrangement (Fig. 5), in agreement with the higher number of resonances seen in the NMR spectrum.
The observed loss of stereoconservation for one of the two stereocenters in the main product, rac-HOMO-1a (along with its relatively high yield), can be explained by the formation of a pseudo[1]rotaxane as an intermediate during cyclization. Liu and coworkers54 explained the high-yielding formation of similar pseudo[1]catenanes (without chiral centers) by invoking the self-inclusion of alkyl chains of optimal length during the ring closure reaction of the pseudo[1]rotaxane intermediate. A similar mechanism may apply in this case, potentially influencing the observed chirality of the stereocenters. The meso-2,11-dibromododecanedioate reactant 4, whose stereochemistry was confirmed by X-ray analysis (Supplementary Fig. S20 and Supplementary Table S6), has previously been used in our laboratories for the synthesis of bis-calix[5]arenes43 and bis-pillar[5]arenes44, consistently yielding meso-bis-macrocycles. A classical SN2 mechanism at both sites should lead to net stereoconservation of relative chirality. However, only a single inversion was observed for the main product of the reaction, rac-HOMO-1a, suggesting that the SN2 mechanism alone cannot fully account for the stereochemistry of this product. The formation of the intermediate with just one covalent bond of the alkyl chain through an SN2 mechanism would produce a racemic mixture of two enantiomeric pairs with homo-chirality (R,R and S,S). At this stage, the helical chirality due to the closure of the ancillary ring is not yet present. However, the planar chirality of the macroring is freely interconvertible by eversion, allowing the alkyl chain to adopt either in or out conformations through direct threading/dethreading or two consecutives eversion events (Fig. 6). This results in a complex equilibrium of conformers, including both enantiomeric pseudo[1]rotaxanes (R,R/S,S) with aligned planar chirality (in-pR/in-pS) (Fig. 6).
Investigating the relative stability of the two conformers in-pR-(R,R) and in-pS-(R,R) (and the energetically equivalent enantiomeric couple in-pS-(S,S) and in-pR-(S,S)) optimized by semiempirical calculations (SEcalc, Supplementary Fig. S21, details are available in the Supplementary Information) indicates that in-pS-(R,R) is more stable than in-pR-(R,R) by about 5 kcal/mol. This suggests that the conformational equilibrium favors in-pS-(R,R) (and in-pR-(S,S). Furthermore, the minimized structures indicate a shorter distance of about 1.0 Å between the nucleophilic hydroxyl group and the chiral center in in-pS-(R,R) compared to in-pR-(R,R), with the bromine leaving group in a less sterically crowded environment (Supplementary Fig. S21). Taken together, these considerations strongly suggest that the reactive pseudo[1]rotaxane conformers are the enantiomeric couple in-pS-(R,R)/in-pR-(S,S). Thus, the formation of the final ArO···CHCO2Me bond, occurring on the rims of the asymmetric pR and pS cavities, with restricted conformational freedom of the alkyl chain, should involve a mechanism that results in both retention and inversion of the chiral center. In this regard, further computational analyses were performed to evaluate the energy of the transition states involved in the final ring-closure step, starting from the most stable pseudo[1]rotaxane intermediates pS-(R,R)/pR-(S,S). Two transition states (TS) for a monomolecular (SN1-like) ring closure were modelled and optimized (again using the SEcalc approach), one leading to the P-(S,S) pseudo[1]catenane (TSS,SSN1), the other to the P-(S,R) configuration (TSS,RSN1, Supplementary Fig. S22). The results show that TSS,SSN1 is favored over TSS,RSN1 by 4.4 kcal/mol. Simulations of the transition state of the SN2 mechanism failed, due to the absence of pseudo[1]rotaxane conformations in which the ArO and the CHBr are in close proximity.
Additional calculations were carried out on the three possible pseudo[1]catenane 1 diastereomers, namely P-(S,S), P-(S,R) and P-(R,R), all in their in conformation. Their geometries were initially optimized using semiempirical calculations and subsequently refined at the DFT level of theory in vacuum (DFTcalc, Supplementary Fig. S23). The results align with the experimental data, showing greater stability of the P-(S,S) isomer with respect to the other two (–2.3 kcal/mol vs P-(S,R) and –9.9 kcal/mol vs P-(R,R)).
Pseudo[1]catenane diester rac-HOMO-1a and rac-HETERO-1b were hydrolyzed to their corresponding diacids using LiOH in THF/H2O, providing rac-HOMO-2a and rac-HETERO-2b in 72% and 65% yields, respectively. 1H NMR spectra recorded in CD2Cl2 and CDCl3 show that rac-HOMO-2a (Fig. 7A) exhibits the solvent-responsive behavior displayed by the parent diester. CD2Cl2 fits perfectly into the cavity of pillar[5]arenes and, as a consequence, forces rac-HOMO-2a to adopt the out conformation, as shown by the disappearance of the resonances for the included CH2 groups in trace 7a. Conversely, the spectrum in CDCl3 (trace 7b, Supplementary Fig. S4 and S6) shows, in addition to traces of out conformer, the coexistence of two different (diastereomeric) in conformers (as a result of a different arrangement of hydrogen bonds, as indicated by the presence of two sets of resonances for the included methylene groups, marked A and B in trace 7b). The addition of CD3OD (CDCl3/CD3OD 10:1 v/v, trace 7c) results in the merging of the two conformers into a single in conformer, disrupting intramolecular hydrogen bonding55.
A 1H NMR spectra (500 MHz, 25 °C) of rac-HOMO-2a in a) CD2Cl2, b) CDCl3, and c) CDCl3/CD3OD 10:1 v/v. * Asterisks indicate residual solvent peaks. The in/out equilibrium shows the P enantiomer. B Solid-state structures of the in- (left) and out- (right) conformers of diacid rac-HOMO-2a (single enantiomer shown).
A 2D TOCSY and a 2D COSY spectrum showed that, in this solvent mixture, approximately 50% of rac-HOMO-2a adopts an out conformation (Fig. S5 and S7). Two distinct spin systems can be traced, corresponding to alkyl chains that reside within or outside the pillararene cavity, allowing the resonances at 4.83 and 4.72 ppm to be assigned to the CHCO2H methine of in-rac-HOMO-2a and out-rac-HOMO-2a, respectively. A similar conformational solvent-dependent conformational behavior is observed for rac-HETERO-2b, although it lacks the diastereomeric in conformers in neat CDCl3 (Supplementary Fig. S2 and S8–S10).
The solid-state structure of in-rac-HOMO-2a and out-rac-HOMO-2a conformers provided further insight in the structural features of these pseudo[1]catenanes. A CHCl3/toluene mixture allowed rac-HOMO-2a to crystallize as a racemic mixture in the in conformation, whereas CH2Cl2 provided centrosymmetric crystals of rac-HOMO-2a in the out conformation, with the cavity filled by a CH2Cl2 guest molecule (Fig. 7B). Similar to the diester, the two CO2H groups show analogous alignment, maintaining trans conformations around the alkoxy-methine O–C bonds. Both solid state structures confirm the above-discussed specific relationship between the stereogenic elements and show that neither ester hydrolysis nor in/out placement of the alkyl chain affects the regular pentagonal conformation of the pillararene macrocycle (Fig. 7B, Supplementary Fig. S18a,b and Supplementary Table S4).
The host-guest properties of diacid rac-HOMO-2a were preliminarily tested with 1,6-diaminohexane (NC6N), a molecule recognized by pillar[5]arenes and possessing ionizable groups ideally positioned for probing host-to-guest proton transfer (host-to-guest proton transfer is favoured by the presence of protic solvents, typically 3–10% v/v37,38,39,40,41,42,43,44,45). Upon addition of an equimolar amount of NC6N to a solution of rac-HOMO-2a (5 mM, CDCl3/CD3OD 10:1 v/v), the 1H NMR spectra of the two compounds underwent significant changes (Fig. 8A). The high-field peaks belonging to the included methylene groups of rac-HOMO-2a disappeared (along with the peaks for free NC6N visible in trace c), while two new broad resonances appeared at –0.41 and –1.37 ppm. In addition, the two resonances assigned to the CHCO2H methine of in- and out-rac-HOMO-2a underwent a complexation-induced shift (CIS) towards higher fields, merging into a single peak at 4.51 ppm. A 2D TOCSY spectrum (Fig. 8B) confirmed that NC6N fully displaces the included alkyl chain, nesting inside the cavity of the pillar[5]arene. In Fig. 8A, trace b, two distinct spin systems can be traced, one for an alkyl chain positioned outside the cavity (with cross-peaks for the methylene groups resonating in the 0.6–2.2 ppm interval) and another for the three resonances of the included NC6N molecule (–1.33, –0.41 and 1.64 ppm, respectively). In the case of rac-HETERO-2b, its efficiency to recognize NC6N was found to be lower, likely due to the less favorable orientation of the CO2H moieties on the pillararene rims, which may impede optimal interactions with NC6N (Supplementary Fig. S11–S13).
A 1H NMR spectra (500 MHz, 25 °C, CDCl3/CD3OD 10:1 v/v) of a) [rac-HOMO-2a] = 5 mM, b) [rac-HOMO-2a] = 5 mM with [NC6N] = 5 mM, c) [NC6N] = 10 mM. B Section of the 2D TOCSY spectrum of [rac-HOMO-2a] = 5 mM with [NC6N] = 5 mM. * Asterisks indicate residual solvent peaks. A single enantiomer is shown in the scheme of the complex. C Top-view and side-view stick models and side-view space fill model of the solid-state structure of out-rac-HOMO-2a ⊃ NC6N complex (single enantiomer). In the space-fill model, the host is represented by the color brown and the guest and solvent molecules are represented by the color cyan.
NMR did not provide sufficient evidence on the proton transfer from the CO2H groups of the host to the NH2 groups of the guest, even though the upfield CIS experienced upon complexation by the methine hydrogen atom resonance suggests, in line with previous observations44,45, that proton transfer may have occurred (facilitated by the protic solvent, CD3OD). The solid-state structure of the out-rac-HOMO-2a⊃NC6N complex confirmed the structural features deduced from the NMR data and provided further insight (Fig. 8C). Single crystals obtained from CHCl3/CH3OH show that NC6N is held within the cavity. The ammonium groups are both involved in three H-bonds: one with a carboxylate group of the macrocycle host, one with a carboxylate group of an adjacent pillararene, and the third with a methoxy group of the macrocycle host for one N-terminal, or with a cocrystallized water molecule for the other N-terminal (Supplementary Fig. S18c and Supplementary Table S7, S8). Thus, in addition to a series of CH···π interactions inside the cavity, guest complexation involves salt bridges between the COO– of the hosts and the NH3+ groups of the guest, indicating that proton transfer indeed takes place. The alkyl chain of the guest adopts a conformation to maximizes the salt bridge interaction between the ammonium cations and the carboxylate anions. In particular, it exhibits an extended zigzag conformation (trans conformation) for five out of six carbon atoms, the exception being a single torsion angle of 78° (gauche conformation). This conformation allows for the formation of H-bonds at both terminal ammonium groups with its host (Fig. 8C and S18c). Accordingly, the carboxylate groups lean toward the ammonium groups, abandoning the trans arrangement they displayed in the solid-state structure of the parent out-rac-HOMO-2a diacid hosting the CH2Cl2 molecule (Fig. 7B), adopting clinal conformations around the alkoxy-methine O–C bonds. Consequently, the oxygen atoms involved in the salt bridge with the guest are positioned inside the pillararene cavity with distances of 0.85 and 0.51 Å from the plane of their aromatic ring (Fig. 8C). In contrast, these atoms were outside the cavity of the parent out-rac-HOMO-2a hosting the CH2Cl2 molecule (Fig. 7B).
Optical resolution of all racemates (i.e., diesters rac-HOMO-1a and rac-HETERO-1b, and diacids rac-HOMO-2a and rac-HETERO-2b) was successfully achieved by enantioselective HPLC on amylose-based chiral stationary phaes (CSPs). In each case, two peaks of equal area were observed (Fig. S24 and S25), and the CD spectra of the fractions collected from each separation appeared as mirror images, confirming the isolation of enantiopure compounds. Notably, the enantiomers of rac-HOMO-2a were separated in their in conformation, as demonstrated by comparing the sign of the CD peaks recorded at 306 nm during the HPLC enantioseparation (n-hexane/ethyl acetate/TFA 75:25:0.1), which matched the CD signal obtained in CHCl3 at the same wavelength (Fig. 9). In fact, the first eluting enantiomer exhibited a negative CD band in the HPLC solvent mixture, which was still negative when recorded in CHCl3 (i.e., in the in conformation, Supplementary Figs. S24 and S25). Single crystals of the enantiopure compounds were obtained from various solvents (Supplementary Table S1). Using 1,2-dichlorobenzene as the solvent, the sample collected as the first fraction crystallized in an orthorhombic lattice with a unit cell belonging to the Sohncke space group P2₁2₁2₁. The contribution of anomalous scattering from chlorine atoms, introduced through co-crystallization in 1,2-dichlorobenzene, was crucial for determining the absolute configuration of this crystal (Supplementary Fig. S19 and Supplementary Table S5). Consequently, diffraction data collected at Elettra synchrotron using cryocooling techniques allowed for the unambiguous assignment of the chirality of the first fraction as P-(S,S). This assignment was further supported by another crystal structure of the first fraction, P-(S,S) in n-PrOH, and one of the second fraction, M-(R,R) in CH3CN (Fig. S19). The two CD spectra of each enantiopure P-(S,S) or M-(R,R) compound in CHCl3 (in conformers) and CH2Cl2 (out conformers) provided conclusive evidence on the chiroptical effect resulting from pR/pS conformational inversion. In both cases, this produced an inversion of the sign of the band in the 300–325 nm region of the CD spectra (Fig. 9 and Supplementary Figs. S25 and S26).
CD spectra of P-(S,S)-2a (red) and M-(R,R)-2a (blue) in CHCl3, showing in-pR and in-pS conformations (left), and corresponding out conformers in CH2Cl2, out-pS and out-pR, respectively (right).
The efficiency of enantiopure 2a as a chiroptical sensor was finally tested with a CD titration in CHCl3/CH3OH 97:3 v/v, using 1,6-diaminohexane (NC6N) as the guest. As shown in Fig. 10a, in this solvent mixture, M-(R,R)-2a adopts the in conformation. The addition of increasing aliquots of NC6N results in the inversion of the sign of the band at λ = 309 nm, demonstrating that the achiral guest, upon recognition, induces the planar chiral inversion from in-pS to out-pR. This experimental data returned a binding constant for the M-(R,R)-2a⊃NC6N complex of 1.36 ± 0.03 × 105 M–1 56,57. Interestingly, the presence of the ancillary chain did not significantly hinder the complexation ability of 2a: a structurally similar dicarboxyl pillar[5]arene was found to bind NC6N with a Ka = 3.13 ± 0.21 × 105 M–1 58.
a CD titration of [M-(R,R)-2a] = 0.1 mM with NC6N in CHCl3/CH3OH 97:3 v/v. b The binding isotherm for M-(R,R)-2a ⊃ NC6N formation. c CD titration with L-LysOEt (in-pS conformation). d Compares binding isotherms for M-(R,R)-2a ⊃ L-LysOEt and M-(R,R)-2a ⊃ D-LysOEt out-pR complexes.
To assess whether enantiopure HOMO-2a pseudo[1]catenanes would be able to perform enantioselective recognition, L-lysine ethyl ester (L-LysOEt) was selected as a model guest for proof of concept59. Given that lysine is known to be recognized by pillar[5]arene, and it has even been shown to be able to transfer chirality to the pillararene macroring60,61, preliminary complex formation between rac-HOMO-2a and L-LysOEt complex formation was assessed by 1H NMR in a CDCl3/CD3OD (10:1 v/v) solvent mixture (Supplementary Fig. S14). The complexation was found to be on a fast exchange regime on the NMR timescale. Addition of up to 10 equiv. of L-LysOEt led to the progressive upfield shift of the resonances belonging to the CHCO2H hydrogen atoms, consistent with previous observations on proton-transfer-mediated recognition of amines43,44 (Supplementary Fig. S15).
Definitive evidence on the enantioselective binding abilities of HOMO-2a was obtained by titrating in-pS-M-(R,R)-2a with L- and D-LysOEt esters (Fig. 10c and Supplementary Fig. S27). In this case, the positively-signed band at 309 nm underwent a complete inversion upon addition of each guest. Data fitting56,57 showed that in-pS-M-(R,R)-2a preferentially recognizes L-LysOEt (KL = 6.78 ± 0.06 × 103 M–1) over D-LysOEt (KD = 1.94 ± 0.03 × 103 M–1), yielding an enantioselectivity ratio (KL/KD) of 3.5 (Fig. 10b)62. Remarkably, the preference of out-pR-M-(R,R)-2a for L-LysOEt aligns perfectly with previously reported data on chiral induction in free-rotating pillar[5]arenes, where the formation of L/pR and D/pS pairs is favored35,60.
Conclusions
We have shown that the synthesis of a dicarboxyl pseudo[1]catenane from a planar-chiral pillar[5]arene and a meso-dibromodiester yields a mixture of diastereomeric derivatives, comprising two pairs of enantiomers (rac-HOMO and rac-HETERO). Unexpectedly, the predominant product is rac-HOMO, in which the meso relationship between the chiral centers of the starting meso-dibromodiester was lost. Interestingly, only one HOMO enantiomeric pair, P-(S,S)/M-(R,R), was isolated from the macro-bicyclization reaction, while the other stereoisomeric pair M-(S,S)/P-(R,R) was not detected.
The product distribution has been rationalized in terms of formation of a pseudo-rotaxane intermediate, featuring an intriguing stereochemical relationship between conformational and configurational chirality, established upon ring closure. Each pseudo[1]catenane enantiomer can adopt two distinct conformations, differing in the position of the ancillary alkyl ring, either being self-included or external to the cavity. This in/out interconversion leads to the inversion of the aligned planar chirality of the pillararene macroring without altering the P/M absolute helicity. The switching of planar chirality is influenced by the solvent, and it can also be triggered by proton-transfer-mediated recognition of diamines, as demonstrated by CD titration and X-ray structural analysis. Furthermore, the racemic mixtures were resolved by chromatography on chiral stationary phase and the absolute configurations were assigned by X-ray diffraction. The enantiopure HOMO-derivative was able to discriminate between L- and D-lysine ethyl esters with an enantioselectivity ratio of 3.5 becoming, to the best of our knowledge, the first pseudo[1]catenane to achieve enantioselective chiroptical recognition.
Methods
General experimental
Octamethyl-pillar[5]arene52 3 with dimethyl meso-2,11-dibromododecanedioate53 4 were synthesized according to literature procedures. 1H NMR spectra (500 MHz) were recorded at 25 °C either in CD2Cl2, CDCl3 or CDCl3/CD3OD, 10:1, v/v. Chemical shifts are reported in ppm and are referenced to the residual solvent peaks (CD2Cl2, δ = 5.32 ppm; CDCl3, δ = 7.26 ppm). 13C NMR spectra were recorded at 25 °C in CD2Cl2 or CDCl3, at 125 MHz. Chemical shifts are reported in ppm and are referenced to the residual solvent peaks (CD2Cl2, δ = 53.5; CDCl3, δ = 77.0 ppm). Where present, 1H NMR peak assignments follow from DQ-COSY experiments. Anhydrous solvents were either obtained commercially or dried by standard methods prior to use, while other chemicals were reagent grade, routinely used without any further purification. Column chromatography was performed on silica gel (Merck, 230–400 mesh).
Synthetic procedures
Pillar[5]arene pseudo[1]catenane dimethyl ester 1
To a solution of octamethyl-pillar[5]arene 3 (450 mg, 0.61 mmol) in anhydrous MeCN (100 mL), dimethyl meso-2,11-dibromododecandioate 4 (385 mg, 0.93 mmol) and K2CO3 (251 mg, 1.5 mmol) were added, and the resulting mixture was heated to reflux for 48 hours under an inert atmosphere. After cooling, the solvent was removed under reduced pressure, and the residue obtained was dissolved in CH2Cl2 (50 mL). The organic solution was washed with brine (2 × 50 mL), dried (MgSO4), and then the solvent was removed under reduced pressure. The crude product was then purified by column chromatography (n-hexane/ethyl acetate 5:1 v/v) yielding the pillar[5]arene pseudo[1]catenane diastereomers rac-HOMO-1a (47 mg, 16%) and rac-HETERO-1b (24 mg, 8%).
rac-HOMO-1a: Mp: 200–203 °C (from MeOH). 1H NMR (500 MHz, CDCl3): δ 7.07, 7.03, 6.86, 6.85, 6.84 (5×s, 2 H each, ArH), 4.96 to 4.93 (dd, 2 H, OCH), 3.87 to 3.69 (m, 10 H, ArCH2Ar), 3.84, 3.82, 3.75, 3.74, 3.71 (5×s, 30 H, OCH3), 1.76 to 1.71(m, 2 H, CHCH2), 1.30 to 1.23 (m, 2 H, CHCH2), 0.09 (q, J = 7.3 Hz, 4 H, CHCH2CH2), –0.64 to –0.68 (m, CH(CH2)2CH2, 4 H), –1.43 to –1.58 (m, CH(CH2)3CH2, 4 H). 13C NMR (500 MHz, CDCl3) δ 172.3, 150.67, 150.54, 150.124, 149.9, 147.46, 129.1, 128.6, 127.91, 127.73, 126.6, 116.7, 115.9, 113.4, 112.90, 112.82, 75.9, 60.4, 55.81, 55.33, 55.24, 55.14, 52.1, 30.5, 29.98, 29.07, 28.5, 26.4, 24.7, 22.1, 21.0 ppm. ESI-MS of 1a: m/z calcd for C57H68O14 ([M+Na]+): 999.45, found: 999.42. Anal. Calcd for C57H68O14: C, 70.06; H, 7.01. Found: C, 69.89; H, 6.92.
rac-HETERO-1b: Mp: 183–186 °C (from MeOH). 1H NMR (500 MHz, CDCl3) δ 7.04, 6.93, 6.88, 6.86, 6.84, 6.83, 6.79, 6.73 (8×s, 10 H, ArH), 4.89 (m, 1 H, OCH), 4.50 to 4.47 (dd, 1 H, OCH), 3.87, 3.82, 3.81, 3.73, 3.72, 3.71, 3.66 (7×s, ratio 1:2:1:2:1:2:1, OCH3, 30 H), 3.84 to 3.79 (m, ArCH2Ar, 5 H), 3.76 to 3.71 (m, ArCH2Ar, 5 H), 1.90 to –1.70 (7×m, CH2, 16 H) ppm.13C NMR (500 MHz, CDCl3) δ 173.1, 172.1, 150.8, 150.7, 150.6, 150.5, 150.3, 150.2, 150.1, 149.9, 129.2, 128.8, 128.5, 128.3, 128.1, 127.9, 126.9, 126.6, 116.1, 115.9, 114.9, 113.4 (×2), 113.3, 113.0, 112.7, 78.5, 75.7, 55.9, 55.7, 55.6, 55.3, 55.2, 55.1, 52.3, 52.0, 30.7, 30.2, 29.8, 28.9, 28.7, 26.6, 26.5, 21.9 ppm. ESI-MS of 1b: m/z calcd for C57H68O14 ([M+Na]+): 999.45, found: 999.25. Anal. Calcd for C57H68O14: C, 70.06; H, 7.01. Found: C, 69.93; H, 6.95.
Pillar[5]arene pseudo[1]catenane diacid 2
This procedure was carried out separately for both diastereomers 1a and 1b. To a solution of 1 (1a 20 mg, 0.02 mmol; 1b 20 mg, 0.02 mmol) in THF (10 mL), aqueous LiOH (2 M, 2 mL) was added, and the reaction was carried out at 50 °C for 72 hours. The mixture was acidified with HCl (1 M, 2 × 7 mL), and the solvents were removed under reduced pressure. The residue was taken up in water (5 mL), and the resulting suspension was extracted with CH2Cl2 (2 × 7 mL), then dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The obtained solid was triturated with MeOH and CH2Cl2 and filtered. The reactions yielded 13 mg of rac-HOMO-2a and 12 mg of rac-HETERO-2b in 72% and 65% yield, respectively.
rac-HOMO-2a: Mp: 187–191 °C (from MeOH). 1H NMR (CD2Cl2, 500 MHz): δ 6.96, 6.89, 6.88, 6.86, 6.60 (5×s, 2 H each, ArH), 4.98 (t, J = 4.9 Hz, OCH, 2 H), 3.77 to 3.72 (m, ArCH2Ar, 6 H), 3.77, 3.76, 3.74, 3.73 (4×s, OCH3, 24 H)), 4.29, 3.38 (AX, J = 13 Hz, ArCH2Ar, 4 H), 2.13 to 2.07 (m, CHCH2, 2 H), 1.92 to 1.87 (m, CHCH2, 2 H), 1.34 to 1.18 (m, CHCH2CH2, 4 H), 1.12 to 1.02 (m, CH(CH2)2CH2, 4 H), 0.74 to 0.66 (m, CH(CH2)3CH2, 4 H) ppm. 13C NMR (500 MHz, CD2Cl2): δ 172.4, 151.8, 151.1, 150.8, 150.3, 147.9, 132.0, 129.6, 128.9, 128.0, 127.2, 119.4, 116.1, 114.1, 113.7, 113.1, 77.6, 57.7, 56.0, 3.3, 30.2 ( ×2), 29.9 ( ×2), 27.8, 27.6, 22.5 ppm ESI-MS of 2a: m/z calcd for C57H68O14 ([M+Na]+): 971.42, found: 971.33. Anal. Calcd for C57H68O14: C, 69.60; H, 6.80. Found: C, 69.47; H, 6.72.
rac-HETERO-2b: Mp: 163–167 °C (from MeOH). 1H NMR (CD2Cl2, 500 MHz): d 7.05, 6.98, 6.92, 6.89, 6.87, 6.85, 6.83, 6.78, 6.69, 6.56 (10×s, ArH, 1 H), 4.92 (t, J = 4.5 Hz, OCH, 1 H), 4.48 (t, J = 6.0 Hz, OCH, 1 H), 4.20 to 3.42 (m, ArCH2Ar, 10 H), 3.79, 3.78, 3.75, 3.73, 3.70, 3.66, 3.65 (7×s, ratio 1:1:2:1:1:1:1, OCH3, 24 H), 2.45 to 0.21 (m, CH2, 16 H) ppm. 13C NMR (500 MHz, CD2Cl2): δ 172.6, 172.3, 152.2, 151.4, 151.2, 150.9, 150.8 ( ×2), 150.0 ( ×2), 148.2, 132.0, 130.2, 129.4, 128.9 ( ×2), 128.5, 127.8, 127.0, 126.9, 126.3, 119.0, 116.7, 114.6, 114.3, 113.9, 113.7 ( ×2), 113.6, 113.1, 80.4, 77.3, 58.1, 56.4, 56.3, 56.0 ( ×2), 55.8, 30.9, 30.4, 29.9, 29.7, 29.2, 27.5, 27.2, 27.0, 25.3, 21.1 ppm. ESI-MS of 2b: m/z calcd for C57H68O14 ([M+Na]+): 971.42, found: 971.50. Anal. Calcd for C57H68O14: C, 69.60; H, 6.80. Found: C, 69.44; H, 6.71.
L- and D-lysine ethyl ester (LysOEt)
To a suspension of L- or D-lysine ethyl ester dihydrochloride (500 mg, 2.0 mmol) in CHCl3 (10 mL), NaHCO3 (424 mg, 5.0 mmol) was added. The suspension was stirred for 10 minutes at room temperature, after which 1 mL of H2O was added and stirring continued for an additional 3 hours. The suspension was filtered, and the filtrate was evaporated under reduced pressure, yielding lysine ethyl ester as a thick oil (353 mg, 97%). 1H NMR (500 MHz, D2O) δ 3.72 (t, J = 6.13 Hz, 1 H), 2.96–3.02 (m, 2 H), 1.82–1.92 (m, 2 H), 1.69 (quin, J = 7.64 Hz, 2 H), 1.34–1.53 (m, 2 H)63.
Computational studies
All calculations related to conformational searches and the structural optimization of both ground and transition states were performed using the software package SPARTAN 10 v.1.1.0 (Wave function Inc., 18401 Von Karman Avenue, Suite 370, Irvine, CA 92612, USA). The structural analysis of pseudo[1]rotaxanes pS-(R,R) and pR-(S,S) was carried out through a conformational search using molecular mechanics calculations (force field: MMFF94), according to the Monte Carlo algorithm implemented in SPARTAN. The conditions for this analysis included: (a) variation of all the rotable bonds; (b) a maximum energy gap of 40 kJ/mol from the lowest energy geometry for retained conformations; and (c) an R2 value of ≥ 0.9 was adopted as the criterion to identify duplicate conformers during the similarity assessment. All conformations obtained within an energy window of 3 kcal were subsequently optimized using semiempirical calculations performed with the PM6 Hamiltonian. This provided the two structures reported in Figure S22. Starting from the pR-(S,S) pseudo[1]rotaxane structure the geometries of the two transition states TSS,SSN1 and TSS,RSN1 were modelled at the semiempirical PM6 level of theory. These were validated by the presence of a single imaginary frequency found at i389 cm–1 for TSS,SSN1 and i243 cm–1 for TSS,RSN1. The geometries of pseudo[1]catenane diastereoisomers in-P-(S,S), in-P-(S,R) and in-P-(R,R) were obtained through a three-step process: a) conformational search viamolecular mechanics calculations (MMFF94 force field), as previously described for pseudo[1]rotaxanes pS-(R,R) and pR-(S,S); b) optimization of the conformations within an energy window of 3 kcal using the semiempirical PM6 method; c) further optimization at the higher DFT M06/6-31 G* level of theory (a meta-hybrid GGA DFT functional) in vacuum for the most stable structures identified in the previous step (structures reported in Figure S24).
HPLC separation
The HPLC separation of the enantiomers and diastereomers investigated in this study was performed using an apparatus consisting of a Perkin-Elmer pump (LC 2000 series) (Norwalk, CT, USA), a Rheodyne injector (Cotati, CA, USA), a 100 μL sample loop, a Jasco CD 2095 Plus UV/CD detector (Tokyo, Japan), and a Perkin-Elmer LC 101 HPLC thermostat (Sunnyvale, CA, USA). The columns used in this study were Chiralpak IG-3 (250 mm × 4.6 mm, 3.0 μm) and Chiralpak IA (250 mm × 4.6 mm, 5 μm) from Chiral Technologies Europe (Illkirch-Graffenstaden, France). Mobile phase: n-hexane-ethyl acetate-TFA 75:25:0.1; column temperature, 40 °C; flow rate, 1.0 mL min–1. HPLC-grade solvents were purchased from Sigma-Aldrich (Milan, Italy). Fresh standard solutions for HPLC analysis were prepared by dissolving the analytes in ethyl acetate at a concentration of approximately 1.0 mg mL–1. Injection volumes were 20–50 μL. Solvents and samples were filtered through 0.22 μm filters. Circular dichroism (CD) spectra were recorded on a Jasco J-720 spectropolarimeter equipped with a JASCO PTC-423S/15 Peltier temperature controller. Spectra were averaged over four instrumental scans and intensities are expressed as ellipticity values (mdeg).
X-ray crystallography
Crystals suitable for single crystal X-Ray diffraction (SCXRD) were obtained by slow evaporation of solutions containing pseudocatenane molecules in various solvents. In selected cases, prospective guest molecules were also included in the solution. Crystallisation conditions are summarised in Table S1. SCRXD data for the pseudocatenane molecules were collected with a monochromatic wavelength of 0.7000 Å at the XRD1 beamline of the Elettra synchrotron, Trieste (Italy), employing the rotating-crystal method and a Dectris Pilatus 2 M area detector. Measurements were performed at 100(2) K using a nitrogen stream cryo-cooler, with paratone as a cryo-protectant. Diffraction data were indexed, integrated and scaled using the XDS package64,65. In the case of meso-2,11-dibromododecandioate 4, data collection was performed at ambient temperature with a Mo K/α wavelength of 0.71073 Å on a Stoe Stadi-IV equipped with a Sapphire I CCD detector, employing the rotating-crystal method. Diffraction data were indexed, integrated and scaled using the CrysAlis RED software. All structures were solved using the SHELXT package66 and structure refinement was performed by the full-matrix least-squares (FMLS) method with SHELXL-19/365 operating through ShelXle Qt GU67 or the WinGX GUI68,69. Hydrogen atoms were included at calculated positions and refined using a riding model. Crystallographic data are reported in Tables S2–S6. Full refinement details are given in the supporting information, pages S25–S28.
1H NMR titrations
1H NMR titration studies on rac-2 with NC6N or L-LysOEt were carried out at a fixed concentration of 2 (5 mM in CDCl3/CD3OD 10:1 v/v). This solution was titrated with a solution of guest (25 mM) prepared in the same [2] = 5 mM solution in CDCl3/CD3OD 10:1 v/v, so that, during the titration, the concentration of 2 did not vary upon addition of increasing aliquots of the guest.
CD titrations
CD titrations experiments involving pseudo[1]catenane M-(R,R)-2a and 1,6-diaminohexane (NC6N), as well as the D- and L-enantiomers of lysine ethyl ester (D- and L-LysOEt), were performed in CHCl3/CH3OH 97:3 v/v. In all experiments, the concentration of M-(R,R)-2a was fixed at 105 µM. Guest solutions were prepared by adding M-(R,R)-2a at the same concentration, ensuring that the host concentration remained constant throughout the titration process as increasing aliquots of the guest were added. All stocks solutions were thermostated and added at the same temperature as the sample holder (298 K). CD spectra were acquired using a quartz cuvette with an optical path length of 0.5 cm.
Data availability
All data generated or analyzed during this study are included in this article (and its Supplementary Information files). The X-ray crystallographic coordinates for structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number CCDC 2445087 for rac-HOMO-1a-CHCl3 [Supplementary Data 1], CCDC 2445088 for rac-HOMO-1a-nPrOH-CHCl3 [Supplementary Data 2], CCDC 2445089 for rac-HOMO-1a-CHCl3-bis [Supplementary Data 3], CCDC 2445090 for rac-HOMO-1a@CH3CN [Supplementary Data 4], CCDC 2445091 for rac-HETERO-1b-CHCl3 [Supplementary Data 5], CCDC 2445092 for rac-HETERO-1b@CH3CN [Supplementary Data 6], CCDC 2445093 for rac-HOMO-2a-Tol-CHCl3 [Supplementary Data 7], CCDC 2445094 for rac-HOMO-2a ⊃ NH2(CH2)6NH2 [Supplementary Data 8], CCDC 2445095 for rac-HOMO-2a@CH2Cl2 [Supplementary Data 9], CCDC 2445096 for P-HOMO-2a@nPrOH [Supplementary Data 10], CCDC 2445097 for P-HOMO-2a-DCB [Supplementary Data 11], CCDC 2445098 for M-HOMO-2a@CH3CN [Supplementary Data 12], CCDC 2445099 for meso-2,11-dibromododecandioate [Supplementary Data 13]. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. The Cartesian coordinates of optimized computational structures are provided for pS-(R,R) pseudo[1]rotaxane [Supplementary Data 14], for pR-(S,S) pseudo[1]rotaxane [Supplementary Data 15], for TSS,SSN1 transition state [Supplementary Data 16], for TSS,RSN1 transition state [Supplementary Data 17], for in-P-(S,S)-1a pseudo[1]catenane [Supplementary Data 18], for in-P-(S,R)-1b pseudo[1]catenane [Supplementary Data 19], for in-P-(R,R) pseudo[1]catenane [Supplementary Data 20].
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Acknowledgements
This work was partially funded by the European Union (NextGenerationEU), through the MUR-PNRR project SAMOTHRACE (ECS00000022). In memory of Professor Sir James Fraser Stoddart.
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The manuscript was written with contributions from all authors. All authors approved the final version of the manuscript. G.G., I.P. and S.G. conceived the study. D.C., M.M. and F.M. the synthesized the compounds, D.C., M.M. and I.P. performed the NMR studies. I.P., A.N. and M.F.P. analyzed NMR data. R.C. carried out the chiral HPLC separation, M.P. provided the computational studies, L.M.S. and R.Z. performed the CD experiments, S.G. and N.H. performed X-ray measurements. G.G., I.P. and S.G. supervised the project.
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Crisafulli, D., Mazzaferro, M., Mancuso, F. et al. Enantioselective sensing driven by the interplay of point, helical and planar chirality in pillar[5]arene Pseudo[1]catenanes. Commun Chem 9, 9 (2026). https://doi.org/10.1038/s42004-025-01816-4
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DOI: https://doi.org/10.1038/s42004-025-01816-4
