# A Chiral [2 + 3] Covalent Organic Cage Based on 1,1'-Bi-2-naphthol (BINOL) Units

Midhun Mohan, David-Jérôme Pham, Audrey Fluck, Simon Chapuis, Alain Chaumont, Brice Kauffmann, Laurent Barloy, Pierre Mobian

► To cite this version:

Midhun Mohan, David-Jérôme Pham, Audrey Fluck, Simon Chapuis, Alain Chaumont, et al. A Chiral [2 + 3] Covalent Organic Cage Based on 1,1'-Bi-2-naphthol (BINOL) Units. Chemistry - A European Journal, In press, 10.1002/chem.202400458. [https://doi.org/10.1002/chem.202400452](https://doi.org/10.1002/chem.202400452)

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# A Chiral [2+3] Covalent Organic Cage Based on 1,1'-Bi-2-naphthol (BINOL) Units

Midhun Mohan,[a] David-Jérôme Pham,[a] Audrey Fluck,[a] Simon Chapuis,[b]

Alain Chaumont,[b] Brice Kauffmann,[c] Laurent Barloy,[a] and Pierre Mobian*[a]

A [2+3] chiral covalent organic cage is produced through a dynamic covalent chemistry approach by mixing two readily available building units, viz. an enantiopure 3,3'-diformyl 2,2'-BINOL compound (A) with a triamino spacer (B). The two enantiomeric (*R*,*R*,*R*) and (*S*,*S*,*S*) forms of the cage C are formed nearly quantitatively thanks to the reversibility of the imine linkage. The X-ray diffraction analysis of cage (*S*,*S*,*S*)-C highlights that the six OH functions of the BINOL fragments are positioned inside the cage cavity. Upon reduction of the imine bonds of cage C, the amine cage D is obtained. The ability of the cage D to host the 1-phenylethylammonium cation (*EH*⁺) as a guest is evaluated through UV, CD and DOSY NMR studies. A higher binding constant for (*R*)-*EH*⁺ cation (Ka=1.7 10⁶±10% M⁻¹) related to (*S*)-*EH*⁺ (Ka=0.9 10⁶±10% M⁻¹) is determined in the presence of the (*R*,*R*,*R*)-D cage. This enantiopreference is in close agreement with molecular dynamics simulation.

Shape-persistent organic cages using dynamic covalent imine
bonds are intensively investigated, since cages characterized by
a large variety of sizes and geometries are accessible from
simple building blocks using straightforward synthetic
protocols.[1] These fascinating molecular architectures have
found many applications including gas sorption,[2] detection of
organic pollutants,[3] metal nanoparticles templating[4] or as
proton conducting materials.[5] However, chiral versions of
organic cages constructed with imine bonds are rare and

represent a highly attractive target for chiral molecular
recognition.[6] An early example is the one-pot synthesis of a
chiral covalent organic [8+12] cage from tris(4-
formylphenyl)amine and enantiopure diaminocyclohexane.[7]
Another example that relies on a helical building block was
obtained by reacting a helicene based dialdehyde with triethyl-
amine as spacer to form a [2+3] cage.[8] Very recently, the use
of binaphthyl derivatives has been proposed to generate cages
where the source of chirality is provided by the axial chirality
originating from the binaphthyl molecular fragments.[9]

2,2'-BINOL (BINOL = 1,1'-bi-2-naphthol) is one of the most
popular chiral reagents in chiral technologies.[10] This readily
available compound in its enantiopure form (S or *R*) shows a
high racemization barrier[11] and its derivatization is well
documented.[12] Therefore, the 2,2'-BINOL motif looked like an
appealing molecular fragment to create chiral organic 3D
architectures where the imine linkage is used to assemble the
starting building blocks.

Thus, we report the synthesis of a [2 + 3] imine covalent
cage based on an enantiopure 2,2'-BINOL motif. The design of
this cage is inspired by the family of cages mainly developed by
Mastalerz and co-workers that has in common a salicylimine
motif where the imine functions are stabilized by hydrogen
bonds completing a six-membered ring and involving a
neighboring hydroxyl group.[13]

The 3,3'-diformyl BINOL (A) and the triamino spacer (B) used to produce the targeted [2+3]-C imine cage are depicted in Figure 1. The reaction conditions were optimized and ended to reach a simple and straightforward protocol. The enantiopure compound A (R or S) was mixed with the chloride salt of B in the presence of Et₃N in nitrobenzene. The reaction mixture was treated after seven days of reaction at 100 °C by the addition of methanol. The pale-yellow solid that precipitated was isolated and analyzed. Using this synthetic method, the two enantiomeric forms, i.e. (S,S,S)-[2+3]-C and (R,R,R)-[2+3]-C, of the [2+3]-C cage were produced almost quantitatively in a multi-hundred-milligram scale (97% yield for (S,S,S)-[2+3]-C). Electro-spray Ionisation Mass Spectrometry (ESI-MS) analysis displayed two intense peaks at m/z=1418.65 and 709.83 corresponding to C+H⁺ and C+2H²⁺ respectively (calcd for C+H⁺, m/z= 1418.66; calcd for C+2H²⁺, m/z=709.83) (see figure S11). ¹H NMR spectrum of [2+3]-C (see figure S7) revealed that the signal of the aldehyde protons of the starting compound A was not found any more, while a peak assigned to the imine proton resonance was identified at δ=8.70 ppm. Furthermore, two doublets integrating for six protons each were observed at δ=4.93 ppm and δ=4.49 ppm, corresponding to the ¹H NMR

<figure><img src="image_2.png" /></figure>

<figure><img src="image_3.png" /></figure>

<footnote>[a] Dr. M. Mohan, D.-J. Pham, A. Fluck, Dr. L. Barloy, Dr. P. Mobian  
Laboratoire de Synthèse et Fonctions des Architectures Moléculaire (SFAM),  
UMR 7140 (CMC)  
Université de Strasbourg  
4, rue Blaise Pascal, CS 90032  
67081 Strasbourg Cedex, France  
E-mail: mobian@unistra.fr</footnote>

<footnote>[b] S. Chapuis, Dr. A. Chaumont  
Laboratoire de Modélisation et Simulations Moléculaires, UMR 7140 (CMC)  
Université de Strasbourg  
4, rue Blaise Pascal, CS 90032  
67081 Strasbourg Cedex, France</footnote>

<footnote>[c] Dr. B. Kauffmann  
Univ. Bordeaux, CNRS, INSERM, IECB, US1, UAR 3033, F-33600 Pessac,  
France</footnote>

<footnote>Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202400458</footnote>

<footnote>© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.</footnote>
<figure><img src="image_2.png" /></figure>

# A Chiral [2+3] Covalent Organic Cage Based on 1,1'-Bi-2-naphthol (BINOL) Units

Midhun Mohan,[a] David-Jérôme Pham,[a] Audrey Fluck,[a] Simon Chapuis,[b] Alain Chaumont,[b] Brice Kauffmann,[c] Laurent Barloy,[a] and Pierre Mobian*[a]

A [2+3] chiral covalent organic cage is produced through a dynamic covalent chemistry approach by mixing two readily available building units, viz. an enantiopure 3,3'-diformyl 2,2'-BINOL compound (A) with a triamino spacer (B). The two enantiomeric (*R*,*R*,*R*) and (*S*,*S*,*S*) forms of the cage C are formed nearly quantitatively thanks to the reversibility of the imine linkage. The X-ray diffraction analysis of cage (*S*,*S*,*S*)-C highlights that the six OH functions of the BINOL fragments are positioned inside the cage cavity. Upon reduction of the imine bonds of cage C, the amine cage D is obtained. The ability of the cage D to host the 1-phenylethylammonium cation (*EH*⁺) as a guest is evaluated through UV, CD and DOSY NMR studies. A higher binding constant for (*R*)-*EH*⁺ cation (Ka = 1.7 10⁶ ± 10% M⁻¹) related to (*S*)-*EH*⁺ (Ka = 0.9 10⁶ ± 10% M⁻¹) is determined in the presence of the (*R*,*R*,*R*)-D cage. This enantiopreference is in close agreement with molecular dynamics simulation.

Shape-persistent organic cages using dynamic covalent imine
bonds are intensively investigated, since cages characterized by
a large variety of sizes and geometries are accessible from
simple building blocks using straightforward synthetic
protocols.[1] These fascinating molecular architectures have
found many applications including gas sorption,[2] detection of
organic pollutants,[3] metal nanoparticles templating[4] or as
proton conducting materials.[5] However, chiral versions of
organic cages constructed with imine bonds are rare and

represent a highly attractive target for chiral molecular
recognition.[6] An early example is the one-pot synthesis of a
chiral covalent organic [8+12] cage from tris(4-
formylphenyl)amine and enantiopure diaminocyclohexane.[7]
Another example that relies on a helical building block was
obtained by reacting a helicene based dialdehyde with triethyl-
amine as spacer to form a [2+3] cage.[8] Very recently, the use
of binaphthyl derivatives has been proposed to generate cages
where the source of chirality is provided by the axial chirality
originating from the binaphthyl molecular fragments.[9]

2,2'-BINOL (BINOL = 1,1'-bi-2-naphthol) is one of the most
popular chiral reagents in chiral technologies.[10] This readily
available compound in its enantiopure form (S or *R*) shows a
high racemization barrier[11] and its derivatization is well
documented.[12] Therefore, the 2,2'-BINOL motif looked like an
appealing molecular fragment to create chiral organic 3D
architectures where the imine linkage is used to assemble the
starting building blocks.

Thus, we report the synthesis of a [2+3] imine covalent
cage based on an enantiopure 2,2'-BINOL motif. The design of
this cage is inspired by the family of cages mainly developed by
Mastalerz and co-workers that has in common a salicylimine
motif where the imine functions are stabilized by hydrogen
bonds completing a six-membered ring and involving a
neighboring hydroxyl group.[13]

The 3,3'-diformyl BINOL (A) and the triamino spacer (B) used to produce the targeted [2+3]-C imine cage are depicted in Figure 1. The reaction conditions were optimized and ended to reach a simple and straightforward protocol. The enantiopure compound A (R or S) was mixed with the chloride salt of B in the presence of Et₃N in nitrobenzene. The reaction mixture was treated after seven days of reaction at 100°C by the addition of methanol. The pale-yellow solid that precipitated was isolated and analyzed. Using this synthetic method, the two enantiomeric forms, i.e. (S,S,S)-[2+3]-C and (R,R,R)-[2+3]-C, of the [2+3]-C cage were produced almost quantitatively in a multi-hundred-milligram scale (97% yield for (S,S,S)-[2+3]-C). Electro-spray Ionisation Mass Spectrometry (ESI-MS) analysis displayed two intense peaks at m/z=1418.65 and 709.83 corresponding to C+H⁺ and C+2H²⁺ respectively (calcd for C+H⁺, m/z= 1418.66; calcd for C+2H²⁺, m/z=709.83) (see figure S11). ¹H NMR spectrum of [2+3]-C (see figure S7) revealed that the signal of the aldehyde protons of the starting compound A was not found any more, while a peak assigned to the imine proton resonance was identified at δ=8.70 ppm. Furthermore, two doublets integrating for six protons each were observed at δ=4.93 ppm and δ=4.49 ppm, corresponding to the ¹H NMR

<footnote>[a] Dr. M. Mohan, D.-J. Pham, A. Fluck, Dr. L. Barloy, Dr. P. Mobian
Laboratoire de Synthèse et Fonctions des Architectures Moléculaire (SFAM),
UMR 7140 (CMC)
Université de Strasbourg
4, rue Blaise Pascal, CS 90032
67081 Strasbourg Cedex, France
E-mail: mobian@unistra.fr</footnote>

<footnote>[b] S. Chapuis, Dr. A. Chaumont
Laboratoire de Modélisation et Simulations Moléculaires, UMR 7140 (CMC)
Université de Strasbourg
4, rue Blaise Pascal, CS 90032
67081 Strasbourg Cedex, France</footnote>

<footnote>[c] Dr. B. Kauffmann
Univ. Bordeaux, CNRS, INSERM, IECB, US1, UAR 3033, F-33600 Pessac,
France</footnote>

<footnote>Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202400458</footnote>

<footnote>© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.</footnote>
<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>**Figure 1.** a) The 3,3'-diformyl BINOL (A) and the triamino spacer (B); b) reaction leading to the formation of the [2+3] imine cage C, reaction conditions: i: Et<sub>3</sub>N, nitrobenzene, 100 °C, 7 days, yield (S,S,S)-[2+3]-C: 97%, yield (R,R,R)-[2+3]-C: 96%; c) representation of the imine [2+3]-cage C.</figcaption></figure>

signature of the diastereotopic N<sub>2</sub>H<sub>2</sub> protons. Additionally, Diffusion Ordered Spectroscopy (DOSY) highlighted that compound C has a lower diffusion coefficient (D = 5.87×10<sup>-10</sup> m<sup>2</sup>.s<sup>-1</sup>) than the 2,2'-BINOL derivative A (D = 1.21×10<sup>-9</sup> m<sup>2</sup>.s<sup>-1</sup>) evidencing that the size of the synthetized compound was much larger than the starting building block.

Single crystals of the (S,S,S)-[2+3]-C cage suitable for X-ray diffraction analysis crystallized directly from the reaction mixture after a few days when methanol vapors were allowed to diffuse in the solution. The crystal contained disordered solvent molecules, which could not be localized, and nitrobenzene molecules interacting strongly with the cage, thus the SQUEEZE command<sup>[14]</sup> was used to solve the structure by removing the disordered molecules. The compound crystallizes in a triclinic crystal system with a chiral space group (P1). The molecular motif of this cage is shown in Figure 2.

The structure evidences that all the OH groups of the BINOL fragments point inside the cage cavity. The highest distance between two oxygen from two different BINOL fragments is 8.640 Å. The six OH groups of the compound are involved into intramolecular N···HO hydrogen bond interactions with neighboring nitrogen atoms (the N···HO distances are found between 1.827 Å and 1.860 Å and the N···HO angles are measured between 147.57° and 148.69°).

The cage cavity is large enough to host two nitrobenzene molecules. One is hosted in the center of the structure, whereas the other one is stacked between two naphthol units. The close distance of 3.612 Å between the centroid of the nitrobenzene phenyl ring and the centroid of the closest phenyl ring of a naphthol unit attests to π-π interactions. This sheds light on why aromatic solvent permitted to afford the desired cage with an excellent yield whereas the use of non-aromatic solvent such as chlorinated solvents led to undesired products. In order to

determine the available void spaces within the structures of (S,S,S)-C, MoloVol calculations based on the crystal structures obtained from XRD were performed.<sup>[15]</sup> Two-probe mode was employed to specifically analyze the internal cavity of the cage. The difference in the radii of the large and small probe is used to determine the measurements of the inner cavity that are only accessible by the small probe. The small probe with radii of 1.6 Å (comparable to CO<sub>2</sub> radii) was employed and the larger probe with the radius of 3 Å. The grid resolution for the calculation was set at 0.2 Å and an optimization depth of 4. The calculations led to values of 463 Å<sup>3</sup> for the internal volume of the cage and to 180 Å<sup>2</sup> for the accessible internal surface area.

Next, having demonstrated the formation of the targeted cage C starting from an enantiopure 3,3'-diformyl BINOL, the chiral self-sorting was evaluated by reacting (rac)-(A) with B. An analysis of the reaction products obtained using the same

<figure><img src="image_6.png" /><figcaption>**Figure 2.** Two representations of the molecular structure of the (S,S,S)-[2+3]-C cage. Carbon atoms are in grey, nitrogen atoms are in blue, oxygen atoms are in red and hydrogen atoms are in light grey. a) The structure of the (S,S,S)-[2+3]-C cage is viewed with the stick representation. The two co-crystallized nitrobenzene molecules are represented in salmon. Hydrogen atoms are omitted for clarity with the exception of the OH hydrogen evidencing intramolecular N···HO interactions the six OH hydrogen atoms of the structure. b) Spacefill representation of (S,S,S)-[2+3]-C evidencing the internal cavity of the architecture. For this representation the co-crystallized nitrobenzene molecules have been removed.</figcaption></figure>
<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /><figcaption>**Figure 1.** a) The 3,3'-diformyl BINOL (A) and the triamino spacer (B); b) reaction leading to the formation of the [2+3] imine cage C, reaction conditions: i: Et₃N, nitrobenzene, 100°C, 7 days, yield (S,S,S)-[2+3]-C: 97%, yield (R,R,R)-[2+3]-C: 96%; c) representation of the imine [2+3]-cage C.</figcaption></figure>

signature of the diastereotopic NCH₂ protons. Additionally, Diffusion Ordered Spectroscopy (DOSY) highlighted that compound C has a lower diffusion coefficient ($D = 5.87 \times 10^{-10} \text{ m}^2 \cdot \text{s}^{-1}$) than the 2,2'-BINOL derivative A ($D = 1.21 \times 10^{-9} \text{ m}^2 \cdot \text{s}^{-1}$) evidencing that the size of the synthetized compound was much larger than the starting building block.

Single crystals of the (S,S,S)-[2+3]-C cage suitable for X-ray diffraction analysis crystallized directly from the reaction mixture after a few days when methanol vapors were allowed to diffuse in the solution. The crystal contained disordered solvent molecules, which could not be localized, and nitrobenzene molecules interacting strongly with the cage, thus the SQUEEZE command[14] was used to solve the structure by removing the disordered molecules. The compound crystallizes in a triclinic crystal system with a chiral space group (P1). The molecular motif of this cage is shown in Figure 2.

The structure evidences that all the OH groups of the BINOL fragments point inside the cage cavity. The highest distance between two oxygen from two different BINOL fragments is 8.640 Å. The six OH groups of the compound are involved into intramolecular N...HO hydrogen bond interactions with neighboring nitrogen atoms (the N...HO distances are found between 1.827 Å and 1.860 Å and the N...HO angles are measured between 147.57° and 148.69°).

The cage cavity is large enough to host two nitrobenzene molecules. One is hosted in the center of the structure, whereas the other one is stacked between two naphthol units. The close distance of 3.612 Å between the centroid of the nitrobenzene phenyl ring and the centroid of the closest phenyl ring of a naphthol unit attests to π-π interactions. This sheds light on why aromatic solvent permitted to afford the desired cage with an excellent yield whereas the use of non-aromatic solvent such as chlorinated solvents led to undesired products. In order to

<figure><img src="image_5.png" /><figcaption>**Figure 2.** Two representations of the molecular structure of the (S,S,S)-[2+3]-C cage. Carbon atoms are in grey, nitrogen atoms are in blue, oxygen atoms are in red and hydrogen atoms are in light grey. a) The structure of the (S,S,S)-[2+3]-C cage is viewed with the stick representation. The two co-crystallized nitrobenzene molecules are represented in salmon. Hydrogen atoms are omitted for clarity with the exception of the OH hydrogen evidencing intramolecular N...HO interactions the six OH hydrogen atoms of the structure. b) Spacefill representation of (S,S,S)-[2+3]-C evidencing the internal cavity of the architecture. For this representation the co-crystallized nitrobenzene molecules have been removed.</figcaption></figure>

determine the available void spaces within the structures of (S,S,S)-C, MoloVol calculations based on the crystal structures obtained from XRD were performed.[15] Two-probe mode was employed to specifically analyze the internal cavity of the cage. The difference in the radii of the large and small probe is used to determine the measurements of the inner cavity that are only accessible by the small probe. The small probe with radii of 1.6 Å (comparable to CO₂ radii) was employed and the larger probe with the radius of 3 Å. The grid resolution for the calculation was set at 0.2 Å and an optimization depth of 4. The calculations led to values of 463 Å³ for the internal volume of the cage and to 180 Å² for the accessible internal surface area.

Next, having demonstrated the formation of the targeted cage C starting from an enantiopure 3,3'-diformyl BINOL, the chiral self-sorting was evaluated by reacting (rac)-(A) with B. An analysis of the reaction products obtained using the same
<figure><img src="image_7.png" /></figure>

synthetic procedure as the one used for the synthesis of the enantiopure cage evidenced no narcissistic self-sorting.[6b] The heterochiral cage isomers (S,S,R)-[2+3]-C or (R,R,S)-[2+3]-C are predominant versus the homochiral cages ((S,S,S)-[2+3]-C and (R,R,R)-[2+3]-C) and the presence of only [2+3] assemblies was confirmed by ESI-MS analysis showing the C+H⁺ and C+2H²⁺ peaks at m/z=1418.65 and 709.83 respectively. The ¹H NMR analysis of the reaction products showed two sets of signals (Figure S13). One set corresponded to the homochiral cage isomers ((S,S,S) or (R,R,R) [2+3]-C). The other set of peaks corresponded to the heterochiral species, i.e. (R,S,S) or (S,R,R). For instance, due to the breaking of symmetry within heterochiral species, the imine protons for the heterochiral cage appeared as three singlets (δ=8.77, 8.84 and 8.87 ppm). Integrating between the two sets of signals revealed that the proportion of the heterochiral species versus the homochiral cage was lower (1.1:1) than the statistical distribution (3:1). This tends to indicate that the homochiral assembly is more stable.

Although the reversibility of imine bonds during the cage
formation favors the thermodynamic product, the stability of
the cage could be a concern considering the host-guest studies.
Reduction of imine bonds to amine linkages was performed to
improve the cage stability.[9a] This is achieved by reduction of
(S,S,S)-C or (R,R,R)-C using NaBH(OAc)₃ in CHCl₃ forming (S,S,S)-D
or (R,R,R)-D (Figure 3) respectively in around 60% yield. After
reduction, by ¹H NMR, the imine proton signal at δ=8.62 ppm
has disappeared and two complex signals are now observed at
δ=4.20 and 3.74 ppm for the NHCH₂ protons (Figure S9). Single
crystals of the (S,S,S)-[2+3]-D cage suitable for X-ray diffraction
analysis were obtained by slow diffusion of acetonitrile into a
solution of the cage in dichloromethane. The molecular
structure is given in Figure S14. As attested by the analysis of
the crystal structure, the reduction induces a slight modification
of the internal volume of the cage. Here, the highest oxygen-
oxygen distance is 9.4 Å, representing an increase of 9% of the
O···O distance related to the imine cage. The accessible internal
surface area and the internal volume were calculated using the
MoloVol software at 125 Å² and 328 Å³ respectively for the
amine cage D. These values reflect a smaller internal volume
related to the imine cage linked to an increase of flexibility after
the imine bond reduction. Concerning the optical properties, in
the UV-visible spectra of the cages, the imine cage absorbs light

<figure><img src="image_8.png" /><figcaption>**Figure 3.** Representation of the amine cage (*R*,*R*,*R*)-D with labelled aromatic protons.</figcaption></figure>

in the visible domain, whereas the amine compound displays
optical properties only in the UV region, revealing a higher
conjugation for the cage C compared to D (Figure S18). A
marked difference concerning the chiroptical properties be-
tween D and C is also found. The circular dichroism spectra of
the two enantiomeric forms of cages C, D and the BINOL
derivative A are compiled in Figure S21. Interestingly, the CD
spectra of cage C and compound A having the same stereo-
chemical descriptor are similar with two notable exceptions:
one concerning the intensity (the CD spectrum of C is roughly
three times more intense) and the second linked to the
presence of a circular dichroism signal above 300 nm for C.
Overall, for two cages having the same stereochemical
descriptors, the CD spectrum of D is hypsochromically-shifted
compared to the spectrum of C.

Initially, several potential chiral and achiral guests (see Table S26) were selected to interact with the imine cage C but no host-guest interactions were observed. Nevertheless, the formation of a complex with the ammonium cation $EH^+$ (Figure 4) and cage D was highlighted. This compound, $EH^+$, was selected due to a previously reported naphthol-based cage showing high binding affinities for different monocharged organic cations.[16] Therefore, the *R* and *S* enantiomers of 1-phenyl-ethyl-ammonium cation ($EH^+$) associated with the tetrakis 3,5-bis(trifluoromethyl)phenyl borate anion ($BARF^−$) were mixed with an enantiopure amine cage *D*.[17] These experiments were monitored by ¹H NMR, circular dichroism and UV-visible spectroscopy. Firstly, for the host-guest experiments conducted with the enantiopure amine *E* in the presence of one enantiomer of the cage *D*, no specific interaction between the cage and the amine was evidenced. By contrast, significant shifts of several sharp resonances of the ¹H-NMR spectrum of (*R*,*R*,*R*)-D were observed upon adding one equivalent of the

<figure><img src="image_9.png" /><figcaption>**Figure 4.** Aromatic region from 6.3 ppm to 8 ppm of the ¹H NMR spectra of the enantiopure cage *D* associated with one equivalent of the (S) or the (*R*) form of the ammonium cation *EH⁺* (500 MHz, CD₂Cl₂). For comparison, the spectra of the cage *D* (500 MHz, CD₂Cl₂) and the *EH-BARF* (300 MHz, CD₂Cl₂) are given. The signals labelled with the stars correspond to the ammonium cation hosted by the cage.</figcaption></figure>
<figure><img src="image_6.png" /></figure>

synthetic procedure as the one used for the synthesis of the enantiopure cage evidenced no narcissistic self-sorting.[6b] The heterochiral cage isomers (S,S,R)-[2+3]-C or (R,R,S)-[2+3]-C are predominant versus the homochiral cages ((S,S,S)-[2+3]-C and (R,R,R)-[2+3]-C) and the presence of only [2+3] assemblies was confirmed by ESI-MS analysis showing the C+H⁺ and C+2H²⁺ peaks at m/z=1418.65 and 709.83 respectively. The ¹H NMR analysis of the reaction products showed two sets of signals (Figure S13). One set corresponded to the homochiral cage isomers ((S,S,S) or (R,R,R) [2+3]-C). The other set of peaks corresponded to the heterochiral species, i.e. (R,S,S) or (S,R,R). For instance, due to the breaking of symmetry within heterochiral species, the imine protons for the heterochiral cage appeared as three singlets (δ=8.77, 8.84 and 8.87 ppm). Integrating between the two sets of signals revealed that the proportion of the heterochiral species versus the homochiral cage was lower (1.1:1) than the statistical distribution (3:1). This tends to indicate that the homochiral assembly is more stable.

Although the reversibility of imine bonds during the cage
formation favors the thermodynamic product, the stability of
the cage could be a concern considering the host-guest studies.
Reduction of imine bonds to amine linkages was performed to
improve the cage stability.[9a] This is achieved by reduction of
(S,S,S)-C or (R,R,R)-C using NaBH(OAc)₃ in CHCl₃ forming (S,S,S)-D
or (R,R,R)-D (Figure 3) respectively in around 60% yield. After
reduction, by ¹H NMR, the imine proton signal at δ=8.62 ppm
has disappeared and two complex signals are now observed at
δ=4.20 and 3.74 ppm for the NHCH₂ protons (Figure S9). Single
crystals of the (S,S,S)-[2+3]-D cage suitable for X-ray diffraction
analysis were obtained by slow diffusion of acetonitrile into a
solution of the cage in dichloromethane. The molecular
structure is given in Figure S14. As attested by the analysis of
the crystal structure, the reduction induces a slight modification
of the internal volume of the cage. Here, the highest oxygen-
oxygen distance is 9.4 Å, representing an increase of 9% of the
O···O distance related to the imine cage. The accessible internal
surface area and the internal volume were calculated using the
MoloVol software at 125 Å² and 328 Å³ respectively for the
amine cage D. These values reflect a smaller internal volume
related to the imine cage linked to an increase of flexibility after
the imine bond reduction. Concerning the optical properties, in
the UV-visible spectra of the cages, the imine cage absorbs light

<figure><img src="image_7.png" /><figcaption>**Figure 3.** Representation of the amine cage (*R*,*R*,*R*)-D with labelled aromatic protons.</figcaption></figure>

in the visible domain, whereas the amine compound displays
optical properties only in the UV region, revealing a higher
conjugation for the cage C compared to D (Figure S18). A
marked difference concerning the chiroptical properties be-
tween D and C is also found. The circular dichroism spectra of
the two enantiomeric forms of cages C, D and the BINOL
derivative A are compiled in Figure S21. Interestingly, the CD
spectra of cage C and compound A having the same stereo-
chemical descriptor are similar with two notable exceptions:
one concerning the intensity (the CD spectrum of C is roughly
three times more intense) and the second linked to the
presence of a circular dichroism signal above 300 nm for C.
Overall, for two cages having the same stereochemical
descriptors, the CD spectrum of D is hypsochromically-shifted
compared to the spectrum of C.

Initially, several potential chiral and achiral guests (see Table S26) were selected to interact with the imine cage C but no host-guest interactions were observed. Nevertheless, the formation of a complex with the ammonium cation $EH^+$ (Figure 4) and cage D was highlighted. This compound, $EH^+$, was selected due to a previously reported naphthol-based cage showing high binding affinities for different monocharged organic cations.[16] Therefore, the *R* and *S* enantiomers of 1-phenyl-ethyl-ammonium cation ($EH^+$) associated with the tetrakis 3,5-bis(trifluoromethyl)phenyl borate anion ($BARF^−$) were mixed with an enantiopure amine cage *D*.[17] These experiments were monitored by ¹H NMR, circular dichroism and UV-visible spectroscopy. Firstly, for the host-guest experiments conducted with the enantiopure amine *E* in the presence of one enantiomer of the cage *D*, no specific interaction between the cage and the amine was evidenced. By contrast, significant shifts of several sharp resonances of the ¹H-NMR spectrum of (*R*,*R*,*R*)-D were observed upon adding one equivalent of the

<figure><img src="image_8.png" /><figcaption>**Figure 4.** Aromatic region from 6.3 ppm to 8 ppm of the ¹H NMR spectra of the enantiopure cage *D* associated with one equivalent of the (S) or the (*R*) form of the ammonium cation *EH⁺* (500 MHz, CD₂Cl₂). For comparison, the spectra of the cage *D* (500 MHz, CD₂Cl₂) and the *EH-BARF* (300 MHz, CD₂Cl₂) are given. The signals labelled with the stars correspond to the ammonium cation hosted by the cage.</figcaption></figure>
<figure><img src="image_10.png" /></figure>

enantiopure ammonium chiral salt ((S)-EH-BARF and (R)-EH-
BARF), (see Figure 4). The chemical shift changes for each
proton resonance of the cage (Δδ), that were different depend-
ing on the *R* or *S* enantiomer of EH⁺ added to the cage, are
compiled in Table S17. It is also important to note that with two
equivalents of the chiral salt the ¹H NMR spectrum looked very
similar to the one recorded with one equivalent. A control
experiment with the addition of HCl (one equivalent) was
conducted where the ¹H NMR spectrum of (R,R,R)-D underwent
no modification, implying that the chemical shift changes did
not originate from protonation of the cage. Concerning the
NMR signature of the salt in the presence of the cage, the
signals of the BARF anion were identical as those observed for
the free salt whereas the signals of the ammonium cation
appeared very broad and strongly shielded compared to the
free salt (all these protons resonate below 7.1 ppm) (see
Figure 4 and Figure S21 and S22 at 298 K). The broadening of
the signals corresponding to the ammonium arose from a
dynamic phenomenon, as drastic modification of these large
signals was observed when the sample was cooled to 203 K.
However, no coalescence was noticed in the range of temper-
ature used. The DOSY 2D map of the host-guest experiment at
room temperature indicated a diffusion coefficient for EH⁺ that
is similar with the diffusion coefficient measured for EH⁺
without the cage at room temperature (Figure S23). The
situation changed drastically when the NMR DOSY experiment
was recorded at 203 K (see Figure S25 and Figure 5). In this
case, two species were present in solution. The diffusion at D =
7.8×10⁻¹¹ m²·s⁻¹ measured for the larger species is much lower
in comparison with the diffusion evaluated for the BARF anion
(D = 1.00×10⁻¹⁰ m²·s⁻¹). Importantly, this diffusion was assigned
to the signals belonging to cage D and the ammonium cation
highlighting the formation of a (S)-EH⁺ ⊂ (R,R,R)-D host-guest
system stable at low temperature on the NMR time-scale.

<figure><img src="image_11.png" /><figcaption>**Figure 5.** Low temperature DOSY NMR (5.8–8.45 ppm) of (*R*,*R*,*R*)-D + (S)-EH-BARF (proton resonances marked with the stars correspond to the ammonium proton signals) (1 : 1) recorded at 203 K (600 MHz, CD₂Cl₂).</figcaption></figure>

Complexation of EH-BARF by the cage in solution was
investigated more in details with UV-visible and circular
dichroism spectroscopy to characterize the host-guest interac-
tion. Upon a gradual addition of the enantiopure EH-BARF into
a stock solution of the (R,R,R)-D in dichloromethane, the circular
dichroism spectra showed several modifications in the region
between 220 and 250 nm similar for both enantiomers of the
cation with a plateau reached upon the addition of one
equivalent of EH-BARF (Figure S28–29). It should be noted that
in this region, both enantiomers of the EH-BARF salt are CD
silent. UV-visible titration of (R,R,R)-D with (S)- or (R)-EH-BARF
was performed in DCM to evaluate the strength of the
interaction (Figure S31). Data were fitted to a 1:1 stoichiometry
and gave a binding constant K_a = 0.9 10⁶ ± 10% M⁻¹ and K_a =
1.7 10⁶ ± 10% M⁻¹ for (S)-EH-BARF or (R)-EH-BARF respectively
showing that the (R)-EH⁺ cation bound more strongly the cage
versus the (S)-EH⁺ enantiomer (Figure S33).[18]

Further insights on the microscopical level of the previous
investigated systems have been obtained via classical molecular
dynamics (cMD). (See SI for Methodological details). At first 2
cMD trajectories of 2.5 µs each have been obtained for the
systems composed of an equimolecular ratio of the (R,R,R)-D
cage and either (S)-E or (R)-E amine in DCM. During these
simulations the (S)-E or (R)-E amine are found at an average
distance of about 30.0 ± 8.0 Å from the centre of mass (CoM) of
the (R,R,R)-D cage showing no strong interactions between the
(R,R,R)-D cage and the amine molecules (Figure S35). Further-
more, calculated interaction energies, averaged over the whole
trajectory, between (R,R,R)-D cage and either the (R)-E (–0.1 ±
0.6 kcal/mol) or (S)-E amine (–0.2 ± 1.4 kcal/mol), confirm the
lack of interaction between the (R,R,R)-D cage and both amines.
This may result from the fact that inside the cavity of the
(R,R,R)-D cage two DCM molecules can be found (Figure S36)
interacting via hydrogen bonds with the (R,R,R)-D cage, and
interactions between the amines and the (R,R,R)-D cage may
not be sufficiently strong to chase the molecules outside of
(R,R,R)-D. In a second step two further molecular dynamics
simulations of 10 µs were computed, each containing an
equimolar ratio of either (S)-EH-BARF or (R)-EH-BARF and (R,R,R)-
D cage. During both simulations, we observe the capture of the
ammonium cation by the (R,R,R)-D cage. While the complex-
ation of the (S)-EH⁺ cation is seen to take place after about
30 ns, complexation of the (R)-EH⁺ is found to happen after
15 ns, indicating that there is only a small to no energy barrier
for it to enter the (R,R,R)-D cage. Once these complexes are
formed, they were found to remain stable during the rest of the
remaining dynamics (Figure S36). Radial distribution functions
(RDF) of the CoM of the ammonium cation around the CoM of
the (R,R,R)-D cage (Figure 6) point to the fact that the position,
and the dynamics, of both ammonium cations inside the cavity
differ. While the (R)-EH⁺ ammonium cation fits nicely inside the
cavity of the (R,R,R)-D cage remaining throughout the dynamics
at an average distance of 0.7 Å from the CoM of the (R,R,R)-D
cage, the (S)-EH⁺ cation is found to jiggle between two distinct
positions within the (R,R,R)-D cage, with a first conformation at
a distance of about 1.0 Å from the centre of the cavity and a
second conformation at about 2.6–2.7 Å (Figure 6). Insights into
<figure><img src="image_9.png" /></figure>

enantiopure ammonium chiral salt ((S)-EH-BARF and (R)-EH-
BARF), (see Figure 4). The chemical shift changes for each
proton resonance of the cage (Δδ), that were different depend-
ing on the *R* or *S* enantiomer of EH⁺ added to the cage, are
compiled in Table S17. It is also important to note that with two
equivalents of the chiral salt the ¹H NMR spectrum looked very
similar to the one recorded with one equivalent. A control
experiment with the addition of HCl (one equivalent) was
conducted where the ¹H NMR spectrum of (R,R,R)-D underwent
no modification, implying that the chemical shift changes did
not originate from protonation of the cage. Concerning the
NMR signature of the salt in the presence of the cage, the
signals of the BARF anion were identical as those observed for
the free salt whereas the signals of the ammonium cation
appeared very broad and strongly shielded compared to the
free salt (all these protons resonate below 7.1 ppm) (see
Figure 4 and Figure S21 and S22 at 298 K). The broadening of
the signals corresponding to the ammonium arose from a
dynamic phenomenon, as drastic modification of these large
signals was observed when the sample was cooled to 203 K.
However, no coalescence was noticed in the range of temper-
ature used. The DOSY 2D map of the host-guest experiment at
room temperature indicated a diffusion coefficient for EH⁺ that
is similar with the diffusion coefficient measured for EH⁺
without the cage at room temperature (Figure S23). The
situation changed drastically when the NMR DOSY experiment
was recorded at 203 K (see Figure S25 and Figure 5). In this
case, two species were present in solution. The diffusion at D =
7.8×10⁻¹¹ m²·s⁻¹ measured for the larger species is much lower
in comparison with the diffusion evaluated for the BARF anion
(D = 1.00×10⁻¹⁰ m²·s⁻¹). Importantly, this diffusion was assigned
to the signals belonging to cage D and the ammonium cation
highlighting the formation of a (S)-EH⁺ ⊂ (R,R,R)-D host-guest
system stable at low temperature on the NMR time-scale.

<figure><img src="image_10.png" /><figcaption>**Figure 5.** Low temperature DOSY NMR (5.8–8.45 ppm) of (R,R,R)-D + (S)-EH-BARF (proton resonances marked with the stars correspond to the ammonium proton signals) (1:1) recorded at 203 K (600 MHz, CD₂Cl₂).</figcaption></figure>

Complexation of EH-BARF by the cage in solution was
investigated more in details with UV-visible and circular
dichroism spectroscopy to characterize the host-guest interac-
tion. Upon a gradual addition of the enantiopure EH-BARF into
a stock solution of the (R,R,R)-D in dichloromethane, the circular
dichroism spectra showed several modifications in the region
between 220 and 250 nm similar for both enantiomers of the
cation with a plateau reached upon the addition of one
equivalent of EH-BARF (Figure S28–29). It should be noted that
in this region, both enantiomers of the EH-BARF salt are CD
silent. UV-visible titration of (R,R,R)-D with (S)- or (R)-EH-BARF
was performed in DCM to evaluate the strength of the
interaction (Figure S31). Data were fitted to a 1:1 stoichiometry
and gave a binding constant K_a = 0.9 10⁶ ± 10% M⁻¹ and K_a =
1.7 10⁶ ± 10% M⁻¹ for (S)-EH-BARF or (R)-EH-BARF respectively
showing that the (R)-EH⁺ cation bound more strongly the cage
versus the (S)-EH⁺ enantiomer (Figure S33).[18]

Further insights on the microscopical level of the previous
investigated systems have been obtained via classical molecular
dynamics (cMD). (See SI for Methodological details). At first 2
cMD trajectories of 2.5 µs each have been obtained for the
systems composed of an equimolecular ratio of the (R,R,R)-D
cage and either (S)-E or (R)-E amine in DCM. During these
simulations the (S)-E or (R)-E amine are found at an average
distance of about 30.0 ± 8.0 Å from the centre of mass (CoM) of
the (R,R,R)-D cage showing no strong interactions between the
(R,R,R)-D cage and the amine molecules (Figure S35). Further-
more, calculated interaction energies, averaged over the whole
trajectory, between (R,R,R)-D cage and either the (R)-E (–0.1 ±
0.6 kcal/mol) or (S)-E amine (–0.2 ± 1.4 kcal/mol), confirm the
lack of interaction between the (R,R,R)-D cage and both amines.
This may result from the fact that inside the cavity of the
(R,R,R)-D cage two DCM molecules can be found (Figure S36)
interacting via hydrogen bonds with the (R,R,R)-D cage, and
interactions between the amines and the (R,R,R)-D cage may
not be sufficiently strong to chase the molecules outside of
(R,R,R)-D. In a second step two further molecular dynamics
simulations of 10 µs were computed, each containing an
equimolar ratio of either (S)-EH-BARF or (R)-EH-BARF and (R,R,R)-
D cage. During both simulations, we observe the capture of the
ammonium cation by the (R,R,R)-D cage. While the complex-
ation of the (S)-EH⁺ cation is seen to take place after about
30 ns, complexation of the (R)-EH⁺ is found to happen after
15 ns, indicating that there is only a small to no energy barrier
for it to enter the (R,R,R)-D cage. Once these complexes are
formed, they were found to remain stable during the rest of the
remaining dynamics (Figure S36). Radial distribution functions
(RDF) of the CoM of the ammonium cation around the CoM of
the (R,R,R)-D cage (Figure 6) point to the fact that the position,
and the dynamics, of both ammonium cations inside the cavity
differ. While the (R)-EH⁺ ammonium cation fits nicely inside the
cavity of the (R,R,R)-D cage remaining throughout the dynamics
at an average distance of 0.7 Å from the CoM of the (R,R,R)-D
cage, the (S)-EH⁺ cation is found to jiggle between two distinct
positions within the (R,R,R)-D cage, with a first conformation at
a distance of about 1.0 Å from the centre of the cavity and a
second conformation at about 2.6–2.7 Å (Figure 6). Insights into
<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /><figcaption>**Figure 6.** Radial distribution function of the Centre of Mass of the (R)-EH⁺ or (S)-EH⁺ around the center of the (R,R,R)-D cage and representative structures of the complex structures corresponding to the various maxima of the RDFs.</figcaption></figure>

the energetics reveal that the interaction energies between the (R,R,R)-D cage and either the (R)-EH⁺ or the (S)-EH⁺ are found to be identical (−83.2 ± 5.1 kcal.mol⁻¹ and −83.2 ± 6.8 kcal.mol⁻¹, respectively). However, solvation energy of the (R,R,R)-D cage is found to be larger in the case of the (R)-EH⁺ complex (−164.8 ± 8.3 kcal.mol⁻¹) than in the system containing (S)-EH⁺ (−157.5 ± 10.5 kcal.mol⁻¹), while on the other hand the (S)-EH⁺ ammonium cation is to be better solvated (−31.2 ± 7.4 kcal.mol⁻¹) than the (R)-EH⁺ ammonium cation (−26.7 ± 7.0 kcal.mol⁻¹). Overall this shows that the (R)-EH⁺ ⊂ (R,R,R)-D is slightly better solvated by about 2.8 kcal.mol⁻¹ than its (S)-EH⁺ ⊂ (R,R,R)-D counterpart (−191.5 vs. −188.7 kcal.mol⁻¹, respectively), pointing to the fact that the selectivity of the (R,R,R)-D cage results from solvation effects. To further investigate the selectivity of the (R,R,R)-D host we performed thermodynamic integration calculations. The obtained results reveal a ΔG<sub>Comp</sub> in the case of the (R)-EH⁺ ammonium cation of about −29.0 kcal.mol⁻¹ and about −26.7 kcal.mol⁻¹ in the case of the (S)-EH⁺ ammonium cation (Figure S38). The difference in free energy (ΔΔG<sub>Comp</sub>) is about 2.3 kcal.mol⁻¹ in favour of the (R)-EH⁺ ammonium cation confirming the experimental results.

In summary, the efficient formation of an enantiopure [2+3]-cage based on imine bonds starting from readily accessible building blocks was reported. The X-ray diffraction analysis attested the formation of the desired assembly where the OH functions of the BINOL moieties are located inside the cavity of the architecture. The imine cage was converted into the stable cage D by using NaBH(OAc)₃ as a reducing agent. The reduction impacts the morphology of the cage in the crystalline solid-state. The presence of a large cavity allowed the interaction with a guest. The host-guest complex formation was evidenced by mixing in solution the cage (R,R,R)-D with enantiopure cations EH⁺ associated with the BARF counter-anion. Low temperature DOSY NMR analysis proved the generation of the EH⁺ ⊂ (R,R,R)-D association whereas the amine E did not interact with the cage. Remarkably, a preference of the (R,R,R)-D cage to host the R enantiomer of EH⁺ related to (S)-EH⁺ was evidenced through the determination of the binding constants. This host-guest enantioselectivity was supported by molecular dynamic simulations. Whereas the chiral organic cages built from the 2,2'-BINOL fragment reported until now concerned mostly BINOL protected cages,[9] the cages D or C contains six OH groups decorating the internal environment of the 3D architecture which opens fascinating opportunities in chiral technologies, molecular recognition or coordination chemistry.

## Acknowledgements

We thank the USIAS (Institut d'études avancées de l'Université de Strasbourg), the University of Strasbourg and the CNRS for financial support. Dr. M. Mohan thanks the USIAS for his post-doctoral fellowship. In the framework of the CNRS AÉCIPROCS network, this work has benefited from the X-ray facility of the Biophysical and Structural Chemistry platform at IECB, CNRS UMS3033, INSERM US001, Bordeaux University. Also, we owe a debt of gratitude to Dr. Jean-Claude Chambron for fruitful discussions. For the purpose of Open Access, a CC-BY public copyright licence has been applied by the authors to the present document and will be applied to all subsequent versions up to the Author Accepted Manuscript arising from this submission.

## Conflict of Interests

The authors declare no conflict of interest.

## Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.

**Keywords:** Chirality · Organic cage · BINOL · host-guest
<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /><figcaption>**Figure 6.** Radial distribution function of the Centre of Mass of the (*R*)-EH⁺ or (*S*)-EH⁺ around the center of the (*R*,*R*,*R*)-D cage and representative structures of the complex structures corresponding to the various maxima of the RDFs.</figcaption></figure>

the energetics reveal that the interaction energies between the (*R*,*R*,*R*)-D cage and either the (*R*)-EH⁺ or the (*S*)-EH⁺ are found to be identical (−83.2 ± 5.1 kcal.mol⁻¹ and −83.2 ± 6.8 kcal.mol⁻¹, respectively). However, solvation energy of the (*R*,*R*,*R*)-D cage is found to be larger in the case of the (*R*)-EH⁺ complex (−164.8 ± 8.3 kcal.mol⁻¹) than in the system containing (*S*)-EH⁺ (−157.5 ± 10.5 kcal.mol⁻¹), while on the other hand the (*S*)-EH⁺ ammonium cation is to be better solvated (−31.2 ± 7.4 kcal.mol⁻¹) than the (*R*)-EH⁺ ammonium cation (−26.7 ± 7.0 kcal.mol⁻¹). Overall this shows that the (*R*)-EH⁺ ⊂ (*R*,*R*,*R*)-D is slightly better solvated by about 2.8 kcal.mol⁻¹ than its (*S*)-EH⁺ ⊂ (*R*,*R*,*R*)-D counterpart (−191.5 vs. −188.7 kcal.mol⁻¹, respectively), pointing to the fact that the selectivity of the (*R*,*R*,*R*)-D cage results from solvation effects. To further investigate the selectivity of the (*R*,*R*,*R*)-D host we performed thermodynamic integration calculations. The obtained results reveal a ΔG<sub>Comp</sub> in the case of the (*R*)-EH⁺ ammonium cation of about −29.0 kcal.mol⁻¹ and about −26.7 kcal.mol⁻¹ in the case of the (*S*)-EH⁺ ammonium cation (Figure S38). The difference in free energy (ΔΔG<sub>Comp</sub>) is about 2.3 kcal.mol⁻¹ in favour of the (*R*)-EH⁺ ammonium cation confirming the experimental results.

In summary, the efficient formation of an enantiopure [2+3]-cage based on imine bonds starting from readily accessible building blocks was reported. The X-ray diffraction analysis attested the formation of the desired assembly where the OH functions of the BINOL moieties are located inside the cavity of the architecture. The imine cage was converted into the stable cage D by using NaBH(OAc)₃ as a reducing agent. The reduction impacts the morphology of the cage in the crystalline solid-state. The presence of a large cavity allowed the interaction with a guest. The host-guest complex formation was evidenced by mixing in solution the cage (*R*,*R*,*R*)-D with enantiopure cations EH⁺ associated with the BARF counter-anion. Low temperature DOSY NMR analysis proved the generation of the EH⁺ ⊂ (*R*,*R*,*R*)-D association whereas the amine E did not interact with the cage. Remarkably, a preference of the (*R*,*R*,*R*)-D cage to host the *R* enantiomer of EH⁺ related to (*S*)-EH⁺ was evidenced through the determination of the binding constants. This host-guest enantioselectivity was supported by molecular dynamic simulations. Whereas the chiral organic cages built from the 2,2'-BINOL fragment reported until now concerned mostly BINOL protected cages,[9] the cages D or C contains six OH groups decorating the internal environment of the 3D architecture which opens fascinating opportunities in chiral technologies, molecular recognition or coordination chemistry.

## Acknowledgements

We thank the USIAS (Institut d'études avancées de l'Université de Strasbourg), the University of Strasbourg and the CNRS for financial support. Dr. M. Mohan thanks the USIAS for his post-doctoral fellowship. In the framework of the CNRS AÉCIPROCS network, this work has benefited from the X-ray facility of the Biophysical and Structural Chemistry platform at IECB, CNRS UMS3033, INSERM US001, Bordeaux University. Also, we owe a debt of gratitude to Dr. Jean-Claude Chambron for fruitful discussions. For the purpose of Open Access, a CC-BY public copyright licence has been applied by the authors to the present document and will be applied to all subsequent versions up to the Author Accepted Manuscript arising from this submission.

## Conflict of Interests

The authors declare no conflict of interest.

## Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.

**Keywords:** Chirality · Organic cage · BINOL · host-guest
<figure><img src="image_14.png" /></figure>

[1] a) For a general review on covalent cage see: G. Montà-González, F. Sancenón, R. Martínez-Máñez, V. Martí-Centelles, *Chem. Rev.* **2022**, *122* (16), 13636; For a review dedicated on imine covalent cage exclusively see: b) K. Acharyya, P. S. Mukherjee, *Angew. Chem. Int. Ed.* **2019**, *58*, 8640; c) X. Liu, Y. Liu, G. Li, R. Warmuth, *Angew. Chem. Int. Ed.* **2006**, *45*, 901; for for metal-based assemblies formed with imine linkage see: d) T. K. Ronson, S. Zarra, S. P. Black, J. R. Nitschke, *Chem. Commun.* **2013**, *49*, 2476.

[2] a) K. Qu, J. Xu, L. Dai, Y. Wang, H. Cao, D. Zhang, Y. Wu, W. Xu, K. Huang, C. Lian, X. Guo, W. Jin, Zhi Xu, *Angew. Chem. Int. Ed.* **2022**, *61*(31), e202205481; b) K. Jie, N. Onishi, J. A. Schott, I. Popovs, D. E. Jiang, S. Mahurin, S. Dai, *Angew. Chem. Int. Ed.* **2020**, *59*, 2268; *Angew. Chem.* **2020**, *132*, 2288; c) M. Liu, L. Chen, S. Lewis, S. Y. Chong, M. A. Little, T. Hasell, I. M. Aldous, C. M. Brown, M. W. Smith, C. A. Morrison, L. J. Hardwick, A. I. Cooper, *Nat. Commun.* **2016**, *7*, 12750; d) M. Liu, M. A. Little, K. E. Jelfs, J. T. A. Jones, M. Schmidtmann, S. Y. Chong, T. Hasell, A. I. Cooper, *J. Am. Chem. Soc.* **2014**, *136*, 7583; e) Q. Song, S. Jiang, T. Hasell, M. Liu, S. Sun, A. K. Cheetham, E. Sivaniah, A. I. Cooper, *Adv. Mater.* **2016**, *28*, 2629; f) T. Hasell, S. Y. Chong, K. E. Jelfs, D. J. Adams, A. I. Cooper, *J. Am. Chem. Soc.* **2012**, *134*, 588.

[3] a) K. Acharyya, A. Chowdhury, B. Mondal, S. Chakraborty, P. S. Mukherjee, *Chem. Eur. J.* **2017**, *23*, 8482; b) M. A. Zwijnenburg, E. Berardo, W. J. Peveler, K. E. Jelfs, *J. Phys. Chem. B* **2016**, *120*, 5063; c) K. Acharyya, P. S. Mukherjee, *Chem. Eur. J.* **2015**, *21*, 6823; d) K. Acharyya, P. S. Mukherjee, *Chem. Commun.* **2014**, *50*, 15788; e) M. Brutschy, M. W. Schneider, M. Mastalerz, S. R. Waldvogel, *Chem. Commun.* **2013**, *49*, 8398; f) M. Brutschy, M. W. Schneider, M. Mastalerz, S. R. Waldvogel, *Adv. Mater.* **2012**, *24*, 6049.

[4] a) L. Qiu, R. McCaffrey, Y. Jin, Y. Gong, Y. Hu, H. Sun, W. Park, W. Zhang, *Chem. Sci.* **2018**, *9*, 676; b) Y. Zhang, Y. Xiong, J. Ge, R. Lin, C. Chen, Q. Peng, D. Wang, Y. Li, *Chem. Commun.* **2018**, *54*, 2796; c) B. Mondal, K. Acharyya, P. Howlader, P. S. Mukherjee, *J. Am. Chem. Soc.* **2016**, *138*, 1709; d) J. K. Sun, W. W. Zhan, T. Akita, Q. Xu, *J. Am. Chem. Soc.* **2015**, *137*, 7063; e) R. McCaffrey, H. Long, Y. Jin, A. Sanders, W. Park, W. Zhang, *J. Am. Chem. Soc.* **2014**, *136*, 1782.

[5] M. Liu, L. Chen, S. Lewis, S. Y. Chong, M. A. Little, T. Hasell, I. M. Aldous, C. M. Brown, M. W. Smith, C. A. Morrison, L. J. Hardwick, A. I. Cooper, *Nat. Commun.* **2016**, *7*, 12750.

[6] a) For a general review see: F. Begato, G. Licini, C. Zonta, *Angew. Chem. Int. Ed.* **2023**, *62* (51), e202311153; b) F. Esteve, B. Altava, E. Garcia-Verdugo, S. V. Luis, J.-M. Lehn, *Chem.* **2022**, *8*, 2023; c) M. Wierzbicki, A. A. Glowacka, M. P. Szymańska, A. Szumna, *Chem. Commun.* **2017**, *53*, 5200; d) Y.-L. Sun, Z. Wang, H. Ma, Q.-P. Zhang, B.-B. Yang, X. Meng, Y. Zhang, C. Zhang, *Chem. Commun.* **2023**, *59*, 302.

[7] K. E. Jelfs, X. Wu, M. Schimdtmann, J. T. A. Jones, J. E. Warren, D. J. Adams, A. I. Cooper, *Angew. Chem. Int. Ed.* **2011**, *50*, 10653.

[8] A. U. Malik, F. Gan, C. Shen, N. Yu, R. Wang, J. Crassous, M. Shu, H. Qiu, *J. Am. Chem. Soc.* **2018**, *140*, 2769.

[9] a) E. Ramakrishna, J.-D. Tang, J.-J. Tao, Q. Fang, Z. Zhang, J. Huang, S. Li, *Chem. Commun.* **2021**, *57*, 9088; b) D.-X. Cui, Y. Geng, J.-N. Kou, G.-G. Shan, C.-Y. Sun, K.-H. Zhang, X.-L. Wang, Z.-M. Su, *Nat. Commun.* **2022**, *13*, 4011.

[10] J. M. Brunel, *Chem. Rev.* **2005**, *105*(3), 857.

[11] L. Meca, D. Reha, Z. Havlas, *J. Org. Chem.* **2003**, *68*(14), 5677.

[12] Y. Chen, S. Yekta, A. K. Yudin, *Chem. Rev.* **2003**, *103*, 3155.

[13] a) P. Wagner, F. Rominger, J. H. Gross, M. Mastalerz, *Angew. Chem. Int. Ed.* **2023**, *62*, e202217251; b) B. P. Benke, T. Kirschbaum, J. Graf, J. H. Gross, M. Mastalerz, *Nat. Chem.* **2023**, *15*, 413; c) F. Uhrmacher, S. M. Elbert, F. Rominger, M. Mastalerz, *Eur. J. Inorg. Chem.* **2022**, e202100864; d) M. Holsten, S. Feierabend, S. M. Elbert, F. Rominger, T. Oeser, M. Mastalerz, *Chem. Eur. J.* **2021**, *27*, 9383; e) P. Wagner, F. Rominger, W.-S. Zhang, J. H. Gross, S. M. Elbert, R. R. Schröder, M. Mastalerz, *Angew. Chem. Int. Ed.* **2021**, *60*, 8896; f) Michael Mastalerz, *Acc. Chem. Res.* **2018**, *51*, 2411; g) D. Beaudoin, F. Rominger, M. Mastalerz, *Angew. Chem. Int. Ed.* **2017**, *56* 1244.

[14] A. L. Spek, *Acta Crystallogr. Sect. C* **2015**, *71*, 9.

[15] J. B. Maglic, R. Lavendomme, *J. Appl. Crystallogr.* **2022**, *55*(4), 1033.

[16] F. Jia, H. Hupatz, L. P. Yang, H. V. Schröder, D. H. Li, S. Xin, D. Lentz, F. Witte, X. Xie, B. Paulus, C. A. Schalley, W. Jiang, *J. Am. Chem. Soc.* **2019**, *141*, 4468.

[17] An initial experiment was performed with the hexafluorophosphate salt of $EH^+$ ($EHPF_6$) in the presence of the imine cage C. The $EH-PF_6$ salt was unstable due to the decomposition of the $PF_6^-$ anion according to $^{19}F$ NMR analysis. Also, when cage C was mixed with $EH-PF_6$, ESI-MS and DOSY analysis indicated that the cage has partially collapsed to form 3,3'-bis--((1-phenylethyl)imino)methyl)-1,1'-binaphthtol as a major product (see Figure S32). However, by ESI-MS, a peak at m/z = 1538.75 (calcd for $EH^+ + C_6H_5$; m/z = 1538.74) was detected demonstrating the presence of the host-guest system in solution.

[18] P. Thordarson, *Chem. Soc. Rev.* **2011**, *40*, 1305.

Manuscript received: February 1, 2024

Accepted manuscript online: March 1, 2024

Version of record online: ■■, ■■
<figure><img src="image_13.png" /></figure>

[1] a) For a general review on covalent cage see: G. Montà-González, F. Sancenón, R. Martínez-Máñez, V. Martí-Centelles, *Chem. Rev.* **2022**, *122* (16), 13636; For a review dedicated on imine covalent cage exclusively see: b) K. Acharyya, P. S. Mukherjee, *Angew. Chem. Int. Ed.* **2019**, *58*, 8640; c) X. Liu, Y. Liu, G. Li, R. Warmuth, *Angew. Chem. Int. Ed.* **2006**, *45*, 901; for for metal-based assemblies formed with imine linkage see: d) T. K. Ronson, S. Zarra, S. P. Black, J. R. Nitschke, *Chem. Commun.* **2013**, *49*, 2476.

[2] a) K. Qu, J. Xu, L. Dai, Y. Wang, H. Cao, D. Zhang, Y. Wu, W. Xu, K. Huang, C. Lian, X. Guo, W. Jin, Zhi Xu, *Angew. Chem. Int. Ed.* **2022**, *61*(31), e202205481; b) K. Jie, N. Onishi, J. A. Schott, I. Popovs, D. E. Jiang, S. Mahurin, S. Dai, *Angew. Chem. Int. Ed.* **2020**, *59*, 2268; *Angew. Chem.* **2020**, *132*, 2288; c) M. Liu, L. Chen, S. Lewis, S. Y. Chong, M. A. Little, T. Hasell, I. M. Aldous, C. M. Brown, M. W. Smith, C. A. Morrison, L. J. Hardwick, A. I. Cooper, *Nat. Commun.* **2016**, *7*, 12750; d) M. Liu, M. A. Little, K. E. Jelfs, J. T. A. Jones, M. Schmidtmann, S. Y. Chong, T. Hasell, A. I. Cooper, *J. Am. Chem. Soc.* **2014**, *136*, 7583; e) Q. Song, S. Jiang, T. Hasell, M. Liu, S. Sun, A. K. Cheetham, E. Sivaniah, A. I. Cooper, *Adv. Mater.* **2016**, *28*, 2629; f) T. Hasell, S. Y. Chong, K. E. Jelfs, D. J. Adams, A. I. Cooper, *J. Am. Chem. Soc.* **2012**, *134*, 588.

[3] a) K. Acharyya, A. Chowdhury, B. Mondal, S. Chakraborty, P. S. Mukherjee, *Chem. Eur. J.* **2017**, *23*, 8482; b) M. A. Zwijnenburg, E. Berardo, W. J. Peveler, K. E. Jelfs, *J. Phys. Chem. B* **2016**, *120*, 5063; c) K. Acharyya, P. S. Mukherjee, *Chem. Eur. J.* **2015**, *21*, 6823; d) K. Acharyya, P. S. Mukherjee, *Chem. Commun.* **2014**, *50*, 15788; e) M. Brutschy, M. W. Schneider, M. Mastalerz, S. R. Waldvogel, *Chem. Commun.* **2013**, *49*, 8398; f) M. Brutschy, M. W. Schneider, M. Mastalerz, S. R. Waldvogel, *Adv. Mater.* **2012**, *24*, 6049.

[4] a) L. Qiu, R. McCaffrey, Y. Jin, Y. Gong, Y. Hu, H. Sun, W. Park, W. Zhang, *Chem. Sci.* **2018**, *9*, 676; b) Y. Zhang, Y. Xiong, J. Ge, R. Lin, C. Chen, Q. Peng, D. Wang, Y. Li, *Chem. Commun.* **2018**, *54*, 2796; c) B. Mondal, K. Acharyya, P. Howlader, P. S. Mukherjee, *J. Am. Chem. Soc.* **2016**, *138*, 1709; d) J. K. Sun, W. W. Zhan, T. Akita, Q. Xu, *J. Am. Chem. Soc.* **2015**, *137*, 7063; e) R. McCaffrey, H. Long, Y. Jin, A. Sanders, W. Park, W. Zhang, *J. Am. Chem. Soc.* **2014**, *136*, 1782.

[5] M. Liu, L. Chen, S. Lewis, S. Y. Chong, M. A. Little, T. Hasell, I. M. Aldous, C. M. Brown, M. W. Smith, C. A. Morrison, L. J. Hardwick, A. I. Cooper, *Nat. Commun.* **2016**, *7*, 12750.

[6] a) For a general review see: F. Begato, G. Licini, C. Zonta, *Angew. Chem. Int. Ed.* **2023**, *62* (51), e202311153; b) F. Esteve, B. Altava, E. Garcia-Verdugo, S. V. Luis, J.-M. Lehn, *Chem.* **2022**, *8*, 2023; c) M. Wierzbicki, A. A. Glowacka, M. P. Szymańska, A. Szumna, *Chem. Commun.* **2017**, *53*, 5200; d) Y.-L. Sun, Z. Wang, H. Ma, Q.-P. Zhang, B.-B. Yang, X. Meng, Y. Zhang, C. Zhang, *Chem. Commun.* **2023**, *59*, 302.

[7] K. E. Jelfs, X. Wu, M. Schimdtmann, J. T. A. Jones, J. E. Warren, D. J. Adams, A. I. Cooper, *Angew. Chem. Int. Ed.* **2011**, *50*, 10653.

[8] A. U. Malik, F. Gan, C. Shen, N. Yu, R. Wang, J. Crassous, M. Shu, H. Qiu, *J. Am. Chem. Soc.* **2018**, *140*, 2769.

[9] a) E. Ramakrishna, J.-D. Tang, J.-J. Tao, Q. Fang, Z. Zhang, J. Huang, S. Li, *Chem. Commun.* **2021**, *57*, 9088; b) D.-X. Cui, Y. Geng, J.-N. Kou, G.-G. Shan, C.-Y. Sun, K.-H. Zhang, X.-L. Wang, Z.-M. Su, *Nat. Commun.* **2022**, *13*, 4011.

[10] J. M. Brunel, *Chem. Rev.* **2005**, *105*(3), 857.

[11] L. Meca, D. Reha, Z. Havlas, *J. Org. Chem.* **2003**, *68*(14), 5677.

[12] Y. Chen, S. Yekta, A. K. Yudin, *Chem. Rev.* **2003**, *103*, 3155.

[13] a) P. Wagner, F. Rominger, J. H. Gross, M. Mastalerz, *Angew. Chem. Int. Ed.* **2023**, *62*, e202217251; b) B. P. Benke, T. Kirschbaum, J. Graf, J. H. Gross, M. Mastalerz, *Nat. Chem.* **2023**, *15*, 413; c) F. Uhrmacher, S. M. Elbert, F. Rominger, M. Mastalerz, *Eur. J. Inorg. Chem.* **2022**, e202100864; d) M. Holsten, S. Feierabend, S. M. Elbert, F. Rominger, T. Oeser, M. Mastalerz, *Chem. Eur. J.* **2021**, *27*, 9383; e) P. Wagner, F. Rominger, W.-S. Zhang, J. H. Gross, S. M. Elbert, R. R. Schröder, M. Mastalerz, *Angew. Chem. Int. Ed.* **2021**, *60*, 8896; f) Michael Mastalerz, *Acc. Chem. Res.* **2018**, *51*, 2411; g) D. Beaudoin, F. Rominger, M. Mastalerz, *Angew. Chem. Int. Ed.* **2017**, *56* 1244.

[14] A. L. Spek, *Acta Crystallogr. Sect. C* **2015**, *71*, 9.

[15] J. B. Maglic, R. Lavendomme, *J. Appl. Crystallogr.* **2022**, *55*(4), 1033.

[16] F. Jia, H. Hupatz, L. P. Yang, H. V. Schröder, D. H. Li, S. Xin, D. Lentz, F. Witte, X. Xie, B. Paulus, C. A. Schalley, W. Jiang, *J. Am. Chem. Soc.* **2019**, *141*, 4468.

[17] An initial experiment was performed with the hexafluorophosphate salt of $EH^+$ ($EHPF_6$) in the presence of the imine cage C. The $EH-PF_6$ salt was unstable due to the decomposition of the $PF_6^-$ anion according to $^{19}F$ NMR analysis. Also, when cage C was mixed with $EH-PF_6$, ESI-MS and DOSY analysis indicated that the cage has partially collapsed to form 3,3'-bis--((1-phenylethyl)imino)methyl)-1,1'-binaphthtol as a major product (see Figure S32). However, by ESI-MS, a peak at m/z = 1538.75 (calcd for $EH^+ + C_6H_5$; m/z = 1538.74) was detected demonstrating the presence of the host-guest system in solution.

[18] P. Thordarson, *Chem. Soc. Rev.* **2011**, *40*, 1305.
COMMUNICATION

A chiral cage formed with three 2,2'-
BINOL units was prepared through a
dynamic covalent chemistry
approach. This architecture contains
six OH functions pointing inside the
cavity. Host-guest studies demon-
strated enantiopreference of the cage
for a chiral ammonium cation.

<figure><img src="image_15.png" /></figure>

Dr. M. Mohan, D.-J. Pham, A. Fluck, S.
Chapuis, Dr. A. Chaumont, Dr. B.
Kauffmann, Dr. L. Barloy, Dr. P.
Mobian*

1 – 7

A Chiral [2 + 3] Covalent Organic
Cage Based on 1,1'-Bi-2-naphthol
(BINOL) Units

<figure><img src="image_16.png" /></figure>
COMMUNICATION

A chiral cage formed with three 2,2'-
BINOL units was prepared through a
dynamic covalent chemistry
approach. This architecture contains
six OH functions pointing inside the
cavity. Host-guest studies demon-
strated enantiopreference of the cage
for a chiral ammonium cation.

<figure><img src="image_14.png" /></figure>

Dr. M. Mohan, D.-J. Pham, A. Fluck, S.
Chapuis, Dr. A. Chaumont, Dr. B.
Kauffmann, Dr. L. Barloy, Dr. P.
Mobian*

1 – 7

A Chiral [2 + 3] Covalent Organic
Cage Based on 1,1'-Bi-2-naphthol
(BINOL) Units

<figure><img src="image_15.png" /></figure>