# Electron-Deficient Confined Space: Synthesis and Recognition Properties of a Covalent Molecular Cage Built upon Naphthalene Diimides and Benzene Triimides

Daryna Shymon, Elise Antonetti, Sabine Chevallier-Michaud, Paola Nava, Alexandre Martinez, Yoann Cotelle

► To cite this version:

Daryna Shymon, Elise Antonetti, Sabine Chevallier-Michaud, Paola Nava, Alexandre Martinez, et al. Electron-Deficient Confined Space: Synthesis and Recognition Properties of a Covalent Molecular Cage Built upon Naphthalene Diimides and Benzene Triimides. Organic Letters, 2026, 28 (4), pp.1312-1316. 10.1021/acs.orglett.5c05115. [https://doi.org/10.1021/acs.orglett.5c05115](https://doi.org/10.1021/acs.orglett.5c05115)

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# Electron Deficient Confined Space: Synthesis and Recognition Properties of a Covalent Molecular Cage Built Upon Naphthalene Diimides and Benzene Triimides

Daryna Shymon, Elise Antonetti, Sabine Chevallier-Michaud, Paola Nava, Alexandre Martinez*, Yoann Cotelle*

Aix Marseille Univ, CNRS, Centrale Med, ISM2, Marseille, France.

Supporting Information Placeholder

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

**ABSTRACT:** The synthesis of neutral electron deficient molecular containers is highly challenging. Nonetheless, the presence of $\pi$-acidic units within the confined space of a molecular cage should enable strong anion binding through synergistic anion-$\pi$ interactions. Here, we report the synthesis of a neutral molecular cage containing five electron-deficient units: two benzene triimide as roof and floor, and three naphthalene diimide as walls. The study of the cage's conformational isomerism is presented together with the high affinity of the receptor for acetate.

Anion recognition is of utmost importance considering their roles in the transport of the genetic code, the regulation of metabolism or their potency as pollutants. Several interactions can promote the sequestration of anions such as ion pairing,¹ hydrogen² or chalcogen bonding³ or anion-$\pi$ interactions.⁴ The latter has received much less attention due to its relative weakness. Anion-$\pi$ interactions can be defined as electrostatic interactions between an electron deficient aromatic surface with a high positive quadrupolar moment ($Q_{ZZ}$) and an anion. Since the binding affinity of electron deficient surfaces is correlated to $Q_{ZZ}$, naphthalene diimides (NDIs, $Q_{ZZ}$= 13.7 B, MP2/aug-cc-pVTZ level) are excellent candidates to promote anion-$\pi$ interactions.⁵,⁶ However, the interaction between a single NDI unit and an anion remains weak in solution,⁷ while the synergistic effect of several electron deficient surfaces within the confined space of a molecular cage could increase the affinity for anions.⁸ Only few cages incorporating NDIs have been reported and were mainly obtained through metal directed self-assembly⁹ or dynamic covalent bonds.¹⁰, ¹¹, ¹² To the best of our knowledge, only one covalent cage having NDIs connected with non-labile bonds was described.¹³ The cage was obtained by

the condensation of three bispyridil-NDIs onto 1,3,5-tris(bromomethyl)benzene giving a cage with six positive charges (Figure 1a), which demonstrated recognition properties towards $I_2$ and $I_3^-$ through electrostatic and anion-$\pi$ interactions. Apart from NDI receptors, benzene triimide (BTI) based cages are of interest due to their even higher $Q_{ZZ}$ compared to NDIs ($Q_{ZZ}$= 17.2 B, MP2/aug-cc-pVTZ level).¹⁴ A cage based on two BTI units connected by *meta*-xylylene spacers demonstrated selectivity for azide owing to effective anion-$\pi$ interactions (Figure 1a).¹⁵ Later, this design was expanded using naphthalene spacers.¹⁶ More recently, our group described a BTI based hemicryptophane able to recognize anions through synergistic anion-$\pi$ interactions in confined space.¹⁷ In order to increase the affinity of electron deficient cages for anions through anion-$\pi$ interactions, we decided to build a molecular cage incorporating two electron deficient BTI units connected by three NDI spacers to obtain a highly electron deficient cage. As far as we know, this design of a covalent cage involving electron deficient roof, floor and walls is unprecedented. In this communication we will describe the synthesis, the study of its conformational isomerism and finally anion recognition.
<figure><img src="image_3.png" /><figcaption>**Figure 1.** a) Representation of the electron deficient receptors synthesized by Wang,<sup>15</sup> Li<sup>13</sup> and in this paper. b) Synthesis of the [3NDI+2BTI] electron deficient cage 1. Conditions a) 3 (1.5 equiv.), BTI (1.0 equiv.), DIPEA (3.6 equiv.), NMP, 7 days, 80°C, Ar. c) DFT optimized structure in the gas phase.</figcaption></figure>

The synthesis of the [3NDI+2BTI] cage 1 was performed by mixing three equivalents of m-bisbromobenzyl-NDI 3 (See SI) and two equivalents of BTI, as inspired by the synthesis of the NDI cage developed by Li.<sup>13</sup> First, the reaction was tested in the presence of DIPEA in DMF at 3 mM concentration, producing traces of the desired molecular cage that, unfortunately, could not be isolated (Table 1, entry 1). Due to the very low solubility of the precursors, NMP was selected as the solvent and the concentration reduced to 1 mM. These conditions allowed the isolation of the cage with 2% yield (Table 1, entry 2). Next, the use of an anionic template was tested with the introduction of nitrate (tetrabutylammonium salt, 12.0 equiv.), however the cage could not be isolated under these conditions (Table 1, entry 3). Iodine (tetrabutylammonium salt, 12.0 equiv.) was then selected to act as both a template and a halogen exchange reagent and gave the [3NDI+2BTI] cage 1 with an increased 7% yield (Table 1, entry 4). Further optimizations were undertaken by lowering the concentration of the reaction to 0.5 mM, however the yield decreased to 2% (table 1, entry 6). Finally, the optimal conditions where applied (7.2 equiv of DIPEA, 1 mM concentration, 12.0 equiv. of TBAI) but replacing NMP by oDCB which did not show any traces of the molecular cage (Table 1, entry 7). In the end, the highest

<table><caption>**Table 1.** Optimization of the reaction conditions for the synthesis of [3NDI+2BTI] cage 1.</caption><thead><tr><th>Entry</th><th>Additive</th><th>Solvent</th><th>Concentration</th><th>Yield</th></tr></thead><tbody><tr><td>1</td><td>-</td><td>DMF</td><td>3.0 mM</td><td>n.i.</td></tr><tr><td>2</td><td>-</td><td>NMP</td><td>1.0 mM</td><td>2%</td></tr><tr><td>3</td><td>TBANO<sub>3</sub><sup>b</sup></td><td>NMP</td><td>1.0 mM</td><td>n.i.</td></tr><tr><td>4</td><td>TBAI<sup>c</sup></td><td>NMP</td><td>1.0 mM</td><td>7%</td></tr><tr><td>5</td><td>TBAI<sup>c</sup></td><td>NMP</td><td>1.0 mM<sup>d</sup></td><td>&lt; 4%</td></tr><tr><td>6</td><td>TBAI<sup>c</sup></td><td>NMP</td><td>0.5 mM</td><td>2%</td></tr><tr><td>7</td><td>TBAI<sup>c</sup></td><td>oDCB</td><td>1.0 mM</td><td>0%</td></tr></tbody></table>

<sup>a</sup> 3 (1.5 equiv.), BTI (1.0 equiv.), DIPEA (3.6 equiv.), 7 days, 80°C, Ar<sup>b</sup> 6 equiv., <sup>c</sup> 6 equiv., <sup>d</sup> slow addition of 3.

yield of 7% was obtained and should be regarded as a success considering that six non-reversible nucleophilic substitutions are occurring. A stepwise reaction was also attempted, first by reacting one equivalent of BTI with three equivalents of NDI 3, followed by the reaction of the
second equivalent of BTI. However, this strategy inspired
by the work of Wang did not allow the isolation of the
desired product in this case.¹⁵

Single crystals were grown from the slow evaporation of
1,1,2,2-tetrachloroethane. However, due to the high disor-
der in the crystal, X-ray diffraction afforded low resolu-
tion data and a refined structure with poor criteria (Fig-
ure S28). To complement these results, we turned our
attention to the structure obtained by DFT (BP86-
D4/def2-SV(P), see SI) of the [3NDI+2BTI] cage 1 in the gas-
phase. The optimization with C3 symmetry led to a helical
arrangement of the NDI walls, induced by meta-
substituted benzylene linkers connected to the BTI plat-
form. The computed conformation, which is a minimum
on the potential energy surface, adopts an hourglass-like
topography in accordance with the structural model ob-
tained by XRD (Figures 1c and S23). Due to the helical
arrangement of the NDI units, it is expected that the
naphthalene core becomes unsymmetrical with one side
pointing within the cavity while the other points outside.

The [3NDI+2BTI] cage 1 was fully characterized by NMR (See SI, Figure S5-10), MS techniques and cyclic voltammetry (Figure S12). The ¹H NMR was first recorded in CDCl₃ at 25°C, but showed very broad signals for the protons A of the naphthalene core as well as the methylenic protons F which could indicate aggregation or the presence of several restricted conformations (Figure S5). To gain further insights, variable temperature (VT) ¹H NMR experiments were performed in C₂D₂Cl₄ as the solvent (Figures 2 and S11). Interestingly, at 0°C the aromatic naphthalene protons A are now well resolved and appear as two singlets, one at 8.77 ppm corresponding to protons A<sub>out</sub> pointing outward the cavity and one singlet at 8.50 ppm corresponding to inward protons A<sub>in</sub>. At this tem-

<figure><img src="image_4.png" /><figcaption>**Figure 2.** Variable temperature experiments between 0°C and 120°C for cage 1 followed by ¹H NMR spectroscopy (600 MHz).</figcaption></figure>

perature, the methylenic protons are also well resolved
and appear as two diastereotopic doublets at 5.37 and
4.64 ppm (²J<sub>H-H</sub>= 14.7 Hz). Such spectroscopic features are
in good accordance with the optimized DFT structure
describing an hourglass conformation (Figure 1c). Next,
the sample was heated and led to the coalescence of pro-
tons A and F at 40°C and 60 °C respectively and gave ¹H
NMR spectra with sharp peaks above 80°C, consistent
with the presence of several locked conformations at
lower temperatures. At 120°C, the naphthalene protons
appear as a singlet at 8.66 ppm and the methylene pro-
tons are observed as a singlet at 5.07 ppm. VT ¹H NMR
experiments revealed two coalescence points: for the NDI
core protons at T<sub>c</sub>= 40°C and for the methylene bridges at
T<sub>c</sub>= 60°C., giving a mean value of ΔG<sup>‡</sup> = 62.1 kJ.mol<sup>-1</sup> in
C<sub>2</sub>D<sub>2</sub>Cl<sub>4</sub>.

In order to understand the intramolecular motions of
the cage leading to the interconversion between different
conformations, we studied some conformational trans-
formation of the system by DFT (PBEo-D4/def2-TZVP//
BP86-D4/def2-SV(P), gas phase, see SI). As a starting
point, conformation (I) (see Figure S25) was obtained by
relaxing the C₃ symmetry constraint, nonetheless (I)
maintains the helical arrangement and provides two dif-
ferent chemical environments for protons A and F. The
computed mechanism is initiated by the simultaneous

<figure><img src="image_5.png" /></figure>

rotation of the two *meta*-benzylene units of one arm giv-
ing TS<sub>12</sub> (Figure 3a). Here, one benzylene is pointing inside
the cage, while the second linker is pointing outside. TS<sub>12</sub>
implies a global movement of the cage, where the NDI
units adapt their relative orientation to allow for the
complete rotation of the red arm. Intermediate (II) pre-
sents a somewhat larger cavity than in (I), permitting an
easier rotation of a second arm (blue one in Figure 3a).

<caption>**Figure 3.** a) The structure of TS<sub>12</sub> is displayed. b) ΔG profile of conformational transformations of (I), PBEo-D4/def2-TZVP//BP86-D4/def2-SV(P) level.</caption>
The benzylene units turns, with a linker pointing inside and the other outside the cage giving TS<sub>23</sub> and (III). Then, the NDI unit tilts, through a transition state with C<sub>s</sub> symmetry, leading to (IV). From here, the conversion continues by following the same steps in a reverse order to complete the rotation. The transformation can be monitored by the evolution of the dihedral (Figure S26) and suggests that the rotation happens stepwise. Concerning energies, the largest barrier is due to transition state TS<sub>12</sub> (58.1 kJ.mol<sup>-1</sup>). The computed barrier fits well with the estimated experimental one and explains the coalescence of the NMR signals by the rotation of the NDI arms. In conclusion, we found a possible stepwise mechanism for conformational isomerism of molecular cage 1, where the rotations of the arms happen one after the other.

Finally, the binding constant of the [3NDI+2BTI] electron
deficient cage **1** for anions was obtained by titrations fol-
lowed by UV-visible spectroscopy assuming a 1:1 stoichi-
ometry (Figure 4). Titrations were performed at constant
concentrations (0.017 mM, CHCl<sub>3</sub>) by adding aliquots of
tetrabutylammonium salts. Receptor **1** has the highest
affinity for acetate (K<sub>a</sub> = 27.3 10<sup>3</sup>), among the tested anions,
and a remarkable selectivity compared to trifluoroacetate
(TFA') (S= 91). This high selectivity highlights the ability
of cage **1** to discriminate between two acetates with simi-
lar structures. A DFT optimized structure of the complex
AcO<sup>-</sup>@[3NDI+2BTI] cage **1** was achieved and shows that the
carboxylate moiety points towards one BTI unit. The
shortest distance is obtained between the BTI and the
acetate, in accordance with the higher Q<sub>zz</sub> of the BTI
surface. An additional short distance is also observed
between the acetate and one NDI unit supporting syner-
gistic anion-π interactions within cage **1** (Figure S27).
Other anions were also tested, including N<sub>3</sub><sup>-</sup> (K<sub>a</sub>= 12.5 10<sup>3</sup>),
SCN<sup>-</sup> (K<sub>a</sub> = 10.1 10<sup>3</sup>) and Br<sup>-</sup> (K<sub>a</sub> = 10.7 10<sup>3</sup>) which display

moderate affinities, while NO₃⁻ (Kₐ = 4.0 10³), Γ (Kₐ = 3.4 10³) and Cl⁻ (Kₐ = 2.6 10³) have lower binding constants. Taken together, these results show the benefit of our strategy

<figure><img src="image_6.png" /><figcaption>**Figure 4.** Binding constants of cage **1** for several anions obtained by titrations followed by UV-visible spectroscopy.</figcaption></figure>

using the synergy of several electron deficient surfaces for
the selective recognition of acetate, a biologically relevant
anion, through anion-π interactions.

In conclusion, the [3+2] cage **1** was synthesized with an
optimized yield of 7%. This receptor features five electron

deficient aromatic surfaces which is unprecedented in the
literature. The geometry optimization by DFT calcula-
tions, together with a partially resolved X-ray diffraction
structure, revealed an hourglass conformation which was
confirmed by ¹H NMR variable temperature experiments.
The coalescence of the ¹H NMR signals led us to investi-
gate the conformational isomerism of the cage by further
calculations and the mechanism leading to the rotation of
the NDI arms seems to indicate a stepwise process, which
could be of interest for controlled molecular motions.
Due to the presence of multiple electron deficient surfac-
es, cage 1 as the ability to bind anions through anion-π
interactions with an interesting affinity for acetate. Current
efforts are focusing on expanding our design in order
to recognize biologically relevant substrates with carbox-
ylate moieties.

ASSOCIATED CONTENT

**Data Availability Statement**

The data underlying this study are available in the pub-
lished article and its Supporting Information.

**Supporting Information**

The supporting information includes: the synthetic proce-
dure for the synthesis of 1, the NMR spectra for all new syn-
thesized compounds, the full NMR spectrum for the VT
NMR, cyclic voltammetry for cage 1, the experimental proce-
dures for titration experiments together with the corre-
sponding spectra and titration isotherms, the details for the
DFT calculations and the XRD analysis (PDF).

The Supporting Information is available free of charge on the
ACS Publications website.

AUTHOR INFORMATION

**Corresponding Author**

alexandre.martinez@centrale-marseille.fr

yoann.cotelle@univ-amu.fr

**Author Contributions**

All authors have given approval to the final version of the
manuscript.

ACKNOWLEDGMENT

Y.C. thank the Agence Nationale de la Recherche for funding the APICOCAT project, grant ANR-21-CE07-0011. We would like to thank Michel Giorgi for XRD and the Spectropole in Marseille for characterizations. We thank the ‘Centre de Calcul Intensif d’Aix-Marseille’ for granting us access to its high-performance computing resources.

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