# Electron-deficient hemicryptophanes for the recognition of anions through anion-π interactions

Louise Miton, Pierre-Antoine Dupin, Elise Antonetti, Marion Jean, Paola Nava, Alexandre Martinez, Yoann Cotelle

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Louise Miton, Pierre-Antoine Dupin, Elise Antonetti, Marion Jean, Paola Nava, et al. Electron-deficient hemicryptophanes for the recognition of anions through anion-π interactions. Organic & Biomolecular Chemistry, 2025, 23 (18), 10.1039/D5OB00245A. http://dx.doi.org/10.1039/D50245A

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Cite this: DOI: 10.1039/d5ob00245a

Received 11th February 2025,
Accepted 3rd April 2025

DOI: 10.1039/d5ob00245a

rsc.li/obc

Electron-deficient hemicryptophanes for the
recognition of anions through anion-π
interactions†

Louise Miton, ID a Pierre-Antoine Dupin, ID a Elise Antonetti, ID a Marion Jean, b

Paola Nava, ID a, *a and Yoann Cotelle ID *a

The selective recognition and encapsulation of anions are crucial in many biological and environmental processes. Anion-π interactions, characterized by attractive non-covalent interactions between anions and electron-deficient aromatic surfaces, have gained significant attention for their potential in anion binding. However, due to the weak nature of these interactions, receptors that rely solely on anion-π interactions are scarce. To promote anion binding via electron-deficient surfaces, we constructed a cavity within the hemicryptophane framework using tetrafluoroxylethylene arms and a benzene triimide unit, thereby displaying multiple electron-deficient surfaces. Binding studies revealed that the electron-deficient receptor exhibits significantly higher anion binding constants compared to a less electron-deficient hemicryptophane. For example, the affinity for chloride (Kₐ = 207) is ten times higher for the most electron-deficient hemicryptophane. More impressive is the unique affinity for triiodide (Kₐ = 416), representing the first example of triiodide recognition by a BTI-based receptor. The enhanced binding properties of this receptor result from the combination of different π-acidic surfaces in a single cage molecule.

Introduction

Anions are involved in many biological and environmental pro-
cesses, making their selective recognition and encapsulation
highly interesting. ¹⁻⁵ Among others, the anion-π interaction
has recently emerged as a promising mode of interaction. ⁶⁻¹⁰
Nonetheless, only a limited number of receptors able to bind
anions solely through anion-π interactions have been
reported. ¹¹⁻¹⁶ Anion-π interactions are defined as attractive
non-covalent interactions between an electron-deficient aro-
matic surface with a positive quadrupolar moment (Q<sub>ZZ</sub>) and

an anion.¹⁷ In order to increase the strength of this inter-
action, we aim to explore the synergy of several π-acidic aro-
matic surfaces within a hemicryptophane to create a well-
defined electron-deficient confined space.¹⁸
Hemicryptophanes are composed of a preorganizing cyclotri-
veratrylene unit covalently linked to another unit having a C₃
symmetry axis.¹⁹ To maximize interactions with anions, our
attention turned towards the use of benzene triimides
(BTIs),²⁰⁻²² which possess a high quadrupolar moment (Q<sub>ZZ</sub> =
17.2 B, computed at the MP2/aug-cc-pVTZ level) and a suitable
geometry. BTIs have recently been used in the design of mole-
cular cages by bridging two BTI units with three *meta*-xylylene
linkers, showing strong affinity and selectivity for azide.²³
Moreover, increasing the length of the spacers using naphtha-
lene units has an impact on the selectivity for anions with
different geometries.²⁴ We have recently described the syn-
thesis of the BTI-based hemicryptophane 2 with xylylene
linkers, showing promising lone pair-π interactions in the
solid state.²⁵ Consequently, we introduced additional electron-
withdrawing groups on the linkers to increase the binding for
anions. Herein, we report the synthesis and characterization of
an electron-deficient hemicryptophane and its increased anion
binding ability compared to the hemicryptophane lacking
additional electron-deficient linkers (Fig. 1).

<figure><img src="image_3.png" /><figcaption>**Fig. 1** Structure of the electron-deficient hemicryptophane **1** and the parent hemicryptophane **2** lacking electron-deficient linkers.</figcaption></figure>

<footnote><sup>a</sup>Aix Marseille Univ, CNRS, Centrale Med, ISM2, Marseille, France.
E-mail: alexandre.martinez@centrale-marseille.fr, yoann.cotelle@univ-amu.fr</footnote>

<footnote><sup>b</sup>Aix Marseille Université, CNRS, FSCM, Chiropole, F-13397 Marseille, France</footnote>

<footnote>†Electronic supplementary information (ESI) available. See DOI: https://doi.org/
10.1039/d5ob00245a</footnote>
<figure><img src="image_4.png" /></figure>

Results and discussion

Hemicryptophane **1** was synthesized in three steps from the
vanillyl alcohol precursor **3**. The first step involved the mono-
alkylation of precursor **3** using an excess of bis(bromomethyl)-
2,3,5,6-tetrafluorobenzene reagent and K₂CO₃ in acetone,
resulting in compound **4** with a reasonable yield (49%). Then,
the formation of the cyclotriveratrylene (CTV) unit was
achieved through a triple Friedel-Crafts reaction, catalyzed by
Sc(OTf)₃ in acetonitrile, giving the desired product **5** with a
moderate yield (36%). Finally, a nucleophilic substitution on
precursor **5** using BTI and DIPEA in DMF gave hemicrypto-
phane **1** (38% yield) (Scheme 1).

The final compound was fully characterized by ¹H NMR, ¹³C NMR and MS techniques (see ESI†). The ¹H NMR spectrum of receptor **1** is consistent with C₃ symmetry in solution (Fig. 2). Protons Hₐ and H₉ are observed as doublets at 3.52 and 4.73 ppm, respectively. Methoxy protons appear as a singlet at 3.74 ppm, while the methylene bridges of the tetra-fluoroparaxylylene spacers appear as doublets at 4.88 and 5.21 ppm for protons H₃ and at 5.26 and 5.53 for protons H₄. Finally, the aromatic protons of the CTV unit appear as sing-lets at 6.81 and 7.14 ppm for H₁ and H₂.

It was previously demonstrated that hemicryptophane 2 is a
solvent-dependent chiral molecular switch, with an open CTV
configuration in common organic solvents (including chloro-
form) and an inverted configuration in bulky polar aromatic
solvents (such as 2-t-butylphenol).²⁵ Thus, we evaluated the
configurational stability of hemicryptophane 1. The racemic
mixture of hemicryptophane 1 was resolved by chiral stationary
phase HPLC on analytical and semi-preparative scales using a
Chiralpak IA stationary phase and an ethanol/dichloro-
methane mixture (40/60) as the eluent (Fig. 3a). Contrary to

<figure><img src="image_5.png" /><figcaption>**Scheme 1** Synthesis of hemicryptophane **1**. Conditions: (a) 1,4-bis(bromomethyl)-2,3,5,6-tetrafluorobenzene, K₂CO₃, acetone, 70 °C, 18 h. (b) Sc(OTf)₃, CH₃CN, 65 °C, 48 h. (c) BTI, DIPEA, DMF, 60 °C, 72 h.</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>Fig. 2 ¹H NMR of hemicryptophane 1 (CDCl₃, 400 MHz, 298 K).</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>**Fig. 3** (a) Analytical chiral HPLC chromatogram. (b) ECD spectra of the first eluted compound (M)-1 (in green, c = 0, 140 mmol L⁻¹, CH₃CN) and the second eluted (P)-1 (in red, c = 0.125 mmol L⁻¹, CH₃CN).</figcaption></figure>

the chromatogram of hemicryptophane 2, we could observe
only two peaks in the chromatogram of hemicryptophane 1.
Hence, no inverted configuration was observed in the chroma-
togram of cage 1. This behavior strongly differs from that of
cage 2, which gives a mixture of in and out configurations
under similar conditions, supporting the higher configura-
tional stability of cage 1 compared to cage 2. Subsequently,
ECD spectra were recorded (Fig. 3b). The ECD spectra show
two mirror images typical of the open configuration, confirm-
ing their enantiomeric nature. The absolute configuration of
each enantiomer can be assigned by referring to the work of
André Collet and Giovanni Gottarelli published in 1985.²⁶
Their study on cyclotriveratrylenes demonstrated that the
absolute configuration of a CTV moiety could be determined
by analyzing the sign changes of bands in the ECD spectrum,
particularly at the ¹Lₐ transition (around 240 nm), as this tran-
sition was less sensitive to the substituents on the CTV. Thus,
based on the ECD spectrum of hemicryptophane 1, we
propose that the first eluted enantiomer (green spectrum) is
associated with the stereodescriptor *M*, while the second
eluted enantiomer (red spectrum) is linked to the stereo-
descriptor *P*.
<figure><img src="image_8.png" /></figure>

Next, DFT calculations were performed to propose a structure as well as to determine the volume and ESP (electrostatic potential) maps of hemicryptophanes **1** and **2**. Hemicryptophane **1** was optimized as a $C_3$ symmetric object, in agreement with the ¹H NMR spectrum (Fig. 2), and has a large cavity ($V = 327 Å^3$), comparable to that of hemicryptophane **2** ($V = 310 Å^3$). Thus, both cages have a very similar shape and inner volume, and the change in binding affinity should arise from their differences in electron distribution. The ESP maps depict a strong difference in electron distribution between the two receptors. Hemicryptophane **1** with tetrafluoroxylylene linkers has more electron-deficient aromatic spacers, which should increase the binding for anionic species through anion-π interactions (Fig. 4c).

Finally, the recognition of anions by hemicryptophanes **1** and **2** was investigated. ¹H NMR titrations were performed in $CDCl_3$ by adding aliquots of tetrabutylammonium salts, to avoid inclusion of the counter ion, to a solution of the host.²⁷ All the constants were obtained by plotting the chemical shifts of the methylenic protons ($H_4$) of the linkers and fitting the data using a 1:1 stoichiometry with the BindFit program.²⁸ Receptor **1** with tetrafluorolinkers has higher binding constants for anions than receptor **2** (except for nitrate), showing the efficiency of the π-acidic surfaces' additivity within the confined space of our receptor. For halides, it can be observed that receptor **1** exhibits the strongest association constant with chloride ($K_a = 207$, Table 1, entry 1). The binding constant is better than those previously reported for BTI receptors and more than ten times higher compared to that for hemicryptophane **2**, presenting less π-acidic surfaces.²³,²⁴ These observations are also supported by ¹⁹F NMR (Fig. S20†) as well as ESI-MS (Fig. S41†). Bromide and iodide affinities are weaker (Table 1, entries 2 and 3), which demonstrate slight selectivity. As postulated, hemicryptophane **2** shows much lower affinities for halides, 5 to 17 times lower for bromide and iodide, respectively. Next, we investigated the linear guest triiodide (Table 1, entry 4). Hemicryptophane **2** has no affinity for this guest, while hemicryptophane **1** shows the highest affinity ($K_a = 416$) among the tested anions. The highest polarizability of $I_3^-$ could lead to stronger London and anion-π interactions, which might account for these experimental results. Moreover, this is the first example of the recognition of triiodide by a BTI-based receptor. Finally, we set out to investigate trigonal planar anions that might better fit the geometry of our molecular cages. Nitrate was evaluated since it is known to have a good affinity for electron-deficient receptors.²⁹ However, the titrations show very low affinity for our hosts, with the best binding obtained for receptor **2** ($K_a = 66$, Table 1, entry 5). The complex between hemicryptophane **2** and $NO_3^-$ was also observed by ESI-MS (Fig. S44†). It could be suggested that the lack of recognition ability of **1** toward the nitrate anion might be due to electronic repulsion between nitrate and the fluorine atoms on the xylylene linkers. Acetate was also tested, and again higher binding constants were observed for the most electron-deficient receptor **1** ($K_a = 99$) (Table 1, entry 6). Anion screening was continued with larger volume anions such as hexafluorophosphate, perrhenate, dihydrogenphosphate and picrate, but these showed low or no affinity for hemicryptophanes **1** and **2** ($K_a = 22, 28, <1, <1$ for **1**, respectively, Table 1, entries 7–10).

We then performed DFT geometry optimization for the complex between chloride and hemicryptophane **1**. It was observed that the anion is positioned close to the BTI surface with a short distance to the carbon of the benzene moiety ($d = 2.82 Å$), supporting functional anion-π interactions (Fig. 5).

<figure><img src="image_9.png" /><figcaption>**Fig. 4** (a) DFT optimized structure of hemicryptophanes **1** and **2**, together with their (b) calculated cavity volumes (MoloVol) and (c) electrostatic potential (ESP) maps. The ESP is mapped on the electron density iso-surface of 0.003 a.u. The red colour corresponds to a negative region of the electrostatic potential (−0.04 au), and the blue colour corresponds to the region where the potential is positive (+0.04 au).</figcaption></figure>

<table><caption>**Table 1** Binding constants of hemicryptophanes **1** and **2** for anions obtained by ¹H NMR titrations in $CDCl_3$ at 298 K (estimated error <20%)</caption><thead><tr><th>Entry 1</th><th>Guest</th><th>1</th><th>2</th></tr></thead><tbody><tr><td>1</td><td>Cl<sup>-</sup></td><td>207</td><td>20</td></tr><tr><td>2</td><td>Br<sup>-</sup></td><td>21</td><td>4</td></tr><tr><td>3</td><td>I<sup>-</sup></td><td>84</td><td>5</td></tr><tr><td>4</td><td>I<sub>3</sub><sup>-</sup></td><td>416</td><td>2</td></tr><tr><td>5</td><td>NO<sub>3</sub><sup>-</sup></td><td>&lt;1</td><td>66</td></tr><tr><td>6</td><td>AcO<sup>-</sup></td><td>99</td><td>&lt;1</td></tr><tr><td>7</td><td>PF<sub>6</sub><sup>-</sup></td><td>22</td><td>14</td></tr><tr><td>8</td><td>ReO<sub>4</sub><sup>-</sup></td><td>28</td><td>21</td></tr><tr><td>9</td><td>H<sub>2</sub>PO<sub>4</sub><sup>-</sup></td><td>&lt;1</td><td>&lt;1</td></tr><tr><td>10</td><td>Picrate</td><td>&lt;1</td><td>&lt;1</td></tr></tbody></table>
<figure><img src="image_10.png" /><figcaption>Fig. 5 Optimized structure of the complex $Cl^-@hemicryptophane 1$.</figcaption></figure>

Moreover, the electron-deficient perfluoroxylylene linker exposes its aromatic surface towards the chloride, which could increase anion recognition.

## Conclusions

In conclusion, we have designed and synthesized an electron-deficient hemicryptophane receptor capable of effectively recognizing anions solely through enhanced anion-π interactions. By incorporating perfluoroxylylene arms and a benzene triimide (BTI) unit into the hemicryptophane structure, we created an electron-deficient confined environment that significantly improved anion affinity. Our binding studies revealed improved association constants for the hemicryptophane equipped with tetrafluoroxylylene linkers, particularly for chloride ($K_a$ = 207), and a unique affinity for triiodide, representing the first instance of triiodide recognition by a BTI-based receptor. These results underscore the effectiveness of combining π-acidic surfaces within the receptor's cavity to strengthen binding affinities with anions. Moving forward, this strategy could be applied to develop more selective and efficient systems for complex biological and environmental applications where precise anion recognition is crucial.

## Data availability

The data supporting this article have been included as part of the ESI.†

## Conflicts of interest

There are no conflicts to declare.

## Acknowledgements

Y. C. and A. M. thank the Agence Nationale de la Recherche for funding the APICOCAT project (grant ANR-21-CE07-0011)

and the Co-LAB project (grant ANR-19-CE07-0024). We would like to thank Sabine Chevallier Michaud for low-resolution mass spectrometry and the Spectropole in Marseille for characterization. We also acknowledge the 'Centre de Calcul Intensif d'Aix-Marseille' for granting us access to its high-performance computing resources.

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