# Unveiled Impact of 211 At-Labeled Compounds' Ability to Form Halogen Bonds on their In Vivo Stability

Samuel D Mador, Thibault Yssartier, Jean-Yves Le Questel, Gilles Montavon,

François Guérard, Nicolas Galland

► To cite this version:

Samuel D Mador, Thibault Yssartier, Jean-Yves Le Questel, Gilles Montavon, François Guérard, et al. Unveiled Impact of 211 At-Labeled Compounds' Ability to Form Halogen Bonds on their In Vivo Stability. ACS Physical Chemistry Au, 2025, 10.1021/acsphyschemau.5c00091. inserm-05387652

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https://inserm.hal.science/inserm-05387652v1

Submitted on 28 Nov 2025

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Distributed under a Creative Commons Attribution 4.0 International License
# Unveiled Impact of <sup>211</sup>At-Labeled Compounds' Ability to Form Halogen Bonds on their *In Vivo* Stability

Samuel D. Mador,<sup>a</sup> Thibault Yssartier,<sup>a</sup> Jean-Yves Le Questel,<sup>a</sup> Gilles Montavon,<sup>b</sup> François Guérard,<sup>*c</sup> and Nicolas Galland<sup>*a</sup>

<sup>a</sup> Nantes Université, CNRS, CEISAM, UMR 6230, F-44000 Nantes, France. <sup>b</sup> IMT Atlantique, CNRS, SUBATECH UMR 6457, F-44307 Nantes, France. <sup>c</sup> Nantes Université, Inserm, CNRS, Université d'Angers, CRC12NA, Nantes, France.

KEYWORDS: astatine, halogen bonding, radiolabeling, deastatination, reaction mechanism, molecular recognition, DFT

**ABSTRACT:** <sup>211</sup>At is a radionuclide of great interest in nuclear medicine for cancer therapy, provided it is firmly bound to an appropriate targeting agent. In recent year, original <sup>211</sup>At-labeled compounds have shown promising *in vivo* stability, without the underlying logic being identified. Herein, molecular modeling (two-component relativistic DFT) is used to assess the hypothesis that the degradation mechanism(s), leading to the release of free <sup>211</sup>At, is related to the ability of labeled compounds to form halogen-bond interactions involving astatine. We highlight inhibition phenomena at play for a variety of compounds, in line with observations of enhanced stability, paving the way for a potentially applicable strategy to access robust radiopharmaceuticals.

## INTRODUCTION

The astatine-211 radioisotope (<sup>211</sup>At) is the subject of a growing interest as a promising radionuclide for targeted alpha therapy of cancers.<sup>1,2</sup> This stems from its intrinsic properties, especially its half-life of 7.2 h, with emission of a single high-energy α-particle per decay (5.9 – 7.4 MeV) with a short path length (80 – 100 μm). The main challenge of its successful application resides in finding a stable <sup>211</sup>At-labeled motif, coupled to a carrier biomolecule, that would avoid indiscriminate release of free <sup>211</sup>At in non-targeted tissues. The main labeling strategy is the formation of astatoaryl bonds such as in *N*-succinimidyl 3-[<sup>211</sup>At]astatobenzoate (SAB, Chart 1), but the At-C<sub>aryl</sub> bond lacks *in vivo* stability when small carrier molecules are used or when internalized within cells.<sup>1,3,4</sup> Uncovering the mechanism of *in vivo* deastatination of astatoaryl com-

pounds is a pressing concern, but is hampered by the impossibility of using spectroscopic tools. Indeed, astatine only has radioisotopes with short half-lives (<8.1 h) and its longest-lived can only be produced artificially in minute quantities (~ppb).<sup>5</sup> Modeling therefore appears to be a key technique for evaluating astatine chemistry at the molecular level.

Because astatine is seen as the strongest halogen-bond (XB) donor atom,<sup>6,7</sup> one possible hypothesis is that *in vivo* deastatination mechanism is triggered by XB interactions with protein functional groups, especially the selenocysteine residue present in T1 and T3 iodothyronine deiodinases. Using relativistic DFT calculations, this hypothesis has recently been put to the test of clarifying the improved stability of *N*-succinimidyl 3-[<sup>211</sup>At]astato-4-

<figure><img src="image_2.png" /><figcaption>Chart 1. <sup>211</sup>At-Labeled Scaffolds (top) and their Simplified Models (bottom) Studied Previously and in this Work</figcaption></figure>
guanidinomethylbenzoate (SAGMB, Chart 1) derivatives,⁸ still unexplained at the time. More recently, astatoaryl compounds sharing the [²¹¹At]astato-2,3-phenylene dimethanol motif (APDMR, Chart 1) also showed significantly greater resistance to deastatination and *in vivo* stability than the SAB analogs.⁹,¹⁰ These new compounds, which are neutral, in contrast to SAGMB, represent an interesting opportunity to confirm or refute the hypothesis of an enzymatic mechanism of astatoaryl dehalogenation that is controlled by the formation of an XB interaction with a selenocysteine residue.

Departing from SAB and other astatoaryls, we generalize our computational investigation to the possibility that deastatination is simply triggered by the formation of an At-mediated XB. Whereas the intrinsic strength of an At-C<sub>sp3</sub> bond is significantly weaker than that of At-C<sub>aryl</sub>,¹¹,¹² a recent compound based on the [²¹¹At]astatoneopentyl glycol motif (BHAN, Chart 1) has demonstrated much lower *in vivo* release of free ²¹¹At than its SAB counterpart.¹³ This improved stability motivated the evaluation of other compounds built on the BHAN scaffold,¹⁴ and our interest to elucidate this behavior on the basis of the hypothesis presented above. Prospects are also sketched for ²¹¹At-labeling of gold-based carriers, for which there is growing interest in targeted alpha therapy,¹⁵⁻¹⁷ with a focus here on a ²¹¹At-labeled gold(I) N-heterocyclic carbene complex, AuAt(IPr) (Chart 1), that has shown promising stability against deastatination.¹⁸

# RESULTS AND DISCUSSION

## Astatoaryl Compounds

Molecular modeling based on DFT calculations, and the use of models of ²¹¹At-labeled compounds to keep calculations tractable (Chart 1), showed that the formation of a XB interaction by an astatoaryl group with a deprotonated selenocysteine residue markedly activates the carbon bearing At.⁸ Attack by a nucleophile in a subsequent step of the enzymatic mechanism, controlled by iodothyronine deiodinases can lead to bond breaking with the halogen. Using the meta-hybrid PW6B95 and hybrid B3LYP functionals, that were extensively tested for astatine compounds,¹⁹⁻²¹ previous computations support the difference in *in vivo* stability between SAB and SAGMB conjugates.⁸ As shown with the OABG model (Chart 1), the introduction of the guanidinium group strongly favors the formation of hydrogen bonds (HBs) with the selenium atom of a selenocysteine model, ¹SeC₂H₅. Consequently, the formation of At-mediated XBs is totally inhibited,⁸ and the enzymatic deastatination mechanism cannot be triggered in SAGMB derivatives.

Interestingly, APDMR compounds exhibit two hydroxymethyl groups, which are HB donors, at the *ortho*-positions to ²¹¹At, and may compete with the XB-forming ability of such astatoaryls. Two-component relativistic DFT calculations enable us to quantify this competition between the HB and XB donor potentials towards the selenocysteine active site, on the basis of the APDM compound. The discussion below will be based on the PW6B95 results while the B3LYP results will only be invoked where they notably differ. APDM features a total of 25 stable

structures, i.e. conformers (Figure S1). Of these, 7 present one intramolecular

<figure><img src="image_3.png" /><figcaption>**Figure 1.** PW6B95 calculated structures of the most stable XB complexes between APDM and ¹SeC₂H₅. Atom color codes: violet for At, red for O, orange for Se, gray for C, and white for H.</figcaption></figure>

<figure><img src="image_4.png" /><figcaption>**Figure 2.** PW6B95 calculated structures of the most stable HB complexes between APDM and ¹SeC₂H₅. Atom color codes: violet for At, red for O, orange for Se, gray for C, and white for H.</figcaption></figure>

hydrogen bond (IMHB) involving one hydroxyl group hydrogen and the astatine atom as acceptor. In addition to these 7 conformers, 2 have two IMHBs, but 16 have no IMHB, respectively constituting 50, 7 and 43% of the mixture according to a Boltzmann distribution.

On complexation of APDM with ¹SeC₂H₅, the 5 most stable complexes keep 2 IMHB (Figure 1) and account for 91% of the population. These complexes show a strong XB interaction between At and Se atoms, owing to their linear C-At-Se bond angle (~178°) and At-Se interaction distances about 77% of the sum of the atoms' van der Waals radii.²² The next 7 more stable XB complexes have 1 IMHB and constitute 8% of the distribution (Figure S2, **1f-1l**), while the remaining XB complexes (1% of the conformational mixture) have at most 1 IMHB. The average interaction energy (weighted by Boltzmann populations) is -117.3 kJ/mol, which is much higher than the previously computed
ed XB interaction between PhAt and ·SeC₂H₅ (-86.6 kJ/mol).⁸ It should be noted that, based on a well-known synergistic mechanism,²³ the formation of IMHB with the nucleophilic belt of the atstatine

<table><caption>**Table 1 Relative Stabilities (ΔG°r, kJ/mol), Boltzmann Populations (pᵢ, %) and Free Energy of Solvation in the Aqueous Phase (ΔG*sol, kJ/mol) for the Main Complexes Between APDM and ·SeC₂H₅* a**</caption><thead><tr><th></th><th>1a</th><th>1b</th><th>1c</th><th>1d</th><th>1e</th><th>1f</th></tr></thead><tbody><tr><td>ΔG°r</td><td>0.0</td><td>0.6</td><td>2.6</td><td>2.7</td><td>3.1</td><td>7.5</td></tr><tr><td>pᵢ</td><td>33</td><td>26</td><td>12</td><td>11</td><td>9</td><td>2</td></tr><tr><td>ΔG*sol</td><td>-197.2</td><td>-197.2</td><td>-197.0</td><td>-197.4</td><td>-196.6</td><td>-204.2</td></tr><tr><td>pᵢ(aq)</td><td>5</td><td>4</td><td>2</td><td>2</td><td>1</td><td>4</td></tr><tr><td><strong>1g</strong></td><td><strong>1h</strong></td><td><strong>1i</strong></td><td><strong>1j</strong></td><td><strong>1k</strong></td><td><strong>1l</strong></td><td></td></tr><tr><td>ΔG°r</td><td>7.8</td><td>7.8</td><td>7.9</td><td>7.9</td><td>8.8</td><td>9.0</td></tr><tr><td>pᵢ</td><td>1</td><td>1</td><td>1</td><td>1</td><td>1</td><td>1</td></tr><tr><td>ΔG*sol</td><td>-204.5</td><td>-204.4</td><td>-204.3</td><td>-204.4</td><td>-203.7</td><td>-203.4</td></tr><tr><td>pᵢ(aq)</td><td>4</td><td>4</td><td>4</td><td>4</td><td>2</td><td>2</td></tr><tr><td><strong>1m</strong></td><td><strong>1n</strong></td><td><strong>1o</strong></td><td><strong>1p</strong></td><td><strong>1q</strong></td><td><strong>1r</strong></td><td></td></tr><tr><td>ΔG°r</td><td>13.0</td><td>13.6</td><td>36.5</td><td>38.4</td><td>39.9</td><td>41.3</td></tr><tr><td>pᵢ</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>ΔG*sol</td><td>-211.7</td><td>-211.8</td><td>-232.6</td><td>-233.8</td><td>-238.6</td><td>-235.8</td></tr><tr><td>pᵢ(aq)</td><td>9</td><td>8</td><td>3</td><td>2</td><td>9</td><td>2</td></tr></tbody></table>

a 1a-n are XB complexes while 1o-r are HB complexes.

enhances the electrophilic character of the halogen σ-hole, thereby reinforcing its XB donating ability.

The hydroxymethyl groups equally lead to the formation of HB interactions with ·SeC₂H₅ (Figure 2). The average interaction energy (weighted by Boltzmann populations) for these complexes is -83.6 kJ/mol, which is about 29% lower than for the XB complexes. Hence, the HB complexes account for less than 1% of the total population. From this finding, it seems the presence of the two hydroxymethyl groups should not hinder the formation of At-mediated XBs between APDMR compounds and a selenocysteine residue.

## Hydrophilic Biological Medium

The competition between the ability of APDMR compounds to interact via HB or XB was also investigated for hydrophilic and polar conditions. For each complex, its Gibbs energy of solvation in aqueous phase (ΔG*sol) was calculated using the SMD solvent model. The results for the main complexes are shown in Table 1, with Boltzmann populations recalculated for these conditions. The HB complexes solvate much better than the XB ones, at least by 21 kJ/mol. In the aqueous environment, the mixture is much more varied and the structures that stand out with the most populations are two XB complexes (9 and 8%) and one HB complex (9%). The HB complexes account overall for 26%, the XB complexes being 2.6 kJ/mol in average more stable than HB ones. Note that the B3LYP calculations predict, conversely, that the XB complexes account for 12% while the HB complexes represent 88% of the mixture (the HB complexes being 4.9 kJ/mol more stable). The HB complexes change from minority to majority between the two levels of theory. The main and interest-

ing point is that the XB complexes do not account for 100% of the population as it should be for SAB conjugates: this reduced probability of forming a XB complex implies an even lower probability to initiate the following steps of the deastatination mechanism proposed previously.⁸ The root cause is the introduction of

<table><caption>**Table 2 Relative Stabilities (ΔG°r, kJ/mol), Boltzmann Populations (pᵢ, %) and Free Energy of Solvation in the Aqueous Phase (ΔG*sol, kJ/mol) for the Main Complexes Between AtNpG and ·SeC₂H₅* a**</caption><thead><tr><th></th><th>2a</th><th>2b</th><th>2c</th><th>2d</th><th>2e</th><th>2f</th></tr></thead><tbody><tr><td>ΔG°r</td><td>0.0</td><td>4.0</td><td>4.0</td><td>4.5</td><td>-17.7</td><td>-17.6</td></tr><tr><td>pᵢ</td><td>0</td><td>0</td><td>0</td><td>0</td><td>35</td><td>33</td></tr><tr><td>ΔG*sol</td><td>-202.8</td><td>-200.6</td><td>-200.2</td><td>-210.4</td><td>-202.1</td><td>-202.4</td></tr><tr><td>pᵢ(aq)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>16</td><td>18</td></tr><tr><td><strong>2g</strong></td><td><strong>2h</strong></td><td><strong>2i</strong></td><td><strong>2j</strong></td><td><strong>2k</strong></td><td><strong>2l</strong></td><td></td></tr><tr><td>ΔG°r</td><td>-15.5</td><td>-14.4</td><td>-12.9</td><td>-11.0</td><td>-6.6</td><td>0.1</td></tr><tr><td>pᵢ</td><td>15</td><td>9</td><td>5</td><td>2</td><td>0</td><td>0</td></tr><tr><td>ΔG*sol</td><td>-202.5</td><td>-202.7</td><td>-202.9</td><td>-208.7</td><td>-212.9</td><td>-216.7</td></tr><tr><td>pᵢ(aq)</td><td>8</td><td>5</td><td>3</td><td>16</td><td>14</td><td>4</td></tr></tbody></table>

a 2a-d are XB complexes while 2e-l are HB complexes.

<figure><img src="image_5.png" /><figcaption>**Figure 3.** PW6B95 calculated structures of the most stable XB complexes between AtNpG and ·SeC₂H₅. Atom color codes: violet for At, red for O, orange for Se, gray for C, and white for H.</figcaption></figure>

hydroxymethyl groups, which will hinder the ability of the astatoaryl to form XBs with the selenocysteine residue in deiodinase enzymes. The HB donating ability of hydroxymethyl groups will impair enzyme recognition and explain the improved stability observed for APDMR compounds.⁹,¹⁰

## Neopentyl Glycol Scaffold

We then turned our attention to compounds other than astatoaryls. The two hydroxymethyl groups at the ortho-positions in APDMR mimic the structural arrangement around ²¹¹At in BHAN scaffold. A recent work by Suzuki and colleagues has also shown greater *in vivo* stability of a BHAN derivative than its astatoaryl counterpart,¹³ which is linked to the presence of hydroxyl groups, although their role is not specified. While it is unlikely that the enzymatic mechanism of astatoaryl dehalogenation is common to BHAN derivatives, the At-C₅₃ bond breaking may well
remain enzymatic and governed by specific interactions
with protein functional groups. The active site of
selenocysteine may then provide a suitable probe for
quantifying potential interactions with nucleophilic pro-
tein sites, AtNpG serving as a model for BHAN derivatives.
In AtNpG, the hydroxyl groups can form IMHBs with each
other (OH···O type) or with the astatine atom as acceptor
(OH···At type). PW6B95 calculations yielded 84 stable
conformers (Figure S3). About 21% of the mixture are
structures with no IMHB

<figure><img src="image_6.png" /></figure>

**Figure 4.** PW6B95 calculated structures of the most stable HB complexes between AtNpG and ·SeC₂H₅. Atom color codes: violet for At, red for O, orange for Se, gray for C, and white for H.

while 48% have 1 IMHB (32% of OH···O type and 16% of
OH···At type). The remaining 31% have 2 IMHBs, with one
of OH···O type and the other of OH···At type.

Interaction of AtNpG with ·SeC₂H₅ gives XB complexes (Figure 3) characterized by linear interaction angles of ~179° and interaction energies of about -91 kJ/mol for the most stable complexes. However, the XB complexes are not represented (≈ 0%, Table 2) in the mixture of the AtNpG···SeC₂H₅ complexes, which is dominated by complexes formed by HB interactions. The four most stable of these are shown in Figure 4 and account for 92% of the population. The interaction distances are short, indicating strong interactions. They range from 77 to 79% of the sum of the atom's van der Waals radii.²² The HB interaction energies are at least -119 kJ/mol, i.e. ~30 kJ/mol stronger than the most stable XB complexes. Hydroxyl groups most probably control the ability of motifs like AtNpG to interact with nucleophilic protein sites.

To validate this finding, the influence of a hydrophilic
and polar environment was accounted for by means of the
SMD solvent model. The Gibbs energies of aqueous solva-
tion for the complexes are given in Table 2. Because the
ΔG<sub>sol</sub><sup>°</sup> values are in general slightly higher for the HB com-
plexes, the population of the XB complexes remain near-
zero while that of HB complexes is ~100%. The B3LYP
calculations perfectly match, AtNpG being definitively a
much better HB donor than XB donor, as should be the
case for BHAN derivatives. This outcome must be seen in
the context of much higher *in vivo* stability observed for
the halogenated neopentyl glycol (NpG) structure than its

non-hydroxylated counterpart.¹³ Therefore, a coherent
explanation is that the presence of hydroxyl groups pre-
vents the formation of At-mediated XB interactions with
protein functional groups, which inhibits the subsequent
steps of a deastatination mechanism. This reasoning shows
clear similarities with the explanation given for the im-
proved stability of APDMR compounds.

Gold-Based Carriers

The hypothesis of potentially improved stability by mini-
mizing the ability of radiopharmaceutical candidates to
interact through At-mediated XBs, is now assessed in the
case

<figure><img src="image_7.png" /></figure>

**Figure 5.** PW6B95 calculated local electrophilicity for PhAt and AuAt(IME) at their molecular surfaces (defined by 0.001 a.u. isovalues of the electron density), with the maximum value, ω<sup>+</sup><sub>S,max</sub>, given at the astatine σ-hole. Color code: from red (lowest values) to blue (highest values).

of a compound further differentiating itself from
astatoaryls. The use of gold nanoparticles as carriers for
transporting <sup>211</sup>At in targeted alpha therapy has already
been the subject of several studies, very recently reviewed
by Tanudji et al.<sup>17</sup> On our side, we have designed the first
monogold astatine complex that was found highly stable in
phosphate-buffered saline (PBS), an isotonic solution mim-
icking pH and chloride concentration in blood.<sup>18</sup> The At-Au
bond in AuAt(IPr) highlights a significant charge-shift
character,<sup>24</sup> which is known to translate into a weakened
electrophilicity at the astatine σ-hole and eventually weak-
er XB interactions.<sup>20,21,25</sup> Furthermore, it has been shown
that the nature of the Au-At bond would be little affected
by the gold atom's environment,<sup>24</sup> and <sup>211</sup>At-labeled gold
nanoparticles have demonstrated stability *in vivo*.<sup>17</sup> The
question arises as to whether the *in vivo* stability of our
monogold astatine complex can be anticipated by its ability
to form XBs, for example when compared with the refer-
ence compound SAB.

Figure 5 shows the local electrophilicity ω⁺(*r*) calculat-
ed at the molecular surface of AuAt(IME) and PhAt, which
serve as models for AuAt(IPr) and SAB, respectively. A high
value of ω⁺(*r*) indicates an electrophilic zone, clearly high-
lighting for example the σ-hole structure at the astatine
atom in PhAt. The local maximum value, ω<sup>+</sup><sub>S,max</sub>, can be
used to probe the intrinsic potential to form XB interac-
tions.<sup>20</sup> From the values shown in Figure 5, it is clear that
AuAt(IME) is a weak XB donor. Its maximum
electrophilicity value at the σ-hole is only 5% of that of
PhAt (9% according to B3LYP calculations). This trans-
lates, when AuAt(IME) and PhAt are brought into interac-
tion with ·SeC₂H₅ as a nucleophilic probe, into average
interaction energies of 23.3 and -86.6 kJ/mol, respectively.
The positive interaction energy value, confirmed by B3LYP
calculations (26.2 kJ/mol), indicates even unfavorable XB interaction with the astatine atom of AuAt(IME). The potential influence of an aqueous environment has also been taken into account, using the SMD solvent model. It appears that the XB structures of the AuAt(IME)···SeC₂H₅ complex (Figure S5) dissociate in such conditions, confirming the low propensity of compounds such as AuAt(IPr) to interact through At-mediated XBs. This finding may justify the promising stability against deastatination very recently shown for AuAt(IPr).¹⁸

## CONCLUSIONS

In this work, we evaluated the hypothesis of a dehalogenation mechanism of ²¹¹At-labeled aryl compounds initiated by the formation of an At-mediated halogen bond with the selenocysteine residue present in some iodothyronine deiodinases. In addition to rationalizing the high *in vivo* stability of SAGMB derivatives,⁸ our relativistic DFT calculations show that this hypothesis supports the improved stability of compounds with an APDMR motif. We then considered that the deastatination mechanism could be more general, *i.e.* essentially under the control of the initial formation of a halogen-bonded interaction between the astatine atom and a nucleophilic site present in the biological environment. Molecular modelling results may indeed justify the limited *in vivo* deastatination of BHAN derivatives, while the enzymatic mechanism specific to astatoaryls would not be applicable, but the common presence with APDMR of hydroxymethyl groups protects from the formation of At-mediated halogen bonds.

A potential strategy for accessing effective ²¹¹At-radiopharmaceuticals is therefore emerging, which would be to control their ability to establish halogen-bonded interactions. One option is to introduce competitive functional groups, *e.g.* hydroxymethyl groups at the *ortho*-positions as illustrated above, and/or electron-donating groups that would weaken the *σ*-hole at the astatine site. An alternative option would be to play on the nature of the bond between the astatine and the carrier molecule, *i.e.* limiting the covalent character. The charge-shift character recently established for the At-Au bond in AuAt(IPr),²⁴ minors the astatine's propensity to form halogen bonds, which could justify the remarkable stability found for this monogold complex.¹⁸ This may coincide with the growing interest in targeted alpha therapy for ²¹¹At-radiolabeling of gold compounds.¹⁷

## METHODS

The two-component (2c) relativistic density functional theory (DFT) was proven to be accurate for investigating At-containing species.¹⁹,²⁶ The Generalized Kohn-Sham (GKS) method of the Gaussian 16 program²⁷ takes advantages of relativistic pseudo-potentials containing scalar and spin-dependent terms to treat the electron correlation and the relativistic effects on an equal footing. We opted for the global-hybrid B3LYP and meta global-hybrid PW6B95 functionals, which are two of the very best among 36 DFT methods tested in a benchmark study focusing on At-species.¹⁹ In addition, these two DFT functionals have been shown to accurately describe At-mediated halogen-

bond interactions, compared with results obtained with the CCSD(T) "gold standard" method.²⁰,²¹ The small core pseudo-potentials ECPnMDF with *n* = 10 and 60 were used for the Se and At atoms, respectively.²⁸,²⁹ Two sets of basis functions were used for describing the explicitly treated electrons. The AVDZ set of double zeta quality, selected solely for the geometry optimizations and subsequent frequency calculations, combines the aug-cc-pVDZ-PP basis sets²⁸ supplemented with two-component extensions for At,²⁶ the aug-cc-pVDZ-PP basis set for Se,²⁸ and the cc-pVDZ basis sets for the remaining atoms, augmented with diffuse functions for non-H atoms.³⁰⁻³² The TZVPD set of triple zeta quality, used solely for single-point energy calculations on previously optimized geometries, combines the dhf-TZVPD-2c basis sets for the At atom,³³ and the def2-TZVP basis sets for the remaining atoms,³⁴ augmented with diffuse functions for non-H atoms.³⁵ Energies of all complexes were corrected from the basis set superposition error (BSSE) using the counterpoise method.³⁶

For each species, its Gibbs free energy at *T* = 298.15 K is estimated using (i) the energy computed with one DFT functional (B3LYP or PW6B95) and the TZVPD basis set, and (ii) the thermodynamic corrections from the frequency calculation performed with the same functional and the AVDZ basis set. Note that some species exhibit several competitive conformers, their Gibbs free energies have been then evaluated using a Boltzmann distribution:

$$G_{\{x\}} = -RT \ln \left( \sum_{i \in \{x\}} \exp(-G_i / RT) \right)$$

where the summation runs over all the conformers of the *x* species. The influence of the solvent on some of the studied species was introduced by means of an implicit solvent model, namely SMD.³⁷ Indeed, accurate Gibbs free energies of solvation can be predicted using such models, provided that specific parameters are used to build atomic cavities. The recommended Coulomb radius for astatine is 2.93 Å.⁸ The procedure used to compute free energies of aqueous solvation (*T* = 298.15 K, 1 mol/L standard state) was to perform, on top of previously optimized geometries, gas-phase and SMD single-point energy calculations using the TZVPD basis set.

Conceptual density functional theory provides appealing and general-purpose models for chemical reactivity. In addition to descriptors used to probe the charge-control in molecular interactions, *e.g.* the local maximum value of the electrostatic potential at the molecular surface (*V*<sub>S,max</sub>), we have proposed to use the local electrophilicity *ω*(*r*) to characterize the *σ*-hole properties.³⁸ This function is defined as the product between the global electrophilicity index *ω* of the system and the *f*(*r*) Fukui function. The Fukui function for nucleophilic attack is obtained using the finite difference method as:

$$f^*(r) \approx \rho_{N+1}(r) - \rho_N(r)$$

where *ρ*<sub>N</sub> and *ρ*<sub>N+1</sub> are the electron densities of the neutral species (*N* electrons) and of the corresponding anion (*N*+1 electrons) at the geometry of the neutral species. Furthermore, the electronegativity, *χ* = ½(IP+EA), and the hardness, *η* = (IP-EA), were obtained from the vertical ionization potential (IP) and electron affinity (EA) values. The
global electrophilicity index then reads as $\omega=\chi^2/2\eta$. The local maximum value of $\omega^*(r)$ at the molecular surface, $\omega_{S,max}^+$, can be viewed as the complementary analogue of the $V_{S,max}$ descriptor, dedicated to probe the orbital-control in the XB interaction.³⁸ All local descriptors have been determined from 2c-DFT/TZVPD calculations.

## ASSOCIATED CONTENT

**Supporting Information.** The Supporting Information is available free of charge at https://pubs.acs.org.
Additional figures as mentioned in the text, geometries as Cartesian coordinates for the most relevant complexes, additional discussions (DOC).

## AUTHOR INFORMATION

### Corresponding Author

François Guérard, e-mail: francois.guerard@univ-nantes.fr

Nicolas Galland, e-mail: nicolas.galland@univ-nantes.fr

### Author Contributions

J.-Y.L.Q. and N.G. conceived and coordinated the project; S.D.M., T.Y. and N.G. performed the calculations and wrote the manuscript draft; S.D.M., T.Y., J.-Y.L.Q., G.M., F.G. and N.G have given contributions to the final version of the manuscript. Views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them.

### Funding Sources

This work was supported by the French National Agency for Research, grants ANR-11-LABX-18-01 (Labex IRON), ANR-16-IDEX-0007 (ISITE NExT), the French National Cancer Institute, grant INCa-DGOS-INSERM-ITMO Cancer_18011 (SIRIC ILIAD), and co-funded by the European Union (ERC, SAt-Radio, 101087175).

### Notes

The authors declare no competing financial interest.

## ACKNOWLEDGMENT

This work was carried out using HPC resources from CCIPL ("Centre de Calcul Intensif des Pays de la Loire").

## ABBREVIATIONS

2c, two-component; DFT, density functional theory; HB, hydrogen bond; IMHB, intramolecular hydrogen bond; PhAt, astatobenzene; SAB, N-succinimidyl 3-[²¹¹At]astatobenzoate; XB, halogen bond.

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