# Chalcogen Bonds: How to Characterize Them in Solution ?

Patrick Pale, Victor Mamane

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## To cite this version:

Patrick Pale, Victor Mamane. Chalcogen Bonds: How to Characterize Them in Solution?. ChemPhysChem, 2022, 24 (4), 10.1002/cphc.202200481. [https://doi.org/10.1002/cphc.202200481](https://doi.org/10.1002/cphc.202200481)

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# Chalcogen Bonds: How to Characterize Them in Solution?

Patrick Pale*<sup>[a]</sup> and Victor Mamane*<sup>[a]</sup>

Chalcogen bonds (ChBs) occur between molecules containing Lewis acidic chalcogen substituents and Lewis bases. Recently, ChB emerged as a pivotal interaction in solution-based applications such as anion recognition, anion transport and

catalysis. However, before moving to applications, the involvement of ChB must be established in solution. In this Concept article, we provide a brief review of the currently available experimental investigations of ChB in solution.

## Introduction

According to IUPAC, a chalcogen bond (ChB) results from *net attractive interaction between an electrophilic region associated with a chalcogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity*. [1] In other words, the term ChB describes the inter- or intra-molecular non-covalent interaction (NCI) occurring between a Lewis base ($B_L$) and a chalcogen atom ($Ch=S, Se, Te$) acting as Lewis acid (Figure 1).

Such NCI is very similar to the more common halogen bond (XB). [2] Both are now understood through the concept of σ-hole, resulting of anisotropic electronic densities within covalently-bonded atoms. [3] Regions of lower density lying on the extension of a σ bond are called σ-holes. [4] Associated with positive electrostatic surface potentials, σ-holes can induce attractive interactions with negative sites (lone pairs, anions, π-electrons). In sharp contrast to hydrogen bonds (HB), the high directionality of XB and ChB (Figure 1) and experimental and theoretical studies have also suggested that dispersion and orbital delocalization effects, especially n-σ* orbital interactions, make important contributions to σ-hole interactions. [5]

Whatever its exact nature, ChB possesses many similarities to XB, [6] but with a different interaction pattern. Due to the divalent nature of Ch atoms, two σ-holes can be identified and even three for chalcogenonium, [7] instead of one for halogen atom. More than one ChB can thus be established, and due to the lone pairs of Ch atoms, the latter can act both as Lewis base ($B_L$) and as Lewis acid through its σ-holes.

As for XB, but roughly a decade later, [8] ChB has been mostly investigated in solid state, [9] has been identified in biological systems [10] and is currently raising increasing interest in coordination chemistry [11] and organic chemistry, especially in anion recognition, anion transport and organocatalysis. [12]

<figure><img src="image_13.png" /><figcaption>**Figure 1.** Halogen and chalcogen atoms: their electrostatic surface potential maps highlighting their σ-holes (blue zones) and the resulting NCI with Lewis base.</figcaption></figure>

However, the latter aspects require exploiting and controlling ChB in solution. Unfortunately, characterizing and measuring such interactions in solution remains a difficult task, due to their weakness but also to possible competition with solvent molecules.

As guidelines to do so, the present essay covers the so far applied and possible experimental investigations of ChB in solution.

## Assessing ChB presence

The main tool to establish the presence of ChB remains X-ray diffraction (XRD), able to provide geometric information, especially bond distances and angles, although ChB weakness sometimes induce the formation of crystals assembled through other (stronger) NCI. [13] Unfortunately, ChB observed through XRD may or not be maintained in solution for the same reasons. In solution, ChB presence can be assessed by a handful set of techniques and their adequate combination. They are briefly surveyed here.

Besides using the techniques mentioned below, ChB assessment is often supported by theoretical calculations. [14] However, the correct evaluation of solvent effects in ChB systems through calculations is not an easy task. [15] In this respect, molecular balances represent an interesting alternative (see below). [16]

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

<footnote>[a] Prof. Dr. P. Pale, Dr. V. Mamane
UMR 7177, LASYROC
CNRS and Strasbourg University
4 rue Blaise Pascal, 67000 Strasbourg, France
E-mail: vmamane@unistra.fr
ppale@unistra.fr</footnote>

<footnote>© 2022 The Authors. ChemPhysChem published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</footnote>
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## Multinuclear NMR

Although identified as early as 1998 through crystallographic studies on enzyme inhibitors,[17] S···O close contacts, as it was named at that time, were analyzed by theoretical tools in 2011,[18] but it is only very recently that the use in solution of such Ch···O interactions was reported (Figure 2).[19]

In crystals, hexafluorophosphate salts **1-COR** (Ch=S, Se) exhibit intramolecular ChB, but not the corresponding isourea (Ch=O) (Figure 2A). <sup>13</sup>C NMR confirms in CDCl<sub>3</sub> its respective presence and absence with carbonyl chemical shifts deshielded in S and Se compounds (δ<sub>C</sub>=174.5 and 174.0 ppm), compared to the oxygenated compound (δ<sub>C</sub>=169.7 ppm). nOe enhancement was observed for the corresponding *N*-acetyl isothio- and seleno-uronium salts **1-COCH<sub>3</sub>** but not for the isourea (Figure 2B). These results show that *N*-acyl isochalcogenuroniums **1-COR** adopt a locked conformation due to ChB which activates the carbonyl group and thus allows enantioselective acyl transfer in catalytic reactions.

Interestingly, such ChB induced conformational preferences have also been developed in molecular balances used to examine and evaluate solvent and substituent effects on ChB.[5b,16]

Besides the common <sup>1</sup>H and <sup>13</sup>C NMR, <sup>17</sup>O, <sup>77</sup>Se and <sup>125</sup>Te NMR can be used to identify and study ChB. The main interest

of using such Ch nuclei is their direct involvement in ChB, associated with their sensitivity and wide chemical shift range. In a seminal study,[20] δ<sub>O</sub> and δ<sub>Se</sub> values were collected for a series of specifically designed *ortho*-selenobenzaldehydes, alcohols and ethers. These values offer a good experimental measure for the strength of the Se···O interaction (Figure 3). Indeed, the shorter the Se–O atomic distance, the larger the <sup>17</sup>O NMR upfield shift for **2a–f** relative to PhCHO (dashed line in Figure 3, right) and this shift became larger as the electron-withdrawing ability of the Se substituent increased.

In a preliminary study for applications in organocatalysis, a series of diphenylmethyltelluronium derivatives **3** carrying electron-rich or -poor substituents was prepared (Figure 4A) and their ChB intensity evaluated through a combination of techniques.[7] Crystal structures revealed three ChBs between the more nucleophilic anions and the tellurium centre (Figure 4B). DFT calculations confirmed the presence of three σ-holes and allowed to assess their deepness (Figure 4C). In CD<sub>2</sub>Cl<sub>2</sub> solution, addition of <sup>17</sup>OPPh<sub>3</sub> induced significant shifts of <sup>17</sup>O, <sup>31</sup>P and <sup>125</sup>Te NMR signals, which can be correlated to the substituents σ Hammett constants and to the coordination ability of the anions. Furthermore, nOe were also detected between the *ortho*-protons of Ph<sub>3</sub>PO and the methyl group of the tellurium (Figure 4D), and *in situ* mass spectrometry allowed to detect the mass peak (849.0448) with isotopic distribution typical of a 1:1 adduct between **3-CF<sub>3</sub>** and Ph<sub>3</sub>PO (not shown). As expected, the largest NMR shifts and nOe were observed for the more electrodeficient tellurium [<sup>3-CF<sub>3</sub></sup>]<sup>+</sup>, the one having the largest σ holes with the less coordinating BAr<sub>4</sub><sup>F</sup> anions. Nevertheless, this in solution study also revealed that the effect of Ph<sub>3</sub>PO addition is balanced by other parameters, related to competition with the anions for interaction with the tellurium σ holes and may be some modifications of the tellurium geometry depending on interaction strength of the anion and/or Ph<sub>3</sub>PO.

<figure><img src="image_16.png" /><figcaption>**Figure 2.** Evidence of ChB in isochalcogenurea-based catalysis through XRD (A) and NMR (B).</figcaption></figure>

<figure><img src="image_17.png" /><figcaption>**Figure 3.** Variation of Se···O strength with NMR shifts δ<sub>O</sub> and δ<sub>Se</sub>. Reproduced from ref. [20]. Copyright (2004), with permission from American Chemical Society.</figcaption></figure>

<figure><img src="image_18.png" /><figcaption>**Figure 4.** Te···O ChB interaction between telluriums **3** and Ph<sub>3</sub>PO. Reproduced/adapted from ref. [7]. Copyright (2021), with permission from Wiley.</figcaption></figure>
<figure><img src="image_19.png" /></figure>

The strategy of combining XRD, theoretical calculations, ¹H and ¹²⁵Te NMR, and 2D NMR also allowed detection of Te···O ChB in solution between diaryl ditellurides and phosphine oxides.[13]

ChB between selenonium salts and dimethylacetamide could also be detected through carbonyl and selenium shifts in ¹³C and ⁷⁷Se NMR.[21]

The heteronuclear multiple quantum coherence (HMQC) NMR involving selenium and tellurium atoms was applied for the detection of ChB in supramolecular polymers between chalcogen-containing macrocyclic receptors 4 and bispyridine N-oxide 5 (Figure 5A).[22] In the ¹H-¹²⁵Te HMQC NMR spectrum, the two cross-correlation resonances corresponding to ³J<sub>T<sub>eq</sub>-H<sub>1</sub></sub> and ³J<sub>T<sub>eq</sub>-H<sub>3</sub></sub> couplings in 4-Te were altered upon addition of 5 (red signals compared to blacks ones in Figure 5B) because of the enhanced shielding effect caused by the N-oxide moiety trapped into the macrocyclic core through ChB with the four Te atoms (Figure 5C).

Isothermal Titration Calorimetry (ITC)

ITC is a technique measuring the thermodynamic data occur-
ring upon interactions in solution, which leads to accurate
estimation of binding constants. Mostly applied to
supramolecular and biological systems, this method has been
used since 2012 to investigate XB, especially solvent and
temperature effects as well as couteranion effects in the case of
charged molecules.[23] Regarding ChB study, the use of ITC is
scarce probably because of the Ch ability to interact with more
than one base.

<figure><img src="image_20.png" /><figcaption>**Figure 5.** (A) Structures of chalcogen-containing macrocyclic receptors 4 and bispyridine N-oxide 5. (B) 2D ¹H-¹²⁵Te HMQC NMR spectra of 4-Te in the absence (black signals) and presence of equimolar solution of 5 (red signals). (C) ChBs between 4a and 5. Reproduced/adapted from ref. [22], Copyright (2020), with permission from American Chemical Society.</figcaption></figure>

Te-derivative **6-Te** was shown to catalyze the addition of
methoxyindole to *trans*-β-nitrostyrene while the S- and Se-
analogs were almost inactive (Figure 6A).[24] Moreover, the BA*rf*<sub>4</sub>
salt **6-Te(BAr**<sub>4</sub><sup>F</sup>) proved to be more active than **6-Te(BF**<sub>4</sub><sup>-</sup>). To
explain it, their association constants K<sub>a</sub> to nBu<sub>4</sub>N<sup>+</sup>Cl<sup>-</sup> in CH<sub>2</sub>Cl<sub>2</sub>
were determined by ITC and those to *trans*-β-nitrostyrene by ¹H
NMR titrations. Expectedly, K<sub>a</sub>(Cl<sup>-</sup>) proved much higher com-
pared to K<sub>s</sub>(substrate), and in agreement with the catalysis
experiments, the more active catalyst **6-Te(BAr**<sub>4</sub><sup>F</sup>) binds slightly
more strongly than **6-Te(BF**<sub>4</sub><sup>-</sup>).

ITC is also a powerful tool for anion binding studies of ChB-
based anion receptors in water.[25] The **7-Te** receptor resulted in
very high affinity and selectivity for I⁻ over other anions (Br⁻,
Cl⁻, ReO₄⁻, NCS⁻ and ClO₄⁻). ITC experiments attested the
formation of a 2:1 **7-Te-I⁻** complex and molecular dynamics
simulations revealed that the I⁻ guest is actually held by an
average of five ChBs (Figure 6B).

The ITC technique was also used to determine the binding affinity of a few supramolecular assemblies,[26] including the supramolecular polymers between species 4 and 5 (see Figure 5).[22]

UV-Visible, Fluorescence and IR Spectroscopies

In a few cases, UV-vis, fluorescence or IR spectroscopies were
applied to investigate ChB strength.

In an interesting approach, benzochalcogenadiazoles **8** have been designed to monitor changes in their UV-vis absorbance or emission spectra upon ChB formations in solution.[27] Addition of increasing amount of nBu₄N⁺Cl⁻ to **8** in THF solution was accompanied by a chromophore red-shift (Figure 7A). This change could be fitted to a 1:1 binding

<figure><img src="image_21.png" /><figcaption>**Figure 6.** Binding constant (K) values from ITC experiments with catalysts 6-Te (A) and receptor 7-Te (B). Reproduced/adapted from ref. [25]. Copyright (2019), with permission from American Chemical Society.</figcaption></figure>
<figure><img src="image_22.png" /></figure>

isotherm by nonlinear regression analysis and allowed to determine a Kₐ of 970 ± 10 M⁻¹. Such titrations were performed with different substituents and in various solvents. The so-obtained Kₐ varied here again according to the solvent coordination ability.

This method, well-suited for the detection of ChB involving π-extended ChB donors, was employed for measuring dissociation constants K_D involving dithienothiophene-S,S-dioxides 9 as ChB-based anion transporters[12c] and benzodiselenazoles 10 as ChB catalysts (Figure 7B).[28] Chloride binding to these compounds in THF caused appreciable hypo- and bathochromism in their absorption spectra. For S-compounds 9, the stronger binding was observed with 9a bearing two strong electron-acceptor cyano groups. Substitution of cyano by sulfones (9b) or aldehydes (9c) moderately affected their K_D. Coherently, removing one cyano acceptor (9d) resulted in weaker binding. Se-compounds 10 with deeper σ-holes delivered much higher K_D, in the micromolar range. In this series, deepening the σ-hole of Se atoms by increasing the oxidation state of the side-sulfur substituents and thus their electron-withdrawing power, induced higher binding to Cl⁻.

In some cases, the detection of ChB in solution could be achieved by fluorescence spectroscopy. In particular, dithienothiophenes[29] such as derivatives 9 showed increased emission upon addition of chloride anions, as a result of ChB formation.[12c] In contrast, fluorescence quenching arose from the ChB formation between benzoselenadiazole-based derivative 11 and trimethylarsine (Me₃As) (Figure 7C).[30]

<figure><img src="image_23.png" /><figcaption>**Figure 7.** Binding *K* values from UV-visible titrations of compounds 8 (A), 9 and 10 (B) with Cl⁻. (C) Structure of benzoselenadiazole-based derivative 11. Reproduced/adapted from ref. [27]. Copyright (2015), with permission from American Chemical Society.</figcaption></figure>

Nevertheless, the use of IR spectroscopy is very limited because of the complexity of the recorded spectra at room temperature. It was however successfully used in order to confirm the intramolecular ChB in 1-COCH₃ (Figure 2). Indeed, IR stretching frequencies of the C=O bond in S- and Se-derivatives (1709 cm⁻¹ and 1713 cm⁻¹) were significantly shifted compared to the O-derivative (1748 cm⁻¹), as expected from the weakening of the carbonyl bond arising from n<sub>O</sub>→σ*<sub>S/Se-C</sub> delocalization.

IR spectra can be simplified by working at very low temperature in liquid krypton (120 K) and with a rigid ChB donor such as 2,2,4,4-tetrafluoro-1,3-dithiethane 12.[31,32] Under these conditions, simplified spectra could be obtained in the presence of 1,2-dimethoxyethane (DME), with appearance of several new bands associated with the Ch-bonded 12-DME 1:1 dimer, as confirmed by theoretical calculations (Figure 8). Furthermore, by working at various temperatures, the complexation enthalpy (−13.5(1) kJmol⁻¹) could be determined, again in good agreement with theory.

## Summary and Outlook

The presence of 2 or 3 σ-holes confers to chalcogens more possibilities of binding, while σ-hole deepness can be fine-tuned according to substituent, anion and solvent nature. In term of strength, ChB is comparable to HB, but its high directionality allows greater precision in 3D control. These interesting properties have initiated over the last five years the increasing ChB exploitation for solution-based applications such as anion recognition, anion transport and catalysis. Nevertheless, it is important to ascertain the real involvement of ChB when moving to applications, especially for (enantioselective) catalyst design.

Although significant progress has been achieved in probing σ-hole based interactions, ChB detection and characterization in solution is still challenging due to its weakness. As shown in this Concept article, multinuclear NMR spectroscopy is currently the method of choice, allowing to access binding constants *K* by titration and to detect ChB through 1D and 2D techniques. In a few cases, ITC as well as UV-vis, fluorescence or IR spectroscopies have also been used to determine *K* values and energies of association.

<figure><img src="image_24.png" /><figcaption>**Figure 8.** IR spectra of selected spectral regions for the mixtures of 12 with DME. Reproduced/adapted from ref. [31]. Copyright (2017), with permission from Wiley.</figcaption></figure>
<figure><img src="image_25.png" /></figure>

Acknowledgements

We thank the University of Strasbourg, the CNRS and the French
National Research Agency (ANR-21-CE07-0014) for financial
support.

Conflict of Interest

The authors declare no conflict of interest.

Data Availability Statement

Data sharing is not applicable to this article as no new data
were created or analyzed in this study.

Keywords: chalcogen bond • IR spectroscopy • ITC • Mmultinuclear NMR • UV-visible spectroscopy

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Manuscript received: July 7, 2022

Revised manuscript received: October 7, 2022

Accepted manuscript online: October 7, 2022

Version of record online: November 22, 2022