Aurélien Cocq

Cyril Rousseau

Hervé Bricout

Estefanía Oliva

Véronique Bonnet

Florence Djedaïni-Pilard

Eric Monflier

Sébastien Tilloy

Highly Water-Soluble Amphiphilic Cyclodextrins bearing Branched and Cyclic Oleic Grafts

Keywords: Cyclodextrin, Maleinisation, Oleic acid, Rhodium, Succinic anhydride

Amphiphilic β-cyclodextrins bearing various amounts of branched and cyclic oleic grafts are synthetized. The first step of this synthesis is the alkenylation of maleic anhydride by oleic acid derivatives, in the presence of a rhodium catalyst, to produce oleic succinic anhydrides with different ratios of cyclic to branched groups. The second step is the grafting of the oleic succinic anhydrides mixtures on β-cyclodextrin. The obtained cyclodextrins are highly water-soluble and surface active.

Introduction

To increase sustainability in chemical transformations, the utilization of renewable resources and catalytic processes has become an important field of research. [1] More precisely, vegetable oils are interesting resources to produce value-added products. [2] In this context, the maleinisation of oleic acid derivatives was described to produce interesting monomers for biobased polymers. More precisely, the addition of maleic anhydride on oleic acid derivatives can be performed either by a thermic way or by a rhodium-catalyzed way. The thermic way produced branched succinic anhydrides (BSA) at high temperature (around 220°C) as published by Candy and coll. (Scheme 1a). [3] The catalytic way enabled low reaction temperatures compared to the thermic way. Behr and coll. were the first to describe the rhodium catalyzed maleinisation of oleic acid derivative [4] followed by Eschig and al. (Scheme 1b). [5] This catalytic way mainly produced cyclic succinic anhydrides (CSA) but also BSA which are similar to the products formed by thermic way. Note that the CSA was not obtained without the use of a catalyst. In this context, we recently published the synthesis of new amphiphilic oleic succinyl-cyclodextrins obtained by esterification of various cyclodextrins (CDs) with branched oleic succinic anhydrides made from oleic acid or its methyl ester by thermic maleinisation. [6] In this publication, the aim was to synthetize oleic succinic anhydrides by using various amounts of rhodium catalyst to access different ratios of cyclic to branched products. These anhydrides were then Scheme 1: (a) Thermic and (b) rhodium-catalysed maleinisation of an oleic derivative.

____________________________________________________________ [a]

Dr. A. Cocq, Dr. C. Rousseau, Dr. H. Bricout, Prof. Dr. E. Monflier, Prof. Dr. S. Tilloy Univ. Artois, CNRS, Centrale Lille, ENSCL, Univ. Lille, UMR 8181, Unité de Catalyse et de Chimie du Solide (UCCS), 62300 Lens, France E-mail: sebastien.tilloy@univ-artois.fr Homepage: http://www.uccs.univ-artois.fr/sebastientilloy.htm [b] E. Oliva, Dr. V. Bonnet, Prof. Dr. F. Djedaïni-Pilard Laboratoire de Glycochimie des Antimicrobiens et des Agroressources,

LG2A UMR 7378 CNRS, Université de Picardie Jules Verne, 33 rue Saint-Leu, 80039 Amiens, France Supporting information for this article is given via a link at the end of the document used to esterify β-cyclodextrin producing amphiphilic βcyclodextrins bearing various amounts of branched and cyclic oleic grafts. The impact of the cyclic to branched ratio on physicochemical properties (aqueous solubility, critical aggregation concentration and surface tension) was also studied.

Branched

Results and Discussion

The oleic succinyl-β-CDs were synthetized in two steps. The first step of the synthetic pathway is the rhodium catalyzed addition of maleic anhydride (MA) to oleic acid derivative (methyl oleate (MO) or oleic acid (OA)) to produce branched succinic anhydrides and cyclic succinic anhydrides (BSA and CSA, respectively -Scheme 2). The addition reaction of the maleic anhydride (MA) to methyl oleate or oleic acid gave an anhydrides mixture named Z- [1]-BSA/CSA:X/Y. Z is a methyl group or a hydrogen atom, according to the MO or OA nature of the reactant. [1] or [0] is the number of C=C double bonds on the fatty acid derivative. X/Y are relative molar proportions in percentage of BSA and CSA. The BSA products are a mixture of 4 regioisomers [7] (represented as a single compound for simplification) whereas CSA product corresponds to 1 regioisomer (Scheme 1). This mixture of branched and cyclic products was originated from two catalytic mechanisms as described by Behr [4] and Eschig. [5] The mechanisms of thermic and rhodium-catalyzed maleinisations are presented in supporting information (see supporting information; Schemes S1 and S2, respectively). The table 1 summarized the obtained yields and distributions of branched and cyclic succinic anhydrides. From MA and MO in the presence of Rh2(OAc)4 at 140°C, a mixture of branched and cyclic anhydrides was obtained.

The ratio Me- [1]-BSA/Me- [1]-CSA increased when the amount of rhodium catalyst decreased whereas the yields were similar (Table 1; entries 1-2). The same conditions were also applied to the reaction with oleic acid instead of methyl oleate. The ratio H- [1]-BSA/H- [1]-CSA and the yield were equal to 56/44 and 42%, respectively (Table 1; entry 3). In the absence of catalyst and at the same temperature (140°C), only the branched compounds were produced with a low yield (14% -Table 1; entry 4).

Table 1. Catalytic and thermic maleinisation of methyl oleate (MO) and oleic acid (OA) [a] Entry Oleic Acid derivative %Rh [b] T(°C) t(h)

Obtained mixture Z-[x]-BSA/CSA:X/Y [c] Yield(%) [d] Me- [1]-BSA 40 [e] 6 OA -220 3 H- [1]-BSA 27 [e] [a] Maleic anhydride/oleic acid derivative molar ratio = 2 for entries 1-4 and 1.2 for entries 5 and 6; reaction without solvent; [b] Molar % of rhodium atom with respect to the oleic acid derivative used (catalyst = Rh2(OAc)4); [c] X/Y = relative molar proportions of BSA and CSA (%); [d] Maleinisation global yield; [e] Previous works used for comparison in italic. [6] H Entry Substrate Z- [1]-BSA/CSA:X/Y [b] Product Z-[0]-BSA/CSA:X/Y [b] Yield(%) [c] 1 [d] 4

H- [1]-BSA H-[0]-BSA 85 [d] [a] 2 mol. % of [Rh/C; 5% w/w], H2 (40 bar), THF (10 mL/g of initial mixture), 50°C, 24h; [b] X/Y = relative molar proportions of BSA and CSA (%); [c] Hydrogenation reaction yield; [d] Previous works used for comparison in italic. [6] This result confirmed that a rhodium catalyst was necessary to produce the cyclic anhydrides. For comparison, the entries 5 and 6 recalled our already published branched anhydrides obtained by thermic way. [6] The two results showed that higher temperature (220°C vs 140°C) was necessary to produce a higher quantity of branched products in a shorter time. To evaluate if the carboncarbon double bond of the branched chain or of the cyclic moiety could influence the physico-chemical properties of the oleic succinyl-β-CDs, hydrogenation of this bond from the anhydrides obtained by maleinisation was also performed in the presence of Rh/C (see supporting information). The hydrogenated mixture Me-[0]-BSA/CSA:64/36 and H-[0]-BSA/CSA:56/44 were obtained with yields of 85% and 90%, respectively (Table 2; entries 1 and 2). For comparison, the entries 3 and 4 recalled the already published results. The linear or cyclic nature of the carbon-carbon double bond did not influence the yields of hydrogenation reaction.

Table 3. Esterification of b-CD by the anhydride mixtures [a] Entry Anhydrides mixture used Z-[x]-BSA/CSA:X/Y [b] Obtained modified cyclodextrin β-CD-Z-[x]-Bn-Cm [c] n+m [d] Yield(%) [e] 1 [a] 1) Anhydride (2 molar eq./b-CD), Pyridine, 95 °C, 36 h, 2) HCl, 3) NaOH aq.

(1 eq. / CO2H), R.T., 3 h; [b] X/Y = relative molar proportions of BSA and CSA (%); [c] n = number of branched grafts (B) per CD; m = number of cyclic grafts (C) per CD; [d] n+m = average total number of grafts per CD; [e] Yield after neutralization with NaOH aq.; [f] Previous works used for comparison in italic. [6] Scheme 3: Names and representations of the synthetized modified cyclodextrins.

The second step of the synthetic pathway is the grafting of the unsaturated or saturated BSA/CSA mixture on β-CD. This step was performed as described for the syntheses of amphiphilic β-CD esters of alkenyl succinic acids published mainly by the group of de Rossi [8] and others groups. [6,9] The reaction was done in pyridine with 2 molar equivalents of the anhydride functions of the BSA/CSA mixture with respect to β-CD and allowed to produce various oleic succinyl-β-CDs (Scheme 3 and table 3). These products were named β-CD-Z- [1]-Bn-Cm and β-CD-Z-[0]-Bn-Cm. [1] or [0] is for the number of C=C double bounds on each graft (branched or cyclic). Z is methyl group or a sodium ion. m and n are the average number of branched and cyclic groups per β-CD, respectively. For B and C grafts, only one kind of structure is represented, among the two possible, knowing that each hydroxyl group of the CD can react with one or the other carbonyl group of the succinic anhydride used. Various oleic succinyl-β-CDs were obtained with a degree of substitution (n+m) between 0.9 and 1.6 and with yields from 36% to 87 % (table 3). The ratio branched/cyclic grafts in oleic succinyl-CDs is similar to that of in the anhydrides mixture (for example, for entry 1: Me-[1]-BSA/CSA:13/87 led to β-CD-Me-[1]-B0.2-C1.3 corresponding to percentages equal to 0.2/(1.3+0.2)x100=13% and 1.3/(1.3+0.2)x100=87%). This result showed that species BSA and CSA have the same reactivity towards β-CD. The yields obtained with mixed anhydrides are lower than those obtained with branched anhydrides (Table 3; compare entries 1-2 and3; 4 and5; 6 and7; 8 and9). The degrees of substitution are generally comprised between 1. 4 and1.6 (table 3, entries 1-7) except for CD grafted with saturated oleic acid anhydride (table 3, entries 8 and9). The aqueous solubility, critical aggregation concentration in water (CAC) and surface tension of aqueous solutions were measured for the synthesized CDs and were gathered in the table 4. The values of aqueous solubility of all CDs (50 -480 g/L at 20°C) were high compared to CDs possessing pure hydrophobic chains due to the presence of one or two carboxylate functions. At a similar substitution degree, the aqueous solubilities of modified CDs possessing cyclic grafts are higher than those with only branched grafts (table 4; compared entries 1, 2 and3; 4 and5; 6 and7; 8 and9). More precisely, at similar DS, the presence of cyclic grafts enabled to multiply the water-solubility by a factor 9, 1.6, 5 and 1.7 (table 4; compared entries 1 and 3; 4 and 5; 6 and 7; 8 and 9; respectively). This increase was higher for the CDs bearing the terminal methyl ester functions (table 4; entries 1 and3; 6 and7). Indeed, the aqueous solubilities of modified CDs with the terminal methyl ester functions were lower compared with those with the terminal carboxylate functions (table 4; compared entries 2 and 4; 6 and 8). This increase in water-solubility was due to the number of carboxylate functions per graft (one for the first series (Table 4; entries 1, 2, 3, 6 and 7) against two for the second series (Table 4; entries 4, 5, 8 and 9). For each compound, the critical aggregation concentration (CAC) and the surface tension value obtained at this concentration were determined by the Wilhelmy method. It should be noted that the lowest CAC values were obtained with CDs exhibiting cyclic grafts (Table 4; entries 1, 6 and8). The values of surface tension at the CAC at 20°C were situated between 29 and 48 mN/m. These values indicated that these modified cyclodextrins possessed a good surface activity compared to the native CDs which are not surface active. [10] Conclusions Amphiphilic β-cyclodextrins bearing various amounts of branched and cyclic oleic grafts were synthetized. These compounds were produced by esterification of β-cyclodextrin by oleic succinic anhydride derivatives obtained from oleic acid derivatives and maleic anhydride in the presence of a rhodium catalyst. These amphiphilic β-cyclodextrins are highly soluble in water (50-480 g/L). It is important to underline than modified CDs possessing cyclic grafts are more soluble in water than those with only branched grafts. In addition, these CDs possess low critical aggregation concentrations in water and aqueous solutions of these CDs exhibit low surface tensions. These properties could allow these new compounds to find applications in the field of surfactants and pharmaceuticals.

Table 4. Physico-chemical properties of the modified cyclodextrins

Entry

β-CD-Z-[x]-Bn-Cm [a] n+m [b] B/C(%) [c] Solubility at 20°C (g/L) CAC at 20°C (mg/L) Surface Tension (mN/m) [d] 1 β-CD-Me-[1]-B0. [e] 4 β-CD-Na-[1]-B0.9-C0. [e] 8 β-CD-Na-[0]-B0.5-C0.4 0.9 56/44 480 6 47 9 β-CD-Na-[0]-B0.9 0.9 100/0 280 170 38 [e] [a] n = number of branched grafts (B) per CD; m = number of cyclic grafts (C) per CD; [b] n+m = average total number of grafts per CD; [c] Relative amounts of branched and cyclic grafts on the CD (%); [d] Surface tension value determined at 20°C at the CAC (critical aggregation concentration); [e] Previous works used for comparison. [6]

Scheme 2 :

 2 Scheme 2: Synthesis methodology of the modified cyclodextrins (MA = maleic anhydride; SA = succinic anhydride; BSA = branched succinic anhydride; CSA = cyclic succinic anhydride; Z = moiety bound or associated to the terminal carboxylate group of fatty acid derivatives or of CD grafts; [1] or [0] = number of C=C double bonds of fatty acid derivatives or of CD grafts; X/Y = relative molar proportions of BSA and CSA (%); B = branched graft; C = cyclic graft; n = number of branched grafts per CD; m = number of cyclic grafts per CD.

(

  -CD, Pyridine, 95 °C, 36 h 2) HCl 3) NaOH aq. (1 eq./ CO 2 H), R.T., 3 h -Z-[1]-B n -C m b-CD-Z-[0]-B n -C mCyclodextrins bearing oleic grafts (Z = Me or Na)Cyclodextrins bearing stearic grafts (Z = Me or Na)

  Cyclodextrins bearing methyl oleate grafts (Me-and -CH=CH-) Cyclodextrins bearing sodium stearate grafts (Na + and -CH 2 Cyclodextrins bearing methyl stearate grafts (Me-and -CH 2 -CH 2 -) Cyclodextrins bearing sodium oleate grafts (Na + and -CH=CH-)

Table 2 .

 2 Hydrogenation of the anhydrides mixtures[a]

Acknowledgments

This work was performed, in partnership with the SAS PIVERT, within the frame of the French Institute for the Energy Transition (Institut pour la Transition Energétique (ITE) P.I.V.E.R.T.) (http://www.institut-pivert.com) selected as an Investment for the Future (Investissements d'Avenir). This work was supported, as part of the Investments for the Future, by the French Government under the reference ANR-001-01. Jérémy Ternel, Nicolas Kania, and Dominique Prévost are acknowledged for NMR analysis and technical assistance. PIVERT is acknowledged for the financial support of AC thesis.

Experimental Section

All chemicals were purchased from Fisher Scientific and Aldrich Chemicals in their highest purity. All solvents were used as supplied without further purification. Distilled water was used in all experiments. Analytical thinlayer chromatography (TLC) was performed on E. Merck aluminiumbacked silica gel (Silica Gel F254). Compounds were identified by using UV fluorescence and/or staining with a solution of phosphomolybdic acid in aqueous sulfuric acid and ethanol. NMR spectra were recorded with a Bruker DRX300 spectrometer operating at 300 MHz for 1 H nuclei and at 75 MHz for 13 C nuclei. CDCl3 (99.50% isotopic purity), [D6]DMSO (99.80% isotopic purity) and D2O (99.92% isotopic purity) were purchased from Euriso-Top.

Syntheses of the Z-[1]-BSA/CSA:X/Y anhydrides (Z=Me or H)

Me- [1]-BSA/CSA:13/87: 6 g of methyl oleate (74 % of purity) (4.44 g, 15.0 mmol), 2.94 g of maleic anhydride (29.9 mmol, 2 eq.), 26.5 mg of Rh2(OAc)4 (0.060 mmol, 0.4 mol%, so 0.8 mol% of Rh with respect to the methyl oleate) were mixed and heated in a schlenk tube under nitrogen at 140°C during 24 h. The brown oil obtained was purified by distillation with a Kugelrohr apparatus under reduced pressure. At P = 2.5 mbar, Me- [1]-BSA/CSA:13/87 was isolated at 275 °C. A yellow oil was obtained with a yield of 68 %.

Me-[1]

-BSA/CSA:64/36: 6 g of methyl oleate (74 % of purity) (4.44 g, 15.0 mmol), 2.94 g of maleic anhydride (29.9 mmol, 2 eq.), 6.6 mg of Rh2(OAc)4 (0.015 mmol, 0.1 mol%, so 0.2 mol% of Rh with respect to the methyl oleate) were mixed and heated in a schlenk tube under nitrogen at 140°C during 24 h. The brown oil obtained was purified by distillation with a Kugelrohr apparatus under reduced pressure. At P = 2.5 mbar, Me- [1]-BSA/CSA:64/36 was isolated at 275 °C. A yellow oil was obtained with a yield of 60 %.

H-[1]

-BSA/CSA:56/44: 6 g of oleic acid (87 % of purity) (5.22 g, 18.5 mmol), 3.62 g of maleic anhydride (37.0 mmol, 2 eq.), 8.2 mg of Rh2(OAc)4 (0.018 mmol, 0.1 mol%, so 0.2 mol% of Rh with respect to the oleic acid) were mixed and heated in a schlenk tube under nitrogen at 140°C during 24 h. The brown oil obtained was purified by distillation with a Kugelrohr apparatus under reduced pressure. At P = 2.5 mbar, H- [1]-BSA/CSA:56/44 was isolated at 300 °C. A yellow oil was obtained with a yield of 42 %.

Me-[1]

-BSA: 28 g of methyl oleate (74 % of purity) (20.72 g, 69.9 mmol) and 8.22 g of maleic anhydride (83.9 mmol, 1.2 eq.) were mixed and heated under microwaves at 220°C during 3 h. The brown oil obtained was purified by distillation with a Kugelrohr apparatus under reduced pressure. At P = 2.5 mbar, Me- [1]-BSA was isolated at 275 °C. Me- [1]-BSA was purified by chromatography on silica gel with hexane/dichloromethane. A yellow oil was obtained with a yield of 40 %.

H-[1]

-BSA: 27 g of oleic acid (87 % of purity) (23.49 g, 83.2 mmol) and 9.79 g of maleic anhydride (99.8 mmol, 1.2 eq.) were mixed and heated under microwaves at 220 °C during 3 h. The brown oil obtained was purified by distillation with a Kugelrohr apparatus under reduced pressure. At P = 2.5 mbar, H- [1]-BSA was isolated at 300 °C. H- [1]-BSA was purified by chromatography on silica gel with hexane/acetone. A yellow oil was obtained with a yield of 27 %.

Hydrogenation of the Z-[1]-BSA/CSA:X/Y anhydrides into Z-[0]-BSA/CSA:X/Y (Z=Me or H)

Me-[0]-BSA/CSA:64/36: 1 g of Me- [1]-BSA/CSA:64/36 (2.5 mmol) in 10 mL of THF was mixed with 106 mg of Rhodium on carbon 5% (51 µmol, 0.02 eq.) at 50°C under 40 bar of dihydrogen during 24 h. The crude product was filtered on celite and the THF was evaporated. A yellow oil was obtained with a yield of 85 %.

H-[0]

-BSA/CSA:56/44: 1 g of H- [1]-BSA/CSA:56/44 (2.5 mmol) in 10 mL of THF was mixed with 106 mg of Rhodium on carbon 5% (51 µmol, 0.02 eq.) at 50°C under 40 bar of dihydrogen during 24 h. The crude product was filtered on celite and the THF was evaporated. A yellow oil was obtained with a yield of 90 %.

Me-[0]-BSA: 1 g of Me- [1]-BSA (2.5 mmol) in 10 mL of THF was mixed with 106 mg of Rhodium on carbon 5% (51 µmol, 0.02 eq.) at 50°C under 40 bar of dihydrogen during 24 h. The crude product was filtered on celite and the THF was evaporated. A yellow oil was obtained with a yield of 90 %.

H-[0]-BSA: 1g of H- [1]-BSA (2.6 mmol) in 10 mL of THF was mixed with 108 mg of Rhodium on carbon 5% (53 µmol, 0.02 eq.) at 50°C under 40 bar of dihydrogen during 24 h. The crude product was filtered on celite and THF was evaporated. A yellow oil was obtained with a yield of 85 %.

Syntheses of the β-CD-Z-[x]-Bn-Cm cyclodextrins

The β-cyclodextrin to be esterified was firstly dried by heating 2 h at 80 °C, 2 h at 100 °C, and 2 h at 120 °C under reduced pressure. Then, 2.50 g of dried β-cyclodextrin were dissolved in 75 mL of anhydrous pyridine under nitrogen and 2 eq. of the Z-[x]-BSA/CSA:X/Y anhydride were added. The mixture was stirred 36 h at 95 °C under nitrogen. At the end of the reaction, 15 mL of water were added and solvents were evaporated under reduced pressure. The lightly brown solid obtained was acidified with aqueous HCl until pH = 2 (approximately 2 mL of a solution at 35 %), filtered, washed with water until pH = 5-6, dried and then washed with diethyl ether. The β-CD-Z-[x]-Bn-Cm(CO2H form) was obtained as a white solid. Then, β-CD-Z-[x]-Bn-Cm(CO2H form) was dispersed in water (20 mL/g). Then, 1 equivalent of Na + OH -per CO2H group was added and the mixture was then stirred during 3 h at 20 °C up to a total solubilisation. Water was then evaporated under reduced pressure. β-CD-Z-[x]-Bn-Cm(CO2Na form) was obtained as a white solid.


Aurélien Cocq

Cyril Rousseau

Hervé Bricout

Estefanía Oliva

Véronique Bonnet

Florence Djedaïni-Pilard

Eric Monflier

Sébastien Tilloy

Oleic Acid Based Cyclodextrins for the Development of New Hydrosoluble Amphiphilic Compounds

Keywords: Cyclodextrin, Maleic anhydride, Maleinisation, Oleic acid, Succinic anhydride

A new family of amphiphilic cyclodextrins produced from oleic acid derivatives and maleic anhydride is described. These amphiphilic cyclodextrins are synthetized in two steps. The first step is the alkenylation of maleic anhydride by oleic acid derivatives to produce the oleic succinic anhydrides. The second step is the grafting of the oleic succinic anhydrides on various cyclodextrins. A selfinclusion of the alkyl chain or an inclusion of one alkyl chain in the cavity of another CD is showed by NMR experiments. The twelve amphiphilic cyclodextrins described possess high solubility in water (50-500 g/L at 20°C) and low critical aggregation concentration (16-360 mg/L).

Introduction

Native cyclodextrins (CDs), named ,  and -CD, are cyclic oligosaccharides made from enzymatic starch degradation and composed respectively of 6, 7 or 8 glucose units linked via -1,4 glycosidic bonds. Native CDs are water-soluble compounds and are able to form inclusion complexes with numerous organic molecules. [1] CDs have been intensively employed in pharmaceutical, [2] cosmetics, [3] textile [4] and food industries. [5] Chemical modifications of native CDs into more sophisticated molecules can improve their interest for industrial applications. Among all these modified cyclodextrins, amphiphilic cyclodextrins are an interesting family as they can form supramolecular assemblies such as vesicles, micellar systems and nanospheres. [6] Since thirty years, chemists have developed various amphiphilic cyclodextrins. The first was reported by the group of Kabawata. [7] Different kinds of CDs can be obtained depending on the functionalization (polysubstitution or monosubstitution) with a direct impact on the physico-chemical properties. The lipophilic grafts are generally alkyl chains linked to the CD structure via ether, [8] ester, [9] thioether, [10] or amide [11] functions. Inclusion complexes can also be observed between the hydrophobic cavity and the alkyl chain depending on its length. The major drawback of these amphiphilic CDs is their poor water solubility. This solubility generally decreases with the number of lipophilic groups linked to the CD. To counterbalance the lipophilic character and so to increase the solubility in water of the amphiphilic CDs, some other substituents such as polyethylene oxide grafts [12] or ionic [13] functions can be linked. For example, surface active alkenyl succinyl-CDs were synthesized by the same methodology described for starch succinylation and other natural polymers. [14] More precisely, the group of de Rossi has showed that it was possible to synthesize amphiphilic β-CD esters of alkenyl succinic acids. [15] These alkenyl succinyl-β-CDs were synthesized in two steps (Scheme 1). This first step was the reaction of a terminal alkene (from 1-octene to 1-tetradecene) with maleic anhydride to give an alkenyl succinic anhydride (maleinisation reaction). In the second step, this latter reacted with native β-CD to produce the various alkenyl succinyl-β-CDs with a number of grafts per CD (Degree of Substitution: DS) generally low (DS≤1). The hydrophobicity of the alkyl chain is counterbalanced, in this case, by the presence of a free carboxylate group obtained after the grafting of the alkenyl succinic anhydride onto β-CD. Physicochemical studies of these amphiphilic CDs were performed. Interesting properties such as aggregation, self-organized properties between the alkyl chain and the CD cavity, emulsifying properties and supramolecular organization in water were described. [16] Recently, Lu showed that octadecenyl succinyl-β-CD with low DS (0.02-0.13) can be used to stabilize pickering emulsions [17] and the group of Luo found that octenyl succinyl-β-CD with DS of 0.016 to 0.045 can be used as emulsion stabilizer. [18] It is important to underline that all synthesized CDs were obtained as a mixture. In order to improve the eco-compatibility of this kind of CD derivatives, the coupling between a CD and oleic succinic anhydride was envisaged. Indeed, oleic acid derivatives are industrially produced from renewable resources. We described here the synthesis of several amphiphilic oleic succinyl-CDs formed by coupling various CDs (native, methylated or hydroxypropyl-CDs) with oleic succinic anhydrides. The physicochemical properties of these new CDs were also described. Scheme 1: Schematic representation of the formation reaction of alkenyl succinyl-CDs (for simplification, only one kind of graft is represented, among the two possible, knowing that each hydroxyl groups of the β-CD can react with one or the other carbonyl group of the succinic anhydride used).

____________________________________________________________ [a]

Dr. A.

Results and Discussion

These oleic succinyl-CDs were synthetized in two steps. The first step of the synthetic pathway is the alkenylation of maleic anhydride by oleic acid derivatives to produce oleic succinic anhydrides (OSA). This synthesis was inspired by previous works of Candy describing the synthesis of various oleic succinic anhydrides. [19] Firstly, we tried to reproduce the synthesis with methyl oleate (or oleic acid) and maleic anhydride in an autoclave during 8 h at 220°C (Scheme 2a). The addition reaction of the maleic anhydride to methyl oleate or oleic acid gave a mixture of regio-and stereoisomers. [20] This mixture of compounds originated from two coexisting mechanisms (an ene-reaction and a radical reaction). [21] However, for reasons of simplification, the mixture was represented as a single compound in this work. The nomenclature used to name these compounds is OSA-[1]-Me and OSA-[1]-H for methyl oleate and oleic acid derivatives, respectively (Scheme 2). The term OSA is for Oleic Succinic Anhydride. [1] or [0] is for the number of unsaturation on the aliphatic chain and finally, Z is a methyl or a H group, according to the nature of methyl oleate or oleic acid of the reactant. From methyl oleate and maleic anhydride, OSA-[1]-Me was obtained with the same yield than those reported by Candy (36 %). To improve the efficiency of the reaction, microwave assistance was used to heat the reaction mixture. With microwave activation, the reaction time was significantly reduced from 8 hours to 3 hours with a small improvement in the reaction yield (from 36% to 40%). The same conditions were also applied to the reaction with oleic acid instead of methyl oleate and in this case, the yield in the corresponding product (OSA- of Ru per OSA / Heptane / P(H2)=40 bar / 50 °C / 15 h), no reduction of the oleic part but a degradation of the anhydride structure was observed. This kind of behavior was already described in the presence of nickel and platinum catalysts. [22] The best results for reduction of carbon-carbon double bond were obtained with Rh/C (5 wt. %; 0.01 eq of Rh per OSA / Heptane / P(H2) = 40 bar / 30°C / 4h). The hydrogenated compounds were obtained in yield of 90% and 85 % for OSA-[0]-Me and OSA-[0]-H, respectively. The second step of the synthetic pathway is the grafting of the unsaturated or saturated OSA on native CDs (α-CD, β-CD or γ-CD), RAndomlyMEthylated-β-CD (RAME-β-CD) or HydroxyPropylated-β-CD (HP-β-CD). The reaction was done in pyridine with 2 equivalents of OSA with respect to CD and allowed to produce various oleic succinyl-CDs (Scheme 3a). These products were named CD-(OSD-[x]-Z)y with OSD for Oleic Succinic Derivative. [1] or [0] is for the number of unsaturation on the aliphatic chain. Z is H or methyl and y the degree of substitution (DS). Various oleic succinyl-CDs were obtained with DS between 0.9 and 1.8 and with yields from 28% to 92 % (table 1). With native CDs and unsaturated OSA (table 1, entries 1-6), no noticeable difference in the reaction yields (around 80%) and in the substitution degrees (around 1.6) was evidenced except for -CD and OSA-[1]-Me since the yield dropped to 30% but with a higher DS (1.8). The reaction with the saturated OSA and β-CD (Table 1, compare entries 3-4 and 7-8) gave the corresponding product in a lower yield and when the OSA with the free carboxylic acid was used (entry 8) the DS dropped from 1.5 to 0.9. With RAME-β-CD (compare entries 3-4 and 9-10), the reaction yield and DS were lower than with native β-CD since the DS dropped to 0.9 and 1. This behavior could be explained by the fact that RAME-β-CD possesses already an average of 12.6 methylated groups per CD and supplementary substitution was more difficult. In the case of HP-β-CD (possessing an average of 5.3 of 2hydroxypropyl group Scheme 3: Schematic representation of the formation reaction of the oleic succinyl-CDs (a) and their sodium salts (b) (for simplification, only one kind of graft is represented, among the two possible, knowing that each hydroxyl groups of the CD can react with one or the other carbonyl group of the succinic anhydride used). [a] Entry OSD-CD DS [b] Yield [%] [c] per CD), the obtained DS value was similar to that obtained for native β-CD. These results can be explained by the fact that HPβ-CD and native β-CD possess the same amount of hydroxyl groups. Indeed, the hydroxyl group of 2-hydroxypropyl moiety can be also esterified. The synthesized OSD-CDs were insoluble in water. To solubilize these compounds in water, the carboxylic functions were deprotonated to give the corresponding carboxylates by treatment with stoichiometric amount of an aqueous sodium hydroxide solution (Scheme 3b). The corresponding OSD-CD-Na were obtained in a quantitative yield.

Table 1. Degrees of substitution and yields of various OSD-CDs

Various physical properties such as aqueous solubility, critical aggregation concentration in water (CAC) and surface tension of aqueous solutions were measured for the synthesized OSD-CDs-Na and were gathered in the table 2. The values of aqueous solubility of all OSD-CDs-Na (50 -500 g/L at 20°C) were high compared to CDs possessing hydrophobic chains. Indeed, one or two carboxylate functions on the succinyl moiety are enough to counterbalance the hydrophobicity of the oleic chain. The aqueous solubilities of OSD-CDs-Na with the terminal methyl ester functions were lower compared with those of OSD-CDs-Na with the terminal carboxylate functions. This increase in watersolubility was due to the number of carboxylate functions per graft (one for the first series (Table 2; entries 1, 3, 5, 7, 9 and 11) against two for the second series (Table 2; entries 2, 4, 6, 8, 10 and 12). For each compound, the critical aggregation concentration (CAC) and the surface tension (ST) value obtained at this concentration were determined by the Wilhelmy method. For the CAC, two trends are emerging: one for OSD-CDs-Na possessing the methyl ester group (one carboxylate function -table 2, entries 1, 3, 5 and 7), and another for those possessing the carboxylic acid groups (two carboxylate functions -table 2, entries 2, 4, 6 and 8). The dicarboxylate derivatives have a higher CAC than their ester counterparts. For RAME-β-CD and HP-β-CD derivatives (Table 2, entries 9-12), the variation of CAC are less marked. All OSD-CDs-Na have a value of surface tension from 28 to 52 mN/m at the CAC at 20°C. These values indicated that they possessed a good surface activity compared to the native CDs which are not surface active. [23] A self-inclusion of the alkyl chain and also inclusion of one alkyl chain in the cavity of other CDs were already described with cyclodextrins mono-substituted with alkenylsuccinyl chains possessing 8 to 12 carbons for the aliphatic moiety. [24] Thus, the possibility of a such behavior was checked for β-CD-(OSD-Na-[1]-Me)1.6. Two different kinds of complexes could be formed either by an intra-or an inter-molecular inclusion (Scheme 4). We performed T-ROESY NMR experiments to demonstrate the interactions between the protons situated inside the CD cavity (H3 and H5) and those of the aliphatic chain (Figure 1). The experiment highlighted correlation spots between the internal CD protons (3-4 ppm) and the protons of the aliphatic chain (0.5-1.5 ppm) indicating that these protons are spatially close (Figure 1a). To obtain a better insight into the inclusion phenomenon, the same T-ROESY NMR experiment was performed in [D6]DMSO instead of D2O. Indeed, DMSO was known as a dissociate solvent for inclusion complex with CD. [25] The spectrum showed also correlation spots between the internal CD protons and the protons of the aliphatic chain (see supporting information). Another T-ROESY NMR experiment was realized with a mixture of β-CD and sodium oleate in DMSO (see supporting information). In this case, no correlation peak was observed. These two experiments confirmed the stability of the intra-molecular complexes. To estimate the stability of these inclusion complexes, NMR experiments were performed in the presence of selected guests possessing high affinity for the β-CD cavity. The selected compounds were tris(3-sulfonatophenyl) phosphane sodium salt (TPPTS -Figure 1b), adamantane carboxylate sodium salt (SAC -Figure 1c) and tris[4-(4-sulfonatophenyl)phenyl] phosphane sodium salt (P(Biph)3TS -Figure 1d). These molecules form inclusion complexes with β-CD with a binding constant of 1.2 × 10 3 mol -1 .L, [26] 40 × 10 3 mol -1 .L [27] and 100 × 10 3 mol -1 .L, [28] respectively. The T-ROESY spectra of the different mixtures show that only P(Biph)3TS displaces totally the alkyl chain from the inside of the CD cavity. With TPPTS and the adamantane carboxylate sodium salt, a mixture was observed since alkyl chains and selected guests are inside the CD cavity. These experiments show that the inclusion complexes formed between alkyl chains and the CDs cavities are very stable.

Scheme 4: Representation of the two different kinds of inclusion complexes

Conclusions

We have described the synthesis of new amphiphilic oleic succinyl-CDs obtained by esterification of various CDs by oleic succinic anhydride derivatives made from oleic acid or its methyl ester. Although the work-up led to a mixture of modified CDs, the syntheses were reproducible and did not necessitate tedious and time-consuming purifications. In addition, the physicochemical properties of these compounds were significant. Indeed, the oleic succinyl-CDs possess a high solubility in water (50-500 g/L), a low surface tension and a low critical aggregation concentration. These properties confer to these compounds a great ability to be used for emulsion stabilizer or as surfactant.

Experimental Section

All chemicals were purchased from Fisher Scientific and Aldrich Chemicals in their highest purity. All solvents were used as supplied without further purification. Distilled water was used in all experiments. Analytical thinlayer chromatography (TLC) was performed on E. Merck aluminiumbacked silica gel (Silica Gel F254). Compounds were identified by using UV fluorescence and/or staining with a solution of phosphomolybdic acid in aqueous sulfuric acid and ethanol. NMR spectra were recorded with a Bruker DRX300 spectrometer operating at 300 MHz for 1 H nuclei and at 75 MHz for 13 C nuclei. CDCl3 (99.50% isotopic purity), [D6]DMSO (99.80% isotopic purity) and D2O (99.92% isotopic purity) were purchased from Euriso-Top.

General procedure for the synthesis

The detailed syntheses and characterizations of the products are gathered in supporting information.

OSA OSA-[0]-Me: Hydrogenated maleinisated methyl oleate 1 g of OSA-[1]-Me (2.52 mmol) in 10 mL of THF was mixed with 106 mg of Rhodium on carbon 5% (50.6 µmol, 0.02 eq.) at 50°C under 40 bar of dihydrogen during 24 h. The crude product was filtered on celite and the THF was evaporated. A yellow oil was obtained with a yield of 90 %.

OSA-[0]-H: Hydrogenated maleinisated methyl oleate 1g of OSA-[1]-H (2.63 mmol) in 10 mL of THF was mixed with 108 mg of Rhodium on carbon 5% (52.5 µmol, 0.02 eq.) at 50°C under 40 bar of dihydrogen during 24 h. The crude product was filtered on celite and THF was evaporated. A yellow oil was obtained with a yield of 85 %.

OSD-CDs: Oleic succinyl-CDs

Native or modified cyclodextrins were firstly dried by heating 2 h at 80 °C, 2 h at 100 °C, and 2 h at 120 °C under reduced pressure. Then, 2.50 g of dried cyclodextrin were dissolved in 75 mL of anhydrous pyridine under nitrogen and 2 eq. of maleinisated oleic derivative were added. The mixture was stirred 36 h at 95 °C under nitrogen. At the end of the reaction, 15 mL of water were added and solvents were evaporated under reduced pressure. The lightly brown solid obtained was acidified with aqueous HCl until pH = 2 (approximately 2 mL of a solution at 35 %), filtered, washed with water until pH = 5-6 and dried. The diacid resulting of the hydrolysis of the maleinisated oleic derivative which has not reacted was eliminated by washing with diethyl ether, except for the RAME-β-CD. In this case, the crude product was purified by chromatography on silica gel with acetonitrile/water (from 100/0 to 70/30, Rf: 0.70 in 70/30 acetonitrile/water).

A white solid was obtained in all cases.

OSD-CDs-Na: Sodium salts of oleic succinyl-CDs 1 g of esterified cyclodextrin was dispersed in 20 mL of water. Then, 1 equivalent of Na + OH -per CO2H group was added and the mixture was then stirred during 3 h at 20 °C up to a total solubilization. Water was then evaporated under reduced pressure. A white solid was obtained with a quantitative yield.

  Scheme 2: Representation of the different structures of the OSA (Oleic Succinic Anhydrides)

  -(OSD-[1]-Me)1.6 α-CD-(OSD-[1]-H)1.6 β-CD-(OSD-[1]-Me)1.6 β-CD-(OSD-[1]-H)1.6 γ-CD-(OSD-[1]-Me)1.8 γ-CD-(OSD-[1]-H)1.4 β-CD-(OSD-[0]-Me)1.5 β-CD-(OSD-[0]-H)0.9 RAME-β-CD-(OSD-[1]-Me)0.9 RAME-β-CD-(OSD-[1]-H)1.0 HP-β-CD-(OSD-[1]-Me)1.7 HP-β-CD-(OSD-[1]-H)1.6

  -(OSD-Na-[0]-Na)0.9 RAME-β-CD-(OSD-Na-[1]-Me)0.9 RAME-β-CD-(OSD-Na-[1]-Na)1.0 HP-β-CD-(OSD-Na-[1]-Me)1.7 HP-β-CD-(OSD-Na-[1]-Na)1Surface tension value at the CAC concentration and at 20°C.

Figure 1 :

 1 Figure 1: T-ROESY NMR Spectrum of the β-CD-(OSD-Na-[1]-Me)1.6 with different guests (10 mM CD, 1 eq. guest or 5 eq for the TPPTS, D2O, 20°C)

Table 2 .

 2 Physico-chemical properties of the OSD-CDs-Na

	Entry	OSD-CD-Na	Solubility	CAC	Surface
			at 20°C	at 20°C	Tension
			(g/L) -(mM)	(mg/L) -(µM)	(mN/m) [a]

Acknowledgments

This work was performed, in partnership with the SAS PIVERT, within the frame of the French Institute for the Energy Transition (Institut pour la Transition Energétique (ITE) P.I.V.E.R.T.) (http://www.institut-pivert.com) selected as an Investment for the Future (Investissements d'Avenir). This work was supported, as part of the Investments for the Future, by the French Government under the reference ANR-001-01. Jérémy Ternel, Nicolas Kania, and Dominique Prévost are acknowledged for NMR analysis and technical assistance. PIVERT is acknowledged for the financial support of AC thesis.

Entry for the Table of Contents

Layout 2:


Shiv Kumar

Carole Body

Tom Leyssens

Kristof Van Hecke

Gilles Berger

Arie Van Der Lee

Danielle Laurencin

Sébastien Richeter

Sébastien Clément

Franck Meyer

Halogen-Bonded Thiophene Derivatives Prepared by Solution and/or Mechanochemical Synthesis. Evidence of N×××S Chalcogen Bonds in Homo-and Cocrystals

Keywords: halogen bond, chalcogen bond, thiophene, mechanochemical synthesis, solid state NMR

come

Introduction

The fabrication of next generation nanoelectronic devices requires precise control over the reorganization of its active layer components at the nanometer scale. [START_REF] Zhang | Self-Assembled Vertically Aligned Nanocomposite Systems Integrated on Silicon Substrate: Progress and Future Perspectives[END_REF] To achieve this goal, "top-down" or "bottom-up" approaches represent the two main strategies to create highly ordered 2-or 3-dimensional nanostructures. [START_REF] Han | From Self-Assembly to Charge Transport with Single From Self-Assembly to Charge Transport with Single Molecules -An Electrochemical Approach[END_REF] The former strategy is deemed to be too costly to reach a degree of miniaturization lower than 10 nm by a lithographic approach, [START_REF] Chen | Sub-10 Nm Fabrication: Methods and Applications[END_REF] whereas the latter approach can be highly cost effective and reliable, owing to the self-assembly of purposely-built elemental constituents through recognition processes. [START_REF] Morris | Directed Self-Assembly of Block Copolymers for Nanocircuitry Fabrication[END_REF][START_REF] Cummins | Enabling Future Nanomanufacturing through Block Copolymer Self-Assembly: A Review[END_REF] The "bottom-up" approach for the construction of nanoscale architectures can thus benefit from the wide array of non-covalent interactions available in the supramolecular chemistry toolbox. [START_REF] Lu | Nanoelectronics from the Bottom Up[END_REF] Now, it is well established that the electron donating or accepting strength of a substituent affects the energetics of a -conjugated semiconducting material. [START_REF] Hashemi | Design Principles for the Energy Level Tuning in Donor/Acceptor Conjugated Polymers[END_REF] Among the various molecular design principles to tune the bandgap and improve the charge transport in organic semiconducting materials, the fluorine substitution stands out as a very appealing strategy, by both lowering the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) level, and also, acting on morphological aspects by intra-or intermolecular S [START_REF] Meyer | Fluorinated Conjugated Polymers in Organic Bulk Heterojunction Photovoltaic Solar Cells[END_REF] Simultaneously, halogen bonding (XB), i.e. the ability of a halogen to act as an electron density acceptor, has accounted for an upsurge of interest in the scientific community in the last two decades. [START_REF] Cavallo | The Halogen Bond[END_REF][START_REF] Gilday | Halogen Bonding in Supramolecular Chemistry[END_REF] This interaction was initially reported as an intermolecular force in crystal engineering. In subsequent studies, some remarkable features of XB like high directionality, hydrophobicity, or tunable strength were observed and harnessed successfully in biological and materials sciences. [START_REF] Berger | Halogen Bonding in Polymer Science: From Crystal Engineering to Functional Supramolecular Polymers and Materials[END_REF][START_REF] Berger | Halogen Bonding for Molecular Recognition : New Developments in Materials and Biological Sciences[END_REF] In the field of organic electronic materials, XB has already been used to guide the arrangement of molecules, as observed in tetrathiafulvalene (TTF) chemistry. [START_REF] Fourmigué | Activation of Hydrogen-and Halogen-Bonding Interactions in Tetrathiafulvalene-Based Crystalline Molecular Conductors[END_REF] In the same spirit, an improved 3D organization of poly(3-(ω-bromoalkyl)thiophenes) compared to poly(3-alkylthiophenes) has been attributed to S•••Br contacts. [START_REF] Bocheux | Self-Templating Polythiophene Derivatives : Electronic Decoupling of Conjugated Strands through Staggered Packing[END_REF] From a physical point of view, XB was found to enhance the performance of perovskite and dye-sensitized solar cells through reduction of the recombination rate constant and regeneration of the dye, respectively, due to X•••I¯ interactions (X = Cl, Br, I). [START_REF] Abate | Supramolecular Halogen Bond Passivation of Organic -Inorganic Halide Perovskite Solar Cells[END_REF][START_REF] Simon | Halogen Bonding Promotes Higher Dye-Sensitized Solar Cell Photovoltages[END_REF] Halogenation can thereby exert different levels of control over the performance of these functional materials.

•••F, H•••F, F•••F or π•••F interactions.
Thiophene derivatives are versatile and key constituents of many organic semiconducting materials. [START_REF] Barbarella | The Versatile Thiophene: An Overview of Recent Research on Thiophene-Based Materials[END_REF][START_REF] Zhang | Oligothiophene Semiconductors: Synthesis, Characterization, and Applications for Organic Devices[END_REF] It has already been demonstrated that the supramolecular features of these building blocks can be translated at the macromolecular level to govern the organization of corresponding unit-containing polymers. [START_REF] Clément | Synthesis and Supramolecular Organization of Regioregular Polythiophene Block Oligomers[END_REF][START_REF] Zacca | New Layered Polythiophene-Silica Composite through the Self-Assembly and Polymerization of Thiophene-Based Silylated Molecular Precursors[END_REF] With this in mind, we decided to investigate the supramolecular organization of modified thiophene with the groups prone to interact by halogen bonding. [START_REF] Berger | Interplay between Halogen Bonding and Lone Pair-π Interactions: A Computational and Crystal Packing Study[END_REF] Several studies have already reported the X-ray structures of halogen bonded arrays based on brominated thiophenes at positions 2 and/or 5, along with other bromine-containing analogs. [START_REF] Barrès | On Dimensionality of Halogen-Bonded Thiophene Solid-State Assemblies[END_REF] Herein, we turned our attention towards the thiophene functionalized at position 3 with pyridyl (4-(thiophen-3-ylmethoxy)pyridine, ThioPy) and tetrafluoroiodobenzene (3-((2,3,5,6-tetrafluoro-4iodophenoxy)methyl)thiophene, ThioI) groups in combination with complementary XB donor or acceptor partners. [START_REF] Baldrighi | Halogen-Bonded and Interpenetrated Networks through the Self-Assembly of Diiodoperfluoroarene and Tetrapyridyl Tectons[END_REF] We performed the synthesis of polymorphic adducts by solution and mechanochemical approaches and analyzed them by single crystal and powder X-ray diffraction as well as [START_REF] Fourmigué | Activation of Hydrogen-and Halogen-Bonding Interactions in Tetrathiafulvalene-Based Crystalline Molecular Conductors[END_REF] C solid state NMR (SSNMR). Interestingly, in some of the complexes, both the halogen and chalcogen bonds (ChBs) were teamed up to form supramolecular self-assembly. The occurrence of halogen bonding interactions in the solution phase was also investigated by NMR spectroscopy. Density functional theory (DFT) investigations were employed to emphasize their respective contributions to the formation of these supramolecular architectures. [START_REF] Widdifield | Multinuclear Solid-State Magnetic Resonance as a Sensitive Probe of Structural Changes upon the Occurrence of Halogen Bonding in Co-Crystals[END_REF][START_REF] Bryce | Solid-State NMR Study of Halogen-Bonded Adducts[END_REF] Local energy decomposition analysis (DFT/DLPNO-CCSD(T)/def2-TZVP/Def2-TZVP/C) was performed on fully optimized self-assembled crystal structures to quantify the interactions. Details of specific intermolecular interactions and stabilization energies (Gibb's free energy) of these supramolecular self-assemblies are presented.

Experimental section

Materials

3-Thiophenemethanol (98%, CAS registry no. 71637-34-8) was obtained from Merck, Belgium. The solid-state NMR spectra were recorded at the Institut Charles Gerhardt in France, on a VNMRS 600 MHz (14.1 T) NMR spectrometer, using a Varian 3.2 mm probe tuned to 1 H (599.82 MHz) and 13 C (150.81 MHz), and working under magic angle spinning (MAS) at a spinning rate of 18 kHz. The temperature control unit was set to ~0°C during all measurements. The crosspolarization (CP) MAS sequence was used, with contact times (CT) of 0.2 or 4 ms, allowing to distinguish [START_REF] Fourmigué | Activation of Hydrogen-and Halogen-Bonding Interactions in Tetrathiafulvalene-Based Crystalline Molecular Conductors[END_REF] C resonances depending on their relative proximity to protons in the crystal structure (and thereby identifying the [START_REF] Fourmigué | Activation of Hydrogen-and Halogen-Bonding Interactions in Tetrathiafulvalene-Based Crystalline Molecular Conductors[END_REF] C-I resonance in particular). Recycle delays used were adapted sample by sample (with values as long as 400 s for ThioPy). The number of transients acquired ranged from 126 to 826, depending on the sample and contact time. [START_REF] Fourmigué | Activation of Hydrogen-and Halogen-Bonding Interactions in Tetrathiafulvalene-Based Crystalline Molecular Conductors[END_REF] C chemical shifts were referenced to adamantane, used as a secondary reference (high frequency peak at 38.5 ppm with respect to tetramethylsilane).

Melting points were measured using one side open-ended capillaries on Buchi melting point B-545 apparatus and are uncorrected.

Ball milling in neat grinding and LAG conditions

Grinding was performed on a Retsch MM400 using a grinding frequency of 30Hz for a period of 90 min. About 19.12 mg of ThioPy (0.1 mmol, 1 equiv.) and 38.81 mg of ThioI (0.1 mmol, 1 equiv.) were placed in a polypropylene Eppendorf of 2mL to which 3 grinding stainless steel beads of 3 mm were added. 10 µL of solvent was added to all except the neat sample.

Differential Scanning Calorimetry

DSC measurements were performed on a TA DSC2500 instrument. Samples were deposited in the aluminum Tzero pans with punctured lid and heated from 25 °C up to 100 °C using a heating rate of 20 °C/min under a 50 mL/min continuous nitrogen flow.

Single-crystal X-ray diffraction analysis

The crystal evaluation and data collection of ThioI (at 175 K) and ThioPya (at 173 K) were performed on a Rigaku Oxford-Diffraction Gemini-S diffractometer with sealed-tube MoKα ( = 0.71073 Å) radiation using the CrysAlis Pro program (Rigaku Oxford-Diffraction, 2012). [START_REF]CrysAlisPro Software systems[END_REF] This program was also used for the integration of the data using default parameters, for the empirical absorption correction using spherical harmonics employing symmetry-equivalent and redundant data, and the correction for Lorentz and polarization effects. The ab-initio iterative charge flipping method was used to solve the crystal structures with parameters described elsewhere [START_REF] Van Der Lee | Charge Flipping for Routine Structure Solution[END_REF] employing the Superflip [START_REF] Palatinus | SUPERFLIP -A Computer Program for the Solution of Crystal Structures by Charge Flipping in Arbitrary Dimensions[END_REF] program and they were refined using full-matrix least-squares procedures on structure factor amplitudes F as implemented in CRYSTALS 29 using all independent reflections with I>2σ(I). The thiophene rings appeared to be positionally disordered with respect to the sulfur atoms and the neighbouring carbon atom. The site occupancy factors S/C were 0.717(4)/0.283(4), 0.671(2)/0.329 (2) for ThioI, and ThioPya respectively.

For the structure of ThioPy-1,2TFIB, ThioPy-1,4TFIB, ThioPy-diIC4, ThioPy-diIC6, ThioI-BiPy, ThioI-BiPyethy, ThioI-BiPyetha and ThioPyb, X-ray intensity data were collected at 100 K, on a Rigaku Oxford Diffraction Supernova Dual Source (Cu at zero) diffractometer equipped with an Atlas CCD detector using  scans and MoK ( = 0.71073 Å) radiation. The images were interpreted and integrated with the program CrysAlisPro. [START_REF]CrysAlisPro Software systems[END_REF] Using Olex2, [START_REF] Dolomanov | OLEX2: A Complete Structure Solution, Refinement and Analysis Program[END_REF] the structures were solved by direct methods using the ShelXT structure solution program and refined by full-matrix least-squares on F 2 using the ShelXL program package. [START_REF] Sheldrick | SHELXT -Integrated Space-Group and Crystal-Structure Determination[END_REF][START_REF] Sheldrick | Crystal Structure Refinement with SHELXL[END_REF] Non-hydrogen atoms were anisotropically refined and the hydrogen atoms in the riding mode with isotropic temperature factors fixed at 1.2 times U(eq) of the parent atoms.

Mechanochemical synthesis and X-ray powder diffraction analyses of ThioI-ThioPy complexes

The X-ray powder diffraction analyses were carried out with Siemens D5000 diffractometer equipped with a Cu cathode (λ(Cu Kα)=1.5418 Å), operating at 40 kV and 40 mA and using a Bragg Brentano geometry.

The small shifts in the positions of the diffraction peaks in the products recovered after ballmilling, compared to the simulations done from the single-crystal X-ray diffraction data, can be due to the difference in analysis conditions (especially temperature).

Cambridge Structural Database (CSD) survey (version 2021.1, 5.42 updates May 2021)

A single query was built using ConQuest via the Draw option and searching for N•••S distances lower than 3.35 Å for compounds possessing thiophene and pyridyl rings. This was done by defining an intermolecular contact (up to exactly 3.35 Å) between the thiophene S-atom and pyridyl N-atom. The search (using no additional filters) returned the following hitlist with refcodes: FAJDED, AJUMAT, APUSUB, DELDEG, DUBTIF, FOPZUI, LODREE, NOTFOT, QOWNOI, QUDSOX, RAVTAJ, TASTIR, WITVAY, XIGVIV and YODFAB. NOTFOT and XIGVIV involve pyridinium derivatives.

Theoretical methods

All calculations were carried out using ORCA 5.0.2 package as single points from the X-ray geometries. [START_REF] Neese | The ORCA Program System[END_REF][START_REF] Neese | Software Update: The ORCA Program System-Version 5.0[END_REF] Local energy decomposition (LED) analysis was then performed to assess interaction energies at the domain-based local pair natural orbital level of theory [DLPNO-CCSD(T)]; [START_REF] Riplinger | An Efficient and near Linear Scaling Pair Natural Orbital Based Local Coupled Cluster Method[END_REF][START_REF] Schneider | Decomposition of Intermolecular Interaction Energies within the Local Pair Natural Orbital Coupled Cluster Framework[END_REF] using the tight PNO setting, the def2-TZVP basis set [START_REF] Weigend | Accurate Coulomb-Fitting Basis Sets for H to Rn[END_REF] and the corresponding auxiliary bases for the Resolution of Identity (RI) approximation, exchange and coulomb fitting.

The interaction energies have been calculated as previously reported. [START_REF] Schneider | Decomposition of Intermolecular Interaction Energies within the Local Pair Natural Orbital Coupled Cluster Framework[END_REF] EintraX and EintraY are the electronic energies of both fragments in the complex, Ex and Ey are the energies of the isolated fragments, and Eprep is the required energy from the isolated ground state to the electronic structure in the interacting fragments. ΔExy is the final interaction energy.

Results and Discussion

The synthesis of 3-((2,3,5,6-tetrafluoro-4-iodophenoxy)methyl)thiophene (ThioI) and 4-(thiophen-3-ylmethoxy)pyridine (ThioPy) as XB donor and acceptor, respectively, was carried out according to a procedure already described in the literature (Scheme 1). [START_REF] Berger | Interplay between Halogen Bonding and Lone Pair-π Interactions: A Computational and Crystal Packing Study[END_REF] Scheme 1. Syntheses of thiophene derivatives ThioPy and ThioI (top). Halogen bond donors (red) and acceptors (blue) were used in this study (bottom).

Single crystal X-ray diffraction analysis of ThioI

Subsequently, the high-quality single crystals suitable for X-ray diffraction analysis of halogenated thiophene derivative, ThioI, were obtained through slow evaporation of dichloromethane solution. ThioI units follow a S•••I XB-driven supramolecular structure (Figure 1). The S•••I distance (3.597 Å) is around 5% shorter than the sum of van der Waals radii and the S•••I-C angle is about 158°, which is consistent with the electron-donation from sulfur to iodine (interaction energy ~ -11.6 kcal mol -1 , Table S5). [START_REF] Arman | Complementary Halogen and Hydrogen Bonding: Sulfur⋯iodine Interactions and Thioamide Ribbons[END_REF] the chalcogen bond energy is -3.4 kcal mol -1 which is in the same order of magnitude that was calculated for a thiophene-pyridine complex. [START_REF] Haberhauer | The Nature of Strong Chalcogen Bonds Involving Chalcogen-Containing Heterocycles[END_REF] Other weak hydrogen bonds, namely H

•••O (2.854 Å) and H•••π interactions (H•••centroid distance = 3.420 Å) operate between the parallel chains.
The single crystal X-ray diffraction analysis of pure thiophenes ThioI and ThioPy confirmed the role of the aromatic groups as structure directing agents for these supramolecular assemblies. Next, we investigated the cocrystallization of these building blocks with selected partners.

X-ray diffraction analysis of cocrystals involving ThioPy and diiodoperfluorinated compounds

Halogenoperfluorinated chains are commonly used in halogen bonding driven self-assemblies.

In fact, the strong electron withdrawing fluorine atoms behave as activating agents toward the associated halogens by increasing their σ-hole size. Furthermore, the rod-like character of the perfluorinated core allows a reliable transfer of molecular information. [START_REF] Kumar | Halogen Bonded Borromean Networks by Design : Topology Invariance and Metric Tuning in a Library of Multi-Component Systems[END_REF] Firstly, ThioPy and diiodoperfluorobutane (diIC4) were cocrystallized, leading to a supramolecular trimeric structure held together by N•••I halogen bonds (Figure 3 top). The distance between these two atoms is 2.817 Å, i.e. about 20% shorter than the sum of van der Waals radii, and the N•••I-C angle is almost linear (~170°). In this particular complex, we can consider that S and N compete to make XB with I, but the strongest prevails. These trimeric systems develop undulating chains making an angle of about 93° with thiophene rings at both extremities pointing toward one another, as observed in ThioPya. The stabilization of this architecture is further ensured by weak H•••O hydrogen bonds (2.530 Å) that link parallel trimers. Subsequently, we studied the self-assembly of ThioPy with a longer analog, i.e. diiodoperfluorohexane (diIC6) (Figure 3 The repetition of the trimeric architecture forms infinite parallel chains with two thiophene rings pointing toward each other. The S•••S separation is measured at 3.846 Å which is slightly longer than the sum of van der Waals radii. In ThioPy-diIC6, all units belonging to parallel planes run in the same direction which contrasts with ThioPy-diIC4 and its zig-zag motif (Figure S2). The planar organization features a clear segregation between ThioPy and diIC6, emphasizing the low affinity between perfluorocarbons and hydrocarbons. It is worth noting that this aspect is consistent, and observed in ThioPy-diIC4 as well.

We then turned our attention toward diiodoperfluoroarenes. In particular, 1,4diiodotetrafluorobenzene (1,4TFIB) belongs to a class of halogen bond donors that has been frequently engaged in supramolecular functional materials. [START_REF] Ding | Halogen Bonding in the Co-Crystallization of Potentially Ditopic Diiodotetrafluorobenzene : A Powerful Tool for Constructing Multicomponent Supramolecular Assemblies[END_REF] Some relevant findings concern its role in the construction of organic cocrystal micro-lasers and haptic memory materials. [START_REF] Chu | Tailoring the Energy Levels and Cavity Structures toward Organic Cocrystal Microlasers[END_REF][START_REF] Bai | Halogen-Assisted Piezochromic Supramolecular Assemblies for Versatile Haptic Memory[END_REF] Interestingly, ThioPy-1,4TFIB complexes develop a similar linear organization as ThioPy-diIC6 (Figure 4 S5). Although all three diiodoperfluorinated compounds (diIC4, diIC6, and 1,4-TFIB) used in the formation of self-assemblies are linear in geometry, it remains difficult to explain the structural variation from zig-zag (ThioPy-diIC4) to linear (ThioPy-1,4TFIB and ThioPy-diIC6) chains with these results. The absence of conjugation in the ThioPy core prevents any competitive/cooperative phenomenon of electron transfer from intermolecular interactions. [START_REF] Berger | Halogen Bonding in a Multi-Connected 1,2,2-Triiodo-Alkene Involving Geminal and/or Vicinal Iodines: A Crystallographic and DFT Study[END_REF] Further investigations are under progress to explain this structural variation. The use of 1,2diiodotetrafluorobenzene (1,2TFIB) as an XB building block has been reported less frequently than 1,4TFIB, probably due to the difficulty to anticipate the geometry of the resulting complex.

However, recent works have highlighted its potential in inducing phosphorescence in the presence of diazaphenanthrenes and the self-organization of photoresponsive block copolymers. 4647 The cocrystal formation involving ThioPy and 1,2TFIB led to a supramolecular architecture with a complex packing pattern. In this case, a multitude of non-covalent bonds co-exists in which almost ΔE = -6.1 kcal mol -1 ΔE = -0.9 kcal mol -1 all halogen atoms of 1,2TFIB are involved. As expected, ThioPy and 1,2TFIB were linked through strong N•••I interactions, but only one iodine atom is involved which is rather uncommon in light of the literature (Figure 4 bottom). [START_REF] Du | Photoresponsive Iodine-Bonded Liquid Crystals Based on Azopyridine Derivatives with a Low Phase-Transition Temperature[END_REF] The refined crystal structure parameters show a N•••I separation of 2.844 Å (~ 80% of the sum of van der Waals radii) and an N•••I-C angle of 175°. In addition, the short distances between iodine atoms arise within the limit of precision for halogen bonds of type I and II, taking into consideration the sum of van der Waals radii for iodine (3.96 Å). Since the distance between I1 and I2 is 3.977 Å and C-I1•••I2 and C-I2•••I1 angles are 119.2° and 173.9°, respectively, the halogen-halogen interactions between I1 and I2 can be concluded, by definition, as XB type II contacts. A weak halogen-halogen interaction present between two I2 atoms exhibits XB type I as revealed by a distance of 4.032 Å and identical C-I2•••I2 angles of 118.9°. [START_REF] Shen | Cocrystals Assembled by Pyrene and 1,2-or 1,4-Diiodotetrafluorobenzenes and Their Phosphorescent Behaviors Modulated by Local Molecular Environment[END_REF] Surprisingly, F1 points towards the oxygen atom of ThioPy, but the distance (3.169 Å) appears slightly longer than the sum of van der Waals radii (O + F = 2.99 Å). [START_REF] Metrangolo | Fluorine-Centered Halogen Bonding: A Factor in Recognition Phenomena and Reactivity[END_REF][START_REF] Pavan | Halogen Bonding in Fluorine Experimental Charge Density Study on Intermolecular F⋯F and F⋯S Donor-Acceptor Contacts[END_REF] It is worth mentioning that examples showing a fluorine atom as a halogen bond donor are scarce in the literature. [START_REF] Eskandari | Does Fluorine Participate in Halogen Bonding ?[END_REF][START_REF] Fonseca | Computational Evidence for Intramolecular Hydrogen Bonding and Nonbonding X-O Interactions in 2'-Haloflavonols[END_REF] For instance, the first examples of Csp3F •••O sp3 interactions were reported in palladium complexes only in 2019. [START_REF] Elakkat | The First Two Examples of Halogen Bonding with a Sigma Hole-Donating Fluorine in the Csp3-F_ _ _Osp3 Interaction from Polyfluorinated Trans-Dihalopalladium( II) Di-Substituted Pyridine Complexes[END_REF] Despite the longer distance than the sum of van der Waals radii between O and F, using the Hirshfeld surface representation, we were able to successfully establish that there is indeed an F•••O interaction in the ThioPy-1,2TFIB complex (Figure 5). [START_REF] Spackman | Hirshfeld Surface Analysis[END_REF] We were also able to quantify the contribution of overlapped surface area to 0.5% in total electrostatic potential surface, and the calculated interaction energy was determined to be around -6.1 kcal mol -1 . Finally, S•••S and S•••F2 chalcogen bonds of 3.638 Å and 2.988 Å, respectively, lock the structure and give rise to a planar organization of these modules.

X-ray diffraction analysis of cocrystals involving ThioI and bipyridyl derivatives

Next, we decided to investigate the self-assemblies by reversing the XB counterparts through ThioI and bipyridyl derivatives, namely bipyridine ethane (BiPyetha), bipyridine ethylene (BiPyethy), and bipyridine (BiPy). The self-assembly of ThioI with BiPyetha was allowed to form in a dichloromethane/n-hexane mixture using a 2:1 ratio. As expected, the refinement of single crystal X-ray diffraction data analysis revealed a similar arrangement as the one found for ThioPy-diIC6 (Figure 6 S5). In the same way, the successive trimer modules develop a chain with thiophene rings pointing toward each other. The S•••S separation is slightly shorter than in ThioPy-diIC6 (3.728 Å) but it

F•••O 0.5%
remains longer than the sum of van der Waals radii for S. These thiophene groups are also hydrogen bonded with a neighboring ThioI unit due to two H•••F contacts of 2.620 and 2.675 Å, respectively.

Following the same protocol, ThioI and BiPyethy were cocrystallized under the same conditions. The supramolecular organization was mirrored as observed for ThioI-BiPyetha (Figure 6 S5). Likewise, the linear arrangement reveals thiophene rings pointing toward each other, but in contrast to the previous case, the S•••S distance is now lower than the sum of van der Waals radii (3.562 Å). The attractive nature of this contact is attested by weak interaction energy of about -1.7 kcal mol -1 (Table S5). This architecture is also comprised of other weak contacts linking parallel chains to one another. energy was found to be approximately -6.5 kcal mol -1 (Table S5). The N•••S distance (3.307 Å) represents a very weak interaction considering the sum of van der Waals radii (S+N = 3.35 Å).

According to DFT calculations, the chalcogen bond energy is around -3.0 kcal mol -1 , contributing substantially to the crystal cohesion. [START_REF] Haberhauer | The Nature of Strong Chalcogen Bonds Involving Chalcogen-Containing Heterocycles[END_REF] In that complex, parallel chains are also stabilized due to a plethora of H•••F hydrogen bonds. This unexpected self-assembly convinced us to get more information on such intermolecular N•••S contacts through a Cambridge Structural Database (CSD) survey.

N•••S chalcogen bonds in the Cambridge Structural Database

In the last few years, the chalcogen bonds have gained significant attention in chemical sciences and protein-ligand complexes due to their similarities with the halogen bonds, notably due to an anisotropic charge distribution. [START_REF] Scilabra | The Chalcogen Bond in Crystalline Solids: A World Parallel to Halogen Bond[END_REF][START_REF] Koebel | N Sulfur Bonding Interactions in Protein-Ligand Complexes: Empirical Considerations and Scoring Function[END_REF] Typically, the ability of an element of group 16 to form chalcogen bonds depends upon the nature of neighboring residues. Hence, electron withdrawing groups tend to increase the size of the positive σ hole on the chalcogen atom and give rise to stronger attractive interactions. Moreover, the elements like selenium (Se) and tellurium (Te) are more polarizable chalcogen atoms than S which makes the latter less prone to form a chalcogen bond through recognition processes. [START_REF] Lim | Sigma-Hole Interactions in Anion Recognition[END_REF] Whereas the intramolecular N•••S interactions are frequently encountered in stabilizing a planar conformation (e.g. in conducting materials), [START_REF] Réthoré | NS Intramolecular Nonbonded Interactions in Neutral and Radical Cation Salts of TTF-Oxazoline Derivatives : Synthesis , Theoretical Investigations , Crystalline Structures , and Physical Properties[END_REF] the same contacts are rarely reported at the intermolecular level. To find out the frequency of referred to in the database by the following refcodes: OGUTIV, [START_REF] Suresh | Novel Synthons in Sulfamethizole Cocrystals Structure-Property[END_REF] NAQPUT, [START_REF] Mondal | Exploring Solid State Diversity and Solution Characteristics in a Fluorine-Containing Drug Riluzole[END_REF] FAFSEL, [START_REF] Sesto | Charge Transfer Complexes of 2,4,6-Tricyano-s-Triazine with Tetrathiafulvalene (TTF) and Y,\,Y,V-Tetramethyl-/j-Phenylenediamine (TMPD)[END_REF] SUKPAS [START_REF] Sarmah | Mechanochemical Synthesis of Drug-Drug and Drug-Nutraceutical Multicomponent Solids of Olanzapine[END_REF] and NUSLOE. [START_REF] Sakai | Structural and Spectroscopic Study of 6,7-Dicyano-Substituted Lumazine with High Electron A Ffi Nity and Proton Acidity[END_REF] This led us to the conclusion that N•••S chalcogen bonds-driven selfassemblies of complementary partners arise as a rare phenomenon in crystal engineering.

Mechanochemical syntheses of ThioI-ThioPy complexes

Mechanochemistry is one of the important synthetic techniques in modern chemistry to prepare (nano)materials. [START_REF] Avvakumov | Soft Mechanochemical Synthesis: A Basis for New Chemical Technologies[END_REF] This technique can produce homogeneous nanosized composite materials at an industrial scale and offers the opportunity to study both the stoichiometric and nonstoichiometric composition of nanomaterials. As mentioned in the introduction, controlling, and understanding the formation of different polymorphs are crucial aspects considering the associated structureproperty relationship at the molecular or bulk level. The supramolecular organizations of two polymorphic structures of complementary thiophenes ThioI-ThioPy (called ThioI-ThioPy A and ThioI-ThioPy B, see Figures S3 andS4) have already been studied in previous work. [START_REF] Berger | Interplay between Halogen Bonding and Lone Pair-π Interactions: A Computational and Crystal Packing Study[END_REF] Single crystals of ThioI-ThioPy A and ThioI-ThioPy B were grown from dichloromethane/n-hexane and acetone, respectively. However, the scaling up of the solution-based synthesis of such complexes is a challenge. Therefore, complex ThioI-ThioPy was considered as a model system to investigate how the mechanochemistry conditions can exert a control on polymorphic outcome.

To purposely address these issues, the mechanochemical synthesis of ThioI-ThioPy was carried out by ball milling in neat conditions, and also, through a liquid-assisted grinding approach (LAG) method using methanol, toluene, THF, water, and dichloromethane (ca. 0.2 µL/mg). Subsequently, the produced materials were characterized by powder X-ray diffraction (PXRD) and compared with the starting compounds as well as ThioI-ThioPy complexes obtained by solution synthesis (see Figures S5-S14). As a result, the ThioI-ThioPy A was obtained under a neat and methanol-assisted grinding process whereas the ThioI-ThioPy B formed only by the LAG method in the presence of toluene, THF, water, and dichloromethane as solvent (Table 1). In a mechanochemical synthesis performed under LAG conditions, the protic/aprotic character and polarity of the added solvent can influence the yielded forms. But, in our case study, no clear trend could be observed considering the results that show highly polar and protic methanol and water led to two different polymorphs. Both polymorphs were found to be stable at room temperature in the solid state for over a month (Figure S13). On the other hand, when creating a supersaturated suspension in acetone containing both forms A and B, a complete transformation of form B to form A was observed, showing the latter to be the thermodynamically stable form at this temperature and in this solvent environment (Figure S14). This solvent was chosen as the cocrystal behaves congruently in this solvent. Lastly, it is worth mentioning that both forms show similar melting temperatures of 69 °C, which lies in between the melting points of Thiol (63 °C) and ThioPy (84 °C) (Figures S15-S18). As form A also has the highest melting enthalpy, both forms are likely monotropically related.

C solid state NMR spectroscopy analysis

Solid state nuclear magnetic resonance (SSNMR) spectroscopy has become an important analytical tool that complements powder X-ray diffraction analysis, particularly for disordered systems and structures showing internal dynamics. [START_REF] Xu | Solid-State NMR Spectroscopy for the Analysis of Element-Based Non-Covalent Interactions[END_REF] As far as the study of halogen bonded complexes is concerned, the solid state NMR analyses have proven to be highly informative, especially by looking at the local environments of 15 N, [START_REF] Fourmigué | Activation of Hydrogen-and Halogen-Bonding Interactions in Tetrathiafulvalene-Based Crystalline Molecular Conductors[END_REF] C, 31 P, [START_REF] Barbarella | The Versatile Thiophene: An Overview of Recent Research on Thiophene-Based Materials[END_REF] O, and/or 35 Cl SSNMR, for example. [START_REF] Vioglio | Solid-State Nuclear Magnetic Resonance as a Tool for Investigating the Halogen Bond[END_REF] Here, [START_REF] Fourmigué | Activation of Hydrogen-and Halogen-Bonding Interactions in Tetrathiafulvalene-Based Crystalline Molecular Conductors[END_REF] C SSNMR analyses were carried out for solid samples of ThioI, ThioPy, and ThioI-ThioPy to highlight the XB. The C-I resonance (C9) is only observed when measurements are performed at longer contact times (CT = 4 ms), due to the absence of a direct bond between the C9 and protons. Moreover, the broadness of this C9 resonance is due to the quadrupolar nature of the bound iodine. The 13 C SSNMR spectrum of ThioI-ThioPy exhibits a deshielding of ~9 ppm of the C9 resonance compared to pure ThioI, which is consistent with the formation of a halogen bond, as reported elsewhere (Figure 7). [START_REF] Vioglio | Solid-State Nuclear Magnetic Resonance as a Tool for Investigating the Halogen Bond[END_REF][START_REF] Viger-Gravel | Correlation between 13C Chemical Shifts and the Halogen Bonding Environment in a Series of Solid Para-Diiodotetrafluorobenzene Complexes[END_REF] A small shielding from 153.1 to 150.7 ppm was also observed for C8 and C8' of the pyridyl ring, further attesting to the formation of a halogen bonded cocrystal in the solid state.

XB interactions in the solution phase

After direct evidence of XB in the solid state, efforts were put together to detect these interactions in the solution state. In this regard, the binary systems were studied by UV-visible absorption spectroscopy and solution state 1 H or [START_REF] Clément | Synthesis and Supramolecular Organization of Regioregular Polythiophene Block Oligomers[END_REF] F{ [START_REF] Zhang | Self-Assembled Vertically Aligned Nanocomposite Systems Integrated on Silicon Substrate: Progress and Future Perspectives[END_REF] H} NMR (see supporting information).

Because both ThioI and ThioPy strongly absorb in the same UV region, the UV-visible absorption 8). [START_REF] Frangville | Stimuli Responsive Materials Supported by Orthogonal Hydrogen and Halogen Bonding or I ••• Alkene Interaction[END_REF] This observation broadens up the scope of ion-mediated self-assembly of neutral thiophene-based conductive π-conjugated polymers. Similarly, the chemical shift in [START_REF] Clément | Synthesis and Supramolecular Organization of Regioregular Polythiophene Block Oligomers[END_REF] F{ 1 H} NMR spectra of diIC4 and diIC4/ThioPy (ratio 1:5) confirms the existence of I•••N interaction in the solution phase (Figure S19). In contrast, no chemical shift in [START_REF] Clément | Synthesis and Supramolecular Organization of Regioregular Polythiophene Block Oligomers[END_REF] F{ 1 H} NMR spectra was observed for the ThioI-ThioPy XB pair (Figure S20).

However, as the relative ratio of the ThioPy was increased in the ThioI-ThioPy system, a significant upfield chemical shift for pyridyl hydrogen of the ThioPy unit was observed in 1 H NMR spectra indicating strong π-π interactions in the solution state (Figure S21). The same trend was observed in [START_REF] Fourmigué | Activation of Hydrogen-and Halogen-Bonding Interactions in Tetrathiafulvalene-Based Crystalline Molecular Conductors[END_REF] C{ 1 H} NMR spectra as well (Figure S22). The competition between XB and lone pain (lp)•••π interaction in the solution state is well-known for aromatic XB donors/acceptors.

A downfield trend is expected in solution state NMR if XB prevails. [START_REF] Ma | Structural Competition between Halogen Bonds and Lone-Pair⋯π Interactions in Solution[END_REF]

Conclusion

In summary, we have investigated the supramolecular organization of two XB donor/acceptor modified thiophene derivatives with complimentary XB acceptor/donor component through halogen bonding, prepared via both solution and mechanochemical routes. The X-ray diffraction analysis of single crystals obtained from the solution confirmed the presence of XB driven supramolecular self-assemblies. Interestingly, the evidence of chalcogen bonds acting concomitantly with XB and contributing to the crystal cohesion in some adducts were found. Most In general, the strength and high directionality of XB have proven to be successful in reliably organizing the complementary units. As far as the chalcogen bonds are concerned, the current rational design of supramolecular systems is mainly achieved using selenium and tellurium as electrophilic species for strong intermolecular interactions. [START_REF] Vogel | Chalcogen Bonding: An Overview[END_REF] However, some limitations exist such as a relatively high sensitivity towards light, oxygen, and certain experimental difficulties associated with (organo)selenium or tellurium chemistry. 74,75 Here, a simple thiophene moiety functionalized at position 3 with pyridyl ring allowed the intermolecular chalcogen bonding (ChB) via N•••S contacts. Considering the large panel of pyridyl and thiophenyl-based compounds applied in materials and biological sciences, the rationalization of this intermolecular interaction deserves an ample investigation to obtain a critical structural information. Moreover, the halogen and chalcogen bonds can team up and exert a different level of control over the supramolecular organization. Further experiments are however needed to establish a hierarchy among selected XB and ChB donors. More prospectively, the strategy of relying on the combination of both interactions is an appealing approach in designing conducting polymeric materials with F.M. and S.K. thank ULB (PDR 35275398) and FNRS (PDR T.0150.22.F) for the financial support.

4 -

 4 Chloropyridine hydrochloride (97%, CAS registry no. 7379-35-3) was obtained from BLD Pharma, Belgium. Iodopentafluorobenzene (99%, CAS registry no. 827-15-6) was obtained from Fluorochem, UK. Sodium Hydride (60%, dispersion in Paraffin Liquid, CAS registry no. 7646-69-7) and potassium tert-butoxide (>97%, CAS registry no. 865-47-4) were obtained from TCI Chemicals, Belgium. Tetrahydrofuran (99.5%, extra dry over molecular sieve, stabilized, AcroSeal™, ACROS Organics™, CAS registry no. 109-99-9, 128-37-0) was obtained from Fisher Scientific. Dimethyl sulfoxide (99.9+%, CAS registry no. 67-68-5) was obtained from Chem-Lab Analytical NV, Belgium. All materials were used as received. Air-sensitive reactions were performed using standard Schlenk techniques under argon atmosphere. Flash column chromatography was carried out using silica gel (60 Å, 70-200 µm) purchased from DAVISIL® -Grace GmbH, Germany. Analytical thin-layer-chromatography (TLC) was performed using silica plates with aluminium backings (250 µm with F-254 indicator) and were visualized using a 254/365 nm UV lamp. Solution NMR spectroscopy analyses were performed at the Laboratoire de Mesures Physiques of the University of Montpellier in France and at the Centre d'Instrumentation en REsonance Magnétique (CIREM) of the Université Libre de Bruxelles in Belgium. 1 H,[START_REF] Fourmigué | Activation of Hydrogen-and Halogen-Bonding Interactions in Tetrathiafulvalene-Based Crystalline Molecular Conductors[END_REF] C{ 1 H},[START_REF] Clément | Synthesis and Supramolecular Organization of Regioregular Polythiophene Block Oligomers[END_REF] F{ 1 H} NMR spectra were recorded on Bruker 300 MHz Avance III HD, 500 MHz Avance III or 600 MHz Avance III, and JEOL 400 Hz spectrometers at 298K. CDCl3 was used as received (purchased from Eurisotop, France). 1 H and 13 C{ 1 H} NMR spectra were calibrated to TMS on the basis of the relative chemical shift of the residual non-deuterated solvent, used as an internal standard. Chemical shifts (δ) are expressed in ppm from the residual non-deuterated solvent signal and coupling constants values ( n J) are expressed in Hz. Abbreviations used for NMR spectra are as follows: s, singlet; m, multiplet.

Figure 1 .

 1 Figure 1. Packing arrangement in the X-ray structure of ThioI at 175 K developing circular motifs

Figure 2 .

 2 Figure 2. Packing arrangement in the X-ray structures of the two ThioPy polymorphs developing

  bottom). In a similar way, the telechelic perfluorinated unit links both compounds into a trimeric structure due to N•••I halogen bonds. The N•••I separation drops to 78% of the sum of van der Waals radii, and the N•••I-C angle makes ~178°. However, a comparison of ThioPy-diIC4 and ThioPy-diIC6 at the macromolecular level highlights a different organization.

Figure 3 .

 3 Figure 3. Packing arrangement in the X-ray structures of halogen bonded complexes ThioPy-

  top); halogen bonding parameters appear almost identical (N•••I distance = 2.757 Å, N•••I-C angle ~178°) while the distance that separates the thiophene groups turns out to be shorter. Now, the S•••S contact is measured at 3.657 Å which is within the limit of the sum of van der Waals radii (interaction energy ~ -1.7 kcal mol -1 , Table

ΔE = - 1 .

 1 7 kcal mol -1

Figure 4 .

 4 Figure 4. Packing arrangement in the X-ray structures of halogen bonded complexes ThioPy-

Figure 5 .

 5 Figure 5. Hirshfeld surface of the ThioPy-1,2TFIB complex displaying overlapping electron

  top). This trimeric system (ThioI•••BiPyetha•••ThioI) forms an almost linear geometry with N•••I-C angle of ~174° and an interatomic distance of 2.791 Å (79% of the sum of van der Waals radii) due to N•••I halogen bond (interaction energy ~ -6.7 kcal mol -1 , Table

1 Figure 6 .

 16 Figure 6. Packing arrangement in the X-ray structures of halogen bonded complex ThioI-

  The S•••F2 chalcogen bonds with an average bond length of 3.053 Å (~7% interactions of the sum of van der Waals radii) are supplemented by three H•••F hydrogen bonds with bond lengths of 2.468 Å (H10•••F1), 2.562 Å (H21•••F3) and 2.640 Å (H20•••F4), respectively. As for ThioPy-1,2TFIB, two thiophenes belonging to parallel planes show a short O•••F distance of only 3.084 Å (O•••F4-C angle ~109°). Lastly, ThioI-BiPy highlighted the most surprising system (Figure 6 bottom). In comparison to the other ThioI-bipyridine adducts studied here, this particular module develops a linear arrangement not just with N•••I interactions even supplemented by N•••S chalcogen bonds, leading to infinite chains running in opposite directions. XB is slightly weaker than in the previous complexes (N•••I distance = 2.849 Å and N•••I-C angle ~174°), and the calculated interaction

  occurrence of the unusual N•••S chalcogen bond as observed in ThioI-BiPy, a preliminary Cambridge Structural Database (CSD) survey (version 2021.1, 5.42 updates May 2021) was carried out focusing on structures comprised of S and N atoms and were connected to 2 C atoms with N•••S bond distance smaller than 3.35 Å. As a result, a total number of 181 compounds came out with such inter-or intramolecular interactions. This number dropped to 13 structures when thiophene and pyridine derivatives were considered, and all of these were homo-crystals (see supporting information). Screening further, we then focused on crystalline systems where two different units are linked through intermolecular N•••S interactions and this number further dropped to 5. Only 5 molecular entities featured the same parameters (N•••S distance < 3.35 Å),

Figure 7 .

 7 Figure 7. 13 C solid state NMR spectra of ThioPy (blue), ThioI (green), and the ThioI-ThioPy

  inconclusive to confirm XB interactions in the solution state; therefore, omitted. Nevertheless, 1 H and 19 F{ 1 H} NMR spectroscopy experiments were successful to confirm the types of interactions acting in the solution state. ThioI and ThioPy were thereby challenged with complementary electron donors, namely an ammonium chloride and diIC4. The shift in 19 F{ 1 H} NMR spectra of ThioI and ThioI/TBACl (ratio 1:10; TBACl = n-tetrabutylammonium chloride) in CDCl3 suggests the ability of ThioI to be engaged in I•••Cl¯ halogen bonding (Figure

Figure 8 .

 8 Figure 8. 19 F{ 1 H} NMR spectra of ThioI/TBACl in CDCl3 suggesting the I•••Cl¯ halogen bonds

  strikingly, the cocrystal ThioI-BiPy develops a linear arrangement of alternating units as the result of N•••I and N•••S noncovalent bonds, ThioPyb being also organized by N•••S contacts. A Cambridge Structural Database survey further confirmed that the occurrence of such intermolecular N•••S contacts is a rare phenomenon and scarcely reported in the literature.Moreover, the theoretical calculations attested to the substantial contribution of this interaction to the supramolecular scaffold. For scaling-up purposes, further insight was sought into the formation and characterization of two polymorphic forms of the ThioI-ThioPy cocrystal. The mechanochemical synthesis by ball milling in neat grinding conditions and by the LAG method gave rise to both polymorphic forms A and B without any particular relationship with the solvent polarity. The most thermodynamically stable form A was also obtained through a supersaturated suspension in acetone. Mechanochemistry thus offers an appealing alternative to control the organization of the ThioI-ThioPy complex compared to the solution synthesis. A[START_REF] Fourmigué | Activation of Hydrogen-and Halogen-Bonding Interactions in Tetrathiafulvalene-Based Crystalline Molecular Conductors[END_REF] C solid state NMR analysis also highlighted the formation of a cocrystal with XB by the variation of C-I (ThioI) resonance compared to pure units. Solution state NMR spectroscopy measurement also established the presence of interactions in the solution phase.

Table 1 .

 1 Preparation of ThioI-ThioPy complexes by ball milling in neat grinding conditions and

	using LAG (with ca 0.2 µL/mg)
	Conditions	Dielectric constants 66,67	isolated complexes
	Neat	-	ThioI-ThioPy A
	Methanol	32.6	ThioI-ThioPy A
	Water	78.5	ThioI-ThioPy B
	Toluene	2.41	ThioI-ThioPy B
	Dichloromethane	8.9	ThioI-ThioPy B
	THF	7.4	ThioI-ThioPy B

ACKNOWLEDGMENT D. L., S. R., and S. C. are grateful to the University of Montpellier, the CNRS, and the French Ministry of Research for financial support.

complementary donor/acceptor partners and targeting their self-assembly into supramolecular architectures at the nanometer scale.

ASSOCIATED CONTENT Supporting Information. Crystallographic data; X-ray structures of complexes of ThioI, ThioPy-diIC4, ThioI-ThioPy A and ThioI-ThioPy B; X-ray powder diffractograms; DSC thermograms; 1 H, [START_REF] Clément | Synthesis and Supramolecular Organization of Regioregular Polythiophene Block Oligomers[END_REF] The supramolecular self-assemblies of modified thiophenes bearing complementary halogen bond donor/acceptor groups were prepared via both solution and mechanochemical routes. Some of the X-ray structures showed the presence of halogen and chalcogen bonds acting concomitantly. [START_REF] Fourmigué | Activation of Hydrogen-and Halogen-Bonding Interactions in Tetrathiafulvalene-Based Crystalline Molecular Conductors[END_REF] C solid state NMR analysis and density functional theory (DFT) calculations provided further information on the formation and respective contributions of these interactions.

Halogen Bonding

Chalcogen Bonding