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Article The Balance between Bonds, Bonds, and Bonds in the Crystal Structures of a Series of 1,3,4-Chalcogenadiazoles

Viraj De Silva, Boris B. Averkiev, Abhijeet S. Sinha and Christer B. Aakeröy *

Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA; [email protected] (V.D.S.); [email protected] (B.B.A.); [email protected] (A.S.S.) * Correspondence: [email protected]; Tel.: +1-785-532-6096

Abstract: In order to explore how specific -to-atom replacements change the electrostatic potentials on 1,3,4-chalcogenadiazole derivatives, and to deliberately alter the balance between inter- molecular interactions, four target molecules were synthesized and characterized. DFT calculations indicated that the atom-to-atom substitution of Br with I, and S with Se enhanced the σ-hole potentials, thus increasing the structure directing ability of halogen bonds and chalcogen bonds as compared to intermolecular hydrogen bonding. The delicate balance between these intermolecular forces was further underlined by the formation of two polymorphs of 5-(4-iodophenyl)-1,3,4-thiadiazol-2-amine; Form I displayed all three interactions while Form II only showed hydrogen and chalcogen bonding. The results emphasize that the deliberate alterations of the electrostatic potential on polarizable

 can cause specific and deliberate changes to the main synthons and subsequent assemblies in the  structures of this family of compounds.

Citation: De Silva, V.; Averkiev, B.B.; Keywords: Sinha, A.S.; Aakeröy, C.B. The ; ; ; intermolecular interactions; polymor- Balance between Hydrogen Bonds, phism; σ-hole Halogen Bonds, and Chalcogen Bonds in the Crystal Structures of a Series of 1,3,4-Chalcogenadiazoles. Molecules 2021, 26, 4125. https:// 1. Introduction doi.org/10.3390/molecules26144125 One of the main goals of is to employ intermolecular interactions in the assembly of crystalline materials with desired physiochemical properties [1–3]. To Academic Editor: Borys Osmialowski realize this objective, and to effectively manipulate these synthetic vectors, we need to further improve our understanding of the nature of these interactions. Received: 22 May 2021 The most influential and well-understood is, undoubtedly, the Accepted: 5 July 2021 hydrogen bond [4], and, consequently, the active use of this supramolecular tool has Published: 7 July 2021 been extensively mapped out [5–7]. Hydrogen bonding as a structure directing force has found many practical applications in pharmaceutical co-crystallizations [8,9], new Publisher’s Note: MDPI stays neutral agricultural formulations [10], as well as in the design of new energetic materials [11]. with regard to jurisdictional claims in However, over the past few decades, the recognition and understanding of potentially published maps and institutional affil- iations. competing intermolecular interactions, such as halogen and chalcogen bonding, have opened alternative ways for bottom-up design of new crystalline materials [12–14]. Hydrogen bonding is a noncovalent interaction involving the positive electrostatic potential on the hydrogen atom and a negative electrostatic potential of the acceptor atom (Scheme1). Electrostatic models can predict the directionality of the hydrogen bond rea- Copyright: © 2021 by the authors. sonably well; however, consideration of other components, such as charge transfer and Licensee MDPI, Basel, Switzerland. dispersion, is needed to properly understand the directionality [15,16]. Like hydrogen This article is an open access article bonds, halogen bonds share some of the same characteristics, whereby a positive electro- distributed under the terms and conditions of the Creative Commons static potential on a halogen atom and the negative electrostatic potential on an acceptor Attribution (CC BY) license (https:// atom can produce a ‘halogen bond’. In fact, this interaction is even more directional than creativecommons.org/licenses/by/ the hydrogen bond; however, it is worth keeping in mind that halogen bonds are not purely 4.0/). electrostatic. Using high-level theoretical models, such as symmetry-adapted perturbation

Molecules 2021, 26, 4125. https://doi.org/10.3390/molecules26144125 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 13

Molecules 2021, 26, 4125 2 of 13

purely electrostatic. Using high-level theoretical models, such as symmetry-adapted per- turbationtheory (SAPT), theory it is(SAPT), possible it tois obtainpossible the to breakdown obtain the of breakdown the intermolecular of the forcesintermolecular into indi- forcesvidual into components individual of components electrostatic, of polarization, electrostatic, repulsion, polarization, and repulsion, dispersion and for adispersion complete forunderstanding a complete understanding of the forces at of play, the whichforces at shows play, electrostatics which shows alone electrostatics cannot completely alone can- notdescribe completely and predict describe the and structure predict directing the structure ability directing of non-covalent ability of interactionsnon-covalent [17 inter-,18]. actionsSAPT calculations [17,18]. SAPT and calculations other periodic and other DFT calculationsperiodic DFT can calculations be computationally can be computa- taxing, tionallyhence one taxing, of the hence simplest one waysof the to simplest estimate ways the directionality to estimate the of directionality such systems withof such accept- sys- temsable accuracywith acceptable is through accuracy the use is through of molecular the use electrostatic of molecular potential electrostatic maps potential (MEPs). maps This (MEPs).approach This provides approach a simple provides method a simple for mapping method outfor mapping the distribution out the ofdistribution electron of elec- tronin molecular densities systemsin molecular (in vacuo), systems whereby (in vacuo), electron-efficient whereby electron-efficient and -deficient and areas -deficient can be areasidentified can be [19 identified,20]. The most[19,20]. prominent The mostσ -holesprominent (electron-deficient σ-holes (electron-deficient areas) of a areas) of can a moleculebe identified can bybe theidentified positive by electrostatic the positive potential. electrostatic The σ potential.-hole on halogen The σ-hole atoms on provideshalogen atomsthe main provides electrostatic the main driver electrostatic for halogen driver bonding for halogen interactions bonding [21, 22interactions]. [21,22].

Scheme 1. A simple view of the electrostatic component of hydrogen, halogen, and chalcogen bonds. Scheme 1. A simple view of the electrostatic component of hydrogen, halogen, and chalcogen bonds.Chalcogen bonds, a relatively recent ‘discovery’, also share the same aspects of the halogen bond, including the high directionality. However, chalcogen atoms can form Chalcogen bonds, a relatively recent ‘discovery’, also share the same aspects of the two highly directional chalcogen bonding interactions as a result of the presence of two halogenσ-holes directlybond, including opposed the to high R-Ch directionali bonds (Schemety. However,1)[ 23–26 chalcogen]. Importantly, atoms can by changingform two highlythe electrostatic directional potentials chalcogen on bo thesending donor interactions atoms, theseas a result noncovalent of the presence interactions of two can beσ- holesfine-tuned directly to beopposed strong structureto R-Ch bonds directing (Scheme tools that1) [23–26]. can be utilizedImportantly, in crystal by changing engineering the electrostaticfor creating competitionpotentials on between these donor hydrogen, atoms, halogen, these noncovalent and chalcogen interactions bonding can [27, 28be]. fine- tunedMany to bedrug strong molecules structure contain directing multiple tools th functionalat can be groups utilized comprising in crystal engineering hydrogen, halo- for creatinggen, and competition chalcogen atoms, between and hydrogen, the presence halogen, of these and can chalcogen to increasing bonding [27,28]. complexity as to howMany molecules drug molecules interact notcontain only multiple in drug formulations,functional groups such comprising as co-crystals, hydrogen, but also hal- at ogen,an active and sitechalcogen of specific atoms, receptors and the [8 ,presence29]. Each of approved these can drug lead costs to increasing billions of complexity dollars in asresearch to how and molecules development interact and not many only potentially in drug formulations, useful candidates such fail as dueco-crystals, to low solubility but also ator an poor active stability, site of and specific such receptors problems [8,29]. may be Each addressed approved with drug a more costs complete billions understand-of dollars in researching of how and the development balance between and many intermolecular potentially forces useful candidates to a specific fail due structure to low solu- with bilityunique or bulk poor properties. stability, and Furthermore, such problems 1,3,4-chalcogenadiazole may be addressed moieties with a more are known complete to show un- derstandinganti-inflammatory of how andthe balance anticancer between properties intermol [30ecular,31], and forces broadly leads to speaking, a specific chalcogen structure withatoms unique and their bulk structural properties. influence Furthermore, can also 1,3,4-chalcogenadiazole positively impact synthetic moieties transformations are known to showand . anti-inflammatory Given the factand that anticancer chalcogenadiazole properties [30,31], moieties and contain broadly a variety speaking, of domains chalco- genthat atoms can act and as chalcogen-bondtheir structural influence donor/acceptor can also sites, positively they present impact a synthetic unique source transfor- for mationsthe formation and catalysis. of a multitude Given the of fact intermolecular that chalcogenadiazole interactions. moieties The balance contain and a variety competi- of domainstion between that can these act non-covalent as chalcogen-bond interactions donor/a willcceptor significantly sites, they impact present solid-state a unique structure source forand the subsequently formation of the a multitude properties of of intermolecular the resulting bulk interactions. solid. In The addition, balance the and presence competi- of tionchalcogen between bonds these can, non-covalent in principle, interactions compete withwill significantly or disrupt an impact intended solid-state supramolecular structure andsynthetic subsequently strategy. the These properties increased of the complexities resulting bulk can givesolid. rise In addition, to unexpected the presence or unpre- of chalcogendictable structural bonds can, influences, in principle, hence compete a systematic with studyor disrupt of the an possible intended structure supramolecular directing syntheticinteractions strategy. of these These moieties increased are required.complexities Herein, can give we rise present to unexpected a systematic or unpredict- structural ablestudy structural on how theinfluences, increased henc complexitye a systematic of multiple study of competing the possible intermolecular structure directing forces in in- a teractionssingle molecule of these is moieties manifested arein required. the solid-state. Herein, Wewe focuspresent on a the systematic 1,3,4-chalcogenadiazole structural study onmoiety how (Figurethe increased1) with complexity different of multiple in competing the second intermolecular and fifth position forces as this in a allows single us to alter the chalcogen-bond donor from S to Se and the halogen-bond donor from Br to I, allowing us to explore the balance between these interactions. Such atom-to-atom

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Molecules 2021, 26, 4125 molecule is manifested in the solid-state. We focus on the 1,3,4-chalcogenadiazole moiety3 of 13 (Figure 1) with different substituents in the second and fifth position as this allows us to alter the chalcogen-bond donor from S to Se and the halogen-bond donor from Br to I, allowing us to explore the balance between these interactions. Such atom-to-atom substi- tutionssubstitutions can potentially can potentially result in result significant in significant changes changesto the properties, to the properties, such as, for such example, as, for increasedexample, increasedbinding affinity binding of affinity halogenated of halogenated I ligands> Br [32], I >as Br well [32 ],as as increased well as increased catalytic activitycatalytic of activity -containing of selenocysteine-containing proteins over proteins over [33,34], cysteine which [33,34 ],could which be couldasso- ciatedbe associated with the with shorter the halogen shorter halogen or chalcogen or chalcogen bond formation bond formation in biological in biological systems. systems. In TTF- TCNQIn TTF-TCNQ semiconductor systems, systems, replacement replacement of S with of Se S results with Se in results M-I transitions in M-I transitions at lower temperaturesat lower temperatures due to stronger due to coupling stronger between coupling the between donor and the acceptor donor and [35]. acceptor With an [im-35]. provedWith an insight improved into insight how chalcogen into how chalcogenatoms form atoms intermolecular form intermolecular interactions, interactions, we may webe ablemay to be (i) able deepen to (i) our deepen understanding our understanding of the origins of the of origins photophysical of photophysical behavior behavior of charge- of transfercharge-transfer complexes complexes and (ii) develop and (ii) developmore effective more effectivebottom-up bottom-up syntheses syntheses for new classes for new of semi-conductorsclasses of semi-conductors and other andhigh-v otheralue high-value molecular molecularmaterials. materials.

Figure 1. 1,3,4-Chalcogenadiazole1,3,4-Chalcogenadiazole derivative with multiple donor and acceptor sites.

Based on relevant relevant structures in the CSD CSD [36–39], [36–39], as as well well as as on on preliminary preliminary hydrogen- hydrogen- bond propensity calculations (Table S1, Scheme S1) [[40],40], it was deemed likely that a formationformation through through a a pair of identical hydrogenhydrogen bonding (hydrogen-bond dimer) would be most prominent in this system. However, the tunability of the different interactions thatthat can be produced within single component systems (Figure 22)) can,can, inin principle,principle, leadlead toto a a range range of of different different synthons synthons and and structural structural arrangements. arrangements. In Inthis this study, study, we we wanted wanted to mapto map out out the the structural structural landscape landscape of a of series a series of 1,3,4-chalcogenadiazoles of 1,3,4-chalcogenadiazoles and andaddress address the followingthe following specific specific questions: questions: (i) (i)To Towhat what ex extenttent do do atom-to-atom atom-to-atom replacements replacements change electrostatic potentials? (ii) Which structure directing synthons are formed and how do Molecules 2021, 26, x FOR PEER REVIEWelectrostatic potentials? (ii) Which structure directing synthons are formed and how4 of do 13 theythey control control assembly? assembly? and and (iii) (iii) Can Can the the bala balancence between between hydrogen hydrogen bonds, bonds, halogen halogen bonds, bonds, and chalcogen bonds be deliberately modulated?

FigureFigure 2.2.Postulated Postulated interactionsinteractions inin thethe solid-statesolid-statelandscape landscape of of 1,3,4-chalcogenadiazoles. 1,3,4-chalcogenadiazoles.

2. Results The four target molecules are shown in Figure 3. Molecular electrostatic potential( MEP) maps (in vacuo) of these molecules reveal how the magnitude of the MEPs change in response to atom-to-atom replacements. A summary of the results is given in Table 1. Based on these calculations, the positive electrostatic potentials on the more polarizable atoms were observed to be larger, as expected. Electrostatic potentials on the same atom type on different analogs did not change considerably when atom-to-atom replacements were done.

Table 1. MEP (kJ/mol) data for chalcogen and halogen atoms of the different target analogs.

Donor Atom T1-S-Br T1-Se-Br T1-S-I T1-Se-I Chalcogen 96.6 118.8 95.7 117.5 Halogen 74.6 73.1 103.0 103.0

Figure 3. Molecular electrostatic potential maps (MEPs) of the (a) T1-S-Br (b) T1-Se-Br (c) T1-S-I (d) T1-Se-I.

The previously reported of T1-S-Br, CCDC refcode XUVTAK [41], showed the hydrogen-bonded dimer formation with N3-H1···N1 and a single hydrogen bond between N3-H2···N2 (Figure 2, far left schematic). The atom did not partic- ipate in any notable halogen bonds; however, the atom engaged in a chalcogen bond with the π-electron cloud, S1···C5, at 3.497 Å and 161.20° (Figure 4).

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Figure 2. Postulated interactions in the solid-state landscape of 1,3,4-chalcogenadiazoles.

2. Results The four target molecules are shown in Figure 3. Molecular electrostatic potential( Molecules 2021, 26, 4125 MEP) maps (in vacuo) of these molecules reveal how the magnitude of the MEPs change4 of 13 in response to atom-to-atom replacements. A summary of the results is given in Table 1. Based on these calculations, the positive electrostatic potentials on the more polarizable atoms were observed to be larger, as expected. Electrostatic potentials on the same atom 2.type Results on different analogs did not change considerably when atom-to-atom replacements wereThe done. four target molecules are shown in Figure3. Molecular electrostatic potential (MEP) maps (in vacuo) of these molecules reveal how the magnitude of the MEPs change inTable response 1. MEP to(kJ/mol) atom-to-atom data for chalcogen replacements. and haloge A summaryn atoms of of the the different results target is given analogs. in Table 1. Based on these calculations, the positive electrostatic potentials on the more polarizable atomsDonor were Atom observed to T1-S-Br be larger, as expected. T1-Se-Br Electrostatic T1-S-I potentials on the T1-Se-I same atom typeChalcogen on different analogs96.6 did not change considerably 118.8 when 95.7 atom-to-atom replacements 117.5 wereHalogen done. 74.6 73.1 103.0 103.0

Figure 3. Molecular electrostatic potential maps (MEPs)(MEPs) ofof thethe ((aa)) T1-S-BrT1-S-Br ((bb)) T1-Se-BrT1-Se-Br ((cc)) T1-S-IT1-S-I ((dd)) T1-Se-I.T1-Se-I.

TableThe 1. MEP crystal (kJ/mol) structure data for previously chalcogen andreported halogen of atomsT1-S-Br, of the CCDC different refcode target XUVTAK analogs. [41], showed the hydrogen-bonded dimer formation with N3-H1···N1 and a single hydrogen Donor Atom T1-S-Br T1-Se-Br T1-S-I T1-Se-I bond between N3-H2···N2 (Figure 2, far left schematic). The bromine atom did not partic- ipate in anyChalcogen notable halogen bonds; 96.6 however, the 118.8 sulfur atom engaged 95.7 in a chalcogen 117.5 bond with theHalogen π-electron cloud, S1···C5, 74.6 at 3.497 Å and 73.1 161.20° (Figure 103.0 4). 103.0

The crystal structure previously reported of T1-S-Br, CCDC refcode XUVTAK [41], showed the hydrogen-bonded dimer formation with N3-H1···N1 and a single hydrogen bond between N3-H2···N2 (Figure2, far left schematic). The bromine atom did not partici- Molecules 2021, 26, x FOR PEER REVIEW 5 of 13 pate in any notable halogen bonds; however, the sulfur atom engaged in a chalcogen bond with the π-electron cloud, S1···C5, at 3.497 Å and 161.20◦ (Figure4).

Figure 4. Structure directing interactions in the crystal structure of T1-S-Br [[41].41].

The crystal structure of T1-Se-Br contains two unique molecules in the asymmetric unit with each of them showing different interactions with respect to the surrounding molecules. The halogen atom in one of them formed a near-linear halogen bond (Figure 5), Br···π electron cloud, Br27···C4 at 3.517(6) Å and 170.0(2)°, while the other formed an irregular Br7···Br27 contact in an almost perpendicular fashion, 99° (Figure S1). The sele- nium atoms formed a bifurcated chalcogen bond, Se···π electron cloud and Se···N (Figure 5, Figure S1).

Figure 5. Primary intermolecular interactions in the crystal structure of T1-Se-Br.

T1-S-I crystallized in two different polymorphs. Form I was obtained from acetoni- trile, and Form II from methanol. The polymorphs had different numbers of symmetry- independent molecules (Z’) and completely different intermolecular connectivity. Form I resulted in Z’ = 4, where all of them displayed closely related intermolecular connectivity but with different bond geometries (Figure S2). Two molecules in the asymmetric unit

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Figure 4. Structure directing interactions in the crystal structure of T1-S-Br [41].

The crystal structureThe crystal of T1-Se-Br structurecontains of T1-Se-Br two unique contains molecules two unique in the molecules asymmetric in the asymmetric unit with eachunit of them with showingeach of them different showing interactions different with interactions respect towith the respect surrounding to the surrounding molecules. Themolecules. halogen atom The in halogen one of thematom formedin one of a near-linearthem formed halogen a near-linear bond (Figure halogen5) , bond (Figure ◦ Br···π electron5), cloud, Br···π Br27 electron···C4 atcloud, 3.517(6) Br27···C4 Å and at 170.0(2)3.517(6) Å, whileand 170.0(2)° the other, while formed the other an formed an ◦ irregular Br7···irregularBr27 contact Br7···Br27 in an contact almost in perpendicular an almost perp fashion,endicular 99 fashion,(Figure 99° S1). (Figure The S1). The sele- atomsnium formed atoms a bifurcatedformed a bifurcated chalcogen chalcogen bond, Se bond,···π electron Se···π electron cloudand cloud Se and···N Se···N (Figure (Figure5, Figure5, S1). Figure S1).

Figure 5. PrimaryFigure 5. intermolecularPrimary intermolecular interactions interactions in the crystal in the structure crystal structure of T1-Se-Br. of T1-Se-Br.

T1-S-I crystallizedT1-S-I in twocrystallized different in polymorphs. two different Formpolymorphs. I was obtained Form I was from obtained acetoni- from acetoni- trile, and Formtrile, II from and methanol. Form II from The methanol. polymorphs The had poly differentmorphs numbershad different of symmetry- numbers of symmetry- independent moleculesindependent (Z’) andmolecules completely (Z’) and different completely intermolecular different intermolecular connectivity. Formconnectivity. I Form I resulted in Z’ =resulted 4, where in all Z’ of = them4, where displayed all of them closely displa relatedyed closely intermolecular related intermolecular connectivity connectivity but with differentbut bondwith different geometries bond (Figure geometries S2). Two (Figure molecules S2). Two in themolecules asymmetric in the unit asymmetric unit formed Type II halogen bonds that formed with the electrophilic area on one halogen atom with an electron-rich area on the other halogen. In this halogen bonding, the halogen atom simultaneously acted as both the donor and acceptor and the other two unique

molecules did not show any halogen bonds. The sulfur atoms engaged in chalcogen bonds between S···N in which the atom acted as a chalcogen-bond acceptor as well as a hydrogen-bond acceptor, indicating that the hydrogen bond was most likely the prominent interaction. In addition, two hydrogen bonds per molecule were formed between NH···N (Figure6), leading to a 2-D chain-like assembly (Figure S3). Molecules 2021, 26, x FOR PEER REVIEW 6 of 13 Molecules 2021, 26, x FOR PEER REVIEW 6 of 13

formed Type II halogen bonds that formed with the electrophilic area on one halogen formed Type II halogen bonds that formed with the electrophilic area on one halogen atom with an electron-rich area on the other halogen. In this halogen bonding, the halogen atom with an electron-rich area on the other halogen. In this halogen bonding, the halogen atom simultaneously acted as both the donor and acceptor and the other two unique mol- atom simultaneously acted as both the donor and acceptor and the other two unique mol- ecules did not show any halogen bonds. The sulfur atoms engaged in chalcogen bonds ecules did not show any halogen bonds. The sulfur atoms engaged in chalcogen bonds between S···N in which the nitrogen atom acted as a chalcogen-bond acceptor as well as a between S···N in which the nitrogen atom acted as a chalcogen-bond acceptor as well as a hydrogen-bond acceptor, indicating that the hydrogen bond was most likely the promi- hydrogen-bond acceptor, indicating that the hydrogen bond was most likely the promi- nent interaction. In addition, two hydrogen bonds per molecule were formed between Molecules 2021, 26, 4125 nent interaction. In addition, two hydrogen bonds per molecule were formed between6 of 13 NH···N (Figure 6), leading to a 2-D chain-like assembly (Figure S3). NH···N (Figure 6), leading to a 2-D chain-like assembly (Figure S3).

FigureFigure 6. (a 6.) (aAsymmetric) Asymmetric unit unit and and (b) (mainb) main intermolecular intermolecular interactions interactions in one in one of the of the four four unique unique molecules molecules in the in the crystal crystal Figure 6. (a) Asymmetric unit and (b) main intermolecular interactions in one of the four unique molecules in the crystal structure of T1-S-I, Form I. structurestructure of of T1-S-I, T1-S-I, Form Form I. I. TheThe crystal crystal structure structure of Form of Form II (Figure II (Figure 7) 7contains) contains a hydrogen a hydrogen bond bond dimer dimer between between The crystal structure of Form II (Figure 7) contains a hydrogen bond dimer between N6-H6B···N4N6-H6B··· N4and and a single a single hydrogen hydrogen bond bond betw betweeneen N6H6A···N5 N6H6A··· N5of the of theheterocycle heterocycle moiety. moiety. N6-H6B···N4 and a single hydrogen bond between N6H6A···N5 of the heterocycle moiety. NoNo halogen halogen bonds bonds were were present present in the in Form the FormII (Figure II (Figure 7). Finally,7). Finally, a chalcogen a chalcogen bond com- bond No halogen bonds were present in the Form II (Figure 7). Finally, a chalcogen bond com- prisedcomprised of S···π ofring, S··· S2···C9,π ring, S2at··· 3.568(7)C9, at 3.568(7)Å and 162.1(2)° Å and 162.1(2) was observed.◦ was observed. prised of S···π ring, S2···C9, at 3.568(7) Å and 162.1(2)° was observed.

FigureFigure 7. Primary 7. Primary intermolecular intermolecular contacts contacts in the in thecrystal crystal structure structure of T1-S-I, of T1-S-I, Form Form II. II. Figure 7. Primary intermolecular contacts in the crystal structure of T1-S-I, Form II. In the crystal structure of T1-Se-I, a hydrogen-bond dimer, N13-H13A···N11 (Figure8) , is present along with a single N13-H13B···N12 hydrogen bond, which is similar to T1-S-Br and Form II of T1-S-I. Consistent with the interaction observed for Se in T1-Se-Br, the sele- nium atom of T1-Se-I also showed bifurcated chalcogen bonding, Se9···C3(π), at 3.487(4)Å and 165.75(14)◦, and Se9···N12, at 3.613(3) Å and 154.88(13)◦. In addition, the structure contains one Type II halogen bond, I7···I7, at 4.0468(4) Å and 162.8(1)◦. All relevant hydrogen, halogen and chalcogen bond geometries of T1-S-Br, T1-Se-Br, T1-S-I and T1-Se-I are given in Table2. Molecules 2021, 26, x FOR PEER REVIEW 7 of 13

In the crystal structure of T1-Se-I, a hydrogen-bond dimer, N13-H13A···N11 (Figure 8), is present along with a single N13-H13B···N12 hydrogen bond, which is similar to T1- S-Br and Form II of T1-S-I. Consistent with the interaction observed for Se in T1-Se-Br, the selenium atom of T1-Se-I also showed bifurcated chalcogen bonding, Se9···C3(π), at Molecules 2021, 26, 4125 7 of 13 3.487(4)Å and 165.75(14)°, and Se9···N12, at 3.613(3) Å and 154.88(13)°. In addition, the structure contains one Type II halogen bond, I7···I7, at 4.0468(4) Å and 162.8(1)°.

Figure 8. StructureStructure directing interactions in the crystal structure of T1-Se-I.

TableAll 2. Hydrogen,relevant hydrogen, halogen, and halogen chalcogen and bond chalcoge parametersn bond of geometries the five crystal of T1-S-Br, structures. T1-Se-Br, T1-S-I and T1-Se-I are given in Table 2. DH/X/Ch—A D/X/Ch—A Å DH/X/Ch—A(deg) Table 2. Hydrogen, halogen, and chalcogenN3-H1 bond para···N1meters of the five 2.957 crystal structures. 163.42 1-S-Br N3-H2···N1 2.996 167.10 DH/X/Ch---A D/X/Ch---A Å DH/X/Ch---A(deg) S1···C5 3.497 161.20 N3-H1···N1 2.957 163.42 N33-H33b···N11 2.943(8) 165.3(2) 1-S-Br N3-H2···N1 N13-H13b···N312.996 2.942(8) 167.10 166.1(2) S1···C5 N33-H33a···N323.497 2.981(7)161.20 157.05(19) N33-H33b···N11 N13-H13a···N122.943(8) 2.976(7) 165.3(2) 157.82(19) Se29···N32 3.646(5) 154.39(19) N13-H13b···N31T1-Se-Br 2.942(8) 166.1(2) Se29···C25 3.416(6) 162.6(2) N33-H33a···N32 Se9···N122.981(7) 3.603(6) 157.05(19) 155.39(19) N13-H13a···N12 Se9-C32.976(7) 3.406(6) 157.82(19) 163.3(2) T1-Se-Br Se29···N32 Br27···C43.646(5) 3.517(6)154.39(19) 170.0(2) Se29···C25 N1B-H1BA···N3D3.416(6) 3.013(13) 162.6(2) 176.8(7) ··· Se9···N12 N1A-H1AA N3C3.603(6) 3.016(13)155.39(19) 179.2(7) N1C-H1CA···N3A 3.028(13) 179.2(7) Se9-C3 N1D-H1DA···N3B3.406(6) 3.008(13)163.3(2) 178.9(8) Br27···C4 N1C-H1CB···N2B3.517(6) 3.031(12) 170.0(2) 157.4(6) N1B-H1BA···N3D N1A-H1AB···N2D3.013(13) 2.992(12) 176.8(7) 155.5(6) N1D-H1DB···N2A 3.033(13) 158.7(13) T1-S-IN1A-H1AA···N3C Form I 3.016(13) 179.2(7) N1B-H1BB···N2C 3.027(12) 159.5(6) T1-S-I Form I N1C-H1CA···N3A S1C···N2B3.028(13) 3.507(9) 179.2(7) 163.6(4) N1D-H1DA···N3B S1D···N1A3.008(13) 3.517(10) 178.9(8) 164.6(4) N1C-H1CB···N2B S1A···N2D3.031(12) 3.525(10) 157.4(6) 162.4(4) S1B···N2C 3.559(10) 163.1(4) I1C···I1A 3.892(1) 174.7(3) I1A···I1B 3.813(1) 176.3(3)

N6-H6B···N4 2.979(8) 178(8) T1-S-I Form II N6-H6A···N5 3.019(7) 172(6) S2···C9 3.568(7) 162.1(2) Molecules 2021, 26, 4125 8 of 13

Table 2. Cont.

DH/X/Ch—A D/X/Ch—A Å DH/X/Ch—A(deg) N13-H13A···N11 2.940(5) 165.6(3) N13-H13B···N12 2.957(4) 157.7(3) Se9···N12 3.613(3) 154.88(13) T1-Se-I Se9···C3 3.487(4) 165.75(14) I7···I7 4.0468(4) 162.8(1) I7···I7 4.0468(4) 93.14(11)

3. Discussion The calculated MEPs showed that when the smaller atoms (Br, S) were replaced by a more polarizable alternative (I, Se), the electrostatic potentials undergo significant transformations (Table1, Figure3). Changing bromine to resulted in a 40% increase in the positive σ-hole potential, while a selenium replacement of sulfur produced a 23% enhancement. Even though intermolecular halogen bonds and chalcogen bonds are the result of contributions from electrostatic, polarization, repulsion, and dispersion, it is helpful to note that a relatively simplistic focus on the electrostatic component alone still offers valuable guidance for predicting which synthons are going to be more likely to appear in an extended structure. The increases in the electrostatic potential produce atoms that are more likely to form more prominent halogen and chalcogen bonds, respectively, which directly impacts their ability to more frequently deliver structure directing interactions in the solid state. Geometry optimizations (in vacuo) of all target molecules showed the two rings, phenyl and 1,3,4-chalcogenadiazole, in each molecule to be close to coplanar geometry with a range of torsion angles of −0.55 to +0.55◦ (Figure S4). The planarity of these optimized structures only allows one of the two σ-holes to be accessed by the acceptors. In the solid-state, however, these were not planar and had torsion angles ranging from 30–40◦ (Figure S4). In the sulfur analogs of 1,3,4-chalcogendiazole published in the CSD (Figure9, based on 152 relevant crystal structures), the majority had torsion angles less than 40◦and most of them formed single chalcogen bond formation. The structures of the selenium analogues in this study contained bifurcated chalcogen bond comprising both σ-holes. As Molecules 2021, 26, x FOR PEER REVIEW 9 of 13 a result of the substitution of sulfur with selenium, an additional chalcogen bond becomes structurally active and the supramolecular assembly proceeds along a different path.

Figure 9. Distribution of torsion angles based on 152 CSD-reported 1,3,4-thiadiazol1,3,4-thiadiazol structures.structures.

Atom-to-atom replacement of halogen atoms resulted in a more significant enhance- ment of the electrostatic potentials compared to those noted in the case of the chalcogen replacement. Despite this difference, only 3/5 structures contained noteworthy halogen bonds, whereas chalcogen bonds were present in all five crystal structures examined herein. Only one of the two bromine-based compounds formed halogen bonds, whereas the iodine compounds showed Type II halogen bond formation in 2/5 structures, Scheme 2. All iodine-containing structures not undergoing halogen bonding show that despite the predictability of the MEPs, it was not always perfect; however, in general, the increased structural influence can be attributed to larger σ-hole potentials of the more polarizable iodine atom. The lack of halogen bonds in previously reported [38] and [39] analogs further validates the expectation that a more polarizable halogen atom is more likely to influence the solid-state assembly in ways to go beyond simple (and less directional) packing forces.

Scheme 2. Summary of notable intermolecular interactions in the crystal structures examined herein. sHB: Single Hydro- gen Bond. sChB: Single Chalcogen Bond. bChB: Bifurcated Chalcogen Bond.

A comparison of the frequency of occurrence of hydrogen, halogen, and chalcogen bonds in the crystal structures of these 1,3,4-chalcogendiazole shows that the former was the most prominent; hydrogen bonding exists in all of them and 4/5 exist as hydrogen bond dimers and 5/5 as single hydrogen bond formation. The significance of the hydrogen bonding and the delicate balance between the hydrogen, halogen, and chalcogen bonding was clearly displayed in the two polymorphic structures. The melting points of Form I

Molecules 2021, 26, x FOR PEER REVIEW 9 of 13

Molecules 2021, 26, 4125 9 of 13 Figure 9. Distribution of torsion angles based on 152 CSD-reported 1,3,4-thiadiazol structures.

Atom-to-atom replacement of halogen atoms resulted in a more significant significant enhance- ment of the electrostatic potentials compared to those noted in thethe casecase ofof thethe chalcogenchalcogen replacement. Despite this difference,difference, onlyonly 3/53/5 structures containedcontained noteworthynoteworthy halogenhalogen bonds, whereaswhereas chalcogen chalcogen bonds bonds were were present present in all in five all crystalfive crystal structures structures examined examined herein. Onlyherein. one Only of theone two of the bromine-based two bromine-based compounds compounds formed formed halogen halogen bonds, bonds, whereas whereas the io- dinethe iodine compounds compounds showed showed Type Type II halogen II halogen bond bond formation formation in 2/5 in 2/5 structures, structures, Scheme Scheme2. All2. All iodine-containing iodine-containing structures structures not not undergoing undergoing halogen halogen bonding bonding show show that that despitedespite thethe predictability of the MEPs, it waswas notnot alwaysalways perfect;perfect; however,however, inin general,general, thethe increasedincreased structural influenceinfluence can be attributed to largerlarger σσ-hole-hole potentialspotentials ofof thethe moremore polarizablepolarizable iodine atom. atom. The The lack lack of of halogen halogen bonds bonds in inpreviously previously reported reported fluorine fluorine [38] [38 and] and chlorine chlo- rine[39] [analogs39] analogs further further validates validates the the expectation expectation that that a amore more polarizable polarizable halogen halogen atom isis more likely to influenceinfluence thethe solid-statesolid-state assembly in ways to gogo beyondbeyond simplesimple (and(and lessless directional) packing forces.

SchemeScheme 2.2. SummarySummary ofof notablenotable intermolecular intermolecular interactions interactions in in the the crystal crystal structures structures examined examined herein. herein. sHB: sHB: Single Single Hydrogen Hydro- Bond.gen Bond. sChB: sChB: Single Single Chalcogen Chalcogen Bond. Bond bChB:. bChB: Bifurcated Bifurcated Chalcogen Chalcogen Bond. Bond.

A comparison of the frequencyfrequency ofof occurrenceoccurrence ofof hydrogen,hydrogen, halogen,halogen, andand chalcogenchalcogen bonds in the crystal structures ofof thesethese 1,3,4-chalcogendiazole1,3,4-chalcogendiazole showsshows thatthat thethe formerformer waswas the mostmost prominent;prominent; hydrogenhydrogen bondingbonding existsexists inin allall ofof themthem andand 4/54/5 existexist asas hydrogenhydrogen bond dimers and 5/5 as as single single hydrogen hydrogen bond bond formation. The significance significance of the hydrogen bonding and the delicate balance between thethe hydrogen, halogen, and chalcogen bonding was clearly displayed in the two polymorphic structures. structures. The The melting melting points points of of Form Form I I and Form II only differed by 1–2 ◦C, implying that their lattice energies (and relative stabilities) are closely matched. Since Form I contains halogen and hydrogen bonds (chalcogen bonding was overshadowed by the hydrogen bonding), and Form II contains

chalcogen and hydrogen bonds, we can surmise that the impacts on the stability and physical properties of the two σ-hole interactions are very similar.

4. Materials and Methods 4.1. and General Methods All were used as received without any further purification. MEPs were calculated using functional theory on molecules optimized in the phase using Spartan’ 08 program with B3LYP/6-311++G** level of theory. All the NMRs were recorded on a Bruker 400 MHz spectrophotometer. Single crystal X-ray diffraction data were obtained using a Bruker MicroStar and a Rigaku XtaLAB Synergy-S with CuKα and MoKα sources. The melting points were collected using a TA instrument DSC Q20 differential scanning calorimeter.

4.2. Crystallization Experiments Single crystals of the pure products of T1-Se-Br and T1-Se-I were obtained using the slow evaporation method with methanol as the . The pure product of T1-S-I was Molecules 2021, 26, 4125 10 of 13

recrystallized using the slow evaporation method from acetonitrile and methanol to obtain Form I and Form II, respectively.

4.3. Synthesis of Selenosemicarbazide Thiosemicarbazide (3.64 g, 0.04 mol) was dissolved in dry ethanol and to this, iodomethane (5.67 g, 0.04 mol) was added and the mixture was refluxed at 80 ◦C for 3 h. Upon cooling the mixture in an ice bath, the product, hydrazinyl(methylthio)methanamine, precipitated and this was air dried overnight and used for the following step. ◦ To a mixture of Se and NaBH4 cooled to 0 C with ice, dry ethanol was added under N2 atmosphere. Once all the Se dissolved, hydrazinyl(methylthio)methanamine dissolved in dry ethanol was added slowly. This was stirred overnight, and the resulting precipitate was filtered in the fume hood, and the product was purified through column chromatography 1 as a grey/violet solid [31]. Yield 60%. Decomp: 174–176. H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.97 (s, 1H), 7.64 (s, 1H), 4.52 (s, 2H), 13C NMR (101 MHz, DMSO) δ 175.80. 77 Se NMR (400 MHz, DMSO-d6) δ 146.16.

4.4. Synthesis of 5-(4-Bromophenyl)-1,3,4-thiadiazol-2-amine, T1-S-Br First, 4-bromobenzoic (2.01 g; 0.01 mol), thiosemicarbazide (0.91g, 0.01 mol), ◦ and POCl3 (5.0 mL) were mixed in a round-bottomed flask. This was refluxed at 75 C for 3 h. After cooling to room temperature, (50.0 mL) was added slowly to the mixture and the reaction mixture was further refluxed for 4 h. The progress of the reaction was monitored using TLC and after the completion, the mixture was cooled to room temperature and was basified to pH 8 using 30% NH4OH. The resulting precipitate was filtered, and the product was purified using column chromatography. The product was a ◦ 1 light-yellow solid with a yield of 85%. MP: 212–214 C. H NMR (400 MHz, DMSO-d6) δ 7.68 (q, J = 8.7 Hz, 4H), 7.50 (s, 2H). 13C NMR (101 MHz, DMSO) δ 169.32, 155.66, 132.55, 130.66, 128.60, 123.08.

4.5. Synthesis of 5-(4-Bromophenyl)-1,3,4-selenadiazol-2-amine, T1-Se-Br First, 4-bromobenzoic acid (2.01g, 0.01 mol), selenosemicarbazide (1.38g, 0.01 mol), ◦ and POCl3 (5.0 mL) were mixed in a round-bottomed flask. This was refluxed at 75 C for 3 h. After cooling to room temperature, water (50.0 mL) was added slowly to the mixture and the reaction mixture was further refluxed for 4 h. The progress of the reaction was monitored using TLC and after the completion, the mixture was cooled to room temperature and was basified to pH 8 using 30% NH4OH. The resulting precipitate was filtered, and the product was purified using column chromatography. The product was a ◦ 1 light pink color solid with a yield of 65%. MP: 222–224 C. H NMR(400 MHz, DMSO-d6) δ 7.64 (m, J = 8.5 Hz, 4H). 13C NMR (101 MHz, DMSO) δ 173.10, 160.83, 133.54, 132.42, 129.30, 77 122.91. Se NMR (400 MHz, DMSO-d6) δ 562.04.

4.6. Synthesis of 5-(4-Iodophenyl)-1,3,4-thiadiazol-2-amine, T1-S-I First, 4-iodobenzoic acid (2.48g, 0.01 mol), thiosemicarbazide (0.91g, 0.01 mol), and ◦ POCl3 (5.0 mL) were mixed in a round-bottomed flask. This was refluxed at 75 C for 3 h. After cooling to room temperature, water (50.0 mL) was added slowly to the mixture and the reaction mixture was further refluxed for 4 h. The progress of the reaction was monitored using TLC and after the completion, the mixture was cooled to room temperature and was basified to pH 8 using 30% NH4OH. The resulting precipitate was filtered, and the product was purified using column chromatography. The product was a white solid with a ◦ ◦ 1 yield of 70%. MP: Form I 239–241 C, From II 240–242 C. H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz 2H), 7.49 (s, 2H). 13C NMR (101 MHz, DMSO) δ 169.45, 156.11, 138.57, 131.16, 128.75, 96.62. Molecules 2021, 26, 4125 11 of 13

4.7. Synthesis of 5-(4-Iodophenyl)-1,3,4-selenadiazol-2-amine, T1-Se-I First, 4-iodobenzoic acid (2.48g, 0.01 mol), selenosemicarbazide (1.38g, 0.01 mol), ◦ and POCl3 (5.0 mL) were mixed in a round-bottomed flask. This was refluxed at 75 C for 3 h. After cooling to room temperature, water (50.0 mL) was added slowly to the mixture and the reaction mixture was further refluxed for 4 h. The progress of the reaction was monitored using TLC and after the completion, the mixture was cooled to room temperature and was basified to pH 8 using 30% NH4OH. The resulting precipitate was filtered, and the product was purified using column chromatography. The product was a ◦ 1 greyish solid with a yield of 55%. MP: 219–221 C. H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 8.4 Hz, 2H), 7.61 (s, 2H), 7.51 (d, J = 8.4 Hz, 2H). 13C NMR (101 MHz, DMSO) δ 173.00, 77 161.07, 138.27, 133.86, 129.30, 96.24. Se NMR (400 MHz, DMSO-d6) δ 560.97.

5. Conclusions In summary, it is clear that atom-to-atom substitution can lead to significant changes in crystal structures especially when the less polarizable sulfur is replaced by a more polar- izable selenium atom (a better chalcogen donor), leading to a more structurally influential σ-hole. Despite the fact that chalcogen bonds comprise a variety of components, MEPs offer a simple way of mapping out electrostatic potentials in the 1,3,4-chalcogenadiazole sys- tems. This information can provide reliable guidelines for predicting which intermolecular interactions are going to be prominent in the solid state. By altering these electrostatic po- tentials through covalent means, the influence of σ-hole interactions (such as halogen and chalcogen bonds) can be controlled. Ultimately, this is of considerable practical importance when designing crystal engineering strategies that involve a combination of reversible non-covalent interactions.

Supplementary Materials: The following are available online. Table S1: Hydrogen bond propensity (HBP) calculations using , Scheme S1: Schematic of 1,3,4-Chalcogenadiazole and the num- bering used in HBP calculations, Figure S1: T1-Se-Br Secondary interactions of the second unique molecule of the asymmetric unit, Figure S2: T1-S-I Form I Halogen bonding interactions formed by each unique molecule in the asymmetric unit showing different bond geometries, Figure S3: T1-S-I Form I Hydrogen bonder 2-D chain, Figure S4: T1-S-Br a) torsion angle of the optimized structure in vacuum b) torsion angle of the molecule in the crystal structure, refcode XUVTAK, Table S2: Crystallographic data. 1H, 13C and 77Se NMR spectrums. Author Contributions: Conceptualization, investigation and writing V.D.S. and C.B.A.; X-Ray inves- tigation, A.S.S., B.B.A. and C.B.A. All authors have read and agreed to the published version of the manuscript. Funding: Viraj De Silva acknowledges support from the Kansas State University and the NSF- MRI grant CHE-2018414, which was used to purchase the single-crystal X-ray diffractometer and associated software employed in this study. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Crystallographic data (CCDC 2083577, 2083645, 2083656, 2083657) can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif (accessed on 14 May 2021), or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. Acknowledgments: We acknowledge Victor W. Day for collecting XRD data for on T1-S-I (Form II). Victor W. Day acknowledge NSF-MRI grant CHE-0923449, which was used to purchase the X-ray diffractometer and software used in this study. Conflicts of Interest: Authors declare no conflicts of interest. Sample Availability: Samples of the compounds are not available from the authors. Molecules 2021, 26, 4125 12 of 13

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