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1,4-Diiodotetrafluorobenzene 3,5-di-(pyridin-4-yl)-1,2,4-thiadiazole <1/1>

Enrico Podda
Anna Pintus
Vito Lippolis
Francesco Isaia
Alexandra M. Z. Slawin
Cameron L. Carpenter-Warren
John Derek Woollins
4 and
Maria Carla Aragoni
Department of Chemical and Geological Sciences, University of Cagliari, S.S. 554 Bivio Sestu, Monserrato, 09042 Cagliari, Italy
Centre for Research University Services (CeSAR), University of Cagliari, S.S. 554 Bivio Sestu, Monserrato, 09042 Cagliari, Italy
EaStCHEM School of Chemistry, University of St Andrews, St Andrews KY16 9ST, UK
Department of Chemistry, Khalifa University, Abu Dhabi 127788, United Arab Emirates
Authors to whom correspondence should be addressed.
Molbank 2024, 2024(2), M1801;
Submission received: 15 February 2024 / Revised: 24 March 2024 / Accepted: 26 March 2024 / Published: 1 April 2024
(This article belongs to the Section Structure Determination)


The reactivity of 3,5-di-(pyridin-4-yl)-1,2,4-thiadiazole (L1) with 1,4-diiodotetrafluorobenzene (1,4-DITFB) was explored and the halogen-bonded 1:1 co-crystal (1) was successfully isolated and structurally characterized.

Graphical Abstract

1. Introduction

1,2,4-Thiadiazoles have been recognized as effective scaffolds in medicinal chemistry, since many derivatives are biologically active and very promising candidates in drug design [1]. Inspired by Cefozopran [2], the first 1,2,4-thiadiazole derivative to enter the market as an antibiotic, extensive synthetic efforts led to the isolation of numerous 1,2,4-thiadiazoles with potential biomedical applications, such as high cytotoxicity against human myeloid leukemia cells [3], inhibitors of Factor XIIIa in the blood coagulation process [4], neuroprotectors, [5] and in the treatment of Alzheimer’s disease [6]. The synthesis of 1,2,4-thiadiazoles is typically achieved starting from thioamides, whose oxidation is followed by cyclization, and several methods have been reported using a range of oxidants and reaction solvents [7,8]. A valid protocol reported the use of alcoholic thioamide solutions, which can be easily oxidized by molecular dihalogens, leading to the corresponding thiadiazole in good yields [9].
1,2,4-Thiadiazoles featuring pyridyl substituents, such as 3,5-di-(pyridin-4-yl)-1,2,4-thiadiazole (L1) and 3,5-di-(pyridin-3-yl)-1,2,4-thiadiazole (L2) (Scheme 1), have been successfully used as building blocks in supramolecular chemistry by exploring their reactivity towards metal ions in the preparation of coordination polymers and polygons [10,11]. The versatility of donors L1 and L2 as supramolecular synthons became evident when their reactivity towards dihalogens, interhalogens, and other halogenated derivatives was investigated [12,13]. In this regard, the reaction of L1 and L2 with dihalogens and interhalogens was previously reported by our research group [12], and the self-assembly outcomes are summarized in Scheme 1. The results showed that donors L1 and L2 can give either Charge-Transfer (CT) adducts or salts with variable degrees of N-protonation (e.g., HL+, H2L2+) depending on the solvent polarity and the experimental setup (Scheme 1). The reaction of L2 with diiodine in CH2Cl2 resulted in the bis-adduct L2·2I2 with a short N⋯I bond distance (2.505 Å) and a linear N⋯I–I fragment as typically observed in CT-adducts. Notably, the reaction of L1 with diiodine under the same experimental conditions did not produce a crystalline product and its nature as L1·2I2 was established by microanalytical determinations and Raman spectroscopy [12].
The role of the solvent becomes crucial when considering the products obtained from the reactions between L1 or L2 and I2 or IBr in ethyl alcohol, where the following ionic compounds were obtained: (HL1+)(IBr2), (HL1+)(I3), (HL2+)(IBr2), (HL2+)(I3), (H2L22+)(I3)2L2, (HL2+)(I5) (Scheme 1) [12,13]. These structures share cations HL1+ or HL2+ with only one of the two pyridyl nitrogen atoms being protonated, resulting in the formation of head-to-tail polymeric arrays held by NH+⋯N hydrogen bonds (dN⋯N distances up to 2.770 Å), whose motif is shaped by the geometrical features of the former donors: wavy chains for cations HL1+ and either helices or zig-zag chains in the case of cations HL2+ [12]. The only exception among these ionic compounds is represented by (H2L22+)(I3)2L2, where the donor L2 appears in both the neutral and the doubly charged HL22+ form.
When acetonitrile was used as a solvent and the donors L1 and L2 were reacted with I2, (H2L12+)(I3)2∙2H2O and (HL2+)(I)∙4CH3CN were isolated [13]. Moreover, the reaction of L2 with I2 in an iodoform/acetone mixture produced compound (H2L22+)(I)2L2∙2CHI3 [13]. To further investigate the reactivity of L1 and L2 toward dihalogens, Pennington and coworkers introduced bismuth triiodide as a building block, producing self-assembled salts with formula (H2L12+)2(Bi8I284−)∙4CH3CN, [(H2L12+)(HL1+)](Bi2I93−)∙3H2O, (H2L22+)2(Bi4I164−)∙2CH3CN∙2I2, and (H2L22+)2(Bi6I224−)∙2CH3OH, whose crystal structures show L1 and L2 in their mono- or diprotonated forms along with four unusual polyiodobismuthate counterions [13].
On the contrary, the interaction of L1 and L2 with the halogen atoms of halo-organic compounds has not yet been reported. This interaction falls into the realm of halogen bonding because it involves a halogen atom acting as an electrophilic site and the lone pair of a pyridine nitrogen atom as a nucleophilic site [14,15,16]. Following our interest in the study of σ-hole interactions between halogen-rich compounds and pyridine tectons [17,18], we report here on the synthesis and characterization of the novel halogen-bonded 1:1 co-crystal (1) formed between L1 and 1,4-diiodotetrafluorobenzene (1,4-DIFTB). In this halo-organic compound, the σ-hole effect for the iodide atoms is enhanced by the presence of the four electronegative fluorides, and numerous co-crystals formed by the halogen bonding between 1,4-DIFTB and pyridine donors can be found in the literature [14,19,20,21,22,23].

2. Results

The slow evaporation of a chloroform solution of L1 and 1,4-DITFB in 1:1 molar ratio at room temperature afforded colorless crystals, established by means of X-ray diffraction analysis as a 1:1 halogen-bonded co-crystal with formula L11,4-DITFB (compound 1; Figure 1). Compound 1 crystallizes in the triclinic space group P−1 with two units in the unit cell (see Table S1 for structural data and refinement parameters).
Crystal data for compound 1: C18H8F4I2N4S, (Mr = 642.14 g mol−1) triclinic, P−1, a = 5.6690(4) Å, b = 12.3300(9) Å, c = 14.1339(9) Å, α = 91.644(6), β = 96.314(6)°, γ = 92.400(6)°, V = 980.54(12) Å3, T = 173(2) K, Z = 2, ρcalc = 2.175 g/cm3, µ(Mo Kα) = 3.363 mm−1. The final R1 was 0.0333 [F2 ≥ 2 σ(F2)], wR2 was 0.0960 (all data), and the GooF = 1.043.
The 1,4-DITFB molecules interact with L1 to form neutral adducts at both N-pyridyl atoms with dN⋯I distances of 2.801(5) and 2.947(4) Å and C–I⋯N angles of 177.4(2) and 168.3(2)° for N1⋯I1 and N4⋯I2i, respectively (entries a and b in Figure 2; i = 2 + x, −1 + y, −1 + z; Tables S2 and S3). These values are similar to the average N⋯I value of 2.9(2) Å retrieved from the CSD database (version 5.43, three updates) for the structurally characterized compounds in which 1,4-DITFB interacts with pyridyl-based donors (the search was constrained to N⋯I distances up to the sum of the atomic van der Waals radii: 3.53 Å).
The resulting (L11,4-DITFB) 1D-chains propagate approximately along the [ 2 ¯ 11] direction and pack into 2D sheets via weak C–H⋯F interactions (entries c–e in Figure 2 and Table 1) [23]. The FT-IR spectrum (Figure S1) recorded for compound 1 showed a shift towards lower frequency of the ν(C–I) stretching mode from 760 to 748 cm−1 on passing from free 1,4-DITFB to the co-crystal, as a consequence of the halogen bonding between the two species [14].

3. Materials and Methods

3.1. General

L1 was synthesized according to a method in the literature [9]. 1,4-DIFTB and chloroform were purchased from Merck and used without any further purification. Elemental analysis determinations were performed with a Perkin Elmer EA CHN elemental analyzer. The FT-IR spectra (4000–400 cm−1) were recorded on KBr pellets on a Thermo Nicolet 5700 spectrometer. Melting point determination was performed on a FALC mod. C apparatus. Single crystal X-ray diffraction data were collected at 173 K on a Rigaku SCX mini diffractometer using graphite monochromated Mo Kα radiation (0.71073 Å). Data collection and processing were carried out using CrysAlisPro [24]. The structure was solved with the ShelXT [25] solution program using dual methods and the model was refined using full matrix least squares minimization on F2 with ShelXL [26] 2018/3. The crystal was found to be a non-merohedral twin and the model was refined as a two-component twin. Olex2 1.5 [27] was used as the graphical interface.

3.2. Preparation of L1·1,4-DITFB (1)

L1 (12.0 mg; 5.00 × 10−5 mol) and 1,4-DITFB (20.1 mg; 5.00 × 10−5 mol) were dissolved in chloroform (5 mL) and the mixture was stirred at room temperature for 20 min. The resulting solution was filtered through a PTFE filter and the solvent allowed to evaporate slowly to afford compound 1 as colorless crystals suitable for X-ray diffraction analysis (10.8 mg; 1.68 × 10−5 mol; 34%). Elemental analysis calcd (%) for C18H8F4I2N4S: C 32.67, H 1.26, N 8.73. Found: C 31.88, H 0.66, N 8.21. M.p. = 186 °C. FT-IR (KBr, 4000–400 cm−1): 1599 m, 1458 vs, 1410 s, 1335 m, 1290 m, 1207 m, 1124 m, 1063 m, 995 m, 939 s, 825 ms, 748 m, 733 ms, 712 ms, 677 m, 636 ms, 505 m, 474 w, 422 w cm−1(Figure S1).

4. Conclusions

The halogen-bonded co-crystal (1) was obtained by the self-assembly of 3,5-di-(pyridin-4-yl)-1,2,4-thiadiazole (L1) and 1,4-diiodotetrafluorobenzene (1,4-DITFB) in chloroform. The crystal structure of 1, determined by means of crystallographic tools, corresponds to the formulation L11,4-DITFB. A comparison between the FT-IR spectra of 1 and 1,4-DITFB provided further evidence for the halogen bonding between the two building blocks.

Supplementary Materials

The following supporting information is available online. Figure S1: Solid-state FT-IR spectrum of compound 1 (500–3500 cm−1, KBr pellet); Table S1: Crystal data and structure refinement parameters for compound 1; Tables S2: Bond lengths (Å) for compound 1; Tables S3: Bond angles (°) for compound 1.

Author Contributions

Conceptualization and writing (original draft): E.P., M.C.A.; Data analysis and presentation of results: M.C.A., E.P. and A.P., M.C.A., V.L. and F.I. are experts in the field of halogen bonding and extensively investigated the reactivity of L1 towards various halogenated species. A.M.Z.S., J.D.W. and C.L.C.-W. performed the XRD analysis of compound 1. All authors have read and agreed to the published version of the manuscript.


The authors acknowledge Fondazione di Sardegna (FdS Progetti Biennali di Ateneo, annualità 2022). The authors acknowledge the Ministero per l’Ambiente e la Sicurezza Energetica (MASE; formerly Ministero della Transizione Ecologica, MITE)—Direzione generale Economia Circolare for funding (RAEE—Edizione 2021).

Data Availability Statement

Crystallographic data were deposited at CCCD (CIF deposition number 2332380).

Conflicts of Interest

The authors declare no conflicts of interest.


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Scheme 1. CT adducts and ionic compounds isolated from the reactions between N-donors L1 and L2 and halogenated species. Refcodes are given in parentheses.
Scheme 1. CT adducts and ionic compounds isolated from the reactions between N-donors L1 and L2 and halogenated species. Refcodes are given in parentheses.
Molbank 2024 m1801 sch001
Figure 1. X-ray crystal structure of compound 1 with the numbering scheme adopted. Displacement ellipsoids were drawn at the 50% probability level.
Figure 1. X-ray crystal structure of compound 1 with the numbering scheme adopted. Displacement ellipsoids were drawn at the 50% probability level.
Molbank 2024 m1801 g001
Figure 2. Partial view of the crystal packing of 1 showing (a) a single layer with the relevant intermolecular interactions ae are labelled according to Table 1, and (b) adjacent layers viewed along the [110] direction.
Figure 2. Partial view of the crystal packing of 1 showing (a) a single layer with the relevant intermolecular interactions ae are labelled according to Table 1, and (b) adjacent layers viewed along the [110] direction.
Molbank 2024 m1801 g002
Table 1. Compound 1 intermolecular interactions.
Table 1. Compound 1 intermolecular interactions.
C–I⋯NdC–I (Å)dI⋯N (Å)αC–I⋯N (°)
C–H⋯FdC–H (Å)dH⋯F (Å)dC⋯F (Å)αC–H⋯F (°)
Symmetry codes: i = 2 + x, −1 + y, −1 + z; ii = 1 − x, 2 − y, 1 − z; iii = −x, 1 − y, 1 − z.
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MDPI and ACS Style

Podda, E.; Pintus, A.; Lippolis, V.; Isaia, F.; Slawin, A.M.Z.; Carpenter-Warren, C.L.; Woollins, J.D.; Aragoni, M.C. 1,4-Diiodotetrafluorobenzene 3,5-di-(pyridin-4-yl)-1,2,4-thiadiazole <1/1>. Molbank 2024, 2024, M1801.

AMA Style

Podda E, Pintus A, Lippolis V, Isaia F, Slawin AMZ, Carpenter-Warren CL, Woollins JD, Aragoni MC. 1,4-Diiodotetrafluorobenzene 3,5-di-(pyridin-4-yl)-1,2,4-thiadiazole <1/1>. Molbank. 2024; 2024(2):M1801.

Chicago/Turabian Style

Podda, Enrico, Anna Pintus, Vito Lippolis, Francesco Isaia, Alexandra M. Z. Slawin, Cameron L. Carpenter-Warren, John Derek Woollins, and Maria Carla Aragoni. 2024. "1,4-Diiodotetrafluorobenzene 3,5-di-(pyridin-4-yl)-1,2,4-thiadiazole <1/1>" Molbank 2024, no. 2: M1801.

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