1,4-Diiodotetrafluorobenzene 3,5-Di-(Pyridin-4-Yl)-1,2, 4-Thiadiazole

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⁻)₂∙L2, (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 (d_N···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⁻)₂∙L2 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⁻)₂∙L2∙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].

Following our interest in the study of σ-hole interactions between halogen-rich compounds and pyridine tectons [15,16], 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).

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 L2∙1,4-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) ų, T = 173(2) K, Z = 2, ρ_calc = 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 d_N∙∙∙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 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 (L1∙1,4-DITFB)_∞ 1D-chains propagate approximately along the [$\overline{2}$11] direction and pack into 2D sheets via weak C‒H∙∙∙F interactions (entries c–e in Figure 2 and Table 1) [17]. 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 literature method [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 [18]. The structure was solved with the ShelXT [19] solution program using dual methods and the model was refined using full matrix least squares minimization on F² with ShelXL [20] 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 [21] was used as the graphical interface.

3.2. Synthesis 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 colourless 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): 1599m, 1458vs, 1410s, 1335m, 1290m, 1207m, 1124m, 1063m, 995m, 939s, 825ms, 748m, 733ms, 712ms, 677m, 636ms, 505m, 474w, 422w cm^–1.

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 L1∙(1,4-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.