Unusual C–N Coupling Reactivity of Thiopyridazines: Efficient

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Unusual C−N Coupling Reactivity of Thiopyridazines: Efficient Synthesis of Iron Diorganotrisulfide Complexes Michael Tüchler,† Stefan Holler,† Jörg A. Schachner,† Ferdinand Belaj,† and Nadia C. Mösch-Zanetti*,† †

Institute of Chemistry, University of Graz, Schubertstrasse 1, 8010 Graz, Austria S Supporting Information *

ABSTRACT: The reaction of iron(II) triflate with 6-tert-butyl-3-thiopyridazine (PnH) and 4-methyl-6-tert-butyl-3thiopyridazine (MePnH) respectively led to iron bis(diorganotrisulfide) complexes [Fe(RPnS3PnR)2](OTf)2 [R = H (1a) and Me (2a)]. The corresponding perchlorate complexes were prepared by using the iron(II) chloride precursor and the subsequent addition of 2 equiv of NaClO4, giving [Fe(RPnS3PnR)2](ClO4)2 [R = H (1b) and Me (2b)]. The compounds were fully characterized including single-crystal X-ray diffraction analysis. All four compounds exhibit nearly perfect octahedral geometries with an iron center coordinated by four nitrogen atoms from two RPnS3PnR ligands and by two sulfur atoms of the central atom in the S3 unit. The diamagnetic complexes exhibit unusually high redox potentials for the Fe2+/3+ couple at E1/2 = 1.15 V (for 1a and 1b) and 1.08 V (for 2a and 2b) versus Fc/Fc+, respectively, as determined by cyclic voltammetry. Furthermore, the source of the extra sulfur atom within the S3 unit was elucidated by isolation of C−N-coupled pyridazinylthiopyridazine products.

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INTRODUCTION Polysulfide-containing molecules, such as diallyl trisulfide, or the natural products esperamicin, chalicheamicin, or varacin are known to exhibit significant anticancer activity.1,2 They all contain a S3 group, or it is suggested to be formed after administration. For this reason, the organic chemistry and the biological activity of trisulfides are well investigated.3−6 Established synthetic procedures for organotrisulfides use a combination of thiols together with a sulfur source such as H2S, SCl 2 , or S 8 . Furthermore, rearrangement reactions of polysulfides may also lead to the formation of organotrisulfides.4−6 However, the coordination chemistry of trisulfide-containing molecules is far less investigated, which is surprising in view of the high abundance of metals in biological systems.7−23 A Cambridge database search revealed only four crystallographically characterized examples of a metal complex with a directly coordinated S3 unit.9,11,16,23 Some of them were prepared by the solvo- and hydrothermal synthesis of mercaptopyrimidine disulfide and a metal precursor.14,16,23 While this gives some insight into the coordination properties of the biologically active class of compounds, the thermal synthesis is usually nonselective because several sulfurcontaining products were detected.14,16,23 Thus, there is a high need for a better understanding of the coordination chemistry of S3 units, as well as for their formation from sulfur precursors in the presence of metal salts. © 2017 American Chemical Society

We recently developed new members of soft scorpionate ligands based on thiopyridazine and started to explore their coordination chemistry toward a variety of transition metals.24−29 The introduction of a six-membered pyridazine heterocycle leads to interesting reactivities, which we attribute to its electron-deficient nature. These ligands were found to exhibit an unusually high tendency to form cobalt, nickel, and copper boratrane complexes with the concomitant reduction of the metal,24,28,29 while the respective iron boratrane complexes are as yet elusive. The highly interesting reactivities of reported iron boratrane systems toward small-molecule activation30−32 led us explore the reaction of our scorpionate ligand with iron(II) salts. However, we found only mixtures containing several products, among them considerable amounts of an iron diorganotrisulfide complex. In-depth investigations allowed us to conclude that it is formed upon reaction of iron(II) centers not with the scorpionate ligand but with the parent thiopyridazine heterocycle. Here, the unprecedented and high-yield formation of iron diorganotrisulfide complexes with the concomitant formation of a desulfurized, C−N-coupled pyridazinylthiopyridazine is presented. All compounds were fully characterized by various spectroscopic means and by single-crystal X-ray diffraction analyses. Received: April 6, 2017 Published: June 27, 2017 8159

DOI: 10.1021/acs.inorgchem.7b00865 Inorg. Chem. 2017, 56, 8159−8165

Article

Inorganic Chemistry

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RESULTS AND DISCUSSION Complex Synthesis. The reaction of iron(II) triflate with 6-tert-butyl-3-thiopyridazine (PnH) and 4-methyl-6-tert-butyl3-thiopyridazine (MePnH) respectively led to iron bis(diorganotrisulfide) complexes [Fe(RPnS3PnR)2](OTf)2 [R = H (1a) and Me (2a)], as shown in Scheme 1. The

formation of 1a, would result in a 6:1 ratio. However, the 8:1 ratio found points toward a more complicated desulfurization and sulfur insertion mechanism. Furthermore, the formation of the diorganotrisulfide ligand requires oxidation of the thiopyridazine, followed by the formal insertion of a sulfur atom in the oxidation state of 0. The necessary oxidation of the thiopyridazine might be one reason for the oxygen dependency of the reaction that was found. Sulfur transfer was also reported upon the reaction of pyrimidinedisulfide with copper(I)14,16 or nickel(II)23 under solvothermal conditions, forming among others the respective diorganotrisulfide complexes (copper, 5%; nickel, 73%). In these cases, the extra sulfur atom in the S3 unit may be explained by the concomitant formation of thioethercoordinated complexes. Additionally, with copper, 2-(pyrimidin-2-ylamino)-1,3-thiazole-4-carbaldehyde was also formed. In the system reported here, we were able to not only unambiguously elucidate the nature of the desulfurized thiopyridazine product but also isolate it in good yields (78 and 62%). The organic products 3 and 4 were obtained as described in detail in the Experimental Section: after reaction of the thiopyridazines with the iron precursor, the iron complexes precipitated from the CH2Cl2 solution and were isolated by filtration. The filtrate contained compounds 3 and 4, respectively, which were isolated upon evaporation of the solvents. Depending on the stoichiometry of the reaction, the products might be contaminated with unreacted thiopyridazine, which made purification by column chromatography necessary. The compounds could be recrystallized from pentane or acetonitrile. They were stable toward an ambient atmosphere and soluble in all organic solvents, including pentane, cyclohexane, dichloromethane, tetrahydrofuran, or acetonitrile. Characterization by 1H and 13C NMR spectroscopy as well as by single-crystal X-ray diffraction analysis (vide infra) revealed the products to be C−N-coupled pyridazinylthiopyridazine molecules. This clearly explains the need for 8 rather than 6 equiv of thiopyridazines in the overall reaction shown in Scheme 1. The coupling of two thiopyridazines to 3 or 4, respectively, liberates only one sulfur atom, leading to the formal reaction sequence shown in Scheme 2.

Scheme 1. Synthesis of Bis(diorganotrisulfide) Complexes 1a, 1b, 2a, and 2b under the Formation of Coupled Dipyridazinyl Products 3 and 4

corresponding perchlorate complexes were prepared by using the iron(II) chloride precursor and the subsequent addition of 2 equiv of NaClO4, giving [Fe(RPnS3PnR)2](ClO4)2 [R = H (1b) and Me (2b)]. Generally, the complexes were synthesized by suspending the starting materials in dichloromethane and purging the flask with oxygen. The orange suspension turned into a dark-red solution, and after stirring overnight under an O2 atmosphere, the suspension was filtered to obtain the pure complexes as light-red powders in high yields. In the solid state, complexes 1a, 1b, 2a, and 2b are stable at ambient conditions. They are slightly soluble in dichloromethane and soluble in polar solvents like acetonitrile, methanol, tetrahydrofuran, or dimethyl sulfoxide. However, they are only stable in dichloromethane and acetonitrile solutions and decompose to unidentified species in other solvents, as is evident by a color change from red to yellow. The methyl-substituted complexes 2a and 2b are significantly more soluble than their unsubstituted analogues 1a and 1b. The increased solubility of MePnH-based complexes compared to that of PnH complexes has previously been observed.24 Interestingly, the complexes can only be obtained working under an ambient atmosphere or after the addition of O2 to the reaction flask, while working under an inert atmosphere led to an orange powder. The 1H NMR spectrum of the latter reveals broad, shifted resonances for neutral thiopyridazine, suggesting the formation of “Werner-type” complexes of a putative formula such as [Fe(PnH)n](OTf)2 (n = 2−6), depending on the hapticity of PnH. However, no further efforts were made to isolate these species. The only source of sulfur in the reaction solution represents the thiopyridazines. Thus, in order to account for the extra sulfur in the S3 unit, some kind of desulfurization within the heterocycle must occur. This is supported by the fact that upon an increase in the ratio of PnH:Fe(OTf)2 the yield of complex 1a increased correspondingly. Thus, using a ratio of 4:1, 1a was isolated in 45% yield, with 6:1 in 85%, and with 8:1 in 92%. Higher ratios did not increase the yield further. Simple stoichiometry, counting the needed sulfur atoms for the

Scheme 2. Proposed Formal Reaction Sequence for the C− N-Coupled Pyridazinylthiopyridazines 3 and 4

The mechanism of this reaction might be similar to the one proposed for the C−N coupling of pyridine-2-disulfides to form 1-(2-pyridyl)pyridinium-2-thiolate and elemental sulfur.33 Also, for this reaction, oxidizing agents, like dioxygen or ceric ammonium nitrate, were found to be crucial, which was attributed to the oxidation of copper(I) to copper(II). Similarly here, the oxidation of iron(II) to iron(III) might occur, which increases the electrophilicity of the CS carbon of a coordinated thiopyridazine. The electron-deficient nature of the thiopyridazine favors its thione over the thiole form, rendering the nitrogen atom a good nucleophile (Scheme 2). While in the reported copper system the surplus sulfur is recovered as S8, here we assume the formation of an iron− 8160

DOI: 10.1021/acs.inorgchem.7b00865 Inorg. Chem. 2017, 56, 8159−8165

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Inorganic Chemistry

(Figure 2). These potentials are remarkably high because many iron complexes exhibit potentials smaller than ferrocene (0.4 V

sulfur intermediate, which serves as a reactive sulfur(0) donor for the observed diorganotrisulfide complexes. It is worth noting that this reaction occurs selectively irrespective of the substitution pattern within the thiopyridazine heterocycle so that this synthetic protocol might be of general use for generating differently substituted C−N-coupled thiopyridazines. Characterization of the Bis(diorganotrisulfide) Complexes. 1H NMR spectroscopy of the complexes in CD3CN reveals one set of signals for a thiopyridazine heterocycle. Thus, for example, for 1a the spectrum shows two doublets for the aromatic protons at 7.74 and 7.65 ppm and one singlet at 1.40 ppm for the tert-butyl group. This represents a strong downfield shift compared to the thiopyridazine starting material (7.57, 7.30, and 1.25 ppm), indicative for a decreased electron density and as expected upon coordination to an electrophilic metal center. Because we were unable to isolate noncoordinated dipyridazinyltrisulfide, the resonances of 1a are compared to those of 6-tert-butylpyridazinedisulfide, which was synthesized via the reaction of PnH and H2O2 in water. As shown in Figure 1, they are found with comparable shifts, with one of the

Figure 2. Cyclic voltammogram of complexes [Fe(RPnS3PnR)2](ClO4)2 [R = H (1b) and Me (2b)] in an acetonitrile solution with 0.1 mM NBu4(ClO4) measured with a scan rate of 200 mV/s.

vs NHE). For example, for [Fe(CN)5(H2O)]3−, the Fe2+/3+ couple is found at 0.370 V versus NHE, which is hardly influenced upon coordination of deprotonated cysteine instead of H2O (0.350 V vs NHE) but is significantly increased with a neutral sulfur donor such as methionine (0.575 V vs NHE).34 Thus, we assume that the combination of the neutral sulfur donor and the electron-deficient nature of the thiopyridazine leads to the observed high potentials. Characterization of the Pyridazinylthiopyridazines 3 and 4. The 1H NMR spectrum of 3 in CD3CN shows two sets of resonances indicative for two pyridazine heterocycles. Therefore, four doublets appear at 7.88, 7.78, 7.73, and 7.40 ppm, integrating in a 1:1:1:1 ratio for the aromatic protons and two singlets at 1.48 and 1.28 ppm, each integrating for nine protons for the tert-butyl groups (Figures S2 and S3). This is confirmed by the 13C NMR spectrum, where resonances for 12 carbon atoms can be found supporting the formation of the C− N-coupled product. The formation of C−N-coupled products under extrusion of sulfur has previously been observed in rare cases by reacting copper(II) and 2-pyridinedisulfide 33 or copper(I) and thiazolidine-2-thione.35 Also, in those examples, C−N-coupled product formed under aerobic conditions only. In contrast to the system reported here, the coupled products were not isolated as pure compounds but rather coordinated to copper(I). For the thiazolidine-2-thione, the complex was obtained in about 60% yield after a reaction time of 1 week with concomitant oxidation of sulfur and the formation of CuSO4. For the 2-pyridinedisulfide, the complex with the coupling product as a ligand could be obtained in low yields (8−12%) using copper(I) halides and, after the addition of an oxidizing agent, in quantitative yield. Furthermore, they were able to isolate the uncoordinated coupling product in about 40% yield after the addition of potassium cyanide. In this reaction, the extruded sulfur crystallized out as elemental sulfur (S8), in contrast to forming diorganotrisulfide units. Therefore, the synthesis reported herein represents a high-yielding and fast protocol for the formation of metal-free C−N-coupled pyridazinylthiopyridazines. In addition, it is worth mentioning that the reaction with neither 2-pyridinedisulfide nor thiazolidine-2-thione led to the formation of a diorganotrisulfide-coordinated complex.

Figure 1. Aromatic region of the 1H NMR spectra of PnH, PnS2Pn, and complex 1a in CD3CN.

doublets of 1a slightly upfield-shifted. This implies that in the diorganotrisulfide complex 1a the aromatic protons experience a slightly increased electron density compared to the uncoordinated disulfide. This might be due to the additional sulfur atom in the diorganotrisulfide or to back-bonding of the iron center into the ligand. The sharp resonances in the 1H NMR spectra point to diamagnetic compounds, indicative of octahedral low-spin iron(II) complexes. Therefore, the dipyridazinetrisulfide might be considered as a strong ligand, similar to CO or CN−, with good π-acceptor properties. This also suggests a possible π-back-bonding of the iron center into the ligand. UV−vis spectra of the perchlorate complexes 1b and 2b were measured as 0.346 and 0.374 μM solutions in acetonitrile. The spectra reveal five absorption maxima, with a slight hypsochromic shift going from 1b to 2b (Table S1 and Figure S1). Therefore, the absorption maximum at 223 nm in 1b shifts to 207 nm in 2b, and similarly the absorption maximum at 472 nm in 1b shifts to 465 nm in 2b. This is conclusive with the increased electron density in the complexes, going from 1b to 2b. Cyclic voltammetry of the complexes reveals a quasireversible redox process at E1/2 = 1.15 V versus Fc/Fc+ (1.444 V vs NHE) for 1b and 1.08 V versus Fc/Fc+ (1.374 V vs NHE) for 2b, which probably belong to Fe2+/3+ oxidation 8161

DOI: 10.1021/acs.inorgchem.7b00865 Inorg. Chem. 2017, 56, 8159−8165

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Figure 3. Molecular structures of 1a and 2a. Hydrogen atoms, solvent molecules, and triflate ions are omitted for clarity.

Table 1. Selected Bond Lengths [Å] and Angles [deg] of 1a and 2a length

1a

2a

angle

1a

2a

Fe1−N12 Fe1−N22 Fe1−N32 Fe1−N42 Fe1−S12 Fe1−S34 S3−S34 S4−S34 S1−S12 S2−S12

1.9724(14) 1.9700(14) 1.9701(14) 1.9765(14) 2.2353(4) 2.2338(4) 2.0780(6) 2.0826(6) 2.0831(6) 2.0743(6)

1.975(4) 1.981(3) 1.975(4) 1.981(3) 2.2450(14) 2.2450(14) 2.0801(17) 2.0854(15) 2.0854(15) 2.0801(17)

N12−Fe1−N32 N22−Fe1−N42 S12−Fe1−S32 S1−S12−S2 S3−S34−S4

179.08(6) 179.39(6) 179.111(18) 103.82(2) 103.67(2)

180.0 180.0 180.0 101.77(7) 101.77(7)

Molecular Structures. The molecular structures of the triflate complexes 1a and 2a, as well as their desulfurized products 3 and 4, were determined by single-crystal X-ray diffraction analysis. Single crystals of 1a and 2a could be obtained by the slow evaporation of a dichloromethane solution, and single crystals of 3 and 4 were obtained by the slow evaporation of an acetonitrile solution. In the crystal structure of 1a, the asymmetric unit consists of three independent molecules, which mainly differ in the orientation of the tert-butyl groups. Because of the marginal differences in the bond lengths and for clarity reasons, only the Fe1 molecule is described. The molecular structures of 1a and 2a are displayed in Figure 3; those of 3 and 4 can be found in Figures S11 and S12. In both complexes, the S−Fe−S, as well as the N−Fe−N, bond angles are nearly 180° (slightly disordered in 1a) and the S−Fe−N angles are virtually 90° (see Table 1), revealing an almost perfect octahedral coordination. This only slightly distorted geometry in combination with the diamagnetic nature of the complexes, therefore, indicates a low-spin iron(II) complex and a strong field ligand. Furthermore, when the Fe−N and Fe−S bond lengths in the iron diorganotrisulfide complexes are compared, it is evident that in 1a all bonds are slightly shorter than those in 2a (see Table 1). While in the former, the Fe−N bond lengths vary from 1.9701(14) to 1.9765(14) Å, in 2a, they are only slightly elongated [1.975(4)−1.981(3) Å]. Similarly, the Fe−S bond lengths in 1a [2.2353(4) Å] are approximately 0.01 Å shorter

than those in 2a [2.2450(14) Å]. These slightly elongated bond lengths are conclusive with the increased electron-donating properties, going from the unsubstituted pyridazine to the methyl-substituted pyridazine backbone in 2a. This is also evident in the cyclic voltammogram of the compounds, where 2a revealed a lower potential than 1a. In this view, complexes with unsubstituted thiopyridazines or those containing an electron-withdrawing group might possibly lead to even higher potentials. A search in the Cambridge Crystallographic Database Centre (CCDC) revealed only four complexes with a directly coordinated RS3R unit, three with copper and one with nickel.9,11,16 Furthermore, a general CCDC search for iron complexes with coordinated polysulfides (Fe−Sn, where n > 3) did not yield any results, and also disulfide-coordinated iron complexes were found to be rare because the search revealed only five examples.36−40 Thus, complexes 1a, 1b, 2a, and 2b are quite unique. Possibly, the best-comparing compounds represent S/N-coordinated iron(II) complexes with coordinated thioethers, where the Fe−S bond lengths vary from 2.220 and 2.593 Å.41,42 This is similar to the Fe1−S12 and Fe1−S34 bond lengths of 2.2353(4) and 2.2338(4) Å in 1a and 2.2450(14) Å in 2a.

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CONCLUSIONS Here we present the reaction of thiopyridazines and 4methylthiopyridazines with iron(II) salts that lead to the selective formation of unique iron(II) bis(diorganotrisulfide) complexes. Their molecular structure represents only the fifth 8162

DOI: 10.1021/acs.inorgchem.7b00865 Inorg. Chem. 2017, 56, 8159−8165

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Inorganic Chemistry

min, whereupon the light-orange suspension turned into a dark-red solution. After 12 h stirring under an O2 atmosphere, the dark-red, almost black, solution was poured onto 100 mL of pentane. The redorange precipitate was isolated by filtration, washed with 30 mL of pentane, and dried under vacuum to obtain 223 mg of 1a in 92% yield. 1 H NMR (CD3CN): δ 7.74 (d, J = 8.9 Hz, 4H, ArH), 7.65 (d, J = 8.9 Hz, 4H, ArH), 1.40 (s, 36H, CH3). 13C NMR (CD3CN): δ 173.2 (Ar−C), 171.0 (Ar−C), 129.3 (Ar−C), 127.3 (Ar−C), 38.6 (tBu−C), 29.6 (tBu−CH3). 19F NMR (CD3CN): δ −78.3 (CF3). HR-ESI-MS (CH3CN). Calcd for [M − 2OTf]2+: m/z 394.0078. Found: m/z 394.0681. Calcd for [M − OTf]+: m/z 937.0878. Found: m/z 937.0884. Single crystals suitable for X-ray diffraction analysis were obtained by the slow evaporation of a dichloromethane solution. Isolation of the Coupling Product 3. The pentane phase of 1a was evaporated to dryness, and the yellow crude material was purified by column chromatography (8:1 cyclohexane/ethyl acetate) to obtain 104 mg (78%) of the coupled product 3. 1H NMR (CD3CN): δ 7.88 (d, J = 9.0 Hz, 1H, ArH), 7.78 (d, J = 9.4 Hz, 1H, ArH), 7.73 (d, J = 9.0 Hz, 1H, ArH), 7.40 (d, J = 9.4 Hz, 1H, ArH), 1.48 (s, 9H, CH3), 1.28 (s, 9H, CH3). 13C NMR (CD3CN): δ 181.72 (Ar−C), 172.21 (Ar−C), 162.06 (Ar−C), 160.55 (Ar−C), 144.04 (Ar−C), 127.34 (Ar−C), 126.97 (Ar−C), 125.15 (Ar−C), 37.91 (tBu−C),), 37.27 (tBu−C), 30.15 (tBu−CH3) 28.73 (tBu−CH3). Calcd for C16H22N4S (302.2): C, 63.54; H, 7.33; N, 18.53; S, 10.60. Found: C, 63.71, H, 7.30; N, 18.26; S, 10.39. HR-ESI-MS (CH3CN). Calcd for [M + H]+: m/z 303.1638. Found: m/z 303.1637. Single crystals suitable for X-ray diffraction analysis were obtained by the slow evaporation of an acetonitrile solution. [Fe(PnS3Pn)2](ClO4)2 (1b). A Schlenk flask was charged with 300 mg (1.78 mmol, 8 equiv) of 6-tert-butyl-3-thiopyridazine and 28 mg (0.22 mmol, 1 equiv) of FeCl2 and suspended in 8 mL of dichloromethane. Oxygen was bubbled through the suspension for 15 min, whereupon the light-orange suspension turned into a dark-red solution. Afterward, 125 mg (0.89 mmol, 4 equiv) of NaClO4·H2O was added, and the suspension was stirred for 16 h under an O2 atmosphere. The dark-red suspension was filtrated over a pad of Celite. To the filtrate were added 100 mL of pentane, whereupon a small amount of brown precipitate was formed. After filtration, the yellow solution was evaporated in vacuo to obtain 90 mg (67%) of the coupling product 3 as a crystalline solid. The red solid collected on the pad of Celite was eluted with 10 mL of acetonitrile, and the obtained red solution was evaporated to dryness. To remove unreacted NaClO4, the crude complex was extracted into 100 mL of dichloromethane. After filtration, the solvent was removed in vacuo and the complex was recrystallized from acetonitrile, giving 100 mg (45%) of 1b as red crystals. 1H NMR (CD3CN): δ 7.74 (d, J = 8.9 Hz, 4H, ArH), 7.65 (d, J = 8.9 Hz, 4H, ArH), 1.40 (s, 36H, CH3). 13C NMR (CD3CN): δ 173.2 (Ar−C), 171.0 (Ar−C), 129.3 (Ar−C), 127.3 (Ar−C), 38.6 (tBu−C), 29.6 (tBu−CH 3 ). Calcd for C 32 H 44 Cl 2 FeN 8 O 6 S 6 · 0.85CH3CN (986.0): C, 36.32; H, 4.21; N, 11.12; S, 17.26. Found: C, 36.51; H, 4.43; N, 10.68; S, 17.00. [Fe(MePnS3MePn)2](OTf)2 (2a). A Schlenk flask was charged with 300 mg (1.65 mmol, 8 equiv) of 4-methyl-6-tert-butyl-3-thiopyridazine and 73 mg (0.21 mmol, 1 equiv) of Fe(OTf)2 and suspended in 5 mL of dry dichloromethane. Oxygen was bubbled through the light-orange suspension for 5 min, whereupon it turned into a dark-red solution. After 12 h stirring under an O2 atmosphere, the dark-red, almost black, solution was poured onto 100 mL of pentane, whereupon an orange precipitate formed upon a yellow supernatant. The red-orange precipitate was isolated by filtration, washed with 30 mL of pentane, and dried in vacuo to obtain 248 mg of 2a in 79% yield. 1H NMR (CD3CN): δ 7.50 (s, 4H, ArH), 2.24 (s, 12H, CH3), 1.39 (s, 36H, CH3). 13C NMR (CD3CN): δ 174.0 (Ar−C), 169.9 (Ar−C), 141.0 (Ar−C), 127.2 (Ar−C), 38.1 (tBu−C), 29.5 (tBu−CH3), 20.6 (Ar− CH3). 19F NMR (CD3CN): δ −77.8 (CF3). HR-ESI-MS (CH3CN). Calcd for [M − 2OTf]2+: m/z 422.0989. Found: m/z 422.0992. Calcd for [M − OTf]+: m/z 993.1503. Found: m/z 993.1510. Crystals suitable for X-ray diffraction analysis could be obtained by the slow evaporation of a dichloromethane solution.

and sixth examples of any transition metal directly coordinated by a RS3R unit. The iron diorganotrisulfide complexes exhibit an unusual, very high, and quasi-reversible redox potential for the Fe2+/3+ couple at E1/2 = 1.15 V versus Fc/Fc+ for 1b and 1.08 V versus Fc/Fc+ for 2b, respectively. This is most likely due to the electron-deficient nature of the pyridazine heterocycle. Furthermore, the source of the extra sulfur atom in the S3 unit is fully elucidated by the isolation of C−Ncoupled pyridazinylthiopyridazine products in high yields. Presumably, the nucleophilic attack at the electrophilic CS carbon by nitrogen is facilitated by the electron-poor nature of the thiopyridazine and by coordination to iron. This reaction occurs independently of their substitution pattern within the thiopyridazine, suggesting a general reactivity in electron-poor thio-containing nitrogen heterocycles. Therefore, electronwithdrawing groups at the heterocycle might facilitate such reactivities.

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EXPERIMENTAL SECTION

General Considerations. All reactions were carried out using standard Schlenk techniques under a N2 atmosphere. Solvents were dried via a PureSolv solvent purification system, and their water contents were periodically checked via a Metrohm 831 KF coulometer. 6-tert-Butyl-3-thiopyridazine (PnH)43 and 4-methy-6-tert-butyl-3-thiopyridazine (MePnH)24 were synthesized according to literature procedures. All other chemicals were purchased from commercial sources and used without further purification. NMR spectra were measured on a Bruker Avance III 300 MHz spectrometer at 25 °C. Chemical shifts were reported in parts per million (ppm) and referenced to the residual proton signal of the solvent. IR spectra were recorded on a Bruker Alpha Platinum ATR spectrometer. Highresolution mass spectrometry (HR-MS) was carried out with a ThermoScientific Q-Exactive electrospray ionization (ESI) mass spectrometer by direct infusion at the Institute of Chemistry− Analytical Chemistry of the University of Graz. Elemental analyses were carried out at the Microanalytical Laboratory of the University of Vienna using a EuroVector EA3000 instrument and at the Institute for Inorganic Chemistry of the Graz University of Technology. Electrochemical measurements were performed under an inert atmosphere in a glovebox in dry solvents with a Gamry Instruments Reference 600 potentiostat using a three-electrode setup. Glassy carbon was used as the working electrode, platinum wire (99.99%) was used as the supporting electrode, and the reference electrode was a silver wire immersed in a 0.01 M AgNO3/0.1 M NBu4(PF6) CH3CN solution, separated by a Vycor tip. NBu4(PF6) (0.1 M) was used as the supporting electrolyte. X-ray Structure Determination. X-ray structure determinations were performed on a Bruker AXS SMART APEX 2 CCD diffractometer equipped with an Incoatec microfocus sealed tube and a multilayer monochromator (Mo Kα, 0.71073 Å) at 100 K. The structures were solved by direct methods (SHELXS-97)44 and refined by full-matrix least-squares techniques against F2 (SHELXL-2014/6).44 The non-hydrogen atoms were refined with anisotropic displacement parameters without any constraints. The hydrogen atoms of the pyridazine rings were put at the external bisectors of the C−C−C angles at C−H distances of 0.95 Å, and a common isotropic displacement parameter was refined for these hydrogen atoms. The hydrogen atoms of the methyl groups were refined with common isotropic displacement parameters for the hydrogen atoms of the same methyl or tert-butyl group and idealized geometries with tetrahedral angles, enabling rotation around the C−C bond, and C−H distances of 0.98 Å. The hydrogen atoms of the methyl group were refined with common isotropic displacement parameters and idealized geometry with approximately tetrahedral angles and C−H distances of 0.99 Å. [Fe(PnS3Pn)2](OTf)2 (1a). A Schlenk flask was charged with 300 mg (1.79 mmol, 8 equiv) of 6-tert-butyl-3-thiopyridazine and 80 mg (0.22 mmol, 1 equiv) of Fe(OTf)2 and suspended in 5 mL of dry dichloromethane. Oxygen was bubbled through the suspension for 5 8163

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Inorganic Chemistry

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Isolation of the Coupling Product 4. The pentane phase of 2a was evaporated to dryness, and the yellow crude material was purified by column chromatography (8:1 cyclohexane/ethyl acetate) to obtain 98 mg (72%) of the coupled product 4. 1H NMR (CD3CN): δ 7.75 (s, 1H, ArH), 7.56 (s, 1H, ArH), 2.45 (s, 3H, CH3), 2.11 (s, 3H, CH3), 1.47 (s, 9H, CH3), 1.29 (s, 9H, CH3). 13C NMR (CD3CN): δ 182.15 (Ar−C), 172.29 (Ar−C), 161.64 (Ar−C), 161.31 (Ar−C), 151.63 (Ar−C), 136.64 (Ar−C), 128.04 (Ar−C), 123.85 (Ar−C), 37.64 (tBu−C), 37.23 (tBu−C), 30.24 (tBu−CH3), 28.96 (tBu−CH3), 22.10 (Ar−CH3), 16.54 (Ar−CH3). Calcd for C18H26N4S·0.3 C6H12 (302.2): C, 66.85; H, 8.39; N, 15.75; S, 9.01. Found: C, 66.69; H, 8.08; N, 15.51; S, 9.00. HR-ESI-MS (CH3CN). Calcd for [M + H]+: m/z 331.1951. Found: m/z 331.1955. Single crystals suitable for X-ray diffraction analysis could be obtained by the slow evaporation of an acetonitrile solution. [Fe(MePnS3MePn)2](ClO4)2 (2b). A Schlenk flask was charged with 200 mg (1.10 mmol, 8 equiv) of 4-methyl-6-tert-butyl-3-thiopyridazine and 18 mg (0.14 mmol, 1 equiv) of FeCl2 and suspended in 8 mL of dichloromethane. Oxygen was bubbled through the light-orange suspension for 15 min, whereupon it turned into a dark-red solution. Afterward, 50 mg (0.35 mmol, 2.5 equiv) of NaClO4·H2O was added, and the suspension was stirred for 16 h under an O2 atmosphere. The dark-red suspension was filtered over a pad of Celite. To the filtrate was added 100 mL of pentane, whereupon a small amount of brown precipitate formed. After filtration, the yellow solution was evaporated and purified by column chromatography (8:1 cyclohexane/ethyl acetate) to obtain 57 mg (63%) of the coupling product 4 as a crystalline solid. The red solid collected on the pad of Celite was eluted with 10 mL of acetonitrile, and the obtained red solution was evaporated to dryness. To remove unreacted NaClO4, the crude complex was extracted into 70 mL of dichloromethane. After filtration, the solvent was removed in vacuo and recrystallized from acetonitrile, giving 71 mg (46%) of 2b as red crystals. 1H NMR (CD3CN): δ 7.50 (s, 4H, ArH), 2.24 (s, 12H, CH3), 1.39 (s, 36H, CH3). 13C NMR (CD3CN): δ 174.0 (Ar−C), 169.9 (Ar−C), 141.0 (Ar−C), 127.2 (Ar− C), 38.1 (tBu−C), 29.5 (tBu−CH3), 20.6 (Ar−CH3). Calcd for C36H52Cl2FeN8O8S6·0.4CH3CN (1042.1): C, 40.97; H, 4.97; N, 10.91; S, 17.83. Found: C, 40.91; H, 4.89; N, 10.81; S, 17.74. 6-tert-Butylpyridazinedisulfide. A beaker was charged with 1.045 g (6.22 mmol, 1.0 equiv) of 6-tert-butyl-3-thiopyridazine and suspended in 5 mL of water. Thereafter, 0.5 mL of a 30% H2O2 solution was added dropwise, and the suspension was allowed to stir at room temperature for 1.5 h. The white solid was filtered, washed with 20 mL of water and 20 mL of ethyl acetate, and dried at 60 °C for 4 h to obtain 810 mg (78%) of the product as a white solid. 1H NMR (C6D6): δ 7.27 (d, J = 9.1 Hz, 2H, ArH), 6.49 (d, J = 9.1 Hz, sH, ArH), 1.20 (s, 18H, CH3). 13C NMR (C6D6): δ 168.5 (Ar−C), 161.0 (Ar−C), 124.2 (Ar−C), 124.0 (Ar−C), 36.7 (tBu−C), 29.9 (tBu− CH3). Single crystals suitable for X-ray diffraction analysis could be obtained by the slow evaporation of a dichloromethane solution.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Nadia C. Mösch-Zanetti: 0000-0002-1349-6725 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

The authors gratefully acknowledge support from NAWI Graz.

REFERENCES

(1) Li, N.; Guo, R.; Li, W.; Shao, J.; Li, S.; Zhao, K.; Chen, X.; Xu, N.; Liu, S.; Lu, Y. A proteomic investigation into a human gastric cancer cell line BGC823 treated with diallyl trisulfide. Carcinogenesis 2006, 27, 1222−1231. (2) Hosono, T.; Fukao, T.; Ogihara, J.; Ito, Y.; Shiba, H.; Seki, T.; Ariga, T. Diallyl trisulfide suppresses the proliferation and induces apoptosis of human colon cancer cells through oxidative modification of beta-tubulin. J. Biol. Chem. 2005, 280, 41487−41493. (3) Block, E. The Organosulfur Chemistry of the Genus Allium Implications for the Organic Chemistry of Sulfur. Angew. Chem., Int. Ed. Engl. 1992, 31, 1135−1178. (4) Clennan, E. L.; Stensaas, K. L. Recent progress in the synthesis, properties and reactions of trisulfanes and their oxides. Org. Prep. Proced. Int. 1998, 30, 551−600. (5) Steudel, R. The Chemistry of Organic Polysulfanes R−Sn − R (n > 2). Chem. Rev. 2002, 102, 3905−3946. (6) Nielsen, R. W.; Tachibana, C.; Hansen, N. E.; Winther, J. R. Trisulfides in proteins. Antioxid. Redox Signaling 2011, 15, 67−75. (7) Furuhashi, A.; Kawano, M.; Tashiro, N.; Ouchi, A. The syntheses and properties of certain metal adducts of trithiodiacetylacetone. J. Inorg. Nucl. Chem. 1972, 34, 2960−2962. (8) Brodersen, K.; Jordan, G. Stabile Quecksilber(I)-SchwefelVerbindungen. Chem. Ber. 1978, 111, 1221−1222. (9) Jeannin, S.; Jeannin, Y.; Lavigne, G. Unusual Sulfur Insertion in a Copper(I)- Mercaptobenzothiazole Complex. Inorg. Chem. 1979, 18, 3528−3535. (10) Wang, S.; Fackler, J. P. Unusual resonance structures of organic thiones formed and stabilized by gold(I) complexation. The isolation and characterization of an alkyl substituted thiabenzenethione and a trithiapentalene co-ordinated to gold(I). J. Chem. Soc., Chem. Commun. 1988, 22. (11) Ingham, S. L.; Long, N. J. The First Metal Complexes with a Doubly S3-Bridged Ferrocene Ligand. Angew. Chem., Int. Ed. Engl. 1994, 33, 1752−1753. (12) Ohba, Y.; Ito, K.; Nagasawa, T. Synthesis of mono- and polysulfur-bridged bisphenols and their application to new type Lewis acids. Heterocycl. Commun. 1998, 4, 529−534. (13) Salivon, N. F.; Olijnik, V. V.; Shkurenko, A. A. Synthesis and crystal structure of π complex of copper(I) chloride with diallyl trisulfide 2CuCl · DATrS. Russ. J. Coord. Chem. 2007, 33, 908−913. (14) Delgado, S.; Gallego, A.; Castillo, O.; Zamora, F. Unexpected multiple bond cleavage and rearrangement of organosulfide ligands in the presence of Cu(II) assisted by solvothermal and solvothermalmicrowave conditions. Dalton Trans. 2011, 40, 847−852. (15) Constable, E. C.; Housecroft, C. E.; Neuburger, M.; Price, J. R.; Zampese, J. A. Redox addressable ligands in copper(i) coordination chemistry. CrystEngComm 2010, 12, 2928. (16) Gallego, A.; Castillo, O.; Gómez-Garcia, C. J.; Zamora, F.; Delgado, S. Electrical conductivity and luminescence in coordination

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CCDC 1532932−1532936 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 8164

DOI: 10.1021/acs.inorgchem.7b00865 Inorg. Chem. 2017, 56, 8159−8165

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Inorganic Chemistry polymers based on copper(I)-halides and sulfur-pyrimidine ligands. Inorg. Chem. 2012, 51, 718−727. (17) Abel, E. W.; Long, N. J.; Osborne, A. G.; Hursthouse, M. B.; Mazid, M. A. The synthesis and crystal structure of 1,2,3-trithia[3]osmocenophane. J. Organomet. Chem. 1992, 430, 117−122. (18) Sato, M.; Miyagawa, Y.; Shigetoh, Y. The synthesis and properties of ferroceno[1′,2′;1″,2″]bis(1,3-dithiol-2-thione and −2one) derivatives. J. Organomet. Chem. 2007, 692, 2529−2538. (19) Elschenbroich, C.; Lu, F.; Harms, K.; Burghaus, O. Synthesis, electrochemical behavior and EPR study of organometallic [5]trovacenylthiol (η7-C7H7)V(η5-C5H4SH) and structural characterization of ansa-trithio[3]trovacenophane. J. Organomet. Chem. 2014, 755, 58−63. (20) Rekken, B. D.; Brown, T. M.; Fettinger, J. C.; Lips, F.; Tuononen, H. M.; Herber, R. H.; Power, P. P. Dispersion forces and counterintuitive steric effects in main group molecules: heavier group 14 (Si-Pb) dichalcogenolate carbene analogues with sub-90 degrees interligand bond angles. J. Am. Chem. Soc. 2013, 135, 10134−10148. (21) Herberhold, M.; Brendel, H.-D.; Thewalt, U. Derivatives of 1,1″Biferrocene with Sulfur and Selenium Bridges. Angew. Chem., Int. Ed. Engl. 1991, 30, 1652−1654. (22) Reboucas, J. S.; Patrick, B. O.; James, B. R. Thiol, disulfide, and trisulfide complexes of Ru porphyrins: potential models for iron-sulfur bonds in heme proteins. J. Am. Chem. Soc. 2012, 134, 3555−3570. (23) Gallego, A. I.; Castillo, O.; Zamora, F.; Delgado, S. Dynamic combinatorial chemistry in a solvothermal process between nickel(ii), halides and organosulphur ligands. RSC Adv. 2013, 3, 18406. (24) Holler, S.; Tüchler, M.; Belaj, F.; Veiros, L. F.; Kirchner, K.; Mö sch-Zanetti, N. C. Thiopyridazine-Based Copper Boratrane Complexes Demonstrating the Z-type Nature of the Ligand. Inorg. Chem. 2016, 55, 4980−4991. (25) Tüchler, M.; Holler, S.; Rendl, S.; Stock, N.; Belaj, F.; MöschZanetti, N. C. Zinc Scorpionate Complexes with a Hybrid (Thiopyridazinyl) (thiomethimidazolyl)borate Ligand. Eur. J. Inorg. Chem. 2016, 2016, 2609−2614. (26) Tüchler, M.; Belaj, F.; Raber, G.; Neshchadin, D.; MöschZanetti, N. C. Photoinduced Reactivity of the Soft Hydrotris(6-tertbutyl-3-thiopyridazinyl)borate Scorpionate Ligand in Sodium, Potassium, and Thallium Salts. Inorg. Chem. 2015, 54, 8168−8170. (27) Nuss, G.; Ozwirk, A.; Harum, B. N.; Saischek, G.; Belaj, F.; Mösch-Zanetti, N. C. Copper Complexes with a Hybrid Scorpionate Ligand Containing Pyridazine-3-thione. Eur. J. Inorg. Chem. 2012, 29, 4701−4707. (28) Nuss, G.; Saischek, G.; Harum, B. N.; Volpe, M.; Belaj, F.; Mösch-Zanetti, N. C. Pyridazine based scorpionate ligand in a copper boratrane compound. Inorg. Chem. 2011, 50, 12632−12640. (29) Nuss, G.; Saischek, G.; Harum, B. N.; Volpe, M.; Gatterer, K.; Belaj, F.; Mösch-Zanetti, N. C. Novel pyridazine based scorpionate ligands in cobalt and nickel boratrane compounds. Inorg. Chem. 2011, 50, 1991−2001. (30) Spicer, M. D.; Reglinski, J. Soft Scorpionate Ligands Based on Imidazole-2-thione Donors. Eur. J. Inorg. Chem. 2009, 2009, 1553− 1574. (31) Anderson, J. S.; Rittle, J.; Peters, J. C. Catalytic conversion of nitrogen to ammonia by an iron model complex. Nature 2013, 501, 84−87. (32) Bouhadir, G.; Bourissou, D. Complexes of ambiphilic ligands: reactivity and catalytic applications. Chem. Soc. Rev. 2016, 45, 1065− 1079. (33) Kinoshita, I.; James Wright, L.; Kubo, S.; Kimura, K.; Sakata, A.; Yano, T.; Miyamoto, R.; Nishioka, T.; Isobe, K. Design and synthesis of copper complexes of novel ligands based on the pyridine thiolate group. Dalton Trans. 2003, 1993−2003. (34) Toma, H.; Batista, A. A.; Gray, H. B. Pentacyanoferrate(II) complexes of amino acids. J. Am. Chem. Soc. 1982, 104, 7509−7515. (35) Lobana, T. S.; Sultana, R.; Butcher, R. J.; Castineiras, A.; Akitsu, T.; Fernandez, F. J.; Vega, M. C. Chemistry of Heterocyclic 2-Thiones. Eur. J. Inorg. Chem. 2013, 2013, 5161−5170.

(36) Bertrand, J. A.; Breece, J. L. Preparation and structure of chloro(bis{salicylideniminephenyl}disulfido)iron(III). Inorg. Chim. Acta 1974, 8, 267−272. (37) Elmali, A.; Elerman, Y.; Svoboda, I. {Bis[2-(2-oxido-1naphthylmethylideneamino)phenyl] disulfide}chloroiron(III). Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2001, 57, 375−376. (38) Elmali, A.; Elerman, Y. Crystal Structure of Chloro[bis(5chlorosalicylideniminephenyl)disulfido]-iron(III) Complex. Anal. Sci. 2001, 17, 1137−1138. (39) Elmali, A.; Elerman, Y. Crystal Structure of Chloro[bis(5bromo-salicylideniminephenyl)disulfide]-iron(III) Complex. Anal. Sci. 2002, 18, 1399−1400. (40) Roy, N.; Sproules, S.; Weyhermuller, T.; Wieghardt, K. Trivalent iron and ruthenium complexes with a redox noninnocent (2mercaptophenylimino)-methyl-4,6-di-tert-butylphenolate(2-) ligand. Inorg. Chem. 2009, 48, 3783−3791. (41) Sharrad, C. A.; Gahan, L. R. Characterization of [Fe(AMN3S3sarH)]3+ a rigorously low-spin iron(II) complex. Polyhedron 2003, 22, 45−51. (42) Hogue, R. W.; Feltham, H. L. C.; Miller, R. G.; Brooker, S. Spin Crossover in Dinuclear N4S2 Iron(II) Thioether-Triazole Complexes: Access to HS-HS, HS-LS, and LS-LS States. Inorg. Chem. 2016, 55, 4152−4165. (43) Coates, W. J.; Mckillop, A. One-Pot Preparation of 6Substituted 3(2H)-Pyridazinones from Ketones. Synthesis 1993, 1993, 334−342. (44) Sheldrick, G. M. A short history of SHELX. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112−122.

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DOI: 10.1021/acs.inorgchem.7b00865 Inorg. Chem. 2017, 56, 8159−8165