Fundamental chemistry of iodine. The reaction of di-iodine towards thiourea and its methyl-derivative: formation of aminothiazoles and aminothiadiazoles through dicationic disulfides.

The reactivity of di-iodine towards thiourea (TU) and its derivative methylthiourea (MeTU) was studied. A diversity of products was obtained from these reactions. TU reacted with di-iodine in the absence or presence of hydroiodic or hydrochloric acids in a 1 : 1, 1 : 1 : 1 or 1 : 1 : 2 (TU : I2 : HX (X = I, Cl)) molar ratio to form the ionic compounds [(TU2)(2+)2(I(-))·H2O] (1), [2(TU2) (2+)·(Cl(-))·2(I(-))·(I3(-))] (2) and [(TUH)(+) (I3(-))] (3). The compounds [(TU2)(2+)(Br(-))(I3(-))] (4) and [(TU2)(2+)2(Br(-))·H2O] (5) were derived from the reactions of TU with di-iodine in the presence of hydrobromic acid in a 1 : 1 : 1 or 1 : 2 : 1 (TU : I2 : HBr) molar ratio. However, when the product of the reaction between TU and di-iodine in a 2 : 1 (TU : I2) molar ratio was crystallized in acetone-ethylether media the ionic salt of formula [(DAThdH(+))(I(-))] (6) (DAThd = 3,5-diamino-1,2,4-thiadiazole) was obtained. Methylthiourea (MeTU) reacted with di-iodine in the presence of hydrobromic acid (1 : 1 : 1, MeTU : I2 : HBr) in dichloromethane to form a solid product which gives [2(MeTU2) (2+)·(2Br(-))(I4(2-))] (7). Moreover, MeTU reacted with I2 in 2 : 1 (MeTU : I2) to form an intermediate powder product which was crystallized in acetone to give the 2-amino-3,4-dimethylthiazolium cation in [(DMeAThH(+))(I(-))(H2O)] (8). Upon changing the crystallization medium to ethanol, instead of acetone, the cationic 5-amino-3-methylamino-4-methyl-1,2,4-thiadiazolium (AMeAThdH)(+) in [(AMeAThdH(+))(I3(-))] (9) was formed. The compounds were characterized by m.p., FT-IR, UV-Vis, (1)H-NMR spectroscopy and mass spectrometry. The crystal structures of compounds 1-9 were determined by X-ray crystallography.

Thioamides, like carbimazole (CBZ, 3-methyl-2-thioxo-4imidazoline-1-carboxylate) and methimazole (MMI, N-methylimidazoline-2-thione), are used as clinical drugs for the treatment of hyperthyroidism disease. 2 Moreover, iodine compounds can be applied in semiconductors or superconductors depending on the number of iodine atoms in these materials. [7][8][9][10] Also these compounds were used as oxidation agents, oxidizing the metals, even noble ones, 4h and they were investigated for their magnetic properties. 10 Both these applications result from the ability of the elements of Group 16 of the periodic table, like sulfur, to form charge transfer complexes. 11 In 1947, King et al. 12 demonstrated that ketones react with thiourea and halogens or certain oxidizing agents to give substituted 2-aminothiazoles (Reaction Scheme 1).
Due to the importance of aminothiazoles and their derivatives in synthetic organic chemistry Metwally et al. have reviewed the preparation routes for them. 13 Substituted 2-aminothiazoles and their derivatives have been used as biologically active molecules, 14a as antibacterial, antifungal, 14b-e and anthelmintic agents, 14f as inhibitors 14g and as activators of many biological processes. 14h 2-Aminothiazole derivatives are used in treatment of head twitches, 15a tumors, 15b,c malaria, 15d ulcers, 15e anoxia, 15f and tuberculosis, 15g anxieties, 15h and as chelating agents. 16a-c They are also used in syntheses of dyes 17a and as chemosensors. 17b,c They have also found applications in jet fuels as anticorrosive additives 17d and in radiochemistry as protective compounds. 17e 1,2,4-Thiadiazole (Thd) and its derivatives, on the other hand, exhibit many applications and therefore the synthesis of these compounds has been developed for many years. 18a Thd and its derivatives are essentially biologically active compounds. They reveal actions in antihypertensive 19a and cardioprotective treatment. 19b,c They have potential activity as G-protein coupled receptors. 19d Thd inactivates enzymes with active cysteine residues 19e (e.g. bacterial enzymes 19f ) and they are constituents of non-steroidal anti-inflammatory agents. 19g The everyday antibiotic drug cefozopram 19h is also a Thd derivative. Moreover there are indications that it possesses an effective influence on Alzheimer's disease. 19i One of the synthetic routes developed for 1,2,4-thiadiazole derivatives involves the reaction of arylothioamides with chloride or bromide anions and acid in DMSO solution 18b (Reaction Scheme 2).
In this paper we report the synthesis, and the structural and spectroscopic characterization of compounds 1-5 and 7 resulting from the reaction between thiourea (TU) or methylthiourea (MeTU) with di-iodine in the presence or absence of hydrochloric, hydrobromic or hydroiodic acids towards dicationic disulfides with mono-or poly-iodides as counter anions. The ionic salts 6 and 8-9 which contain substituted aminothiazole or thiadiazole rings were obtained by modifying the stoichiometry of the reaction between thiourea or methylthiourea (MeTU) and di-iodine followed by crystallization in acetone or ethanol.

Reactions
It is well known that interesting products with a variety of nuclearities could be isolated when chalcogen donors (D) were reacted with halogen independently of the molar ratios of the reactants. [1][2][3][4][5][6][7][8][9] For example the poly-iodide chain [I 17 reacts with di-iodine in a 1 : 2 molar ratio. 2e Conductivity titration experiments confirm that even poly-iodides of very high nuclearities were obtained at a 1 : 2 (D : I 2 ) molar ratio of the reactants. 2c-e To ascertain the number of the ionic species derived by the di-iodine and TU or MeTU interaction, conductivity titrations in acetonitrile solution were carried out ( Fig. 1). At zero I 2 concentration, the solutions of either TU or MeTU exhibit almost zero conductivity. The conductivity of the solutions increases to a rate value when the [I 2 ] : [ligand] molar ratio is 2 : 1 where a stable species is formed in the solution. Further addition of di-iodine increases the conductivity of the solution to higher values, indicating that many types of ionic species could also be obtained in higher ratios.
Since the presence of hydrohalogens in the reaction mixtures might lead to different products (see Reaction Schemes 1 and 2), we extended our studies to the redox reactions of thiourea (TU) or methylthiourea (MeTU) with di-iodine in 2 : 1, 1 : 2 and 1 : 1 (TU : I 2 ) molar ratios in the presence or absence of HX (X = Cl, Br, I). All products derived from the reactions were characterized by X-ray analysis. Crystals grown from the reaction solutions were refined, even those of the same products. Crystals of [(TU 2 ) 2+ 2(I − )·H 2 O] (1), were grown from the crystallization of the product derived from the reaction of TU with di-iodine (Reaction Scheme 3a). It was also directly formed in the presence of hydroiodic or hydrochloric acids in a 1 : 1 : 1 (TU : I 2 : HX X = I, Cl) ratio (Reaction Scheme 3b and 3c1), since hydrohalogens enhance the oxidizing potential of the solution leading to the cationic disulfide formation. Crystals of [2(TU 2 ) 2+ ·(Cl − )·2(I − )·(I 3 − )] (2) (Reaction Scheme 3c2),  (8) (Reaction Scheme 3i and 3k), which contains the cationic 2-amino-3,4-dimethylthiazole (DMeAThH + ), was grown from acetone solution when MeTU reacts with an excess of di-iodine, while when ethanol was used the [(AMeAThdH + )(I 3 − )] (9) compound (Reaction Scheme 3m), which contains the cationic 5-amino-3-methylamino-4-methyl-1,2,4-thiadiazole (AMe2AThdH) + , was isolated. Compound 8 was derived possibly through de-oxygenation of acetone which simultaneously reacts with the MeTU residue formed from the degradation of the corresponding disulfide dication in a similar manner to the synthetic pathway shown in Reaction Scheme 1. 12 However, the isolation of compounds 6 and 9 might be due to the reaction between the residues formed from the degradation of the corresponding dicationic disulfides which have been desulfurated previously (Reaction Scheme 4). Crystals of elemental S 8 were also isolated from Reaction Scheme 3m. The isolation of elemental sulfur further supports our assumption. The formation of S 8 is in accordance with the stoichiometry of the reaction and is also observed during the synthesis which involves arylothioamides in DMSO solution (Reaction Scheme 2). 18b Johnson and Edens 20a reacted ethylenethiourea with di-iodine in water and they formulated the (red crystalline) product as the di-sulfide. The repetition of this reaction by Herbstein and Schwotzert 20b showed that a condensation product was unexpectedly formed, by the N-substitution of ethylenethiourea, from its desulfurated species, indicating that desulfuration of the thiol had taken place.

Solution studies
Solution studies (UV and 1 H-NMR) were employed for the interpretation of the species formed in solution, based on the solid-state compounds observed by XRD.

NMR spectroscopy
The 1 H-NMR spectrum of the free ligand TU (Fig. S1 †) shows resonance signals for the amine protons at 7.06 ppm (br, H(NH 2 )) in DMSO-d 6 solution. The spectra of compounds 1-5, however, are dominated by two broad resonances based on the preparation procedures applied; (1_a): 7.6-7.1 and 6.19 ppm, (1_b): 8.2-7.6 and 6.19 ppm, (1_c1): . It is therefore concluded that there exists two types of hydrogen atoms in solution in the case of 1-5 (which are varied according to the preparation method). The formation of the disulfide dication (TU) 2 2+ is derived by lengthening of the C-S bond and subsequently of the S-S bond (Scheme 6). Therefore, the resonance signal 6.19 ppm is attributed to the neutral H(NH 2 ), while signals at higher values are assigned to the H + (NH 2 ) group (Scheme 6). Moreover, variations in the resonance signals are also due to the hydrogen bonds established in solution with the oxygen of water molecules in the case of 1 and 5 or the halogen anion in all cases and those which are interacting with iodides (see Crystal structures).  Fig. 2A shows UV spectra of thiourea and complexes 1-6. The UV-Vis spectra of the complexes were recorded in diluted dichloromethane solution (5 × 10 −5 M). Methanol (5 μL) was added into each stock solution (10 −2 M) in order to increase the solubility of the samples in the concentrated solution (10 −2 M). The UV spectrum of TU shows an intense band at 256 nm (ε = 3.44 mol −1 cm −1 ) in CH 2 Cl 2 . The addition of di-iodine into dichloromethane solution of TU causes an absorbance decrease of this band and a new band at 300 nm ( Fig. 2A) appears. In the case of compounds 2, 3, 4 and 5, a third band or shoulder also appears at 365 nm. The spectra of compounds MeTU, 7, 8 and 9 are shown in Fig. 2B. The addition of di-iodine into dichloromethane solution of MeTU causes the appearance of a new band at 300 nm, which is accompanied by an additional band at 365-367 nm in 7-9.

UV-Vis spectroscopy
The band at 255 nm is attributed to the intra-ligand transition (π*←π) (for both TU and MeTU). The absorption bands at 365 and 300 nm in the UV spectra of iodine compounds could be assigned to the I 3 − species (λ max = 360 and 295 nm). 2d Based on a large body of data on the CT bands of di-iodine complexes with cyclic thiourea derivatives, Laurence et al. have shown that their UV spectra constitute a CT band in the 294-302 nm range typical of planar complexes or a CT band absorbs at significantly longer wavelengths (321-350 nm) characterizing perpendicular complexes. 21 Thus, among TU and MeTU complexes 1-9, the spectra of compounds 2, 3, 4, 7 and 9 show the presence of the poly-iodides anions I n −x (n = 3 or 4 and x = −1 or −2 respectively) with a band at 300 nm accompanied by one band or shoulder at 365 nm. The two absorption bands at λ max 257 and 301 nm in the spectrum of compound 1 where only iodide anions are present as counterparts of a dicationic disulfide are attributed to the dication. This is further supported by the presence of this absorption in all spectra of 1, 2, 4 and 5 which are salts containing the same dication and different anions. The spectra of the ionic heterocyclic compounds 6, 8 and 9 contain absorptions at 255 and 370 nm (6), at 267, 299 and 367 nm (8) and at 299 and 365 nm (9) due to the delocalized double bonds of the heterocyclic cationic ring (see Crystal structure). However the spectrum 5 is dominated by three absorption bands at 267, 296 and 366 nm which might be due to the stronger cationanion interaction because of the precedence of the bromide anion instead of iodide.

Dalton Transactions Paper
This The asymmetric part of the unit cell of compound 5 contains a half of the dicationic disulfide [(H 2 N) 2 CS] 2 2+ , a bromide ion and half of a water molecule (Fig. 6A). The oxygen atom and the middle point of the S-S distance lie on a two-fold axis, so the symmetry of these two species is C 2 . The structure of 5 is similar to 1, with bromide counter anions instead of iodides. Strong hydrogen interactions among water molecules, bromide anions and N-H groups create a 3D supramolecular assembly (Fig. 6B). A water molecule accepts two N-H⋯O hydrogen bonds and acts as a donor in two O-H⋯Br − hydrogen-bond interactions (Fig. 11A). Amine groups also take part in four hydrogen-bond type interaction with a bromide anion. Bromide lies in close contact with carbon (C1⋯Br1 = 3.578(4) Å) and interacts with π electrons localized on the N-C-N moiety (Fig. 11B). The S-S bond distances found in 1-5 lie between 2.0244(14) and 2.038(2) Å (while the C-S-S-C torsion angles vary from 86.4(3) to 102.7(5)°). The S-S bond distances in 1-5 are shorter than those in neutral disulfides {(2-mercapto-benzoic acid) 2 · 1/2(CH 3 CN)}, {(2-mercapto-nicotinic acid) 2 ·(H 2 O)}) and (2-mercapto-pyrimidine) 2 which lie in the range of 2.043-2.045 Å. 2k However, these bond lengths are closer to the corresponding S-S distances determined in the [(PYS−PYSH) + ·I 3 − ] (PYSH = 2-mercaptopyridine) 2d where the mean value of the S-S bond length in the four symmetry-independent cation-anion pairs is 2.032 Å. 2d We have previously shown that the torsion angles are well correlated with the S-S bond lengths. 2j Computational studies have also shown that the S-S bonds of the disulfide molecules for the lowest energy conformation were shorter when the C-S-S-C torsion angles were between 85. 1 and 90°. 23 This general trend seems to be followed also in the case of structures 1-5. However, unconformities are observed for 5 which has the lowest torsion angle and for 2 with the longest bond length. These might be due to the strong S⋯O interaction (S1⋯O1W contact of 3.320(1) Å) in the case of 5 and to the Cl⋯S interactions around 3.4 Å (in the case of 2 (Fig. 4B)).
The asymmetric part of the crystal structure of 7 contains a half of a C 2 -symmetrical dicationic disulfide (middle point of the S-S bond is on the two-fold axis) of (MeTU) 2 2+ , one-quarter of the tetraiodide dianionall iodine atoms lie on the mirror plane of symmetry, and the middle point of the central I-I bond lies on the center of symmetry at (0, 0, 0), and a half of the bromide which lies on the mirror plane of the symmetric anion (Fig. 9A). Tetraiodide is very close to linearity (I2-I1-I1 = 178.46(4) Å). Disulfides are built of two methylthiourea moieties, which are planar (max deviation from the least-squares plane is 0.081(6) Å). The S1-S1 bond length (2.011(4) Å) is similar to the one in 1 (2.022(2) Å), but the S-C-C-S torsion angle (98.0(5)°) is slightly larger than the appropriate value in 1 (94.7(2)°). This might be due to the presence of an additional methyl group. Hydrogen bonding interactions of N-H⋯Br and N-H⋯I type stabilize the crystal structure (Fig. 9B). The structure of compound 3 consists of a protonated thiourea TU [(H 2 N) 2 CSH] + and a tri-iodide counter anion [I 3 − ] (Fig. 5A). The bond lengths and angles are generally in accordance with those reported for the free ligand, 24 but the C-S bond, of 1.739(3) Å, is longer than that of the free ligand (1.71(1) Å 24 ) due to the protonation of the sulfur atom. The C-N bonds are almost equal and shorter than the corresponding bonds in a free ligand (1.33(1) Å 24 ). The tri-iodide anion is highly asymmetrical and strictly linear (I1-I2 = 2.8558(3) Å, I2-I3 = 2.9961(3) Å, I1-I2- I3 = 179.102(9)°). In the crystal, a number of hydrogen bonds accepted by the terminal iodine atoms are observed (Fig. 5B). Crystals of 6 contain the protonated 3,5-diamino-1,2,4-thiadiazole cation (DAThd) + and an iodide counter anion (Fig. 6A). The same product was also obtained by reacting (1-diaminomethylene)thiourea with either copper(II) chloride or chromium trichloride. 25a Comparative study of C-N bonds in the neutral ligand (1.367(2), 1.377(2) Å, 1.339(2) Å respectively 25b ) reveals that they are significantly longer than in 6 (1.334 (3) Crystals of 8 contain a 3,4-dimethyl-2-aminothiazole (DMeAThH) + cation, an iodine anion and a water molecule (Fig. 10A). The neutral 3,4-dimethyl-2-aminothiazole (DMeATh) was obtained previously by treatment of benzothiazol-2-ylamine of F 3 CSO 3 Me and KH, and its crystal structure was reported. 26 Significant differences are observed between the protonated (DMeAThH + ) and the neutral species: the two C-N bonds (C2- N21 = 1.323(4), N3-C31 = 1.469(4) Å) in 8 are longer than the corresponding ones found in DMeATh (1.280 (3) 26 This indicates that the positive charge is located on the [S-C(NH 2 )vN] + moiety (Scheme 7). However, the cation is essentially planar (max. deviation of 0.063(5) Å), which may suggest that in fact the charge is delocalized over the whole molecule.
Strong N⋯I, O⋯N and O⋯I interactions join the 2D layers of cations with water molecules and iodide anions which fill the space between these layers (Fig. 10B).
The elemental S 8 crystals which happened to result from one of the reactions turned out to be those of an α-sulfur polymorphic form (Fddd space group, a = 10.319(1), b = 12.669 (1), c = 24.321(2) Å).

Conclusions
A variety of products were obtained from the reaction of diiodine with thiourea or methylthiourea. The reaction of TU or MeTU with di-iodine in the absence or presence of hydroiodic, hydrobromic or hydrochloric acids in 1 : 1, 1 : 1 : 1 or 1 : 1 : 2 yields ionic salts which contain dicationic disulfides (compounds 1, 2, 4, 5, and 7), while the type of the counter anions and the whole crystal structure of these compounds are dependent on the reaction conditions (stoichiometry, presence or absence of acid, etc). The anionic species in the crystal structures of compounds 1, 2, 4, and 5 contains iodide, tri-iodide and/or chloride and/or bromide. In the case of compound 7 the counter anion consists of the di-anionic tetra-iodide I 4 2− .
By increasing the acidity however, of the media, the formation of the dicationic disulfide is prevented and the mono-cationic TUH + species precipitates (3). Cyclic compounds 6, 8 and 9 were also derived by the reaction of TU or MeTU with di-iodine followed by crystallization in polar solvent media: Thus the use of acetone leads to the formation of compound 8 which contains the 2-amino-3,4-dimethylthiazole cation from the interaction of the MeTU with the de-oxygenated solvent while by using ethanol instead, the compounds 6 and 9 are obtained, which contain the 5-amino-3-methylamino-4-methyl-1,2,4thiadiazole cation from the interaction of TU or MeTU with desulfurated reagents. King et al. 12 demonstrate that ketones react with thiourea and halogens, or certain oxidizing agents to give substituted 2-aminothiazoles through dicationic disulfide intermediate (Reaction Scheme 1). Since dicationic disulfides were isolated when TU or MeTU react with di-iodine (Reaction Scheme 3a-c, 3e-f ) a similar mechanism could be assumed for the preparation of 8. Florani et al. also reported the formation of 1,2,4thiadiazole derivatives from the reaction of arylothioamides and chloride or bromide anions and acid in DMSO (Reaction Scheme 2). 18b This further supports our assumption of the formation of 6 and 9 through a dicationic disulfide intermediate followed by the formation of reactive radicals.
We have previously shown that a relationship between the S-S distance and torsion C-S-S-C exists, 2j which is also supported by the reported computational studies on small molecules. 23 Experimental data (Fig. 12) are presented that show a hyperbola correlation is obtained by comparing d(S-S) vs. <(C-S-S-C). The closer S-S distance is adopted for the best molecule conformation (minimum energy state) which in the case of [(H 2 N) 2 CS] 2 2+ corresponds to the torsion angle C-S-S-C of 94.05°, and to the S-S bond length of 2.0215 Å. The exceptions observed in 2_c2 are attributed to the strong intermolecular interactions S⋯Cl which are lengthening the S-S bond distance, and in 3_e, to the low refinement (high value of the R factor) of 9.24%.

Dalton Transactions Paper
This

Crystal data
Data for compounds studied were collected by the ω scan technique: for 1a, 1b, 1c1, 2c2, 4e1, 4f, 5e2 and 8i on a Supernova diffractometer with Atlas CCD detector using graphite-filtered CuK α. (λ = 1.5418 Å) radiation and for 3d, 6g, 7h, 8k, 9m, and S 8 on an XCALIBUR diffractometer with EOS CCD detector using graphite-filtered MoK α. (λ = 0.71073 Å) radiation. Cell parameters for 1-9 were determined by least-squares fit. All data were corrected for Lorentz-polarization effects and absorption. 28a The structures were solved with direct methods with SIR92 28b and refined by full-matrix least-squares procedures on F 2 with SHELXL97. 28c All non-hydrogen atoms were refined anisotropically, and hydrogen atoms were located at calculated positions and refined as a 'riding model' with isotropic thermal parameters fixed at 1.2 times the U eq 's of the appropriate carrier atom. The structure of 2 has been refined as twinned (using HKLF 5 command), and the data were reduced as twinned. The BASF factor was refined at 0.78.