1.2.4- Thiadiazoles 2 molecules

As mentioned in Section 4.10.6.5, substituents on C(2) and C(5) are strongly activated and control the reactivity of the thiadiazole molecule as a whole. The amino group is by far the most popular substituent for further modifications, due to its nucleophilicity and ease of ring formation with the annular N(3). To a somewhat lesser extent, the thiol group has also been utilized in further derivatizing, with the carbon and halogen substituents being the least amenable to further reactions. 

Electron diffraction data obtained by the sector microphotometer method and data obtained by microwave spectroscopy indicate that 1,2,5-thiadiazoIe is a planar pentagon of symmetry to within 0.1 A. The shape of this molecule is very similar to thiophene except for a scale factor shift of 5 % to shorter bond length for the thiadiazole molecule. Table V shows refined comparative data for benzene, thiophene, and 1,2,5-thiadiazole. Data for pyrazine and 1,2,5-oxa-diazole are included for information. If Pauling s equation for computation of double bond character is assumed to hold it can be seen that the Cj—C2 bond in thiophene and the C—bond in thiadiazole both have a high degree of double bond character ( 70%). The... 

In most molecules studied, the SN double bonds prove to be 0.08 to 0.15 A shorter than the formally single bonds of the thiadiazole molecule. Electron-withdrawing substituents (F, Cl) cause shortening or elongation of these bonds, depending on the atom (S or N) to which they are bonded. 

The structure of the isomeric benzo-l,2,3-thiadiazole 11.30 is unknown, but the 1 1 adduct with AsFs (11.31) has been structurally characterized. The AsFs molecule is coordinated to the carbon-bonded nitrogen atom. Cycloocteno-l,2,3-selenadiazole is an effective source of selenium for the production of semi-conductors such as cadmium selenide." ... 

Li H, Xu J, Yan H (2009) Ratiometric fluorescent determination of cysteine based on organic nanoparticles of naphthalene-thiourea-thiadiazole-linked molecule. Sensor Actuat B-Chem... 

Type G syntheses are typified by the 1,3-dipolar cycloaddition reactions of nitrile sulfides with nitriles. Nitrile sulfides are reactive 1,3-dipoles and they are prepared as intermediates by the thermolysis of 5-substituted-l,3,4-oxathiazol-2-ones 102. The use of nitriles as dipolarophiles has resulted in a general method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 103 (Scheme 11). The thermolysis is performed at 190°C with an excess of the nitrile. The yields are moderate, but are satisfactory when aromatic nitrile sulfides interact with electrophilic nitriles. A common side reaction results from the decomposition of the nitrile sulfide to give a nitrile and sulfur. This nitrile then reacts with the nitrile sulfide to yield symmetrical 1,2,4-thiadiazoles <2004HOU277>. Excellent yields have been obtained when tosyl cyanide has been used as the acceptor molecule <1993JHC357>. 

A number of patent applications that describe small molecule inhibitors of SCD-1 have recently published. For example, a series of patent applications describe related piperazine-based inhibitors of SCD-1 (exemplified by 19) [85]. Piperazine replacements, such as piperidine, 4-aminopiperidine, and 3-amino-azetidine are tolerated, as are thiadiazole and pyridine surrogates of the 1,2-diazine [86-90]. 

Imidazo[2,l-/][[l,3,4]thiadiazoles 161 (Figure 33), containing practically planar and rigid heteroaromatic systems with two condensed heterocycles, which have different Tt-conjugation, have been identified as useful fragments for liquid crystal molecules <2002MI6>. 

Thiophene-1-oxide and 1 -substituted thiophenium salts present reduced aromaticity.144 A variety of aromaticity criteria were used in order to assess which of the 1,1-dioxide isomers of thiophene, thiazole, isothiazole, and thiadiazole was the most delocalized (Scheme 46).145 The relative aromaticity of those molecules is determined by the proximity of the nitrogen atoms to the sulfur, which actually accounts for its ability to participate in a push-pull system with the oxygen atoms of the sulfone moiety. The relative aromaticity decreases in the series isothiazole-1,1-dioxide (97) > thiazole-1,1 -dioxide (98) > thiophene-1-dioxide (99) then, one has the series 1,2,5 -thiadiazole-1,1 -dioxide (100) > 1, 2,4-thiadiaz-ole-1,1-dioxide (101) > 1,2,3-thiadiazole-1,1 -dioxide (102) > 1,3,4-thiadiazole-l,1-dioxide (103) in the order of decreasing aromaticity. As 1,2,5-thiadiazole-1,1-dioxide (100) was not synthesized, the approximations used extrapolations of data obtained for its 3,4-dimethyl-substituted analogue 104 (Scheme 46). 

However, there are some cases when an unpaired electron is localized not on the n, but on the o orbital of an anion-radical. Of course, in such a case, a simple molecular orbital consideration that is based on the n approach does not coincide with experimental data. Chlorobenzothiadiazole may serve as a representative example (Gul maliev et al. 1975). Although the thiadiazole ring is a weaker acceptor than the nitro group, the elimination of the chloride ion from the 5-chlorobenzothiadiazole anion-radical does not take place (Solodovnikov and Todres 1968). At the same time, the anion-radical of 7-chloroquinoline readily loses the chlorine anion (Fujinaga et al. 1968). Notably, 7-chloroquinoline is very close to 5-chlorobenzothiadiazole in the sense of structure and electrophilicity of the heterocycle. To explain the mentioned difference, calculations are needed to clearly take into account the o electron framework of the molecules compared. It would also be interesting to exploit the concept of an increased valency in the consideration of anion-radical electronic structures, especially of those anion-radicals that contain atoms (fragments) with available d orbitals. This concept is traditionally derived from valence-shell expansion through the use of d orbital, but it is also understandable in terms of simple (and cheaper for calculations) MO theory, without t(-orbital participation. For a comparative analysis refer the paper by ElSolhy et al. (2005). Solvation of intermediary states on the way to a final product should be involved in the calculations as well (Parker 1981). 

A mechanism for 1,2,5-thiadiazole formation was proposed in the 1960s (1967JOC2823) and seems to be reliable this includes the formation of the M-chlorodithio intermediate followed by chlorination of the nitrile function, ring closure, addition of the second molecule of sulfur monochloride and formation of the heteroaromatic 1,2,5-thiadiazole cycle (Scheme 18). 

Treatment of 1,2,4-thiadiazole (1) with a weak base (K2CO3) in D2O gives the monodeutero derivative (36) (Equation (7)). Under strongly alkaline conditions, the molecule is completely... 

The reaction of sulfur dichloride with benzonitrile in the presence of a Lewis acid catalyst yields 3,5-diphenyl-l,2,4-thiadiazole (39), along with the 3-o-chlorophenyl (278) and 3-p-chlorophenyl (279) analogues in a total yield of 80%. The proposed mechanism proceeds via a complex between benzonitrile, Lewis acid for example, aluminum trichloride, and sulfur dichloride to give an intermediate (280) which then adds a second molecule of nitrile (Scheme 62) <83BCJ180>. 

Little has been added to the firm body of evidence that 1,2,5-thiadiazole (2) is a planar, cyclic molecule of C2, symmetry. The previous edition of this series <84CHEC-I(6)513> details the molecular geometry, molecular calculations, and electronic structures of the ring systems. A few recent efforts,... 

In attempting to approximate (CNDO/2) the nature of the 1,2,5-thiadiazole ring (2a vs. 2b), a nontraditional view has been proposed <83IJC(B)802> with two C=N bonds and one three-center two-electron 7t-bond delocalized over the N—S—N system. This would account for the electron-rich N—S—N nature of the molecule. Classical structures (2a, 2b) are viewed as unlikely versus a hybrid structure (2c). 

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