Bis(α‐bromo ketones): Versatile Precursors for Novel Bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) and Bis(as‐triazino[3,4‐b][1,3,4]thiadiazines)

A synthesis of bis(α‐bromo ketones) 5a‐c and 6b,c was accomplished by the reaction of bis(acetophenones) 3a‐c and 4b,c with N‐bromosuccinimide in the presence of p‐toluenesulfonic acid (p‐TsOH). Treatment of 5a‐c and 6b,c with each of 4‐amino‐3‐mercapto‐1,2,4‐triazoles 9a,b and 4‐amino‐6‐phenyl‐3‐mercapto‐1,2,4‐triazin‐5(4H)‐ones 13 in refluxing ethanol afforded the novel bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) 10a‐d and 11a‐c as well as bis(as‐triazino[3,4‐b][1,3,4]thiadiazines) 14a‐c and 15 , respectively, in good yields. Compounds 11b and 11c underwent NaBH₄ reduction in methanol to give the target 1,ω‐bis{4‐(6,7‐dihydro‐3‐substituted‐5H‐1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazin‐6‐yl)phenoxy}butanes 12a and 12b in 42 and 46% yields, respectively.     

Facile routes to 1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazines and 1,2,4‐triazino[3,4‐b][1,3,4]thiadiazine by heteropolyacides

Cyclization of 4‐amino‐6‐methyl‐3‐propargylmercapto‐1,2,4‐triazine‐5‐one 3 and 4‐amino‐3‐propargyl mercapto‐1,2,4‐triazole derivatives 6 were afforded 1,2,4‐triazino[3,4‐b][1,3,4]thiadiazines 4 and 1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazines 7 in presence of heteropolyacids, H₁₄[NaP₅W₂₉MoO₁₁₀] and H₆P₂W₁₈O₆₀ in high yields. Among used heteropoly acids, the yields were higher with H₁₄‐P₅Mo, caused to their high acid strengths.     

The different modes of chiral [1,2,3]triazolo[5,1‐b][1,3,4]thiadiazines: crystal packing,conformation investigation and cellular activity

The crystal structures of four new chiral [1,2,3]triazolo[5,1‐b][1,3,4]thiadiazines are described, namely, ethyl 5′‐benzoyl‐5′H,7′H‐spiro[cyclohexane‐1,6′‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine]‐3′‐carboxylate, C₁₉H₂₂N₄O₃S, ethyl 5′‐(4‐methoxybenzoyl)‐5′H,7′H‐spiro[cyclohexane‐1,6′‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine]‐3′‐carboxylate, C₂₀H₂₄N₄O₄S, ethyl 6,6‐dimethyl‐5‐(4‐methylbenzoyl)‐6,7‐dihydro‐5H‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine‐3‐carboxylate, C₁₇H₂₀N₄O₃S, and ethyl 5‐benzoyl‐6‐(4‐methoxyphenyl)‐6,7‐dihydro‐5H‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine‐3‐carboxylate, C₂₁H₂₀N₄O₄S. The crystallographic data and cell activities of these four compounds and of the structures of three previously reported similar compounds, namely, ethyl 5′‐(4‐methylbenzoyl)‐5′H,7′H‐spiro[cyclopentane‐1,6′‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine]‐3′‐carboxylate, C₁₉H₂₂N₄O₃S, ethyl 5′‐(4‐methoxybenzoyl)‐5′H,7′H‐spiro[cyclopentane‐1,6′‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine]‐3′‐carboxylate, C₁₉H₂₂N₄O₄S, and ethyl 6‐methyl‐5‐(4‐methylbenzoyl)‐6‐phenyl‐6,7‐dihydro‐5H‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine‐3‐carboxylate, C₂₂H₂₂N₄O₃S, are contrasted and compared. For both crystallization and an MTT assay, racemic mixtures of the corresponding [1,2,3]triazolo[5,1‐b][1,3,4]thiadiazines were used. The main manner of molecular packing in these compounds is the organization of either enantiomeric pairs or dimers. In both cases, the formation of two three‐centre hydrogen bonds can be detected resulting from intramolecular N—H…O and intermolecular N—H…O or N—H…N interactions. Molecules of different enantiomeric forms can also form chains through N—H…O hydrogen bonds or form layers between which only weak hydrophobic contacts exist. Unlike other [1,2,3]triazolo[5,1‐b][1,3,4]thiadiazines, ethyl 5′‐benzoyl‐5′H,7′H‐spiro[cyclohexane‐1,6′‐[1,2,3]triazolo[5,1‐b][1,3,4]thiadiazine]‐3′‐carboxylate contains molecules of only the (R)‐enantiomer; moreover, the N—H group does not participate in any significant intermolecular interactions. Molecular mechanics methods (force field OPLS3e) and the DFT B3LYP/6‐31G+(d,p) method show that the compound forming enantiomeric pairs via weak N—H…N hydrogen bonds is subject to greater distortion of the geometry under the influence of the intermolecular interactions in the crystal. For intramolecular N—H…O and S…O interactions, an analysis of the noncovalent interactions (NCIs) was carried out. The cellular activities of the compounds were tested by evaluating their antiproliferative effect against two normal human cell lines and two cancer cell lines in terms of half‐maximum inhibitory concentration (IC₅₀). Some derivatives have been found to be very effective in inhibiting the growth of Hela cells at nanomolar and submicromolar concentrations with minimal cytotoxicity in relation to normal cells.     

Efficient Routes for the Synthesis of Novel Bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines)

Bis(triazolo[3,4‐b]thiadiazine) 4 in which the fused system is linked directly to the benzene core can be synthesized in 75% yield by, firstly, preparation of bis(s‐triazole) 2 followed by reaction with phenacyl bromide 3 in refluxing EtOH/DMF mixture containing piperidine. Bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) 8 and 11 in which the triazolothiadiazines are linked to benzene core via alkyl or ether linkage were synthesized in 70 and 72% yields, respectively, starting from dicarboxylic acids 5 and 9 upon treatment with two moles of thiocarbohydrazide 6 to give the corresponding bis(4‐amino‐5‐mercapto‐s‐triazolo‐3‐y1) derivatives 7 and 10 and subsequent reaction with two equivalents of phenacyl bromide. Bis(6‐phenyl‐7H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines) 15a , 15b , 15c , 15d , 15e , 15f , which are linked to arene cores via sulfanylmethylene spacers, were prepared by the reaction of 4‐amino‐4H‐1,2,4‐triazole‐3,5‐dithiol 12 with the appropriate bis(bromomethyl)benzenes 13a , 13b , 13c , 13d , 13e , 13f to give bis(4‐amino‐5‐mercapto‐4H‐3‐sulfanylmethyl)arenes 14a , 14b , 14c , 14d , 14e , 14f and subsequent reaction with phenacyl bromide. Compounds 15a , 15b , 15c , 15d , 15e , 15f were alternatively obtained in 60–70% yields by twofold substitution of 13a , 13b , 13c , 13d , 13e , 13f with two equivalents of 6‐phenyl‐7H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazine‐3‐thiol 16 in refluxing EtOH/DMF mixture containing KOH. Bis(triazolothiadiazine) 22 attached to the benzene core through the thiadiazine ring via an amine linkage was prepared in 70% yield starting from p‐phenylenediamine 19 by, firstly, acylation with chloroacetyl chloride 18 followed by bis‐alkylation with 1,2,4‐triazole 20 and subsequent intramolecular ring closure upon treatment with phosphorus oxychloride.     

Synthesis of heterocycles. Part VII Synthesis and antimicrobial activity of some 7H-s-triazolo[3,4-b][1,3,4]thiadiazine and s-triazolo[3,4-b][1,3,4]thiadiazole derivatives

The cyclization of 4-amino-5-aryl-3-cyanomethylthio-1,2,4-triazoles II in the presence of concentrated sulfuric acid yields 7H-6-amino-s-triazolo[3,4-b][1,3,4]thiadiazines III . Cyclization of 4-amino-5-aryl-1,2,4-tria-zole-3-thiones I with phenacyl chloride yields 7H-3-aryl-6-phenyl-s-triazolo[3,4-b][1,3,4]thiadiazines IV . Similarly, compounds I condensed with cyanogen bromide, phenyl isothiocyanate and carbon disulfide to give the corresponding cyclized products 6-amino-3-aryl-s-triazolo[3,4-b][1,3,4]thiadiazoles V , 3-aryl-6-phenyl-amino-s-triazolo[3,4-b][1,3,4]thiadiazoles VI and 3-aryl-striazolo[3,4-b][1,3,4]thiadiazol-6(5H)thiones VII , respectively. Also in the presence of phosphoryl chloride, compounds I underwent cyclization with monocarbo-xylic acids and oxalic acid to 3,6-diaryl-s-triazolo[3,4-b][1,3,4]thiadiazole VIII and 6,6′-bis(3-aryl-s-triazolo-[3,4-b][1,3,4]thiadiazoles) IX . The above compounds were screened for their antimicrobial activity.     

Synthesis of 3-Alkyl-6-aryl(arylamino)-7H-[1,2,4]triazolo- [3,4-b][1,3,4]thiadiazines

Starting from 5-alkyl-4-amino-4H-1,2,4-triazole-3-thiols and substituted chloroacetanilides, the corresponding (5-alkyl-4-amino-4H-1,2,4-triazol-3-ylsulfanyl)acetanilides were synthesized. The products underwent intramolecular cyclization in boiling phosphoryl chloride to afford 3-alkyl-6-arylamino-7H-[1,2,4]-triazolo[3,4-b][1,3,4]thiadiazines. 3-Alkyl-6-aryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hydrobromides were obtained by reaction of 5-alkyl-4-amino-4H-1,2,4-triazole-3-thiols with substituted phenacyl bromides.     

A Facile Synthesis of Aryl‐Substituted Hydrazono‐Pyrazolyl[1,2,4]triazolo[3,4‐b][1,3,4][thiadiazol]‐coumarin Derivatives

Some inimitable and therapeutic coumarin‐substituted fused[1,2,4]triazolo‐[3,4‐b][1,3,4]thiadizole derivatives were synthesized by the cyclocondensation reaction of 2‐oxo‐2H‐chromene‐3‐carboxylic acid ( 1 ) and 4‐amino‐5‐hydrazinyl‐4H‐[1,2,4]‐triazole‐3‐thiol ( 2 ) by using phosphorous oxychloride as a cyclizing agent. This cyclized intermediate 3‐(3‐hydrazino‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazol‐6‐yl)‐chromen‐2‐one ( 3 ) later condensation with various ethyl 2‐(2‐arylhydrazono)‐3‐oxobutanoates ( 4 ) in NaOAc/MeOH under reflux conditions afforded the corresponding new series of aryl‐substituted hydrazono‐pyrazolyl‐[1,2,4]triazolo[3,4‐b][1,3,4][thiadiazol]‐coumarin derivatives ( 5 ) in good to excellent yields. The structures of newly synthesized compounds were established on the basis of elemental analysis, IR, ¹H NMR and mass spectroscopic studies.     

Synthesis of Some 7H‐s‐Triazolo[3,4‐b]‐1,3,4‐thiadiazine Derivatives

The cyclization of 1‐amino‐2‐mercapto‐5‐[5‐methyl‐1‐(4‐methylphenyl)‐1,2,3‐triazol‐4‐yl]‐1,3,4‐triazole with various α‐haloketone in absolute ethanol yields 7H‐3‐[5‐methyl‐1‐(4‐methylphenyl)‐1,2,3‐triazol‐4‐yl]‐6‐substituted‐s‐triazolo[3,4‐b]‐1,3,4‐thiadiazines and their structures are established by elemental analysis, MS, IR and ¹H NMR spectral data.     

Facile one‐pot synthesis of [1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines and 3,7‐dimethyl‐4H‐[1,2,4]triazino[3,4‐b][1,3,4]thiadiazin‐6‐one using heteropolyacid catalysts

[1,2,4]Triazolo[3,4‐b][1,3,4]thiadiazines 2a , 2b , 2c , 2d , 2e , 2f and 3,7‐dimethyl‐4H‐[1,2,4]triazino[3,4‐b][1,3,4]thiadiazin‐6‐one 4 were synthesized by one‐pot cyclocondensation reaction with α‐chloroacetonitrile and α‐haloketones in the presence of catalytic amounts of heteropolyacids in very high yields and rates. J. Heterocyclic Chem., (2011).     

Synthesis and Biological Activities of 7‐Arylazo‐7H‐pyrazolo[5,1‐c][1,2,4] Triazol‐6(5H)‐Ones and 7‐Arylhydrazono‐7H‐[1,2,4]triazolo[3,4‐b] [1,3,4]thiadiazines

Two series of 7‐arylazo‐7H‐3‐(2‐methyl‐1H‐indol‐3‐yl)pyrazolo[5,1‐c][1,2,4]triazol‐6(5H)‐ones 4 and 7‐arylhydrazono‐7H‐3‐(2‐methyl‐1H‐indol‐3‐yl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines 7 were prepared via reactions of 4‐amino‐3‐mercapto‐5‐(2‐methyl‐1H‐indol‐3‐yl)‐1,2,4‐triazole 1 with ethyl arylhydrazono‐chloroacetate 2 and N‐aryl‐2‐oxoalkanehydrazonoyl halides 5 , respectively. A possible mechanism is proposed to account for the formation of the products. The biological activity of some of these products was also evaluated.     

Different patterns of supramolecular assembly in constitutionally similar 6‐arylimidazo[2,1‐b][1,3,4]thiadiazoles

Four imidazo[2,1‐b][1,3,4]thiadiazoles containing a simply‐substituted 6‐aryl group have been synthesized by reaction of 2‐amino‐1,3,4‐thiadiazoles with bromoacetylarenes using microwave irradiation and brief reaction times. 6‐(2‐Chlorophenyl)imidazo[2,1‐b][1,3,4]thiadiazole, C₁₀H₆ClN₃S, (I), 6‐(2‐chlorophenyl)‐2‐methylimidazo[2,1‐b][1,3,4]thiadiazole, C₁₁H₈ClN₃S, (II), 6‐(3,4‐dichlorophenyl)imidazo[2,1‐b][1,3,4]thiadiazole, C₁₀H₅Cl₂N₃S, (III), and 6‐(4‐fluoro‐3‐methoxyphenyl)‐2‐methylimidazo[2,1‐b][1,3,4]thiadiazole, C₁₂H₁₀FN₃OS, (IV), crystallize with Z′ values of 2, 1, 1 and 2 respectively. The molecular skeletons are all nearly planar and the dihedral angles between the imidazole and aryl rings are 1.51 (8) and 7.28 (8)° in (I), 9.65 (7)° in (II), 10.44 (8)° in (III), and 1.05 (8) and 7.21 (8)° in (IV). The molecules in (I) are linked by three independent C—H...N hydrogen bonds to form ribbons containing alternating R₂²(8) and R₄⁴(18) rings, and these ribbons are linked into a three‐dimensional array by three independent π‐stacking interactions. Both (II) and (III) contain centrosymmetric dimers formed by π‐stacking interactions but hydrogen bonds are absent, and the molecules of (IV) are linked into centrosymmetric R₂²(8) dimers by C—H...N hydrogen bonds. Comparisons are made with a number of related compounds.     

Synthesis of 6‐Aryl‐4H‐imidazo[1,2‐b][1,2,4]triazoles and 6‐Aryl‐thiazolo[3,2‐b][1,2,4]triazoles

The cyclization of the derivatives of 3‐aminotriazole, 2‐(5‐substituted 4H‐1,2,4‐triazol‐3‐ylamino)‐1‐arylethanones and 2‐(4H‐1,2,4‐triazol‐3‐ylthio)‐1‐arylethanones to yield 6‐aryl‐4H‐imidazo[1,2‐b][1,2,4]triazoles and 6‐aryl‐thiazolo[3,2‐b][1,2,4]triazoles has been described.     

Synthesis and opening of the thiadiazine ring in 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines

A reaction of 3-benzylthiotriazole-4-amines with aromatic aldehydes leads to the formation of 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines. A dihydrothiadiazine ring opening along the N-N bond occurs by the action of strong bases. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1249–1252, June, 2008.     

Facile synthesis of some novel triazolo[3,4-b]thiadiazines and triazolo[4,3-b]tetrazines

4-Amino-5-ethyl-4H-1,2,4-triazole-3-thiol was used as a key intermediate for the synthesis of triazolo[3,4-b][1,3,4]thiadiazines, triazolo[4,3-b][1,2,4,5]tetrazines and Schiff’s base via reactions with various hydrazonoyl halides and salicyaldehyde, respectively. Moreover triazolyl-N-N′-triazole derivatives were prepared from reaction of Schiff’s base with various hydrazonoyl halides. The structures of all the newly synthesized heterocyclic compounds were established by considering elemental analysis and spectral data.     

Syntheses of New Unsymmetrical 2,5‐Disubstituted‐1,3,4‐oxadiazoles and 1,2,4‐Triazolo[3,4‐b]‐1,3,4‐thiadiazoles Bearing Thieno[2,3‐c]pyrazolo Moiety

New series of (thieno[2,3‐c]pyrazolo‐5‐yl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazoles 10a , 10b , 10c and (thieno[2,3‐c]pyrazol‐5‐yl)‐1,3,4‐oxadiazol‐3(2H)‐yl)ethanones 6a , 6b , 6c has been synthesized from thieno[2,3‐c]pyrazole‐5‐carbohydrazide 3 by multistep reaction sequence. (5‐Aryl‐1,3,4‐oxadiazol‐2‐yl)‐1H‐thieno[2,3‐c]pyrazoles 4a , 4b , 4c were also synthesized from thieno[2,3‐c]pyrazole‐5‐carbohydrazide 3 by cyclization with various aromatic carboxylic acids. The hydrazide 3 was obtained by reaction of thieno[2,3‐c]pyrazole‐5‐carboxylate 2 with hydrazine hydrate in good yield, and compound 2 was obtained by the reaction of 5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde 1 and 2‐ethyl thioglycolate in presence of sodium alcoholate in good yield.     

C5‐Alkyl‐1,3,4‐Oxadiazol‐2‐ones Undergo Dealkylation upon Nitrogen Insertion to Form 2H‐1,2,4‐Triazol‐3‐ones: Synthesis of 1,2,4‐Triazol‐3‐one Hybrids with Triazolothiadiazoles and Triazolothiadiazines

The present study emphasizes on the dealklylation of 3‐aryl‐5‐alkyl‐2‐oxo‐Δ⁴‐1,3,4‐oxadiazoles when reacted with formamide resulting in the formation of 2‐aryl‐2H‐1,2,4‐triazol‐3(4H )‐ones as major product. Subsequent reactions of 2‐aryl‐2H‐1,2,4‐triazol‐3(4H )‐one gave triazolo[3,4‐b ][1,3,4]thiadiazoles and triazolo[3,4‐b ][1,3,4]thiadiazines derivatives incorporated with 1,2,4‐triazol‐3‐one.     

Bis(α‐bromo ketones): Versatile Precursors for Novel Bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) and Bis(thiazoles)

A synthesis of novel bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) 4 , 5 , 6 in which the triazolothiadiazine is linked to the benzene core through the thiadiazine ring via phenoxymethyl spacers was reported. First attempt to synthesize 4 , 5 , 6 by the reaction of the appropriate bis(acetophenones) with 4‐amino‐3‐mercapto‐1,2,4‐triazole derivatives using an acidified acetic acid method were unsuccessful. On the other hand, reaction of the corresponding bis(α‐bromoketones) with 4‐amino‐3‐mercapto‐1,2,4‐triazole derivatives afforded 4 , 5 , 6 in good yields. The reaction pathway is assumed to involve S‐alkylation to give bis(aminotriazole) intermediates, followed by intramolecular cyclocondensation to give 4 , 5 , 6 . The successful isolation of the corresponding bis(aminotriazole) intermediates provides strong evidence for the proposed mechanism. The novel bis(thiazoles) 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , linked to alkyl or aryl spacers can also be synthesized by reaction of the appropriate bis(bromoacetyl) compounds 12a , 12b , 12c and 14 , 15 , 16 , 17 , 18 , 19 with the corresponding thioamide derivatives 20 , 21 , 22 .     

A Facile Synthesis of Novel Dihydroindeno[1,2‐e][1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines Using HTIB

The synthesis of a series of 21 novel 3‐alkyl/aryl‐7/9‐methyl‐10,10a‐dihydroindeno[1,2‐e][1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines ( 4 ) has been achieved by the cyclocondensation between 4/6‐methyl‐2‐tosyloxy‐1‐indanones ( 2 ) and 3‐alkyl/aryl‐4‐amino‐5‐mercapto‐1,2,4‐s‐triazoles ( 3 ). 4/6‐Methyl‐2‐tosyloxy‐1‐indanones ( 2 ) were readily accessible through hypervalent iodine oxidation of 4/6‐methyl‐1‐indanones using [(hydroxy)tosyloxyiodo]benzene (HTIB, Koser's reagent) in acetonitrile.     

Synthesis of [1,2,5]selena(or thia)diazolo[3,4‐e][1,4]diazepines, [1,2,5]selena(or thia)diazolo[3,4‐e][1,4]oxazepines and [1,2,5]selena(or thia)diazolo[3,4‐c] [1,2,6]thiadiazines

Novel heterocycles [1,2,5]selenadiazolo[3,4‐e][1,4]diazepines 3a‐c , [1,2,5]thiadiazolo[3,4‐e]‐[1,4]diazepines 7a‐c , [1,2,5]selenadiazolo[3,4‐e][1,4]oxaepines 4a,b , [1,2,5]thiadiazolo[3,4‐e]‐[1,4]oxazepines 9a‐c and [1,2,5]selena(or thia)diazolo[3,4‐c][1,2,6]thiadiazines 10a,b were synthesized starting form 4,6‐dimethyl[1,2,5]se]enadiazolo[3,4‐d]pyrimidine‐5,7(4H,6H)‐dione 1 or 4,6‐dimethyl‐[1,2,5]thiadiazolo[3,4‐d]pyrimidine‐5,7(4H,6H)‐dione 5 .     

Facile Synthesis of Naphtho[2,3‐d]thiazoles,Naphtho[2,3‐e][1,3,4]thiadiazines and Bis(naphtho[2,3‐d]thiazolyl)copper(II) Derivatives from Heteroylthiosemicarbazides

A one step synthesis protocol for the conversion of heteroylthiosemicarbazides and 2,3‐dichloro‐1,4‐naphthoquinone to naphtho[2,3‐d]thiazoles, naphtho[2,3‐e][1,3,4]thiadiazines as well as bis(naphtho[2,3‐d]thiazolyl)copper(II) derivatives is described. The products were conclusively confirmed by single crystal X‐ray analyses. A mechanism for the formation of the products is presented.