Generation of a substituted 1,2,4-thiadiazole ring via the [3+2] cycloaddition reaction of benzonitrile sulfide toward trichloroacetonitrile. A DFT study of the regioselectivity and of the molecular mechanism

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A theoretical study of the [3+2] cycloaddition (32CA) reaction between benzonitrile sulfide BNS1 and trichloroacetonitrile TCAN2 at the MPWB1 K/6-311G(d) level was undertaken. Among two feasible C1 N5 and C1 C4 regioisomeric channels, the former is completely preferred, in the presence of toluene, over the latter, both kinetically, ΔΔ G activation = 17.5 kcal/mol, and thermodynamically, ΔΔ G reaction = –12.8 kcal/mol, in excellent agreement with experimental outcomes. The strong global electrophilic and nucleophilic characters found for TCAN2 and BNS1 , respectively, allow the studied 32CA reaction to take place via a polar process. Interestingly, the analysis of the TSs geometries clarifies that in the case under study, regioselectivity is controlled by destabilizing steric repulsion interactions rather than electronic ones. The ELF topological patterns indicate that while the formation of S3 C4 single bond takes place exactly according to Domingo's model, that of the C1 N5 single bond is a direct consequence of the nucleophilic attack of the C5 carbon atom on the N5 nitrogen atom supporting a two-stage one-step molecular mechanism.