The [3+2] cycloaddition (32CA) reactions of diphenyl nitrilimine and phenyl nitrile oxide with (R)-carvone have been studied within the Molecular Electron Density Theory (MEDT). Electron localisation function (ELF) analysis of these three-atom-components (TACs) permits its characterisation as carbenoid and zwitterionic TACs, thus having a different reactivity. The analysis of the conceptual Density Functional Theory (DFT) indices accounts for the very low polar character of these 32CA reactions, while analysis of the DFT energies accounts for the opposite chemoselectivity experimentally observed. Topological analysis of the ELF along the single bond formation makes it possible to characterise the mechanisms of these 32CA reactions as cb- and zw-type. The present MEDT study supports the proposed classification of 32CA reactions into pdr-, pmr-, cb- and zw-type, thus asserting MEDT as the theory able to explain chemical reactivity in Organic Chemistry.

Aseries of novel 1,4-disubstituted 1,2,3-triazoles were synthesized from an (R)-carvone terminal alkyne derivative via a Cu (I)-catalyzed azide–alkyne cycloaddition reaction using CuSO₄,5H₂O as the copper (II) source and sodium ascorbate as a reducing agent which reduces Cu (II) into Cu (I). All the newly synthesized 1,2,3-triazoles 9a–h were fully identified on the basis of their HRMS and NMR spectral data and then evaluated for their cell growth inhibition potential by MTS assay against HT-1080 fibrosarcoma, A-549 lung carcinoma, and two breast adenocarcinoma (MCF-7 and MDA-MB-231) cell lines. Compound 9d showed notable cytotoxic effects against the HT-1080 and MCF-7 cells with IC₅₀ values of 25.77 and 27.89 µM, respectively, while compound 9c displayed significant activity against MCF-7 cells with an IC₅₀ value of 25.03 µM. Density functional calculations at the B3LYP/6-31G* level of theory were used to confirm the high reactivity of the terminal alkyne as a dipolarophile. Quantum calculations were also used to investigate the mechanism of both the uncatalyzed and copper (I)-catalyzed azide–alkyne cycloaddition reaction (CuAAC). The catalyzed reaction gives complete regioselectivity via a stepwise mechanism streamlining experimental observations. The calculated free-energy barriers 4.33 kcal/mol and 29.35 kcal/mol for the 1,4- and 1,5-regioisomers, respectively, explain the marked regioselectivity of the CuAAC reaction.

In the current study, natural (R)-carvone was used as starting material for the efficient synthesis of several 1,2,3-triazole derivatives. The produced products were obtained in good yields and characterized by ¹H and ¹³C NMR and HRMS analysis. The newly synthesized monoterpenic 1,2,3-triazole 4 and derivatives were analyzed by viability tests (MTT) for their cytotoxic activity against three human cancer cells. Product 5 showed a medium antitumor activity, for which the IC₅₀ values against selected cells HT-1080, A-549 and MCF-7 were 29.25 μM, 31.62 μM and 26.02 μM, respectively. The regioselectivity of the condensation reaction and the molecular structure of the title compounds were determined by Density Functional Theory (DFT) using B3LYP calculations at 6-311 + G(d,p) level. The orbitals HOMO and LUMO were studied to determine the electronic properties of the synthesized compounds. In addition, the global reactivity indices were used to explain the regioselectivity for the formation of compound 6, and the theoretical results agree well with the experimental results. Molecular docking and molecular dynamics confirmed the empirical test results and confirmed the stability of the complex during inhibition of the anti-apoptotic protein for killing cancer cells. Graphical Abstract Communicated by Ramaswamy H. Sarma

In the title molecule, C₇H₆N₄O₃, the bicyclic ring system is planar with the carboxymethyl group inclined by 81.05 (5)° to this plane. In the crystal, corrugated layers parallel to (010) are generated by N—H...O, O—H...N and C—H...O hydrogen-bonding interactions. The layers are associated through C—H...π(ring) interactions. A Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H...O/O...H (34.8%), H...N/N...H (19.3%) and H...H (18.1%) interactions. The volume of the crystal voids and the percentage of free space were calculated to be 176.30 ų and 10.94%, showing that there is no large cavity in the crystal packing. Computational methods revealed O—H...N, N—H...O and C—H...O hydrogen-bonding energies of 76.3, 55.2, 32.8 and 19.1 kJ mol⁻¹, respectively. Evaluations of the electrostatic, dispersion and total energy frameworks indicate that the stabilization is dominated via dispersion energy contributions. Moreover, the optimized molecular structure, using density functional theory (DFT) at the B3LYP/6–311G(d,p) level, was compared with the experimentally determined one. The HOMO–LUMO energy gap was determined and the molecular electrostatic potential (MEP) surface was calculated at the B3LYP/6–31G level to predict sites for electrophilic and nucleophilic attacks.