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Copper-catalyzed azide-alkyne cycloadditions (CuAAC) produce 1,4-disubstituted 1,2,3-triazoles, molecules that have many applications in pharmaceuticals. Click reactions are atom-efficient and produce 1,4-disubstituted triazoles selectively with high yields at room temperature. Byproducts are rarely observed, and the product is easily separated by washing, eliminating the need for purification measures such as column chromatography. We tested various copper complexes for ease of use as homogeneous catalysts at various conditions. The 1,4-disubstituted triazole products were obtained in moderate to excellent yields. The progress of reaction was determined using TLC and IR spectroscopy, and products were characterized by GC-MS and NMR spectroscopy. We found that there is little that changes the outcome of the reaction upon variations in solvent and temperature conditions. However, preliminary results show that the anion of the copper salt used in preparing the copper complexes affects the kinetics of the triazole formation. A significant finding was that copper(II)-catalyzed reactions appear to form product even in the absence of a reducing agent.
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New 1,2,3-Triazoles from (R)-Carvone: Synthesis, DFT Mechanistic Study and In Vitro Cytotoxic Evaluation
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.
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- PAR ID:
- 10356529
- Date Published:
- Journal Name:
- Molecules
- Volume:
- 27
- Issue:
- 3
- ISSN:
- 1420-3049
- Page Range / eLocation ID:
- 769
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/molecules27030769
