The copper(I) catalyzed azide–alkyne [3 + 2] cycloaddition (32CA) reaction and its uncatalyzed version have been studied for systematic understanding of this relevant organic transformation, using DFT calculations at the B3LYP/6-31G(d) (LANL2DZ for Cu) computational levels. In the absence of a copper(I) catalyst, two regioisomeric reaction paths were studied, indicating that the 32CA reaction takes place through an asynchronous one-step mechanism with a very low polar character. The two reactive channels leading to 1,4- and 1,5-regisomer present similar high activation energies of 18.84 and 18.51 kcal mol⁻¹, respectively. The coordination of copper(I) to alkyne produces relevant changes in this 32CA reaction. Analysis of the global and local electrophilicity/nucleophilicity allows explaining correctly the behaviors of the copper(I) catalyzed cycloaddition. Coordination of the copper to alkyne changes the mechanism from a non-polar one-step mechanism to a polar stepwise one, as a consequence of the high nucleophilic character of the dinuclear Cu(I)-acetylide complex. Parr and Fukui functions and Dual Descriptor correctly explain the observed regioselectivity by means of the most favorable two-center interaction that takes place along the 1,4 reaction path.

A novel sustainable hydrogel catalyst based on the reaction of sodium alginate naturally extracted from brown algae Laminaria digitata residue with copper(II) was prepared as spherical beads, namely Cu(II)-alginate hydrogel (Cu(II)-AHG). The morphology and structural characteristics of these beads were elucidated by different techniques such as SEM, EDX, BET, FTIR and TGA analysis. Cu(II)-AHG and its dried form, namely Cu(II)-alginate (Cu(II)-AD), are relatively uniform with an average pore ranging from 200 nm to more than 20 μm. These superporous structure beads were employed for the copper catalyzed [3 + 2] cycloaddition reaction of aryl azides and terminal aryl alkynes (CuAAC) via click chemistry at low catalyst loading, using water as a solvent at room temperature and pressure. The catalytic active copper(I) species was generated by the reduction of copper(II) by terminal alkyne via the oxidative alkyne homocoupling reaction. The prepared catalysts were found to be efficient (85–92%) and regioselective by affording only 1,4-disubstituted-1,2,3-triazoles. They were also recoverable and reused in their dried form for at least four consecutive times without a clear loss of efficiency. A mechanistic study was performed through density functional theory (DFT) calculations in order to explain the regioselectivity outcome of Cu(II)-alginate in CuAAC reactions. The analysis of the local electrophilicity (ω_k) at the electrophilic reagent and the local nucleophilicity (N_k) at the nucleophilic confirms the polar character of CuAAC. This catalyst has the main advantage of being sustainably ligand-free and recyclable.

The copper(I)-catalyzed azide−alkyne cycloaddition (CuAAC) reaction is considered to be the most representative ligation process within the context of the “click chemistry” concept. This CuAAC reaction, which yields compounds containing a 1,2,3-triazole core, has become relevant in the construction of biologically complex systems, bioconjugation strategies, and supramolecular and material sciences. Although many CuAAC reactions are performed under homogenous conditions, heterogenous copper-based catalytic systems are gaining exponential interest, relying on the easy removal, recovery, and reusability of catalytically copper species. The present review covers the most recently developed copper-containing heterogenous solid catalytic systems that use solid inorganic/organic hybrid supports, and which have been used in promoting CuAAC reactions. Due to the demand for 1,2,3-triazoles as non-classical bioisosteres and as framework-based drugs, the CuAAC reaction promoted by solid heterogenous catalysts has greatly improved the recovery and removal of copper species, usually by simple filtration. In so doing, the solving of the toxicity issue regarding copper particles in compounds of biological interest has been achieved. This protocol is also expected to produce a practical chemical process for accessing such compounds on an industrial scale.

A series of new heterocycle hybrids incorporating pyrazole and isoxazoline rings was successfully synthesized, characterized, and evaluated for their antimicrobial responses. The synthesized compounds were obtained utilizing N-alkylation and 1,3-dipolar cycloaddition reactions, as well as their structures were established through spectroscopic methods and confirmed by mass spectrometry. To get more light on the regioselective synthesis of new hybrid compounds, mechanistic studies were performed using DFT calculations with B3LYP/6-31G(d,p) basis set. Additionally, the results of the preliminary screening indicate that some of the examined hybrids showed potent antimicrobial activity, compared to standard drugs. The results confirm that the antimicrobial activity is strongly dependent on the nature of the substituents linked pyrazole and isoxazoline rings. Furthermore, molecular docking studies were conducted to highlight the interaction modes between the investigated hybrid compounds and the Escherichia coli and Candida albicans receptors. Notably, the results demonstrate that the investigated compounds have strong protein binding affinities. The stability of the formed complexes by the binding between the hybrid compound 6c, and the target proteins was also confirmed using a 100 ns molecular dynamics simulation. Finally, the prediction of ADMET properties suggests that almost all hybrid compounds possess good pharmacokinetic profiles and no signs of observed toxicity, except for compounds 6e, 6f, and 6g.