The Diels-Alder cycloaddition of cyclopentadienone derivative 3-methyl-5,6,7,8-tetrahydroazulen-1(4H)-one with a series of maleimide derivatives is studied using Molecular Electron Density Theory at the B3LYP/6-311++G(d,p) computational level. Conceptual Density Functional Theory analysis predicts low reaction polarity, which is confirmed by global electron density transfer analysis at the transition structures. Topological analysis reveals the electron distribution and evolution of multiple covalent and non-covalent interactions at the transition structures. The results indicate that these Diels-Alder reactions follow an asynchronous one-step mechanism under kinetic control, favouring the endo product formation. Bonding Evolution Theory shows that the reaction mechanism can further be decomposed into five distinct bonding evolution phases. In addition, a molecular docking study is conducted to assess the antimicrobial potential of the reaction products against Escherichia coli and Staphylococcus aureus. An evaluation of the results of binding affinity and molecular interactions concludes that the products are viable as antimicrobial agents.

The study of cycloaddition reactions between cyclopenta-1,3-diene and benzyl-acrylate, as well as benzyl-2-fluoroacrylate with and without the catalyst (TiCl4), was conducted using MEDT. The results of the energy profiles suggest that these reactions are stereoselective, meaning that they favor the formation of certain stereoisomers over others. Furthermore, the addition of TiCl4 as a catalyst appears to enhance the selectivity of these reactions, which is in line with experimental observations. Additionally, a docking study was carried out to predict the effect of stereochemistry and the presence of specific atoms, such as fluorine, on their ability to bind to viral proteins responsible for SARS-Covid-19 and HIV. Moreover, the notable affinity of Ligand 4 for HIV renders it a pivotal contender for extended research, possibly paving the way for enhanced antiretroviral drugs. Similarly, the encouraging affinity demonstrated by Ligand 1 towards the Covid-19 protein highlights its promise for Covid-19 drug development.

This study employs Molecular Electron Density Theory (MEDT) to explore the [3+2] cycloaddition mechanisms involving 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene (2-R) and nitrile oxide (3-R). Density Functional Theory (DFT) calculations using the B3LYP/6-311(d,p) method were performed to determine reactivity indices, activation energies, and reaction energies. The conceptual DFT analysis indicates that 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene 2-R acts as a nucleophile, while nitrile oxide 3-R functions as an electrophile. The reaction exhibits notable chemoselectivity and regioselectivity, supported by activation energies that align with experimental data. BET analysis suggests a one-step mechanism with asynchronous bond formation. Additionally, molecular docking studies of the reaction products against HIV-1 and COVID-19 reveal that the presence of oxygen and nitrogen atoms enhances the interaction energy with proteins, indicating potential therapeutic benefits.

Molecular electron density theory has been performed with the B3LYP/6-31(d,p) method to study the [3+2] cycloaddition processes between azidobenzene and propionaldehyde, the reactivity indices, activation and reaction energies are computed. The reaction and activation energies indicate that this [3+2] cycloaddition reaction is regiospecific, in good agreement with the experimental results. ELF examination revealed that the mechanism of these cycloaddition reactions takes place in two steps. In addition, a docking approach was performed on the products investigated, and the interaction with the protein protease COVID-19 (PDB ID: 6LU7), the results confirm that the presence of triazole and isoxazole rings increases the affinity of these products.