Molecular Electron Density Research Articles

Mechanistic aspects of the synthesis of seven-membered internal nitronates via stepwise [4 + 3] cycloaddition involving conjugated nitroalkenes: Molecular Electron Density Theory computational study.

The density functional theory computational study indicates the possibility of the synthesis of seven-membered internal nitronates via cycloaddition reactions involving Z-C-aryl-N-methylnitrones and E-2-aryl-1-cyano-1-nitroethenes. The detailed exploration of the reaction paths indicates a polar, stepwise reaction mechanism through the zwitterionic intermediate. Using bonding evolution theory (BET), we have deciphered the molecular mechanism of the [4 + 3] cycloaddition reaction between E-2-phenyl-1-cyano-1-nitroethene and Z-C-phenyl-N-methylnitrone. The BET study has revealed that the formation of two CO single bonds takes place in the same way, through the depopulation of NC and CC bonding regions and monosynaptic basins, respectively. The first O1C7 single bond was formed in the sixth phase, while the second C3O4 bond was formed in the last ninth phase.

Predicting new potential antimalarial compounds by using Zagreb topological indices

Molecular topology allows describing molecular structures following a two-dimensional approach by taking into account how the atoms are arranged internally through a connection matrix between the atoms that are part of a structure. Various molecular indices (unique for each molecule) can be determined, such as Zagreb, Balaban, and topological indices. These indices have been correlated with physical chemistry properties such as molecular weight, boiling point, and electron density. Furthermore, their relationship with a specific biological activity has been found in other reports. Therefore, its knowledge and interpretation could be critical in the rational design of new compounds, saving time and money in their development process. In this research, the molecular graph of antimalarials already in the pharmaceutical market, such as chloroquine, primaquine, quinine, and artemisinin, was calculated and used to compute the Zagreb indices; a relationship between these indices and the antimalarial activities was found. According to the results reported in this work, the smaller the Zagreb indices, the higher the antimalarial activity. This relationship works very well for other compounds series. Therefore, it seems to be a fundamental structural requirement for this activity. Three triazole-modified structures are proposed as possible potential antimalarials based on this hypothesis. Finally, this work shows that the Zagreb indices could be a cornerstone in designing and synthesizing new antimalarial compounds, albeit they must be proved experimentally.

Effect of hydrogen bonds and CF3 group on the regioselectivity and mechanism of [3 + 2] cycloaddition reactions between nitrile oxide and 2,4-disubstitutedcyclopentenes. A MEDT study.

The mechanism and the regioselectivity of the non-polar [3 + 2] cycloaddition reactions between nitrile oxide and two cyclopentenes were theoretically investigated within the molecular electron density theory (MEDT) using DFT methods, namely the B3LYP, MPWB1K and ωB97XD functionals together with the standard 6-31G(d) basis set. The activation energies of these 32CA reactions are relatively high, due to the low nucleophilic power of both cycloalkenes and the relatively moderate electrophilic nature of the nitrile oxide. The B3LYP and MPWB1K functionals reproduced high relative energies values, while the ωB97XD one yields better values in the kinetic and thermodynamic energies. The completely 4-regioselectivity that observed experimentally has been explained by the analysis of the relative energies, in which the formation of 4-regioismeric cycloadducts is always the more kinetically favored one. The electron localization function (ELF) topological analysis showed that the studied 32CA reactions proceed through two-stage one-step nonconcerted mechanism. The effects of the hydrogen bonds on the regioselectivity determination have been investigated by mean both noncovalent interactions (NCI) and quantum theory of atoms in molecule (QTAIM) analyses, which confirm the presence of high strength N - H···O hydrogen bond and a supplementary weak stabilized H…F hydrogen bonds.

Supplementary Data: Non-bonded force field parameters from MBIS partitioning of the molecular electron density improve CB7 host-guest affinity predictions

Supplementary Data: Non-bonded force field parameters from MBIS partitioning of the molecular electron density improve CB7 host-guest affinity predictions

On the Mechanism of the Synthesis of Nitrofunctionalised Δ2-Pyrazolines via [3+2] Cycloaddition Reactions between α-EWG-Activated Nitroethenes and Nitrylimine TAC Systems

We investigated the reactivity of different substituted nitrylimine-type three atom components (TACs) in [3+2] cycloaddition (32CAs) reactions with electrophilically activated nitroethenes within molecular electron density theory (MEDT). In parallel research, the molecular mechanism of the considered transformation was examined through analysis of all possible reaction channels and full optimization of all critical structures. In particular, the existence of zwitterionic intermediates on reaction paths was verified. On the basis of the bonding evolution theory (BET), the mechanism of the 32CA reaction between C,N-diphenylnitrylimine and (E)-2-phenyl-1-cyano-1-nitroethene should be treated as a one-step two-stage mechanism.

Unveiling the reactions of triethylphosphite and its diethylamino substituted derivatives to carbon tetrachloride with a molecular electron density theory perspective

A molecular electron density theory study is presented herein for the reactions of triethylphosphite (TEP) and its diethylamino substituted derivatives (DEAP and MEAP) to carbon tetrachloride (CCl4). Analysis of the Electron localization function (ELF) has allowed characterizing the electronic structure of the reagents and the conceptual density functional theory (CDFT) study predicted the polar character of the reactions with the electronic flux from TEP, DEAP and MEAP to CCl4. Analysis of the relative energies along the potential energy surfaces has indicated energetically favoured attack on the chlorine atom of CCl4 relative to that on the carbon atom and the reactions became energetically more facile due to introduction of the electron donating diethylamino substituent. This allowed formulating the heterolytic mechanism of the reactions in which the quick exchange of CCl3- with the chlorine atom takes place for TEP, while the exchange is slowed down in DEAP and MEAP due to mesomeric stabilization of the phosphonium ion. The ELF and Atoms in molecules (AIM) studies indicated early transition states (TSs) with no new covalent bond formation, and the non-covalent interactions at the interatomic bonding regions of the TSs are analysed from the Independent Gradient Model (IGM) analysis based on the Hirshfield partition of electron density.

Independent gradient model based on Hirshfeld partition: A new method for visual study of interactions in chemical systems.

The powerful independent gradient model (IGM) method has been increasingly popular in visual analysis of intramolecular and intermolecular interactions in recent years. However, we frequently observed that there is an evident shortcoming of IGM map in graphically studying weak interactions, that is its isosurfaces are usually too bulgy; in these cases, not only the graphical effect is poor, but also the color on some areas on the isosurfaces is inappropriate and may lead to erroneous analysis conclusions. In addition, the IGM method was originally proposed based on promolecular density, which is quite crude and does not take actual electronic structure into account. In this article, we propose an improvement version of IGM, namely IGM based on Hirshfeld partition of molecular density (IGMH), which replaces the free-state atomic densities involved in the IGM method with the atomic densities derived by Hirshfeld partition of actual molecular electron density. This change makes IGM have more rigorous physical background. A large number of application examples in this article, including molecular and periodic systems, weak and chemical bond interactions, fully demonstrate the important value of IGMH in intuitively understanding interactions in chemical systems. Comparisons also showed that the IGMH usually has markedly better graphical effect than IGM and overcomes known problems in IGM. Currently IGMH analysis has been supported in our wavefunction analysis code Multiwfn (http://sobereva.com/multiwfn). We hope that IGMH will become a new useful method among chemists for exploring interactions in wide variety of chemical systems.

A Comparative Study on Electronic Transport Behavior of Silicene and B40-Nano Onions

Density Functional Theory is utilized to scrutinize the electronic state of silicene and boron nano-onion which is a round compact mass formed by placing an N20, C20, and B20 fullerene within its parent atom fullerene B40. The NEGF is used to investigate the quantum transport at both equilibrium and non-equilibrium. Firstly the I-V curve for both silicene and boron-based devices is studied. From the results, it is concluded that boron-based devices are better than silicene. Therefore to get deeper insights into why boron-based devices are better transport properties of boron-based devices are suited. Later on, the transport mechanism is analyzed by computing the DOS, transmission and molecular spectra, HLG, I-V curve, electron densities, and differential conductance. When the Boron nano-onion is placed between the pair of Au electrodes. The calculated results are evaluated and a comparative study is done. From the results, it is deduced that the N20 variant nano-onion has reduced the HOMO-LUMO gap (HLG) and highest value of current in comparison to other devices. Thus by infusing a smaller fullerene of N20 inside the hollow cage of B40 fullerene the amplification of current and conductance can be observed in Boron-nano-onion in comparison to other devices.

Unveiling the synthesis of spirocyclic, tricyclic, and bicyclic triazolooxazines from intramolecular [3 + 2] azide-alkyne cycloadditions with a molecular electron density theory perspective

The intramolecular [3+2] cycloaddition (32CA) reactions of azido alkynes leading to spirocyclic, tricyclic, and bicyclic triazolooxazines has been studied within the molecular electron density theory (MEDT) at the MPWB1K/6-311G(d,p) level. The electron localization function (ELF) characterizes the azido alkynes as zwitterionic species. Analysis of the conceptual DFT indices allows classifying the azide moiety as the electrophilic counterpart and the alkyne as the nucleophilic one. These 32CA reactions are under kinetic control with the activation free energies of 23.4–26.7 kcal mol−1. Along the reaction path, the pseudoradical centre is created initially at C4, consistent with the Parr function analysis; however, the sequence of bond formation is controlled by the energetically feasible formation of the six-membered oxazine ring. The intermolecular interactions at the transition states were characterized from the quantum theory of atoms in molecules (QTAIM) study and the non-covalent interaction (NCI) gradient isosurfaces.

A non-decomposable approximation on the complete density function space for the non-additive kinetic potential.

A new non-decomposable approximation of the non-additive kinetic energy potential is constructed starting from the same exact property in the limit (ρA → 0 and ∫ρB = 2), as introduced in the work of Lastra et al. [J. Chem. Phys. 129, 074107 (2008)]. In order to cover the complete function space for exponentially decaying densities, the kernel of a differential operator Dγ[ρ] is introduced and analyzed in dependence of γ. The conclusive choice of γ = 1 assures that the solution functions span the complete space of molecular electron densities. As a result, the new approximant preserves the desired feature of the older approximation, which is the reciprocal singularity if the electron density decays exponentially, and eliminates artificial shallow wells (holes), which are responsible for an artificial "charge leak." Numerical considerations using the standard validation procedure introduced by Wesolowski and Weber [Chem. Phys. Lett. 248, 71-76 (1996)] demonstrate the numerical performance of the developed approximation, which increases the range of applicability of semilocal functionals.

A Molecular Electron Density Theory Study of the Lewis Acid Catalyzed [3+2] Cycloaddition Reactions of Nitrones with Nucleophilic Ethylenes

AbstractThe BF3Lewis acid (LA) catalyzed [3+2] cycloaddition (32CA) reaction of 1‐pyrroline‐1‐oxide (PNO) with 2,3‐dihydrofuran (DHF) has been studied within the molecular electron density theory (MEDT) at theωB97X‐D/6‐311G(d,p) computational level. Electron localization function (ELF) characterizes PNO and the corresponding PNO : BF3complex as zwitterionic species. Conceptual DFT indices allow classifying PNO and DHF as marginal electrophiles and strong nucleophiles, while the PNO : BF3complex is a strong electrophile. Consequently, while the non‐catalyzed 32CA reaction is non‐polar, the BF3catalyzed one has a high polar character, revealed by the analysis of the global electron density transfer (GEDT) at the transition state structures. The BF3catalyzed 32CA reaction, which is classified as of reverse electron density flux (REDF), presents highexostereoselectivity, and totalorthoregioselectivity. The presence of the BF3catalyst decreases the activation enthalpy of the 32CA reaction in dichloromethane by 7.5 kcal mol−1, as a consequence of the increase of the polar character of the reaction, in complete agreement with the experimentally observed acceleration.

Highly delocalised molecular orbitals in boron-, carbon- and nitrogen-based linear chains: a DFT study

In the present work a comparison of the electronic structures of the Linear carbon chains (LCC) with Boron linear chains (BnH2 and BnH4) and boron–nitrogen linear chains (Bn/2Nn/2H2 and Bn/2Nn/2H4) is made using B97X-D/6-311++G** level of theory. BnH2 and BnH4 show comparatively more delocalised molecular orbitals and lower electron densities than CnH2 and CnH4. CnH2 and CnH4 show much more efficient charge delocalisation than the other chains. For the first time it is reported that BnH4 chains also show helical molecular orbitals for n = 2,6,10. Modification of the helical orbitals of the cumulene chains was observed upon the introduction of boron atoms.

Unveiling the regioselective synthesis of antiviral 5-isoxazol-5-yl-2´-deoxyuridines from the perspective of a molecular electron density theory

The regioselective synthesis of a potent antiviral sugar nucleoside isoxazole analogue in the [3+2] cycloaddition (32CA) reaction of acetonitrile- -N-oxide (ANO) and acetyl-protected 5-ethynyl-2?-deoxyuridine (EDU) has been studied at the MPWB1K/6-311G(d,p) level within perspective of the molecular electron density theory (MEDT). From an electron localization function (ELF) analysis, ANO is classified as a zwitterionic species devoid of any pseudoradical or carbenoid centre. The ortho regioisomer is energetically preferred over the meta one by the activation enthalpy of 21.7?24.3 kJ mol-1, suggesting complete regioselectivity in agreement with the experiment. The activation enthalpy increases from 53.9 kJ mol-1 in the gas phase to 71.5 kJ mol-1 in water, suggesting more facile reaction in low polar solvents. The minimal global electron density transfer (GEDT) at the TSs suggests non-polar character and the formation of new covalent bonds has not been started at the located TSs, showing non-covalent intermolecular interactions from an atoms-in- -molecules (AIM) study and in the independent gradient model (IGM) isosurfaces. The AIM analysis shows more accumulation of electron density at the C?C interacting region relative to the C?O one, and earlier C?C bond formation is predicted from a bonding evolution theory (BET) study.

Understanding the higher–order cycloaddition reactions of heptafulvene, tropone, and its nitrogen derivatives, with electrophilic and nucleophilic ethylenes inside the molecular electron density theory

The reactivity and selectivity in higher–order cycloadditions of cycloheptatrienes A–D with ethylenes E–G are studied within the MEDT.

A molecular electron density theory study of the higher-order cycloaddition reactions of tropone with electron-rich ethylenes. The role of the Lewis acid catalyst in the mechanism andpseudocyclicselectivity

Weak attractive/repulsive electronic interactions control the [4+2]/[8+2]pseudocyclicselectivity in Lewis acid catalyzed cycloaddition reactions of tropone with nucleophilic ethylenes.

Unveiling the non-polar [3+2] cycloaddition reactions of cyclic nitrones with strained alkylidene cyclopropanes within a molecular electron density theory study.

The role of cyclopropane substitution on the ethylene in zw-type [3+2] cycloaddition (32CA) reactions of cyclic nitrones has been studied within Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) computational level. Electron Localization Function (ELF) analysis of the ethylenes shows that the presence the cyclopropane only slightly increases the electron density in the C–C bonding region. Analysis of the Conceptual DFT reactivity indices indicates that the presence of the cyclopropane does not produce any remarkable change in the reactivity of these strained ethylenes. The marginal electrophilic character of ethylene makes the zw-type 32CA reactions of non-polar character. The presence of the cyclopropane in the ethylene decreases the activation enthalpy of the 32CA reactions by only 1.7 and 2.6 kcal mol−1, and also decreases the ortho regioselectivity. The loss of the strain present in the cyclopropane is responsible for the reduction of the activation enthalpy and the increase of the reaction enthalpy in these non-polar 32CA reactions. The presence of the cyclopropane does not cause any change, neither in the transition state structure (TS) geometries nor in their electronic structure. The very low global electron density transfer (GEDT) computed at the TSs confirms the non-polar character of these 32CA reactions. The ortho regioselectivity experimentally observed in these non-polar 32CA reactions is determined by the most favorable two-center interaction between the less electronegative C1 carbon of nitrone and the non-substituted methylene C5 carbon of the ethylenes.

Unveiling the [3+2] cycloaddition between difluoromethyl diazomethane and 3-ylideneoxindole from the perspective of molecular electron density theory

Evolution of some key ELF basins along the IRC of the most favorable ortho/endo reaction path.

The Participation of 3,3,3-Trichloro-1-nitroprop-1-ene in the [3 + 2] Cycloaddition Reaction with Selected Nitrile N-Oxides in the Light of the Experimental and MEDT Quantum Chemical Study.

The regioselective zw-type [3 + 2] cycloaddition (32CA) reactions of a series of aryl-substituted nitrile N-oxides (NOs) with trichloronitropropene (TNP) have been both experimentally and theoretically studied within the Molecular Electron Density Theory (MEDT). Zwitterionic NOs behave as moderate nucleophiles while TNP acts as a very strong electrophile in these polar 32CA reactions of forward electron density flux, which present moderate activation Gibbs free energies of 22.8–25.6 kcal·mol−1 and an exergonic character of 28.4 kcal·mol−1 that makes them irreversible and kinetically controlled. The most favorable reaction is that involving the most nucleophilic MeO-substituted NO. Despite Parr functions correctly predicting the experimental regioselectivity with the most favorable O-CCCl3 interaction, these reactions follow a two-stage one-step mechanism in which formation of the O-C(CCl3) bond takes place once the C-C(NO2) bond is already formed. The present MEDT concludes that the reactivity differences in the series of NOs come from their different nucleophilic activation and polar character of the reactions, rather than any mechanistic feature.

Molecular orbital study of Fe(II) and Fe(III) complexation with salicylate and citrate ligands: Implications for soil biogeochemistry

AbstractThe formation of mineral‐associated organic matter (OM), typically with Fe oxy(hydr)oxide minerals, contributes to the long‐term storage of soil C. However, the changing climate is predicted to alter precipitation frequency and intensity patterns such that soils may experience greater periods of anoxic conditions leading to the reductive dissolution of the Fe oxy(hydr)oxide minerals. This would subject the released OM to microbial decomposition and the Fe cation to react with soil solution constituents. Using salicylate and citrate as model soil ligands, this study uses density functional theory to provide physical insights into the chemical bonds formed between Fe(II) and Fe(III) cations with the organic acids. The ΔG° for the complexation reactions of both salicylate and citrate were negative indicating that the complex formation is energetically favorable. Furthermore, the ΔG0 was more negative for the salicylate ligand as compared with the citrate ligand suggesting that the involvement of carboxyl‐O and phenoxyl‐O to form a complex is more thermodynamically favorable. We show from the molecular electron density data that the bonds involved in the complexation are more electrostatic than covalent in nature. Molecular orbital calculations show that the energies of the highest occupied orbitals of Fe(II)–salicylate and Fe(II)–citrate complexes are less negative than that of the uncomplexed Fe(II)–(H2O)6, suggesting that the complexed Fe(II)–organic species will be preferentially oxidized upon return of the soil to aerobic conditions. Our results provide a more fundamental chemical understanding of the reactions involved in the biogeochemical cycling of soil Fe and C. This knowledge may assist in evaluating the potential role of enhanced soil C sequestration as one approach to mitigate climate change.

Divulging the regioselectivity of epoxides in the ring-opening reaction, and potential himachalene derivatives predicted to target the antibacterial activities and SARS-CoV-2 spike protein with docking study

• α-Himachalene could be a potential drug for SARS-CoV-2. • Bromine atoms located at the epoxy group in compound 8 increased the drug binding affinity. • The attack of the epoxide 1 and 2 by hydride ion H − presented a high regioselectivity. The ring-opening reaction of epoxides 1b and 1c utilizing LiAlH 4 , have been studied within the Molecular Electron Density Theory (MEDT) at the B3LYP/6–31(d) computational level. The regioisomeric reaction paths including the two oxiranes cycles of epoxides 1b and 1c have been explored. DFT calculations show that the attack of the hydride ion H − is favorable on the carbon C 3 for the epoxide 1b, while this action is realized on carbon C 2 for the epoxide 1c in the highest conformity with the experimental outcomes. Furthermore, we have operated a docking calculation to examine the antibacterial activities of the products 1a-1f, further more we have performed a docking calculation to scrutinize the products 1–9 against SARS-CoV-2. Indeed, the docking results showed that α-himachalene ( 2 ) possess a higher affinity to the main protease.