Atomic Spin Densities Research Articles

Exploring the specific chemistries of the cycloaddition reactions of 5‐benzoyl‐3(2H)‐isothiazolone and stable nitrile oxides: Insights from Density Functional Theory analysis

AbstractIsothiazolones are important heterocyclics with pharmacological potency such as anti‐inflammatory, anticancer, antimicrobial, and robust biocidal (used in agrochemicals). This study seeks to provide mechanistic insight into the chemo‐ and regio‐selectivities of the [3 + 2] cycloaddition reaction of 5‐benzoyl‐3(2H)‐isothiazolone (A1) with two stable nitrile oxides, that is, mesitonitrile oxide (A2) and dichlorobenzonitrile oxide (A3) using M06‐2X hybrid density functional calculations coupled with the 6‐311G (d, p) basis sets. Mesitonitrile oxide A2 chemo‐selectively adds across the carbonyl of the benzyl group of A1 while dichloro benzonitrile oxide A3 preferentially adds across the ethylene center of A1. Derivatization of A1 with electron‐donating groups lowers the activation barriers by a very minute margin ranging from 0.1 to 0.5 kcal/mol whereas electron‐withdrawing groups significantly decrease the energetics of the reaction by a margin of 1.1 to 2.5 kcal/mol. Solvation with chloroform does not affect the selectivity of the reaction but tends to increase both activation and reaction energies of the various routes. Analysis of the Parr function on different reactive sites of A1 shows the addition of A2 via the atomic center with the largest Mullikan atomic spin densities. Substitution of the S‐heteroatom with C, O, or N does not affect the regioselectivity of the reaction but lowers the activation energies in the reaction of A1 with A3. The global electron density transfer (GEDT) values predict a polar reaction between A1 and A2 whereas the reaction of A1 and A3 is non‐polar.

Flavonoid Oxidation Potentials and Antioxidant Activities-Theoretical Models Based on Oxidation Mechanisms and Related Changes in Electronic Structure.

Herein, I will review our efforts to develop a comprehensive and robust model for the estimation of the first oxidation potential, Ep1, and antioxidant activity, AA, of flavonoids that would, besides enabling fast and cheap prediction of Ep1 and AA for a flavonoid of interest, help us explain the relationship between Ep1, AA and electronic structure. The model development went forward with enlarging the set of flavonoids and, that way, we had to learn how to deal with the structural peculiarities of some of the 35 flavonoids from the final calibration set, for which the Ep1 measurements were all made in our laboratory. The developed models were simple quadratic models based either on atomic spin densities or differences in the atomic charges of the species involved in any of the three main oxidation mechanisms. The best model takes into account all three mechanisms of oxidation, single electron transfer-proton transfer (SET-PT), sequential proton loss electron transfer (SPLET) and hydrogen atom transfer (HAT), yielding excellent statistics (R2 = 0.970, S.E. = 0.043).

STRUCTURES, ELECTRONIC, AND MAGNETIC PROPERTIES OF TRANSITION METAL-INSERTED H2DBP CLUSTERS

The configurations, electronic, and magnetic properties of the H2DBP-M clusters have been investigated via density functional theory. The results reveal that the TM atoms for the H2DBP-M ([Formula: see text], Y, Zr, Nb, Lu, and Hf) clusters deviate from the center planes of the clusters. The H2DBP-M ([Formula: see text], Y, and Lu) clusters display the largest dipole magnitudes. Based on the binding energy per atom and HOMO-LUMO gap, the H2DBP-Ni and H2DBP-Lu clusters are the most favorable for synthesis. The charge transfer amounts of the TM ([Formula: see text], Zn, Y, Cd, Hf, and Hg) atoms for the H2DBP-M clusters are larger. The TM-d orbitals of the H2DBP-M ([Formula: see text]Co and Cu) clusters contribute significantly to the Fermi levels. The spin densities of the TM atoms for the H2DBP-M clusters reduce to 0 except for that ([Formula: see text]) of the H2DBP-V clusters.

Quantum chemical analysis of the molecular mechanism and selectivity of the 32CA reaction of nitrile oxides with 5-(ethylthio) furan-2(5H)-ones and N-substituted-2-azanorborn-5-ene

Isoxazolines are well-known five-membered heterocyclic scaffolds that exhibit a variety of biological activities. These compounds can be synthesized via a 32CA reaction, but the stereo and the regiochemical factors affecting the formation of a targeted isoxazoline are not well understood despite the importance of this scaffolds. The mechanism and the selectivities of the 32CA reaction of acetonitrile oxides (1) with 5-(ethylthio) furan-2(5H)-ones (2) and benzonitrile oxides (5) with N-substituted-2-azanorborn-5-enes (4) for the formation of isoxazolines have been investigated at the M06-2X, in conjunction with the 6–311++G(d,p) basis set. The reaction between 1 and 2 proceeds with a clear-cut regio and diastereoselectivity. Substituting 4 with varying electronic and steric effects have minimal influence on the regio and stereoselectivity between 4 and 5. The exo cycloadducts are favored over the endo cycloadduct. Analysis of the electrophilic Pk+ and nucleophilic Pk− Parr functions at the different reaction sites in the 5-(ethylthio) furan-2(5H)-one indicates that the acetonitrile oxide adds across the atomic centers with the highest Mulliken atomic spin densities. Results from the global electron density transfer (GEDT) reveal the polar nature of the reactions.

Density functional theory calculation on structures, electronic and magnetic properties of the FemOnC70 and FemOn@C70 (m=1–3, n=1–4) clusters

The tendency of iron oxide molecules to adsorb or embed carbon cages is a more noteworthy issue in terms of cluster size. The structures, electronic and magnetic properties of the FemOnC70 and FemOn@C70 (m = 1–3, n = 1–4) clusters have been investigated by using first-principles. Iron oxide molecules prefer to be adsorbed rather than coated by C70 cages. The chemical stability of FeOC70 and Fe2O3C70 clusters is higher than that of the corresponding FeO@C70 and Fe2O3@C70 clusters, while the chemical stability of Fe3O4C70 clusters is lower than that of Fe3O4@C70 clusters. A small amount of electrons (0.026 |e|∼0.205 |e|) are transferred from iron oxide molecules to C70 cages except for Fe3O4@C70 clusters. Spin densities of Fe atoms of the FemOnC70 and FemOn@C70 clusters decreases to zero except for the Fe3O4@C70 clusters.

Quantum Mechanical Elucidation on [3+2] cycloaddition reaction of aryl nitrile oxide with cyclopentenones

The [3 + 2] cycloaddition (32CA) reaction of benzonitrile oxide (BNO) with 4-substituted 4-hydroxy-2-cyclopentenone has been investigated using molecular electron density theory (MEDT) at the Density Functional Theory (DFT) B3LYP/6-31G (d), M06/6-311G (d,p) and M06-2X/6–311++G (d,p) levels. The present theoretical computations indicate that the reaction of BNO with 4-substituted 4-hydroxy-2-cyclopentenones is via [3 + 2] cycloaddition, where the three atom component (TAC) chemo-selectively adds across the alkene functionality in the 2-cyclopentenones (Path A). Analysis of the electrophilic PA+ and nucleophilic PA− Parr functions at the different reaction sites in the alkene counterpart indicates that the aryl nitrile oxides add across the atomic centers with the highest Mulliken atomic spin densities. The results reported in this study are in good agreement with previous experimental work. The GEDT calculations unravel the low polar character of the [3 + 2] cycloaddition reactions. This reaction occurs with poor enantioselectivity, but a high degree of stereo-, peri-, diastereo, and regioselectivity is seen for the reaction of the BNO with 4-hydroxy-4-methyl-2-cyclopentenones. The regioselectivity of the reactions is the same in all the solvents investigated.

A quantum mechanistic insight into the chemo- and regio-selective [3 + 2]-cycloaddition reaction of aryl hetaryl thioketones with diazoalkanes and nitrile oxide derivatives

In this quantum mechanistic study, density functional theory computations at the B3LYP hybrid level of theory, in addition to triple zeta basis set 6-311G (d, p), were utilized to investigate the chemoselectivities and regioselectivities of the [3 + 2] cycloaddition reaction of phenyl (2-thienyl) thioketone (B1) derivatives with nitrile oxide (B2) and diazopropane derivatives (B3). From the computations obtained, the reactions of nitrile oxide and diazopropane derivatives with phenyl (2-thienyl) thioketone proceed through an asynchronous one-step mechanism. The initial [3 + 2] cycloaddition reaction of B1 and B3 is followed by a nitrogen extrusion which is also highly asynchronous. Despite the steric and electronic effects of the substituent on the energetics, the reaction center is selectively observed at the thiocarbonyl site of B1. A study of the Parr functions at the different reaction sites in B1 indicates the addition of B2 and B3 via the atomic centers with the largest Mulliken atomic spin densities. These results show that the thiocarbonyl site is the most reactive center compared to the other ethylene groups on B1, irrespective of the three atom components used. The global electron density transfer results are in agreement with the selectivity and activation barriers observed in the reaction. Our results agree well with experimental observations.

Extending machine learning beyond interatomic potentials for predicting molecular properties.

Machine learning (ML) is becoming a method of choice for modelling complex chemical processes and materials. ML provides a surrogate model trained on a reference dataset that can be used to establish a relationship between a molecular structure and its chemical properties. This Review highlights developments in the use of ML to evaluate chemical properties such as partial atomic charges, dipole moments, spin and electron densities, and chemical bonding, as well as to obtain a reduced quantum-mechanical description. We overview several modern neural network architectures, their predictive capabilities, generality and transferability, and illustrate their applicability to various chemical properties. We emphasize that learned molecular representations resemble quantum-mechanical analogues, demonstrating the ability of the models to capture the underlying physics. We also discuss how ML models can describe non-local quantum effects. Finally, we conclude by compiling a list of available ML toolboxes, summarizing the unresolved challenges and presenting an outlook for future development. The observed trends demonstrate that this field is evolving towards physics-based models augmented by ML, which is accompanied by the development of new methods and the rapid growth of user-friendly ML frameworks for chemistry.

Experimental and theoretical study on Fe(VI) oxidative degradation of dichlorophen in water: Kinetics and reaction mechanisms.

Dichlorophenol (DCP), a commonly used fungicide and insecticide, is widely found in waters and wastewaters. Herein, the degradation of DCP by Ferrate (Fe(VI)) in different matrices was comprehensively investigated. In pure water, a complete removal of DCP was achieved in 300 s at [Fe(VI)]:[DCP] molar ratio of 2:1. The presence of HA (10 mg L−1) inhibited DCP degradation to a certain extent. A total of twenty degradation products were identified by HPLC/MS analysis. Based on these products, reaction pathways including the cleavage of C–C bridge bond, hydroxylation, and radical coupling were proposed. These reaction mechanisms were further rationalized by theoretical calculations. The analyses of Wiberg bond orders and transition state indicated that C7–C8 bond was the most vulnerable site for cleavage, and C12 site was the most likely site for hydroxyl addition. Mulliken atomic spin densities distribution suggested that self-coupling products was easily generated via C–O–C coupling ways. Finally, the feasibility of applying Fe(VI) to degrade DCP (20 μM) in a municipal wastewater effluent and a lake water was evaluated and verified. The findings in this study are of relevance in designing Fe(VI)-based treatment strategy for chlorine-containing persistent pesticides.

Reaction mechanisms of the initial steps for the oxidation of (000[formula omitted]) C and (0001) Si faces of SiC with OH radicals

The reaction mechanisms of OH radicals on the C and Si faces of SiC were analyzed using density functional theory calculations to understand the difference in reactivity. For the first OH radical, it was shown that the O–H bond dissociation occurs on both faces, but at different spin states, i.e., the reaction proceeds at a lower spin multiplicity on the Si face. Then, the generated surface O atom causes dissociation of a C–Si bond to form a C–O–Si structure on the C face, whereas it binds to two surface Si atoms to form a Si–O–Si structure on the Si face. These differences are explained by the atomic charge and spin density of the surface atoms. The second OH radical generates a CO molecule on the C face, and a second Si–O–Si structure is formed on the Si face. These results shed light on the reasons why the grinding technique using a tribocatalytic abrasive, which is considered to be promoted by oxidation of the surface by oxidants such as the OH radical, is inefficient on the Si face of SiC.

Theoretical studies on cycloaddition reactions of N-allyl substituted polycyclic Isoindole-1,3-dione with nitrones and nitrile oxides

Bridged polycyclic molecular skeletons and related systems are key structural motifs in medicinal chemistry. The most efficient and widely accepted method for the syntheses of the bridged molecular polycyclic scaffolds is the 1,3-dipolar cycloaddition reactions. Herein, a systematic study on (3 + 2) cycloaddition reaction (32CA) of norbornene imide A with three-atom components (TACs), nitrile oxides and nitrones are presented at the M06-2X/6–311++G(d,p)-PCM(toluene), M06-2X-D3/6–311++G(d,p)-PCM(toluene) and MPWB1K/6–311++G(d,p)-PCM(toluene) levels of theory. The different reactivities of the strained endocyclic CC bond in the carbocyclic fragment and the less hindered N-allyl imide double bond in the alkene are evaluated. In the reaction of A and the nitrile oxides, four reaction pathways are characterized whereas eight distinctive reactive channels are located for nitrones. Trends in the calculated activation energies show that the 32CA reaction between A and nitrile oxides competitively occur at the endocyclic CC bond in the carbocyclic fragment and the N-allyl imide double bond. The cycloaddition of the nitrones favorably add across the less hindered N-allyl imide double bond. The trends in reactivity are in perfect agreement with local reactivity descriptors. Evaluation of TS geometries and bond distances validate that these 32CA reactions follow a one-step asynchronous molecular mechanism as proposed by Domingo. The activation energies suggest favored exo approach along all the reaction pathways, for that leads to better stabilization. Frontier molecular orbital analysis and global reactivity descriptors demonstrate that all the 32CA reactions proceed via an inverse electron demand character. Results from the local electrophilic (PK+) and nucleophilic (PK-) Parr functions show that the 32CA takes place at the atomic centers with the largest radical atomic spin densities in complete agreement with experimental outcomes.

Structures, electronic and magnetic properties of half-capped C80 adsorbed and encapsulated iron oxides

ABSTRACT The structures, electronic and magnetic properties of half-capped C80 adsorbed and encapsulated iron oxides have been investigated by using PBE functional. The results reveal that the Fe m O n C80 clusters are more structurally stable than the corresponding Fe m O n @C80 clusters. Fe2O3C80 is more kinetically stable than the other Fe m O n @C80 while Fe2O3@C80 is more kinetical activity than the other Fe m O n @C80. A few electrons (0.063 |e|∼0.563 |e|) are transferred between the Fe m O n molecules and half-capped C80. The spin densities of Fe atoms of the Fe2O3C80, Fe2O3@C80 and Fe3O4C80 clusters prefer to offset and the O atoms of the Fe2O3C80, Fe2O3@C80 and Fe3O4C80 clusters maintain a few spin densities.

Coordination of reduced Schiff base anion to Pd(II): Synthesis, characterization, DFT calculation and catecholase activity

The article reports the synthesis and characterization of a new palladium(II) complex of type [(LNNN1−)PdCl] (1) where LNNN1− is a mono anionic Schiff's base having a imine bond in reduced state. The LNNN1− is generated from a tridentate NNN donor ligand (LNNN) through in-situ reduction using sodium borohydride, where LNNN is [(E)-N-(phenyl(pyridine-2-yl)methylene)quinoline-8-amine)]. 1 is characterized by the single crystal X-ray diffraction study, IR, mass and UV–Vis spectroscopy. The X-ray bond parameter authenticates the imine bond of the coordinated Schiff's base anion is in reduced state. 1 exhibits catalytic activity towards the oxidation of 3,5-ditertiarybutyl catechol(3,5-DTBC) with turnover number (Kcat) ​= ​135.6 h-1. The catalytic oxidation of 3,5-DTBC is authenticated by the UV–Vis, mass and EPR spectroscopy. An isotropic EPR signal with g ​= ​2.011 of a solution containing 1 and 3,5-DTBC authenticating the generation of organic radical during the oxidation process. Cyclic voltammogram of 1 displays an irreversible anodic wave at +0.22 ​V may be due to the oxidation of N− to N•−. The atomic spin density of 1+ obtained from DFT calculation is also supporting the N-centre oxidation process.

Exploring the chemo-, regio-, and stereoselectivities of the (3 + 2) cycloaddition reaction of 5,5-dimethyl-3-methylene-2-pyrrolidinone with C,N-diarylnitrones and nitrile oxide derivatives: a DFT study

The (3 + 2) cycloaddition (32CA) reaction is an efficient method for the synthesis of many biologically active heterocyclic compounds, but there are several regio- and stereochemical issues that must be fully understood to exploit the full utility of its synthetic power. We herein explored the chemo-, regio-, and stereoselectivities of the 32CA reaction of 5,5-dimethyl-3-methylene-2-pyrrolidinone (B1) to C,N-diarylnitrones (B2), and nitrile oxide derivatives (B3) with DFT at the M06/6-311G(d,p) level of theory. The reactions occur via an asynchronous one-step mechanism, with the chemoselective addition of the C,N-diarylnitrones, and nitrile oxide derivatives across the olefinic bond of 5,5-dimethyl-3-methylene-2-pyrrolidinone being the most preferred kinetically and thermodynamically. The regio- and stereoselectivities of the reactions are affected by the electronic and steric nature of substituents on B2 but they are not affected by the electronic and steric nature of substituents on B3. The C,N-nitrones and the nitrile oxide derivatives add across the atomic centers with the largest atomic spin densities on 5,5-dimethyl-3-methylene-2-pyrrolidinone as seen through the local electrophilic ([Formula: see text]) and nucleophilic ([Formula: see text]) Parr functions of the various reaction centers. Results from the global electron density transfer (GEDT) reveal the low polar nature of the reactions.

(3 + 2) cycloaddition reaction of 7-isopropylidenebenzonorbornadiene and diazomethane derivatives: A theoretical study

The ability to synthesize targeted molecules hinges on detailed mechanistic insight of the reaction. The 1,3-dipolar cycloaddition reaction between diazomethane derivatives and 7-isopropylidenebenzonorbornadiene have been extensively studied using density functional theory (DFT) at the M06–2X/6-311G(d,p) level of theory in order to delineate the peri-, regio-, and stereo-selectivities of the reaction. The diazomethane is shown to periselectively add across the endocyclic olefinic bond of the 7-isopropylidenebenzonorbornadiene and stereoselectively in the exo fashion, yielding the exo-cycloadduct as the major product, with a rate constant of 3.83 × 104 s−1. The endo approach of this periselective path is the closest competing pathway with a rate constant of 8.78 × 101 s−1. Neither electron-donating groups (R = methyl, ethyl, amine, cyclopropyl) nor electron-withdrawing groups (R = cyano, nitro, carbonyl) on the diazomethane alters the peri- and stereo-selectivity of the reaction. However, the substituents do have an effect on whether the addition follow normal or inverse electron demand mechanisms. EDGs favor a normal electron demand mechanism while EWGs favor an inverse electron demand 1,3-dipolar cycloaddition reaction. While EDGs-substituted diazomethane derivatives behave as nucleophiles in reactions with 7-isopropylidenebenzonorbornadiene, EWGs-substituted diazomethane derivatives behave as electrophiles. The 1,3-dipole adds across the dipolarophile via a concerted asynchronous mechanism, but a stepwise diradical mechanism has been ruled out. The selectivities observed in the title reaction are kinetically controlled. Analysis of the nucleophilic Parr function (PK−) at the different reaction sites in the dipolarophile indicates that the diazomethane adds across the atomic centers with highest NBO and Mulliken atomic spin densities.

Dual roles of [NCN]2- on anatase TiO2: A fully occupied molecular gap state for direct charge injection into the conduction band and an interfacial mediator for the covalent formation of heterostructured g-C3N4/a-TiO2 nanocomposite

When low density of melamine is calcined with a-TiO2 at 550 °C, two FT-IR peaks observed at 2048 and 2066 cm−1 are assigned to NCN2- covalently attached to a five-coordinated Ti atom and an oxygen vacancy, respectively, complemented by DFT computation. Admixture of NCN2- HOMO(π2p, 87.5 %) with the high energy Ti(3d, 12.5 %) destabilizes and upshifts the NCN2- HOMO into the a-TiO2 bandgap. A five-line EPR pattern derived from 71 % of atomic spin density localized on two equivalent 14N nuclei, observed under sub-bandgap excitation, verifies the presence of a molecular gap-state. The NCN2--a-TiO2 exhibits excellent H2 production at a rate of 5101 μmol.h-1.g-1. Upon increasing melamine concentration, the rapid and simultaneous decreases of NCN2- FT-IR and NCN1- EPR signals accompanied by transitions of other spectroscopic data to those characteristic of tri-s-triazine demonstrate that the formation of heterostructured g-C3N4/a-TiO2 proceeds via the intermediacy of NCN2--a-TiO2, thereby a mechanism is proposed.

Peri-, Chemo-, Regio-, Stereo- and Enantio-Selectivities of 1,3-dipolar cycloaddition reaction of C,N-Disubstituted nitrones with disubstituted 4-methylene-1,3-oxazol-5(4H)- one: A quantum mechanical study

The peri-, chemo-, regio-, stereo- and enantio-selectivities of 1,3-dipolar cycloaddition reaction of C,N-disubstituted nitrones with disubstituted 4-methylene-1,3-oxazol-5(4H)-one have been studied using density functional theory (DFT) at the M06–2X/6-311G (d,p) level of theory. The 1,3-dipole preferentially adds chemo-selectively across the olefinic bond in a (3 + 2) fashion forming the corresponding spirocycloadduct. The titled reaction occurs with poor enantio- and stereo-selectivities, but a high degree of regio-selectivity is observed for the addition of the 1,3-dipole across the dipolarophile. Electron-withdrawing groups on the dipolarophile significantly reduce the activation barriers while electron-donating groups on the dipolarophile increase the activation barriers. Analysis of the HOMO and LUMO energies of the two reacting species indicates that the 1,3-dipole reacts as a nucleophile while the dipolarophile reacts as the electrophile. Investigation of the electrophilic Parr function (PK+) at the various reaction centers in the dipolarophile indicates that the 1,3-dipole selectively adds across the atomic species with the largest electrophilic Mulliken and NBO atomic spin densities which is in accordance with the energetic trends observed.

Hybrid density functional calculations of hyperfine coupling tensor for hole-type defects in MgAl2O4

We have performed the density functional calculations (DFT) on the hole-type defects (V-centres) in magnesium aluminate spinel (MgAl2O4) following the results of recent paramagnetic resonance measurements (EPR) in Nucl. Inst. Methods Phys. Res. B 435 (2018) 31–37. The hybrid B3LYP functional calculations using large supercells of 448 atoms have demonstrated excellent results not only for bulk properties but also properties of the V-centres in MgAl2O4. Three types of V-centres have been considered and confirmed, namely V1, V2 and V22. The DFT calculations have revealed the atomic relaxation pattern and spin density distribution around the hole-type defects that is suggested as an important complement to the experiments. Moreover, the calculated hyperfine coupling constants (HCCs) have been analyzed and compared with those from the measured EPR spectra. A good agreement between the calculated and measured HCC values is observed and discussed.

Diradical-singlet character of 1,3-dipoles affects reactivity of 1,3-dipolar cycloaddition reactions and intramolecular cyclization.

1,3-Dipolar cycloaddition (1,3-DC) reactions are powerful synthetic tool to obtain highly functionalized 5-membered heterocycles, starting from a 1,3-dipole and a dipolarophile in a single step. The reactivity of these systems is usually rationalized in terms of Frontier Molecular Orbital Theory (FMOT), which neglects a possible contribution of an open-shell weakly coupled singlet-diradical specie. In this work, the broken-symmetry approach is used to estimate the singlet-diradical character of 18 dipoles of the second period of the periodic table, classified as allyl-type N-centered, allyl-type O-centered, and propargyl-type 1,3-dipoles, providing a rationalization for 1,3-DC reactivity. The intramolecular cyclization of bent allyl-type N- and O-centered dipoles into 3-membered rings was also analyzed, and revealed that the energetic change is associated with the spin densities of peripheral atoms. Finally, a close relationship between the energy for the ring-opening process of the cyclic configuration and the reactivity of 1,3-dipoles toward 1,3-dipolar cycloaddition reaction was also found. Graphical abstract.

1, 3-Dipolar cycloaddition reactions of selected 1,3-dipoles with 7-isopropylidenenorbornadiene and follow-up thermolytic cleavage: A computational study

The mechanism, regio-, stereo-, and enantio-selectivities of the 1,3-dipolar cycloaddition reactions of 7-isopropylidenenorbornadiene (DENBD) with nitrones and azides to form pharmaceutically relevant isoxazolidine and triazole analogues have been studied computationally at the M06/6-31G(d), 6-31G(d,p), 6-311G(d,p), 6–311++G(d,p) and M06-2X/6-31G(d) levels of theory. In the reactions of DENBD with phenyl nitrones, the cycloaddition steps have low activation barriers, with the highest being 16 kcal/mol; and the Diels-Alder cycloreversion steps have generally high barriers, with the lowest being 20 kcal/mol, suggesting that the isolable products in these reactions are the bicyclic isoxazolidine cycloadducts and not the thermolytic products. This is in contrast to the reactions of DENBD with phenyl azide where the isolable products are predicted to be the thermolytic products since the Diels-Alder cycloreversion steps had relatively lower activation barriers. Electron-donating substituents on the dipolarophile substrate favour attack of the nitrone on the least hindered side of the DENBD substrate while electron-withdrawing substituents on the dipolarophile substrate favour attack on the more hindered side of the DENBD, indicating that site-selectivity is affected by nature of substituents. Global reactivity indices calculations are in good agreement with the activation barriers obtained. Analysis of the electrophilic (PK+) and nucleophilic (PK−) Parr functions at the reactive centres reveal that the cycloaddition occurs between atoms with the largest Mulliken and NBO atomic spin densities which agrees well with the energetic trends and the experimental product outcomes.