Theoretical insight into the unexpected initial (3 + 2) cycloaddition reaction of mesitonitrile oxide with 1, 4-diazepine derivatives: A computational study.

1,4-Diazepine as an active drug component underlies the potency of most psychotic, anticancer, anticonvulsant, and antibacterial drugs in the market and is, therefore crucial in chemotherapeutic treatment in biomedicine. Proper functionalization of this moiety can afford even more potent drugs. As a result of their therapeutic significance, this study aims at precisely giving a comprehensive computational insight into the unexpected initial reactivity of 1,4-diazepine derivatives and mesitonitrile oxide. The initial reaction between mesitonitrile oxide and 1,4-diazepine derivatives proceeds via a (3 + 2) cycloaddition reaction which leads to the formation of a cycloadduct where the mesitonitrile oxide unexpectedly adds across the imine functionality at the expense of the potential olefinic carbon-carbon double bond. Calculations at the density functional theory (DFT) M06/6-311G (d, p) level of theory indicate that the initial (3 + 2) cycloaddition reaction of mesitonitrile oxide (1,3-dipole) and 1,4-diazepine derivatives (dipolarophile) in all cases proceeds to form the cycloadduct where the 1,3-dipole adds preferentially to the imine functionality at the expense of the potential olefinic carbon-carbon double bond. In light of the parent reaction, the most kinetically favored cycloadductP3A had a rate constant of 5.1 × 106 M-1s-1, which is about 12 manifolds faster than the next competing stereoisomer P1A with a rate constant of 4.1 × 105 M-1s-1 and about 1024 faster than the most favored cycloadduct P3B with a rate constant of 7.2 × 10-19 M-1s-1 in the unfavored pathway (Path B). Irrespective of the electronic and steric nature of the electron-donating (EDG) and electron-withdrawing (EWG) substituents placed on the dipolarophile, the selectivities of the reaction were maintained. Rationalization of the potential energy surface depicts that the 1,3-dipole adds across the dipolarophile via an asynchronous concerted mechanism. Rationalization of the HOMO-LUMO energies of the mesitonitrile oxide (1,3-dipole) and the 1,4-diazepine derivatives (dipolarophile) depict that the EDG-substituted dipolarophile react as nucleophiles, whereas the dipole reacts as an electrophile. Conversely, the HOMO-LUMO interaction between the EWG-substituted dipolarophile indicates that the EWG-substituted dipolarophile react as electrophiles, whereas the dipole reacts as a nucleophile. The electrophilic parr function at various reactive sites of the dipolarophile shows that the 1,3-dipole preferentially adds across the local centers with the largest electrophilic NBO or Mulliken spin densities which is consistent with the energetic trend observed. The reactivity of the 1,4-diazepine derivatives and the mesitonitrile oxide showed poor stereoselectivity.

Exploring the peri- and stereo- selectivities of the cycloaddition reaction of 2-(2- dimethylaminovinyl)-1-benzopyran-4-one with N-phenylmaleimide (NPM) and dimethylacetylenedicarboxylate (DMAD) - A DFT study.

The [4 + 2] cycloaddition reactions of 2-styrylchromones have been predominantly described as one of the efficient methods for the synthesis of xanthones-a prominent class of tricyclic molecules that occur widely in nature. These xanthones are well known for their pharmacological activities especially their role as anti-cancer agents in the medicinal world. In this study, the mechanistic insight into the unusual (peri- and stereo-) selectivities of the reaction of 2-(2-dimethylaminovinyl)-1-benzopyran-4-one (A1) with N-phenylmaleimide (NPM) and dimethylacetylenedicarboxylate (DMAD) has been studied using density functional theory (DFT) at the M06-2X/6-311G (d, p) level of theory. The reaction of A1 and NPM in dimethylformamide (DMF) is periselective towards the initial formation of a [4 + 2] cycloadduct and stereoselectively in an exo fashion with an activation energy of 6.8kcalmol-1 and a rate constant of 6.43×107s-1 which occurs about 878 million times faster than the closest competing pathway for the initial [2 + 2] cycloaddition fashion with an activation energy of 19.0kcalmol-1 and a rate constant of 7.32×10-2s-1. For the substituent effect on the reaction, the reaction selectivity is still maintained where the exo intermediate remains the most kinetically favored cycloadduct. However, the magnitude of the barriers increases slightly with a margin of about 0.1-4.8kcalmol for the electron-donating groups (EDGs) in the order; strong EDGs (OH < NH2 < OCH3) < weak EDGs (

The catalytic hydrogenolysis of compounds derived from guaiacol on the Cu (111) surface: mechanisms from DFT studies.

Pyrolysis oils have inferior properties compared to liquid hydrocarbon fuels, owing to the presence of oxygenated compounds such as guaiacol, C6H4(OH)(OCH3). The catalytic hydro-deoxygenation (HDO) of phenolic compounds derived from guaiacol, i.e. catechol, phenol and anisole were investigated over the Cu (111) surface to unravel the elementary steps involved in the process of bio-oil upgrade. The phenolic compounds adsorb through their π systems to the surface, where steric effects of the methoxy group reduce the stability of anisole on the surface. To produce benzene, hydroxyl removal from catechol and phenol occurs in a stepwise fashion, where dehydroxylation of catechol is more challenging than phenol. Thermodynamically, catechol is the preferred oxygenated product, but it is the most challenging to transform to benzene, requiring an energy barrier of 1.8 eV to be overcome, which is similar to the HDO of anisole with an activation energy of 1.7 eV but more difficult than the HDO of phenol with an activation energy of 1.2 eV. The rate limiting steps in the HDO reactions are catechol dehydroxylation, anisole demethoxylation and phenol dehydroxylation. Our results show that ortho substituents impede C-O bond cleavage, as seen for catechol, whereas in the absence of an ortho substituent -OH cleavage is easier than -OCH3 cleavage to form benzene.

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.

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 DFT Mechanistic Study on Base-Catalyzed Cleavage of the ß-O-4 Ether Linkage in Lignin: Implications for Selective Lignin Depolymerization.

The detailed mechanism of the base-catalyzed C-C and C-O bond cleavage of a model compound representing the ß-O-4 linkage in lignin is elucidated using DFT calculations at the M06/6-31G* level of theory. Two types of this linkage have been studied, a C2 type which contains no γ-carbinol group and a C3 type which contains a γ-carbinol. Cleavage of the C2 substrate is seen to proceed via a 6-membered transition structure involving the cation of the base, the hydroxide ion and the α-carbon adjacent to the ether bond. The reaction with KOH has the lowest activation barrier of 6.1 kcal mol-1 with a calculated rate constant of 2.1 × 108 s-1. Cleavage of the C3 substrate is found to proceed via two pathways: an enol-formation pathway and an epoxide-formation pathway. The first path is the thermodynamically favored pathway which is similar to the pathway for the C2 substrate and is the preferred pathway for the isolation of an enol-containing monomer. The second path is the kinetically favored pathway, which proceeds via an 8-membered transition state involving a hydrogen hopping event, and is the preferred pathway for the isolation of an epoxide-containing monomer. The KOH-catalyzed reaction also has the lowest activation barrier of 10.1 kcal mol-1 along the first path and 3.9 kcal mol-1 along the second path, with calculated rate constants of 2.4 × 105s-1 and 8.6 × 109s-1 respectively. Overall, the results provide clarity on the mechanism for the base-catalyzed depolymerization of lignin to phenolic monomers. The results also suggest both NaOH and KOH to be the preferred catalysts for the cleavage of the ß-O-4 linkage in lignin.

Does the reaction of nitrone derivatives with allenoates proceed by an initial (3 + 2) cycloaddition or O-Nucleophilic addition? A quantum chemical investigation.

The question of whether the reaction between nitrone derivatives and allenoates proceeds with initial (3 + 2) cycloaddition (32CA) or the oxygen-nucleophilic (O-nucleophilic) addition has been theoretically investigated using density functional theory (DFT) at the M06-2X/6-311G(d,p) level of theory. In all of the reactions considered, the initial 32CA route is kinetically and thermodynamically preferred over the initial O-nucleophilic addition. Increasing the steric bulk of the substituents on the reactants bridges the kinetic and thermodynamic gap between the initial 32CA and O-nucleophilic addition but the 32CA is still energetically preferred, showing that with increasing steric bulk, the O-nucleophilic addition may become competitive with the 32CA route. Within the 32CA reactions, analysis of electrophilic (Pk+) and nucleophilic (Pk-) Parr functions at the various reaction centers in the allenoate indicates that the three-atom-components (TACs) chemo-selectively add across the olefinic bond bearing the ester functionality (COOMe) with the largest Mulliken spin density coefficients and this observation agrees with the energetic trends and experimental outcomes. The global electron density transfer (GEDT) analysis reveals a high polar character associated with the 32CA reaction of methylbuta-2,3-dienoate with N-methyl-C-phenylnitrone while that of the 32CA reaction of methylpenta-2,3-dienoate with N-cyclohexenylnitrone has a low polar character.

A DFT study of the double (3 + 2) cycloaddition of nitrile oxides and allenoates for the formation of spirobiisoxazolines.

The molecular mechanism of the double (3 + 2) cycloaddition (32CA) reaction between nitrile oxides and allenoates has been studied using density functional theory at the M06-2X/6-311G (d,p) level of theory. In the first 32CA, the nitrile oxide adds chemo- and regio-selectively to the C-C double bond of the allenoate closest to the carboxylate group followed by a subsequent regioselective addition to the olefinic bond of the isoxazoline intermediate. The rate constant for the preferred pathway (formation of 4-methylene-2-isoxazoline intermediate) in the reaction of ethyl substituted allenoate and mesitonitrile oxide is 5.3 × 102 s-1 in THF which is about 13 times faster than the closest competing step (formation of its regioisomer 5-methylene-2-isoxazoline intermediate) which has a rate constant of 4.4 × 101 s-1. Strong electron-donating groups (EDGs) and electron-withdrawing groups (EWGs) decrease activation barriers and hence increase the reaction rate. Also, the dimerization of nitrile oxide to form furaxon is found to be kinetically unfavored.

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.

Investigating the site-, regio-, and stereo-selectivities of the reactions between organic azide and 7-heteronorbornadiene: a DFT mechanistic study.

The site-, regio-, and stereo-selectivities of the title reactions have been studied using density functional theory (DFT) at the M06/6-311G(d,p) level of theory. The effects of substituents on both the three-atom component (TAC) and norbornadiene derivatives have been investigated with a focus on the site-selectivity. The reaction of benzylazide with (1S,4R)-2-tosyl-7-oxabicyclo[2.2.1]hepta-2,5-diene and (1R,4S)-2-bromo-3-tosyl-7-oxabicyclo[2.2.1]hepta-2,5-diene proceeds via addition across the substituted olefinic bond of the two norbornadiene derivatives. Substituents on the TAC do not affect the selectivity of the reaction while substituents on the norbornadiene significantly affect the selectivity of the reaction. Benzylazide preferentially adds across the substituted olefinic bond of the norbornadiene derivative when strong electron-withdrawing group (EWGs) and electron-releasing group (ERGs) substituents are on the norbornadiene while weak ERGs and EWGs on the norbornadiene significantly decreases the site-selectivity such that addition across either double is no longer favored over the other. The formation of exo-cycloadducts is generally favored over the endo-cycloadducts. The reaction of benzylazide and norbornadiene derivatives is a highly irreversible exergonic reaction. The direction of electron density flux is dependent on the nature of the substituent on the reactants. Global reactivity indices and Parr function calculations are in good agreement with the activation barriers and the selectivity of the reactions.

A DFT mechanistic study on oxidative dehydrogenative Diels-Alder reaction of alkylbenzenes.

Cross-dehydrogenative Diels-Alder cycloaddition reaction between readily-available alkyl benzenes and electron-deficient dienophiles is an attractive synthetic route to access carbocyclic compounds which have high utility in the chemical and pharmaceutical industries. This work reports a study at the M06-2X/6-311G(d) and M06-2X/6-311++G(d,p) levels of theory on the reaction of alkyl benzenes with electron-deficient dienophiles in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as an oxidant and hydroquinone as an activator, so as to understand the chemoselectivity of the reaction (addition across the alkene functionality versus the ketone functionality), the role of the activator, the effects of substituents and the effect of solvent on the reaction. The results show the addition of the alkene bonds of methylstyrene across the alkene functionality of the electron-deficient dienophiles has generally low barriers compared to the addition across the carbonyl functionality of the electron-deficient dienophile. Powerful electron-withdrawing group (cyano) on the electron-deficient dienophile decrease the energy barrier for the cycloaddition and decrease the stability of the product whiles weak electron-withdrawing (bromine and chlorine) and electron-donating groups increase the energy barrier for the cycloaddition and decrease the stability of the product. The hydroquinone as an activator decreases the activation barrier for the Diels-Alder cycloaddition reaction.

Computational study on the mechanism of the reaction of benzenesulfonyl azides with oxabicyclic alkenes.

The reaction of benzenesulfonyl azides with oxabicyclic alkenes to form aziridines could either proceed via initial [3 + 2] cycloaddition to form triazoline intermediates which then leads to aziridines, or via initial dinitrogen cleavage of the benzenesulfonyl azide to afford a nitrene intermediate followed by addition of this nitrene species across the olefinic C-C bond of the oxabicyclic alkene. Calculations at the DFT M06-2X/6-311G(d,p) level indicate that the initial [3 + 2] cycloaddition reaction of benzenesulfonyl azide and oxabicyclic alkene has barriers of 15.0 kcal/mol (endo) and 10.3 kcal/mol (exo) and rate constants of 5.23 × 103 s-1 (endo) and 3.86 × 106 s-1 (exo) whereas the pathway involving initial formation of nitrene species has a high activation barrier of 39.2 kcal/mol and rate constant of 8.92 × 10-12 s-1, indicating that the reaction will go through the former route to form an exo triazoline intermediate. The exo triazoline can either undergo a concerted C-C, N-N bond cleavage to form a ring-opened intermediate, a reaction that has a barrier of 23.4 kcal/mol, followed by dinitrogen extrusion and C-C, C-N bond regeneration with barriers of 29.1 and 23.5 kcal/mol respectively to form endo aziridines, or it can undergo direct nitrogen extrusion to form the exo product, a reaction with a barrier of 38.3 kcal/mol. Since the rate-determining step of the former route is 9.2 kcal/mol more favored than the latter, the former route rate is favored. The rate constants of the rate-determining steps are 1.30 × 10-5 s-1 (endo) and 3.16 × 10-11 s-1 (exo), indicating that endo aziridine would be formed as the major product and this is in conformity with the experimental observations of Chen et al. (J. Org. Chem. 18:11863-11872, 2019). The position of substituents on the benzene group of the benzenesulfonyl azide affects the endo/exo diastereoselectivity.Graphical abstract.

(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.

Investigating the regio-, stereo-, and enantio-selectivities of the 1,3-dipolar cycloaddition reaction of C-cyclopropyl-N-phenylnitrone derivatives and benzylidenecyclopropane derivatives: A DFT study.

The biomedical importance of spirocyclopropane isoxazolidine derivatives is widely known. The 1,3-dipolar cycloaddition (1,3-DC) of C-cyclopropyl-N-phenylnitrone derivative and benzylidenecyclopropane derivatives leading to the formation of 5- and 4-spirocyclopropane isoxazolidines derivatives have been studied using density functional theory (DFT) at M06-2X/6-311G (d,p) level of theory. An extensive exploration of the potential energy surface shows that the 1,3-dipole adds across the dipolarophile via an asynchronous concerted mechanism. While electron-donating groups (EDGs) on the benzylidenecyclopropane favor the formation of the 4-spirocyclopropane isomer, electron-withdrawing groups (EWGs) favor the reaction channels that furnish the 5-spirocyclopropane isoxazolidine isomer. Both EWDs and EDGs on the 1,3-dipole favor the formation of the 5-spirocyclopropane isoxazolidine isomer. Irrespective of the electronic nature of substituents on the C-cyclopropyl-N-phenylnitrone, the reaction channels that regioselectively lead to the formation of the 5-spirocyclopropane isoxazolidine isomer are favored. In all reactions considered, the channels that selectively lead to the formation of the cis-diastereoisomers proceed with lower activation barriers than the trans-diastereoisomers. In all cases, the observed selectivities in the title reaction are kinetically controlled.

Permanganyl chloride-mediated oxidation of tetramethylethylene: A density functional theory study.

The mechanisms of the oxidation of tetramethylethylene (TME) by permanganyl chloride (MnO3Cl) have been explored on the singlet and triplet potential energy surfaces at the B3LYP LANL2DZ/6-31G (d) level of theory. The results show that the pathway leading to the formation of the five-membered dioxylate through concerted [3 + 2] addition is favored kinetically and thermodynamically over the three other possible pathways, namely the [2 + 2] addition via the transient metallaoxetane intermediate, epoxidation, and hydrogen transfer pathways. The epoxide precursor that on hydrolysis would yield the epoxide product will most likely arise from a stepwise path through the intermediacy of an organometallic intermediate. This pathway affords the product that is more stable (thermodynamically favorable). However, kinetically, both the stepwise and the concerted [2 + 1] addition pathways leading to the epoxide precursors are very competitive (activation barrier difference of <0.7 kcal/mol).

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.

DFT mechanistic studies on the regio-, stereo-, and enantio-selectivity of 1,3 dipolar cycloadditions of quinolinium imides with olefins, maleimides, and benzynes for the synthesis of fused N,N'-heterocycles.

This work investigated computationally the regio-, stereo-, and enantio-selectivity of the reactions of azomethine imines with olefins, maleimides, and benzynes, important reactions towards the synthesis of heteropolycyclic, N,N'-fused, spirocyclic systems, which serve as building blocks for the synthesis of many pharmaceuticals, agrochemicals, and biologically active compounds. The results show that the thermally controlled diastereoselective [3 + 2] cycloaddition reaction between quinolinium imide and methyl acrylate provides two regio-isomers: 1,4-regioisomer (N-C1, C-C2) and 1,3-regioisomer (N-C2, C-C1). The 1,4-regioisomer has cis and trans-stereoisomers while the 1,3-regioisomer has R-enantiomer and S-enantiomer, and the barriers for the formation of these isomers are 5.1, 19.1, 10.7, and 10.5 kcal/mol, respectively. The reaction between quinolinium imide and maleimide leads to the formation of two stereoisomers; cis-isomer and trans-isomer in which the cis-isomer is kinetically and thermodynamically favoured by 6.1 kcal/mol and 8.7 kcal/mol, respectively. The reaction between quinolinium imide and benzyne also leads to the formation of two stereoisomers through one transition state, with a barrier of 3.0 kcal/mol. Global electrophilicity index calculations show that the dipole acts as a good electrophile in the reaction and decreasing or increasing electrophilicity index has no correlation with the activation barriers. Graphical abstractPathways of the 1,3 dipolar cycloadditions of quinolinium imides with olefins, maleimides, and benzynes for the synthesis of fused N,N'-heterocycles.

The mechanisms of gallium-catalysed skeletal rearrangement of 1,6-enynes - Insights from quantum mechanical computations.

The transition metal-catalysed skeletal reorganization of 1,6-enynes can lead to three types of products - a type I product occurring via the cleavage of the alkene C-C bonds and the migration of the terminal alkene carbon to the terminus of the alkyne; a type II product arising from cleavage of both the double and the triple bonds followed by insertion of the terminal alkene carbon into the alkyne C-C triple bond; and a type III product which is obtained when there is a cleavage of the olefinic bond followed by formation of two new bonds from each carbon to each of the acetylenic carbons. The course of these reactions is highly dependent on the metal catalyst used and type of substitution at the alkene and alkyne moieties of the enyne. In this mechanistic study of the re-organization of 1,6-enynes catalysed by GaCl3, performed at the DFT M06/6-311G(d,p) level of theory, the parent reaction selectively leads to the formation of the type I product through the formation of the open cyclopropane ring. The presence of substituents at the acetylenic moiety governs the preferred position of the metal along the alkyne bond within the pi-complex: with electron-withdrawing groups (EWGs), the metal prefers the terminal carbon while electron-donating groups (EDGs) lead to the metal preferring the internal carbon. EWGs at the alkyne moiety efficiently favour the formation of the type I product. Substituents at the olefin moiety alter the mechanism of the reaction which may favour the selective formation of the type I or III product depending on the type of substituent. EWGs at the olefinic moiety favour formation of the type III product when the alkyne moiety is unsubstituted whiles EDGs forms the type I product selectively. Solvent and temperature have no substantial effects on the energetic trends and product distribution. Hence, gas-phase calculations are deemed adequate for the problem at hand.

Mechanistic studies on tandem cascade [4 + 2]/ [3 + 2] cycloaddition of 1,3,4-oxadiazoles with olefins.

The mechanism of the reaction of 1,3,4-oxadiazoles with alkenes (ethylene) and cycloalkenes (cyclobutene, cyclopentene, cyclohexene and cycloocene) have been studied computationally at the DFT M06-2X/6-311G* level. The reaction is found to proceed via a concerted [4 + 2] addition followed by nitrogen extrusion and then [3 + 2] addition in a tandem cascade fashion, which in the case of cycloalkenes leads to exo-fused or endo-fused subframes, the exo of which is kinetically and thermodynamically favored. The [4 + 2] step is the rate-determining step of the reaction. CF3 as a substituent on the 1,3,4-oxadiazole decreases the activation barriers of the rate-determining step, while CO2Me on the oxadiazole increases the activation barriers of the rate-determining step, markedly in the case of the reaction with cyclopentene and only marginally in the reactions with ethylene. Increasing temperature decreases the barrier of the rate-determining step and stability of the products but increases the rate of the nitrogen extrusion step. The low barriers of the second and third steps of the reaction compared to the first step means that the intermediates will not be isolated in the reaction, confirming the experimental observations of earlier workers. Based on calculated activation barriers, the reactivity of the various cycloalkenes considered in this study follows the order: cyclooctene > cyclopentene > cyclohexene > cyclobutene which is consistent with the trends in product yields obtained in earlier experimental studies.

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.