Unveiling the Intramolecular Ionic Diels–Alder Reactions within Molecular Electron Density Theory

The intramolecular ionic Diels–Alder (IIDA) reactions of two dieniminiums were studied within the Molecular Electron Density Theory (MEDT) at the ωB97XD/6-311G(d,p) computational level. Topological analysis of the electron localization function (ELF) of dieniminiums showed that their electronic structures can been seen as the sum of those of butadiene and ethaniminium. The superelectrophilic character of dieniminiums accounts for the high intramolecular global electron density transfer taking place from the diene framework to the iminium one at the transition state structures (TSs) of these IIDA reactions, which are classified as the forward electro density flux. The activation enthalpy associated with the IIDA reaction of the experimental dieniminium, 8.7 kcal·mol−1, was closer to that of the ionic Diels–Alder (I-DA) reaction between butadiene and ethaniminium, 9.3 kcal·mol−1. However, the activation Gibbs free energy of the IIDA reaction was 12.7 kcal·mol−1 lower than that of the intermolecular I-DA reaction. The strong exergonic character of the IIDA reaction, higher than 20.5 kcal·mol−1, makes the reaction irreversible. These IIDA reactions present a total re/exo and si/endo diastereo selectivity, which is controlled by the most favorable chair conformation of the tetramethylene chain. ELF topological analysis of the single bond formation indicated that these IIDA reactions take place through a non-concerted two-stage one-step mechanism. Finally, ELF and atoms-in-molecules (AIM) topological analyses of the TS associated with the inter and intramolecular processes showed the great similarity between them.

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Unveiling the Intramolecular Ionic Diels-Alder Reactions within the Molecular Electron Density Theory

10.20944/preprints202106.0568.v1 ◽

2021 ◽

Author(s):

Luis R. Domingo ◽

Mar Ríos-Gutiérrez ◽

María José Aurell

Keyword(s):

Electron Density ◽

Activation Enthalpy ◽

Topological Analysis ◽

Chair Conformation ◽

Diels Alder ◽

Molecular Electron ◽

One Step ◽

Molecular Electron Density Theory ◽

Step Mechanism ◽

Density Transfer

The intramolecular ionic Diel-Alder (IIDA) reactions of two dieniminiums have been studied within the Molecular Electron Density Theory (MEDT) at the B97XD/6-311G(d,p) computational level. ELF topological analysis of dieniminiums shows that its electronic structure can been seen as the sum of those of butadiene and ethaniminium. The superelectrophilic character of dieniminiums accounts for the high intramolecular global electron density transfer taking place between the diene and iminium frameworks at the transition state structures (TSs) of these IIDA reactions. The activation enthalpy associated to the IIDA reaction of the experimental dieniminium, 8.7 kcal·mol-1, is closer to that of the ionic Diels-Alder (I-DA) reaction between butadiene and ethaniminium, 9.3 kcal·mol-1. However, the activation Gibbs free energy of the IIDA reaction is 12.7 kcal·mol-1 lower than that of the intermolecular I-DA reaction. The strong exergonic character of the IIDA reaction, higher than 17 kcal·mol-1, makes the reaction irreversible. These IIDA reactions present a total re/exo and si/endo diastereoselectivity, which is controlled by the most favourable chair conformation of the tetramethylene chain. Electron localization function (ELF) topological analysis of the single bond formation indicates that these IIDA reactions take place through a non-concerted two-stage one-step mechanism. Finally, ELF and atoms-in-molecules (AIM) topological analyses of the TS associated to inter and intramolecular processes show the great similitude among them.

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Participation of Phosphorylated Analogues of Nitroethene in Diels–Alder Reactions with Anthracene: A Molecular Electron Density Theory Study and Mechanistic Aspect

Organics ◽

10.3390/org1010004 ◽

2020 ◽

Vol 1 (1) ◽

pp. 36-48

Author(s):

Agnieszka Kącka-Zych

Keyword(s):

Electron Density ◽

Density Functional ◽

Diels Alder ◽

Single Bond ◽

Conceptual Density Functional Theory ◽

Molecular Electron ◽

Bet Analysis ◽

One Step ◽

Molecular Electron Density Theory ◽

Step Mechanism

The structure and the contribution of the bis(2-chloroethyl) 2-nitro 1a and 2-bromo-2-nitroethenylphosphonates 1b with anthracene 2 in the Diels–Alder (DA) reactions have been studied within the Molecular Electron Density Theory (MEDT) at the B3LYP functional together with 6-31G(d), 6-31+G(d) and 6-31+G(d,p) basic sets. Analysis of the Conceptual Density Functional Theory (CDFT) reactivity indices indicates that 1a and 1b can be classified as a strong electrophile and marginal nucleophile, while 2 is classified as a strong electrophile and strong nucleophile. The studied DA reactions take place through a one-step mechanism. A Bonding Evolution Theory (BET) of the one path associated with the DA reaction of 1a with 2 indicates that it is associated with non-concerted two-stage one-step mechanism. BET analysis shows that the first C2-C3 single bond is formed in Phase VI, while the second C1-C6 single bond is formed in the Phase VIII. The formation of both single bonds occurs through the merging of two C2 and C3, C1 and C6 pseudoradical centers, respectively.

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A Molecular Electron Density Theory Study of the Reactivity of Azomethine Imine in [3+2] Cycloaddition Reactions

10.20944/preprints201705.0005.v1 ◽

2017 ◽

Author(s):

Luis R. Domingo ◽

Mar Ríos-Gutiérrez

Keyword(s):

Electron Density ◽

Topological Analysis ◽

Complete Agreement ◽

Azomethine Imine ◽

Molecular Electron ◽

One Step ◽

Molecular Electron Density Theory ◽

Dft Reactivity Indices ◽

Step Mechanism

The electronic structure and the participation of the simplest azomethine imine (AI) in [3+2] cycloaddition (32CA) reactions have been analysed within the Molecular Electron Density Theory (MEDT) using DFT calculations at the MPWB1K/6-311G(d) level. Electron localisation function (ELF) topological analysis reveals that AI has a pseudoradical structure, while the conceptual DFT reactivity indices characterise this TAC as a moderate electrophile and a good nucleophile. The non-polar 32CA reaction of AI with ethylene takes place through a one-step mechanism with low activation energy, 5.3 kcal/mol-1. A bonding evolution theory (BET) study indicates that this reaction takes place through a non-concerted [2n+2τ] mechanism in which the C–C bond formation is clearly anticipated prior to the C–N one. On the other hand, the polar 32CA reaction of AI with dicyanoethylene takes place through a two-stage one-step mechanism. Now, the more favourable regioisomeric transition state structure (TS) is located 8.5 kcal•mol−1 below the reagents, in complete agreement with the high polar character of the TS. The current MEDT study makes it possible to extend Domingo’s classification of 32CA reactions to a new pra-type of reactivity.

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Unveiling the Unexpected Reactivity of Electrophilic Diazoalkanes in [3+2] Cycloaddition Reactions within Molecular Electron Density Theory

10.20944/preprints202012.0364.v1 ◽

2020 ◽

Author(s):

Luis R. Domingo ◽

Mar Ríos-Gutiérrez ◽

Nivedita Acharjee

Keyword(s):

Electron Density ◽

Complete Agreement ◽

Slowing Down ◽

Molecular Electron ◽

One Step ◽

Molecular Electron Density Theory ◽

Electrophilic Character ◽

Step Mechanism ◽

Computational Level ◽

Density Transfer

The [3+2] cycloaddition (32CA) reactions of strongly nucleophilic norbornadiene (NBD) with simplest diazoalkane (DAA) and three DAAs of increased electrophilicity have been studied within the Molecular Electron Density Theory (MEDT) at the MPWB1K/6-311G(d,p) computational level. These pmr-type 32CA reactions follow an asynchronous one-step mechanism with activation enthalpies ranging from 17.7 to 27.9 kcal·mol-1 in acetonitrile. The high exergonic character of these reactions makes them irreversible. The presence of electron-withdrawing (EW) substituents in the DAA increases the activation enthalpies, in complete agreement with the experimental slowing-down of the reactions, but contrary to the Conceptual DFT prediction. Despite the nucleophilic and electrophilic character of the reagents, the global electron density transfer at the TSs indicates rather non-polar 32CA reactions. The present MEDT study allows establishing that the depopulation of the NNC core in this series of DAAs with the increase of the EW character of the substituents present at the carbon center is responsible for the experimentally found deceleration.

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Understanding the Reactivity of Trimethylsilyldiazoalkanes Participating in [3+2] Cycloaddition Reactions towards Diethylfumarate with a Molecular Electron Density Theory Perspective

Organics ◽

10.3390/org1010002 ◽

2020 ◽

Vol 1 (1) ◽

pp. 3-18

Author(s):

Luis R. Domingo ◽

Nivedita Acharjee ◽

Haydar A. Mohammad-Salim

Keyword(s):

Electron Density ◽

Energy Cost ◽

Trimethylsilyl Group ◽

Gibbs Energies ◽

Molecular Electron ◽

One Step ◽

Molecular Electron Density Theory ◽

Non Covalent Interactions ◽

Covalent Interactions ◽

Step Mechanism

A Molecular Electron Density Theory (MEDT) study is presented here for [3+2] cycloaddition (32CA) reactions of three trimethylsilyldiazoalkanes with diethyl fumarate. The presence of silicon bonded to the carbon of these silyldiazoalkanes changes its structure and reactivity from a pseudomonoradical to that of a zwitterionic one. A one-step mechanism is predicted for these polar zw-type 32CA reactions with activation enthalpies in CCl4 between 8.0 and 19.7 kcal·mol−1 at the MPWB1K (PCM)/6-311G(d,p) level of theory. The negative reaction Gibbs energies between −3.1 and −13.2 kcal·mole−1 in CCl4 suggests exergonic character, making the reactions irreversible. Analysis of the sequential changes in the bonding pattern along the reaction paths characterizes these zw-type 32CA reactions. The increase in nucleophilic character of the trimethylsilyldiazoalkanes makes these 32CA reactions more polar. Consequently, the activation enthalpies are decreased and the TSs require less energy cost. Non-covalent interactions at the TSs account for the stereoselectivity found in these 32CA reactions involving the bulky trimethylsilyl group.

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Unveiling the Ionic Diels-Alder Reactions within the Molecular Electron Density Theory

10.20944/preprints202105.0672.v1 ◽

2021 ◽

Author(s):

Luis R. Domingo ◽

Mar Ríos-Gutiérrez ◽

María J. Aurell

Keyword(s):

Electron Density ◽

Topological Analysis ◽

Activation Energies ◽

High Reactivity ◽

Diels Alder ◽

Electron Density Transfer ◽

Molecular Electron ◽

Iminium Cations ◽

Molecular Electron Density Theory ◽

Density Transfer

The ionic Diels-Alder (I-DA) reactions of a series of six iminium cations with cyclopentadiene have been studied within the Molecular Electron Density Theory (MEDT). The superelectrophilic character of iminium cations,  > 8.20 eV, accounts for the high reactivity of these species participating in I-DA reactions. The activation energies are found between 13 and 20 kcal·mol-1 lower in energy than those associated to the corresponding Diels-Alder (DA) reactions of neutral imines. These reactions are low endo selective as a consequence of the cationic character of the TSs, but highly regioselective. Solvents have poor effects on the relative energies, and an unappreciable effect in the geometries. In dichloromethane the activation energies increase slightly as a consequence of the better solvation of the iminium cations than the cationic TSs. ELF topological analysis of the bonding changes along the I-DA reactions shows that they are very similar to those in polar DA reactions. The present MEDT study makes it possible establishing that the global electron density transfer (GEDT) taking place at the TSs of I-DA reactions, and not steric (Pauli) repulsions such as have been recently proposed, are responsible for the features of these type of DA reactions.

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Unveiling the Ionic Diels–Alder Reactions within the Molecular Electron Density Theory

Molecules ◽

10.3390/molecules26123638 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3638

Author(s):

Luis R. Domingo ◽

Mar Ríos-Gutiérrez ◽

María José Aurell

Keyword(s):

Electron Density ◽

Topological Analysis ◽

Activation Energies ◽

High Reactivity ◽

Diels Alder ◽

Electron Density Transfer ◽

Molecular Electron ◽

Iminium Cations ◽

Molecular Electron Density Theory ◽

Density Transfer

The ionic Diels–Alder (I-DA) reactions of a series of six iminium cations with cyclopentadiene have been studied within the Molecular Electron Density Theory (MEDT). The superelectrophilic character of iminium cations, ω > 8.20 eV, accounts for the high reactivity of these species participating in I-DA reactions. The activation energies are found to be between 13 and 20 kcal·mol−1 lower in energy than those associated with the corresponding Diels–Alder (DA) reactions of neutral imines. These reactions are low endo selective as a consequence of the cationic character of the TSs, but highly regioselective. Solvents have poor effects on the relative energies, and an unappreciable effect on the geometries. In acetonitrile, the activation energies increase slightly as a consequence of the better solvation of the iminium cations than the cationic TSs. Electron localization function (ELF) topological analysis of the bonding changes along the I-DA reactions shows that they are very similar to those in polar DA reactions. The present MEDT study establishes that the global electron density transfer (GEDT) taking place at the TSs of I-DA reactions, and not steric (Pauli) repulsions such as have been recently proposed, are responsible for the features of these types of DA reactions.

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Mpro-SARS-CoV-2 Inhibitors and Various Chemical Reactivity of 1-Bromo- and 1-Chloro-4-vinylbenzene in [3 + 2] Cycloaddition Reactions

Organics ◽

10.3390/org2010001 ◽

2021 ◽

Vol 2 (1) ◽

pp. 1-16

Author(s):

Mohammed El Idrissi ◽

Mohamed El Ghozlani ◽

Asli Eşme ◽

Mar Ríos-Gutiérrez ◽

Anas Ouled Aitouna ◽

...

Keyword(s):

Electron Density ◽

Chemical Reactivity ◽

Cycloaddition Reactions ◽

Two Stage ◽

Docking Analysis ◽

Molecular Electron ◽

One Step ◽

Molecular Electron Density Theory ◽

Step Mechanism ◽

Computational Level

The regioselectvity and the mechanism of the (32CA) cycloadditions reactions of 1-bromo-4-vinylbenzene 1 and 1-chloro-4-vinylbenzene 2 with benzonitrile oxide 3 were investigated under the molecular electron density theory (MEDT) at the B3LYP/6-311++G(d,p) computational level. Evaluation of the ELF reveals that these zwitterionic type (zw-type) 32CA reactions take place in a two-stage one-step mechanism. This MEDT study shows that the meta isoxazolines are kinetically and thermodynamically favored over the ortho ones, these 32CA reactions being completely regioselective, in agreement with experimental outcomes. In addition, the efficiency of isoxazolines against SARS-CoV-2 have been also investigated. According to the docking analysis, the present study concludes that 5-(p-bromophenyl)-3-phenyl-2-isoxazoline (B-m) shows better interactions for the inhibition of SARS-CoV-2 in comparison to chloroquine.

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Unveiling the Lewis Acid Catalyzed Diels–Alder Reactions Through the Molecular Electron Density Theory

Molecules ◽

10.3390/molecules25112535 ◽

2020 ◽

Vol 25 (11) ◽

pp. 2535 ◽

Cited By ~ 5

Author(s):

Luis R. Domingo ◽

Mar Ríos-Gutiérrez ◽

Patricia Pérez

Keyword(s):

Electron Density ◽

Lewis Acid ◽

Diels Alder ◽

Strong Electron ◽

High Acceleration ◽

Molecular Electron ◽

One Step ◽

Molecular Electron Density Theory ◽

Acid Catalyzed ◽

Zwitterionic Intermediate

The effects of metal-based Lewis acid (LA) catalysts on the reaction rate and regioselectivity in polar Diels–Alder (P-DA) reactions has been analyzed within the molecular electron density theory (MEDT). A clear linear correlation between the reduction of the activation energies and the increase of the polar character of the reactions measured by analysis of the global electron density transfer at the corresponding transition state structures (TS) is found, a behavior easily predictable by analysis of the electrophilicity ω and nucleophilicity N indices of the reagents. The presence of a strong electron-releasing group in the diene changes the mechanism of these P-DA reactions from a two-stage one-step to a two-step one via formation of a zwitterionic intermediate. However, this change in the reaction mechanism does not have any chemical relevance. This MEDT study makes it possible to establish that the more favorable nucleophilic/electrophilic interactions taking place at the TSs of LA catalyzed P-DA reactions are responsible for the high acceleration and complete regioselectivity experimentally observed.

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Unveiling the Unexpected Reactivity of Electrophilic Diazoalkanes in [3+2] Cycloaddition Reactions within Molecular Electron Density Theory

Chemistry ◽

10.3390/chemistry3010006 ◽

2021 ◽

Vol 3 (1) ◽

pp. 74-93

Author(s):

Luis R. Domingo ◽

Mar Ríos-Gutiérrez ◽

Nivedita Acharjee

Keyword(s):

Electron Density ◽

Complete Agreement ◽

Slowing Down ◽

Molecular Electron ◽

One Step ◽

Molecular Electron Density Theory ◽

Electrophilic Character ◽

Step Mechanism ◽

Computational Level ◽

Density Transfer

The [3+2] cycloaddition (32CA) reactions of strongly nucleophilic norbornadiene (NBD), with simplest diazoalkane (DAA) and three DAAs of increased electrophilicity, have been studied within the Molecular Electron Density Theory (MEDT) at the MPWB1K/6-311G (d,p) computational level. These pmr-type 32CA reactions follow an asynchronous one-step mechanism with activation enthalpies ranging from 17.7 to 27.9 kcal·mol−1 in acetonitrile. The high exergonic character of these reactions makes them irreversible. The presence of electron-withdrawing (EW) substituents in the DAA increases the activation enthalpies, in complete agreement with the experimental slowing-down of the reactions, but contrary to the Conceptual DFT prediction. Despite the nucleophilic and electrophilic character of the reagents, the global electron density transfer at the TSs indicates rather non-polar 32CA reactions. The present MEDT study establishes the depopulation of the N–N–C core in this series of DAAs with the increase of the EW character of the substituents present at the carbon center is responsible for the experimentally found deceleration.

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