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

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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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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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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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 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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A molecular electron density theory study of the [3 + 2] cycloaddition reaction of nitrones with ketenes

Organic & Biomolecular Chemistry ◽

10.1039/c6ob02768g ◽

2017 ◽

Vol 15 (7) ◽

pp. 1618-1627 ◽

Cited By ~ 22

Author(s):

Mar Ríos-Gutiérrez ◽

Andrea Darù ◽

Tomás Tejero ◽

Luis R. Domingo ◽

Pedro Merino

Keyword(s):

Electron Density ◽

Cycloaddition Reaction ◽

Molecular Electron ◽

One Step ◽

Molecular Electron Density Theory ◽

Electrophilic Character

The zw-type 32CA reactions of nitrones with ketenes are controlled by the nucleophilic character of the nitrone and the electrophilic character of the ketene. They are chemo- and regio-selective and the use of electrophilic ketenes changes the mechanism from one-step to two-step.

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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 Intramolecular Ionic Diels–Alder Reactions within Molecular Electron Density Theory

Chemistry ◽

10.3390/chemistry3030061 ◽

2021 ◽

Vol 3 (3) ◽

pp. 834-853

Author(s):

Luis R. Domingo ◽

Mar Ríos-Gutiérrez ◽

María José Aurell

Keyword(s):

Electron Density ◽

Electronic Structures ◽

Activation Enthalpy ◽

Topological Analysis ◽

Chair Conformation ◽

Diels Alder ◽

Molecular Electron ◽

One Step ◽

Molecular Electron Density Theory ◽

Step Mechanism

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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Understanding the Molecular Mechanism of the Rearrangement of Internal Nitronic Ester into Nitronorbornene in Light of the MEDT Study

Molecules ◽

10.3390/molecules24030462 ◽

2019 ◽

Vol 24 (3) ◽

pp. 462 ◽

Cited By ~ 7

Author(s):

Agnieszka Kącka-Zych

Keyword(s):

Density Functional ◽

Functional Theory ◽

Molecular Electron ◽

Bet Analysis ◽

One Step ◽

Molecular Electron Density Theory ◽

Step Mechanism ◽

Nitronic Ester ◽

Computational Level

The characterization of the structure of nitronic esters and their rearrangement into nitronorbornene reactions has been analyzed within the Molecular Electron Density Theory (MEDT) using Density Functional Theory (DFT) calculations at the B3LYP/6-31G(d) computational level. Quantum-chemical calculations indicate that this rearrangement takes place according to a one-step mechanism. The sequential bonding changes received from the Bonding Evolution Theory (BET) analysis of the rearrangement of internal nitronic ester to nitronorbornene allowed us to distinguish seven different phases. This fact clearly contradicts the formerly-proposed concerted pericyclic mechanism.

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

Journal of the Serbian Chemical Society ◽

10.2298/jsc211014106a ◽

2021 ◽

pp. 106-106

Author(s):

Nivedita Acharjee ◽

Haydar Mohammad-Salim ◽

Mrinmoy Chakraborty

Keyword(s):

Gas Phase ◽

Electron Density ◽

Activation Enthalpy ◽

Regioselective Synthesis ◽

Polar Solvents ◽

Aim Analysis ◽

Covalent Bonds ◽

Molecular Electron ◽

Molecular Electron Density Theory ◽

Density Transfer

The regioselective synthesis of a potent antiviral sugar nucleoside isoxazole analogue from the [3+2] cycloaddition (32CA) reaction of aceto-nitrile-N-oxide (ANO) and acetyl-protected 5-ethynyl-2?-deoxyuridine (EDU) has been studied at MPWB1K/6-311G(d,p) level within the molecular electron density theory (MEDT) perspective. ANO is classified as a zwitterionic species devoid of any pseudoradical or carbenoid center from the electron localization function (ELF) analysis. 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 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 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 the bonding evolution theory (BET) study.

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