An electron localization function analysis of the molecular mechanism and the C–O bond formation in the [3+2] cycloaddition reaction involving zwitterionic type between a nitrone and an electron deficient ethyne

The mechanistic nature of a [3+2] cycloaddition reaction involving zwitterionic species has been investigated, and the changes of electron density related to the O–C and C–C bond formation along the intrinsic reaction coordinate have been characterized. This polar [3+2] cycloaddition reaction, which takes place through a non-concerted two-stage one-step mechanism, proceeds with a moderate Gibbs free activation energy of 21 kcal mol−1. The reaction begins by the creation of a pseudoradical centre at the central carbon, first on the dimethyl acetylenedicarboxylate, and second on the nitrone framework. This immediately favours the formation of the first O–C single bond by donation of some electron density of the oxygen atom lone pairs, which represents the most attractive centre in this cycloaddition reaction.

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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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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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On the Question of Zwitterionic Intermediates in the [3 + 2] Cycloaddition Reactions between C-arylnitrones and Perfluoro 2-Methylpent-2-ene

Molecules ◽

10.3390/molecules26237147 ◽

2021 ◽

Vol 26 (23) ◽

pp. 7147

Author(s):

Katarzyna Mitka ◽

Katarzyna Fela ◽

Aleksandra Olszewska ◽

Radomir Jasiński

Keyword(s):

Dft Calculations ◽

Molecular Mechanism ◽

Intermolecular Interactions ◽

Cycloaddition Reaction ◽

Reaction Centers ◽

Cycloaddition Reactions ◽

Reaction Paths ◽

One Step ◽

Step Mechanism

The molecular mechanism of the [3 + 2] cycloaddition reaction between C-arylnitrones and perfluoro 2-methylpent-2-ene was explored on the basis of DFT calculations. It was found that despite the polar nature of the intermolecular interactions, as well as the presence of fluorine atoms near the reaction centers, all reactions considered cycloaddition proceed via a one-step mechanism. All attempts for the localization of zwitterionic intermediates on the reaction paths were not successful. Similar results were obtained regardless of the level of theory applied.

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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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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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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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The Participation of 3,3,3-Trichloro-1-Nitroprop-1-Ene in the [3 + 2] Cycloaddition Reaction with Selected Nitrile N-oxides in the Light of the Experimental and MEDT Quantum Chemical Study

Molecules ◽

10.3390/molecules26226774 ◽

2021 ◽

Vol 26 (22) ◽

pp. 6774

Author(s):

Karolina Zawadzińska ◽

Mar Ríos-Gutiérrez ◽

Karolina Kula ◽

Przemysław Woliński ◽

Barbara Mirosław ◽

...

Keyword(s):

Electron Density ◽

Quantum Chemical Study ◽

Cycloaddition Reaction ◽

Chemical Study ◽

Free Energies ◽

Molecular Electron ◽

One Step ◽

Molecular Electron Density Theory ◽

Favorable Reaction ◽

Type 3

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

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Quantum Chemical Investigation of the Formation of Spiroheterocyclic Compounds Via the (3 + 2) Cycloaddition Reaction of 1-methyl-3-(2,2,2-trifluoroethylidene)pyrrolidin-2-one with Diazomethane and Nitrone Derivatives

10.3762/bxiv.2021.32.v1 ◽

2021 ◽

Author(s):

George Baffour Pipim ◽

Richard Tia ◽

Evans Adei

Keyword(s):

Electron Density ◽

Cycloaddition Reaction ◽

Mechanism Analysis ◽

Olefinic Bond ◽

Activation Barriers ◽

Atomic Spin ◽

One Step ◽

Complex Architecture ◽

Electron Donating Groups ◽

Polar Reaction

Spirocycles are important structures in drug development due to their inherent biological activity. Their complex architecture usually presents many synthetic difficulties which are efficiently resolved with detailed theoretical studies. The chemo-, regio- and stereoselectivities of the formation of spiroheterocyclic compounds via the (3 + 2) cycloaddition (32CA) reaction of 1-methyl-3-(2,2,2-trifluoroethylidene)pyrrolidin-2-one (A1) derivatives with diazomethane and nitrone derivative have been studied at the M06-2X/6-311G(d,p) level of theory. The reactions of diazomethane (A2) and N-methyl-C-phenyl nitrone (A3) derivatives with 1-methyl-3-(2,2,2-trifluoroethylidene)pyrrolidin-2-one derivatives (A1) occurs chemoselectively along the olefinic bond of A1 via an asynchronous one-step mechanism. Analysis of the electrophilic ( and nucleophilic ( Parr functions at the different reaction sites in A1 shows that A2 and A3 add across the atomic centers with the largest Mulliken and NBO atomic spin densities. Both electron-donating groups (EDGs) and electron-withdrawing groups (EWGs) on the A3 molecule do not affect the observed preferred pathway in its 32CA reaction with A1 whereas the electronic and steric nature of the substituent on the A2 molecule influences the preferred pathway in the 32CA reaction of A1 and A2. The title reaction proceeds via forward electron denisity flux (FEDF), where electron density fluxes from the three-atom components (A2 and A3) to A1. The computed global electron density transfer (GEDT) values suggest that the 32CA of A1 with diazomethane is a polar reaction while the 32CA reaction of A1 with N-methyl-C-phenyl nitrone is a non-polar reaction, and an inverse relationship has been established between the polar character of the reactions and activation barriers. In all the reactions studied, the selectivities are kinetically controlled.

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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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