A Molecular Electron Density Theory Study of the Chemoselectivity, Regioselectivity, and Diastereofacial Selectivity in the Synthesis of an Anticancer Spiroisoxazoline derived from α-Santonin

Domingo, Luís R.; Ríos‐Gutiérrez, Mar; Acharjee, Nivedita

doi:10.3390/molecules24050832

Cited by 47 publications

(39 citation statements)

References 41 publications

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“…Nitrile oxides are linear propargylic TACs, which have a zwitterionic structure participating in zw-type [64]. An ELF topological analysis of nitrile oxide R3 shows the presence of a V(O) basins integrating a total population of 5.73e indicating the presence of three lone pairs of electrons.…”

Section: Elf Topological Analysis Of the Electronic Structure Of R1 mentioning

confidence: 99%

The Theoretical Study on the Mechanism of [3+2] Cycloaddition Reactions between α,β-unsaturated Selenoaldehyde with Nitrone and with Nitrile Oxide

Mohammad‐Salim¹,

Hassan²,

Abdallah³

et al. 2020

J. Mex. Chem. Soc.

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Abstract. The reaction mechanisms of [3+2] cycloaddition (32CA) between the α,β-unsaturated selenoaldehyde with nitrone and nitrile oxide were investigated theoretically using the molecular electron density theory (MEDT). Selenoaldehyde has two unsaturations which allow for the cycloaddition occurring. It was expected to undergo four regioisomeric reaction paths in two separate reactions with nitrone and nitrile oxide. The study was conducted using ab initio approach at MP2/6-31G(d) level of theory. Potential energy surfaces were generated from the energies of the stationary points involved in the mechanisms and the dominant reaction pathways were identified. It was found that Pathway 3 and 4 are the two competing reaction channels, where the cycloaddition reaction occurs at the selenium-analogue carbonyl group of selenoaldehyde. The reactivity indices were analysed at the ground state of the reactants to predict the reactivity of studied organic molecules in 32CA reactions. Analysis of the electronic structure of nitrone and nitrile oxide, the three-atom-components (TACs), and their participation in 32CA reactions towards selenoaldehyde allows establishing a useful classification of 32CA reactions into zwitterionin-type (zw-type) reactions involving TACs with a high zwitterionic character. Resumen. Se estudia teóricamente, utilizando la teoría de la densidad electrónica molecular (MEDT), el mecanismo de reacción de la cicloadición [3+2] (32CA) entre selenoaldehídos α, β insaturados con nitrona y óxido de nitrilo. El selenoaldehído tiene dos insaturaciones que permiten la cicloadición. Se esperaba que la reacción se llevara a cabo a lo largo de cuatro caminos regioisoméricos en dos reacciones separadas con la nitrona y el óxido de nitrilo. Se realizó un estudio ab initio con el nivel de teoría MP2/6-31G(d). Se generaron superficies de energía potencial a partir de las energías de los puntos estacionarios involucrados en el mecanismo y se identificaron los caminos de reacción dominantes. Se encontró que dos rutas, la 3 y la 4, son los canales de reacción que compiten para que ocurra la cicloadición en el grupo carbonilo análogo al selenio del selenoaldheído. Se analizaron los índices de reactividad de los estados basales de los reactivos para predecir la reactividad de las moléculas orgánicas estudiadas en las reacciones 32CA. El análisis de la estructura electrónica de la nitrona y el óxido de nitrilo, de las componentes triatómicas (TACs) y de su participación en las reacciones 32CA hacia el selenoaldheído permite clasificar a las reacciones 32CA en tipo zwitteriónico (zw) que involucran a los TACs con un elevado carácter zwitteriónico.

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Section: Elf Topological Analysis Of the Electronic Structure Of R1 mentioning

confidence: 99%

The Theoretical Study on the Mechanism of [3+2] Cycloaddition Reactions between α,β-unsaturated Selenoaldehyde with Nitrone and with Nitrile Oxide

Mohammad‐Salim¹,

Hassan²,

Abdallah³

et al. 2020

J. Mex. Chem. Soc.

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“…Molecular electron density theory 3 (MEDT) proposed by Domingo in 2016 states that change in electron density is responsible for molecular reactivity in organic reactions. This theory has been widely illustrated for 32CA reactions [4][5][6] as well as for other processes, for which one-step "pericyclic mechanism" has been earlier postulated such as Diels-Alder reactions, 7,8 thermal elimination reaction, 9,10 [3,3] sigmatropic shifts, 11 etc. Initially, topological analysis of the electron localisation function 12 (ELF) and detailed analysis of conceptual density function theory (CDFT) indices 13 at the ground state of the reagents is performed within MEDT.…”

Section: Introductionmentioning

confidence: 99%

“…Monosynaptic basins, denoted by V(A), are associated with non-bonding regions (lone pairs and pseudoradical centers) and disynaptic regions, denoted by V(A,B) are associated with the bonding region between A and B. ELF valence basin populations can be used to recover the Lewis bonding model and provide a reasonably suggestive chemical representation of the molecular system. Topological analysis of the ELF and visualization of ELF localisation domains has been employed in several MEDT studies [4][5][6] to analyse the reactivity of three--atom components [4][5][6] (TACs) participating in 32CAs. This has allowed the classification of TACs into pseudodiradical (pdr-) 15 type, pseudo(mono)radical 16 (pmr-) type, carbenoid (cb-) 15 type and zwitter-ionic (zw-) 5,6,17 type.…”

Section: Introductionmentioning

confidence: 99%

“…Topological analysis of the ELF and visualization of ELF localisation domains has been employed in several MEDT studies [4][5][6] to analyse the reactivity of three--atom components [4][5][6] (TACs) participating in 32CAs. This has allowed the classification of TACs into pseudodiradical (pdr-) 15 type, pseudo(mono)radical 16 (pmr-) type, carbenoid (cb-) 15 type and zwitter-ionic (zw-) 5,6,17 type. Monosynaptic V(A) basin integrating at a population of less than 1e is associated with pseudoradical center, while that integrating at a population of 2e in neutral molecules is associated with carbenoid centre.…”

Section: Introductionmentioning

confidence: 99%

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Understanding the regio-and diastereoselective synthesis of a potent antinociceptive isoxazolidine from C-(pyridin-3-yl)-N-phenylnitrone in the light of molecular electron density theory

Acharjee

2020

JSCS

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[3+2] cycloaddition reaction of C-(pyridin-3-yl)-N-phenylnitrone and 2-propen-1-ol yields stereochemically defined potent antinociceptive isoxazolidine derivative. Computational quantum calculations (CQC) are performed for this synthesis to predict the polar character, mechanism and selectivity within the framework of molecular electron density theory (MEDT). Topological analysis of the electron localization function (ELF) classifies the nitrone as a zwitter-ionic(zw-) type three atom component (TAC) showing absence of any pseudoradical or carbenoid centre. Four reaction channels corresponding to the possible regio-and stereoselective pathways are studied at DFT/ /B3LYP/6-311G(d,p) level of theory. The reaction follows one-step mechanism with asynchronous transition states and the computed activation energies agree well with experimental data. The reaction can be differentiated into nine ELF topological phases, with faster CC bond formation. Global electron density theory (GEDT) at the favoured transition state and conceptual density functional theory (CDFT) indices at the ground state of the reagents indicate non-polar character. Non-covalent interactions are predicted by atoms-in-molecules (AIM) analysis and non-covalent interaction (NCI) plots at the transition states.

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“…[48] Since 2016, MEDT has provided a rationalisation for numerous 32CA reactions. [49][50][51] Herein, an MEDT study of the SP-32CA reactions of PDM 4 and EDA 5 with DIBO 6, experimentally reported by Moran et al, [13] and with acetylene 20, is carried out using quantum chemical procedures at the MPWB1K/6-311G(d,p) computational level in order to understand the origin of the acceleration observed in the SP-32CA reactions of diazoalkanes with strained DIBO 6 (see Scheme 2).…”

Section: Introductionmentioning

confidence: 99%

Unveiling the high reactivity of strained dibenzocyclooctyne in [3 + 2] cycloaddition reactions with diazoalkanes through the molecular electron density theory

Domingo

Acharjee

2020

J of Physical Organic Chem

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The strain-promoted [3 + 2] cycloaddition (SP-32CA) reactions of two diazoalkanes with strained dibenzocyclooctyne (DIBO) have been studied within the molecular electron density theory. Analysis of the electron localisation function of diazoalkanes allows characterising their pseudoradical structures. These pmr-type 32CA reactions, which follow a one-step mechanism with high asynchronicity and some polar character, have lower activation enthalpies, 11.4 and 15.4 kcal mol −1 , than those with acetylene, 19.7 and 23.1 kcal mol −1 , in agreement with the experimental outcomes. Analysis of the changes in electron density along the SP-32CA reaction of phenyldiazomethane with DIBO indicates that the strain favours the depopulation of the CC triple bond of DIBO, reducing the activation energy.

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A Molecular Electron Density Theory Study of the Chemoselectivity, Regioselectivity, and Diastereofacial Selectivity in the Synthesis of an Anticancer Spiroisoxazoline derived from α-Santonin

Cited by 47 publications

References 41 publications

The Theoretical Study on the Mechanism of [3+2] Cycloaddition Reactions between α,β-unsaturated Selenoaldehyde with Nitrone and with Nitrile Oxide

The Theoretical Study on the Mechanism of [3+2] Cycloaddition Reactions between α,β-unsaturated Selenoaldehyde with Nitrone and with Nitrile Oxide

Understanding the regio-and diastereoselective synthesis of a potent antinociceptive isoxazolidine from C-(pyridin-3-yl)-N-phenylnitrone in the light of molecular electron density theory

Unveiling the high reactivity of strained dibenzocyclooctyne in [3 + 2] cycloaddition reactions with diazoalkanes through the molecular electron density theory

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