Unveiling [3 + 2] Cycloaddition Reactions of N-Methyl-C-3-Bromophenyl-Nitrone to Dimethyl Maleate: Molecular Electron Density Theory Perspective

Abstract

Abstract. The zwitterionic-type (zw-type) [3+2] cycloaddition (32CA) reactions of N-methyl-C-3-bromophenyl-nitrone 1 with dimethyl maleate 2 with increased electrophilicity were investigated using the Molecular Electron Density Theory (MEDT) at the MPWB95/6-311++G(d,p) computational level. Both reactivity and selectivity are rationalized in relation to the polarity of the reaction. The associated zw-type 32CA reactions are accelerated due to the high nucleophilic character of N-methyl-C-3-bromophenyl-nitrone 1 and the strong electrophilic character of dimethyl maleate 2, which also play a critical part in the mechanism of the reaction, influencing the stereoselectivity, with activation enthalpies in between 34.04 and 38.37 kJ.mol-1 in the gas phase. The CDFT indices are used to anticipate global electron density flux from the nucleophilic N-methyl-C-3-bromophenyl-nitrone 1 to the electrophilic dimethyl maleate 2. These exergonic 32CA reactions have negative Gibbs free energy along the endo and exo stereochemical pathways. The endo stereochemical process is preferred over the exo stereochemical pathway in this kinetically controlled 32CA reaction. The predictions of bonding evolution theory (BET) for the endo and exo pathways indicate a one-step process with early transition states, which is compatible with the ELF topological examination of transition states. Resumen. Las reacciones de cicloadición de tipo zwitteriónico (tipo zw) [3+2] (32CA) de N-metil-C-3-bromofenil-nitrona 1 con maleato de dimetilo 2 con aumento de la electrofilicidad se investigaron utilizando la Teoría de la Densidad Electrónica Molecular (MEDT, por sus siglas en inglés) utilizando el nivel de teoría MPWB95/6-311++G(d,p). Tanto la reactividad como la selectividad se racionalizan en relación con la polaridad de la reacción. Las reacciones asociadas de tipo zw 32CA se aceleran debido al alto carácter nucleofílico de N-metil-C-3-bromofenil-nitrona 1 y al fuerte carácter electrofílico del maleato de dimetilo 2, que también juega un papel crítico en el mecanismo de la reacción, influyendo en la estereoselectividad, con entalpías de activación entre 34.04 y 38.37 kJ.mol-1, en fase gaseosa. Los índices de la Teoría de Funcionales de la Densidad Conceptual (CDFT, por sus siglas en inglés) se utilizan para anticipar el flujo global de densidad de electrones desde el nucleófilo N-metil-C-3-bromofenil-nitrona 1 hasta el maleato de dimetilo electrofílico 2. Estas reacciones exergónicas 32CA tienen energías libres de Gibbs negativa a lo largo de las vías estereoquímicas endo y exo. El proceso estereoquímico endo es preferido sobre la vía estereoquímica exo en esta reacción 32CA controlada cinéticamente. Las predicciones de la teoría de la evolución de enlaces (BET, por sus siglas en inglés) para las vías endo y exo indican un proceso de un paso con estados de transición temprana, que es compatible con el examen topológico de la Función de Localización Electrónica (ELF, por sus siglas en inglés) de los estados de transición.

A combined BET and IQA–REG study of the activation energy of non-polar zw-type [3+2] cycloaddition reactions

“…35,36 Nitrones are one of the most common zwitterionic TACs. Many BET studies 15,[37][38][39][40][41][42][43] of several inter-and intramolecular experimental 32CA reactions of substituted nitrones with ethylene derivatives of different nature have shown that the chemical events taking place in these zw-type 32CA reactions follow: (a) depopulation of the CQN double bond with formation of the carbon pseudoradical center and nitrogen nonbonding electron density region, (b) depopulation of the CQC double bond with formation of the corresponding pseudoradical centers, and (c) formation of the new C-C and C-O single bonds in different asynchronicity depending on the substituents and polar character of the 32CA reaction. Among these steps, the early depopulation of the CQN bond is usually the most drastic change in terms of population and total energy variations in the corresponding phase.…”

Theoretical insight into the mechanism and selectivity of the [3+2] Cycloaddition Reaction of N-methyl-1-phenylmethanimine Oxide and Bicyclopropylidene with a MEDT Perspective

“…In the past four years, MEDT has effectively analyzed the experimental results of numerous 32CA reactions [26][27][28][29]. Recently, MEDT has been utilized to evaluate the experimental outcomes of strain-promoted and catalyzed 32CA reactions and the reported chemo-, regio-, and stereoselective production of spiroisoxazolines [30,31]. Based on their electronic structure, the three-atom components (TACs) that play a role in 32CA reactions are classified as pseudodiradical, pseudo(mono)radical, carbenoid, and zwitterionic.…”

Expounding the Mechanism and Regioselectvity of [3+2] Cycloloaddition between N-phenylmethanimine oxide Nitrone and 2-methylene-1,3-dithiolane 1,3-dioxide

“…Analysis of the experimentally observed reactivity, region, stereo-and chemoselectivity, catalysis, strain promotion, substituent effects, and other aspects of 32CA reactions have all benefited from the MEDT perspective over the past seven years [7][8][9][10][11][12]. Recently, the MEDT viewpoint has also been used to report on the successful interaction between experiment and theory in many 32CA reactions [13][14][15][16][17][18][19][20][21].…”