Theoretical insight into the unexpected initial (3 + 2) cycloaddition reaction of mesitonitrile oxide with 1, 4-diazepine derivatives: A computational study

The number of new sigma bonds formed or the number of atoms linked in the ring formed is commonly employed to divide cycloaddition reactions [1,2]. In the most common case, two reactants react to produce a cyclic molecule, creating two new sigma bonds at the expense of two pi-bonds [[3], [4], [5]]. The 1,3-dipolar [ 3 + 2] cycloaddition is a process that involves the addition of two molecules, a dipolarophile, and a 1,3-dipole, to generate a five-membered heterocyclic complex [5]. The reaction process is often concerted, stereo, and region-specific to 1,3-dipole and dipolarophile [5].

The 1,3-dipole is an organic molecule with delocalized electrons and charge dispersion over three atomic centers [6,7]. The center element of a 1,3-dipole is often oxygen or nitrogen, amongst other higher-row elements like Sulphur and phosphorus, which are seldom used. Depending on the chemical structure, a 1,3-dipole can be classified as an allyl-type or a propargyl/allenyl-type zwitterionic organic molecule [4]. The allyl 1,3-dipole category possesses a bent geometry and four electrons in their Pz orbital [1,4]. The propargyl/allenyl type of 1,3-dipole has a linear geometry, as opposed to the allyl type class of 1,3-dipoles [6].

The 32CA reaction of nitrile oxides with multiple bonds leads to the formation of useful five-membered heterocycles. In many situations, their reactions with different dipolarophiles proceed with almost complete stereochemical and superior regiochemical control [8].

The synthetic application of (3 + 2) cycloaddition reactions (32CA) in contemporary chemistry is astounding [9,10]. The 1, 3-dipolar [ 3 + 2] cycloaddition (1,3-DC) reaction, introduced and comprehensively studied by Huisgen [11], provides an expedient route to access synthetically- and pharmaceutically-important heterocyclic compounds [12].

1,4-diazepines, which can be synthesized easily by condensing ethylene-diamine with 1,3-diketones, are valuable precursors in the generation of polycyclic systems because their double bonds can undergo numerous cycloaddition reactions [13]. 1,4-diazepines (a kind of azepine) constitute a class of heterocycles that have been found to possess consideration usages in terms of their activity as the core framework in specific drugs. And so, forming the underlying chemistry of several drugs in the market. It has been the object of immense studies since the early 1960s because of their biological activities such as antibacterial, anticancer, psycho-topics, anticonvulsant and antiviral [14]. Proper functionalization of this ring affords an even more potent group and a finer insight into their chemistry.

Some drugs of interest in the drug market such as Diazepam (Valium), Medazepam (Nobrium), Nitrazepam (Mogadon), Chlordiazepoxide, etc., that possess the active 1,4-diazepine backbone are functional in the treatment of anxiety disorder, restless leg syndrome, insomnia, seizures, alcohol withdrawal, anxiety and anesthesia [15].

1,3-DC reaction, such as the (3 + 2) cycloaddition (32CA) reaction, has been the means of carrying out transformations on azepine ring moieties owing to its unsaturated functionalities, be it in the form of Cdouble bondC or Cdouble bondN.

Baouid et al. [16] reported their preliminary results on the reaction of mesitonitrile oxide with 1, 4-diazepines. They observed an unusual reaction product outcome (P1). The unusual product outcome arises from the unreactive nature of the potential endocyclic olefinic carbon-carbon double bond at the initial stage, even under forced conditions. The Cdouble bondN functionality in dipolarophic substrates is known to poorly undergo 1,3-dipolar cycloaddition reaction because of its poorer dipolarophilic nature compared to the Cdouble bondC group with nitrile oxides [17].

Baouid et al. reported their preliminary results where it was observed that, the initial reaction proceeded to yield exclusively the cycloadduct P1 (Scheme 1), which involves a 32CA to the poorer Cdouble bondN bond at the expense of the potential Cdouble bondC bond noted for high reactivity in cycloaddition reactions with nitrile oxides (Scheme 1). For the 1, 4-diazepines employed, it was reported that no amount of dipolar addition across the olefinic carbon-carbon endocyclic double bond was observed, even under forced conditions at the initial stage of the reaction [16].

This observation raises question of what accounts for this unique, unusual reactivity of nitrile oxides towards 1,4-diazepines. How is the chemistry of this reaction affected by strongly activating and deactivating the Cdouble bondC or Cdouble bondN bond? Moreover, what is responsible for these observations made by Baouid et al.?

In this study, in attempts to answer these questions, we employ the Density functional theory (DFT) approach to establish the mechanism and rationale the effect of different substituents on the 1,4-diazepine substrate on the energetics of the reaction. We further utilize the conceptual density functional tools to rationalize the uniquely observed product outcome to shed insight into this observation. In addition, the effect of solvent on the energetics of the reaction is also explored.

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