Theoretical insight into the unexpected initial (3 + 2) cycloaddition reaction of mesitonitrile oxide with 1,...

1,4-Diazepine as an active drug component underlies the potency of most psychotic, anticancer, anticonvulsant, and antibacterial drugs in the market and is, therefore crucial in chemotherapeutic treatment in biomedicine. Proper functionalization of this moiety can afford even more potent drugs. As a result of their therapeutic significance, this study aims at precisely giving a comprehensive computational insight into the unexpected initial reactivity of 1,4-diazepine derivatives and mesitonitrile oxide. The initial reaction between mesitonitrile oxide and 1,4-diazepine derivatives proceeds via a (3 + 2) cycloaddition reaction which leads to the formation of a cycloadduct where the mesitonitrile oxide unexpectedly adds across the imine functionality at the expense of the potential olefinic carbon-carbon double bond. Calculations at the density functional theory (DFT) M06/6-311G (d, p) level of theory indicate that the initial (3 + 2) cycloaddition reaction of mesitonitrile oxide (1,3-dipole) and 1,4-diazepine derivatives (dipolarophile) in all cases proceeds to form the cycloadduct where the 1,3-dipole adds preferentially to the imine functionality at the expense of the potential olefinic carbon-carbon double bond. In light of the parent reaction, the most kinetically favored cycloadductP3A had a rate constant of 5.1 × 10⁶ M^-1s^-1, which is about 12 manifolds faster than the next competing stereoisomer P1A with a rate constant of 4.1 × 10⁵ M^-1s^-1 and about 10²⁴ faster than the most favored cycloadduct P3B with a rate constant of 7.2 × 10^-19 M^-1s^-1 in the unfavored pathway (Path B). Irrespective of the electronic and steric nature of the electron-donating (EDG) and electron-withdrawing (EWG) substituents placed on the dipolarophile, the selectivities of the reaction were maintained. Rationalization of the potential energy surface depicts that the 1,3-dipole adds across the dipolarophile via an asynchronous concerted mechanism. Rationalization of the HOMO-LUMO energies of the mesitonitrile oxide (1,3-dipole) and the 1,4-diazepine derivatives (dipolarophile) depict that the EDG-substituted dipolarophile react as nucleophiles, whereas the dipole reacts as an electrophile. Conversely, the HOMO-LUMO interaction between the EWG-substituted dipolarophile indicates that the EWG-substituted dipolarophile react as electrophiles, whereas the dipole reacts as a nucleophile. The electrophilic parr function at various reactive sites of the dipolarophile shows that the 1,3-dipole preferentially adds across the local centers with the largest electrophilic NBO or Mulliken spin densities which is consistent with the energetic trend observed. The reactivity of the 1,4-diazepine derivatives and the mesitonitrile oxide showed poor stereoselectivity.