Theoretical and Computational Chemistry Laboratory, Department of Chemistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
Department of Basic Sciences, University of Health and Allied Sciences, Ho, Ghana.
J Mol Graph Model. 2023 Sep;123:108515. doi: 10.1016/j.jmgm.2023.108515. Epub 2023 May 12.
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 × 10 Ms, which is about 12 manifolds faster than the next competing stereoisomer P1A with a rate constant of 4.1 × 10 Ms and about 10 faster than the most favored cycloadduct P3B with a rate constant of 7.2 × 10 Ms 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.
1,4-二氮杂环作为大多数精神药物、抗癌药物、抗惊厥药物和抗菌药物的有效药物成分，在市场上具有强大的功效，因此在生物医学中的化学治疗中至关重要。对该部分进行适当的功能化可以提供更有效的药物。由于其治疗意义，本研究旨在全面深入了解 1,4-二氮杂环衍生物和亚甲硝胺氧化物的意外初始反应性。亚甲硝胺氧化物与 1,4-二氮杂环衍生物之间的初始反应通过（3+2）环加成反应进行，该反应导致形成环加成产物，其中亚甲硝胺氧化物出人意料地在亚胺官能团处加成，而不是潜在的烯烃碳-碳双键。在密度泛函理论（DFT）M06/6-311G（d，p）理论水平的计算表明，在所有情况下，亚甲硝胺氧化物（1,3-偶极子）和 1,4-二氮杂环衍生物（偶极子）的初始（3+2）环加成反应都进行形成环加成产物，其中 1,3-偶极子优先在亚胺官能团处加成，而不是在潜在的烯烃碳-碳双键处加成。根据母体反应，最动力学有利的环加成产物 P3A 的速率常数为 5.1×10 Ms，比下一个竞争的立体异构体 P1A 的速率常数 4.1×10 Ms 快约 12 倍，比最有利的环加成产物 P3B 的速率常数 7.2×10 Ms 快约 10 倍在不利途径（Path B）中。无论电子给体（EDG）和电子受体（EWG）取代基在偶极子上的电子和空间性质如何，反应的选择性都得到了保持。势能面的合理化表明，1,3-偶极子通过异步协同机制穿过偶极子加成。亚甲硝胺氧化物（1,3-偶极子）和 1,4-二氮杂环衍生物（偶极子）的 HOMO-LUMO 能量的合理化表明，EDG 取代的偶极子作为亲核试剂反应，而偶极子作为亲电试剂反应。相反，EWG 取代的偶极子的 HOMO-LUMO 相互作用表明，EWG 取代的偶极子作为亲电试剂反应，而偶极子作为亲核试剂反应。偶极子在偶极子各个反应位点的亲电 Parr 函数表明，1,3-偶极子优先在具有最大亲电 NBO 或 Mulliken 自旋密度的局部中心加成，这与观察到的能量趋势一致。1,4-二氮杂环衍生物和亚甲硝胺氧化物的反应性表现出较差的立体选择性。
