1, 3-Dipolar cycloaddition reactions of selected 1,3-dipoles with 7-isopropylidenenorbornadiene and follow-up thermolytic cleavage: Acomputational study

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Elsevier Inc.
The mechanism, regio-, stereo-, and enantio-selectivities of the 1,3-dipolar cycloaddition reactions of7-isopropylidenenorbornadiene (DENBD) with nitrones and azides to form pharmaceutically relevantisoxazolidine and triazole analogues have been studied computationally at the M06/6-31G(d), 6-31G(d,p), 6-311G(d,p), 6e311þþG(d,p) and M06-2X/6-31G(d) levels of theory. In the reactions of DENBDwith phenyl nitrones, the cycloaddition steps have low activation barriers, with the highest being 16 kcal/mol; and the Diels-Alder cycloreversion steps have generally high barriers, with the lowest being 20 kcal/mol, suggesting that the isolable products in these reactions are the bicyclic isoxazolidine cycloadductsand not the thermolytic products. This is in contrast to the reactions of DENBD with phenyl azide wherethe isolable products are predicted to be the thermolytic products since the Diels-Alder cycloreversionsteps had relatively lower activation barriers. Electron-donating substituents on the dipolarophile sub-strate favour attack of the nitrone on the least hindered side of the DENBD substrate while electron-withdrawing substituents on the dipolarophile substrate favour attack on the more hindered side ofthe DENBD, indicating that site-selectivity is affected by nature of substituents. Global reactivity indicescalculations are in good agreement with the activation barriers obtained. Analysis of the electrophilic(PþKÞand nucleophilic (P KÞParr functions at the reactive centres reveal that the cycloaddition occursbetween atoms with the largest Mulliken and NBO atomic spin densities which agrees well with theenergetic trends and the experimental product outcomes.
An article published by Elsevier Inc and also available at https://doi.org/10.1016/j.jmgm.2019.08.004
Density functional theory, Norbornadiene, Isoxazolidines 1,3-Dipoles, Reaction mechanism
G. Arhin et al. / Journal of Molecular Graphics and Modelling 92 (2019) 267e279. https://doi.org/10.1016/j.jmgm.2019.08.004