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From the first ambimodal bispericyclic cycloaddition reaction reported by Caramella et al.[1] in 2002, the number of reactions observed to show a post-transition state bifurcation (PTSB) have steadily increased. [2,3] Many of these ambimodal transitions states (TSs) involve a single PTSB. That is, one TS leads to a reaction coordinate that bifurcates after crossing the TS region into two paths to different reaction products without an intervening minimum.[4] Others, show an ambimodal TS where the reaction coordinate splits into different paths leading to different cycloaddition products as a result of sequential bifurcations. [5]
In this work [6] we present the first example of a tetrapericyclic reaction featuring a single TS that leads to four distinct cycloaddition products: [4+6], [2+8], [8+2], and [6+4], without intervening minima. We used DFT calculations to design the tetrapericyclic TS by optimizing orbital interactions between reactants. Quasiclassical molecular dynamics simulations (M06-2X/6-31G) started at the TS were employed to investigate the nature of the potential energy surface (PES) governing this reaction.
Trajectory analysis confirmed the formation of the four products without intervening minima and allowed to stablish product ratios. We also found strong correlation between product ratios and geometric similarity to the TS, measured via root-means-square deviation (RMSD). Notably, the dynamically preferred product exhibits the smallest RMSD from the TS structure. Additionally, we identified three subsequent TSs interconverting the cycloadducts, further elucidating the role of PES topography in product selectivity.
Our findings provide new insights into the role of dynamic effects in complex reactions featuring PTSBs. These results offer a predictive framework for designing reactions with multiple product pathways, which could have significant implications for synthetic applications and controlling selectivity in reactions with PTSB.
References
[1] Caramella, P.; Quadrelli, P.; Toma, L. J. Am. Chem. Soc. 2002, 124, 1130−1131.
[2] Hare, S. R.; Tantillo, D. J. Pure Appl. Chem. 2017, 89, 679−698.
[3] Houk, K. N.; Liu, F.; Yang, Z.; Seeman, J. L. Angew. Chem., Int. Ed. 2021, 60, 12660−12681.
[4] Singleton, D. A.; Hang, C.; Szymanski, M. J.; Meyer, M. P.; Leach, A. G.; Kuwate, K. T.; Chen, S. J.; Greer, A.; Foote, C. S.; Houk, K. N J. Am. Chem. Soc. 2003, 125, 1319−1328.
[5] Xue,X.-S.;Jamieson,C.S, Garcia-Borras̀,M.;Dong,X.;Yang, Z.; Houk, K. N. J. Am. Chem. Soc. 2017, 141, 1217−1221.
[6] A. Martin-Somer, X.-S. Xue, C.S. Jamieson, Y. Zou, and K. N. Houk J. Am. Chem. Soc 2023, 145, 4221-4230.
