Interplay between\nEnergy and Entropy Mediates Ambimodal\nSelectivity of Cycloadditions

One ambimodal transition state can lead to the formation\nof multiple\nproducts. However, it remains fundamentally unknown how the energy\nand entropy along the post-TS pathways mediate ambimodal selectivity.\nHere, we investigated the energy and entropy profiles along the post-TS\npathways in four [4 + 2]/[6 + 4] cycloadditions. We observe that the\npathway leading to the minor product involves a more pronounced entropic\ntrap. These entropic traps, resulting from the conformational change\nin the dynamic course of ring closure, act as a reservoir of longer-lived\ndynamic intermediates that roam on the potential energy surface and\nhave a higher likelihood of redistributing to form the other product.\nThe SpnF-catalyzed Diels–Alder reaction produces [4 + 2] and\n[6 + 4] adducts with nearly equal product distribution and relatively\nflat energy profiles, in contrast to other cycloadditions. Unexpectedly,\nthe entropy profiles for these two adducts are distinctly different.\nThe formation of the [6 + 4] adduct encounters an entropic barrier\nacting as a dynamical bottleneck, while the [4 + 2] adduct involves\na substantial entropic trap to maintain long-lived intermediates.\nThese opposing effects hinder both product formations and likely cancel\neach other out so that an equal product distribution is observed.