Interplay between Energy and Entropy Mediates Ambimodal Selectivity of Cycloadditions - PubMed (original) (raw)
Interplay between Energy and Entropy Mediates Ambimodal Selectivity of Cycloadditions
Wook Shin et al. J Chem Theory Comput. 2024.
Abstract
One ambimodal transition state can lead to the formation of multiple products. However, it remains fundamentally unknown how the energy and entropy along the post-TS pathways mediate ambimodal selectivity. Here, we investigated the energy and entropy profiles along the post-TS pathways in four [4 + 2]/[6 + 4] cycloadditions. We observe that the pathway leading to the minor product involves a more pronounced entropic trap. These entropic traps, resulting from the conformational change in the dynamic course of ring closure, act as a reservoir of longer-lived dynamic intermediates that roam on the potential energy surface and have a higher likelihood of redistributing to form the other product. The SpnF-catalyzed Diels-Alder reaction produces [4 + 2] and [6 + 4] adducts with nearly equal product distribution and relatively flat energy profiles, in contrast to other cycloadditions. Unexpectedly, the entropy profiles for these two adducts are distinctly different. The formation of the [6 + 4] adduct encounters an entropic barrier acting as a dynamical bottleneck, while the [4 + 2] adduct involves a substantial entropic trap to maintain long-lived intermediates. These opposing effects hinder both product formations and likely cancel each other out so that an equal product distribution is observed.
Conflict of interest statement
The authors declare no competing financial interest.
Figures
Figure 1
Overview of the BGAN—entropic path sampling method. Step 1 initiates reaction dynamics trajectories from the TSS, obtaining a minimum number of ca. 100 trajectories for each product formation. Step 2 involves training the BGAN model with molecular configurations sampled from step 1, which accelerates the evaluation of the probability density function of molecular configurations by generating statistically indistinguishable pseudomolecular configurations. Step 3 plots the configurational entropy profile along a user-defined reaction coordinate (i.e., reacting bond) using pseudomolecular configurations generated from step 2.
Figure 2
Reaction schemes and product ratios of the diene/triene cycloaddition, the tethered-diene/triene cycloaddition, the NgnD-catalyzed Diels–Alder reaction, and the SpnF-catalyzed Diels–Alder reaction in the gas phase. Blue represents the [4 + 2] adduct and red represents the [6 + 4] adduct.
Figure 3
Energy (left) and entropy (right) profiles, alongside the ambimodal TSS of the diene/triene cycloaddition. Bond 2 formation leads to the [4 + 2] adduct P1 (blue), and bond 3 formation leads to the [6 + 4] adduct P2 (red). The _x_-axes show changes in bond lengths from the ambimodal TSS, with blue and red dashed lines indicating 2.0 Å. The energy and entropy values for each structural window are computed with reference to those of the first post-TS points. Error bars on energy and entropy profiles are invisible due to its small scale (
Supporting Information
Table S9).
Figure 4
Energy (left) and entropy (right) profiles, alongside the ambimodal TSS of the tethered-diene/triene cycloaddition. Bond 2 formation leads to the [4 + 2] adduct P3 (blue), and bond 3 formation leads to the [6 + 4] adduct P4 (red). The _x_-axes show changes in bond lengths from the ambimodal TSS, with blue and red dashed lines indicating 2.0 Å. The energy and entropy values for each structural window are computed with reference to those of the first post-TS points. Error bars on energy and entropy profiles represent the standard error of the mean.
Figure 5
Energy (left) and entropy (right) profiles, alongside the ambimodal TSS of the NgnD-catalyzed Diels–Alder reaction. Bond 2 formation leads to the [4 + 2] adduct P5 (blue), and bond 3 formation leads to the [6 + 4] adduct P6 (red). The _x_-axes show changes in bond lengths from the ambimodal TSS, with blue and red dashed lines indicating 2.0 Å. The energy and entropy values for each structural window are computed with reference to those of the first post-TS points. Error bars on energy and entropy profiles represent the standard error of the mean.
Figure 6
Energy (left) and entropy (right) profiles, alongside the ambimodal TSS of the SpnF-catalyzed Diels–Alder reaction. Bond 2 formation leads to the [4 + 2] adduct P7 (blue), and bond 3 formation leads to the [6 + 4] adduct P8 (red). The _x_-axes show changes in bond lengths from the ambimodal TSS, with blue and red dashed lines indicating 2.0 Å. The energy and entropy values for each structural window are computed with reference to those of the first post-TS points. Error bars on energy and entropy profiles represent the standard error of the mean.
References
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