The pressing need for new pharmaceuticals and materials requires synthetic methods that can be performed in efficient and controllable ways. Understanding the mechanisms of new organic reactions from a physical point of view, in terms of the underlying thermodynamics and kinetics, can lead to the development of new synthetic approaches that can help fulfill these goals. Electronic structure methods provide a powerful tool that can be used to determine how thermodynamics and kinetics guide underlying chemical reactions while providing a molecular picture of how the energetic properties are tied to changes in the molecular structure. Along these lines, we set out to understand how the addition of a tert-butyldimethylsilyl ether (OTBS) protecting group to an N-enoxyphthalimide compound (a) would affect the activation barrier and thermodynamics of an intra-molecular oxygen bond rearrangement and the diastereoselectivity of the products (Fig). Our experimentalist collaborators found that the addition of the OTBS protecting group (b) allowed the rearrangement reaction to occur at a lower temperature and resulted in the formation of diastereoselective products. Using density functional theory, we were able to calculate transition state structures for the protected and unprotected reactions, in addition to finding transition states for all possible diastereomer combinations. Comparison of the barrier heights and corresponding transition state structures showed that the OTBS group is able to stabilize the transition state via steric interactions, thus lowering the activation barrier. Additionally, this effect is increased for the reactions that form the experimentally observed diastereomer products. By understanding why the activation barrier is lowered from a molecular structure point of view, our collaborators hope to design new reactions that that can be performed at lower temperatures, lowering the overall energy cost of the method. Additionally, these findings can lead to the development of general synthetic methods that can be applied to the creation of novel drugs and materials.

Intramolecular oxygen bond rearrangement reactions studied with density functional theory: Thermodynamics vs. kinetics

249th National Meeting (2015)

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