Reinvigorating and extending the scope of obscure using computational quantum chemistry. (2022)
The literature has many examples of obscure reactions and functional groups, that typically appear only once or a handful of times in the context of synthesizing a single, specific product. The reasons for obscurity are varied, including practical difficulties like difficulty accessing or handling the reagents required, raising the barrier to studying the reaction to the point where the reaction is insufficiently studied to lower the barriers, and consequently is not used. However, obscurity does not mean lack of utility. Obscure reactions may allow comparatively facile routes to products that are hard to make via other routes, or have yet to be made at all. Computational modelling is a powerful tool for exploring whether and/or how obscure reactions may be extended or generalized to open up new regions of chemical space, at the same time avoiding spending substantial time, energy, and money on attempting synthetic routes that are likely to be unproductive.
Many computational methods exist, due to the fact that it is impossible to exactly solve the Schrödinger equation for multi-electron systems. Different theories use different approximations and result in different models of varying computational cost and accuracy. Density functional theories generally lie at the “sweet spot” of moderate-to-high accuracy for moderate-to-low computational cost, but are not guaranteed to be universally applicable nor systematically improvable. Therefore it is necessary to benchmark them against higher level quantum chemical methods. In this work, λ6-sulfanenitriles were chosen as a prototypical system for benchmarking, because they are sufficiently exotic and obscure to provide a challenging test case but can be small enough that it is possible to compute a range of properties - interatomic distances, angles, NMR shifts, electronic energies, reaction coordinate profiles, vibrational frequencies, enthalpies and entropies – using a comprehensive set of quantum chemical methods. B3LYP was identified as the functional that provided the best trade-off between accuracy and computational cost, particularly because it is one of the few functionals for which analytic second derivatives of the energy with respect to atomic displacements are available, required for calculating frequencies and confirming the nature of stationary points on the potential energy surface while mapping out reaction coordinate profiles.
The B3LYP functional was applied in conjunction with the 6-311G* basis set and a polarizable continuum solvation model to compute the minimum energy reaction pathway for the key 1,2- migration step of the Biltz reaction (a condensation reaction between a 1,2-diketone and a urea, forming a 5 membered heterocycle called a hydantoin) and determining the energy barriers and net energy changes for a range of migrating groups. Aryl groups were found to migrate with relative ease as anticipated, and no intermediate between the N-acyliminium ion and the protonated hydantoin was found. Conformation-dependent effects were found for alkyl groups which may contribute to stabilization of the intermediate N-acyliminium ion. Hyperconjugation in a σ,σ manner instead of the anticipated σ,π manner is likely the cause of the effects, and these effects were most pronounced in the case of the migrating group being tertiary. Variations to the core structure were also investigated, including cases where progression of the reaction resulted in a ring contraction. Contractions from 7 to 6 membered rings were found to be highly thermodynamically favourable, while contractions from 6 or lower to smaller rings are thermodynamically unfavourable. These studies will help guide future experimental work, and in particular suggest that the Biltz reaction would be well suited for forming sterically crowded hydantoins, as well as spirocyclic compounds with a hydantoin substructure.
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