Authors: Katie A. Rykaczewski
Source: Deep Blue (University of Michigan) (article, 2023-01-01)
Field: Chemistry — Organic Chemistry

Synthesis and Applications of Strained Heterocycles Heterocyclic compounds account for greater than 50% of all known compounds including a majority of FDA approved drugs, nucleic acids, and energy sources.1 The introduction of a heteroatom in lieu of a carbon atom alters the structural properties and therefore the activity of the compound. Of these substitutions, oxygen and nitrogen atoms have been widely incorporated into valuable compounds across multiple industries: pharmaceuticals, agrichemicals, electronics, and energetic materials. This wide use of oxygen and nitrogen heterocycles stems from their ability to participate in hydrogen bonding, alter the pKa, influence geometry and function as Lewis or Brønsted bases. More specifically, small, strained rings offer unique properties and can influence binding, store energy to be later released, and modulate physicochemical properties (solubility, lipophilicity, etc.). Accessing heterocycles, especially four-membered heterocycles is therefore of importance to the aforementioned industries. While the high ring strain makes them advantageous, this also poses a significant synthetic challenge. This dissertation discusses synthetic strategies towards accessing tetrahydropyridines from amino acids as well as employing visible-light-photocatalysis to access four-membered heterocycles, oxetanes and azetidines, and investigations into applications as energetic materials. The first chapter of this dissertation studies the reactivity of carbonyls and olefins to cyclize, generating six-membered tetrahydropyridine products. Herein, it is demonstrated that a simple Lewis acid, FeCl3, can catalyze the transformation of amino-acid-derived substrates. Furthermore, the inclusion of a strongly electron-withdrawing protecting group on the nitrogen atom attenuates the Lewis-basicity to avoid undesired Lewis-acid/base interactions. The second chapter of this dissertation studies the use of visible light to promote a Paternò-Büchi reaction to generate oxetane products. This strategy is advantageous as it results in densely substituted oxetanes in one-step from commercially available starting materials without any pre-functionalization required. Triplet energy transfer from an iridium-based photocatalyst allows for the use of blue LEDs instead of UV light which has been traditionally used. The third chapter of this dissertation studies the applications of azetidines as energetic materials. This work was done in collaboration with scientists at the U.S. Army Research Laboratory. Synthetic routes are evaluated to synthesize highly-substituted azetidines that function as nitration precursors. Systematic variation of the regio- and stereochemistry results in nitroazetidine analogs that exhibit varying energetic properties. Scalable and robust inter- and intramolecular aza Paternò-Büchi reactions ultimately facilitate the synthesis of various azetidine products in an efficient manner. Evaluation of the synthesized azetidines resulted in superior materials to state-of-the-art compounds. This work greatly expands our knowledge of azetidine-based energetic materials and offers synthetic strategies to access unique products of interest to a variety of fields. Computer science ; Materials science ; Chemistry Synthesis and biological activity ; Synthesis and Biological Evaluation ; Multicomponent Synthesis of Heterocycles