Substituent Effects Govern the Efficiency of Isoxazole Photoisomerization to Carbonyl-2H-Azirines
Persistent URL
Author(s)
Jackson, Kyra E.
Szeto, Isabelle
Seebald, Leah M.
Shepard, Samuel G.
Allegheny College
Date Issued
December 1, 2025
Abstract
The photoisomerization of isoxazoles is an atom-economical route to carbonyl-2H-azirines, which are valuable in both synthetic and biological applications. However, isolation of the carbonyl-2H-azirine is challenged by reverse photoisomerization back to the isoxazole and irreversible rearrangement to an oxazole. In this work, we demonstrate that substituent selection on 3,5-disubstituted isoxazoles plays a critical role in driving the photochemical isoxazole–azirine equilibrium toward the carbonyl-2H-azirine while avoiding oxazole formation. We find that substituents affect the degree of overlap in the absorption spectra of isoxazole–azirine pairs, where reducing overlap increases the efficiency of photoisomerization. We use time-dependent density functional theory to predict absorption spectra for isomer pairs with varied 3,5-disubstituents, identifying tert-butyl- and trifluoromethyl-substituted 5-aminoisoxazoles as promising structures. We then tested these predictions experimentally, revealing efficient formation of carbonyl-2H-azirines in high yields with minimal oxazole formation. This is in contrast to a phenyl-substituted 5-aminoisoxazole, which was found to readily form oxazoles, precluding isolation of the carbonyl-2H-azirine. These results demonstrate the utility of substituent-driven design for tuning photoisomerization equilibria and provide an atom-economical option for generating carbonyl-2H-azirines on synthetically useful scales.
Journal
ACS Organic & Inorganic Au
Citation
ACS Org. Inorg. Au 2026, 6, 1, 41–46
Publisher
American Chemical Society (ACS)
Version of Article
Version of Record
DOI
10.1021/acsorginorgau.5c00105
ISSN
2694-247X
2694-247X
Rights
Copyright © 2025 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0 .
Type of Publication
Journal Article
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2025_Shepard_Substituent.pdf
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