Computational Investigation of the Formation of Substituted Isoindole N-Oxides through the Photo-oxidative Cyclization of 2'-Alkynylacetophenone Oximes.

Our recently published joint experiment-theory study of the photo-oxidative intramolecular cyclization of 2'-alkynylacetophenone oximes, performed in collaboration with the de Lijser group, presented the first reported formation of isoindole N-oxides. That study focused on determining a mechanistic explanation for the unexpected chemistry observed when three 2'-alkynylacetophenone oximes were photo-oxidized with 9,10-dicyanoanthracene (DCA), specifically the derivatives with a phenyl, isopropyl, or n-butyl substituent at the alkynyl group. Here, we use density functional theory to develop a broader understanding of the scope of this chemistry. In particular, we demonstrate that substituents on the alkynyl group and on the central benzene ring can significantly modulate the thermodynamic driving force for oxime radical cation generation when DCA is used as the photosensitizer. In contrast, substituents are shown to have a small impact on the chemical reactivity of the radical cation intermediates. In particular, 5-exo radical cation cyclization, which ultimately results in an isoindole N-oxide product, is always kinetically and sometimes also thermodynamically preferred over 6-endo radical cation cyclization, which would produce an isoquinoline N-oxide product. Overall, this study provides mechanistic insights into the diversity of isoindole N-oxides that can be produced through the photo-oxidative cyclization of 2'-alkynylacetophenone oximes.