Theoretical modulation of singlet/triplet chemiexcitation of chemiluminescent imidazopyrazinone dioxetanone via C8-substitution

Abstract

Coelenterazine, a member of the imidazopyrazinone class of chemiluminescent substrates, presents significant potential as a dynamic probe of reactive oxygen species in a biological environment, such as a superoxide anion, in which these species are important in cellular biology and pathology. The objective of the current study was to understand in what way the efficiency of singlet and triplet chemiexcitation could be modulated, towards a more efficient use of imidazopyrazinone-based compounds as dynamic chemiluminescent probes. To this end the thermolysis of imidazopyrazinone dioxetanone, substituted at the C-position with electron-donating or electron-withdrawing groups, was characterized with a theoretical approach based on density functional theory. Substituents with different electron-donating/withdrawing characters have only a limited effect on the singlet chemiexcitation of anionic dioxetanone. For neutral dioxetanone, both electron-withdrawing and weak electron-donating substituents increase singlet chemiexcitation, to the contrary of strong electron-donating groups. During their thermolysis reaction, all molecules presented regions of degeneracy with triplet states, thereby indicating the possibility of triplet chemiexcitation.

Mechanistic insights into the efficient intramolecular chemiexcitation of dioxetanones from TD‐DFT and multireference calculations

“…As consistent with existent data, the thermolysis of the four dioxetanones here studied (Scheme ) proceeds via a stepwise biradical mechanism. This was determined by the calculation of ( S 2 ) values higher than 0.4 and by analysis of the evolution of the OO and CC bond length of the cyclic peroxide during thermolysis (Supporting Information Figure S1).…”

“…More specifically, previous studies have already correlated efficient chemiexcitation with the presence of a long and flat region of S 0 ‐ S 1 degeneracy (which is not present in all dioxetanones) . However, and despite significant research, the reason for the presence of this region has not been presented.…”

“…However, even CTIL have failed to explain some experimental and theoretical results. Theoretical calculations have shown that neutral imidazopyrazinone‐based dioxetanones present more efficient S 0 →S 1 chemiexcitation pathways than anionic dioxetanones . This results from the fact that neutral peroxides have access to a large and flat potential energy surface (PES) region of degeneracy between S 0 and S 1 states found within the biradical region.…”

“…Ionic dioxetanones have been found to not have access to this region of degeneracy. Moreover, the S 0 →S 1 energy gap within the biradical region for ionic peroxides is significantly higher than for neutral dioxetanones, which indicates a lower efficiency of chemiexcitation . These conclusions have been supported by experimental studies on imidazopyrazinones and other systems .…”

“…We found that despite both molecules undergoing different chemiexcitation pathways, both dioxetanone species decompose with significant ET/BET and CT/BCT between the imidazopyrazinone and dioxetanone moieties . Furthermore, other neutral dioxetanones allowed for efficient chemiexcitation, but their thermolysis occurred without significant ET/CT . Thus, neither ET/BET nor CT/BCT has any clear relationship with efficient chemiexcitation.…”