A Computational Modeling of <scp>ADLumin</scp> Chemiluminescence: Oxygenation and Dioxetanone Formation

ABSTRACT ADLumin is a new class of turn‐on chemiluminescent probes that have shown increased luminescent intensity in the presence of amyloid beta () plaques, which are commonly associated with Alzheimer's disease (AD). ADLumin shares an imidazopyrazinone (IPO) moiety with the well‐known Cypridina luciferin, which reacts with O 2 and produces bioluminescence. While the reaction mechanism for many other luciferins has been studied extensively, the chemiluminescent mechanism for ADLumin molecules has yet to be modeled computationally. In this work, we focus on the exploration of potential reaction mechanism for the dioxetanone formation in ADLumin‐5, which has shown stronger chemiluminescence in the presence of plaques than other ADLumin molecules. Our density functional theory calculations predict thermally accessible energy barriers for three separate reaction paths, which we refer to as A, B, and B′, respectively. These mechanisms differ in binding sites, all with comparable singlet‐triplet minimum energy crossing point (MECP) energies. While paths A and B are similar to those previously studied for the oxidation of Cypridina luciferin, our calculations revealed a bifurcating crossing point connecting path B and an alternative path B′. Overall, our results suggest that path B is the most energetically favorable among the three pathways for ADLumin‐5.