Competition Between Cyclization and Unusual Norrish Type I and Type II Nitro-Acyl Migration Pathways in the Photouncaging of 1-Acyl-7-nitroindoline Revealed by Computations

Abstract

The 7-nitroindolinyl family of caging chromophores has received much attention in the past two decades. However, its uncaging mechanism is still not clearly understood. In this study, we performed state-of-the-art density functional theory calculations to unravel the photo-uncaging mechanism in its entirety, and we compared the probabilities of all plausible pathways. We found competition between a classical cyclization and acyl migration pathways, and here we explain the electronic and steric reasons behind such competition. The migration mechanism possesses the characteristics of a combined Norrish Type I and a 1,6-nitro-acyl variation of a Norrish Type II mechanism, which is reported here for the first time. We also introduced a computational procedure that allows the estimation of intersystem crossing rate constants useful to compare the relative quantum yield of substituted cages. This procedure may pave the way for improved cage designs that possess higher quantum yields and a more efficient agonist release.<br>

Theoretical Design, Synthesis, and In Vitro Neurobiological Applications of a Highly Efficient Two-Photon Caged GABA Validated on an Epileptic Case

“…Our original starting point was the chemical structure of DNI-Glu, which was confirmed to be an outstanding caged glutamate compound reported in several publications by both experimental and QM methods. 15,52 Therefore, the first and directly derived GABA compound is DNI GABA (1, Figure 1, step I), which is used primarily as the reference point. According to our hypothesis, the TPA can be originated by the quadrupole moment of a molecule, which is in contrast with the onephoton transition, which is depending on the dipole moment.…”

“…The E(T 1 ) minima were also confirmed in an earlier publication. 52 The forming F(T 1 ) triplet state is considerably stable, lying close to its ground-state analogue [I(S 0 )], which allows the spontaneous de-excitation via a second ISC. This F(T 1 ) state also leads to the triplet product state [G(T 1 )] through TS3, resulting in the ground-state zwitterionic free GABA by the process of A → C → D → F → I → A can be considered as an undesired "short circuit" of the uncaging process, which only emits and dissipates the laser energy to heat, recovering the starting state.…”