Unusual Norrish Type I and Type II Nitro-Acyl Migration Transition State in the Photo-Uncaging of 1-Acyl-7-Nitroindolines Revealed by Computations

The 7-nitroindolinyl family of caging chromophores has received a lot of attention in the past two decades. However, it is not clear if they undergo cyclization or migration upon photo-uncaging to release the active compound. In this study, we performed state-of-the-art density functional theory calculations to fully understand the photo-uncaging mechanism and we compared the probabilities of all plausible pathways. We found that the key transition state in the lowest¬ energy pathway involves an acyl migration. It possesses the characteristics of a combined Norrish Type I and a 1,6-nitro-acyl variation of a Norrish Type II mechanism, which has not been previously reported. We also introduced a new 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 more efficient agonist release.