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 an acyl migration pathway, 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 found negligible energetic differences in the uncaging mechanisms of the 4-methoxy-5,7-dinitroindolinyl (MDNI) cages and their mononitro analogues (MNI). We traced the experimentally observed improved quantum yields of MDNI to a higher population of the reactants in the triplet surface. This fact is supported by a more favorable intersystem crossing due to the availability of a higher number of triplet excited states with the correct symmetry in MDNI than in MNI. Our findings may pave the way for improved cage designs that possess higher quantum yields and a more efficient agonist release.

Synthesis and Photoreactivity of 7-Nitroindoline-S-thiocarbamates

“…Synthesis of 5-Bromo-7-nitroindoline-(S-ethyl)-thiocarbamate (7). In a round bottom flask, commercially available 5-bromo-7-nitroindoline (5) (0.411 mmol) was dissolved in anhydrous DCM (2.0 mL) under argon.…”

“…Here we have developed a simple, high-yield synthesis of 7nitroindoline thiocarbamates, a new group of photoreactive compounds, and studied their photolysis. The photoreactivity of one representative of this class of compounds, that is, 5bromo-7-nitroindoline-(S-ethyl)-thiocarbamate (7), was studied in more detail both by one-photon and two-photon absorption mechanisms. Surprisingly, the photolysis path and products differ from those of N-acyl-7-nitroindolines.…”

“…2,3 Different mechanisms for the formation of the common nitronic anhydride precursor (2) have been proposed, 2,4−7 including an addition−elimination via a cyclic intermediate, 2 and a combined Norish type I and type II acyl migration from the indoline nitrogen to the neighboring nitro group. 7 Several applications of N-acyl-7-nitroindolines have been described. For example, neuroactive amino acids that had been caged as N-acyl-7-nitroindolines were released ("uncaged") by one-photon as well as two-photon photolysis.…”

“…These N -acyl-7-nitroindolines ( 1 ) are activated by near UV or indigo-colored light, generating highly reactive nitronic anhydride intermediates ( 2 ) that cannot be isolated (Scheme ). The nitronic anhydrides react further by two different pathways that are solvent-dependent: (a) they are capable of acylating nucleophiles such as water, amines, and alcohols in inert aprotic solvents producing carboxylic acids, amides, and esters, respectively, as well as 7-nitroindolines ( 3 ) by an addition–elimination reaction. , (b) Alternatively, in aqueous media, an ε-elimination followed by a tautomerization takes place, resulting in carboxylic acids and 7-nitrosoindoles ( 4 ). , Different mechanisms for the formation of the common nitronic anhydride precursor ( 2 ) have been proposed, ,− including an addition–elimination via a cyclic intermediate, and a combined Norish type I and type II acyl migration from the indoline nitrogen to the neighboring nitro group …”