Self-Immolative System for Disclosure of Reactive Electrophilic Alkylating Agents: Understanding the Role of the Reporter Group

Abstract

The development of stable, efficient chemoselective self-immolative systems, for use in applications such as sensors, requires the optimization of the reactivity and degradation characteristics of the self-immolative unit. In this paper, we describe the effect that the structure of the reporter group has upon the self-immolative efficacy of a prototype system designed for the disclosure of electrophilic alkylating agents. The amine of the reporter group (a nitroaniline unit) was a constituent part of a carbamate that functioned as the self-immolative unit. The number and position of substituents on the nitroaniline unit were found to play a key role in the rate of self-immolative degradation and release of the reporter group. The position of the nitro substituent ( meta - vs para -) and the methyl groups in the ortho -position relative to the carbamate exhibited an influence on the rate of elimination and stability of the self-immolative system. The ortho -methyl substituents imparted a twist on the N–C (aromatic) bond leading to increased resonance of the amine nitrogen’s lone pair into the carbonyl moiety and a decrease of the leaving character of the carbamate group; concomitantly, this may also make it a less electron-withdrawing group and lead to less acidification of the eliminated β-hydrogen.

Recent advances in self-immolative linkers and their applications in polymeric reporting systems

“…8 Inspired by work from Kunz 169 and Verducci, 170 Recent optimisation studies by Gavriel et al, to probe both electronic and steric effects of the reporter unit, identified the self-immolative system 152 as the best balance of stability and reactivity. 171 Scheme 33 Taran and LeGall's FRET-based detection system 148 for electrophilic alkylating agents. 9 Scheme 34 (a) Self-immolative system 150 for disclosure of electrophilic alkylating agents, as described by Acton et al; 8 (b) optimisation of 150 to afford compound 152.…”

“…9 Scheme 34 (a) Self-immolative system 150 for disclosure of electrophilic alkylating agents, as described by Acton et al; 8 (b) optimisation of 150 to afford compound 152. 171…”

“…Recent optimisation studies by Gavriel et al , to probe both electronic and steric effects of the reporter unit, identified the self-immolative system 152 as the best balance of stability and reactivity. 171…”