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.
Highlights
Stimuli-responsive compounds,1−3 such as self-immolative molecules and polymers,4−7 have become significant targets in organic-based material development as systems of this type offer enormous potential in a diverse range of applications that span drug delivery,8−10 biological and chemical sensors,11,12 diagnostics,13 and degradable polymers or degrade-on-demand adhesives.14−19 The seminal report by Katzenellenbogen and co-workers,20 based upon the “prodrug” concept discussed by Albert,21 set in place the key molecular design for selfimmolative materials that have been explored and refined by several groups in recent years, one in which a substrate-specific trigger is coupled via a degradable linker group to a reporter moiety
In a recent communication,23 we reported the first examples of selective solution-phase self-immolative systems triggered by a nonacidic electrophilic species, such as methyl, allyl, and benzylic halides, to afford a facile colorimetric visual disclosure of toxic electrophilic alkylating agents (Scheme 1)
We have recently reported a novel self-immolative system23 for the selective disclosure of reactive electrophilic alkylating agents that is stable in solution (>72 h in CD3CN) and when exposed to water (10% D2O in CD3CN)
Summary
Stimuli-responsive compounds,− such as self-immolative molecules and polymers,− have become significant targets in organic-based material development as systems of this type offer enormous potential in a diverse range of applications that span drug delivery,− biological and chemical sensors, diagnostics, and degradable polymers or degrade-on-demand adhesives.− The seminal report by Katzenellenbogen and co-workers, based upon the “prodrug” concept discussed by Albert, set in place the key molecular design for selfimmolative materials that have been explored and refined by several groups in recent years, one in which a substrate-specific trigger is coupled via a degradable linker group to a reporter moiety. The effect of the structure of the linker group upon selfimmolative pathway and degradation rates has been shown to be pivotal in this design rationale.. Phillips and co-workers have elegantly shown the effect that the structure of aromatic self-immolative linkers has on a selfimmolative process and were able to tune the controlled release of phenols under neutral conditions The effect of the structure of the linker group upon selfimmolative pathway and degradation rates has been shown to be pivotal in this design rationale. In a detailed study, Phillips and co-workers have elegantly shown the effect that the structure of aromatic self-immolative linkers has on a selfimmolative process and were able to tune the controlled release of phenols under neutral conditions
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