A self-immolative system for disclosure of reactive electrophilic alkylating agents: understanding the role of the reporter group

Gavriel, A. G., Leroux, F., Khurana, G. S., Lewis, V. G., Chippindale, A. M. ORCID: https://orcid.org/0000-0002-5918-8701, Sambrook, M. R., Hayes, W. ORCID: https://orcid.org/0000-0003-0047-2991 and Russell, A. T. (2021) A self-immolative system for disclosure of reactive electrophilic alkylating agents: understanding the role of the reporter group. Journal of Organic Chemistry, 86 (15). pp. 10263-10279. ISSN 0022-3263 doi: 10.1021/acs.joc.1c00996

Abstract/Summary

The development of stable, efficient chemoselective self-immolative systems, for use in applications such as sensors, requires the optimisation 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 beta-hydrogen.