Computational characterisation of transition states for several π-spacers adopted in self-immolative elimination reactions allows rationalising electronic effects on reaction rates, paving the way towards the in silico design of new spacers.

Abstract

The controlled release of chemicals, especially in drug delivery, is crucial, often employing “self–immolative” spacers to enhance reliability. These spacers separate the payload from the protecting group, ensuring a more controlled release. Over the years, design rules have been proposed to improve the elimination process's reaction rate by modifying spacers with electron–donating groups or reducing their aromaticity. The spacer design is critical for determining the range of functional groups released during this process. This study explores various strategies from the literature aimed at improving release rates, focusing on the electronic nature of the spacer, its aromaticity, the electronic nature of its substituents, and the leaving groups involved in the elimination reaction. Through computational analysis, I investigate activation free energies by identifying transition states for model reactions. My calculations align qualitatively with experimental results, demonstrating the feasibility and reliability of computationally pre–screening model self–immolative eliminations. This approach allows proposing optimal combinations of spacer and leaving group for achieving the highest possible release rate.