Steric substitution in phenylazo indoles reveals interplay of steric and electronic effects on photophysical dynamics

Abstract

Indole-containing azo dyes have the potential to add photocontrol to pharmaceuticals, as substituted indoles are prevalent in biological systems. It is critical to understand the complex interplay substitution has on the photophysical properties in order to enable control of the on and off states of a drug. This work identifies the impact of steric and electronic effects of four steric R-groups on the photoisomerization and thermal reversion processes of a series of phenylazo indole dyes and demonstrates that protonation can be used to control bulk isomerization. Four phenylazo indole dyes were synthesized with varying steric bulk, a proton (H), a methyl group (Me), a tert-butyl group (tBu), or a phenyl group (Ph), at the C₂ position of the indole adjacent to the azo bond. 2D NOESY NMR and computational methods were used to identify the rotational conformation of each trans-isomer as the anti-rotamer. The cis-isomer of the unsubstituted moiety accesses the eclipsed-rotamer while all other dyes adopt the anti-rotamer after photoexcitation. The Taft and Charton free energy models were employed to identify if the steric or electronic contributions of the steric R-group more strongly impact photoisomerization and thermal reversion dynamics. Surprisingly, in these indole dyes, electron donation strength, measured by the electronic Taft parameter of the steric R-group, correlated with the increasing photoisomerization rate. Thermal reversion rates were found to decrease with increasing steric substitution following the steric Taft parameter. However, the unsubstituted compound deviated from the trends in both photoisomerization and reversion dynamics. Acidity constants increase with increasing bulk of the steric R-group using the Charton steric model and protonation of the azo bond eliminated bulk photoisomerization. Thus, the impact of steric modification does not result in straightforward effects on the photophysical behavior, even when choosing a site close to the azo bond.