Harnessing Thorpe–Ingold Dialkylation to Access High-Hill-Percentage pH Probes

Sensitivity is an important parameter for a molecular probe. Hill-type pH probes exhibit improved detection sensitivity compared to the traditional pH probes following the Henderson–Hasselbalch equation. Exploiting positive cooperativity, we recently devised a novel molecular scaffold (PHX) to offer such an unconventional Hill-type pH titration profile. We previously confirmed that PHX is not a pure Hill-type probe yet. Only 64% of its absorbance/fluorescence turn-on is the result of a Hill-type pathway. The remaining 36% is from an undesired Henderson–Hasselbalch-type pathway (HH pathway). In this work, the Thorpe–Ingold dialkylation was harnessed to further suppress the percent contribution of the HH pathway down to 16%. We also propose that PHX is a viable molecular model for assessing the efficacy of the steric compressing effect induced by different Thorpe–Ingold dialkylations.