Spotlight on Mechanosterics: A Bulky Macrocycle Promotes Functional Group Reactivity in a [2]Rotaxane

Macrocycles are typically thought to hinder the reactivity of adjacent functional groups in mechanically interlocked mole-cules due to steric shielding. Yet, we report a [2]rotaxane in which a bulky macrocycle in fact accelerates deprotection of a 2,7-tBu2-9-fluorenylmethoxycarbonyl (Fmoc*) stopper by over 35-fold compared to a non-interlocked control. We ra-tionalize this by a preorganization of the macrocycle and the Fmoc* stopper, exposing its reactive site for base abstrac-tion. This is evidenced by extensive NMR, SC-XRD, and DFT studies, revealing highly directional CH–π interactions and hydrogen bonding between the interlocked components. Our findings challenge the prevailing view that mechanical bonds inherently inhibit the reactivity of nearby functional groups, demonstrating that entanglement can instead promote reactivity through precise spatial control. This concept paves the way for designing molecular machines with functional, reactivity-enhancing components.