The lower click reactivity of h4P2 (6) compared to 5 (620 vs. 1500 M - s -1 in PBS) aligns with our recent findings about the critical role of distortion due to intramolecular N-N repulsion in 2pyridyl-substituted Tz. Given their higher IEDDA reactivity and water-solubility compared to Tz 4, we primarily focused on Tz 5 and 6 for further investigation.