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Interest in mutually exclusive pairs of bioorthogonal labeling reagents continues to drive the design of new compounds
capable of fast and predictable reactions. The ability to easily modify heterocyclic strained cyclooctynes containing sulfamate
backbones (SNO-OCTs) enables electronic tuning of the relative rates of reactions of SNO-OCTs in cycloadditions with Type I–III
dipoles. As opposed to optimizations based on just one specific dipole class, the electrophilicity of the alkynes in SNO-OCTs can be
manipulated to achieve divergent reactivities and furnish mutually orthogonal dual ligation systems. Significant rate enhancements
for reactions of a difluorinated SNO-OCT derivative compared to the parent scaffold were noted, with the second-order rate constant
in cycloadditions with diazoacetamides exceeding 1 M−1
. Computational and experimental studies were employed to inform the
design of triple ligation systems that encompass three orthogonal reactivities. Finally, polar SNO-OCTs are rapidly internalized by
mammalian cells and remain functional in the cytosol for live-cell labeling, highlighting their potential for diverse in vitro and in vivo