Experimental study demonstrates orthogonal bioorthogonal cycloadditions controlled by frontier molecular orbital energies, enabling simultaneous dual-protein labeling with distinct fluorophores.
Chemoselective pairs of bioorthogonal reactants enable the simultaneous labeling of several biomolecules. Here, we access orthogonal click reactions by exploiting differences in frontier molecular orbital interaction energies in transition states. We establish that five-membered cyclic dienes are inert to isonitriles but readily react with strained alkynes, while tetrazines with bulky substituents readily react with isonitriles. Strained alkynes show an opposite reactivity pattern. The approach was demonstrated by orthogonally labeling two proteins with different fluorophores.
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Svatunek et al. (2023) studied this question.
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