Spot the difference in reactivity: a comprehensive review of site-selective multicomponent conjugation exploiting multi-azide compounds

Abstract

Going beyond the conventional approach of pairwise conjugation between two molecules, the integration of multiple components onto a central scaffold molecule is essential for the development of high-performance molecular materials with multifunctionality. This approach also facilitates the creation of functionalized molecular probes applicable in diverse fields ranging from pharmaceuticals to polymeric materials. Among the various click functional groups, the azido group stands out as a representative click functional group due to its steric compactness, high reactivity, handling stability, and easy accessibility in the context of multi-azide scaffolds. However, the azido groups in multi-azide scaffolds have not been well exploited for site-specific use in molecular conjugation. In fact, multi-azide compounds have been well used to conjugate to the same multiple fragments. To circumvent problems of promiscuous and random coupling of multiple different fragments to multiple azido positions, it is imperative to distinguish specific azido positions and use them orthogonally for molecular conjugation. This review outlines methods and strategies to exploit specific azide positions for molecular conjugation in the presence of multiple azido groups. Illustrative examples covering di-, tri- and tetraazide click scaffolds are included.