siteselective

Site-selective, sometimes written as siteselective, describes a chemical transformation that occurs preferentially at a single site within a substrate that contains multiple potentially reactive locations. It is a form of selectivity focused on choosing one specific site—such as among several C–H bonds, different functional groups, or distinct residue positions in a biomolecule—in contrast to broader categories like chemoselectivity or general regioselectivity. Site-selectivity is a central concept in complex molecule functionalization, enabling modification without protecting every other site.

Approaches to achieving site-selectivity rely on directing groups, intrinsic differences in site reactivity, and careful catalyst or ligand design. Directing groups can guide catalysts to a particular location, while differences in electronics, sterics, or conformation bias the reaction toward one site. In addition, advances in transition-metal catalysis, radical-based methods, and biocatalysis have expanded the range of site-selective transformations. Remote or site-specific activation, where a catalyst reaches less accessible sites through templating or concerted mechanisms, also contributes to this field. Examples include site-selective C–H activation and functionalization in complex molecules, and enzyme-catalyzed site-specific modifications in biological contexts.

Applications span late-stage functionalization in medicinal chemistry, enabling diversification of drug candidates without de novo synthesis, and selective labeling or isotopic labeling for mechanistic studies. In natural product synthesis, site-selective strategies allow targeted modifications without extensive protection schemes. Ongoing challenges include achieving high selectivity in densely functionalized substrates, minimizing competing pathways, and translating laboratory conditions into scalable processes.

See also: regioselectivity, chemoselectivity, enantioselectivity, C–H activation.