Pillar[5]arene-catalyzed anti-Markovnikov halogenations through cationic intermediates stabilization in confined spaces.

The confinement of reactants within catalytic cavities is important for achieving efficient and selective chemical transformations. Macrocyclic organic covalent hosts, which mimic enzymatic environments, offer well-defined, tunable cavities capable of substrate accommodation. These robust and synthetically accessible hosts can be engineered into catalysts by functionalizing their rims, where substrate selectivity emerges from size- or shape-complementary binding. This positioning brings reactive sites into proximity with catalytic functional groups at the rims of covalent hosts, accelerating reactions. Cationic intermediates are pivotal in many chemical transformations, and stabilizing these reactive species within confined microenvironments could unlock unconventional selectivity for synthesizing high-value compounds. Despite this potential, leveraging the cavities of covalent hosts to stabilize and confine cationic intermediates for regioselective reactions remains underexplored. Here we report that the π-basic cavity of pillar[n]arenes can effectively stabilize bromiranium intermediates generated during olefin halogenation, confining them in a controlled microenvironment. This strategy overrides the intrinsic Markovnikov preference, enabling highly selective anti-Markovnikov halogenation. Furthermore, we extend this catalytic system to achieve size-selective anti-Markovnikov halogenation of olefins. This approach opens new pathways for selective transformations through the confinement of a cationic intermediate.