The selective halogenation of pyridine rings is a synthetically valuable transformation that remains challenging to accomplish due to a lack of efficient methods. In particular, the C3 and C5 positions are hardest to halogenate due to the low reactivity of pyridine towards electrophilic substitutions processes. Conventionally, these reactions require a strong electronic bias in the pyridine or harshly acidic conditions that often lead to inefficient reactions with limited scope. We describe mechanistic studies into a newly developed pyridine halogenation method developed in the McNally laboratory using dearomatized intermediates. Quantum chemical calculations were used to study mechanistic details and to account for the high-levels of regioselectivity for the C3 position of pyridine. These results are compared with experimental studies including isotopically labelled substrates. We have identified two regimes controlling rate and selectivity dependent upon the electrophilic used, and a model has been developed to relate regioselectivity with the position of the carbon-halogen bond forming transition structure. These results provide a general framework to predict the site and level of regioselectivity with different substrates and electrophiles and are being used for further reaction development.

Mechanism and regioselectivity in an open-and-shut case of pyridine halogenation

ACS Spring 2022

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