The reactivity of 2-fluoro- and 2-chloropyridines toward sodium ethoxide: Factors governing the rates of nucleophilic (het)aromatic substitutions

The relative displacement rates of the halide substituent from 2-fluoro- and 2-chloropyridines by EtONa in EtOH at +25 Deg were assessed by competition kinetics. The 2-fluoropyridine reacts 320 times faster than the chloro analog. A CF3 group increases the reactivity more than single halogen atoms do, whatever the element, and the latter are superior to Me3Si groups. Substituents accommodated at the 4-position operate through their inductive effect, whereas at the 3-position, this action may be attenuated by steric hindrance. Almost all 5-substituents enhance the rate of the nucleophilic substitution occurring at the 2-position. The sole exception concerns the F-atom at the 5-position which retards the reaction, presumably by lone-pair/lone-pair repulsion with the neg. charge building up at the central C-atom of the intermediate Meisenheimer complex. The substituent effects are additive. Therefore, by using the increments derived from the present work, the rates of future reactions should be predictable with fair accuracy. [on SciFinder (R)]