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The Reactivity of 2‐Fluoro‐ and 2‐Chloropyridines toward Sodium Ethoxide: Factors Governing the Rates of Nucleophilic (Het)Aromatic Substitutions
Author(s) -
Schlosser Manfred,
Rausis Thierry
Publication year - 2005
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200590104
Subject(s) - chemistry , substituent , lone pair , steric effects , halogen , reactivity (psychology) , nucleophile , nucleophilic aromatic substitution , leaving group , medicinal chemistry , stereochemistry , nucleophilic substitution , alkyl , organic chemistry , molecule , medicine , alternative medicine , pathology , catalysis
The relative displacement rates of the halide substituent from 2‐fluoro‐ and 2‐chloropyridines by EtONa in EtOH at +25° were assessed by competition kinetics. The 2‐fluoropyridine reacts 320 times faster than the chloro analog. A CF 3 group increases the reactivity more than single halogen atoms do, whatever the element, and the latter are superior to Me 3 Si 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 negative 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.