The Reactivity of 2‐Fluoro‐ and 2‐Chloropyridines toward Sodium Ethoxide: Factors Governing the Rates of Nucleophilic (Het)Aromatic Substitutions

Abstract

Rolf Huisgen in Bewunderung und VerbundenheitThe relative displacement rates of the halide substituent from 2-fluoro-and 2-chloropyridines by EtONa in EtOH at 258 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.

Ruthenium (II) and iridium (III) complexes of N-heterocyclic carbene and pyridinol derived bidentate chelates: Synthesis, characterization, and reactivity

“…[82] The alkylation of the (Im-py OR ) compound with CH 3 I, CH 3 OTf, or CH 3 CH 2 Br resulted in the formation of imidazolium salts (Im R -py OtBu )X, that differ in the R’ and OR groups on the imidazole and pyridine ring, respectively, where R’ = Me, Et and OR = O t Bu, OMe (Table 1). Variation in the counter anion gave four compounds: (Im Me -py OtBu )I ( 1 ), (Im Me -py OtBu )PF 6 ( 2 ), (Im Et -py OMe )Br ( 3 ), and (Im Me -py OtBu )OTf ( 4 ) (Table 1).…”

Are reactions between allylpotassiums and halotrimethylsilanes diffusion-controlled?

“…The leaving group effect observed in hexane with halotrimethylsilanes (with rates varying by up to 25-fold) and in tetrahydrofuran with halotriisopropylsilanes (up to 8-fold rate increases along the halogen series) suggests an S N 2-like concerted displacement mechanism, in which the nucleofugal mobility of the halogen typically increases with its size. [16][17][18][19] Conversely, the alternate associative addition/elimination route passing through a transient ate complex should markedly privilege the smaller elements chlorine and, in particular, fluorine [20][21][22][23] due to the presence of a larger dipole between silicon and fluorine. As reviewed by Corriu,13b four-or sixcenter processes of the type S N i(Si) are also unlikely, as (1) substitution of halotrialkylsilanes with allyllithiums proceed with inversion of configuration, thereby impeding on a cyclic transition state, and (2) increasingly polar solvents, which are expected to disrupt metal-halide interactions in a cyclic process, promote faster reactions and favour retention over inversion.…”

Metal‐Bearing and Trifluoromethyl‐Substituted Pyrimidines: Generation and Functionalization

“…If nucleophilic addition to metal-free precursors was the sole menace for the survival of metalated pyrimidines, 2,4-difluoropyrimid-5-yllithium [16] should be less and not more stable than the 2,4-dichloro analog [13] as the lightest halogen is the better nucleofugal leaving group. [22] It is also not immediately intelligible why reactions involving 4,6-dichloropyrimid-5-yllithium give excellent yields but those passing through 2,4,6-trichloropyrimid-5-yllithium only miserable ones.…”