title: Predicting regioselectivity in nucleophilic aromatic substitution.
abstract: We have investigated practical and computationally efficient methods for the quantitative prediction of regioisomer distribution in kinetically controlled nucleophilic aromatic substitution reactions. One of the methods is based on calculating the relative stabilities of the isomeric σ-complex intermediates using DFT. We show that predictions from this method can be used quantitatively both for anionic nucleophiles with F(-) as leaving group, as well as for neutral nucleophiles with HF as leaving group. The σ-complex approach failed when the leaving group was Cl/HCl or Br/HBr, both for anionic and neutral nucleophiles, because of difficulties in finding relevant σ-complex structures. An approach where we assumed a concerted substitution step and used such transition state structures gave quantitatively useful results. Our results are consistent with other theoretical works, where a stable σ-complex has been identified in some cases, whereas others have been indicated to proceed via a concerted substitution step.
authors.affiliation: AstraZeneca, Sweden Operations, S-151 85 Södertälje, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Liljenberg
authors.forename: Tore
authors.initials: T
authors.lastname: Brinck
authors.forename: Björn
authors.initials: B
authors.lastname: Herschend
authors.forename: Tobias
authors.initials: T
authors.lastname: Rein
authors.forename: Simone
authors.initials: S
authors.lastname: Tomasi
authors.forename: Mats
authors.initials: M
authors.lastname: Svensson
mesh_terms: D000838:Anions / Q000737:chemistry*; D003198:Computer Simulation; D007700:Kinetics; D008956:Models, Chemical; D011789:Quantum Theory; D013237:Stereoisomerism
chemical_list: D000838:Anions