title: Validation of a computational model for predicting the site for electrophilic substitution in aromatic systems.
abstract: We have investigated the scope and limitations of a method for predicting the regioisomer distribution in electrophilic aromatic substitution reactions that are under kinetic control. This method is based on calculation of the relative stabilities of the sigma-complex intermediates using density functional theory. Predictions from this method can be used quantitatively for halogenations; it agreed to an accuracy of about 1 kcal/mol with experimental observations in 10 of the 11 investigated halogenation reactions. For nitrations, the method gave useful predictions for heterocyclic substrates. The method failed for nitration of monosubstituted benzenes, and we expect that more elaborate model systems, including explicit solvent molecules, will be necessary to obtain quantitatively useful predictions for such cases. For Lewis acid promoted Friedel-Crafts acylations, the method can be expected to give qualitatively correct predictions, that is, to point out the dominating isomer. For substrates where the regioisomeric outcome is highly dependent on the reaction conditions, the method can only be of qualitative use if the concentration of the free Lewis acid is high during the reaction. We have also compared the predictive capacity of the method to that of a modern reactivity index, the average local ionization energy, I(r). The latter method is found to predict the regisolectivity in halogenations and nitrations qualitatively correctly if the positions for the I(r) minima (I(S,min)) are not too sterically hindered but fails for qualitative predictions of F-C reactions. The downscaled I(S,min) values also perform well for the quantitative prediction of regioisomer distributions of halogenations. The accuracy is slightly lower than that for the new method.
authors.affiliation: Sweden Operations, AstraZeneca, 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: Glen
authors.initials: G
authors.lastname: Rockwell
authors.forename: Mats
authors.initials: M
authors.lastname: Svensson
mesh_terms: D001554:Benzene / Q000737:chemistry*; D003198:Computer Simulation; D004579:Electron Transport; D007477:Ions / Q000737:chemistry*; D007700:Kinetics; D008968:Molecular Conformation; D011789:Quantum Theory; D013237:Stereoisomerism
chemical_list: D007477:Ions; D001554:Benzene