Validation of a Computational Model for Predicting the Site for Electrophilic Substitution in Aromatic Systems

• Published in: Journal of organic chemistry 2010-07, Vol.75 (14), p.4696-4705
• Main Authors: Liljenberg, Magnus, Brinck, Tore, Herschend, Björn, Rein, Tobias, Rockwell, Glen, Svensson, Mats
• Format: Article
• Language: English
• Subjects: BENZENE; Benzene - chemistry; Chemistry; Computer Simulation; CONJUGATED MOLECULES; Electron Transport; Exact sciences and technology; FRIEDEL-CRAFTS ACYLATION; GROUND-STATES; Ions - chemistry; Kemi; Kinetics; Kinetics and mechanisms; LOCAL IONIZATION ENERGIES; MECHANISM; Molecular Conformation; NATURAL SCIENCES; NATURVETENSKAP; NITRATION; NITROGEN-HETEROCYCLES; Noncondensed benzenic compounds; Organic chemistry; Preparations and properties; Quantum Theory; RATE CONSTANTS; Reactivity and mechanisms; STABLE CARBOCATIONS; Stereoisomerism
• ISSN: 0022-3263; 1520-6904; 1520-6904
• DOI: 10.1021/jo100310v

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 σ-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.