title: Computational Methods to Predict the Regioselectivity of Electrophilic Aromatic Substitution Reactions of Heteroaromatic Systems.
abstract: The validity of calculated NMR shifts to predict the outcome of electrophilic aromatic substitution reactions on different heterocyclic compounds has been examined. Based on an analysis of >130 literature examples, it was found that the lowest predicted (13)C and/or (1)H chemical shift of a heterocycle correlates qualitatively with the regiochemical outcome of halogenation reactions in >80% of the investigated cases. In the remaining cases, the site of electrophilic aromatic substitution can be explained by the calculated HOMO orbitals obtained using density functional theory. Using a combination of these two methods, the accuracy increases to >95%.
authors.affiliation: Discovery Chemistry and DMPK, Neuroscience Drug Discovery, H. Lundbeck A/S , Ottiliavej 9, 2500 Valby, Denmark.|Department of Drug Design and Pharmacology, Faculty of Health and Medical Science, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Monika
authors.initials: M
authors.lastname: Kruszyk
authors.affiliation: Discovery Chemistry and DMPK, Neuroscience Drug Discovery, H. Lundbeck A/S , Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Mikkel
authors.initials: M
authors.lastname: Jessing
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Science, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Jesper Langgaard
authors.initials: JL
authors.lastname: Kristensen
authors.affiliation: Discovery Chemistry and DMPK, Neuroscience Drug Discovery, H. Lundbeck A/S , Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Jørgensen