Computational Methods to Predict the Regioselectivity of Electrophilic Aromatic Substitution Reactions of Heteroaromatic Systems

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Monika Kruszyk, Mikkel Jessing, Jesper L Kristensen, Morten Jorgensen

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 calculated 13C and/or 1H 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%.

Original languageEnglish
JournalJournal of Organic Chemistry
Volume81
Issue number12
Pages (from-to)5128–5134
Number of pages7
ISSN0022-3263
DOIs
Publication statusPublished - 13 May 2016

ID: 161390337