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%.

Revisiting the Structure and Chemistry of 3(5)-Substituted Pyrazoles

“…Hence, for studies of tautomerism in pyrazoles, measurement of chemical shifts permits accurate identification of the species present in each condition evaluated as well as the ascertainment of tautomer equilibrium constants, upon the adequate treatment of the samples and data [39]. Additionally, it has been shown that NMR data can be used for reactivity predictions in heterocyclic compounds, in light of the development of more efficacious syntheses [85].…”

“…In these circumstances, a paramount need to elucidate the precise chemical potential of the entities present in a specific reactant mixture emerges. HOMO and LUMO states and energies of the tautomeric structures represent the parameters that mostly contribute to their chemical potential; as such, variations alter the acidic/basic and electrophilic/nucleophilic properties of the compounds [85,115]. It was already shown that in heterocycles, including 3(5)-aminopyrazoles, the different characteristics of molecular orbitals promote distinct reactivities of each of the tautomeric species [66,85].…”

Multitask prediction of site selectivity in aromatic C–H functionalization reactions

“…16,17 Later, models using estimated 1 H and 13 C NMR shifts (using ChemDraw's linear additives rules), motivated by the same principle of estimating nucleophilicity, achieved 80% accuracy on a collection of 130 EAS reactions limited to electron rich aromatics and heterocycles. 18 When supplemented with density functional theory (DFT) calculations, 19 the accuracy of predictions was reported to be >95% on the same dataset and formed the basis for a followup semi-empirical quantum mechanical (SQM) method. The SQM model predicts selectivity based on estimated energies of carbocations generated from protonation at each site, meant to represent potential intermediates.…”

Fast and Accurate Prediction of the Regioselectivity of Electrophilic Aromatic Substitution Reactions

“…This paper provides a fast, reliable, and easy-to-use computational tool to predict the site selectivity of EAS reactions more robustly than our previously reported NMRbased method. 6 In a broader sense, the ability to block the more reactive site(s) in complex heteroaromatics may increase the use of halogens as protective groups in arene chemistry. 7,8 It was recently reported that empirically calculated 1 H and 13 C chemical shis can be applied to retrospectively account for the regiochemical outcome of ca.…”

“…95%. 6 The chemical shis were obtained immediately from the structure using ChemDraw. Conversely, DFT calculations are time-consuming for larger compounds and cannot be performed by non-expert users and there is a certain degree of subjectiveness in predicting the regioselectivity based on the HOMO orbitals.…”