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

TY - JOUR

T1 - Computational Methods to Predict the Regioselectivity of Electrophilic Aromatic Substitution Reactions of Heteroaromatic Systems

AU - Kruszyk, Monika

AU - Jessing, Mikkel

AU - Kristensen, Jesper L

AU - Jorgensen, Morten

PY - 2016/6/17

Y1 - 2016/6/17

N2 - 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 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%.

AB - 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 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%.

U2 - 10.1021/acs.joc.6b00584

DO - 10.1021/acs.joc.6b00584

M3 - Journal article

C2 - 27176051

SN - 0022-3263

VL - 81

SP - 5128

EP - 5134

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

IS - 12

ER -