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

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

doi:10.1021/acs.joc.6b00584

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

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

10 Citations (Scopus)

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 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 language	English
Journal	Journal of Organic Chemistry
Volume	81
Issue number	12
Pages (from-to)	5128–5134
Number of pages	7
ISSN	0022-3263
DOIs	https://doi.org/10.1021/acs.joc.6b00584
Publication status	Published - 17 Jun 2016

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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 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%.",

author = "Monika Kruszyk and Mikkel Jessing and Kristensen, {Jesper L} and Morten Jorgensen",

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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 -

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

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