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Utilizing the sigma-complex stability for quantifying reactivity in nucleophilic substitution of aromatic fluorides
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Applied Physical Chemistry.ORCID iD: 0000-0003-2673-075X
2013 (English)In: Beilstein Journal of Organic Chemistry, ISSN 1860-5397, Vol. 9, 791-799 p.Article in journal (Refereed) Published
Abstract [en]

A computational approach using density functional theory to compute the energies of the possible sigma-complex reaction intermediates, the "sigma-complex approach", has been shown to be very useful in predicting regioselectivity, in electrophilic as well as nucleophilic aromatic substitution. In this article we give a short overview of the background for these investigations and the general requirements for predictive reactivity models for the pharmaceutical industry. We also present new results regarding the reaction rates and regioselectivities in nucleophilic substitution of fluorinated aromatics. They were rationalized by investigating linear correlations between experimental rate constants (k) from the literature with a theoretical quantity, which we call the sigma stability (SS). The SS is the energy change associated with formation of the intermediate sigma-complex by attachment of the nucleophile to the aromatic ring. The correlations, which include both neutral (NH3) and anionic (MeO-) nucleophiles are quite satisfactory (r = 0.93 to r = 0.99), and SS is thus useful for quantifying both global (substrate) and local (positional) reactivity in SNAr reactions of fluorinated aromatic substrates. A mechanistic analysis shows that the geometric structure of the sigma-complex resembles the rate-limiting transition state and that this provides a rationale for the observed correlations between the SS and the reaction rate.

Place, publisher, year, edition, pages
2013. Vol. 9, 791-799 p.
Keyword [en]
computational, DFT, nucleophilic aromatic substitution, reactivity, substrate selectivity, reactive intermediates
National Category
Chemical Sciences
URN: urn:nbn:se:kth:diva-123629DOI: 10.3762/bjoc.9.90ISI: 000318481600002ScopusID: 2-s2.0-84877285731OAI: diva2:628257

QC 20130613

Available from: 2013-06-13 Created: 2013-06-13 Last updated: 2013-06-13Bibliographically approved

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Brinck, Tore
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