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1,3-Dipolar Cycloaddition Reactivities of Perfluorinated Aryl Azides with Enamines and Strained Dipolarophiles
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry. Univ Massachusetts Lowell, Dept Chem, Lowell, MA 01854 USA.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry. Department of Chemistry, University of Massachusetts Lowell, Lowell, MA, United States .
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2015 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 137, no 8, 2958-2966 p.Article in journal (Refereed) Published
Abstract [en]

The reactivities of enamines and predistorted (strained) dipolarophiles toward perfluoroaryl azides (PFAAs) were explored experimentally and computationally. Kinetic analyses indicate that PFAAs undergo (3 + 2) cycloadditions with enamines up to 4 orders of magnitude faster than phenyl azide reacts with these dipolarophiles. DFT calculations were used to identify the origin of this rate acceleration. Orbital interactions between the cycloaddends are larger due to the relatively low-lying LUMO of PFAAs. The triazolines resulting from PFAAenamine cycloadditions rearrange to amidines at room temperature, while (3 + 2) cycloadditions of enamines and phenyl azide yield stable, isolable triazolines. The 1,3-dipolar cycloadditions of norbornene and DIBAC also show increased reactivity toward PFAAs over phenyl azide but are slower than enamineazide cycloadditions.

Place, publisher, year, edition, pages
2015. Vol. 137, no 8, 2958-2966 p.
National Category
Organic Chemistry
URN: urn:nbn:se:kth:diva-164457DOI: 10.1021/ja511457gISI: 000350614700029PubMedID: 25553488ScopusID: 2-s2.0-84924311187OAI: diva2:807257

QC 20150423

Available from: 2015-04-23 Created: 2015-04-17 Last updated: 2015-09-03Bibliographically approved
In thesis
1. Perfluroaryl azides: Reactivities, Unique Reactions and their Applications in the Synthesis of Theranostic Agents
Open this publication in new window or tab >>Perfluroaryl azides: Reactivities, Unique Reactions and their Applications in the Synthesis of Theranostic Agents
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The work centersaround perfluoroaryl azides (PFAAs), and theirability to undergo certain fast and robusttransformations. The chemistry was furtherappliedfor biomedical applications.

The first section focuses on the azide-aldehyde-amine cycloaddition using PFAAs. Experimental and computational investigations uncovered a fast azide-enamine cycloaddition to form triazolines, which spontaneously rearrange into stable amidine products. In addition, this transformation was explored in the formulation of pure nanodrugs. Because this reaction can introduce a phenyl and a perfluoroaryl moiety enabling supramolecular interactions near the antibiotic drug, the resulting ciprofloxacin derivatives formed nano-sized aggregates by precipitation, which displayed aggregation-induced emission for bacterial imaging as well as enhanced size-dependent antibacterial efficacy.

In the second section, the high electrophilicity of PFAAs was explored to transform azides to aryl amides. The reactivity of PFAAs in the thioacid/azide reaction was studied. In addition, PFAAs were discovered to react with phenylacetaldehyde to form aryl amidesviaan azide-enol cycloaddition, similar tothe perfluoroaryl azide-aldehyde-amine reaction.This strategyof amide synthesiswas furthermoregeneralized through a combination of base-catalyzed azide-enolate cycloaddition reaction and acid-or heat-promoted rearrangement of triazolines.

The last section describes a type of azide fluorogens whose fluorescence can be switched on by alight-initiated intramolecular nitrene insertion intoa C-H bond in the neighboring aromaticring. These fluorogenic structures were efficiently accessed via the direct nucleophilic aromatic substitution of PFAAs.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2015. 68 p.
TRITA-CHE-Report, ISSN 1654-1081 ; 2015:37
Click Chemistry, Dipolar Cycloaddition, Enamine, Triazoline, Amidine, Aggregation-induced emission, pure nanodrugs, aryl amide, thioacid/azide reaction, nucleophilic aromatic substitution, azide-masked fluorophore, nitrene insertion
National Category
Engineering and Technology Natural Sciences
Research subject
urn:nbn:se:kth:diva-172950 (URN)978-91-7595-647-3 (ISBN)
Public defence
2015-09-25, F3, Lindstedtsvägen 26, KTH, Stockholm, 14:00 (English)

QC 20150903

Available from: 2015-09-03 Created: 2015-09-02 Last updated: 2015-09-03Bibliographically approved

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