title: S-Trifluoromethylation of Thiols by Hypervalent Iodine Reagents: A Joint Experimental and Computational Study.
abstract: The radical trifluoromethylation of thiophenol in condensed phase applying reagent 1 (3,3-dimethyl-1-(trifluoromethyl)-1λ(3),2-benziodoxol) has been examined by both theoretical and experimental methodologies. On the basis of ab initio molecular dynamics and metadynamics we show that radical reaction mechanisms favourably compete with polar ones involving the S-centred nucleophile thiophenol, their free energies of activation, ΔF(≠), lying between 9 and 15 kcal mol(-1). We further show that the origin of the proton activating the reagent is important. Hammett plot analysis reveals intramolecular protonation of 1, thus generating negative charge on the sulfur atom in the rate-determining step. The formation of a CF3 radical can be thermally induced by internal dissociative electron transfer, its activation energy, ΔF(≠), amounting to as little as 10.8 and 2.8 kcal mol(-1) for reagent 1 and its protonated form 2, respectively. The reduction of the iodine atom by thiophenol occurs either subsequently or in a concerted fashion.
authors.affiliation: Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zürich, Vladimir-Prelog-Weg 2, CH-8093, Zürich, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Sala
authors.affiliation: Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zürich, Vladimir-Prelog-Weg 2, CH-8093, Zürich, Switzerland.|Organisch Chemisches Institut, Westfälische Wilhelms-Universität, Münster Corrensstrasse 40, Münster, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Santschi
authors.affiliation: Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zürich, Vladimir-Prelog-Weg 2, CH-8093, Zürich, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Jungen
authors.affiliation: Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zürich, Vladimir-Prelog-Weg 2, CH-8093, Zürich, Switzerland.
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Lüthi
authors.affiliation: University of Zurich, Department of Chemistry, Winterthurerstr. 190, 8057, Zürich, Switzerland.
authors.forename: Marcella
authors.initials: M
authors.lastname: Iannuzzi
authors.affiliation: Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zürich, Vladimir-Prelog-Weg 2, CH-8093, Zürich, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hauser
authors.affiliation: Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zürich, Vladimir-Prelog-Weg 2, CH-8093, Zürich, Switzerland. togni@inorg.chem.ethz.ch.
authors.forename: Antonio
authors.identifier: http://orcid.org/0000-0003-3868-1799
authors.initials: A
authors.lastname: Togni
keywords: ab initio calculations; hypervalent iodines; linear free energy relationship; radical reactions; trifluoromethylation