DOI: 10.1002/chem.201503774
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Reaction Mechanisms
S-Trifluoromethylation of Thiols by Hypervalent Iodine Reagents:
A Joint Experimental and Computational Study
Oliver Sala,[a] Nico Santschi,[a, c] Stefan Jungen,[a] Hans Peter Lüthi,[a] Marcella Iannuzzi,[b]
Abstract: The radical trifluoromethylation of thiophenol in
condensed phase applying reagent 1 (3,3-dimethyl-1-(tri-
fluoromethyl)-1l3,2-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 thiophe-
nol, their free energies of activation, DF°, lying between 9
and 15 kcalmolÀ1. We further show that the origin of the
proton activating the reagent is important. Hammett plot
analysis reveals intramolecular protonation of 1, thus gener-
ating negative charge on the sulfur atom in the rate-deter-
mining step. The formation of a CF3 radical can be thermally
induced by internal dissociative electron transfer, its activa-
tion energy, DF°, amounting to as little as 10.8 and 2.8 kcal
molÀ1 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.
the activation of reagent 1 by protonation is essential.[22] N-Tri-
fluoromethylation of the solvent acetonitrile (MeCN) by pro-
tonated reagent 1, as the key step in a Ritter-type reaction,[14]
likely proceeds by polar reductive elimination (RE), whereas S-
nucleophiles follow concomitantly RE and nucleophilic substi-
tution (SN) pathways.[30] In addition, these reactions are very
sensitive to solvent effects.[22,30] Radical trifluoromethylations
with l3-iodane reagents were reported involving a breadth of
initiators. Among these, copper and photocatalysis by rhodium
or iridium catalysts feature most prominently.[31–33] Recently,
also the application of iodide and iPrSH as reductants have
been considered.[34–37] In the course of an ab initio metadynam-
ics study on the trifluoromethylation of a thiol it was observed
that a radical mechanism possibly plays an important role.[30]
Moreover, a radical pathway appears to be realistic also for al-
kynylations of thiols with l3-iodanes.[38]
Introduction
Hypervalent iodine compounds, in particular l3-iodanes, have
become important reagents in organic synthesis for electro-
philic group-transfer reactions to a variety of nucleophiles.[1–10]
Corresponding reagents for the trifluoromethylation of a vast
array of substrates, as reported from our laboratory, for exam-
ple, 3,3-dimethyl-1-(trifluoromethyl)-1l3,2-benziodoxol (1)[11–16]
contributed to recent significant developments in organofluor-
ine chemistry.[17] Indeed, reagents such as 1 are well suited for
late-stage trifluoromethylation reactions, in particular of thiols.
This functional group displays a high degree of chemoselectivi-
ty, as demonstrated, for example, by an octapeptide derived
from Sandostatin,[18,19] or by co-enzyme A.[20] Although the
chemistry of iodanes is well established, only recent computa-
tional studies revealed the mechanistic versatility of l3-iodanes,
reminiscent of that of transition metals.[21–30] We previously in-
vestigated the electronic and structural properties leading to
the distinct reactivity of reagent 1 as well as polar mechanistic
details in combination with N- and S-nucleophiles.[24,25,30] Thus,
We present a combined experimental and computational
study of the trifluoromethylation of thiols, with thiophenol as
model substrate. This involves classical physical-organic meth-
ods (Hammett-type linear free energy relationships and radical
trapping experiments) and ab initio molecular dynamics
(AIMD) techniques,[39,40] in order to fully account for solvent
and entropy effects. Accelerated, non-equilibrium AIMD (meta-
dynamics)[41] enables to investigate rare events that would
occur “once in a blue moon” on the time scale of typical AIMD
simulations when just applying equilibrium AIMD. (Further de-
tails concerning metadynamics are provided in the Supporting
Information.)
[a] O. Sala, N. Santschi, S. Jungen, H. P. Lüthi, N. Hauser, A. Togni
Department of Chemistry and Applied Biosciences
Swiss Federal Institute of Technology, ETH Zürich
Vladimir-Prelog-Weg 2, CH-8093 Zürich (Switzerland)
[b] M. Iannuzzi
University of Zurich, Department of Chemistry
Winterthurerstr. 190, 8057 Zürich (Switzerland)
[c] N. Santschi
In this study, we take into consideration an electron-transfer
pathway in addition to polar mechanisms. We present possible,
competitive radical reaction pathways, and show that indeed
free radical species can be monitored. Furthermore, we discuss
the consequences of inter- and intramolecular protonation of
Present address: Organisch Chemisches Institut
Westfälische Wilhelms-Universität
Münster Corrensstrasse 40, Münster (Germany)
Supporting information and ORCID(s) from the author(s) for this article are
Chem. Eur. J. 2016, 22, 1704 – 1713
1704
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