Mechanistic insight into the thermal activation of Togni's trifluoromethylation reagents

Article abstract of DOI:10.1039/c7cp01396e

Herein we investigate the propensity of hypervalent iodine based electrophilic trifluoromethylating agents to undergo thermally induced fragmentation of the F₃C-I-O motif. For the first time we are able to observe a dissociative electron transfer mechanism using mass spectroscopy techniques to generate and trap CF₃ radicals. Consistent with this mechanism, alkyl radical elimination from these reagents is in full support of an intermediate cyclic iodanyl radical and a reagent-specific temperature of maximum radical production was found to correlate with reported solution phase reactivity.

Full text of DOI:10.1039/c7cp01396e

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Trifluoromethyl Radical Formation
Alkyl Radical Formation
F3C
I
O
I
O
I
O
I
O
∆
+
F3C
R
R
R
DET
1a–f
TEMPO-CF3
TEMPO-R
·
Scheme 2 Dissociative electron transfer in 1a (R = CH3) affords F3C and, concomitantly, R via cyclic intermediate RI . These radical species are
·
·
detectable by scavenging with TEMPO.
able trapping reactions such as scavenging with 2,2,6,6-
tetramethylpiperidinyloxyl (TEMPO). In this regard, it is note-
worthy that TEMPO undergoes almost no direct reaction with
reagent 1. In stark contrast, when its congener 2 is exposed to
the reduced form of TEMPO, i.e. 2,2,6,6-tetramethylpiperidin-1-
olate (TEMPO-), a very efficient CF3 radical production ensues
with regeneration of the TEMPO radical. This process can, for ex-
ample, be used to effect oxy-trifluoromethylations across various
double bonds.18 Most intriguingly a recent computational study
also investigated the propensity to generate CF3 radicals under
thermal activation from 1 and 2 and found these structures to
be more suitable than CF3I.19 Cognizant of this precedence, we
wondered whether this thermal fragmentation of the F3C−I−O
bonding motif in 1 could be achieved experimentally, in analogy
to the DET process, and studied by TEMPO trapping (Scheme 2,
green box).
and 1 mM for TEMPO and 1, respectively, to afford a good signal-
to-noise ratio. TEMPO was employed in fivefold excess to scav-
enge the resultant radical products efficiently (vide infra).
By applying this methodology, we identified several mechanis-
tic regimes for the decomposition of Togni’s reagent 1a, these
being directly dependent on the temperature of the injection
port (T). Namely, at low injection port temperatures (160 ◦C –
200 ◦C) reagent 1a apparently predominantly decomposes by a
non-radical pathway or by generation of radical products that are
not readily intercepted by TEMPO. At higher temperatures (T >
200 ◦C), a decomposition pathway furnishing CF3 and CH3 rad-
icals becomes prevalent, in keeping with our initial mechanistic
hypothesis (Scheme 2). Further corroboration for this decomposi-
tion regime was also obtained by alternative experimental strate-
gies (thermogravimetric analysis in conjunction with selective ion
monitoring mass spectrometry, vide infra). Notably, the amount of
radicals generated and trapped under these conditions increases
non-linearly up to T ≈ 260 ◦C with an inflection point at 220 ◦C
(TIP). The abundances then level off and remain stable up to
T ≈ 340 ◦C, where observations become dominated by different
processes. In the following sections we will outline in detail the
individual experiments performed and present our interpretation
of the data.
Previously, the analogous fragmentation of structurally related
·
λ3-(tert-butylperoxy)iodinanes to tBuO2 and the cyclic iodanyl
·
radical RI had been studied and these reagents would be ex-
pected to operate in a similar fashion.20,21 If present, the in-
·
termittent iodanyl radical RI should also exist in equilibrium
with the corresponding oxy-radical and importantly, tertiary alky-
loxy radicals are well known to undergo β-scission to alkyl radi-
cals and corresponding ketones.22 As a consequence, the thermal
TEMPO Blank. Initially, the background signal for TEMPO (tR
= 6.0 min, M+ = 156 m/z) was recorded by varying the inlet
temperature from 160 ◦C to 360 ◦C in 20 ◦C increments (Figure 1A,
light grey diamonds). Over most of this range a constant relative
abundance, relative to the value obtained at 160 ◦C, was detected
.
fragmentation of 1 is expected to yield CH3 in conjunction to the
·
desired CF3 radicals if intermediate RI existed.
Due to compound 1’s elevated thermal stability, conventional
solution phase-based approaches towards studying the thermal
activation of this reagent are impractical (see ESI†). Therefore,
we elected to conduct these thermolysis reactions in the injection
port of a gas chromatography/mass spectroscopy (GC-MS) instru-
ment, an approach that has been previously well-established for
studying chemical reactions in a high-through put fashion.23–27
For example, the sample is injected into the injection port (160-
360 ◦C) before being transferred to the separation column by the
carrier gas (He, 1.71 mL min-1) allowing online retention time-
and mass-based product analysis and identification, respectively.
Thus, sample solutions were prepared in CH2Cl2 (b.p. 39.6 ◦C)
and optimal solute concentrations were determined to be 5 mM
(
5%). This indicates (1) high precision of the injection volume
and reliable signal integration and importantly, (2) transport ef-
ficiency of TEMPO is not impeded at lower inlet temperatures.
Above 320 ◦C the relative abundance decreases significantly, con-
current to an exponential increase in abundance of TEMPO-CH3
(see ESI†) implying a thermally induced disproportionation-type
reaction.
On the TEMPO & 1a Co-injection. In the presence of 1a,
two distinctive regions were observed for the TEMPO signal (Fig-
ure 1A, black circles). At 220 ◦C the relative abundance of (free)
TEMPO decreases to a constant value of 0.75 and at 300-320 ◦C
2 |
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expulsion of the CH3 radical is accompanied by the preferential
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For every reagent a characteristic parameter of highest rate of
radical production, TIP, could be obtained by fitting the recorded
temperature-dependent abundances with a logistic function. The
TIP values were found to correlate to the previously reported so-
lution phase reactivity v0 of theses reagents. However, the differ-
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tative reactivity assessment, these values would have to be deter-
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Acknowledgements
This work was generously supported by the Swiss National Sci-
ence Foundation (N. S.; P3P3P2_167744), the National Science
and Engineering Research Council of Canada (B. Jelier) and ETH
Zürich (Prof. D. Günther, Prof. A. Togni). The authors thank Erik
Schrader (ETH Zürich) for assistance with acquiring the TGA-MS
and DSC data.
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The thermal activation of Togni’s reagent was studied by GC-MS and shown to
generate CF3 and, concomitantly, alkyl radicals.