Determination of rate constants for trifluoromethyl radical addition to various alkenes via a practical method

Article abstract of DOI:10.1039/c5ob02210j

A simple and practical method for the determination of rate constants for trifluoromethyl radical addition to various alkenes by applying competition kinetics is introduced. In the kinetic experiments the trifluoromethyl radicals are generated in situ from a commercially available hypervalent-iodine-CF₃ reagent (Togni-reagent) by SET-reduction with TEMPONa in the presence of TEMPO and a π-acceptor. From the relative ratio of TEMPOCF₃ and CF₃-addition product formed, which is readily determined by ¹⁹F-NMR spectroscopy, rate constants for trifluoromethyl radical addition to the π-acceptor can be calculated. The practical method is also applicable to measure rate constants for the addition of other perfluoroalkyl radicals to alkenes as documented for CF₃CF₂-radical addition reactions.

Full text of DOI:10.1039/c5ob02210j

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Determination of rate constants for
trifluoromethyl radical addition to various
alkenes via a practical method†
Cite this: DOI: 10.1039/c5ob02210j
M. Hartmann, Y. Li and A. Studer*
A simple and practical method for the determination of rate constants for trifluoromethyl radical addition
to various alkenes by applying competition kinetics is introduced. In the kinetic experiments the trifluoro-
methyl radicals are generated in situ from a commercially available hypervalent-iodine-CF3 reagent
(Togni-reagent) by SET-reduction with TEMPONa in the presence of TEMPO and a π-acceptor. From the
relative ratio of TEMPOCF3 and CF3-addition product formed, which is readily determined by 19F-NMR
spectroscopy, rate constants for trifluoromethyl radical addition to the π-acceptor can be calculated. The
practical method is also applicable to measure rate constants for the addition of other perfluoroalkyl
radicals to alkenes as documented for CF3CF2-radical addition reactions.
Received 26th October 2015,
Accepted 4th November 2015
DOI: 10.1039/c5ob02210j
www.rsc.org/obc
α-methylstyrene by laser flash photolysis studies.10 However,
a larger list on rate constants of the CF3-radical addition to
Introduction
Fluorinated compounds are highly valuable in medicinal different π-acceptors is clearly missing. Kinetic data are highly
chemistry, in the agrochemical industry, and also in materials important for reaction design in radical chemistry. Herein, we
science.1–5 It is therefore not surprising that various synthetic introduce a novel highly practical method to determine rate
methods for the preparation of fluorinated or perfluoroalky- constants for CF3-radical addition to various acceptors by com-
lated compounds have been developed. Several reviews cover- petition kinetics. Kinetic experiments are very easy to conduct
ing the state-of-the-art in this active research area have recently and special equipment such as a laser flash photolysis appar-
appeared.6 The trifluoromethyl substituent, as judged from atus is not necessary. The method relies on 19F-NMR spec-
the high recent activities, has attracted particular attention troscopy which is nowadays available in most research
along these lines, and ionic as well as transition-metal-based laboratories. We will also show that the novel approach can be
processes have been developed for the introduction of the tri- applied to measure rate constants for the addition of the
fluoromethyl group.6
CF3CF2-radical to π-acceptors.
Radical chemistry has also been successfully applied to
alkene and arene trifluoromethylation and many methods for
the generation of the trifluoromethyl radical have been intro-
duced.7 The trifluoromethyl and more generally perfluoroalkyl
Results and discussion
radicals exhibit high reactivity which largely derives from their We recently introduced the use of sodium aminoalkoxide 2
high electrophilicity and their pyramidal geometry.8,9 Surpris- (TEMPONa), which is readily generated by the reduction of the
ingly, despite the great importance of the trifluoromethyl commercially available 2,2,6,6-tetramethylpiperidine-N-oxyl
radical in organic synthesis, to our knowledge only very few radical (TEMPO) in tetrahydrofuran (THF), as a mild single
absolute rate constants for the addition of the CF3-radical to electron transfer (SET) reagent for clean generation of the tri-
alkenes have been disclosed to date. Ingold, Lusztyk and fluoromethyl radical from the hypervalent I(III)–CF3 reagent 1
Dolbier Jr measured the rate constant for CF3-radical addition (Togni-reagent, Scheme 1).11
to styrene, to pentafluorostyrene (C6F5CHvCH2) and to
Reaction of the reagent 16b with TEMPONa 2 in the pres-
ence of an alkene provided the corresponding trifluoromethyl-
aminoxylation product 3 in good to excellent yields.11 This
sequence proceeds via the following mechanism. Reaction of
TEMPONa with 1 first generates the CF3-radical along with the
persistent TEMPO radical.12 Na-ortho-iodobenzoate is formed
Organisch-Chemisches Institut, Westfäliscihe Wilhelms-Universität Münster,
Corrensstraße 40, 48149 Münster, Germany. E-mail: studer@uni-muenster.de
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob02210j
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which evolves from kinetic eqn (1) where the alkene and the
TEMPO concentrations are constant and known:
ð1Þ
ð2Þ
In order to apply eqn (2), the rate constant for CF3-radical
trapping by TEMPO (ktrap) had to be determined first. To this
end, we used the known absolute rate constant for CF3-radical
addition to styrene (kadd = 5.3 × 107 M−1 s−1 10
as a radical
)
clock and conducted a series of trifluoromethylaminoxylations
with styrene (20 equiv.) and TEMPONa (1.2 equiv.) in the pres-
ence of TEMPO (3.3 equiv.). From the ratio of 4 (TEMPOCF3)
and the trifluoromethylaminoxylated product 3a the rate con-
stant of ktrap was calculated using eqn (3) evolved from kinetic
eqn (1) (Scheme 2). Reactions were very clean, and in the
19F-NMR spectrum only the resonances belonging to 3a and 4
were observed. The kinetic experiment was repeated 5 times
and the product ratio was averaged over all these runs. A value
of 8.1 ( 0.3) × 108 M−1 s−1 was obtained for TEMPO-trapping
(ktrap) of the CF3-radical at room temperature.
With this novel radical clock in hand we then determined
rate constants for radical addition of the trifluoromethyl
radical to various π-acceptors by competition kinetics using
eqn (2) with ktrap = 8.1 × 108 M−1 s−1. The alkene was used in a
20 fold excess in these kinetic experiments (pseudo-first
order). Reactions were clean and the product ratio was readily
determined by 19F-NMR spectroscopy of the reaction
mixture.15 Experiments were repeated at least 2 times and data
obtained were averaged. The rate constants determined for
various acceptors are summarized in Table 1.
Scheme 1 Radical trifluoromethylaminoxylation of alkenes mediated
by TEMPONa. General reaction and mechanism.
as a side product (not shown in the scheme). The CF3-radical
then adds to the alkene to give the corresponding adduct
radical which is eventually trapped by TEMPO to provide the
trifluoromethylaminoxylated product 3.13 If the addition of the
CF3-radical to the alkene is slow, competing direct trapping of
the CF3 radical by TEMPO to give TEMPOCF3 (4) can occur as a
side reaction. To suppress the formation of 4 in preparative
experiments, the concentration of TEMPO was kept low by
adding TEMPONa via a syringe pump and by generally using
the alkene in excess.
Based on these findings, we decided to use the direct
TEMPO-trapping of the CF3-radical (side reaction in the pre-
parative experiments) as a radical clock14 for determining rate
constants for CF3-radical addition to various alkenes. If the
trifluoromethylaminoxylation depicted in Scheme 1 is con-
ducted with a large excess of the alkene the concentration of
the alkene can be considered to be constant during the whole
reaction (pseudo-first order conditions). Moreover, if free
TEMPO is added to the reaction mixture its concentration is
held constant throughout the whole process because the
amount of TEMPO generated in the reaction of 1 with 2 gets
consumed in the formation of 3 or TEMPOCF3. Therefore, the
concentration of added free TEMPO corresponds to the con-
stant concentration of free TEMPO in the reaction mixture
during the whole process. By knowing the rate constant for the
reaction of TEMPO with the CF3-radical, one can determine
the rate constant for CF3-radical addition to an alkene by
simply determining the relative ratio of TEMPOCF3 (4) with
respect to the trifluoromethylaminoxylation product 3 formed.
This ratio can readily be determined by 19F-NMR spectroscopy
without any prior work-up of the reaction mixture. The rate
constant for addition kadd can then be calculated with eqn (2)
It is expected that the trifluoromethyl radical behaves in
alkene addition reactions as the perfluoropropyl radical for
which a larger set of data is available in the literature.9c Reac-
tions which occur via early transition states will be fast and
kinetics will be governed by polar effects (electron rich double
Scheme 2 Determination of the rate constant for CF3-radical trapping
with TEMPO.
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constant measured for CF3-addition to C6F5CHvCH2 is in
good agreement with the literature value (2.6 × 107 M−1 s−1),10
further confirming the usefulness of the introduced practical
and simple method. The reported rate constant for the corres-
ponding CF3CF2CF2-radical addition is smaller (1.3 × 107 M−1 s−1).10
Steric factors affect CF3-radical addition rate constants and
for trans-β-methylstyrene a value of 1.1 × 107 M−1 s−1 was
measured. Interestingly, cis-β-methylstyrene reacts measurably
more slowly (0.62 × 107 M−1 s−1). In the latter case due to the
cis-methyl substituent the vinyl group and the activating
phenyl substituent are not in perfect conjugation and this
likely explains the lower reactivity of the cis-derivative as com-
pared to its trans-congener. For indene a rate constant of 1.5 ×
107 M−1 s−1 was measured. In line with other alkenes,
CF3CF2CF2-radical addition to β-methyl styrene (configuration
not specified in the paper) was reported to occur with a
smaller rate constant (0.38 × 107 M−1 s−1).9c
Table 1 Rate constants for CF3 radical addition to various alkenes
(unless noted otherwise, kinetic experiments were conducted with 3.3
equiv. of TEMPO)
kadd/107
kadd/107
[M−1 s−1
]
[M−1 s−1
]
7.6 ( 0.5)
0.54 ( 0.02)
11 ( 0.3)
6.5 ( 0.1)
0.54 ( 0.02)
1.2 ( 0.3)
1.9 ( 0.6)
1.1 ( 0.4)
0.72 ( 0.08)
1.5 ( 0.3)
2.0 ( 0.3)
We also investigated rate constants for addition to non-acti-
vated double bonds and examined 1-hexene first. As expected,
due to the lower nucleophilicity of this alkene as compared to
styrene, a smaller rate constant was measured (0.63 × 107 M−1
0.62 ( 0.19)
s
−1). 5-Hexen-1-ol reacted slightly faster with a rate constant of
0.88 × 107 M−1 s−1 and a slightly lower rate constant was
obtained for the corresponding TBDMS-protected derivative
1.5 ( 0.7)a
2.0 ( 0.1)
(0.54 × 107 M−1
s
−1). The same rate constant was also
0.63 ( 0.16)
0.13 ( 0.03)a
measured for the lower homologue TBDMSOCH2CH2CHvCH2
(0.54 × 107 M−1 s−1). Allyl trimethylsilane is electronically acti-
vated by the silyl group and as compared to the unactivated
1-hexene a 2 fold larger rate constant was found (1.2 × 107 M−1
0.88 ( 0.15)
s
−1). A slightly larger value (1.5 × 107 M−1 −1) was measured for
s
a Reactions were carried out using 0.5 equiv. of TEMPO.
butylvinyl ether and to our surprise bis allyl ether reacts fast with
the trifluoromethyl radical (2.0 × 107 M−1 s−1). Under the applied
conditions, 5-exo cyclization was fully suppressed and we only
bonds are more reactive as compared to electron deficient observed the trifluoromethylaminoxylation product (see ESI†). As
radical acceptors).
expected, a remote epoxide entity does not alter the addition rate
Comparing the three known rate constants for CF3-radical constant to a large extent (0.72 × 107 M−1 s−1). Due to the higher
addition10 to styrene derivatives with the corresponding values nucleophilicity of the double bond in 2-ethyl-1-butene as com-
for CF3CF2CF2-radical addition, we assume the CF3-radical due pared to 1-hexene, the rate constant increases (2.0 × 107 M−1 s−1).
to its higher electrophilicity to be generally slightly more reac-
Whereas we failed to measure rate constants for CF3-radical
tive than the perfluoropropyl radical. For the second order rate addition to non-activated arenes, for a single example (benzo-
constant of the CF3-radical addition to α-methylstyrene we furan) our method was applicable and a value of 0.13 × 107
measured a value of 7.6 × 107 M−1 s−1 which is similar to the M−1 s−1 was obtained. As previously shown,11 the CF3-radical
reported rate constant for the CF3CF2CF2-radical adding to adds to the α-position of the O-atom in benzofuran and the
α-methylstyrene (7.8 × 107 M−1 s−1).10 Our value compares well benzylic adduct radical gets trapped by TEMPO with complete
with the rate constant measured by using laser flash photolysis diastereocontrol (trans-product). Hence in the kinetic compe-
(8.7 × 107 M−1 s−1),10 validating our novel practical method. tition experiment only two resonances were identified in
Small differences are expected due to the fact that solvent the 19F-NMR spectrum. For values <106 M−1 s−1 we see the
polarity should influence to some extent the rate constants.9e lower limit for a measurable rate constant using our novel
The laser flash-photolysis experiments were conducted in method. If the addition reaction with the trifluoromethyl
Freon 11310 whereas our kinetics were run in THF.
As expected based on polar effects, the rate constant in- sive pathway.
creases for the para-methoxy-substituted styrene (11 × 107 M−1 s−1
To document the generality of our method we also applied
radical is too slow, direct TEMPO trapping becomes the exclu-
)
as compared to the parent styrene and the electron-poorer the approach to measure rate constants for pentafluoroethyl
pentafluorostyrene showed a significantly smaller rate constant radical addition to alkenes. The CF3CF2-Togni-reagent 5 was
(1.9 × 107 M−1 s−1). For 4-chlorostyrene (6.5 × 107 M−1 s−1
)
previously introduced by us.11 As for the CF3-case, the TEMPO-
and styrene similar values were obtained. Notably, the rate trapping rate constant had to be determined first. To this end,
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ments are very easy to conduct and special equipment is not
necessary. As an analytical tool 19F-NMR spectroscopy is used.
The 19F-NMR spectra are recorded directly on the reaction
mixture and workup or product isolation is not necessary. This
is important because some perfluoroalkylated compounds are
volatile and product loss during isolation will lead to errors in
the kinetic data. Internal standards are not required to run
these kinetic competition experiments.
We determined rate constants for the TEMPO-trapping of
the trifluoromethyl and pentafluoroethyl radical. These reac-
tions have then been used as radical clocks in kinetic compe-
tition experiments. As is known for perfluoroalkyl radicals,
rate constants for radical additions to alkenes are large and
show polar effects. The trifluoromethyl radical is generally
slightly more reactive than the heptafluoropropyl radical
but slightly less reactive than the perfluoroethyl radical.16
Importantly, our method should be generally applicable to
measure kinetics for alkene perfluoroalkyl radical additions. A
prerequisite is that the corresponding perfluoroalkyl-Togni-
reagent can be prepared and that at least one absolute alkene
addition rate constant for this particular perfluoroalkyl radical
is known from the literature to clock the TEMPO trapping
reaction.
Scheme 3 Determination of the rate constant for C2F5-radical trapping
with TEMPO and addition rate constants to various styrene derivatives.
we chose the known rate constant for the addition of the
CF3CF2-radical to α-methylstyrene (9.4 × 107 M−1 s−1 9c
as a
)
radical clock in competition experiments (Scheme 3). Reac-
tions were conducted by using a large excess of α-methyl-
styrene (20 equiv.) in the presence of 2.9 equiv. of free TEMPO.
TEMPONa (1.2 equiv.) was added. Along with the pentafluoro-
ethylaminoxylation product 6a we also identified the perfluoro-
alkylated styrene 7a as a side product (ratio 1 : 1.6, see ESI†).
7a either derives from TEMPOH elimination in product 6a or
via direct H-abstraction of the benzylic adduct radical by
TEMPO. Since 6a and 7a both derive from CF3CF2-radical
addition to α-methylstyrene, the rate constant ktrap for the reac-
tion of the CF3CF2-radical with TEMPO can be calculated from
the ratio of TEMPOC2F5 (8) and the sum of products 6a and 7a
according to eqn (4). The kinetic experiment was repeated 5
times and 8.6 ( 0.3) × 108 M−1 s−1 was measured for the
second order TEMPO-trapping rate constant ktrap at room
temperature, similar to the rate constant for TEMPO-trapping
of the CF3-radical.
Finally, the TEMPO/CF3CF2-radical trapping reaction was
used as a radical clock to determine rate constants for the
addition of the CF3CF2-radical to styrene, para-methoxy styrene
and para-chloro styrene. Kinetic experiments were performed
as described above for the reactions with the Togni-reagent 2.
The measured rate constants for C2F5-radical addition com-
pared to CF3-radical addition are slightly larger and governed
by polar effects. This is in agreement with literature
reports.9c,10 Since these three experiments were mainly con-
ducted to show the potential of the method, additional rate
constants for CF3CF2-radical additions were not determined.
Acknowledgements
The Deutsche Forschungsgemeinschaft (DFG) is acknowledged
for financial support.
Notes and references
1 (a) K. Müller, C. Faeh and F. Diederich, Science, 2007, 317,
1881; (b) J. Wang, M. Sánchez-Roselló, J. L. Acena,
C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok
and H. Liu, Chem. Rev., 2015, 115, 2432.
2 C. Isanbor and D. O’Hagan, J. Fluorine Chem., 2006, 127,
303.
3 S. Purser, P. R. Moore, S. Swallow and V. Gouverneur,
Chem. Soc. Rev., 2008, 37, 320.
4 P. Jeschke, ChemBioChem, 2004, 5, 570.
5 R. Berger, G. Resnati, P. Metrangolo, E. Weber and
J. Hulliger, Chem. Soc. Rev., 2011, 40, 3496.
6 (a) C. Alonso, E. M. de Marigorta, G. Rubiales and
F. Palacios, Chem. Rev., 2015, 115, 1847; (b) J. Charpentier,
N. Früh and A. Togni, Chem. Rev., 2015, 115, 650;
(c) T. Besset, T. Poisson and X. Pannecouke, Chem. – Eur. J.,
2014, 20, 16830; (d) C. Zhang, Adv. Synth. Catal., 2014, 356,
2895; (e) S. Barata-Vallejo, B. Lantano and A. Postigo,
Chem. – Eur. J., 2014, 20, 16806; (f) E. Merino and
C. Nevado, Chem. Soc. Rev., 2014, 43, 6598; (g) H. Egami
and M. Sodeoka, Angew. Chem., Int. Ed., 2014, 53, 8294;
(h) T. Liang, C. N. Neumann and T. Ritter, Angew. Chem.,
Int. Ed., 2013, 52, 8214; (i) P. Chen and G. Liu, Synthesis,
2013, 2919.
Summary and conclusions
In conclusion, we have introduced a novel practical method for
the determination of rate constants for the addition of the tri-
fluoromethyl and the pentafluoroethyl radical to various
alkenes (20 values measured). Kinetic competition experi-
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7 (a) W. R. Dolbier Jr. and X. X. Rong, Chem. Rev., 1996, 96,
1557; (b) W. R. Dolbier Jr. in Topics in Current Chemistry,
ed. R. D. Chambers, Springer, Berlin, 1997, vol. 192, p. 97;
(c) A. Studer, Angew. Chem., Int. Ed., 2012, 51, 8950.
8 J. M. Tedder and J. C. Walton, Tetrahedron, 1980, 36, 701.
9 (a) W. R. Dolbier Jr. and X. X. Rong, J. Fluorine Chem., 1995,
72, 235; (b) B. Delest, A. B. Shtarev and W. R. Dolbier Jr.,
Tetrahedron, 1998, 54, 9273; (c) D. V. Avila, K. U. Ingold,
J. Lusztyk, W. R. Dolbier, H.-Q. Pan and M. Muir, J. Am.
Chem. Soc., 1994, 116, 99; (d) X. X. Rong, H.-Q. Pan,
W. R. Dolbier and B. E. Smart, J. Am. Chem. Soc., 1994, 116,
4521; (e) L. Zhang, W. R. Dolbier Jr., B. Sheeller and
K. U. Ingold, J. Am. Chem. Soc., 2002, 124, 6362.
The corresponding product could not be isolated and
assigned. However, since it is always the same side product
for different alkenes it cannot be derived from CF3-radical
addition to the alkene. Therefore, kinetics will not be dis-
turbed. We also performed the reaction with styrene
without any workup and directly subjected the crude reac-
tion mixture to 19F NMR-analysis to determine whether
CF3H is generated. However, only 3a and 4 were identified
in the crude reaction mixture indicating that H-abstraction
by the CF3 radical does not occur. Additional experiments
on selected examples (4 systems) with an internal standard
also revealed perfect mass balance showing that the Togni
reagent is fully converted to either the perfluoroalkylation
product or the direct trapping product (see ESI†). In agree-
ment with this observation, we never identified TEMPO-
trapping products derived from H-abstraction from the
solvent THF or from an alkene.
10 D. A. Avila, K. U. Ingold, J. Lusztyk, W. R. Dolbier Jr. and
H.-Q. Pan, J. Org. Chem., 1996, 61, 2027.
11 Y. Li and A. Studer, Angew. Chem., Int. Ed., 2012, 51, 8221.
12 (a) T. Vogler and A. Studer, Synthesis, 2008, 1979;
(b) L. Tebben and A. Studer, Angew. Chem., Int. Ed., 2011, 16 Pauling-electronegativity for F = 4.0 and CF3 = 3.4, see:
50, 5034.
E. V. Anslyn and D. A. Dougherty, in Modern Physical
Organic Chemistry, Universal Science Books, Sausalito,
California, 2006, p. 12. σmeta-Substituent constant for CF3 =
0.46 and F = 0.34 indicating that the CF3 group shows
13 The use of TEMPONa as a SET reagent is not limited to the
generation of trifluoromethyl radicals. We also developed
analogous procedures for aryl, azidyl or bissulfonamidyl
radical generation, see: (a) M. Hartmann, Y. Li and
A. Studer, J. Am. Chem. Soc., 2012, 134, 16516; (b) B. Zhang
and A. Studer, Org. Lett., 2013, 15, 4548; (c) Y. Li,
M. Hartmann and A. Studer, Chem. Commun., 2015, 51,
5706.
a
stronger inductive effect, see: E. V. Anslyn and
D. A. Dougherty, in Modern Physical Organic Chemistry, Uni-
versal Science Books, Sausalito, California, 2006, p. 445.
Hence, the pentafluoroethyl radical is likely slightly more
electronegative. In contrast, the CF3-radical is smaller than
the CF3CF2-radical and obviously the electronic effect over-
rides the steric effect: the CF3CF2-radical shows higher
reactivity than the CF3-radical.
14 M. Newcomb, Tetrahedron, 1993, 49, 1151.
15 In some experiments we identified in very small amounts
of a doublet at around −60 ppm in the 19F-NMR spectrum.
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