On the reactivity of anodically generated trifluoromethyl radicals toward aryl alkynes in organic/aqueous media

Article abstract of DOI:10.1039/C9OB00456D

An in-depth study of the reaction of electrochemically generated trifluoromethyl radicals with aryl alkynes in the presence of water is presented. The radicals are readily generated by anodic oxidation of sodium triflinate, an inexpensive and readily avai

Full text of DOI:10.1039/C9OB00456D

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DOI: 10.1039/C9OB00456D
ARTICLE
On the reactivity of anodically generated trifluoromethyl radicals
toward aryl alkynes in organic/aqueous media
Wolfgang Jud,a,b C. Oliver Kappe,*a,b and David Cantillo*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
An in-depth study of the reaction of electrochemically generated of trifluoromethyl radicals with aryl alkynes in the presence
of water is presented. The radicals are readily generated by anodic oxidation of sodium triflinate, an inexpensive and readily
available CF3 source, with concomitant reduction of water. Two competitive pathways, i.e. aryl trifluoromethylation vs
oxytrifluoromethylation of the alkyne, which ultimately leads to the generation of α-trifluoromethyl ketones, have been
observed. The influence of several reaction parameters on the reaction selectivity, including solvent effects, electrode
material and substitution pattern on the aromatic ring of the substrate have been investigated. A mechanistic rationale for
the generation α-trifluoromethyl ketones based on cyclic voltammetry data and radical trapping experiments is also
presented. DFT calculations carried out at the M062X/6-311+G(d,p) level on the two competing pathways account for the
observed selectivity.
DOI: 10.1039/x0xx00000x
trifluoromethylation of alkenes14 or alkynes15 in the presence of
an oxidizing agent (e.g. molecular oxygen) or a hydroxyl source,
respectively.
Introduction
Incorporation of perfluoroalkyl moieties to organic molecules
typically enhances some of their biological properties such as
metabolic stability, lipophilicity and bioavailability,1 and hence
represents an important type of modification in the production
of agrochemicals, materials and pharmaceuticals (Fig. 1).2 In the
past two decades, a plethora of synthetic methods for the
generation of C-C bonds between perfluoroalkyl groups and
organic scaffolds have been reported.3 In particular, research on
the introduction of trifluoromethyl groups (CF3) has gained
significant attention.4 To this end, a variety of different
trifluoromethyl donors have been developed, ranging from
simple and inexpensive compounds, such as triflyl chloride,5
CF3
CF3
N
N
H
O
N
O
S
H2N
O
Celecoxib
OH
Fluoxetine
H
N
O
N
O
H
trifluoroiodomethane,6
trifluoromethyltrialkylsilane7
and
Cl
F3C
sodium triflinate8 to more complex and expensive chemicals like
the Umemoto’s or Togni’s reagents.9 In particular, the
generation of α-trifluoromethyl ketones, which may serve as
versatile building blocks for a diverse set of CF3-containing
molecules, has been subjected to intense research and is
considered to be an especially challenging task.10 Common
synthetic protocols involve electrophilic or radical
trifluoromethylations of silyl enol ethers,10-12 or enamines,13
which are generated as reactive intermediates from the parent
ketone. Ideally, isolation of these intermediates is avoided,
affording a one-pot, two step procedure.12 Alternatively, α-
trifluoromethyl ketones can be obtained by direct radical
F3C
N
CF3
Mefloquine
Efavirenz
Fig. 1 Examples of CF3-containing active pharmaceutical ingredients.
Radical trifluoromethylations are typically promoted by
chemical oxidation of a CF3 source or photochemical methods
(e.g. photoredox catalysis).4 Generation of CF3 radicals can also
be achieved by electrochemical methods, enabling the
aforementioned redox process without the need for metal- or
photocatalysts or stoichiometric amounts of hazardous
oxidizing or reducing agents, giving rise to highly sustainable
processes.16 In fact, owing to the “inherently green” character
of electroorganic synthesis,17 this technology has seen a
considerable resurgence over the past few years. Generation of
CF3 radicals by anodic oxidation of several CF3 sources, including
CF3COOH,18 CF3SO2Na,19 or (CF3SO2)2Zn,20 and its application for
a. Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010,
Graz, Austria. E-mail: oliver.kappe@uni-graz.at; david.cantillo@uni-graz.at.
b. Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center
Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria.
Electronic Supplementary Information (ESI) available: Supplementary Figures and
Tables, copies of NMR spectra and Cartesian coordinates and energies of all
calculated structures. See DOI: 10.1039/x0xx00000x
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Journal Name
the trifluoromethylation of arenes and alkenes has been analysis. Thus, in addition to the expected trifluoromethylaryl
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reported. Recently, we have developed a novel route for the alkyne 3a, aryl trifluoromethylation ofDtOhIe: 10α.1-0tr3i9f/luCo9OroBm00e4t5h6yDl
oxytrifluroromethylation of alkenes, enabled by the ketone 2a (compound 4a) was also observed. Formation of 4a
electrochemical oxidation of CF3SO2Na in the presence of is expected to take place in the late stage of the reaction, when
water.21
high concentrations of 2a are present in the mixture (vide infra).
Herein, the reactivity of anodically generated CF3 radicals in Minor amounts (<5%) of trifluoromethylsulfonylated aromatics
organic/aqueous media is extended to more challenging aryl were also observed in some cases (for a GC-FID chromatogram
alkyne substrates. The rather similar nucleophilic character of of an example of crude reaction, see Fig. S1 in the ESI).
the alkyne and the aromatic moiety results in competition of
Using acetone as solvent, a series of anode/cathode
two reaction pathways: oxytrifluoromethylation of the alkyne, material combinations were evaluated (Table 1, entries 1-4).
which leads to the corresponding α-trifluoromethyl ketone While maintaining graphite as the anode, altering the cathode
after tautomerization of the ensuing enol, and arene material (graphite, Pt, Ni, stainless steel) only had a minor
trifluoromethylation (Fig. 2). In an attempt to harness reaction influence on the reaction outcome, with 2a being formed with
selectivity, the effect of several reaction parameters on product highest selectivity (Table 1, entries 1-4). In contrast, complex
distribution has been carefully studied. Formation of α- mixtures of products were obtained with both Pt and RVC as
trifluoromethyl ketones was favored in most cases, although
mixtures with trifluoromethyl-aryl products were always
Table 1 Influence of the electrode type, solvent and electrolyte on the outcome of
observed. DFT calculations at the M06-2X/6-311+G(d,p) level of
the two competing pathways have been carried out to explain
the observed selectivity.
the reaction of 1a with CF3SO2Na under constant current electrolysis in
organic/aqueous media.[a]
(a) Electrochemical generation of CF3 radicals and hydroxide
tBu
O
CF3
O
CF3SO2Na
org. solv./H2O
CF3
3a
anodic
+
oxidation
(+)graphite/(-)cathode
constant current
tBu
tBu
CF3SO2Na
2 H2O
CF3
CF3
2a
1a
(0.2 M)
cathodic
reduction
tBu
CF3
H2 + 2 OH-
4a
Conv.
[%]c
92
2a
[%]c
63
3a-4a
[%]c
37
Entry Solventb Anode Cathode Electrolyte
(b) Competing reactions observed in the presence of aryl alkynes
1
2
Acetone Graphite Graphite Et4NBF4
OH
CF3
CF3
OH-
CF3
Acetone Graphite
Acetone Graphite
Acetone Graphite
Pt
Ni
SS
SS
Pt
SS
SS
SS
SS
SS
SS
SS
SS
SS
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Bu4NBF4
LiClO4
93
94
90
99
85
51
24
62
73
99
85
85
97
61
67
63
10
22
23
35
44
48e
41
62
46
64
25
33
37
20
21
53
65
43
52f
31
34
37
36
R
R
R
3
CF3
O
CF3
4
R
5
Acetone
Acetone
THF
RVCd
Pt
Fig. 2 (a) Generation of CF3 radicals by anodic oxidation of sodium triflinate with
concomitant water reduction of water and (b) competition between
oxytrifluoromethylation and aryl trifluoromethylation in the presence of aryl
alkynes.
6
7
Graphite
8
MeTHF Graphite
MeCN Graphite
MeOH Graphite
CH2Cl2 Graphite
Acetone Graphite
Acetone Graphite
Results and Discussion
Aryl vs Alkyne Trifluoromethylation: Effect of Solvent
9
10
11
12
13
Composition and Electrode Materials on Reaction Selectivity
Our investigation was carried out using 4-tert-
butylphenylacetylene (1a) as model aryl alkyne. All experiments
were carried out in a standardized electrochemical reactor (IKA
ElectraSyn) at constant current under nitrogen atmosphere. An
initial set of experiments was performed to evaluate the
influence of the organic solvent, electrode material and
electrolyte on the reaction outcome. All experiments were
carried out on a 0.5 mmol scale, using a 0.2 M concentration for
the alkyne and 1.2 equiv. CF3SO2Na. A constant current of 30
mA and a total charge of 2.2 F/mol (10% excess over the
theoretical charge required) were applied. Notably, good to
excellent conversions were obtained in all cases and, as
anticipated, mixtures of the α-trifluoromethyl ketone 2a and
trifluoromethyl-aryl derivatives 3a-4a were detected by GC
14g Acetone Graphite
15h Acetone Graphite
Et4NBF4
Et4NBF4 <LOD <LOD <LOD
a
Conditions: 0.5 mmol scale, 1.2 equiv. CF3SO2Na, 0.1 M electrolyte, 2.2 F/mol,
constant current (30 mA) electrolysis under N2 atmosphere, 400 rpm stirring, IKA
ElectraSyn 2.0 reactor. 20:1 Mixture of the solvent and water. Determined by
GC-FID peak area integration. d Reticulated vitreous carbon. e Selectivity calculated
for α-trifluoromethyl methyl-enol ether (see SI for details). f Selectivity calculated
b
c
g
for trifluoromethylation of substrate or enol ether on aromatic ring. Constant
voltage (4 V) applied. h Without electricity
anodes (Table 1, entries 5-6). This could be attributed to lower
overpotentials for some undesired oxidations on Pt, or the fact
2 | J. Name., 2012, 00, 1-3
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that its surface may be catalytically active for such side- total charge, was next investigated (Fig. 3). Conversion
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reactions, and a poor mixing of the reaction mixture within the increased when low amounts of water DwOeIr:e10u.1t0i3li9z/eCd9O(FBi0g0.435a6D).
pores in the case of the RVC material.
Notably, the 2a:3a-4a ratio decreased with increasing amounts
Next, a series of solvents covering a wide range of dielectric of water, and the favored product was inverted when the
constants were screened (ε = 35.7 for MeCN and ε = 7.5 and 7.0 amount of water increased from 47 to 97 equiv. Increase of
for MeTHF and THF, respectively). The solvent choice may temperature, substrate concentration, amount of CF3SO2Na
influence both the electrolysis efficiency, as the maximum and charge had positive effects on the reaction conversion, but
amount of current that can be passed to the reagent solution a less important influence on the 2a:3a-4a product ratio (Fig.
while keeping the voltage in a 3-4 V range depends on the 3b-e). Low currents (Fig. 3f) favored higher 2a:3a-4a ratios, as
dielectric constant of the solvent, and the selectivity of the well as higher substrate conversion. In most cases, α-
reaction itself. Best conversions were typically obtained in trifluoromethyl ketone 2a was the favored product of the
acetone. In addition, acetone favored the formation of 2a, with reaction. As mentioned above, an excess of CF3SO2Na was
a selectivity of up to 67% (Table 1, entry 3). Notably, the required to achieve high conversions. 19F-NMR monitoring of
selectivity could be inverted in THF and MeTHF (entries 7-8). A the reaction mixture revealed consumption of more than one
selectivity of 65% toward aryl trifluoromethylation was equivalent of sodium triflinate at conversions below 90%. This
observed in MeTHF as solvent (entry 8), although the reaction effect could be ascribed to trapping of some of the CF3 radicals
conversion was significantly lower than for acetone. In MeOH by e.g. water and formation of volatile species.
as solvent, an α-trifluoromethyl methyl-enol ether was formed
as product with 48% selectivity, resulting from methoxide acting Effect of Substrate Substituents. Reaction Scope
as nucleophile instead of water (Table 1, entry 10) (see Fig. S2
To evaluate the functional group tolerance under the
in the ESI). Although full conversion was obtained in DCM, ca.
electrolysis conditions and assess their effect on the reaction
30% of an undesired, unidentified side-product was detected by
selectivity, a diverse set of aryl alkynes was subjected to the
electrochemical trifluoromethylation (Scheme 1). α-
Trifluoromethyl ketones 2 were favored in most cases. For that
reason, derivatives 2 were isolated and characterized. Yields for
GC. The type of electrolyte used had little influence on the
product distribution (Table 1, entries 12-13). An additional
experiment under potentiostatic conditions (constant voltage
at 4 V) showed no noticeable difference with the reaction at
constant current (Table 1, entry 14 vs entry 4). As expected, the
reaction did not proceed in the absence of electricity, proving
that an electrochemical redox process was involved in the
generation of the CF3 radicals (Table 1, entry 15).
An additional set of reaction parameters, namely amount of
water and CF3SO2Na, temperature, concentration, current and
2
and the trifluoromethyl-aryl adducts 3-4 were also
determined by 19F NMR for comparison. Since the reactions
were carried out in acetone, minor amounts (< 10%) of the
acetone aldol condensation products were detected in some
reaction mixtures, which were likely formed under the basic
conditions generated during the reaction. These impurities
could easily be removed by evaporation.
Fig. 3 Electrochemical transformation of 1a. Typical conditions: 0.5 mmol substrate, 1.2 equiv CF3SO2Na, acetone:H2O 20:1 (v/v), 0.1 M Et4NBF4, 2.2 F/mol, constant current (30 mA),
anode: graphite, cathode: stainless steel, 2.625 mL reaction volume. For a more detailed representation, including the amounts of all side products, see Fig. S3 in the ESI).
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C9OB00456D
ARTICLE
Aromatic alkynes bearing both electron withdrawing and
In an attempt to improve the reaction for oxidatively labile
electron donating substituents, as well as a heterocyclic aryl substances (e.g. 1c and 1k), three common oxidation mediators
alkyne, were reacted with NaSO2CF3 under electrolytic [triphenylamine, TEMPO and manganese(III) acetate dihydrate]
conditions (see Experimental Section for details). Surprisingly, were evaluated for the trifluoromethylation of these substrates
despite the presence of deactivating functional groups on the as well as the model alkyne 1a. Although a decrease of the
arene in substrates 1b and 1f, the ratio of products did not shift current from 30 mA to 5 mA had a positive effect on conversion
in favor of the α-trifluoromethyl ketone 2. In contrast, during of 1a and 1c, the presence of mediators did not significantly
the reaction of the electron-rich 4-methoxyphenyl acetylene change the reaction outcome (see Table S1 in the ESI). Notably,
(1e), trifluoromethylation of the ring was clearly favored the reaction of 1k did not afford the expected ketone 2, but
(Scheme 1). The CF3 radical addition reaction proved to be trifluoromethylacrylophenone 5 (Scheme 2). This compound is
tolerant to steric effects, as both para methyl (1h) and ortho likely formed by intramolecular trapping of the carbocation
methyl (1g) phenylacetylene could be functionalized with intermediate 6 by the OH group (instead of water, which leads
similar yields. A non-terminal alkyne (1j) was also successfully to the expected product 2). The ensuing unstable oxetane 7
derivatized under the standard reactions conditions. Notably, rearranges to compound 5. Although 5 was observed in good
even the oxidatively labile substrate 1c was converted into the yields (54%) by GC, its high reactivity did not allow its isolation
α-trifluoromethyl ketone 2c in modest yield. Isolation of pure α- in pure form (see Fig. S4 in the ESI).
trifluoromethyl ketones from the other reaction products was
OH
O
O
CF3SO2Na
acetone/H2O
possible by simple column chromatography. Separation of 2e
from 3e and 2j from 3j was problematic due to the very similar
polarity of the products.
CF3
OH
CF3
electricity
X
1k
5
2k
1) CF3
2) -e
R2
OH
O
-H+
R
R2 CF3SO2Na (1.2 equiv)
O
CF3
CF3
CF3
CF3
3
acetone/H2O
7
6
R1
R
+
O
R2
EtN4BF4 (0.1 M)
(unstable)
CF3
(+)graphite/(-)steel
undivided cell
2
1
(0.2 M)
R
R2
Scheme 2 Reaction outcome for alkyne 1j utilizing the typical electrolysis conditions
constant current
CF3
(Scheme 1).
4
2 (isolated yield)a 3+4a
2 (isolated yield)a 3+4a
Substrate
Substrate
Proposed Mechanism for the Generation of α-
Trifluoromethyl Ketones
33%
37%
26% (10%)
35% (29%)
1f
38%
40% (36%)
1a
Br
tBu
F
1g
Cyclic voltammograms of the starting materials (Fig. 4a)
revealed that oxidation of sodium triflinate occurs at 1.1 – 1.3 V
(vs Ag/AgCl), and is followed by an irreversible reaction, while
the model aryl alkyne substrate 1a and even oxidatively labile
alkynes require much higher oxidation potentials (2.2 – 2.5 V)
(see Fig. 4a and Fig. S5 in the ESI for other alkynes). Thus,
oxidation at the anode should involve the CF3 source with good
selectivity.
Oxidation of triflinate is known to generate CF3 radicals,8,19
likely by decomposition of the initially formed CF3SO2 radical, as
pointed out by the side products observed in the reaction (see
Fig. S6 in the ESI). To provide evidence for a radical reaction
mechanism, we carried out a control experiment using the
typical electrolysis conditions (Scheme 1) for the model
substrate 1a and using 1 equiv of butylated hydroxytoluene
30%
33% (19%)
1b
1c
33%
36% (35%)
1h
17%
34%
12% (11%)
29% (27%)
H
28% (27%)
38% (--)d
37%
9%
S
1i
1j
O
1d
1e
OH
--c
--c
28% (19%)b
45%
1k
O
Scheme 1 Reaction scope for the electrochemical transformation of alkynes in the
presence of NaSO2CF3. Conditions: 1.0 mmol substrate, 1.2 equiv. NaSO2CF3,
Acetone:H2O 20:1 (v/v), 0.1 M Et4NBF4, 2.2 F/mol, constant current (15 mA), anode:
graphite, cathode: stainless steel, 5 mL reaction volume a Determined by 19F-NMR b Essay
corrected; the isolated material (32%) contained 3e. c See Scheme 2. d Ketone 2k could
not be separated from the side products by column chromatography.
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(2,6-di-tert-butyl-4-methylphenol, BHT) as additive. Cyclic generated at the cathode, affording an enol ethVieewr A6rt,iclewOhnilcinhe
DOI: 10.1039/C9OB00456D
voltammetry confirmed that BHT is oxidized at
tautomerizes to the ketone 2. The proposed mechanism
represents an example of a paired electrochemical reaction: the
hydroxide ions generated at the cathode during the electrolysis
are also involved in the reaction, as one equivalent of hydroxide
is incorporated in the final molecule.
Differential Selectivity Analysis and Computational
Evaluation
As described above, reactions of aryl alkynes with
electrochemically generated CF3 radicals in the presence of
water produced mixtures of α-trifluoromethyl ketones 2 and
products derived from trifluoromethylation of the aromatic ring
(3a-4a). This occurred under all reaction conditions evaluated
(Table 1, Fig. 2) and with all aryl alkynes tested (Scheme 1).
Motivated by these somewhat surprising results–the reaction
could not be directed to one of the two expected products, we
decided to have a more detailed look into the reaction kinetics
and assess the two competing pathways by DFT calculations,
with the aim of providing an explanation to the observed
product distribution.
HPLC monitoring of the model reaction (Fig. S8) revealed the
expected formation of compounds 2a and 3a from the initial
reaction stage, and a gradual increase in the amount of 4a
starting after 0.5 F/mol. This is due to the fact that 4a is formed
from 2a. The reaction selectivity can be more clearly visualized
by analyzing the corresponding differential selectivity plots (Fig.
6), which represent the relative amount of the reaction
products at different reaction stages. Thus, the linear
differential selectivity plot obtained for 2a vs 3a (Fig. 6a)
showed that generation of the two compounds occurs
simultaneously during the whole process, with a constant
relative rate. The slope of the linear plot (ca. 0.32) indicated that
the formation of 2a is approximately 3 times faster than for 3a.
Selectivity values for 2a did not match this relative rate (cf.
Table 1) due to the formation of other side products (e.g. 4a),
which take place at later stages of the reaction as shown in Fig.
6b. Thus, the differential selectivity of 2a vs the sum of all
trifluoromethyl-aryl products (3a, 4a and minor amounts of
trifluoromethylsulfonyl derivatives) has a curved concave
shape, indicating that the rate of formation of trifluoromethyl
arenes increases with respect to the formation of 2a with the
reaction progress. These results were expected, as the rate of
formation of 4a is proportional to the amount of 2a in the
reaction mixture.
Fig. 4 (a) Cyclic voltammograms of CF3SO2Na, 4-tert-butylphenylacetylene (1a) and a
typical reaction mixture (see ESI for Details). (b) Species detected by GC-MS that point to
the presence of the radical species highlighted in red.
higher potential than CF3SO2Na, and therefore it is a suitable
radical trapping agent for this reaction (see Fig. S5 in the ESI).
GC-MS analysis of the mixture after electrolysis revealed (see
Fig. S7 in the ESI) the presence of a large amount of unreacted
1a, confirming that BHT quenched the reaction, as well as
trifluoromethylated BHT and small amounts of α-
trifluoromethyl ketones 2a and 3a. To our delight, compound 8
(Fig. 3b), corresponding to the trapping of a plausible
trifluoromethylalkenyl radical, could also be detected by GC-MS
analysis.
Thus, the proposed mechanism for the formation of α-
trifluoromethyl ketones (Fig. 5) starts with the anodic oxidation
of the triflinate anion, producing a trifluoromethylsulfonyl
radical which decomposes into a CF3 radical and SO2.
Subsequently, the CF3 radical adds to the triple bond of the
substrate in an anti-Markovnikov fashion, giving rise to the
secondary alkyl radical 9 stabilized by the adjacent aromatic
ring. Further oxidation of 9 produces carbocation 10. The
carbocationic species is trapped by water or the hydroxide
anode
-e-
-e-
OH
-
CF3
CF3
CF3
+
CF3SO2
CF3SO2
CF3
O
9
SO2
10
R
R
11
R
CF3
2
R
1
+2e
R
H2
+ OH
+
2H2O
OH
cathode
Fig. 5 Proposed reaction mechanism for the formation of α-trifluoromethyl ketones 2 from alkynes and electrochemically generated CF3 radicals in the presence of water.
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C9OB00456D
ARTICLE
the CF3 radical to the alkyne and aromatic ring were modelled
using M06-2X functional22 and the 6-311+G(d,p) basis set. All
calculations incorporated solvent effects with the SMD
model,[23] both for geometry optimization and frequency
analyses, using acetone as solvent. To reduce the
computational cost of the calculations, the reaction of phenyl
acetylene (1d) was selected as model. The results were
compared with the reaction of styrene (1d´) (Fig. 7a), which in
previous studies had shown clear preference for the radical
addition to the olefin in detriment of the addition to the
aromatic ring.21 While the reaction of the CF3 radical with the
alkyne and the alkene were simply modelled for the C-2
addition, matching experimental observations, the radical
addition to the aromatic ring was calculated for the ortho-,
meta-, and para- positions. In the case of styrene, the two
possible isomers for the ortho- and meta- addition of the CF3
radical (depending on the alkene orientation) were taken into
account. The energy of the most stable isomer is presented.
The energy profile obtained for the reaction of phenyl
acetylene (1d) with the CF3 radical (Fig. 7b, black color) revealed
analogous energy barriers for all possible radical addition
pathways, being all within a range of ca. 2 kcal/mol. The
difference in energy between the transition state for the radical
addition to the triple bond (TS1d-9d) and the most favored of the
arene additions (o-TS1d-12d) was only 1.3 kcal/mol. Importantly,
the similar energetics for the competing reactions satisfactorily
explain the mixtures of products observed in all cases (cf. Table
1 and Fig. 2). As expected, the generation of adducts 9d and 12d
was exergonic. 31.2 kcal/mol and 11.6-16.4 kcal/mol are
released for during the formation of 9d and 12d, respectively.
Fig. 6 Differential selectivity plots for the formation of 2a vs 3a (a) and 2a vs aryl-
trifluoromethyl species (b), obtained by HPLC monitoring of the reaction mixture.
The two reaction pathways, leading to the generation of
compounds 2 and 3, were then assessed by DFT calculations to
ascertain the origin of the product distribution experimentally
observed. Thus, the stationary points involved in the addition of
(a)
(b)
G
(kcal/mol)
CF3
TS1d12d
TS1d9d
CF3
F3C
o-TS1d´-12d´
m-TS1d´-12d´
p-TS1d´-12d´
+10.5
+12.2
+11.3
,
, -TS
o m p
1d 12d

, , -TS
o m p
1d´ 12d´
+

TS1d
9d

12d
9d
1d
TS1d´
9d´

TS1d´-9d´
+7.5
CF3
TS1d´12d´
TS1d´9d´
CF3
F3C
(c)
0.0
0.0
o-TS1d-12d
m-TS1d-12d
p-TS1d-12d
+11.2
+12.4
+11.3
+
1d
+
CF3
1d´
+
CF3
12d´
1d´
9d´
TS1d-9d
+9.9
,
, -12d
o m p
,
, -12d´
o m p
o-12d
m-12d
p-12d
-14.2
-11.6
-16.4
o-12d´
m-12d´
p-12d´
-15.1
-12.5
-17.8
9d
-31.2
9d´
-36.8
9d
TS1d-9d
o-TS1d-12d
9d´
reaction coordinate
Fig. 7 (a) Computed radical additions to the aromatic ring and the alkyne (1d) or alkene (1d´); (b) Energy profiles calculated at the M06-2X/6-311+G(d,p) level. The similar energy
barriers obtained for the radical additions to the alkyne and arene of 1d explain the mixtures of products observed experimentally; (c) structures of selected transition states.
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB00456D
ARTICLE
19F NMR monitoring was carried out in a Magritek Spinsolve 43
On the other hand, the energy profile for the reaction of the CF3 benchtop NMR instrument. Chemical shifts (δ) are expressed in
radical with styrene 1d´ (Fig. 7b, blue color) presented ppm downfield from TMS as internal standard. The letters s, d,
analogous energy barriers for the addition of the radical to the t, q, and m are used to indicate singlet, doublet, triplet,
arene (10.5-12.2 kcal/mol). However, the barrier for the quadruplet, and multiplet, respectively. GC-FID analysis was
addition to the alkene moiety resulted in significantly smaller performed on a ThermoFisher Focus GC with a flame ionization
values (7.5 kcal/mol). This difference (3 kcal/mol) accounts for detector, using a TR-5MS column (30 m × 0.25 mm ID × 0.25 μm)
the selective oxytrifluoromethylations achieved when styrene and helium as carrier gas (1 mL min–1 constant flow). The
derivatives are reacted with CF3 radicals in organic aqueous injector temperature was set to 280°C. After 1 min at 50°C, the
media.[21] The fate of the trifluoromethylsulfonyl (CF3SO2) temperature was increased by 25°C min–1 to 300°C and kept
radical that is initially formed and triggers the reaction constant at 300°C for 4 min. The detector gases used for flame
mechanism (Fig. 5) was also modelled at the same level of ionization were hydrogen and synthetic air (5.0 quality). GC-MS
theory. Notably, the calculations also predicted rapid spectra were recorded using a ThermoFisher Focus GC coupled
decomposition of the radical with extrusion of SO2, with an with a DSQ II (EI, 70 eV). A TR-5MS column (30 m × 0.25 mm ×
energy barrier of only 5.9 kcal/mol. This low barrier explained 0.25 μm) was used, with helium as carrier gas (1 mL min–1
that only minor amounts of products containing the constant flow). The injector temperature was set to 280°C. After
trifluoromethylsulfonyl moiety, via trapping of this radical, were 1 min at 50°C, the temperature was increased by 25°C min–1 to
observed experimentally.
300°C and kept at 300°C for 3 min. Analytical HPLC analysis was
carried out on a C18 reversed-phase (RP) analytical column (150
× 4.6 mm, particle size 5 mm) at 37 °C by using mobile phases A
[water/acetonitrile 90:10 (v/v) + 0.1% TFA] and B (acetonitrile +
0.1% TFA) at a flow rate of 1.5 mL min–1. The following gradient
was applied: linear increase from solution 30% B to 100% B in 8
min, hold at 100% solution B for 2 min. Flash chromatography
purifications were carried out on an automated flash
chromatography system using cartridges packed with KP-SIL, 60
Å (32–63 μm particle size). Sodium trifluoromethanesulfinate
(Code: 743232, Lot: BCBX4470), tetrabutylammonium
Conclusions
In summary, the present work provides a detailed experimental
and theoretical study on the reactivity of electrochemically
generated CF3 radicals with aryl alkynes in the presence of
water. The radicals were generated by anodic oxidation of
CF3SO2Na in an undivided cell. Similar reactivity toward radicals
of the alkyne and arene moieties led to two major reaction
pathways: trifluoromethylation of the aromatic ring and
tetrafluoroborate
(Code:
217964,
Lot:
BCBV1430),
oxytrifluoromethylation
of
the
alkyne.
The
tetraethylammonium tetrafluoroborate (Code: 242144, Lot:
BCBV4670) and lithium perchlorate (Code: 634565, Lot:
0000011388) were purchased from Aldrich. All other chemicals
were obtained from standard commercial vendors and were
used without any further purification. Electrochemical reactions
and cyclic voltammetry experiments were carried out in an IKA
ElectraSyn 2.0.
oxytrifluoromethylation process produced a 2-trifluoromethyl
enol, that upon tautomerization resulted in the formation of an
α-trifluoromethyl ketone. The effect on the product distribution
of several reaction parameters was evaluated. Formation of α-
trifluoromethyl ketones was favored in most cases, except
when THF of MeTHF were used as solvent. Several aryl alkynes
decorated with electron-withdrawing and donating groups
were tested. The reaction performed well in all cases, although
always led to mixtures of products from the two competing
pathways. A computational study of the radical additions to the
arene and alkyne, leading to the two competing mechanisms,
was carried out at the M06-2X/6-311+G(d,p) level. The
analogous energy barriers calculated for all the radical additions
successfully explained the selectivity observed experimentally.
Computational details. All calculations were carried out with
the Gaussian 09 package.24 The M06-2X density functional
method22 in conjunction with the 6-311+G(d,p) basis set was
selected for all the geometry optimizations and frequency
analysis. The geometries were optimized with inclusion of
solvation effects. For this purpose, the SMD solvation method23
was employed using acetone as solvent. Frequency calculations
at 298.15 K on all stationary points were carried out at the same
level of theory as the geometry optimizations to ascertain the
nature of the stationary points. Ground and transition states
were characterized by none and one imaginary frequency,
Experimental Section
General: 1H NMR spectra were recorded on a 300 MHz
instrument. 13C NMR and 19F NMR spectra were recorded on the
same instrument at 75 MHz and 282 MHz, respectively. Routine
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Organic & Biomolecular Chemistry
Page 8 of 10
ARTICLE
Journal Name
respectively. All of the presented relative energies are free 139.7, 136.0, 132.7, 132.6, 129.6, 129.1, 126.2, 124.1 (q, J =
View Article Online
energies at 298.15 K.
Experimental procedure
277.1 Hz), 44.5 (q, J = 27.7 Hz), 21.7. 19F DNOMI:R10(.2108329/MC9HOzB,0C0D45C6l3D)
electrochemical δ -62.09 (t, J = 10.0 Hz). MS-EI: m/z 202 (10%), 119 (74%), 91
for
the
transformation of aromatic alkynes on preparative Scale: All (100%).
reactions were carried out in an IKA ElectraSyn 2.0 using an IKA 3,3,3-trifluoro-1-(p-tolyl)propan-1-one (2h). 66 mg (35%);
Graphite SK-50 anode and an IKA Stainless steel cathode. In a 5 yellow oil; H NMR (300 MHz, CDCl3) δ 7.83 (d, J = 8.3 Hz, 2H),
mL IKA ElectraSyn vial, equipped with a stir bar, 0.5 mmol 7.30 (d, J = 8.3 Hz, 2H), 3.77 (q, J = 10.0 Hz, 2H), 2.43 (s, 3H). 13
1
C
electrolyte (tetraethylammonium tetrafluoroborate, Et4NBF4), NMR (75 MHz, CDCl3) δ 189.4 (d, J = 2.4 Hz), 145.5, 133.5 (d, J =
1.2 mmol NaSO2CF3 and 1 mmol alkyne were mixed with 5 mL 1.6 Hz), 129.8, 128.6, 124.2 (q, J = 275.3 Hz), 42.12 (q, J = 28.1
Acetone and 250 µL water. After assembly of the Hz), 21.9. 19F NMR (282 MHz, CDCl3) δ -62.02 (t, J = 10.0 Hz). MS-
electrochemical cell, the reaction mixtures were purged with N2 EI: m/z 202 (11%), 119 (99%), 91 (100%).
for five minutes prior to switching on electricity to assure an
3,3,3-trifluoro-1-(thiophen-2-yl)propan-1-one (2i). 47 mg
Oxygen- and CO2-free atmosphere. The instrument was (27%); yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.76-7.72 (m, 2H),
operated under constant current mode (15 mA) and 2.2 F/mol 7.18 (dd, J = 4.9, 3.9 Hz, 1H), 3.71 (q, J = 10.1 Hz, 2H). 13C NMR
of charge were passed. After completion of the reaction, the (75 MHz, CDCl3) δ 182.3 (d, J = 2.8 Hz), 143.3 (d, J = 2.0 Hz),
crude product mixture was concentrated under reduced 135.9, 133.6, 128.6, 123.8 (q, J = 277.3 Hz), 43.2 (q, J = 28.7 Hz).
pressure and the residue was purified by flash column 19F NMR (282 MHz, CDCl3) δ -61.94 (t, J = 10.1 Hz). MS-EI: m/z
chromatography using as eluent petroleum ether/ethyl acetate. 194 (9%), 111 (100%), 83 (23%).
1-(4-tert-butyl)phenyl-3,3,3-trifluoropropan-1-one (2a). 86
mg (36%); yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 8.1
Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 3.77 (q, J = 10.0 Hz, 2H), 1.35 (s,
9H). 13C NMR (75 MHz, CDCl3) δ 189.4, 158.3, 133.4 (d, J = 1.8
Hz), 128.4, 126.0, 124.0 (q, J = 244.5 Hz), 42.1 (q, J = 28.1 Hz),
35.4, 31.1. 19F NMR (282 MHz, CDCl3) δ -61.98 (t, J = 10.1 Hz).
Conflicts of interest
There are no conflicts to declare
MS-EI: m/z 229 (75%), 201 (24%), 161 (30%), 110 (100%).
Acknowledgements
The CC FLOW Project (Austrian Research Promotion Agency FFG
3,3,3-trifluoro-1-(4-fluorophenyl)propan-1-one (2b). 35 mg
1
(19%); yellow oil; H NMR (300 MHz, CDCl3) δ 8.02 – 7.92 (m,
No. 862766) is funded through the Austrian COMET Program by
2H), 7.25 – 7.11 (m, 2H), 3.77 (q, J = 9.9 Hz, 2H). 13C NMR (75
the Austrian Federal Ministry of Transport, Innovation and
MHz, CDCl3) δ 188.3, 168.2, 164.8, 132.4, 131.4, 131.2, 124.0 (q,
Technology (BMVIT), the Austrian Federal Ministry of Science,
J = 277.1 Hz), 116.5, 116.2, 42.3 (q, J = 28.3 Hz). 19F NMR (282
Research and Economy (BMWFW), and by the State of Styria
MHz, CDCl3) δ -62.03 (t, J = 10.0 Hz, 3F), -102.86 (m, 1F). MS-EI:
(Styrian Funding Agency SFG).
m/z 206 (6%), 123 (100%), 95 (76%).
4-(3,3,3-trifluoropropanoyl)benzaldehyde (2c). 23 mg
(11%); yellow oil; 1H NMR (300 MHz, CDCl3) δ 10.13 (s, 1H), 8.09
(d, J = 8.4 Hz, 2H), 8.02 (d, J = 8.4 Hz, 2H), 3.85 (q, J = 9.8 Hz, 2H).
13C NMR (75 MHz, CDCl3) δ 191.4, 189.3, 139.8, 130.1, 129.1,
123.8 (q, J = 276.0 Hz), 42.7 (q, J = 28.6 Hz). 19F NMR (282 MHz,
CDCl3) δ -62.01 (t, J = 9.8 Hz). MS-EI: m/z 216 (7%), 133 (80%),
105 (35%).
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DOI: 10.1039/C9OB00456D
TOC graphic and text
Two competing pathways have been experimentally observed
and the selectivity explained by means of DFT calculations
+
-
CF3
R
OH-
CF3
OH
O
CF3
CF3
R
R
R
CF3
10 | J. Name., 2012, 00, 1-3
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