Csp3-Csp3 Bond-Forming Reductive Elimination from Well-Defined Copper(III) Complexes

Article abstract of DOI:10.1021/jacs.8b12632

Carbon-carbon bond-forming reductive elimination from elusive organocopper(III) complexes has been considered the key step in many copper-catalyzed and organocuprate reactions. However, organocopper(III) complexes with well-defined structures that can undergo reductive elimination are extremely rare, especially for the formation of Csp³-Csp³ bonds. We report herein a general method for the synthesis of a series of [alkyl-Cu^III-(CF₃)₃]^- complexes, the structures of which have been unequivocally characterized by NMR spectroscopy, mass spectrometry, and X-ray crystal diffraction. At elevated temperature, these complexes undergo reductive elimination following first-order kinetics, forming alkyl-CF₃ products with good yields (up to 91%). Both kinetic studies and DFT calculations indicate that the reductive elimination to form Csp³-CF₃ bonds proceeds through a concerted transition state, with a ΔH^? = 20 kcal/mol barrier.

Full text of DOI:10.1021/jacs.8b12632

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Article
Csp3-Csp3 Bond-Forming Reductive Elimination
from Well-Defined Copper(III) Complexes
Matthew Paeth, Sam B. Tyndall, Liang-Yu Chen, Jia-Cheng Hong, William P.
Carson, Xingwu Liu, Xiaodong Sun, Jinjia Liu, Kundi Yang, Elizabeth M. Hale, David
L. Tierney, Bin Liu, Zhi Cao, Mu-Jeng Cheng, William A. Goddard, and Wei Liu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 25 Jan 2019
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Csp -Csp Bond-Forming Reductive Elimination from Well-
Defined Copper(III) Complexes
†
†
§
§
†
Matthew Paeth, Sam B. Tyndall, Liang-Yu Chen, Jia-Cheng Hong, William P. Carson, Xingwu Liu,
Xiaodong Sun, Jinjia Liu, Kundi Yang, Elizabeth M. Hale, David L. Tierney, Bin Liu, Zhi Cao*
Mu-Jeng Cheng, William A. Goddard, III and Wei Liu
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†
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*,#
*,†
†Department of Chemistry and Biochemistry, Miami University, Oxford, OH, 45056, United States
§Department of Chemistry, National Cheng Kung University, Tainan, 701, Taiwan
||State Key Laboratory of Coal Conversion, Institute of Coal Chemistry, Chinese Academy of Sciences, Taiyuan, Shanxi
30001 (P. R. China); National Energy Center for Coal to Liquids, Synfuels China Technology Co., Ltd, Beijing, 101400, (P.
R. China
⊥A Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Shaanxi Key
Laboratory of Physico-Inorganic Chemistry, College of Chemistry and Materials Science, Northwest University, Xi'an
10127, P. R. China
#Materials and Process Simulation Center (MC 139-74), California Institute of Technology, Pasadena, California
1125, United States
0
7
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KEYWORDS trifluoromethyl • reductive elimination • high-valent copper • DFT calculation • organometallic reactions
ABSTRACT: Carbon-carbon bond-forming reductive elimination from elusive organocopper(III) complexes has been considered
the key step in many copper-catalyzed and organocuprate reactions. However, organocopper(III) complexes with well-defined
structures that can undergo reductive elimination are extremely rare, especially for the formation of Csp -Csp bonds. We report
herein a general method for the synthesis of a series [alkyl-Cu -(CF
characterized by NMR, mass spectrometry and X-ray crystal diffraction. At elevated temperature, these complexes undergo reductive
elimination following first-order kinetics, forming alky-CF products with good yields (up to 91%). Both Kinetic studies and DFT
calculations indicate that the reductive elimination to form Csp -CF
ΔH =20 kcal/mol barrier.
3
3
III
-
3 3
) ] complexes, the structures of which have been unequivocally
3
3
3
bonds proceeds through a concerted transition state, with a
‡
INTRODUCTION
can undergo intramolecular C-C bond-forming reductive
elimination. However, these reported examples require special
ligands and/or are limited to specific structures and, as a result,
considerable controversy remains over the mechanism of the
As an inexpensive, earth-abundant and non-toxic metal,
copper has found a wide range of applications in homogenous
catalysis, allowing for the construction of important
pharmaceuticals, materials and commodity chemicals. High-
valent organocopper(III) compounds have long been proposed
as key intermediates in many copper-catalyzed reactions, in
which the carbon-carbon or carbon-heteroatom bond-forming
reductive elimination from Cu species is considered the final
product-releasing step.
work have been conducted to synthesize organocopper(III)
complexes and understand their reactivity.
III
1
-4
reductive elimination from Cu species.
Trifluoromethyl groups (CF
3
) have been playing an important
groups
are known to stabilize Cu complexes, probably due to the
role in organocopper(III) chemistry. On one hand, CF
3
III
III
III
strong Cu -CF
3
sigma bond and thus the high thermal
5-12
30-32
Therefore, significant amounts of
stability.
characterized copper(III) complex, [Cu (CF
Burton has reported the first crystallographically
III
3
)
2
(SC(S)NEt
anion was first synthesized by
Neumann and, very recently, by Grushin using an optimized
2
)], in
1
3-21
III
22
III
-
However, Cu
3 4
1989. Later, Cu (CF )
3
3
complexes with well-defined structures remain rather limited
and most reported examples were stabilized by rigid
macrocyclic chelating ligands or perfluorinated groups,
1
8
III
3
method. Cu -CF complexes bearing nitrogen-containing
1
8, 22-26
ligands or a methyl group have recently been synthesized by
1
8
34-36
37
few of which provide experimental evidence for reductive
Grushin , Zhang
properties of CF
and Li. On the other hand, the unique
III
38-39
elimination of Cu species to form C-C or C-heteroatom
3
groups in medicinal chemistry
have driven
2
7-29
bonds.
Seminal work by Stahl and Ribas have shown that a
the development a large number of copper-promoted C-CF
3
III
40-49
series of Cu -mono-aryl species stabilized by an electron-
donating macrocyclic ligand can undergo C-heteroatom bond-
forming reductive elimination reactions. The Xi group has
recently reported a novel organocopper(III) spiro complex that
bond-forming reactions.
In some of these reactions, C-CF
3
III
bond-forming reductive elimination from Cu is indicated as
50-51
the key step.
However, this elementary reductive
elimination step remains poorly understood, especially for the
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Page 2 of 8
3
III
Csp -CF
3
bond-forming reductive elimination. Although aryl-
Cu -CF
3
] complexes. Thus, we synthesized complex 1,
III
1
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5
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7
8
9
1
1
1
1
1
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CF bond-forming reductive elimination has been studied on
3 3
[PyCu (CF ) ] (Py = pyridine), following the literature
3
II/IV
III
III
4, 52-55
3
36
Pd , Ni and Au complexes,
Csp -CF
3
bond-forming
method. Although the structure of compound 1 with a DMF
ligand (1-DMF) has been reported, the crystal of compound 1
without additional ligands can be obtained by the slow diffusion
of pentane to a DCM solution of 1. In contrast to the square
pyramidal structure of 1-DMF, crystal structure of 1 adopts the
square-planar geometry (Fig. S1), with the pyridine ring
perpendicular to the plane of copper.
reductive elimination from any transition metal complexes with
well-defined structures remains essentially unknown. Toste has
3
recently reported a formal Csp -CF
3
reductive elimination from
III
56
Au via a fluoride-rebound mechanism. This work represents
3
3
the first net Csp -CF bond-forming reaction from structurally-
defined complexes, although the C-C bond is formed via the
alkyl-migration pathway. Li’s group and our group have shown
Treating 1 with 1 equiv. of various alkyl zinc reagents at
room temperature affords the corresponding [(alky)Cu (CF ) ]
3 3
I
that a [Cu CF
reductive elimination of
trifluoromethylation of alkyl radicals.
3
] species generated possibly in situ via the
III
-
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III
a
Cu
complex promotes
species within 5 mins in nearly quantitative yields (Fig. 1).
3
7, 49
However, the
19
Compound 1 displays two F-NMR signals at 38 ppm and 24
reductive elimination is only limited to a methyl-containing
copper(III) complex.
III
-
ppm, while [(alky)Cu (CF
at ~ -35 ppm and -36 ppm, with an integral of 1:2, consistent
with a planar structure with two inequivalent CF groups. In
3 3
) ] complexes show two new peaks
3
III
-
1
addition, [(alky)Cu (CF
spectrum, consistent with a low spin d configuration of Cu .
For example, the proton of the CH groups connecting to copper
3 3
) ] display well-resolved H-NMR
8
III
2
in 1a and 1d displays chemical shifts at 3.6 and 2.4 ppm,
respectively, indicating the moderate electron-deficiency nature
III
of the Cu
center. The moderate stability of these
III
-
[
3 3
(alky)Cu (CF ) ] (hours at r.t. and weeks at -20C) allowed us
to confirm their composition using high-resolution electrospray
ionization mass spectrometry (HR ESI-MS). Gratifyingly, these
III
-
[
3 3
(alky)Cu (CF ) ] anions can be easily detected at negative
mode with normal ESI parameters (See SI for details). For
example, compound 1a and 1d show peaks at m/z = 360.9695
and 326.9854, respectively, consistent with the formation of
III
-
III
-
[(benzyl)Cu (CF
3
)
3
] and [(nBu)Cu (CF
3
)
3
] anions.
III
Due to the importance of Cu in copper catalysis and the lack
III
of isolable yet reactive Cu complexes, development of general
methods for the synthesis of structurally-defined
organocopper(III) complexes and study their ability for C-C
bond-forming reductive elimination will be vital in the
progression of Cu-based organometallic chemistry and
3
catalysis. Furthermore, understanding the Csp -CF
3
bond-
forming reductive elimination from high-valent metal
complexes will also help the development of novel alkyl
trifluoromethylation reactions, which are highly important in
medicinal chemistry but remain less-explored compared to
well-developed aryl trifluoromethylation reactions. In this
article, we report the design, synthesis and reductive
elimination activity of a novel class of organometallic copper
III
-
(
3 3
III) complexes, [alkyl-Cu -(CF ) ] , with diverse functional
groups. The molecular structures of these complexes have been
determined by NMR, MS and X-ray crystal structure. More
3
importantly, these complexes undergo Csp -CF
3
reductive
products with
excellent yields. These copper(III) complexes, for the first time,
III
]- species. Yields
Figure 1. Synthesis of [(alkyl)Cu (CF
3
)
3
elimination, forming the corresponding alkyl-CF
3
1
9
determined by F-NMR using 1-fluoro-3-nitrobenzene as the
internal standard. Isolate yields as [nBu
parenthesis.
+
3
3
4
N] salts are included in
allow for the study of Csp -Csp bond-forming reductive
elimination on well-defined copper(III) complexes.
This transmetallation protocol allows for the synthesis of a
RESULTS AND DISCUSSION
III
-
3 3
large variety of [(alkyl)Cu (CF ) ] complexes (Fig. 1).
III
3 3
Synthesis and characterizations of [(alkyl)Cu (CF )
]-
Common functional groups, including alkenyl, nitrile, acetal,
thiol ether etc. are compatible with the reaction conditions. In
III
complexes. We reason that a [Cu -CF
3
] complex containing a
replaceable ligand could serve as the precursor for the [alkyl-
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addition, molecules containing different heterocycles are also
temperature reveals that reductive elimination of 1d proceeded
with activation enthalpy of 20.3 kcal/mol and activation entropy
of -12.4 e.u. (Fig. 4C), comparable to the reductive elimination
1
2
3
4
5
6
7
8
9
tolerated under this condition. This method works well for the
III
construction of both primary and secondary alkyl-Cu species,
III
II
57
but our attempts to the synthesis of tertiary alkyl-Cu species
of aryl-Pd -CF
Reductive elimination of CuIII complexes bearing benzyl
groups (1a, 1g-1j) affords the corresponding
3
complexes reported by Buchwald.
(1x) were not successful, probably due to slow transmetallation
of 1 with the bulky adamantyl zinc reagent as well as the
III
instability of the resulting Cu species. Nevertheless, we were
trifluoromethylated products in moderate yields (32-62%).
Analysis of the crude reaction mixtures by GC/MS reveals that
dimerized products (bibenzyl) were formed. In addition, when
the reductive elimination reactions were conducted under air,
benzyl alcohol and benzaldehyde were also formed, while the
yields of trifluoromethylated products were not affected. These
able to detect the transient formation of 1x using HR ESI-MS
(Fig. S2).
The structures of these CuIII complexes were further
confirmed by single crystal X-ray diffraction. One equivalent of
tetrabutylammonium bromide (n-Bu NBr) was added to the
1
1
1
1
1
1
1
1
1
1
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2
2
2
2
2
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3
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0
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0
1
2
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4
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0
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2
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0
4
III
+
III
Cu solutions to form the corresponding [n-Bu
4
N] salts, which
results suggest that the homolytic cleavage of the Cu -benzyl
can be purified by silica gel column chromatography at -78 C.
bonds to form benzylic radicals competes with the reductive
+
III
The crystals of 1a-1c as [n-Bu
4
N] salts were grown by the slow
elimination pathway. As expected, homolytic cleavage of Cu
II
-
diffusion of pentane into a methylene chloride solution at –20
3 3
complexes leads to the formation of [Cu (CF ) ] , which has
C over a week. 1a-1c display square planar geometry with
been detected by ESI-MS (Fig. S5) and EPR (Fig. S6).
Moreover, studying the reductive elimination of 1a and 1g-1j
reveals that reductive elimination generally proceeds faster with
electron-donating substituents on the para position of the
phenyl ring. A Hammet plot of log(kobs/kobs(H)) (kobs are
calculated using initial rates for the formation of
trifluoromethylated products) vs σpara yields a ρ value of –0.602
III
3
slight distortion (Fig. 2). The bond lengths of Cu -CF bonds
trans to the alkyl group are in a range of 1.979 – 1.987 Å,
III
3
slightly longer than that of Cu -CF bonds cis to the alkyl
groups (Cu-C 1.944 -1.961 Å). The bond lengths of Cu-Calky
bonds are longer in 1a and 1b (1.997(3) Å and 1.988(3) Å),
which contain benzyl groups, than that in 1c (1.956(3) Å). In
addition, on the contrary to the perpendicular geometry of
pyridine and copper plane in compound 1, the aryl rings in
compounds 1a and 1b form V-shape geometry with the copper
2
and a modest correlation (R = 0.840) (Fig. S7), suggesting that
alkyl groups act as the nucleophilic partners in C-C bond
formation. The yields of bibenzyl products derived from radical
dimerization decreased with electron-donating substituents on
plane with
a dihedral angle of ~105. Well-defined
III
the para position. Furthermore, the Cu complex bearing a
organocopper(III) complexes are rare and it is noteworthy that
compounds shown here represent the only isolated
organocopper(III) complexes containing alkyl groups other
than a simple methyl group.
secondary alkyl group, 1w, is much more reactive toward
reductive elimination than its primary analogues. More than
95% 1w reductively eliminates within 5 minutes at 55 C. At
2
5, 1w can also reductively eliminates, forming 2w with a first-
-3
-1
order rate constant kobs = 2.7  10 s . (Fig. S8)
Figure 2. X-ray crystal structures of complexes 1a, 1b and 1c as
+
[nBu
4
N] salts. Oak Ridge thermal ellipsoid plot (ORTEP) drawing
+
4
with atoms at 50% probability; hydrogen atoms and [nBu N]
counter cations omitted for clarity.
III
3 3
Reductive elimination activity of [(alkyl)Cu (CF )
]-
III
complexes. With these Cu complexes in hand, we then studied
their reductive elimination reactivity. At elevated temperature
(
55 C), these complexes undergo reductive elimination,
III
leading to the consumption of starting Cu and concomitant
formation alkyl-CF products with varying yields (Fig. 3). We
3
followed the reductive elimination of 1d in a temperature range
19
of 45 - 65C by F-NMR (Fig. 4A and Fig. S3). At all
temperature, reductive elimination of 1d follows a first-order
rate law (Fig. 4B) forming 2d as the major products with yield
I
ranging from 85-89%. The Cu byproducts of the reactions are
-
III
]- affords the
Cu(CF
3
)
2
, which has been detected by ESI-MS (Fig. S4). We
Figure 3. Reductive elimination of [(alkyl)Cu (CF)
3
III
-
also observed the formation of Cu (CF
via aerobic oxidation of the Cu complexes. The observed first-
3
)
4
, presumably formed
corresponding alkyl-CF
3
products. Reductive elimination reactions
I
19
were conducted in CD CN at 55C; Yield determined by F-NMR
3
using 1-fluoro-3-nitrobenzene as the internal standard.
order rates for the reductive elimination of 1d is k65 = 1.04 
-
3
-1
-4 -1
1
0
s
at 65C and k45 = 1.45  10
s
at 45C, respectively.
Given the mild conditions for both the transmetallation and
reductive elimination steps, this procedure allows for the late-
Eyring plot analysis of the reductive elimination rate at different
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3 3
[(alkyl)Cu(CF )
]- species, whereas, in Path B, homolytic
cleavage of the Cu-alkyl bond takes place first to generate an
alkyl radical which then rebounds to one of the copper-bounded
stage trifluoromethylation of complex organozinc reagents
(Fig. 5). We synthesized the organozinc derivatives of five
bioactive molecules, including estrone, gemfibrozil, Vitamin E,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
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6
CF
elimination occurs on the neutral intermediate. Finally,
considering the fluoride-rebound mechanism for C-CF bond
3 3
. In Path C, a CF anion dissociates and then the reductive
3
5
6
formation, recently discovered by Toste, we proposed Path D
which involves fluoride dissociation, migratory insertion and C-
F reductive elimination to achieve net C-CF bond formation.
3
The energetics of these four pathways for the reductive
elimination of 1d are shown in Fig. 6. Although Path D is
0
1
2
3
4
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0
III
involved in Toste’s Au reductive elimination in the presence
56
of a borane catalyst, this pathway is not likely involved in our
system due to the high energy of the difluorocarbene
intermediate formed in the absence of a catalyst (estimated to
be 39.1 kcal/mol). Likewise, the dissociation of
a
trifluoromethyl anion in Path C leads to the formation of a high
energy neutral intermediate (H = 31.3 kcal/mol). In Path B,
we find that the homolytic dissociation of n-butyl is barrierless
with H = 21.6 kcal/mol, in which case there is no free n-butyl
radical available to recombine with a copper-bounded CF
3
to
form the target product. We assign the concerted alkyl-CF
3
bond-forming pathway (Path A) as the mechanism. This has
Figure 4. Kinetic studies of the reductive elimination of compound
‡
1
9
the lowest predicted activation enthalpy (ΔH =21.4 kcal/mol),
[
nBu
elimination of [nBu
elimination of [nBu N]-1d at different temperature; C. Erying Plot
analysis of the reductive elimination of [nBu N]-1d.
indomethacin and thalidomide. Upon treating 1 with these
4
N]-1d. A. Representative F-NMR spectra of the reductive
‡
in excellent agreement with the experimental result (ΔH =20.3
4
N]-1d; B. First-order plot of reductive
kcal/mol) from the Eyring analysis. As shown by Low and
4
3
3
Goddard, reductive coupling of such Csp -Csp bonds has a
4
6
0
high barrier unless the reaction is made very exothermic. The
reaction in path A, is very exothermic (ΔH = -57.9 kcal/mol)
and hence is expected to yield a low barrier for the concerted
reaction as observed from both theory and experiment.
Moreover, the calculated reductive elimination activation
1
9
organozinc reagents at room temperature, a new set of F-NMR
peaks appeared consistent with the formation of the
-
III
[

(alkyl)Cu(CF
C for 2 hours afforded the corresponding trifluoromethylated
products in excellent yields. Although trifluoromethylation of
3 3
) ] species. Heating the solutions of Cu at 55
‡
energy for 1w is lower (ΔH = 20.0 kcal/mol) than that of 1d,
consistent with its faster reductive elimination rate.
5
8-59
alkyl halides have been reported,
the late-stage incorporation of CF
our procedure allows for
into complex molecules
3
within a short amount of time and with excellent yields.
Figure 6. Reaction coordinate of reductive elimination of 1d and
1
a (in parentheses) via four different pathways. The numbers in
‡
bold style are H s, whereas those in plain style are Hs.
Figure 5. Late-stage trifluoromethylation of highly-functionalized
19
organozinc reagents. Yields determined by F-NMR using 1-
fluoro-3-nitrobenzene as the internal standard. Isolated yields are
listed in parenthesis.
Given the formation of free radicals observed in benzyl-
III
containing Cu species, we also calculated activation energy
DFT calculations of the reductive elimination reactions.
for the reductive elimination of 1a via Path A and B.
Interestingly, the homolytic dissociation of 1a has a lower
3
To gain more insights into this Csp -CF
3
bond-forming
‡
reductive elimination, we performed DFT calculations at the
B3LYP level combined with Poisson-Boltzmann continuum
solvation to probe the mechanism of this elementary reaction
activation energy (H /H = 12.6/12.5 kcal/mol) than that of
‡
direct reductive elimination pathway (H /H = 19.7/-53.6
kcal/mol), consistent with our experimental results that benzyl
radicals are formed. In addition, the activation energy of the
reversible reaction, in which the generated benzyl radical
(full details in SI). Based on literature precedents and our
experimental results, four pathways were considered (Fig. 6).
In Path A, reductive elimination occurs directly on the
II
recombines with the Cu intermediate reforming compound 1a,
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is only 0.1 kcal/mol. This suggests that a fast equilibrium might
exist between 1a and the radical pair. The direct transfer of the
CF group to the benzyl radical is unlikely as indicated by the
high activation energy (H /H
Rakovan for the assistance of X-ray crystal diffraction. W.A.G.
acknowledge financial support from NSF (NSF CBET 1512759)
1
2
3
4
5
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‡
REFERENCES
=
41.1/-66.1 kcal/mol).
Moreover, our calculation results have shown that the activation
energy of direct reductive elimination decreases with electron-
1.
Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.;
Kozlowski, M. C., Aerobic Copper-Catalyzed Organic Reactions.
Chem. Rev. 2013, 113 (8), 6234-6458.
‡
donating groups at the para positions of the phenyl rings; H
2
.
Hickman, A. J.; Sanford, M. S., High-valent organometallic
copper and palladium in catalysis. Nature 2012, 484, 177.
3. Evano, G.; Blanchard, N.; Toumi, M., Copper-Mediated
decreases from 21.1kcal/mol for 1i to 20.0 kcal/mol for 1h, 19.7
kcal/mol for 1a, and 17.7 kcal/mol for 1g. In addition, the
activation energy of radical dissociation (Path B) increases
with electron-donating group at the para-position (12.6
kcal/mol for 1a and 13.0 kcal/mol for 1g). These calculation
results are consistent with our experimental observations that
the formation of benzyl radicals competes with the direct
Coupling Reactions and Their Applications in Natural Products and
Designed Biomolecules Synthesis. Chem. Rev. 2008, 108 (8), 3054-
3131.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4.
Bakhmutov, V. I.; Bozoglian, F.; Gómez, K.; González, G.;
Grushin, V. V.; Macgregor, S. A.; Martin, E.; Miloserdov, F. M.;
Novikov, M. A.; Panetier, J. A.; Romashov, L. V., CF3–Ph Reductive
Elimination from [(Xantphos)Pd(CF3)(Ph)]. Organometallics 2012,
III
reductive elimination of benzyl-containing Cu species and
that the formation radical-derived products decreases with
electron-donating substituents on the phenyl rings. Finally,
3
5
1 (4), 1315-1328.
. Beletskaya, I. P.; Cheprakov, A. V., Copper in cross-
6
1
through natural bond orbital (NBO) analysis, we have found
that the NBO charge on Cu decreases from 0.84 e in the reactant,
to 0.71 e in the transition state, and finally to 0.35 e in the
product, demonstrating that this is indeed a reductive
elimination process.
coupling reactions: The post-Ullmann chemistry. Coord. Chem. Rev.
2
6
004, 248 (21), 2337-2364.
. Monnier, F.; Taillefer, M., Catalytic C-C, C-N, and C-O
Ullmann-Type Coupling Reactions. Angew. Chem. Int. Ed. 2009, 48
(38), 6954-6971.
7.
Sperotto, E.; van Klink, G. P. M.; van Koten, G.; de Vries,
CONCLUSIONS
J. G., The mechanism of the modified Ullmann reaction. Dal. Trans.
2010, 39 (43), 10338-10351.
To conclude, we have reported a highly efficient procedure to
III
-
the synthesis of novel [alkyl-Cu (CF
3
)
3
]
complexes, the
8.
Nakamura, S.; Nakagawa, R.; Watanabe, Y.; Toru, T.,
structures of which have been well-characterized. The
organocopper(III) molecules reported here represent the first
class of organocopper(III) complexes containing complicated
alkyl groups. These high-valent organocopper (III) species
undergo reductive elimination to form the corresponding alkyl-
Enantioselective Reactions of Configurationally Unstable α-
Thiobenzyllithium Compounds. Angew. Chem. Int. Ed. 2000, 39 (2),
353-355.
9
.
Santo, R.; Miyamoto, R.; Tanaka, R.; Nishioka, T.; Sato,
K.; Toyota, K.; Obata, M.; Yano, S.; Kinoshita, I.; Ichimura, A.;
Takui, T., Diamagnetic–Paramagnetic Conversion of Tris(2-
pyridylthio)methylcopper(III) through a Structural Change from
Trigonal Bipyramidal to Octahedral. Angew. Chem. Int. Ed. 2006, 45
(45), 7611-7614.
I
-
3 3 2
CF compounds and [Cu (CF) ] via a concerted pathway. We
anticipate that this procedure could help to elucidate the
structure and reactivity of other important, yet elusive CuIII
complexes and that the insights we learned from this reductive
10.
Cohen, T.; Wood, J.; Dietz, A. G., Organocopper
intermediates in the exchange reaction of aryl halides with salts of
copper(I). The possible role of copper(III). Tetrahedron Lett. 1974, 15
(40), 3555-3558.
elimination reaction will guide the development of novel Cu-
3
catalyzed C-C bond-forming reactions. This work on Csp -CF
3
III
bond-forming reductive elimination from Cu species indicates
11.
Dorigo, A. E.; Wanner, J.; von Ragué Schleyer, P.,
a possible catalytic oxidative pathway for trifluoromethylation
Computational Evidence for the Existence of CuIII Intermediates in
Addition and Substitution Reactions with Dialkylcuprates. Angew.
Chem. Int. Ed. 1995, 34 (4), 476-478.
III
in which an alkyl-Cu -CF
3
intermediate is generated in situ via
chemical oxidation, which reductively eliminates to form the
I
CF
3
products and regenerate Cu complexes. These research is
12.
Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.; Zultanski,
currently ongoing in our laboratory.
S. L.; Peters, J. C.; Fu, G. C., Asymmetric copper-catalyzed C-N
cross-couplings induced by visible light. Science 2016, 351 (6274),
6
1
81.
3.
ASSOCIATED CONTENT
Supporting Information
McDonald, M. R.; Fredericks, F. C.; Margerum, D. W.,
Characterization of Copper(III)−Tetrapeptide Complexes with
Histidine as the Third Residue. Inorg. Chem. 1997, 36 (14), 3119-
3124.
Supplementary figures, characterizations of new compounds,
computational details and crystal structures. This material is
available free of charge on the ACS Publications website.
1
4.
Bertz, S. H.; Cope, S.; Murphy, M.; Ogle, C. A.; Taylor, B.
J., Rapid Injection NMR in Mechanistic Organocopper Chemistry.
Preparation of the Elusive Copper(III) Intermediate. J. Am. Chem.
Soc. 2007, 129 (23), 7208-7209.
AUTHOR INFORMATION
Corresponding Author
15.
Bertz, S. H.; Cope, S.; Dorton, D.; Murphy, M.; Ogle, C.
A., Organocuprate Cross-Coupling: The Central Role of the
Copper(III) Intermediate and the Importance of the Copper(I)
Precursor. Angew. Chem. Int. Ed. 2007, 46 (37), 7082-7085.
*
*
caozhi@sxicc.ac.cn
wag@caltech.edu; ORCID:0000-0003-0097-5716
* wei.liu@miamioh.edu; ORCID: 0000-0001-6249-3179
1
6.
Snyder, J. P., Mechanism of Lithium Cuprate Conjugate
Addition: Neutral Tetracoordinate CuI Cuprates as Essential
Intermediates. J. Am. Chem. Soc. 1995, 117 (44), 11025-11026.
ACKNOWLEDGMENT
17.
The Square-Planar “CuIII” Intermediate. J. Am. Chem. Soc. 2007, 129
23), 7210-7211.
8. Romine, A. M.; Nebra, N.; Konovalov, A. I.; Martin, E.;
Hu, H.; Snyder, J. P., Organocuprate Conjugate Addition:ꢀ
W.L. thanks Miami University for the start-up funding. L.Y.C,
J.C.H, and M.J.C acknowledge financial support from the
Ministry of Science and Technology of the Republic of China
under grant no. MOST 107-2113-M-006-008-MY2.We also thank
Dr. Theresa Ramelot for the assistance of HR-ESI and Prof. John
(
1
Benet-Buchholz, J.; Grushin, V. V., Easy Access to the Copper(III)
Anion [Cu(CF3)4]−. Angew. Chem. Int. Ed. 2015, 54 (9), 2745-2749.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 8
1
9.
Anson, F. C.; Collins, T. J.; Richmond, T. G.; Santarsiero,
38.
Muller, K.; Faeh, C.; Diederich, F., Fluorine in
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
B. D.; Toth, J. E.; Treco, B. G. R. T., Highly stabilized copper(III)
complexes. J. Am. Chem. Soc. 1987, 109 (10), 2974-2979.
pharmaceuticals: Looking beyond intuition. Science 2007, 317
(5846), 1881-1886.
2
0.
Ribas, X.; Jackson, D. A.; Donnadieu, B.; Mahía, J.;
39.
introduction to the C-F bond. Chem. Soc. Rev. 2008, 37 (2), 308-319.
40. Liu, T. F.; Shen, Q. L., Copper-Catalyzed
O'Hagan, D., Understanding organofluorine chemistry. An
Parella, T.; Xifra, R.; Hedman, B.; Hodgson, K. O.; Llobet, A.; Stack,
T. D. P., Aryl C-H Activation by CuII To Form an Organometallic
Aryl–CuIII Species: A Novel Twist on Copper Disproportionation.
Angew. Chem. Int. Ed. 2002, 41 (16), 2991-2994.
Trifluoromethylation of Aryl and Vinyl Boronic Acids with An
Electrophilic Trifluoromethylating Reagent. Org. Lett. 2011, 13 (9),
2342-2345.
2
1.
Casitas, A.; Canta, M.; Solà, M.; Costas, M.; Ribas, X.,
Nucleophilic Aryl Fluorination and Aryl Halide Exchange Mediated
by a CuI/CuIII Catalytic Cycle. J. Am. Chem. Soc. 2011, 133 (48),
19386-19392.
41.
Oishi, M.; Kondo, H.; Amii, H., Aromatic
trifluoromethylation catalytic in copper. Chem Commun. 2009, (14),
1909-1911.
42.
Knauber, T.; Arikan, F.; Roschenthaler, G. V.; Goossen, L.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
22.
Willert-Porada, M. A.; Burton, D. J.; Baenziger, N. C.,
Synthesis and X-ray structure of bis(trifluoromethyl)(N,N-
diethyldithiocarbamato)-copper; a remarkably stable
perfluoroalkylcopper(III) complex. Chem. Comm. 1989, (21), 1633-
J., Copper-Catalyzed Trifluoromethylation of Aryl Iodides with
Potassium (Trifluoromethyl)trimethoxyborate. Chem-Eur. J. 2011, 17
(9), 2689-2697.
1
634.
43.
Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F.,
23.
Furuta, H.; Maeda, H.; Osuka, A., Doubly N-Confused
A Broadly Applicable Copper Reagent for Trifluoromethylations and
Perfluoroalkylations of Aryl Iodides and Bromides. Angew. Chem.
Int. Ed. 2011, 50 (16), 3793-3798.
Porphyrin:ꢀ A New Complexing Agent Capable of Stabilizing Higher
Oxidation States. J. Am. Chem. Soc. 2000, 122 (5), 803-807.
2
4.
Maeda, H.; Ishikawa, Y.; Matsuda, T.; Osuka, A.; Furuta,
44.
Zhang, C. P.; Wang, Z. L.; Chen, Q. Y.; Zhang, C. T.; Gu,
H., Control of Cu(II) and Cu(III) States in N-Confused Porphyrin by
Protonation/Deprotonation at the Peripheral Nitrogen. J. Am. Chem.
Soc. 2003, 125 (39), 11822-11823.
Y. C.; Xiao, J. C., Copper-Mediated Trifluoromethylation of
Heteroaromatic Compounds by Trifluoromethyl Sulfonium Salts.
Angew. Chem. Int. Ed. 2011, 50 (8), 1896-1900.
2
5.
Maeda, H.; Osuka, A.; Furuta, H., Trans Doubly N-
45.
Dubinina, G. G.; Furutachi, H.; Vicic, D. A., Active
Confused Porphyrins:ꢀ Cu(III) Complexation and Formation of
Rodlike Hydrogen-Bonding Networks. J. Am. Chem. Soc. 2003, 125
(51), 15690-15691.
trifluoromethylating agents from well-defined copper(I)-CF(3)
complexes. J. Am. Chem. Soc. 2008, 130 (27), 8600-+.
46.
Senecal, T. D.; Parsons, A. T.; Buchwald, S. L., Room
26.
Adinarayana, B.; Thomas, A. P.; Suresh, C. H.; Srinivasan,
Temperature Aryl Trifluoromethylation via Copper-Mediated
Oxidative Cross-Coupling. J. Org. Chem. 2011, 76 (4), 1174-1176.
A., A 6,11,16-Triarylbiphenylcorrole with an adj-CCNN Core:
Stabilization of an Organocopper(III) Complex. Angewandte Chemie
47.
Dai, J. J.; Fang, C.; Xiao, B.; Yi, J.; Xu, J.; Liu, Z. J.; Lu,
2
2
015, 127 (36), 10624-10628.
7. King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.;
X.; Liu, L.; Fu, Y., Copper-Promoted Sandmeyer
Trifluoromethylation Reaction. J. Am. Chem. Soc. 2013, 135 (23),
8436-8439.
Ribas, X.; Stahl, S. S., Copper-Catalyzed Aerobic Oxidative
Functionalization of an Arene C−H Bond: Evidence for an Aryl-
Copper(III) Intermediate. J. Am. Chem. Soc. 2010, 132 (34), 12068-
48.
Xu, X. L.; Chen, H. H.; He, J. B.; Xu, H. J., Copper-
Catalysed Decarboxylative Trifluoromethylation of beta-Ketoacids.
Chinese J. Chem. 2017, 35 (11), 1665-1668.
1
2
2073.
8.
Liu, L.; Zhu, M.; Yu, H.-T.; Zhang, W.-X.; Xi, Z.,
49.
Paeth, M.; Carson, W.; Luo, J.-H.; Tierney, D.; Cao, Z.;
Organocopper(III) Spiro Complexes: Synthesis, Structural
Characterization, and Redox Transformation. J. Am. Chem. Soc. 2017,
Cheng, M.-J.; Liu, W., Copper-Mediated Trifluoromethylation of
Benzylic Csp3−H Bonds. Chem. Eur. J. 2018, 24 (45), 11559-11563.
1
2
39 (39), 13688-13691.
9. Huffman, L. M.; Stahl, S. S., Carbon−Nitrogen Bond
50.
Konovalov, A. I.; Lishchynskyi, A.; Grushin, V. V.,
Mechanism of Trifluoromethylation of Aryl Halides with CuCF3 and
the Ortho Effect. J. Am. Chem. Soc. 2014, 136 (38), 13410-13425.
Formation Involving Well-Defined Aryl−Copper(III) Complexes. J.
Am. Chem. Soc. 2008, 130 (29), 9196-9197.
51.
Guo, S.; AbuSalim, D. I.; Cook, S. P., Aqueous Benzylic
30.
Clark, H. C.; Tsai, J. H., Bonding in fluorinated
C–H Trifluoromethylation for Late-Stage Functionalization. J. Am.
Chem. Soc. 2018, 140 (39), 12378-12382.
organometallic compounds. J. Organometallic. Chem. 1967, 7 (3),
5
3
15-517.
1.
52.
Ball, N. D.; Kampf, J. W.; Sanford, M. S., Aryl-CF3 Bond-
Hall, M. B.; Fenske, R. F., Electronic structure and bonding
Forming Reductive Elimination from Palladium(IV). J. Am. Chem.
Soc. 2010, 132 (9), 2878-+.
in methyl- and perfluoromethyl(pentacarbonyl)manganese. Inorg.
Chem. 1972, 11 (4), 768-775.
53.
Grushin, V. V.; Marshall, W. J., Facile Ar−CF3 Bond
3
2.
Bond Orbital Analysis of the Electronic Structure of [LnM(CH3)] and
LnM(CF3)] Complexes. Organometallics 2012, 31 (4), 1467-1476.
3. Naumann, D.; Roy, T.; Tebbe, K.-F.; Crump, W., Synthesis
Algarra, A. G.; Grushin, V. V.; Macgregor, S. A., Natural
Formation at Pd. Strikingly Different Outcomes of Reductive
Elimination from [(Ph3P)2Pd(CF3)Ph] and [(Xantphos)Pd(CF3)Ph].
J. Am. Chem. Soc. 2006, 128 (39), 12644-12645.
[
3
54.
Bour, J. R.; Camasso, N. M.; Meucci, E. A.; Kampf, J. W.;
and Structure of Surprisingly Stable
Tetrakis(trifluoromethyl)cuprate(III) Salts. Angew. Chem. Int. Ed.
Canty, A. J.; Sanford, M. S., Carbon–Carbon Bond-Forming
Reductive Elimination from Isolated Nickel(III) Complexes. J. Am.
Chem. Soc. 2016, 138 (49), 16105-16111.
1
3
993, 32 (10), 1482-1483.
4. Zhang, S.-L.; Bie, W.-F., Isolation and characterization of
55.
Winston, M. S.; Wolf, W. J.; Toste, F. D., Photoinitiated
copper(iii) trifluoromethyl complexes and reactivity studies of aerobic
trifluoromethylation of arylboronic acids. RSC Adv. 2016, 6 (75),
70902-70906.
Oxidative Addition of CF3I to Gold(I) and Facile Aryl-CF3
Reductive Elimination. J. Am. Chem. Soc. 2014, 136 (21), 7777-7782.
56.
Levin, M. D.; Chen, T. Q.; Neubig, M. E.; Hong, C. M.;
3
5.
Zhang, S.-L.; Bie, W.-F., Ligand-dependent formation of
Theulier, C. A.; Kobylianskii, I. J.; Janabi, M.; O'Neil, J. P.; Toste, F.
D., A catalytic fluoride-rebound mechanism for C(sp(3))-CF3 bond
formation. Science 2017, 356 (6344), 1272-1275.
ion-pair CuI/CuIII trifluoromethyl complexes containing
bisphosphines. Dal. Trans. 2016, 45 (44), 17588-17592.
3
6.
Zhang, S.-L.; Xiao, C.; Wan, H.-X., Diverse copper(iii)
57.
Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson,
trifluoromethyl complexes with mono-, bi- and tridentate ligands and
their versatile reactivity. Dal. Trans. 2018, 47 (14), 4779-4784.
D. A.; Buchwald, S. L., The Palladium-Catalyzed
Trifluoromethylation of Aryl Chlorides. Science 2010, 328 (5986),
1679-1681.
3
7.
Tan, X. Q.; Liu, Z. L.; Shen, H. G.; Zhang, P.; Zhang, Z.
Z.; Li, C. Z., Silver-Catalyzed Decarboxylative Trifluoromethylation
of Aliphatic Carboxylic Acids. J. Am. Chem. Soc. 2017, 139 (36),
12430-12433.
58.
Shen, H.; Liu, Z.; Zhang, P.; Tan, X.; Zhang, Z.; Li, C.,
Trifluoromethylation of Alkyl Radicals in Aqueous Solution. J. Am.
Chem. Soc. 2017, 139 (29), 9843-9846.
ACS Paragon Plus Environment

Page 7 of 8
Journal of the American Chemical Society
5
9.
Chen, Y.; Ma, G.; Gong, H., Copper-Catalyzed Reductive
bis(phosphine) complexes. J. Am. Chem. Soc. 1986, 108 (20), 6115-
1
2
3
4
5
6
7
8
9
Trifluoromethylation of Alkyl Iodides with Togni’s Reagent. Org.
Lett. 2018, 20 (15), 4677-4680.
6128.
61.
Reed, A. E.; Curtiss, L. A.; Weinhold, F., Intermolecular
6
0.
Low, J. J.; Goddard, W. A., Theoretical studies of oxidative
Interactions from a Natural Bond Orbital, Donor-Acceptor Viewpoint.
Chem. Rev. 1988, 88 (6), 899-926.
addition and reductive elimination. 3. Carbon-hydrogen and carbon-
carbon reductive coupling from palladium and platinum
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