Aryl-Fluoride Bond-Forming Reductive Elimination from Nickel(IV) Centers

Article abstract of DOI:10.1021/jacs.9b06896

The treatment of pyridine- and pyrazole-ligated Ni^II σ-aryl complexes with Selectfluor results in C(sp²)-F bond formation under mild conditions. With appropriate design of supporting ligands, diamagnetic Ni^IV σ-aryl fluoride intermediates can be detected spectroscopically and/or isolated during these transformations. These studies demonstrate for the first time that Ni^IV σ-aryl fluoride complexes participate in challenging C(sp²)-F bond-forming reductive elimination to yield aryl fluoride products.

Full text of DOI:10.1021/jacs.9b06896

Article
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Aryl−Fluoride Bond-Forming Reductive Elimination from Nickel(IV)
Centers
Elizabeth A. Meucci,† Alireza Ariafard,‡ Allan J. Canty,‡ Jeff W. Kampf,† and Melanie S. Sanford*,†
†Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States
‡School of Natural Sciences − Chemistry, University of Tasmania, Hobart, Tasmania 7001, Australia
S
* Supporting Information
ABSTRACT: The treatment of pyridine- and pyrazole-ligated NiII σ-
aryl complexes with Selectfluor results in C(sp2)−F bond formation
under mild conditions. With appropriate design of supporting ligands,
diamagnetic NiIV σ-aryl fluoride intermediates can be detected
spectroscopically and/or isolated during these transformations. These
studies demonstrate for the first time that NiIV σ-aryl fluoride
complexes participate in challenging C(sp2)−F bond-forming reductive
elimination to yield aryl fluoride products.
A more recent advance in the field of Ni-mediated
fluorination came in a 2012 report by Ritter and co-workers
demonstrating oxidatively induced aryl−F and aryl−18F
coupling reactions of NiII(σ-aryl) complexes.16 These trans-
formations were proposed to proceed via high-valent Ni
intermediates. However, the structures and oxidation states
(NiIII versus NiIV) of these species were not identified in the
original report. More recently, Ritter has shown that the
stoichiometric reaction of the NiII model complex A with
Selectfluor affords a transient NiIII(aryl)(F) species with
proposed structure B (Figure 1A).17 Intermediate B was
detected in situ via EPR spectroscopy and shown to undergo
C(sp2)−F coupling upon heating to 70 °C. These results
implicate the feasibility of aryl−F bond formation from NiIII
centers. However, key questions remain about what other
classes of ligands and oxidation states of Ni enable this
transformation.
Recent work from our group has shown that multidentate
pyridine- and pyrazole-containing ligands support organo-
metallic NiIII and NiIV complexes that participate in
challenging reductive elimination reactions, including C-
(sp3)−heteroatom and C(sp2)−CF3 couplings.18−20 We
hypothesized that analogous ligand systems might enable
the isolation and reactivity studies of high-valent Ni(σ-
aryl)(F) intermediates. We demonstrate herein that a variety
of pyridine and pyrazole-ligated NiII complexes participate in
oxidatively induced C(sp2)−F bond formation upon treat-
ment with Selectfluor. Furthermore, we show for the first
time that several of these transformations proceed via
INTRODUCTION
■
Over the past decade, there has been significant progress in
the development of Pd-, Cu-, and Ag-mediated/catalyzed
methods for the formation of aryl−fluoride bonds.1,2 These
protocols are finding increasing application in the synthesis of
fluorine-containing pharmaceutical candidates3 as well as 18F-
labeled radiotracers.4 Given that C(sp2)−F bond formation is
typically the most challenging step of these transformations,5
fundamental studies of C(sp2)−F reductive elimination from
transition metal σ-aryl fluoride complexes have been critical
for the advancement of this field.2a,c,d,6−11 For instance,
organometallic investigations of C(sp2)−F coupling at Pt, Pd,
Cu, and Ag complexes6a,2a,h,7b,8 have guided the identification
of ligand scaffolds that are most effective for promoting this
transformation. Related studies have provided critical insights
into the types of electrophilic fluorinating reagents that
enable oxidatively induced C(sp2)−F bond formation at
different metals.2g,6a,9,12 Furthermore, stoichiometric studies
have provided detailed information about factors impacting
the selectivity of productive C(sp2)−F coupling versus
competing side reactions such as carbon−heteroatom13 and
phosphorus−fluorine8c,d,14 bond-forming pathways.
Moving forward, a key frontier for this field is to find new
transition metals/oxidation states that participate in this
challenging transformation, in order to further expand the
scope and diversity of synthetic methods for C(sp2)−F bond
formation. Nickel has been known to mediate the formation
of C−F bonds under oxidative conditions since the
introduction of the Simons process in the 1930s. This
electrochemical fluorination method involves the use of Ni-
plated anodes to access perfluorinated molecules.15
Received: June 28, 2019
© XXXX American Chemical Society
A
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accompanied by the formation of the cationic NiII complex 4.
As predicted, the subsequent in situ oxidation of this
intermediate with Selectfluor resulted in a significantly
improved ratio of 2 to 3 (40% and 23% yield, respectively)
(Scheme 1b). This result demonstrates the feasibility of
selective aryl−F coupling from Ni complexes supported by
pyridine ligands.
The reactions in Scheme 1 proceed rapidly at room
temperature, and no intermediates are detected by 19F NMR
or EPR spectroscopy. Thus, we next sought to design systems
that would enable the detection and isolation of high-valent
Ni intermediates in analogous transformations. Previous work
has shown that organometallic NiIII and NiIV complexes are
stabilized by ligands that are rigid, multidentate, and strongly
electron donating.13−15 23 As such, we envisioned that NiII
,
precursor 5, which contains bidentate bipyridine and biphenyl
ligands, could allow for intermediates of this oxidatively
induced fluorination to be observed at room temperature
(Scheme 2).
Figure 1. Intermediates in oxidatively induced aryl−F coupling from
organometallic NiII complexes. (A) NiIII intermediate detected by
Ritter. (B) This work (NiIV intermediate detected and isolated).
Scheme 2. Synthesis of NiII Complex 5
detectable and even isolable NiIV σ-aryl fluoride intermediates
(Figure 1B).
RESULTS AND DISCUSSION
■
The NiII complex 1 was selected as an initial model system
for exploring oxidatively induced aryl−fluoride coupling at Ni.
The pyridine donor ligands of 1 are similar to those
employed in a variety of Ni-catalyzed carbon−heteroatom
cross-coupling reactions.21 Additionally, previous work from
our group has demonstrated that the treatment of 1 with Cl+
oxidants (e.g., PhICl2) results in C(sp2)−Cl and C(sp2)−Br
bond formation to afford a mixture of 2-(2-chlorophenyl)-
pyridine (53%) and 2-(2-bromophenyl)pyridine (25%).22
Based on these results, we hypothesized that F+ oxidants
might induce an analogous C(sp2)−F coupling reaction to
generate 2. Indeed, the reaction of 1 with Selectfluor for 0.5
h at 25 °C afforded 2 in modest (16%) yield (Scheme 1).
However, the major product of this reaction was 2-(2-
bromophenyl)pyridine (3, 70% yield), which is derived from
competitive C(sp2)−Br bond formation.
Complex 5 was prepared via the treatment of Ni(PEt3)4
with biphenylene in the presence of 2,2′-bipyridine. The NiII
product was isolated in 77% yield as an analytically pure dark
blue solid and was characterized by 1H and 13C NMR
spectroscopy. X-ray quality crystals were obtained by
recrystallization from a tetrahydrofuran/acetone solution of
5 at −35 °C, and an ORTEP diagram is shown in Figure 2.
The most notable feature of this structure is the significant
distortion from the square plane, with an angle of 24.2°
between the N1−Ni−N2 and C11−Ni−C22 planes.
We reasoned that the formation of the undesired aryl
bromide product 3 could be minimized by abstraction of the
bromide ligand from 1 prior to oxidation with Selectfluor.
The treatment of 1 with 1 equiv of sodium tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate (NaBArF) in the presence
of 4 equiv of 2-picoline resulted in the precipitation of NaBr,
Figure 2. ORTEP diagram for complex 5. Hydrogen atoms have
been omitted for clarity; thermal ellipsoids are drawn at 50%
probability. Bond lengths (Å): Ni1−N1 = 1.952, Ni1−N2 = 1.964,
Ni1−C11 = 1.902, Ni1−C22 = 1.898. Bond angles (deg): N1−
Ni1−N2 = 82.6, C11−Ni1−C22 = 83.8.
Scheme 1. Oxidatively Induced Aryl−Fluoride Coupling
from 1
The treatment of 5 with 1.3 equiv of Selectfluor in MeCN
at room temperature resulted in an immediate color change
from purple to orange. This coincided with the appearance of
a
19F NMR resonance at −417.6 ppm, implicating the
formation of a diamagnetic nickel fluoride intermediate.24 1H
NMR spectroscopic analysis of this species shows eight
aromatic signals that each integrate to two protons (Figure
S4). Furthermore, analysis of a solution of in situ-generated 6
by EPR spectroscopy did not show the presence of any
paramagnetic species (Figure S11). These data along with the
B
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observed reactivity of this complex (vide infra) implicate a
symmetrical NiIV cation with fluoride and solvent ligands at
the axial positions (Scheme 3). The observation of this
Further insight into the reactivity of 5 was obtained by
conducting a computational analysis of the transformations
depicted in Scheme 3.27 Gaussian 09 was used at the
B3LYP28 level of density functional theory (DFT) for
geometry optimization (see SI for complete details). These
studies focused on intermediates that are expected to lead to
the experimentally observed isomer of complex 6. On the
basis of these calculations, an energetically plausible pathway
for the formation of 6 is shown in Figure 4. It commences
with the transfer of one electron from 5 to Selectfluor to
generate A. Interaction of the organometallic product A with
solvent (MeCN) affords the NiIII intermediate A-MeCN,
which then receives the F atom from the reduced Selectfluor
to form 6.29,30 Conversion of 6 to other isomers is precluded
by the low barrier for reductive elimination (see Figure S24
for details). Overall, the favorability of each step within the
oxidation pathway depicted in Figure 4 shows the
competence of Selectfluor as an oxidant for accessing NiIV
species from NiII precursors.
Scheme 3. Aryl−Fluoride Bond Formation from Putative
NiIV Intermediate (6)
We also evaluated the possibility that complex 6 might
exist as a NiIII species that is antiferromagnetically coupled to
a ligand-centered radical. However, all attempts to optimize
for a structure containing two unpaired electrons of opposite
spin by DFT were unsuccessful, either directly or via an
attempted triplet state exhibiting expulsion of MeCN from
the coordination sphere. In contrast, the proposed
diamagnetic NiIV structure for complex 6 underwent facile
optimization.
We next calculated a pathway for reductive elimination
from complex 6, resulting in an overall reaction profile
(Figure 5) consistent with the experimentally observed
process in Scheme 3. Both dissociative and concerted
mechanisms were considered (see SI for complete details),
revealing a preference for a concerted mechanism that
proceeds through a single transition state (TS-6/7) with
ΔG⧧ = 9.3 kcal/mol to afford reductive elimination product
7. This low barrier is consistent with experimental
observations that in situ generated 6 undergoes C(sp2)−F
bond formation under mild conditions (2 h at 35 °C).
These calculations motivated us to seek experimental
evidence in support of the single-electron transfer mechanism
for the oxidation of 5 with Selectfluor. The addition of 1
equiv of TEMPO to this oxidation reaction completely
inhibited formation of complex 6 (Figure S6). These results,
in addition to the well-precedented one-electron reactivity of
Selectfluor, are consistent with a pathway like that depicted in
Figure 4.31
putative NiIV fluoride intermediate (6) stands in notable
contrast to Ritter’s oxidation of NiII complex A with
Selectfluor, which yielded a NiIII-fluoride (B, Figure 1a).
Heating an acetonitrile solution of in situ-generated 6 for 2
h at 35 °C resulted in the disappearance of the Ni−F
resonance at −417.6 ppm and concomitant formation of an
aryl−fluoride signal at −118.7 ppm in the 19F NMR spectrum
(Figure S8). This is consistent with C(sp2)−F bond-forming
reductive elimination from 6 to afford the diamagnetic NiII
product 7. 19F NMR spectroscopic monitoring of this
reaction shows that the rate of consumption of 6 closely
tracks that of the formation of this aryl fluoride product
(Figure 3). Furthermore, the yield of this product is
quantitative relative to the initial concentration of 6.
A final set of studies focused on designing a NiIV(aryl)-
(fluoride) complex that could be isolated and fully
characterized. Our previous work has shown that replacing
the neutral bidentate 2,2′-bipyridyl ligand with the anionic
tridentate tris(pyrazolyl)borate (Tp) ligand dramatically
enhances the stability of high-valent Ni complexes.18 As
such, we reacted the anionic TpNiII complex 9 with
Selectfluor in MeCN. Within 30 min at 25 °C this
transformation afforded the NiIV−F complex 10, which was
isolated in 48% yield (Scheme 4).
Figure 3. Reaction profile for C(sp2)−F bond formation from 6.
Reaction was monitored by 19F NMR spectroscopy using 4-
fluoroanisole as an internal standard.
The proposed NiII product 7 could not be isolated cleanly.
As such, a reductive workup with hydrazine was performed to
release the σ-aryl ligand from Ni, and both GC and NMR
spectroscopic analysis of the isolated organic product
confirmed the formation of aryl fluoride 8.25,26 Overall,
these experiments demonstrate the first example of C(sp2)−F
coupling from a detectable NiIV(aryl)(F) complex.
1
Complex 10 was characterized via H, 19F, and 11B NMR
spectroscopy. In addition, X-ray quality crystals of 10 were
obtained via recrystallization from MeCN at −35 °C, and the
solid-state structure is shown in Figure 6. Overall, these data
are all consistent with a diamagnetic octahedral NiIV−fluoride
structure in both solution and the solid state.
C
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Figure 4. Relative energies of intermediates in the SET pathway for reaction of 5 with Selectfluor to afford 6. Energies ΔG (ΔH) are in kcal/
mol relative to 5.
elimination yields could be improved by conducting this
reaction in ethereal solvents.32 Similarly, the yield of the
aryl−fluoride product increased to 60% by changing the
solvent from MeCN to tetrahydrofuran (THF). We
hypothesize that this aryl fluoride product is the NiII-σ-aryl
complex 11 (Scheme 5); however, this species proved
Scheme 5. Aryl−Fluoride Bond Formation from
(Tp)NiIV(C6H4-o-C6H4)(F) (10)
Figure 5. Energy profile for C(sp2)−F bond formation from 6.
Energies ΔG (ΔH) in kcal/mol relative to 5.
Scheme 4. Synthesis of (Tp)NiIV(C6H4-o-C6H4)(F) (10)
challenging to isolate cleanly. As such, a reductive workup
with hydrazine was performed to release the σ-aryl ligand
from Ni, and GC analysis confirmed the identity of the
organic product as aryl fluoride 8. Overall, these studies of
complex 10 represent the first demonstration of C(sp2)−F
coupling from an isolated NiIV complex.
We next used DFT to interrogate whether reductive
elimination from complex 10 proceeds via a concerted or
dissociative mechanism. Figure 7 illustrates the energy
profiles for these two different pathways. The barriers for
C(sp2)−F bond-forming reductive elimination in this system
range from approximately 20 to 23 kcal/mol, consistent with
the much slower rate of reductive elimination from 10
compared to that from the bipyridine complex 6. These
calculations show a relatively small 3.2 kcal/mol preference
for the concerted pathway (via TS_10/IV) compared to the
dissociative pathway (via TS_I/II).
Figure 6. ORTEP diagram for complex 10. Hydrogen atoms have
SUMMARY AND CONCLUSIONS
been omitted for clarity; thermal ellipsoids are drawn at 50%
probability. Bond lengths (Å): Ni1−N1 = 1.888, Ni1−N4 = 2.031,
Ni1−C7 = 1.952. Bond angles (deg): N4−Ni1−N4 = 84.9, C7−
Ni1−C7 = 84.0.
■
In conclusion, this article demonstrates that the treatment of
a variety of nitrogen-ligated σ-aryl NiII complexes with
Selectfluor results in C(sp2)−F coupling. In several of these
systems, diamagnetic NiIV σ-aryl fluoride intermediates were
detected and/or isolated. These results demonstrate the
viability of C(sp2)−F bond-forming reductive elimination
from NiIV complexes under mild conditions. In addition, they
stand in interesting contrast to NiIII-mediated fluorination
reactions demonstrated by Ritter. Future work will focus on
leveraging these results to develop NiII/IV-catalyzed fluorina-
tion reactions.
Complex 10 is stable at −35 °C for several hours in
MeCN. However, heating a MeCN solution of 10 at 50 °C
for 12 h results in complete consumption of this NiIV species
and the formation of an aryl fluoride product in 10% yield as
determined by 19F NMR spectroscopy (δ −118.1 ppm,
Figure S13). Previous investigations of aryl−oxygen coupling
from similar NiIV complexes revealed that reductive
D
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Figure 7. Energy profile for the reductive elimination steps from complex 10. Complex I also forms an adduct with solvent THF, at ΔG (ΔH)
9.0 (0.6) kcal/mol. Energies ΔG (ΔH) are in kcal/mol.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
■
S
ACS Publications website at DOI: 10.1021/jacs.9b06896.
Crystallographic data (CIF)
3D chemical structure (XYZ)
Experimental details, optimization tables, and complete
characterization data for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*mssanfor@umich.edu
ORCID
Allan J. Canty: 0000-0003-4091-6040
Melanie S. Sanford: 0000-0001-9342-9436
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
Grant CHE-1111563, the Australian Research Council, and
the Australian National Computing Infrastructure. E.A.M.
thanks Rackham Graduate School (RMF) and the NSF for
graduate fellowships. We gratefully acknowledge funding from
NSF Grant CHE-0840456 for X-ray instrumentation.
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