Aryl Fluoride Activation through Palladium-Magnesium Bimetallic Cooperation: A Mechanistic and Computational Study

Article abstract of DOI:10.1021/acscatal.0c01301

Herein is described a mechanistic study of a palladium-catalyzed cross-coupling of aryl Grignard reagents to fluoroarenes that proceeds via a low-energy heterobimetallic oxidative addition pathway. Traditional oxidative additions of aryl chlorides to Pd complexes are known to be orders of magnitude faster than with aryl fluorides, and many palladium catalysts do not activate aryl fluorides at all. The experimental and computational studies outlined herein, however, support the view that at elevated Grignard/ArX ratios (i.e., 2.5:1), a Pd-Mg heterobimetallic mechanism predominates, leading to a remarkable decrease in the energy required for Ar-F bond activation. The heterobimetallic transition state for the C-X bond cleavage is proposed to involve simultaneous Pd backbonding to the arene and Lewis acid activation of the halide by Mg to create a low-energy transition state for oxidative addition. The insights gained from this computational study led to the development of a phosphine ligand that was shown to be similarly competent for Ar-F bond activation.

Full text of DOI:10.1021/acscatal.0c01301

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Article
Aryl Fluoride Activation Through Palladium-Magnesium
Bimetallic Cooperation: A Mechanistic and Computational Study
Chen Wu, Samuel P McCollom, Zhipeng Zheng, Jiadi Zhang,
Sheng-Chun Sha, Minyan Li, Patrick J. Walsh, and Neil C. Tomson
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c01301 • Publication Date (Web): 22 Jun 2020
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ACS Catalysis
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Aryl Fluoride Activation Through Palladium-Magnesium Bimetallic
Cooperation: A Mechanistic and Computational Study
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‡
Chen Wu, Samuel P. McCollom, Zhipeng Zheng, Jiadi Zhang, Sheng-chun Sha, Minyan Li,
Patrick J. Walsh,* Neil C. Tomson*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street,
Philadelphia, Pennsylvania 19104-6323, United States
Inorganic Chemistry, Organic Chemistry, Catalysis, Organometallics
ABSTRACT: Herein is described a mechanistic study of a palladium-catalyzed cross-coupling of aryl Grignard reagents to
fluoroarenes that proceeds via a low-energy heterobimetallic oxidative addition pathway. Traditional oxidative additions of aryl
chlorides to Pd complexes are known to be orders of magnitude faster than with aryl fluorides, and many palladium catalysts do not
activate aryl fluorides at all. The experimental and computational studies outlined herein, however, support the view that at elevated
Grignard : ArX ratios (i.e. 2.5 : 1) a Pd-Mg heterobimetallic mechanism predominates, leading to a remarkable decrease in the energy
required for Ar–F bond activation. The heterobimetallic transition state for C–X bond cleavage is proposed to involve simultaneous
Pd backbonding to the arene and Lewis acid activation of the halide by Mg to create a low-energy transition state for oxidative
addition. The insights gained from this computational study led to the development of a phosphine ligand that was shown to be
similarly competent for Ar–F bond activation.
2
2
1
. Introduction
aryl fluorides, which have been shown to couple with amines,
22
16, 22
organotin reagents, organoboron reagents,
terminal
and Grignard reagents. In the sole example of
cross-coupling aryl fluorides with Grignard reagents,
Dankwardt described the use of Pd(dba) (5 mol%)/ PCy Ph
(7.5 mol%) with 3 equiv of ArMgCl at 80 °C for 60 h (Figure
C–F bonds have garnered widespread attention as
23-25
22
alkynes
challenging and attractive targets for materials science,
pharmaceuticals, and agrochemicals.
1
-5
At a bond strength of
2
2
1
26 kcal/mol, the C–F bond in fluorobenzene is among the
strongest in organic chemistry, and as a result, it is considerably
more difficult to cleave than the C–Cl bond in aryl chlorides (96
kcal/mol). Due in large part to this high bond strength, aryl
fluorides are inert in the presence of most cross-coupling
catalysts. Therefore, the development of methods for facile aryl
fluoride activation can allow for selective, late-stage
modifications following passage through a range of demanding
1
5
1d). The coupling products were formed with GC yield of 21
to 65 % (6 substrates), limiting the potential utility of this
process. In one example it was shown that microwave
irradiation in THF at 150 °C led to 98% GC yield. In late 2019,
Zhao and coworkers published a high yielding palladium
catalyzed Sonogashira-type coupling reaction with aryl
fluorides and terminal alkynes (Figure 1e). An unconventional
3
, 6-9
synthetic transformations.
3 2
palladium catalyst, prepared by addition of LiN(SiMe ) to
Many examples are known in which nickel is able to promote
25
2 3
Pd (dba) was found to be active in this coupling reaction.
1
0-14
cross coupling with Ar–F-based electrophiles.
The nickel
We have previously reported use of the Bronsted acidic
NIXANTPHOS ligand, designed by van Leeuwen and
chemistry typically requires sterically demanding and electron-
rich ligands. The lower electronegativity of nickel relative to
palladium engenders nickel catalysts with greater ability to
26-27
coworkers,
bromides and chlorides.
needed to effect C–C bond formation, the NIXANTPHOS
ligand’s N–H was deprotonated (pK = ~21 in DMSO),
generating an anionic ligand that binds potassium to both the
for the coupling of diarylmethanes with aryl
2
8-29
10
Under the basic reaction conditions
oxidatively add strong bonds, including aryl fluorides.
Compared with nickel catalysts, however, palladium catalysts
have been extensively studied across a variety of cross-coupling
reactions. Towards this end we focused on Pd, as there are a
wide variety of phosphine ligands geared toward Pd cross-
coupling catalysis.
In comparison with nickel,10 palladium-catalyzed
cross-coupling chemistry with aryl fluorides is rare, and
typically the aryl fluoride must be activated.
activation (Figure 1) include the  -coordination of the aryl
fluoride to transition metal complexes such as Cr(CO)
a
2
8-
nitrogen and the backbone of the ligand’s aromatic π-system.
2
9
This heterobimetallic catalyst was shown to oxidatively add
unactivated aryl chlorides at room temperature, indicating a
substantial decrease in activation energy compared to other
3
0-33
palladium catalysts bearing bidentate ligands.
We
1
5-21
Modes of
hypothesized that the exceptional reactivity of this system stems
from the cooperativity between the main group metal and the
palladium catalyst (Figure 2a). Support for this cooperativity
via cation- interactions has recently been shown through both
6
1
8-19
3
,
the
use of aryl fluorides with strongly electron withdrawing
1
6, 21
groups,
palladium in close proximity to the C–F bond.
examples exist of Pd-catalyzed cross-coupling of unactivated
and the use of directing groups to position the
3
4
the chemoselective functionalization of 2-benzylfuran and the
1
7-18
Few
3
5-36
arylation of toluene.
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The use of heterobimetallic catalysts to activate strong bonds
Kumada-Tamao-Corriu (KTC) cross-coupling reactions44 with
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has been studied over the years. Noteworthy bimetallic
transition states for C–X bond activation by Nakamura are
a variety of potential auxiliary ligands identified a class of
phosphines that promote Ar–F bond activation under mild
conditions and short reaction times. Following initial
mechanistic studies, density functional theory (DFT)
calculations were used to support the proposal that a Mg ion
from the Grignard reagent is intimately involved in oxidative
addition of the C–F bond. These findings point to a novel
mechanism for KTC cross-coupling reactions that can occur
under Grignard : electrophile ratios commonly used in cross-
coupling reactions.
3
7-38
39-40
shown in Figure 2b
and c.
Of particular note, this group
developed a strategy to activate C–F bonds for nickel-catalyzed
cross-couplings using a novel hydroxyphosphine ligand in
which an alkoxy-bridged Ni–Mg heterobimetallic complex was
3
9
proposed as key to Ar–F activation (Figure 2c). This
heterobimetallic catalyst system can activate aryl fluorides in
4
1
good yields at 5 mol % loading. It would be advantageous to
perform heterobimetallic aryl fluoride activation using ligands
that are more readily available.
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Figure 2. Key transition states involving heterobimetallic
cooperativity. From left to right: a. Our prior work; b. Nakamura
(2004); c. Nakamura (2005); d. this work.
2. Results and Discussion
2
.1 Catalyst Identification and Optimization
The KTC cross-coupling of 4-fluorobiphenyl, 1a, and 4-tert-
butyl-phenyl magnesium bromide (2a) was used as a test
reaction. A ligand screen was performed using high-throughput
experimentation (10 μmol of Ar–F 1a, 25 μmol of Grignard
2
reagent 2a, 10 mol % of Pd(OAc) , 20 mol % for monodentate
phosphines, 10 mol % for bidentate ligands, 80 °C, in THF for
16 h). Of the 48 phosphine ligands, the most promising were
cataCXium PCy, DavePhos and CyJohnPhos, all of which share
a similar structural motif of two cyclohexyl groups and one
biphenyl-type group (Table 1). Notably, without added
phosphine ligand, Pd(OAc)
2 % under these conditions, and the exclusion of Pd(OAc)
from the reaction mixture gave 0 % yield.
These three ligands were then optimized on laboratory scale
0.1 mmol) with 5 mol % loading of Pd(OAc) (Table 1, entry
–3). CyJohnPhos and DavePhos gave similar assay yields
2
alone provided an assay yield of
2
2
(
1
2
Figure 1. Literature examples of Pd-catalyzed cross-coupling
reactions with aryl fluorides. Activation of the substrates by: a.
coordination to a transition metal; b. use of directing groups; c.
employing electron poor aryl fluorides. d. Cross-coupling of
unactivated aryl fluorides with Grignard reagents by Dankwardt
and coworkers; e. Coupling of aryl fluorides with a palladium
catalyst by Zhao.
4
5
(89–90 % AY) with cataCXium PCy lagging (45 % AY).
Changing the solvent from THF to dimethoxyethane (DME)
resulted in an increase in AY to 98 % with DavePhos (Table 1,
entry 4) and no change with CyJohnPhos (89 % AY, Table 1,
entry 5).
Attempts at lowering the ligand loading and the temperature
were found to be successful with optimization at a 5 : 10 mol %
Pd : L ratio and a 50 °C reaction temperature (Table 1, entries
Building on this precedent with the use of the
2
8-29
NIXANTPHOS-based catalyst,
we sought a class of ligands
6
–9). When the ratio of Grignard reagent to electrophile
that would promote the cleavage of Ar–F bonds through a
heterobimetallic activation processes. Although there are many
(hereafter referred to as Mg : ArX) was reduced to 2.0, the yield
dropped to 75 % (Table 1, entry 10). Finally, further
optimization for reaction time found that the reaction was
complete within 4 h under the optimized conditions (Table 1,
entry 7) and a 99 % isolated yield was determined (Table 1,
entry 11).
Grignard reagents that are readily available or easily
42-43
synthesized,
we chose to focus on the characteristics of the
ligand that enabled activation of strong C–F bonds. A high-
throughput experimentation screen of Pd-catalyzed
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Table 1. Optimization of cross-coupling between 1a and 2a.a
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Entry
Ligand
Pd/L (mol %)
Solvent
1a:2a
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2
T (°C)
80
Assay Yieldb
45%
0
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0
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0
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10
cataCXium PCy
DavePhos
CyJohnPhos
DavePhos
CyJohnPhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
5/20
5/20
5/20
5/20
5/20
5/10
5/10
5/10
2.5/5
5/10
THF
THF
80
89%
THF
80
90%
DME
DME
DME
DME
DME
DME
DME
DME
80
98%
80
89%
80
100%
100%
33%
50
25
50
74%
50
75%
1
1
5/10
1:2.5
50
100% (99% c)
a
b
1
Reactions conducted on a 0.1 mmol scale at 0.1 M. Assay yields determined by H NMR spectroscopy of the crude reaction mixture using
CH Br as the internal standard. Isolated yield after chromatographic purification and 4 h reaction time.
2 2
c
As outlined in Figure 1 and elsewhere,46 oxidative additions
are known to be dependent on the electronic nature of the aryl
group, with electron poor aryl halides undergoing faster
oxidative addition than analogous electron rich derivatives.
Thus, various aryl fluorides were employed with
phenylmagnesium bromide to determine if the reaction was
general with respect to Ar–F (Table 2). Aryl fluorides bearing
weak electron donating groups at the para position, such as
phenyl, or strong electron donating groups, like methoxy and
N,N-dimethylamino, provided high yields of the products 3a,
using DavePhos. Switching the ligand to CyJohnPhos allowed
for the remaining heterocyclic substrates to be successfully
coupled in 52–59 % yields (3j–3l). Finally, substrates bearing
hydroxyl (1m) and alkynyl (1n) groups were also examined.
DavePhos again gave low yields for these substrates but the
related CyJohnPhos provided products 3m and 3n in 44 and
55 % yields, respectively.
2.2 Mechanistic Insights
In Pd-mediated KTC cross-coupling chemistry, the accepted
turnover-limiting step (TLS) involves the oxidative addition of
the Ar–X prior to transmetallation by a Grignard reagent.
However, the inability of typical L Pd(0) complexes to
oxidatively add Ar–F bonds prompted further investigation into
the means by which the present system is able to mediate this
transformation.
3
b, and 3c in 99, 95, and 91 %, respectively. Electron
withdrawing 3-fluoroanisole was a viable substrate, furnishing
the product 3d in 99 % yield. Interestingly, when strong
electron withdrawing groups at the para position were used,
such as trifluoromethyl (1e), no coupling products were
observed. In contrast, use of NIXANTPHOS (7.5 mol %) at
4
7-48
1
8
0 °C for 12 h furnished the coupling product 3e in 78 %.
Sterically hindered aryl fluorides, such as 1-fluoro naphthalene
or 2-methyl and 2-methoxy 1-fluorobenzene, were also tested
but only gave moderate yields (around 50 %) under the standard
conditions. Furthermore, it proved difficult to isolate the
products by chromatography due to their nonpolar nature.
When a higher reaction temperature (80 °C) and an alternative
Grignard reagent (4-methoxyphenylmagnesium bromide, to aid
in chromatographic isolation) were used, the desired products
3f–3h were isolated in 73–96 % yield. Heterocyclic substrates,
Competition experiments were conducted using equimolar
mixtures
4-methoxyfluorobenzene
phenylmagnesium bromide. These were catalyzed by 5 mol %
of
4-tert-butoxychlorobenzene
with varying amounts
and
of
o
Pd(OAc) and 10 mol% DavePhos in 1 mL DME at 50 C for 4
2
h (Table 3). If the Grignard reagent is not involved in (or before)
the TLS, then we expect to see a clear preference for the
activation of the aryl chloride at all Mg : ArX ratios, as aryl
chloride will undergo oxidative addition faster than the aryl
fluoride.
including
1-(4-fluorophenyl)-1H-pyrrole
(1i),
6
5
1
-fluoroquinoline (1j), 5-fluorobenzofuran (1k) and
-fluorobenzothiophene (1l) were examined, but only
-(4-fluorophenyl)-1H-pyrrole gave product (3i, 91 % yield)
There were several interesting observations from these
competition experiments. First, at Mg : ArX ratios of 0.1 : 1, we
only observed the C–Cl bond activation product, 3p. Second,
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the ratio of C–F activation product (3o) to C–Cl activation We next turned to DFT computations to inform our
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product (3p) increases when Mg : ArX ratios are increased from
0.1 : 1 to 1 : 1, with rates of C–F to C–Cl activation becoming
equitable above Mg : ArX ratios of ~0.75 : 1. Third, when the
reaction was run under the optimized conditions, with a Mg :
ArX ratio of 2.5 : 1, the ratio of C–F to C–Cl activation is 1 : 1.
We conducted time course experiments tracking the formation
of 3o from Ar–F and 3p from Ar–Cl in parallel reactions under
the optimized conditions. At a Mg : ArX ratio of 1 : 1, a faster
reaction rate was observed for Ar–Cl (1 h, 27%; 4 h, 50%)
compared to Ar–F (1 h, 20%; 4 h, 38%) (Figure 3). However,
when the Mg : ArX ratio was increased to 2.5 : 1, the rates of
both reactions increased and became more equal between Ar–
Cl (1 h, 46%; 4 h, 91%) and Ar-F (1 h, 45%; 4 h, 100%) (Figure
3).
understanding of the manner in which this system is able to
promote Ar–F cross coupling. Of the 48 screened phosphine
ligands, the three that were most successful share a common
structural motif that includes two cyclohexyl groups and one
biphenyl-type unit. We chose one of these (DavePhos) as a case
study for identifying a mechanism that is able to account for the
experimental data.
Table 3. Aryl fluoride and aryl chloride competition
experiments as a function of Mg : ArX ratio.
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Taken together, these data suggest that a non-traditional KTC
mechanism is being accessed at higher ratios of Mg : ArX
concentrations. This dependence on the ratio of concentrations
indicates that it may be possible for both PhMgBr and Ar–X to
associate with Pd(0), with Ar–X association leading to a
traditional KTC mechanism for Ar–Cl, which is favored at low
Mg : ArX ratios, and PhMgBr association leading to an
alternative pathway for both Ar–Cl and Ar–F at high Mg : ArX
ratios.
3o
(mmol)
3p
(mmol)
Entry
PhMgBr:ArX
3o : 3p
1
2
3
4
5
0.1 : 1
0.25 : 1
0.5 : 1
0.75 : 1
1 : 1
0.0000
0.0019
0.00
0.34
0.66
1.08
1.08
0.0039
0.0162
0.0243
0.0416
0.0114
0.0248
0.0225
0.0385
Table 2. Examples of aryl fluorides suitable for cross-coupling
a,b
with aryl Grignard reagents.
6
7
8
1.5 : 1
2 : 1
0.0446
0.0485
0.0447
0.0425
0.0462
0.0453
1.05
1.05
0.99
2.5 : 1
Figure 3. Parallel-reaction monitoring at Mg : ArX ratios of 1 : 1
and 2.5 : 1.
The monophosphine Pd(0) complex (DavePhos)Pd (4) was
2
found to be stabilized by an intramolecular η -π-interaction
between Pd and the o-aryl group of the phosphine (denoted as
4
9
P
Ar ), as previously noted by Buchwald (Figure 4). For
–
complex 4, this interaction creates a 14 e metal center and
provides a 17 kcal/mol stabilization (see SI). Minor changes to
a
b
Reactions conducted on a 0.1 mmol scale at 0.1 M. Isolated
the Pd–P bond length and the Pd–P–Cipso angle compared to
c
yields after chromatographic purification. NIXANTPHOS (7.5
mol %), 80 °C, 12 h. 4-methoxyphenylmagnesium bromide (2.5
equiv.), 80 °C, 12 h. 80 °C, 12 h. Pd(OAc) (10 mol %),
2
CyJohnPhos (20 mol %), 80 °C, 12 h and 3.5 equiv Grignard
–
those in the 12 e L
1
Pd isomer indicate that Ar
P
binding to Pd
d
does not result in significant structural changes to the ligand
backbone. In addition to Ar , the coordination of other donors
e
f
P
present in the reaction mixture (DME, DavePhos, arenes)
provided stabilization with respect to 4 (see SI). These include
the adduct of 4 with the biphenyl C–C coupling product 4-
methoxybiphenyl (3o), which forms the Pd(0)-biphenyl adduct
reagent for 3l.
2
.3 Computational Study
5
. The free energy of 5 plus those of PhMgBr, ArCl, and ArF is
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used to define the zero point on the energy surfaces described
below.
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Figure 4. Proposed traditional KTC cross-coupling catalytic cycle.
Figure 5. Potential energy diagrams for traditional (left) and heterobimetallic (right) KTC cross-coupling catalytic cycles. Dashed lines
connect local minima; smooth lines connect local minima with transition states.
The traditional cross-coupling catalytic cycle involves the
formation of an adduct between an aryl halide and the Pd(0)
species 4 (Figure 4). This could be envisioned to occur along
the catalytic cycle via either dissociation of the biphenyl
product (3o) from 5, followed by association of ArX, or by
associative substitution of ArX for 3o. Stahl, Landis, and
co-workers have used kinetic experiments and DFT studies to
The ligand exchange process yields the π-ArX complexes 6X
(X = F, Cl), which exhibit Pd–CArX distances of ca. 2.21 Å (6Cl)
2
and 2.40 Å (6F) as well as η Pd-Ar
P
distances of ca. 2.83 Å
(6Cl) and 2.81 Å (6F). The subsequent Ar–X oxidative
addition transition states (TS6-7X) were located at +14.0
(TS6-7Cl) and +29.4 (TS6-7F) kcal/mol from 6X (Figure 5, left).
The significant difference in energy between the
rate-determining steps for this catalytic cycle are in line with
the conventional understanding that monophosphine Pd
complexes undergo facile Ar–Cl oxidative addition and slow
Ar–F cleavage. The geometries of TS6-7X exhibit typical three-
centered TS character, in line with significant Pd–C and Pd–X
bond formation as well as C–X bond cleavage.
–
show that a 14 e Pd complex undergoes associative ligand
2
exchange involving η -bound olefins, with activation barriers of
5
0
10–14 kcal/mol. In the present example, attempts to locate
transition states for either dissociative or associative ligand
exchange processes were unsuccessful. The coordination
sphere about Pd in 5 is too hindered to accommodate an
additional π-arene interaction, but ring-slippage of biphenyl or
The oxidative addition steps lead to the formation of Ar–
Pd(II)–X compounds (7X). Evaluation of the various possible
isomers of TS6-7X and 7X revealed both a kinetic and
thermodynamic preference for placing the halide trans to the
phosphine. The products 7Cl (–21.9 kcal/mol from 6Cl) and 7F
P
dissociation of Ar could be envisioned to create enough space
for binding ArX prior to dissociation of 3o. A dissociative
pathway is also feasible; loss of 3o from 5 is endergonic by 10.0
kcal/mol and requires minimal reorganization of the
coordination sphere about Pd, indicating that 10 kcal/mol may
be considered an upper bound for the activation energy required
to form a Pd(0) complex of ArX from 5.
(
–8.4 kcal/mol from 6F) exhibited T-shaped core geometries
2
P
with added η -cation-π interactions between Pd and Ar , which
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Page 6 of 12
complete square-planar coordination environments about the the non-traditional pathway of the KTC-coupling of aryl
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Pd(II) metal centers.
fluorides described herein.
Repeated attempts to locate
a transition state for
transmetallation (TS7-8X) were unsuccessful. Transmetallation
3
2
51
has been shown to be turnover-limiting for Suzuki and Stille
couplings, but oxidative addition is thought to be turnover-
limiting for the more closely related Negishi coupling
5
2-53
reactions.
For transmetallation to be turnover-limiting, the
putative TS7-8X steps would need to lie >30 kcal/mol above 7X.
For comparison, the computed barrier to transmetallation in the
aforementioned Negishi cycle is ca. 10 kcal/mol from the
oxidative addition product.
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The product of transmetallation with PhMgBr yields the Ar–
Pd(II)–Ph species, 8, and MgBrX. Compound 8 again exhibits
2
an η -cation-π interaction between Pd and Ar
P
(Pd–
P
Ar = ca. 2.77 Å). Reductive elimination (TS8-5) is calculated to
be facile (ca. –40 kcal/mol versus 6) en route to regenerating
the Pd(0) species 5, which closes the catalytic cycle.
Figure 6. Mg-Ni cooperative activation of ArX proposed by
Nakamura and co-workers.
3
9
The calculations thus predict that the rate of the traditional
KTC pathway is turnover-limited at the oxidative addition step
during both Ar–F and Ar–Cl activation. The predicted kinetic
We and others have previously shown that cation-π
interactions can be used to house Lewis acidic metals near a Pd
center, and Mg(II) has been shown to form intramolecular
‡
preference for Ar–Cl bond activation (ΔΔG = 15.4 kcal/mol)
5
5-58
contrasts, however, with the competitive Ar–F and Ar–Cl bond
activation observed experimentally, suggesting that an
alternative pathway is likely operative. The traditional KTC
pathway also does not account for the experimental observation
that Ar–F cross-coupling depends on the relative concentration
of Grignard to electrophile, which suggests that the Grignard
reagent may compete with the electrophile for binding to Pd(0).
cation-π interactions.
In addition, a handful of reports of
heterobimetallic activation of Ar–X electrophiles have been
described in the literature. The most salient example involved a
3
9-40
Ni-Mg heterobimetallic complex.
In this case, the proposed
reaction coordinate included a nickel hydroxyphosphine
complex, the alkoxy group forming a bridge between the Pd and
Mg (Figure 2c and Figure 6). The close proximity of the two
metal centers allowed for the activation of Ar–X substrates
through the concerted delivery of X to Mg and Ar to Ni
Crystallographic examples are known of alkyl magnesium
complexes forming Lewis acid-base adducts with Fe, Co, Ni,
(Figure 6). Transition states were identified for
OP(O)(OMe) , OC(O)NMe , OMe, and SMe, but attempts to
locate transition states for aryl halide activation (X = F, Cl, Br)
X =
5
4-58
and Cu.
heterobimetallic core by bridging between the two metal centers
M–Mg = ca. 2.6 Å). During the final stages of preparation of
this manuscript, Crimmin and coworkers reported hexagonal
planar palladium Pd(H) [Mg(nacnac)] complexes, including
In most cases, the alkyl group stabilizes the
2
2
(d
3
9-40
were unsuccessful.
With DavePhos as a supporting ligand, the interaction
between Pd(0) (5) and PhMgBr was computed to be mildly
exergonic (ΔG = –2.2 kcal/mol) on formation of an association
complex (9). The Grignard is Mg-bound to Pd, leading to a Pd–
Mg distance of 2.57 Å. A transition state corresponding to both
binding of the Grignard Cipso carbon to Pd and concurrent
3
3
5
9
their characterization by X-ray diffraction. The Pd–Mg bonds
in these compounds range from 2.485(1) to 2.567(1) Å.
Addition of phosphines to the hexagonal planar complex
2
3 2
resulted in formation of R P–Pd[η -H–Mg(nacnac)] , with the
phosphine and hydrides in the equatorial plane. These are the
first examples of Pd–Mg adducts characterized structurally.
The interaction of the Mg and Pd in such complexes supports
our speculation that bimetallic Pd–Mg interactions are viable in
2
dissociation of the η -bound biphenyl unit was located at
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Figure 7. Proposed heterobimetallic catalytic cycle.
6.6 kcal/mol vs. 5. The product of this ligand exchange
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+
Relaxation from this transition state toward the formation of
process is a heterobimetallic palladate species, 10 (–
.8 kcal/mol; Figure 7). Compound 10 features a Pd–Mg
the Pd–ArX π-bond reveals a high-energy intermediate (12X)
2
1
characterized by η π-bonding to Pd, a dative Mg–X interaction
distance of 2.44 Å, which, like 9, is similar to those observed in
(Mg–Cl = 2.57 Å; Mg–F = 2.14 Å), and significant activation
of the Ar–F bond. Ar returns to Mg in 12X, forming cation-π
P
59
the structures reported by Crimmin. The Pd–Mg interaction
in 10 is supported with both a µ-phenyl bridge (Pd–Cipso = 2.11
interactions at distances of ca. 2.92 Å (Cl) and 2.83 Å (F). The
modest increase in free energy on formation of 12X (+13.6
kcal/mol vs. {10 + Ar–X}) masks the substantial activation of
the aryl halides, which both exhibit 0.11 Å increases in the Ar–
X bond distances and pyramidalization of the ArX ipso carbon
(sum of angles about Cipso = 343.2°; <Pd-Cipso-Cpara = 107.3°).
2
Å, Mg–Cipso = 2.35 Å; Pd–Cipso–Cpara = 158.2°) and an η –
cation-π interaction between Mg and the biphenyl portion of the
phosphine ligand. The Mg–C
π
distances of ca. 2.79 Å are
comparable with crystallographically characterized compounds
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that share the η -cation-π motif (Mg–C
ca. 2.62 Å).
π
distances of
5
4
Nakamura and co-workers used constrained geometry scans
to support the notion that aryl halide bond activation is nearly
barrierless in the Ni : Mg heterobimetallic system. In the
present system, the transition states for Ar–X bond cleavage
(TS10-8X) were located and found to exhibit exceedingly small
activation energies with respect to 12X: +0.2 kcal/mol for
TS12-8Cl and +1.1 kcal/mol for TS12-8F. The structures of
TS12-8X are similar to those of 12X, in accord with Hammond’s
postulate (Figure 9). Both of the Ar–X distances in TS12-8X are
elongated by 0.32 Å from 12X, while the Mg–X and Pd–
Considering that the KTC cross-coupling reaction produces
magnesium halide salts, we also investigated the binding of
alternative Mg-containing salts to Pd(0) to form analogs of 10
(
see SI). The formation of Pd(0)–MgXY complexes (MgXY =
MgBr , MgF , MgBrF) were found to be endergonic from 5 by
10 kcal/mol. These results, compared to the exergonic
2
2
>
formation of 10 from 5, suggest that the µ-Ph linkage in 10
provides a particular advantage in the present system.
The formally anionic Pd(0) center of 10 adopts a T-shaped
geometry, with the µ-phenyl ipso carbon located trans to the
phosphine (<P–Pd–Cipso = 170.3°) and the Mg center cis to the
phosphine (<P–Pd–Mg = 117.8°). This geometry did not
provide a direct pathway for approach of ArX that would allow
for cooperative action by Pd and Mg; however, it was found that
halide-binding of ArX to Mg was viable to give a product that
was mildly endergonic (11X; +3.5/+4.0 kcal/mol for X = F/Cl).
These complexes displayed a similarly inaccessible core
geometry as 10, but the search for a C–X bond activation
pathway was advanced by scanning the P–Pd–Cipso angle on 10.
Doing so from 175° to 100° revealed a flat potential energy
surface that results from the lack of directional bonding at Pd(0)
C
ipso(ArX) distances decrease by 0.11 Å, as expected for Ar–X
bond breaking and Pd–Ar/Mg–X bond formation. We note that
2
P
Ar retains η cation-π interactions of ca. 2.9 Å with Mg in the
transition states. We were unable to locate intermediates
following TS12-8X that retain MgBrX in the coordination sphere
of Pd. Presumably, oxidation to Pd(II) weakens the Pd–Mg
interaction such that salt loss requires a negligible amount of
energy. The resulting Ph-Pd(II)-Ar species (8, described above)
undergoes reductive elimination through the previously
described three-center transition state (TS8-5), calculated to lie
>45 kcal/mol lower in energy than TS12-8X (see SI).
P
(see Figure 8). The binding of Ar migrates through the scan,
2
2
from an η interaction with Mg in the ground state to an η π-
interaction with Pd(0) at P–Pd–Cipso = 100°. The structure with
the most acute angle lies a mere 4.5 kcal/mol higher in energy
than the ground state geometry and contains space for
heterobimetallic Ar–X binding.
Figure 8. Relative energies of 10 in its ground state geometry (left)
and with a constrained P–Pd–Cipso angle of 100° (right).
With this in mind, scanning the Pd–Cipso,ArX distance of 11X
identified late transition states for formation of a π-bond
between Pd and ArX. This step takes advantage of the shallow
potential energy surface defined by the P–Pd–Cipso,Mg angle to
create space for interaction between the aryl π-system and Pd
but appears to be guided by the interaction between Mg and X,
as the Mg–X distances are nearly invariant from the ground
state to the transition state. The energy of this transition state
was determined to be ca. 10 kcal/mol, which places it on par
with the C–Cl activation energy in the tradition KTC pathway
described above.
Figure 9. DFT optimized structure of TS12-8F; all hydrogen atoms
were removed for clarity. Important bond lengths (Å) and angles
deg): Pd–C1 2.166, Pd–C2 2.076, Pd–C3 2.474, Pd–Mg 2.610,
Pd–P 2.381, F–C2 1.683, Mg–C1 2.320, Mg–C4 2.798, Mg–C5
(
3
.044, F–Mg–Br 107.1, Pd–Mg–C1 51.7, C2–F–Mg 96.3.
It was found experimentally that increasing the Grignard
concentration mitigated the difference in rates of formation of
Ar–F and Ar–Cl coupling products. This suggests that at low
Mg : ArX ratios, the traditional KTC pathway is favoured,
yielding higher proportions of Ar–Cl over Ar–F activation
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products. However, with high Mg : ArX ratios, the available
Page 8 of 12
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Pd(0) in solution accesses a heterobimetallic pathway. This is
consistent with the results of the competition experiment, which
found that Ar–F and Ar–Cl activation occurred at comparable
rates under conditions with high Mg:ArX ratios. It should be
noted that the heterobimetallic mechanism offers a significant
stabilization in Ar–F bond activation compared to the
‡
traditional KTC mechanism (i.e. TS6-7F vs. TS12-8F). The ΔG
for the Ar–F bond cleavage step was found to decrease by 16.9
kcal/mol in the heterobimetallic mechanism.
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.4 Experimental support for a heterobimetallic mechanism.
Additional experimental work was used to further probe the
heterobimetallic reaction mechanism that is proposed to occur
at elevated Mg : ArX ratios. We envisioned that the different
steric profiles between the traditional KTC mechanism and the
heterobimetallic pathway might provide an opportunity to probe
these competing modes of oxidative addition. The rates of
traditional KTC cycles are known to show little variation in
49
response to the steric profile of the electrophile. In contrast,
the constrained environment imposed by the heterobimetallic
architecture might be expected to inhibit the binding of
sterically hindered aryl halides. To probe this hypothesis,
2
1
Figure 10. Parallel-reaction competition experiments at Mg : ArX
Ratios of 0.25 : 1, 1 : 1 and, 2.5 : 1 using 2,6-dimethyl-
,6-dimethyl-1-fluorobenzene
and
3,5-dimethyl-
1
-fluorobenzene or 2,6-dimethyl-1-chlorobenzene.
-fluorobenzene were evaluated as substrates under the
optimized reaction conditions described above, with Mg : ArX
2.5 : 1. The use of 3,5-dimethyl-1-fluorobenzene resulted in
a slower reaction rate compared to 4-phenyl-1-fluorobenzene
80% vs. 99% yield after 4 h), and the use of 2,6-dimethyl-1-
In order to probe the origin of the steric interaction that is
=
causing the dimethyl-substituted substrates to diverge from the
reactivity described above, we computed the energies of 12F-
xyl and TS12-8F-xyl, in which 2,6-dimethyl-1-fluorobenzene is
substituted for the 4-methoxy-1-fluorobenzene substrate of 12F
and TS12-8F. The modest increase in ground state and transition
state energies (+13.2 and +15.8 kcal/mol, respectively, vs. 5)
indicate that this step is not responsible for preventing the
formation of cross-coupled products under high Mg : ArX ratios
(Figure 10). This information, coupled with the observation
that product is formed under low Mg : ArX ratios, led us to
reason that i) Grignard effectively outcompetes ArX for Pd(0),
and ii) that the steric profile of the 2,6-dimethyl-halobenzenes
prevents them from forming 12X.
(
fluorobenzene halted the reaction entirely.
This outcome was further used to support the notion that the
Mg : ArX ratio controls access to either the traditional KTC or
heterobimetallic mechanisms.
With the 2,6-dimethyl-1-
halobenzenes as substrates, we anticipated that low Mg : ArX
ratios would provide cross-coupling with both substrates, with
a preference for Ar–Cl activation through the traditional KTC
pathway, but at high Mg : ArX ratios, 2,6-dimethyl-1-
chlorobenzene would join 2,6-dimethyl-1-fluorobenzene as an
inactive substrate under these conditions. Indeed, at a Mg : ArX
ratio of 0.25 : 1, coupling to Ar–Cl was favored, forming the
cross-coupling product in 23 % yield, compared to 7 % yield
when the Ar–F was evaluated under identical conditions (Figure
On evaluation of the full energy surface provided in Figure 5,
we are left with the conclusion that the heterobimetallic
mechanism is governed by either the formation of the high-
energy intermediate 12X (TS11-12X) or the Ar–X bond cleavage
process (TS12-8X), depending on the steric profile of the
electrophile. For the p-OMe substrates these transition states
are nearly equal in energy, but the experimental data indicate
that TS11-12X, which involves formation of a Pd--complex with
the aryl halide, becomes turnover-limiting when the 2,6-
1
0). When the Mg : ArX ratio was raised to 1 : 1, both yields
decreased dramatically, resulting in 2% and 0% yield for Ar–Cl
and Ar–F, respectively. At a Mg : ArX ratio of 2.5 : 1, no
product was observed for either substrate. These findings
corroborate the hypothesis that at low Mg : ArX ratios, the
cross-coupling reaction proceeds through a traditional KTC
mechanism, with coupling to Ar–Cl proceeding more quickly.
This is consistent with literature reports, which indicate that
o-dimethyl substitutions provide little steric hinderance to
oxidative addition at low-coordinate Pd(0). These results also
comport with the data presented in Table 3 that show a similar
ratio of Ar–F : Ar–Cl activation products (0.34) under a Mg :
ArX ratio of 0.25 : 1.00. At Mg : ArX ratios ≳ 1, the inability
of the 2,6-dimethyl substrates to undergo cross-coupling
supports the view that this system is accessing a unique
mechanism that both prevents access to the traditional KTC
pathway and presents a pathway that is susceptible to the
presence of o-substitutions on the electrophile.
6 3 2
C H -Me substitution pattern is present. With less sterically
demanding electrophiles, the C–X activation energies of the
heterobimetallic pathways are similar to the C–Cl activation
energy of the traditional KTC pathway, meaning the species
that exist on these energy surfaces prior to Ar–X bond
activation would be in equilibrium with one another. This fits
with the experimental observation that Ar–F bond activation
does not occur until roughly equal measures of Grignard and
ArX are present in solution. Even so, the tendency toward
access to the heterobimetallic activation pathway is non-
negligible, as noted from the ratios of 3o : 3p listed in Table 3.
The 0.34 : 1.00 ratio of products, for example, obtained under
reaction conditions that used a Mg : ArX ratio of 0.25 : 1.00,
may be thought to represent equal access to the two pathways,
4
9
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ACS Catalysis
if one assumes that all of the Ar–F activation is from the
heterobimetallic pathway and that the Ar–F and Ar–Cl bond
activation steps are equivalent in energy in this new
heterobimetallic mechanism. This preference for the
heterobimetallic pathway would then result from the lower
relative energies of 9 and 10 (ca. –2 kcal/mol) compared to the
endergonic Pd–ArX intermediates (6X, ca. +5 kcal/mol)
observed on the traditional KTC pathway. The equilibrium
population of the species along the heterobimetallic pathway
will be greater. With similar energy barriers to Ar–X activation
via either pathway, the thermodynamic preference for the
heterobimetallic intermediates will lead to greater usage of the
Pd–Mg architecture for C–X bond activation.
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Finally, the proposed Pd-Mg heterobimetallic structure was
supported through the use of a novel phosphine ligand, Cy
Bn-C ), in which an ortho position on the aryl ring of Cy
2
P(o-
PPh
6
H
4
2
was substituted with a benzyl group. Under the optimized
reaction conditions described above, this ligand provided a 68%
yield of Ar–F cross-coupling (Figure 11). Additional support
for the ability of Cy P(o-Bn-C H ) to mediate a heterobimetallic
2 6 4
mechanism similar to TS12-8F was obtained using DFT
computations. A transition state (TS12-8F-oBn) was identified
Figure 12. DFT optimized structure of TS12-8F-oBn; all hydrogen
atoms were removed for clarity. Important bond lengths (Å) and
angles (deg): Pd–C1 2.158, Pd–C2 2.061, Pd–C3 2.405, Pd–Mg
2.662, Pd–P 2.386, F–C2 1.690, Mg–C1 2.294, Mg–C4 2.776, Mg–
C5 3.062, Mg–F 1.993, F–Mg–Br 105.9, Pd–Mg–C1 51.1 C2–F–
Mg 95.0.
2 6 4
with the Cy P(o-Bn-C H ) ligand and found to closely match
the structure of TS12-8F (Figure 12). TS12-8F-oBn exhibits an
Ar–F distance of 1.690 Å (vs. 1.683 Å in TS12-8F), along with a
Mg–F distance of 1.993 Å (1.987 Å for TS12-8F) and a Pd–
3. Conclusion
The most significant accomplishment of this work is that a
mechanism for oxidative addition of aryl chlorides and
fluorides has been identified that proceeds via a bimetallic Pd-
Mg transition state. A range of aryl fluorides with different
electronic and steric profiles lead to products in moderate to
excellent yields. A computational study was used to evaluate
two possible reaction mechanisms. In sub-stoichiometric Mg :
ArX ratios, it is proposed that the electrophile outcompetes the
Grignard for binding to Pd(0). This leads to a traditional KTC
pathway involving oxidative addition of the electrophile,
followed by transmetallation from the Grignard reagent.
C
ipso(ArX) distance of 2.061 Å (2.076 Å for TS12-8F). Ar
P
was
2
found to retain an η cation-π interaction of ca. 2.9 Å with Mg
in both TS12-8F and TS12-8F-oBn.
Pd(OAc)2 5 mol%
Phosphine 10 mol%
Ph
F
+
BrMg
0.25 mmol
Ph
DME 1 mL
o
0
.1 mmol
50
C
Yield by Phosphine
PCy2
PCy2
None
However, due to the Ar -assisted binding of Mg, coordination
P
NMe2
of Grignard competes for Pd(0) at elevated Mg : ArX ratios,
2
2%
0%
99%
68%
PCy2
such as those usually employed in KTC coupling reactions. The
resulting heterobimetallic complex appears to be equally
competent at Ar–F and Ar–Cl activation, while providing a
substantial decrease in the activation energy for Ar–F compared
to the traditional oxidative addition pathway. The cooperativity
of Mg and Pd was facilitated by a cation-π interaction with a
biphenyl group on the phosphine. This interaction supported the
close proximity of Mg and Pd, which was shown to be integral
to efficient aryl halide bond activation via the bimetallic
pathway. Further exploitation of this bimetallic cooperativity
is underway.
PPh2
PCy2
2
13%
18%
Figure 11. Reactions with modified phosphines.
Further modifications to the phosphine revealed the
importance of both the cyclohexyl and pendant aryl moieties;
use of either Ph
comparable activity to the phosphine-free conditions (20% and
8% yield, respectively). We propose that the aliphatic
2 6 4 2 6 4
P(o-Bn-C H ) or Cy P(o-C H -Me) resulted in
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website. Procedures, characterization data for all new
compounds and calculation for mechanisms (PDF).
1
cyclohexyl groups are necessary for creating an electron rich
Pd(0) center, and that the o-Bn group aids the electron rich
metal in retaining Mg in the coordination sphere of Pd. The
2 6 4
diminished yield observed for Cy P(o-Bn-C H ) compared to
CyJohnPhos/DavePhos suggests, however, that the
heterobimetallic activation of Ar–X is highly sensitive to the
manner in which the Lewis acid is supported and positioned.
AUTHOR INFORMATION
Corresponding Author
* E-mail: tomson@upenn.edu (N.C.T.).
E-mail: pwalsh@sas.upenn.edu (P.J.W.).
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Author Contributions
C−F Activation of Polyfluoronitrobenzene Derivatives in
Suzuki−Miyaura Coupling Reactions. J. Org. Chem. 2010, 75
(17), 5860-5866.
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‡
These authors contributed equally. (C.W. and S.P.M.)
1
7. Bahmanyar, S.; Borer, B. C.; Kim, Y. M.; Kurtz, D. M.; Yu, S.,
Proximity Effects in the Palladium-Catalyzed Substitution of Aryl
Fluorides. Org. Lett. 2005, 7 (6), 1011-1014.
Notes
The authors declare no competing financial interest.
18. Ishikawa, S.; Manabe, K., Synthesis of Substituted
Monohalobenzenes via Ortho-Selective Cross-Coupling of
Dihalobenzenes with Electron-Donating Ortho-Directing Groups.
Synthesis 2008, 2008 (19), 3180-3182.
19. A. Widdowson, D.; Wilhelm, R., Palladium catalysed cross-
coupling of (fluoroarene)tricarbonylchromium(0) complexes.
Chem. Commun. 1999, (21), 2211-2212.
ACKNOWLEDGMENT
N.C.T. acknowledges the National Institute of General Medical
Sciences (NIGMS) of the National Institutes of Health (NIH) for
support of this work under award number R35GM128794 and the
Charles E. Kaufman Foundation, a supporting organization of The
Pittsburgh Foundation, for support in the form of a New
Investigator Research Grant (KA2016-85227). P.J.W. thanks the
National Science Foundation (CHE-1902509) and the Petroleum
Research Fund managed by the American Chemical Society (PRF
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2
0. Widdowson, D. A.; Wilhelm, R., Palladium catalysed Suzuki
reactions of fluoroarenes. Chem. Commun. 2003, (5), 578-579.
1. Yu, D.; Shen, Q.; Lu, L., Selective Palladium-Catalyzed C–F
Activation/Carbon–Carbon Bond Formation of Polyfluoroaryl
Oxazolines. J. Org. Chem. 2012, 77 (4), 1798-1804.
2. Kim, Y. M.; Yu, S., Palladium(0)-Catalyzed Amination, Stille
Coupling, and Suzuki Coupling of Electron-Deficient Aryl
Fluorides. J. Am. Chem. Soc. 2003, 125 (7), 1696-1697.
2
5
9570-ND1) for financial support.
2
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C
F
BrMg
R’
R’
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DME, 4 h, 50 °C
R
Me2N
R'
Heterobimetallic
Transition State
• Mild Conditions
• High yields (up to 99%)
Cy2P
Pd
MgBr
F
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MeO
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