Small Phosphine Ligands Enable Selective Oxidative Addition of Ar-O over Ar-Cl Bonds at Nickel(0)

Article abstract of DOI:10.1021/jacs.0c06995

Current methods for Suzuki-Miyaura couplings of nontriflate phenol derivatives are limited by their intolerance of halides including aryl chlorides. This is because Ni(0) and Pd(0) often undergo oxidative addition of organohalides at a similar or faster rate than most Ar-O bonds. DFT and stoichiometric oxidative addition studies demonstrate that small phosphines, in particular PMe3, are unique in promoting preferential reaction of Ni(0) with aryl tosylates and other C-O bonds in the presence of aryl chlorides. This selectivity was exploited in the first Ni-catalyzed C-O-selective Suzuki-Miyaura coupling of chlorinated phenol derivatives where the oxygen-containing leaving group is not a fluorinated sulfonate such as triflate. Computational studies suggest that the origin of divergent selectivity between PMe3 and other phosphines differs from prior examples of ligand-controlled chemodivergent cross-couplings. PMe3 effects selective reaction at tosylate due to both electronic and steric factors. A close interaction between nickel and a sulfonyl oxygen of tosylate during oxidative addition is critical to the observed selectivity.

Full text of DOI:10.1021/jacs.0c06995

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Article
Small Phosphine Ligands Enable Selective Oxidative
Addition of Ar—O over Ar—Cl Bonds at Nickel(0)
Emily D. Entz, John Russell, Leidy Hooker, and Sharon R. Neufeldt
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c06995 • Publication Date (Web): 17 Aug 2020
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Small Phosphine Ligands Enable Selective Oxidative Addition of
Ar—O over Ar—Cl Bonds at Nickel(0)
Emily D. Entz,‡ John E. A. Russell,‡ Leidy V. Hooker,† and Sharon R. Neufeldt*
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Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59717, United States
KEYWORDS. Chemoselectivity, Cross-coupling, Density functional calculations, Ligand effects, Nickel.
ABSTRACT: Current methods for Suzuki-Miyaura couplings of non-triflate phenol derivatives are limited by their intolerance of
halides including aryl chlorides. This is because Ni(0) and Pd(0) often undergo oxidative addition of organohalides at a similar or
faster rate than most Ar—O bonds. DFT and stoichiometric oxidative addition studies demonstrate that small phosphines, in particular
PMe3, are unique in promoting preferential reaction of Ni(0) with aryl tosylates and other C—O bonds in the presence of aryl
chlorides. This selectivity was exploited in the first Ni-catalyzed C—O-selective Suzuki-Miyaura coupling of chlorinated phenol
derivatives where the oxygen-containing leaving group is not a fluorinated sulfonate such as triflate. Computational studies suggest
that the origin of divergent selectivity between PMe3 and other phosphines differs from prior examples of ligand-controlled
chemodivergent cross-couplings. PMe3 effects selective reaction at tosylate due to both electronic and steric factors. A close
interaction between nickel and a sulfonyl oxygen of tosylate during oxidative addition is critical to the observed selectivity.
Among these, a large percentage (~38%) are chlorinated.12 As
such, development of methods for selective cross-coupling of
INTRODUCTION
The Suzuki-Miyaura cross-coupling reaction is among the
chlorinated phenol derivatives via C—O cleavage (Scheme 1D)
most widely used strategies for C—C bond formation in organic
could streamline access to pharmacologically relevant targets.
synthesis. This transformation is traditionally catalyzed by
Scheme 1. Ni- and Pd-Catalyzed Suzuki-Miyaura
Couplings of Non-Triflate Chlorophenol Derivatives.
palladium and employs aryl halides or arenes substituted by
highly labile fluorinated sulfonates (especially triflates) as
electrophilic coupling partners.1 However, recent advances in
nickel-catalyzed cross-couplings have facilitated the use of
more robust phenol derivatives such as aryl sulfamates,
tosylates, mesylates, carbamates, and esters.2 The ability to
exploit less labile phenol derivatives as alternatives to aryl
halides has several advantages. First, phenols can be cheaper or
more accessible than organohalides. Second, many phenol
derivatives can be carried through multiple synthetic steps,
including those involving Pd-catalysis (e.g., Scheme 1A).3
Third, some phenol derivatives can direct other synthetic steps
prior to their use in cross-coupling, such as ortho metalation,
catalytic C—H functionalization, and electrophilic aromatic
,
substitution.4 5
Despite numerous reports of Ni-catalyzed cross-coupling of
robust phenol derivatives, a critical limitation of current
methods is that aryl halides such as chloride are not tolerated.
This is because organohalides tend to react with Ni(0) at a
,
similar or faster rate than Ar—O bonds.6 7 Efforts to achieve
Ni-catalyzed Suzuki-Miyaura coupling of chlorophenol
derivatives have rarely been reported, but the few existing
examples demonstrate preferential coupling of the chloride
(e.g., Scheme 1B), poor yields, and/or low selectivity to form a
mixture of products (e.g., Scheme 1C).8 9 10 This functional
group incompatibility severely limits the utility of phenol-
derived electrophiles, as myriad biologically-relevant synthetic
targets contain halogens. For example, about 40% of drugs
currently on the market or in clinical trials and about 50% of
molecules in high-throughput screening are halogenated.11
Herein we demonstrate that small phosphine ligands for
Ni(0), especially PMe3, facilitate selective oxidative addition of
Ar—OTs bonds in the presence of Ar—Cl bonds. This
selectivity is accurately predicted by DFT calculations, and a
series of stoichiometric studies confirm that methylphosphines
are unique in enabling this C—O-selective oxidative addition.
By using a Ni/PMe3 catalytic system, we provide proof-of-
principle for a highly selective Suzuki-Miyaura cross-coupling
,
,
of chloroaryl tosylates through C—O cleavage.10,13 14 Our DFT
,
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studies suggest that trimethylphosphine’s unique effect on same trend in preference for oxidative addition of tosylate
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selectivity can be attributed to a combination of electronic and
steric factors. In particular, trimethylphosphine's small size
enables a close stabilizing interaction between a sulfonyl S=O
and Ni during oxidative addition at C—OTs.
(PMe3 > PCy3 > PPh3; see SI for details). With the majority of
methods tested, Ni(PMe3)2 is predicted to favor reaction at
tosylate, while Ni(PPh3)2 is usually predicted to react at
chloride. As such, DFT calculations suggest that the small
phosphine PMe3 is more likely to facilitate the desired
chemoselectivity than traditional ligands like PCy3 and PPh3.
RESULTS AND DISCUSSION
DFT Calculations With PMe3. We conducted density
functional theory (DFT) calculations on oxidative addition at
Ni(0) to gather insight into the effect of ligands on this step.15
Our initial DFT studies examined the reaction of Ni(PMe3)2
with 4-chlorophenyl tosylate (1). We chose to focus on aryl
tosylates because they are generally reactive toward Ni(0), but
are often inert toward other reaction conditions including Pd-
catalysis (e.g., Scheme 1A). PMe3 was chosen as a model
phosphine ligand due to its computational simplicity. Previous
DFT studies suggested that bis-phosphine ligated nickel is
likely favored over mono-ligated analogues during oxidative
addition when dispersion is considered,16 so two PMe3 ligands
were included in these calculations. Geometry optimizations
were conducted using the functional MN15L,17 and energies
were further refined with MN15L using a larger basis set and
1,4-dioxane as an implicit solvent (see SI for details).
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Figure 2. Calculated free energies of activation (in kcal mol-1) for
oxidative addition with PMe3, PPh3, and PCy3, measured from the
preceding π-complex.
Stoichiometric Oxidative Addition Studies. Stoichiometric
oxidative addition studies with PCy3, PPh3, and PMe3 were
undertaken and the results were compared to the DFT
predictions. When Ni(cod)2 and PCy3 (1:2) are combined in 1,4-
dioxane, a new signal appears in the 31P NMR spectrum
assigned to a Ni(0)/PCy3 adduct (46.0 ppm, Figure 3A). Free
PCy3 (9.9 ppm) is also still detectable after 2 h. Upon addition
of 1-chloronaphthalene (7) a new signal grows in within 2 h
(11.9 ppm) corresponding to the oxidative addition adduct 9
(Figure 3B). A smaller signal at 12.9 ppm was identified as the
Ni(II)-2-naphthyl adduct resulting from oxidative addition of 2-
chloronaphthalene, which is a contaminant in commercial 7.21
Alternatively, addition of aryl tosylate 8 leads to a new signal
at 10.9 ppm corresponding to 10 (Figure 3C). Finally, when a
Ni(cod)2/PCy3 solution is combined with a mixture of 7 and 8
(1.0 equiv each), signals for both 9 and 10 appear in a 1.5 : 1
ratio (Figure 3D).22 These results show that Ni(0)/PCy3 has a
slight preference for oxidative addition of Ar—Cl over Ar—
OTs in an intermolecular competition.
Surprisingly, our initial calculations predict that oxidative
addition of C—OTs at Ni(PMe3)2 should be significantly faster
than oxidative addition of C—Cl (Figure 1). Transition
structure 4a-TS is ~3.0 kcal mol-1 lower in energy than 3-TS,
suggesting that selective cross-coupling at tosylate might occur
with Ni/PMe3. We initially assumed that this prediction
reflected error in the DFT energies, since it contradicts literature
results with PCy3,8a 1,2-bis(diphenylphosphino)ethane,8h and
triarylphosphines8f—ligands that are more conventional for
catalysis. To our knowledge, PMe3 had not been experimentally
-
evaluated in Ni-catalyzed Suzuki-Miyaura cross-couplings.18 20
Figure 1. Free energy profile for oxidative addition of the C—O
and C—Cl bonds of 1 at Ni(PMe3)2.
DFT Calculations Using PCy3 and PPh3. We next
calculated oxidative addition transition structures with the more
experimentally relevant phosphine ligands PCy3 and PPh3
(Figure 2). In contrast to the calculations with PMe3, oxidative
addition at Ni(PPh3)2 is predicted to be faster at chloride than
tosylate (∆∆G‡ = 2.0 kcal mol-1). Ni(PCy3)2 favors reaction at
tosylate, but only by 1.2 kcal mol-1 (compared to 3.0 kcal mol-1
with PMe3). These predictions are consistent with experimental
8a
reports using PCy3 or triarylphosphines in catalysis,8f and
Figure 3. 31P{1H} NMR studies on oxidative addition at Ni/PCy3
(reaction conditions = 2 h at room temperature in 1,4-dioxane).
contrast with our DFT results using PMe3.
Several additional DFT methods were evaluated with each of
the ligands PMe3, PCy3, and PPh3. Most methods predict the
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The analogous experiments using PPh3 demonstrate much
PPhMe2 gives similar selectivity (entry 4). Interestingly, the
analogous ethyl phosphines PPhEt2 and PEt3 slightly favor
reaction at chloride instead of tosylate (entries 5 and 11),
suggesting that the small size of a methyl group on phosphine
is important.
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higher selectivity for oxidative addition of C—Cl. In a
competition reaction between 7 and 8 with Ni(cod)2/PPh3 (1:2),
the only oxidative addition adduct detected results from
reaction at chloride (see SI for details). These results are
consistent with the trends predicted by DFT, as well as Zou’s
catalytic studies using a triarylphosphine (Scheme 1B).8f
We next evaluated the selectivity when competing 1-
chloronaphthalene 7 against a variety of other 1-naphthol
derivatives for oxidative addition at Ni(0)/PMe3 (Table 2).
Excitingly, reaction of an aryl triflate (entry 1), as well as the
more robust phenol derivatives mesylate (entry 3) and
sulfamate (entry 4) are preferred over reaction of naphthyl
chloride when using PMe3. The use of PCy3 or PPh3 results in a
slight preference for reaction of triflate over chloride, but
oxidative addition of chloride is preferred over all other types
of C—O bonds depicted in Table 2 with these ligands.
In stark contrast to PCy3 and PPh3, the combination of a
mixture of 7 and 8 with a 1:2 solution of Ni(cod)2/PMe3 gives
preferential oxidative addition at C—OTs (Figure 4). The
putative oxidative addition adducts 11 and 12 are formed in
about a 1 : 6.3 ratio based on 31P NMR integrations. Taken
together, the results of the intermolecular competition studies
with the three ligands are consistent with the DFT-predicted
trend in preference for oxidative addition at C—OTs (PMe3 >
PCy3 > PPh3).
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Table 2. Selectivity of Ni/PR3 for Reaction of Various
Phenol Derivatives in Competition with 1-
Chloronaphthalene.
The chemoselectivity of oxidative addition with PMe3 was
further evaluated in an intramolecular competition. A 1:2
solution of Ni(cod)2/PMe3 was combined with chloronaphthyl
tosylate 13 (Scheme 2). Tentative assignment of product signals
was made by analogy to the reaction of Ni(cod)2/PMe3 with 7
or 8. The product resulting from reaction at tosylate is favored
over the putative nickel chloride adduct by about 90:1,
suggesting that tosylate selectivity can be even stronger in an
intramolecular versus intermolecular competition.23 The major
oxidative addition adduct 14 was isolated in 80% yield and its
identity was confirmed by X-ray crystallography.
Figure 4. 31P{1H} NMR studies on oxidative addition at Ni/PMe3
(reaction conditions = 2 h at room temperature in 1,4-dioxane).
Table 1. Ligand Effect on Selectivity of Oxidative
Addition.
Scheme 2. Chemoselective Oxidative Addition with PMe3.
Taken together, these stoichiometric studies indicate that
PMe3 and PPhMe2 are unique in providing good selectivity for
oxidative addition of aryl tosylates over aryl chlorides at Ni(0).
Catalytic Studies on Chemoselective Cross-coupling.
Trimethylphosphine was investigated as a ligand for a
chemoselective Ni-catalyzed Suzuki-Miyaura coupling of
chloroaryl tosylates. Initial conditions were modeled after
A variety of additional phosphine ligands were evaluated for
their effect on oxidative addition selectivity (Table 1). The
results show a trend that triarylphosphines strongly favor
reaction at chloride (entries 1–3), while most alkyl phosphines
give a mixture of products (entries 4–12). The best selectivity
for reaction at tosylate is obtained with PMe3 (entry 12), but
previously reported cross-couplings of aryl tosylates.8a,
24
Substrate 1, 4-methoxyphenylboronic acid (15), and K3PO4
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aGC yields calibrated against undecane as the internal standard.
were combined with Ni(cod)2 and PMe3 in 1,4-dioxane (Table
3). Excitingly, heating to 80 ºC led to formation of products 17
and 18 in about a 1:13 ratio favoring C—OTs cleavage (entry
1). However, the yield of 18 is fair and mass balance is poor
under these conditions. Moreover, PMe3 and Ni(cod)2 are both
highly air-sensitive, and PMe3 is a volatile liquid that is difficult
to measure accurately in small volumes. This latter feature of
PMe3 proved to be particularly problematic for reproducibility,
as the reaction outcome is sensitive to the PMe3/Ni(cod)2 ratio.
The best ratio is PMe3:Ni  2:1 (9-10 mol % of PMe3, entries 1
and 3), but a higher or lower ratio gives worse yield of 18 and/or
worse mass balance (entries 2, 4, and 5).
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Average of two runs. Small quantities of diarylation observed in all
cases (~3-10%). PMP = para-methoxyphenyl. bWith H2O (50 mol
%). cIsolated yield in parentheses. dSet up on benchtop. eWith 4 mol
% of the mono-THF adduct of precatalyst 22.
The generality of the Ni/PMe3 catalytic system was further
explored with a modest scope of boronic ester coupling partners
and chlorophenol derivatives (Table 4). Unsurprisingly, the
high selectivity for reaction at tosylate was unaffected by the
electronics of the arylboronic ester (entries 1-6), although in
some cases larger amounts of diarylated products were detected
(entries 1 and 6).27 High selectivity for reaction at tosylate was
retained using chloroaryl tosylates with different substitution
patterns (33 and 35). However, ortho-chlorophenyl tosylate 31
gives diarylation as the major product (32).28 4-Chlorophenyl
dimethylsulfamate and triflate also provide 18 as the major
product, resulting from oxidative addition of the C—O bond
(entries 8-9). A considerable amount of unproductive substrate
decomposition occurred when using the aryl triflate 30.29 An
aryl tosylate was successfully cross-coupled with a chloro-
substituted boronic ester (eq. 1). However, the attempted cross-
coupling of heteroaryl substrates or boronic esters was
unproductive and led to recovery of starting material or a
complex mixture of products (see SI).30 We anticipate that the
generality of this chemoselective cross-coupling can be
improved in the future by better understanding the mechanisms
of catalyst deactivation or conversion to less-selective catalytic
species.31
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For this reason, we synthesized the Ni(II) precatalyst 19. This
precatalyst ensures a phosphine:nickel ratio of 2:1. Use of 19
together with boronic ester 16 led to much better mass balance
and better reproducibility (entry 6). Finally, addition of a small
quantity of water (0.5 equiv) enabled high yield of 18 with
excellent mass balance (entry 7). Use of the chloride analogue
of the precatalyst (20) gave similar results (entry 8).25 The
reaction could be set up on the benchtop by using the semi-air-
stable precatalyst 21 and sparging the reaction mixture briefly
with N2 prior to heating, although the yield of 18 was somewhat
eroded (entry 9).26 For comparison, a variety of other phosphine
ligands were also evaluated in this catalytic system. Consistent
with the stoichiometric studies, PPhMe2 gave comparable
results to PMe3, albeit with slightly lower selectivity and yield
(entry 10). All other phosphines evaluated in this catalytic
reaction favored reaction at choride or gave poor selectivity
and/or yield (see SI).
Table 3. Optimization of a Chemoselective Suzuki-
Miyaura Cross-Coupling of 4-Chlorophenyl Tosylate.a
Computational Analysis of Selectivity Origin. Previous
examples of ligand-controlled chemoselective cross-coupling
have a mechanistic origin in the metal’s ligation state during
oxidative addition. Perhaps the best-studied example is the case
of Pd/phosphine-catalyzed Suzuki-Miyaura coupling of
chloroaryl triflates.32 In the coupling of 30, electron-rich
bisligated Pd(PCy3)2 prefers to react at C—OTf due to a
stronger attractive interaction energy in the transition state
(Figure 5A). In contrast, the less electron-rich monoligated
Pd(PtBu3) reacts at C—Cl due to lower distortion energy.32b
Ligation state is likely also the determining factor in other
examples of Pd-catalyzed chemodivergent cross-couplings of
chloro-33 or bromoaryl triflates.34 Very bulky monodentate
ligands which promote a monoligated active catalyst can favor
reaction at the halide, and bidentate or smaller monodentate
ligands that promote a bisligated catalyst favor reaction at
triflate. Similarly, bulky monodentate and bidentate phosphine
ligands can effect divergent selectivity between activation of
C(aryl)—O and C(acyl)—O bonds of aryl esters by Ni(0)
(Figure 5B).35 DFT studies suggest that this selectivity relates
entry [B]
[Ni]
PMe3
(mol%)
1 (%) 17
(%)
18
(%)
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4
5
6
7b
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16
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
19
10%
6%
9%
12%
15%
--
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to nickel’s coordination number by phosphine.35b,
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19
--
2
88
(72)c
8b
9b,d
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16
20
21
--
--
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2
3
83
21
61
(57)c
10b,e
16
22
--
9
5
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Table 4. Suzuki-Miyaura Cross-coupling of Chlorophenol Derivatives through Selective Cleavage of C—O Bonds.
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Figure 6. (A) Calculated NBO charges and HOMO energies for
optimized Ni(PR3)2 structures, (B) NBO charges at carbon in
Figure 5. Chemodivergent oxidative addition with selectivity
controlled by the metal’s ligation state.
chlorophenyl tosylate.39
One hypothesis to explain the divergent behavior between
In contrast, nickel’s ligation state is unlikely to be relevant to
PMe3 and PPh3 relates to the greater electron-donating character
the selectivity observed in the current chemodivergent
,
of PMe3.40 Nickel is calculated to be more negatively charged
when ligated by PMe3 than by PPh3 (Figure 6A). Furthermore,
Ni(PMe3)2 has a higher-energy HOMO than Ni(PPh3)2. Because
C—O bonds are more polarized than C—Cl bonds, the carbon
of C—OTs is more electrophilic (compare the charges at carbon
in Figure 6B). A more electron-rich Ni(PMe3)2 might be
expected to have a stronger attractive interaction at the more
electrophilic site (C—OTs). A similar argument has been used
to explain the divergent selectivity of mono- vs. bis-ligated
palladium in the cross-coupling of chloroaryl triflates (Figure
5A).32b However, this electronic explanation is unsatisfying in
system.37 38 PMe3 and PPh3 give opposite preferences for
reaction at tosylate and chloride, respectively, yet both are
monodentate and neither ligand is particularly bulky. DFT
calculations suggest that, for PMe3, PPh3, and PCy3, the lowest-
energy transition state for oxidative addition at C—Cl or C—
OTs involves bisphosphine-ligated nickel16 (moreover, a 2:1
ratio of phosphine to nickel was used in our experimental
studies). As such, it appears that selectivity in this system has a
different origin than prior examples of ligand-controlled
chemodivergent cross-coupling. We undertook further DFT
calculations to understand the unique selectivity preference of
Ni/PMe3.
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Figure 7. Oxidative addition transition structures using Ni(PMe)3 and Ni(PCy3)2. Most of the carbons and hydrogens of tosylate, as well as
the hydrogens on PCy3, are hidden for clarity (see SI for complete structures).
the current system when considering PCy3, which is usually
thought of as more electron-donating than either PPh3 or
PMe3.40 Ni(PCy3)2 has a higher-energy HOMO than PMe3 and
a more negatively-charged metal center, yet PCy3 effects only
poor selectivity between tosylate and chloride. As such, ligand
electronics are not sufficient to explain the unique selectivity
observed with PMe3, especially when compared to other
electron-rich alkyl phosphines like PCy3.
also electron-donating—albeit perhaps not as strongly as
PCy3—and it has the added advantage of minimal sterics. The
reason why small ligand size promotes reaction at tosylate is
because of the possibility for a close stabilizing interaction
between a sulfonyl S=O and Ni during the 5-centered transition
state (4a-TS). This interaction is also possible with PCy3 (37a-
TS), but it is less stabilizing due to a longer NiO=S distance
(2.52 vs. 2.33 Å). Apparently, PCy3 sterically shields nickel
from having a close interaction with oxygen. As a result, the 5-
centered mechanism with PCy3 is not more facile than the
dissociation mechanism. In contrast, the 5-centered mechanism
with PMe3 is about 3 kcal mol-1 lower in energy than both the
corresponding dissociation mechanism and the mechanism for
reaction at chloride.
To understand the difference between the behavior of PMe3
and PCy3, we more carefully examined the calculated oxidative
addition transition structures using these ligands (Figure 7).
With both of these ligands, insertion of Ni(0) into C—Cl
proceeds through a concerted 3-centered transition structure in
which nickel interacts with the departing chloride (3-TS and 38-
TS). In contrast, 3-centered concerted transition structures for
tosylate activation could not be located. Instead, C—O cleavage
occurs through a nucleophilic displacement mechanism: nickel
does not interact significantly with the departing oxygen.
During reaction at tosylate, nickel has a closer association with
the ortho carbon of the substrate: the NiCortho distances range
from 2.10–2.31 Å in the transition structures for oxidative
addition at C—OTs (4a-TS, 4b-TS, 37a-TS, and 37b-TS)
compared to 2.33-2.37 Å for reaction at C—Cl (3-TS and 38-
TS, NiCortho distances not labeled). Oxidative addition of
tosylate can occur through a conformation in which the S=O
bonds point away from nickel, referred to as a “dissociation”
mechanism (4b-TS and 37b-TS), or through a conformation in
which one of the sulfonyl oxygens interacts with nickel,
referred to as a “5-centered” mechanism41 (4a-TS and 37a-TS).
With PMe3, this NiO=S interaction results in a lower energy
structure compared to the dissociation mechanism. However,
with PCy3, the two mechanisms for reaction at tosylate are
energetically similar.
We conducted a distortion-interaction analysis on the
relevant PMe3- and PCy3-containing transition structures to
gather further evidence for the role of ligand sterics on
selectivity. This type of analysis, also called an activation-strain
analysis, involves dissecting the activation energy (∆E‡) into a
distortion (∆Edist) and an interaction term (∆Eint, Figure 8A).42
The distortion term is typically a positive value (unfavorable)
and represents the energy penalty for distorting the reactants
into the transition state geometry. The interaction term is
usually attractive (a negative value), and represents the
favorable interaction between substrate and catalyst due to
factors like orbital mixing, electron correlation, and coulombic
pairing of opposite charges. The relationship between distortion
and interaction is defined as ∆E‡ = ∆Edist + ∆Eint. Distortion and
interaction energies of the transition structures were measured
from the lowest-energy preceding π complexes.
The geometries and energetics of these transition structures
are consistent with a steric argument for the different selectivity
seen with PMe3 compared to PCy3. If reaction at tosylate is
desired, then PCy3 has the advantage of being more electron-
donating than PMe3 (see discussion above). However, PMe3 is
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A more negative value of ∆∆Eint indicates a more powerful
1
influence of interaction energy in favor of reaction at tosylate.
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If reaction at tosylate is desired, the dissociation mechanism
with Ni(PCy3)2 (37b-TS) has a larger distortion disadvantage
than either 5-centered mechanism 37a-TS or 4a-TS (compare
the values of ∆∆Edist in Table 5). This may be due to the larger
bending of tosylate out-of-plane of the arene in 37b-TS.
However, this bending also leads to a large interaction energy
advantage for the dissociation mechanism (∆∆Eint), likely due
to better orbital overlap between nickel’s HOMO and the C—
OTs * (the Ni–C–O bond angle is 117º in 37b-TS compared
to 107º in 37a-TS and 101º in 4a-TS). The effects of ∆∆Edist and
∆∆Eint nearly cancel each other out for 37b-TS, and this
dissociation mechanism for reaction at tosylate using PCy3 is
only slightly lower-energy than reaction at chloride. The 5-
centered mechanism with PCy3 (37a-TS) has a much smaller
distortion disadvantage than either 37b-TS or 4a-TS due to the
earliness of the transition structure 37a-TS.43 However, 37a-
TS also has less of an interaction energy advantage than the
corresponding transition structure using PMe3 (4a-TS). This is
because the stabilizing NiO=S interaction in 37a-TS is less
significant, as evidenced by the longer distance. In fact, when
the intrinsic reaction coordinate for 37a-TS is followed, the
NiO distance remains longer than that of 4a-TS until well
after the transition state (when the breaking COTs bond is
elongated to 2.55 Å). As a result, the effects of ∆∆Edist and
∆∆Eint again nearly cancel out and 37a-TS has a similar energy
barrier as that for reaction at chloride (38-TS). In contrast, the
Figure 8. (A) Definition of distortion and interaction energy. (B)
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Selectivity is determined by the difference in distortion energy
(∆∆Edist) and interaction energy (∆∆Eint) when comparing oxidative
addition at tosylate vs. chloride.
With both PCy3 and PMe3, reaction at tosylate involves
greater distortion energy than reaction at chloride (compare
total ∆Edist values in Table 5). This is due to greater distortion
of both the substrate and the catalyst. The substrate is more
distorted during reaction at tosylate because of nickel’s more
extensive interaction with the arene π system (both the ipso and
the ortho carbons) as well as distortion of several bond angles
in the departing tosylate group. The larger catalyst distortion
energies during reaction at tosylate reflect the more constrained
geometry of NiL2. During reaction at chloride, the ligands have
more room to spread out because Ni is further away from the
substrate aryl ring. In fact, the catalyst distortion energy is
actually slightly negative (favorable) during insertion of
Ni(PCy3)2 into C—Cl (38-TS), reflecting a relaxation of the P–
Ni–P bond angle in the TS compared to the preceding π
complex (122º in 38-TS vs. 115º in the corresponding π-
complex). Although distortion energy favors reaction at
chloride for both ligands, interaction energy strongly favors (is
more negative) reaction at tosylate. This can be rationalized by
(1) the stronger coulombic attraction between Ni and the
electron-deficient carbon of C—OTs and (2) the ability for
another oxygen of S=O to interact with Ni during a 5-centered
mechanism.
5-centered mechanism with Ni(PMe3)2 has
a stronger
interaction between Ni and O=S, resulting in a value of ∆∆Eint
for 4a-TS that outweighs the influence of distortion energy
(∆∆Edist) and makes reaction at tosylate more facile than
reaction at chloride.
CONCLUSION
Prior Ni-catalyzed Suzuki-Miyaura cross-couplings of non-
triflate phenol derivatives do not tolerate aryl chlorides, a
feature that limits their synthetic utility. We have shown that
DFT calculations accurately predict the following ligand trend
for reaction of tosylate over chloride at Ni(0): PMe3 > PCy3 >
PPh3. In stoichiometric studies evaluating a wider range of
phosphine ligands, we demonstrate that methylphosphines are
uniquely capable of promoting chemoselective oxidative
addition of aryl tosylates in the presence of aryl chlorides. Good
to excellent selectivity for reaction of aryl triflates, mesylates,
and sulfamates over aryl chlorides was also observed. This
selectivity was exploited to demonstrate proof-of-principle for
a C—O-selective Suzuki-Miyaura coupling of chlorinated non-
triflate phenol derivatives. We anticipate that a detailed
understanding of catalyst decomposition mechanisms will lead
to improvements to the scope of the catalytic process.
Table 5. Distortion-Interaction Analysis of Relevant PMe3-
and PCy3-Containing Transition Structures.
It appears that the unique behavior of methyl phosphines
compared to other phosphines does not relate to the catalyst’s
ligation state by ancillary ligands, and thus differs from prior
examples of ligand-controlled chemodivergent cross-couplings.
Computational analysis suggests that the unusual selectivity of
Ni(PMe3)2 for insertion into C—OTs is due to both electronic
and steric factors. In contrast to arylphosphines, the use of an
alkyl phosphine results in an electron-rich active catalyst that
can more effectively donate into the more electrophilic carbon
of C—OTs. Furthermore, the small size of PMe3 allows for a
close interaction between Ni and a sulfonyl oxygen of tosylate
during a 5-centered oxidative addition mechanism. This
Selectivity of oxidative addition depends on the differences
between the distortion and interaction energies for reaction at
the two possible sites. These differences are defined as ∆∆Edist
= ∆Edist(OTs) – ∆Edist(Cl) and ∆∆Eint = ∆Eint(OTs) – ∆Eint(Cl) (Figure
8B). ∆∆Edist is always a positive value, and a larger ∆∆Edist
signifies a more powerful influence of distortion energy in favor
of reaction at chloride. Conversely, ∆∆Eint is always negative.
7
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interaction helps to stabilize the buildup of positive charge at
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nickel during its oxidation from Ni(0) to Ni(II), and is less
significant with bulkier alkyl phosphines. Notably, the
differences observed between PMe3 and PCy3 caution against
relying on PMe3 as a computational model for more complex
alkylphosphines.
Reactions of Unreactive Phenolic Electrophiles via C–O Bond
Activation. Top. Curr. Chem. (Z) 2016, 374, 41; (d) Zarate, C.; van
Gemmeren, M.; Somerville, R.; Martin, R. Phenol Derivatives: Modern
Electrophiles in Cross-Coupling Reactions. In Advances in
Organometallic Chemistry; Pérez, P. J., Ed.; Elsevier, 2016, 66, 143–
122; (e) Zeng, H.; Qiu, Z.; Domínguez-Huerta, A.; Hearne, Z.; Chen,
Z.; Li, C.-J. An Adventure in Sustainable Cross-Coupling of Phenols
and Derivatives via Carbon−Oxygen Bond Cleavage. ACS Catal. 2017,
7, 510–519.
3. Nguyen, H. N.; Huang, X.; Buchwald, S. L. The First General
Palladium Catalyst for the Suzuki-Miyaura and Carbonyl Enolate
Coupling of Aryl Arenesulfonates. J. Am. Chem. Soc. 2003, 125,
11818–11819.
ASSOCIATED CONTENT
Supporting Information
9
The Supporting Information is available free of charge on the ACS
Publications website.
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Experimental and computational details, NMR spectra,
crystallographic details, and calculated energies (PDF). X-ray
crystallographic data for 14 (CIF). Cartesian coordinates of
minimum-energy calculated structures (XYZ).
4. Snieckus, V. Directed ortho metalation. Tertiary amide and O-
carbamate directors in synthetic strategies for polysubstituted
aromatics. Chem. Rev. 1990, 90, 879–933.
5. For examples, see Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu,
Z.; Zhang, Y. Transition metal-catalyzed C–H bond functionalizations
by the use of diverse directing groups. Org. Chem. Front. 2015, 2,
1107–1295.
AUTHOR INFORMATION
Corresponding Author
6. (a) Everson, D. A.; Jones, B. A.; Weix, D. J. Replacing
Conventional Carbon Nucleophiles with Electrophiles: Nickel-
Catalyzed Reductive Alkylation of Aryl Bromides and Chlorides. J.
Am. Chem. Soc. 2012, 134, 6146–6159; (b) Bajo, S.; Laidlaw, G.;
Kennedy, A. R.; Sproules, S.; Nelson, D. J. Oxidative Addition of Aryl
Electrophiles to a Prototypical Nickel(0) Complex: Mechanism and
Structure/Reactivity Relationships. Organometallics 2017, 36, 1662–
1672. (c) Huang, L.; Ackerman, L. K. G.; Kang, K.; Parsons, A. M.;
Weix, D. J. LiCl-Accelerated Multimetallic Cross-Coupling of Aryl
Chlorides with Aryl Triflates. J. Am. Chem. Soc. 2019, 141, 10978–
10983.
* sharon.neufeldt@montana.edu.
Present Addresses
†Department of Chemistry, Colorado State University, Fort
Collins, Colorado 80523.
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
7. In concurrent work, an exception was reported using a bipyridine
ligand for nickel during a cross-electrophile coupling: Kang, K.;
Huang, L.; Weix, D. J. Sulfonate Versus Sulfonate: Nickel and
Palladium Multimetallic Cross-Electrophile Coupling of Aryl Triflates
with Aryl Tosylates. J. Am. Chem. Soc. 2020, 142, 10634–10640.
8. (a) Zim, D.; Lando, V. R.; Dupont, J.; Monteiro, A. L.
NiCl2(PCy3)2: A Simple and Efficient Catalyst Precursor for the Suzuki
Cross-Coupling of Aryl Tosylates and Arylboronic Acids. Org. Lett.
2001, 3, 3049–3051; (b) Guan, B.-T.; Wang, Y.; Li, B.-J.; Yu, D.-G.;
Shi, Z.-J. Biaryl Construction via Ni-Catalyzed C—O Activation of
Phenolic Carboxylates. J. Am. Chem. Soc. 2008, 130, 14468–14470;
(c) Baghbanzadeh, M.; Pilger, C.; Kappe, C. O. Rapid Nickel-
Catalyzed Suzuki-Miyaura Cross-Couplings of Aryl Carbamates and
Sulfamates Utilizing Microwave Heating. J. Org. Chem. 2011, 76,
1507–1510; (d) Li, X.-J.; Zhang, J.-L.; Geng, Y.; Jin, Z. Nickel-
Catalyzed Suzuki−Miyaura Coupling of Heteroaryl Ethers with
Arylboronic Acids. J. Org. Chem. 2013, 78, 5078–5084; (e) Chen, L.;
Lang, H.; Fang, L.; Yu, J.; Wang, L. Nickel-Catalyzed Desulfitative
Suzuki–Miyaura Cross-Coupling of N,N-Disulfonylmethylamines and
Arylboronic Acids. Eur. J. Org. Chem. 2014, 6385–6389; (f) Chen, X.;
Ke, H.; Zou, G. Nickel-Catalyzed Cross-Coupling of Diarylborinic
Acids with Aryl Chlorides. ACS Catal. 2014, 4, 379–385; (g) LaBerge,
N. A.; Love, J. A. Nickel-Catalyzed Decarbonylative Coupling of Aryl
Esters and Arylboronic Acids. Eur. J. Org. Chem. 2015, 5546–5553;
(h) Piontek, A.; Ochedzan-Siodlak, W.; Bisz, E.; Szostak, M. Nickel-
Catalyzed C(sp2)—C(sp3) Kumada Cross-Coupling of Aryl Tosylates
with Alkyl Grignard Reagents. Adv. Synth. Catal. 2019, 361, 2329–
2336.
ACKNOWLEDGMENT
This work was supported by NSF CAREER (CHE-1848090) and
Montana State University. Calculations were performed on Comet
at SDSC through XSEDE (CHE-170089), which is supported by
NSF (ACI-1548562). NMR spectra were recorded on an instrument
funded by NSF (NSF-MRI:DBI-1532078) and the Murdock
Charitable
Trust
Foundation
(2015066:MNL).
X-ray
crystallographic data were collected at the University of Montana
X-ray diffraction core facility (NIH, CoBRE NIGMS
P20GM103546) using an instrument principally supported by NSF
(MRI CHE-1337908). We thank Daniel A. Decato for his
assistance in solving crystal structures. Troy Bearcomesout, Kayla
Creelman, Rosalia Martinez, Mike Giroux, and Emily K. Reeves
are gratefully acknowledged for early work. The authors thank
Steven M. Rehbein for synthesizing PMe3 during early stages of
the project.
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27. Interestingly, diarylation tended to be more problematic when
using older batches of Ni(II) precatalyst, even though the precatalysts
were stored in a glovebox at -25 ºC.
28. A time study indicated that the diarylation product is the major
product even early on in the reaction.
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about 40% GC yield of 18 with about 7:1 selectivity for reaction at
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13. Selective C—O cleavage of chloroaryl tosylates has been
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calculations were performed at the CPCM(1,4-dioxane)-MN15L/6-
311++G(2d,p)/SDD(Ni)//MN15L/6-31G(d)/6-
31+G(d)(Cl,O)/LANL2DZ(Ni) level of theory. See SI for details.
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with Aromatic Alkyl Ethers: An Efficient Synthesis of Unsymmetrical
Biaryls. Angew. Chem. Int. Ed. 2004, 43, 2428–2432; (d) Yang, X.;
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Widdowson, D. A.; Wilhelm, R. Palladium catalysed cross-coupling of
(fluoroarene)tricarbonylchromium(0) complexes. Chem. Commun.
1999, 2211–2212; (b) Wilhelm, R.; Widdowson, D. A.; Palladium
catalysed cross-coupling of (fluoroarene)tricarbonylchromium(0)
complexes. J. Chem. Soc., Perkin Trans. 1 2000, 3808–3813; (c)
Miller, J. A. C—C Bond activation with selective functionalization:
preparation of unsymmetrical biaryls from benzonitriles. Tetrahedron
33. Representative examples: (a) Proutiere, F.; Schoenebeck, F.
Solvent Effect on Palladium-Catalyzed Cross-Coupling Reactions and
Implications on the Active Catalytic Species. Angew. Chem. Int. Ed.
2011, 50, 8192–8195; (b) Reeves, E. K.; Humke, J. N.; Neufeldt, S. R.
N‐Heterocyclic
Carbene
Ligand-Controlled
Chemodivergent
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Suzuki−Miyaura Cross-coupling. J. Org. Chem. 2019, 84, 11799–
11812; (c) Reeves, E. K.; Bauman, O. R.; Mitchem, G. B.; Neufeldt, S.
R. Solvent Effects on the Selectivity of Palladium-Catalyzed Suzuki-
Miyaura Couplings. Isr. J. Chem. 2020, 60, 406–409.
34. Representative examples: (a) Kamikawa, T.; Hayashi, T.
Control of Reactive Site in Palladium-Catalyzed Grignard Cross-
Coupling of Arenes Containing both Bromide and Triflate.
Tetrahedron Lett. 1997, 38, 7087–7090; (b) Espino, G.; Kurbangalieva,
A.; Brown, J. M. Aryl bromide/triflate selectivities reveal mechanistic
divergence in palladium-catalysed couplings; the Suzuki–Miyaura
anomaly. Chem. Commun. 2007, 1742–1744; (c) Ansari, N. N.;
Cummings, M. M.; Söderberg, B. C. G. Chemoselectivity in the
Kosugi-Migita-Stille coupling of bromophenyl triflates and bromo-
nitrophenyl triflates with (ethenyl)tributyltin. Tetrahedron 2018, 74,
2547–2560.
35. (a) Amaike, K.; Muto, K.; Yamaguchi, J.; Itami, K.
Decarbonylative C−H Coupling of Azoles and Aryl Esters:
Unprecedented Nickel Catalysis and Application to the Synthesis of
Muscoride A. J. Am. Chem. Soc. 2012, 134, 13573–13576; (b)
Chatupheeraphat, A.; Liao, H.-H.; Srimontree, W.; Guo, L.; Minenkov,
Y.; Poater, A.; Cavallo, L.; Rueping, M. Ligand-Controlled
Chemoselective C(acyl)−O Bond vs C(aryl)−C Bond Activation of
Aromatic Esters in Nickel Catalyzed C(sp2)−C(sp3) Cross-Couplings.
J. Am. Chem. Soc. 2018, 140, 3724–3735.
36. Hong, Z.; Liang, Y.; Houk, K. N. Mechanisms and Origins of
Switchable Chemoselectivity of Ni- Catalyzed C(aryl)−O and
C(acyl)−O Activation of Aryl Esters with Phosphine Ligands. J. Am.
Chem. Soc. 2014, 136, 2017–2025.
37. Cis-chelating bidentate ligands provide poor yields in our hands;
see examples in Table S1 in the Supporting Information.
38. Another piece of evidence against ligation state being the
determining factor in selectivity is that several smaller phosphines—
albeit not as small as methylphosphines—that are unlikely to promote
mono-ligated nickel also give poor selectivity, similar to PCy3 (e.g.,
PEt3, PPhEt2, and PBu3; see Table 1).
39. Calculated at the CPCM(dioxane)-MN15L/BS2//MN15L/BS1
level of theory (see SI). The NBO charge at Ni in parentheses is from
NiL2 in the distorted geometry taken from the 5-centered C—OTs
oxidative addition transition structure.
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40. Tolman, C. A. Steric Effects of Phosphorus Ligands in
Organometallic Chemistry and Homogeneous Catalysis. Chem. Rev.
1977, 77, 313–348.
41. Uthayopas, C.; Surawatanawong, P. Aryl C–O oxidative
addition of phenol derivatives to nickel supported by an N-heterocyclic
carbene via a Ni0 five-centered complex. Dalton Trans. 2019, 48,
7817–7827.
42. Bickelhaupt, F. M.; Houk, K. N. Analyzing Reaction Rates with
the Distortion/Interaction-Activation Strain Model. Angew. Chem. Int.
Ed. 2017, 56, 10070–10086.
43. When analyzing a later point on the IRC where the C---O
distance is 2.06 Å, ∆∆Edist becomes very similar to that of the
dissociation mech (47.2 kcal mol-1; see Table S21).
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