Modifications to the Aryl Group of dppf-Ligated Ni σ-Aryl Precatalysts: Impact on Speciation and Catalytic Activity in Suzuki-Miyaura Coupling Reactions

Article abstract of DOI:10.1021/acs.organomet.8b00589

There is currently significant interest in the development of efficient nickel precatalysts for cross-coupling. In this work, 14 nickel(II) precatalysts of the form (dppf)Ni(aryl)(X) (dppf = 1,1′-bis(diphenylphosphino)ferrocene, X = Cl, Br) were synthesiz

Full text of DOI:10.1021/acs.organomet.8b00589

Article
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Cite This: Organometallics XXXX, XXX, XXX−XXX
Modifications to the Aryl Group of dppf-Ligated Ni σ‑Aryl
Precatalysts: Impact on Speciation and Catalytic Activity in Suzuki−
Miyaura Coupling Reactions
Megan Mohadjer Beromi, Gourab Banerjee, Gary W. Brudvig, David J. Charboneau, Nilay Hazari,*
Hannah M. C. Lant, and Brandon Q. Mercado
The Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520, United States
S
* Supporting Information
ABSTRACT: There is currently significant interest in the
development of efficient nickel precatalysts for cross-coupling.
In this work, 14 nickel(II) precatalysts of the form
(dppf)Ni(aryl)(X) (dppf = 1,1′-bis(diphenylphosphino)-
ferrocene, X = Cl, Br) were synthesized. In particular, both
the electronic and steric properties of the aryl group were
modified to understand how this affects precatalyst activation.
Using EPR spectroscopy, it was demonstrated that the
amount of off-cycle nickel(I) species which are formed via
comproportionation during precatalyst activation varies depending on the nature of the aryl group. For example, sterically bulky
aryl groups reduce comproportionation. Additionally, the catalytic activity of the family of precatalysts was evaluated in five
different Suzuki−Miyaura coupling reactions. The results from these catalytic studies provide information about how precatalyst
structure affects catalytic efficiency, which may be useful for the rational design of improved nickel precatalysts for cross-
coupling.
metal and as a consequence improves catalytic efficiency.
Additionally, there are practical advantages associated with
utilizing precatalysts, as they are typically bench stable and easy
to use in high-throughput experimentation methods, which can
aid in ligand screening or reaction optimization. Therefore, it is
likely that the design and development of nickel-based
precatalysts instead of in situ based systems will increase the
utility and efficiency of nickel-catalyzed cross-coupling
reactions.
To date there are relatively few examples of well-defined
bench-stable nickel precatalysts for cross-coupling reactions
(Scheme 1).8 One of the most popular and active families of
precatalysts comprises complexes of the type (L)Ni(aryl)(X),
where L is an ancillary ligand and X is a halide ligand (usually
Cl or Br).1j These complexes are typically air-stable solids that
can be synthesized readily from nickel(II) salts, which means
that, unlike other nickel precatalysts, an expensive nickel(0)
source, such as Ni(COD)2, is not required for their
preparation.9 Known aryl substituents for this precatalyst
scaffold include 1-naphthyl,10 4-trifluoromethylphenyl,11 4-
methoxyphenyl,12 phenanthryl,13 and anthracenyl13 ligands,
which are competent for Suzuki−Miyaura reactions and
Buchwald−Hartwig aminations. Additionally, Jamison and
co-workers recently described (L)Ni(aryl)(X) type precata-
lysts, which feature a pendant olefin on the aryl ligand.14 These
INTRODUCTION
■
Cross-coupling is one of the most powerful synthetic methods
and is commonly used to synthesize pharmaceuticals, agro-
chemicals, ligands for metal complexes, and precursors for
materials chemistry.1 In recent years, the development of
nickel-catalyzed cross-coupling reactions has attracted signifi-
cant interest.1j,2 In comparison to traditional cross-coupling
reactions, which use palladium catalysts, nickel-based systems
could provide cost-effective and sustainable alternatives.
Additionally, in some cases nickel catalysts can promote
reactivity that is not possible with palladium-based systems.
For example, nickel catalysts can promote reactions using sp3-
hybridized substrates3,4 and aryl ether and ester electrophiles.5
Nevertheless, despite the intense research aimed at developing
systems for nickel-catalyzed cross-coupling, in general these
reactions are hindered by the need for high catalyst loadings,
long reaction times, and elevated temperatures.1j,6 This can
limit the synthetic utility of nickel-catalyzed cross-coupling
reactions.
At this stage, the procedures for most nickel-catalyzed cross-
coupling reactions generate the catalytically active species by
mixing a nickel(II) salt or a nickel(0) precursor, such as
Ni(COD)2 (COD = 1,5-cyclooctadiene), with free ligand in
situ.2 In contrast, many modern procedures for palladium-
catalyzed cross-coupling use well-defined precatalysts, in which
the ligand is already bound to the metal.1h,j,7 The use of
precatalysts limits the formation of off-cycle species which
contain more than the desired number of ligands bound to the
Received: August 16, 2018
© XXXX American Chemical Society
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Scheme 1. Previous Examples of Ni(II) σ-Aryl Precatalysts and Summary of the Present Work
Scheme 2. Summary of Previous Work Exploring Comproportionation during the Activation Process To Form Catalytically
Inactive Nickel(I) Complexes
complexes activate via an intramolecular Heck reaction and are
active for carbonyl-ene coupling reactions. However, the most
common aryl group in precatalysts of the type (L)Ni(aryl)(X)
is an o-tolyl ligand. Precatalysts containing an o-tolyl ligand
have been used with both NHC and phosphine ligands, as well
as with recently developed ancillary ligands such as JosiPhos
and PAd-DalPhos.1j,9a,15 To date it has been demonstrated that
(L)Ni(o-tolyl)(X) precatalysts can facilitate Suzuki−Miyaura
coupling reactions with heteroaryl chloride and sulfamate
electrophiles,16 the benzylation of terminal alkenes,17 carbonyl-
ene reactions,9a and Buchwald−Hartwig amination reactions
with heteroaryl halide and pseudohalide substrates.15c,18
Additionally, this precatalyst scaffold is one of the few nickel-
containing precatalysts that can be used for rapid screening of
ancillary ligands when it is ligated by the more labile TMEDA
(TMEDA = N,N,N′,N′-tetramethylethylenediamine) ligand,
which can be substituted by a variety of monodentate and
bidentate phosphine and NHC ligands in situ.19
Ni(o-tolyl)(X) (dppf = 1,1′-bis(diphenylphosphino)ferrocene,
X = Cl, Br).16 We determined that, during the activation of the
precatalyst, there is a competing comproportionation process
between the active nickel(0) catalyst and unreacted nickel(II)
precatalyst that siphons nickel from the catalytic cycle in the
form of catalytically inactive nickel(I) species (Scheme 2).
Furthermore, in subsequent work, we isolated one of the
nickel(I) products and determined that the rate of
disproportionation, the reverse process to comproportionation
during activation, can be inhibited by increasing the steric bulk
on the aryl group of the nickel(I) species.20 On the basis of
these results, we hypothesized that we could control the extent
of comproportionation during precatalyst activation through
modification of the (dppf)Ni(aryl)(X) scaffold. Herein, we
have prepared 14 different compounds of the type (dppf)Ni-
(aryl)(X) with sterically and electronically diverse aryl groups.
The effects of the aryl group on both comproportionation and
catalytic performance in Suzuki−Miyaura reactions are
described. This work provides insight into the factors that
control speciation during the activation of the precatalyst,
which may lead to improved systems for nickel-catalyzed cross-
coupling.
Even though precatalysts of the type (L)Ni(o-tolyl)(X) are
often used in catalysis,1j there are relatively few detailed studies
exploring their activation.13c,b,16b Previously, we described
mechanistic studies on the nickel-catalyzed Suzuki−Miyaura
cross-coupling of aryl chlorides and sulfamates using (dppf)-
B
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Figure 1. Precatalysts examined in this work.
Supporting Information). The choice of bromide as the halide
ligand instead of chloride greatly simplified the synthesis of the
precatalysts, as arylmagnesium bromide reagents can easily be
prepared if they are not commercially available. Additionally,
the bromide ligand provides a useful handle for the
identification of paramagnetic bromide-containing species by
EPR spectroscopy, as bromide has two relatively abundant
spin-active isotopes (79Br, I = 3/2, 50% abundance; 81Br, I = 3/
2, 50% abundance) (vide infra). All precatalysts are stable over
several months as solids on the benchtop. It is noteworthy that
at least one ortho substituent is required on the aryl group to
generate species that are stable in solution and can be isolated.
We were unable to prepare (dppf)NiII(Ph)(Br), as the
transmetalation reaction between 17 and phenylmagnesium
bromide immediately resulted in the formation of a black,
intractable mixture. Similarly, synthesis of the chloride
analogue (dppf)NiII(Ph)(Cl) via oxidative addition of
chlorobenzene to a nickel(0) source is known to yield the
paramagnetic comproportionation product (dppf)NiICl (19-
Cl) instead of the desired nickel(II) complex.21 Furthermore,
the attempted preparation of (dppf)NiII(2-naphthyl)(Br) via
transmetalation resulted in the formation of an unstable
species, which suggests that meta and para substitution by itself
is not sufficient to generate stable σ-aryl precatalysts using this
ancillary ligand.
RESULTS AND DISCUSSION
■
Precatalyst Synthesis. Fourteen precatalysts of the form
(dppf)Ni(aryl)(X) containing aryl groups with different steric
and electronic properties were synthesized to compare with the
literature compounds 1-Cl, 1-Br, and 16 (Figure 1).9a,16b,20 In
our series of complexes, trends based on steric effects can be
assessed by comparing precatalysts 2, 3, 6, 11, 14, and 16.
Additionally, for most groups of precatalysts with similar steric
properties, representative complexes with both electron-
withdrawing and electron-donating substituents on the aryl
group were prepared; for example, within the family of 2,4-
substituted precatalysts a complex with an electron-deficient
aryl group, 8, and a complex with an electron-rich aryl group,
9, were synthesized for comparison with the parent complex 6.
Except for complex 7, the precatalysts were synthesized via
transmetalation of (dppf)NiBr2 (17) with the appropriate
arylmagnesium bromide Grignard reagent (Scheme 3a). These
reactions proceeded with modest to good yields (see the
Scheme 3. (a) Generic Synthesis of Precatalysts from
Transmetalation of 17 with Arylmagnesium Bromide
a
Grignard Reagents and (b) Synthesis of 7 via Oxidative
Addition of 2-Bromo-5-nitrotoluene to 18
Complex 7, which contains a 2-methyl-4-nitrophenyl ligand,
could not be synthesized using the Grignard-based route, as it
is not possible to prepare the appropriate Grignard reagent.
Instead, 7 was synthesized by oxidative addition of 2-bromo-5-
nitrotoluene to (dppf)Ni0(C2H4) (18) (Scheme 3b). In this
case, the oxidative addition reaction between the aryl halide
and the nickel(0) source is presumably fast enough to
outcompete comproportionation reactions between the nickel-
(II) product and unreacted starting material that generate
nickel(I) species. However, this is not a general phenomenon
(vide infra) and as a consequence this route cannot always be
used to prepare σ-aryl type precatalysts.
1
The H NMR spectra of the singly ortho substituted aryl
species 2−10 are not fluxional and are consistent with the
complexes having C1 symmetry. For example, they contain
eight distinct resonances for the cyclopentadienyl protons of
a
Specific reaction conditions for each precatalyst are given in the
Supporting Information.
C
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1
Figure 2. H NMR spectra of the region containing the cyclopentadienyl resonances for precatalyst 11 at (a) 25 °C and (b) −50 °C.
the dppf ligand at both room temperature and low temper-
ature. In contrast, the 1H NMR spectra of species 11 and 13−
16, containing symmetric diortho substitution on the aryl ring,
are fluxional (see Figure 2 for a representative example). In
these complexes, at room temperature one broad signal is
observed for both of the methyl groups in the ortho position of
the aryl ligand, whereas at low temperature, two distinct signals
are present. The peaks associated with the aromatic protons
directly bound to the aryl group are also broad at room
temperature but sharp at low temperature. We propose that
the fluxionality arises because of restricted rotation of the Ni−
Caryl bond, which is slow on the NMR time scale at low
temperature but rapid at room temperature. A consequence of
this restricted rotation is that at room temperature only four
broad, but distinct, resonances are present for the eight
cyclopentadienyl protons of the dppf ligand, whereas at low
temperature eight distinct signals are observed for these
protons. Effectively, the rapid rotation about the Ni−Caryl bond
renders the cyclopentadienyl protons C2 symmetric on the
NMR time scale. A special case of the restricted rotation occurs
in complex 12, which contains asymmetric diortho substitution
on the aryl ligand. At room temperature the 1H NMR
spectrum of 12 is broad and difficult to interpret. However, the
spectrum at −50 °C is sharp and contains twice the expected
number of signals, indicating that two chemically distinct
species are present. The ratio between the two species is
approximately 2:1. We propose that in this case restricted
rotation of the Ni−Caryl bond results in the presence of two
chemically distinct rotamers in solution due to the asymmetric
substitution of the aryl group. In complexes 11 and 13−16,
which contain symmetric diortho substitution on the aryl ring,
the corresponding rotamers are chemically equivalent and lead
to one set of resonances in the NMR spectrum. Consistent
with this hypothesis, the 31P NMR spectrum of 12 at −50 °C
contains two sets of doublets in approximately a 2:1 ratio due
to the presence of the rotamers. At room temperature, the 31P
NMR spectrum contains only two broad peaks, indicating that
interconversion between the rotamers is rapid on the NMR
time scale. The 19F NMR spectrum of 12 also shows a 2:1 ratio
of rotamers, and disorder resulting from the rotation of the aryl
group is observed in the solid-state structure, as determined by
X-ray crystallography (see the Supporting Information). Apart
from 12, the room-temperature 31P NMR spectra for all other
complexes contain two well-resolved resonances, consistent
with a cis-ligated dppf ligand with each phosphorus atom in a
different chemical environment (one phosphorus atom is trans
to the aryl group, while the other is trans to the bromide). For
complexes 1−3, 5−11, and 13−16, both of the resonances in
the 31P NMR spectra are doublets, while in the case of 4, one
of the phosphorus signals appears as a doublet of quartets due
to coupling to the trifluoromethyl group on the aryl ring.
X-ray-quality single crystals of complexes 2−8, 10, and 12−
14 were obtained either from concentrated solutions in THF
layered with pentane or concentrated solutions in dichloro-
methane layered with hexanes at −15 °C. In all cases the
structures indicate a square-planar coordination geometry
around the nickel center with a cis-ligated dppf ligand,
consistent with the symmetry indicated by 31P NMR
spectroscopy. Comparison of the structures of 4, 5, 6, 8, and
14 provides insight into the effect of varying the steric and
electronic properties of the aryl group on the precatalyst
structure (Figure 3). Complex 4 has an electron-withdrawing
trifluoromethyl group in the 2-position of the aryl group, while
complex 5 contains an electron-donating methoxy group in the
same position. Nevertheless, there is little difference in the
solid-state structures of the two complexes. The Ni−Caryl bond
lengths are the same within error, and the Ni−Ptrans (where
Ptrans denotes the phosphorus atom trans to the aryl group on
D
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Figure 3. ORTEP drawings of 4, 5, 6, 8, and 14. Thermal ellipsoids are shown at the 50% probability level. Hydrogen atoms and solvent of
crystallization have been omitted for clarity. Only one of the structures is shown in the case of 5, in which there are two independent molecules in
the unit cell.
the precatalyst) bond length of 4 is only an average of 0.015 Å
shorter than that of 5. Similarly, the structures of 6 and 8,
which have the same electron-withdrawing and -donating
substituents in the 4-position of the aryl ligand, are essentially
identical. In contrast, steric factors have a large influence on
the Ni−Caryl bond length, and in our series of complexes as the
steric bulk of the aryl group increases the Ni−Caryl bond length
increases (Table 1). For example, the Ni−Caryl bond length of
1.960(7) Å in 1620 is significantly longer than the Ni−Caryl
bond length of 1.906(6) Å in the next-smallest analogue, 14
(Table 1). While the Ni−Caryl bond length increases with
increasing steric bulk on the aryl ligand, the Ni−Ptrans bond
length decreases. A comparison of the bond lengths for Ni−
Caryl and Ni−Ptrans in 6 and 14 indicates that a lengthening of
approximately 0.02 Å occurs in Ni−Caryl with a subsequent
reduction in length of approximately 0.03 Å in Ni−Ptrans. The
exception to this trend is 16, where, presumably, the very bulky
ortho substitution prevents the shortening of Ni−Ptrans that
would otherwise coincide with the lengthening of Ni−Caryl
bond. There is also a trend in the size of the dppf bite angle as
the sterics on the aryl group increases. The most sterically
congested analogues, 14 and 16, have bite angles of
Table 1. Selected Bond Lengths and Angles of the
Crystallized Precatalysts
Species
Ni−Caryl (Å)
1.922(10)
Ni−Ptrans (Å)
P−Ni−P (deg)
102.02(1)
a
1-Cl
2.2874(3)
4
5
1.897(6)
1.896(18),
1.898(17)
2.2564(17)
2.274(6),
2.263(5)
101.39(6)
100.08(19),
100.09(19)
b
6
8
14
16
1.890(7)
1.891(9)
1.906(6)
1.960(7)
2.278(2)
2.280(3)
2.2460(17)
2.290(2)
102.54(8)
101.77(10)
100.11(6)
99.81(8)
c
a
b
Data obtained from ref 17. Two sets of geometric parameters are
included because there are two independent molecules in the unit cell.
c
Data obtained from ref 19.
approximately 100°, which is contracted by about 2° in
comparison to that of the less sterically hindered 6. All
synthesized analogues have bond and angle metrics that
deviate minimally from those seen in the state of the art
precatalyst 1-Cl.18
Speciation of Precatalysts during Activation via EPR
Spectroscopy. In Suzuki−Miyaura coupling reactions, it is
E
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Figure 4. Yields and in situ low-temperature, X-band EPR spectra for the reaction of naphthalen-1-yl sulfamate with 4-methoxyphenylboronic acid
catalyzed by precatalysts of the form (dppf)NiII(aryl)(Br).
proposed that activation of the σ-aryl precatalysts occurs
through transmetalation of the halide ligand with boronic acid
and base to generate a nickel(II) bis-aryl species.9a,16b This
nickel(II) bis-aryl species then reductively eliminates the biaryl
organic product to form a nickel(0) species, which enters the
catalytic cycle. We have previously shown that a competing
comproportionation reaction can occur between the zerovalent
nickel species and unreacted nickel(II) precatalyst to yield off-
cycle nickel(I) halide and aryl species, which lowers the
selectivity of activation (Scheme 2). To examine the selectivity
of precatalyst activation on the basis of the properties of the
aryl group, a selection of the precatalysts prepared in this work
were utilized in Suzuki−Miyaura reactions between naph-
thalen-1-yl sulfamate and 4-methoxyphenylboronic acid
(Figure 4). As the steric bulk on the aryl group increased,
there was a decrease in the yield of the cross-coupled product.
Control experiments suggest that this is due to a decrease in
the rate of activation as the size of the aryl group was increased.
For example, at room temperature only 34% of 16 was
activated in comparison to 87% for the standard 1-Br. When
the temperature was raised to 50 °C, 64% of 16 was activated,
and after 4 h a quantitative yield of cross-coupled product was
obtained. The effect of varying the electronic properties of the
aryl group on the yield of cross-coupled product is less
pronounced, as both the electron-deficient 8 and electron-rich
9 operate as efficiently in catalysis as the parent species 6.
Furthermore, there is only a slight difference (∼10%) in
precatalyst activation between 8 and 9nevertheless, catalytic
efficiency is not greatly affected by this difference in the
amount of activated nickel.
The tendency of the nickel(II) precatalysts to form nickel(I)
during activation was probed using EPR spectroscopy. When
the reaction between naphthalen-1-yl sulfamate and 4-
methoxyphenylboronic acid is catalyzed by 1-Br and 11
(Figure 4), we see clear evidence for the formation of
(dppf)NiIBr (19-Br) (by comparison of the EPR spectra of the
catalytic reaction mixtures with authentic 19-Br).16b This
strongly suggests that in these systems precatalyst activation is
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not selective and off-cycle nickel(I) species are formed. When
the same reaction is catalyzed by 6, 14, and 16, an EPR-active
species is detected. However, this species does not have
bromide hyperfine coupling and is not 19-Br, which indicates
that no significant quantity of nickel(I) is formed during
activation. Instead, the EPR spectra are consistent with the
formation of (dppf)NiI(sulfamate), which we have previously
characterized using EPR spectroscopy.16b This species forms as
a result of comproportionation during oxidative addition,
which is a well-documented process.16b,21,22 Furthermore, the
amount of nickel(I) formed in the cases of 14 and 16 is
significantly less than that of 6, suggesting that less nickel is in
an inactive form when the sterically bulky precatalysts are used.
These EPR results also indicate that electronic factors do not
have a drastic effect on the speciation of nickel during catalysis.
Electronically distinct precatalysts 8 and 9 appear to behave
similarly to that of their structural analogue 6that is, there is
no comproportionation occurring during the activation
process, and the only nickel(I) seen by EPR is (dppf)-
NiI(sulfamate). When these determinations are taken together,
it appears that ortho and para substitution is sufficient to
prevent comproportionation during the activation process,
regardless of the identity and size of the para substituent. Our
results indicate that, although increasing the steric bulk on the
aryl group increases the selectivity of activation by decreasing
the formation of nickel(I) species, it can result in less active
catalysts because the overall rate of precatalyst activation is
significantly slower. Furthermore, electronic factors appear to
minimally affect activation and speciation during catalysis for
the specific reaction examined in this set of experiments;
rather, the steric properties of the aryl group of the precatalysts
dictate speciation.
Catalytic Performance of the Full Precatalyst Family.
Given that steric and to a lesser extent electronic effects have
an effect on the yield of cross-coupled product for a
prototypical Suzuki−Miyaura reaction (vide supra), we
evaluated the catalytic performance of the full family of
precatalysts in a series of Suzuki−Miyaura coupling reactions
with different electrophiles and nucleophiles, as shown in
Figure 5a. The goal was to determine if a precatalyst could be
found that was generally superior to the commonly used 1-Cl.
The five different reactions all represent challenging Suzuki−
Miyaura reactions for nickel catalysts and were chosen to
evaluate different aspects of precatalyst performance. Reaction
A is a standard coupling reaction between naphthalen-1-yl
sulfamate, a substrate that readily undergoes oxidative addition,
and 4-methoxyphenylboronic acid, a nucleophile that is
relatively activated for transmetalation. It is the same reaction
we used to study precatalyst activation and connects our
activation studies with catalysis (vide supra). Variation in the
number of equivalents of boronic acid and base used in this
reaction (A′ and A′′) provides a method to evaluate the effect
of nucleophile concentration on the performance of the
precatalyst family. Reaction B differs from reaction A because a
more electron deficient boronic acid, 4-trifluoromethylphenyl-
boronic acid, is used. This allows us to assess the effect of a less
nucleophilic transmetalation partner, which could affect
precatalyst activation. The effect of a less nucleophilic
transmetalation reagent is also probed in reaction C; however,
in this system, a relatively activated chloride electrophile,
naphthalen-1-yl chloride, is employed. This system explores if
there are differences in relative precatalyst performance based
on use of a chloride electrophile in comparison to a sulfamate
electrophile. In reaction D, the effect of an electrophile, 4-
trifluoromethylphenyl sulfamate, which does not readily
undergo oxidative addition was evaluated, while in reaction E
the effect of heteroatoms on both the electrophile and
nucleophile are probed. The yields for each of the precatalysts
for all five reactions are presented in Figure 5b. It is
noteworthy that 1-Cl and 1-Br perform comparably in all
five reactions, indicating that the identity of the halide ligand
does not greatly affect catalytic activity. It also suggests that the
trends elucidated for our family of bromide-containing
precatalysts are also likely relevant for chloride-containing
systems.
The majority of the precatalysts evaluated gave the cross-
coupled product in 90% or greater yield for the standard
reaction A. This activity is comparable to that obtained with
the state of the art precatalysts 1-Cl and 1-Br. The exceptions
are precatalysts 7, 12, and 16, which performed poorly. In fact,
the poor performance of 7, 12, and 16 is general to all
reactions studied, except for reaction E (vide infra). In the
cases of precatalysts 12 and 16 yields of around 50% are
obtained in reaction A, and we propose that activation is
hindered by the steric bulk of the aryl groups, which lowers
catalytic efficiency. For 7, which contains a nitro substituent,
the reasons for the poor catalytic performance are unclear;
however, it is possible that the highly reactive nitro group may
undergo unproductive side reactions that cause decomposition
of the catalyst. For example, nickel(0) complexes are known to
undergo oxygen atom transfer reactions with nitro groups,
which, in this case, would siphon active nickel out of the
catalytic cycle.23 Further support for the hypothesis that the
nitro group interferes in catalysis is provided by an experiment
in which 1 equiv of 3-nitrotoluene (relative to the catalyst) is
added to reaction A catalyzed by 1-Br. In this case, no cross-
coupled product is formed (see the Supporting Information).
When the amounts of boronic acid and base are reduced to
1.5 and 2.5 equiv, respectively (reaction A′), all precatalysts
except 7, 12, and 16 formed the cross-coupled product in 80%
or greater yield, performing only slightly worse than in reaction
A. However, both precatalysts 12 and 16 produced only
approximately 10% yield in reaction A′, which is a 30−40%
lower yield in comparison with reaction A. When the amounts
of boronic acid and base are reduced even further to 1.05 and 2
equiv, respectively (reaction A′′), there are differences in the
efficiency of the precatalysts that had performed well in
reactions A and A′. Notably, five precatalysts still generated
cross-coupled product in 80% yield or greater: 2, 5, 9, 10, and
15. The yield of cross-coupled product in each of these cases is
significantly higher (∼15−20%) than that of 1-Cl and 1-Br,
highlighting their efficiency for this catalytic reaction. Although
there does not appear to be a common structural connection
among all five of these precatalysts, it is interesting to note that
all three of the methoxy-functionalized precatalysts 5, 9, and
15 evaluated are contained within this high-performing group.
The excellent performance of the methoxy-functionalized
precatalysts 5, 9, and 15 relative to other precatalysts in
reaction A′′ does not apply in the case of reaction B, in which
4-trifluoromethylphenylboronic acid was coupled with naph-
thalen-1-yl sulfamate. 5, 9, and 15 did not produce more than
30% of the cross-coupled product over 8 h, in comparison to
57% for the standard precatalyst 1-Cl. A potential explanation
for these results may be related to the relative difficulty in
transmetalating a nickel center containing an aryl ligand with
an electron-rich methoxy group with a relatively weakly
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Figure 5. (a) Reactions screened in this work. (b) Heat map of cross-coupled product yield as a function of precatalyst and reaction screened. The
values in the cells correspond to GC yields of cross-coupled product, reported as the average of at least two runs. The variability between runs was
typically between 0 and 10%. Specific conditions for each reaction are provided in the Supporting Information.
nucleophilic boronic acid.24 Consistent with this hypothesis,
complexes 2 and 10, which contain less electron rich aryl
groups, performed slightly better than 1-Cl, although this
difference (∼10% above 1-Cl) is much less pronounced than
the difference between methoxy-substituted species and 1-Cl
(20−40% below 1-Cl). Our results indicate that, when a
relatively deactivated boronic acid is used as the nucleophile, a
more electron deficient nickel center is preferable, most likely
because this leads to easier activation.
onic acid. In this reaction, two precatalysts achieved yields
significantly higher than that of 1-Clnamely, the 2,4,6-aryl-
substituted complexes 13 and 14. Given that reaction C
requires a long reaction time (16 h) and that 13 and 14 both
contain very large aryl groups, the increased efficiency of these
precatalysts may be related to the fact that a larger amount of
nickel likely enters the catalytic cycle. This is because systems
with more sterically bulky aryl groups form fewer off-cycle
nickel(I) complexes (vide supra). In a slower reaction the rate
of activation presumably becomes relatively less important and
the amount of nickel that eventually enters the catalytic cycle is
In reaction C, 1-chloronaphthalene was paired with a
relatively deactivated nucleophile, 4-trifluoromethylphenylbor-
H
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Figure 6. Yield of cross-coupled product for catalytic reactions in which reaction A was spiked with additional electrophile after 4 h. Reaction
conditions: 0.133 mmol of naphthalen-1-yl sulfamate, 0.333 mmol of 4-methoxyphenylboronic acid, 0.599 mmol of K3PO4, 0.00333 mmol of
precatalyst, 0.0665 mmol of naphthalene (internal standard), 1 mL of toluene. Catalysis was run for 4 h, after which another 0.133 mmol of
naphthalen-1-yl sulfamate in 500 μL of toluene was added. Reactions were run in duplicate, and yields are reported as the average of two runs.
Yields are reported relative to the total amount of electrophile added to the reaction.
more important. Nevertheless, with the most sterically bulky
precatalyst 16, almost no product is obtained. We suggest that
this is because the slow rate of precatalyst activation means
that a significant amount of nickel(0) is never generated in the
reaction. In general, for reaction C, apart from the almost
universally poorly performing 7, 12, and 16 and the high
performance of 12 and 13, all other precatalysts gave
comparable performance. This includes the methoxy-function-
alized precatalysts 5, 9, and 15.
experiment lasted 8 h in total), after which the yield of cross-
coupled product was analyzed (Figure 6). This experiment was
conducted using precatalysts 1-Br, 6, 11, 14, and 16, which are
similar electronically but have different steric properties. The
bulkiest precatalyst, 16, is able to produce the highest total
yield of cross-coupled product after spiking, in contrast to our
original results from reaction A. In fact, the yield of cross-
coupled product in the reaction catalyzed by 16 is
approximately 20% higher than that of any of the other
precatalysts tested. These data are consistent with our model in
which 16 is activated more slowly and does not compropor-
tionate, leaving more unreacted precatalyst available in the
second 4 h to activate and couple the freshly added
electrophile. In contrast, the relatively small precatalysts are
proposed to activate rapidly during the first 4 h and undergo
significant decomposition, leaving no viable catalyst to couple
the additional electrophile added in the second segment.
Overall, there are several conclusions that can be made on
the basis of our catalytic data. (1) None of the aryl ligands
tested in this work are more efficient than the o-tolyl ligand in
the state of the art 1-Cl/Br system across the entire suite of
catalytic reactions performed. (2) The performance of each
precatalyst is reaction-dependent; this is exemplified, for
example, in the nature of the nucleophile having a drastic
effect on the performance of the methoxy-substituted species
(reaction A versus reaction B) and the fact that the use of
heteroaryls as the electrophile and nucleophile (reaction E)
resulted in similar performance from all precatalysts, even
those that did not work for previous reactions. Additionally,
attempts to correlate the performance of our precatalyst family
with quantifiable properties, such as percent buried volume26
or Hammett parameters,27 did not lead to meaningful
associations (see the Supporting Information). (3) As
indicated by the results from reaction C, it may be
advantageous to use bulkier precatalysts for more challenging
reactions where the rates of the elementary steps are slower. In
these reactions, the fact that more sterically bulky precatalysts
form fewer off-cycle nickel(I) species is more important than
the fact that they also activate more slowly. However, at this
stage there is a tradeoff between rapid activation and the
selectivity of activation. Unfortunately, our results suggest that
it is unlikely that there is a “universal” aryl ligand which is
optimal for all reactions; rather, within a given set of design
rules (for example, sterically bulky aryl ligands result in slower
activation) the aryl group may need to be optimized on a case
In reaction D, an electrophile that is difficult to oxidatively
add, 4-trifluoromethylphenyl sulfamate, was coupled with an
electron-rich boronic acid, 4-methoxyphenylboronic acid. For
this reaction all precatalysts performed poorly. The only
precatalyst able to achieve greater than a 50% yield of cross-
coupled product was 1-Cl. There are no obvious trends in the
performance of other precatalysts, and the exact reasons 1-Cl
gives better activity are unclear. The results from reaction E are
perhaps the most surprising. In this case all precatalysts gave
approximately 35% yield, even the precatalysts that were
unable to catalyze reactions A−D. One explanation for these
results may be that the presence of coordinating heteroatoms
generates common intermediates that undergo slow elemen-
tary steps; this scenario negates any differences in the rates of
activation that arise from different structural features on the
precatalyst. For example, pyridyl electrophiles are known to
generate off-cycle, pyridyl-bridged Ni(II) dinuclear complexes
in Buchwald−Hartwig amination reactions after oxidative
addition.25 In this reaction, the 2-chloroquinoline electrophile
may result in similar off-cycle species and the catalytic activity
may be governed by the rate at which this off-cycle species,
which will be the same regardless of the initial structure of the
precatalyst, re-enters the catalytic cycle.
In several of our test reactions, we hypothesize that the
differences in yields are related to the rate at which a
precatalyst activates and the amount of unproductive
comproportionation that occurs. For reactions requiring longer
reaction times, we propose that bulkier precatalysts may be
superior because they activate more slowly and do not undergo
as much comproportionation during activation, resulting in an
increased lifetime in catalysis. To probe the lifetime of the
active catalyst as a function of the steric bulk of the precatalyst,
we devised a spiking experiment. In this experiment, we
performed reaction A as previously described but then added
an additional 1 equiv of electrophile after 4 h. The reaction was
then allowed to proceed for another 4 h (so that the
I
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Article
and 13C NMR spectra and 31P{1H} NMR spectra are referenced via
the 1H resonances based on the relative gyromagnetic ratios. Gas
chromatography was performed on a ThermoFisher Trace 1300 GC
apparatus equipped with a flame ionization detector and a Supelco
fused silica capillary column (5 Å molecular sieves, 30 m × 0.53 mm)
using the following parameters: flow rate 1.23 mL/min constant flow,
column temperature 50 °C (held for 5 min), 20 °C/min increase to
300 °C (held for 5 min), total time 22.5 min. GC yields were
calculated on the basis of calibration curves generated using the
independently synthesized biaryl product of interest. Naphthalen-1-yl
sulfamate and 4-trifluoromethylphenyl sulfamate were prepared
according to literature procedures.29 1-Cl,9a 1-Br,9a and 1620 were
prepared following literature procedures. X-band EPR spectra were
recorded on a Bruker ELEXSYS E500 EPR spectrometer equipped
with an SHQ resonator and an Oxford ESR-900 helium-flow cryostat
with the following settings: microwave frequency, 9.4 GHz;
modulation frequency, 100 kHz; modulation amplitude, 10 G;
sweep time, 84 s; conversion time, 41 ms; time constant, 20 ms.
One millimolar solutions of the samples of interest were prepared in
the glovebox using toluene for a total of 200 μL of solution per tube.
The tubes were sealed in the glovebox and immediately frozen in
liquid nitrogen. Robertson Microlit Laboratories, Inc., performed the
elemental analyses (inert atmosphere).
General Procedure for the Synthesis of Nickel(II) Precata-
lysts via Transmetalation. All compounds, except for 7, were
synthesized by modification of the previously described literature
method for the preparation of 1-Br.9a,16b (dppf)NiBr2 (17; 100 mg,
0.129 mmol) was placed in a 100 mL Schlenk flask containing a stir
bar. A 10 mL portion of THF was cannula-transferred into the flask,
and the contents were stirred until dissolution. The flask was cooled
to 0 °C in an ice bath, after which the appropriate arylmagnesium
bromide Grignard reagent (0.129 mmol) was added dropwise using a
gastight syringe. The solutions turned from dark green to orange in all
cases by the end of the addition. The flask was warmed to room
temperature, after which the THF was removed under vacuum to
yield an orange residue. A 5 mL portion of methanol was placed in the
flask, and the heterogeneous mixture was sonicated for 3 min until a
uniform suspension was obtained. The flask was cooled in an ice bath
for 15 min, and the resulting bright yellow solid was isolated by
vacuum filtration and analyzed by 1H, 31P, 13C, and 19F (if applicable)
NMR spectroscopy as well as elemental analysis. The synthesis of 7 is
detailed in the Supporting Information, along with characterization
data and yields for compounds 1−6 and 8−15.
Crystallographic Information. Single crystals of precatalysts
were grown from a concentrated THF solution layered with pentane
or a concentrated dichloromethane solution layered with hexanes at
−15 °C. Low-temperature diffraction data (ω-scans) were collected
on a Rigaku SCX Mini diffractometer coupled to a Rigaku
Mercury275R CCD with Mo Kα radiation (λ = 0.71073 Å). The
diffraction images were processed and scaled using Rigaku CryAlisPro
software.30 The structure was solved with SHELXT and was refined
against F2 on all data by full-matrix least squares with SHELXL.31 All
non-hydrogen atoms were refined anisotropically. Hydrogen atoms
were included in the model at geometrically calculated positions and
refined using a riding model. The isotropic displacement parameters
of all hydrogen atoms were fixed to 1.2 times the U value of the atoms
to which they are linked (1.5 times for methyl groups). See the
Supporting Information for more information about the structures
solved in this work.
General Procedure for EPR Spectroscopy. A stock solution
containing naphthalen-1-yl sulfamate (0.266 mmol), naphthalene
(0.133 mmol), and precatalyst (2.5 mol %, 0.00665 mmol) in 2 mL of
toluene was prepared. 4-Methoxyphenylboronic acid (50.0 mg, 0.333
mmol) and K3PO4 (127.2 mg, 0.599 mmol) were weighed into a 1
dram vial containing a stir bar. A 1 mL portion of the stock solution
was placed via micropipet in the vial. The vial was tightly capped and
removed from the glovebox. The vial was then placed in an aluminum
heating block with a thermocouple at room temperature, and the
contents were stirred for 4 h. In order to record an EPR spectrum, 61
μL of the reaction mixture was removed from the catalytic reaction in
by case basis for each individual reaction. Furthermore, in
many cases significant improvements in catalyst performance
will not be possible by changing the aryl ligand.
CONCLUSIONS
■
In this work we have prepared a family of precatalysts for cross-
coupling of the form (dppf)Ni(aryl)(Br) with electronically
and sterically diverse aryl groups. In most cases these species
can be formed readily through the reaction of (dppf)NiBr2
with the appropriate Grignard reagent. Studies using EPR
spectroscopy indicate that the nature of the aryl group
influences the selectivity of precatalyst activation in a
prototypical Suzuki−Miyaura reaction. More sterically bulky
systems are less likely to form off-cycle nickel(I) species;
however, there is a tradeoff, as these precatalysts activate more
slowly, which can lead to a less efficient catalytic system. When
the performance of our family of precatalysts was compared for
a diverse variety of Suzuki−Miyaura reactions, general trends
which indicate that a particular aryl group is more desirable
than another were not observed. In fact, our results show that
precatalyst performance is highly variable depending on the
nature of both the electrophile and nucleophile and that
precatalysts which give poor performance in comparison to
other systems with one set of substrates can give very good
performance with a different set of substrates. For example,
precatalysts containing a more sterically bulky aryl group are
generally better for substrates which undergo slow elementary
reactions because they increase the amount of nickel that is in
an active form during catalysis. However, they are less desirable
for substrates which undergo rapid elementary steps because
they activate slowly. Given the complex dependence of
precatalyst performance on the nature of the aryl group and
our inability to find a universally better system, we conclude
that the original 1-Cl/Br system is an excellent choice for
initial investigations aimed at finding a precatalyst to perform a
particular reaction, especially given its commercial availabili-
ty.5b,28 If further optimization of a reaction is required,
modifying the aryl group of 1-Cl/Br could lead to an improved
system, but in most cases it will be difficult to predict which
modification will result in better performance. It is also unclear
if the results described in this work will be general to
precatalysts containing other ancillary ligands, for example if
the ancillary ligand is changed to bipyridine instead of dppf,
and further research is required to address this issue.
EXPERIMENTAL SECTION
■
General Methods. Experiments were performed under an
atmosphere of dinitrogen in an MBraun glovebox or using standard
Schlenk techniques, unless specified otherwise. Purging of the
glovebox atmosphere was not performed between uses of pentane,
benzene, toluene, diethyl ether, and THF; as such, trace amounts of
the solvents may have been present in the box atmosphere and
intermixed in the solvent bottles. All chemicals were used as received
unless otherwise stated. Air- or moisture-sensitive liquids were
transferred using stainless steel cannulas on a Schlenk line or in a
glovebox. Solvents were dried via passage through a column of
activated alumina and subsequently stored under dinitrogen.
Deuterated solvents were obtained from Cambridge Isotope
Laboratories. Powdered K3PO4 was purchased from Acros Organics,
finely ground using a mortar and pestle, heated in an oven at 120 °C
for at least 24 h, and stored in a glovebox. NMR spectra were
recorded on Agilent 400, 500, and 600 MHz spectrometers at ambient
probe temperatures unless otherwise stated. Chemical shifts are
reported in ppm with respect to residual internal protio solvent for 1H
J
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Article
a glovebox and placed in an EPR tube along with 139 μL of toluene.
The tube was sealed, removed from the glovebox, and immediately
frozen in liquid nitrogen. The EPR spectrum was then recorded. The
presence of bromide-ligated nickel(I) species was verified by the
septet hyperfine splitting pattern in g⊥.
Accession Codes
CCDC 1860562−1860572 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
General Procedure for Catalysis for Reactions A, A′, A′′, B,
and D. A stock solution containing aryl sulfamate (0.266 mmol),
naphthalene (0.133 mmol), and precatalyst (2.5 mol %, 0.00665
mmol) in 2 mL of toluene was prepared. Boronic acid and K3PO4
were weighed into a 1 dram vial containing a stir bar. A 1 mL portion
of the stock solution was placed via micropipet in the vial. The vial
was tightly capped and removed from the glovebox. The vial was then
placed in an aluminum heating block with a thermocouple at room
temperature, and the contents were stirred for the appropriate amount
of time. In order to prepare a GC sample, the reactions were
quenched by exposure to air, after which 100−200 μL of the reaction
mixture was placed on an ∼5 cm plug of silica and eluted with ethyl
acetate. The yield of cross-coupled product was determined by gas
chromatography, referenced to the naphthalene internal standard. All
reactions were performed in duplicate, and the reported yields are the
average of two runs.
General Procedure for Catalysis for Reactions C and E. A
stock solution containing aryl chloride (0.4 mmol), naphthalene (0.2
mmol), and precatalyst (2.5 mol %, 0.01 mmol) in 680 μL of 1,4-
dioxane and 320 μL of benzene was prepared. Boronic acid (0.4
mmol, 2 equiv) and K3PO4 (0.8 mmol, 4 equiv) were weighed into a 1
dram vial containing a stir bar. A 500 μL portion of the stock solution
was placed via micropipet in the vial. The vial was tightly capped and
removed from the glovebox. The vial was then placed in an aluminum
heating block with a thermocouple at room temperature, and the
contents were stirred for the appropriate amount of time. In order to
prepare a GC sample, the reactions were quenched by exposure to air,
after which 50−100 μL of the reaction mixture was placed on an ∼5
cm plug of silica and eluted with ethyl acetate. The yield of cross-
coupled product was determined by gas chromatography, referenced
to the naphthalene internal standard. All reactions were performed in
duplicate, and the reported yields are the average of two runs.
General Procedure for Spiking Experiments. A stock solution
containing naphthalen-1-yl sulfamate (66.6 mg, 0.266 mmol),
naphthalene (16.8 mg, 0.133 mmol, 0.5 equiv), and precatalyst (2.5
mol %, 0.00665 mmol) in 2 mL of toluene was prepared. 4-
Methoxyphenylboronic acid (49.9 mg, 0.333 mmol, 2.5 equiv) and
K3PO4 (127.2 mg, 0.599 mmol, 4.5 equiv) were weighed into a 1
dram vial containing a stir bar. A 1 mL portion of the stock solution
was placed via micropipet in the vial. The vial was tightly capped and
removed from the glovebox. The vial was then placed in an aluminum
heating block with a thermocouple at room temperature, and the
contents were stirred for 4 h. Another stock solution was prepared,
containing naphthalen-1-yl sulfamate (66.6 mg, 0.266 mmol) in 1 mL
of toluene. After 4 h, the vial was brought back into the glovebox, after
which 500 μL of the stock solution containing only naphthalen-1-yl
sulfamate was added. The vial was capped tightly and removed from
the glovebox, and the contents were stirred in the aluminum heating
block at room temperature for another 4 h. In order to prepare a GC
sample, the reactions were quenched by exposure to air, after which
50−100 μL of the reaction mixture was placed on an ∼5 cm plug of
silica and eluted with ethyl acetate. The yield of cross-coupled
product was determined by gas chromatography, referenced to the
naphthalene internal standard. All reactions were performed in
duplicate, and the reported yields are the average of two runs.
AUTHOR INFORMATION
Corresponding Author
*E-mail for N.H.: nilay.hazari@yale.edu.
■
ORCID
Gary W. Brudvig: 0000-0002-7040-1892
Nilay Hazari: 0000-0001-8337-198X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
N.H. acknowledges support from the NIHGMS under Award
Number R01GM120162. M.M.B. thanks the NSF for support
as an NSF Graduate Research Fellow. The EPR spectroscopy
work was supported by the Department of Energy, Office of
Basic Energy Sciences, Division of Chemical Sciences grant
DE-FG02-05ER15646 (H.M.C.L., G.B., and G.W.B.). N.H. is a
Camille and Henry Dreyfus Foundation Teacher Scholar.
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* Supporting Information
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