Mechanistic study of an improved Ni precatalyst for Suzuki-Miyaura reactions of aryl sulfamates: Understanding the role of Ni(I) species

Article abstract of DOI:10.1021/jacs.6b11412

Nickel precatalysts are potentially a more sustainable alternative to traditional palladium precatalysts for the Suzuki-Miyaura coupling reaction. Currently, there is significant interest in Suzuki-Miyaura coupling reactions involving readily accessible phenolic derivatives such as aryl sulfamates, as the sulfamate moiety can act as a directing group for the prefunctionalization of the aromatic backbone of the electrophile prior to cross-coupling. By evaluating complexes in the Ni(0), (I), and (II) oxidation states we report a precatalyst, (dppf)Ni(σ-tolyl)(Cl) (dppf = 1,1'-bis(diphenylphosphino)-ferrocene), for Suzuki-Miyaura coupling reactions involving aryl sulfamates and boronic acids, which operates at a significantly lower catalyst loading and at milder reaction conditions than other reported systems. In some cases it can even function at room temperature. Mechanistic studies on precatalyst activation and the speciation of nickel during catalysis reveal that Ni(I) species are formed in the catalytic reaction via two different pathways: (i) the precatalyst (dppf)Ni(σ-tolyl)(Cl) undergoes comproportionation with the active Ni(0) species; and (ii) the catalytic intermediate (dppf)Ni(Ar) (sulfamate) (Ar = aryl) undergoes comproportionation with the active Ni(0) species. In both cases the formation of Ni(I) is detrimental to catalysis, which is proposed to proceed via a Ni(0)/Ni(II) cycle. DFT calculations are used to support experimental observations and provide insight about the elementary steps involved in reactions directly on the catalytic cycle, as well as off-cycle processes. Our mechanistic investigation provides guidelines for designing even more active nickel catalysts.

Full text of DOI:10.1021/jacs.6b11412

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Article
Mechanistic Study of an Improved Ni Precatalyst for Suzuki-Miyaura
Reactions of Aryl Sulfamates: Understanding the Role of Ni(I) Species
Megan Mohadjer Beromi, Ainara Nova, David Balcells, Ann M. Brasacchio,
Gary W. Brudvig, Louise M Guard, Nilay Hazari, and David J. Vinyard
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b11412 • Publication Date (Web): 23 Dec 2016
Downloaded from http://pubs.acs.org on December 25, 2016
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Mechanistic Study of an Improved Ni Precatalyst for Suzuki-Miyaura
Reactions of Aryl Sulfamates: Understanding the Role of Ni(I) Species
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Megan Mohadjer Beromi,a Ainara Nova,b David Balcells,b,* Ann M. Brasacchio,a Gary W.
Brudvig,a Louise M. Guard,a Nilay Hazari a,* and David J. Vinyarda
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aThe Department of Chemistry, Yale University, P. O. Box 208107, New Haven, Connecticut,
06520, USA; bCentre for Theoretical and Computational Chemistry (CTCC), Department of
Chemistry, University of Oslo, P. O. Box 1033, Blindern, 0315 Oslo, Norway. E-mail:
david.balcells@kjemi.uio.no, nilay.hazari@yale.edu
Abstract
Nickel precatalysts are potentially a more sustainable alternative to traditional palladium
precatalysts for the Suzuki-Miyaura coupling reaction. Currently, there is significant interest in
Suzuki-Miyaura coupling reactions involving readily accessible phenolic derivatives such as aryl
sulfamates, as the sulfamate moiety can act as a directing group for the prefunctionalization of
the aromatic backbone of the electrophile prior to cross-coupling. By evaluating complexes in
the Ni(0), (I), and (II) oxidation states we report a precatalyst, (dppf)Ni(o-tolyl)(Cl) (dppf = 1,1'-
bis(diphenylphosphino)ferrocene), for Suzuki-Miyaura coupling reactions involving aryl
sulfamates and boronic acids, which operates at significantly lower catalyst loading and at milder
reaction conditions than other reported systems. In some cases it can even function at room
temperature. Mechanistic studies on precatalyst activation and the speciation of nickel during
catalysis reveal that Ni(I) species are formed in the catalytic reaction via two different pathways:
(i) the precatalyst (dppf)Ni(o-tolyl)(Cl) undergoes comproportionation with the active Ni(0)
species; and (ii) the catalytic intermediate (dppf)Ni(Ar)(sulfamate) (Ar = aryl) undergoes
comproportionation with the active Ni(0) species. In both cases the formation of Ni(I) is
detrimental to catalysis, which is proposed to proceed via a Ni(0)/Ni(II) cycle. DFT calculations
are used to support experimental observations and provide insight about the elementary steps
involved in reactions directly on the catalytic cycle, as well as off-cycle processes. Our
mechanistic investigation provides guidelines for designing even more active nickel catalysts.
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Introduction
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The Suzuki-Miyaura cross-coupling (SMC) reaction is regarded as one of the most versatile and
powerful methods to construct C˗C bonds.1 While palladium based catalysts have traditionally
been employed for SMC reactions,2 recent efforts have focused on the development of nickel-
catalyzed methods as cost effective and sustainable alternatives.3 Additionally, nickel catalysts
exhibit unique chemical reactivity as they can often couple electrophiles that are unreactive in
SMC reactions using palladium systems such as aryl nitriles,4 aryl trimethylammonium salts,5 N-
acyliminium and quinolinium ions,6 aryl fluorides7 and sp3-based electrophiles.8 In particular,
phenol-derived substrates, which are robust and easy to synthesize from ubiquitous phenols, are
an interesting class of electrophile where nickel catalysts provide superior activity compared to
palladium systems.3a,9 Substrates containing aryl carbamates and sulfamates are especially
attractive,10 as these moieties can act as directing groups for the prefunctionalization of the
aromatic backbone of the electrophile prior to cross-coupling.11 This concept has been elegantly
utilized by Garg et al. in the synthesis of the anti-inflammatory drug flurbiprofen via a nickel-
catalyzed SMC reaction.10c Unfortunately, the current methodology for nickel-catalyzed SMC
reactions of aryl carbamates and sulfamates is limited by the use of high catalyst loadings and
harsh reaction conditions.10 In fact, the only SMC reactions involving aryl sulfamates that occur
at room temperature use neopentylglycolboronates, which are not commercially available,
instead of boronic acids, and require catalyst loadings ranging from 5-10 mol%.10d,10g,10j,10l
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The rational design of improved catalytic systems for the coupling of aryl sulfamates is difficult
due to the paucity of mechanistic information about precatalyst activation, the nature of the
active species during catalysis and the catalyst resting state.10c In fact, in general, there is
considerably less knowledge about these important aspects of catalysis for nickel based cross-
coupling reactions compared to palladium systems.2,3c,12 Several different catalytic cycles have
been proposed for nickel-catalyzed cross-coupling reactions including: (i) a traditional Ni(0)/(II)
cycle in which oxidative addition precedes transmetallation and reductive elimination,3c,10c (ii) a
Ni(I)/(III) cycle with steps analogous to the traditional (0)/(II) cycle,13 or (iii) radical pathways
which access Ni(0)/(I)/(II)/(III) species, with not all necessarily being catalytically active.14
Recently,
we
reported
preliminary
studies
into
the
speciation
of
1,1'-
bis(diphenylphosphino)ferrocene (dppf) supported nickel catalysts during SMC reactions using
aryl chlorides as substrates.15 Notably, we demonstrated that a catalytically active Ni(I) species
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forms during the reaction regardless of the starting oxidation state of the nickel precatalyst and is
the predominant species at the conclusion of the reaction (Figure 1). However, although we
proposed that the Ni(I) complex forms from comproportionation between Ni(0) and Ni(II)
species, which are present in the reaction mixture, the elementary steps involved in the formation
of Ni(I) complexes were not elucidated. Furthermore, the specific role of the catalytically active
Ni(I) complex in the reaction was not clarified; we were unable to conclude whether it was an
off-cycle species or a species directly on the catalytic cycle. As a result it was still unclear if
Ni(I) formation should be promoted or inhibited to increase catalytic activity.
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Figure 1. Precatalysts in the Ni(0), Ni(I) and Ni(II) oxidation state are all catalytically active for the SMC reaction with
aryl chlorides. All precatalysts form a significant amount of a catalytically active Ni(I) species during the reaction.15
Here, we present a comprehensive study into nickel-catalyzed SMC reactions with aryl sulfamate
substrates. From a synthetic perspective, by evaluating complexes in the Ni(0), (I), and (II)
oxidation states, we report a precatalyst that operates at a lower catalyst loading and at milder
reaction conditions than other reported systems for SMC reactions involving sulfamates.10c,10a In
some cases, it can even function at room temperature with boronic acid coupling partners. From
a mechanistic perspective, we provide strong evidence that the formation of Ni(I) complexes,
which occurs during catalysis using our optimized system, is detrimental as it siphons
catalytically active compounds out of the cycle. It is proposed that the active species in catalysis
are Ni(0)/(II) compounds and, based in part on DFT calculations, we present a detailed pathway
for the formation of Ni(I) complexes via comproportionation of Ni(0) and Ni(II) species. Our
results provide guidelines on how to design improved catalysts for SMC reactions involving aryl
sulfamates and related electrophiles and provide information that could be relevant to improving
other types of nickel-catalyzed cross-coupling reactions including Kumada, Negishi, Hiyama,
and Buchwald-Hartwig reactions,3a-e which may involve similar active species.
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Results and Discussion
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Preliminary Catalyst Screening
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Previous examples of nickel-catalyzed SMC reactions of aryl sulfamate substrates and boronic
acids have predominantly utilized the simple coordination complex PCyNiII
as the
Cl2
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precatalyst.10a,10c In general, to obtain high yields, a catalyst loading of 5 mol% is required and
reactions need to be heated at more than 100 °C for 24 hours. To improve the reaction
conditions, we synthesized a series of Ni(0), Ni(I), and Ni(II) precatalysts supported by either
PCy3 or the bidentate ligand dppf and tested their catalytic activity (see Table 1 for room
temperature results and Table S1 for results at elevated temperature and additional
precatalysts).14m,16
Our results for the coupling of naphthalen-1-yl dimethylsulfamate with 4-methoxyphenylboronic
acid show that the most commonly used system in the literature,10a,10c PCyNiIICl2, is the least
active of the precatalysts we tested (Entry 1 and Table S1). We suggest that this is in part due to
its poor solubility at temperatures lower than 100 °C. In general, dppf-ligated Ni(II) and Ni(0)
precatalysts are more active than their PCy3-ligated counterparts (Entries 2 & 4 vs Entries 5 &
7). This trend is reversed for Ni(I) precatalysts and PCyNiICl is more active than dppfNiICl (Entry 3
vs 6). Although dppfNiICl is active, especially at elevated temperatures (Table S1), at room
temperature it displays reduced activity compared to Ni(0) and Ni(II) species. In fact, dppfNiICl
shows almost no activity at room temperature. This is in direct contrast to our previous work
studying SMC reactions involving aryl chlorides, where dppfNiICl was highly active at room
temperature,15 and indicates that dppf-supported Ni(0) and Ni(II) precatalysts are not generating
dppfNiICl as the active species in the coupling of aryl sulfamates.
The most active systems were dppfNiII(o-tol)(Cl) and dppf2Ni0, which at 2.5 mol% catalyst loading
quantitatively generated the product at room temperature (Entries 5 & 8). Remarkably, excellent
conversion was even observed using only 1 mol% dppfNiII
at room temperature
(o-tol)(Cl)
demonstrating the incredible activity of this precatalyst. We propose that the increased activity of
dppfNiII compared to the Ni(0) precatalyst, dppf2Ni0, as well as the related system
(o-tol)(Cl)
dppfNi0C2H4, is due to its rapid activation (see below and SI).
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Table 1. GC Yields (%) for PCy3- and dppf-supported precatalysts for a SMC reaction involving a
naphthyl sulfamate.
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Entry
Precatalyst
Yield
<1
55
50
5
1
2
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4
PCyNiII
Cl2
PCyNiII
(o-tol)(Cl)
PCyNiICl
PCyNi0
C2H4
5
6
7
8
dppfNiII
>99 (87)a
<1
(o-tol)(Cl)
dppfNiICl
dppfNi0
27 (<1)a
>99 (39)a
C2H4
dppf2Ni0
Reaction conditions: 0.133 mmol naphthalene-1-yl dimethylsulfamate, 0.333 mmol 4-methoxyphenylboronic acid, 0.599 mmol
K3PO4, 0.0665 mmol naphthalene (internal standard), 2.5 mol% precatalyst, and 1 mL toluene. Yields are the average of two
runs and were determined using GC. a Yields in parentheses are for 1 mol% catalyst loading.
Substrate Scope
Using dppfNiII
as the precatalyst, the substrate scope was explored (Table 2). Boronic
(o-tol)(Cl)
acids containing both electron withdrawing and donating substituents were coupled in high
yields with naphthalen-1-yl dimethylsulfamate at room temperature (Entries 1-5). When a di-
ortho-substituted boronic acid (Entry 7) was used elevated temperature (60 °C) was required and
the yield was slightly reduced. Rapid coupling at room temperature was also observed with
naphthalen-2-yl dimethylsulfamate (Entry 10), although in the case of a naphthalen-2-yl
dimethylsulfamate with an electron withdrawing group, longer reaction times were required to
achieve high yields, due to the low solubility of the sulfamate in toluene (Entries 11 & 12). The
reaction is compatible with a naphthalen-1-yl dimethylsulfamate with an electron donating
moiety, but elevated temperature was required, presumably because oxidative addition is more
challenging (Entry 13). Similarly, when either the boronic acid or naphthyl sulfamate contains
heteroatoms, which are ubiquitous in pharmaceuticals,17 elevated temperatures were necessary
(Entries 6, 8, 9 & 14).
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Table 2. Isolated yields for SMC reactions involving naphthyl sulfamate substrates using dppfNiII
as the precatalyst.
(o-tol)(Cl)
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Entry
1
Sulfamate
Boronic Acid
Time (hr)
Yield
Temp (°C)
RT
4
95%
2
RT
4
85%
3
4
5
6
RT
RT
RT
40
4
4
88%
92
24
16
79%
91%
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60
4
64
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9
80
80
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16
75%
87%
OSO2NMe2
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12
RT
RT
RT
4
84%
90%
93%
24
24
13
14
60
80
24
24
91%
86%
Reaction conditions: 0.133 mmol naphthalenyl dimethylsulfamate, 0.333 mmol boronic acid, 0.599 mmol K3PO4, 2.5 mol%
dppfNiII
, and 1 mL toluene. Yields are the average of two runs.
(o-tol)(Cl)
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Table 3. Isolated yields for SMC coupling reactions involving phenyl sulfamate substrates using
dppfNiII(o-tol)(Cl) as the precatalyst.
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Entry
1
Sulfamate
Boronic Acid
Time (hr)
Yield
Temp (°C)
80
4
93%
2
80
16
94%
3
4
80
80
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16
84%
86%
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6
80
80
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71%
75%
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7
80
24
69%
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9
80
80
80
80
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24
72%
73%
63%
58%
(HO)2B
CF3
CF3
CF3
(HO)2B
(HO)2B
10
11
12
80
24
87%
Reaction conditions: 0.133 mmol phenyl dimethylsulfamate, 0.333 mmol boronic acid, 0.599 mmol K3PO4, 2.5 mol%
, and 1 mL toluene. Yields are the average of two runs.
dppfNiII
(o-tol)(Cl)
The data in Table 3 show that the SMC reaction of phenyl sulfamates is more challenging than
naphthyl sulfamates and elevated temperatures and slightly longer reaction times were required;
however, the scope is still broad. As with naphthyl sulfamates, both electron deficient and rich
electrophiles are tolerated (Entries 1, 4, 5, 8, 9 & 11). Notably, the precatalyst is compatible with
sterically more demanding di-ortho substituted substrates (Entries 2 & 7). Significantly, the tri-
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ortho substituted cross-coupled product, 2,2',6'-trimethylbiphenyl can be obtained in good yield
(Entry 12). However, the tetra-ortho substituted analogue, 2,2',6,6'-tetramethylbiphenyl, could
not be generated in appreciable yield. The efficiency of coupling of phenyl sulfamates was also
significantly impacted by the electronic properties of the boronic acid. Reduced yields were
obtained when using the more electron deficient phenylboronic acid and 4-trifluoromethylphenyl
boronic acid (Entries 5-11) compared to the more electron rich 4-methoxyphenylboronic acid
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(Entries 1-4). Although we were able to couple quinoline electrophiles using dppfNiII
(o-tol)(Cl)
(Table 2, Entry 12), we were not able to couple pyridyl derivatives under the same mild
conditions.
The combined results in Tables 2 and 3 indicate that the most facile reactions occur between
electron withdrawing sulfamates and electron donating boronic acids. This is consistent with
previous observations that oxidative addition is easier for substrates with electron-withdrawing
groups18 and that boronic acids with electron-donating substituents are less likely to undergo
protodeboronation.19 Overall, the mild conditions that can be used with dppfNiII
(o-tol)(Cl)
demonstrate that it generates a significantly better catalyst for the SMC reaction of aryl
sulfamates and boronic acids than any other previously reported system.10a,10c In fact, its activity
is comparable to the systems reported by Percec and co-workers for couplings between aryl
sulfamates and neopentylglycolboronates,10d,10g,10j with the major advantage that boronic acids
are readily available. Additionally, not only does dppfNiII(o-tol)(Cl) exhibit remarkable efficiency as
a precatalyst, but it is also a preferred system from a practical standpoint due to its facile
preparation from inexpensive nickel salts, bench stability, and commercial availability.20
Precatalyst Activation and the Speciation of Nickel During Catalysis
To fundamentally understand the exceptional catalytic activity of dppfNiII(o-tol)(Cl) and discern the
factors that are important for the development of improved precatalysts, we performed
mechanistic studies. It has previously been proposed that dppfNiII
activates via initial
(o-tol)(Cl)
transmetallation and subsequent reductive elimination to generate a putative catalytically active
Ni(0) species10c,15 but this process has not been studied under catalytic conditions. In a catalytic
reaction between naphthalen-1-yl dimethylsulfamate and 4-methoxyphenylboronic acid, we
quantified the amount of the activation product 2-methyl-4'-methoxybiphenyl and the cross-
coupled product, 1-(4'-methoxyphenyl)naphthalene, as a function of time (Figure 2). Our results
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indicate that activation of dppfNiII
methoxybiphenyl based on dppfNiII(o-tol)(Cl) is approximately 85%. The amount of 2-methyl-4'-
methoxybiphenyl does not increase after 15 minutes and there is no dppfNiII
is fast; within 15 minutes, the yield of 2-methyl-4'-
(o-tol)(Cl)
remaining
(o-tol)(Cl)
after the reaction. This suggests that activation is not completely selective. Nevertheless, after 4
hours quantitative conversion to the cross-coupled product is observed. The same experiment
was also conducted using 4-trifluoromethylphenyl sulfamate as the electrophile which, as shown
in Table 3, is a substrate that requires elevated temperatures to achieve appreciable conversion.
Quantifying the amount of the cross-coupled product 4-trifluoromethyl-4'-methoxybiphenyl and
the amount of the activation product 2-methyl-4'-methoxybiphenyl at room temperature indicates
that activation is still fast (~85% after 15 minutes), even when conversion to product is slow
(Figure 2). In a similar fashion to the reaction using the naphthyl substrate, the maximum yield
of 2-methyl-4'-methoxybiphenyl is 85% and there is no precatalyst present at the end of the
reaction. This demonstrates that the same processes are likely occurring in activation regardless
of whether a naphthyl or phenyl electrophile is utilized. Similarly, changing the boronic acid
gives analogous results. When the reaction of unactivated phenylboronic acid, and naphthalen-1-
yl dimethylsulfamate was monitored by GC, only ~70% of the activation product 2-
methylbiphenyl was observed, despite essentially quantitative conversion to the cross-coupled
product (see SI). Activation of the precatalyst is not affected when using the mono-ortho
substituted 2-methylphenyl boronic acid, with approximately 87% of the activation product
obtained (see SI). However, both activation of the precatalyst (~70%) and yield of cross-coupled
product (57%) is decreased when using the di-ortho substituted 2,6-dimethylphenyl boronic acid
(see SI).
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One explanation for the observation of less than quantitative yields of the biphenyl activation
products is that dppfNiII
undergoes a competing comproportionation reaction to initial
(o-tol)(Cl)
transmetallation to generate Ni(I) species (Scheme 1).13,15,21 To probe for Ni(I) formation, the
speciation of nickel was investigated using EPR spectroscopy in the reaction of naphthalen-1-yl
dimethylsulfamate and 4-methoxyphenylboronic acid using dppfNiII(o-tol)(Cl) as the precatalyst. An
axial spectrum exhibiting hyperfine splitting consistent with two similar, but not identical
phosphorus nuclei was observed both during and at the end of the reaction (Figure 3a).
Quantification of the nickel at the end of the reaction indicated that 23% of the precatalyst was in
an EPR active form (Figure 3a). Timecourse experiments (see SI) indicate that the quantity of
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EPR active material increases throughout the reaction, showing that Ni(I) is formed while
catalysis is occurring. Additionally, Ni(I) formation is not restricted to room temperature
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0
Naphthyl Coupled Product
Naphthyl Activation Product
Trifluoromethylphenyl Coupled Product
Trifluoromethylphenyl Activation Product
0
1
2
3
4
Time (hr)
Reaction conditions: 0.133 mmol sulfamate, 0.333 mmol 4-methoxyphenylboronic acid, 0.599 mmol K3PO4, 2.5 mol%
dppfNiII(o-tol)(Cl), 0.0665 mmol naphthalene (internal standard) and 1 mL toluene. Yields are the average of two runs.
Figure 2. (a) Yield of cross-coupled and activation product as a function of time in selected SMC
reactions using dppfNiII(o-tol)(Cl). (b) & (c) Schematic showing formation of activation and cross-coupled
products in reactions using naphthalen-1-yl dimethylsulfamate and 4-trifluoromethylphenyl sulfamate
as the substrates.
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reactions in toluene; the same phenomenon occurs at elevated temperature and in other solvents
amenable to cross-coupling (see SI).
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Comparison of the EPR spectra obtained in the reaction using dppfNiII
as a precatalyst to
(o-tol)(Cl)
9
an authentic spectrum of dppfNiICl (shown in Figure 3c),15,22 a potential product of
comproportionation, indicates that they are not identical (see SI). The authentic dppfNiICl
spectrum has g values of 2.09 and 2.32, and two axial hyperfine values of [190, 150] and [220,
170] MHz arising from the 31P nuclei.15 However, the spectrum from catalysis using
dppfNiII(o-tol)(Cl) has less resolution in g|| and the g|| value also shifts to approximately 2.34 (see SI).
Additionally, shouldering in the lineshape around 330 mT implies that another species is
superimposed on the major contributor to the spectra; in fact, the spectra obtained in the reaction
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using dppfNiII
as a precatalyst are consistent with the presence of multiple EPR active
(o-tol)(Cl)
species.
2 hr
4 hr
2 hr
4 hr
(a)
(b)
(c)
260 280 300 320 340 360 260 280 300 320 340 360 260 280 300 320 340 360
Field (mT)
Field (mT)
Field (mT)
P
P
P
P
NiI Cl
NiII
Ni0
(c) = authentic
(a) =
(b) =
P
P
Cl
P
P
Figure 3. Low temperature X-band EPR spectra of catalytic mixtures from the SMC reaction of
naphthalen-1-yl sulfamate and 4-methoxyphenylboronic acid catalyzed by dppfNiII
(b). The spectrum in (c) is that of authentic dppfNiICl,15 provided for comparison.
(a) or dppf2Ni0
(o-tol)(Cl)
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We propose that two Ni(I) species are present in detectable quantities in reactions using
dppfNiII
as the precatalyst. One of these species is the known compound dppfNiICl,15,22
(o-tol)(Cl)
which is most likely formed via comproportionation between the unactivated dppfNiII
(o-tol)(Cl)
precatalyst and a dppf-supported Ni(0) species formed after activation of dppfNiII(o-tol)(Cl) (Scheme
1). Both our group and Schoenebeck and co-workers have previously synthesized dppfNiICl via
comproportionation reactions,15,22 which are well precedented for the formation of Ni(I)
complexes even though the elementary steps are often unclear (vide infra).13,14b,14f,14o,21,23 In our
case the other product from comproportionation is the Ni(I) aryl species: dppfNiIo-tol, which we do
not directly observe. Stable three-coordinate Ni(I) aryl species are rare and limited to those with
perfluorinated aryl groups;24 as such, the Ni(I) aryl species generated through
comproportionation in our reactions are expected to be unstable and degrade either through
hydrogen abstraction or disproportionation followed by reductive elimination to yield mono- or
biaryl organic species and Ni(0) species (see SI).15,25 Organic products consistent with these
processes were observed using GC in both catalytic and stoichiometric reactions (vide infra). It is
likely that the Ni(0) species generated from Ni(I) aryl degradation can re-enter the catalytic
cycle.15
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We suggest that the other Ni(I) species detected by EPR spectroscopy in reactions using
dppfNiII
as the precatalyst is dppfNiIsulf, which we were unable to isolate. In this case,
(o-tol)(Cl)
comproportionation between dppfNiII(nap)(sulf), generated via oxidative addition of the substrate,
and a Ni(0) species would give rise to a Ni(I) sulfamate product, dppfNiIsulf, and an unstable Ni(I)
naphthyl species, dppfNiInap, as shown in Scheme 2. Indirect support for the formation of a Ni(I)
sulfamate complex was provided by monitoring the catalytic reaction of naphthalen-1-yl
dimethylsulfamate and 4-methoxyphenylboronic acid using dppf2Ni0 as the precatalyst by EPR
spectroscopy. Using this precatalyst, it is impossible to generate dppfNiICl. Nevertheless, a clear
signal attributed to dppfNiIsulf that accounts for 14% of the total nickel in solution is observed at
the end of the reaction (Figure 3b). Timecourse experiments (see SI) indicate that the
concentration of this species increases over the duration of the catalytic reaction. Using this
authentic dppfNiIsulf spectrum as a guide, we modeled the EPR spectra observed when using
dppfNiII
as the precatalyst as a linear combination of dppfNiICl and dppfNiIsulf (see SI). This
(o-tol)(Cl)
provides a better model for the spectra than that obtained using only dppfNiICl or dppfNiIsulf, as
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Scheme 1. Comproportionation of dppfNiII
degradation products.
with activated Ni(0) to produce dppfNiICl and aryl
(o-tol)(Cl)
Scheme 2. Comproportionation of activated Ni(0) and dppfNiII
degradation products.
to produce dppfNiIsulf and naphthyl
(nap)(sulf)
indicated by regression analysis. Furthermore, monitoring the reaction of naphthalen-1-yl
sulfamate with 4-methoxyphenylboronic acid by EPR spectroscopy using dppfNiII(o-tol)(Br) (the Br
analogue of dppfNiII(o-tol)(Cl)) as the precatalyst also provides evidence for the presence of multiple
EPR active species (see SI). In this case, hyperfine splitting from Br makes assignment more
straightforward.
To further probe Ni(I) formation we performed stoichiometric reactions. These experiments are
consistent with the pathway depicted in Scheme 3b, which involves a Ni(0)/Ni(II) catalytic
cycle, with off-cycle processes to generate Ni(I) complexes. Initially, we treated dppfNiII
(o-tol)(Cl)
with naphthalen-1-yl dimethylsulfamate and 4-methoxyphenylboronic acid in the presence of 4.5
equivalents of K3PO4 (Scheme 3a), which generated the cross-coupled product 1-(4'-
methoxyphenyl)naphthalene in 80% yield. In this reaction dppfNiII
is only 77% activated
(o-tol)(Cl)
to Ni(0), as determined by the amount of 2-methyl-4'-methoxybiphenyl formed, while
approximately 10% of the dppfNiII(o-tol)(Cl) remains unreacted. EPR spectroscopy indicates 13% of
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the initial precatalyst undergoes comproportionation to form dppfNiICl and dppfNiIo-tol. As
discussed in Scheme 1 the latter is unstable and forms aryl degradation products. Consistent with
this hypothesis we detected toluene and 2,2-dimethylbiphenyl by GC.
3
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6
7
8
Other aryl products detected by GC:
OMe
9
OMe
OSO2NMe2
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P
P
C6H6, RT
4 hr
B(OH)2
NiII
+
+
+
K3PO4
Cl
1 equiv.
MeO
2.5 equiv.
4.5 equiv.
1 equiv.
~80% yield
Scheme 3a. Stoichiometric reaction of dppfNiII(o-tol)(Cl) with all catalytic components. Reaction conditions:
0.01352 mmol dppfNiII(o-tol)(Cl), 0.01352 mmol sulfamate, 0.0338 mmol 4-methoxyphenylboronic acid,
0.599 mmol K3PO4, 0.0665 mmol 4,4'-dimethoxybiphenyl (internal standard) and 1 mL benzene.
Scheme 3b. Proposed pathways of formation of aryl degradation products observed in stoichiometric
reaction of dppfNiII
with all catalytic components. Quantification based on total moles of starting
a
(o-tol)(Cl)
precatalyst. Quantification based on sulfamate substrate as the limiting reagent.cCombined yield of
these products exceeds 100% presumably due to the error associated with GC integrations. Organic
products were quantified by GC, while nickel containing species were quantified using either NMR or
EPR spectroscopy.
b
The organic products naphthalene and 1,1'-binaphthalene were also detected in 20% yield. We
propose that they are formed from the decomposition of dppfNiInap, which is one product from the
comproportionation of dppfNiII(nap)(sulf) with a Ni(0) species (see Scheme 2).26 The other product
of this comproportionation, dppfNiIsulf, was detected by EPR spectroscopy. The low yield of
cross-coupled product (80%) is explained by the electrophile being consumed in the
comproportination between dppfNiII
and a Ni(0) species. In catalytic reactions this
(nap)(sulf)
pathway would be expected to consume considerably less substrate due to the lower
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concentration of nickel present in solution. In agreement with this hypothesis, yields approaching
complete conversion to cross-coupled product are obtained in catalytic reactions where the
catalyst loading is often only 2.5 mol% (see Tables 1, 2 & 3) but we still observe small amounts
of the aryl products from degradation of dppfNiInap. Given the propensity of naphthyl
electrophiles to exhibit markedly more activity than their phenyl counterparts,3a these
experiments were repeated with phenyl electrophiles for congruency (see SI). The
comproportionation phenomena seen with naphthyl electrophiles are also present in these
reactions.
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Additional evidence for the postulated dppfNiInap and dppfNiIsulf complexes was obtained through a
reaction between 0.5 equivalents of naphthalen-1-yl dimethylsulfamate and dppf2Ni0 at room
temperature (Scheme 4). After 24 hours 68% of the aryl sulfamate had reacted. EPR
spectroscopy showed the generation of dppfNiIsulf and GC analysis indicated naphthyl degradation
products consistent with dppfNiInap formation and subsequent decomposition. Quantification of
these organic products is also consistent with incomplete consumption of the aryl sulfamate and
gives a 17% yield of naphthyl species based on dppf2Ni0. This is in agreement, within error, with
the 20% yield of dppfNiIsulf obtained using EPR spectroscopy. The results of this reaction are
consistent with a model in which: (i) a Ni(I) sulfamate species is formed congruent with
dppfNiInap; and (ii) this process occurs through comproportionation of activated Ni(0) with the
Ni(II) oxidative addition intermediate dppfNiII(nap)(sulf). Further evidence in support of this model
was obtained by changing the electrophile (see SI). As expected a substrate which underwent
more facile oxidative addition generated less Ni(I), as in this case the Ni(0) species was
relatively more likely to undergo oxidative addition compared to comproportionation.
In support of our competing off-cycle comproportionation model, a marked effect on Ni(I)
formation was observed depending on the concentration of boronic acid (see SI). Our data
indicate that higher boronic acid concentrations promote transmetallation of dppfNiII
and
(o-tol)(Cl)
dppfNiII(nap)(sulf) before comproportionation can occur, facilitating productive catalysis by keeping
more nickel in the catalytic cycle. When less boronic acid was used in catalytic reactions,
precatalyst activation is decreased and the total amount of Ni(I) generated is increased, consistent
with previous observations with aryl chloride electrophiles.15 Furthermore, when using only 1.5
or 1.05 equivalents of boronic acid in stoichiometric reactions of dppfNiII(o-tol)(Cl), the yields of
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Scheme 4. Proposed route for Ni(I) formation via oxidative addition in the stoichiometric reaction of
dppf2Ni0 with substrate. Quantification of aryl degradation products performed using GC with 2-(4'-
methoxyphenyl)naphthalene as an internal standard. Yields based on total amount of precatalyst.
Table 4. Stoichiometric reactions using dppfNiII
as a precatalyst for SMC reactions involving
(o-tol)(Cl)
different numbers of equivalents of boronic acid.
OMe
OMe
+
OSO2NMe2
P
P
B(OH)2
Activation
Product
Cross-Coupled
Product
benzene, RT
4 hr
NiII
+
+
+
K3PO4
Cl
MeO
x equiv.
+
1 equiv.
1 equiv.
4.5 equiv.
Indicators of Ni(I) formation
Equivalents Yield Cross-
Yield
Activation
Product
77%
Total Yield Ni(I)d
(
Ratio
dppfNiIsulf
dppfNiICl
2:1
Boronic
Acid
2.5a
Coupled
Product
80%
51%
23%
dppfNiIsulf and
dppfNiICl)
:
32% (36%)e
45% (54%)e
48% (62%)e
1.5b
54%
35%
1:2.5
1:7
1.05c
Reaction conditions: 0.01352 mmol dppfNiII
,
0.01352 mmol sulfamate, 0.0338a, 0.0203b, or 0.0142c mmol 4-
(o-tol)(Cl)
methoxyphenylboronic acid, 0.599 mmol K3PO4, 0.0665 mmol 4,4'-dimethoxybiphenyl (internal standard) and 1 mL benzene.
e
dYield based on the total amount of precatalyst initially present. Number in parenthesis is the yield based on the amount of
precatalyst that was activated.
cross-coupled product and activation product are once again reduced (Table 4). Notably, the ratio
of dppfNiIsulf to dppfNiICl decreases drastically upon using less boronic acid. This is quantified
indirectly by comparing the total amount of naphthyl and binaphthyl degradation products
formed (indicating the formation of dppfNiIsulf) to the total amount of phenyl and biphenyl
degradation products formed (indicating the formation of dppfNiICl). The decrease in the ratio of
dppfNiIsulf to dppfNiICl is also an artifact of a decrease in the rate of precatalyst activation, as this
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causes an increase in the amount of dppfNiII
Ni(0) is more likely to comproportionate with dppfNiII(o-tol)(Cl) to form dppfNiICl compared with
relative to dppfNiII(nap)(sulf). Consequently,
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(o-tol)(Cl)
dppfNiII
to form dppfNiIsulf. As a result, the majority of the Ni(I) produced in the
(nap)(sulf)
stoichiometric reaction using 1.05 equivalents of boronic acid is in the form of dppfNiICl.
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Overall, our results on the activation of dppfNiII(o-tol)(Cl) and its speciation during catalysis indicate
that even under our optimized conditions, catalyst activation is not selective for Ni(0). The
predominant reason for the less than quantitative activation of the precatalyst to Ni(0) is a
comproportionation reaction between a Ni(0) species formed after activation and dppfNiII
(o-tol)(Cl)
to form an unstable Ni(I) aryl species and catalytically inactive dppfNiICl. Increasing the rate of
activation by increasing the concentration of boronic acid reduces the amount of dppfNiICl but it is
still formed in detectable quantities under our optimized conditions and reduces catalyst
performance. Furthermore, a second detrimental process that consumes substrate also occurs to
generate Ni(I) species. In this pathway, Ni(0) undergoes comproportionation with dppfNiII
(Ar)(sulf)
to form an unstable Ni(I) aryl species and dppfNiIsulf. Our results confirm that in a similar fashion
to Negishi and Kumada reactions involving alkyl halides14a,14d-f,14k,14o-q and SMC reactions of
aryl halides,13,15 Ni(I) species are present in SMC reactions involving aryl sulfamates. However,
in the latter case, unlike previous studies on the role of Ni(I) species in SMC reactions involving
aryl halides,13,15 the almost negligible catalytic activity of dppfNiICl at room temperature clearly
establishes that the generation of this species is detrimental to catalysis; the first time it has
definitively been established that Ni(I) formation needs to be avoided in a nickel-catalyzed SMC
reaction. Our findings are also distinct from other nickel-catalyzed reactions where Ni(I) species
are proposed to be inactive, such as Buchwald-Hartwig and trifluoromethylthiolation
reactions,22,25d as in these cases there is no direct evidence that Ni(I) complexes are formed in
situ during catalysis.
DFT Calculations on the Comproportionation of Ni(II) and Ni(0)
Our experimental results suggest that by suppressing comproportionation to generate Ni(I)
complexes, we could generate improved precatalysts. This is difficult because the elementary
steps in comproportionation are not well understood. In catalysis, the extent of
comproportionation of dppfNiII(o-tol)(Cl) with Ni(0) to yield essentially inactive dppfNiICl depends on
the relative rates of three different processes: (1) the activation of Ni(II) to Ni(0), (2) the
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oxidative addition of the electrophile and (3) the comproportionation reaction itself (see Scheme
3b). Ni(0) catalysts do not involve process (1), but they still require activation; e.g., the exchange
of ethylene by toluene in dppfNi0C2H4, which is endoergic by 15.7 kcal mol-1 (Figure S19). In
contrast, Ni(II) activation involves transmetallation followed by reductive elimination.15,27
Although transmetallation is proposed to be facile it is a difficult process to model due to a lack
of understanding about the exact role of the base (K3PO4 in this case),28 especially for nickel-
catalyzed reactions in non-polar solvents such as toluene.29 Furthermore, the speciation of K3PO4
in toluene is not clear, which complicates modeling, and the exact concentration of K3PO4 is
unknown, resulting in problems obtaining accurate energies. Therefore, herein we focus on steps
(2) and (3) by means of DFT calculations at the M06L-DZP/M06-TZP SMD(benzene) level,30
which has been benchmarked against X-Ray structures and CCSD(T) energies (Tables S17-19
and Figure S18).31
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Comproportionation was initially studied by optimizing both the Ni(II) precatalyst dppfNiII
(o-tol)(Cl)
and the coordinatively unsaturated Ni(0) complex, (dppf)Ni (dppfNi0), within a single “super-
molecule” in the singlet state S-dimerCl (Figure 4 and 5). After assessing different
conformations, it was found that in the most stable conformation the Ni(II) center is still in a
square planar geometry with the dppf ligand bound in a bidentate fashion and the metal bound to
both the o-tolyl and Cl ligands (Ni(1)-Cl(3) = 2.27 Å and Ni(1)-C(6) = 1.92 Å). The Ni(0) center
adopts a distorted tetrahedral geometry with the metal weakly bound to the Cl ligand (Ni(2)-
Cl(3) = 2.56 Å) and strongly bound to one of the delocalized C=C bonds of a phenyl ring of the
dppf ligand coordinated to the Ni(II) center (the Ni(2)-C(4) and Ni(2)-C(5) distances are 2.05
and 2.09 Å, respectively). The phosphine ligand is thus playing an unexpected bridging role,
which contributes to the exoergic formation of S-dimerCl from the separated dppfNiII
and
(o-tol)(Cl)
(dppf)Ni(benzene) (dppfNi0benz) complexes; G = -6.2 kcal mol-1 (see Figure 5). The complex
dppfNi0 is used as the energy reference instead of naked dppfNi0, because the solvent, upon
benz
coordination, stabilizes the system by ~10 kcal mol-1 (see Eqs. S5 and S6 in the SI).
The transformation of the Ni(II)/Ni(0) core into a Ni(I)/Ni(I) core requires singlet-to-triplet spin
crossover accompanied by the migration of the Cl ligand. This feature was explored by re-
optimizing the geometry of S-dimerCl in the triplet state, which yielded T-dimerCl as an energy
minimum (Figure 4 and Table S20). As expected, in this structure one metal is bound to the o-
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tolyl ligand (Ni(1)-C(6) = 1.97 Å), whereas the other is bound to the Cl ligand (Ni(2)-Cl(3) =
2.23 Å), both in a distorted T-shaped coordination geometry. The bridging -Ph feature from the
dppf ligand is not present in T-dimerCl (the Ni(2)-C(4) and Ni(2)-C(5) distances are now 3.58
and 3.63 Å, respectively) and the long Ni(1)···Cl(3) contact (3.08 Å) suggests that the Cl ligand
does not connect the two Ni(I) centers either. The natural local spin densities () are consistent
with the presence of two ferromagnetic-coupled Ni↑(I) centers; (Ni) = 0.77 (o-tolyl-bound) and
0.85 (Cl-bound) a.u.. The free energy difference between T-dimerCl and S-dimerCl is only 1.2
kcal mol-1 in favor of the singlet state.
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Figure 4. Fully optimized geometries of S-dimerCl, T-dimerCl, S-dimersulf, and T-dimersulf. For clarity, the
dppf ligand is drawn in a “tube” representation, except for the phenyl ring interacting with nickel. Color
code: Light blue (Ni), dark blue (N), green (Cl), grey (C), orange (P), lilac (Fe), red (O), yellow (S).
The kinetics of comproportionation were modeled using a relaxed energy scan (Figure S23). This
scan shows how the potential energy of the system varies by freezing a set of internal coordinates
at different values and allowing the remainder of the molecule to relax in a series of restrained
geometry optimizations. These optimizations were performed for both the singlet and triplet
states with the aim of finding a crossing point between them. Shortening of the Ni(2)-Cl(3)
distance in the S-dimerCl geometry does not trigger the reaction – even when the Cl ligand is
fully transferred to the Ni(2) center (Ni(2)-Cl(3) = 2.25 Å), the Ni(2) center remains strongly
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Figure 5. Singlet (blue) and triplet (red) free energy profiles in benzene in kcal mol-1 for the oxidative
addition of naphthalene-1-yl dimethylsulfamate (naphOSO2NMe2) to dppfNi0
(right) and
(left). The energy for the MECP has been
benz
comproportionation of dppfNi0
with dppfNiII
benz
(o-tol)(Cl)
estimated by means of a relaxed energy scan (Figure S23).
bound to the phenyl ligand of the Ni(1)(dppf) moiety. Instead, the reaction is triggered by
elongation of the Ni(2)-(C4=C5) -bond distance. When the Ni(2)-C(5) bond distance was
increased in sixteen +0.10 Å steps from 2.35 to 3.95 Å, the energy of the singlet state rises from
3.5 to 13.8 kcal mol-1 above S-dimerCl. When the Ni(2)-C(5) bond distance is 3.65 Å, the energy
of the singlet state geometry (S-dimer’Cl; Table S20), 12.2 kcal mol-1 above S-dimerCl, becomes
lower upon re-optimization in the triplet state (T-dimer’Cl), 11.7 kcal mol-1 above S-dimerCl.
Energy refinement by thermochemistry corrections and basis set expansion reduce this spin
crossover energy to 6.4 kcal mol-1 relative to S-dimerCl. The similar energies and geometrical
parameters of S-dimer’Cl and T-dimer’Cl suggest that these structures are close to the minimum
energy crossing point (MECP) between the two spin states. In line with this, their full
optimization without any geometry or symmetry constraints in the singlet and triplet states
yielded the expected S-dimerCl and T-dimerCl complexes, respectively. Both the dissociation of
T-dimerCl into products, dppfNiICl and dppfNiIo-tol, and the formation of the latter from the initial
reactants, dppfNiII
and dppfNi0benz, are thermodynamically favorable, with G = -5.0 kcal
(o-tol)(Cl)
mol-1 and -9.8 kcal mol-1, respectively (see Figure 5). These data show that comproportionation
between dppfNiII
and Ni(0) should be a facile low-barrier exoergic process and illustrate
(o-tol)(Cl)
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the elementary steps involved. The calculations also showed that the Ni(I)-aryl product can yield
the biaryl species observed experimentally (vide supra), because disproportionation to dppfNiII
(o-
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and a Ni(0) species and the subsequent reductive elimination of 2,2'-dimethyl-1,1'-biphenyl
tol)2
are both exoergic (Figure S22).
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Comproportionation was also studied from Ni(0) and dppfNiII (nap)(sulf), which was modelled using
a phenyl ligand instead of a naphthyl ligand (dppfNiII(ph)(sulf)) (Figure 6). The singlet state dimer of
this system (S-dimersulf), shows that Ni(II) and Ni(0) are bridged by two oxygens of the
sulfamate anion (O(3) and O(4)). In addition, the Ni(0) center is stabilized by the -2
coordination of
Similar to S-dimerCl, these interactions contribute to the exergonic formation of S-dimersulf
from dppfNiII dppfNi0benz; G = -7.4 kcal mol-1. The formation of the triplet state dimer
a
phenyl ring of the dppf ligand bound to Ni(II).
+
(ph)(sulf)
(T-dimersulf), which is almost isoenergetic to S-dimersulf, is also exergonic by -8.0 kcal mol-1.
The structure of this species contains two distorted T-shaped Ni(I) centers, one bound to the
phenyl and the other to the sulfamate (Figure S24). As in the chloride system, the singlet-to-
triplet spin crossover, which was also investigated by means of a relaxed energy scan (Figure
S24), requires the elongation of the Ni(2)-C(6)=C(7) bond. In this case, at 2.45 Å, the triplet state
energy becomes lower than that of the singlet by 1.7 kcal mol-1. Upon adding the
thermochemistry corrections and refining the energy, this approximate MECP structure stands
1.6 kcal mol-1 above S-dimersulf (-5.8 kcal mol-1 below the initial reactants). Overall, after
dissociation of T-dimersulf into dppfNiIph
+
dppfNiIsulf,32 comproportionation is exergonic by -15.8
kcal mol-1 and becomes more favorable when the phenyl ring is replaced by naphthyl (G
= -18.5 kcal mol-1). The structure and energy data compiled in Figures 4-6 suggests that
comproportionation to Ni(I) is a facile low-barrier exoergic process, which, for both the chloride
and sulfamate systems, seems to be favored by the interaction between nickel and a dppf phenyl.
In line with this, the re-optimization of the comproportionation pathway without this interaction
in the sulfamate system yield a higher MECP with an energy of 9.5 kcal mol-1 above dppfNi0
+
benz
dppfNiII
.
(ph)(sulf)
The oxidative addition of naphthalene-1-yl dimethylsulfamate (naphOSO2NMe2) to dppfNi0
benz
was calculated for comparison with the comproportionation energy barriers (Figure 5).
Substitution of the coordinated solvent benzene by naphOSO2NMe2 is exergonic by 10.1 kcal
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mol-1. From this species, the oxidative addition has an energy barrier of 17.5 kcal mol-1 and it
proceeds through a transition state containing a 5-membered ring. Calculations on the alternative
3-membered ring transition state suggested that this involves a higher energy barrier (G‡ > 29
kcal mol-1, see SI). The proposed pathway is consistent with others that have been calculated for
related systems.10c,33 A similar pathway was also calculated for oxidative addition of phenyl
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sulfamate (phOSO2NMe2, see Figure S25). Formation of the final dppfNiII
product is
(nap)(sulf)
exergonic by 16.2 kcal mol-1. In contrast, oxidative addition to dppfNiICl is strongly endoergic by
28.5 kcal mol-1 (Figure S20). Comparison of the energy profiles depicted in Figures 5 and 6 for
oxidative addition and comproportionation suggest that the latter is kinetically preferred,
consistent with the off-cycle processes proposed for dppfNiII(o-tol)(Cl) and dppfNiII(nap)(sulf) in Scheme
3b. Indeed, the low spin-crossover barriers for comproportionation make this process
competitive even with oxidative addition of aryl chloride substrates, which have a lower energy
barrier than aryl sulfamates (Figure S26). This is consistent with experimental observations that
dppfNiICl is formed in SMC reactions with aryl chlorides using dppfNiII(o-tol)(Cl) as the precatalyst.15
However, it should be noted that in all these systems, the concentration of substrate is far greater
than the concentration of nickel, which increases the likelihood of oxidative addition over
comproportionation.
Figure 6. Free energy profile in benzene in kcal mol-1 for the comproportionation of dppfNi0
and
benz
dppfNiII(ph)(sulf). The energy for the MECP between the singlet (blue) and triplet (red) energy profiles has
been estimated by means of a relaxed energy scan (Figure S24). The thermochemistry found for
comproportionation starting from dppfNiII(nap)(sulf) instead of dppfNiII(ph)(sulf) is given in brackets.
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Probing the Active Species in Catalysis using dppfNiICl
3
4
Improving the catalytic activity of Ni(I) species such as dppfNiICl could provide an alternative
strategy to increase precatalyst performance, as then formation of Ni(I) complexes would be less
problematic. Although a poor precatalyst at room temperature, dppfNiICl is a competent
precatalyst for SMC reactions of aryl sulfamates at elevated temperature suggesting that this
approach is feasible (Table S1). However, the pathway for activation of dppfNiICl and the
intermediates during catalysis at elevated temperature are unknown, preventing rational
improvements. There is no detectable reaction between dppfNiICl and 1 equivalent of the
electrophile naphthalen-1-yl sulfamate; however, a relatively slow reaction occurs with the
nucleophile 4-methoxyphenylboronic acid in the presence of base at elevated temperature (see
SI). In this reaction, diamagnetic species are formed, implying that the Ni(I) complex can form
closed-shell Ni complexes under the catalytic conditions. Although the exact speciation of the
products is currently unclear, this reactivity is consistent with the similar trends in catalytic
performance observed for precatalysts in the Ni(0), Ni(I), and Ni(II) oxidation state (vide infra).
Furthermore, in a stoichiometric experiment containing dppfNiICl, 1 equivalent naphthalen-1-yl
sulfamate, 2.5 equivalents 4-methoxyphenylboronic acid, and 4.5 equivalents of K3PO4, cross-
coupled product is observed (see SI), along with, a very small amount of organic by-products
consistent with the presence of a Ni(I) naphthyl species, such as dppfNiInap. This suggests that
some of the comproportionation processes that are operative in the dppfNiII(o-tol)(Cl) cycle may be
applicable here as well.
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The efficiency of dppfNiICl as a precatalyst is heavily influenced by the ease at which substrates
undergo oxidative addition. Previous studies have demonstrated that phenyl halides are more
difficult to oxidatively add than naphthyl halides,3a though aryl halides in general are more likely
to undergo oxidative addition compared to aryl sulfamates.3c We compared the GC yields of
cross-coupled product using dppfNiICl as a precatalyst at 50 °C for 4 hours for the SMC reactions
of 1-chloronaphthalene, naphthalen-1-yl sulfamate and 4-trifluoromethylphenyl sulfamate with
4-methoxyphenylboronic acid (Scheme 5). The yield of product with 4-trifluoromethylphenyl
sulfamate was only 9%, while when naphthalen-1-yl sulfamate was used as the substrate a 24%
yield was obtained. Both of these are vastly inferior to 1-chloronaphthalene, which gave a yield
of 90%. The trend in yields based on the difficulty of oxidative addition parallels that seen when
using dppfNiII(o-tol)(Cl) as a precatalyst (as indicated by the substrate scope), as well as when using
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dppf2Ni0 as a precatalyst (see SI), which may imply that the same catalytically active species play
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9
a role in the catalytic cycle using dppfNiICl and dppfNiII
.
(o-tol)(Cl)
OSO2NMe2
Cl
OSO2NMe2
<
<
F3C
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relative ease of oxidative addition
2.5 mol% dppfNiICl
CF3
OSO2NMe2
B(OH)2
4.5 equiv. K3PO4
9% yield
+
toluene, 50 °C
F3C
MeO
MeO
4 hr
MeO
2.5 equiv.
OMe
2.5 mol% dppfNiICl
OSO2NMe2
B(OH)2
4.5 equiv. K3PO4
+
24% yield
toluene, 50 °C
4 hr
2.5 equiv.
OMe
2.5 mol% dppfNiICl
4.5 equiv. K3PO4
Cl
B(OH)2
+
90% yield
toluene, 50 °C
MeO
2.5 equiv.
4 hr
Scheme 5. SMC reactions catalyzed by dppfNiICl using substrates that are increasingly more difficult to
oxidatively add.
To further assess whether catalysis using dppfNiICl proceeds through similar intermediates to
dppfNiII(o-tol)(Cl), a preferential product formation reaction in which sulfamate substrates with
opposite electronic properties were coupled with only 1 equivalent of boronic acid catalyzed by
2.5 mol% of dppfNiII
,
dppfNiICl, or dppf2Ni0 at 80 °C for 24 hours was performed (Scheme
(o-tol)(Cl)
6). Comparison of the resulting ratio of cross-coupled products formed provides evidence on the
mechanisms of each precatalyst – if the ratios are similar, then the precatalysts most likely
operate through similar intermediates, implying a similar catalytic cycle. However, if the ratios
are drastically different, the catalytic cycles may be distinct from one another. The results
indicate that, within error, the Ni(II), Ni(I), and Ni(0) systems give the same ratio of products,
with preference for the electron-withdrawing cross-coupled product. This suggests that,
regardless of the starting oxidation state of the precatalyst, the intermediates in the catalytic cycle
are potentially similar.
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Scheme 6. Preferential product formation for SMC reactions catalyzed by dppfNiII
,
dppfNiICl, or
(o-tol)(Cl)
dppf2Ni0 with aryl sulfamates of differing electronic properties and only one equivalent of boronic acid.
Ratios are the average of two runs with naphthalene as an internal standard.
All of our current evidence indicates that dppfNiICl is forming the same active catalyst as dppfNiII
(o-
tol)(Cl). We suggest that dppfNiICl can be converted to diamagnetic species (Ni(0) or Ni(II)) in the
presence of boronic acid and base, which can subsequently enter the same catalytic cycle as that
of dppfNiII(o-tol)Cl.. With substrates that undergo rapid oxidative addition the Ni(0) species is more
likely to enter into the Ni(0)/Ni(II) catalytic cycle rather than comproportionate back to Ni(I).
This explains why the catalytic activity of dppfNiICl is dependent on the electrophile and is
consistent with the observation that aryl chlorides undergo coupling at room temperature15
whereas aryl sulfamates are only reactive at elevated temperature. At this stage it is unclear
whether activation of dppfNiICl occurs via disproportionation into Ni(0) and Ni(II) species, via
direct transmetallation to a Ni(I) aryl, followed by decomposition to a Ni(0) complex or through
an alternative pathway. In future work, we will explore this process in more detail, which may
lead to the development of improved Ni precatalysts.
Conclusions
We have shown that dppfNiII(o-tol)(Cl) is a highly active precatalyst for SMC reactions involving
aryl sulfamates. This system is so active that it can couple some substrates using low catalyst
loading at room temperature. Mechanistic studies reveal that part of the reason for the high
activity of dppfNiII(o-tol)(Cl) is that it undergoes rapid activation to Ni(0). However, the reduction to
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Ni(0) is not completely selective and some of the Ni(I) complex, dppfNiICl, is formed via
comproportionation during the activation process. Although dppfNiICl is catalytically active at
elevated temperature, it is not as active as dppfNiII(o-tol)(Cl), and therefore the suppression of Ni(I)
formation should result in more active precatalysts. Computational studies reveal that a key step
in the generation of dppfNiICl is the formation of a dinuclear species that contains a bridging dppf
ligand. In this complex, one of the nickel centers binds to the phenyl ring of dppf, which suggests
that the modification of the ligand to prevent bridge formation may be a viable strategy to
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prevent the generation of dppfNiICl. Our studies also reveal that a second Ni(I) species, dppfNiIsulf
,
is formed during catalysis using dppfNiII(o-tol)(Cl). This species is also formed via a
comproportionation reaction between Ni(0) and Ni(II) species. Preventing this process from
occurring is also likely to result in more active systems, as this off-cycle reaction requires both
active nickel species and the electrophile. Overall, even though we report a highly active
precatalyst, our results show that there is significant room for further precatalyst improvement.
This will be the goal of future research in our laboratory.
Acknowledgements
NH acknowledges support from the NSF through Grant CHE-1150826 and NIHGMS under
Award Number R01GM120162. DB and AN acknowledge support from the Norwegian
Research Council through the Center of Excellence for Theoretical and Computational
Chemistry (CTCC) (Grant No. 179568/V30) and the Norwegian Metacenter for Computational
Science (NOTUR; Grant nn4654k). DB also thanks the EU REA for a Marie Curie Fellowship
(Grant CompuWOC/618303). AN thanks the Norwegian Research Council for the grants
221801/F20 and 250044/F20. MM 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 (GWB and
DJV). NH is a Camille and Henry-Dreyfus Foundation Teacher Scholar. We thank Professors
James M. Mayer and Nathan D. Schley for valuable discussions and Dr. Brandon Q. Mercado for
assistance with X-ray crystallography.
Supporting information available
Full characterizing data and experimental and computational procedures are available free of
charge via the Internet at http://pubs.acs.org.
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26. The organic product 1-(2'-methylphenyl)naphthalene was also detected by GC. This is likely formed via
disproportionation of dppfNiIo-tol and dppfNiInap to generate dppfNiII(o-tol)(nap) followed by reductive elimination; see the
SI.
27. Standley, E. A.; Jamison, T. F. J. Am. Chem. Soc. 2013, 135, 1585.
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catalysts see: Lennox, A. J. J.; Lloyd-Jones, G. C. Angew. Chem. Int. Ed. 2013, 52, 7362.
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30. Benzene was used instead of toluene as the solvent for computational simplicity, as some reactions required the
use of explicit solvent. For further details refer to the SI.
31. The DZP basis sets used with the M06L functional include the relativistic-ECP LANL2DZ(f) for Ni, 6-31+G(d)
for Cl and 6-31G(d,p) for P, C, K and H. This theory level was used for full geometry optimization, without any
geometry or symmetry constraints. Analytical frequencies were also computed with this DFT method to classify all
stationary points as either minima (no imaginary frequencies) or transition states (single imaginary frequency).
These calculations were used to determine the thermochemistry, including the zero-point, thermal and entropy
energies for a 1M standard state. The potential energies were further refined with the M06 functional and the TZP
basis sets, including the relativistic-ECP LANL2TZ(f) for Ni, 6-311+G(d) for Cl and 6-311G(d,p) for P, C, K and H.
Further details on the computational methods are provided in the SI.
32. Based on a recent report (see Matsubara, K.; Yamamoto, H.; Miyazaki, S.; Inatomi, T.; Nonaka, K.; Koga, Y.;
Yamada, Y.; Veiros, L. F.; Kirchner, K. Organometallics 2016, In Press) we also modelled dppfNiIsulf as a dimeric
species. The formation of the dimeric species is endoergic from the monomer by 2.6 kcal mol-1.
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