Evidence for Photocatalyst Involvement in Oxidative Additions of Nickel-Catalyzed Carboxylate O-Arylations

Article abstract of DOI:10.1021/jacs.0c02848

Dual photocatalysis and nickel catalysis can effect cross-coupling under mild conditions, but little is known about the in situ kinetics of this class of reactions. We report a comprehensive kinetic examination of a model carboxylate O-arylation, comparing a state-of-the-art homogeneous photocatalyst (Ir(ppy)3) with a competitive heterogeneous photocatalyst (graphitic carbon nitride). Experimental conditions were adjusted such that the nickel catalytic cycle is saturated with excited photocatalyst. This approach was designed to remove the role of the photocatalyst, by which only the intrinsic behaviors of the nickel catalytic cycles are observed. The two reactions did not display identical kinetics. Ir(ppy)3 deactivates the nickel catalytic cycle and creates more dehalogenated side product. Kinetic data for the reaction using Ir(ppy)3 supports a turnover-limiting reductive elimination. Graphitic carbon nitride gave higher selectivity, even at high photocatalyst-to-nickel ratios. The heterogeneous reaction also showed a rate dependence on aryl halide, indicating that oxidative addition plays a role in rate determination. The results argue against the current mechanistic hypothesis, which states that the photocatalyst is only involved to trigger reductive elimination.

Full text of DOI:10.1021/jacs.0c02848

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Article
Evidence for Photocatalyst Involvement in Oxidative
Additions of Nickel-Catalyzed Carboxylate O-Arylations
Jamal A. Malik, Amiera Madani, Bartholomäus Pieber, and Peter H Seeberger
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 May 2020
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Evidence for Photocatalyst Involvement in Oxidative
Additions of Nickel-Catalyzed Carboxylate O-Arylations
Jamal A. Malik,† Amiera Madani,†‡ Bartholomäus Pieber,*† and Peter H. Seeberger*†‡
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†Department of Biomolecular Systems, Max-Planck-Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476
Potsdam, Germany.
‡Department of Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin, Germany.
ABSTRACT: Dual photo- and nickel-catalysis can effect cross-coupling under mild conditions, but little is known about the in
situ kinetics of this class of reactions. We report a comprehensive kinetic examination of a model carboxylate O-arylation,
comparing the state-of-the-art homogeneous photocatalyst (Ir(ppy)3) with a competitive heterogeneous photocatalyst
(graphitic carbon nitride). Experimental conditions were adjusted such that the nickel catalytic cycle is saturated with excited
photocatalyst. This approach was designed to remove the role of the photocatalyst, by which only the intrinsic behavior of
the nickel catalytic cycles are observed. The two reactions did not display identical kinetics. Ir(ppy)3 deactivates the nickel
catalytic cycle and creates more dehalogenated side product. Kinetic data for the reaction using Ir(ppy)3 supports a turnover-
limiting reductive elimination. Graphitic carbon nitride gave higher selectivity, even at high photocatalyst-to-nickel ratios.
The heterogeneous reaction also showed a rate dependence on aryl halide, indicating that oxidative addition plays a role in
rate determination. The results argue against the current mechanistic hypothesis, which states that the photocatalyst is only
involved to trigger reductive elimination.
INTRODUCTION
Palladium catalysis is key to many conceptual and practical
advances in modern organic chemistry, but the scarcity of
palladium projects poorly for long-term use. As such,
transferring well-defined reactivities of palladium to nickel,
an isoelectronic and more abundant metal, has been an
explicit goal of catalysis for more than fifty years. Low-
valent nickel species are capable of undergoing oxidative
additions readily, but the subsequent reductive
eliminations (RE), particularly for Ni(II) complexes, are
thought to be comparatively difficult.1 Nickel couplings are
hence believed to go through higher-valent intermediates,2-
3
accessed by stoichiometric redox modulators, such that
the RE is more favorable.4-5
The combination of photocatalysis with nickel catalysis has
provided an elegant pathway by which nickel can turn over
without adding excessive reductants or harsh conditions.6-7
Iridium polypyridyl complexes were found to act as
photocatalysts (PCs) to effect C–N, C–O, C–S, and C–C
couplings using nickel(II) precatalysts.8-11 Subsequent
reports showed that the homogeneous iridium
photocatalysts can be replaced with heterogeneous
graphitic carbon nitride (g-CN) semiconductors, rendering
the overall transformations noble-metal-free.12-16
Scheme 1. A) The two dual photo- and nickel-catalyzed
reactions studied in this work. Standard conditions shown.
Deviations from these conditions in any subsequent figure will
be noted. B) Mechanistic hypothesis (2017).17
photocatalyst, which enables C–O bond formation.18-19
Stern-Volmer quenching studies,17 transient absorption
spectroscopy,18 and computational studies19 have been
used to support quenching of Ir(ppy)3 by a potential
nickel(II) intermediate.
The current mechanistic proposal for a relatively well-
studied carboxylate O-arylation (Scheme 1A) in this family
of reactions is depicted in Scheme 1B.17 Numerous common
nickel(II) precatalysts are viable, which are thought to
undergo two single-electron transfers to a bipyridyl Ni(0) 4.
From this reduced species, oxidative addition to form 5 is
facile. The catalyst resting state 6 is unable to undergo the
necessary reductive elimination. To close the cycle, 6
receives an energy transfer from the excited state of the
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Broadly, the substrate scopes for both homogeneous
interaction between photocatalyst and metal catalyst.19, 28
However, no in-depth kinetics studies of any of these
reactions have been disclosed.
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(Ir(ppy)3) and heterogeneous (g-CN) variations of carbon–
heteroatom couplings contain only electron-poor aryl
halides and electron-neutral or rich coupling partners
(HNR2, HOR, HSR, etc.). To our knowledge, these limitations
have not been explicitly discussed in a mechanistic context.
Kinetics studies of catalytic systems that observe native
reaction conditions throughout their entire course can
afford a wealth of qualitative and quantitative information
usually inaccessible from studies of a narrower scope.29-30
However, “native” reaction conditions are typically based
on the methodology studies where the primary aim is the
optimization of yield. Studies of dual photo- and nickel
catalytic reactions under such conditions may give data
obfuscated by rate-limiting processes derived from
interaction between the PC and metal catalyst. Kinetically,
this may paint an incomplete picture of the reaction, but
these data could arguably be useful to synthetic chemists
considering using such a method. We therefore sought to
observe the homogeneous and heterogeneous dual photo-
and nickel-catalyzed O-arylations in two regimes each. The
first would be closer to the standard conditions obtained
during methodology development (“photon-limited”),
geared toward understanding overall reaction behavior.
The second would be in a regime in which the metal catalyst
is saturated with excited photocatalyst species (“photon-
unlimited”). Under such conditions, photons are essentially
treated as a reagent in high excess. Data obtained in this
regime allow us to both evaluate the intrinsic kinetics of the
nickel cycle, as well as enable a more rigorous comparison
between data sets of different photocatalysts.
The Ir(ppy)3-catalyzed homogeneous
carboxylate O-
arylation accommodates only electron-withdrawing aryl
bromides, and electron-withdrawing carboxylic acids are
absent. Such a combination could be explained by arguing
that an SNAr-type reductive elimination is required.
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However, tension between the existing mechanism and the
resulting substrate scopes surfaced during our
development of the heterogeneous congener using
graphitic carbon nitride photocatalysts.12 During a cursory
kinetic study, methyl 4-iodobenzoate 1 (96%, 4h) coupled
considerably faster than methyl 4-bromobenzoate (88%,
48h) with N-Boc proline 2. Once the nickel catalytic cycle is
at the resting state 6, the differences between an aryl iodide
and bromide are irrelevant, as only the aryl ring remains on-
cycle. This discrepancy in rate must therefore arise from the
oxidative addition or ligand exchange step. As even aryl
chlorides show facile proclivities towards oxidative
addition with low-valent nickel in non-photochemical
reactions,20 and the homogeneous analogue converted aryl
bromides efficiently, we began to question whether the
currently accepted mechanism is operational with the
heterogeneous congener. Given that we found the same
electronic substituent limitations with g-CN as for Ir(ppy)3,
albeit with iodides instead of bromides, we further
wondered if there were mechanistic commonalities among
the two O-arylations.
As no in situ studies exist to date for any dual nickel- and
photocatalyzed cross-couplings, comparison of the photon-
limited and photon-unlimited regimes with each other for
the two reactions would be of general interest. We
anticipated that we would see differences between the
photon-limited and photon-unlimited regimes, potentially
in the magnitude of the reagents’ coefficients in the rate
laws.
Electron deficiency of an aryl halide can accelerate oxidative
additions, as the aryl halide is itself formally reduced. In this
vein, aryl halide limitations in this class of reactions could
be explained by scission of the aryl halide bond that pushes
at the energetic boundaries of photocatalytic reductions.
Reduction potentials of common aryl halides range from –
1.0 to –3.5V vs. SCE21-22, with electron-donating groups and
higher-row halides ranking as more difficult. The iridium
polypyridyl complex Ir(ppy)3 used in the homogeneous O-
arylation has a reduction potential of –1.73V, and substrate
limitations could be a marker of the Ir(III)*/Ir(IV) potential
within the aforementioned range.23 Such logic has been
invoked for the thioetherification of aryl iodides24 as well as
dehalogenations25-26 with this exact photocatalyst. Stern-
Volmer and transient absorption studies showed that aryl
iodides could in fact quench the excited triplet state of
Ir(ppy)3,24 forming an aryl radical.
Most importantly, the intrinsic, photon-unlimited kinetics
of both reactions should be compared with each other and
to the extant mechanistic hypothesis. The kinetics in
photon-unlimited regimes of the homogeneous and
heterogeneous reactions should be identical since the PC
should drop out of the rate law. The extant hypothesis for
the dual photo- and nickel-catalyzed carboxylate O-
arylation, congruent with the accrued understanding of
nickel catalysis, is that the PC enables a turnover-limiting
reductive elimination.17 Thus, we predicted that the photon-
unlimited regime for both reactions would give rate ~ k[Ni].
RESULTS
I. Heterogeneous (graphitic carbon nitride) PC
With these considerations in mind, we set out to answer
three basic questions: 1) do the heterogeneous and
homogeneous reactions proceed by the same mechanism?;
if so, 2) do they both conform to the extant hypothesis, in
which reductive elimination is turnover-limiting; and 3) are
the turnover-limiting steps and the steps which require a
photocatalyst the same?
a. Photon-limited (3.33 mg/mL g-CN, 5 mM Ni•L, 50% lamp
power)
First, the kinetics of the carboxylate O-arylation of aryl
iodides using the graphitic carbon nitride CN-OA-m31 as a
photocatalyst in photon-limited conditions were analyzed.
These photocatalytic reactions can be tracked by attaching
a custom vial to an in situ infrared probe.12 Using a stronger
LED lamp for increased photon flux and improved
reproducibility, we ensured that the infrared technique
tracked reaction progress by verification with an
orthogonal method (Figure S2).
RESEARCH PLAN AND HYPOTHESES
Numerous mechanistic studies have been undertaken for
photocatalytic reactions in general.27 Inquiries on dual
nickel- and photocatalyzed carbon–heteroatom cross-
couplings have largely focused on the character of the
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From a cursory, qualitative glance, these reactions at the
native conditions display no unusual behavior, except for
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exhibiting a short induction period. A series of experiments
were conducted to assess which reagents were responsible
for this induction (Figure S5). Delaying the injection of
NiCl2•glyme and its bipyridyl ligand or aryl iodide 1 resulted
in immediate productive catalysis. Delayed injection of
carboxylic acid
2
retains the induction period.
Conspicuously, delaying addition of the base N-tert-
butylisopropylamine (BIPA) resulted in a reaction profile
slightly suggestive of catalyst activation,32 indicating that
the secondary amine plays a role more significant than
simply that of a Brønsted base.
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Varying the nickel concentration from 5-20 mM
unsurprisingly resulted in no rate change (Figure S6). At 5
mM Ni, no catalyst deactivation or product inhibition was
observed (Figure S8), which is expected at such a high metal
catalyst concentration. Surprisingly, modulation in [1]
resulted in a fractionally positive order (Figure S9) for the
aryl iodide. Carboxylic acid 2 showed a zero-order
dependence (Figure S10). Reagent orders obtained in this
regime should be considered with some measure of caution
as the interactions between PC and Ni are ill-defined.
However, we were curious if the reagent order of the aryl
iodide would persist in the photon-unlimited regime, as it
would be a significant clue to help resolve the questions
posed above.
b. Photon-unlimited (3.33 mg/mL g-CN, 0.2 mM Ni•L, 100%
lamp power)
To switch from the photon-limited to the photon-unlimited
regime, we needed to increase the ratio of photons and/or
PC to nickel. Although numerous photocatalytic reactions
with metal centers have been tracked with in situ
apparatuses,33 to our knowledge only one study has
described finding a region in which the metal’s access to
excitation is carefully controlled to be unimpeded.34 In the
work of Lehnherr et al., light directly excited a metal
catalyst, with no photocatalytic intermediary. To find a
region in which their metal catalyst was not limited by
throughput of photons, initial rate was plotted against
catalyst concentration, and at lower concentrations a
roughly linear correlation is apparent. To make a
comparable plot, we retained a high PC loading and
maximum lamp power (Figure 2A).
Figure 2. Key experiments of heterogeneous congener. A)
Overview of where the photon-limited and unlimited regimes
could be identified. B) Time-shifted same excess
experiments. Overlay indicates lack of catalyst deactivation
or product inhibition. C) Positive-order dependence of aryl
iodide observed.
Moving from high to low nickel concentrations along this
plot surprisingly did not provide an identical shape to that
of the literature precedent. Specifically, we observed an
unexpected “peak” where catalysis has a much higher rate,
around 1 mM. Although further studies are required to
account for this behavior, it is possible that, above a certain
threshold, the metal catalyst engages in some combination
of comproportionation35-36 and/or higher-order nickel
species thought to be catalytically relevant.37-38
produce data that reflect the intrinsic characteristics of the
nickel cycle.
To probe the robustness of the nickel catalyst, two “same-
The area at very low concentration of nickel would likely
provide a regime in which the nickel catalytic cycle was not
limited by access to an excited photocatalytic species. To
confirm this was the case, at low concentrations we used
Variable Time Normalization Analysis (VTNA)39 to find a
first-order dependence on nickel between 0.15–0.25 mM
(Figure S11). Kinetic studies in this area are expected to
40
excess” experiments were conducted29,
under photon-
unlimited conditions and the less concentrated was time-
shifted on the x-axis (Figure 2B). Overlay here indicates that
the product does not inhibit catalysis, nor does meaningful
or disproportionate catalyst deactivation occur.
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Experiments to determine the reagent orders of the deactivation of the nickel throughout the course of the
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substrates revealed that aryl iodide again exhibited a
positive order dependence (Figure 2C). Due to the induction
period, first attempts at VTNA overlay were found to be
problematic (Figure S12). Elegant mathematical solutions
to this common issue have been disclosed,41 but the most
rigorous would require spectroscopic determination of the
active catalyst concentration. Repeating the different excess
experiments with delayed catalyst injections (Figure S13),
which bypass the induction period as described above,
cleanly leads to a reagent order of 0.3 between 0 and 150
mM [1].
reaction (Figure S19). In contrast to the heterogeneous
congener, no rate dependence was found for 1 or 2 (Figure
S20). Interestingly, increasing concentration of base
increases the rate (Figure S21). Again, some caution is
advised in mechanistic interpretation from these data, as
these conditions are designed to maximize yield. However,
the lack of rate dependence on aryl iodide could be a
significant finding if it persisted in photon-unlimited
conditions.
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b. Photon-unlimited (1 mM Ir(ppy)3, 0.2 mM Ni•L, 100% lamp
power)
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Examination of the dependence on reagents’ concentrations
In order to draw meaningful comparisons between the two
photon-unlimited data sets, we sought to use the same
[Ni]t=0 as was used for the heterogeneous system. As such,
finding the photon-unlimited regime for the homogeneous
reaction occurred through a reverse process from the
heterogeneous case. A short series of experiments was
conducted in which the nickel concentration was kept
constant and the photocatalyst concentration was raised,
similar to Figure 3A (Figure S22). VTNA analysis showed
first-order nickel dependence in the concentration range
around 0.2 mM Ni at 1 mM Ir(ppy)3 (Figure S24).
Corroboration that this approach gives a photon-unlimited
regime was found through data obtained in a similar regime
derived from an initial-rate plot (Figures S27-S31).
Ir(ppy)3 [X mM]
H
OH
NiCl2•glyme (0.1 mM)
dtbbpy (0.1 mM)
100 mM
150 mM
O
O
Me
Me
3
1
2
BIPA (300 mM)
DMSO (3.0 mL)
product
O
O
ArI
RCOOH
440 nm lamp (100%)
8
9
mM PC
1
3
1
0
0
0
0
8
9
Mass balance
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83
82
90
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10
8
6
4
3
5
86
97
0.5
0.25
0.125
94
5
100
Table 1. Screening to determine photocatalyst loading for
photon-limited regimes of the homogeneous reaction. Final
concentrations of product and side products determined by 1H
NMR using 1,3,5-trimethoxybenzene as an internal standard.
A major difference between the heterogeneous and
homogeneous reaction was apparent from the same-excess
experiment, where no overlay was observed (Figure 3B).
Should the product inhibit catalysis, an effect in the
heterogeneous reaction would have been observed, so we
can attribute this behavior to catalyst deactivation.
for 2, the base, and the photocatalyst provided a much less
straightforward picture. All three reagents exhibit positive
order dependence at lower concentrations and inhibitory
effects at higher concentrations (Figures S14-16).
Experiments varying the amounts of substrate and coupling
partner were conducted to obtain the reagent orders of our
reactants. In contrast to the heterogeneous reaction, we
found the rate to be essentially independent of the
concentration of 1 (Figure 3C). The dependence on [2] was
not found to be significant (Figure S25). Last, we modified
the amount of base while keeping all other reagents
constant. Similar to the observation from the photon-
limited data set, this change was the sole factor that
accelerates the homogeneous reaction (Figure S26).
II. Homogeneous (Ir(ppy)3) PC
We began the homogeneous studies by attempting to
determine a proper photocatalyst loading that would
enable photon-limited conditions. Initial experiments with
0.1 mM Ni•L and the standard (1 mM) photocatalyst
concentration17 gave unsatisfactory yields. We observed
dehalogenation accompanying productive catalysis (Table
1). Formation of the phenol side product 9 appears to be
independent of an unfavorable PC-to-Ni ratio.
DISCUSSION
High concentrations of Ir(ppy)3 accelerate the consumption
of 1 but not significantly the rate of product formation
(Figure 3A). This finding is in striking contrast to the
heterogeneous analogue, where slower product formation
is a function of slower consumption of 1 at higher PC
loading (Figure S16). Experiments with 0.125 mM PC
loading (Figure 3A, blue) appear to be limited by the relay
of energy from PC to Ni (Figure S17), and are the basis for
the photon-limited studies.
The most conspicuous finding of this study was the
rejection of the hypothesis that the kinetics of both systems
would give identical rate laws. In other words, as particular
care was taken such that the nickel cycle was saturated with
excited photocatalyst species for both systems, the intrinsic
kinetics of a nickel cross-coupling cycle should have been
identical between the two had the mechanisms been the
same.
The chief quantitative finding of this study is the fractional
dependence of aryl iodide 1 in the heterogeneous rate law.
To some degree in the heterogeneous congener, oxidative
addition is turnover-limiting. We propose that this is a
result of direct photocatalytic activation of the substrate
(Figure 4B). The fractional order arises as this activation
occurs off of the nickel cycle. Nickel is first-order as it
intercepts the radical species on the nickel catalytic cycle.
a. Photon-limited (0.125 mM Ir(ppy)3, 0.1 mM Ni•L, 100%
lamp power)
The first noteworthy qualitative observation of iridium-
catalyzed O-arylations is the lack of induction period.
Catalysis begins immediately in a positive-order fashion.
Increasing concentration of nickel leads to increased rate,
which was determined to be a first-order dependence by
VTNA (Figure S18). A same-excess experiment shows no
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formation of oxidative addition intermediate 5 is still
1
limited by the kinetically relevant halide fragmentation.
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We reject the hypothesis that photocatalysts are required
only as a late-cycle trigger for RE. We contend that the
photocatalyst is required for at least one additional point on
the catalytic cycle, namely for single-electron transfer to the
aryl halide. Substrate limitations for dual photo- and nickel-
catalyzed carbon–heteroatom cross-couplings derive from
this elementary step. The most obvious example is the far
superior conversion of aryl bromides in this homogeneous
O-arylation compared to the heterogeneous congener. Such
a framework also harmonizes the mechanisms by which
these transformations occur with the existing body of
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photocatalytic
dehalogenations
and
radical-based
transformations.25-26
To augment our understanding of the heterogeneous
reaction, we created a Hammett plot examining rate
dependencies on aryl iodides with substituents of varying
electronic character (Figure 4C). Qualitatively, this shape is
also
seen
for
the
oxidative
addition
of
tris(triphenylphosphine)nickel(0) to aryl chlorides.20 The ρ
value (2.1) is far below that of this more traditional
oxidative addition (8.8), thought to proceed through an
SNAr-type
mechanism. This could be explained by
differences in ligand systems and halides, but also could
point to a lowered dependence on the electronic substituent
due to a nonconcerted oxidative addition.
With
a rate law proportional only to the nickel
concentration, data for the homogeneous reaction could
reasonably fit three turnover-limiting steps: a unimolecular
rearrangement, ligand dissociation, or reductive
elimination. We have observed nothing to support or reject
the first two. Given that the incumbent hypothesis is that RE
is turnover-limiting, our data support the existing
proposals. As we had originally predicted, our kinetic data
here likely reflects the limitations inherent to nickel
catalysis.
Whether or not 6 requires a photocatalyst to trigger RE
likely depends on the oxidation state of this intermediate. It
has been clearly demonstrated that a Ni(II) resting state
cannot undergo RE without photocatalytic excitation.17-19
However, extensive literature precedent points to the
viability of multiple nickel oxidation states in cross-
coupling reactions in very different conditions,35, 44-45 and
the oxidation state of the on-cycle intermediate for these
photochemical reactions has yet to be convincingly
resolved. Should this intermediate require activation via
energy/electron transfer in the homogeneous reactions, it
would not be turnover-limiting, given the photon-unlimited
environment.
Figure 3. Key experiments of homogeneous congener. A)
Identification of photon-limited regime by reaction
fingerprint; reactions progress of blue curve appears to be
limited by interaction between PC and Ni. B) Same excess
experiment shows catalyst deactivation intrinsic to iridium-
catalyzed O-arylations. C) Rate is independent of [1].
Of note is the fact that the only way to accelerate the
homogeneous reaction was by addition of more secondary
amine base, which is already in large excess. We offer three
potential explanations. First, and most likely, the secondary
amine donates an electron to [Ir(ppy)3]+ to regenerate the
photocatalytic cycle. We can assume that the concentration
of 2 requires equimolar amounts of base for deprotonation,
and extra amine beyond that point fulfills various roles
including weak ligand and electron source. Second, the base
is potentially involved in the organization of the nickel
catalyst to some degree, evinced by the “reaction
This process may have been overlooked because it is not
necessarily turnover-limiting. The reduction potential of
Ir(III)*/Ir(IV), –1.73V, is sufficient to donate an electron to
the aryl halide 1;25, 42-43 this step is photocatalyst-dependent
but fast for aryl iodides (Figure 4B). In contrast, the
analogous excited state of the graphitic carbon nitride used
in this study is less reducing (up to –1.65V vs. SCE). The
capacity for electron transfer is worse, and therefore even
in conditions that can be considered photon-unlimited,
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fingerprint” of the heterogeneous reaction when the base is
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injected after a delay (Figure S5). As such, it is possible that
its presence does not outright accelerate the reaction as
much as it is as guard against decelerating or deactivating
processes. Alternatively, or additionally, weak coordination
of the base to the square planar pre-RE complex could
create a more encumbered five-coordinate complex that is
more prone to elimination,46-47 or is better tuned to absorb
an energy transfer.28
Qualitatively, two main observations stand out for iridium-
catalyzed carboxylate O-arylations. First, this system
inherently tends to be less selective. In the photon-
unlimited regime, at reactions with reasonable
concentrations of substrates, yields were frequently in the
70-80% range, often accompanied by significant
dehalogenation of the aryl iodide. We believe that this
results from speeding up photocatalytic activation of the
aryl iodide beyond the capacity of the nickel species to trap
the radical on-cycle.
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Second, the homogeneous reactions have an intrinsic
propensity for catalyst deactivation. Kinetics for the
photon-limited and photon-unlimited regimes were
essentially the same outside of the fact that catalyst
deactivation was not observed in the photon-limited
regime. We contend that all dual iridium- and nickel-
catalyzed processes operate at inflated nickel
concentrations to compensate for this inherent
deactivation.
Qualitatively, the induction period in the heterogeneous
congener notably differs from the homogeneous reaction.
We observe small amounts of consumption of aryl iodide
during the delay before product begins to form. If reduction
of the Ni(II) precatalyst to a lower-valent species is
requisite for productive catalysis, it is possible that this
reduction is parallel to or intertwined with dehalogenation.
An unexpected revelation of the heterogeneous reaction is
seen in the studies modulating the photocatalyst loading
(Figure S16). In contrast to the homogeneous reaction, in
which additional PC accelerates consumption of
1
indiscriminately, excess g-CN loading shows slower
catalysis but with reasonable preservation of selectivity. We
again attribute this to the weaker reduction potential of
graphitic carbon nitrides, and is a potential upside to the
more limited scope. Such a finding portends well for
scalability as well as for sensitive or late-stage
functionalization. Careful optimization of the ratios of
photocatalyst, nickel, and substrate is far less likely to be
necessary with graphitic carbon nitrides.
CONCLUSION
Efforts to swap photocatalysts in dual photo- and metal-
catalytic systems may not preserve the inherent reactivity
of the metal catalytic cycle. Homogeneous and
heterogeneous esterifications differ primarily in that the
heterogeneous congener showed a rate dependence on the
aryl halide substrate. We ascribe this to the nickel trapping
an off-cycle radical anion generated by the photocatalyst
and the aryl halide. In this sense, the requirements for
electron-withdrawing substrates may be ascribed to an
energetic barrier that is independent of the nickel catalytic
cycle. Overcoming such limitations likely must occur
Figure 4. (A) Key findings of this study. (B) Updated
mechanistic proposal. Secondary amine base is proposed to
close the photoredox cycle by serving as single electron donor
(SED). (C) Hammett plot for heterogeneous congener
supports that oxidative addition is to some degree turnover-
limiting.
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(Janssen Pharmaceutical) and anonymous reviewers for
helpful discussions.
through photocatalyst development and tuning to maximize
1
the reduction potential of the excited PC. Alternatively,
methods to front-load the energetic relay from external
source to photocatalyst to substrate show great promise.48
However, as our PC and nickel screenings to find different
regimes show, using a PC that is too reducing for the chosen
substrate and/or metal catalyst can lead to overreduction
and catalyst deactivation. Countering this requires careful
modulation of PC and metal catalyst concentrations. Hence,
for the Ir(ppy)3-catalyzed O-arylation shown here, a
photon-limited approach is desirable. Optimization of the
graphitic carbon nitride conditions did not require such
considerations. At least partially due to the reduction
potential of the PC*, nickel catalyst concentration could be
lowered up to 50x from what was used in methodological
development without observing a significant amount of
nickel catalyst deactivation. Additionally, peak catalytic
activity was found at a much lower concentration of nickel
than used in method development. The choice of
photocatalyst may, among other things, be determined by
the electronic character of the substrate, as less
dehalogenation was observed in the g-CN case. We believe
that photocatalysts with weaker reduction potentials, such
as graphitic carbon nitrides, are less likely to participate in
a Ni(0)/Ni(II) cycle.
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AUTHOR INFORMATION
Corresponding Author
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* E-mail: bartholomaeus.pieber@mpikg.mpg.de
peter.seeberger@mpikg.mpg.de
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Highly Chemoselective Iridium Photoredox and Nickel Catalysis
for the Cross-Coupling of Primary Aryl Amines with Aryl
Halides. Angew. Chem., Int. Ed. 2016, 55, 13219-13223.
Jamal A. Malik: 0000-0003-3726-5902
Amiera Madani: 0000-0001-8995-0966
Bartholomäus Pieber: 0000-0001-8689-388X
Peter H. Seeberger: 0000-0003-3394-8466
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Notes
The authors declare no competing financial interest. A version
of this research was previously posted to ChemRxiv: DOI
10.26434/chemrxiv.11973141.v1
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We gratefully acknowledge the Max-Planck Society for
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Deutsche Forschungsgemeinschaft (DFG, German Research
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2008/1 (UniSysCat)–390540038 for financial support. B.P.
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