Unveiling Potent Photooxidation Behavior of Catalytic Photoreductants

Article abstract of DOI:10.1021/jacs.1c00399

We describe a photocatalytic system that reveals latent photooxidant behavior from one of the most reducing conventional photoredox catalysts, N-phenylphenothiazine (PTH). This aerobic photochemical reaction engages difficult to oxidize feedstocks, such as benzene, in C(sp2)-N coupling reactions through direct oxidation. Mechanistic studies are consistent with activation of PTH via photooxidation and with Lewis acid cocatalysts scavenging inhibitors inextricably formed in this process.

Full text of DOI:10.1021/jacs.1c00399

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Unveiling Potent Photooxidation Behavior of Catalytic
Photoreductants
Karina Targos,† Oliver P. Williams,† and Zachary K. Wickens*
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ABSTRACT: We describe a photocatalytic system that reveals latent photooxidant behavior from one of the most reducing
conventional photoredox catalysts, N-phenylphenothiazine (PTH). This aerobic photochemical reaction engages difficult to oxidize
feedstocks, such as benzene, in C(sp2)−N coupling reactions through direct oxidation. Mechanistic studies are consistent with
activation of PTH via photooxidation and with Lewis acid cocatalysts scavenging inhibitors inextricably formed in this process.
eactions driven by single electron transfer (SET) are
pervasive in organic chemistry. Consequently, new
(Figure 1C).36 Given the difficulty applying multiple photons
toward a challenging SET oxidation, photoredox reactions
initiated by SET oxidation are typically limited to electron-rich
hydrocarbon substrates.6,37−42
R
strategies to induce redox events are poised to profoundly
impact synthetic chemistry.1−4 Photoredox catalysis has
unlocked a broad range of attractive new transformations
through conversion of energy from readily accessible LEDs
into chemical redox potential.5−8 However, only a portion of
this energy9 can be harnessed due to inevitable energy losses
from vibrational relaxation, internal conversion, and inter-
system crossing.10 Despite tremendous effort in photoredox
catalyst design,10−17 excited state potentials beyond roughly
−2 and +2 V vs SCE remain difficult to achieve using
conventional photocatalyst design principles wherein a single
photon from commercial LEDs is used as the primary energy
source (Figure 1A).18−22 Unfortunately, this redox window
excludes numerous abundant hydrocarbon feedstocks from
facile photoinduced electron transfer.23
We questioned whether conventional photoreductants,
which typically possess persistent radical cation states, could
be repurposed as strong photooxidants using a conPET
strategy.43 We hypothesized photochemical conditions de-
signed to drive these photocatalysts toward their oxidized
congeners could reveal potent photooxidation behavior. To
probe this hypothesis, we targeted cyclic triarylamine photo-
reductants. These are a well-established and modular family of
photocatalysts21,44 and photophysical studies conducted by
Wasilewski and co-workers indicate that their radical cation
congeners exhibit photochemical activity.45 Furthermore,
intriguing studies from Wagenknecht and co-workers have
implicated photoexcitation of triarylamine radical cations
formed via SF6 reduction in alkene pentafluorosulfonylation
processes.46,47 We envisioned that photochemically accessing
these radical cations using a bystanding oxidant would offer an
ideal avenue to explore the potency of these radical cation
photooxidants.
To overcome the energetic limitations intrinsic to conven-
̈
tional photoredox catalysis, Konig and co-workers recently
designed a photocatalytic system that drives challenging
reductive SET events using the energy of two photons rather
than one. This consecutive photon-induced electron transfer
(conPET)24,25 strategy relies on a catalytic photooxidant and
sacrificial reductant that, upon irradiation, result in a potent
radical anion photoreductant (Figure 1B). Despite its
mechanistic complexity, this approach is practical and
operationally simple; it leverages inexpensive and safe LEDs
to accomplish reactions that otherwise require UV photo-
reactors or harsh chemical reductants. Following proof-of-
concept aryl halide reductions,24,26−33 this approach has
enabled photochemical alternatives to alkali metal reductants
in reactions such as Birch reductions34 and sulfonamide
cleavage.35
We selected the Nicewicz-type41 oxidative coupling of
arenes and N-heterocyclic nucleophiles as a model reaction.
This synthetically valuable transformation is representative of
the general challenges in oxidative photoredox catalysis. It has
been predominantly limited to electron-rich arene substrates,
such as anisole derivatives48 and also requires a bystanding
terminal oxidant. Difficult to oxidize arene substrates, such as
benzene, typically mandate high energy UV light (UVB or
shorter)18 or strong ground state oxidants (e.g., DDQ) that
absorb visible light.49,50 Recent progress by Lambert and co-
In contrast to the progress in photoreductions, oxidations
driven by the consumption of multiple photons have remained
elusive. We suspect that this is the consequence of two
inextricable challenges: (1) the catalyst must be a competent
photocatalyst in both the closed shell and radical cation
states5,25 and (2) the terminal oxidant must efficiently activate
the catalyst but not otherwise interfere with the reaction
Received: January 12, 2021
Published: March 16, 2021
https://dx.doi.org/10.1021/jacs.1c00399
J. Am. Chem. Soc. 2021, 143, 4125−4132
© 2021 American Chemical Society
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Figure 1. (A) Overview of redox potentials in photoredox catalysis. (B) Overview of multiphoton photoreductants. Full catalyst structures available
in SI. (C) Overview of research described herein.
a d
−
Table 1. Survey of Oxidants and Photoreductants
1
Figure 2. H NMR spectroscopic evidence supporting the working
model for catalyst deactivation pathways.
envisioned that promoting this transformation using a bench
stable and commercially available photocatalyst simply with
inexpensive LEDs would be a synthetically useful complement
to existing methods. Accordingly, this constitutes an appealing
context for our proof-of-concept experiments.
a
Reactions were conducted on a 0.05 mmol scale in 1:1 MeCN:PhH
for 24 h, unless noted otherwise, using 2 equiv oxidant or 1 atm O2.
First, we examined three distinct photoreductants21,6566, and
a range of oxidants for activity in the oxidative coupling of
benzene (Eox = 2.5 V vs SCE)67 and pyrazole 1 (Table 1). We
initially aimed to generate the catalyst radical cation congener
via photoreduction of reagents that undergo irreversible
decomposition after SET to avoid catalyst deactivation via
back electron transfer (BET). Excitingly, these data revealed
that N-phenylphenothiazine (PTH), the most reducing
photocatalyst of the series, could promote this challenging
oxidative coupling in low yield using organohalides as the
oxidant. A sufficiently strong oxidant to oxidize each catalyst to
the corresponding radical cation without additional energy
from light, NOPF6,68 provided low yield of benzene oxidation
b
Ar1 = 4-biphenyl. Ar2 = 2-naphthyl. PTH irradiated using 390 nm
c
Kessil lamp. PC-1 and PC-2 irradiated using Tuna Blue Kessil lamp.
d
1:1 TFE:PhH.
workers has introduced an alternative electrophotocatalytic
approach that employs electrochemistry and photochemistry in
concert to accomplish this energetically demanding oxida-
tion.51−53 However, while electrophotocatalysis is an exciting
emerging area of research,51,52,54−63 these reactions require
specialized electrochemical equipment (e.g., divided cells,
electrodes, and power supplies) and are technically complex
relative to purely photochemical processes.64 Thus, we
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a
photocatalyst deactivation by triplet−triplet annihilation with
O2.
Table 2. Reaction Optimization
We suspected that BET between PTH radical cation and
superoxide73 might attenuate reactivity under these conditions
(Figure 2).74 Indeed, when synthetically prepared PTH radical
cation is treated with KO2, we observe a rapid color change
1
entry
additive
yield (%)
and reformation of PTH by H NMR. Given that superoxide
generation is inextricable from aerobic catalyst activation, this
observation could account for the modest reactivity of this
catalytic system (Table 2, entry 1). As expected, addition of 5
mol % KO2 to the reaction mixture completely suppressed
product formation (entry 2). We hypothesized that additives
capable of sequestering or scavenging this inhibitor would
enhance the observed reactivity. Guided by this model, we
found addition of one equivalent of an inexpensive, redox
innocent Lewis acid, LiClO4, dramatically improved the yield
of oxidative coupling product (entry 3). Reduction of the
LiClO4 loading to a substoichiometric quantity (20 mol %)
retained the benefits of the additive, suggesting a cocatalytic
role for LiClO4 rather than it purely sequestrating stoichio-
metric byproducts (entry 4). In principle, the lithium
cocatalyst could mitigate BET by promoting superoxide
disproportionation.75,76 Consistent with this proposed Lewis
acidic role, alkylammonium salts had no impact on the reaction
(entry 5), whereas other Lewis acidic lithium salts retained the
catalytic effect (entries 6 and 7). Final tuning of the reaction
parameters revealed adjusting the solvent mixture to include a
small amount of hexafluoroisopropanol (HFIP) delivered the
desired product in 89% yield (entry 8). Substitution of PTH
with other triarylamine photoreductants or a classic metal-
based photoreductant, Ir(ppy)3, resulted in only trace yield of
1
2
3
4
5
6
7
8
none
KO2 (5 mol %)
LiClO4 (1 equiv)
LiClO4 (20 mol %)
n-Bu4NClO4 (20 mol %)
LiPF6 (20 mol %)
LiOTf (20 mol %)
LiClO4 (20 mol %)
PC-1 (5 mol %), LiClO4 (20 mol %)
PC-2 (5 mol %), LiClO4 (20 mol %)
Ir(ppy)3 (1 mol %), LiClO4 (20 mol %)
31
<2
86
73
29
64
56
89
<2
<2
<2
b
bc
,
9
10
11
bc
,
b c
,
a
Reactions were conducted on a 0.05 mmol scale in 1:1 TFE:PhH for
24 h. See SI for details. 9:1:10 TFE:HFIP:PhH solvent mixture.
Tuna Blue Kessil lamp irradiation.
b
c
products using all three catalysts. However, under 1 atm of O2,
PTH promoted oxidative coupling in promising yield (14%).
Given the enhanced stability of radical cations in fluorinated
alcohol solvents,19,53,69−71 we substituted MeCN for trifluor-
oethanol (TFE). This resulted in a modest increase in reaction
yield with PTH but only traces of product with the other two
catalysts. Of note, while most photoredox catalysts undergo
rapid intersystem crossing to a long-lived triplet,5,13 PTH is a
singlet excited state reductant.72 This property circumvents
a b
,
Table 3. Scope of Arene C−H Amination
a
Reactions conducted using 0.4 mmol of heterocycle, 8 mL of arene, and irradiated with two 390 nm Kessil lamps for 24 h with fan cooling. See the
b
c
d
e
f
g
h
i
SI for further experimental details. Isolated yields. 20% LiPF6. 1:1 HFIP:PhH solvent. NMR yield. 0% r.s.m. 31% r.s.m. 10% r.s.m. 1:1:2
MeCN:HFIP:arene solvent with 10% t-dodecyl mercaptan. 10 equiv arene, 0.1 M in 1:1 MeCN:HFIP, 10% t-dodecyl mercaptan. 5 equiv arene,
0.1 M in 1:1 MeCN:HFIP, 10% t-dodecyl mercaptan.
j
k
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Scheme 1. Light-Dependence on Induction Period and
Product Formation Regimes: (A) Standard Reaction Profile
with Continuous Irradiation; (B) Suspended Irradiation
during Induction Period; (C) Suspended Irradiation during
Scheme 3. Impact of Added Substoichiometric KO2 on Rate
with and without LiClO4
a
a
Product Formation
a
Reactions were conducted on a 0.05 mmol scale in 9:1:10
TFE:HFIP:PhH. See the Supporting Information (SI) for further
b
details. Final yield after 22 h.
ketones (3), aldehydes (4), nitriles (5), and trifluoromethyl
groups (6) were oxidatively coupled to benzene. Halogenated
pyrazoles (7 and 8) were also productively coupled despite the
fact that PTH is a potent photoreductant. Prior approaches
capable of oxidizing benzene have not been readily amenable
to the arylation of neutral heterocyclic substrates.77 In contrast,
we observed coupling of both parent pyrazole (9) and even an
electron-rich analogue (10), albeit in diminished yield relative
to the electron deficient heterocyclic coupling partners. In
addition to pyrazole derivatives, we found that 1,2,3-triazoles
(11 and 12) were amenable to oxidative coupling with
benzene. Even an exceptionally challenging to oxidize electron-
deficient arene, chlorobenzene, could be engaged in productive
C(sp2)−N coupling via arene photooxidation (13). To probe
the limits of what this catalytic system can oxidize, we
evaluated acetophenone as an arene substrate and detected at
most traces of oxidative coupling products. This result
indicates that this arene is too electronically deactivated for
oxidation under these conditions. We recognized that benzylic
C−H bonds could be a liability under these aerobic conditions;
however, we found reasonable C(sp2)−N coupling yields could
be obtained from toluene using our standard conditions and
these yields could be further improved by tuning the reaction
conditions to mitigate benzylic oxidation processes.78 Under
these modified conditions, PTH promoted the photochemical
coupling of toluene, m-xylene, and mesitylene with pyrazole
derivatives in high yield (14−21). The oxidation of m-xylene
and mesitylene could be achieved using a smaller excess of
arene, presumably due to the significantly lower oxidation
potential relative to benzene.79 Of note, while the scope and
reagent stoichiometries required for this approach are similar
to prior electrophotocatalytic systems, these photocatalytic
conditions exclusively require commercially available catalysts
and no specialized equipment outside of LED lamps.
Furthermore, this simple photocatalytic system delivers
coupling products with substantially shorter reaction times.80
Overall, these data illustrate that the scope of this photo-
chemical process described herein is on par with comple-
mentary electrophotocatalytic approaches.51,52
a
Reactions were conducted on a 0.05 mmol scale in 9:1:10
TFE:HFIP:PhH. See the Supporting Information (SI) for overlays
of total irradiation time.
a
Scheme 2. Saturation in Lithium Cocatalyst
a
Reactions were conducted on a 0.05 mmol scale in 9:1:10
TFE:HFIP:PhH.
oxidation product under these otherwise optimal conditions
(entries 9−11).
Having identified a promising catalytic system, we examined
the scope of this new process (Table 3). Pyrazole nucleophiles
bearing a range of electron-withdrawing moieties, including
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Next, we aimed to uncover preliminary mechanistic insight
into this new and unusually oxidizing photocatalytic system.
First, we collected the full reaction profile by monitoring the
yield of coupling product 2 as a function of time (Scheme 1A).
These data revealed an induction period, wherein only a trace
amount of product is formed, followed by zeroth order
formation of product that continues until nearly all of the
pyrazole is consumed (see SI for complete reaction profile). If
irradiation is temporarily suspended during the induction
period, the onset of product formation is correspondingly
delayed (Scheme 1B). Similarly, when irradiation is halted
during the product-forming regime, the reaction ceases until
irradiation resumes (Scheme 1C). Overall, these data are
consistent with a mechanism involving an initial photochemical
catalyst activation step (e.g., photooxidation of PTH to the
radical cation) followed by a product-forming regime with
either rate-limiting catalyst oxidation or benzene oxidation,
given both benzene and O2 are present in excess throughout
the reaction. Additionally, we determined the O2 stoichiometry
of the reaction by measuring gas consumption within a sealed
reaction vessel equipped with a pressure transducer (Figure
S16).81 These data indicate that just over 2 equiv of O2 are
consumed over the course of the reaction, consistent with O2
acting as only a one-electron oxidant.82 As anticipated, we
found that only minimal oxygen is consumed during the
induction period.
fully consistent with photocatalyst activation via photo-
reduction of O2. Intriguingly, we found that Lewis acid
cocatalysts could promote and maintain catalyst activation.
Beyond providing the first example of purely photochemical
benzene oxidation using inexpensive LEDs, this study provides
a roadmap to exploit known photocatalysts in new and
unconventional ways. We anticipate that continued examina-
tion of reaction conditions that force photocatalysts into
destabilized oxidation states will dramatically expand the scope
of oxidative photoredox catalysis.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00399.
■
sı
Experimental procedures, characterization data, and
spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Zachary K. Wickens − Department of Chemistry, University of
Wisconsin−Madison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0002-5733-5288;
Email: wickens@wisc.edu
Authors
Given the initially unanticipated cocatalytic role of LiClO4 in
this system, we next carefully investigated the origin of its
impact on the reaction. Omission of this additive resulted in a
modest elongation of the induction period and, subsequently,
slower product formation (see SI for details). Systematic
variation of the concentration of LiClO4 revealed that the
impact of this reaction component on rate saturates at roughly
20 mol % (Scheme 2). These data are consistent with our
working model wherein LiClO4 catalytically scavenges
inhibitory reactive oxygen species produced through photo-
chemical O2 reduction. Once the inhibitor is scavenged at a
sufficiently rapid rate, its steady state concentration will
approach zero and additional increase in cocatalyst loading is
expected to have no impact on the process. When the reaction
is charged with 5 mol % KO2 shortly after the induction
period, we observe that the reaction halts thereafter in the
absence of LiClO4. In stark contrast, a reaction containing 2
equiv of LiClO4 was unperturbed by direct addition of this
inhibitor (Scheme 3).83
On the basis of the data presented herein, we have
constructed a plausible mechanistic model, which involves:
(1) initial oxidative activation of PTH via photoreduction of
O2; (2) photoexcitation of a triarylamine radical cation to
oxidize the arene substrate;84,85 (3) trapping of arene radical
cation with pyrazole nucleophile. While lithium salts are not
mechanistically necessary to promote the photocatalytic
transformation, we suspect that these Lewis acidic cocatalysts
accelerate the reaction by promoting the disproportionation of
superoxide, an inhibitor inextricably formed in the aerobic
catalyst activation step. We envision the lithium cocatalyst is
turned over by protonation of Li2O2 by HFIP.86
Karina Targos − Department of Chemistry, University of
Wisconsin−Madison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0002-9945-0719
Oliver P. Williams − Department of Chemistry, University of
Wisconsin−Madison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0002-3897-6426
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00399
Author Contributions
†K.T. and O.P.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Tehshik Yoon and Prof. Alison Wendlandt for
helpful suggestions and manuscript proofreading. We thank the
Stahl, Weix, Yoon, and Schomaker groups for sharing their
chemical inventory. We thank Dr. Chase Salazar and Dr. Jack
Twilton (Stahl lab) for assistance measuring O2 uptake. This
work was financially supported by the Office of the Vice
Chancellor for Research and Graduate Education at the
University of Wisconsin−Madison with funding from the
Wisconsin Alumni Research Foundation. Acknowledgment is
made to the Donors of the American Chemical Society
Petroleum Research Fund for partial funding of this research
(60677-DNI1). This material is based upon work supported by
the National Science Foundation Graduate Research Fellow-
ship Program under Grant No. DGE-1747503 (K.T.). Any
opinions, findings, and conclusions or recommendations
expressed in this material are those of the author(s) and do
not necessarily reflect the views of the National Science
Foundation. Spectroscopic instrumentation was supported by a
generous gift from Paul. J. and Margaret M. Bender, NSF
(CHE-1048642), and NIH (S10OD012245 and
1S10OD020022-1).
Overall, we have identified a catalytic system that unlocks
potent photooxidant behavior from one of the most reducing
conventional photoredox catalysts, PTH. This approach
enables oxidative C(sp2)−N coupling via photooxidation of
arene substrates outside of the redox window of reported
photoredox approaches. Preliminary mechanistic studies are
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Horton, M. E.; Nicewicz, D. A. Nucleophilic Aromatic Substitution of
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̌
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