Potent Reductants via Electron-Primed Photoredox Catalysis: Unlocking Aryl Chlorides for Radical Coupling

Article abstract of DOI:10.1021/jacs.9b12328

We describe a new catalytic strategy to transcend the energetic limitations of visible light by electrochemically priming a photocatalyst prior to excitation. This new catalytic system is able to productively engage aryl chlorides with reduction potentials hundreds of millivolts beyond the potential of Na⁰ in productive radical coupling reactions. The aryl radicals produced via this strategy can be leveraged for both carbon-carbon and carbon-heteroatom bond-forming reactions. Through direct comparison, we illustrate the reactivity and selectivity advantages of this approach relative to electrolysis and photoredox catalysis.

Full text of DOI:10.1021/jacs.9b12328

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Potent Reductants via Electron-Primed Photoredox Catalysis:
Unlocking Aryl Chlorides for Radical Coupling
Nicholas G. W. Cowper,† Colleen P. Chernowsky,† Oliver P. Williams, and Zachary K. Wickens*
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ABSTRACT: We describe a new catalytic strategy to transcend the energetic limitations of visible light by electrochemically
priming a photocatalyst prior to excitation. This new catalytic system is able to productively engage aryl chlorides with reduction
potentials hundreds of millivolts beyond the potential of Na0 in productive radical coupling reactions. The aryl radicals produced via
this strategy can be leveraged for both carbon−carbon and carbon−heteroatom bond-forming reactions. Through direct comparison,
we illustrate the reactivity and selectivity advantages of this approach relative to electrolysis and photoredox catalysis.
ctivation of organic molecules through single electron
transfer (SET) is a pillar of preparative chemistry. New
provide a general catalyst design platform to transcend the
energetic limitations of visible light.
A
We hypothesized that electrochemistry18,19 could offer a
more flexible approach than photoreduction to generate
electron-primed photoredox catalysts. In addition to providing
access to new catalysts, this approach eliminates the
complications20 that can arise from the terminal reductants
commonly used in photoredox catalysis, such as Et3N. This
strategies to induce redox events have the potential to
significantly impact organic synthesis.1 In the past decade,
visible-light photoredox catalysis has enabled a tremendous
array of carbon−carbon and carbon−heteroatom bond-
forming reactions.2,3 Unfortunately, blue light (440 nm)
possesses sufficient energy for a maximum driving force of
only 2.8 eV, and the available energy is further diminished by
nonradiative pathways and intersystem crossing.4 Thus, despite
catalyst design improvements,5,6 many desirable substrates
remain inert to visible-light photoredox catalysis.7 As a result of
this limitation, dissolving metal conditions,8 which employ
reactive alkali metals in condensed ammonia, remain uniquely
potent reductants in the synthetic arsenal9 and are still
commonly used despite significant hazards and poor chemo-
selectivity.10,11 Aiming to provide safer and more scalable
conditions for challenging reductions, recent efforts have
exploited overcharge protection to unlock deeply reducing
cathodic potentials for electroorganic synthesis.12 However,
the requisite electrode overpotentials intrinsically limit the
functional group tolerance. Furthermore, radical intermediates
generated at a cathode are prone to reduction to anions.13
Overall, a new catalytic paradigm to access extremely reducing
potentials under mild conditions and without reduction of
radical intermediates would address a long-standing challenge
in organic synthesis (Figure 1).
To overcome the energetic limitations of blue photons,
̈
Konig and co-workers recently introduced an appealing
approach designed to drive challenging SET events using the
energy of two photons rather than one.14,15 This strategy relies
on the light-mediated generation and subsequent photo-
chemical excitation of catalytic radical anion intermediates.
Although these systems push the limits of photoredox catalysis,
they remain many orders of magnitude less reducing than alkali
metals. Inspired by photophysical studies suggesting that other
organic radical ions can serve as potent photoreductants,16,17
we questioned whether an alternative means of priming a
photoredox catalyst with an electron prior to excitation could
Figure 1. Strategies to induce SET reduction. All potentials shown are
relative to SCE. PTH = 10-phenylphenothiazine.
Received: November 14, 2019
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© XXXX American Chemical Society
A

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strategy builds on both long-standing21 and recent22 pioneer-
ing efforts combining electrochemistry with photochemistry.23
The majority of these examples take advantage of the desirable
features of electrochemistry to generate known photochemi-
cally active intermediates or catalysts. However, electro-
chemical generation of new families of photocatalysts for
organic synthesis remains largely unexplored. Recently,
Lambert and co-workers reported a new and highly oxidizing
photocatalyst (with a calculated potential of +3.3 V vs SCE)
that is electrochemically accessible under a mildly oxidizing
potential.22d Concurrently, we were exploring the use of
electrochemistry to access new, electronically destabilized
photocatalysts for challenging reductions.24 Herein we
demonstrate that electrochemistry is a viable strategy to
generate highly reducing electron-primed photoredox catalysts.
We exploit this approach to identify an aryl imide photo-
catalyst capable of engaging substrates with reduction
potentials on par with alkali metals in SET-initiated radical
coupling reactions under otherwise mild conditions.
Table 1. Electrochemical Access to Electron-Primed
Photocatalysts
a b c
, ,
To explore this idea, we targeted the reductive generation of
aryl radicals from unactivated precursors. These reactive
intermediates are known to participate in a range of
synthetically useful carbon−carbon and carbon−heteroatom
bond-forming reactions; however, they are typically generated
from diazonium salts or aryl iodides using modern photoredox
catalysts.25 With the most reducing visible-light photoredox
catalysts, aryl bromides are suitable radical precursors.26,27
Unfortunately, aryl chlorides comprise over half of the
commercially available aryl halides28 yet are inert under
conventional visible-light photoredox catalysis unless they bear
electron-withdrawing groups.29−31 This limitation is a result of
the combination of thermodynamically challenging SET and
the low fragmentation rate due to the relatively strong C(sp2)−
Cl bond.32
a
b
All redox potentials given relative to SCE. Ar = 2,6-diisopropyl-
c
phenyl. Reactions were conducted on a 0.4 mmol scale in DMF (0.1
M Bu4NPF6) in the presence of 2,4,6-tri-tert-butylphenol (10 mol %)
and isopropyl alcohol (1 equiv). See the Supporting Information (SI)
for further details.
To assess the viability of the proposed electrophotocatalytic
approach, we investigated the dehalogenation of 4-bromobi-
phenyl (1) because of its reduction potential beyond the
standard range of photoredox catalysts (−2.4 V vs SCE) and
rapid fragmentation after reduction, as this provides a high-
fidelity readout for successful SET.32 Using this model
reaction, we assessed a series of aryl imides for activity under
visible-light irradiation and an appropriate electrochemical
potential to reductively activate the imide (Table 1). The
radical anion derived from perylene diimide (PDI) can act as
an electron-primed photoredox catalyst under two-photon
conditions14a and is also well-behaved electrochemically.33
Unfortunately, PDI proved ineffective in the dehalogenation of
1 under these conditions. Photophysical studies have indicated
that naphthlene-based analogues (NpDI and NpMI) are more
potent photoreductants after they are primed with an
electron,17c but they have yet to be leveraged in synthesis.
Excitingly, under electrophotocatalytic conditions both NpDI
and NpMI promoted the dehalogenation of 1, despite
significant electrochemical underpotentials in each case (1.6
and 1.1 V vs SCE respectively). While both NpMI and NpDI
are sufficiently potent photoreductants to reduce 1, NpMI
promoted dehalogenation significantly more efficiently. How-
ever, further stripping down the aromatic core to a phthalimide
derivative, PhMI, resulted in a less effective photocatalyst than
NpMI. On the basis of these data, we selected NpMI for
further study after verifying that no significant conversion was
observed in the absence of an applied voltage, light, or the
catalyst.
Having identified a promising electrochemically accessible
photocatalyst, we explored whether this system could engage
abundant but much more challenging aryl chlorides in radical
coupling reactions. We first probed the viability of a photo-
Arbuzov process,34 a classic carbon−heteroatom bond-forming
reaction that proceeds through an aryl radical intermedi-
ate (Table 2). For these studies, we employed more
convenient constant-current conditions.35 We found that
under simultaneous electrolysis and irradiation, NpMI induced
the high-yielding coupling of aryl chlorides with reduction
potentials at and beyond the limits of conventional visible-light
photoredox catalysis (2−3). To identify the limits of this
catalytic system, we next evaluated increasingly electron-rich
aryl chloride substrates. Excitingly, aryl chloride substrates
bearing electron-donating groups still underwent efficient SET-
induced phosphorylation (4−7) even though they possess
reduction potentials comparable to that of Na0 (−2.9 V vs
SCE). Notably, an exceptionally electron-rich aryl chloride
(−3.4 V vs SCE)36 was successfully reduced to produce 7. This
result indicates that these conditions provide potency
comparable to that of Li0 (−3.3 V vs SCE). To our delight,
despite the presence of such a potent reductant, aryl chloride
substrates bearing potentially sensitive functional groups7,37
such as esters (8), nitriles (9), carbamates (10), organoboron
reagents (11), and heterocycles (12 and 13) all underwent
productive SET-induced radical phosphorylation, and the
B
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a
a
Table 2. Scope of Aryl Chloride Phosphorylation
Table 3. Scope of Aryl Chloride (Hetero)arylation
a
Reactions were conducted on a 0.4 mmol scale and run for 27 h.
Et3N (2 equiv) was employed in the anode as the counter reaction.
See the SI for further experimental details.
redox system was used, each substrate delivered the desired
product with excellent selectivity for radical coupling over
dehalogenation. In contrast, 10-phenylphenothiazine (PTH),
an exceptionally reducing photoredox catalyst (−2.1 V vs
SCE),26a could only induce the coupling of the electron-
deficient aryl chloride. The neutral and electron-rich substrates
were unconverted by PTH, consistent with the energetic
limitations of visible-light photoredox. Direct electrolysis, on
the other hand, provided significantly diminished selectivity for
coupling of the electron-deficient substrate (2:1) and the other
two substrates yielded in exclusively dehalogenation. These
results are consistent with over-reduction at the electrode
surface that precludes radical coupling reactions at the
requisite potentials for aryl chloride reduction.
We next subjected radical clock 22 to both electron-primed
photoredox and direct electrolysis conditions to probe the
presence of an aryl radical intermediate and benchmark the
rate of its over-reduction (Scheme 1). The aryl radical derived
from 22 undergoes radical cyclization with a rate of 8 × 109
s−1.39 As anticipated, NpMI under blue-light irradiation and
constant-current electrolysis delivered selective cyclization
(54% yield, ≥20:1 selectivity for cyclization over dehalogena-
tion and aryl anion-derived40 isomerization products). This
result is fully consistent with the proposed intermediacy of an
aryl radical intermediate and high selectivity for radical
chemistry instead of over-reduction. Direct electrolysis,
a
Reactions were conducted on a 0.4 mmol scale and run for 8 h. Et3N
(2 equiv) was employed in the anode as the counter reaction. See the
b
SI for further experimental details. The reaction was run for 14 h.
c
d
Ered was determined by differential pulse voltammetry 0.4 mA
current.
corresponding products were isolated in good to excellent
yields.
Having established the viability of carbon−heteroatom
bond-forming reactions from diverse aryl chlorides, we next
aimed to intercept the aryl radical intermediate with a
heterocycle to form a new carbon−carbon bond (Table 3).
We found that the aryl radical intermediates generated under
these conditions from neutral to electron-rich aryl chlorides
(14−18) could be effectively coupled to N-methylpyrrole, a
classic radical trap.38 Again, reductively sensitive functional
groups were well-tolerated despite the potency of the
photoreductant employed (19−21).
With a new catalytic strategy in hand, we next compared its
efficacy to those of traditional photochemical and electro-
chemical approaches for the reductive activation of aryl
chlorides (Figure 2). To this end, we investigated the relative
yields of N-methylpyrrole coupling and dehalogenation within
a subset of aryl chloride substrates ranging from electron-
deficient to electron-rich. When the electron-primed photo-
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Figure 2. Comparison of reactivities and selectivities observed with various methods of generating aryl radical intermediates using N-methylpyrrole
as a radical trap. Yields of coupling and dehalogenation were measured relative to an internal standard. The electron-primed photoredox conditions
were the same as in Table 3. The photoredox conditions followed pyrrole coupling procedures from the literature employing PTH as a
photocatalyst. Several direct electrolysis conditions were attempted. The reported conditions provided the highest yield of A and were standard
reaction conditions from Table 3 without catalyst. For further details, see the SI.
a
To this end, we conducted a series of one-pot intermolecular
competition experiments between bromo- and chlorobiphenyl
(Figure 3). These halogen congeners possess the same
Scheme 1. Comparison of Radical Clock Outcomes
a
The reaction was conducted on a 0.4 mmol scale for 20 h.
however, provided no observable cyclization and generated
only dehalogenation and isomerization products consistent
with anionic intermediates. This indicates that under the direct
electrolysis conditions investigated, any radical reactions with
rate constants lower than 109 s−1 will not be viable because of
competitive electrochemical reduction of the radical. This is
consistent with the facile reduction of aryl radical intermediates
at electrode surfaces (phenyl radical Ered = +0.05 V vs SCE).41
Finally, we aimed to gain preliminary insight into the
promising chemoselectivity observed with this potent catalytic
reductant. Notably, classic photoredox approaches are sensitive
to not only the reduction potential of the substrate but also the
fragmentation rate of the radical anion formed via SET.25a This
is likely due to competition between back electron transfer and
the productive fragmentation and coupling. Although back
electron transfer can be a hindrance,42 we suspect that this
feature also contributes to the excellent chemoselectivity
profiles observed in photoredox catalysis. Thus, we wanted
to ascertain whether the exceptionally potent photoreductant
explored herein exhibited analogous reactivity or whether SET
was irreversible.
Figure 3. Comparison of one-pot competition experiments. krel is
given as kBr/kCl and was measured by gas chromatography based on
reactions run to low conversion (<20%). The electron-primed
photoredox conditions followed from Table 1. The direct electrolysis
conditions were those reported in ref 44. Previously reported
photoredox conditions were employed 26a. See the SI for details.
reduction potential (−2.4 V vs SCE), but their radical anions
exhibit significantly different fragmentation rates.32,43 We
subjected a 1:1 mixture of the two aryl halides to NpMI
under simultaneous irradiation and a working potential of −1.3
V vs SCE. We found that the initial rate of C(sp2)−Br cleavage
was significantly higher than that of C(sp2)−Cl cleavage (krel
=
8) despite the fact the two aryl halides possess identical
reduction potentials. This observation excludes that conversion
is based exclusively on the reduction potential. In stark
contrast, the two substrates are converted at similar rates under
direct electrolysis conditions (krel = 2).44 Consistent with prior
work in photoredox catalysis, PTH promoted the dehalogena-
D
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tion of bromobiphenyl more rapidly than that of the chloride
(krel = 15). Taken together, these data indicate that productive
conversion is not governed exclusively by the reduction
potential under either electron-primed or conventional photo-
redox catalysis. This observation provides a plausible rationale
for the promising chemoselectivity observed under the
conditions reported herein relative to deeply reducing direct
electrolysis, which predominantly commits to product
formation on the basis of the substrate reduction potential.
Overall, we have demonstrated that electrochemical
stimulation is a viable strategy to generate catalytic photo-
reductants capable of transcending the limits of modern
photoredox catalysis. We report effective radical couplings of
substrates hundreds of millivolts more challenging to reduce
than previous photoredox strategies, including substrates with
reduction potentials well beyond that of Na0 and more
negative than that of Li0. Crucially, despite accessing such
negative potentials, the reactions possess functional group
tolerance profiles more consistent with traditional photoredox
catalysis than direct electrolysis and result in high selectivity for
radical coupling over dehalogenation. Beyond unlocking
electronically diverse aryl chlorides as aryl radical precursors,
these data lay the foundation for a new catalyst design
paradigm. We anticipate that electrochemically priming
photocatalysts prior to excitation will allow much more
challenging reductions than are feasible with blue light alone
and will result in a myriad of transformations inspired by what
is feasible under dissolving metal conditions and beyond.
ACKNOWLEDGMENTS
■
We thank Prof. Alison Wendlandt, Prof. Tehshik Yoon, Prof.
Daniel Weix, Prof. Bill Morandi, and Sara Alektiar for helpful
suggestions and manuscript proofreading. Additionally, we
thank the entire Weix group for allowing us to use their GC
and the Stahl, Weix, Yoon, and Schomaker groups for sharing
their chemical inventory. Dr. Blaise J. Thompson is acknowl-
edged for his assistance with galvanostat design and fabrication.
Tracy Drier is acknowledged for electrochemical glassware
fabrication. We also acknowledge the invaluable support and
helpful suggestions from group members Dylan Holst and
Diana Wang throughout this project. 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. Spectroscopic instrumentation was supported by a
generous gift from Paul. J. and Margaret M. Bender, NSF
(CHE-1048642), and NIH (1S10 OD020022-1).
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.9b12328.
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Experimental procedures, electrochemical characteriza-
tion, radical clock and competition experiments,
comparison of reductive activation methods, constant-
current control experiments, product isolation and
characterization, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Zachary K. Wickens − University of Wisconsin-Madison,
Madison, Wisconsin; orcid.org/0000-0002-5733-
5288; Email: wickens@wisc.edu
Other Authors
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Nicholas G. W. Cowper − University of Wisconsin-
Madison, Madison, Wisconsin
Colleen P. Chernowsky − University of Wisconsin-
Madison, Madison, Wisconsin
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Oliver P. Williams − University of Wisconsin-Madison,
Madison, Wisconsin
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.9b12328
Author Contributions
†N.G.W.C. and C.P.C. contributed equally.
Notes
́
(c) Joshi-Pangu, A.; Levesque, F.; Roth, H. G.; Oliver, S. F.;
The authors declare no competing financial interest.
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