Electrochemical Activation of Diverse Conventional Photoredox Catalysts Induces Potent Photoreductant Activity**

Article abstract of DOI:10.1002/anie.202107169

Herein, we disclose that electrochemical stimulation induces new photocatalytic activity from a range of structurally diverse conventional photocatalysts. These studies uncover a new electron-primed photoredox catalyst capable of promoting the reductive cleavage of strong C(sp²)?N and C(sp²)?O bonds. We illustrate several examples of the synthetic utility of these deeply reducing but otherwise safe and mild catalytic conditions. Finally, we employ electrochemical current measurements to perform a reaction progress kinetic analysis. This technique reveals that the improved activity of this new system is a consequence of an enhanced catalyst stability profile.

Full text of DOI:10.1002/anie.202107169

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Electrochemical activation of diverse conventional photoredox
catalysts induces new potent photoreductant activity
Authors: Colleen P. Chernowsky, Alyah F. Chmiel, and Zach Wickens
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202107169
Link to VoR: https://doi.org/10.1002/anie.202107169

10.1002/anie.202107169
Angewandte Chemie International Edition
RESEARCH ARTICLE
Electrochemical Activation of Diverse Conventional Photoredox
Catalysts Induces Potent Photoreductant Activity
Colleen P. Chernowsky, Alyah F. Chmiel, and Zachary K. Wickens*[a]
[a]
C. P. Chernowsky, A. F. Chmiel, Prof. Z. K. Wickens
Department of Chemistry
University of Wisconsin–Madison
1101 University Ave, Madison, WI 53706
E-mail: wickens@wisc.edu
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein, we disclose that electrochemical stimulation
induces new photocatalytic activity from a range of structurally diverse
conventional photocatalysts. These studies uncover a new electron-
primed photoredox catalyst capable of promoting the reductive
cleavage of strong C(sp2)–N and C(sp2)–O bonds even when
reduction potentials hundreds of mV more negative than Li0 are
required. We illustrate several examples of the synthetic utility of
potentials more negative than –2 V vs. SCE.[29] The conPET
strategy requires a carefully balanced system; both catalyst
oxidation states must engage in excited state intermolecular SET
under a single set of reaction conditions.[19] Additionally, the
byproducts of catalyst activation, which are typically reactive
amine radical cations and easily reduced iminium ions, must not
deactivate the catalyst or interfere in subsequent steps.[30] These
these deeply reducing but otherwise safe and mild catalytic conditions. fundamental challenges associated with catalyst generation and
Finally, we employ electrochemical current measurements to perform
a reaction progress kinetic analysis. This technique reveals that the
improved activity of this new system is a consequence of an enhanced
catalyst stability profile.
turnover have resulted in only a small collection of electron-
primed photocatalytic systems being identified in the subsequent
years[29,31] despite photophysical studies establishing that
numerous persistent radical anions absorb visible light.[32–36]
We envisioned that electrochemistry would offer a flexible
approach to generate electron-primed photoredox catalysts as
Introduction
Reductive activation of organic molecules through single electron
transfer (SET) is a fundamental elementary step at the heart of a
myriad of synthetically useful transformations.[1–4] In recent years,
photoredox catalysis has emerged as a mild and chemoselective
method to induce redox events.[5–10] Unfortunately, while 400 nm
light possesses sufficient energy for a maximum driving force of
3.1 eV, this energy is diminished by 25–50% through vibrational
relaxation, internal conversion, and intersystem crossing.[11] As a
consequence, many abundant but thermodynamically stable
molecules remain inert to photoredox activation.[12],[13] Indeed, in
the context of reductions, alkali metals have remained reductants
of unparalleled potency for over a century. These reagents
continue to be used in both academic[14,15] and industrial[16]
settings despite their implicit hazards, poor chemoselectivity, and
inextricable chemical waste. To address this, the development of
new strategies to deliver extreme reduction potentials
(significantly more negative than –2 V vs. SCE) with the safety
and chemoselectivity profile of photoredox catalysis is an
emerging area of considerable contemporary interest.[11,17–22]
Over the past several years, numerous groups,[23–28]
including ours,[26] have examined catalytic systems designed to
leverage mildly reducing radical species as a new family of
photocatalysts (Figure 1, top). We have dubbed these reductively
activated species electron-primed photoredox catalysts to
distinguish them from more conventional photocatalytic
reductants. Pioneering work from König used a consecutive
photoinduced electron transfer (conPET) approach to
photochemically generate an electron-primed photocatalyst,
albeit one that did not possess an excited state reduction
1
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RESEARCH ARTICLE
cathodic reduction is highly tunable and divided cell electrolysis
excludes interfering oxidized byproducts.[37–39] Indeed, we
previously used this approach to introduce a novel electron-
primed photocatalyst capable of reducing aryl chloride substrates
with Ered more negative than Li0.[26] Contemporaneous efforts by
Lambert and Lin disclosed that 9,10-dicyanoanthracene, an
electron-primed photoredox catalyst previously accessed via
conPET,[31] exhibits enhanced reactivity towards aryl chloride
substrates when driven electrochemically.[25] However, while
these two discoveries validated the use of electrochemistry to
photocatalytic conditions.[55,56] Within the past year, Larionov and
König illustrated that anilide and thiolate photocatalysts are
capable of promoting the borylation of anilinium salts and
activated phenols via photoreduction.[57,58] However, boron plays
a non-innocent role in these processes and photochemical net-
reductive transformations of these substrates remains limited.
Reductive defunctionalization is a powerful synthetic tactic to
leverage aniline and phenol activating groups in a traceless
manner.[59–62] Current methods to remove these directing groups
rely on harsh dissolving metal conditions[63,64] or palladium
catalysis.[65,66] We envisioned that cleavage of these strong bonds
was a perfect arena to explore new potent reductants given
recently reported halogen-atom transfer strategies, which in some
cases can circumvent deeply reducing potentials,[67] are unlikely
to be amenable to the cleavage of these less polarizable
heteroatoms.[68,69]
We initiated our studies with the reductive cleavage of an
N,N,N-trimethyl anilinium salt, 1 (Table 1). We anticipated that the
thermodynamic and kinetic challenges presented by aryl C(sp2)–
N bond cleavage would expose the limitations of current electron-
primed photocatalysts. We found that NpMI, the electron-primed
photoredox catalyst we recently reported,[26] could cleave the
C(sp2)–N bond in 42% yield under a constant cathodic potential
and visible light irradiation. This result validated that an electron-
primed photoredox system is capable of engaging this substrate
but also highlighted the need for improved catalysts. We next
evaluated a collection of structures related to the NpMI core.
Electrochemistry facilitated rapid catalyst evaluation in two
primary ways: (1) cyclic voltammetry studies established the
generate
potent
photoreductants,
both
of
these
electrophotocatalysts remained structurally analogous to
established conPET-based photocatalysts. While rapid progress
has been made in net-oxidative electrophotocatalytic
transformations,[40–48] electrophotocatalytic reductions remain
comparatively underdeveloped.[49,50] Herein, we employ cathodic
reduction to elicit new photocatalytic activity from numerous
organic and inorganic structures. These studies reveal a new
electron-primed photoredox catalyst that enables cleavage of
strong C(sp2)–N and C(sp2)–O bonds.
Results and Discussion
The generation of aryl radical intermediates is a well-
established arena to benchmark new photoreductants. Bench-
stable[51–54] trialkylanilinium salts and activated phenols are
readily accessible and can be reductively cleaved to aryl radical
intermediates through deeply reducing direct electrolysis or alkali
metal reductants, however, they remain difficult to activate under
2
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10.1002/anie.202107169
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RESEARCH ARTICLE
minimum cathodic potential to generate the radical anion
photocatalyst and (2) evaluation of wavelength dependent
photocurrent established the optimal irradiation wavelength (see
SI for details).[70] These studies revealed that various derivatives
of NpMI including NpDI, PMI, and NpImz each provided the
defunctionalized product, albeit in reduced yield relative to NpMI.
Given these data, we concluded that a fundamentally different
catalyst scaffold was likely necessary to efficiently promote these
challenging reductions.
We next targeted more structurally diverse persistent radical
anion precursors that have not been explored as electron-primed
photocatalysts.[36,71–74] We found that phenazine, fluorenone, and
fluorescein each promote reduction of 1 in comparable yields to
NpMI under appropriate electrophotocatalytic conditions. Control
reactions revealed that no conversion is observed in the absence
of electrolysis indicating that the photoactivity of the neutral
structures is insufficient to drive defunctionalization of 1. These
data suggest that electrochemical reduction can coax potent
photocatalytic activity out of a much broader range of molecules
than previously appreciated. Next, we recognized that nearly all
photoredox catalysts, by design, undergo reversible redox events
and many possess persistent radical anion congeners.[6,10,75] We
questioned whether the structural features that render molecules
effective as conventional photoredox catalysts would translate to
the electron-primed photoredox manifold.[76,23,77] Intriguingly, we
found that electrolysis at the Ered of several commonly employed
photoredox catalysts Ru(bpy)3,[78] Ir(dF-CF3-ppy)2(dtbpy),[78] and
4-CzIPN[79] turned on photocatalytic activity in this challenging
reduction.[80] While there is a sole report proposing photochemical
activity of the reduced congener of an Ir-based photoredox
catalyst,[81] these are the first data consistent with either Ru-based
(5), esters (6), and amides (7) as well as heterocycles such as
piperazine (7), pyrrolidine (8), and morpholine (9) were all well-
tolerated. Notably, this reaction enables a molecular editing
strategy wherein an N-aryl ring can be replaced by an alkyl group
through an alkylation/reductive cleavage sequence (11) as both
aryl and amine fragments can be recovered after C(sp2)–N
reduction. Given the promising activity of this catalytic system in
the cleavage of anilinium salts, we turned our attention to more
difficult to reduce C(sp2)–O bonds. Phenol derivatives (e.g.
triflates and phosphates) possess deep reduction potentials
(typically <–2.7 V vs. SCE).[84–86] Despite the energetic demands
of C(sp2)–O cleavage, phosphate ester substrates bearing a
range of functional groups such as esters (13), amides (14),
ethers (15), benzylic amines (16), unprotected alcohols and
tertiary amines (18) as well as heterocycles such as imidazole
(17) and piperazine (19) each underwent productive C(sp2)–O
cleavage. While each of these reactions are conducted far below
the cathodic potential required to reduce the substrate, we
questioned whether deeply reducing electrolysis could
recapitulate this electrophotocatalytic activity. To probe this, we
carried out direct electrolysis reactions on two substrates bearing
functional groups to investigate the role of the catalyst in
preserving chemoselectivity. Under constant current conditions in
the absence of catalyst, 16 and 19 showed significant conversion
to an intractable mixture containing <20% product. By promoting
or isophthalonitrile structures
photoredox catalysts. Given that cathodic reduction of 4-CzIPN
resulted in meaningful improvement in photochemical
acting as electron-primed
a
deamination yield, we examined other isophthalonitrile catalysts.
This investigation revealed that 4-DPAIPN[82] promotes the
reduction of model substrate 1 in nearly quantitative yield under
electrophotocatalytic conditions. Overall, the structural diversity of
the potent photocatalysts identified through these studies suggest
that reductively induced photoactivity is a general phenomenon
and provides a clear link between catalyst structure and reaction
outcome.
We next evaluated whether 4-DPAIPN was promoting this
reaction through excitation of a cathodically generated species.
Under electrochemical stimulation 4-DPAIPN acts as a far more
potent photoreductant than anticipated by its established redox
potentials (E1/2 PC+/PC*) = –1.3 V and E1/2 (PC/PC• –) = –1.5 V vs.
SCE)[82] (Figure 2). First, we conducted a series of control
experiments and found that catalyst, electrolysis, and light were
all required for product formation. Next, we examined whether
electrochemical reduction of 4-DPAIPN was necessary to
promote the defunctionalization reaction. Inspired by an elegant
experiment conducted by Lambert and Lin,[25] we measured the
defunctionalization yield at varied cathodic potentials. Overlaying
these data with the cyclic voltammogram of 4-DPAIPN illustrates
that reactivity is observed only when a sufficient potential to
reduce 4-DPAIPN is applied. These data are fully consistent with
cathodic catalyst reduction and subsequent excitation as
necessary steps for this difficult reductive transformation.[83]
We next probed the scope of this catalytic C(sp2)–N
cleavage process (Table 2). We found ethers (4), free alcohols
reduction through
a
photocatalytic mediator under mild
electrochemical potentials, chemoselectivity and functional group
3
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RESEARCH ARTICLE
meta-substituted arene products from simple precursors using a
phenol-directed alkylation-defunctionalization sequence (20-23).
As a direct comparison, we subjected 23 to constant current
conditions in the absence of catalyst and observed high
conversion with substantially diminished yield. To demonstrate
the value of a phenol-directed alkylation-defunctionalization
approach, we targeted the synthesis of a tricyclic resorcinol
derivative that was developed as a conformationally restricted
cannabinoid agonist. The route, devised by Makriyannis,[93]
hinged on phenol-enabled Friedel–Crafts alkylation followed by a
Li0-promoted excision of the phenol activating group. In our hands,
the Friedel–Crafts process and subsequent phosphorylation
proceeded smoothly to deliver tricyclic intermediate 24.
Gratifyingly, electron-primed photoredox C(sp2)–O cleavage
furnished intermediate 25 despite a nearly 2 V underpotential
supplied at the cathode. Global demethylation furnished 26 in
18% yield over 4 steps. These data demonstrate how this new
catalytic platform can directly fit into synthetic sequences and
circumvent the need for more hazardous chemical reductants in
the preparation of complex biologically active molecules.
tolerance can be vastly improved compared to direct electrolysis
conditions.
Phenols are electron-donating groups that enable a wide
range of reactions at the arene core.[87–91] We envisioned that the
scope of products accessible using these processes could be
expanded through a chemoselective excision of the phenolic
activating group via an electrophotocatalytic system (Figure 3).
For example, this strategy allows selective formation of meta-
substituted products inaccessible via direct Friedel–Crafts
reactions.[92] To illustrate this strategy, we prepared a suite of
We next questioned whether the aryl radical intermediates
generated upon reductive cleavage of anlinium salts and
phosphate esters could be intercepted by classic aryl radical traps.
We investigated several aryl radical coupling reactions:
4
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10.1002/anie.202107169
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RESEARCH ARTICLE
phosphonylation, borylation, and heteroarylation (27-29). We
found that both C(sp2)–N and C(sp2)–O radical precursors were
amenable to each of these radical coupling reactions (Figure 4).
Having established that 4-DPAIPN is a broadly effective
electron-primed photoredox catalyst with immediate synthetic
utility, we next aimed to understand the origin of the improved
performance of 4-DPAIPN relative to prior electron-primed
photoredox catalysts. Specifically, we questioned whether 4-
DPAIPN possessed enhanced reactivity, superior catalyst
stability,[94] or both. To address this question, we envisioned that
electrochemical current could be employed as a non-invasive in
situ rate monitoring technique to unlock tools from reaction
progress kinetic analysis (RPKA).[95] This method can reveal
phenomena such as catalyst decomposition and product
inhibition typically invisible to classic initial rate kinetics because
the analysis is conducted under typical preparative conditions.
We conducted a "same excess” experiment with both our
previously reported electron-primed photocatalyst, NpMI, and 4-
DPAIPN to compare the extent of catalyst deactivation in each
case (Figure 5). We selected aryl chloride 30 as the model
substrate because both catalysts can engage this substrate under
constant potential conditions and preliminary investigations
indicated it exhibited a well-behaved kinetic profile.[96,97] We
carried out two separate constant potential experiments for NpMI
at different initial concentrations of 30 (traces a and b). When the
conversion rate of 30 is plotted as a function of [30], the two
curves do not overlay. This indicates either catalyst death or
product inhibition.[98] Inhibition by the arene product was excluded
by addition of 31, which did not restore overlay between the
curves. Furthermore, NpMI exhibited an unusual kinetic profile
consistent with decomposition into a new catalytically active
species that subsequently decomposes. These data implicate
rapid deactivation of NpMI under these conditions. In stark
contrast, an analogous “same excess” experiment with 4-DPAIPN
resulted in clean first order reaction profiles that nearly overlay.
These data are consistent with turnover limiting photoreduction of
30 and minimal catalyst decomposition or product inhibition (see
SI for details). As with NpMI, addition of 31 excluded product
inhibition and suggests 4-DPAIPN decomposition occurs[99–102]
but is attenuated relative to NpMI. These data indicate that the
improved performance of 4-DPAIPN can be attributed to it forming
a more robust electron-primed photoredox catalyst. Indeed, the
initial rate of dehalogenation promoted by NpMI is faster than 4-
DPAIPN but rapid decomposition of this catalyst renders it
ineffective for more challenging substrates that are slower to
fragment following reduction.
Conclusion
Overall, we have demonstrated that electrochemistry is an
effective tool to explore structurally diverse electron-primed
photoredox
catalysts.
These
investigations
revealed
electrochemical reduction can induce potent photoreductant
behavior from structurally diverse catalyst precursors. Among
these,
a common photoredox catalyst, 4-DPAIPN, is an
exceptionally reducing electron-primed photoredox catalyst. This
discovery enabled a new catalytic system to promote the
reductive cleavage of diverse C(sp2)–N and C(sp2)–O bonds,
which we anticipate will enable an array of synthetic sequences
that previously would have mandated alkali metal reductants.
5
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Acknowledgements
We thank Prof. Alison Wendlandt for helpful suggestions. We
thank the Stahl lab for their assistance in use of
spectroelectrochemical equipment. Additionally, we thank the
Stahl, Weix, Yoon, and Schomaker groups for sharing their
chemical inventory. Tracy Drier is acknowledged for
electrochemical glassware fabrication. 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. This
material is based upon work supported by the National Science
Foundation under Grant No. (2047108). Acknowledgment is
made to the Donors of the American Chemical Society Petroleum
Research Fund for partial funding of this research (60677-DNI1).
Spectroscopic instrumentation was supported by a generous gift
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Keywords: electron-primed photoredox catalysis •
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7
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RESEARCH ARTICLE
Entry for the Table of Contents
+e–
hν
*
Cat
Cat
Cat
conventional
photocatalyst
photoactive
species
potent
reductant
Electron-Primed Photocatalyst Cleavage of Strong Bonds
Me
Me
Cat
=
HO
N
N
N
N
O
NC
N
CN
N
EtO
EtO
O
Me
P
OMe
O
MeO
Me Me
4-DPAIPN
Electrochemical activation of numerous conventional photocatalysts was found to induce potent photoreductant activity. These studies resulted in
the discovery of an electron-primed photoredox catalyst capable of cleaving strong aryl C–N and C–O bonds to aryl radical intermediates.
Mechanistic experiments revealed that enhanced activity relative to previously developed electron-primed photoredox systems was a result of
improved catalyst stability.
8
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