Non-innocent Radical Ion Intermediates in Photoredox Catalysis: Parallel Reduction Modes Enable Coupling of Diverse Aryl Chlorides

Article abstract of DOI:10.1021/jacs.1c05988

We describe a photocatalytic system that elicits potent photoreductant activity from conventional photocatalysts by leveraging radical anion intermediates generated in situ. The combination of an isophthalonitrile photocatalyst and sodium formate promotes diverse aryl radical coupling reactions from abundant but difficult to reduce aryl chloride substrates. Mechanistic studies reveal two parallel pathways for substrate reduction both enabled by a key terminal reductant byproduct, carbon dioxide radical anion.

Full text of DOI:10.1021/jacs.1c05988

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Non-innocent Radical Ion Intermediates in Photoredox Catalysis:
Parallel Reduction Modes Enable Coupling of Diverse Aryl Chlorides
Alyah F. Chmiel, Oliver P. Williams, Colleen P. Chernowsky, Charles S. Yeung,*
and Zachary K. Wickens*
Cite This: J. Am. Chem. Soc. 2021, 143, 10882−10889
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ABSTRACT: We describe a photocatalytic system that elicits potent photoreductant activity from conventional photocatalysts by
leveraging radical anion intermediates generated in situ. The combination of an isophthalonitrile photocatalyst and sodium formate
promotes diverse aryl radical coupling reactions from abundant but difficult to reduce aryl chloride substrates. Mechanistic studies
reveal two parallel pathways for substrate reduction both enabled by a key terminal reductant byproduct, carbon dioxide radical
anion.
eductive activation of organic molecules via single
electron transfer (SET) is a fundamental elementary
R
step that underpins diverse and powerful synthetic trans-
1
−4
formations.
Photoredox catalysis promotes SET through
conversion of energy from visible light into chemical redox
potential and has enabled a suite of carbon−carbon and
5
−9
carbon-heteroatom bond-forming reactions.
When consid-
ering whether a substate will be suitable for photoredox
reduction, two primary catalyst parameters are initially
•
+
considered: (1) E (PC /PC*) and (2) E1/2(PC/
1
/2
•
−
7,10,11
PC ).
These values reflect redox potentials bounded
by the energy of photons in the visible region, a limitation
12
compounded by energy losses to intersystem crossing. As a
result, many abundant but challenging to reduce substrates are
excluded from photoredox activation based on these guidelines
1
3−15
(Figure 1A).
Aryl radicals are reactive intermediates that engage in a
16−18
myriad of synthetically valuable transformations.
Classi-
cally, aryl radical intermediates are generated from aryl
19−29
diazonium salts, iodides, or bromides.
Aryl chlorides are
rarely used as radical precursors despite the fact they comprise
3
0
over two-thirds of commercially available aryl halides (Figure
3
1−35
1
B).
This is a consequence of their resistance to reductive
13 36,37
2
activation, and high C(sp )−Cl BDE.
pioneered an elegant strategy, termed consecutive photo-
induced electron transfer (conPET), wherein a photochemi-
Konig recently
̈
38,39
cally generated radical anion is subsequently excited.
This
Figure 1. (A) Energy limitations for photoredox catalysis and
electron-primed photoredox catalysis. (B) Aryl chloride abundance
and reactivity as aryl radical precursors. (C) Strategy employing
chemical reductants to exploit electron-primed photoredox catalysis.
All V vs SCE.
approach primes the photocatalyst with an electron prior to
excitation and, in principle, can generate much deeper
•
−
reduction potentials through E1/2(PC/PC *). Indeed, later
implementations of this conPET strategy unlocked exception-
40,41
ally challenging reductions.
However, all recent advances
Received: June 9, 2021
Published: July 13, 2021
in visible light photoredox methods that reduce electronically
diverse chloroarenes have been limited to proteodefunction-
4
0,42−45
alization and borylation reactions.
Recent electro-
approaches have directly generated these
4
6−49
photocatalytic
electron-primed photocatalysts cathodically.
strategy has begun to expand the range of radical coupling
50,51
While this
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2021 American Chemical Society
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1
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Figure 2. (A) Unlocking radical anion photocatalyst reactivity by evaluation of reductant for catalyst activation. Reactions were conducted on 0.1
mmol scale with 10 mol % 4-DPAIPN and 3 equiv of NaCHO . Reactions were analyzed via gas chromatography. (B) Overview of key
2
considerations for chemical reducants as catalyst activators. All V vs SCE.
reactions that engage aryl chlorides, a general approach to
leverage the expansive pool of aryl chloride substrates in radical
couplings has remained elusive and the need for electro-
photocatalysts under investigation. Therefore, activity in this
assay would implicate in situ formation of a distinct and potent
reductant. Initially, we examined a range of trialkylamine
reductants because these are common reductants in photo-
redox catalysis, including in conPET strategies (Figure
52,53
chemical equipment remains a barrier in some settings.
In
particular, net-reductive radical coupling processes, such as
54−56
38,40,61
alkene hydroarylation,
have remained elusive for aryl
2
A).
We found that each catalyst modestly promoted
chloride substrates for all modern methods. We suspect that
the paucity of net-reductive processes is a consequence of the
intrinsic challenges of circumventing premature reduction of
this energetically demanding dehalogenation reaction. The
isophthalonitrile catalysts, which are both excellent neutral
62
chromophores as well as electron-primed photoredox
•
−
the aryl radical intermediate (E (Ph /Ph ) = +0.05 V vs
58
red
catalysts, promoted the reaction most efficiently albeit still
5
7
SCE) in the presence of a stoichiometric reductant.
Our group recently used electrochemistry to examine a
diverse set of organic radical anions for photocatalytic activity
in poor yield. To exclude halogen atom transfer (XAT) aryl
63−65
radical generation,
we examined the reductive defunction-
2
2
alization of anilinium and aryl phosphate salts (Table 1). These
in the reductive cleavage of strong C(sp )−O and C(sp )−N
6
6,67
5
8
are each challenging reductive cleavage reactions
of
bonds. These experiments revealed that numerous radical
anions, including those derived from commonly employed
photoredox catalysts, can serve as potent photocatalytic
reductants upon cathodic reduction. These data fit into a
Table 1. Evaluation of Catalytic System , ,
a b c
59
40,60
growing body of literature from our group and others
that suggest photocatalyst-based redox events can engender
more potent activity from conventional photocatalysts. Taken
together, these data led us to consider whether we could
redesign a photocatalytic system to favor formation of
photoactive radical anion intermediates to elicit deeply
reducing potentials and expand the repertoire of coupling
reactions available from aryl chlorides under operationally
simple conditions (Figure 1C). Herein, we disclose that
selection of an appropriate reductant to generate and maintain
an active electron-primed photoredox catalyst in situ enables
reduction potentials far beyond those expected from conven-
tional catalyst selection criteria. These new reduction
conditions promote a diverse array of intermolecular coupling
reactions, including net-reductive coupling processes, from
readily available aryl chloride substrates.
We first evaluated a suite of organic compounds recently
found to possess photocatalytically active radical anion
5
8
congeners for activity in the dehalogenation of PhCl (Ered
a
=
−2.8 V vs SCE). Considering only conventional photoredox
Reactions were run on 0.1 mmol scale with 10 mol % 4-DPAIPN, 3
•
−
•+
b
c
catalyst selection parameters (PC/PC and PC*/PC ), this
equiv of NaCHO , and 5 mol % CySH. All V vs SCE. NMR yield.
2
e
d
reduction would be exceedingly endothermic (>1 V) for the
GC yield. 15 mol % 4-DPAIPN.
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a
Table 2. Intermolecular Couplings from Challenging Aryl Chloride Precursors
a
b
c
d
Reactions were run on 0.4 mmol scale. Isolated yield unless otherwise noted. NMR yield. GC yield. Reactions were run with 4-DPAIPN (12−
e
1
5 mol %), NaCHO (3 equiv), and P(OEt) (5 equiv). Reactions were run with 4-DPAIPN (5 mol %), NaCHO (3 equiv), B pin (3 equiv),
2 3 2 2 2
f
and Cs CO (3 equiv). Reactions were run with 4-DPAIPN (6 mol %), NaCHO (3 equiv), N-vinyl carbamate (2.5 equiv), and CySH (5 mol %).
2
3
2
g
h
Reactions were run with 4-DPAIPN (6 mol %), NaCHO (3 equiv), alkene (5 equiv), and CySH (5 mol %). Reactions were run with conditions
2
d−g, using either EtN(iPr) or NaCHO as the reductant. See the Supporting Information for details.
2
2
nonpolarizable leaving groups unlikely to undergo XAT
processes. We found both substrates underwent productive
defunctionalization, albeit in diminished yield (Figure S13).
A broader survey of reductants less commonly employed in
photoredox catalysis (Figure S14) revealed that sodium
formate substantially enhanced the photoreductant activity of
We next evaluated the potency of this new catalytic system.
Having established that chlorobenzene could be reduced (−2.8
V vs SCE), we probed dehalogenation of increasingly electron-
rich aryl chlorides. These experiments revealed that substrates
with reduction potentials as low as −3.4 V vs SCE are
efficiently reduced. Additionally, these conditions promoted
the challenging reductive cleavage of both an anilinium and
aryl phosphate substrate. Taken together, these data clearly
implicate processes beyond a conventional photoredox
manifold. For example, the reduction of 6 would be predicted
to be endothermic by nearly 2 V (>40 kcal/mol at room
temperature) based on the most reducing conventional redox
4-DPAIPN (Figure 2A). We suspect this improvement occurs
because formate salts undergo a second-order hydrogen atom
68
transfer (HAT) process upon oxidation that results in formic
69−72
acid and carbon dioxide radical anion.
As a consequence,
a second reducing equivalent is liberated from formate after
initial oxidation. We suspect that the carbon dioxide radical
anion can either reduce another equivalent of photocatalyst or
promote the reaction by direct reduction of substrate
•−
76
couple of 4-DPAIPN (E1/2(PC/PC ) = −1.5 V vs SCE).
We next attempted to validate the intermediacy of an aryl
radical in this formate driven system. As anticipated, these
conditions furnished the five-membered ring product 9 in high
selectivity for radical cyclization. Despite its exceptionally
reducing potentials, we suspected that this operationally simple
procedure would be amenable to high-throughput techniques
widely employed in medicinal chemistry. To this end, we
rapidly evaluated the tolerance of complex drug-like scaffolds
using a commercially available informer plate designed to
•
−
73
(
E1/2(CO /CO ) = −2.2 V vs SCE). In each mechanistic
2
2
manifold, the SET is rendered irreversible by the release of
CO gas. This scenario contrasts starkly with the trialkylamine
2
reductants, which result in oxidizing amine radical cation
•
+
intermediates (E1/2(NR3 /NR ) = <1 V vs SCE) that could
3
deactivate the radical anion photocatalyst via back electron
61,74,75
transfer (Figure 2B).
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•
−
Figure 3. (A) UV−vis absorption spectrum demonstrating 4-DPAIPN generation in the presence of sodium formate and light. (B) UV−vis
•
−
absorption spectrum demonstrating that 4-DPAIPN reverts to 4-DPAIPN upon exposure to PhCl and subsequent irradiation.
challenge modern cross-coupling technology. We found that
not only was photocatalytic activity retained in the well-plate
format but that several of these functional group rich molecules
were effectively transformed (Figure S16).
radical couplings, we found aryl chlorides bearing reductively
sensitive functional groups were tolerated. We also found these
conditions promoted the coupling of aryl chlorides and
unactivated alkenes despite the fact that such a hydroarylation
remains challenging with any aryl radical precursor. Finally,
we questioned whether formate was uniquely effective for each
of these radical coupling reactions or whether alkylamines were
80
Although, in principle, aryl radicals are highly versatile
synthetic intermediates, premature reduction precludes radical
coupling reactions in many cases. This is particularly
problematic when potent reductants are required. To evaluate
selectivity for radical coupling, we targeted redox-neutral
photo-Arbuzov and radical borylation processes. These
established aryl radical transformations produce biologically
suitable terminal reductants. While EtN(i-Pr) and 4-DPAIPN
2
promote photoreduction of chlorobenzene, both reactivity and
radical selectivity were diminished in each coupling reaction.
Of note, competitive proteodehalogenation nearly precluded
7
7
relevant aryl phosphonates and versatile organoboron
81
net-reductive hydroarylation when alkylamines were used.
7
8
products. In both cases, we found that chloroarene substrates
Having established a generally applicable catalytic system to
engage aryl chloride substrates in radical coupling reactions, we
next conducted a preliminary mechanistic investigation into
the process. First, we probed whether an electron-primed
photoredox mechanismwherein the 4-DPAIPN radical
anion is generated and subsequently excitedwas feasible
under these conditions. We irradiated a mixture of 4-DPAIPN
and sodium formate while monitoring speciation by absorption
spectroscopy (Figure 3A). This resulted in a decrease in 4-
DPAIPN features and growth of new features consistent with
electrochemically reduced 4-DPAIPN (Figure S20). Next, we
probed the photoreduction of aryl chlorides. Chlorobenzene
was added to the reaction mixture and, upon irradiation, the
absorption features of 4-DPAIPN were restored (Figure 3B).
As expected based on the >1 V underpotential, no return of 4-
DPAIPN was observed upon addition of chlorobenzene to 4-
DPAIPN radical anion in the absence of light. Consistent with
this mechanistic picture, Stern−Volmer analysis resulted in no
measurable quenching of excited 4-DPAIPN by chloroben-
zene. In contrast, formate salts did quench the excited state.
Cyclohexanethiol, which was added to the net-reductive
transformations as an HAT cocatalyst, also quenches the
excited state and likely mediates the electron-transfer events in
these systems by an analogous mechanism (Figure S18).
Taken together, these experiments are consistent with our
working hypothesis that photooxidation of formate results in
79
readily underwent the desired radical coupling process. We
found that both difficult to reduce electron-rich aryl chlorides
and substrates bearing potentially reducible functional groups
such as esters and amides were well-tolerated (Table 2).
Furthermore, the catalytic system tolerated medicinally
relevant heterocycles.
Next, we evaluated the reductive hydroarylation of alkenes.
This challenging aryl radical reaction requires precise control
over the relative rates of radical coupling versus proteodeha-
logenation. HAT is mechanistically required to furnish product
and cannot be simply suppressed. Initially, we targeted the
synthesis of arylethylamines via hydroarylation. Recently, Jui
and co-workers reported that aryl radical intermediates
productively couple with vinyl carbamates to produce the
56
arylethylamine pharmacophore. Although one of the most
reducing conventional photocatalysts was employed, the
majority of the reaction scope was composed of aryl iodide
substrates and only aryl chloride substrates bearing with-
drawing groups were viable. Intriguingly, we found that
although the vinylcarbamate substrate is thermodynamically
easier to reduce than most chloroarenes (Ered = −2.2 V vs
SCE), these potent reductive conditions selectively trans-
formed chlorobenzene into N-Boc phenethylamine in high
yield. Even as the gap between the chloroarene and vinyl
carbamate coupling partner widens, synthetically useful
arylethylamine yields are still observed. Similar to the other
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the 4-DPAIPN radical anion, which can be subsequently
excited to photoreduce chlorobenzene and return 4-DPAIPN.
While the UV−vis experiments indicate that an electron-
primed photoredox mechanism is feasible, we recognized that
carbon dioxide radical anion is sufficiently reducing
catalysts have appeared to reduce substrates beyond their
65,85
expected redox potentials
and, more broadly, illustrate the
importance of radical ion intermediates in photoredox
catalysis.
•−
73
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05988.
(
E (CO /CO ) = −2.2 V vs SCE) to promote reductive
red
2
2
■
fragmentation of some of the aryl chloride substrates studied
without the intervention of an electron-primed photoredox
manifold. To evaluate the relative contribution of direct
substrate reduction by CO2 , we attempted to generate this
radical anion directly by homolysis of (PhS) under 370 nm
*
•
−
Experimental procedures, characterization data, and
spectra (PDF)
2
82
light in the absence of 4-DPAIPN. We envisioned thiyl
radical could abstract a hydrogen atom from formate to
AUTHOR INFORMATION
Corresponding Authors
•
−
71,83,84
■
directly generate CO2 in situ (Figure S23).
These
conditions resulted in quantitative conversion of 4-chloroben-
zonitrile (Ered = −2.1 V vs SCE). However, only 9% conversion
of chlorobenzene (Ered = −2.8 V vs SCE) and <5% conversion
of chloroanisole (Ered = −2.9 V vs SCE) were observed under
these photocatalyst-free conditions. In contrast, all three of
these substrates are dehalogenated in comparable efficiency
through use of the 4-DPAIPN conditions. We suspect both
mechanisms operate in parallel for substrates within the bound
Charles S. Yeung − Discovery Chemistry, Merck & Co., Inc.,
Boston, Massachusetts 02115, United States; orcid.org/
0000-0001-7320-7190; Email: charles.yeung@merck.com
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
•−
of the potency of CO2 (−2.2 V vs SCE) but that an electron-
Authors
primed photoredox manifold supports more thermodynami-
Alyah F. Chmiel − Department of Chemistry, University of
WisconsinMadison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0002-4859-6689
Oliver P. Williams − Department of Chemistry, University of
WisconsinMadison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0002-3897-6426
•
−
cally demanding reductions. In both cases, the CO2
reductant byproduct plays an active role either (a) reducing
the substrate directly or (b) reducing the photocatalyst to
reactivate it without requiring persistent multiphoton ex-
citation (Scheme 1).
Colleen P. Chernowsky − Department of Chemistry,
University of WisconsinMadison, Madison, Wisconsin
53706, United States; orcid.org/0000-0003-2073-1428
Scheme 1. Plausible Mechanism for Aryl Chloride
Reduction and the Roles of Formate and Its Byproducts
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05988
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Alison Wendlandt for helpful suggestions. We
thank the Stahl, Weix, Yoon, and Schomaker groups for sharing
their chemical inventory. We thank Dr. Wesley Swords (Yoon
group) for assistance with Stern−Volmer quenching experi-
ments. We thank Sara Alektiar for cyclic voltammetry data.
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. Acknowledgement is
made to the Donors of the American Chemical Society
Petroleum Research Fund for partial funding of this research
Overall, we have illustrated that use of a formate-based
terminal reductant in combination with an isophthalonitrile
photocatalyst can engage aryl chlorides in diverse synthetically
useful coupling reactions. We anticipate that these operation-
ally simple reaction conditions comprise a broadly useful
approach to photochemically induce difficult reductive
processes. Beyond the immediate synthetic utility, these results
are important because they challenge the notion that the
terminal reductant can be viewed as merely an electron-source
to turn over the photocatalyst. These data fit within a growing
body of literature that suggests terminal reductant byproducts
(
60677-DNI1). Spectroscopic instrumentation was supported
by a generous gift from Paul J. and Margaret M. Bender, NSF
(
1
CHE-1048642), and NIH (S10OD012245 and
S10OD020022-1).
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