Radical Chain Reduction via Carbon Dioxide Radical Anion (CO2?-)

Article abstract of DOI:10.1021/jacs.1c04427

We developed an effective method for reductive radical formation that utilizes the radical anion of carbon dioxide (CO2?-) as a powerful single electron reductant. Through a polarity matched hydrogen atom transfer (HAT) between an electrophilic radical and a formate salt, CO2?- formation occurs as a key element in a new radical chain reaction. Here, radical chain initiation can be performed through photochemical or thermal means, and we illustrate the ability of this approach to accomplish reductive activation of a range of substrate classes. Specifically, we employed this strategy in the intermolecular hydroarylation of unactivated alkenes with (hetero)aryl chlorides/bromides, radical deamination of arylammonium salts, aliphatic ketyl radical formation, and sulfonamide cleavage. We show that the reactivity of CO2?- with electron-poor olefins results in either single electron reduction or alkene hydrocarboxylation, where substrate reduction potentials can be utilized to predict reaction outcome.

Full text of DOI:10.1021/jacs.1c04427

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•−
Radical Chain Reduction via Carbon Dioxide Radical Anion (CO2 )
Cecilia M. Hendy,‡ Gavin C. Smith,‡ Zihao Xu, Tianquan Lian, and Nathan T. Jui*
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ABSTRACT: We developed an effective method for reductive radical formation that utilizes the radical anion of carbon dioxide
(CO2•−) as a powerful single electron reductant. Through a polarity matched hydrogen atom transfer (HAT) between an
electrophilic radical and a formate salt, CO2•− formation occurs as a key element in a new radical chain reaction. Here, radical chain
initiation can be performed through photochemical or thermal means, and we illustrate the ability of this approach to accomplish
reductive activation of a range of substrate classes. Specifically, we employed this strategy in the intermolecular hydroarylation of
unactivated alkenes with (hetero)aryl chlorides/bromides, radical deamination of arylammonium salts, aliphatic ketyl radical
formation, and sulfonamide cleavage. We show that the reactivity of CO2•− with electron-poor olefins results in either single electron
reduction or alkene hydrocarboxylation, where substrate reduction potentials can be utilized to predict reaction outcome.
More recently, the Jamison group developed a continuous
ingle electron reduction is a key mechanistic step in the
Sformation of radical species from many different electron- flow-based approach that allows for photochemical produc-
17
•−
tion and interception of CO2
.
We developed a novel
poor substrate classes. In this context, dissolving metal
conditions1,2 and electrochemical techniques3,4 are out-
standing approaches for accomplishing challenging reductions
(those of substrates with very negative reduction potentials).
However, these strategies are limited in their ability to
promote free radical reactivity. Because sequential two-
electron reduction occurs rapidly at metal surfaces, over-
reduction of transient radicals to the corresponding anions
occurs. This principle is particularly acute in reductive
activation of organic halides,5 as depicted in Figure 1. In
contrast, single electron reduction using photoredox catal-
ysis6,7 allows for precise tuning of kinetic factors (e.g.,
reduction potential, effective reductant concentration), which
enables the interception of transient radicals. Although the
use of visible light as an energy source is highly appealing,
reducing power is inherently limited by the energy contained
in a blue photon (up to 2.8 eV).8 To overcome this,
strategies that involve photoexcitation of radical anions have
been recently developed to yield super-reductants that readily
perform a range of challenging reductions.9−11 We were
interested in developing a new radical chain approach to
single electron reduction. We understood that the value of
this technology would largely depend on its ability to engage
unreactive substrates and grant reliable access to radical
intermediates in a simple manner.
•−
system that utilizes the reducing power of CO2
to
accomplish difficult reduction events that is centered around
the ability of thiol catalysts to shuttle hydrogen atoms. This
radical chain mechanism allows for direct production of
CO2 through hydrogen atom transfer (HAT) from formate.
Under these conditions, CO2 acts as a potent reductant for
single electron activation of many different substrate classes
that are typically redox inert (shown in Figure 1). This
method utilizes inexpensive inputs (no metal required) and
accomplishes a range of valuable radical processes.
We envisioned the mechanistic scenario that is outlined in
Figure 2A, where the radical chain is comprised of hydrogen
shuttling from a thiol catalyst. Reaction of thiyl radical with
formate affords the key reductant (CO2•−) that is able to
accomplish general substrate reduction. For example, single
electron transfer to an aryl chloride would give rise to the
corresponding arene radical anion, along with carbon dioxide
(providing a thermodynamic driving force). This HAT event
is essentially thermoneutral (formate C−H BDE: 88 kcal/
mol, thiol S−H BDE: 88−90 kcal/mol, see Supporting
Information). Mesolytic C−Cl fragmentation would generate
the corresponding aryl radical, which would undergo
reduction through H atom abstraction from the catalytic
thiol, propagating the radical chain. Importantly, as indicated
in Figure 2B, the principal feature of this approach is thiyl
formation in the presence of formate. This can be
conveniently accomplished from a thiol using the combina-
•−
•−
The carbon dioxide radical anion (CO2•−) is a highly
reactive intermediate that is routinely accessed through
electrochemical reduction of CO2.12,13 Given the combination
of its very negative reduction potential (E1/2° = −2.2 V vs
SCE)14 and reactive radical character, CO2 is a potentially
•−
Received: April 28, 2021
Published: June 9, 2021
valuable synthetic intermediate. However, it has not yet been
generally deployed in this context. Early studies by Kubiak15
and Barba16 demonstrated that single electron reduction of
CO2 can be utilized in carboxylation processes under
photochemical or electrochemical conditions, respectively.
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HAT catalyst. While light and formate were critical to
substrate conversion under these conditions (see the
Supporting Information for details), quantitative reduction
was observed when thiyl generation was performed via
photolysis of dimethyl disulfide (no photoredox catalyst) or
with thiol and persulfate (20 mol %) at 100 °C. However,
because trace amounts of thiol impurities that are present in
DMSO19−21 are capable of promoting this reaction,
mechanistic experiments were conducted with freshly purified
DMSO (however, solvent from particularly old bottles was
capable of promoting this reactivity without added thiol
cocatalyst). We found the quantum yield (Φ) of the reaction
under our standard conditions (P1, mesna) to be 2.63, which
strongly indicates radical chain character. Using transient
absorption spectroscopy (see Supporting Information for
details), we determined the rate of thiyl formation under the
standard (photoredox initiation) conditions (4.0 × 103 M−1·
s−1) as well as the quantum yield of the triplet excited state
(Φ = 0.0072). These rates indicate the average radical chain
length to be greater than or equal to 365 (standard
conditions).
•−
With the understanding that CO2 can be accessed under
mild conditions, we sought to utilize this radical chain
reduction in other valuable synthetic processes. First, we
considered the intermolecular coupling of aryl radical species
with unactivated olefins (radical hydroarylation). As shown in
Table 1, reaction of 4-chlorobenzonitrile (Ep/2 = −2.1 V vs
SCE)18 with 1-octene afforded alkylation product 1 in 66%
yield with photoredox initiation. Though slightly less efficient
for intermolecular radical coupling, alternative initiation
systems also promoted the desired reactivity (disulfide: 50%
yield, persulfate: 42% yield). We reported a number of radical
hydroarylation systems;22−24 however, these conditions are
unique in that they allow for direct coupling of benzene-
derived radicals with unactivated olefins. Moreover, this
process operates without the need for directing groups on
either reaction component. Monosubstituted alkenes bearing
alcohol and alkyl chloride functional groups reacted to give
alkylated products 2 and 3 in 46 and 85% yield, respectively,
where the remaining material was direct arene reduction. The
more electron-rich olefins 2-methyl-2-butene and isopropenyl
acetate also underwent smooth hydroarylation to yield 4
(66%) and 5 (81%). Evaluation of the aryl radical scope with
1-octene revealed that a number of electron-poor aryl and
heteroaryl chlorides can be engaged under this protocol (6−
14, 32−80% yield), though hydroarylation with ortho-
chloromethylbenzoate was less effective (10, 32% yield). In
addition, aryl radical coupling reactions employing bromo-
benzene, 4-chlorobenzonitrile, and 2-bromothiazole all
smoothly engaged tert-butylvinyl carbamate (3 equiv) to
afford the corresponding phenethylamines (15−17, 74−98%
yield). Here, reductive activation of aryl halide substrates can
be reliably predicted by reduction potential; reduction occurs
smoothly with substrates whose reduction potentials lie
•−
Figure 1. Novel approach to SET through reactivity of CO2
.
tion of a photoredox catalyst and visible light. In addition,
chain initiation can be easily conducted by other means. For
example, direct photolysis of disulfides or thermal decom-
position of persulfate (in the presence of catalytic thiol) are
equally effective.
To interrogate this proposal, we considered the reductive
dechlorination of methyl-2-chloro benzoate (Figure 2C).
Subjecting this aryl chloride to sodium formate (5 equiv) in
the presence of different combinations of photoredox
catalysts and HAT catalysts resulted in radical hydro-
dechlorination. With mesna (an inexpensive and odorless
alkyl thiol), a range of photoredox catalysts accomplished this
transformation in nearly quantitative yield (as determined by
1H NMR). These data illustrate the value of this radical chain
•−
•−
within the range of CO2 (i.e., less negative than −2.1 V
approach; while SET from CO2 to substrate would be
vs SCE). Substrates with E1/2° ≤ −2.1 V vs SCE (e.g.,
electron-rich aryl chlorides, ketones, amides, nitriles,
sulfonamides, phosphonates) are well-tolerated under these
conditions.
To further illustrate the value of this radical chain, we
applied it to the reduction of other challenging substrates.
For example, aryl trimethylammonium salts have been
demonstrated as electrophilic coupling partners25 that also
expected to occur with ease (based on reduction potential),
SET from these photocatalysts would be highly unfavored.
Indicated in Figure 2C are the most strongly reducing states
(ground state radical anions, given by reductive quenching),
which are at least ca. 600 mV more positive than that of the
chloride (−2.1 V vs SCE).18 A range of thiols were found to
perform this reaction, as was DABCO (albeit to a lesser
extent), and no conversion was observed in the absence of
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Figure 2. (A) Proposed mechanistic scenario for radical chain SET activation of aryl chloride substrates. (B) Methods for radical chain
initiation. (C) Experimental data in support of this radical chain proposal.
undergo deamination under Birch conditions. Under standard
conditions, we found that electron-poor arylammonium salts
undergo clean deamination (18−20, 70−94% yield). At
present, this process is limited to substrates that contain
electron-withdrawing groups in the meta-position. This
limitation stems from competitive nucleophilic demethylation
processes and challenges associated with trialkylammonium
salt formation. Nicewicz recently demonstrated a consecutive
photoinduced electron transfer process of acridinium salts
that effectively cleaves arylsulfonamide N−S bonds.9 We
engage a broad range of olefin substrates through SET
(Figure 3). Indeed, we observed efficient transformation of a
pyridyl cinnamate ester (Ep/2 = −1.6 V vs SCE) to the
hydrogenated product 34 (95% yield). To understand this
reductive process, we prepared a β-cyclopropyl enone
•−
substrate with a reduction potential within range of CO2
.
Reaction of this system under standard conditions resulted in
effective ring opening, giving rise to 33 (79% yield), in strong
support of the proposed SET event. With the analogous ester,
a substrate outside the reducing power of the CO2•−, we
instead observed very clean formation of Giese-type addition
product 32 (66% yield), where cyclopropyl ring opening was
not observed. These data indicate that olefin reduction
potential and reaction outcome are correlated, where more
electron-poor olefins (E1/2° ≥ − 2.1 V vs SCE) undergo SET
and less electron-poor olefins (E1/2° ≤ −2.1 V vs SCE)
undergo radical hydrocarboxylation. In line with this
assertion, CO2 incorporation was observed with both an
α,β-unsaturated nitrile and amide to afford the subsequent
hydrocarboxylated products (31 to 30, 67−69% yield) with
complete regiocontrol. While electrophilic carboxylation
reactions are commonplace (e.g., nucleophile trapping with
•−
found that CO2 is a competent reductant in achieving the
same, where radical chain deprotection gave 21−23 in 52−
84% yield. This system also accomplishes defluoroalkylation
of trifluoromethyl aromatics, a strategy that our group has
developed,26,27 to give difluoroalkyl products 24−26 (30−
59% yield). Finally, we found that these conditions effectively
achieve reduction of aliphatic aldehydes, where ketyl
formation is presumably followed by protonation and HAT
to deliver the corresponding alcohol products (27−29, 70−
87% yield).
Photochemical reduction of electron-deficient olefins has
been established as a powerful method for directly accessing
radical character at the β-position of Michael acceptors.28,29
We posited that our radical chain method would reductively
•−
CO2), this approach leverages nucleophilic behavior of CO2
in the construction of 1,4-dicarbonyls, motifs that are valuable
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Table 1. Radical Reactivity via CO2 Radical Chain Conditions: Coupling of Radicals with Olefins and Hydrogen Atom
a
Reaction conditions: substrate (1 equiv), olefin (5 equiv), P1 (1 mol %), mesna (20 mol %), sodium formate (5 equiv), MeCN/DMSO (1:1, v/
b
c
d
v), blue light, 16 h. Yield determined by 1H NMR with internal standard. Reaction conducted with aryl bromide. Reaction conducted at 100 °C.
e
f
DMSO used as solvent. 20% H2O/DMSO (v/v) used as solvent.
in the synthesis of heterocycles30−32 and bioactive small
molecules.33
substrates, where single electron reduction grants access to
radical reactivity. This radical chain can be initiated using
either photochemical or thermal pathways, where SET
reactivity generically occurs with substrates with reduction
potentials ≥ −2.1 V vs SCE. In the presence of Michael
acceptors that possess more negative reduction potentials, we
In summary, we developed a novel radical chain
•−
mechanism in which CO2 is easily produced from formate
through thiol-mediated HAT. This highly reducing inter-
mediate readily activates a broad array of challenging
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Figure 3. Reaction of carbon dioxide radical anion with electron-deficient alkenes: divergent reactivity based on reduction potential.
observed clean hydrocarboxylation, demonstrating the
ACKNOWLEDGMENTS
■
•−
nucleophilic character of CO2
.
Financial support for this work was provided by Emory
University and the National Institutes of Health
(GM129495), and NMR data were collected under support
of the National Science Foundation (CHE-1531620). We
acknowledge the financial support from the U.S. Department
of Energy, Office of Science, Office of Basic Energy Sciences,
Solar Photochemistry Program under Award DE-FG02-07ER-
15906 (to T.L.).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04427.
Experimental procedures, characterization data, and
spectra (PDF)
REFERENCES
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AUTHOR INFORMATION
■
Corresponding Author
Nathan T. Jui − Department of Chemistry and Winship
Cancer Institute, Emory University, Atlanta, Georgia 30322,
United States; orcid.org/0000-0001-5315-0270;
Email: njui@emory.edu
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Authors
Cecilia M. Hendy − Department of Chemistry and Winship
Cancer Institute, Emory University, Atlanta, Georgia 30322,
United States
Gavin C. Smith − Department of Chemistry and Winship
Cancer Institute, Emory University, Atlanta, Georgia 30322,
United States
Zihao Xu − Department of Chemistry and Winship Cancer
Institute, Emory University, Atlanta, Georgia 30322, United
States; orcid.org/0000-0003-0805-8533
Tianquan Lian − Department of Chemistry and Winship
Cancer Institute, Emory University, Atlanta, Georgia
30322, United States; orcid.org/0000-0002-8351-3690
Complete contact information is available at:
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‡C.M.H and G.C.S. contributed equally.
Notes
The authors declare no competing financial interest.
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