Unveiling Extreme Photoreduction Potentials of Donor-Acceptor Cyanoarenes to Access Aryl Radicals from Aryl Chlorides

Article abstract of DOI:10.1021/jacs.1c05994

Since the seminal work of Zhang in 2016, donor-acceptor cyanoarene-based fluorophores, such as 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN), have been widely applied in photoredox catalysis and used as excellent metal-free alternatives to noble metal Ir- and Ru-based photocatalysts. However, all the reported photoredox reactions involving this chromophore family are based on harnessing the energy from a single visible light photon, with a limited range of redox potentials from -1.92 to +1.79 V vs SCE. Here, we document the unprecedented discovery that this family of fluorophores can undergo consecutive photoinduced electron transfer (ConPET) to achieve very high reduction potentials. One of the newly synthesized catalysts, 2,4,5-tri(9H-carbazol-9-yl)-6-(ethyl(phenyl)amino)isophthalonitrile (3CzEPAIPN), possesses a long-lived (12.95 ns) excited radical anion form, 3CzEPAIPN?-*, which can be used to activate reductively recalcitrant aryl chlorides (Ered ≈ -1.9 to -2.9 V vs SCE) under mild conditions. The resultant aryl radicals can be engaged in synthetically valuable aromatic C-B, C-P, and C-C bond formation to furnish arylboronates, arylphosphonium salts, arylphosphonates, and spirocyclic cyclohexadienes.

Full text of DOI:10.1021/jacs.1c05994

pubs.acs.org/JACS
Article
Unveiling Extreme Photoreduction Potentials of Donor−Acceptor
Cyanoarenes to Access Aryl Radicals from Aryl Chlorides
Jinhui Xu, Jilei Cao, Xiangyang Wu, Han Wang, Xiaona Yang, Xinxin Tang, Ren Wei Toh, Rong Zhou,*
Edwin K. L. Yeow, and Jie Wu*
Cite This: J. Am. Chem. Soc. 2021, 143, 13266−13273
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Since the seminal work of Zhang in 2016, donor−acceptor cyanoarene-based fluorophores, such as 1,2,3,5-
tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN), have been widely applied in photoredox catalysis and used as excellent metal-
free alternatives to noble metal Ir- and Ru-based photocatalysts. However, all the reported photoredox reactions involving this
chromophore family are based on harnessing the energy from a single visible light photon, with a limited range of redox potentials
from −1.92 to +1.79 V vs SCE. Here, we document the unprecedented discovery that this family of fluorophores can undergo
consecutive photoinduced electron transfer (ConPET) to achieve very high reduction potentials. One of the newly synthesized
catalysts, 2,4,5-tri(9H-carbazol-9-yl)-6-(ethyl(phenyl)amino)isophthalonitrile (3CzEPAIPN), possesses a long-lived (12.95 ns)
excited radical anion form, 3CzEPAIPN•−*, which can be used to activate reductively recalcitrant aryl chlorides (Ered ≈ −1.9 to −2.9
V vs SCE) under mild conditions. The resultant aryl radicals can be engaged in synthetically valuable aromatic C−B, C−P, and C−C
bond formation to furnish arylboronates, arylphosphonium salts, arylphosphonates, and spirocyclic cyclohexadienes.
centered radicals, which can participate in a plethora of
transformations. The reaction scope is therefore restricted by
the energy of a photon. Visible light energy (e.g., a 440 nm
blue photon possesses a maximum driving force of 2.8 eV) is
typically diminished by 25%−50% through vibrational
relaxation, internal conversion, and intersystem crossing,
which is difficult to activate challenging nonactivated aryl
chlorides,9 that normally requires carcinogenic high-energy
ultraviolet (UV) light.10,11
INTRODUCTION
■
Aryl chlorides are versatile building blocks in organic synthesis,
being widely utilized as electrophilic partners in nucleophilic
aromatic substitutions, in transition metal catalysis, and as
precursors to organometallic complexes. Compared to the
corresponding bromides or iodides, aryl chlorides are more
abundant (Figure 1A), are frequently present in natural
products and pharmaceutical molecules, and are often lower
in cost and more stable, serving as excellent functional groups
for late-stage derivatizations.1,2
Photoredox catalysis offers numerous opportunities for the
convenient synthesis of active organic radical species through
single electron transfer (SET), which is complementary to
conventional two-electron processes.3−6 However, compared
to aryl bromides and iodides, aryl chlorides in photoredox
catalysis have been largely underexplored due to the high
energetic barrier for C(sp2)−Cl bond activation (PhCl at ∼97
kcal/mol).7,8 Upon absorption of a photon, the excited
photoredox catalyst promotes the single-electron reduction of
aryl halides. Subsequent C−X bond cleavage delivers carbon-
Several strategies have been developed during the past
several years to address these challenges and enable the
activation of aryl chlorides under visible light irradiation and
Received: June 9, 2021
Published: August 16, 2021
https://doi.org/10.1021/jacs.1c05994
J. Am. Chem. Soc. 2021, 143, 13266−13273
© 2021 American Chemical Society
13266

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Figure 1. (A) Photocatalytic activation of aryl halides. (B) Disclosure of donor−acceptor cyanoarenes as efficient ConPET catalysts for aryl
chloride activation. aCommercial availability of different arene sources: SciFinder, accessed April 2, 2021. bSee details in Table S6, potentials vs SCE
(saturated calomel electrode).
mild conditions, such as consecutive photoinduced electron
transfer (ConPET), sensitization-initiated electron transfer
(SenI-ET), electrophotocatalysis, and solvated electrons.8,12,13
Among these strategies, ConPET represents the most
operationally simple and green method12,14 and does not
require additives such as metal catalysts,15 additional photo-
sensitizers,16 micelles,17 electrolytes, or specialized electro-
chemical equipment.18,19 The ConPET strategy relies on a
photocatalyst and a sacrificial electron donor that, upon visible
light irradiation, results in a long-lived radical anion, which can
be excited by a second photon to induce a much more
the cyanobenzene scaffold to expand the redox window (−1.92
to +1.79 V vs SCE).32 Upon absorption of a blue photon, the
excited 4CzIPN can be quenched via single-electron reduction,
resulting in the formation of the radical anion 4CzIPN•−. In
the established 4CzIPN-based photoredox catalysis process,
this radical anion species is typically oxidized to regenerate the
parent catalyst to complete the catalytic cycle (Figure 1B, left
cycle). We herein report an unprecedented discovery27,33 that
donor−acceptor cyanoarenes can effectively undergo a
ConPET process to achieve a very strongly reducing
photocatalytic system that can effectively reduce unactivated
and electron-rich aryl chlorides (with reduction potentials, Ered,
as low as −2.94 V vs SCE) for aromatic C−B, C−P, and C−C
bond formation (Figure 1B, right cycle). This strategy features
advantages such as not requiring transition metals, being
operationally simple, proceeding under mild conditions, and
functioning with a wide range of aryl halides including complex
pharmaceutical molecules for late-stage derivatizations.
powerful reducing species.20 The Konig group pioneered this
̈
field by developing a perylene bisimide (PDI) photocatalyst
whose photoreduced form can undergo consecutive absorption
of a second photon to achieve a much stronger reducing
species for aryl halide reduction.21 Subsequently, several other
organic dyes, including rhodamine 6G,22 9,10-dicyanoanthra-
cene (DCA),23 anthraquinone,24 acridinium salts (Mes-
Acr+),25 and benzo[ghi]perylene (BPI),26 were disclosed to
be competent ConPET catalysts for aryl halide reduction,21−25
Birch reduction,26 and sulfonamide cleavage.25 However, the
majority of these ConPET catalysts are still effective only for
electron-poor aryl chlorides,21−24 and efficient catalytic
systems for reductively recalcitrant aryl chlorides are rare25,27
but highly desirable.8
RESULTS AND DISCUSSION
■
Reaction Design and Optimization. Our study was first
inspired by the observation that the radical anion of 4CzIPN
(4CzIPN•−) generated from photoexcited 4CzIPN* and an
electron donor N,N-diisopropylethylamine (DIPEA) is a long-
lived radical anion species (stable for more than 3 h under
Carbazoyl dicyanobenzenes were first reported as highly
efficient thermally activated delayed fluorescence (TADF)28
emitters by Adachi and co-workers.29 Among these donor−
acceptor fluorophores, 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicya-
nobenzene (4CzIPN) has been widely applied as a versatile
metal-free photoredox catalyst to replace Ru− and Ir−
polypyridyl photocatalysts.30,31 Its photophysical and electro-
chemical properties can be fine-tuned by structural mod-
ification of the electron donor or electron acceptor moieties of
argon in the dark, Figure S20). This species can be further
em
max
excited by blue LED light to give a fluorescence band (λ
=
448 nm) which is distinctly different from that of 4CzIPN*
em
(λ
= 545 nm, Figure S8G). The reductive potential of
max
4CzIPN [E1/2(PC/PC•−) = −1.24 V vs SCE] (Figure S13) is
more negative than those of DCA (−0.82 V vs SCE),18 PDI
(−0.43 V vs SCE),21 and Mes-Acr+ (−0.60 V vs SCE)25 and is
similar to that of BPI (−1.30 V vs SCE),26 indicating that
13267
https://doi.org/10.1021/jacs.1c05994
J. Am. Chem. Soc. 2021, 143, 13266−13273

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Table 1. Optimization of Conditions for the Visible-Light-Induced Borylation of Aryl Chlorides
a
b
Yields based on analysis of the 1H NMR spectra of the crude product mixture by using CH2Br2 as an internal standard. Blue LED (4 × 40 W, 456
c
nm); the reaction was performed for 36 h. Isolated yields. 4-CN-Py = 4-cyanopyridine; L-AscNa2 = L(+)-ascorbic acid disodium salt; E0,0 = excited
state energy; εmax = molar extinction coefficient at the maximum absorption wavelength; τf = lifetime of the excited state; CzH = carbazole.
4CzIPN•−* could be a powerful reducing species that can
effectively reduce difficult aryl halides.
an improved yield was obtained when using tri(9H-carbazol-9-
yl)-6-(methyl(phenyl)amino)isophthalonitrile (3CzMPAIPN)
as the photocatalyst (entry 3), and further improvement to
95% isolated yield could be achieved by replacing the methyl
substituent with an ethyl group (3CzEPAIPN, entry 1). The
control experiments (Figure S30) illustrated that 3CzEPAIPN
(in a radical anion form) could exist for a much longer time
during the reaction process, although both 4CzIPN and
3CzEPAIPN decomposed after an extended reaction time
(>24 h). When DIPEA was used as the electron donor instead
of sodium oxalate, a moderate yield (52%) was achieved due to
competing dechlorinated byproduct formation (Table 1A,
entry 4). Using sodium ascorbate as the electron donor
afforded the same efficiency as that with sodium oxalate (entry
5); thus, inexpensive sodium oxalate was employed in the
scope study. Eliminating the catalytic 4-cyanopyridine led to a
substantially reduced yield (entry 6), indicating its important
role for the stable boryl radical formation.41 The reaction
became less efficient in the absence of K3PO4 (entry 7).
Control experiments revealed the essential roles of both
On the basis of the proposed ConPET process, we first
attempted to develop a synthetically useful borylation reaction
of chloroarenes, of which meaningful progresses have been
made by Schelter,10 Lambert−Lin,18 Jiao,34 Marder,35
37
Larionov,36 and Konig. Our initial optimization revealed
̈
that when 4CzIPN was used as a photocatalyst, with a catalytic
amount of 4-cyanopyridine, sodium oxalate as an electron
donor, and K3PO4 as a base, borylation of p-chlorotoluene (1)
afforded the corresponding boronic ester (3) in 76% yield
under 2 × 40 W blue LED irradiation (Table 1A, entry 2).
4CzIPN was not stable38,39 and easily decomposed to
carbazoles under the reaction conditions (see details in Figures
S29 and S31), which may cause a lower reaction efficiency. We
thus synthesized a group of new donor−acceptor dicyano-
benzenes through a straightforward two-step procedure (Table
1B)30,40 by replacing one of the carbazole groups with amines
to alleviate or avoid the decomposition of photocatalysts
(Table S2). Among all the newly synthesized photocatalysts,
13268
https://doi.org/10.1021/jacs.1c05994
J. Am. Chem. Soc. 2021, 143, 13266−13273

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
sodium ascorbate and photoirradiation as no product was
detected in the absence of either of them (entries 8 and 9).
Gram-scale synthesis was easily achieved by employing more
intensive light irradiation and a longer reaction time (entry
10), demonstrating the synthetic practicality of this method.
Scope of Borylation. With the optimized conditions in
hand, we examined the scope of borylation of aryl chlorides
through the ConPET process. We found that this protocol was
effective with not only activated aryl chlorides (15−25) but
also challenging nonactivated aryl chlorides (14) and electron-
rich aryl chlorides (3−13) that possess very negative reduction
potentials (up to −2.94 V, Table 2A). A number of functional
groups were well tolerated, including ethers (8−11), phenols
(12), sulfides (13), trifluoromethyl (24), and borates (25) as
well as those potentially sensitive to strongly reducing
conditions, such as aryl fluorides (16−19), nitriles (20−22),
esters (23), indoles (26), and epoxides (27). Only moderate
yields were obtained with some substrates (9 and 11−13),
which were mainly due to the competing dechlorination side
reaction and starting material recovery even with prolonged
reaction time (36 h). No obvious correlation between the
substrate reduction potential and reactivity was observed,
indicating the radical anion fragmentation and borylation steps
also played important roles to achieve an overall efficient
transformation.19 Diborylation products (25, 28, and 29),
which have found wide application in materials science, were
obtained in good to excellent yields when dihaloarenes were
employed, probably because the generated monoborylated
chloride intermediates were more reducible than dihaloarenes.
Aryl borates other than pinacolborate could be smoothly
generated by using the corresponding diboron esters (30−32,
Table 2B). However, B2(OH)4 was not compatible with our
method due to its insolubility in acetonitrile (33).
Table 2. Scope of Visible-Light-Induced Borylation of Aryl
Chlorides
a
A wide range of pharmaceutical compounds performed well
under a slightly modified borylation protocol by using DIPEA
as the electron donor, which possesses multiple Lewis basic
atoms and heterocyclic moieties that can potentially coordinate
and be problematic in transition metal catalysis (Table 2C).
Borylated derivatives of loratadine (34), meclizine (35),
indomethacin (36), carbinoxamine (37), chloropyramine
(38), cloperastine (39), chlorpromazine (40), and clofibrate
(41) were generated in moderate to good yields. Some of the
borylation products were isolated as organotrifluoroborate salts
as a part of the work-up procedure to assist product isolation.
Transformations Other than Borylation. The scope of
this carbazoyl dicyanobenzene-promoted ConPET strategy
could be extended to the formation of C−P bonds by
employing phosphines or phosphites as radical trapping agents.
Arylphosphonium salts are widely used as organocatalysts,
phase transfer reagents, ionic liquids, and so on. In addition,
they can also be used as functional handles for further C−O,
C−S, C−N, and C−C bond formation.42−45 However, existing
methods for the preparation of arylphosphonium salts from
aryl halides or pseudohalides rely on transition metal catalysis
and high-temperature processes.46−48 We herein developed a
metal-free synthesis of arylphosphonium salts under ambient
conditions using 3CzEPAIPN as the photocatalyst and
substoichiometric DIPEA as the electron donor (Figure 2A).
Notably, this reactivity enabled engagement of both electron-
rich and electron-poor aryl chlorides (42−51) as well as
various arylphosphines (52−54), delivering the desired
phosphonium salts in good to excellent yields. Moreover,
exposure of aryl exclusively in chlorides with trimethyl
a
Reaction conditions: aryl chloride (0.2 mmol), B2Pin2 (2.0 equiv), 4-
CN-Py (10 mol %), Na2C2O4 (1.5 equiv), K3PO4 (2.0 equiv), and
3CzEPAIPN (5 mol %) in MeCN (1 M) under irradiation with Kessil
light (456 nm, 2 × 40 W) at rt for 24 h under argon. Isolated yields.
b
c
See references in Table S6; potentials vs SCE. The reaction was
d
performed for 36 h. Only diborylation products were obtained.
e
Reaction conditions were slightly modified; see details in the
Supporting Information.
phosphite to slightly modified conditions enabled a visible
light promoted Arbuzov reaction for the generation of aryl
phosphonates (55−60, Figure 2B).49
The synthetic utility of this ConPET protocol was further
extended to dearomative hydroarylation of aryl chlorides to
produce spirocyclic cyclohexadienes (61−63), probably
through a reductive radical-polar crossover mechanism, as
reported by Jui50 (Figure 2C). The catalytic system could also
be applied to reductive defluorination of trifluoromethylarenes
to methylarenes (64, Figure 2D).51 Moreover, the developed
phosphorylation was amenable to scale-up with an operation-
ally simple continuous-flow setup, which resulted in
13269
https://doi.org/10.1021/jacs.1c05994
J. Am. Chem. Soc. 2021, 143, 13266−13273

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Figure 2. Various transformations promoted by the donor−acceptor cyanoarene-catalyzed reductive ConPET process. Using 4CzIPN as the
photocatalysts instead of 3CzEPAIPN.
phosphonium salts in good yield and gram-scale production
with reduced amounts of Ph3P (1.2 equiv) and photocatalyst
(2.5 mol %), highlighting the excellent efficiency of micro-
tubing flow reactors in photochemical synthesis (Figure 2E).
Mechanistic Investigations. To gain more insight into
the proposed ConPET process, various spectroscopic studies
and control experiments were performed (Figure 3). First,
upon irradiation of a solution of 3CzEPAIPN and DIPEA with
a blue LED light, a color change from yellow to light yellow
was observed. UV−vis spectroscopy demonstrated a blue-shift
was detected by 19F NMR spectra (step 4), which is consistent
with our proposal that photoexcited 3CzEPAIPN•−* is capable
of reducing aryl chlorides to reactive aryl radicals.
The long lifetime of unexcited 3CzEPAIPN•− allows it to
absorb a photon by using an LED light source to generate the
excited state, whose properties were explored by time-
correlated single photon counting (TCSPC) (Figure 3F).26,54
Excitation of 3CzEPAIPN•− by irradiation at 375 nm resulted
em
max
in a characteristic emission band of 3CzEPAIPN•−* (λ
=
488 nm), whose average lifetime was measured to be 12.95 ns,
much longer than the 6.33 ns of 4CzIPN•−*. The time-
resolved emission quenching experiments revealed a linear
photoluminescence lifetime quenching of 3CzEPAIPN•−* by
aryl chlorides, which further supported the ConPET process
(Figure 3G).
of the maximum absorption peak (Figure 3A). The emission of
em
max
these mixtures clearly underwent a hypsochromic shift (λ
from 597 to 488 nm, Figure 3B; a very weak energy emission
em
max
band was observed at λ = 546 nm when excited by ∼525 nm
green light, Figure S12) resulted from the formation of a new
species, which is similar to the result observed for 4CzIPN. To
verify that this new species was the long-lived radical anion
3CzEPAIPN•−, electron paramagnetic resonance (EPR) spec-
troscopy was conducted. The experimental EPR spectrum
matches well with the simulated spectrum of 3CzEPAIPN•−
(Figure 3C).52 Near quadratic dependency of the conversion
of aryl chlorides on the irradiation density further supported
that the aryl radical formation mechanism involves an overall
two-photon excitation (Figure 3D).53
In light of all the experimental data, a plausible mechanistic
pathway was proposed by using aryl borylation as a
representative example (Figure 3H). Following light excitation,
3CzEPAIPN engages in single-electron transfer with an
electron donor to generate a long-lived radical anion species,
which is then excited by visible light irradiation again to afford
excited 3CzEPAIPN•−*. 3CzEPAIPN•−* possesses strong
reductive potential to undergo electron transfer with
reductively recalcitrant aryl chloride, which generates a reactive
aryl radical after fragmentation and re-forms 3CzEPAIPN in
the ground state. The resulting aryl radical then couples with a
Lewis base stabilized boryl radical,41 yielding the desired
arylboronate product (see the Supporting Information for the
proposed mechanisms for C−P and C−C bond formations).
Direct evidence of the ConPET process was obtained by 1H
NMR investigation (Figure 3E). The characteristic NMR
signals of 3CzEPAIPN were detected with a mixture of the
photocatalyst and DIPEA in CD3CN (step 1). Upon direct
exposure of the solutions within the NMR tube to blue light,
line broadening and signal disappearance were observed,
probably due to the generation of unpaired electron species
(step 2), which have a strong influence on NMR resonance
transverse relaxation rates of neighboring protons, indicating
the generation of 3CzEPAIPN•−. This radical anion species
was stable under argon for at least 3 h and could be quenched
by air to convert back to the ground state catalyst (Figure
S21). The addition of aryl chlorides showed no effect on the
radical anion species in the absence of light (step 3). However,
in the presence of light, they quenched the radical anion
species back to 3CzEPAIPN, and the dehalogenation product
CONCLUSION
■
In conclusion, we have disclosed that donor−acceptor
cyanoarene-based fluorophores can undergo ConPET to access
catalysts with exceedingly high reducing power, which
complements the well-established single-photon-promoted
redox chemistry associated with this family of fluorophores.
A new catalyst 3CzEPAIPN can be activated through this
strategy to enable robust and efficient activation of aryl
chlorides with very negative reduction potentials for C−B, C−
P, and C−C bond formations to furnish a broad scope of
13270
https://doi.org/10.1021/jacs.1c05994
J. Am. Chem. Soc. 2021, 143, 13266−13273

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Figure 3. Proposed mechanism with supporting evidence. (A) Absorbance profiles for 3CzEPAIPN and 3CzEPAIPN•− (3.3 × 10−5 M, 1.0 cm path
length). (B) Emission profiles (excitation at 390 nm) for 3CzEPAIPN and 3CzEPAIPN•− (3.3 × 10−5 M, 1.0 cm path length). (C) Experimental
and simulated EPR spectra to support the presence of 3CzEPAIPN•−. (D) Near quadratic dependency of the conversion of aryl chlorides on the
irradiation density to support the overall two-photon absorption process. R2 is the coefficient of determination, known as the goodness of fit. (E)
NMR spectroscopic evidence supporting the proposed ConPET process. (F) Determination of the average lifetime (τ0) of the excited state of
3CzEPAIPN•− by time-correlated single-photon counting measurements. (G) Measurement of the electron transfer rate constant (ket) between
various concentrations of chlorobenzene and 3CzEPAIPN•−* by time-resolved emission quenching experiments. τ is the lifetime of
3CzEPAIPN•−* in different concentrations of chlorobenzene. (H) Plausible mechanism of borylation of aryl chlorides through the ConPET
process.
arylboronates, arylphosphonium salts, arylphosphonates, and
spirocyclic cyclohexadienes. The ConPET process has been
unambiguously supported by various spectroscopic investiga-
tions. The advantages associated with cyanoarene-based
fluorophores, such as being inexpensive, metal-free, and
modular, allow wide applications in the synthetic community
and provide a platform to further explore and understand the
design principles for more potent photocatalysts based on the
ConPET process.
General procedures, tables of reaction optimizations,
analytical data, and NMR spectra (PDF)
Accession Codes
CCDC 2088426 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Authors
■
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05994.
Rong Zhou − College of Chemistry and Chemical Engineering,
Taiyuan University of Technology, Taiyuan 030024, P. R.
13271
https://doi.org/10.1021/jacs.1c05994
J. Am. Chem. Soc. 2021, 143, 13266−13273

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(6) Tucker, J. W.; Stephenson, C. R. J. Shining Light on Photoredox
Catalysis: Theory and Synthetic Applications. J. Org. Chem. 2012, 77,
1617−1622.
(7) Blanksby, S. J.; Ellison, G. B. Bond Dissociation Energies of
Organic Molecules. Acc. Chem. Res. 2003, 36, 255−263.
(8) Cybularczyk-Cecotka, M.; Szczepanik, J.; Giedyk, M. Photo-
catalytic Strategies for the Activation of Organic Chlorides. Nat. Catal.
2020, 3, 872−886.
China; orcid.org/0000-0002-0322-9199;
Email: zhourong@tyut.edu.cn
Jie Wu − Department of Chemistry, National University of
Singapore, 117545, Singapore; orcid.org/0000-0002-
9865-180X; Email: chmjie@nus.edu.sg
Authors
Jinhui Xu − Department of Chemistry, National University of
Singapore, 117545, Singapore; orcid.org/0000-0001-
6832-3736
Jilei Cao − College of Chemistry and Chemical Engineering,
Taiyuan University of Technology, Taiyuan 030024, P. R.
China
(9) Shon, J.-H.; Kim, D.; Rathnayake, M. D.; Sittel, S.; Weaver, J.;
Teets, T. S. Photoredox Catalysis on Unactivated Substrates with
Strongly Reducing Iridium Photosensitizers. Chem. Sci. 2021, 12,
4069−4078.
(10) Qiao, Y.; Yang, Q.; Schelter, E. J. Photoinduced Miyaura
Borylation by
a Rare-Earth-Metal Photoreductant: The
Xiangyang Wu − Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, 637371, Singapore
Han Wang − Department of Chemistry, National University of
Singapore, 117545, Singapore
Xiaona Yang − College of Chemistry and Chemical
Engineering, Taiyuan University of Technology, Taiyuan
030024, P. R. China
Hexachlorocerate(III) Anion. Angew. Chem., Int. Ed. 2018, 57,
10999−11003.
(11) Mfuh, A. M.; Doyle, J. D.; Chhetri, B.; Arman, H. D.; Larionov,
O. V. Scalable, Metal- and Additive-Free, Photoinduced Borylation of
Haloarenes and Quaternary Arylammonium Salts. J. Am. Chem. Soc.
2016, 138, 2985−2988.
(12) Glaser, F.; Kerzig, C.; Wenger, O. S. Multi-Photon Excitation in
Photoredox Catalysis: Concepts, Applications, Methods. Angew.
Chem., Int. Ed. 2020, 59, 10266−10284.
Xinxin Tang − Department of Chemistry, National University
of Singapore, 117545, Singapore
(13) Liu, J.; Lu, L.; Wood, D.; Lin, S. New Redox Strategies in
Organic Synthesis by Means of Electrochemistry and Photochemistry.
ACS Cent. Sci. 2020, 6, 1317−1340.
Ren Wei Toh − Department of Chemistry, National
University of Singapore, 117545, Singapore
Edwin K. L. Yeow − Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, 637371, Singapore;
orcid.org/0000-0003-0290-4882
(14) Goez, M.; Kerzig, C.; Naumann, R. An “All-Green” Catalytic
Cycle of Aqueous Photoionization. Angew. Chem., Int. Ed. 2014, 53,
9914−9916.
(15) Connell, T. U.; Fraser, C. L.; Czyz, M. L.; Smith, Z. M.; Hayne,
D. J.; Doeven, E. H.; Agugiaro, J.; Wilson, D. J. D.; Adcock, J. L.;
Scully, A. D.; Gomez, D. E.; Barnett, N. W.; Polyzos, A.; Francis, P. S.
The Tandem Photoredox Catalysis Mechanism of [Ir(ppy)2(dtb-
bpy)]+ Enabling Access to Energy Demanding Organic Substrates. J.
Am. Chem. Soc. 2019, 141, 17646−17658.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05994
Notes
(16) Ghosh, I.; Shaikh, R. S.; König, B. Sensitization-Initiated
Electron Transfer for Photoredox Catalysis. Angew. Chem., Int. Ed.
2017, 56, 8544−8549.
The authors declare no competing financial interest.
(17) Naumann, R.; Lehmann, F.; Goez, M. Generating Hydrated
Electrons for Chemical Syntheses by Using a Green Light-Emitting
Diode (LED). Angew. Chem., Int. Ed. 2018, 57, 1078−1081.
(18) Kim, H.; Kim, H.; Lambert, T. H.; Lin, S. Reductive
Electrophotocatalysis: Merging Electricity and Light to Achieve
Extreme Reduction Potentials. J. Am. Chem. Soc. 2020, 142, 2087−
2092.
(19) Cowper, N. G. W.; Chernowsky, C. P.; Williams, O. P.;
Wickens, Z. K. Potent Reductants via Electron-Primed Photoredox
Catalysis: Unlocking Aryl Chlorides for Radical Coupling. J. Am.
Chem. Soc. 2020, 142, 2093−2099.
ACKNOWLEDGMENTS
■
We are grateful for the financial support provided by Pharma
Innovation Programme Singapore (A*STAR, SERC
A19B3a0014), the National University of Singapore (R-143-
000-B60-114), and the National Natural Science Foundation
of China (Grants 22071170 and 21502135). The authors
thank Saif A. Khan (NUS Singapore), Shunsuke Chiba (NTU
Singapore), Joel M. Hawkins (Pfizer), Thomas Knauber
(Pfizer), François Le Lévesque (Merck), Lee Edwards
(GSK), and Jean-Philippe Krieger (Syngenta) for helpful
discussions.
(20) Other than the reductive ConPET, an oxidative ConPET was
recently reported: Targos, K.; Williams, O. P.; Wickens, Z. K.
Unveiling Potent Photooxidation Behavior of Catalytic Photo-
reductants. J. Am. Chem. Soc. 2021, 143, 4125−4132.
(21) Ghosh, I.; Ghosh, T.; Bardagi, J. I.; Konig, B. Reduction of Aryl
Halides by Consecutive Visible Light-Induced Electron Transfer
Processes. Science 2014, 346, 725−728.
REFERENCES
■
(1) Grushin, V. V.; Alper, H. In Activation of Unreactive Bonds and
Organic Synthesis; Murai, S., Ed.; Springer-Verlag: Berlin, 1999; pp
193−226.
(22) Ghosh, I.; König, B. Chromoselective Photocatalysis:
Controlled Bond Activation through Light-Color Regulation of
Redox Potentials. Angew. Chem., Int. Ed. 2016, 55, 7676−7679.
(2) Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas,
A. W.; Wilson, D. M.; Wood, A. Organic Synthesis Provides
Opportunities to Transform Drug Discovery. Nat. Chem. 2018, 10,
383−394.
(23) Neumeier, M.; Sampedro, D.; Májek, M.; de la Pena O’Shea, V.
̃
A.; Jacobi von Wangelin, A.; Pérez-Ruiz, R. Dichromatic Photo-
catalytic Substitutions of Aryl Halides with a Small Organic Dye.
Chem. - Eur. J. 2018, 24, 105−108.
(3) Marzo, L.; Pagire, S. K.; Reiser, O.; König, B. Visible-Light
Photocatalysis: Does It Make a Difference in Organic Synthesis?
Angew. Chem., Int. Ed. 2018, 57, 10034−10072.
(24) Bardagi, J. I.; Ghosh, I.; Schmalzbauer, M.; Ghosh, T.; König, B.
Anthraquinones as Photoredox Catalysts for the Reductive Activation
of Aryl Halides. Eur. J. Org. Chem. 2018, 2018, 34−40.
(4) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis.
Chem. Rev. 2016, 116, 10075−10166.
(5) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light
Photoredox Catalysis with Transition Metal Complexes: Applications
in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363.
(25) MacKenzie, I. A.; Wang, L.; Onuska, N. P. R.; Williams, O. F.;
Begam, K.; Moran, A. M.; Dunietz, B. D.; Nicewicz, D. A. Discovery
13272
https://doi.org/10.1021/jacs.1c05994
J. Am. Chem. Soc. 2021, 143, 13266−13273

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
and Characterization of an Acridine Radical Photoreductant. Nature
2020, 580, 76−80.
(42) Hilton, M. C.; Dolewski, R. D.; McNally, A. Selective
Functionalization of Pyridines via Heterocyclic Phosphonium Salts.
J. Am. Chem. Soc. 2016, 138, 13806−13809.
(43) Hwang, L. K.; Na, Y.; Lee, J.; Do, Y.; Chang, S.
Tetraarylphosphonium Halides as Arylating Reagents in Pd-catalyzed
Heck and Cross-coupling Reactions. Angew. Chem., Int. Ed. 2005, 44,
6166−6169.
(44) Ramanjaneyulu, B. T.; Pareek, M.; Reddy, V.; Vijaya Anand, R.
Direct Esterification of Aromatic Aldehydes with Tetraphenylphos-
phonium Bromide under Oxidative N-Heterocyclic Carbene Catalysis.
Helv. Chim. Acta 2014, 97, 431−437.
(26) Cole, J. P.; Chen, D.-F.; Kudisch, M.; Pearson, R. M.; Lim, C.-
H.; Miyake, G. M. Organocatalyzed Birch Reduction Driven by
Visible Light. J. Am. Chem. Soc. 2020, 142, 13573−13581.
(27) A similar method of activation of nonactivated aryl chlorides
was reported after we submitted this manuscript, where isophthaloni-
trile was the photocatalyst and formate was used as the terminal
reductant: Chmiel, A. F.; Williams, O. P.; Chernowsky, C. P.; Yeung,
C. S.; Wickens, Z. K. Non-Innocent Radical Ion Intermediates in
Photoredox Catalysis: Parallel Reduction Modes Enable Coupling of
Diverse Aryl Chlorides. ChemRxiv. 2021, DOI: 10.26434/chem-
rxiv.14755134.v1.
(45) Deng, Z.; Lin, J. H.; Xiao, J. C. Nucleophilic Arylation with
Tetraarylphosphonium Salts. Nat. Commun. 2016, 7, 10337.
(46) Huang, W.; Zhong, C. H. Metal-Free Synthesis of
Aryltriphenylphosphonium Bromides by the Reaction of Triphenyl-
phosphine with Aryl Bromides in Refluxing Phenol. ACS Omega 2019,
4, 6690−6696.
(28) Bryden, M. A.; Zysman-Colman, E. Organic Thermally
Activated Delayed Fluorescence (TADF) Compounds Used in
Photocatalysis. Chem. Soc. Rev. 2021, 50, 7587−7680.
(29) Uoyama, H.; Goushi, K.; Shizu, K.; Nomura, H.; Adachi, C.
Highly Efficient Organic Light-emitting Diodes from Delayed
Fluorescence. Nature 2012, 492, 234−238.
(30) Luo, J.; Zhang, J. Donor-Acceptor Fluorophores for Visible-
Light-Promoted Organic Synthesis: Photoredox/Ni Dual Catalytic
C(sp3)-C(sp2) Cross-Coupling. ACS Catal. 2016, 6, 873−877.
(31) Shang, T.-Y.; Lu, L.-H.; Cao, Z.; Liu, Y.; He, W.-M.; Yu, B.
Recent Advances of 1,2,3,5-Tetrakis(carbazol-9-yl)-4,6-dicyanoben-
zene (4CzIPN) in Photocatalytic Transformations. Chem. Commun.
2019, 55, 5408−5419.
(32) Speckmeier, E.; Fischer, T. G.; Zeitler, K. A Toolbox Approach
To Construct Broadly Applicable Metal-Free Catalysts for Photo-
redox Chemistry: Deliberate Tuning of Redox Potentials and
Importance of Halogens in Donor-Acceptor Cyanoarenes. J. Am.
Chem. Soc. 2018, 140, 15353−15365.
(33) A related paper on photoexcited donor−acceptor cyanoarenes
radical anion as powerful reducing species was preprinted in
ChemRxiv: Chernowsky, C. P.; Chmiel, A. F.; Wickens, Z. K.
Photocatalytic Activity of Diverse Organic Radical Anions: Catalyst
Discovery Enables Cleavage of Strong C(sp2)-N and C(sp2)-O Bonds.
Chemrxiv. 2021, DOI: 10.26434/chemrxiv.14710398.v1.
(34) Zhang, L.; Jiao, L. Visible-Light-Induced Organocatalytic
Borylation of Aryl Chlorides. J. Am. Chem. Soc. 2019, 141, 9124−
9128.
(35) Tian, Y.-M.; Guo, X.-N.; Krummenacher, I.; Wu, Z.; Nitsch, J.;
Braunschweig, H.; Radius, U.; Marder, T. B. Visible-Light-Induced
Ni-Catalyzed Radical Borylation of Chloroarenes. J. Am. Chem. Soc.
2020, 142, 18231−18242.
(47) Marcoux, D.; Charette, A. B. Palladium-catalyzed Synthesis of
Functionalized Tetraarylphosphonium Salts. J. Org. Chem. 2008, 73,
590−593.
(48) Marcoux, D.; Charette, A. B. Nickel-Catalyzed Synthesis of
Phosphonium Salts from Aryl Halides and Triphenylphosphine. Adv.
Synth. Catal. 2008, 350, 2967−2974.
(49) Shaikh, R. S.; Dusel, S. J. S.; König, B. Visible-Light Photo-
̈
Arbuzov Reaction of Aryl Bromides and Trialkyl Phosphites Yielding
Aryl Phosphonates. ACS Catal. 2016, 6, 8410−8414.
(50) Flynn, A. R.; McDaniel, K. A.; Hughes, M. E.; Vogt, D. B.; Jui,
N. T. Hydroarylation of Arenes via Reductive Radical-Polar
Crossover. J. Am. Chem. Soc. 2020, 142, 9163−9168.
(51) Sap, J. B. I.; Straathof, N. J. W.; Knauber, T.; Meyer, C. F.;
Medebielle, M.; Buglioni, L.; Genicot, C.; Trabanco, A. A.; Noel, T.;
Am Ende, C. W.; Gouverneur, V. Organophotoredox Hydro-
defluorination of Trifluoromethylarenes with Translational Applic-
ability to Drug Discovery. J. Am. Chem. Soc. 2020, 142, 9181−9187.
(52) Stoll, S.; Schweiger, A. EasySpin, A Comprehensive Software
Package for Spectral Simulation and Analysis in EPR. J. Magn. Reson.
2006, 178, 42−55.
(53) Chatterjee, A.; König, B. Birch-Type Photoreduction of Arenes
and Heteroarenes by Sensitized Electron Transfer. Angew. Chem., Int.
Ed. 2019, 58, 14289−14294.
(54) Tian, X.; Karl, T. A.; Reiter, S.; Yakubov, S.; de Vivie-Riedle, R.;
König, B.; Barham, J. P. Electro-mediated PhotoRedox Catalysis for
Selective C(sp3)-O Cleavages of Phosphinated Alcohols to
Carbanions. Angew. Chem. 2021, DOI: 10.1002/ange.202105895.
(36) Jin, S.; Dang, H. T.; Haug, G. C.; He, R.; Nguyen, V. D.;
Nguyen, V. T.; Arman, H. D.; Schanze, K. S.; Larionov, O. V. Visible
Light-Induced Borylation of C-O, C-N, and C-X Bonds. J. Am. Chem.
Soc. 2020, 142, 1603−1613.
(37) Wang, S.; Wang, H.; König, B. Photo-induced Thiolate
Catalytic Activation of Inert Caryl-hetero Bonds for Radical
Borylation. Chem. 2021, 7, 1653−1665.
(38) Donabauer, K.; Maity, M.; Berger, A. L.; Huff, G. S.; Crespi, S.;
Konig, B. Photocatalytic Carbanion Generation - Benzylation of
Aliphatic Aldehydes to Secondary Alcohols. Chem. Sci. 2019, 10,
5162−5166.
(39) Kong, D.; Munch, M.; Qiqige, Q.; Cooze, C. J. C.; Rotstein, B.
H.; Lundgren, R. J. Fast Carbon Isotope Exchange of Carboxylic
Acids Enabled by Organic Photoredox Catalysis. J. Am. Chem. Soc.
2021, 143, 2200−2206.
(40) Takaoka, A.; Yokokohji, O.; Yamaguchi, Y.; Isono, T.;
Motoyoshi, M.; Ishikawa, N. Preparation of Tetrafluoroisophthaloni-
trile and Its Nucleophilic Substitution at 4-Position. Nippon Kagaku
Kaishi 1985, 1985, 2155−2160.
(41) Wang, G.; Zhang, H.; Zhao, J.; Li, W.; Cao, J.; Zhu, C.; Li, S.
Homolytic Cleavage of a B-B Bond by the Cooperative Catalysis of
Two Lewis Bases: Computational Design and Experimental
Verification. Angew. Chem., Int. Ed. 2016, 55, 5985−5989.
13273
https://doi.org/10.1021/jacs.1c05994
J. Am. Chem. Soc. 2021, 143, 13266−13273