Cercosporin-bioinspired photoreductive activation of aryl halides under mild conditions

Article abstract of DOI:10.1016/j.jcat.2019.09.036

Bioinspired by the naturally-occurring cercosporin-driven infection process of plant pathogenic fungi Cercospora sp., here we took advantage of the photophysical properties of cercosporin, and used it as a metal-free photocatalyst to develop an unpreceden

Full text of DOI:10.1016/j.jcat.2019.09.036

Journal of Catalysis 380 (2019) 1–8
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Journal of Catalysis
journal homepage: www.elsevier.com/locate/jcat
Cercosporin-bioinspired photoreductive activation of aryl halides under
mild conditions
Zhaocheng Tang a,1, Jia Li a,1, Fulin Lin b,c,1, Wenhao Bao a, Shiwei Zhang d, Baodang Guo a,
Shuping Huang e, Yan Zhang d, , Yijian Rao a,
⇑
*
a Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, PR China
b CAS Key Laboratory of Design and Assembly of Functional Nanostructures, and Fujian Provincial Key Laboratory of Nanomaterials, Fujian Institute of Research on the Structure
of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, PR China
c Xiamen Institute of Rare Earth Materials, Haixi Institutes, Chinese Academy of Sciences, Xiamen 361021, PR China
d School of Pharmaceutical Science, Jiangnan University, Wuxi 214122, PR China
e College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Bioinspired by the naturally-occurring cercosporin-driven infection process of plant pathogenic fungi
Cercospora sp., here we took advantage of the photophysical properties of cercosporin, and used it as a
metal-free photocatalyst to develop an unprecedented cercosporin-driven photocatalysis under mild
conditions. Furthermore, the forming conditions and excited-state dynamics of radical anions of cer-
cosporin have been systematically investigated. In particular, transient femtosecond absorption spec-
troscopy was employed to unveil the excited-state dynamics of cercosporin, a key step that dictates its
function in photocatalysis. We showed that cercosporin was able to be sufficiently activated through a
two-step excitation, ultimately boosting its photocatalytic activity for the reductive activation of sub-
strates with very low reactivity. Since large quantities of cercosporin can be easily produced through
microbial fermentation like other commercially available perylenequinonoid pigments, such as hypocre-
llin A and hypocrellin B, we expect that all advantages of these naturally-occurring perylenequinonoid
pigments as green photocatalysts can be further explored to a wide range of synthetic transformations.
Ó 2019 Elsevier Inc. All rights reserved.
Received 24 July 2019
Revised 19 September 2019
Accepted 24 September 2019
Keywords:
Cercosporin
Metal-free photocatalyst
Transient absorption
Excited-state radical anion
1. Introduction
produce a naturally-occurring perylenequinonoid pigment cer-
cosporin (CP) [4,5], a phytotoxin, which can absorb visible light
Sunlight is one of strong environmental cues to modulate major
aspects of an organism’s physiology. Thus, nature endows living
organisms with different pigments as ambient light sensors to
absorb sunlight to carry out various biological functions. Biological
photosynthesis as the omnipresent example exploits antenna pig-
ments, such as chlorophyll b and b-carotene, to absorb light energy
and convert into chemical free energy to drive photosynthetic
reactions, providing most of necessary energy and organic nutri-
ents for life on earth [1,2]. However, in some cases plant patho-
genic fungi develop this kind of strategy by using pigments to
absorb sunlight as a ‘‘weapon” to infect plants for propagation
(Fig. 1a) [3]. For instance, plant pathogenic fungi Cercospora species
energy to convert itself to an excited state. Then it reacts with oxy-
gen in the air to form both radical and nonradical species of acti-
vated oxygen through energy transfer (EnT) and electron transfer
(ET) process (Fig. 1a) [6–12]. These activated oxygen then target
and destroy biomolecules common in host plant cells to provide
nutrients for fungi propagation, but causing damaging leaf spot
and blight diseases on many economically important crops world-
wide [6–12]. Behind this natural cercosporin-driven infection pro-
cess, it implies that cercosporin has the potential photophysical
properties as a photoredox catalyst (Fig. 1b), but has barely been
investigated [13,14]. Since visible light-driven photocatalysis is
the cutting-edge of organic synthesis and has emerged into a green
and mild method to achieve unique chemical reactivity [15–17],
thus, we envision if cercosporin can be used as a ‘‘metal-free” cat-
alyst to carry out visible light-driven photocatalysis for chemical
synthesis (Fig. 1b).
⇑
Corresponding authors.
E-mail addresses: zhangyan@jiangnan.edu.cn (Y. Zhang), raoyijian@jiangnan.
Initially, we used Escherichia coli cell lysates to investigate how
cercosporin targeted and destroyed biomolecules. Surprisingly, the
edu.cn (Y. Rao).
1
These authors contributed equally.
https://doi.org/10.1016/j.jcat.2019.09.036
0021-9517/Ó 2019 Elsevier Inc. All rights reserved.

2
Z. Tang et al. / Journal of Catalysis 380 (2019) 1–8
Fig. 1. Cercosporin as a phytotoxin (a) and a photoredox catalyst through reductive quenching cycle (b).
color of cell lysates with cercosporin changed (Fig. S1). The color of
cell lysates first changed from light red (the original color of cer-
cosporin at low concentration) to yellowish, then turned to orange
and remained under anaerobic conditions. However, it slowly went
back to the initial red color when the test tube was opened. This
phenomenon implied that a stable colored cercosporin radical
anion was generated, which was supported by previous studies
and it could be greatly intensified by the addition of electron
donors, such as amines and other biological substrates
[6,8,10,12,18]. Interestingly, the half-lifetime of this radical anion
of cercosporin was approximately one hour after illumination was
stopped [18]. Recent studies suggest that this kind of stable colored
radical anions may be further excited by visible light to overcome
the energetic barrier of visible light-driven photocatalytic conver-
sion of less reactive chemical bonds in chemical synthesis [19].
Although these stable radical anions of naturally-occurring
perylenequinonoid pigments have been found for decades [6–12,
18,20–29], their applications in photocatalytic transformations
are yet to be explored. Herein, we systematically investigated the
formation conditions and the excited-state dynamics of different
radical anions of cercosporin to unveil its mechanism as a photocat-
alyst, and developed an unprecedented cercosporin-driven photo-
catalysis for important CAC bond formation with less reactive
aryl halides under mild conditions.
UV-3600plus spectrophotometer and F-2700 spectrofluorometer.
The lifetime of ground state emission was measured on Edinburgh
FLS920 fluorescence spectrometer. Household CFLs (compact
fluorescent lamps) were used as the light source. The emission
spectrum of each light source was measured with Hitachi F-2700
spectrofluorometer (Fig. S2). The intensity of irradiation was
measured by a FZ-A radiometer (Photoelectric Instrument Factory
of Beijing Normal University) equipped with a 400–1000 nm sensor.
The sample was placed at an approximate distance of 2 cm to the
lamp. The light intensity was measured to be 21.3 mW/cm2 for
23 w CFL. Additionally, the light intensity was also measured to be
6.51 mW/cm2 for 5 w blue LED and 2.39 mW/cm2 for 5 w green LED.
2.2. Biosynthesis of cercosporin
Cercosporin was biosynthesized from microbial fermentation
with cheap glucose as starting material by a new cercosporin pro-
ducing strain in our laboratory [13,14]. Briefly, cercosporin was
produced by liquid fermentation, purified by Sephadex LH-20 col-
umn after extraction by dichloromethane and identified by HPLC,
LC-MS and NMR. When Cercospora sp. JNU001 strain was culti-
vated in continuous light with S-7 culture medium at pH = 8.5, a
maximum of cercosporin production was obtained (128.2 mg/L),
providing adequate amounts for further analysis.
2. Experimental
2.3. Transient spectroscopy
2.1. Materials and instrumentation
The fs-TA measurements were performed based on a femtosec-
ond Ti: Sapphire regenerative amplified Ti: sapphire laser system
(Spectra Physics, Spitfire-Pro) and an automated data acquisition
system (Ultrafast Systems, Helios model). The amplifier was
seeded with the 120 fs output from the oscillator (Spectra Physics,
Maitai). The probe pulse was obtained by using approximately 5%
of the amplified 800 nm output from the Spitfire to generate a
white-light continuum (450–800 nm) in a sapphire plate. The max-
imum extent of the temporal delay was 3300 ps. The instrument
response function was determined to be 150 fs. At each temporal
delay, data were averaged for 0.5 s or 1 s and collected by the
acquisition system. The probe beam was split into two before pass-
ing through the sample. One probe beam traveled through the
sample, the other was sent directly to the reference spectrometer
that monitored the fluctuations in the probe beam intensity. Fiber
optics was coupled to a multichannel spectrometer with a CMOS
sensor that had a 1.5 nm intrinsic resolution. For the experiments
described in this study, the sample solution was excited by a
Aryl halides, heteroaryl halides, amines, trapping reagents were
commercially available and used without further purification
unless otherwise stated. Cercosporin was biosynthesized by a
new cercosporin producing strain in our laboratory. Hypocrellins
A and B were commercially available and used without further
purification.
1H and 13C NMR spectra were recorded on Bruker AV400
(400 MHz) spectrometers in CDCl3 and DMSO d6 solutions High
resolution mass spectra (HRMS) were recorded on Waters Xevo
G2 Q-TOF instrument. Gas chromatography (GC) and gas
chromatography coupled to low-resolution mass spectrometry
(GC–MS) analysis were performed through a capillary column
(length: 30 m; diam.: 0.25 mm; film: 0.25 lM) using He gas as car-
rier. GC (TRACE 1300) was equipped with an FID detector. GC–MS
(TSQ 8000) was performed on triple quadruple detector. UV–Vis
and fluorescence measurements were performed with Shimadzu

Z. Tang et al. / Journal of Catalysis 380 (2019) 1–8
3
430 nm or 726 nm pump beam (pump laser pulses were generated
3. Results and discussion
from a Light Conversion TOPAS-C optical parametric amplifier).
The solutions were excited in a flowing 2 mm path-length cuvette
with a sample concentration of 0.1 mM throughout the data acqui-
sition. The data were stored as three-dimensional (3D)
wavelength-time-absorbance matrices that were exported for use
with the fitting software. The kinetics obtained in both of these
ranges did not fit well to a single-exponential decay but can be fit-
ted adequately by a sum of two exponentials convoluted with the
instrument response function.
3.1. Forming conditions and excited-state dynamics of radical anions
of cercosporin
In order to study the potential photoactivity of cercosporin, we
first recapitulated the phenomenon of the color change of cer-
cosporin in the presence of N,N-diisopropylethylamine (DIPEA) as
an electron donor with DMSO as solvent, instead of Escherichia coli
cell lysates, as it can happen many chemical reactions in cell
lysates to make it difficult to interpret. Consistent with other per-
ylenequinonoid pigments, the absorption spectra of cercosporin in
the visible region consists of three strong, broad absorption bands
(Ia, IIa and IIIa) without irradiation [20] (Fig. 2a). However, the
sample turned from red to green and remained under anaerobic
conditions after irradiating (Fig. S3), and the intensity of maximum
absorption (k = ca. 476 nm) of cercosporin gradually decreased
when irradiation time increased (Fig. 2b). Meanwhile, three new
absorption bands (k = ca. 430 nm, ca. 630 nm, ca. 726 nm)
appeared and the intensity increased accordingly (Fig. 2b). Further-
more, the fluorescence emission of CP gradually decreased upon
irradiation when the proportion of DIPEA was increased (Fig. 2c).
These data suggest that CP formed a stable colored semiquinone
radical anion CPÅ–, which has been confirmed by EPR spectra in pre-
vious studies [18].
2.4. Theoretical calculations of cercosporin
All calculations are performed using the Gaussian 09 package
[30].The geometries of the neutral molecule of cercosporin, anion
radical were optimized without imposing symmetry constraints
by density functional theory (DFT) calculations at the B3LYP den-
sity functional level[31,32] using the 6–31 + g(d,p) basis set. The
minima were confirmed with all real frequencies. The excited state
geometry of the anion radical and the excited properties of the
neutral molecule, anion radical were calculated by the time-
dependent density functional theory (TD-DFT) method at the same
functional and basis set used in the DFT calculations.
2.5. Typical experimental procedure for photocatalytic test
In view of stability of CPÅ–, we attempted to perform a transient
absorption spectroscopy to investigate whether the stable CPÅ– can
be further excited to CPÅ–*. Transient absorption spectroscopy using
150 fs laser pulses was performed to measure the transient differ-
ence spectra and lifetimes of the excited states radical anion CPÅ–*.
The radical anion excited states were investigated by exciting its
typical absorption wavelength at ca. 430 nm and ca. 726 nm,
respectively. As shown in Fig. 2d, when excitated at 430 nm, the
In a 10 mL schlenk tube with magnetic stirring bar, cercosporin
(0.05 equiv), aryl halide 1 (0.2 mmol), arene 2 (20 equiv), DIPEA (4
equiv) were dissolved in CH3CN (2 mL) and the resulting mixtures
were placed under 23 W CFL under N2 atmosphere. When the reac-
tion was finished, the reaction mixture was washed with brine. The
aqueous phase was re-extracted with ethyl acetate. The combined
organic extracts were dried over Na2SO4, concentrated in vacuum,
and the resulting residue was purified by silica gel column chro-
matography to afford the desired product 3.
transient absorption spectrum exhibited a strong negative
DA at
ca. 430 nm (Fig. 2d), which was originated from overlap of dis-
Fig. 2. Spectroscopic investigations on the formation of semiquinone radical anion CPÅ– and CPÅ–*. (a) The absorption spectra of CP in DMSO solution (3 * 10ꢀ5 mol/L). (b) The
absorption spectra of CPÅ– in DMSO solution (3 * 10ꢀ5 mol/L) upon addition of DIPEA (0.20 mol/L) as electron donor and photoirradiation (23 W CFL) under nitrogen
atmosphere. Three new absorption bands at ca. 430 nm, ca. 630 nm and ca. 726 nm) are indicated by the arrows. (c) The fluorescence spectra of CP (3 * 10ꢀ5 mol/L) upon
gradual addition of DIPEA (0.20 mol/L) under the condition of (b). (d, e) Transient femtosecond absorption spectra of radical anion CPÅ– at different times after excitation.
Transient absorption spectra of radical anions of CP excited at 430 nm (d) and at 726 nm (e), respectively. Pump wavelengths are indicated by the vertical arrows. The spectra
are distorted at the pump wavelengths due to scattered laser light. Times are given for the delay of the probe beam relative to the excitation beam. (f) Excited-state transient
absorption decay kinetics of radical anion CPÅ–. Laser excitation at 726 nm was used in both cases.

4
Z. Tang et al. / Journal of Catalysis 380 (2019) 1–8
torted laser light and the radical anion CPÅ– ground-state bleach.
Interestingly, a broad negative A at ca. 726 nm was also observed
drastically (Table 1, entry 4), most likely due to quenching of CPÅ–
by molecular oxygen (Fig. S3). Light source was crucial for the reac-
tion. Irradiation of the reaction mixture with either blue LED or
green LED delivered only traces of the desired product (Table 1,
entries 5–6) as these individual LEDs could not cover all maximum
absorption spectra of CP and its excited-states (Figs. 2, S2). A series
of control experiments (i.e., omitting each individual component)
confirmed that all components, including CP as the photocatlyst,
the electron donor DIPEA and visible-light irradiation, are essential
(Table 1, entries 7–9) for the photocatalytic CAH arylation
activation.
Using the optimized conditions, different bromo- and chloro-
(hetero)aryl halides were used as (hetero)aryl radical precursors
(Scheme 1) to react with a broad range of (hetero)arenes. Aryl bro-
mides with electron–withdrawing (ACN, ACOCH3, ACO2Me, ACO2-
Et, 3aa–3ae and 3ag–3ai) as well as electron–donating (–OMe, 3af)
groups gave the corresponding coupling products in moderate
yields. Furthermore, partially fluorinated aryl bromides can also
be activated with the desired products 3aj–3al in good yields.
Although aryl chlorides are inexpensive and easily accessible, they
are not commonly considered to be activated by visible light
D
(Fig. 2d). Similarly, when excitated at 726 nm, the scattered laser
light distorted the spectra to varying degrees at the pump wave-
length in a manner as excitation at 430 m (Fig. 2e), meanwhile,
additional less negative
D
A at ca. 430 nm appeared owing to CPÅ–
ground-state bleach and stimulated emission (Fig. 2e). These data
suggest that the typical absorption bands of CPÅ– are centered at
ca. 430 nm and ca. 726 nm, but not 630 nm (Fig. 2b). Importantly,
the excited-state absorption of CPÅ– with strong positive
DA was
observed around 450–640 nm region in both 430 nm and 726 nm
excitation conditions, which can be assigned to the optically for-
bidden S1 state of CPÅ– and the so-called CPÅ–* state [33]. This con-
clusion can be further verified by the recovery of the CPÅ– ground
state as well as the decay of the transient spectra due to CPÅ–* with
a lifetime of 19 ps (Fig. 2f).
3.2. Cercosporin-catalyzed photoreductive activation of aryl halides
Since the excited radical anion CPÅ–* was truely observed here,
we next investigated whether it can activate bromo- and chloro-
(hetero)aryl halides with very low reactivities to obtain aryl radi-
cals for some important chemselective transformations. To test
our hypothesis, a mixture of 40-bromoacetophenone (1aa), N-
methyl pyrrole (2a) (acts as trapping reagent), CP as a photocata-
lyst, and DIPEA as sacrificial electron donors in CH3CN solution
was photoirradiated by a 23 W compact fluorescent light bulb
(CFL) at room temperature under nitrogen atmosphere (Tables 1
and S1). To our delight, when the reaction was conducted in the
presence of CP (5.0 mol%) and a slight excess of DIPEA (4 equiv)
in CH3CN solution at room temperature, the CAHA arylated pro-
duct 3aa was obtained within 48 h and isolated in 62% yield
(Table S1). When the amount of CP was reduced, the reaction time
was extended (Table S1, entries 1–4). Among the sacrificial elec-
tron donors, DIPEA was slightly more effective than Et3N (triethy-
lamine), and much more effective than TBA (tributylamine)
(Table S1, entries 5–6). Although all dipolar aprotic solvents
(DMSO, DMF, CH3CN, DMAC, pyridine, acetone) gave CAHA ary-
lated product, CH3CN gave the best yield of 3aa (Table S1, entries
7–11). For other solvents (EtOH, MeOH, DCE, DCM, THF, toluene),
trace product was produced (Table S1, entries 12–17). Other com-
mercially available perylenequinonoid pigments were also tested.
Significant yield drop was observed with hypocrellin A as a cata-
lyst, but hypocrellin B gave slightly less yields of 3aa (Table 1,
entries 2–3). Under O2 atmosphere, the yield of product decreased
driven-photocatalysis owing to their low reactivity [34–36]. Based
red
on the reduction potential of E CP/CPÅ– [–0.46 V versus saturated
1=2
calomel electrode (SCE)] [13,14] and the E0,0 transition energy of
CPÅ– [1.39 eV] (DFT calculation data is provided in Supporting Infor-
mation), the reducing power of the excited radical anion CPÅ–* was
estimated according to the Rehm-Weller equation [37] as Eox (CP/
CPÅꢀ*) = ꢀ1.85 V vs SCE, showing that it reaches or exceeds the
reduction potentials of substituted aryl chlorides. Indeed, we
showed that aryl chlorides with electron–withdrawing functional
groups such as ACN, ACO2Me or ACO2Et (3ba–3bb, 3bd–3be,
3bg–3bi), or chlorinated N-heterocycles including pyridine (3bc),
quinoline (3bf) and pyrimidines (3bj–3bl) were able to be
sufficiently activated. They gave the corresponding products in
moderate yields when pyrrole, N-methyl pyrrole, N-benzyl pyrrole,
and 1,3,5-trimethoxy-benzene were used as reaction partners.
Therefore, here we developed a green and atom economic method
to activate aryl halides with a broad range of functional groups by
visible light-driven photocatalysis with cercosporin as the
photocatalyst.
3.3. Mechanistic studies
Last, mechanistic studies were investigated. First, since the
obvious solvent effect was relative to the photocatalytic activity
of cercosporin (Table 1), it prompted us to study the formation
ability and stability of CPÅ– in different solvent conditions. Previous
studies show that electrochemical reduction of quinone undergo a
two-step consecutive single-electron process rather than a one-
step two-electron process, and the decision of radical anion or
dianion highly depends on the nature of solvent [38–40]. Thus, it
indicates that CP can selectively form monovalent radical anion
CPÅ– or divalent anion CP2– on the control of solvents. In fact, we
found that the obvious color change of sample and the typical
absorption bands of CPÅ– were only observed in dipolar aprotic sol-
vents, such as DMSO, DMF, CH3CN, DMAC, pyridine and acetone
(Fig. S4), but not in other solvents (Fig. S5), which was correlated
to the photocatalytical activity of cercosporin as show in
Table S1. It suggested that both of effect of dipole moment and
effect of proton are crucial for the generation and the stability of
the semiquinone radical anion CPÅ–. The strong dipole solvent can
reduce the barrier of the intramolecular hydrogen transfer (IPT)
process of CPÅ– and accelerate the IPT rate, which is beneficial to
the stabilization of CPÅ– [41]. However, according to previous stud-
ies [38,39], the OAH bond in protic solvents, such as MeOH and
Table 1
Optimization of the reaction conditions.
Entry
Deviation from abovea
Yield of 3aab
1
None
62
43
59
6
Trace
Trace
Trace
Trace
Trace
2c
3d
4
HA instead of CP
HB instead of CP
O2 instead of N2
Blue LED instead of 23 W CFL
Green LED instead of 23 W CFL
Without light
5e
6f
7
8
9
Without CP
Without DIPEA
a
Reaction conditions: 1a (0.2 mmol), N-methyl pyrrole (20 equiv), CP (5 mol%),
DIPEA (4 equiv), CH3CN (2 mL), N2, under 23 W CFL irradiation at room tempera-
ture. See Supporting Information for catalyst loading and DIPEA equivalent.
b
Yield of isolated product.
5 mol% of hypocrellin A as a photocatalyst.
5 mol% of hypocrellin B as a photocatalyst.
5 W blue LED was used.
c
d
e
f
5 W green LED was used.

Z. Tang et al. / Journal of Catalysis 380 (2019) 1–8
5
Scheme 1. The CAH arylation products obtained from (hetero) aryl halides with arenes and biologically important heterocycles.
EtOH, provide sufficiently high concentration of hydrogen-bond
donor and then promotes the formation of strong hydrogen bonds
between CP2– and protic solvents as compared to CPÅ–, thus making
CPÅ– shift towards to CP2ꢀ with a absorption band at ca. 630 nm
(Fig. S5). This was further proved with the simultaneous disappear-
ance of the bands at 430 nm and 726 nm and the appearance of the

6
Z. Tang et al. / Journal of Catalysis 380 (2019) 1–8
CN
mixture was re-illuminated with 23 W CFL, which again supports
our conclusion that the formation of CPÅ–* with high reduction
potentials through a two-step excitation, but not CPÅ–, was required
for the photoreductive activation of aryl halides with low
reactivity.
Cercosporin
(5 mol%)
CN
H
N
H
2a
Additive
(2.0 equiv)
standard reaction conditions
N
H
Br
1ab
3ab
Combined with spectroscopic and experimental results in cur-
rent study and other recent reports [19,42–53], we propose a
mechanism for the photocatalytic cycles involving excited semi-
quinone radical anion CPÅ–* as the active redox species for the for-
mation of important CAC bonds (Fig. 3). Cercosporin was first
activated to excited state CP* after irradiation. This CP* was then
reductively converted into CPÅ– with the addition of electron donor
DIPEA through SET while the radical cation of DIPEA (DIPEAÅ+) was
formed. Upon the second excitation, CPÅ– was further activated to
CPÅ–*, which had the capability to activate the very low reactive
substrates, like bromo- and chloro-(hetero)aryl halides, to yield
the aryl radical (Ar-XÅ– or ArÅ) and regenerate the neutral CP. Then,
these activated aryl radical Ar-XÅ– or ArÅ has the ability to react with
(het)arenes to yield CAC coupling products.
Additive
3ab
Yield of
trace
TEMPO
BHT
trace
trace
NC
1,1-diphenylethylene
NC
=
M
281
=
M
283
Scheme 2. Effect of radical inhibitors.
4. Conclusions
band at 630 nm when using a sample mixed solvent of CH3CN and
water (10:1) (Figs. 2b, S6). Combined with transient femtosecond
absorption spectra analysis (Fig. 2d and e), we concluded that the
typical absorption bands of CPÅ– are centered at ca. 430 nm and
ca. 726 nm and it only formed in dipolar aprotic solvents upon irra-
diation, which are relative to its photocatalytic activity.
Bioinspired by the naturally-occurring cercosporin-driven
infection process of plant pathogenic fungi Cercospora sp., here
we took advantage of the photophysical properties of cercosporin,
and used it as a metal-free photoredox catalyst to develop a
cercosporin-driven photocatalysis under mild conditions. We
showed that cercosporin has to be activated to its radical anion
CPÅ– state to perform its photocatalysis, and both of generating
ability and stability of this CPÅ– are critical for its photocatalytic
activity, which only can be achieved in dipolar aprotic solvents.
Confirmed by transient absorption spectroscopy and density func-
tional theory (DFT) calculations, this radical anion CPÅ– can be fur-
ther excited to CPÅ–* to reach or exceed the reduction potentials for
activation of aryl halides, particularly, (hetero) aryl chlorides, to
drive synthetic transformations. Furthermore, like other commer-
cially available perylenequinonoid pigments, such as hypocrellin
A and hypocrellin B, large quantities of cercosporin can be easily
produced with high yield through liquid fermentation method,
thus we expect that all advantages of these naturally-occurring
perylenequinonoid pigments as green photocatalysts can be fur-
ther explored to a wide range of synthetic transformations.
Next, we investigated whether the activation of aryl halides
proceeds through a single-electron transfer (SET) process in a rad-
ical pathway. Indeed, the additions of radical trapping reagents
(TEMPO, BHT) significantly inhibits the transformation, and the
1,1–diphenylethylene intermediates was detected by MS analysis
(Scheme 2 and Fig. S7). The reaction did not yield any CAH arylated
products (see Table 1, entry 7) in the dark. A series of control spec-
troscopic investigations confirmed that no reaction existed
between CP and aryl halide (Figs. S8 and S9). Furthermore, when
40-bromoacetophenone (1aa) and N-methyl pyrrole (2a) were
added to a photochemically generated CP radical anion containing
reaction system (by photo-irradiating the mixture of CP and DIPEA)
and kept in the dark for 4 h, no product (3aa) was converted. How-
ever, CAHA arylated product 3aa was recovered in a yield compa-
rable to the normal photocatalytic protocol when this reaction
Fig. 3. Biosynthesis of cercosporin and a proposed catalytic mechanism of cercosporin as an organic photocatalyst.

Z. Tang et al. / Journal of Catalysis 380 (2019) 1–8
7
[19] I. Ghosh, T. Ghosh, J.I. Bardagi, B. Konig, Reduction of aryl halides by
consecutive visible light-induced electron transfer processes, Science 346
(2014) 725–728.
[20] Z. Diwu, J.W. Lown, Photosensitization by anticancer agents 12. Perylene
quinonoid pigments, a novel type of singlet oxygen sensitizer, J. Photoch.
Photobio. Chem. 64 (1992) 273–287.
[21] R.C. Guedes, L.A. Eriksson, Photophysics, photochemistry, and reactivity:
molecular aspects of perylenequinone reactions, Photoch. Photobio. Sci. 6
(2007) 1089–1096.
Declaration of Competing Interest
There are no conflicts of interest to declare.
Acknowledgements
We thank for the National Key R&D Program of China
(2018YFA0901700), National Natural Science Foundation of China
(21703036), Natural Science Foundation of Jiangsu Province
(Grants No BK20160167), the Thousand Talents Plan (Young Pro-
fessionals), the Fundamental Research Funds for the Central
Universities (JUSRP51712B), Postdoctoral Foundation in Jiangsu
Province (2018K153C) and the National First-class Discipline
Program of Light Industry Technology and Engineering
(LITE2018-14) for the funding support.
[22] Y.Z. Hu, J.Y. An, L.J. Jiang, D.W. Chen, Spectroscopic study on the
photoreduction of hypocrellin-a – generation of semiquinone radical-anion
and hydroquinone, J. Photoch. Photobio. A 89 (1995) 45–51.
[23] Y.Z. Hu, L.J. Jiang, L.C. Chiang, Characteristics of the reaction between
semiquinone radical anion of hypocrellin A and oxygen in aprotic media, J.
Photoch. Photobio. A 94 (1996) 37–41.
[24] M.H. Zhang, M. Weng, S. Chen, W.L. Xia, L.J. Jiang, D.W. Chen, Study of electron
transfer interaction between hypocrellin and N, N-diethylaniline by UV-
visible, fluorescence, electron spin resonance spectra and time-resolved
transient absorption spectra, J. Photoch. Photobio. A 96 (1996) 57–63.
[25] M. Weng, M.H. Zhang, T. Shen, Electron transfer interaction between
hypocrellin
A and biological substrates and quantitative analysis of
superoxide anion radicals, J. Chem. Soc. Perkin Trans. 2 (1997) 2393–2397.
[26] K.K. So, I.S. Jo, M.S. Chae, J.M. Kim, H.J. Chung, M.S. Yang, B.T. Kim, J.K. Kim, J.K.
Choi, D.H. Kim, Improved production of phleichrome from the phytopathogenic
fungus Cladosporium phlei using synthetic inducers and photodynamic ROS
production by phleichrome, J. Biosci. Bioeng. 119 (2015) 289–296.
[27] J.B. Hudson, V. Imperial, R.P. Haugland, Z. Diwu, Antiviral activities of
photoactive perylenequinones, Photochem. Photobiol. 65 (1997) 352–354.
[28] Y.Y. He, J.Y. An, L.J. Jiang, pH Effect on the spectroscopic behavior and
photoinduced generation of semiquinone anion radical of hypocrellin B, Dyes
Pigments 41 (1999) 79–87.
Appendix A. Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jcat.2019.09.036.
References
[29] C. Li, Y.P. He, L.C. Ou, M.J. Tian, Z. Yao, M.B. Guo, Photophysical and
photosensitive properties of Elsinochrome A, Chinese Sci. Bull. 51 (2006)
1050–1054.
[1] I. Vass, K. Cser, O. Cheregi, Molecular mechanisms of light stress of
photosynthesis, Ann. Ny. Acad. Sci. 1113 (2007) 114–122.
[2] T. Mirkovic, E.E. Ostroumov, J.M. Anna, R. van Grondelle, Govindjee, G.D.
Scholes, Light absorption and energy transfer in the antenna complexes of
photosynthetic organisms, Chem. Rev. 117 (2017) 249–293.
[30] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman,
G. Scalmani, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M.
Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, T. Vreven, J.A. Montgomery, J.E.P. Jr., F. Ogliaro, M.
Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov, T. Keith, R.
Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J.
Tomasi, M. Cossi, N. Rega, J.M. Millam, M. Klene, J.E. Knox, J.B. Cross, V.B. akken,
C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R.
Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin, K. Morokuma, V.G. Zakrzewski,
G.A. Voth, P. Salvador, J.J. Dannenberg, S. Dapprich, A.D. Daniels, O. Farkas, J.B.
Foresman, J.V. Ortiz, J. Cioslowski, D.J. Fox, Gaussian, Inc., Wallingford CT,
2013.
[31] P.J. Stephens, F.J. Devlin, C.F. Chabalowski, M.J. Frisch, Ab-initio calculation of
vibrational absorption and circular-dichroism spectra using density-functional
force-fields, J. Phys. Chem-Us 98 (1994) 11623–11627.
[32] F.J. Devlin, J.W. Finley, P.J. Stephens, M.J. Frisch, Ab-initio calculation of
vibrational absorption and circular-dichroism spectra using density-functional
force-fields – a comparison of local, nonlocal, and hybrid density functionals, J.
Phys. Chem-Us 99 (1995) 16883–16902.
[33] R. Berera, R. van Grondelle, J.T. Kennis, Ultrafast transient absorption
spectroscopy: principles and application to photosynthetic systems,
Photosynth. Res. 101 (2009) 105–118.
[34] L. Pause, M. Robert, J.M. Saveant, Can single-electron transfer break an
aromatic carbon-heteroatom bond in one step? A novel example of transition
between stepwise and concerted mechanisms in the reduction of aromatic
iodides, J. Am. Chem. Soc. 121 (1999) 7158–7159.
[35] E. Cahard, F. Schoenebeck, J. Garnier, S.P.Y. Cutulic, S.Z. Zhou, J.A. Murphy,
Electron transfer to benzenes by photoactivated neutral organic electron
donor molecules, Angew. Chem. Int. Ed. 51 (2012) 3673–3676.
[3] G.Y. Liu, V. Nizet, Color me bad: microbial pigments as virulence factors,
Trends Microbiol. 17 (2009) 406–413.
[4] S. Kuyama, T. Tamura, Cercosporin.
A pigment of Cercosporina kikuchii
Matsumoto et Tomoyasu. I. Cultivation of fungus, isolation and purification
of pigment, J. Am. Chem. Soc. 79 (1957) 5725–5726.
[5] S. Kuyama, T. Tamura, Cercosporin.
A pigment of cercosporina kikuchii
matsumoto et tomoyasu. ii. Physical and chemical properties of cercosporin
and its derivatives, J. Am. Chem. Soc. 79 (1957) 5726–5729.
[6] M.E. Daub, R.P. Hangarter, Light-induced production of singlet oxygen and
superoxide by the fungal toxin, cercosporin, Plant Physiol. 73 (1983) 855–857.
[7] M.E. Daub, Resistance of fungi to the photosensitizing toxin, cercosporin,
Phytopathology 77 (1987) 1515–1520.
[8] M.E. Daub, G.B. Leisman, R.A. Clark, E.F. Bowden, Reductive detoxification as a
mechanism of fungal resistance to singlet oxygen-generating photosensitizers,
P. Natl. Acad. Sci. 89 (1992) 9588–9592.
[9] M.A. Jalal, M.B. Hossain, D.J. Robeson, D. Van der Helm, Cercospora beticola
phytotoxins: cebetins that are photoactive, magnesium ion-binding,
chlorinated anthraquinone-xanthone conjugates, J. Am. Chem. Soc. 114
(1992) 5967–5971.
[10] P. Bilski, M.Y. Li, M. Ehrenshaft, M.E. Daub, C.F. Chignell, Vitamin B6
(pyridoxine) and its derivatives are efficient singlet oxygen quenchers and
potential fungal antioxidants, Photochem. Photobiol. 71 (2000) 129–134.
[11] M.E. Daub, M. Li, P. Bilski, C.F. Chignell, Dihydrocercosporin singlet oxygen
production and subcellular localization: a possible defense against cercosporin
phototoxicity in Cercospora, Photochem. Photobiol. 71 (2000) 135–140.
[12] M.E. Daub, M. Ehrenshaft, The photoactivated Cercospora toxin cercosporin:
contributions to plant disease and fundamental biology, Annu. Rev.
Phytopathol. 38 (2000) 461–490.
[36] C. Costentin, M. Robert, J.M. Saveant, Fragmentation of aryl halide pi anion
radicals. Bending of the cleaving bond and activation vs driving force
relationships, J. Am. Chem. Soc. 126 (2004) 16051–16057.
[37] D. Rehm, A. Weller, Kinetics of fluorescence quenching by electron and H-atom
transfer, Israel J. Chem. 8 (1970) 259–271.
[38] J. Kim, T.D. Chung, H. Kim, Determination of biologically active acids based on
the electrochemical reduction of quinone in acetonitrile plus water mixed
solvent, J. Electroanal. Chem. 499 (2001) 78–84.
[39] M.E. Tessensohn, M. Lee, H. Hirao, R.D. Webster, Measuring the relative
hydrogen-bonding strengths of alcohols in aprotic organic solvents,
Chemphyschem 16 (2015) 160–168.
[40] M.E. Tessensohn, H. Hirao, R.D. Webster, Electrochemical properties of phenols
and quinones in organic solvents are strongly influenced by hydrogen-bonding
with water, J. Phys. Chem. C 117 (2013) 1081–1090.
[41] F. Gai, M.J. Fehr, J.W. Petrich, Role of solvent in excited-state proton-transfer in
hypericin, J. Phys. Chem-Us 98 (1994) 8352–8358.
[42] I. Ghosh, B. Konig, Chromoselective photocatalysis: controlled bond activation
through light-color regulation of redox potentials, Angew. Chem. Int. Ed. 55
(2016) 7676–7679.
[13] S. Zhang, Z. Tang, W. Bao, J. Li, B. Guo, S. Huang, Y. Zhang, Y. Rao,
Perylenequinonoid-catalyzed photoredox activation for the direct arylation
of (het)arenes with sunlight, Org. Biomol. Chem. 17 (2019) 4364–4369.
[14] Y. Zhang, Y. Cao, L.S. Lu, S.W. Zhang, W.H. Bao, S.P. Huang, Y.J. Rao,
Perylenequinonoid-catalyzed [4+1] and [4+2] annulations of azoalkenes:
photocatalytic access to 1,2,3-thiadiazole/1,4,5,6-tetrahydropyridazine
derivatives, J. Org. Chem. 84 (2019) 7711–7721.
[15] M.D. Karkas, J.A. Porco Jr., C.R. Stephenson, Photochemical approaches to
complex chemotypes: applications in natural product synthesis, Chem. Rev.
116 (2016) 9683–9747.
[16] N. Corrigan, S. Shanmugam, J. Xu, C. Boyer, Photocatalysis in organic and
polymer synthesis, Chem. Soc. Rev. 45 (2016) 6165–6212.
[17] L. Marzo, S.K. Pagire, O. Reiser, B. Konig, Visible-light photocatalysis: does it
make a difference in organic synthesis?, Angew. Chem. Int. Ed. 57 (2018)
10034–10072.
[18] Z.J. Diwu, J.W. Lown, Photosensitization with anticancer agents. 14.
Perylenequinonoid pigments as new potential photodynamic therapeutic
agents – formation of tautomeric semiquinone radicals, J. Photoch. Photobio. A
69 (1992) 191–199.

8
Z. Tang et al. / Journal of Catalysis 380 (2019) 1–8
[43] D. Gosztola, M.P. Niemczyk, W. Svec, A.S. Lukas, M.R. Wasielewski, Excited
doublet states of electrochemically generated aromatic imide and diimide
radical anions, J. Phys. Chem. A 104 (2000) 6545–6551.
[44] J.I. Bardagi, I. Ghosh, M. Schmalzbauer, T. Ghosh, B. Konig, Anthraquinones as
photoredox catalysts for the reductive activation of aryl halides, Eur. J. Org.
Chem. 34–40 (2018).
[45] A. Arora, J.D. Weaver, Photocatalytic generation of 2-azolyl radicals:
intermediates for the azolylation of arenes and heteroarenes via C-H
functionalization, Org. Lett. 18 (2016) 3996–3999.
[46] S.O. Poelma, G.L. Burnett, E.H. Discekici, K.M. Mattson, N.J. Treat, Y.D. Luo, Z.M.
Hudson, S.L. Shankel, P.G. Clark, J.W. Kramer, C.J. Hawker, J.R. de Alaniz,
Chemoselective radical dehalogenation and C-C bond formation on aryl halide
substrates using organic photoredox catalysts, J. Org. Chem. 81 (2016) 7155–
7160.
[48] I. Ghosh, L. Marzo, A. Das, R. Shaikh, B. Konig, Visible light mediated photoredox
catalytic arylation reactions, Acc. Chem. Res. 49 (2016) 1566–1577.
[49] J.D. Nguyen, E.M. D’Amato, J.M.R. Narayanam, C.R.J. Stephenson, Engaging
unactivated alkyl, alkenyl and aryl iodides in visible-light-mediated free
radical reactions, Nat. Chem. 4 (2012) 854–859.
[50] H. Kim, C. Lee, Visible-light-induced photocatalytic reductive transformations
of organohalides, Angew. Chem. Int. Ed. 51 (2012) 12303–12306.
[51] E.H. Discekici, N.J. Treat, S.O. Poelma, K.M. Mattson, Z.M. Hudson, Y.D. Luo, C.J.
Hawker, J.R. de Alaniz, A highly reducing metal-free photoredox catalyst:
design and application in radical dehalogenations, Chem. Commun. 51 (2015)
11705–11708.
[52] L. Marzo, I. Ghosh, F. Esteban, B. Konig, Metal-free photocatalyzed cross
coupling of bromoheteroarenes with pyrroles, ACS Catal. 6 (2016) 6780–6784.
[53] A.U. Meyer, T. Slanina, A. Heckel, B. Konig, Lanthanide ions coupled with
photoinduced electron transfer generate strong reduction potentials from
visible light, Chem. Eur. J. 23 (2017) 7900–7904.
[47] I. Ghosh, R.S. Shaikh, B. Konig, Sensitization-initiated electron transfer for
photoredox catalysis, Angew. Chem. Int. Ed. 56 (2017) 8544–8549.