Visible-light photocatalytic activation of N-chlorosuccinimide by organic dyes for the chlorination of arenes and heteroarenes

Article abstract of DOI:10.1016/j.tet.2019.130498

A variety of arenes and heteroarenes are chlorinated in moderate to excellent yields using N-chlorosuccinimide (NCS) under visible-light activated conditions. A screening of known organic dye photocatalysts resulted in the identification of methylene green as the most efficient catalyst to use with NCS. According to mechanistic studies described within, the reaction is speculated to proceed via a single electron oxidation of NCS utilizing methylene green under visible-light photoredox pathway. The photo-oxidation of NCS amplifies the electrophilicity of the chlorine atom of the NCS, thus leading to enhanced reactivity as a chlorinating reagent with aromatic substrates.

Full text of DOI:10.1016/j.tet.2019.130498

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Visible-light photocatalytic activation of N-chlorosuccinimide by organic dyes for the
chlorination of arenes and heteroarenes
David A. Rogers, Jillian M. Gallegos, Megan D. Hopkins, Austin A. Lignieres, Amy K.
Pitzel, Angus A. Lamar
PII:
S0040-4020(19)30825-7
https://doi.org/10.1016/j.tet.2019.130498
TET 130498
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 June 2019
Revised Date: 28 July 2019
Accepted Date: 1 August 2019
Please cite this article as: Rogers DA, Gallegos JM, Hopkins MD, Lignieres AA, Pitzel AK, Lamar AA,
Visible-light photocatalytic activation of N-chlorosuccinimide by organic dyes for the chlorination of
arenes and heteroarenes, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130498.
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Visible-light photocatalytic activation of N-
chlorosuccinimide by organic dyes for the
chlorination of arenes and heteroarenes
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David A. Rogers, Jillian M. Gallegos, Megan D. Hopkins, Austin A. Lignieres, Amy K. Pitzel, and Angus A.
Lamar*
Department of Chemistry and Biochemistry, The University of Tulsa, 800 S. Tucker Dr., Tulsa, OK, 74104.

1
Tetrahedron
journal homepage: www.elsevier.com
Visible-light photocatalytic activation of N-chlorosuccinimide by organic dyes for the
chlorination of arenes and heteroarenes
a
a
a
a
a
David A. Rogers, Jillian M. Gallegos, Megan D. Hopkins, Austin A. Lignieres, Amy K. Pitzel, and
a,
Angus A. Lamar ∗
a
Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, Tulsa, Oklahoma, 74104, USA.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A variety of arenes and heteroarenes are chlorinated in moderate to excellent yields using N-
chlorosuccinimide (NCS) under visible-light activated conditions. A screening of known organic
dye photocatalysts resulted in the identification of methylene green as the most efficient catalyst
to use with NCS. According to mechanistic studies described within, the reaction is speculated
to proceed via a single electron oxidation of NCS utilizing methylene green under visible-light
photoredox pathway. The photo-oxidation of NCS amplifies the electrophilicity of the chlorine
atom of the NCS, thus leading to enhanced reactivity as a chlorinating reagent with aromatic
substrates.
Available online
Keywords:
Photocatalysis
Methylene green
Electrophilic chlorination
Electron transfer
Thiazine dye
2
009 Elsevier Ltd. All rights reserved.
1
. Introduction
regard to selectivity and economy, the use of stable, inexpensive
2
chlorinating reagents that operate through direct C(sp )-H
Chlorinated arenes and heteroarenes are prevalent as end-
11
“
Friedel-Crafts” electrophilic aromatic substitution (S Ar)
E
products and intermediates in a wide range of synthetic
applications including the production1-2of pharmaceuticals,
polymeric materials, and agrochemicals. Numerous methods
for arene chlorination are available to the synthetic community,
however, there are a range of limitations in systems currently
available. For example, some readily available chlorinating
mechanistic pathways are attractive. Functional group tolerance,
however, remains a concern due to the necessary activation
(typically using acidic conditions) of the stable chlorinating
reagent. Thus, further exploration toward the development of an
inexpensive, mild, and selective chlorination reaction of arenes
and heteroarenes that are relevant to drug discovery and
development remains a valuable pursuit.
t
3
agents are highly reactive but hazardous (Cl , SO Cl , BuOCl).
2
2
2
4
N-Chloro reagents such as N-chlorosuccinimide (NCS), 1,3-
5
In terms of reagent stability, availability, and practicality,
NCS is an attractive source of electrophilic chlorine.
Traditionally, activation of NCS by a Bronsted or Lewis acid is
dichloro-5,5-dimethylhydantoin
(DCDMH),
chloro-
6
bis(methyoxycarbonyl)guanidine (CBMG or “Palau’chlor”),
7
trichloroisocyanuric
acid
(TCCA),
N-chloro-N-9
1
2
8
required in order to increase the electrophilicity of the Cl atom.
fluorobenzenesulfonylamine (CFBSA) and N-chlorosaccharin
are relatively stable, but frequently require activation by redox
active metals, Bronsted or Lewis acids, or radical initiators. In
addition, some of these reagents either require synthesis
Recently, Hering and Konig demonstrated that the polarization of
the N-Cl bond in NCS could be enhanced by a one-electron
oxidation using a Ru(II) visible-light photoredox catalyst
13
(CFBSA) or are costly when commercially available (CBMG, N-
(Scheme 1, Method A). In their pioneering study, oxidized NCS
was used to chlorinate aromatic compounds in modest yields,
though the substrate scope was limited to electron rich arenes,
and heteroarene substrates were unexplored. Inspired by this
initial report, our research group has previously reported an
organic dye catalyzed amplification of N-bromosuccinimide
chlorosaccharin).
The balance between reactivity, selectivity, functional group
tolerance, economy, and safety are necessary considerations
when selecting an appropriate chlorinating reagent. Within the
domain of drug discovery and development, the installation of a
chlorine atom to an aromatic/heterocyclic scaffold can provide
synthetic intermediates for further functionalization or end-
(NBS) in which the electrophilic bromine atom is activated by
erythrosine B under visible-light-promoted conditions (Scheme
14
1
, Method B).
2, 10
products with altered electronic and physical properties.
The
synthesis and transformation of complex molecules requires the
balance of chlorinating agent characteristics to favor selectivity,
economy, and functional group tolerance above others. With
—
——
∗
Corresponding author. Tel.: +1-918-631-3024; fax: +1-918-631-3404; e-mail: angus-lamar@utulsa.edu

2
Tetrahedron
strong enough to oxidize NCS, but not too strong to oxidize
naphthalene and lead to unwanted by-products. The initial
reaction conditions shown in Table 1 were chosen to screen for a
highly practical system (open to air, ambient temperature) under
white LED irradiation as well as in the absence of light. To our
delight, several catalysts performed more efficiently than
uncatalyzed (Table 1, entry 1) reaction. The most effective VLPC
catalysts (Table 1, entries 10-13) have excited state reduction
potentials between +1.10 and +1.64, and the formation of 1 was
halted in light-free conditions, providing strong evidence of a
photocatalytic mechanism.
Scheme 1. Visible-light photoredox catalytic (VLPC) methods
for amplification of N-halosuccinimide electrophilicity.
The bromination of arenes via oxidative activation of NBS by
catalytic erythrosine B has joined a growing number of systems
within the recent explosion of visible-light photoredox catalysis
(VLPC) transformations in which inexpensive organic dyes can
have comparable, or even superior, activity when compared to
15
their expensive Ru(II) and Ir(III) transition-metal counterparts.
Even though organic dyes (Figure 1) have the potential to be
superior catalysts, they are largely overlooked during the
screening of catalysts in favor of the well-understood Ru(II) and
16
Ir(III) VLPCs. Herein, we describe a photoredox catalysis
approach that employs VLPC organic dyes to amplify the
electrophilicity of NCS for chlorination of arenes and
heteroarenes. This strategy offers a cost-effective, practical
alternative for the production of valuable chlorinated compounds
under non-acidic conditions.
Table 1. Screening of organic dye VLPCs for chlorination of
naphthalene using NCS.
A variety of structurally different catalysts were screened,
however, there appeared to be no correlation to the efficiency of
1
-chloronaphthalene 1 formation and the structural classification
of the organic dyes. Compared to their Ru(II) and Ir(III)
counterparts, the use of organic dyes to activate NCS for
chlorination of arenes is complicated by the structural
constitution of the organic dye. For example, chlorination of the
aromatic region of the dye instead of the arene substrate is a
distinct possibility. In addition, transfer of the electrophilic
chlorine from NCS to a nitrogen atom of a dye is also plausible,
which may account for some of the dyes serving as catalysts for
chlorination in the absence of light (Table 1, entries 7-9). In
contrast, a comparison of the known excited state one-electron
reduction potentials of the organic dye VLPCs with the formation
of 1 resulted in an observable trend.
Figure 1. Structural classification of the VLPC organic dyes used
in this investigation.
2
. Results and Discussion
To begin our investigation, known VLPC organic dyes were
selected to screen for activity in the chlorination of naphthalene
using NCS (all dye structures are shown in supporting
information, Figure S1). We hypothesized that a VLPC catalyst
with an excited state one-electron reduction potential that lies
13
between the oxidation potential of NCS (+1.10V vs SCE) and
17
that of naphthalene (+1.64V vs SCE) could serve as a catalyst

3
Following the screening of organic dyes, methylene green was
selected as the best performing photoredox catalyst. Methylene
green (MetG) is a commercially available member of the thiazine
family of VLPCs that has been used as a catalyst in a variety of
products 13-19 were formed with significant improvement over
uncatalyzed background reaction. In general, a number of
functionalities are tolerated by the reaction conditions including
aryl halide, ether, phenol, nitro, nitrile, ketone, aldehyde, ester,
15d, 18
3
light-promoted systems.
Using naphthalene as a test
amide, benzylic and α to carbonyl C(sp )-H’s, and 1° and 3°
substrate with NCS and catalytic MetG, an optimization of
stoichiometry and reaction conditions was performed (Table 2).
The best conversion to 1-chloronaphthalene 1 (72%, entry 15)
was obtained using 1 equiv. naphthalene, 1.1 equiv. NCS, 0.05
equiv. MetG, 0.1 equiv. ammonium peroxodisulfate in
acetonitrile (0.2M relative to naphthalene) open to air in a white
LED photochamber for 24 hours at ambient (20 °C) temperature.
amine. Catalysis using the organic dye, methylene green, offers
notable advantages over the Ru(II) catalyst including catalyst
cost (MetG = $1.41/g – MP Biomedicals; Ru(bpy) Cl = $65.20/g
– Sigma-Aldrich), increased product yield with comparable
substrates, and ability to chlorinate arenes with deactivating
groups and heteroarenes. These results validate the inclusion of
NCS/MetG as a viable option for cost-effective and practical
chlorination of arenes and heteroarenes.
3
2
H
Cl
N
Cl
cat. methylene green
O
O
+
white LED, solvent,
20 °C, air, time, additive
1
equiv.
1
Entry
NCS
solvent
catalyst
time
additive
(equiv.)
Yield 1
(%)a
(
equiv.) (0.1 M)
(mol %) (hours)
1
2
3
4
5
6
7
8
9
1.1
1.1
3
1.1
1.1
1.1
1.1
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
DCM
5
2
2
1
0
5
5
5
5
5
5
5
5
0
5
24
24
24
24
24
24
24
24
24
24
-
-
-
-
-
-
-
-
-
-
42
20
33
20
3
9
1
3
52
7
1.1 4:1 MeCN/H O
1.1 MeCN (0.2M)
1.1 MeCN (0.05M)
1.1
1.1
1.1
1.1
2
10
11
12
13
14
15
MeCN
MeCN
MeCN
MeCN
24 (NH ) S O (1)
6
24 (NH ) S O (0.1)
24 (NH ) S O (0.1)
44
21
63
3
4
2
2
8
(NH ) S O (1)
4 2 2 8
4
2
2
8
4
2
2
8
1.1 MeCN (0.2M)
24 (NH ) S O (0.1)
72
4
2
2
8
a) Gas chromatography (GC) yields calculated using adamantane as the
internal standard.
Table 2. Optimization of reaction conditions for chlorination of
naphthalene by NCS.
With optimized reaction conditions in hand, the substrate
scope of the reaction was investigated (Table 3). Disubstituted
benzene derivatives that contain an activating (electron-donating)
and deactivating (electron-withdrawing) group were tested, and
good to excellent product yields (2-7) were obtained with high
regioselectivity, indicative of a S Ar mechanism. A mixture of
E
mono- and dichlorinated product was formed when using
standard conditions (1.1 equiv. of NCS) with 4-bromoaniline, so
the reaction was performed with 2.2 equivalents NCS in order to
cleanly produce the dichlorinated product 3 without observation
of oxidation of the amine functionality. It is also noteworthy that
chlorination was not observed α to the carbonyl using 4-
methoxyacetophenone 6, and the aldehyde functionality was not
oxidized under the reaction conditions (product 7). Acetanilide
was chlorinated (89% total) at both the para (69%) and ortho
Table 3. Substrate scope of arene and heteroarene chlorination.
(
20%) positions (Table 3, product 8), which is a departure from
the uncatalyzed reaction that only produces the para isomer
36%). A number of additional substituted arenes with electron-
In order to verify that a photoredox mechanism was
responsible for chlorination of (hetero)arene substrates, a series
of control and mechanistic experiments were conducted (Scheme
(
donating groups were chlorinated using catalytic MetG with
improvement over background reaction (products 9-12). 2-
Methylnaphthalene and m-xylene were both chlorinated under
photocatalytic conditions without chlorination of the benzylic C-
H position (10 and 11). A number of N-heteroarenes were also
tested using the standard reaction conditions. Pyridine, pyrrole,
indazole, and indole heteroarenes were all tested, and chlorinated
2
). The absence of catalyst resulted in a significant reduction in
product formation from 72% (catalyzed) to 6% yield. In addition,
air plays a key role in the reaction as observed by the decreased
efficiency of the reaction under anaerobic conditions, with or
without external oxidant (NH ) S O . The elimination of light
4
2
2
8
from the standard reaction conditions produced 1 in a similar

4
Tetrahedron
yield to the catalyst-free reaction, implicating both light and
catalyst as integral components of the reaction. Variation of the
LED light source (red, green, and blue LED) was also
investigated, and the most efficient production of 1 resulted when
using white LEDs. Finally, known radical inhibitors such as
TEMPO and BHT were separately added to a standard reaction,
and suppression of naphthalene chlorination was observed.
Scheme 3. Plausible mechanism.
3
. Conclusions
Methylene green has been developed as an organic dye,
visible-light photoredox catalyst to chlorinate arenes and
heteroarenes by operating through an amplification of the
electrophilic chlorine of N-chlorosuccinimide via a one-electron
oxidation of NCS. The methylene green catalyzed reaction
operates under mild, practical conditions and produces
chlorinated arenes in high regioselectivity and with dramatic
enhancement relative to the analogous uncatalyzed reaction. A
variety of aromatic and heteroaromatic substrates were
chlorinated in good to excellent yields and many functionalities
are tolerated. According to mechanistic studies, the reaction is
speculated to operate via a single electron oxidation of NCS by
methylene green, which is in turn oxidized back to its ground
state. The reaction provides a useful chlorinating method by
activating NCS without the use of traditional (acidic) conditions.
The employment of a VLPC strategy to activate additional
reagents containing N-X bonds for electrophilic transformations
are currently underway in our laboratory and will be reported in
due course.
Scheme 2. Control and mechanistic experiments.
The iodide test (NaI in glacial acetic acid) was performed to
attempt to observe the presence of H O following completion of
2
2
the reaction. The presence of hydrogen peroxide would indicate
the formation of superoxide anion under the photocatalyzed
conditions. Ammonium peroxodisulfate was intentionally
excluded from the standard reaction mixture in order to prevent a
false positive test that would result from the oxidation of iodide
by (NH ) S O . The reaction was performed for 24 hours, and the
4
2
2
8
formation of hydrogen peroxide was observed, albeit in low
concentration, as a yellowish-orange appearance of iodine (see
Supporting Information Figure S3). This indicates that oxygen
does play a small role, but another species is primarily
responsible for oxidation of the reduced catalyst back to its
ground state.
Based upon the observed mechanistic experimental results and
13-14, 19
literature reports of related systems,
a plausible reaction
4
. Experimental
mechanism is proposed in Scheme 3. The photo-excited state of
methylene green induces a single-electron oxidation of NCS A to
cationic radical species B, thus amplifying the positive
polarization on the chlorine atom. The arene substrate then
undergoes electrophilic aromatic chlorination, and methylene
green is returned to its ground state primarily by either an
external oxidant (such as ammonium peroxodisulfate) or by the
resulting charged succinimide species C which could oxidize the
reduced state of the catalytic methylene green to form the
succinimide anion D.
4.1. Materials and Instrumentation
All reagents and solvents were purchased from commercial
sources and used without further purification. Methylene Green
(Basic Green 5) was purchased from MP Biomedicals (CAS #
284533; FW = 364.86). A description of the construction of our
light bath (LED) photochamber is provided in the supporting
1
13
information. H and C NMR spectra were recorded on a Varian
00/100 (400 MHz) spectrometer in deuterated chloroform
CDCl ), dimethyl sulfoxide (DMSO), or methanol (CD OD)
4
(
3
3
with the solvent residual peak as internal reference unless
1
13
otherwise stated (CDCl : H = 7.26 ppm, C = 77.02 ppm;
3
1
13
1
DMSO: H = 2.50 ppm, C = 39.52 ppm; CD OD: H = 3.31
3
13
ppm, C = 49.00 ppm). Data are reported in the following order:
Chemical shifts (δ) are reported in ppm, and spin-spin coupling
constants (J) are reported in Hz, while multiplicities are
abbreviated by s (singlet), bs (broad singlet), d (doublet), dd
(doublet of doublets), t (triplet), dt (double of triplets), td (triplet
of doublets), m (multiplet), q (quartet). Infrared spectra were
recorded on a Nicolet iS50 FT-IR spectrometer, and peaks are
-
1
reported in reciprocal centimeters (cm ). Melting points (m.p.)
were recorded on a Mel-Temp II (Laboratory Devices, USA) and
were uncorrected. Nominal MS (EI) were obtained using a
Shimadzu GC-2010 Plus with GCMS-QP2010. Relative intensity

5
(in percentage) is shown in parentheses following the fragment
photochamber for 24 hours. Upon completion of the reaction,
three, nine, and fifteen drops of the crude reaction mixture were
immediately transferred via pipette to three separate, freshly
prepared KI/AcOH test solutions in three 4-dram vials. The vials
were capped and shaken, giving an opaque yellow color
resembling the color of a diluted control test, indicating that a
small amount of hydrogen peroxide was forming.
peak where appropriate.
4
.2. General procedure for the chlorination of arenes and
heteroarenes
To an oven-dried flask was added a magnetic stir bar, methylene
green (9.1 mg, 0.05 equiv, 0.025 mmol), ammonium
peroxodisulfate (11.4 mg, 0.1 equiv, 0.05 mmol),
arene/heteroarene (1 equiv, 0.5 mmol), acetonitrile (2.5 mL), and
then N-chlorosuccinimide (73.4 mg, 1.1 equiv, 0.55 mmol). The
reaction mixture was stirred open to air at room temperature (20
4.5. Compound characterization
All chloroarenes were isolated according to general procedure
unless otherwise noted and display the characterizational data
shown below (spectra available in electronic supporting
information). Known compounds were verified by comparison to
literature reports.
°
C) in a white LED chamber for 24 hours. For substrates that
produced a mixture of mono- and di-brominated products upon
full conversion, 2.2 equivalents (1.1 mmol) of N-
chlorosuccinimide was employed. Upon completion of the
reaction, the crude mixture was evaporated under pressure and
the chlorinated product was isolated via column chromatography
on silica gel.
4.5.1. 1-Chloronaphthalene (1) The title compound was prepared
according to the general procedure and quantified using gas
chromatography with adamantane as an internal standard. A
standard curve of 1-chloronaphthalene (Supporting Information,
Figure S4) was prepared in 6 separate reaction vessels by adding
varying amounts of 1-chloronaphthalene (between 0 and 0.25
mmol) to 3 mL of acetonitrile. To each of the 3 mL acetonitrile
solutions was added 8 mL of hexanes and 0.156 mmol (20 mg) of
adamantane. The acetonitrile solution was extracted with the
hexanes, and 1 mL of the hexanes portion was removed for gas
chromatography injection. Gas chromatography was performed
using a Shimadzu GC-2010 Plus with GCMS-QP2010 with a
Restek Rtx-5MS capillary column (30m; 0.25 mmID; 0.25 µm
df; Crossbond – 5% diphenyl/95% dimethyl pilosiloxane). The
GC method was as follows: 40 °C for 5 minutes, then increase at
4
.3. Procedure for light-dependent chlorination of naphthalene
Using visible-light photochambers assembled in our laboratory
(
see supporting information, Figure S2), the yield of product 1
1
was calculated using H NMR integration with nitrobenzene as
internal standard according to the following procedure: to an
oven-dried reaction vessel was added naphthalene (64 mg, 0.5
mmol), ammonium peroxodisulfate (11.4 mg, 0.05 mmol), NCS
(73.4 mg, 0.55 mmol), methylene green (9.1 mg, 0.025 mmol),
and nitrobenzene as internal standard (1 equiv., 10.3 µL, 0.1
1
0 °C/minute for 16 minutes (up to 200 °C). 200 °C is
mmol), in CH CN (2.5 mL) at ambient temperature in a visible-
3
maintained for 10 additional minutes. As seen in Supporting
Information Figure S5, 1-chloronaphthalene is observed at 16.8
minutes, and confirmed by MS (EI): m/z 164(M+2, 31), 162(M+,
light photochamber that has been protected from any external
background light (inside a light-proof chamber constructed in our
laboratory) for 24 h. The crude was analyzed directly by H
NMR and a yield was calculated in comparison to internal
standard signals. Reactions were run in triplicate and the three
trials for each LED photochamber were averaged. For the dark
reaction, the reaction flask was wrapped in aluminum foil and the
reaction was shielded from light in a darkened laboratory with a
light-proof chamber constructed in our laboratory.
1
1
6
00), 127(43), 126(20), 81(18), 77(10), 75(14), 74(11), 68(10),
3(33), 51(44), 50(23).
19
4
.5.2. 4-Bromo-2-chloro-1-methoxybenzene (2)
The title
compound was prepared according to the general procedure.
Orange solid. 60% yield (66.5 mg); purification (hexanes:EtOAc
1
=
9:1). R = 0.66. H NMR (400 MHz, CDCl ) δ = 7.43 (d, J =
f
3
2
.4 Hz, 1H), 7.25 (dd, J = 8.6 Hz, J = 2.4 Hz, 1H), 6.71 (d, J =
1 2
13
4
.4. Iodide Test
8.6 Hz, 1H), 3.81 (s, 3H) ppm. C NMR (100 MHz, CDCl ) δ =
3
1
2
4
54.0, 132.3, 130.3, 123.2, 113.0, 112.1, 56.0 ppm. MS (EI): m/z
22(M+2, 10), 220(M+, 10), 207(11), 205(11), 63(13), 44(100),
3(23), 40(30).
Test solution preparation: 0.100g KI dissolved in 10 mL glacial
acetic acid.
Control test: Three drops of 3% H O solution were added by
2
2
19
4
.5.3. 4-Bromo-2,6-dichloroaniline (3) The title compound was
pipette to the KI/AcOH test solution in a 4 dram vial. The vial
was capped and shaken, resulting in an opaque red-brown color
prepared according to the general procedure. Red solid; m.p. 78-
8
8
4
1
1
2 °C. 86% yield (103.8 mg); purification (hexanes:EtOAc =
(see supporting information, Figure S3, for photos of all
1
0:20). R = 0.75. H NMR (400 MHz, CDCl ) δ =7.31 (s, 2H),
experiments pertaining to the iodide test).
f
3
13
.45 (bs, 2H) ppm. C NMR (100 MHz, CDCl ) δ = 139.4,
3
0
-minute test: A reaction vessel was loaded with methylene
green (9.1 mg, 0.025 mmol), naphthalene (0.062 g, 0.50 mmol),
.5 mL CH CN, and N-chlorosuccinimide (0.097 g, 0.55 mmol).
30.2, 120.0, 107.9 ppm. MS (EI): m/z 243(M+4, 44), 241(M+2,
00), 239(M+, 58), 162(20), 160(32), 124(36), 63(51), 61(54),
2
3
52(25).
After addition of all reagents, the reaction vessel was lightly
shaken to mix contents. Three drops of the crude reaction mixture
was immediately transferred via pipette to a freshly prepared
KI/AcOH test solution in a 4-dram vial. The vial was capped and
shaken, giving a green color resembling the color of the reaction
mixture.
20
4
.5.4. 3-Chloro-4-hydroxybenzonitrile (4) The title compound
was prepared according to the general procedure. Pale yellow
solid. 55% yield (42.6 mg); purification (hexanes:DCM = 1:2). R
0.05. H NMR (400 MHz, CDCl ) δ = 7.66 (d, J = 2.0 Hz, 1H),
f
1
=
7
3
.50 (dd, J = 8.6 Hz, J = 2.0 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H),
1 2
13
2
4-hour test: A reaction vessel was loaded with methylene green
6.71 (bs, 1H) ppm. C NMR (100 MHz, CDCl ) δ = 155.3,
3
(
9.1 mg, 0.025 mmol), naphthalene (0.062 g, 0.50 mmol), 2.5 mL
133.0, 132.8, 120.8, 117.7, 117.2, 105.0 ppm. MS (EI): m/z
155(M+2, 33), 153(M+, 100), 89(39), 63(31), 62(47), 53(13),
44(12), 39(12), 38(24), 37(18).
CH CN, and N-chlorosuccinimide (0.097 g, 0.55 mmol). After
addition of all reagents, the reaction vessel was equipped with a
stir bar and allowed to react open to air in a white LED
3

6
Tetrahedron
21
4
.5.5. 2-Chloro-4-nitrophenol (5) The title compound was
the reaction as internal standard. MS (EI): m/z 142(M+2, 15),
prepared according to the general procedure. Red solid; m.p. 108-
140(M+, 27), 105(100), 79(16), 77(18), 51(36), 39(16).
1
0
8
6
1
1
7
3
10 °C. 45% yield (38.9 mg); purification (DCM = 100%). R =
f
1
26
.14. H NMR (400 MHz, CDCl ) δ = 8.31 (d, J = 2.3 Hz , 1H),
4.5.11. 1-Chloro-2-methylnaphthalene (11) The title compound
3
.13 (dd, J = 9.0 Hz, J = 2.3 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H),
was prepared according to the general procedure. Pink oil. 80%
1
2
1
3
1
.19 (bs, 1H) ppm.
C NMR (100 MHz, CDCl ) δ = 156.8,
yield (69.7 mg); purification (100% hexanes). R
NMR (400 MHz, CDCl
= 8.2 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.59 (m, 1H), 7.49 (m,
f
= 0.57. H
3
41.6, 125.3, 124.6, 120.3, 116.3 ppm. MS (EI): m/z 175(M+2,
8), 173(M+, 54), 143(45), 107(30), 99(59), 91(35), 79(27),
3
) δ = 8.31 (d, J = 8.2 Hz, 1H), 7.82 (d, J
13
3(44),
63(100),
62(46),
53(66),
51(41),
39(33),
1H), 7.35 (d, J = 8.2 Hz, 1H), 2.60 (s, 3H) ppm. C NMR (100
MHz, CDCl ) δ = 133.4, 133.0, 131.1, 130.6, 128.7, 128.0, 127.0,
26.4, 125.6, 124.1, 20.8 ppm. MS (EI): m/z 178(M+2, 16),
76(M+, 50), 141(100), 139(34), 115(25), 70(70).
8(26), 37(22).
3
1
1
22
4
.5.6. 1-(3-Chloro-4-methoxyphenyl)ethan-1-one (6) The title
27
compound was prepared according to the general procedure. Pink
4.5.12. 5-Chloro-1,3-benzodioxole (12) The title compound was
solid; m.p. 72-74 °C. 56% yield (51.3 mg); purification
prepared according to the general procedure. Clear oil. 93%
1
(
hexanes:EtOAc = 1:1). R = 0.15. H NMR (400 MHz, CDCl ) δ
yield (72.7 mg); purification (hexanes:EtOAc = 90:10). R =
f
3
f
1
=
7.98 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.6 Hz, J = 2.0 Hz,
1 2
13
0.56. H NMR (400 MHz, CDCl ) δ =6.80 (m, 2H), 6.72 (d, J =
.8 Hz, 1H), 5.97 (s, 2H) ppm. C NMR (100 MHz, CDCl ) δ =
48.3, 146.4, 126.2, 121.3, 109.6, 108.9, 101.7 ppm. MS (EI):
3
13
1
H), 6.96 (d, J = 8.6 Hz, 1H), 3.96 (s, 3H), 2.55 (s, 3H) ppm.
C
7
1
3
NMR (100 MHz, CDCl ) δ = 195.7, 158.7, 130.7, 130.6, 128.8,
3
1
1
6
22.8, 111.2, 56.4, 26.3 ppm. MS (EI): m/z 186(M+2, 8),
84(M+, 25), 171(22), 169(100), 141(12), 77(27), 75(11),
3(34), 62(12), 43(41).
m/z 157(37), 156(M+, 76), 155(100), 63(99), 62(36), 65(22).
2
8
4
.5.13. 3,5-Dichloro-4-(N,N-dimethylamino)pyridine (13) The
2
1
title compound was prepared according to the general procedure
4
.5.7. 3-Chloro-4-methoxybenzaldehyde (7) The title compound
using 2.2 equiv. of NCS. Yellow oil. 63% yield (50.0 mg);
was prepared according to the general procedure. Red solid. 56%
yield (48.3 mg); purification (hexanes:DCM = 3:1). R = 0.51. H
NMR (400 MHz, CDCl ) δ = 9.85 (s, 1H), 7.91 (d, J = 2.0 Hz,
H), 7.78 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.05 (d, J = 8.4 Hz,
1
1
purification (hexanes:EtOAc = 70:30). R = 0.62. H NMR (400
f
f
13
MHz, CDCl ) δ = 8.30 (s, 2H), 3.01 (s, 6H) ppm. C NMR (100
3
3
MHz, CDCl ) δ 152.6, 149.11, 149.08, 128.2, 42.6 ppm. MS
3
1
1
1
1
5
1
2
13
(EI): m/z 194(M+4, 7), 193(M+3, 12), 192(M+2, 31), 191(M+1,
H), 3.99 (s, 3H) ppm. C NMR (100 MHz, CDCl ) δ = 189.7,
3
6
4
4), 190(M+, 52), 189(100), 112(21), 59(17), 51(20), 44(19),
2(61).
59.8, 131.2, 130.6, 130.3, 123.7, 111.7, 56.5 ppm. MS (EI): m/z
72(M+2, 20), 170(M+, 59), 169(100), 99(24), 75(23), 73(17),
0(19), 63(48), 62(18), 51(15).
28
4
.5.14. 4-Chloro-1-phenylpyrazole (14) The title compound
1
9, 23
was prepared according to the general procedure. White solid;
m.p. 75-76 °C. 92% yield (82.31 mg); purification
hexanes:EtOAc = 85:15). R = 0.53. H NMR (400 MHz,
4
.5.8. 4’-Chloroacetanilide and 2’-chloroacetanilide (8)
The
title compounds were prepared according to the general
procedure. 4’-Chloroacetanilide: Red solid; m.p. 175-178 °C.
9% yield (57.7 mg); purification (hexanes:EtOAc = 80:20). R =
.09. H NMR (400 MHz, CDCl ) δ = 7.45 (d, J = 8.8 Hz, 2H),
.27 (d, J = 8.8 Hz, 2H), 2.17 (s, 3H) ppm. C NMR (100 MHz,
CDCl ) δ = 168.3, 136.4, 129.3, 129.0, 121.0, 24.6 ppm. MS
(
f
CDCl ) δ =7.90 (s, 1H), 7.63 (m, 3H), 7.45 (m, 2H), 7.31 (tt, J =
3
1
6
0
7
13
f
7
1
.2 Hz, J = 1.0 Hz, 1H) ppm. C NMR (100 MHz, CDCl ) δ
1
2
3
3
39.4, 129.51, 129.49, 127.0, 124.8, 118.9, 112.3 ppm. MS (EI):
13
m/z 180(M+2, 29), 178(M+, 91), 152(21), 143(19), 116(27),
115(20), 90(14), 89(32), 77(90), 63(20), 51(100).
3
(
6
EI): m/z 171(M+2, 3), 169(M+, 19), 129(29), 127(96), 65(17),
3(17), 43(100), 39(12). 2’-chloroacetanilide: Red solid. 20%
yield (16.7 mg); purification (hexanes:EtOAc = 80:20). R =
4
b
4
.5.15. 3-Chloro-1H-indazole (15) The title compound was
prepared according to the general procedure. Pale yellow solid;
m.p. 133-138 °C. 69% yield (26.10 mg); purification
hexanes:EtOAc = 80:20). R = 0.36. H NMR (400 MHz,
CDCl ) δ = 10.88 (bs, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.54 (d, J =
.6 Hz, 1H), 7.46 (m, 1H), 7.25 (m, 1H) ppm. H NMR (400
MHz, DMSO) δ = 12.34 (bs, 1H ), 6.70 (dt, J = 8.2 Hz, J = 1.0
Hz, 1H), 6.61 (dt, J = 8.2 Hz, J = 1.0, 1H), 6.49 (m, 1H), 6.27
m, 1H) ppm. C NMR (100 MHz, CDCl ) δ = 141.4, 135.1,
28.1, 121.7, 120.5, 119.6, 110.4 ppm.
f
1
0
7
1
.34. H NMR (400 MHz, CDCl ) δ = 8.36 (d, J = 8.2 Hz, 1H),
3
(
.62 (bs, 1H), 7.36 (dd, J = 7.8 Hz, J = 1.2 Hz, 1H), 7.27 (m,
f
1
2
13
H), 7.04 (t, J =J = 7.8, 1H), 2.24 (s, 3H) ppm. C NMR (100
3
1
2
1
8
MHz, CDCl ) δ = 168.3, 134.6, 129.0, 127.7, 124.6, 122.5, 121.6,
3
2
1
4
4.9 ppm. MS (EI): m/z 171(M+2, 2), 169(M+, 10), 134(35),
29(27), 127(94), 99(10), 92(15), 65(17), 64(12), 63(19),
3(100), 39(17).
1
2
1
2
13
(
1
3
3
1
C NMR (100 MHz,
24
4
.5.9. 4-Chloroanisole and 2-chloroanisole (9) The title
DMSO) δ = 141.2, 132.3, 127.7, 121.6, 119.5, 118.7, 111.1 ppm.
MS (EI): m/z 154(M+2, 27), 152(M+, 100), 117(40), 90(57),
64(25), 63(42), 62(27), 39(31), 38(24), 37(17).
compounds were prepared according to the general procedure in
9
1
:1 para/ortho ratio, according to H NMR, and signals were in
1
agreement with reported values. Yield was calculated by H
NMR integration with nitrobenzene (52 mL, 0.5 mmol, 1 equiv.
relative to anisole) added at the beginning of the reaction as
internal standard. MS (EI) of 4-chloroanisole: m/z 144(M+2, 33),
2
8
4
.5.16. Ethyl 3-chloro-1H-indole-2-carboxylate (16) The title
compound was prepared according to the general procedure. Pale
yellow solid; m.p. 150-152 °C. 98% yield (110.0 mg);
purification (hexanes:EtOAc = 80:20). R = 0.47. H NMR (400
MHz, CDCl ) δ = 7.84 (bs, 1H), 7.72 (dt, J = 8.2 Hz, J = 1.0
1
f
1
42(M+, 100), 127(70), 99(86).
3
1
2
2
5
Hz, 1H), 7.38 (m, 2H), 7.22 (ddd, J = 8.2 Hz, J = 6.3 Hz, J =
1 2 3
4
.5.10. 1-Chloro-2,4-dimethylbenzene (10) The title compound
1
2.0 Hz, 1H), 4.49 (q, J = 7.3 Hz, 2H), 1.47 (t, J = 7.3 Hz, 3H)
13
ppm. C NMR (100 MHz, CDCl ) δ 161.2, 134.8, 126.5, 126.2,
22.3, 121.2, 120.2, 112.2, 112.1, 61.5, 14.4 ppm. MS (EI): m/z
25(M+2, 10), 223(M+, 29), 179(32), 178(18), 177(100),
49(27), 123(17), 114(26).
was prepared according to the general procedure, and H NMR
signals were in agreement with reported values. Yield was
calculated by H NMR integration with nitrobenzene (52 mL, 0.5
3
1
2
1
1
mmol, 1 equiv. relative to m-xylene) added at the beginning of

7
1
9
4
.5.17. 5-Chloro-2-methoxy-3-pyridinecarboxaldehyde (17)
5. a) Lied, F.; Lerchen, A.; Knecht, T.; Mück-Lichtenfeld, C.;
Glorius, F. ACS Catalysis 2016, 6, 7839-7843. b) Xiong, X.;
Yeung, Y. Y. Angew Chem Int Ed Engl 2016, 55, 16101-16105.
Rodriguez, R. A.; Pan, C. M.; Yabe, Y.; Kawamata, Y.; Eastgate,
M. D.; Baran, P. S. J Am Chem Soc 2014, 136, 6908-11.
a) Mendonça, G. F.; Mattos, M. C. S. d. Química Nova 2008, 31,
798-801. b) Akhlaghinia, B.; Rahmani, M. Turkish Journal of
Chemistry 2009, 33, 67-72. c) Mendonça, G. F.; Senra, M. R.;
Esteves, P. M.; de Mattos, M. C. S. Applied Catalysis A: General
2011, 401, 176-181. d) Mendonça, G. F.; Mattos, M. C. S. d.
Current Organic Synthesis, 2013, 10, 820-836. e) Mendonça, G.
F.; Bastos, A. R.; Boltz, M.; Louis, B.; Pale, P.; Esteves, P. M.; de
Mattos, M. C. S. Applied Catalysis A: General 2013, 460–461, 46-
The title compound was prepared according to the general
procedure. Pale yellow solid; m.p. 87-90 °C. 10% yield (8.5 mg);
purification (hexanes:EtOAc = 90:10). R = 0.54. H NMR (400
MHz, CDCl ) δ = 10.29 (s, 1H), 8.30 (d, J = 2.9 Hz, 1H), 8.03
d, J = 2.9 Hz, 1H), 4.05 (s, 3H) ppm. C NMR (100 MHz,
CDCl ) δ = 188.0, 162.7, 151.0, 136.8, 125.1, 119.0, 54.4 ppm.
MS (EI): m/z 173(M+2, 21), 171(M+, 37), 144(34), 143(28),
42(95), 140(17), 127(14), 116(13), 115(21), 114(52), 113(65),
12(30), 111(14), 78(100), 76(46), 73(33), 64(49), 50(53).
6
7
.
.
1
f
3
13
(
3
1
1
5
1.
2
8
4
.5.18. 3-Chloro-1H-indole (18) The title compound was
8
9
1
.
.
Lu, Z.; Li, Q.; Tang, M.; Jiang, P.; Zheng, H.; Yang, X. Chem
Commun 2015, 51, 14852-5.
Souza, S. P. L. d.; Silva, J. F. M. d.; Mattos, M. C. S. d. Journal of
the Brazilian Chemical Society 2003, 14, 832-835.
prepared according to the general procedure. Pale yellow solid;
m.p. 87-89 °C. 79% yield (58.91 mg); purification
hexanes:EtOAc = 70:30). R = 0.42. H NMR (400 MHz,
CDCl ) δ = 7.96 (bs, 1H ), 7.64 (d, J = 7.8 Hz, 1H), 7.32 (d, J =
.8 Hz, 1H), 7.22 (m, 2H), 7.12 (d, J = 2.7 Hz, 1H) ppm.
(
f
0. a) Petrone, D. A.; Ye, J.; Lautens, M. Chem Rev 2016, 116, 8003-
3
1
2
04. b) Zha, G.-F.; Qin, H.-L.; Kantchev, E. A. B. RSC Advances
016, 6, 30875-30885.
13
7
C
NMR (100 MHz, CDCl ) δ = 134.9, 125.3, 123.1, 120.8, 120.5,
11. De la Mare, P. B. D. Electrophilic halogenation: reaction
pathways involving attack by electrophilic halogens on
unsaturated compounds; Cambridge University Press: London;
New York, 1976.
3
1
1
18.2, 111.5, 106.5 ppm. MS (EI): m/z 153(M+2, 32), 151(M+,
00), 116(23), 89(57), 63(28), 62(22), 58(21), 76(21).
19
1
2. Prakash, G. K. S.; Mathew, T.; Hoole, D.; Esteves, P. M.; Wang,
Q.; Rasul, G.; Olah, G. A. Journal of the American Chemical
Society 2004, 126, 15770-15776.
4
.5.19. 3-Chloro-1H-indole-5-carboxaldehyde (19) The title
compound was prepared according to the general procedure. Pale
yellow solid; m.p. 134-136 °C. 81% yield (35.8 mg); purification
1
3. Hering, T.; König, B. Tetrahedron 2016, 72, 7821-7825.
1
(
hexanes:EtOAc = 50:50). R = 0.51. H NMR (400 MHz,
f
14. Rogers, D. A.; Brown, R. G.; Brandeburg, Z. C.; Ko, E. Y.;
CDCl ) δ = 10.08 (s, 1H), 8.63 (bs, 1H), 8.18 (d, J = 0.8 Hz, 1H),
Hopkins, M. D.; LeBlanc, G.; Lamar, A. A. ACS Omega 2018, 3,
3
1
2868-12877.
15. a) Fukuzumi, S.; Ohkubo, K. Organic & Biomolecular Chemistry
014, 12, 6059-6071. b) Hari, D. P.; Konig, B. Chemical
7
7
9
=
.83 (dd, J = 8.6 Hz, J = 2.3 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H),
1
2
1
.30 (d, J = 2.3 Hz, 1H) ppm. H NMR (400 MHz, CD OD) δ =
3
2
.97 (s, 1H), 8.11 (dd, J = 1.6 Hz, J = 0.8 Hz, 1H), 7.74 (dd, J
1
2
1
Communications 2014, 50, 6688-6699. c) Nicewicz, D. A.;
Nguyen, T. M. ACS Catalysis 2014, 4, 355-360. d) Joshi-Pangu,
A.; Levesque, F.; Roth, H. G.; Oliver, S. F.; Campeau, L. C.;
Nicewicz, D.; DiRocco, D. A. J Org Chem 2016, 81, 7244-9. e)
Pitre, S. P.; McTiernan, C. D.; Scaiano, J. C. ACS Omega 2016, 1,
8.6 Hz, J = 1.6 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.40 (s, 1H)
2
13
ppm. C NMR (100 MHz, CD OD) δ = 194.2, 140.2, 131.0,
3
1
1
1
5
26.5, 125.0, 124.4, 123.2, 113.7, 108.0 ppm. MS (EI): m/z
81(M+2, 28), 180(M+1, 39), 179(M+, 89), 178(100), 152(30),
50(84), 114(28), 89(40), 87(21), 75(22), 63(35), 62(31), 60(21),
7(37).
6
1
6-76. f) Romero, N. A.; Nicewicz, D. A. Chemical Reviews 2016,
16, 10075-10166.
1
6. a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chemical
Reviews 2013, 113, 5322-5363. b) Day, J. I.; Teegardin, K.;
Weaver, J.; Chan, J. Org Process Res Dev 2016, 20, 1156-1163.
7. Nicewicz, D.; Roth, H.; Romero, N. Synlett 2015, 27, 714-723.
8. a) Lin, C.; Chang, T. C. Chemosphere 2007, 66, 1003-11. b)
Marin, M. L.; Santos-Juanes, L.; Arques, A.; Amat, A. M.;
Miranda, M. A. Chem Rev 2012, 112, 1710-50. c) Glusko, C. A.;
Previtali, C. M.; Vera, D. M. A.; Chesta, C. A.; Montejano, H. A.
Dyes and Pigments 2011, 90, 28-35.
9. Rogers, D. A.; Bensalah, A. T.; Espinosa, A. T.; Hoerr, J. L.;
Refai, F. H.; Pitzel, A. K.; Alvarado, J. J.; Lamar, A. A. Organic
Letters 2019, 21, 4229-4233.
0. Chinnagolla, R. K.; Pimparkar, S.; Jeganmohan, M. Chemical
Communications 2013, 49, 3146-3148.
5
. Acknowledgements
1
1
The research results discussed in this publication were made
possible in part by funding through the award for project number
HR18-013, from the Oklahoma Center for the Advancement of
Science and Technology (OCAST). We are grateful for the
financial support provided by the lab start-up contribution from
The University of Tulsa. We would also like to thank the Tulsa
Undergraduate Research Challenge (TURC) and Chemistry
Summer Undergraduate Research Program (CSURP) for support.
Lastly, we would like to acknowledge Dr. Gabriel LeBlanc for
helpful discussions and advice involving electrochemical
interpretation.
1
2
2
1. Mostafa, M. A. B.; Bowley, R. M.; Racys, D. T.; Henry, M. C.;
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2
2
3. Li, Z. L.; Sun, K. K.; Cai, C. Org Biomol Chem 2018, 16, 5433-
6
. Supplementary data
5
440.
2
4. a) Wu, H.; Hynes, J. Organic Letters 2010, 12, 1192-1195. b)
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Falivene, L.; Cavallo, L.; Dorta, R. Chemistry – A European
Journal 2011, 17, 12886-12890.
1
13
The supporting information ( H and C NMR spectra) is
available free of charge on the Elsevier Tetrahedron website at X.
. References and notes
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2
7
1
.
a) Gribble, G. W. Accounts of Chemical Research 1998, 31, 141-
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1
L.; Bao, Z. Chemistry of Materials 2011, 23, 446-455.
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3
4
.
.
Watson, W. D. The Journal of Organic Chemistry 1985, 50, 2145-
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Organic Letters 2015, 17, 1042-1045.

Highlights
-
-
-
-
The first example of non-metal photo-oxidative activation of N-chlorosuccinimide (NCS)
by a visible-light photoredox catalyst.
The reaction utilizes methylene green, an inexpensive and conspicuously overlooked
visible-light photoredox catalyst in the thiazine family of organic dyes.
Good to excellent yields of chlorinated arenes and heteroarenes using mild reaction
conditions (ambient temperature, open to air).
Wide range of functional group tolerance – a feature important for fine chemical
chlorination of complex molecules.