N -Hydroxyphthalimide/benzoquinone-catalyzed chlorination of hydrocarbon C-H bond using N -chlorosuccinimide

Article abstract of DOI:10.1039/c9ob00216b

The direct chlorination of C-H bonds has received considerable attention in recent years. In this work, a metal-free protocol for hydrocarbon C-H bond chlorination with commercially available N-chlorosuccinimide (NCS) catalyzed by N-hydroxyphthalimide (NHPI) with 2,3-dicyano-5,6-dichlorobenzoquinone (DDQ) functioning as an external radical initiator is presented. Aliphatic and benzylic substituents and also heteroaromatic ones were found to be well tolerated. Both the experiments and theoretical analysis indicate that the reaction goes through a process wherein NHPI functions as a catalyst rather than as an initiator. On the other hand, the hydrogen abstraction of the C-H bond conducted by a PINO species rather than the highly reactive N-centered radicals rationalizes the high chemoselectivity of the monochlorination obtained by this protocol as the latter is reactive towards the C(sp³)-H bonds of the monochlorides. The present results could hold promise for further development of a nitroxy-radical system for the highly selective functionalization of the aliphatic and benzylic hydrocarbon C-H.

Full text of DOI:10.1039/c9ob00216b

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COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Page 1 of 18
Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB00216B
N-Hydroxyphthalimide/Benzoquinone-Catalyzed
Chlorination of Hydrocarbon C−H Bond with N-
Chlorosuccinimide
†
,
#, ‖
‡
, †
,‡,§
Zi-Hao Li, , Béla Fiser, Biao-Ling Jiang, Jian-Wei Li,* Bao-Hua Xu,* and
Suo-Jiang Zhang‡,§
†
State Key Laboratory of Chemical Resource Engineering, Beijing University of
Chemical Technology, Beijing 100029, China
‡
Beijing Key Laboratory of Ionic Liquids Clean Process, Key Laboratory of Green
Process and Engineering, State Key Laboratory of Multiphase Complex Systems,
Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR
China
§
College of Chemistry and Chemical Engineering, University of Chinese Academy of
Sciences, Beijing, 100049, PR China
#
Ferenc Rákóczi II. Transcarpathian Hungarian Institute, 90200-Beregszász,
Transcarpathia, Ukraine, Computational Molecular Design Research Group, Institute
of Chemistry, University of Miskolc, Miskolc, 3515, Hungary
*
Author to whom correspondence should be addressed; E-Mail:
lijw@mail.buct.edu.cn, bhxu@ipe.ac.cn

On leave to Institute of Process Engineering
‖Quantum chemical calculations
Abstract
The direct chlorination of CH bond received considerable attentions in recent
years. In this work, a metal-free protocol of hydrocarbon C−H bond chlorination with
the commercially available N-chlorosuccinimide (NCS) catalyzed by N-
hydroxyphthalimide (NHPI) with 2,3-dicyano-5,6-dichlorobenzoquinone (DDQ)
functioning as an external radical initiator is presented. Not only aliphatic and benzylic

Organic & Biomolecular Chemistry
Page 2 of 18
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DOI: 10.1039/C9OB00216B
substituents, but also heteroaromatic ones were found well tolerated. Both of
experiments and theoretical analysis support the reaction is going through a process,
wherein NHPI functions as a catalyst rather than an initiator. On the other hand, the
hydrogen abstraction of CH bond was conducted by PINO species rather than the
highly reactive N-centered radicals rationalizes the high chemoselectivity of
3
monochlorination obtained by this protocol since the latter is reactive towards C(sp )H
bonds of the monochlorides. The present results may hold promise for further
development of nitroxy-radical system in the aliphatic and benzylic hydrocarbon CH
highly selective functionalization.
Introduction
Direct chlorination of CH bond has the advantages of high efficiency and atomic
economy which can be widely used in bulk and fine chemistry and therefore attracts
1
-5
much attentions. Thermal chlorination using elemental chlorine represents one of the
industrial methods, but often results in multiple side-chain chlorinated products and the
maximum yield of alkyl chlorides based on chlorine is only 50% with equivalent HCl
formed as a byproduct.6-9 The growing significance of regioselectivity and mass
efficiency have urged scientists to develop catalytic methods with various aliphatic
C−H bond chlorination agents.10-25 For instance, compounds consisting of NCl
structural motif are the most common ones of such chlorination agents. Noteworthily,
3
a key challenge in the use of them for the C(sp )–H chlorination of aromatic compounds
is their tendency to give benzylic chlorination, which is imposed by the electrophilic
character of chlorine therein.17,23-25 It has not been clearly demonstrated how to control
such characters for chemoselective reactions, but we consider the key to achieve this
3
selectivity is to launch an excellent catalytic system of C(sp )–H abstraction, which is
able to efficiently generate the corresponding carbon radical and thereafter grasp

Page 3 of 18
Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB00216B
chlorine from NCl moiety in-situ while suppressing the detrimental electrophilic
chlorination.
Scheme 1. Proposed pathway for the nitroxyl radical-mediated chlorination of
hydrocarbon C−H bond with N−Cl reagent.
Nitroxyl radicals (-NO·), produced by oxidation of their precursors (-NOH), can
effectively abstract hydrogen atoms from hydrocarbons and have therefore been
successfully employed to accelerate the autoxidation efficiency.26-29 In addition,
catalytic systems consisting of the -NOH precursors and varied initiators have been
well used in the oxidative functionalization of hydrocarbons to construct CO, CN,
and CC bonds.30,31 N-hydroxyphthalimide (NHPI) represents the most common -NOH
reagent, which were evidently used as catalyst/initiator for halogenation of
hydrocarbons. Still, only two examples were available for chlorination to date.
Specifically, the Minisci group developed NHPI-catalyzed halogenation of
hydrocarbons with stoichiometric amounts of CuCl as the chlorine source and HNO
2
3
3
2
as the external oxidant. The higher chemoselectivity of monochlorination obtained by
3
this protocol was mainly attributed to deactivated C(sp )H towards phthalimide N-
oxyl (PINO) radical upon introduction of a chlorine atom. In comparison, the Schreiner
group presented a method using trichloroisocyanuric acid (TCCA) as the chlorine

Organic & Biomolecular Chemistry
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source, wherein NHPI was found reacting as a radical initiator.33,34 And the moreView Article Online
DOI: 10.1039/C9OB00216B
general N-chlorosuccinimide (NCS) was found not tolerated as the chlorination reagent
under this protocol. Mechanistic study suggested the N-centered radical released from
the chlorine transfer step is reactive enough and responsible to the hydrogen abstraction
3
35-37
of C(sp )H bond during the catalysis.
Besides, the addition of catalytic amounts
of CBr was requisite to considerably reduce the reaction times due to the formation of
4
chain-carrying CBr radicals. We envisioned the nitroxyl radical mediated chlorination
3
of aliphatic and benzylic hydrocarbon C−H bond with NCl chlorinating reagent could
be attained under a CBr -free condition. As presented in Scheme 1, the reaction starts
4
with generation of -NO· (I) from -NOH (3) in the mediation of a proper external
initiator. Subsequent hydrogen abstraction of hydrocarbon CH bond (1) by -NO· (I)
provides the corresponding carbon radical (II) and -NOH (3) is regenerated thereby.
Chlorination product (4) was thereafter generated from attack of II to NCl bond of the
chlorine reagent (2), with coincidently forming N-centered radial species (III). The
3
released III is supposed reactive enough towards the C(sp )H bond. It then reacts with
substrate 1 to provide carbon radical II, which constitutes a catalytic cycle together
with the chlorination step (path A). In this case, nitroxy reagent functions as an initiator
rather than a catalyst. However, OH bond in -NOH (3) is relatively weak as compared
3
38
to hydrocarbon C(sp )H bond in 1. Consequently, one-electron oxidation of 3 in the
presence of N-centered radical (III) may be preferred and the cycling between -NOH
(3) and -NO· (I) locates as a part of the catalytic pathway (path B). In this regard,
whether -NOH reacts as an initiator or a catalyst is controversial, which needs to be
stated more clearly. Besides, challenges remain in the search for a system that employs
both nitroxyl radical and NCl chlorinating reagent of proper structures, which (i) keeps
3
the rate of hydrogen abstraction of C(sp )–H bond matching that of subsequent

Page 5 of 18
Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB00216B
chlorination via NCl homogeneous cleavage, and (ii) maintains proper reactivity of
hydrogen abstraction for benzylic chlorination, while suppressing the electrophilic
substitution for ring chlorination in the case of aromatic substrates.
Herein, we present a metal-free protocol of aliphatic and benzylic hydrocarbon
C−H bond chlorination with commercially available NCS catalyzed by NHPI with 2,3-
dicyano-5,6-dichlorobenzoquinone (DDQ) functioning as an external radical initiator.,
which is conducted in the absence of CBr . It exhibits a similar reactivity, but broader
4
substrate tolerance, as compared to that of NHPI/CBr /TCCA protocol discovered by
4
3
4
the Schreiner group in terms of the controlled monochlorination of hydrocarbons
when only one equivalent of substrate is reacted. Under optimized condition of using 5
equivalents of substrate, an up to 93.2% yield of side-chain monochlorination product
could be obtained. Importantly, both of chain length experiments and theoretical
analysis support NHPI functions as a catalyst during the catalysis.
Result and discussion
Chlorination of toluene (1a) with NCS (2a, 2 equiv.) in the presence of NHPI (3a,
1
0 mol%) was selected as a model reaction and conducted with varied external radical
initiators (Table 1). Under the general cobalt-mediated aerobic conditions,39-43
considerable benzoic acid was detected besides ring chlorides (5a) of varied site
selectivity (Table S1), which is imposed by a much faster rate of peroxidation of carbon
radical with O as compared to the desired chlorination with NCS. This side reaction
2
was significantly suppressed when 2,3-dicyano-5,6-dichlorobenzoquinone (DDQ) was
used in the absence of O , which was reported as a two-electron oxidant to convert
2
NHPI into PINO.44-46 Benzylic chlorination product (4a) was obtained with 42% yield
o
when the reaction was conducted in CH CN at 140 C for 16h in the presence of DDQ
3

Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB00216B
(
5 mol%) (Table 1, entry 1). The reaction efficiency was slightly promoted by lowering
o
o
temperature to 80 C (entry 2), but it is not beneficial at further decreased 50 C (entry
). The loading amount of both DDQ and 3a was found extremely crucial (entries 4~10).
3
Under optimized condition, it provided 4a with 54% yield in the presence of 0.5 mol%
DDQ and 10 mol% 3a (entry 6). Reaction conditions varying the structure of nitroxyl
radical precursor 3 (entries 11~14), chlorine reagent 2 (entries 15~17) and solvent
(entries 18~20) were examined. It is found requisite to render the OH group of the
nitroxyl radical precursor (3) a proper bond dissociation energy (BDE) for a high
reactivity towards benzylic chlorination.47-49 For instance, introducing OH group with
a BDE value either less than 88 kcal/mol (entry 11) or more than 90 kcal/mol (entries
1
3~14) resulted in markedly lower yields of 4a and higher ratio of side products 5a.
-1
The best yield of 4a was obtained in the presence of 3c (BDENOH = 88.8 kcal·mol )
entry 12). To our surprise, the reaction efficiency increases with increasing BDE of
(
NCl bond (Table S2) in the chlorine reagent (2) (entries 6 and 15~17), disfavoring the
NCl breakage as a rate-limiting step. Besides, solvents other than CH CN exhibited
3
reduced performance (entries 18~20).
Table 1. Condition screening for chlorination of toluene (1a).a

Page 7 of 18
Organic & Biomolecular Chemistry
CH3
View Article Online
DOI: 10.1039/C9OB00216B
CH3
DDQ
Cl
+
Cl-source (2)
+
Cl
N-OH reagent (3)
1a
4a
5
O
O
O
O
O
Cl
Cl
S
N
N
Structure of 2
N
Cl
N
Cl
N Cl
O
N
O
O
O
O
Cl
2
a
2b
2c
54.2e
2d
BDE (N-Cl)
kcal/mol
6
4.8e
62.6e
50.0e
O
O
O
N
O
O
N
N
N
HO
O
OH
O
O
N
N
Structure of 3
OH
10
N OH
N
OH
O
OH
3
a
3b
85.248
3c
88.847
3d
BDE (NO-H)
kcal/mol
8
8.147
91.949
DDQ
mol%)
3
Conv.
(%)
Entry
2
Solvent
Y (%) R5a/4ab
4
a
(
(mol%)
1c
5
2a
3a (10)
100
42
0.68
CH
CN
3
2
3
4
5
6
7
8
9
5
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (3)
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
100
72
45
27
40
52
54
47
43
54
4
0.35
1.06
0.62
0.24
0.32
0.42
0.43
0.22
7.82
30.28
0.27
1.22
0.45
0.61
0.65
0.85
0
5
10
1
100
100
100
100
91
0.5
0
0.5
0.5
0
3a (16)
3a (0)
100
43
1
1
1
1
1
1
1
1
1
1
2
0
1
2
3
4
5
6
7
8
9
0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
3b (10)
3c (10)
3d (10)
3d (3)
81
3
92
57
37
45
51
42
37
38
85
89
3a (10)
3a (10)
100
83
2dd 3a (10)
100
38
2a
2a
2a
3a (10)
3a (10)
3a (10)
1,2-DCE
THF
0
n.d.
27
0
AcOH
100
0.98
a
o
Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol, 2.0 equiv.), solvent (2 mL), 80 C, 16 h, under
argon, conversion and yield are determined by GC using diphenyl as internal standard and are on
b
the basis of 1a; ratio of aromatic chlorides and benzyl chloride, which is determined by GC with

Organic & Biomolecular Chemistry
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View Article Online
c
o
d
area normalization method; 140 C; 2d (0.3 mmol); n.d. not detected; DDQ (2,3-dic
D
y
O
anI:
o
10
-
.
5
10,639
-
/C9OB00216B
dichlorobenzoquinone); n.d.: not detected.
With the optimized structure of chlorine reagent and nitroxyl radical precursor in
hand, we subsequently turned to adjust the ratio of two substrates (1a and 2a) to further
improve the reaction efficiency (Table 2). To our surprise, it did not bring a positive
effect to increase the ratio of 1a to 2a in the presence of a high concentration of 2a
(entry 2 vs. 1), but it is improved remarkably when the concentration of 2a is half
decreased (entries 3 ~ 6). The best yield was obtained when the ratio of 1a to 2a was
set up at 10 (entry 6). Such a high yield was kept when the reaction time was shortened
(entries 7 and 8). In addition, the reaction was found tolerate in the presence of either
water (entry 6) or air (entry 7). Considering the simple operation and the reaction
economy, 5.0 equivalents of 1a was reacted with 2a (0.5 mmol) and the optimized
condition was conducted in the presence of NHPI (10 mol%), DDQ (0.5 mol%) in
o
CH CN (2 mL) at 80 C for 3h under air, offering 4a with 78% yield (entry 10). The
3
formation of ring chlorination was nearly suppressed in this case.
Table 2. Condition optimization for the chlorination of 1a with 2a.a
CH3
Cl
CH3
DDQ (0.5 mol%)
N
Cl
O
O
+
+
Cl
3a (10 mol%)
1a
2a
4a
5a
1
a
2a
entry
t (h)
Y (%)
R5/4ab
4
a
(
mmol) (mmol)
1
2
3
4
0.5
1.0
0.5
1.5
1.0
1.0
0.5
0.5
16
16
16
16
54
42
30
71
0.32
0.29
0.32
0.15
5
6
2.5
5.0
0.5
0.5
16
16
80
0.09
85
0

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7
8
9c
2.5
2.5
2.5
2.5
0.5
0.5
0.5
0.5
8
3
3
3
79
78
82
78
0.09
0.08
0.09
0.07
1
0d
a
o
Reaction conditions: CH CN (2 mL), DDQ (0.5 mol%), NHPI (3a, 10 mol%), 80 C, conversion
3
and yield are determined by GC using diphenyl as internal standard and are on the basis of NCS; b
ratio of aromatic chloride and benzyl chloride, which is determined by GC with area normalization
c
d
method; H O (10 μL); under air.
2
The scope and limitation of this metal-free radical chlorination protocol in terms
of hydrocarbons were examined (Scheme 2). Significant electron effect was found for
toluene derivatives consisting of substituents at the para-position. The corresponding
benzylic chlorination products substituted with electron-withdrawing groups, such as
fluoro (4b), chloro (4c), nitrile (4e), nitro (4f), trifluoromethyl (4g) and methyl ester
(
4h), were obtained in higher yields as compared to those with methyl (4k) and methoxy
4l) group. The exceptional example of para-bromo substituted toluene (1d) provided
(
the corresponding benzylic chloride (4d) with only 38% yield and significant Br/Cl
scrambling was detected leading to 4c as the major side product, which is consistent
5
0
with the result of Muathen’s group. The poor performance of electron-donating group
substituted benzylic hydrocarbons, such as 1l, may be attributed to the readily occurred
nucleophilic substitution at the phenyl site, with leading to considerable amount of ring
chlorides as side products. On the other hand, the relatively strong electron-
withdrawing groups at the para-site (4e, 4f, 4g vs. 4a, 4b, 4c) does negatively influence
the chlorination rate, which was probably reasoned by their reluctance in the rate-
limiting step of hydrogen abstraction. In consistent with this point, the formation of 4i
and 4j proceeds sluggishly with a poor conversion because electron of the menaphthyl

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3
hydrocarbon C(sp )H is well delocalized to the adjacent aromatic site. Besides, as
more positions on the phenyl ring were blocked by electron-withdrawing chloro group,
the yield of the corresponding benzyl chloride slightly decreased (4q vs. 4c and 4m).
In the case of toluene with mono-chloro substituent at the aromatic site, the yield of the
corresponding benzyl chloride deceases in an order para (4c) > ortho (4m) > meta (4n),
suggesting stabilization of the transient benzyl radical plays a crucial role in terms of
the yield. Deactivating substituents, such as electron-withdrawing methyl ester and
hyper conjugated methyl, at either para- or ortho-position of phenyl group mostly
stabilize the adjacent methyl radical; hence, those at the meta-position give the lowest
yield (4o vs. 4h; 4p vs. 4k).51, 52 Noteworthily, methyl 3-(chloromethyl)benzoate (4o),
5
3
an important building block in the synthesis of taprostene, was directly obtained with
a satisfactory yield (70%) by this protocol. The chlorination of ethylbenzene gave a
relatively high yield (71%) of 4r, but a low 2°/1° selectivity (3.5:1) as compared to the
3
4
results Schreiner obtained. Not only benzylic hydrocarbons, but also aliphatic ones
were tolerated, with acceptable yields being obtained under the same conditions (4s ~
3
4
4
v). In contrast to NHPI/CBr /TCCA protocol discovered by of the Schreiner group,
4
heteroaromatic substituents are also tolerated, with providing 4w~y modest to good
yields. Evidently, neither doubly chlorinated product nor oxygenated product was
obtained for any substrate examined. To our delight, the oxidative bromination of
3
C(sp )H bonds is also tolerated with this newly developed protocol. The bromination
of 1a and 1s with N-bromosuccinimide (NBS) under standard conditions proceeded
smoothly, with providing 8a and 8s in a satisfied yield, respectively (Scheme S2).

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Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB00216B
Cl
Cl
Cl
Cl
F
Cl
4c, 93% (3h)c
Br
4d, 37% (3h)c
38% (16h)c
4
a, 80% (3h)b
4b, 75% (3h)c
9% (16h)c
7
Cl
Cl
Cl
Cl
O N
2
F C
3
MeO C
2
NC
4
e, 24% (3h)c
5% (16h)c
4f, 25% (3h)c
4g, 56% (3h)c
87% (16h)c
4h, 74% (3h)c
7
67% (16h)c
77% (16h)c
Cl
Cl
Cl
Cl
MeO
4l, n.d. (16h)e
4
i, 16% (3h)c
4j, 5% (16h)d
4k, 44% (3h)c
1
6% (16h)c
44% (16h)c
Cl
MeO C
Cl
Cl
2
Cl
Cl
Cl
4
m, 91% (3h)c
4n, 88% (3h)c
4o, 11% (3h)c
4p, 25% (3h)c
7
0% (16h)c
26% (16h)c
Cl
Cl
Cl
Cl
Cl
Cl
4
q, 81% (3h)b
4r, 69% (3h)c,f
4s, 55% (3h)b
4t, 45% (3h)b
8
9% (16h)b
71% (16h)c,f
59% (16h)b
64% (16h)b
Cl
N
Cl
Cl
Cl
N
4
u, 35% (16h)d
4u', 15% (16h)d
4v, n.d. (16h)e
4w, 45% (16h)d
Cl
N
Cl
N
4
x, 76% (3h)c
4y, 72% (3h)c
7
8% (16h)c
a
Scheme 2. Substrate scope for the side-chain chlorination. NCS (2a, 0.5 mmol), 1 (2.5
o
b
mmol, 5.0 equiv.), NHPI (3a, 10 mol%), DDQ (5 mol%), CH CN (2 mL), 80 C; yield determined
3
c
d
1
e
by GC using diphenyl as internal standard; isolated yield; yield determined by H NMR. yield
f
determined by GC-MS; yield of (2-chloroethyl)benzene (4r, 1 chloride): 20% (3h); 22% (16h).
n.d.: not detected.
We also investigated the C−H bond chlorination of toluene (1a, 75 mmol) on a
gram scale (Scheme S1), which offers 4a in a yield of 76.2% after reaction for 3h.
Besides, one-pot conversion of 1a into N-benzylsuccinimide (6a) using succinimide
obtained quantitatively in-situ from NCS (2a) was examined as an example,

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considering the nucleophilic substitution of chloride has potential synthetic utility.54
The standard reaction leading to benzyl chloride (4a), followed by addition of
potassium carbonate (2.0 equiv.), gives N-benzylsuccinimide (6a) with 72% yield
(Scheme 3). This result suggests the second step of nucleophilic substitution is
quantitative.
(1) DDQ (5 mol%)
NHPI (10 mol%)
O
CH CN (2 mL)
3
o
8
0 C, 3h
N
+
NCS
(
2) K CO (2.0 equiv.)
2 3
O
o
8
0 C, 13h
1a
2a
6a
(Yield 72%)
(5.0 equiv.) (0.5mmol)
Scheme 3. One-pot conversion of toluene (1a) into N-benzylsuccinimide (6a).
We propose two reaction pathways for this PINO-mediated chlorination of
aliphatic and benzylic hydrocarbon C−H bond with N−Cl reagent as described in
Scheme 1, within which nitroxyl radical is used as an initiator (path A) or a catalyst
(path B). To clarify the role of nitroxyl radical, state of the art DFT calculations at the
B3LYP/6-31+G(d), M06/6-31+G(d) and M06-2X/6-31+G(d) level were conducted
towards the optimized condition for PINO-mediated benzyl CH chlorination of 1a
with NCS (Table S3).55-58 The reaction sequence, Gibbs free energy of each step, and
the transition state of some key structures are presented in Scheme 4. The reaction starts
with the generation of PINO (I) from the reaction of NHPI precursor with DDQ external
initiator (omitted for clarity), which subsequently undergoes hydrogen abstraction of
benzyl CH bond in 1a to form the benzyl radical (II). The hydrogen abstraction step
is endergonic (ΔG353K = 13.7 kcal/mol), proceeding via a transition state (TS1) with
quite high energy barrier value of 29.8 kcal/mol (ΔG‡353K). Thereafter, benzyl radical

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DOI: 10.1039/C9OB00216B
(
II) reacts with NCS (2a) to form product 4a, coincidently releasing N-centered radical
(III). Theoretical analysis demonstrated it is an exergonic step (ΔG353K = 1.7 kcal/mol)
and its energy barrier (ΔG‡
= 17.0 kcal/mol, TS2) is much lower than the previous
53K
3
hydrogen abstraction step. Herein, two pathways could be distinguished from each
other by the fate of N-centered radical (III). In path A, it prefers to react with
hydrocarbon 1a (ΔG353K = 28.4 kcal/mol; ΔG‡
= 13.5 kcal/mol, TS3), but
353K
undergoes hydrogen abstraction of NHPI (3a) (ΔG353K = 42.1 kcal/mol; ΔG‡
=
353K
1
2.5 kcal/mol, TS4) in path B. To better understand the difference, the reaction
coordinate-Gibbs free energy plot for cycling of III in one catalytic run following these
two pathways is presented and compared in Scheme 4. The most stable state of the
pathways can be found in path B, right after the hydrogen abstraction of NHPI (3a) by
III (ΔG353K = 42.1 kcal/mol), while the second most stable point belong to the
regeneration of III which can be seen in both pathways (ΔG353K = 30.2 kcal/mol). It
indicates path B is favored if the reaction is thermodynamically controlled. However,
radical type reactions are usually very fast. In this case, an independent experiment
demonstrated it takes less than 50 min for the reaction under theoretical analysis to
reach the potential conversion (Figure S1). This indicates that, the process is likely to
be kinetically influenced. The lowest energy barrier belongs to TS4 in path B which is
1
kcal/mol lower than lowest barrier in path A (TS3). Therefore, path B is slightly
5
8
favored over path A from a kinetic point of view as well. Both, thermodynamic and
kinetic conditions support path B over A, which shows that NHPI appears as a catalyst
rather than an initiator in the chlorination process. This was subsequently demonstrated

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by chain length experiment, indicating NHPI participates in the whole reaction process
by a chain length value more than one (Table S4).
Scheme 4. Suggested mechanism for the side-chain chlorination of toluene.
Calculations were carried out at the B3LYP/6-31+G(d) level of theory (ΔG353K). Path
A and B are denoted by blue and red curves, respectively.
Conclusions
In summary, we herein report an environmentally benign protocol for the catalytic
chlorination of hydrocarbon CH bonds using NCS as a cheap and efficient chlorine
source. The present approach has the advantage of being safe, cheap, highly
selective/efficient, scalable, and broad substrate tolerance. Mechanistic studies
demonstrated that the process is favored from both kinetic and thermodynamic point of
views, wherein NHPI functions as a catalyst rather than an initiator. During the catalysis,
the hydrogen abstraction of CH bond was conducted by PINO species rather than the
highly reactive N-centered radical may rationalize the high chemoselectivity of

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3
monochlorination obtained by this protocol since hydrogen abstraction of C(sp )H in
monochlorides could occur in the presence of N-centered radical. As demonstrated by
Luca and coworkers in their study of -H-chlorinated alkylaromatic hydrocarbons with
2
2
TCCA by sunlight, a considerable amount of benzal chloride (dichlorination) (22%)
was obtained under optimized condition using the in-situ formed N-centered radical as
the H-abstraction reagent. The present results may hold promise for further
development of nitroxy-radical system in the aliphatic and benzylic hydrocarbon CH
highly selective functionalization.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial support from the National Natural Science Foundation of China (No.
2
1476240 and the Petrochemical Joint Fund U1662133) is gratefully acknowledged.
The GITDA (Govermental Information-Technology Development Agency, Hungary)
is gratefully acknowledged for allocating computing resources used in this work. BF
thanks the support from the EU, Hungary and the European Regional Development
Fund (GINOP-2.3.4-15-2016-00004 project).
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