Selective Aerobic Oxidation of Secondary C (sp3)-H Bonds with NHPI/CAN Catalytic System

Article abstract of DOI:10.1007/s10562-020-03406-6

Abstract: The direct aerobic oxidation of secondarty C(sp³)-H bonds was achieved in the presence of N-hydroxyphthalimide (NHPI) and cerium ammonium nitrate (CAN) under mild conditions. Various benzylic methylenes could be oxidized to carbonyl compounds in satisfied selectivity while saturated cyclic alkanes could be further oxidized to the corresponding lactones with the catalytic system. Remarkably, 25% of isochroman was converted to corresponding ketone with a selectivity of 96%. The reaction was initiated by hydrogen atom abstraction from NHPI by cerium and nitrates under oxygen atmosphere to form PINO radicals. 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) addition experiments showed that the oxidation proceeded via a complex radical chain mechanism and an ion pathway. Graphic Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-020-03406-6

Catalysis Letters
https://doi.org/10.1007/s10562-020-03406-6
3
Selective Aerobic Oxidation of Secondary C (sp )‑H Bonds with NHPI/
CAN Catalytic System
1
1
1
1
1
1,2
Lingyao Wang · Yuanbin Zhang · Haoran Yuan · Renfeng Du · Jia Yao · Haoran Li
Received: 2 July 2020 / Accepted: 24 September 2020
©
Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
3
The direct aerobic oxidation of secondarty C(sp )-H bonds was achieved in the presence of N-hydroxyphthalimide (NHPI)
and cerium ammonium nitrate (CAN) under mild conditions. Various benzylic methylenes could be oxidized to carbonyl
compounds in satisꢀed selectivity while saturated cyclic alkanes could be further oxidized to the corresponding lactones with
the catalytic system. Remarkably, 25% of isochroman was converted to corresponding ketone with a selectivity of 96%. The
reaction was initiated by hydrogen atom abstraction from NHPI by cerium and nitrates under oxygen atmosphere to form
PINO radicals. 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) addition experiments showed that the oxidation proceeded
via a complex radical chain mechanism and an ion pathway.
Graphic Abstract
H OH
O
+
R
1
R
2
R
1
R
2
H H
NHPI / CAN
45 °C
O
2
R
1
R
2
O
Alkyl
Alkyl
O
3
Keywords C (sp )–H bonds · Aerobic oxidation · N-hydroxyphthalimide · Cerium ammonium nitrate · Radical
1
Introduction
pressures is still a long lasting challenge as O is a relatively
2
3
mild oxidant. The cleavage of inert sp C–H bonds gener-
Oxidation reactions are key technologies for transformation
of hydrocarbons from petroleum feedstock into chemicals
ally demand harsh conditions [6–8]. To overcome the high
activation barriers, various catalysts have been applied to
activate oxygen for C–H bond oxidation [9–14].
of higher value [1–5]. Currently, molecular oxygen (O )
2
has been demonstrated as an economical and green oxidant
N-Hydroxyphthalimide (NHPI) is an eꢁective organo-
catalyst for activation of C–H bonds via acting as a precursor
of the phthalimide-N-oxyl radical (PINO) and is well known
as a catalyst in aerobic oxidation of organic compounds
that outperforms other traditional oxidants such as HNO ,
3
H SO , MnO and CrO . However, the selective aerobic oxi-
2
4
2
3
3
dation of sp C–H bonds at low temperatures and normal
[
15–17]. The PINO radicals can be generated in the presence
of transition metal salts, azo compounds, peroxides, alde-
*
Haoran Li
lihr@zju.edu.cn
hydes, enzymes and other additives [18–24]. A Co(OAc)
2
and NHPI catalytic system was used for the oxidation of
organic compounds such as alkylbenzenes and cyclohexane
by Ishii et al. [25]. After that, NHPI and aldehyde catalytic
systems were developed for the oxidation of alkanes [26,
1
Department of Chemistry, ZJU-NHU United R&D
Center, Zhejiang University, Hangzhou 310027,
People’s Republic of China
2
State Key Laboratory of Chemical Engineering, Department
of Chemical and Biological Engineering, Zhejiang
2
7]. The catalytic system of NHPI/Fe(NO ) was adopted
3 3
University, Hangzhou 310027, People’s Republic of China
Vol.:(0
1
123456789)
3

L. Wang et al.
for the oxidation of ethylbenzene at ambient temperature by
Sun et al. [28].
cyclopentanone (99%) were purchased from Energy Chemical
without further puriꢀcation unless indicated.
Ceric ammonium nitrate (CAN) is commonly used as a
strong one-electron oxidizer for the generation of radicals
2.2 General Methods
[
29]. The CAN/NaBrO catalytic system was employed in
3
the transformation of the secondary alcohols to ketones
by Oshima et al. [30]. Afterwards, Kim et al. reported the
study of catalytic oxidation of alcohols by CAN/TEMPO
and CAN/NHPI [31, 32]. In our previous work, we reported
the formation of ε-caprolactone by catalytic oxidation of KA
oil with NHPI/CAN in HFIP solvent via in-situ generation of
hydrogen peroxide [33]. The CAN catalytic system is mainly
used for the oxidation of alcohol compounds. Herein, we
would like to report a facile method for selective and direct
The progress of the reaction was monitored by taking sam-
ples at various intervals to be analyzed using gas chromatog-
raphy (GC) (Agilent 7820A) equipped with a DB-35/ZB-35/
HP-35 column (30 m × 0.32 mm × 0.25 mm) and a Flame
Ionization Detector (FID). The conversion was calculated on
the basis of the peak area ratio of ketones against the internal
standard, biphenyl. The product yields were calculated on
the basis of the peak area ratio of lactones or esters against
the internal standard. The structural analysis of target prod-
uct was conducted on a Gas chromatography/ Mass spec-
trometry (GC/MS) (Agilent 7200-Q-TOF). EPR spectra were
obtained by using a computer controlled X-band (9.5 GHz)
EPR spectrometer (Bruker A300).
3
oxidation of secondary C(sp )-H bonds mediated by NHPI/
CAN with O as the oxidant. (Scheme 1).
2
2
Experimental Section
2.3 General Procedure for Cyclohexane Oxidation
2.1 Materials
In a typical reaction, cyclohexane (2 mmol), CAN
(20 mol%), NHPI (20 mol%) and 1,2-dichloroethane
(20 mL) were placed into a three-necked round bottom ꢂask
(50 mL) equipped with an oxygen balloon and a magnetic
stir bar. The mixture was stirred at 40 °C for 24 h. The reac-
tion was monitored by a GC instrument. The conversion was
calculated on the basis of the peak area ratio of cyclohex-
ane against the internal standard, biphenyl. The product
yields were calculated on the basis of the peak area ratio of
cyclohexanol, cyclohexanone, and ε-caprolactone against the
internal standard.
Cyclohexane (>99.0%), cyclohexanone (>99.0%), cyclohex-
anol (>99.0%), adamantane (99.5%), 1-adamantanol (98%),
2-adamantanol (98%), 2-adamantanone (99%), cyclopentane
(
99%), tertbutylacetate (>99.0%) and were purchased from
TCI without further puriꢀcation unless indicated. 2,2,6,6-tetra-
methyl-1-piperidinyloxy (TEMPO) (98%), N-hydroxyphthal-
imide (NHPI) (98%), biphenyl (99.5%), ethylbenzene (99%),
indane (99%), isobutylbenzene (99%), isochroman (99%) and
ε-caprolactone (99.5%) were purchased from J & K Scientiꢀc
Ltd. without further puriꢀcation unless indicated. Acetoni-
trile, toluene and ethyl acetate were analytical grade and pur-
chased from J & K Scientiꢀc Ltd. 1, 2-Dichloroethane (DCE)
2.4 In‑Situ IR Spectroscopic Experiments
(
99.5%), cyclopentanol (99%), delta-valerolactone (98%),
heptanal (98%), ceric ammonium nitrate (CAN) (98%) and
To a 500 mL glass ꢂask ꢀtted with a magnetic stir bar, an
air inlet pipe, a water-cooled reꢂux condenser was added
8
.42 g (0.1 mol) of cyclohexane and 200 mL of 1,2-dichlo-
Previous work (Kim)
roethane (DCE). The mixture was stirring at 300 rpm while
the temperature was held at 40 °C and air was fed at a rate
of 20 mL/min for 30 min. To the mixture was then added
TEMPO/CAN
OH
O
3
.26 g (0.02 mol) of NHPI and 10.97 g (0.02 mol) of CAN.
R
1
R
2
NHPI/CAN
R
1
R
2
Oxygen uptake proceeded smoothly. The reaction lasted for
7
h. The reaction mixture was analyzed by an in-situ IR
OH
O
This work
instrument (ReactIR 10 with MCT detector). The spectra
were shown in Fig. 1.
+
R
1
R
2
R
1
R
2
H
H
NHPI/CAN
O2
O
R
1
R
2
3
Results and Discussion
Alkyl
Alkyl
O
Initially, the reaction was performed with 10 mol% of
NHPI and 10 mol% of CAN in 1,2-dichloroethane (DCE)
at 45 °C. The cyclohexane conversion was 4.2% with a
Scheme 1 NHPI/CAN mediated aerobic oxidation of secondary oxi-
3
dation of C(sp )–H bonds
1
3

3
Selective Aerobic Oxidation of Secondary C (sp )-H Bonds with NHPI/CAN Catalytic System
of cyclohexane increased to 7.3%, and the selectivity of
KA oil and ε-caprolactone was 86.3% and 8.2%, respec-
tively (entry 3). When the amounts of NHPI and CAN both
increased to 20 mol%, the conversion of cyclohexane was
further increased to 9.3% with selectivity of 79.4% KA oil
and 9.6% ε-CL (entry 4). Varying the temperature to 50 °C
or 40 °C resulted in the loss of yields (entries 5, 6). The
eꢁect of solvents was also studied. Using CCl as the sol-
4
vent provided increased composition of ε-CL but the conver-
sion of cyclohexane was decreased. MeCN is also a proper
solvent for the oxidation of cyclohexane with the KA oil
selectivity of 89% but no production of ε-CL. Other sol-
vents such as ethyl acetate and acetic acid brought about
lower conversion and the major product was cyclohexanone.
(entries 7–10). These results indicated that halogenated sol-
vents beneꢀt the generation of ε-CL, which was consistent
with the previous ꢀndings [22, 27]. Therefore, in the NHPI/
CAN catalytic system, DCE was the optimal solvent with the
best conversion and for the production of ε-CL with higher
value, while acetonitrile was useful for selective oxidation
of cyclohexane to KA oil (entries 4, 8). The cyclohexane
Fig. 1 The in-situ IR spectra recorded during the oxidation reaction
of cyclohexane
9
0.8% selectivity of KA oil (cyclohexanone+cyclohexanol)
(
Table 1, entry 1). As the amount of catalyst increased, the
conversion of cyclohexane increased, together with a small
amount of ε-caprolactone (ε-CL) produced. Increasing the
NHPI amount to 20 mol%, the conversion of cyclohexane
increased to 4.6% with selectivities of 73.0% KA oil and
7
.7% ε-CL (entry 2). With 20 mol% of CAN, the conversion
Table 1 Oxidation of cyclohexane under diꢁerent conditions
OH
O
O
NHPI/CAN
O 1 atm
O
+
+
2
Select. (%)a
CHOL
Entry
NHPI/CAN (mol%)
Solvent
Conv. (%)a
CHONE
ε-CL
1
2
3
4
10/10
20/10
10/20
20/20
20/20
20/20
20/20
20/20
20/20
20/20
20/20
20/20
20/0
DCE
DCE
DCE
DCE
DCE
DCE
CCl4
MeCN
EtOAc
AcOH
DCE
DCE
DCE
DCE
DCE
4.2
4.6
7.3
9.3
7.2
8.1
6.0
9.1
3.1
7.4
8.0
1.7
Trace
Trace
0
14.7
13.6
10.7
9.1
12.9
9.1
18.9
3.6
0
76.1
59.4
75.6
70.3
65.0
72.0
28.5
85.4
83.5
83.3
72.1
81.7
0
0
7.7
8.2
9.6
3.1
8.8
31.9
0
4.3
1.8
6.9
4.1
0
b
5
6
c
7
8
9
10
11
12
13
14
15
0
d
e
6.8
2.8
0
0
0
0/20
0/0
0
0
0
0
Reactions were conducted on a 2.0 mmol scale in 20 mL of solvent in a round bottom ꢂask with an O ballon for 24 h at 45 °C
2
a
GC
b
5
0 °C
c
d
e
4
0 °C
Air instead of O2
N instead of O2
2
1
3

L. Wang et al.
conversion reduced to 8% and 1.7% under air and nitrogen
Table 3 NHPI/CAN-Promoted aerobic oxidation of various substrates
conditions respectively (entries 11, 12), indicating that O
2
Entry Substrate Conv. (%)a
Product (Selec.,%)a
is the main oxidant while the small amount of CAN could
also serve as oxygen source. Control experiments indicated
that no oxidation product was formed in the absence of
NHPI or CAN (entries 13–15), suggesting that both NHPI
and CAN were necessary for the reaction. Other metal
nitrates were also tested to compare the catalytic reactiv-
ity with CAN (Table 2). Ce(NO ) ·6H O, Fe(NO ) ·9H O,
OH
O
O
1
9
O
(
9)
(70)
(10)
O
2
3
8
OH
O
O
(14)
3
3
2
3 3
2
(22)
(42)
OH
Co(NO ) ·6H O and Cu(NO ) ·3H O can also promote the
3
3
2
3 2
2
OH
reaction but with less catalytic reactivity (Table 2, entries
O
O
O
1
–6). Using the metal-free ammonium nitrate, the oxidation
15
reaction hardly occurred.
(
56)
(3)
(11)
(4)
O
The reaction conditions from entry 4, Table 1 was cho-
sen for testing the universality of this catalytic system. The
results were tabularized in Table 3. All saturated naphthenes
were able to transform into lactones while the major oxida-
tive products were the corresponding ketones. The results
of adamantine oxidation indicated that the C–H bond has
a reactivity order of tertiary > secondary (entries 1–3).
Arylated alkane such as ethylbenzene and indane only
converted to ketones and alcohols with a moderate yield
OH
4
5
29
33
(11)
(71)
(80)
OH
O
(4)
O
(
entries 4, 5). Isobutylbenzene and isochroman only selec-
6
7
18
25
(89)
tively transformed their CH units to C=O with selectivities
2
of 89% and 96%, respectively (entries 6, 7).
O
To investigate the changes of chemical bonds in the real-
time reaction system, the cyclohexane oxidation reaction
was monitored by in-situ infrared (IR) spectroscopy (Fig. 1).
After reaction for 0.5 h, there were no distinct visible signals
that belong to cyclohexanol or cyclohexanone, indicating the
C–H bond oxidation was very slow at the beginning. This
was consistent with our precious results that the oxidation
reaction using NHPI as the catalyst needs an initial period
to generate enough PINO radicals. After reaction for 1 h,
O
O
(96)
Reactions were conducted on a 2.0 mmol scale in 20 ml of solvent in
a round bottom ꢂask with an O ballon for 24 h at 45 °C
2
a
GC
indicating the generation of ε-CL. This result conꢀrmed that
the NHPI/CAN catalytic system could promote the oxidation
of cyclohexane to form KA oil and ε-CL.
−
1
two new signals at 1133 and 1706 cm appeared, which
can be assigned to the stretching vibration peaks of C–O
and C=O from cyclohexanol and cyclohexanone. Moreover,
a small C(O)=O signal at~ 1785 cm− was also detected,
To understand whether NHPI/CAN catalyzed the oxi-
dation of cyclohexane in a free radical pathway, several
experiments were carried out in which diꢁerent amounts
of TEMPO were added to the reaction system. The experi-
mental results were shown in Fig. 2. As can be seen, when
20 mol% of TEMPO was added to the reaction system,
both of the cyclohexane conversion and the selectivity of
ε-caprolactone decreased. This might be because NHPI and
TEMPO radical inhibit each other, and thus reducing the
catalytic activity. With the amount of TEMPO increasing
from 20 to 200 mol%, the conversion of cyclohexane gradu-
ally increased, while the selectivities of cyclohexanone and
ε-caprolactone decreased till to zero (entries 3–5). These
suggested that TEMPO/CAN catalytic system may promote
the oxidation of cyclohexane, but the presence of TEMPO is
not favored for the formation of ε-CL. The cascade oxidation
proceeded under both radical and ion pathways.
1
Table 2 Oxidation of cyclohexane with diꢁerent nitrates
Entry Nitrates
Conv. (%)a Select. (%)a
CHOL CHONE ε-CL
1
2
3
4
5
6
Ce(NH ) (NO )
3 6
9.3
1.2
3.8
9.1
10.6
15.6
11.3
9.5
70.3
72.5
68.1
66.6
74.8
0
9.6
0
0
0
0
4
2
Ce(NO ) ⋅6H O
3
3
2
Fe(NO ) ⋅9H O
3
3
2
Co(NO ) ⋅6H O 2.0
3
2
2
Cu(NO ) ⋅3H O 2.0
3
2
2
Trace
0
0
4
NH NO3
Reactions were conducted on a 2.0 mmol scale in 20 mL of solvent in
a round bottom ꢂask with an O ballon for 24 h at 45 °C
2
a
GC
1
3

3
Selective Aerobic Oxidation of Secondary C (sp )-H Bonds with NHPI/CAN Catalytic System
O
H
Ce3+
N OH
R1
R2
O
NHPI
O2
O
N O
Ce4+
CAN)
R1
R2
(
O
PINO
O2
PINO
NHPI
O
OH
R2
O
OH
O
R1
R2
R1
R2
R1
Fig. 2 The inꢂuence of TEMPO for the catalytic oxidations
O
O
[O]
The reaction mechanism using NHPI/CAN as a catalyst
system for the aerobic oxidation of cyclohexane could be
very complicated, for there were multiple reaction steps in
the catalytic system. In accordance with our experiments
and previous reports, a possible mechanism was proposed as
R1
R2
R1
OR2
Fig. 3 Proposed reaction pathway
4+
3+
shown in Fig. 3. Ce could be transformed into Ce during
the conversion of NHPI to PINO free radicals. The reaction
was initiated by hydrogen atom abstraction from NHPI by
cerium and nitrates under oxygen atmosphere to form PINO
radicals. Then PINO abstracted the hydrogen from alkanes
to form corresponding alkane radicals, which were reactive
mechanism using NHPI/CAN as a catalyst system for the
aerobic oxidation of cyclohexane could be very compli-
cated, for there were multiple reaction steps and oxy-
gen source in the catalytic system. In general, our work
provides a facile strategy for the eꢃcient activation of
cyclohexane C–H bonds to access products with diꢁerent
oxidation degree by rational choice of the reaction sol-
vents. Further work will be focused on the investigation
of the reaction mechanism through more characterization
techniques and modeling studies.
to produce peroxyl radical intermediates (II) by O insertion.
2
The radicals (II) abstracted hydrogen from NHPI to form
alkyl hydroperoxide (III) and PINO. Alkyl hydroperoxide
could be converted to form alcohol or ketone. The ketone
could be further oxidized to the corresponding ester. On the
other hand, nitrate was also able to serve additional oxidant
source to oxidize alkanes, but this pathway may be diꢃcult
to illustrate and more work need to be done to explore more
evidence.
Acknowledgements This work was supported by the National Natu-
ral Science Foundation of China (No. 21573196), the Fundamental
Research Funds of the Central Universities, and the National High
Technology Research and Development Program (863 Program) of
China (Grant No. SS2015AA020601). L. Wang gratefully acknowl-
edge the ꢀnancial support for this research by the Zhejiang Province
Postdoctoral Science Foundation (No. ZJ2020159).
4
Conclusion
Author Contributions LW: Conceptualization, Methodology, Investi-
gation, Formal analysis, Data curation, Writing-Original Draft. YZ:
Validation, Formal analysis, Data curation, Writing-Reviewing & Edit-
ing. HY: Writing-Reviewing & Editing. RD: Writing-Reviewing &
Editing. JY: Writing-Reviewing & Editing, Supervision. HL: Writing-
Reviewing & Editing, Supervision.
In conclusion, we have developed a catalytic system of
NHPI and CAN for the aerobic oxidation of secondary
3
C(sp )-H bonds under mild conditions. Various benzylic
methylenes could be oxidized to corresponding carbonyl
compounds in satisꢀed selectivity and saturated cyclic
alkanes could be further oxidized to the correspond-
ing lactones in this catalytic system. Experiments have
shown that in addition to oxygen, nitrate in CAN could
also participate as additional oxygen source. The reaction
Compliance with Ethical Standards
Conflict of interest The authors declare that they have no conꢂict of
interest.
1
3

L. Wang et al.
1
1
7. Hruszkewycz DP, Miles KC, Thiel OR, Stahl SS (2017) Co/
NHPI-Mediated aerobic oxygenation of benzylic C-H bonds in
pharmaceutically relevant molecules. Chem Sci 8:1282–1287.
https://doi.org/10.1039/C6SC03831J
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