Aerobic oxidation of secondary alcohols using NHPI and iron salt as catalysts at room temperature

Article abstract of DOI:10.1016/j.molcata.2014.06.007

Aerobic oxidation of various alcohols has been accomplished by using a novel catalytic system, N-hydroxyphthalimide (NHPI) combined with Fe(NO ₃)₃·9H₂O. Secondary alcohols, especially benzylic and aliphatic alcohols, were smoothly transformed into corresponding ketones with up to 92% yields at room temperature under one atmosphere pressure of oxygen. The influences of reaction conditions such as solvent, different metal catalyst, catalyst loading and the structure of alcohols on the promotion effect were studied. And a possible radical mechanism for the oxidation of secondary alcohols in Fe(NO₃)₃·9H ₂O/NHPI/O₂ system was proposed.

Full text of DOI:10.1016/j.molcata.2014.06.007

Journal of Molecular Catalysis A: Chemical 393 (2014) 62–67
Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Aerobic oxidation of secondary alcohols using NHPI and iron salt as
catalysts at room temperature
a
b
b,∗
a,∗
Hanqing Zhao , Wei Sun , Chengxia Miao , Quanyi Zhao
a
School of Pharmacy, Lanzhou University, Lanzhou 730000, People’s Republic of China
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000,
People’s Republic of China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Aerobic oxidation of various alcohols has been accomplished by using a novel catalytic system, N-
hydroxyphthalimide (NHPI) combined with Fe(NO3)3·9H2O. Secondary alcohols, especially benzylic and
aliphatic alcohols, were smoothly transformed into corresponding ketones with up to 92% yields at
room temperature under one atmosphere pressure of oxygen. The influences of reaction conditions
such as solvent, different metal catalyst, catalyst loading and the structure of alcohols on the promo-
tion effect were studied. And a possible radical mechanism for the oxidation of secondary alcohols in
Fe(NO3)3·9H2O/NHPI/O2 system was proposed.
Received 28 March 2014
Received in revised form 2 June 2014
Accepted 4 June 2014
Available online 13 June 2014
Keywords:
N-hydroxyphthalimide
Secondary alcohols
Aerobic oxidation
Iron salts
©
2014 Elsevier B.V. All rights reserved.
1
. Introduction
the absence of co-catalyst at room temperature, a co-catalyst is
required for this catalytic reaction. Iron has a number of advan-
tages over other transition metals for it’s relatively non-toxic, cheap
and environmentally friendly [27], and iron-based catalyst sys-
tems have been applied in a variety of organic transformations
[28–36], especially in some oxidation reactions using oxygen as
oxidant [37–39]. Therefore, we supposed iron salts have a poten-
tial as good co-catalysts in NHPI catalytic system and applied NHPI
and iron salts as the catalytic system to the oxidation of alcohols.
As we expected, a series of secondary aliphatic and aromatic alco-
hols were smoothly converted to corresponding ketones at room
temperature under an atmosphere pressure of oxygen (Scheme 1).
The selective oxidation of alcohols into their corresponding car-
bonyl compounds is a frequently used transformation in organic
synthesis [1–5], and most of the resulting carbonyl compounds are
important synthetic intermediates in chemicals and pharmaceut-
icals [6,7], hence many scientists tried their best to develop a wide
variety of methods for oxidation of alcohols. Traditional oxidants
mainly include permanganate [8], manganese (IV) oxide [9,10],
chromium (VI) oxide [11], and ruthenium reagents [12,13]. In gen-
eral, these oxidants are needed at least a stoichiometric amount
and usually bring about noxious byproducts. Therefore, oxygen as
clean oxidant for the selective oxidation of alcohols to carbonyl
compounds under mild conditions is more attractive since the main
by-product is water [14–16]. And NHPI is recognized as one of pow-
erful catalysts for aerobic oxidation of various organic compounds
2. Experimental
2.1. General remarks
[
17–22].
Up to now, very few catalytic systems have more advantages
All starting materials and catalysts were purchased from com-
than using NHPI for the oxidation of alcohols with O2 as termi-
nal oxidant [23–26], thus, either from the viewpoint of green or
sustainable chemistry, developing a highly efficient catalytic sys-
tem based on NHPI is very interesting and valuable. However,
because oxygen molecule cannot be activated directly by NHPI in
mercial suppliers and used without further purification. Column
chromatography was generally performed on silica gel (200–300
mesh) and TLC inspections were on silica gel GF254 plates.
GC–MS spectra were recorded on an Agilent Technologies 7890A
GC-system with an Agilent 5975 inert Mass Selective Detector (EI)
1
and a HP-5MS column (0.25 mm × 30 m, Film: 0.25 ␮m). H NMR
and 13C NMR spectra were recorded on a Bruker spectrometer
400 MHz using CDCl3 as the solvent with TMS as an internal ref-
erence.
∗ Corresponding authors. Tel.: +86 931 8915686; fax: +86 931 8915686.
E-mail addresses: chxmiao@licp.cas.cn (C. Miao), zhaoqy@lzu.edu.cn (Q. Zhao).
http://dx.doi.org/10.1016/j.molcata.2014.06.007
1
381-1169/© 2014 Elsevier B.V. All rights reserved.

H. Zhao et al. / Journal of Molecular Catalysis A: Chemical 393 (2014) 62–67
63
Scheme 1. Oxidation of secondary alcohols into corresponding ketones at room temperature in the presence of Fe(NO3)3·9H2O and NHPI under an atmosphere pressure of
oxygen.
2.2. General procedure of oxidation of secondary alcohols
oxidation of ␣-phenylethanol (Table 1, entries 9–11). Obtaining
9% of acetophenone under dinitrogen atmosphere may ascribe
1
Substrate (1 mmol) and the desired amounts of Fe(NO ) ·9H O
to the oxidation of Fe(NO ) ·9H O [40]. The results suggested
3
3
2
3
3
2
and NHPI were added to 1.5 mL of acetonitrile in a 15 mL test tube.
that the anions of iron salts had a great effect on the oxidation of
␣-phenylethanol. That’s to say, nitrate ion may play an important
role in the oxidation. Subsequently, a series of nitrates were
investigated to test whether the metal cation also had certain
effect for the reaction (Table 1, entries 12–19). The results showed
Cu(NO ) ·3H O and Zr(NO ) ·5H O could give 39% and 55% yields
The solution was maintained for 20 h under an atmospheric pres-
◦
sure of O and at 25 C. After the reaction was quenched by Na S O
2
2
2
3
solution, 60 mg of nitrobenzene, serving as an internal standard,
was added to the reaction system. The solution was centrifuged
and the supernatant was diluted with diethyl ether and dried with
anhydrous Na SO for 30 min. The products were analyzed by GC,
3
2
2
3
4
2
respectively (Table 1, entries 13 and 14). As for Co(NO ) ·6H O,
2
4
3
2
2
and further confirmed by GC–MS. The isolated yield was obtained
through column chromatography generally performed on silica gel
200–300 mesh).
only 6% yield was provided (Table 1, entry 12), and for other
nitrates, no products were detected (Table 1, entries 15–19). The
results indicated that metal cation also has some influence on
the reaction. Among tested metal salts, Fe(NO ) ·9H O exhibited
(
3
3
2
best activity. Maybe, this good performance is attributed to the
synergistic effect between iron cation and nitrate anion.
3
. Results and discussion
3.1. Influence of metal salts
3.2. Influence of different solvent
The exploratory experiments were started by testing this
The effect of the solvents on the oxidation of alcohols was also
protocol and screening the metal salts using ␣-phenylethanol
as the model substrate in the presence of NHPI (10 mol%) under
the identical conditions (Table 1). Initially, a variety of iron
salts were used and their reaction activities were evaluated.
We found only Fe(NO ) ·9H O as co-catalyst could obtain high
evaluated (Table 2). It is clear that the solvent has an important
effect on the reaction. Under the same condition, the conversion
of ␣-phenylethanol to acetophenone was achieved in higher yield
in acetonitrile compared to other solvents such as DMSO, THF,
dichloroethane, and toluene and so on (Table 2, entry 1 vs entries
3
3
2
conversion and selectivity (Table 1, entry 8), other iron salts were
almost inert for the reaction (Table 1, entries 1–7); moreover,
Fe(NO ) ·9H O, NHPI and oxygen were essential to the aerobic
2
–7).
3
3
2
3
.3. Influence of the amount of Fe(NO ) ·9H O and NHPI
3
3
2
Table 1
Screening of metal salt as catalyst for the oxidation of ␣-phenylethanol.
Subsequently, the influence of the amount of Fe(NO ) ·9H O
3
3
2
a
and NHPI on the oxidation was examined under the identical reac-
tion conditions, as listed in Table 3. The yield of acetophenone was
14% in the presence of 0.5 mol% Fe(NO3)3·9H2O and 5 mol% NHPI
(Table 3, entry 5). And the yield increased to 75% when the amount
of Fe(NO ) ·9H O reached to 5 mol% (Table 3, entries 2–4), but
Entry
Metal salt
Conv. (%)b
Yield (%)b
NRc
1
2
3
4
5
6
7
8
K4[Fe(CN)6]·3H2O
K3[Fe(CN)6]
Fe2(SO4)3·XH2O
FeCl2·4H2O
–
–
–
–
–
–
8
83
–
19
–
6
39
55
–
c
NR
c
NR
3
3
2
c
NR
there was almost no change by further increasing Fe(NO ) ·9H O
3
3
2
c
FeCl2
NR
to 8 mol% (Table 3, entry 1). Therefore, 5 mol% of Fe(NO ) ·9H O
3
3
2
FeCl3
Fe(OTf)2
6
9
is a desired catalyst loading. Based on that, the desired loading
amount of the NHPI was investigated also (Table 3, entries 6–10).
Fe(NO3)3·9H2O
84
NR
c
9
–
d
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Co(NO3)2·6H2O
Cu(NO3)2·3H2O
Zr(NO3)4·5H2O
Mg(NO3)2·6H2O
Ni(NO3)2·6H2O
Zn(NO3)2·6H2O
Al(NO3)3·9H2O
In(NO3)3·5H2O
20
NR
e
c
Table 2
Solvent optimization.
a
6
39
56
NR
NR
NR
Entry
Solvent
Conv. (%)b
Yield (%)b
c
1
2
3
4
5
6
7
Acetonitrile
CH2Cl2
ClCH2CH2Cl
THF
DMSO
H2O
84
38
7
13
NR
83
38
7
13
–
c
–
–
c
Trace
Trace
Trace
Trace
c
c
NR
NR
–
–
a
␣
-Phenylethanol (1 mmol), metal salt (5 mol%), NHPI (10 mol%), acetonitrile
c
Toluene
(
1.5 mL), O2 (1 atm), room temperature, 20 h.
b
a
Determined by GC using nitrobenzene as an internal standard.
NR = No reaction.
Under dinitrogen atmosphere.
␣-Phenylethanol (1 mmol), Fe(NO3)3·9H2O (5 mol%), NHPI (10 mol%), solvent
c
(1.5 mL), O2 (1 atm), room temperature, 20 h.
d
b
Determined by GC using nitrobenzene as an internal standard.
NR = No reaction.
e
c
Without NHPI.

6
4
H. Zhao et al. / Journal of Molecular Catalysis A: Chemical 393 (2014) 62–67
Table 3
tabulated in Tables 4 and 5. Obviously, all secondary benzylic alco-
hols were converted into corresponding ketones in moderate to
high yields, and aliphatic secondary alcohols gave moderate yields;
as for decan-4-ol, only 17% yield was obtained (Tables 4 and 5). The
different rates probably have some relationships with the inductive
effects and steric effects of the substituents. But for an identical
substituent at different site on the benzene rings, the substituent
group on benzene ring is more away from the alcohol hydroxyl, the
yield is higher (Table 4, entries 2 and 3, 4 and 5, 6 and 7, 8 and 9).
The hydroxyl of aliphatic secondary alcohols is closer terminal of
the carbon chain, they are oxidized easier (Table 5, entries 1 and 2).
As for the reaction mechanism, it was recognized that PINO
radical generated in situ plays an important role in NHPI partic-
ipant system [41]. In order to prove this point, the reaction was
carried out with ␣-phenylethanol as the substrate under opti-
mized reaction conditions. 1,1-Diphenylethylene, which acts as a
radical scavenger [42], was added to the reaction system. When
The influence of the amount of Fe(NO3)3·9H2O and NHPI on the oxidation of ␣-
phenylethanol.a
Entry
Fe(NO3)3·9H2O (mol%)
NHPI (mol%)
Conv. (%)b
Yield (%)b
1
2
3
4
5
6
7
8
9
8
5
2
1
0.5
5
5
5
5
5
5
5
5
5
12
10
5
2
1
77
76
53
27
14
89
84
76
64
48
76
75
53
27
14
86
83
75
63
48
1
0
5
a
␣
-Phenylethanol (1 mmol), O2 (1 atm), acetonitrile (1.5 mL), room temperature,
2
0 h.
b
Determined by GC using nitrobenzene as an internal standard.
1
0 mol% of 1,1-diphenylethylene was used, the yield of the reaction
Good performance was shown with 10 mol% of NHPI (Table 3, entry
decreased from 84% to 47%. And it was shown that the reaction was
inhibited completely by adding 50 mol% of 1,1-diphenylethylene
7
).
(Scheme 2). The phenomena indicated that the mechanism of the
reaction should proceed by a free-radical pathway and PINO radical
is still a key intermediate.
3
.4. Aerobic oxidation of various secondary alcohols catalyzed by
Fe(NO ) ·9H O and NHPI
3
3
2
At present, it is not easy to show how Fe(NO ) ·9H O works
3
3
2
in the process of generation of PINO radical. However, according
to the above results, we speculate that there is a synergistic effect
In order to survey the scope of the substrates, we applied
the present catalyst system to a variety of secondary alcohols as
Table 4
a
Oxidation of secondary benzylic alcohols.
Entry
Substrate
Product
Yield (%)b
1
92c
2
3
77
44
4
45
5
6
59
71

H. Zhao et al. / Journal of Molecular Catalysis A: Chemical 393 (2014) 62–67
65
Table 4 (Continued)
Entry
Substrate
Product
Yield (%)b
7
8
90
92
83
9
1
1
0
1
57
90c
a
b
c
Alcohol (1 mmol), NHPI (10 mol%), Fe(NO3)3·9H2O (5 mol%), acetonitrile (1.5 mL), O2 (1 atm), at room temperature, 48 h.
Isolated yield.
Determined by GC using nitrobenzene as an internal standard.
between iron cation and nitrate anion. In addition, we considered
Based on the previous reports and our aforementioned results,
we propose a possible mechanism delineated in Scheme 3. Ini-
tially, PINO radical is generated from NHPI in the presence of
Fe(NO ) ·9H O and O , then the PINO radical abstracts the hydro-
3
+
2+
that the Fe can be converted into Fe in the process of reaction.
In order to confirm metal chemical state, K [Fe(CN) ] solution was
3
6
added to the reaction system after the reaction lasts for ten hours.
The solution turned to Prussian blue from brownish yellow, which
indicates the generation of Fe2+ during the reaction [43].
3
3
2
2
gen atom from ␣-phenylethanol to produce ␣-hydroxy carbon
radical and regenerate NHPI. And then ␣-hydroxy carbon radical
Table 5
Oxidation of secondary aliphatic alcohols.a
Entry
1
Substrate
Product
Conv. (%)b
95
Yield (%)b
74
2
3
22
90
17
64
4
90
97
60
78
5
a
Alcohol (1 mmol), NHPI (10 mol%), Fe(NO3)3·9H2O (5 mol%), O2 (1 atm), acetonitrile (1.5 mL), at room temperature, 48 h.
b
Determined by GC using nitrobenzene as an internal standard.

6
6
H. Zhao et al. / Journal of Molecular Catalysis A: Chemical 393 (2014) 62–67
Scheme 2. The effect of 1,1-diphenylethylene on generation of acetophenone.
Scheme 3. Proposed mechanism of ␣-phenylethanol oxidation catalyzed by NHPI/Fe(NO3)3·9H2O with O2.
is transformed into a peroxy radical by O . Finally, it is converted
Appendix A. Supplementary data
2
into acetophenone and H O2 through the formation of ␣-hydroxy
2
hydroperoxide [23,44]. Besides, hydrogen peroxide could also oxi-
dize the alcohols to carbonyl compounds under the help of NHPI
and Fe(NO ) ·9H O [45].
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.molcata.
2014.06.007.
3
3
2
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. Conclusions
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