4-OH-TEMPO/TCQ/TBN/HCl: A Metal-Free Catalytic System for Aerobic Oxidation of Alcohols under Mild Conditions

Article abstract of DOI:10.1002/cjoc.201500357

A green and economical catalyst system, 4-OH-TEMPO/TCQ/TBN/HCl, for the aerobic oxidation of a broad range of primary and secondary alcohols to the corresponding carbonyl compounds has been developed. These reactions proceed without transition-metals under mild conditions with excellent yields. A green and economical catalyst system, 4-OH-TEMPO/TCQ/TBN/HCl, for the aerobic oxidation of a broad range of primary and secondary alcohols to the corresponding carbonyl compounds has been developed. These reactions proceed without transition-metals under mild conditions with excellent yields.

Full text of DOI:10.1002/cjoc.201500357

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DOI: 10.1002/cjoc.201500357
4-OH-TEMPO/TCQ/TBN/HCl: A Metal-Free Catalytic System
for Aerobic Oxidation of Alcohols under Mild Conditions
Yanli Dong, Xiaomei Zhao, and Renhua Liu*
School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
A green and economical catalyst system, 4-OH-TEMPO/TCQ/TBN/HCl, for the aerobic oxidation of a broad
range of primary and secondary alcohols to the corresponding carbonyl compounds has been developed. These re-
actions proceed without transition-metals under mild conditions with excellent yields.
Keywords oxidation of alcohols, transition-metal-free, green and economical
Introduction
tives. In 2012, Hu used catalytic amounts of TBN, DDQ
(2,3-dichloro-5,6-dicyano-1,4-benzoquinone), TEMPO,
and TFA, as well as O2 as the terminal oxidant to oxi-
dize alcohols to their corresponding carbonyl com-
pounds.[14] Although it is effective, this TEMPO/TBN/
DDQ/TFA catalyst for aerobic alcohol oxidation has two
drawbacks, namely: (i) the need for an oxygen partial
pressure of 0.2 MPa, which entails the use of an auto-
clave; (ii) the use of expensive TEMPO (836 RMB/kg)
and DDQ (10 000 RMB/kg). We wished to expand this
transition-metal-free alcohol oxidation system, and have
a clear incentive to develop a cheaper, more efficient
protocol that the reaction can proceed under ambient
conditions. Specifically, we hope to seek and find
cheaper and more efficient alternatives of TEMPO and
DDQ, and enable the reaction to proceed at ambient
temperature and oxygen partial pressure, thereby dis-
pensing with the need for autoclaves and minimizing the
risk of explosions on a preparative scale in industrial
organic synthesis.
The oxidation of alcohols to the corresponding car-
bonyl compounds is an important class of reactions in
chemical synthesis.[1] Recently, interest in developing
efficient catalysts for aerobic alcohol oxidation has been
burgeoning.[2] During the past several decades, 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) and its de-
rivatives have been widely used as versatile catalysts for
the aerobic oxidation of alcohols to the corresponding
carbonyl compounds due to their high efficacy and
selectivity.[3] Among them, there is increasing interest in
developing transition-metal-free TEMPO-based catalyst
systems for aerobic alcohol oxidations. A literature sur-
vey showed since Liang and coworkers reported a tran-
sition-metal-free, aerobic alcohol oxidation protocol
(TEMPO/Br2/NaNO2) in 2004,[4] more and more effi-
cient metal-free TEMPO-based catalysts for aerobic
alcohol oxidation were reported, including TEMPO/
TBN/HBr (TBN: tert-Butyl nitrite),[5] TEMPO/HCl/
NaNO2,[6] TEMPO/KNO2,[7] TEMPO/NH2OH,[8] and
TEMPO/HCl/PEG-NO2,[9] AcNHTEMPO/HNO3/HCl,[10]
TEMPO/NaBr-NaBrO3/H2SO4,[11] oxidative systems.
Especially, Iwabuchi et al. reported a highly efficient
organocatalytic aerobic oxidation protocol composed of
5-fluoro-2-azaadamantane N-oxyl (5-F-AZADO) and
NaNO2.[12] It was proved that, 1-methyl-AZADO,[13a,13b]
9-azanoradamantane N-oxyl (Nor-AZADO)[13c] and
9-azabicyclo[3.3.1]-nonane N-oxyl (ABNO)[13d] can
also enhance the efficiency significantly.[13]
Results and Discussion
Upon closer investigation of TEMPO/DDQ/TBN/
TFA catalyst system for the alcohol oxidation, we found
that the requirement of high oxygen partial pressure and
elevated reaction temperature is necessary, because
TEMPO was not active enough to perform the reaction
under ambient oxygen partial pressure. We have recent-
ly evaluated a variety of 4-substituted TEMPO deriva-
tives for their ability in the aerobic alcohol oxidation,[3f]
and found that 4-OH-TEMPO (51 RMB/kg) was a
prominent member in terms of both lower prices and
high catalytic activity. Thus we explored the possibility
of aerobic alcohol oxidation with 4-OH-TEMPO in
place of TEMPO, inexpensive TCQ (tetrachlorobenzo-
This is true especially for laboratory scale operations
and fine chemicals manufactures, where the credible,
operationally convenient and economical, as well as
condition mild oxidation methods are particularly of
importance. As such, one key criterion is the use of
minimum quantities or total nonuse of auxiliary addi-
*
E-mail: liurh@ecust.edu.cn
Received May 6, 2015; accepted July 3, 2015; published online August 12, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500357 or from the author.
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Dong, Zhao & Liu
COMMUNICATION
quinone, 810 RMB/kg) in place of DDQ and HCl in
place of TFA. Initial investigations of the aerobic oxida-
tion were performed by using benzyl alcohol as the
model substrate at room temperature (Table 1). The re-
sults showed that the target product was obtained with
76% conversion and 100% selectivity in 4 h when
4-OH-TEMPO, TCQ and HCl were used at room tem-
perature and under 0.1 MPa oxygen partial pressure
(Entry 5). The preliminary experimental results strongly
suggested that 4-OH-TEMPO, TCQ, and TBN, together
with HCl, could synergistically activate molecular oxy-
gen for the oxidation of benzyl alcohols to the alde-
hydes under 0.1 MPa oxygen partial pressure and at
room temperature.
To our surprise, although 4-OH-TEMPO was decreased
to 1 mol%, the reaction could also obtain quantitative
yield of benzaldehyde at room temperature for 4 h (En-
try 6). Interestingly, when the use of 4-OH-TEMPO was
decreased to 0.5 mol%, we still observed both 100%
selectivity and conversion by prolonging the reaction
time to 8 h (Table 2, Entry 7). A further decrease of
4-OH-TEMPO loading to 0.1 mol% did not reach a sat-
isfying oxidation result even for 12 h reaction (Entry 8).
When O2 balloon was replaced by air, only 42% con-
versation was achieved (Entry 16). In light of the results
shown in Table 2, we found that the catalyst system
4-OH-TEMPO/TCQ/TBN/HCl could be applied to the
conversion of benzyl alcohol to the aldehyde with O2
balloon and ambient temperature.
In addition, we examined the catalytic ability of typ-
ical TEMPOs, quinonoids and organic chlorinated cy-
clic compounds (Table 3, Entries 1－10). Different ac-
ids and NO donor NaNO2 were also screened (Table 3,
Entries 11 － 14). Although some catalytic system
showed high catalytic activity, such as Entries 3, 6, 9, 11,
we selected 1 mol% 4-OH-TEMPO, 2 mol% TCQ, 5
mol% TBN and 1 mol% HCl, O2 balloon at room tem-
perature as the optimal reaction conditions in the view-
point of green and economic chemistry.
Table 1 Experimental exploration based on the previousa
EntryTEMPO/mol%
DDQ/mol% HX/mol% Time/hConv.b/%
1c
4
4
2
4
4
2
1 (TFA)
1 (TFA)
5 (TFA)
12
4
99
59
50
21
76
2
3
4
4
2 (4-OH-TEMPO) 2 (TCQ) 5 (TFA)
2 (4-OH-TEMPO) 2 (TCQ) 1 (HCl)
4
5
4
a The aerobic oxidation was carried out with benzyl alcohol (10
mmol), TBN (5 mmol %), O2 balloon, room temperature. b De-
termined by GC, and all selectivities were 100%. c 0.2 MPa of O2
was used. Referred to ChemCatChem 2012, 4, 7680.
Having established the optimal conditions for the
transition-metal-free and solvent-free catalysis, we next
examined the range of alcohols for this catalytic aerobic
oxidation system. As showed in Table 4, all benzylic
alcohols, including 2-thienyl methanol and 3-pyridine
methanol, were converted into the corresponding ben-
zaldehydes in high isolated yields (Entries 1－7). Simi-
larly, activated secondary aryl alcohols, such as 1-phe-
Having verified the feasibility of the idea, we turned
our attention to the optimization of reaction conditions.
The reaction only provided very low conversion in the
absence of each one of the 4-OH-TEMPO, TCQ, TBN,
and HCl additives (Table 2, Entries 1－4 vs. Entry 5).
Table 2 Oxygen activation in catalytic oxidation of benzyl alcohol at room temperaturea
Entry
1
4-OH-TEMPO/mol%
TCQ/mol%
TBN/mol%
HCl/mol%
t/h
4
4
4
4
4
4
8
4
4
4
4
4
4
4
4
4
Conv.b/%
1
2
—
2
2
2
—
5
1
2
1
5
3
—
2
5
1
31
4
2
5
—
1
14
5
2
2
5
76
6
1
2
5
1
100
100
47
7
0.5
0.1
0.5
0.5
0.5
0.5
0.5
1
2
5
1
8
2
5
1
9
2
5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
1
39
10
11
12
13
14
15
16c
1
5
32
0.5
0.5
0.5
2
5
37
2.5
1
18
13
5
42
1
2
5
28
1
2
5
42
a Reaction conditions: benzyl alcohol (10 mmol), 4-OH-TEMPO, TCQ, TBN, HCl, r.t., O2 balloon for 4 h. b Determined by GC, and all
selectivities were 100%. c In the presence of air.
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Chin. J. Chem. 2015, 33, 1019—1023

A Metal-Free Catalytic System for Aerobic Oxidation of Alcohols under Mild Conditions
Table 3 Further optimization of the oxidation conditionsa
Entry
1
X1-TEMPO/mol%; X1＝4-OH Q/mol%; Q＝TCQ
TBN/mol%
H-X2/mol%; X2＝Cl
Conv.b/%
20
1 (TEMPO)
2
5
1
2
1 (MeO-TEMPO)
2
5
1
78
3
1
1
1
1
1
1
1
1
1
1
1
1
2 (DDQ)
2 (BQ)
2 (BQ)
2 (BQ)
2 (BQ)
2 (TCCA)
2 (TCCA)
2 (NCS)
2
5
1
100
68
4
5
1
5c
6c
7c
8
5
2 (TCCA)
76
5
2 (TCCA)
99
5
2 (NCS)
86
5
1
1
38
9
5
93
10
11
12
13
14
5
83
5
1 (HBr)
99
2
5
5
0.5 mL (CH3COOH)
20
2
5 (HBF4)
20
2
5(NaNO2)
10
35
a The reaction was carried out with benzyl alcohol (10 mmol) under solvent-free reaction conditions. b Determined by GC, and all selec-
tivities were 100%. c TCCA: trichloroisocyanuric acid; TCTA: 4,4',4''-tris(carbazol-9-yl)-triphenylamine; NCS: N-chlorosuccinimide. The
three reactions proceed with TCCA, TCTA and NCS in place of acids.
alcohols, which may contain N or S heteroatoms or
carbon-carbon double bonds at normal temperatures and
pressures. This inexpensive and convenient catalytic
system could be broadly used in laboratory and in fine
chemicals manufacture.
nylethanol, 1-phenyl-1-propanol, could be smoothly
oxidized to the corresponding acetophenone, propiophe-
none respectively by Method A, in nearly quantitative
isolated yields (Entries 8, 9). We were pleased to find
that primary and secondary aliphatic alcohols, which
remain difficult recalcitrant substrates in many aerobic
oxidation protocols, were oxidized to the expected al-
dehydes with high conversions and selectivities.
2-Octanol, 2-ethyl hexanol and cyclohexanol could be
smoothly converted to the corresponding carbonyl
compounds in high isolated yields under the standard
mild conditions (Entries 10－12). Allylic alcohol such
as cinnamyl alcohol was smoothly oxidized with high
selectivity (Entry 13). In Entry 14, the oxidation reac-
tion was applied to pairs of substrates, both of which
bore groups susceptible to oxidation, namely hydroxyl
and sulfide groups. To our delight, the oxidation system
highly selectively oxidized the hydroxyl group to car-
bonyl groups, whereas the sulfide groups remained in-
tact.
Experimental
General procedure for the 4-OH-TEMPO/TCQ/
TBN/ HCl-catalyzed aerobic oxidation of alcohols
The oxidation of alcohols was carried out in a 50 mL
long-necked, round-bottomed flask equipped with a
magnetic stirrer. Typically, the alcohol (10.0 mmol),
4-OH-TEMPO (0.10 mmol) and TCQ (0.20 mmol) were
located. The flask was evacuated and backfilled with O2.
Concentrated hydrochloric acid (0.10 mmol) was added,
followed by TBN (0.50 mmol).
The resulting mixture was stirred at room tempera-
ture and atmospheric pressure. The conversion and se-
lectivity of the product were detected by GC. When GC
showed the reaction was completed, adequate amounts
of hydrochloric acid and saturated Na2S2O3 solution
were added to the reaction mixture for converting the
4-OH-TEMPO to reduced, easy water-soluble com-
pound. The reaction mixture was extracted three times
with ethyl acetate. The organic layer was combined and
dried with anhydrous Na2SO4, and then concentrated on
a rotary evaporator to provide the products. In the case
of incomplete substrate conversion (Table 4, Entries
10－13), the desired product was isolated after column
chromatography on silica gel.
Despite the efficiency of the oxidation reaction, the
substrate scope is limited to liquid alcohols. The solid
alcohols are proven to be inefficient substrates for the
solvent-free catalytic system.
Conclusions
In conclusion, we have shown that the transi-
tion-metal-free and solvent-free catalyst system 4-OH-
TEMPO/TCQ/TBN/HCl permits the selective aerobic
oxidation of a broad range of primary and secondary
Chin. J. Chem. 2015, 33, 1019—1023
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Dong, Zhao & Liu
COMMUNICATION
Table 4 Catalytic aerobic oxidation for various alcoholsa
Entry
1
Product
Method
A
t/h
Conv./%
100
Select./%
100
Yield/%
97
5
A
A
A
A
A
A
8
7
100
100
100
100
100
100
100
100
100
100
100
100
95
99
96
98
97
97
2
O
3
16
6
4
O
O
5
6b
7
24
5
O
A
A
12
12
100
100
100
100
96
97
8
9
10c
11c
B
C
24
30
97
91
93
90
86
84
O
O
12c
D
5
91
94
80
13c
14d
D
A
6
8
87
100
100
85
100
－
a The aerobic oxidation conditions were as follows: alcohols (10.0 mmol), O2 balloon, room temperature. Method A: 4-OH-TEMPO (0.1
mmol), TCQ (0.2 mmol), TBN (0.5 mmol), HCl (0.1 mmol); Method B: 4-OH-TEMPO (0.4 mmol), TCQ (0.2 mmol), TBN (0.5 mmol),
HCl (0.05 mmol); Method C: 4-OH-TEMPO (0.8 mmol), TCQ (0.2 mmol), TBN (1 mmol), HCl (0.025 mmol); Method D:
4-OH-TEMPO (0.8 mmol), TCQ (0.4 mmol), TBN (1 mmol), HCl (0.05 mmol); conversions and selectivities are based on gas chroma-
c
tography (GC) analyses with area normalization. b In the presence of 1.2 equivalents of HOAc. Isolated yield after column chromatog-
raphy. d PhSMe remains intact after the reaction.
Acknowledgement
were appreciated.
Financial supports from the National Natural Sci-
ence Foundation of China (No. 21072055) and the Na-
tional High Technology Research and Development
Program of China (863 Program) (No. 2008AA06Z306)
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