Aerobic oxidation of alcohols by using a completely metal-free catalytic system

Article abstract of DOI:10.1002/ejoc.201301271

A metal-free reaction system of air, NH₄NO_3(cat), 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)_(cat), and H ⁺_(cat) is introduced as a simple, safe, inexpensive, efficient and chemoselective mediator for aerobic oxidation of various primary and secondary benzyl and alkyl alcohols, including those bearing oxidizable heteroatoms (N, S, O) to the corresponding aldehydes or ketones. Air oxygen under slight overpressure plays the role of the terminal oxidant, which is catalytically activated by redox cycles of nitrogen oxides released from a catalytic amount of NH₄NO₃ and cocatalyzed by TEMPO (nitroxyl radical compound), under acidic conditions, which are essential for an overall activation of the reaction system. The synthetic value of this reaction system and its green chemical profile was illustrated by a 10 g scale-up experiment, performed in an open-air system by using a renewable and reusable polymer-supported form of TEMPO (OXYNITROXS100). The reaction solvent was recovered by distillation under atmospheric pressure, and the pure final product was isolated under reduced pressure; the acid activators (HCl or H ₂SO₄) were recovered as ammonium salts. A metal-free reaction system of air/NH₄NO_3(cat)/TEMPO _(cat)/H⁺_(cat) is introduced as a simple, safe, inexpensive, efficient and chemoselective mediator for aerobic oxidation of various primary and secondary benzyl, alkyl and allyl alcohols, including those bearing oxidizable heteroatoms (N, S, O) to the corresponding aldehydes or ketones. Copyright

Full text of DOI:10.1002/ejoc.201301271

FULL PAPER
DOI: 10.1002/ejoc.201301271
Aerobic Oxidation of Alcohols by Using a Completely Metal-Free Catalytic
System
Rok Prebil,[a] Gaj Stavber,[b] and Stojan Stavber*[a,c]
Keywords: Green chemistry / Oxidation / Alcohols / Homogeneous catalysis / Nitrogen oxides
A metal-free reaction system of air, NH4NO3(cat), 2,2,6,6-tet-
ramethylpiperidine-1-oxyl (TEMPO)(cat), and H+
is intro-
TEMPO (nitroxyl radical compound), under acidic condi-
tions, which are essential for an overall activation of the reac-
tion system. The synthetic value of this reaction system and
its green chemical profile was illustrated by a 10 g scale-up
experiment, performed in an open-air system by using a re-
newable and reusable polymer-supported form of TEMPO
(cat)
duced as a simple, safe, inexpensive, efficient and chemo-
selective mediator for aerobic oxidation of various primary
and secondary benzyl and alkyl alcohols, including those
bearing oxidizable heteroatoms (N, S, O) to the correspond-
ing aldehydes or ketones. Air oxygen under slight overpres- (OXYNITROX®S100). The reaction solvent was recovered by
sure plays the role of the terminal oxidant, which is catalyti-
cally activated by redox cycles of nitrogen oxides released
from a catalytic amount of NH4NO3 and cocatalyzed by
distillation under atmospheric pressure, and the pure final
product was isolated under reduced pressure; the acid acti-
vators (HCl or H2SO4) were recovered as ammonium salts.
Introduction
The selective oxidation of alcohols to the corresponding most acceptable and desirable choice of reagent for these
carbonyl compounds is among the most important func- tasks.[3] Hydrogen peroxide has some drawbacks, however,
tional group transformations in organic synthesis on labo- such as the requirement for certain safety precautions when
ratory as well as on industrial scale.[1] Traditionally, these used in larger amounts or in concentrations higher than
transformations have been performed by using stoichiomet- 30% aqueous solution, because higher temperatures and/or
ric amounts of toxic organic or inorganic oxidizing agents impurities and trace amounts of metallic catalysts can in-
such as dimethyl sulfoxide (DMSO), lead acetates, chro- duce undesirable decomposition to H2O and O2 during re-
mates and manganese oxides.[1] Following modern trends in actions.[4] The molecular oxygen, especially when used in its
chemistry, regulated with principles of green and sustaina- natural diluted source as air, is the most abundant terminal
ble chemical demands,[2] the use of such reagents have be- oxidant, with clear benefits from the viewpoints of atom
come unacceptable. During the last two decades there has economy, cost efficiency and green chemistry.[4,5]
been a very intense development in the field, mainly follow-
ing the application of environmentally friendly oxidants
that lead to a minimum amount of waste formation after
catalytic, rather than noncatalytic processes. From the view-
point of cost efficiency, atom economy and overall green
and sustainable development, aqueous hydrogen peroxide
and especially atmospheric molecular oxygen, represent the
To establish the desired reactivity, much effort has been
directed towards the development of oxidation methodolo-
gies under molecular oxygen with either heterogeneous or
homogeneous activation with transition-metal-based cataly-
sis such as Pd, V, W, Mo, Ru, Ag, Co and Au.[6] Neverthe-
less, their scarcity, highly undesirable environmental impact,
high price, and toxicity present a significant limitation in
the industrial use of such catalysts, especially in the last
synthetic stages of the production of flavors, fragrances and
active pharmaceutical ingredients.[6] As a result of these
drawbacks, further efforts have been made, and nonprecious
metal catalysts or transition-metal-free reaction systems for
aerobic oxidation have been developed by taking advantage
of the oxidative power of molecules bearing a nitroxyl radi-
cal functional moiety (TEMPO, TEMINO, NHPI, PINO
etc.,[7] and very recently 2-azaadamantane-N-oxyl-based
compounds[8]), often in combination with metal[9a] and very
seldom with metal-free[10] cocatalysts. Likewise, in the last
few years an aerobic biocatalytic approach based on
[a] Laboratory for Organic and Bioorganic Chemistry at “Jozef
ˇ
Stefan” Institute,
Jamova 39, 1000 Ljubljana, Slovenia
E-mail: Stojan.Stavber@ijs.si
http://www.ijs.si/ijsw/K3
[b] Lek Pharmaceuticals d.d. Sandoz Development Center
Slovenia, API Development, Organic Synthesis Department,
1234 Mengesˇ, Slovenia
[c] Centre of Excellence for Integrated Approaches in Chemistry
and Biology of Proteins,
Jamova 39, 1000 Ljubljana
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301271.
Eur. J. Org. Chem. 2014, 395–402
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
395

R. Prebil, G. Stavber, S. Stavber
FULL PAPER
glycolated copper-containing oxygenase enzyme laccases in
combination with nitroxyl radicals has been estab-
lished.[9b–9e] Among these, nitric oxide donors play an im-
portant role as reactive compounds that are useful in sev-
Results and Discussion
Optimization of Reaction Conditions
To establish a practical, green and economical procedure
eral chemical and biological applications.[11] Inorganic and for the selective aerobic oxidation of a comprehensive range
organic nitrites or even aqueous hydroxylamines were intro- of alcohols to their carbonyl derivatives, we aimed to de-
duced as sources of NO/NO2, which were generated in situ velop a catalytic system with the following criteria: (i) use
and involved in a redox cycle supporting the electron flow of air as the terminal oxidant under slight overpressure or
between oxidizable functional groups and molecular oxy- even under open air; (ii) use of a metal-free catalytic system
gen, often through metal, nonmetal or nitroxyl radical- for its activation; (iii) use of inexpensive standard chemicals
based additional redox moieties. The development of such in the overall process producing minimum waste; (iv) regen-
catalytic methods has led to important improvements in the eration of nitroxyl cocatalyst for potential reuse; (v) large-
area of aerobic oxidation of alcohols but, in most cases, scale efficiency and selectivity of the overall process, with,
the reactions require high operating oxygen pressures up to if possible, organic-solvent-free isolation and purification of
10 bar, temperatures between 80 and 100 °C, special Teflon- final products. If achieved, these attributes would make the
lined autoclave reactors, and the use of undesirable chlorin- aerobic catalytic methodology fully suitable and very useful
ated solvents such as ClCH2CH2Cl, CH2Cl2 and 1,2-dichloro- for industrial oxidation processes.
benzene.[12,13] It should be mentioned that investigations
Based on previous reports dealing with aerobic oxidation
into the use of inorganic nitrates as potential sources of of alcohols, supported by either catalytic or equimolar
nitric oxides in aerobic oxidation are rare,[14,28b] and there amounts of a nitric oxide source, we decided to further in-
is clearly still room for further investigation. Studies dealing vestigate various inorganic nitrates as potential catalytic
with transition-metal nitrates as catalysts such as Fe- promoters of these processes. In our initial experiments, we
(NO3)3, Co(NO3)2 or different copper(II) salts[15] for aero- used benzyl alcohol (1a) as a model substrate. Promising
bic oxidation of alcohols have revealed that transition-metal preliminary results were achieved and are presented in
cations (Fe2+/Fe3+, Co2+/Co3+, Cu+/Cu2 redox pairs) are Table 1. We assumed that nitrates as a potential source of
basic carriers of oxidation potential and are crucial for suc- nitric oxides would not be suitable for the catalytically me-
cessful overall transformation of the substrate alcohols into diated direct oxidation, because NO/NO2 has an insuf-
the desired carbonyl products.[16] In the absence of transi- ficient redox potential [E°(NO2/NO) = 1.03 V]. The pres-
[16c]
tion-metal cations, the use of NaNO3
or HNO3, even in ence of stable nitroxyl radicals as additional electron-flow
equimolar or excess amounts,[17] led to either no or minimal carriers could be beneficial for the efficiency of the overall
conversion of the starting material. In reactions where cata- process. The increased reactivity of the nitroxyl radicals un-
lytic amounts of HNO3 were used, even when combined der ordinary acidic conditions causes disproportionation
with persistent free radicals such as 2,2,6,6-tetramethylpip- and formation of active oxoammonium cation intermedi-
eridine-N-oxyl (TEMPO) derivatives, the aerobic oxidation ates [E°(TEMPO cation/TEMPO) = 0.76 V],[7] as well as
of benzyl alcohol to benzaldehyde was found to be in- nitric oxide sourcing compounds. Accordingly, we chose
efficient in the absence of carbon materials (nanoshell car- TEMPO and HClO4 as cocatalysts to establish an efficient
bon or activated carbon) as crucial additional accelerators and selective aerobic process. We started our investigation
of the overall process of nitric-acid-assisted carbon-cata- with the most widespread and environmentally friendly
lyzed oxidation systems (NACOS).[18] Recently, HNO3 has transition-metal catalyst, iron(III) nitrate, which appeared
been utilized exclusively as a cocatalyst component in an to be a good candidate for the task. However, as much as
efficient 4-acetamido-TEMPO-HNO3 catalytic system for 20 mol-% acid was necessary to achieve good conversion
oxidation of methyl α-d-glucopyranoside[19] or used in com- of alcohol into benzaldehyde at room temperature (Table 1,
bination with a 4-acetamido-TEMPO-HCl catalytic system Entry 1). On the other hand, the use of copper(II) nitrate
for the chemoselective metal-free aerobic oxidation of lig- as an alternative was efficient even without the presence of
nins.[20] A notable report by Hermans and co-workers[21] acid (Entries 2 and 3). Sodium nitrate as an alkali metal
described the aerobic oxidation of different alcohols and candidate was found to be inefficient at room temperature
5-(hydroxymethyl)furfural with an HNO3-imobilized (Entry 5), but catalyzed the reaction to completion at 60 °C
TEMPO system under slight overpressure.
in the presence of 10 mol-% acid (Entry 6). In an attempt
Impressed by the aforementioned chemistry and moti- to establish a fully metal-free catalytic system, ammonium
vated by a desire to develop this field further, in view of our nitrate appeared to be the logical choice and, as it turned
continuing interest in green chemical transformations of or- out, the right one. Under neutral conditions, the catalyst
ganic compounds, especially stressing the role of air was found to be unreactive (Entry 7), but when an appro-
oxygen in these transformations,[22] we now report an ef- priate acidic activator was added at room temperature,
ficient and selective oxidation of various alcohols to alde- moderate efficiency was obtained (Entry 8). Encouraged
hydes or ketones by using a novel three-component, com- with this result, we increased the temperature to 60 °C and
pletely metal-free and cost-beneficial catalytic system achieved quantitative conversion into benzaldehyde (En-
based on NH4NO3/TEMPO/H+ under mild, aerobic condi- try 9). Therefore, the three-component catalytic system
tions.
NH4NO3/TEMPO/H+ was used in subsequent studies.
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Metal-Free Aerobic Oxidation of Alcohols
Table 1. Aerobic oxidation of benzyl alcohol by using nitrate salt/ ronmentally benign reaction media. Good conversion was
TEMPO/HClO4 in acetonitrile.[a]
observed by using cyclopentyl methyl ether (66%), and
quantitative conversion was achieved in acetonitrile (see the
Supporting Information Table S1 for a summary of the
study).
We also checked the efficiency of four chosen nitroxide
radicals, including TEMPO and three TEMPO derivatives
(4-HO-TEMPO, 4-HO-TEMPO benzoate, and 4-MeO-
TEMPO) (Figure 1). Trial oxidations were carried out with
benzyl alcohol (1a) in acetonitrile with variations of ni-
troxide catalyst loading and 5 mol-% HCl (aq. 37%) and
5 mol-% NH4NO3 at mild temperature for 24 h. Under
identical conditions, 4-substituted derivatives were some-
what more efficient than TEMPO; however, because the lat-
ter is considerably less expensive, its use seems to be more
reasonable. Of the tested nitroxide radicals, 4-HO-TEMPO
benzoate seemed to be the most efficient under the same
conditions. Full conversion of benzyl alcohol into benzalde-
hyde was achieved by using only 0.075 mol-% catalyst.
Entry Nitrate catalyst
Acid
(mol-%)
T
[°C]
Time Conv. 1a Ǟ 2a
[h]
[%][b]
1
2
3
4
5
6
7
8
9
Fe(NO3)2
Cu(NO3)2
Cu(NO3)2
NaNO3
NaNO3
NaNO3
NH4NO3
NH4NO3
NH4NO3
HClO4 (20) 20
5
6
7
6
8
5
7
7
4
81
86
100
0
4
100
0
–
–
–
20
60
60
HClO4 (10) 20
HClO4 (10) 60
–
60
HClO4 (10) 20
HClO4 (10) 60
29
100
[a] Reaction conditions: benzyl alcohol (1a; 1 mmol), nitrate salt
(0.1 mmol), HClO4 (0–0.2 mmol), TEMPO (0.05 mmol), MeCN
(2 mL), 20–60 °C, 5–6 h under air balloon (1 L). [b] Conversion of
1a into 2a determined from 1H NMR spectra of crude reaction
mixtures.
We further evaluated the role of the acids in the oxi-
dation process and found that acids with pKa values of at
least –5 support the process quantitatively (Table 2),
whereas weaker acids gave worse or even negative results.
For this reason, HCl (aq. 37%) or H2SO4 (aq. 98%) were
used for further experiments as the most abundant acids.
Table 2. The effect of acid on the aerobic oxidation of benzyl
alcohol with NH4NO3 and TEMPO.[a]
Figure 1. Efficiency of TEMPO, 4-HO-TEMPO, 4-HO-TEMPO
benzoate and 4-MeO-TEMPO cocatalysts in the aerobic oxidation
of benzyl alcohol by using the NH4NO3/TEMPO/HCl catalytic sys-
tem. For reaction conditions see the Supporting Information.
Entry
Acid
pKa
Conv. 1a Ǟ 2a
[%][b]
It is worth mentioning that all control experiments high-
lighting the essential role of each member of the described
reaction system, i.e., air oxygen as reagent and NH4NO3,
TEMPO and HCl as catalysts, were performed; all the con-
trol systems gave negative results under argon or under air.
In the absence of any one of the three components of the
catalytic system, benzyl alcohol was not converted into
benzaldehyde (see the Supporting Information for details).
1
2
3
4
5
6
7
HCOOH
CF3COOH
PTSA
MeSO3H
HClO4
HCl
H2SO4
3.75
–0.6
–2.8
–1.9
–5
–6
–9
0
0
1
83
100
100
100
[a] Reaction conditions: 1a (1 mmol), TEMPO (5 mol-%),
NH4NO3 (10 mol-%), acid (aq., 10 mol-%), MeCN (2 mL), 60 °C,
4 h, air balloon. [b] Conversion of 1a into 2a determined from H
NMR spectra of crude reaction mixtures.
1
Scope of the Reaction
The use of organic solvents in chemical processes is one
of the most conflicting issues from the green-chemistry
Having identified the optimal reaction conditions for the
point of view.[23] The most desirable are solvent-free trans- aerobic oxidation of benzyl alcohols by using the NH4NO3/
formations or those performed in recyclable and reusable TEMPO/H+ catalytic system, we turned our attention to
reaction media such as alcohols, ethyl acetate, green ethers examining the scope and limitations of the present method.
etc. Unfortunately, aerobic oxidation of benzyl alcohol by The results of the reaction of substituted primary and sec-
using our catalytic system under solvent-free reaction con- ondary benzyl alcohols are summarized in Table 3. All
ditions was unsuccessful. Equally unsuccessful were reac- tested primary and secondary benzyl alcohols were quanti-
tions in H2O, MeOH, 2-methyltetrahydrofuran and Solkane tatively and selectively converted into their corresponding
(1,1,1,3,3-pentafluorobutane, HFC 365) as preferred envi- aldehydes or ketones in high isolated yields.
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397

R. Prebil, G. Stavber, S. Stavber
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Table 3. Aerobic oxidation of substituted primary and secondary
benzyl alcohols by using the air/NH4NO3/TEMPO/HCl catalytic
system in acetonitrile.[a]
Table 4. Aerobic oxidation of methoxy- and methyl-polysubstituted
benzyl alcohols by using the NH4NO3/TEMPO/HCl catalytic sys-
tem in acetonitrile.[a]
Entry
Alcohol 1
Time Conv. 1 Ǟ 2 Yield 2
R
H
R1
[h]
[%][b]
[%][c]
Entry
Alcohol 3
Conv. 3 Ǟ 4
Yield 4
R2, R3, R4, R5, R6
[%][b]
[%][c]
1
2
3
H
H
H
a
b
c
d
e
f
g
h
i
6
5
100
100
100
100
100
100
100
100
100
100
100
100
100
90
95
80
82
73
87
95
95
89
80
95
91
82
4-MeO
4-Me
4-Cl
1
2
3
4
5
2,3-(MeO)2
2,3,4-(MeO)3
3,4,5-(MeO)3
3,5-(MeO)2
2,5-(MeO)2
2,3,4,5,6-Me5
3,5-Me2
a
100
100
100
100
90
100
100
75
95
90
95
93
85
80
85
60
3
6
8
21
6
6
5
6
6
b
c
d
e
f
4
H
5
4-F3C
4-O2N
3-F
H
H
H
Me
Me
Me
Me
Me
Me
6[d]
7
6
8
9
10
11
12
13[d]
H
7
g
h
4-MeO
4-Me
4-F
4-F3C
3-O2N
8[d]
3-HO-4-MeO
j
k
l
[a] Reaction conditions: Alcohol 3 (1 mmol), TEMPO (2.5–5 mol-
%), NH4NO3 (5–10 mol-%), HCl (aq. 37%, 5–10 mol-%), MeCN
(2 mL), 60 °C, 5–6 h, air balloon (exact conditions for each reac-
tion are given in the Supporting Information). [b] Determined from
1H NMR spectroscopic analysis of the crude reaction mixture.
[c] Yield determined after purification by flash chromatography
(SiO2; ethyl acetate). [d] Reaction time 21 h.
7
25
m
[a] Reaction conditions: Alcohol
1
(1 mmol), TEMPO (2.5–
12.5 mol-%), NH4NO3 (5–25 mol-%), HCl (aq. 37% , 5–12.5 mol-
%), MeCN (2 mL), 60 °C, 5–7 h, air balloon (1 L); exact conditions
for each reaction are given in the Supporting Information. [b] De-
1
termined from H NMR spectroscopic analysis of the crude reac-
tion mixture. [c] Yield determined after purification by flash
chromatography (SiO2; ethyl acetate). [d] Reaction time 24 h.
Table 5. Aerobic oxidation of aromatic alcohols by using the
NH4NO3/TEMPO/HCl catalytic system in acetonitrile.[a]
The required reaction times could be correlated with the
substituents on the substrate. However, even highly elec-
tron-deficient (4-nitrophenyl)methanol (1f; Table 3, En-
try 6), 1-(3-nitrophenyl)ethanol (1m; Entry 13), [4-(tri-
fluoromethyl)phenyl]methanol (1e; Entry 5), and 1-[4-(tri-
fluoromethyl)phenyl]ethanol (1l; Entry 12) could be
smoothly oxidized to the desired pure product in 73–91%
yield after an extended reaction time. Moreover, the cata-
lytic methodology enabled high chemoselectivity. No
benzoic acid derivatives or any other impurities were de-
tected in the crude reaction mixture.
We extended the range of benzyl alcohols to include po-
lysubstituted derivatives bearing two or more electron-do-
nating substituents (3a–h). As evident from the results col-
lected in Table 4, high to quantitative amounts of the corre-
sponding benzaldehyde derivatives 4a–h were obtained
from the reactions in MeCN, under air by using the
NH4NO3/TEMPO/HCl catalytic system, without the for-
mation of any benzoic acid or quinone derivatives. Signifi-
cantly, phenol 3h (Entry 8) with a structure moiety that is
present in bioactive molecules, could be smoothly converted
into the corresponding aldehyde 4h.
[a] Reaction conditions: Alcohol 5 (1 mmol), TEMPO (2.5–5 mol-
%), NH4NO3 (5–10 mol-%), HCl (aq. 37%, 5–10 mol-%), MeCN
(2 mL), 60 °C, 5–6 h, air balloon (exact conditions for each reac-
tion are given in the Supporting Information). [b] Determined from
1H NMR spectroscopic analysis of the crude reaction mixture.
[c] Yield determined after purification by flash chromatography
(SiO2; ethyl acetate).
Furthermore, benzyl alcohols bearing a cycloalkyl ring
An additional presence of functional groups bearing he-
(5a–d; Table 5, Entries 1–4) or phenyl aromatic backbone teroatoms such as sulfur, nitrogen or oxygen could repre-
(5e; Entry 5) were also quantitatively converted into their sent competitive reaction centers to the oxidation of the
respective carbonyl derivatives 2,3-dihydro-1H-inden-1-one hydroxy functional group in the target molecule. As can be
(6a), 3,4-dihydronaphthalen-1(2H)-one (6b), 9H-fluoren-9- seen from Table 6, we examined the selectivity of oxidation
one (6c), anthracen-9(10H)-one (6d), or 2-naphthaldehyde of some heterocyclic alcohols and made the methodology
(6e).
more general. Sulfur-containing heterocyclic alcohol deriva-
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Metal-Free Aerobic Oxidation of Alcohols
tives such as 2-thienylmethanol (7a; Entry 1), thiochroman- was not very promising using TEMPO, but with the use
4-ol (7b; Entry 2) and 9H-thioxanthen-9-ol (7c; Entry 3) of more active 4-HO-TEMPO benzoate catalyst, cinnamyl
were efficiently converted into their respective carbonyl de- alcohol (9d; Entry 4) and 1-phenylprop-2-en-1-ol (9e; En-
rivatives 8a–c, without any detection of possible sulfoxide try 5) as standard representatives of allylic alcohols were
or sulfone side products. Cyclic ethers 4H-chromen-4-ol fully converted into the corresponding carbonyl com-
(7d; Entry 4) and 9H-xanthen-9-ol (7e; Entry 5) were also pounds.
quantitatively converted into their respective carbonyl de-
rivatives 8d and 8e. In the case of pyridinyl-substituted
alcohols (7f–h; Entries 6–8), longer reaction times and reac-
tion media based on AcOH were necessary to achieve quan-
titative conversion into the corresponding carbonyl deriva-
tives 8f–h.
Table 7. Aerobic oxidation of aliphatic and allylic alcohols cata-
lyzed by the NH4NO3/TEMPO/HCl system in acetonitrile.[a]
Table 6. Aerobic oxidation of benzylic alcohols bearing oxidizable
heteroatoms by using the NH4NO3/TEMPO/HCl catalytic system
in acetonitrile.[a]
[a] Reaction conditions: Alcohol 9 (1 mmol), TEMPO (5–10 mol-
%), NH4NO3 (10–20 mol-%), HCl (aq. 37%, 10–20 mol-%), MeCN
(2 mL), 60 °C, 23–25 h, air balloon (exact conditions for each reac-
tion are given in the Supporting Information). [b] Determined from
1H NMR spectroscopic analysis of the crude reaction mixture.
[c] Yield determined after purification by flash or column
chromatography (SiO2; ethyl acetate/petroleum ether). [d] O2 bal-
loon. [e] 10 mol-% TEMPO was used. [f] 5 mol-% 4-HO-TEMPO
benzoate was used.
Optimization of Reaction Conditions to Fulfill Green-
Chemistry Demands
When exploring and developing new reagents, catalysts
or protocols for any chemical transformation, small-scale
reactions (mmol scale) are typically used to gain basic
knowledge on the system. However, it is very desirable to
demonstrate the practical applicability of a new procedure
at least on the laboratory level, and ideally to indicate its
potential use in industrial applications. We thus believe that
a scale-up investigation should also be performed as part
of the basic level of research, to further evaluate the prepar-
[a] Reaction conditions: Alcohol 7 (1 mmol), TEMPO (2.5–5 mol-
ative potential of a new method, especially in the view of
green chemistry. To demonstrate the practicality of scaling
up the current procedure, we treated 10.8 g (0.1 mol) of
benzyl alcohol in MeCN (40 mL) solution with 5 mol-%
NH4NO3, 5 mol-% 4-MeO-TEMPO, and 5 mol-% of 98%
H2SO4 in a flask (250 mL) equipped with condenser and
%), NH4NO3 (5–10 mol-%), HCl (5–10 mol-%), MeCN (2 mL),
60 °C, 5–6 h, air balloon (exact conditions for each reaction are
given in the Supporting Information). [b] Determined from 1H
NMR spectroscopic analysis of the crude reaction mixture.
[c] Yield determined after purification by flash chromatography
(SiO2; ethyl acetate). [d] AcOH was used as the solvent.
Aliphatic alcohols are usually more resistant to oxi- opened to air. We chose 98% sulfuric acid, rather than 37%
dation, and this was also noticed in the case of the aerobic hydrochloric acid used in the mmol-scale experiments, to
process using the NH4NO3/TEMPO/HCl catalytic system. introduce as little water as possible into the reaction system
Encouragingly, we tested some aliphatic, cycloaliphatic and and exclude chlorides, which very often cause the formation
allylic alcohols, and the results are collected in Table 7. We of chlorinated genotoxic impurities especially in scale-up
found that increased reaction times and loading of TEMPO pharmaceutical industrial processes. After completion of
as well as addition of ammonium nitrate and acid were nec- the reaction, white solid was filtered off and identified as
essary to obtain good conversions to the carbonyl com- almost pure (NH4)2SO4, solvent was recovered (38 mL) by
pounds. Aliphatic alcohols 1- and 2-octanol 9a and 9b (En- distillation at atmospheric pressure, and further distillation
tries 1 and 2) showed good conversions under aerobic con- under reduced pressure gave a colorless liquid (9.8 g,
ditions, whereas the cyclic analogue 4-tert-butylcyclohex- 92.4%) that was identified as benzaldehyde. An attempt to
anol (9c; Entry 3) was oxidized with very satisfying effi- regenerate the 4-MeO-TEMPO cocatalyst for potential re-
ciency. The oxidation of allylic alcohols (Entries 4 and 5) use from the distillation residue failed, which is a limitation
Eur. J. Org. Chem. 2014, 395–402
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399

R. Prebil, G. Stavber, S. Stavber
FULL PAPER
of the green profile of the overall reaction protocol. To radicals have been elaborated several times.[8,12,25] Observa-
avoid this inconvenience, we examined the use of backbone- tions related to the behavior of the NH4NO3/TEMPO/H+
supported and thus potentially regenerative forms of catalytic system, the essential role of each component, isola-
TEMPO catalyst for the aerobic oxidation. It is known that tion and identification of reaction products, and the study
many immobilized forms of TEMPO, typically bridged to of substituent effects on the reaction kinetics based on
a backbone through C(4)–O or C(4)–N bonds, have been Hammett correlation analysis (see the Supporting Infor-
used as cocatalyst in various oxidation processes involving mation for details) of the reaction are consistent with the
alcohol to carbonyl transformations. These potentially re- known sequence of catalytic cycles that take place during
coverable and reusable materials, bearing TEMPO on mag- air oxygen oxidation of alcohols to aldehydes or ketones.
netic supporters,[24] various polymers,[25a] mesoporous ma- The acid is assumed to have two main roles: its first role is
terials[25b] or silica backbone,[25a] ionic liquids matrix,[26] to hydrolyze ammonium nitrate to HNO3 [Equation (1)],
and immobilization on hydrophobic resins[27] were mainly which is in thermally accelerated decomposing equilibrium
studied on the mmol scale. One system that has been pro- with NO2 [Equation (2)], and the second is to accelerate the
moted[25c] and elaborated[7c] on the basic level as PIPO interconversion in the disproportion equilibrium of
(Polyamine Immobilised Piperidyl Oxyl) and used on an in- TEMPO to TEMPO+ and TEMPOH, which function as
dustrial level as OXYNITROX®S100,[28] seemed to be the active intermediates through their redox cycle in the last
most promising choice for our task. Since this material, to phase of oxidation, i.e., proton pumping from an alcohol
the best of our knowledge, has not been tested as a catalyst molecule. On the other hand, higher oxidation potential of
for aerobic oxidation of alcohols under open-air conditions, air oxygen and activation of poorly reactive alcohols in the
we first checked its efficiency under NH4NO3/TEMPO- acidic environment could not be overlooked. Isolation of
based cocatalyst/H+ reaction-system conditions. The results ammonium salts (chloride when HCl was used, or sulfate
of this investigation performed on benzyl alcohol are shown when H2SO4 was used) supports the first role, whereas the
in Figure 2. Recycling and reuse of OXYNITROX®S100 second has already been discussed.[7e] Hammett plots
was performed for five consecutive runs. Quantitative con- (logkrel/σ+) conducted with our catalytic system revealed
versions were achieved in all cycles, although the loss of good correlation for aerobic oxidation of a series of substi-
catalyst per cycle was 9% on average.
tuted benzyl alcohols and the value of the resulting reaction
constant ρ+ = –0.96 supports the development of a partial
positive charge in the transition state of the rate-determin-
ing step of the reaction. This result is consistent with the
accepted model of the interaction of the TEMPO+-active
intermediate and an alcohol molecule. The assumption that
the NO/NO2 redox pair actually collaborates in the catalytic
cycles is supported by the observation that several cycles of
color changes of the reacting solution from brown (NO2)
to colorless (NO) occurred during the reactions. We also
established that HCl-mediated processes are faster than
those catalyzed by H2SO4. This could be explained by pos-
sible formation of NOCl, which has a beneficial effect on
the overall oxidizing power of the reaction system, which
has already been observed when halides are involved in aer-
obic oxidative processes mediated by NOx sources.[12c,22c]
Figure 2. Successful recycling and reuse of cocatalyst OXYNI-
TROX®S100 for efficient aerobic oxidation of benzyl alcohol by
using the NH4NO3/OXYNITROX®S100/HCl catalytic system. Re-
action conditions are given in the Supporting Information.
Encouraged by these results, OXYNITROX®S100 was
used as a TEMPO-based cocatalyst for the scale-up experi-
ment. These experiments also established that, under sim-
ilar reaction conditions, this material could also be regener-
ated for further use. The only concern in our attempt to
optimize the green profile of the method was the potential
emission of NOx; however, such concerns have been techno-
logically resolved.[29]
Conclusions and Perspectives
We have successfully developed a three-component, com-
pletely metal-free catalytic system of NH4NO3/TEMPO/H+
that can be used for efficient and selective oxidation of pri-
mary and secondary alcohols to the corresponding alde-
hydes and ketones under mild aerobic conditions. The pre-
Mechanistic Discussion
Mechanistic elucidation of aerobic oxidation of alcohols, sented catalytic system enables moderate to quantitative,
catalyzed by nitric oxides redox cycle assisted by nitroxyl chemoselective oxidation of a comprehensive range of
400
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 395–402

Metal-Free Aerobic Oxidation of Alcohols
cally changed the color from brown to colorless, the consumption
of starting material was monitored by TLC. After completion of
the reaction, the reaction mixture was cooled to room temperature,
diluted with ethyl acetate (10 mL), insoluble material (identified as
ammonium chloride) was filtered off, the filtrate was washed with
aq. NaHCO3 (10%, 10 mL) and Na2S2O3 (10%, 10 mL), and the
organic phase was dried with anhydrous Na2SO4. Organic solvent
was distilled off under reduced pressure, and the crude product was
analyzed by 1H NMR spectroscopy. Finally, the crude product was
purified by flash chromatography (SiO2; ethyl acetate) to afford
alcohols including those bearing oxidizable heteroatoms (S,
N, O), alkyl-, cycloalkyl-, and allyl-type substituted sub-
strates. To the best of our knowledge, the developed cata-
lytic system constitutes for the first time that an aerobic
oxidative transformation of organic compounds has been
used in which each member has an essential role in the reac-
tion system. A plausible mechanistic interpretation of the
present catalytic system including relative kinetic measure-
ments based on Hammett correlations is also suggested. We
believe that our invention could open new opportunities pure material, which was compared to authentic samples. Detailed
data, including catalyst loading, reaction times, yields of pure prod-
ucts and their spectroscopic and other identification data are given
in the Supporting Information.
and help in the development of more economical, mild,
simple, and environmentally friendly catalytic oxidation
methodologies that use atmospheric air as terminal oxidant.
In addition, the NH4NO3/OXYNITROX®S100/H+ cata-
lytic system, successfully tested for aerobic oxidation of
benzyl alcohols, offers the advantages of easy recycling of
TEMPO-based cocatalyst over several consecutive cycles.
Finally, the promising scale-up procedures with a prepara-
tive example of the catalytic method was achieved; further
modifications of the reaction protocol and isolation and pu-
rification of products were directed towards making the
overall process industrially more acceptable and as green as
possible. The use of NH4NO3 as a simple, inexpensive and
metal-free catalyst, the application of an open-air system
instead of high-oxygen-pressure systems (autoclave), the
generation of minimal amounts of waste and the possibility
of process scale-up including recovery of all possible haz-
ardous solvents and reactants make the methodology useful
and interesting from both environmental and economic
points of view.
Aerobic Oxidation of Benzyl Alcohol with the NH4NO3/4-OMe-
TEMPO/H2SO4 Catalytic System. Scale-Up Procedure: A 250 mL
glass reactor equipped with a magnetic stirring bar and open con-
denser was charged with substrate benzyl alcohol (0.1 mol, 10.8 g)
dissolved in acetonitrile (40 mL). The solution was heated at 60 °C,
then catalyst NH4NO3 (5 mol-%, 0.4 g), cocatalyst 4-MeO-
TEMPO (5 mol-%, 0.93 g) and acid activator aq. 98% H2SO4
(5 mol-%, 278 μL) were added in consecutive 2 min intervals. The
reaction mixture was stirred (600 rpm) under open-air conditions
at 60 °C for 48 h. Upon completion of the reaction, the reaction
mixture was cooled to room temperature, and salt (identified as
ammonium sulfate; 360.4 mg recovered) was filtered off and
washed with acetonitrile (5 mL). To obtain carry-over of the sol-
vent, the filtrate was distilled at atmospheric pressure at 85 °C; full
recovery of acetonitrile was achieved and successfully reused again.
The distillation program was then changed: the pressure was de-
creased to 5 mbar and the temperature raised to 100 °C, whereupon
the desired product benzaldehyde (9.8 g; 92% yield) was obtained
as a colorless liquid.
Aerobic Oxidation of Benzyl Alcohol with the NH4NO3/
OXYNITROX®S100/H2SO4 Catalytic System. Scale-Up Pro-
cedure: A 250 mL glass reactor equipped with magnetic stirring bar
and open condenser was charged with acetonitrile (40 mL). The
solvent was heated at 60 °C, then catalyst NH4NO3 (20 mol-%,
0.8 g), acid activator H2SO4 (aq. 98%, 20 mol-%, 1112 μL) and co-
catalyst OXYNITROX®S100 (10 mol-%, 4.34 g) were added in
consecutive 2 min intervals. After 10 min, model substrate benzyl
alcohol (0.1 mol, 10.8 g) was added, and the reaction mixture was
stirred (600 rpm) under open-air conditions at 60 °C for 48 h. After
completion of the reaction, the reaction mixture was cooled to
room temperature, and salt (identified as ammonium sulfate) was
filtered off (762.4 mg recovered) and washed with acetonitrile
(5 mL). To obtain carry-over of the solvent, the filtrate was distilled
at atmospheric pressure at 85 °C; full recovery of acetonitrile was
achieved and successfully reused. After evaporation of solvent,
cold diethyl ether (20 mL) was added; the precipitated
OXYNITROX®S100 (3.7 g recovered) was filtered off with a sin-
tered glass funnel, washed with cold diethyl ether (3ϫ 5 mL), and
dried in air for further use. Further diethyl ether was distilled from
benzaldehyde under normal pressure at 35 °C. The distillation pro-
gram was then changed: the pressure was decreased to 5 mbar and
the temperature raised to 100 °C, whereupon the desired product
benzaldehyde (9.7 g, 90% yield) was obtained as a colorless liquid.
Experimental Section
General: All chemicals used in this study were analytical grade,
commercially available and used without further purification unless
otherwise noted. Reactions were carried out in 5 or 10 mL glass
flasks. Balloons (1 L) with 10 mil wall thickness were purchased
from Sigma Aldrich and used as air reservoir. Reactions were moni-
tored by thin-layer chromatography on TLC Silica gel 60 F254 alu-
minum sheets (20ϫ20 cm). Column chromatography (CC) and
flash chromatography (FC) were performed by using silica gel 60
(particle size: 0.063–0.200 mm) and preparative thin-layer
chromatography (preparative TLC) with PLC Silica gel 60 F254
2 mm plates.
,
General Measurement: Conversions and yields were determined on
the basis of NMR spectroscopic analysis. NMR spectra were re-
corded with
a
Varian INOVA 300 NMR instrument (1H:
303.0 MHz; 13C: 76.2 MHz) using CDCl3 as solvent with SiMe4
(TMS) as an internal reference. Melting points were determined
with a Büchi 535 instrument.
General Experimental Procedures
Aerobic Oxidation of Alcohols with the NH4NO3/TEMPO/HCl
Catalytic System (mmol Scale). General Procedure: A 10 mL glass
flask equipped with magnetic stirring bar was charged with alcohol
(1 mmol) and acetonitrile (2 mL). To the solution, NH4NO3 (5–
25 mol-%), TEMPO (1.2–12.5 mol-%) and hydrochloric acid (aq.
37%, 5–25 mol-%) were consecutively added in 2 min intervals, and
the flask was further fitted with a balloon filled with air (1 L) and
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental details for each substrate, Hammett corre-
lation, study of solvent effect and characterizations for isolated
magnetically stirred at 60 °C. In the reaction system, which periodi- products (1H and 13C NMR spectra).
Eur. J. Org. Chem. 2014, 395–402
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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401

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gramme ARRS P1-0134 and Young Researchers Fellowship
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Received: August 23, 2013
Published Online: October 29, 2013
402
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