A convenient alternative for the selective oxidation of alcohols by silica supported TEMPO using dioxygen as the final oxidant

Article abstract of DOI:10.1016/j.tetlet.2015.10.099

Various primary and secondary alcohols were selectively oxidized to the corresponding aldehydes and ketones using silica supported TEMPO as a heterogeneous catalyst and nitrosonium tetrafluoroborate as a cocatalyst. No over-oxidation of aldehydes to acids, nitration processes or oxidation of double bonds was observed. The reported procedure is very convenient, and uses mild experimental conditions (room temperature and dioxygen as the terminal oxidant). Furthermore, the reactions proceeded cleanly and the isolation of the desired compounds required minimal work-up. A mechanistic pathway has been proposed, in which nitrogen oxides and oxoammonium ions act as an electron transfer double bridge.

Full text of DOI:10.1016/j.tetlet.2015.10.099

Accepted Manuscript
A convenient alternative for the selective oxidation of alcohols by silica sup-
ported TEMPO using dioxygen as the final oxidant
Ahmed Juwad Shakir, Codruta Paraschivescu, Mihaela Matache, Madalina
Tudose, Alice Mischie, Felicia Spafiu, Petre Ionita
PII:
S0040-4039(15)30296-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.10.099
TETL 46928
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 June 2015
28 September 2015
28 October 2015
Please cite this article as: Shakir, A.J., Paraschivescu, C., Matache, M., Tudose, M., Mischie, A., Spafiu, F., Ionita,
P., A convenient alternative for the selective oxidation of alcohols by silica supported TEMPO using dioxygen as
the final oxidant, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.10.099
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1
Tetrahedron Letters
A convenient alternative for the selective oxidation of alcohols by silica
supported TEMPO using dioxygen as the final oxidant
Ahmed Juwad Shakir,a Codruta Paraschivescu,a Mihaela Matache,a Madalina Tudose,b Alice Mischie,b
Felicia Spafiub and Petre Ionita*a,b
a University of Bucharest, Department of Organic Chemistry, Biochemistry and Catalysis, 90-92 Panduri, Bucharest, Romania.
b
Institute of Physical Chemistry, 202 Spl. Independentei, Bucharest, Romania.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Various primary and secondary alcohols were selectively oxidized to the corresponding
aldehydes and ketones using silica supported TEMPO as a heterogeneous catalyst and
nitrosonium tetrafluoroborate as a cocatalyst. No over-oxidation of aldehydes to acids, nitration
processes or oxidation of double bonds was observed. The reported procedure is very
convenient, and uses mild experimental conditions (room temperature and dioxygen as the
terminal oxidant). Furthermore, the reactions proceeded cleanly and the isolation of the desired
compounds required minimal work-up. A mechanistic pathway has been proposed, in which
nitrogen oxides and oxoammonium ions act as an electron transfer double bridge.
Available online
Keywords:
Alcohols oxidation
TEMPO free radical
Nitrosonium tetrafluoroborate
Silica
2009 Elsevier Ltd. All rights reserved.
Mechanism
———
* Email: pionita@icf.ro

2
Tetrahedron Letters
1. Introduction
stable under normal conditions, and does not dimerize or react
with dioxygen from the air. This free radical can be involved in
acid-base and redox type processes, as shown in Figure 1. The
oxoammonium salt of TEMPO is also well known as a strong yet
specific oxidant.15
Oxidation processes often require harsh experimental
conditions, involving transition metals and strong acids.1 The
oxidation of alcohols leads in the first step to the formation of the
corresponding aldehydes or ketones and in the second step
aldehydes can be converted into carboxylic acids by common
oxidants, including air. Frequently, alcohol oxidation cannot be
stopped at the carbonyl derivative, therefore selective oxidation
methods are highly desirable.2 Many syntheses of medicines or
other fine chemicals require aldehydes and ketones as
intermediates 3 and there is a high demand for specific aldehydes
and ketones: for example, menthone and octanal are used in the
fragrance industry, while cyclohexanone is a precursor in the
plastic industry.
On the other hand, TEMPO is often used in combination with
transition metals and seldomly with metal-free cocatalysts. For
example, copper, iron, manganese and silver have commonly
been used as transition metal cocatalysts,16-19 while halogens
and/or acids have been employed in the metal-free systems.20,21
Furthermore, iron oxide nanoparticles together with TEMPO
(free or covalently attached) were employed as catalytic systems
for the oxidation of benzylic alcohols.22-24
A breakthrough in such systems was the use of nitrogen
oxides as mediators between dioxygen and TEMPO.6,11,13,20,25,26
Initially, NOx was obtained in situ from sodium nitrite and acetic
acid, but the drawbacks associated with removing acetic acid
from the reaction led to the use of gaseous NOx. However,
working with gaseous NOx represents a problematic issue from a
practical point of view. This inconvenience was recently
overcome by our group by absorbing gaseous NOx onto silica
supported TEMPO, thus yielding as an easily handled solid
catalyst which does not require either an additional cocatalyst or
Jones reagent (CrO3, aq. H2SO4) and pyridinium dichromate
(Cornforth reagent, PDC) are some of the most used oxidants.
Because a stoichiometric amount of reagents is needed to convert
primary alcohols into aldehydes,1-4 isolation of the desired
compound from the reaction mixture requires extensive work-up
and generates a large amount of toxic chemical waste. Nowadays
the literature data is rich in novel methods using transition-metal-
free aerobic oxidation, i.e. those involving hypervalent iodine
compounds (Dess-Martin oxidation), oxalyl chloride/DMSO
(Swern oxidation), sodium hypochlorite, nitric acid or its salts,
and nitroxide free radicals.1-10
an
acid.26
Bobbitt’s
salt
(4-acetamido-2,2,6,6-
tetramethylpiperidine-1-oxoammonium tetrafluoroborate),27
a
inexpensive TEMPO derivative, can be easily prepared in a green
manner, using water as the solvent and minimising the use of
environmentally unfriendly materials. Such oxoammonium salts
are metal-free, nontoxic and, after use, the spent oxidant can be
recovered and reused, thereby making the process recyclable.27
Heterogeneous catalysts are preferred in large scale or
industrial applications. Therefore, in this work we continue our
research into conducting practical oxidations of different types of
alcohols employing new NOx and TEMPO based systems. The
newly developed metal-free system employing commercially
available silica supported TEMPO as the catalyst and a
nitrosonium tetrafluoroborate cocatalyst could be used under very
mild reaction conditions to obtain a variety of aldehydes or
ketones in high yields.
Figure 1. Acid-base and redox processes of TEMPO free radical (H. may
stand also for H+ + e-).
One of the commonly used compounds for oxidation is the
stable free radical 2,2,6,6-tetramethylpiperidinyloxy (TEMPO).11-
14
Although it possess an unpaired electron, this chemical is

3
Table 1. Oxidation of various alcohols using silica supported TEMPO as a catalyst and nitrogen dioxide or nitrosonium
tetrafluoroborate as a cocatalyst
Molar ratio: substrate/
catalyst/ cocatalyst
Entry
Substrate
Product
Cocatalyst
NO2
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
4
16
8
40
8
18
18
97
0
1/ 0.2 /0.2
1/ 0.1 /0.1
1/ 0.2 /0.1
1/ 0.1 /0.2
1/ 0.2 /0.2
-
NO+BF4
4
4
16
16
NO2
1/ 0.2 /0.2
0
50
-
NO+BF4
1/ 0.2 /0.2
1/ 0.2 /0.2
1/ 0.2 /0.2
10
NO2
NO+BF4
16
9
-
11
12
13
14
15
16
17
16
4
16
16
16
4
27
0
1
25
38
40
60
NO2
1/ 0.2 /0.2
1/ 0.1 /0.1
1/ 0.2 /0.2
-
NO+BF4
NO2
1/ 0.2 /0.2
1/ 0.2 /0.2
16
-
18
NO+BF4
16
93
19
20
4
99
-
NO+BF4
1/ 0.2 /0.2
16
90
21
22
1
2
73
92
-
NO+BF4
1/ 0.2 /0.2
23
24
1/ 0.2 /0.2
1/ 0.1 /0.1
1
2
100
100
-
NO+BF4
25
26
1
2
50
-
NO+BF4
1/ 0.2 /0.2
67
27
28
NO2
1/0.1/0.1
72
16
99
99
NO+BF4
1/ 0.2 /0.2
-
General conditions: DCM (5 mL), room temperature, dioxygen (balloon), isolated yield.
92% for benzaldehyde (Table 1 Entry 22, 2 h), 100% for
acetophenone (Entry 24, 1 h), and 67% for diphenylketone (Entry
26, 2 h).
2. Results and discussion
As part of our interest in organic reactions mediated by stable
free radicals, we continued our studies aimed at finding improved
and cost-effective strategies for the selective oxidation of a range
of different alcohols (primary, secondary, aliphatic, aromatic, and
cyclic) to the corresponding aldehydes and ketones.
Encouraged by these results, we attempted to extend the
process to a wider range of alcohols. Initially, a series of
reactions were performed using cyclohexanol, menthol, furfuryl
alcohol and 1-octanol, using both NO2 and nitrosonium
tetrafluoroborate as a cocatalyst. Different ratios between
substrate, catalyst and cocatalyst were studied, as well as
different reaction times. As a general rule, longer reaction times
as well as increased amounts of catalyst or cocatalyst improved
the yields of oxidation (Table 1).
We started this study with the previously described catalyst
(NO2 on silica supported TEMPO),26 and employing more
complicated substrates, known for their lower reactivity and
containing moieties that were also suitable for oxidation such as
double bonds (Table 1). Besides the previously explored
activated phenyl alcohols the types of alcohols used was enlarged
from simple ones (1-octanol or cyclohexanol) to steroids (i.e.
testosterone) or hetero-alcohols (furan and pyridine derivatives).
Interestingly, nitrosonium tetrafluoroborate appeared to be a
far better cocatalyst than NO2. In the case of cyclohexanol, after
4 h, the reaction using NO2 proceeded to only 8% conversion into
cyclohexanone (Entry 1), while nitrosonium tetrafluoroborate
gave a yield of 97% (Entry 6). For menthol, no oxidation was
observed in the case of NO2 (Entry 7), even after 16 h (Entry 8),
while nitrosonium tetrafluoroborate gave menthone in 50% yield
after 16 h (Entry 9). Similar results were obtained for furfuryl
Previously used activated alcohols (benzylic alcohol, 1-
phenylethanol and diphenylcarbinol) afforded the corresponding
aldehyde and ketones in over 90% yields after 24 h using NO2 as
a
cocatalyst).26 Using nitrosonium tetrafluoroborate as
a
cocatalyst, similar results were obtained in much shorter times:

4
Tetrahedron
alcohol, where the yield increased from 9% (Entry 9) to 27%
Figure 2. Efficiency of the recovered catalyst (Entry 23). Grey columns- after
(Entry 10), and for 1-octanol where the yield increased from 1%
to 38% (Entries 13 and 15). As no side reactions were noticed,
we proposed that a slow conversion took place. It was previously
noted that TEMPO was not a good catalyst for the oxidation of
aliphatic alcohols, and an AZADO free radical, a less hindered
nitroxide with an adamantane-like structure and hence being
more reactive, needed to be used for better results.20,21
washing with DCM. Black column- after washing with water.
Nevertheless, in our case, the oxoammonium cation is the
intermediate oxidant, as the NO+/NO redox pair in the presence
of TEMPO has been proven to be able to oxidize alcohols in an
anaerobic system.9 Therefore, nitrosonium tetrafluoroborate
oxidizes TEMPO into the corresponding oxoammonium cation,
yielding NO at the same time (Scheme 1).
Using more complicated substrates, the same trend was
observed with yields over 90% (Entry 18, 93%; Entry 19, 99%).
The same result was obtained in the case of a dialcohol (yield
99%, Entry 27 and 28).
Silica is a very good support for TEMPO, as it is stable over a
wide pH range and can be easily modified using silica-coupling
reagents. Additionally, it is a solid that can be simply recovered
and used repeatedly. Previously it was shown that the silica
supported TEMPO/ NOx system could be used in a second
oxidation reaction without the need to be reactivated by passing
through nitrogen dioxide, but its efficiency decreased, requiring
longer reaction times.26 The efficiency of the recycled silica
supported TEMPO in the new system remained very similar to
fresh catalyst, requiring only the addition of nitrosonium
tetrafluoroborate.
As a model we reproduced Entry 23 and recycled the catalyst
(Figure 2). Notably, after 4 reactions, the silica supported
TEMPO kept its original activity. However, after the 4th reaction
the yield fell below 70% and the catalyst needed to be restored by
washing with water or methanol. This loss of activity was
probably due to the accumulation of solid residues on the silica
(i.e. tetrafluoroborate salts) that were not removed by washing
with DCM, but were more easily soluble in water or methanol.
No TEMPO leaking from the silica was observed by TLC or
ESR. The simple separation of the solid heterocatalyst from the
reaction process and its high activity during reuse represents an
economic improvement
Scheme 1. Proposed mechanism involving TEMPO and NOx species
NO reacts easily with dioxygen yielding nitrogen dioxide. It is
worth mentioning that dioxygen, nitrogen oxide and nitrogen
dioxide are all stable free radicals, as they contain in their
molecule an unpaired electron. Nitrogen dioxide oxidises
TEMPOH to TEMPO in a first step; of course, it is also possible
for this to oxidize TEMPO to TEMPO+, thus reforming the active
oxidant species. The NO/NO2 and TEMPO+/TEMPO cycles
represent two active catalytic processes, acting as an electron
transfer double bridge. On the other hand, dioxygen is the final
oxidant and water the by-product of oxidation (Scheme 1). The
solid TEMPO catalyst operates as a trap for NOx, and these
represent the species that activate dioxygen.26,30
Literature data generally shows two types of mechanisms for
such selective oxidations mediated by TEMPO, involving two
different pathways: i) in situ generation of the oxoammonium
cation,5,20 and ii) a complicated cooperative redox mechanism
involving transition metals.28 A simple method to determine the
correct mechanism is to compare the redox potential of the
TEMPO+/TEMPO couple with the involved partner oxidant used
as a cocatalyst. However, this cannot be taken as absolute proof
because the metal ion can alter the reactivity of the TEMPO free
radical.29
Overall, the catalytic system involving NOx as an
unconventional oxidant is a very promising alternative for the
oxidation of a broad array of alcohols with minimal workup.
3. Conclusions
Silica immobilized TEMPO as a catalyst in conjunction with
nitrosonium tetrafluoroborate as cocatalyst was shown to
selectively convert
a wide range of alcohols into the
corresponding aldehydes or ketones. The process minimizes the
drawbacks of classical oxidation systems (acidic media,
halogens, transition metals, or gaseous nitrogen oxides),
proceeding at room temperature under metal, acid and halogen
free conditions. Dioxygen is the final oxidant and water is
obtained as a by-product. The solid catalyst can be easily
recovered and reused directly. This system, which is the first time
that nitrosonium tetrafluoroborate has been used as a cocatalyst,
represents a good alternative for selective alcohol oxidation.
For the first pathway, it is compulsory to conduct the reaction
in the presence of an oxidant which is able to convert the
nitroxide free radical into its oxoammonium cation. If the
cocatalyst cannot directly oxidize TEMPO (i.e. copper salts), a
complicated concerted two-electron alcohol oxidation takes
place. Very recently, this issue was resolved, reconciling a
collection of diverse and seemingly contradictory experimental
and computational data reported previously in the literature.28
100
80
60
40
20
0
Acknowledgements
This work was supported by a grant from the Romanian
National Authority for Scientific Research, CNCS – UEFISCDI,
project number PN-II-ID-PCE-2011-3-0408.
1
2
3
4
5
Runs

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Supplementary Material
Experimental details and typical NMR spectra of the reaction
products.

Graphical Abstract
A convenient alternative for the selective
oxidation of alcohols by silica supported
TEMPO using dioxygen as the final oxidant
Leave this area blank for abstract info.
Ahmed Juwad Shakir, Codruta Paraschivescu,
Mihaela Matache, Madalina Tudose, Alice Mischie,
Florica Spafiu and Petre Ionita

6
Tetrahedron
Highlights:
 Unconventional oxidation of alcohols to the corresponding aldehydes or ketones;
 Clean reactions with minimal work-up in high yields, at room temperature;
 Supported TEMPO free radical as heterogeneous catalyst;
 First time nitrosonium tetrafluoroborate used as cocatalsyt;
 Mechanistic pathway involves nitrogen oxides and oxoammonium ions.