Hydroxylamine as a source for nitric oxide in metal-free 2,2,6,6-tetramethylpiperidine N-oxyl radical (TEMPO) catalyzed aerobic oxidation of alcohols

Article abstract of DOI:10.1002/adsc.201000703

The communication reports on the metal-free 2,2,6,6-tetramethylpiperidine N-oxyl radical (TEMPO) catalyzed aerobic oxidation of various alcohols to aldehydes and ketones. A novel catalyst system that uses 1-4 mol% of TEMPO in combination with 4-6 mol% of aqueous hydroxylamine is introduced. No other additives are necessary and corrosive by-products are not formed during oxidation. Nitric oxide which is important for the catalytic cycle is generated in situ by reaction of the hydroxylamine with TEMPO. A catalytic cycle for the overall oxidation process is suggested.

Full text of DOI:10.1002/adsc.201000703

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DOI: 10.1002/adsc.201000703
Hydroxylamine as a Source for Nitric Oxide in Metal-Free 2,2,6,6-
Tetramethylpiperidine N-Oxyl Radical (TEMPO) Catalyzed
Aerobic Oxidation of Alcohols
Sebastian Wertza and Armido Studera,*
a
Organisch-Chemisches Institut, Westfꢀlische Wilhelms-Universitꢀt, Corrensstrasse 40, 48149 Mꢁnster, Germany
Fax : (+49)-251-833-6523; phone: (+49)-251-833-3291; e-mail: studer@uni-muenster.de
Received: September 11, 2010; Revised: November 4, 2010; Published online: December 30, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000703.
Abstract: The communication reports on the metal-
free 2,2,6,6-tetramethylpiperidine N-oxyl radical
(TEMPO) catalyzed aerobic oxidation of various
alcohols to aldehydes and ketones. A novel catalyst
system that uses 1–4 mol% of TEMPO in combina-
tion with 4–6 mol% of aqueous hydroxylamine is
introduced. No other additives are necessary and
corrosive by-products are not formed during oxida-
tion. Nitric oxide which is important for the catalyt-
ic cycle is generated in situ by reaction of the hy-
droxylamine with TEMPO. A catalytic cycle for the
overall oxidation process is suggested.
plied for oxidation of a broad range of alcohols.[5] Be-
sides other cocatalysts,[6] iron(III)[7] and copper(II)[8]
salts have been intensively studied along this line.
Furthermore, heterogeneous nitroxide-based catalysts,
that might be useful for industrial applications, have
gained high visibility.[9]
A first metal-free aerobic oxidation protocol, which
uses TEMPO as a catalyst and NaNO2/Br2 as cooxi-
dants, was reported in 2004.[10] NaNO2 acts as a pre-
cursor for nitric oxide which is rapidly oxidized by di-
oxygen to generate nitrogen dioxide. NO2 reacts with
HBr to regenerate bromine that oxidizes TEMPO to
its N-oxoammonium bromide salt and HBr. The oxo-
AHCTUNGTRENNUNG
Keywords: aerobic oxidation; alcohols; catalysis;
hydroxylamine; nitric oxide; 2,2,6,6-tetramethylpi-
peridine N-oxyl (TEMPO)
ACHTUNGTRENaNGNU mmonium salt is capable of oxidizing the substrate
alcohol. However, the use of bromine and the forma-
tion of HBr during oxidation make this and related
protocols less attractive for industrial applications.[11]
Nevertheless, the use of NaNO2 in these aerobic oxi-
dation processes has found high impact and several
variants of that protocol have been developed.[12] To
The persistent nitroxide TEMPO (2,2,6,6-tetramethyl- simplify the complicated four-component catalytic
piperidine N-oxyl radical) and derivatives thereof are system, other sources for nitric oxide have been
highly valuable organocatalysts for the conversion of found. For example, tert-butyl nitrite (TBN) was
primary and secondary alcohols to the corresponding shown to be an efficient additive for alcohol oxidation
carbonyl compounds.[1] The catalytically active species in combination with TEMPO and dioxygen.[13] Fur-
in most of these reactions is not the nitroxide itself, thermore, the application of hydroxylamine as an NO
but its oxidized form, the corresponding N-oxo- source was reported very recently.[14] KBrO3 was used
ACHTUNGTRENNUNGammonium salt. In practice, the oxoammonium salt is to generate both NO2 and NO from hydroxylamine
generated in situ by one-electron oxidation using vari- hydrochloride. The bromate is decomposed to bro-
ous organic[2] or inorganic[3] cooxidants. This allows mide anions providing all necessary components for
the nitroxide to be used as a catalyst in these oxida- the generation of N-oxoammonium bromides. Howev-
tions. Although sodium hypochlorite has been highly er, corrosive by-products are formed using this proto-
successfully used as a cooxidant (Anelli conditions),[3a] col.
the identification of cheap and environmental more
Herein we report a new catalyst system for the
friendly alternatives is important and currently an aerobic alcohol oxidation that uses TEMPO and an
active research area. As a result, dioxygen has been aqueous solution of hydroxylamine as catalysts with-
investigated as a terminal oxidant in nitroxide-based out any other additives (Scheme 1). It is important to
oxidation protocols.[4] Nitroxides in combination with note that corrosive HBr is not formed during alcohol
transition metal catalysts have been successfully ap-
Adv. Synth. Catal. 2011, 353, 69 – 72
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69

Sebastian Wertz and Armido Studer
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Table 1. TEMPO/NH2OH-catalyzed aerobic oxidation of al-
cohols.[a]
Entry Product
TEMPO NH2OH Time Yield
[mol%]
[mol%]
[h]
[%][b]
Scheme 1. TEMPO-catalyzed aerobic alcohol oxidation in
the presence of hydroxylamine.
100[c]
(97)
1
2
3
4
1
1
4
4
4
100
(97)
4
oxidation and water is the only side product in these
reactions.
100
(95)
2
2
4
4
4
4
Based on our observation that TEMPO is reduced
to its corresponding hydroxylamine in the presence of
hydroxylamine, we thought that NH2OH might act as
a clean source for NO upon reaction with TEMPO.
First experiments were performed in dichlorome-
thane at room temperature using benzyl alcohol as a
test substrate.
We found that with 40 mol% of TEMPO and
40 mol% of an aqueous solution of hydroxylamine
(50 wt%) under an atmosphere of O2 (balloon tech-
nique) at room temperature, benzaldehyde was quan-
titatively formed within 12 h. In a,a,a-trifluorotol-
100
(98)
100
(99)
5
6
7
2
2
2
2
4
4
4
4
4
6
6
6
100
(94)
100
(97)
ACHTUNGTRENNUNGuene, or a mixture of acetonitrile and water (3:1), or
an aqueous phosphate buffer, the oxidation did not
work. Benzaldehyde was formed quantitatively using
1,2-dichloroethane (DCE) as a solvent under other-
wise identical conditions. In refluxing DCE the reac-
tion time was decreased to 4 h (100% conversion).
Surprisingly, the oxidation did not proceed efficiently
using hydroxylamine hydrochloride and NEt3 in place
of salt-free aqueous hydroxylamine as additives.
Unfortunately, lowering the amount of catalysts led
to a significantly reduced yield. For example, using
TEMPO (5 mol%) and NH2OH (10 mol%), catalysis
stopped at low conversion (13%). At this place we
have to mention that all initial reactions were con-
ducted in Schlenk flasks using balloon technique. The
head space of the reaction mixture was exchanged
several times by flushing dioxgen through the flask.
We made the important observation that, in some
cases, results using this experimental set-up were not
reproducible. We believed that this was due to the
fact that the catalytically active NO and NO2 (see dis-
cussion on the mechanism below) were removed from
100
(99)
8
9
91
(63)
4
4
6
6
3
6
100[c]
(91)
100
(87)
100
(90)
40
10
11
12
4
4
4
6
6
6
6
6
8
13
(21)
[a]
All reactions carried out on a 20 mmol scale of the corre-
sponding alcohol in DCE at 808C and a pressure of 3 bar
of O2.
[b]
[c]
GC conversion (isolated yield).
Full conversion was also achieved using 4-acetamido-
TEMPO as the nitroxide catalyst.
the reaction mixture while flushing the head space identical conditions.
A further lowering of the
with O2. Therefore, we decided to continue our opti- TEMPO loading to 0.5 mol% in combination with
mization studies in a stainless steel autoclave to pre- 4 mol% of NH2OH did not allow for quantitative oxi-
vent leakage of NO and NO2. A constant O2 pressure dation (64%). Moreover, using 1 mol% of TEMPO
of 3 bar was used in most experiments.
and 2 mol% of NH2OH, conversion was also not com-
To our delight, with 1 mol% TEMPO and 4 mol% plete (83%). The electron-rich para-methoxybenzyl
hydroxylamine near quantitative benzaldehyde forma- alcohol was quantitatively oxidized under optimized
tion at 808C for 4 h was achieved (Table 1, entry 1). conditions (entry 2). However, benzyl alcohol deriva-
TEMPO could be replaced by the less expensive 4- tives bearing electron-withdrawing substituents were
acetamido-TEMPO without affecting the yield. The less reactive and TEMPO loading had to be increased
O2 pressure seemed not to influence reaction outcome to 2 mol% in order to reach full conversion (en-
to a large extent, since full conversion was also tries 3–5). Under the same conditions, secondary
achieved with 2 or 4 bar of dioxygen under otherwise benzyl alcohols were quantitatively oxidized to the
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Adv. Synth. Catal. 2011, 353, 69 – 72

Hydroxylamine as a Source for Nitric Oxide
In summary, we have reported a new catalyst
system for the TEMPO-catalyzed aerobic oxidation
of alcohols. The process uses commercially available
catalysts, namely TEMPO and aqueous hydroxyl-
AHCTUNGTREGUNaNN mine. Various primary and secondary alcohols can
be oxidized with this procedure. No corrosive acids
are generated during oxidation and water is the only
side product formed.
Experimental Section
Scheme 2. Catalytic cycle.
General Remarks
All autoclave reactions were performed in a stainless steel
autoclave (Roth high pressure laboratory autoclave model 2
equipped with two needle valves for charging and depres-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
corresponding ketones (entries 6–8). As expected, ali-
phatic alcohols, such as 2-phenylpropan-1-ol, were
more difficult to oxidize. We found that 4 mol% of
TEMPO and 6 mol% of NH2OH were necessary for
high conversion (entry 9). With this substrate we
argon atmosphere. 1,2-Dichloroethane (DCE, 99.8+%,
extra pure) was purchased from Acros Organics and was
used as received. Hydroxylamine solution (50 wt% in H2O,
99.999%) was purchased from Sigma Aldrich and was used
as received. All other chemicals were purchased from Sigma
Aldrich, Acros Organics, and Fluka and were used as re-
ceived. Gas chromatography (GC) was performed on a
Hewlett Packard 6890 chromatograph equipped with a HP-5
column (30 mꢃ0.32 mm, film thickness 0.25 mm) using H2
(ca. 1 bar) as carrying gas. GC/MS (EI, 70 eV) was per-
formed on a combined set-up of an Agilent 6890N chroma-
tograph equipped with a HP-5 column using helium (ca.
1 bar) as carrying gas and a Waters-Micromass Quattro
À
noted oxidative C C bond cleavage of phenylacetal-
dehyde to benzaldehyde under the applied conditions.
Therefore, reaction was stopped at 91% conversion
(3 h). Transformation of phenylacetaldehyde to ben-
zaldehyde has been reported.[15] Other primary ali-
phatic alcohols were cleanly oxidized within 6 h (en-
tries 10–12). Under these conditions, oxidation of sec-
ondary alcohols as exemplified for cyclohexanol was
not efficient (entry 13).
We suggest the following catalytic cycle for oxida-
tion of alcohols under the applied conditions
(Scheme 2). NO is probably generated by oxidation
of H2NOH with TEMPO via H-transfer reactions to
give TEMPOH. Reaction of NO with O2 provides
NO2,[13] which reacts with TEMPOH to give NO and
the TEMPO oxoammonium salt. This salt then reacts
with the substrate alcohol to give the corresponding
aldehyde or ketone.[1] Environmentally friendly water
is the sole by-product formed in this process.
TEMPO has a dual role in our proposed catalytic
cycle: a) it acts as an oxidant to generate the active
cooxidant (NO) and b) it acts as precursor for the N-
oxoammonium cation. We were able to qualitatively
prove the formation of nitric oxide in the reaction of
TEMPO with hydroxylamine by running the
TEMPO-mediated hydroxylamine decomposition in
the presence of 2,3-diaminonaphthalene (DAN).
1
Micro spectrometer. H NMR (300 MHz) spectra were re-
corded on a Bruker DPX 300 spectrometer. HR-MS ESI
(m/z) were recorded on a Bruker MicroTof or an Orbitrap
LTQ XL (Nanospray) of Thermo Scientific. Fluorescence
emission spectra were recorded on an AMINCO-Bowman
Series 2 (AB2) spectrometer of Thermo Fisher Scientific
Inc. Thin layer chromatography (TLC) was carried out on
Merck silica gel 60 F254 plates; detection with UV light or by
dipping into a solution of KMnO4 (1.5 g) and NaHCO3
(5.0 g) in H2O (0.40 L) followed by heating. FC was carried
out on Merck silica gel 60 (40–63 mm) with an argon excess
pressure of about 0.4 bar.
Typical Procedure for Alcohol Oxidation
Oxidation of benzyl alcohol: Benzyl alcohol (2.07 mL,
20.0 mmol, 1 equiv.) was added to a glass barrel equipped
with a stirring bar and dissolved in DCE (20 mL). After ad-
DAN is a well accepted probe for nitric oxide, mostly dition of TEMPO (31.3 mg, 0.200 mmol, 1 mol%) and a so-
applied in biochemistry.[16] Upon treatment with nitro-
lution of NH2OH (53 mL, 0.80 mmol, 4 mol%, 50 wt% in
H2O) the barrel was quickly embedded into a stainless steel
sating agents in acidic media, DAN is smoothly con-
autoclave which was instantaneously closed and charged
verted to the highly fluorescent 2,3-naphthotriazole
with dioxygen (3 bar). The reaction mixture was then vigo-
(NAT).[17] Indeed, small amounts of NAT were
rously stirred (1500 rpm) at 808C for 4 h. After cooling to
formed when DAN was added to a solution of
room temperature, careful depressurization and GC analysis,
TEMPO and hydroxylamine in dichloromethane at
the solvent was removed under reduced pressure to afford
room temperature under an oxygen atmosphere.
after purification by FC (SiO2) benzaldehyde which was an-
alyzed by 1H NMR spectroscopy. 1H NMR (300 MHz,
CDCl3): d=10.02 (s, 1H, CH), 7.95–7.83 (m, 2H, aryl-H),
7.70–7.58 (m, 1H, aryl-H), 7.58–7.47 (m, 2H, aryl-H). Spec-
Analysis by ESI-mass spectrometry and fluorescence
spectroscopy unambiguously confirmed the formation
of NAT.
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71

Sebastian Wertz and Armido Studer
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Adv. Synth. Catal. 2011, 353, 69 – 72