Practical Aerobic Oxidation of Alcohols: A Ligand-Enhanced 2,2,6,6-Tetramethylpiperidine-1-oxy/Manganese Nitrate Catalyst System

Article abstract of DOI:10.1002/cctc.201700710

A highly efficient, ligand-enhanced 2,2,6,6-tetramethylpiperidine-1-oxy (TEMPO)/Mn(NO₃)₂ catalyst system for the aerobic oxidation of alcohols is described. From the series of coordinating ligands studied herein, 2-picolinic acid (PyCOOH) improves the catalytic activity of TEMPO/Mn(NO₃)₂ remarkably. Under ambient air at room temperature in acetic acid, the ligand-enhanced catalyst converts aliphatic and benzylic primary alcohols that bear various functional groups into their respective aldehydes with near quantitative conversions. The applicability of the catalyst for convenient preparative synthesis was demonstrated by conducting oxidations on a gram scale. A change of TEMPO to the sterically less demanding 9-azabicyclo[3.3.1]nonane N-oxyl results in a Mn catalyst that is also able to oxidize secondary alcohols to ketones. Mechanistic studies showed that alcohols are oxidized by the oxoammonium cation derived from the nitroxyl radical. The active oxidant is regenerated by Mn(NO₃)₂, and this process is greatly promoted by the coordination of PyCOOH to Mn.

Full text of DOI:10.1002/cctc.201700710

Accepted Article
Title: Practical Aerobic Oxidation of Alcohols: Ligand Enhanced
TEMPO/Mn(NO3)2 Catalyst System
Authors: Kalle Lagerblom, Emi Lagerspets, Juha Keskiväli, Chris Cook,
Filip Ekholm, Arno Parviainen, and Timo Juhani Repo
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Practical Aerobic Oxidation of Alcohols: Ligand Enhanced
TEMPO/Mn(NO Catalyst System
)
3 2
Kalle Lagerblom, Emi Lagerspets, Juha Keskiväli, Chris Cook, Filip Ekholm, Arno Parviainen and Timo
Repo*[a]
Abstract: A highly efficient, ligand enhanced TEMPO/Mn(NO
3
)
2
by conducting oxidations in a gram scale. A change of TEMPO to
sterically less demanding 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO)
turns the Mn-catalyst also capable for oxidation of secondary alcohols
to ketones. Mechanistic studies showed that alcohols are oxidized by
the oxoammonium cation derived from the nitroxyl radical. The active
catalyst system for the aerobic oxidation of alcohols is described.
From the series of coordinating ligands studied herein, 2-picolinic acid
(PyCOOH) remarkably improves the catalytic activity of
TEMPO/Mn(NO . Under ambient air, at room temperature and in
3 2
)
acetic acid, the ligand-enhanced catalyst converts various functional
group-bearing aliphatic and benzylic primary alcohols to their
respective aldehydes with near quantitative conversions. Applicability
of the catalyst for convenient preparative synthesis was demonstrated.
3 2
oxidant is re-generated by Mn(NO ) and this process is greatly
promoted by the coordination of PyCOOH to Mn.
Introduction
surprisingly, reports on homogeneous Mn catalysts are scarce in
this field. Mixtures of Mn/Co and Mn/Cu nitrate salts with TEMPO
are reported to catalyze the aerobic oxidation of alcohols, but the
use of monometallic Mn-catalysts has remained elusive.[11] The
bimetallic catalysts can oxidize primary benzylic alcohols under
The oxidation of alcohols to aldehydes, ketones, and carboxylic
acids is among the most widely used class of oxidation reactions
in organic chemistry.[1] Classically, these transformations are
achieved using stoichiometric amounts of oxidants, such as CrO
3
,
ambient air, but pure O
aliphatic alcohols. In this respect, we report a novel, ligand-
enhanced monometallic TEMPO/Mn(NO catalyst for the
oxidation of activated and unactivated alcohols under open air at
2
is needed as an oxidant for primary
2
MnO , activated DMSO, and hypervalent iodine, which are all
costly and produce large amounts of hazardous waste.[2] To ease
the environmental and economic burden of these practices,
3 2
)
catalytic approaches using more environmentally benign oxidants, room temperature. The catalyst system is suitable for the
such as H
2
O
2
and O
2
, have lately received great attention.[3] In
oxidation of various alcohols using a simple reaction setup and
workup, which makes it highly practical for preparative scale
synthesis.
particular, aerobic oxidation has gained prominence due to its
projected enhancements to the process economy and waste
treatment. A plethora of catalysts have been reported for this
transformation, usually based on transition metals. However, the
use of noble metals (e.g. Pd, Ru, and Au), expensive ancillary Results and Discussion
ligands, or both, limits their applicability.[4] Furthermore, these
2
catalytic systems often operate under pure O in organic solvents,
Catalyst optimization
which may pose a safety risk.[5] Accordingly, there is an increasing
demand for inexpensive catalyst systems utilizing ambient air as
the oxidant. Recent efforts in this area have led to the
We initiated the study by oxidizing 1-octanol (1a) to octanal (2a)
under ambient air, with three different catalysts consisting of Mn,
Mn-Co and Mn-Cu nitrate salts and TEMPO, which were formed
in situ. In these experiments 1a was converted to 2a in 18 - 26%
yields (Table 1, Entries 1-3). Surprisingly, the highest yield was
obtained when Mn was used as the sole metallic component in
the reaction, instead of the Mn-Co and Mn-Cu mixtures. We were
interested to see if the catalyst activity could be increased by
development of promising first-row transition metal catalysts, (e.g.
Cu,[6] Fe,[7] and V[8]), that facilitate the oxidation of alcohols
selectively under air, either on their own, or in combination with
stable nitroxyl radicals such as TEMPO.
Manganese is an earth-abundant, first row transition metal
with different oxidation states which makes it a suitable catalyst
for oxidation reactions.[9] Manganese oxides are well known as
heterogeneous catalysts for aerobic alcohol oxidation,[10] but
addition of a ligand to the system, as we had observed earlier with
TEMPO/Fe(NO )
3 3
catalyst.[ Ligand investigations were started
by adding 2-picolinic acid (PyCOOH) to the reaction, which
7e]
significantly increased the yield of 2a (from 26% to 97%) with
[
a]
K. Lagerblom, E. Lagerspets, C. Cook, J. Keskiväli, Dr. F. Ekholm,
Dr. A. Parviainen and Prof. Dr. T. Repo
Department of Chemistry
Faculty of Science
A. I. Virtasen aukio 1, 00014 University of Helsinki
P.O. Box 55
3 2
TEMPO/Mn(NO ) catalyst. The enhancement persisted even
when halving the amount of TEMPO (entry 4). The ligand effect
was found to be less pronounced with the Mn-Co and Mn-Cu
catalysts (Table 1, Entries 5 and 6).
Finland
E-mail: timo.repo@helsinki.fi
Supporting information for this article is given via a link at the end of
the document.
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Table 2. The effect of a ligand on the catalytic aerobic oxidation of 2-octanol.
Table 1. Aerobic oxidation of 1-octanol with ligand-enhanced metal
nitrate/TEMPO catalytic system.[
a]
Entry
Ligand
Yield[b] (Conversion[b]) %
Yield[
b]
TEMPO
mol %
Entry
Co-catalyst
Ligand
(Conversion[b]) %
1
2
3
4
5
6
-
16 (16)
97 (99<)
36 (37)
37 (38)
39 (40)
1
2
3
4
5
6
Mn(NO )
3 2
-
-
-
10
10
10
5
26 (26)
18 (18)
21 (21)
97 (99<)
16 (1)
Mn/Co(NO
3
)
2
2
Mn/Cu(NO
3
)
Mn(NO
Mn/Co(NO
Mn/Cu (NO
3 2
)
3
)
2
5
77 (79)
21 (21)
46 (47)
18 (19)
3
)
2
5
56 (58)
7
[
a] Conditions: 1-octanol (1 mmol), co-catalyst (0.04 mmol), ligand (0.06
mmol), AcOH (2 ml), open test tube. [b] Yield and conversion were
determined using GC-FID with acetophenone as internal standard.
8
9
The promising results obtained with PyCOOH motivated us
to study more ligands (Table 2). We used the Mn(NO ) /TEMPO
3 2
catalyst for screening, as the results from Mn-Co- and Mn-Cu-
mediated systems indicated lower yields. The selected ligands (or
their structural analogues) are commonly used to enhance the
10
11
12
18 (18)
11 (11)
6
(6)
efficiency of oxidation catalysts and hence were chosen for these
trials.[
6b,12]
[a] Conditions: 1-octanol (1 mmol), TEMPO (0.05 mmol), Mn(NO
3 2 2
) ∙4H O
Of all the ligands tested, the greatest increase in
(0.04 mmol), ligand (0.06 mmol), AcOH (2 ml), open test tube. [b] Yield
reaction efficiency was obtained with the initial PyCOOH,
resulting in >99% conversion of 1a (Table 2, Entry 2). Structurally
similar thiophenecarboxylic acid and furancarboxylic acid showed
only a slight increase in efficiency (Entries 3 and 4). The same
also was observed for 2,2’-Bipyridine (BiPy), which resulted in
and conversion were determined using GC-FID with acetophenone as
internal standard.
2
products by simple extraction with EtOAc/H O followed by
evaporation of solvent. Minor selectivity issues occurred during
the oxidation of 3-(benzyloxy)propan-1-ol, citronellol, and 3-
phenylprop-2-yn-1-ol under the reaction conditions optimized for
oxidation of 1a. Full conversions were also achieved with these
substrates, but the desired aldehydes (2n-2p) were recovered in
yields of only 31-45%, due to the reported side reactions of
40% conversion (Entry 5). On the other hand, the 4,4’-dimetoxy
analogue of BiPy gave a conversion of 79%, possibly due to the
presence of electron-donating methoxy groups in the molecule
(
Entry 6). Other ligands had only a modest positive effect on the
reaction outcome (Entries 7-10) or even inhibited the reaction, as
observed with pyridine and 2,2’;6’,2”-terpyridine (Entries 11 and
alkenyls, alkynyls, and ethers with the NO
x
and oxoammonium
+
[13]
cation (TEMPO ) present in the reaction media. We resolved
the selectivity issue by lowering the reaction temperature from RT
to 15°C and by using pure oxygen (1 atm) as the oxidant. By
conducting reactions this way, we were able to recover aldehydes
12). Further studies conducted on optimizing the catalyst
composition and reaction conditions are presented in the
supporting information (SI) (Tables S1-S4).
2
n-2p in over 70% isolated yields.
Substrate scope studies
The initial TEMPO/Mn(NO ) /PyCOOH catalyst system was
3 2
also used for oxidation of selected secondary alcohols (table 3).
These reactions showed reduced reaction rates compared to
those observed with primary alcohols. Only the highly activated
diphenylmethanol was completely converted to the respective
ketone (2q) under the conditions optimized for 1a oxidation. The
less reactive 2-octanol and borneol were transformed to the
desired ketones (2r and 2s) in only under 60% yields. This is in
accordance with previous reports showing that TEMPO-mediated
oxidations often proceed sluggishly with secondary alcohols.[
The low reactivity is associated with steric hindrance around the
alcohol α-hydrogen, which hampers the rate-determining hydride
After obtaining good results in the oxidation of 1a, we studied the
oxidation of
other
alcohols
using
the
optimized
Mn(NO ) /TEMPO/PyCOOH system (Table 3). The reaction
3 2
tolerates a variety of reactive and synthetically useful functional
groups, such as double and triple bonds, halogens, esters, ethers
and heteroaromatic structures. No significant difference in
reactivity was detected between aliphatic, allylic benzylic, or
heteroaromatic alcohols. These substrates were smoothly
converted to the respective aldehydes (2b-2m) within 3 h under
ambient air in room temperature. With most substrates, complete
conversions were obtained, which enabled us to obtain pure
14]
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abstraction if the nitroxyl catalyst used is sterically demanding like
TEMPO.[3k, 7d] Secondary alcohol oxidation rates are generally
significantly increased when TEMPO is replaced with a sterically
less hindered nitroxyl catalyst, such as 9-azabicyclo[3.3.1]nonane
N-oxyl (ABNO) (Table 3, method C).[15] We adopted this approach
and successfully oxidized the secondary alcohols to the
respective ketones 2p-2r with 95-97% isolated yields using a
ABNO/Mn(NO ) /PyCOOH catalyst system. Furthermore, only
3 2
half of the catalyst loading was required for the oxidation of
secondary alcohols with ABNO-based catalyst. The efficiency of
the ABNO- mediated catalytic system on primary alcohols was
also examined. This resulted in increased reaction rates but
slightly lowered selectivities compared to TEMPO containing
catalyst (Table S5 in SI).
3 2
Table 3. Substrate scope of TEMPO/Mn(NO )
/PyCOOH oxidation system.[a]
The primary and secondary alcohol oxidations described
above were also conducted in the absence of the PyCOOH ligand
to see if some substrates could be oxidized using a simplified
catalyst system (Table 3). However, the reaction was significantly
less efficient when the coordinating ancillary was not used. Even
the activated benzylic and heteroaromatic alcohols were not
completely converted to the respective aldehydes 2b-2i in ligand-
free conditions, and the aliphatic and allylic alcohols afforded the
corresponding carbonyl products 2j-2m in poor yields.
Ligand (PyCOOH)
No Ligand
Conver Isolated
Product
Method
A
Conver
sion%[
Isolated
Yield%
b]
[b]
sion%
Yield%
99<
98
61
55
2
b
During the substrate scope studies, we recognized some
limitations in the functional group tolerance of the reaction
A
A
A
A
99<
99<
99<
99<
96
96
97
92
94
95
96
93
88
89
90
88
2c
(
Scheme 1). The oxidation of 1,2-benzenedimethanol (1t) yielded
a mixture of the corresponding dialdehyde (2t) and lactone (3t) in
2% and 33% yields, respectively. Full conversion was observed
with 2-pyridinemethanol (1u), but the corresponding aldehyde
2u) was only recovered in 62% yield.
2d
4
2e
(
2f
A
99<
96
95
90
2g
A
A
A
A
99<
99<
99<
99<
94
96
91
92
95
96
45
47
89
91
38
39
2
h
2
i
2
j
2
k
A
A
99<
99<
86
93
30
18
24
12
2l
2m
A
B
99<
85
31
73
9
<5
<5
0
2n
3 2
Scheme 1. Limitations of TEMPO/Mn(NO ) /PyCOOH oxidation system due to
a) low selectivity and b) extensive side reactions.
A
B
99<
82
34
71
21
<5
7
0
2o
A
B
99<
90
45
75
25
<5
11
0
Oxidation of 1,5-pentanediol (1v), N-methyl-4-piperidinol (1w),
and 3-decyn-1-ol (1x) led to formation of complex product
2p
A
C
99<
99<
98
98
78
95
73
69
mixtures, plausibly due to side reactions with NO
Based on these results, selectivity issues might occur if the
TEMPO/Mn(NO /PyCOOH catalyst system is used for oxidation
x
or TEMPO+.[13]
2q
A
C
58
99<
52
95
11
67
8
62
3 2
)
2r
of diols or alcohols containing triple bonds or nitrogen atoms. It is
noteworthy that the use of glacial AcOH as reaction solvent might
limit the compatibility of this oxidation methodology with acid labile
substrates.
A
C
65
99<
59
97
14
73
10
65
2s
[
a] Conditions: substrate (2 mmol), TEMPO (0.1 mmol) Mn(NO
3 2 2
) ∙4H O
(0.08 mmol), PyCOOH (0.12 mmol), AcOH (4 ml), open test tube. [b]
Conversion determined using GC-FID with acetophenone as internal
standard.
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After examining the scope and the limitations of the method,
a
sufficiently acidic environment to facilitate TEMPO
we wanted to assess its applicability for preparative-scale
production of industrially and synthetically interesting aldehydes.
We chose 2,6-diformylfuran (DFF, 2y) as a first target compound,
due to its potential industrial uses as a starting material for
pharmaceuticals, polymers, and chelating ligands.[16] DFF was
synthesized through the oxidation of bio-based 5-
hydroxymethylfurfural (HMF, 1y) in 100 mmol (12.6 g) scale
disproportionation. A control experiment conducted in MeCN did
not lead to benzaldehyde formation.
(
Scheme 2a). The reaction was conducted under the same
catalytic conditions that were previously optimized for oxidation of
a, which resulted in full conversion of HMF to DFF in 3 h. After
1
completion, the reaction was quenched by addition of EtOAc.
Pure DFF was obtained in 85% isolated yield by simply washing
the organic phase with water, followed by evaporation of EtOAc
to dryness. To further exhibit the practicality of the method for
gram-scale synthesis, we oxidized 1,2:3,4-Di-O-isopropylidene-α-
D-galactopyranose (1z) to the corresponding aldehyde (2z) in 25
mmol (6.5 g) scale (Scheme 2b). Again, rapid and complete
oxidation of the starting alcohol took place and 2z was recovered
in 79% yield after a 3 h reaction.
Scheme 3. TEMPO-mediated alcohol oxidation in acidic conditions
After experimentally proving that TEMPO is plausibly the source
of the active oxidant TEMPO+ in AcOH, we focused on the re-
oxidation of reduced nitroxyl catalyst TEMPOH. To determine
which catalyst species can oxidize TEMPOH back to TEMPO, we
conducted more stoichiometric alcohol oxidations under argon. In
these experiments, we combined an equivalent amount of the
alcohol 1aa with TEMPOH and let them react with different Mn
-
and NO
3
sources to identify which ion reacts with TEMPOH (i.e.
acts as a secondary oxidant) (Table 4).
Table 4. Oxidation of benzyl alcohol using stoichiometric amount of
TEMPOH and co-oxidant under argon.
Scheme 2. Gram scale syntheses of a) DFF and b) 1,2:3,4-Di-O-
isopropylidene-α-D-galacto-hexadialdo-1,5-pyranose.
Entry
Additive X
-
Yield[b]
1
2
3
4
5
0
4
Mechanistic studies
KNO
3
Having considered the scope, limitations, and practicality, we
turned our focus to the mechanistic aspects of the reaction. It has
been previously suggested that the catalytic cycle of
Mn(NO
)
3 2
>99
0
TEMPO/Mn(NO
3
)2-mediated alcohol oxidation in AcOH consists
Mn(OAc)
2
3
of acid-induced disproportionation of TEMPO to TEMPOH and
Mn(OAc)
50
+
TEMPO , reaction of the latter with alcohol, and a one-electron
oxidation of TEMPOH back to TEMPO (Scheme 3).[11] However,
the suggested mechanism has not been supported by
experimental data. The first step of the catalyst cycle, the acid-
induced disproportionation of TEMPO, is well established in the
presence of strong acids (such as TfOH) but lacks experimental
evidence from reactions performed in moderately acidic media i.e.
acetic acid.[17] To assess the possibility of the acid-catalyzed
pathway, we added TEMPO (2 eq) into a glacial AcOH solution of
benzyl alcohol (1aa) (1 eq) under argon. This should have
resulted in 100% yield of benzaldehyde (2aa) if all of the nitroxyl
[
(
a] Conditions: benzyl alcohol (0.5 mmol), TEMPOH (0.5 mmol), additive X
0.5 mmol) AcOH (1 ml), argon atmosphere (inside glovebox). [b] Yields
determined by GC-FID using calibration curves with acetophenone as
internal standard.
+
had disproportionated, and the resulting TEMPO had reacted
with the alcohol quantitatively. In this experiment, the aldehyde
2aa was formed in 79% yield, showing that glacial AcOH is indeed
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First, we performed a control experiment using just TEMPOH and
alcohol 1aa, which did not lead to formation of aldehyde 2aa,
providing evidence that a secondary oxidant is necessary for
alcohol oxidation with TEMPOH (Table 4, Entry 1). Addition of
argon, which would explain the alcohol oxidation observed in the
presence of Mn(NO ) and TEMPOH during the experiment
3 2
described in entry 3, Table 4. To prove or dismiss the hypothesis
of Mn(III) formation under argon, we used UV-vis spectroscopy to
KNO
3
into a solution of TEMPOH and 1aa resulted in minor 4%
study AcOH solutions of Mn(NO
3 2
) (Figure 1). In the first
yield of the aldehyde 2aa (Table 4, Entry 2). This suggests that
experiment, Mn(NO was dissolved into glacial AcOH and stirred
3 2
)
-
that are liberated from NO -
NO
3
or other NO
x
3
in acidic solution
under argon, while monitoring the change in the UV-vis absorption
pattern (Figure 1a). At the beginning, a typical Mn(II) spectra was
observed, displaying absorption only under 350 nm.[19] After a
while, a weak Mn(III) shoulder at 400-550 nm started to emerge,
are not active secondary oxidants under our reaction
[
18]
conditions. However, when the reaction was conducted using
Mn(NO instead of KNO , full conversion of the alcohol 1aa to
3
)
2
3
the aldehyde 2aa was observed, indicating that Mn has a central
role in TEMPOH oxidation (Table 4, Entry 3). This said, we
eliminated the nitrate ion from the reaction and reconducted the
oxidation with Mn(OAc) and Mn(OAc) to determine if a generic
2 3
Mn salt could facilitate TEMPOH oxidation without the redox-
active anion (Table 4, Entries 4 and 5). No alcohol oxidation was
indicating that NO
x
slowly oxidizes Mn(II) to Mn(III) under argon.[20]
The experiment was then repeated with PyCOOH (1.5 eq), which
led to a faster and more significant formation of Mn(III) than
observed without the ligand (Figure 1b). This shows that
coordination of PyCOOH to Mn indeed promotes the oxidation of
Mn(II) to Mn(III) by NO
x
through stabilization of the higher
In summary, the data in Figures 1a
oxidation state of Mn.[
12a,21]
detected with Mn(OAc)
TEMPOH. However, the experiment conducted with Mn(OAc)
2
, showing that Mn(II) does not oxidize
led
3
and 1b suggest that dissolution of Mn(NO
3 2
) into glacial AcOH
to formation of the aldehyde 2aa in 50% yield, which indicates that
leads to liberation of NO species that oxidize Mn(II) to Mn(III), and
x
Mn(III) is capable of oxidizing TEMPOH. We then investigated if
Mn(III) would be formed in AcOH solution of Mn(NO ) under
3 2
that the latter oxidizes TEMPOH back to TEMPO during the
catalytic cycle.
3 2 3 2 2 3
Figure 1. UV-visible spectra acquired from a glacial AcOH solution of a) Mn(NO ) under argon b) Mn(NO ) /PyCOOH under argon c) Mn(OAc) + HNO (0.05eq)
2
under air d) Mn(OAc) /PYCOOH + HNO
3
(0.05eq) under air. [a] Absorption peak caused by spectrometer switching lamp.
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After showing that NO
Mn(III) we focused on the role of O
studied if also O could oxidize Mn by dissolving Mn(OAc)
Mn(AcO) /PyCOOH into AcOH under argon and then stirring the
x
is capable of oxidizing Mn(II) to
in the reaction. First, we
and
1d). In this light, NO -
oxidation of Mn(II) to Mn(III) in the presence of PyCOOH , which
stabilizes the Mn(III) by complexation.[
3
derived NO
x
species facilitate the aerobic
2
12a,21]
2
2
2
Based on the mechanistic investigations described above,
solutions under air and observing the change in the UV-vis
spectra over time (see SI Figure S1). However, no change was
3 2
we suggest that the TEMPO/Mn(NO ) /PyCOOH-catalyzed
aerobic oxidation follows an overall mechanism consisting of
multiple subsequent redox cascades (Scheme 4). The reaction is
initiated by acid-catalyzed disproportionation of TEMPO to
detected during the 3 h experiments, which shows that O
directly oxidize Mn(II) to Mn(III) in AcOH solution under ambient
conditions. We then investigated the aerobic NO mediated
oxidation of Mn by introducing a catalytic amount of HNO (0.05
eq) into Mn(AcO) and Mn(AcO) /PyCOOH AcOH solutions under
2
cannot
+
x
TEMPOH and TEMPO (step I). The latter oxidizes alcohol and is
3
reduced to TEMPOH (step II). TEMPOH reacts with
Mn(III)PyCOOH, generating TEMPO and Mn(II)PyCOOH (step
2
2
argon and by monitoring the gradual change in Mn oxidation state
with UV-vis spectroscopy under air (Figure 1c and 1d).
Interestingly, only neglible Mn oxidation was detected in ligand-
III). The metal catalyst is re-oxidized in a reaction with NO -
3
-
derived NO
x 2 x
(step IV). Finally, O recovers the oxidizing NO and
water is formed as a by-product (step V).
free Mn(AcO)
to Mn(III) was evident in the Mn(AcO)
2
solution (Figure 1c), while the conversion of Mn(II)
/PyCOOH system (Figure
2
3 2
Scheme 4. Suggested mechanism for the TEMPO/Mn(NO ) /PyCOOH-catalyzed aerobic alcohol oxidation.
argon was let into the tube. The cycle was repeated three times, after
which the chemicals were transferred into a glove box. Liquid chemicals
Conclusions
2
were frozen in Schlenk tubes by submerging into liquid N , and vacuum
This research shows that addition of PyCOOH ligand enables
selective and efficient aerobic oxidation of primary alcohols to
was then applied for 15 minutes. Schlenk tubes were closed and
heated until the chemicals melted. These steps were repeated five
carbonyl compounds with TEMPO/Mn(NO
3
)
2
catalyst under
1
times, after which the chemicals were transferred into a glove box. H
ambient air. Alcohol oxidations reach quantitative conversions
in just few hours and pure products are generally isolable by
simple extraction with organic solvent and water. The system
is also applicable for the oxidation of secondary alcohols to
ketones by replacing TEMPO with sterically less hindered
ABNO. The ligand-enhanced Mn-catalyst offers, therefore, a
practical method for preparative scale synthesis of aldehydes
and ketones from alcohols. Mechanistic studies support the
oxoammonium ion mediated alcohol oxidation, wherein
and 13
C NMR spectra were recorded on a Varian 300 MHz
spectrometer. The chemical shifts are reported in parts per million (δ)
relative to TMS (0 ppm). The peak patterns are indicated as follows: s
(singlet), d (doublet), t (triplet) q (quartet); dd (doublet of doublets), dt
(doublet of triplets), m (multiplet). J-coupling values are reported in
Hertz (Hz). GC yield determinations of octanal and benzaldehyde were
performed on an Agilent 7890B GC system equipped with FID detector
using calibration curves with acetophenone as internal standard. The
oxidation products that were not isolated were identified with 7890B GC
equipped with 5977B MSD. HRMS measurements were performed on
Bruker Daltonik microTOFLC spectrometer using electrospray ionization.
UV-Visible absorption measurements were performed on a Hewlett
Packard 8453 and Agilent Technologies Cary 60 instruments using 1.0
cm quartz cuvettes at room temperature. Column chromatography was
performed with 60 Å pore size silica gel.
x
Mn(PyCOOH)/NO regenerates the active oxidant.
Experimental Section
General Information
The chemicals used for catalyst optimization study and syntheses of
isolated compounds were purchased from commercial sources and
used as received. The chemicals used in mechanistic studies were
carefully degassed before use as follows. Solid reagents were put in
Schlenk tubes and vacuum was applied for 15 minutes, after which
General procedure for alcohol oxidation
Oxidation of the primary alcohols 1a-1m was conducted according to
the following general procedure. AcOH (4 mL), Mn(NO ) ∙ 4H O (20.1
3 2 2
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2
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following catalyst system: AcOH (4 mL), Mn(NO
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) ∙ 4H O (10.1 mg,
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followed by washing with water to remove the catalyst. Aqueous
phases were combined and extracted with EtOAc. Organic phases
were then combined and dried with MgSO . Solvent was evaporated in
4
vacuo to yield pure 2b-2m, 2q-2s and 2y. Column chromatography was
used to purify 2n-2p and 2z.
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Simply efficient: A highly active and
selective catalyst for the aerobic
oxidation of alcohols was developed.
The method is based on
Page No. – Page No.
Title
3 2
TEMPO/Mn(NO ) catalyst, which
activity was significantly increased by
addition of 2-picolinic acid as a
coordinating ligand. The ligand-
enhanced system was used for the
oxidation of various primary alcohols
to aldehydes using ambient air as
oxidant.
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