Oxidation of alcohols using an oxoammonium salt bearing the nitrate anion

Article abstract of DOI:10.1016/j.tetlet.2019.151464

A methodology for the oxidation of alcohols to the corresponding carbonyl compounds is reported using a sub-stoichiometric quantity of an oxoammonium salt bearing the nitrate counterion. The approach proves successful for the oxidation of a range of alcohol substrates including those bearing an oxygen atom β to the site of oxidation or an α-trifluoromethyl moiety. The mechanism of the reaction has been probed and also gives an insight into the previously reported nitric acid mediated oxidation of alcohols.

Full text of DOI:10.1016/j.tetlet.2019.151464

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Oxidation of alcohols using an oxoammonium salt bearing the nitrate anion
Shelli A. Miller, Arturo León Sandoval, Nicholas E. Leadbeater
PII:
S0040-4039(19)31263-8
DOI:
https://doi.org/10.1016/j.tetlet.2019.151464
TETL 151464
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
28 September 2019
23 November 2019
27 November 2019
Please cite this article as: Miller, S.A., Sandoval, A.L., Leadbeater, N.E., Oxidation of alcohols using an
oxoammonium salt bearing the nitrate anion, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2019.151464
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Oxidation of alcohols using an
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oxoammonium salt bearing the nitrate anion
Shelli A. Miller, Arturo León Sandoval and Nicholas E. Leadbeater*

1
Tetrahedron Letters
Oxidation of alcohols using an oxoammonium salt bearing the nitrate anion
Shelli A. Miller, Arturo León Sandoval and Nicholas E. Leadbeater*
Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269, United States
* Corresponding author: nicholas.leadbeater@uconn.edu (N. E. Leadbeater)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A methodology for the oxidation of alcohols to the corresponding carbonyl compounds is
reported using a sub-stoichiometric quantity of an oxoammonium salt bearing the nitrate
counterion. The approach proves successful for the oxidation of a range of alcohol substrates
including those bearing an oxygen atom  to the site of oxidation or an α-trifluoromethyl
moiety. The mechanism of the reaction has been probed and also gives an insight into the
previously reported nitric acid mediated oxidation of alcohols.
Available online
Keywords:
Oxidation
2009 Elsevier Ltd. All rights reserved.
Oxoammonium salt
Nitrate
Nitric acid
Oxidation reactions play a central role in the synthetic
chemist’s toolkit. They can be used for installing valuable
functional handles in molecules or fragmenting complex
structures. Given their importance, it comes as no surprise that
significant attention has been and continues to be given to the
development of both stoichiometric and catalytic oxidation
methods.1 The design of cleaner, greener approaches to oxidation
is of particular interest.2 To this end, in the field of stoichiometric
oxidation, oxoammonium salts have attracted particular interest.3
They are recyclable, metal-free species that can be employed in
oxidation reactions under mild conditions. The most commonly
used oxoammonium salt used is 4-acetamido-2,2,6,6-
tetramethylpiperidin-1-oxoammonium tetrafluoroborate salt (1).
It has been employed not only for oxidation of alcohols to
carbonyl compounds,4,5 but also for a range of oxidative
functionalization reactions.6 Catalytic processes based around
oxoammonium salt chemistry have also been developed. Many
involve the use of nitroxide species such as 2 or 3.7 In another
case, a hydroxyammonium species 4 is converted to the
nitrate anion showed unexpected reactivity. When using
dichloromethane as the solvent and in the presence of silica gel at
room temperature, oxidation of alcohols using 1 requires one
stoichiometric equivalent of the oxoammonium salt.5 However,
when using 5, one equivalent of the salt was capable of oxidizing
two or more equivalents of alcohol. We explored this observation
further with the objective of developing a methodology for
oxidation of alcohols. We report our results herein.
Oxoammonium salt 5 could be easily prepared from nitroxide
2 by treatment with nitric acid, followed by addition of sodium
hypochlorite to convert the hydroxyammonium component of the
reaction mixture 6 to 5 (Scheme 1). The salt was obtained in 88%
yield.
corresponding oxoammonium salt in-situ by means of
a
secondary oxidant.8
Scheme 1. Preparation of oxoammonium salt 5 bearing the nitrate counterion.
With 5 in hand, we first assessed its use in the oxidation of
1-octanol 7a, to octanal 8a. When performing the reaction using
0.5 eq. of 5, a 93% conversion of 7a to 8a was obtained after 2 h
at room temperature (Table 1, Entry 1). Dichloromethane was
employed as the solvent, and 1 wt. eq. of silica gel was added.9
Halving the quantity of 5 used to 0.25 eq. resulted in a 30%
conversion to 8a after 2 h (Entry 2). Extending the reaction time
Figure 1: Oxoammonium salt 1, nitroxides 2 and 3, and hydroxyamine 4.
While 1, containing the tetrafluoroborate counterion, has been
employed extensively, we have become interested in exploring
the oxidation chemistry of oxoammonium salts bearing other
counterions. In an initial screen we noticed that 5, containing the

2
Tetrahedron
to 24 h increased the conversion to 87% (Entry 3). When using
couple linked to a hydroxylamine / oxoammonium cycle
(Scheme 2). In other reports, nitric acid has been used to oxidize
benzylic alcohols to carbonyl compounds in the absence of
additional reagents.16,17 A mix of nitric and sulfuric acid has also
been reported for this transformation.18 Depending on the
conditions used, either the nitrite ion, [NO2]-, or nitrogen dioxide,
NO2, is proposed as the key oxidizing species.
0.1 eq. of 5, the product conversion plateaued at 16% after 6 h
(Entries 4 and 5). In light of these results, we decided to proceed
with 0.5 eq. of the oxoammonium salt. Performing the reaction in
the absence of silica gel greatly reduced the reaction rate. A
product conversion of only 26% was obtained after 24 h when
using 0.5 eq. of 5 (Entry 6).
To confirm that the oxidation of alcohols using 5 was not as a
result of nitric acid being formed in-situ and this being the
oxidant, we performed a test reaction using 4-tert-butylbenzyl
alcohol as a substrate (Scheme 3). Treatment of this alcohol with
2 eq. nitric acid in dichloromethane as the solvent did not lead to
the formation of aldehyde 8e. This result runs contrary to reports
in the literature suggesting that nitric acid can indeed be used for
the direct oxidation of alcohols in dichloromethane without
additives. The nitric acid used by us was less than one month old.
We also had on hand an older bottle of nitric acid. Using this, we
did observe conversion of the alcohol to 8e, with the reaction
taking 3 d to reach completion. The older acid was yellow in
color, indicating the presence of nitrogen dioxide. Combining the
old and new nitric acid, the oxidation reaction could be
performed in 24 h, with a 99% conversion to 8e being observed.
These results confirm that both nitrogen dioxide and nitric acid
are required for this oxidation to occur and also confirm that our
methodology employing 5 as the oxidant is distinctly different. In
addition, our methodology offers an improved approach over use
of nitric acid in that the substrate scope is wider. Many functional
groups are not tolerated under highly acidic conditions, and the
nitric acid oxidation is limited to highly-activated alcohols.
Table 1. Probing the reactivity of 5 in the oxidation of 1-octanol.a
Entry
5 (eq.)
0.5
Time (h)
Conversion (%)b
1
2
2
2
93
30
87
16
16
23
0.25
0.25
0.1
3
24
6
4
5
0.1
24
24
6c
0.5
a
Reagents and conditions: 1-Octanol (7a, 2 mmol, 1 eq.), silica gel (260 mg,
1 wt. equiv. to 7a), CH2Cl2 (50 mL, 0.04 M in 7a), requisite quantity of 5,
stirred at r.t. for the allotted time. b Determined using 1H-NMR spectroscopy.
c Performed in the absence of silica gel.
Table 2. Exploring the substrate scope of the oxidation of alcohols using 5.a
We next screened a range of alcohol substrates in the reaction
(Table 2).10 Aliphatic and aromatic primary alcohols were
converted to the corresponding aldehydes in 1-3 h (8a-8h). This
includes a heterocyclic example; furfuryl alcohol being oxidized
to furfural (8f) in 1 h. The conversion of geraniol to citral (8i)
took longer, requiring 12 h. A number of secondary alcohols
could also be oxidized in
1 h (8j-8o). When using
tetrafluoroborate salt 1, alcohols bearing an oxygen atom  to the
site of oxidation react so slowly as to be unreactive.5 While the
reaction was still slow using 5 we were able to convert 1-
phenoxy-2-propanol to phenoxyacetone (8p) in 95% yield after
52 h. Another challenging oxidation is the conversion of
α-trifluoromethyl alcohols to the corresponding trifluoromethyl
ketones (TFMKs).11 Classical methods for alcohol oxidation are
typically insufficient due to the presence of the strongly
withdrawing trifluoromethyl group. Using a base-mediated
approach, 1 has found application for accessing TFMKs.12
A
superstoichiometric quantity of the oxoammonium salt is
required because, in the presence of base, the hydroxyammonium
byproduct (4) initially formed undergoes a comproportionation
reaction with a further aliquot of 1 to generate two equivalents of
nitroxide 2. Thus a sacrificial equivalent of 1 is required in order
to affect complete oxidation of the alcohol substrate. Employing
our methodology using a substoichiometric quantity of 5, we
were able to convert a representative α-trifluoromethyl alcohol to
the TFMK (8q), albeit in 10 days.
The observation that 5 can oxidize more than a stoichiometric
equivalent of alcohol and that the substrate scope of the reaction
is wider as compared to the use of 1 made us believe that the
nitrate counterion is not innocent and instead plays a role in the
reaction mechanism. Nitroxides such as 2 and 3 oxidize alcohols
in a catalytic manner in the presence of nitrogen oxide (NOx)
cocatalysts, with O2 being the terminal oxidant.13-15
Mechanistically these processes involve an NO / NO2 redox
a
Reagents and conditions: Alcohol (7, 2 mmol, 1 eq.), 5 (0.275 g, 1 mmol,
0.5 eq.) silica gel (1 wt. equiv. to 7), CH2Cl2 (50 mL, 0.04 M in 7), stirred at
r.t. Reaction monitored by 1H-NMR spectroscopy. Isolated yield reported.

3
nitrate counterion. The approach proves successful for the
oxidation of a range of alcohol substrates including those bearing
an oxygen atom  to the site of oxidation or an α-trifluoromethyl
moiety, both of which cannot be readily oxidized using the
commonly-used tetrafluoroborate analogue 1 without the use of
base and a superstoichiometric quantity of the oxoammonium
salt. The methodology appears to involve an NO / NO2 redox
couple linked to a hydroxylamine / oxoammonium cycle with
dioxygen serving as a terminal oxidant. Probing the mechanism
of the reaction also gave an insight into the previously reported
nitric acid mediated oxidation of alcohols, confirming that both
nitrogen dioxide and nitric acid are required for this oxidation to
occur.
Scheme 2. Oxidation of alcohols by means of an NO / NO2 redox couple
linked to a hydroxylamine / oxoammonium cycle.
Acknowledgments
The University of Connecticut is acknowledged for funding.
We thank Professor James Bobbitt and Dr. Nicholas Eddy
(University of Connecticut) for insightful discussions.
Scheme 3. Oxidation of 4-tert-butylbenzyl alcohol using nitric acid.
To probe whether our methodology involves an NO / NO2
redox couple linked to a hydroxylamine / oxoammonium cycle
with O2 serving as a terminal oxidant, we performed the reaction
firstly under anhydrous, anaerobic conditions, and secondly after
bubbling oxygen through the solution (Scheme 4). Drying all
glassware, reagents, and solvent, and bubbling argon through the
reaction mixture prior to adding 5, we obtained a 50% conversion
of 7a to 8a when employing a 2:1 stoichiometric ratio of
substrate to oxoammonium salt. This result is in line with the
oxoammonium salt behaving as a stoichiometric oxidant under
these conditions, akin to the general reactivity of the
tetrafluoroborate analogue 1. Juxtaposing this result with the
outcome of our standard reaction conditions, does suggest that
oxygen plays a role. This is further supported by the observation
that when the oxidation of 7a is performed after first bubbling
oxygen through the solution of substrate and then adding 5, the
reaction is complete within 45 min as opposed to 2 h under our
standard conditions. It is therefore plausible that the reaction does
indeed involve a NO / NO2 redox couple.
Appendix A. Supplementary data
Supplementary data to this article can be found online at:
…
References and notes
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Organic Synthesis, Wiley-VCH, Weinheim, Germany, 2019.
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Scheme 4. Oxidation of 7a under anaerobic and oxygen-enriched conditions.
In light of our mechanistic investigations, we decided to
perform the oxidation of 7a by bubbling oxygen through the
mixture but in the absence of silica gel as an additive. We
obtained an 87% conversion to 8a (Scheme 5). This opens an
avenue for an alternative strategy to the oxidation of alcohols.
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Scheme 5. Oxidation of 7a under oxygen-enriched conditions in the absence
of silica gel.
In summary, we present a methodology for the oxidation of
alcohols to the corresponding carbonyl compounds using a sub-
stoichiometric quantity of oxoammonium salt 5, bearing the

4
Tetrahedron
10. Alcohol (7, 2 mmol, 1 eq.), silica gel (1 wt. equiv. to 7), and
CH2Cl2 (50 mL, 0.04 M in 7) were added to a round-bottom flask
equipped with a magnetic stirrer bar and the mixture stirred at r.t.
for 5 min before adding 5 (0.275 g, 1 mmol, 0.5 eq.). The reaction
mixture was stirred at r.t. until the oxidation was deemed complete
by 1H-NMR spectroscopy monitoring. Upon completion, the
product mixture was filtered through a pad of silica, the silica
washed with dichloromethane to elute any remaining product. The
solvent was then removed from the filtrate under vacuum,
affording the pure product.
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HIGHLIGHTS
Oxidation of alcohols using an oxoammonium salt
bearing the nitrate counterion
Sub-stoichiometric quantity of the oxidant is used
Successful for the oxidation of a wide range of
alcohol substrates
Reaction involves an NO / NO2 redox couple and a
hydroxylamine / oxoammonium cycle
Mechanism gives an insight into the nitric acid
mediated oxidation of alcohols
19.
20.