Download NACOS with Nitroxy Radicals as Cocatalysts: An Efficient, Green

NACOS with Nitroxy Radicals as Cocatalysts: An Efficient, Green Protocol
for Selective Aerobic Oxidation of Alcohols
Yongbo Kuang (09D51077)
Kakimoto Lab, Department of organic and polymeric materials, Tokyo Institute of Technology
Introduction
Selective oxidation of organic compounds, as
highlighted by Technology Vision 2020 report, is one of
the major challenges facing the chemical industry. The
selective transformation of alcohols to aldehydes and
ketones, in particular, is among the most important
synthetic operations in organic chemistry. Numerous
methods have been reported and widely used for this
purpose involving various organic and inorganic
oxidants, representatively DMSO and CrVI based
regents. However, those conventional oxidants are
usually employed in more than one equivalent amount,
with large quantities of toxic wastes being produced.
From the viewpoints of atom economy, cost efficiency
and green chemistry, atmospheric oxygen is obviously
superior to any other regents, thus represents the
quintessential oxidant. Nevertheless, to harness its
power has never been an easy job. In the past decades,
most of the efforts have been directed to the
development of heterogenous and homogeneous
transition-metal-based catalysts, and these work have
been summarized in many recent review papers. But in
contrast, much less attention has been paid to the
development of non-metallic oxidation systems, largely
ignoring their inherent advantages.
Nitroxy radicals, like TEMPO, have been long known
as efficient catalysts for the selective oxidation of
alcohols. Notably, Hu’s group has recently reported a
series of metal-free aerobic alcohol oxidation protocols
(TEMPO/Br2/NaNO2 system, and its modified versions).
Those methods provided great advances in the field of
non-metallic aerobic oxidation. However, they required
expensive teflon-lined autoclave to achieve high
operating pressures, a Br source which inevitably results
in Br-substituted byproducts, and often chlorine
containing solvents (CH2Cl2 or ClCH2CH2Cl). Although
in their latest report, the use of Br source was eliminated,
the employment of organic nitrite will introduce small
organic molecule contaminants into the final products.
In contrast, the nitroxy radical-enhanced NACOS,
which we will describe herein, involves no halogencontaining reagents, introduces no additional organic
contaminants, delivers desired yields and selectivity for
a wide range of alcohols under solvent-free or minimum
solvent-use conditions depending on the substrates.
Experimental
Typical procedure for the oxidations of liquid alcohol
substrates (benzyl alcohol): 200 mg of AC, 6.3 mg (0.04
mmol) of TEMPO, and 4.228 ml (40 mmol) of benzyl
alcohol were charged sequentially into a test tube. After
the mixture was sonicated for 20 s, 0.1075 ml (1.6
mmol) of 67% HNO3 was added dropwise under stirring.
The tube was then sealed with a head part and evacuated
with an aspirator, followed with the attachment of an
oxygen balloon. The reaction mixture was heated to 90
ºC with aluminum block for 5 h. Samples were taken at
appropriate intervals through a silicon septum using a
hypodermic needle and were filtrated through a 45 nm
syringe filter prior to GC-MS analysis.
Results and Discussion
Six nitroxy radicals were chosen to be evaluated,
including TEMPO, three TEMPO derivatives, 2azaadamantane N-oxyl (AZADO) and 1-Me-AZADO.
Trial oxidations were conducted with benzyl alcohol as
the substrate without any solvent and the loadings of
cocatalysts were initially set at 0.1 mol%. Under
identical conditions, the performance of TEMPO was
much better than its three derivatives, especially the one
with bulk electron withdrawing group. AZADO and 1Me-AZADO were reported to have higher catalytic
efficiency than TEMPO due to less steric hindrance.29
However, they have not yet been employed in aerobic
alcohol oxidations. As expected, the two displayed
enhanced activities than TEMPO under our
conditions.namely,
To our delight, in all these reactions, the selectivity to
aldehyde remained in the range of 95% ~ 99%. As is
well know, it is very difficult to maintain good aldehyde
selectivity while its concentration becomes high,
especially under solvent free conditions. The main
reason is the autoxidation of benzaldehyde. Notably,
with the addition of active nitroxy radicals, roughly
linear reaction curves were obtained, indicating that the
reaction rate is independent of substrate concentration.
Thus it can be easily inferred the reaction between the
oxoammonium ion and benzyl alcohol is quite fast and
is not the rate-determining step.
To study the scope of the modified NACOS, we then
applied it to various primary and secondary alcohols.
We first applied the same solvent-free reaction
conditions as benzyl alcohol to other benzylic alcohols
as shown in table 1. Generally, aliphatic alcohols are
less active than benzylic alcohols towards oxidation.
Among all the tested aliphatic alcohols, 2-adamantanol
showed the highest reactivity (Table 2, Entry 6). 1
mol% of TEMPO was adequate to achieve ideal results.
For the oxidations of other aliphatic alcohols, we
disclosed that even with increased use of TEMPO, good
results could not be obtained when we conducted the
reactions at 90 ºC. Through GC-MS analysis, we
detected that TEMPO was mostly converted to 2,2,6,6tetramethylpiperidine
and
2,2,6,6-tetramethyl-1nitrosopiperidine after reaction. Therefore the reaction
temperature was lowered to 50 ºC in order to solve the
thermal-instability issue. To our delight, our method
then worked well with varied primary and secondary
aliphatic alcohols (entry 1-5). Interestingly, for primary
alcohols, high selectivites to aldehydes were maintained
at the sacrifice of reaction rate. Generally, aliphatic
aldehydes are much less stable than benzylic aldehydes
and have a larger tendency to undergo autoxidation to
form acids, especially at high concentration and high
temperature. Thus lower temperature is favored for the
production of aldehyde by aerobic oxidation, although
with the lose of reaction rate. As for the cyclic alcohols,
high conversions seemed to be very difficult to obtain
(entry 7,8). Initially, we ascribed the failures to the
quick decomposition of TEMPO under these particular
environments. However, most of the TEMPO was
found to remain intact after reaction through careful
examination. Thus we speculate that the main reason is
probably the solvent effect. As there was no other
solvent, the substrate itself played as the solvent. And
with the running of the reaction, the mixture
composition changed due to the formation of ketone
products, resulting in the unfavored change of the
chemical environment for the oxidation reaction.
Conclusions
We have succeeded in improving our reported
oxidation system NACOS through the incorporation of
nitroxy radicals. The enhanced nitroxy radical-NACOS
delivers great benefits, including minimized or no use of
solvents, largely reduced use of nitric acid, improved
reactivity and selectivity, and expanded substrate
accessibility. In our last report, we demonstrated the
feasibility of using carbon-based catalysts to replace
transition-metals in aerobic oxidations. Here we show
further that carbon-based systems can have comparable
performances with those based on transition-metals.
Table 1 The oxidation of benzylic alcohols.
[a] General conditions: substrate (40 mmol), TEMPO (0.2 mol%),
activated carbon (200 mg), 67% HNO3 (1.6 mmol, 4 mol%), 90 ºC.
[b] Determined by GC-MS, based on area normalization. [c]
Additional 1 ml of 1,4-dioxane, 95 ºC. [d] TEMPO (0.4 mol%)
Table 2 The oxidation of aliphatic alcohols.
[a] General conditions: substrate (20 mmol), TEMPO (1 mmol, 5
mol%), AC (100 mg), 67% HNO3 (1.6 mmol, 8 mol%), 50 ºC. [b]
Determined by GC-MS, based on area normalization. [c] substrate (5
mmol), 1,4-dioxane (5 ml), TEMPO (1 mol%), HNO3 (10 mol%), AC
(100 mg). [d] The corresponding acids were the main byproducts.
Future work
To study the underlying mechanism in more detail and
to extend the carbon catalyzed oxidation to other kinds
of organic compounds.
Publications
1. Kuang, Y.; Islam, Nazrul M.; Nabae, Y.; Hayakawa,
T.; Kakimoto, M.-a. Angew. Chem. Int. Ed. 2010, 49,
436.
2. Kuang, Y, Selective Aerobic Oxidation of Benzylci
Alcohols by Solvent free TEMPO/NACOS Oxidation
System. International Symposium on Catalysis and
Fine Chemicals 2009, Seoul, Korea. (Oral & Poster).