Angewandte
Communications
Chemie
Oxidation
Catalytic Fehlingꢀs Reaction: An Efficient Aerobic Oxidation of
Aldehyde Catalyzed by Copper in Water
Mingxin Liu and Chao-Jun Li*
Abstract: The first example of homogeneous copper-catalyzed
aerobic oxidation of aldehydes is reported. This method
utilizes atmospheric oxygen as the sole oxidant, proceeds
under extremely mild aqueous conditions, and covers a wide
range of various functionalized aldehydes. Chromatography is
generally not necessary for product purification.
nature. Recently, we succeeded in a Tollens-type reaction,
which instead of requiring a stoichiometric amount of silver in
the classic reaction, only requires a catalytic amount of silver
using oxygen as the sole oxidant in aqueous conditions
(Figure 1).[8] However, since silver is a precious yet toxic
metal and one of the seriously endangered elements in the
next 100 years,[9] it would be highly desirable to develop
a similar catalytic reaction by using a more earth-abundant
metal as the catalyst. Despite other recent innovations, the
requirement of scarce and expensive noble metals as catalysts
still persists as a major limitation.[10] Herein, we report the
first example of copper-catalyzed aerobic oxidation of
aldehydes in water, a catalytic Fehling reaction, which
proceeds by a different mechanism compared to the well-
established dinuclear copper-oxygen-bridge mechanism for
dioxygen activation,[11] thus representing a potentially new
type of aerobic oxidation pathway.
We began our investigation by examining the oxidation of
benzaldehyde (1a) under aqueous reaction conditions using
various copper catalysts (Table 1). Oxygen gas was simply
flushed into the reaction tube and sealed (without using
a balloon). With the catalyst generated from CuCl2 and 2,2’-
bipyridine (bipy), a widely-used ligand for aerobic oxidation,
at the reaction temperature of the classic Fehlingꢀs reaction
(1008C) we observed 5% yield, by 1H-NMR spectroscopy, of
the desired carboxylic acid (entry 1). With the same ligand,
CuCl was also tested but showed inferior catalytic activity in
this case (entry 2). Surprisingly, lowering the reaction temper-
ature to 508C increased the yield to 13% (entry 3), which may
be due to the increased contact between O2 (in the gas phase)
and the catalyst. Using CuBr2 together with the same ligand
decreased the product yield to 3% (entry 4), and the use of
CuO completely stopped the reaction (entry 5). With Cu-
(OAc)2 the yield was boosted to 68% (entry 6), whereas the
use of [Cu(acac)2] gave a nearly quantitative yield of benzoic
acid (2a; entry 7) and only 50% yield was obtained in the
absence of the ligand (entry 8). However, the same reaction
condition did not work with a more functionalized aldehyde,
piperonal (1b; entry 9). Switching the ligand to phosphine
ligands did not show any improvement (entries 10 and 11).
With IMes, an N-heterocyclic carbene (NHC) ligand, 20%
yield of the oxidation product, piperonylic acid (2b), was
obtained (entry 12). Using the more sterically hindered IPr
ligand reduced the yield to 11% (entry 13). With the more
electron-rich SIMes, a dramatic yield increase to 80% was
observed (entry 14), while SIPr gave 41% yield (entry 15).
Halving the catalyst loading to 5 mol% barely affected the
reaction, with 77% yield of the isolated 2b being obtained
(entry 16). The purification process did not require chroma-
tography, but only acidification and liquid–liquid extraction.
O
xidation of aldehydes into carboxylic acids is a very
important biological process in nature.[1] One of the most
representative examples is the oxidation of acetaldehyde into
acetic acid in liver cells, with aldehyde dehydrogenase as the
catalyst and oxygen as the sole oxidant, at 378C in water.[1b]
Despite being prone to oxidation, most aldehydes are
generally stable and inert towards autoxidation. Even in
modern industry and academia, catalytic oxidations of
aldehydes into carboxylic acids still remain scarce. Most
synthetic processes still rely on oxidations which require
stoichiometric amounts of highly hazardous oxidants such as
dichromate[2]/permanganate,[3] periodate reagent,[4] oxone,[5]
etc. Notably, among all the classical methods for aldehyde
oxidation, the Fehlingꢀs reaction[6] and Tollensꢀ reaction[7] are
extremely useful because of their extraordinarily wide
substrate scopes and high reaction efficiencies. The Achillesꢀ
heel of these methods, however, is that they still require
stoichiometric amounts of either copper or silver reagents and
generate stoichiometric amounts of metal waste, as there are
expensive and wasteful.
Figure 1. Catalytic aerobic oxidation of aldehydes.
Inspired by the efficient and clean biological oxidation of
aldehydes into carboxylic acids in nature, we aim to develop
efficient chemical oxidations of aldehydes into acids, oxida-
tions which are efficient, run under extremely mild reaction
conditions in water, and use only atmospheric oxygen gas (or
air; atmospheric pressure) as the sole oxidant, thus mimicking
[*] M. Liu, Prof. Dr. C.-J. Li
Department of Chemistry and FRQNT Center for Green Chemistry
and Catalysis, McGill University
Montreal, Quebec, H3A 0B8 (Canada)
E-mail: cj.li@mcgill.ca
Supporting information for this article can be found under:
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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