Electroorganic synthesis of nitriles via a halogen-free domino oxidation-reduction sequence

Article abstract of DOI:10.1039/c5cc06437f

A direct electroorganic sequence yielding nitriles from oximes in undivided cells is reported. Despite the fact that intermediate nitrile oxides might be formed, the method is viable to prepare benzonitriles without substituents ortho to the aldoxime moiety. This constant current method is easy to perform for a broad scope of substrates and employs common electrodes, such as graphite and lead.

Full text of DOI:10.1039/c5cc06437f

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COMMUNICATION
Electroorganic Synthesis of Nitriles via a Halogen-free Domino
Oxidation-Reduction Sequence
Marius F. Hartmera and Siegfried R. Waldvogela*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A direct electroorganic sequence yielding nitriles from oximes in
undivided cells is reported. Despite the fact that intermediate
nitrile oxides might be formed, the method is viable to prepare
benzonitriles without substituents ortho to the aldoxime moiety.
This constant current method is easy to perform for a broad scope
of substrates and employs common electrodes, such as graphite
and lead.
In the past, the formation of nitriles from oximes has been
realized by the use of harsh dehydration agents such as
phosphorous pentoxide, thionyl chloride, benzenesulfonyl
chloride, acetic anhydride, and many others.1,2 Unfortunately,
these strongly corrosive agents have to be used
stoichiometrically or even in excess. This results in unattractive
waste generation and considerable safety issues upon work
up. Recently, catalytic approaches have emerged which reduce
the waste generation significantly.3 However, recycling of the
expensive and toxic catalysts still remains an issue.
Consequently, new methods for the aldoxime dehydration are
highly desired.
Scheme 1 Transformation of mesitylaldoxime to mesitylnitrile
We chose mesitylaldoxime (1a) as test substrate. Within the
course of transformation we observe stable nitrile oxide as
intermediate (2a, Scheme 1). Initially, we investigated the
anodic reaction using methyltriethyl ammonium methylsulfate
(MTES) in acetonitrile as electrolyte. Graphite and glassy
carbon were tested as carbon anode materials at room
temperature. Glassy carbon served as cathode material in both
cases. Graphite turned out to be an excellent anode leading to
almost quantitative consumption of the starting material upon
application of 2.5 F (Fig. 1).
Electrochemistry has become an attractive alternative to
conventional methods in organic synthesis, since only
electricity is applied which might even originate from
renewable resources, and therefore no reagent waste is
produced.4 Shono et al. reported an electrochemical protocol
to generate nitriles from oximes with halogenides as a
mediator.5 However, such halogen species cause corrosion at
the precious platinum electrodes.6,7 Additionally, low current
yields make this protocol in particular unattractive. We report
a direct, halogen-free procedure to generate nitriles from
oximes by the application of inexpensive and easily available
electrode materials.
Fig 1. Transformation of mesitylaldoxime (black curve) at graphite to intermediate
nitrile oxide 2a (red curve) in the course of electrolysis.
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Table 1 Optimization of reaction parameters
Entry
T [°C]
0
j [mA/cm2]
Q [F]
2.5
2.5
2.5
2
Isolated yielda [%]
70(4)
1
2
3
4
5
10
5
22
63 (13)
22
10
20
10
81 (0)
22
77 (0)
50
2
66 (0)
a Yield of nitrile oxide determined by 1H NMR in parentheses.
Scheme 2 Domino oxidation-reduction sequence
The best results were obtained with mesitylaldoxime (1a
,
,
However, the conversion at glassy carbon electrodes was poor.
Only the intermediate nitrile oxide was formed, indicating a
possible deactivation of the cathodic surface. It turned out
that the deoxygenation is not promoted. As outlined, the
intermediate was observed and identified via GC-MS. The
anodic conversion leads to nitrile oxide which is the same
intermediate as in the halogenide-mediated electrolysis by
Shono et al. Hence, we consider the transformation as a
domino oxidation-reduction sequence with respect to the
definition of domino reactions, since a stable intermediate is
formed which in turn reacts without manipulating the reaction
conditions to the final product (Scheme 2).8
81%), closely followed by 2,4,6-trimethoxybenzaldoxime (1c
75%) and 2,6-dimethylbenzaldoxime
unexpectedly low yield of the
(
1b
,
73%). The
2,6-
stabilized
dichlorobenzaldoxime (1f, 41%) can be attributed to the
competing dechlorination reaction (see SI for GC-MS data).
The analogue debromination reaction was even more
dominant and disadvantageous for the nitrile formation,
whereas 2,6-difluorobenzaldoxime (1e, 47%) was isolated in a
higher yield due to the higher C,F bond strength (Ar−F:
526 kJ/mol; Ar−Cl: 400 kJ/mol; Ar−Br: 336 kJ/mol).10
Nevertheless, the key for the desired reaction sequence
seemed to be the deoxygenation of nitrile oxide formed.
Having some recent experience with lead electrodes and
variations thereof,9 we tested lead, stainless steel (A5), nickel,
platinum, and boron-doped diamond as cathode materials.
Indeed, lead turned out within the screening (see SI for GC-MS
data) as an excellent cathode material, whereas the
deoxygenation was less favored compared to the other
electrode materials. Surprisingly, platinum showed a very poor
performance although it is known as the cathode material of
choice for this particular deoxygenation reaction.5
Subsequently, the influence of temperature and current
density was studied (Table 1). Performing the electrolysis at
22 °C proved to be an optimum concerning the temperature,
whereas rising (50 °C) or lowering (0 °C) the temperature led
to a drop in yield (entries 1 and 5). Investigating the current
density rendered the best yields with 10 mA/cm2 (entry 3),
whereas lower (5 mA/cm2) or higher (20 mA/cm2) current
densities resulted in decreased yields and selectivity,
respectively (entries 2 and 4).
Scheme 3 Scope a Full conversion after 2.6 F b Full conversion after 2.1 F
With the optimized electrolysis parameters in hand, we
applied the method to a range of substrates in order to
elucidate the scope of the reaction (scheme 3). These
substrates vary in stability for the intermediately formed nitrile
oxides as well as their preference for dimerization.
Stabilization of reactive intermediates such as nitrile oxides
can be achieved by bulky groups ortho to the aldoxime moiety.
The stabilized 2-methoxy-1-naphthaldoxime (1h) resulted in a
yield of 55%, whereas the partially stabilized naphthylaldoxime
(
1g) led to a yield of 40%. Surprisingly the non-stabilized
4-methoxybenzonitrile (3c) was synthesized in an acceptable
yield of 53%.
2 | J. Name., 2012, 00, 1-3
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In general, stabilized substrates result in higher yields than
non-stabilized congeners. However, the corresponding alde-
hyde was detected in all electrolyses by reaction monitoring
3
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Scheme 4: Proposed pathway for the formation of aldehyde and nitrile oxide.
It is noteworthy, that the aldehyde formation was significantly
higher for the non-stabilized substrates. It is known that ald-
oximes are oxidized in a divided cell to iminoxyl radicals which
dimerize to aldazine bis-N-oxides (5
, Scheme 4).11
5
6
7
Average pricing at London Metal Exchange (May 2015):
36716 $/kg
(a) J. A. Bittles and E. L. Littauer, Corrosion Science, 1970, 10
These aldazine bis-N-oxides react further to aldehydes by loss
of nitrogen. We anticipate that the dimerization takes place
prior to the deoxygenation of the intermediate. In contrast,
only small amounts of aldehyde have been observed for
stabilized substrates. We anticipate that the stability of the
iminoxyl radical formed is based on the sterical hindrance and
therefore, no or very little dimerization occurs. Hence the
formation of nitrile oxide is favored which then undergoes
deoxygenation at the cathode leading to the nitrile in high
yield.
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8
9
In conclusion, we developed a direct, halogen-free protocol for
the synthesis of nitriles from oximes with yields up to 81% by
applying inexpensive and readily available electrode materials
such as lead12 and graphite. This protocol is applicable for a
range of substrates under constant current and ambient
conditions. Furthermore, some insight into the mechanistic
scenery can be deduced confirming a domino oxidation-
reduction sequence.
Broekmann, S. R. Waldvogel, ChemElectroChem 2014, 1,
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We wish to acknowledge financial support from the Federal
Ministry of Education and Research (CARLOTTA, FKZ
01DM14005).
12 Average pricing at London Metal Exchange (May 2015): 2
$/kg.
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