Mechanistic studies of reactive oxygen species mediated electrochemical radical reactions of alkyl iodides

Article abstract of DOI:10.1039/d1cc03019a

Mechanistic studies of a reactive oxygen species mediated electrochemical radical reaction of alkyl iodides are described. Hydroxyl radicals and ozone are identified to be the active species involved in the formation of alkyl radicals under mildly reducing potential (-1.0 V vs. Ag QRE) in buffered acidic conditions (pH 3.6).

Full text of DOI:10.1039/d1cc03019a

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Mechanistic studies of reactive oxygen species
mediated electrochemical radical reactions of
alkyl iodides†
Cite this: DOI: 10.1039/d1cc03019a
Received 8th June 2021,
Accepted 26th July 2021
Tsz-Kan Ma,* Diyuan Li
and Jonathan D. Wilden
*
DOI: 10.1039/d1cc03019a
rsc.li/chemcomm
Mechanistic studies of a reactive oxygen species mediated electro- conditions (À1.0 V vs. Ag QRE) in semi-aqueous media with
chemical radical reaction of alkyl iodides are described. Hydroxyl inexpensive graphite electrodes. Molecular oxygen is selectively
radicals and ozone are identified to be the active species involved in activated to mediate the radical reactions of alkyl iodides.
the formation of alkyl radicals under mildly reducing potential Herein, we report results of our studies into the mechanism
(À1.0 V vs. Ag QRE) in buffered acidic conditions (pH 3.6).
of this intriguing and novel reaction sequence.
We first sought to determine the active initiator derived
Carbon-centered radicals are important synthetic intermediates in from molecular oxygen which starts the reaction sequence.
organic synthesis. To date, the generation of alkyl radicals heavily According to our previous studies, the presence of molecular
6
relies on the homolytic cleavage of labile carbon–halogen (C–X) oxygen and water is essential for the reaction to occur. We
bonds. In particular, n-tributyltin hydride and azobisisobutyroni- originally postulated that hydroxyl radicals were involved in the
trile (AIBN) mediated radical chain reaction of alkyl halides is the activation of the iodide, however, subsequent experiments have
dominant approach to produce predictable C-centered radicals suggested that an alternative mediator must also be involved.
1
chemoselectively under mild conditions. Although organotin Accordingly, we wondered if the agent was ozone. To test our
reagents have been proven to be extremely versatile to construct hypothesis that ozone could be the oxidant to activate the alkyl
carbon–carbon (C–C) bonds, the substantial toxicity of organotin iodide, a sample of neat isopropyl iodide was subjected to a
compounds has limited their large-scale applications. To circum- constant stream of ozone and it quickly turned brown. After
vent this issue, alternative tin-free radical chain reaction initiators that, this sample was exposed to a reducing potential (constant
such as organoboranes and thiols have been employed but their potential, 1.0 V vs. Ag wire quasi-reference electrode, graphite
2,3
efficiency and scope are often limited.
rod working electrode, divided cell) in an acidic acetonitrile-
Recent advances in photocatalysed processes provides alter- water solution (pH 2) containing phenyl vinyl sulfone under an
native approaches to generate C-centered radicals, representing inert atmosphere saturated with argon (Scheme 2). Gratifyingly,
a significant step to move away from using any toxic organotin the ozonised alkyl iodide was fully consumed and reacted with
4
reagents. On the other hand, synthetic organic electrochem- phenyl vinyl sulfone to give the corresponding alkyl sulfone
istry has also gained popularity as an alternative method to (74%). It is postulated that ozonation of isopropyl iodide produced
manipulate organic compounds via direct addition or removal an unstable trioxide intermediate, which decomposes into the
5
ꢀ
of electrons to generate reactive radical species. However, corresponding alkyl radical, IO radical and molecular oxygen to
7,8
direct electrochemical activation of alkyl halides via reduction initiate the radical reaction. The proposed trioxide intermediate
has limited synthetic utility due to the requirement of highly is analogous to the reaction between aqueous ozone with halide
7–10
reducing potentials.
anions as well as alkanes.
The necessity of molecular oxygen
Recently, our group has developed a highly efficient metho- and water in the reaction vessel could be explained by the require-
dology to activate alkyl iodides with the use of air and elec- ment of ozone production electro-catalytically. The formation of
6
tricity as the promotors (Scheme 1). The classic Giese reaction
could be carried out electrochemically under mildly reducing
Department of Chemistry, University College London, 20 Gordon Street, London,
WC1H 0AJ, UK. E-mail: j.wilden@ucl.ac.uk
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1cc03019a
Scheme 1 Electrochemical Giese reaction.
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Table 1 Reductive cyclisation of alkyl iodide 1
a
a
Entry
Solvent
pH
Time, h
2, %
3, %
Scheme 2 Reaction between ozonised alkyl iodide and phenyl vinyl
b
sulfone.
1
2
3
4
MeCN–H
MeCN–H
MeCN–H
MeCN–H
2
2
2
2
O (1 : 1)
O (1 : 1)
O (1 : 1)
O (1 : 1)
1
24
6
24
24
31
40
Trace
N/R
23
37
c
3.6c
5.7
33 e
d
e
7
N/R
ozone relies on the reaction between adsorbed hydroxyl free
radicals and molecular oxygen at the anode (eqn (3a)–(3d)) as
direct oxidation of water to ozone requires a much higher potential
a
b
c
Isolated yield. pH adjusted with HCl. pH adjusted with acetate
buffer. pH adjusted with phosphate buffer. Alkyl iodide 1 was fully
d
e
recovered.
(E1 = 1.51 V) and is unlikely to occur under the operating potential
11
(Scheme 3). To further validate this hypothesis, excess ethyl vinyl
ether was added to the anodic chamber to quench the ozone
generated from the anode where another sample of isopropyl
iodide and phenyl vinyl sulfone were subjected to the standard
conditions in the cathodic chamber. Indeed, addition of ethyl vinyl
ether has completely terminated the reaction and the substrates are
fully recovered. In addition, subjecting anethole to the reaction
condition at the anodic chamber resulted in the formation of the
corresponding 4-methoxybenzaldehyde (2%) and 1-(4-methoxy-
phenyl)propane-1,2-diol (30%).
The electrochemical radical reaction of alkyl iodide could
also be extended to intramolecular reductive cyclisation
Scheme 4 Formation of reactive oxygen species.
(Table 1). When alkyl iodide 1 was subjected to a mild reducing
potential (constant potential, 1.0 V vs. Ag wire quasi-reference
electrode, graphite rod working electrode, divided cell) in an
First, a classic Fenton reaction was carried out in the
presence of this molecular probe to validate this approach.
15
acidified MeCN–H O (1 : 1, pH 1) solution, it was reductively
2
An aliquot of the reaction mixture was extracted, and the
fluorescence emission was recorded. By comparing that emis-
sion spectrum (Fig. 1a, blue curve) with the emission spectrum
of sodium terephthalate (Fig. 1a, black curve), hydroxyl radicals
were detected, giving rise to the intense fluorescence emission
at 430 nm. By applying this technique to the cathodic chamber
of the reaction vessel where radical cyclisation of alkyl iodide 1
occurred, the same emission was observed (Fig. 1a, red curve),
confirming the presence of hydroxyl radicals in the reaction
mixture.
cyclised into the corresponding pyrrolidine 2 (31%) with
N-allyltosylamide 3 (23%) as a by-product (Table 1, entry 1).
N-Allyltosylamide 3 is likely to be produced via b-elimination
from an anionic intermediate, terminated by the abstraction of
the hydrogen atom from the solvent. The effect of pH was also
examined by adjusting the pH of the solvent with various buffer
solutions. It was found that optimal conversion occurred
1
2
(Table 1, entry 2) at pH 3.6 and no reaction occurred at pH 7.
To further investigate the role of reactive oxygen species in
the reaction, sodium terephthalate was used as the molecular
With this encouraging result in hand, the focus was
switched to examine the origin of hydroxyl radicals in the
reaction vessel (Fig. 1b). Sodium terephthalate was added to a
solution of acetonitrile–water (pH 3.6) with sodium chloride as
the electrolyte and exposed to a mild reducing potential (con-
stant potential, 1.0 V vs. Ag wire quasi-reference electrode,
graphite rod working electrode, divided cell). It is observed
that hydroxyl radicals are present at both the anodic and
cathodic chambers, but they are more concentrated at the
cathodic chambers relatively. The relative low concentration
of hydroxyl radicals at the anodic chamber is consistent with
the fact that only small amount of adhered hydroxyl radicals are
generated at the anode to facilitate the electro-catalytic ozone
1
3
fluorescence probe for the detection of hydroxyl radicals.
Sodium terephthalate is a non-fluorescent compound that would
react with hydroxyl radicals to form a fluorescent aromatic
hydroxylated product, namely sodium 2-hydroxyterephthalate,
14
that is known to show a characteristic emission at 430 nm.
Therefore, sodium terephthalate was introduced to the reaction
mixture under different conditions to detect the presence of
hydroxyl radicals.
1
6
generation process. The formation of hydroxyl radicals at the
cathodic chamber is possible via various one-electron redox
reactions (eqn (4a)–(4g)) (Scheme 4) under the operating
1
7–19
Scheme 3 Electro-catalytic ozone production.
potential.
The operative reactions generate oxygenic
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Fig. 1 Emission spectra of sodium 2-hydroxyterephthalate under different reaction conditions.
radicals which would lead to the formation of hydrogen per- species that fragment to yield hypoiodous acid and alkyl
2
1
oxide and homolysed to form hydroxyl radicals. This would also radicals. As a result, alkyl iodides could be activated by both
indicate that a buffered acidic solvent system would be essen- productive pathways. Furthermore, additional redox reactions
tial for the steady formation of hydroxyl radicals at the cathodic of molecular oxygen and hydrogen peroxide would also supply
chamber to facilitate the radical reactions of alkyl iodides. more hydroxyl radicals to facilitate the radical reaction of alkyl
Moreover, a low pH environment would also inhibit the auto- iodides.
decomposition of hydrogen peroxide, another reactive oxygen
The reactivity of alkyl iodide 1 could be rationalised as
species that could homolyse into hydroxyl radicals. At higher follows (Scheme 6): Once the primary radical is formed, there
pH, the decomposition of hydrogen peroxide into molecular are two competing reaction pathways, which lead to the for-
oxygen and water would dominate, limiting the supply of mation of pyrrolidine and N-allyltosylamide. When the primary
2
0
hydroxyl radicals and, therefore, lead to no reactivity.
alkyl radical is reduced by the electrode, the resulting anion
Lastly, the effect of alkyl iodide on the consumption of would then undergo rapid elimination to produce ethene and
hydroxyl radicals was examined. Control experiments have an anionic intermediate, which could be protonated to give
shown that the relative concentration of hydroxyl radicals N-allyltosylamide. Another pathway involves the reaction of the
decreases when alkyl iodide 1 is present (Fig. 1c) and indicated primary radical with the allyl group via an intramolecular
that hydroxyl radicals are involved directly in facilitating the pathway to give a cyclised primary radical intermediate, which
radical cyclisation of alkyl iodide 1.
Following with the results of these experiments, we propose anion to be protonated and form the pyrrolidine.
the following mechanism for the generation of alkyl radicals In conclusion, these experimental results indicate that
Scheme 5). Two productive reaction pathways are responsible under the standard electrochemical conditions, alkyl iodide
can then be reduced by the electrode to the corresponding
(
for the oxidation of alkyl iodide. The reaction is initiated by the are first ozonolysed to yield an unstable intermediate that
generation of ozone at the anode via an electro-catalytic process fragments into the corresponding alkyl and IO radicals as well
and the resulting ozone is reacted with the alkyl iodide in the as molecular oxygen. This activates a superoxide radicals and
cathodic chamber, by slow diffusion in the closed divided cell hypoiodous acid mediated ‘redox relay’ reaction sequence to
via the pressure equalizer channel as well as the semiporous oxidise more alkyl iodides into the corresponding unstable I(II)
sintered glass divider. Reaction between ozone and alkyl iodide species to produce more alkyl radicals. The use of sodium
generated an unstable trioxide intermediate that subsequently terephthalate as a fluorescence molecular probe provided
ꢀ
fragment into the corresponding alkyl radical, IO radical and insight to the role of hydroxyl radicals in this reaction
ꢀ
molecular oxygen. The generated IO radicals lead to the sequence. Further studies on other radical reactions with this
accumulation of hypoiodous acid that is known to react with electrochemical approach are ongoing in our laboratory.
superoxide radicals to yield highly reactive hydroxyl radicals to
We wish to thank the Leverhulme Trust (RPG-2019-183) for
oxidise more alkyl iodides into the corresponding unstable I(II) generous financial support of our programme. The authors also
Scheme 5 Proposed reaction mechanism for the generation of alkyl
radicals.
Scheme 6 Reductive cyclisation of alkyl iodide 1.
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gratefully acknowledge Dr D. MacMillan and Dr K. Karu for
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