Paired Electrochemical Reactions and the On-Site Generation of a Chemical Reagent

Article abstract of DOI:10.1002/anie.201900343

While the majority of reported paired electrochemical reactions involve carefully matched cathodic and anodic reactions, the precise matching of half reactions in an electrolysis cell is not generally necessary. During a constant current electrolysis almost any oxidation and reduction reaction can be paired, and in the presented work we capitalize on this observation by examining the coupling of anodic oxidation reactions with the production of hydrogen gas for use as a reagent in remote, Pd-catalyzed hydrogenation and hydrogenolysis reactions. To this end, an alcohol oxidation, an oxidative condensation, intramolecular anodic olefin coupling reactions, an amide oxidation, and a mediated oxidation were all shown to be compatible with the generation and use of hydrogen gas at the cathode. This pairing of an electrolysis reaction with the production of a chemical reagent or substrate has the potential to greatly expand the use of more energy efficient paired electrochemical reactions.

Full text of DOI:10.1002/anie.201900343

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Accepted Article
Title: Paired Electrochemical Reactions and the On-Site Generation of
a Chemical Reagent
Authors: Kevin David Moeller, Tiandi Wu, Bichlien H. Nguyen, and
Michael C. Daugherty
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900343
Angew. Chem. 10.1002/ange.201900343
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10.1002/anie.201900343
Angewandte Chemie International Edition
Paired Electrochemical Reactions and the On-Site Generation of a
Chemical Reagent.
Tiandi Wu, Bichlien H. Nguyen,1 Michael C. Daugherty, and Kevin D. Moeller*
Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130
Supporting Information Placeholder
ABSTRACT: While the majority of reported paired electrochemical reactions involve carefully matched cathodic and anodic reactions, the
precise matching of half reactions in an electrolysis cell is not generally necessary. During a constant current electrolysis almost any oxidation
and reduction reactions can be paired, and in the presented work we capitalize on this observation by examining the coupling of anodic
oxidation reactions with the production of hydrogen gas for use as a reagent in remote, Pd-catalyzed hydrogenation and hydrogenolysis
reactions. To this end, an alcohol oxidation, an oxidative condensation, intramolecular anodic olefin coupling reactions, an amide oxidation,
and a mediated oxidation were all shown to be compatible with the generation and use of hydrogen gas at the cathode. This pairing of an
electrolysis reaction with the production of a chemical reagent or substrate has the potential to greatly expand the use of more energy efficient
paired electrochemical reactions.
Paired electrochemical reactions that produce desirable prod-
ucts at both the anode and cathode are frequently put forth as a
method for optimizing the energy efficiency of oxidation and re-
duction reactions,2-4 and there are outstanding examples of their
utility.5-19 For example, the chloro-alkali process that generates so-
dium hydroxide (reduction of water at the cathode) and chlorine
gas (oxidation of chloride at the anode) from sea water is currently
conducted on a massive scale.20 Many other efforts have been for-
warded as well, particularly in the general area of energy conver-
sion.21-30
significant barrier. If paired electrochemical reactions really do re-
quire “carefully matched” oxidation and reduction reactions that
limit the generality of the products that can be made, then interest
in the reaction among the synthetic community will be equally lim-
ited. Fortunately, the perception that paired electrochemical reac-
tions require “carefully matched” cathodic and anodic processes is
not accurate. In a constant current electrolysis the working potential
at both electrodes automatically adjusts to match that of the sub-
strates in solution.31 In such an electrolysis, any oxidation reaction
can in principle be paired with any reduction reaction as long as
sufficient energy is applied to the cell.
However, in spite of the potential paired electrochemical reac-
tions hold for running more sustainable processes and the impres-
sive examples illustrating this potential, the technique remains pri-
marily of interest to chemists specifically engaged in the develop-
ment of new electrochemical methods. A number of factors con-
tribute to this situation. These factors range from little need to con-
sider the energy efficiency of synthetic methods conducted in an
academic laboratory setting to the impression that paired electro-
chemical reactions require “carefully matched” oxidation and re-
duction reactions and hence have limited synthetic generality. With
respect to the first point, academic chemists are becoming increas-
ingly aware of the need for more sustainable synthetic methods and
strategies. In that context, it makes sense to examine methods that
meet the challenge from both a perspective of atom and energy
economy. Paired electrolysis reactions offer just such an oppor-
tunity. The second point raised above represents a potentially more
This generality offers a way to rethink how the increased sus-
tainability associated with a paired electrochemical reaction can be
implemented within a larger synthetic scheme. Imagine the electro-
chemical pairing of a required oxidation or reduction reaction with
the generation of a chemical reagent or substrate needed for a sec-
ond, potentially non-electrochemical reaction. The on-site produc-
tion of that chemical reagent or substrate would allow the single
electrochemical reaction used to improve the sustainability of more
than one synthetic transformation. In this manuscript, we provide
a proof-of-principle experiment that illustrates how anodic oxida-
tion reactions that occur at different potentials, require the use of
both undivided and divided cells, and involve both direct and indi-
rect electrochemical methods can all be coupled to the on-site pro-
duction of hydrogen gas for use in Pd-catalyzed hydrogenation and
hydrogenolysis reactions. While the chemistry here is illustrated for
the production of hydrogen gas, it is important to keep in mind that
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10.1002/anie.201900343
Angewandte Chemie International Edition
cathodic reductions can be used to generate a wide variety of rea-
gents and catalysts.32
in high yields. The use of the more complex oxidation reaction did
not influence either reduction reaction in any way.
The desire to use cathodic processes to generate chemical rea-
gents grew out of the chemistry shown in Scheme 1a.33 The reac-
tion highlighted was conducted as part of a program to valorize
synthetic building blocks derived from lignin. This effort required
a combination of both oxidation and hydrogenation reactions. The
oxidation reactions were performed electrochemically, transfor-
mations that led to the generation of hydrogen gas at the cathode
from the reduction of methanol. At the same time, the hydrogena-
tion-based lignin valorization methods (Scheme 1a) were per-
formed using hydrogen gas from a cylinder. The question became,
why were we buying hydrogen gas and incurring unnecessary en-
vironmental and financial costs when we were already producing
hydrogen gas during the oxidation reactions? With this in mind, a
cannula was inserted into the headspace above an electrochemical
alcohol oxidation and the hydrogen gas generated was transferred
to a flask containing the unsaturated acid and a palladium catalyst.
Both reactions led to their respective products in good yield.
Scheme 2. A paired oxidative condensation with hydrogen gener-
ation in a divided cell.
The effort was continued with the reactions in shown in Scheme
3. The first oxidation reaction involved the intramolecular trapping
of a radical cation with an alcohol (Scheme 3a).35 The reaction was
selected in order to show the generality of the undivided cell setup
used for the reaction in Scheme 1. As in the earlier reactions, the
oxidation was coupled to both the hydrogenation and the hydrogen-
olysis, and once again, neither reduction was altered by the change
in the oxidation reaction. The oxidation reaction proceeded cleanly,
but in this case the yield of the cyclization was not optimized be-
cause that effort relies more on rapid isolation of the sensitive prod-
uct than it does the electrolysis itself.
In the second reaction (Scheme 3b), the anodic oxidation was
used to generate a C-glycoside.36 This reaction was chosen for the
study because it is a challenging oxidative cyclization that requires
the fast removal of a second electron for the efficient production of
product. The reaction was initially conducted in a divided cell in
spite of the fact the use of such a cell is not optimal for the genera-
tion of C-glycoside 15 and known to result in lower yields of prod-
uct and the formation of polymerized side products.36 This was
done in order to probe the compatibility of the paired reduction re-
action with an anodic reaction that was not optimal. What happens
to the paired reduction reaction if something goes wrong with the
oxidation reaction? The answer to this question is nothing. Even
with a less efficient oxidation reaction, the reduction proceeded
smoothly as long as current was passed through the cell.
Scheme 1. A paired electrolysis coupling an alcohol oxidation to
two one of two reactions requiring hydrogen gas.
The alcohol oxidation reaction was also successfully paired
with a Cbz deprotection reaction (Scheme 1b). While the initial re-
actions used a large excess of the alcohol,33 the optimized condi-
tions shown for the reaction of 3 to 4 and 5 to 6 were conducted
with a ratio of 2.5/1 of the alcohol substrate (1) to the substrate
required for the reduction. Improving techniques for sealing the
flasks to minimize hydrogen loss during the transfer enabled this
optimization.
Following the success of the chemistry highlighted in Scheme
1, we sought to demonstrate the premise stated above that the work-
ing potential at the electrodes in a paired electrolysis will autono-
mously adjust so that any two reactions can be coupled. To this end,
a series of oxidation reactions were screened for their compatibility
with the hydrogenation and hydrogenolysis reactions. For this ef-
fort, a simplified substrate (7) for the debenzylation was used for
convenience. In the first of these reactions (Scheme 2), the oxida-
tive condensation of an aldehyde (also derived from lignin)33 with
a phenyl diamine was paired with the hydrogenation of a different
lignin derived building block. The reaction was used to illustrate
the compatibility of the paired electrolysis with an oxidation reac-
tion that is more mechanistically complex and requires the use of a
divided cell to go to completion.34 To this end, the anode and cath-
ode for the reaction were separated with a Nafion 117 membrane.
The cannula needed for the H2 transfer was placed in the head space
of the cathodic chamber. Once again, all of the reactions proceeded
Of course, the oxidation of substrate 14 could be optimized by
conducting the electrolysis in an undivided cell (data in blue). This
was accomplished without any change to the hydrogenation chem-
istry, a result that highlighted one of the advantages of employing
the paired electrochemical reaction to make a chemical reagent that
is used remotely. In such reactions, the oxidation and reduction re-
actions can be optimized independently, a situation that makes the
paired electrochemical process very easy to implement.
The reaction highlighted in Scheme 3b did expose one weakness
of the experimental setup being used for this study. Due to the lack
of availability of substrate (14), the reactions were run on a smaller
scale. This meant that a much smaller total volume of hydrogen gas
was generated, and it was difficult to transfer that smaller volume
of hydrogen gas quantitatively to the remote flask used for either
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10.1002/anie.201900343
Angewandte Chemie International Edition
the targeted carbon; a transformation that cannot be accomplished
with the use of a direct oxidation because such a process would lead
to oxidation of the amine. The added complexity of the indirect
electrolysis did not interfere with either the hydrogenation or hy-
drogenolysis reaction using the hydrogen generated at the cathode.
In this case the oxidation reaction occurred at a potential of only
+0.31 V vs Ag/AgCl. When compared to the amide oxidation, the
paired electrolyses reactions have been shown compatible with ox-
idation substrates that differ by over 1.6 V in energy. Clearly, any
oxidation reaction can be used to drive the reduction chemistry.
Scheme 4. The use of an indirect oxidation reaction in paired pro-
cesses.
To be clear, we are not suggesting that electrochemistry is the
best way to access the hydrogen gas needed for an isolated syn-
thetic transformation. Instead, we are suggesting that many of the
common oxidation reactions we utilize on a routine basis can be
viewed in the larger context of an overall synthetic effort. If one
needs to conduct a hydrogenation or hydrogenolysis reaction in a
synthetic sequence and they are already conducting a larger scale
oxidation reaction elsewhere in the lab, then why not use that oxi-
dation reaction as an on-site source of hydrogen gas and avoid the
cost and energy required for the purchase and shipping of hydrogen
gas made at a remote location?
Scheme 3. Paired anodic cyclization reactions. * For these exam-
ples a 10:1 ratio of the C-glycoside substrate to the reduction sub-
strates was used.
the hydrogenation or hydrogenolysis. For this reason, the reduction
reactions had to be conducted on a smaller scale relative to the ox-
idaton (a 10:1 ratio of the C-glycoside to the reduction substrate
was employed). This issue can potentially be resolved by either
scaling the oxidation reaction in order to generate more hydrogen
gas or reengineering the current reaction setup to be more efficient
with respect to the hydrogen transfer. Neither was done as part of
the current study since the reactions had already illustrated the main
point for which they were conducted.
Finally, it is important to note that the paired electrolysis reac-
tions illustrated above represent ideal examples. The reduction of
protons to generate hydrogen gas is an extremely efficient cathodic
reaction. For that reason, it is the half reaction selected as the coun-
ter reaction for the vast majority of anodic oxidation reactions re-
ported in the literature. However, cathodic reactions are not re-
stricted to the production of hydrogen gas. Cathodes can be used to
make bases, nucleophiles, radical anions, radicals, transition metal
reagents, etc.2,4,32 So, an anodic reaction can in principle be paired
with the generation of a variety of chemical reagents and synthetic
transformations. For example, the oxidative condensation reaction
shown in Scheme 2 has been paired with the production of carbon
monoxide.30 Efforts to further expand the reactions along these
lines are underway as part a larger program to illustrate how the
inclusion of an electrochemical reaction in a synthetic sequence can
be used to improve the sustainability of not only that particular re-
action, but also a variety of other non-electrochemical reactions in
the sequence.
In the third reaction (Scheme 3c), an amide was oxidized and
paired with two reduction reactions. These paired electrolyses were
conducted to show the versatility of the reactions with respect to
the oxidation potential of the substrate. While the previous reac-
tions involved a number of different substrates, the oxidation pot-
netials required for the reactions all fell within a relatively narrow
range (ca. +1.1 to +1.4 V vs. Ag/AgCl). In contrast, the carbamate
substrate in Scheme 3c undergoes oxidation at a potential over half
a volt higher (+1.95 V vs. Ag/AgCl).37 This difference did not mat-
ter. The anodic oxidation reaction was conducted using the opti-
mized conditions developed previously,38 and the paired hydro-
genation and hydrogenolysis (the deprotection of phenylalanine de-
rivative 5) reactions both led to high yields of product. The working
potential at the anode automatically adjusted to the higher potential
needed for oxidation of the carbamate without any influence on the
paired reduction reactions.
ASSOCIATED CONTENT
Supporting Information
Synthetic procedures and characterization (1H & 13C NMR, IR, and
HRMS data) of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
Finally, each of the reactions above involved the direct oxida-
tion of a substrate at the anode. This is not a requirement. In the
reaction highlighted in Scheme 4, electrochemically generated “I+”
was used as a mediator to functionalize the carbon alpha to a car-
bonyl.39 The oxidation involves the iodination of an enol in the
presence of a nucleophilic amine. This results in a net amination of
AUTHOR INFORMTION
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10.1002/anie.201900343
Angewandte Chemie International Edition
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Corresponding Author
Email: moeller@wustl.edu
ACKNOWLEDGMENT
We thank the National Science Foundation (CHE-1764449 and
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